Cu(I)-catalyzed synthesis of dihydropyrimidin-4-ones toward the preparation of β- And β3-amino acid analogues

Article abstract of DOI:10.1021/jo402670d

A copper(I)-catalyzed synthesis of substituted dihydropyrimidin-4-ones from propargyl amides via the formation of ketenimine intermediate has been successfully developed; the synthesis afforded good isolated yields (80-95%). The mild reaction conditions at room temperature allow the reaction to proceed to completion in a few hours without altering the stereochemistry. Further, by involving a variety of reactive nucleophiles, the obtained substituted dihydropyrimidin-4-ones were elegantly transformed into the corresponding β- and β³-amino acid analogues.

Full text of DOI:10.1021/jo402670d

Article
pubs.acs.org/joc
Cu(I)-Catalyzed Synthesis of Dihydropyrimidin-4-ones toward the
Preparation of β- and β3‑Amino Acid Analogues
Basker Rajagopal, Ying-Yu Chen, Chun-Chi Chen, Xuan-Yu Liu, Huei-Ren Wang, and Po-Chiao Lin*
Department of Chemistry, National Sun Yat-sen University, Kaohsiung 804, Taiwan
S
* Supporting Information
ABSTRACT: A copper(I)-catalyzed synthesis of substituted dihydropyrimidin-4-ones from propargyl amides via the formation
of ketenimine intermediate has been successfully developed; the synthesis afforded good isolated yields (80−95%). The mild
reaction conditions at room temperature allow the reaction to proceed to completion in a few hours without altering the
stereochemistry. Further, by involving a variety of reactive nucleophiles, the obtained substituted dihydropyrimidin-4-ones were
elegantly transformed into the corresponding β- and β3-amino acid analogues.
Scheme 1. Reported Preparation Methods of β-Amino Acids
from α-Amino Acids7,9
INTRODUCTION
■
β-Amino acids are one-carbon homologues of α-amino acids.
They can be incorporated into β-peptide chains to afford new
secondary and tertiary structures and thus obtain new biological
activity.1 β-Amino acids are also vital components of important
pharmaceuticals, such as emeriamine,2 cispentacin, and taxol.3
Hence, there has been an increasing demand for the
development of new synthetic strategies for β-amino acids
and their derivatives in the past decades.4a,b A majority of the
methods employ asymmetry synthesis using non-β-amino acid
substrates and chiral catalysts.5 Moreover, several enantiose-
lective synthetic routes to β-amino acids have been successfully
developed in the past decade; these include Kowalski ester
homologation, the transformation of chiral oxazolines,
enantioselective radical reactions, the Mannich reaction, and
asymmetric alkylation/hydroxylation of 1,3-oxazinan-6-ones.6
Because of the ready availability, low cost, and natural optical
purity of α-amino acids, the direct transformation of α-amino
acids to β-amino acids is of high interest. The classical Arndt-
Eistert reaction and its modified procedures were effective for
the one-carbon conversion of α-amino acids, as shown in
Scheme 1a.7a−e In that strategy the α-amino acids are converted
into the corresponding diazo keteone reactive intermediate by
activating the acid group. Then subsequent Wolff rearrange-
ment of the diazo ketone provides the corresponding β-amino
acid. However, the difficulty in handling the hazardous reagent
diazomethane (CH2N2) and the high cost of the silver catalyst
needed in the Wolff rearrangement step makes it unsuitable for
large-scale synthesis. Longobardo and co-workers have
proposed a method for the synthesis of β-amino acids by the
reduction of N-protected α-amino acids to the corresponding
β-amino alcohol. Followed by an efficient iodide-formation
step, the desired β-amino acids can be obtained without
racemization.8 Recently, Coates et al. reported a catalytic
synthesis of β3-amino acid derivatives from α-amino acids. The
strategy involved the preparation of 2-oxazolines intermediates
in a two-step process from α-amino acids. Then a novel
catalytic carbonylation of these 2-oxazolines by using a
silylcobalt precatalyst produced the important 2-oxazin-6-one
intermediates. These oxazinone intermediates are subsequently
hydrolyzed to the corresponding β3-amino acids of interest, as
shown in Scheme 1b.9 The biorenewable, stereochemically rich
resource of the starting α-amino acids successfully yielded
enantiomerically pure β-amino acids. Therefore, the develop-
ment of new synthetic methods via the formation of
heterocyclic intermediates could provide a practical route to
diverse β-amino acids.
In this study, we propose a scheme for Cu(I)-catalyzed
formation of dihydropyrimidin-4-one (DHPM) (such as
compound 6 in Scheme 2) intermediates, followed by
hydrolysis or nucleophilic substitution reactions, to yield the
desired β-amino acids and their important analogues. The
concept is based on the utilization of labile sulfonyl triazole to
Received: December 3, 2013
Published: January 13, 2014
© 2014 American Chemical Society
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a
Scheme 2. Synthetic Pathway of β-Amino Acid Analogues from α-Amino Acids
a
Reaction conditions: (a) MeO(Me)NH.HCl (1.5 equiv), EDC·HCl (1.5 equiv), HOBt (1.5 equiv), DIEA (2.0 equiv), DCM, rt, 14 h; (b) LiAlH4
(1.1 equiv), 0 °C, 20 min; (c) Dimethyl-2-oxopropylphosponate (2.0 equiv), TsN3 (2.0 equiv), K2CO3 (2.0 equiv), CH3CN, MeOH, rt, 14 h; (d)
TFA and DCM (1:1), rt, 30 min; (e) R1COCl (1.1 equiv), TEA (1.5 equiv), DCM, rt, 2 h; (f) CuI (0.1 equiv), TsN3 (1.1 equiv), K2CO3 (1.5
equiv), DCM, rt, 12 h.
form a ketenimine intermediate via Cu(I)-catalyzed azide−
alkyne cycloaddition (CuAAC).10 The highly electrophilic
ketenimine intermediates are obtained, and these immediately
react with the nucleophiles present in the reaction medium.
Different groups have applied this useful concept to develop a
number of methodologies for the preparation of a variety of
molecules,11 such as amides,12 imidates,13 azetidinimines,14
cumarines,15 and quinolines.16 Inspired by this promising
chemistry, the cyclization of propargyl amides to form the
oxazole or oxazinone hetercycles was believed to potentially
conduct the formation of corresponding β-amino acids. To the
preparation of the oxazole and oxazinone, a number of
transition-metal-catalyzed cyclization reactions from propargyl
amides have been successfully developed, in which gold was
reported as an efficient catalyst.17,18 Cook et al. reported a
method for the preparation of oxazole-substituted steroids
using copper-catalyzed cyclization of steroidal acylaminoacety-
lenes.19 However, the use of the copper catalysts in such cyclic
transformations is still rare. Thus, the reactive intermediate,
sulfonyl ketenimine, obtained from the propargyl amides in the
presence of the Cu(I) catalyst may facilitate the cyclization and
allow further functionalization of the resultant cyclic products.
However, during the synthetic course of this strategy, the
expected oxazinone product was not isolated; DHPM
analogues were obtained, which were identified by X-ray
structural analysis. Nevertheless, the obtained DHPM could
still be converted to the β-amino acid analogues of interest.
DHPMs are well-known for their biological activities and are
present in many natural products. Despite the fact that the
DHPM synthesis was reported in 1893 as the Biginelli
multicomponent reaction,20 the importance of the analogue’s
biological activity has only been realized in the 1980s.21 In
recent years, extensive studies have been reported on the
pharmacological properties involving DHPM core.22 For
example, one of the DHPM analogue has been identified as a
potential new anticancer lead that is involved in blocking
mitosis by the inhibition of a kinesin motor protein.23 In
addition, a number of drugs containing the DHPM core are
reported.24,25 Hence, the development of methods for the
preparation of DHPM analogues remains attractive, despite the
presence of existing methods.26 During the course of
completion of this research, we found that Wang et al. reported
a similar methodology for the production of DHPMs using
propargylamides efficiently. In their study, they had converted
the propargylamides into the corresponding DHPMs by
converting the alkyne group into a reactive ketenimine
intermediate followed by an intramolecular nucleophilic
addition. After, the amide oxygen’s attack on the ketenimine
intermediate subsequent ring-opening and ring closure process
afforded the desired DHPM. The reaction conditions are
involved with the use of molecular sieves under argon
atmosphere in 70 °C. The yields were reported moderate to
excellent.27 In this article we have demonstrated the
preparation of those DHPM analogues using a relatively
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different reaction conditions involving ambient temperature,
different base, nonusage of molecular sieves as a dehydrating
agent and a purification method that avoids the column
chromatography. Further, we have provided a synthetic
pathway to prepare the chiral DHPMs, and consequently by
using these DHPM analogues we have demonstrated the
preparation of β/β3-amino acids and their analogues. On the
basis of a comparative analysis of the two methodologies, we
believe that the relatively mild reaction conditions, better yields,
and the production of a series of novel ring-opening products
by one-pot method make our study important; it will be an
add-on to the recently reported methodology by Wang et al.27
Herein, we report the preparation of substituted DHPMs using
the CuAAC and their subsequent transformation to the β/β3-
amino acids and their analogues.
R1 groups destabilize the already unstable nitrilium inter-
mediate.
Table 1 summarizes the attempts in the optimization of
suitable reaction conditions to produce DHPMs. For instance,
Table 1. Optimization of Reaction Conditions for the
Preparation of 2-Phenyl-3-tosyl-5,6-dihydropyrimidin-
4(3H)-one via Cu(I)-Catalyzed Reaction
temp
time
(h)
yield
(%)
entry
catalyst
CuI
base
TEA
pyridine
solvent
(°C)
1
2
3
4
DCM
DCM
rt
rt
rt
rt
rt
rt
40
rt
rt
rt
rt
rt
rt
rt
rt
3
4
17
22
19
87
85
86
80
−
RESULTS AND DISCUSSION
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuBr
■
2,6-luditine DCM
4
In order to achieve the transformation of the α-amino acids to
the β-amino acids, a synthetic strategy was proposed in Scheme
2. First, Boc-protected α-amino acids were converted to the
corresponding Weinreb amides 1 and subsequently reduced to
aldehydes. Then the aldehydes were subjected to a homo-
logation using Bestmann−Ohira reagent to produce Boc-
protected amino alkynes 2. Deprotection of the Boc group
afforded the substituted propargyl amines, which were then
allowed to couple with benzoylchloride to give the correspond-
ing propargyl amides 3. When the obtained propargyl amides
were treated with tosyl azide in the presence of catalytic
amount of copper iodide (CuI) and potassium carbonate
(K2CO3), the starting materials were consumed to form new
products in a few hours. Isolation and characterization of the
major spot by column chromatography indicated a probable six-
membered cyclized product. We assumed that the highly
electrophilic carbon center in ketenimine intermediate 4 could
be favorably attacked in an intramolecular fashion by the
pendant amide oxygen through a six-membered transition state;
subsequent proton transfer occurs to form 4-sulfanimido-1,3-
oxazines analogues (compound 5, Scheme 2). Characterization
of the isolated product using NMR seems to support the
initially predicted structure of 6-sulfonamido-1,3-oxazine. The
product of the reaction can be rationalized by a mechanistic
pathway in which the initially formed sulfonyl triazole (which is
in equilibrium with the diazoimine) goes through the
copper(I)-catalyzed azide−alkyne cycloaddition (CuAAC)
pathway, the Dimroth rearrangement leads to the formation
of diazoimino copper intermediate, and it is subsequently
transformed to the reactive ketenimine intermediate via the
Wolff rearrangement. Then, the adjacent oxygen atom of the
amide attacks the electrophilic carbon of the ketenimine, and a
subsequent proton transfer takes place with the aid of the base
to form the predicted reaction product 4-sulonamido-1,3-
oxazine. However, the X-ray studies of the compound 6a
indicated that the NTs group is adjacent to the phenyl group,
suggesting a possible rearrangement process during the course
of the reaction. Hence, the initially formed 1,3-oxazine
intermediate probably goes through a ring-opening process to
form an unstable nitrilium intermediate with the equilibrium
between the imidate and the amidate intermediates in which
the amidate was stabilized by an electron-withdrawing Ts
group. Subsequently, an intramolecular reaction was triggered
to close the ring and furnish the DHPMs (6). The stability of
the proposed nitrilium intermediate could be affected by the
electronic nature of the R1 groups. The electron-withdrawing
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DCM
DCM
DCM
DCM
DMF
THF
12
12
12
12
1
a
5
b
6
7
8
9
12
12
12
1
−
10
11
12
13
14
15
DCM
DCM
DCM
DCM
DCM
DCM
40
42
−
68
55
−
CuBr/DMS K2CO3
CuI
CuI
CuI
CuI
Cs2CO3
Na2CO3
NaHCO3
−
12
24
1
a
b
CuI (0.15 equiv). CuI (0.2 equiv).
the use of triethylamine as a base for the reaction (entry 1) and
other organic bases such as pyridine and 2,6-luditine (entries 2
and 3) showed less yields. However, to our surprise, the use of
the inorganic base potassium carbonate (K2CO3) was found to
assist the clean transformation of the starting materials into the
product in 12 h despite its poor solubility in the reaction
medium. However, the reaction time could not be reduced by
increasing the amount of CuI (entries 5 and 6) and elevating
the temperature (entry 7). We assume that the longer reaction
hours are probably due to the poor solubility of K2CO3 in
DCM. Comparison of few different brands of K2CO3 with
different particle size does not show considerable difference in
the reaction optimization. Further, the better results of using
K2CO3 as a base in the reaction may be attributed to the fact
that it can also act as a dehydrating agent, which would prevent
the formed DHPM from being hydrolyzed. Polar solvents such
as DMF and THF resulted in the formation of the complex
mixtures (entries 8 and 9). Screening of the copper catalysts
such as CuBr and CuBr-dimethylsulfide complex afforded low
yields (entries 10 and 11). Further, keeping DCM as the
solvent, different inorganic bases were screened. Cesium
carbonate (Cs2CO3) resulted in the formation of a mixture of
products within 30 min (entry 12). The bases sodium
carbonate (Na2CO3) and sodium bicarbonate (NaHCO3)
were also found to yield moderate results with the drawbacks
of relatively long reaction times and lower yields compared to
the use of K2CO3 (entries 13 and 14). In a control reaction, no
new product was obtained in the absence of the base (entry
15). The yields of the isolated products were greatly influenced
by the workup procedure. Our initial attempts, which employed
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a
Table 2. Screening of Different R1-Substituted Propargyl Amide Groups
a
NR = No reaction; starting materials intact.
the aqueous workup to remove K2CO3 and subsequent silica
gel column chromatography, resulted in low reaction yields
(40−50%) despite the clean conversion of the starting materials
to the products, as observed on the TLC. The low isolated
yields might be attributed to the reason that the product is
unstable under the aqueous workup condition and in the
slightly acidic medium in the silica gel chromatography; this can
decompose the product by ring-opening process. Even the
purification attempts using neutral alumina did not improve the
yield. Eventually, the aqueous workup and the column
chromatography were not used; instead, the reaction mixture
was treated with Cuprisorb resin (for the removal of the copper
ions) and then filtered through a Celite pad to give the crude
compound and followed by a washing step using the ethyl
acetate/hexane solvent system to afford the products in high
yields.
conventional acid−propargylamine or acyl chloride−propargyl-
amine coupling reactions. When the R1 position was substituted
by aliphatic groups including methyl, trans-propene, and
cyclohexyl residues (6b−d), the propargyl amides showed
smooth conversion to the corresponding DHPMs. In case of
substitution with residues containing different aromatic groups,
the results indicated that the electronic effects of the benzene
ring did not affect the yield of the reaction severely. Electron-
donating substituents such as the methyl group (6e and 6f) and
4-methoxy groups (6g) on the benzene ring afforded good
yields (higher than 90%). When phenyl rings with electron-
withdrawing residues such as chloro, dichloro, and iodo (6h−j)
were used, the transformations were slightly affected, but
reasonable yields were obtained (81−90%). Benzyl, trans-2-
phenyl, and naphthalene residues also gave good results (88−
90%, 6k−m). Furthermore, aromatic groups containing
heteroatoms in the ring were found unsuitable for this type
of cyclization. For example, the substrates with the R1 groups
containing a heteroatom did not show any progress of the
reaction (6o and 6p). Use of additional copper catalyst and a
prolonged reaction period accompanied with heating did not
After identifying the optimal reaction condition for the
preparation of compound 6, we screened various R1 groups of
the propargyl amides for the cyclization (Table 2). The starting
materials, i.e., different substituted propargyl amides, were
prepared by the acylation of propargyl amine using the
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improve the result. The results can be rationalized by assuming
that the copper catalyst might be chelated to the heteroatoms
in the R1 substituents, and thereby the formation of sulfonyl
triazoles is arrested. Apparently, a combination of the chelating
effect of the heteroatoms in the R1 ring and its electron-
withdrawing nature, which inhibits the attack of the amide
oxygen on the ketenimine intermediate, could rationalize these
unexpected results. However, when excess CuI catalyst (0.5
equiv) and an extended reaction period (48 h) were used, the
thiophene analogue (6n) afforded 38% product along with
some other nonisolable byproducts. Surprisingly, unlike the
methyl group (6b) the chloromethyl substituent (6q) was
found inert under the reaction conditions. The loading of
excess CuI catalyst (0.4 equiv) and the extension of the reaction
period (48 h) did not improve the result either. Probably, the
electron-withdrawing chloro substituent inhibits the neighbor-
ing carbonyl oxygen atom from attacking the ketenimine
intermediate, thereby preventing the subsequent cyclization.
The complete screening suggests that the substrates containing
electron-donating alkyl, alkene, and aromatic R1 groups can be
elegantly transformed into the corresponding DHPMs (6). On
the contrary, the alkyl groups containing the electron-
withdrawing groups and the aromatic residues with heter-
oatoms are found to be unsuitable for this type of conversion.
The developed method was further evaluated using
substituted propargyl amides (Table 3). We anticipated that
the presence of R2 and R3 alkyl groups adjacent to the alkyne
group may affect the reaction because of the steric effect.
However, the substituted propargyl amide substrates had
shown efficient conversion to furnish the products in good
yields (83−91%) under the optimized conditions. The achiral
dimethyl propargyl amide 3r and the achiral cyclohexyl
propargyl amide 3s were obtained from the available
substituted propargyl amine precursors; however, for the
others, three L-α-amino acids, alanine, valine, and leucine,
were successfully converted to the chirally substituted propargyl
amides using the synthetic pathway depicted in Scheme 2.28
The obtained chiral propargyl amides were then transformed to
the desired chiral DHPMs (6t, 6u, and 6v) with good yields
(83−88%). Furthermore, to examine the stereochemistry, a
racemic mixture of D/L-leucine was used in the preparation of
the racemic isobutyl-substituted DHPM (6w) and used as the
racemic standard for chiral HPLC analysis. The HPLC
chromatogram clearly indicated that the chiral integrity in the
compound 6v derived from L-leucine is reasonably maintained
(enantiomeric excess = 92%) despite the use of a number of
bases in several synthesis steps.28
Table 3. Scope of Substituted Propargyl Amides
a
Enantiomeric excess (ee) = 92.6%
produce β-amino acid analogues with good yields under mild
conditions.
Moreover, we also observed that these ring-opening reactions
work well in a step-by-step manner. When the isolated DHPMs
were treated with alcohols or amines in the absence of a base,
the expected ring-opening products were obtained in high
conversion efficiency.
The DHPMs (6) have similar structural features to that of
the 1,3-oxazines; therefore, we anticipated that the hydrolysis of
the isolated DHPMs (6) would provide the corresponding β-
and β3-amino acids. As predicted, β-alanine (7f) was obtained
in good yield by hydrolyzing the compound 6a using 6 N HCl
at the reflux temperature for 3 h. Similarly, the hydrolysis of the
dimethyl substituted DHPM (6r) afforded the corresponding
β3-methyl amino acid analogue (7g) in 62% yield (Scheme 3).
The structural features of the synthesized DHPMs (6) are
favorable for the nucleophilic attack with the ring-opening
process to produce the substituted β-amino acid analogues.
This may be a potential extension to the proposed method-
ology; the addition of a fourth component, such as amine or
alcohol in the reaction mixture would directly provide the
corresponding amide or ester in a one-pot process (Table 4).
We added the fourth reactant after the formation of DHPMs
(6) in order to avoid the possible attack on the reactive
ketenimine by the added nucleophiles. To our delight, β-amino
acid analogues were formed when amines were added as the
fourth component after the formation of DHPMs (6) in the
reaction mixture (7a (82%) and 7b (75%)). Similarly, the in
situ addition of alcohols provided the corresponding esters
(7c−e, 80−83%) in 3 h at the ambient temperature. The
developed four-component synthetic strategy could be used to
CONCLUSION
■
In summary, we have developed a method for the preparation
of β-amino acid analogues via substituted DHPM intermedi-
ates. The core structure of DHPMs (6) is present in many
medicinally important compounds; therefore, the developed
methodology allows us to rapidly and efficiently expand the
structural complexity of the substituted DHPMs. Further, we
demonstrated that the isolated products could be conveniently
transformed into the β- and β3-amino acid analogues on
hydrolysis or via various nucleophilic reactions by a novel four-
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was stirred at 25 °C for 12 h. After completion of the reaction
monitored by TLC, the reaction mixture was diluted with dichloro-
methane (10 mL), stirred with cuprisorb resin (200 mg) for 20 min to
remove the copper traces in the reaction mixture, and filtered through
a pad of Celite. The Celite pad was washed with excess dichloro-
methane (10 mL), and the combined filtrate was concentrated under
reduced pressure to afford the crude compound. The crude compound
was stirred with 1:9 ethyl acetate in hexane (10 mL) for 30 min at 0 °C
and the resultant solid was filtered, washed with hexane (5 mL) and
dried over high vacuum to afford 2-phenyl-3-tosyl-5,6-dihydropyr-
imidin-4(3H)-one (6a) (179 mg; 87%) as a pale yellow powder.
2-Phenyl-3-tosyl-5,6-dihydropyrimidin-4(3H)-one (6a).27
Pale yellow powder (179 mg, 0.546 mmol, 87%): mp 157−159 °C;
1H NMR (300 MHz, CDCl3) δ 7.85 (d, J = 8.2 Hz, 2H), 7.59 (d, J =
7.4 Hz, 2H), 7.50−7.45 (m, 1H), 7.42−7.37 (m, 2H), 7.31 (d, J = 8.1
Hz, 2H), 3.74 (t, J = 6.3 Hz, 2H), 2.55 (t, J = 6.3 Hz, 2H), 2.45 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 170.7, 154.7, 145.9, 136.4, 136.2,
130.9, 129.6, 128.5, 127.6, 43.6, 34.2, 21.9; IR (KBr) v 3662, 3264,
3072, 2869, 2314, 1738, 1644, 1594, 1493, 1368, 1281, 1002, 882, 770,
669 cm−1; HRMS (ESI-TOF) calcd for C17H17N2O3S [M + H]+,
329.0960, found 329.0959.
Table 4. Nucleophilic Attack on Dihydropyrimid-4-ones by
Amines and Alcohols
2-Methyl-3-tosyl-5,6-dihydropyrimidin-4(3H)-one (6b). Off
1
white powder (233 mg, 0.876 mmol, 85%): mp 116−119 °C; H
NMR (300 MHz, CDCl3) δ 8.01 (d, J = 8.3 Hz, 2H), 7.35 (d, J = 8.2
Hz, 2H), 3.53 (t, J = 6.3 Hz, 2H), 2.49 (s, 3H), 2.47−2.43 (m, 5H);
13C NMR (75 MHz, CDCl3) δ 170.1, 151.8, 145.8, 136.3, 129.8, 129.1,
42.5, 33.4, 24.3, 21.9; IR (KBr) v 3386, 3068, 2924, 2867, 1820, 1733,
1665, 1596, 1557, 1367, 1275, 1224, 816, 667 cm−1; HRMS (ESI-
TOF) calcd for C12H15N2O3S [M + H]+, 267.0803, found 267.0808.
(E)-2-(Prop-1-enyl)-3-tosyl-5,6-dihydropyrimidin-4(3H)-one
1
(6c). White powder (220 mg, 0.75 mmol, 94%): mp 90−95 °C; H
Scheme 3. Hydrolysis of the Dihydropyrimid-4-ones
NMR (300 MHz, CDCl3) δ 7.98 (d, J = 8.2 Hz, 2H), 7.35 (d, J = 8.07
Hz, 2H), 6.75−6.58 (m, 1H), 6.26 (d, J = 15.3 Hz, 1H), 3.57 (t, J = 6.3
Hz, 2H), 2.45 (s, 3H), 2.49−2.40 (m, 2H), 1.90 (d, J = 6.8 Hz, 3H);
13C NMR (75 MHz, CDCl3) δ 170.3, 151.1, 145.7, 136.5, 136.2, 129.7,
129.0, 125.8, 42.7, 33.7, 21.8, 18.4; IR (KBr) v 1735, 1625, 1597, 1443,
1361 cm−1; HRMS (ESI-TOF) calcd for C14H17N2O3S [M + H]+,
293.0960, found 293.0954.
2-Cyclohexyl-3-tosyl-5,6-dihydropyrimidin-4(3H)-one
(6d).27 Off white powder (166 mg, 0.496 mmol, 82%): mp 115−117
°C; 1H NMR (300 MHz, CDCl3) δ 8.02 (d, J = 8.2 Hz, 2H), 7.36 (d, J
= 8.2 Hz, 2H), 3.54 (t, J = 6.3 Hz, 2H), 3.05−2.99 (m, 1H), 2.46 (s,
3H), 2.39 (t, J = 6.3 Hz, 2H), 1.85−1.66 (m, 5H), 1.52−1.22 (m, 5H);
13C NMR (75 MHz, CDCl3) δ170.9, 160.3, 145.6, 136.6, 129.8, 128.8,
44.2, 42.5, 34.2, 31.6, 29.7, 26.2, 26.1, 25.9, 21.9; IR (KBr) v 3295,
3061, 2856, 2667, 1913, 1735, 1654, 1596, 1084, 831, 667 cm−1;
HRMS (ESI-TOF) calcd for C17H23N2O3S [M + H]+, 335.1429, found
335.1423.
component reaction. The mild reaction condition and the good
product yields make the current strategy useful for the
construction of various DHPMs and β-amino acid molecular
libraries.
EXPERIMENTAL SECTION
■
General Considerations. All reactions were performed under an
atmosphere of nitrogen, and the workups were carried out in air. All
the solvents used for the condition optimization were dried using
reported procedures. Unless noted, all materials were purchased from
commercial suppliers and used as received. Cuprisorb resin was dried
in a high vacuum before use. 1H and 13C NMR spectra were recorded
on 300 and 75 MHz spectrometer respectively. NMR data are
reported as follows: chemical shift, multiplicity (s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet, b = broad), coupling
constants (Hz). Solvent residual peaks references for 1H NMR:
CDCl3, 7.2600 ppm; MeOD, 3.3100 ppm. For 13C NMR: CDCl3,
77.2300 ppm; MeOD, 49.1500 ppm. Melting points of the products
were calculated in open capillary tubes. High resolution mass spectra
(HRMS) were performed on electron ionization time-of-flight (EI-
TOF) and fast atom bombardment (FAB) mass spectrometers. Flash
column chromatography was performed using silica gel (43−60 mm).
Representative Procedure for the Preparation of Dihydro-
pyrimid-4-ones (6a−6w): Preparation of 2-Phenyl-3-tosyl-5,6-
dihydropyrimidin-4(3H)-one (6a). To a stirred solution of N-
(prop-2-ynyl)benzamide (3a) (100 mg, 0.628 mmol) in dichloro-
methane (12.5 mL) were added copper iodide (11.9 mg, 0.062 mmol),
potassium carbonate (130 mg, 0.942 mmol) and tosyl azide (136 mg,
0.691 mmol) under nitrogen atmosphere, and the resultant mixture
2-o-Tolyl-3-tosyl-5,6-dihydropyrimidin-4(3H)-one (6e). White
1
powder (180 mg, 0.53 mmol, 91%): mp 95−100 °C; H NMR (300
MHz, CD3CN) δ 7.58 (d, J = 8.2 Hz, 2H), 7.32 (d, J = 7.8 Hz, 3H),
7.25−7.11 (m, 3H), 3.74 (t, J = 6.4 Hz, 2H), 2.58 (t, J = 6.4 Hz, 2H),
2.42 (s, 3H), 2.23 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 170.4,
153.5, 145.7, 136.7, 135.4, 135.0, 130.8, 129.8, 129.3, 128.9, 125.4,
43.6, 34.3, 21.9, 19.4; IR (KBr) v 3059, 1738, 1665, 1451, 1368 cm−1;
HRMS (ESI-TOF) calcd for C18H19N2O3S (M + H)+, 343.1116,
found 343.1119.
2-p-Tolyl-3-tosyl-5,6-dihydropyrimidin-4(3H)-one (6f).27
White powder (187 mg, 0.55 mmol, 95%): mp 170−175 °C; 1H
NMR (300 MHz, CDCl3) δ 7.87 (d, J = 8.2 Hz, 2H), 7.51 (d, J = 8.0
Hz, 2H), 7.32 (d, J = 8.1 Hz, 2H), 7.21 (d, J = 7.8 Hz, 2H), 3.71 (t, J =
6.3 Hz, 2H), 2.53 (t, J = 6.3 Hz, 2H), 2.46 (s, 3H), 2.41 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 170.8, 154.6, 145.8, 141.2, 136.2, 133.6,
129.5, 129.1, 127.5, 43.4, 34.2, 21.8, 21.6; IR (KBr) v 3048, 1744,
1635, 1449, 1344 cm−1; HRMS (ESI-TOF) calcd for C18H19N2O3S
(M + H)+, 343.1116, found 343.1108.
2-(4-Methoxyphenyl)-3-tosyl-5,6-dihydropyrimidin-4(3H)-
one (6g).27 Pale yellow powder (180 mg, 0.501 mmol, 95%): mp
144−146 °C; 1H NMR (300 MHz, CDCl3) δ 7.87 (d, J = 8.2 Hz, 2H),
7.58 (d, J = 8.5 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 6.91 (d, J = 8.6 Hz,
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Article
2H), 3.86 (s, 3H), 3.68 (t, J = 6.2 Hz, 2H), 2.52 (t, J = 6.2 Hz, 2H),
2.45 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 170.9, 161.9, 154.3,
145.8, 136.4, 129.6, 129.5, 129.3, 128.9, 113.9, 55.6, 43.4, 34.3, 21.9; IR
(KBr) v 3374, 3058, 2965, 2934, 2840, 1738, 1636, 1607, 1512, 1366,
1254, 1148, 823, 685 cm−1; HRMS (ESI-TOF) calcd for C18H19N2O4S
[M + H]+, 359.1066, found 359.1073.
6,6-Dimethyl-2-phenyl-3-tosyl-5,6-dihydropyrimidin-4(3H)-
one (6r). Off white powder (169 mg, 0.475 mmol, 89%): mp 133−
1
137 °C; H NMR (300 MHz, CDCl3) δ 7.85 (d, J = 8.2 Hz, 2H),
7.51−7.43 (m, 3H), 7.44−7.29 (m, 4H), 2.49 (s, 2H), 2.45 (s, 3H),
1.35 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 170.2, 150.8, 145.9,
137.1, 135.8, 130.4, 130.0, 129.4, 128.4, 127.5, 54.3, 45.6, 27.5, 21.9; IR
(KBr) v; HRMS (FAB) calcd for C19H21N2O3S [M + H]+, 357.1273,
found 357.1275.
2-Phenyl-3-tosyl-1,3-diazaspiro[5.5]undec-1-en-4-one (6s).
Off white powder (155 mg, 0.377 mmol, 91%): mp 126−128 °C;
1H NMR (300 MHz, CDCl3) δ 7.85 (d, J = 8.3 Hz, 2H), 7.52 (d, J =
7.1 Hz, 2H), 7.45−7.29 (m, 5H), 2.46 (s, 2H), 2.45 (s, 3H), 1.85−1.76
(m, 4H), 1.63−1.60 (m, 1H), 1.54−1.34 (m, 5H); 13C NMR (75
MHz, CDCl3) δ 170.4, 150.0, 135.8, 130.4, 130.0, 129.3, 128.4, 127.6,
56.5, 44.7, 36.4, 25.7, 22.1, 21.9; IR (KBr) v 3448, 3261, 3060, 2931,
1738, 1644, 1582, 1030, 1030, 928, 882; HRMS (ESI-TOF) calcd for
C22H25N2O3S [M + H]+, 397.1586, found 397.1590.
(R)-6-Methyl-2-phenyl-3-tosyl-5,6-dihydropyrimidin-4(3H)-
one (6t). White powder (98 mg, 0.290 mmol, 83%): mp 153−157 °C;
1H NMR (300 MHz, CDCl3) δ 7.84 (d, J = 8.1 Hz, 2H), 7.56 (d, J =
7.5 Hz, 2H), 7.51−7.27 (m, 5H), 3.89−3.72 (m, 1H), 2.57 (dd, J =
17.0, 3.6 Hz, 1H), 2.45 (s, 3H), 2.31 (dd, J = 11.7, 17.1 Hz, 1H′), 1.40
(d, J = 6.9, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 170.63, 152.92,
145.85, 136.50, 136.18, 130.81, 129.64, 129.52, 128.50, 127.71, 50.12,
40.93, 21.92, 20.83 ppm; [α]28D = +61.35 (c, 0.5, CH2Cl2); IR (KBr) ν
3062, 1736, 1686, 1608, 1583, 1371 cm−1; HRMS (ESI-TOF) calcd
for C18H18N2O3SNa [M + Na]+ 365.0936, found 365.0928.
2-(2-Chlorophenyl)-3-tosyl-5,6-dihydropyrimidin-4(3H)-one
(6h).27 Off-white powder (163 mg, 0.45 mmol, 90%): mp 115.1−
1
116.7 °C; H NMR (300 MHz, CDCl3) δ 7.55 (dd, J = 5.8, 3.5 Hz,
1H), 7.51 (d, J = 8.3 Hz, 2H), 7.38 (dd, J = 5.8, 3.5 Hz, 2H), 7.18 (d, J
= 8.3 Hz, 3H), 3.86 (t, J = 6.3 Hz, 2H), 2.67 (t, J = 6.2 Hz, 2H), 2.42
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 170.1, 151.7, 145.7, 135.1,
134.4, 132.5, 132.0, 131.0, 129.3, 129.1, 127.0, 43.8, 34.1, 21.9; IR
(KBr) ν 3058, 1743, 1652, 1596, 1494, 1378 cm−1; HRMS (ESI-TOF)
calcd for C17H16N2O3S35Cl (M + H)+, 363.0570, found 363.0562.
2-(2,4-Dichlorophenyl)-3-tosyl-5,6-dihydropyrimidin-4(3H)-
one (6i). Off white powder (142 mg, 0.359 mmol, 82%): mp 122−124
°C; 1H NMR (300 MHz, CDCl3) δ 7.58 (d, J = 8.2 Hz, 2H), 7.48 (d, J
= 8.3 Hz, 1H), 7.36 (d, J = 9.4 Hz, 1H), 7.23−7.22 (m, 3H), 3.84 (t, J
= 6.3 Hz, 2H), 2.65 (t, J = 6.3 Hz, 2H), 2.44 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 169.8, 150.8, 146.0, 136.5, 135.0, 133.3, 133.1, 132.7,
129.5, 129.1, 129.0, 127.4, 43.8, 33.98, 21.9; IR (KBr) v 3384, 3069,
2128, 1744, 1655, 1589, 1474, 1374, 1286, 1237, 1174, 1006, 885, 786,
666 cm−1; HRMS (ESI-TOF) calcd for C17H15N2O3S35Cl2 [M + H]+,
397.0180, found 397.0183.
2-(2-Iodophenyl)-3-tosyl-5,6-dihydropyrimidin-4(3H)-one
(6j). Off white powder (129 mg, 0.284 mmol, 81%): mp 122−124 °C;
1H NMR (300 MHz, CDCl3) δ 7.65 (d, J = 7.7 Hz, 1H), 7.56−7.54
(m, 1H), 7.49−7.47 (m, 3H), 7.20−7.11 (m, 3H), 3.87 (t, J = 6.42 Hz,
2H), 2.75 (t, J = 6.4 Hz, 2H), 2.43 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 170.5, 154.1, 145.8, 139.6, 138.7, 132.3, 131.1, 129.4, 129.3,
128.1, 96.1, 43.8, 34.3, 21.9; IR (KBr) v 2922, 2127, 1742, 1652, 1596,
1494, 1371, 1174, 1005, 815, 665 cm−1; HRMS (ESI-TOF) calcd for
C17H16N2O3SI [M + H]+, 454.9926, found 454.9922.
2-Benzyl-3-tosyl-5,6-dihydropyrimidin-4(3H)-one (6k). White
powder (174 mg, 0.51 mmol, 88%): mp 118−122 °C; 1H NMR (300
MHz, CDCl3) δ 7.83 (d, J = 8.1, 2H), 7.32−7.16 (m, 7H), 4.23 (s,
2H), 3.58 (t, J = 6.6, 2H), 2.43 (s, 3H), 2.40 (t, J = 6.6, 2H) ppm; 13C
NMR (75 MHz, CDCl3) δ 170.38, 154.71, 145.62, 136.54, 135.88,
129.67, 129.40, 128.90, 128.84, 127.26, 42.90, 42.76, 33.56, 21.86
ppm; IR (KBr) ν 3056, 1723, 1650, 1592, 1560, 1365 cm−1; HRMS
(ESI) calcd for C18H19N2O3S [M + H]+ 343.1116, found 343.1119.
(E)-2-Styryl-3-tosyl-5,6-dihydropyrimidin-4(3H)-one (6l).27
Pale yellow powder (178 mg, 0.50 mmol, 93%): mp 124−126 °C;
1H NMR (300 MHz, CDCl3) δ 8.03 (d, J = 8.4 Hz, 2H), 7.56−7.32
(m, 8H), 6.88 (d, J = 15.6 Hz, 1H), 3.68 (t, J = 6.3, 2H), 2.51 (t, J =
6.3, 2H), 2.47 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 170.26,
151.50, 145.94, 137.33, 136.59, 135.59, 129.87, 129.64, 129.13, 129.04,
127.87, 122.19, 43.05, 33.87, 21.96 ppm; IR (KBr) ν 3059, 1738, 1644,
1607, 1577, 1363 cm−1; HRMS (FAB) calcd for C19H19N2O3S [M +
H]+ 355.1116, found 355.1111.
2-(Naphthalen-2-yl)-3-tosyl-5,6-dihydropyrimidin-4(3H)-one
(6m). White powder (158 mg, 0.42 mmol, 88%): mp 134−137 °C; 1H
NMR (300 MHz, CDCl3) δ 7.95−7.80 (m, 5H), 7.80−7.67 (m, 2H),
7.59−7.48 (m, 2H), 7.29 (d, J = 8.1 Hz, 2H), 3.82 (t, J = 6.3 Hz, 2H),
2.62 (t, J = 6.3, 2H), 2.47 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ
170.88, 154.79, 145.87, 136.21, 134.61, 133.66, 132.50, 129.58, 128.85,
128.62, 128.07, 127.55, 126.82, 124.69, 43.81, 34.43, 21.93 ppm; IR
(KBr) ν 3059, 1728, 1647, 1593, 1369 cm−1; HRMS (ESI-TOF) calcd
for C21H19 N2O3S [M + H]+ 379.1116, found 379.1113.
(S)-6-Isopropyl-2-phenyl-3-tosyl-5,6-dihydropyrimidin-
4(3H)-one (6u). White powder (162 mg, 0.437 mmol, 88%): mp
111−114 °C; 1H NMR (300 MHz, CDCl3) δ 7.85 (d, J = 8.2 Hz, 2H),
7.59 (d, J = 7.2 Hz, 2H), 7.49−7.30 (m, 5H), 3.30−3.25 (m, 1H),
2.60−2.54 (dd, J = 2.8, 2.8 Hz, 1H), 2.46 (s, 3H), 2.3−2.2 (m, 1H),
1.90−1.88 (m, 1H), 1.07 (d, J = 6.6 Hz, 3H), 0.97 (d, J = 6.6 Hz, 3H)
ppm; 13C NMR (75 MHz, CDCl3) δ 171.3, 145.8, 136.5, 136.2, 130.8,
129.6, 129.5, 128.4, 127.8, 60.1, 37.2, 32.2, 21.9, 19.1 ppm; [α]27
=
D
+122.58 (c, 0.5, CH2Cl2) IR (KBr) ν 3451, 3060, 2962, 2874, 1735,
1638, 1596, 1367, 1173, 962, 769, 676 cm−1; HRMS (ESI-TOF) calcd
for C20H23N2O3S [M + H]+ 371.1429, found 371.1420.
(R)-6-Isobutyl-2-phenyl-3-tosyl-5,6-dihydropyrimidin-4(3H)-
one (6v). Off white powder (150 mg, 0.390 mmol, 84%): mp 112−
114 °C; 1H NMR (300 MHz, CDCl3) δ 7.85 (d, J = 8.2 Hz, 2H), 7.57
(d, J = 7.2 Hz, 2H), 7.45−7.29 (m, 5H), 3.8−3.6 (m, 1H), 2.59−2.52
(dd, J = 3.6, 3.6 Hz, 1H), 2.45 (s, 3H), 2.30−2.20 (m, 1H), 1.97−1.90
(m, 1H), 1.70−1.68 (m, 1H), 1.32−1.28 (m, 1H), 0.97−0.93 (m, 6H)
ppm; 13C NMR (75 MHz, CDCl3) δ 170.8, 152.8, 145.9, 136.5, 136.1,
130.8, 129.7, 129.5, 128.5, 127.7, 52.5, 43.8, 39.8, 24.9, 23.1, 22.4, 21.9
ppm; [α]28 = +28.86 (c, 0.5, CH2Cl2) IR (KBr) ν 3061, 2126, 1732,
D
1635, 1371, 1371, 868, 800 cm−1; HRMS (ESI-TOF) calcd for
C21H25N2O3S [M + H]+ 385.1586, found 385.1592.
6-Isobutyl-2-phenyl-3-tosyl-5,6-dihydropyrimidin-4(3H)-
one (6w). Off white powder (148 mg, 0.385 mmol, 83%): mp 112−
114 °C; 1H NMR (300 MHz, CDCl3) δ 7.85 (d, J = 8.2 Hz, 2H), 7.57
(d, J = 7.2 Hz, 2H), 7.45−7.29 (m, 5H), 3.8−3.6 (m, 1H), 2.59−2.52
(dd, J = 3.6, 3.6 Hz, 1H), 2.45 (s, 3H), 2.30−2.20 (m, 1H), 1.97−1.90
(m, 1H), 1.70−1.68 (m, 1H), 1.32−1.28 ((m, 1H), 0.97−0.93 (m,
6H) ppm; 13C NMR (75 MHz, CDCl3) δ 170.7, 152.7, 145.8, 136.4,
136.9, 130.7, 129.5, 129.4, 128.4, 127.6, 52.4, 43.6, 39.6, 24.8, 23.0,
22.2, 21.8 ppm; IR (KBr) ν 3061, 2126, 1732, 1635, 1371, 1371, 868,
800 cm−1; HRMS (ESI-TOF) calcd for C21H25N2O3S [M + H]+
385.1586, found 385.1580.
Representative Procedure for the Preparation of β- and β3-
Amino Acid Analogues (7a−7e): Preparation of Ethyl 3-(N′-
tosylbenzimidamido)propanoate (7c). To a stirred solution of N-
(prop-2-ynyl)benzamide (3a) (100 mg, 0.628 mmol) in dichloro-
methane (12.5 mL) were added copper iodide (11.9 mg, 0.062 mmol),
potassium carbonate (130 mg, 0.942 mmol) and tosyl azide (136 mg,
0.691 mmol) under nitrogen atmosphere, and the resultant mixture
was stirred at rt for 12 h. After the complete formation of the required
intermediate 2-phenyl-3-tosyl-5,6-dihydropyrimidin-4(3H)-one (6a)
was confirmed by TLC, the fourth component ethanol (0.044 mL,
2-(Thiophen-2-yl)-3-tosyl-5,6-dihydropyrimidin-4(3H)-one
(6n). White powder (63 mg, 0.19 mmol, 38%): mp 165.6−167.3 °C;
1H NMR (300 MHz, CDCl3) δ 7.93 (d, J = 8.3 Hz, 2H), 7.50−7.43
(m, 2H), 7.34 (d, J = 8.1 Hz, 2H), 7.10−7.03 (m, 1H), 3.65 (t, J = 6.2
Hz, 2H), 2.50 (t, J = 6.4 Hz, 2H), 2.46 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 170.5, 149.3, 146.0, 139.0, 136.3, 130.2, 129.7, 129.5, 127.4,
43.4, 34.4, 22.0; IR (KBr) ν 3051, 1735, 1622, 1593, 1492, 1362 cm−1;
HRMS (ESI-TOF) calcd for C15H15N2O3S2 (M + H)+, 335.0524,
found 335.0532.
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1.2 equiv) was added to the reaction mixture and further stirred for
another 3 h. The reaction mixture was diluted with dichloromethane
(10 mL), stirred with cuprisorb resin (200 mg) for 20 min to remove
the copper traces, and filtered through a pad of Celite. The Celite pad
was washed with excess dichloromethane (10 mL), and the combined
filtrate was concentrated under reduced pressure, and the resultant
residue was purified using silica gel column chromatography using 20−
30% ethyl acetate in hexane as an eluent to afford ethyl 3-(N′-
tosylbenzimidamido)propanoate (7c) as a colorless liquid (188 mg,
80%).
(Z)-4-Methoxy-N-(3-oxo-3-(piperidin-1-yl)propyl)-N′-tosyl-
benzimidamide (7a). Yellow solid (193 mg, 0.440 mmol, 82%): mp
105−108 °C; 1H NMR (300 MHz, MeOD) δ 7.55 (d, J = 8.7 Hz, 2H),
7.36 (d, J = 8.7 Hz, 2H), 7.24 (d, J = 8.1 Hz, 2H), 6.90 (d, J = 8.7 Hz,
2H), 3.84 (s, 3H), 3.61 (t, J = 7.2 Hz, 2H), 3.51 (t, J = 5.1 Hz, 2H),
3.39 (t, J = 5.1 Hz, 2H), 2.69 (t, J = 7.2 Hz, 2H), 2.38 (s,3H), 1.69−
1.60 (m, 2H), 1.57−1.46 (m, 4H); 13C NMR (75 MHz, MeOD) δ
171.2, 168.0, 163.4, 143.7, 142.6, 131.2, 130.3, 127.6, 127.5, 114.5,
56.1, 48.1, 44.1, 40.0, 32.9, 27.7, 26.8, 25.5, 21.5; IR (KBr) ν 3287,
2936, 2857, 1736, 1686, 1608, 1584 cm−1; HRMS (ESI-TOF) calcd
for C23H28N3O4S (M − H)−, 442.1801, found 442.1807.
(Z)-N-(4-Methoxyphenyl)-3-(N′-tosylcyclohexanecarbox-
imidamido)propanamide (7b). White solid (208 mg, 0.450 mmol,
75%): mp 88−93 °C; 1H NMR (300 MHz, MeOD) δ 7.76 (d, J = 8.1
Hz, 2H), 7.42 (d, J = 9.0 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 6.84 (d, J
= 9.0 Hz, 2H), 3.76 (s, 3H), 3.64 (t, J = 7.0 Hz, 2H), 3.08 (t, J = 7.0
Hz, 2H), 2.41 (s, 3H), 2.17 (t, J = 11.4 Hz, 1H), 1.85−1.71 (m, 4H),
1.51−1.31 (m, 2H), 1.30−1.15 (m, 4H); 13C NMR (75 MHz, MeOD)
δ 179.8, 165.2, 159.1, 144.2, 142.2, 132.1, 130.6, 127.3, 125.0, 115.0,
56.0, 46.6, 38.7, 36.0, 30.8, 27.0, 26.9, 21.6; IR (KBr) ν 3302, 2930,
2855, 1735, 1644, 1540, 1511 cm−1; HRMS (ESI-TOF) calcd for
C24H31N3O4SNa (M + Na)+, 480.1933, found 480.1927.
collected and concentrated under reduced pressure to afford the
desired β-alanine as an off white powder (34 mg, 88%).
3-Aminopropanoic Acid Hydrochloride (7f).29 Off white solid
1
(34 mg, 0.267 mmol, 88%): mp 205−208 °C; H NMR (300 MHz,
D2O) δ 3.33 (t, J = 6.3 Hz, 2H), 2.86 (t, J = 6.4 Hz, 2H); 13C NMR
(75 MHz, MeOD) δ 174.3, 36.6, 32.1; IR (KBr) ν 3626, 3418, 2011,
1723, 1622, 1409, 1219, 813 cm−1; HRMS (EI) calcd for C3H7NO2
(M + H)+, 89.0477, found 89.0476.
3-Amino-3-methylbutanoic Acid Hydrochloride (7g). Off
1
white solid (27 mg, 0.175 mmol, 62%): mp 231−233 °C; H NMR
(300 MHz, MeOD) δ 2.69 (s, 2H), 1.44 (s, 6H); 13C NMR (75 MHz,
MeOD) δ 173.7, 53.4, 43.6, 26.1; IR (KBr) ν 3418, 2983, 2582, 2081,
1722, 1634, 1383, 1085 cm−1 ; HRMS (ESI-TOF) calcd for
C5H11NO2Na (M + Na)+, 140.0687, found 140.0683.
Representative Procedure for the Preparation of Chiral
Propargyl Amides from N-Boc-α-Amino Acids: Preparation of
(R)-N-(4-Methylpent-1-yn-3-yl)benzamide (3u) from N-Boc
Valine. Stage 1: Preparation of (R)-tert-Butyl 1-(methoxy(methyl)-
amino)-3-methyl-1-oxobutan-2-ylcarbamate (1u). To a stirred
solution of N-Boc valine (2.0 g, 9.211 mmol) in dichloromethane
(25 mL) were added EDC·HCl (2.64 g, 13.81 mmol) and HOBt (2.11
g, 13.81 mmol), and the mixture was stirred for 30 min. N,O-
dimethylhydroxyamine·HCl (1.35 g, 13.81 mmol) was added to the
reaction mixture followed by DIEA (3.2 mL, 18.42 mmol), and the
mixture was stirred for 14 h at rt. The reaction mixture was diluted
with H2O (20 mL), extracted with dichloromethane (2 × 25 mL),
washed again with 1 N HCl (10 mL), H2O (10 mL), and brine
solution (10 mL), dried over MgSO4, filtered, and concentrated to
afford the desired product as an off white powder (1.48 g, 80%).
Stage 2: Preparation of (R)-tert-Butyl 3-methyl-1-oxobutan-2-
ylcarbamate. To a stirred solution of (R)-tert-butyl 1-(methoxy-
(methyl)amino)-3-methyl-1-oxobutan-2-ylcarbamate (1.45 g, 7.213
mmol) in THF (20 mL) was added LiAlH4 (301.7 mg, 7.935
mmol) portion wise at 0 °C and stirred for 20 min at 0 °C under
nitrogen. The reaction mixture was carefully quenched with 2 N HCl
by adjusting the pH ∼ 6−7. The reaction mixture was diluted with
H2O, extracted with ethyl acetate (2 × 10 mL), dried over with
MgSO4, filtered, and concentrated under reduced pressure to afford
the desired aldehyde (860 mg, 59%) as an oil, which was taken to the
taken next immediately.
Stage 3: Preparation of (R)-tert-Butyl 4-methylpent-1-yn-3-
ylcarbamate (2u). To a stirred solution of dimethyl 2-oxopropyl-
phosphonate (1.405 g, 8.457 mmol) in acetonitrile (20 mL) was added
tosyl azide (1.667 g, 8.457 mmol) followed by potassium carbonate
(1.167 g, 8.467 mmol) at 0 °C, and the resultant mixture was stirred at
room temperature for 60 min under nitrogen. To this mixture was
added a solution of aldehyde (850 mg, 4.228 mmol) in MeOH (10
mL) at 0 °C dropwise over a period of 10 min, and the mixture was
stirred overnight. The reaction mixture was quenched with H2O (10
mL) and concentrated under reduced pressure, and the resultant
residue was diluted with ethyl acetate (30 mL), washed with H2O (10
mL), dried over with MgSO4, filtered, and concentrated to afford the
crude. The crude was purified by silica gel column chromatography
using 5−7% ethyl acetate in hexane as the solvent system to afford the
desired alkyne as a pale yellow solid (347 mg, 42%).
Ethyl 3-(N′-tosylbenzimidamido)propanoate (7c). Colorless
1
liquid (188 mg, 0.50 mmol, 80%): H NMR (300 MHz, MeOD) δ
7.52−7.41 (m, 3H), 7.38−7.26 (m, 4H), 7.20 (d, J = 8.0 Hz, 2H), 4.14
(q, J = 7.1 Hz, 2H), 3.66 (t, J = 6.7 Hz, 2H), 2.66 (t, J = 6.6 Hz, 2H),
2.38 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, MeOD)IR
δ 173.2, 168.4, 143.8, 142.2, 135.4, 131.7, 130.3, 129.2, 129.1, 127.6,
62.0, 39.3, 33.9, 21.5, 14.7; IR (KBr) ν 3306, 3064, 2928, 1731, 1586,
1542, 1494, 1445, 1376, 720, 691 cm−1; HRMS (ESI-TOF) calcd for
C19H22N2O4SNa (M + Na)+, 397.1198, found 397.1194.
Ethyl 2-(1-(N′-tosylbenzimidamido)cyclohexyl)acetate (7d).
1
Off white solid (151 mg, 0.351 mmol, 78%): mp 104−106 °C; H
NMR (300 MHz, MeOD) δ 7.46−7.44 (m, 3H), 7.33−7.30 (m, 4H),
7.21−7.19 (m, 2H), 4.10 (q, J = 7.1, 14.2 Hz, 2H), 2.96 (s, 2H), 2.35
(s, 3H), 2.34−2.33 (b, 1H), 1.50−1.29 (m, 10H), 1.17 (t, J = 6.8 Hz,
3H); 13C NMR (75 MHz, MeOD) δ 172.3, 167.5, 143.6, 142.2, 136.1,
131.4, 130.2, 129.3, 128.9, 127.5, 61.5, 58.6, 35.6, 42.2, 26.6, 22.8, 21.5,
14.8 cm−1; IR (KBr) ν 3420, 2930, 2857, 1727, 1584, 1530, 1281,
1146, 1087, 725. HRMS (ESI-TOF) calcd for C24H30N2O4SNa (M +
Na)+, 465.1824, found 465.1817.
(S)-Ethyl 5-methyl-3-(N′-tosylbenzimidamido)hexanoate
1
(7e). Colorless liquid (164 mg, 0.500 mmol, 82%): H NMR (300
MHz, MeOD) δ 7.52−7.46 (m, 3H), 7.43−7.31 (m, 4H), 7.22−7.19
(m, 2H), 4.80−4.62 (b, 1H), 4.14 (q, J = 2.6, 7.0 Hz, 2H), 2.56−2.52
(m, 2H), 2.38 (s, 3H), 1.66−1.53 (m, 2H), 1.36−1.22 (m, 4H), 0.95−
0.91 (m, 6H); 13C NMR (75 MHz, MeOD) δ 172.7, 167.8, 143.6,
142.4, 135.6, 131.6, 130.1, 129.1, 129.0, 127.5, 61.9, 49.1, 44.3, 40.7,
Stage 4: Preparation of (R)-4-Methylpent-1-yn-3-amine. A
mixture of trifluoroacetic acid and dichloromethane (1:1) (4 mL)
was added to N-Boc alkyne (140 mg) and stirred for 30 min at rt. The
reaction mixture was evaporated under pressure, and the resultant
residue was diluted with 6 M NaOH (10 mL), extracted with
dichloromethane (2 × 10 mL), dried over with MgSO4, filtered, and
taken to the next stage without evaporation (the yield of this step was
considered as quantitative).
Stage 5: Preparation of (R)-N-(4-Methylpent-1-yn-3-yl)-
benzamide (3u). To a stirred solution of propargylamine (69 mg,
0.709 mmol; considered as quant. yield in the previous stage) in
dichloromethane (20 mL) was added triethylamine (0.1 mL, 1.06
mmol) followed by benzoyl chloride (0.091 mL, 0.779 mmol), and the
resultant mixture was stirred at rt for 4 h under nitrogen atmosphere.
The reaction mixture was diluted with dichloromethane (10 mL),
26.3, 23.6, 22.4, 21.5, 14.7; [α]28 = −14.78 (c, 0.5, CH2Cl2); IR
D
(KBr) ν 3289, 3107, 2958, 2926, 2871, 1911, 1732, 1585, 1445, 1279,
1144, 1030, 728, 662 cm−1; HRMS (ESI-TOF) calcd for C23H31N2O4S
(M + H)+, 431.2005, found 431.1997.
Representative Procedure for the Hydrolysis of the
Dihydropyrimid-4-ones (7f and 7g): Hydrolysis of 2-Phenyl-
3-tosyl-5,6-dihydropyrimidin-4(3H)-one to β-Alanine Hydro-
chloride (7f). 6 M HCl (5 mL) was added to 2-phenyl-3-tosyl-5,6-
dihydropyrimidin-4(3H)-one (6a) and the resultant mixture was
refluxed at 100 °C for 3 h. The reaction mixture was cooled and the
diluted with H2O (5 mL), stirred with ethyl acetate (2 × 10 mL). The
organic layer was separated and discarded. The aqueous layer was
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Article
washed with sat. NaHCO3 solution (5 mL), H2O (5 mL), dried over
with MgSO4, filtered, and concentrated under reduced pressure to
afford the desired chiral propargyl amide as an off white powder (115
mg, 80%).
N-(Prop-2-ynyl)benzamide (3a). Brown powder (208 mg, 1.306
mmol, 78%): mp 112−114 °C; 1H NMR (300 MHz, CDCl3) δ 7.79−
7.54 (m, 2H), 7.54−7.41 (m, 3H), 6.29 (b, 1H), 4.26 (dd, J = 2.6, 5.1
Hz, 2H), 2.28 (t, J = 2.49, 1H) ppm; 13C NMR (75 MHz, CDCl3) δ
167.3, 133.9, 131.9, 128.8, 127.2, 79.7, 72.0, 29.9 ppm; IR (KBr) ν
3292, 3059, 1961, 1998, 1812, 1651, 1603, 1651, 1603, 1492, 1051,
716 cm−1; HRMS (ESI-TOF) calcd for C10H9NO [M + Na]+
182.0582, found 182.0584.
N-(Prop-2-ynyl)acetamide (3b). Brown powder (120 mg, 1.235
mmol, 80%): mp 71−73 °C; 1H NMR (300 MHz, CDCl3) δ 5.68 (b,
1H), 4.04 (dd, J = 2.5, 5.3 Hz, 2H), 2.22 (s, 1H). 2.00 (s, 3H) ppm;
13C NMR (75 MHz, CDCl3) δ 170.3, 79.8, 71.4, 29.3, 23.0 ppm; IR
(KBr) ν 3227, 3086, 2115, 1658, 1569, 1301, 1079, 718 cm−1; HRMS
(ESI-TOF) calcd for C5H7NONa [M + Na]+ 120.0425, found
120.0420.
1589, 1538, 1299, 864, 686 cm−1; HRMS (FAB) calcd for
C10H7NO35Cl2 [M + H]+ 227.9983, found 227.9977.
2-Iodo-N-(prop-2-ynyl)benzamide (3j). Off white powder (378
mg, 1.326 mmol, 73%): mp 106−108 °C; 1H NMR (300 MHz,
CDCl3) δ 7.87 (d, J = 7.9 Hz, 1H), 7.43−7.36 (m, 2H), 7.14−7.08 (m,
1H), 5.95 (b, 1H), 4.26 (dd, J = 2.5, 5.1 Hz, 2H), 2.29 (s, 1H) ppm;
13C NMR (75 MHz, CDCl3) δ 169.0, 141.4, 140.1, 131.5, 128.5, 128.3,
92.6, 79.1, 72.3 29.9 ppm; IR (KBr) ν 3290, 3050, 2912, 2839, 1961,
1658, 1651, 1537, 1063, 947, 637 cm−1; HRMS (FAB) calcd for
C10H8NOI [M]+ 284.9651, found 284.9652.
2-Phenyl-N-(prop-2-ynyl)acetamide (3k). Pale yellow powder
1
(473 mg, 2.73 mmol, 92%): mp 80−81 °C; H NMR (300 MHz,
CDCl3) δ 7.43−7.30 (m, 3H), 7.30−7.22 (m, 2H), 5.56 (b, 1H), 4.01
(dd, J = 2.4, 5.1 Hz, 2H), 3.60 (s, 2H), 2.18 (t, J = 2.4, 1H) ppm; 13C
NMR (75 MHz, CDCl3) δ 170.77, 134.58, 129.67, 129.29, 127.71,
79.55, 71.76, 43.71, 29.53 ppm; IR (KBr) ν 3277, 3239, 3046, 2125,
1666, 1633, 1543 cm−1; HRMS (ESI) calcd for C11H12NO [M + H]+
174.0919, found 174.0917.
N-(Prop-2-ynyl)cinnamamide (3l). White powder (496 mg, 2.68
1
(E)-N-(Prop-2-ynyl)but-2-enamide (3c). White powder (210 mg,
mmol, 95%): mp 107−108 °C; H NMR (300 MHz, CDCl3) δ 7.66
1
1.70 mmol, 94%): mp 114−119 °C; H NMR (300 MHz, CDCl3) δ
(d, J = 15.6, 1H), 7.57−7.46 (m, 2H), 7.44−7.33 (m, 3H), 6.39 (d, J =
15.6, 1H), 5.78 (b, 1H), 4.20 (dd, J = 2.4, 5.1 Hz, 2H), 2.27 (t, J = 2.4,
1H) ppm; 13C NMR (75 MHz, CDCl3) δ 165.77, 142.12, 134.83,
130.09, 129.05, 128.07, 119.99, 79.67, 71.98, 29.66 ppm; IR (KBr) ν
3281, 3226, 3046, 2117, 1657, 1619, 1543 cm−1; HRMS (FAB) calcd
for C12H12NO [M + H]+ 186.0919, found 186.0915.
6.96−6.79 (m, 1H), 5.79 (d, J = 15.5 Hz, 1H), 4.11 (dd, J = 5.1,2.4 Hz,
2H), 2.23 (t, J = 2.3 Hz, 1H), 1.86 (d, J = 6.9 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 166.1, 140.6, 124.7, 79.9, 71.3, 29.1, 17.8; IR (KBr) v
3437, 3247, 2115, 1630 cm−1; HRMS (ESI-TOF) calcd for C7H10NO
[M + H]+, 124.0762, found 124.0761.
N-(Prop-2-ynyl)cyclohexanecarboxamide (3d). Off white
N-(Prop-2-ynyl)-2-naphthamide (3m). White powder (503 mg,
1
powder (230 mg, 1.391 mmol, 89%): mp 100−102 °C; H NMR
1
2.40 mmol, 99%): mp 159−162 °C; H NMR (300 MHz, CDCl3) δ
(300 MHz, CDCl3) δ 5.58 (b, 1H), 4.04 (dd, J = 2.6, 5.1 Hz, 2H), 2.22
(s, 1H), 2.13−2.04 (m, 1H), 1.88−1.78 (m, 4H), 1.68−1.33 (m, 6H)
ppm; 13C NMR (75 MHz, CDCl3) δ 175.8, 79.9, 71.7, 45.4, 29.7, 29.3,
25.8 ppm; IR (KBr) ν 3445, 3302, 3054, 2931, 2855, 1638, 1534,
1450, 1392, 1265, 995, 739 cm−1; HRMS (FAB) calcd for C10H15NO
[M]+ 165.1154, found 165.1149.
8.31 (s, 1H), 7.97−7.80 (m, 4H), 7.63−7.50 (m, 2H), 6.41 (b, 1H),
4.33 (dd, J = 2.4, 4.8 Hz, 2H), 2.32 (t, J = 2.4, 1H) ppm; 13C NMR
(75 MHz, CDCl3) δ 167.41, 135.07, 132.78, 131.15, 129.16, 128.75,
128.01, 127.97, 127.87, 127.03, 123.70, 79.75, 72.15, 30.11 ppm; IR
(KBr) ν 3284, 3324, 3050, 2127, 1644, 1626, 1600 cm−1; HRMS
(FAB) calcd for C14H12NO [M + H]+ 210.0919, found 210.0922.
N-(Prop-2-ynyl)thiophene-2-carboxamide (3n). White powder
(197 mg, 1.19 mmol, 79%): mp 117.3−118.9 °C; 1H NMR (300
MHz, CDCl3) δ 7.62−7.46 (m, 2H), 7.15−7.04 (m, 1H), 6.17 (b,
1H), 4.24 (dd, J = 5, 2.2 Hz, 2H), 2.28 (s, 1H); 13C NMR (75 MHz,
CDCl3) δ 161.8, 138.3, 130.6 128.8, 127.9, 79.5, 72.1, 29.8; IR (KBr) ν
3288, 3084, 2118, 1628, 1550 cm−1; HRMS (FAB) calcd for
C8H8NOS (M + H)+, 166.0327, found 166.0330.
2-Methyl-N-(prop-2-ynyl)benzamide (3e). White powder (360
mg, 2.08 mmol, 99%): mp 68−73 °C; 1H NMR (300 MHz, CD3OD)
δ 7.37−7.29 (m, 2H), 7.28−7.18 (m, 2H), 4.13 (d, J = 2.2 Hz, 2H),
2.61 (t, J = 2.3 Hz, 1H), 2.39 (s, 3H); 13C NMR (75 MHz, CD3OD) δ
172.8, 137.5, 137.1, 131.9, 131.2, 128.1, 126.9, 80.8, 72.2, 29.8, 19.7; IR
(KBr) v 3282, 3265, 2117, 1628 cm−1; HRMS (ESI-TOF) calcd for
C11H12NO [M + H]+, 174.0919, found 174.0926.
4-Methyl-N-(prop-2-ynyl)benzamide (3f). White powder (370
mg, 2.14 mmol, 99%): mp 99−104 °C; 1H NMR (300 MHz, CDCl3)
δ 7.68 (d, J = 8.1 Hz, 2H), 7.23 (d, J = 7.9 Hz, 2H), 4.24 (dd, J = 5.1,
2.4 Hz, 2H), 2.39 (s, 3H), 2.27 (t, J = 2.3 Hz, 1H); 13C NMR (75
MHz, CDCl3) δ 167.5, 142.0, 130.9, 129.1, 127.3, 79.9, 71.3, 29.6,
21.4; IR (KBr) v 3287, 3305, 2120, 1640 cm−1; HRMS (ESI-TOF)
calcd for C11H12NO [M + H]+, 174.0919, found 174.0924.
N-(Prop-2-ynyl)picolinamide (3o). White powder (185 mg, 1.16
mmol, 58%): mp 77.4−78.6 °C; 1H NMR (300 MHz, CDCl3) δ 8.55
(d, J = 4.5 Hz, 1H), 8.37−8.11 (m, 2H), 7.88−7.79 (m, 1H), 7.46−
7.39 (m, 1H), 4.26 (dd, J = 5.6, 2.4 Hz, 2H), 2.26 (t, J = 2.4 Hz, 1H);
13C NMR (75 MHz, CDCl3) δ 164.2, 149.6, 148.4, 137.5, 126.6, 122.5,
79.6, 71.8, 29.3; IR (KBr) ν 3339, 3252, 3056, 2114, 1659, 1520 cm−1;
HRMS (ESI-TOF) calcd for C9H8N2ONa (M + Na)+, 183.0534,
found 183.0527.
N-(Prop-2-ynyl)furan-2-carboxamide (3p). White powder (258
mg, 1.73 mmol, 86%): mp 88.5−89.9 °C; 1H NMR (300 MHz,
CDCl3) δ 7.45 (s, 1H), 7.14 (d, J = 3.4 Hz, 1H), 6.61−6.42 (m, 2H),
4.23 (dd, J = 5.3, 2.4 Hz, 2H), 2.27 (t, J = 2.1 Hz, 1H); 13C NMR (75
MHz, CDCl3) δ 158.1, 147.6, 144.4, 115.0, 112.4, 79.4, 72.0, 29.0; IR
(KBr) ν 3289, 3270, 3050, 2108, 1640, 1528 cm−1; HRMS (ESI-TOF)
calcd for C8H8NO2 (M + H)+, 150.0555, found 150.0556.
4-Methoxy-N-(prop-2-ynyl)benzamide (3g). Off white powder
1
(222 mg, 1.173 mmol, 83%): mp 120−122 °C; H NMR (300 MHz,
CDCl3) δ 7.74 (d, J = 8.7 Hz, 2H), 6.92 (d, J = 8.7 Hz, 2H), 6.23 (b,
1H), 4.23 (dd, J = 2.6, 5.1 Hz, 2H), 3.84 (s, 3H), 2.26 (s, 1H) ppm;
13C NMR (75 MHz, CDCl3) δ 166.8, 162.6, 129.1, 126.3, 114.0, 79.9,
71.9, 55.6, 29.9 ppm; IR (KBr) ν 3263, 2963, 2838, 1641, 1611, 1545,
1249, 1029, 836, 677 cm−1; HRMS (ESI-TOF) calcd for C11H11NO2
[M]+ 189.0790, found 189.0790.
2-Chloro-N-(prop-2-ynyl)benzamide (3h). White powder (276
mg, 1.43 mmol, 71%): mp 78.1−79.3 °C; 1H NMR (300 MHz,
CDCl3) δ 7.74−7.66 (m, 1H), 7.44−7.28 (m, 3H), 6.47 (b, 1H), 4.26
(dd, J = 5.2, 2.5 Hz, 2H), 2.28 (t, J = 2.6 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 166.2, 134.4, 131.9, 131.0, 130.6, 130.5, 127.4, 79.2, 72.3,
30.0; IR (KBr) ν 3285, 3269, 3049, 2126, 1643, 1593 cm−1; HRMS
(ESI-TOF) calcd for C10H9NOCl (M + H)+, 194.0373, found
194.0380.
2-Chloro-N-(prop-2-ynyl)acetamide (3q). Brown powder (200
mg, 1.52 mmol, 84%): mp 68−73 °C; 1H NMR (300 MHz, CDCl3) δ
4.12 (t, J = 4.12 Hz, 2H), 4.08 (s, 2H), 2.28 (s, 1H); 13C NMR (75
MHz, CDCl3) δ 165.9, 78.8, 72.3, 42.5, 29.7; IR (KBr) v 3439, 3278,
2129, 1646 cm−1; HRMS (ESI-TOF) calcd for C5H6NO35Cl [M]+
131.0138, found 133.0115.
N-(2-Methylbut-3-yn-2-yl)benzamide (3r). Off white powder
1
(400 mg, 1.987 mmol, 89%): mp 155−157 °C; H NMR (300 MHz,
2,4-Dichloro-N-(prop-2-ynyl)benzamide (3i). Off white powder
1
CDCl3) δ 7.75 (d, J = 7.3 Hz, 2H), 7.49−7.42 (m, 3H), 6.18 (b, 1H),
2.39 (s, 1H), 1.77 (s, 6H) ppm; 13C NMR (75 MHz, CDCl3) δ 166.6,
134.9, 131.6, 128.6, 127.0, 87.3, 69.5, 48.2, 29.1 ppm; IR (KBr) ν 3243,
3062, 2931, 1640, 1580, 1542, 1361, 1076, 943, 693 cm−1; HRMS
(ESI-TOF) calcd for C12H13NO [M + H]+ 188.1075, found 188.1069.
(308 mg, 1.350 mmol, 62%): mp 98−99 °C; H NMR (300 MHz,
CDCl3) δ 7.68 (d, J = 8.3 Hz, 1H), 7.44 (s, 1H), 7.33 (d, J = 9.6 Hz,
1H), 6.4 (b, 1H), 4.26 (dd, J = 2.5, 5.0 Hz, 2H), 2.29 (s, 1H) ppm; 13C
NMR (75 MHz, CDCl3) δ 165.3, 137.2, 132.7, 131.8, 131.4, 130.2,
127.6, 79.0, 72.2, 29.9 ppm; IR (KBr) ν 3297, 3056, 2824, 1903, 1644,
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N-(1-Ethynylcyclohexyl)benzamide (3s). Off white powder
(139 mg, 0.575 mmol, 81%): mp 132−134 °C; 1H NMR (300
MHz, CDCl3) δ 7.76 (d, J = 7.3 Hz, 2H), 7.50−7.41 (m, 3H), 6.08 (b,
1H), 2.45 (s, 1H), 2.25−1.99 (m, 2H), 1.96−1.92 (m, 2H), 1.76−1.53
(m, 5H), 1.35−1.32 (m, 1H) ppm; 13C NMR (75 MHz, CDCl3) δ
166.5, 135.2, 131.6, 128.7, 127.1, 85.6, 75.8, 71.7, 52.2, 37.1, 25.4, 22.7
ppm; IR (KBr) ν 3287, 2934, 2363, 1639, 1538, 1310, 1076, 714, 619
cm−1; HRMS (FAB) calcd for C15H17NONa [M + Na]+ 250.1206,
found 250.1206.
(R)-tert-Butyl 1-(methoxy(methyl)amino)-1-oxopropan-2-yl-
carbamate (1t). White solid (2.18 g, 9.39 mmol, 89%): mp 144−147
°C; 1H NMR (300 MHz, CD3OD) δ 4.57 (b, 1H), 3.81 (s, 3H), 3.20
(s, 3H), 1.44 (s, 9H), 1.25 (d, J = 6.9, 3H) ppm; 13C NMR (75 MHz,
CD3OD) δ 175.69, 157.81, 80.59, 62.17, 32.73, 30.81, 28.86, 17.58
ppm; [α]28.0D = −3.32 (c, 0.5, CH2Cl2); IR (KBr) ν 3296, 2975, 1704,
1660 cm−1; HRMS (FAB) calcd for C10H21N2O4 [M + H]+ 233.1501,
found 233.1506.
1.76 (m, 1H), 1.58−1.52 (m, 2H), 1.45 (s, 9H), 0.95−0.87 (m, 6H)
ppm; 13C NMR (75 MHz, CDCl3) δ 154.9, 84.0, 79.9, 70.9, 45.3, 41.4,
28.5, 25.1, 22.8, 22.0 ppm; [α]28.7 = −40.22 (c, 0.5, CH2Cl2); IR
D
(KBr) ν 3314, 2959, 2872, 1699, 1515, 1367, 1249, 1171, 1015, 869,
648.7 cm−1; HRMS (FAB) calcd for C12H22NO2 [M + H]+ 212.1651,
found 212.1652.
(R)-N-(5-Methylhex-1-yn-3-yl)benzamide (3v). Off white pow-
der (498 mg, 2.313 mmol, 78%): mp 72−74 °C; 1H NMR (300 MHz,
CDCl3) δ 7.77 (d, J = 7.08 Hz, 2H), 7.50−7.41 (m, 3H), 6.18 (b, 1H),
5.03- 4.99 (m, 1H), 2.30 (d, J = 2.2 Hz, 1H), 1.88−1.84 (m, 1H),
1.65−1.64 (m, 2H), 0.99 (d, J = 6.5 Hz, 6H) ppm; 13C NMR (75
MHz, CDCl3) δ 166.6, 134.3, 131.9, 128.8, 127.2, 83.7, 71.4, 45.1,
40.5, 25.4, 22.9, 22.1 ppm; [α]27.4D = −25.6 (c, 0.5, CH2Cl2); IR (KBr)
ν 3305, 3061, 2870, 1786, 1603, 1531, 1288, 1075, 801, 693 cm−1;
HRMS (FAB) calcd for C14H17NO [M − H]+ 214.1231, found
214.1232.
tert-Butyl 1-(methoxy(methyl)amino)-4-methyl-1-oxopen-
tan-2-ylcarbamate (1w). Colorless oil (1120 mg, 4.082 mmol,
(R)-tert-Butyl but-3-yn-2-ylcarbamate (2t). White powder (275
1
1
95%): H NMR (300 MHz, CDCl3) δ 5.02 (b, 1H), 4.72−4.69 (b,
mg, 1.63 mmol, 41% (two steps)): mp 77−81 °C; H NMR (300
1H), 3.78 (s, 3H), 3.19 (s, 3H), 1.74−1.67 (m, 1H), 0.97−0.92 (m,
6H) ppm; 13C NMR (75 MHz, CDCl3) δ 174.0, 155.8, 79.5, 61.7,
49.1, 42.2, 32.3, 28.5, 24.9, 23.5, 21.7 ppm; IR (KBr) ν 3333, 2959,
2871, 1713, 1660, 1170, 876 cm−1; HRMS (FAB) calcd for
C13H27N2O4 [M + H]+ 275.1971, found 275.1965.
MHz, CDCl3) δ 4.68 (b, 1H), 4.48 (b, 1H), 2.25 (s, 1H), 1.45 (s, 9H),
1.40 (d, J = 6.9, 3H) ppm; 13C NMR (75 MHz, CD3OD) δ 154.84,
84.79, 80.19, 70.33, 38.59, 28.58, 22.79 ppm; [α]28.3D = −38.33 (c, 0.5,
CH2Cl2); IR (KBr) ν 3321, 3288, 1703 cm−1; HRMS (ESI) calcd for
C9H15NO2Na [M + Na]+ 192.0995, found 192.0995.
tert-Butyl 5-methylhex-1-yn-3-ylcarbamate (2w). Off white
(R)-N-(But-3-yn-2-yl)benzamide (3t). White powder (163.1 mg,
0.94 mmol, 58%): mp 78−81 °C; 1H NMR (300 MHz, CDCl3) δ 7.78
(d, J = 7.4 Hz, 2H), 7.55−7.41 (m, 3H), 6.27 (b, 1H), 5.12−4.94 (m,
1H), 2.31 (d, J = 1.9 Hz, 1H), 1.53 (d, J = 6.9 Hz,3H) ppm; 13C NMR
(75 MHz, CDCl3) δ 166.53, 134.20, 131.95, 128.84, 127.20, 84.36,
70.93, 37.71, 22.60 ppm; [α]26.4D = −0.09 (c, 0.5, CH2Cl2); IR (KBr)
ν 3296, 3062, 2145, 1644, 1602, 1531 cm−1; HRMS (EI) calcd for
C11H11NO [M]+ 173.0841, found 173.0844.
1
powder (270 mg, 1.007 mmol, 29% (2 steps)): mp 82−84 °C; H
NMR (300 MHz, CDCl3) δ 4.60 (b, 1H), 4.42 (b, 1H), 2.24 (d, J =
1.8 Hz; 1H), 1.83−1.76 (m, 1H), 1.58−1.52 (m, 2H), 1.45 (s, 9H),
0.95−0.90 (m, 6H) ppm; 13C NMR (75 MHz, CDCl3) δ 154.9, 84.0,
79.9, 70.9, 45.3, 41.4, 28.5, 25.1, 22.8, 22.0 ppm; IR (KBr) ν 3314,
2959, 2872, 1699, 1515, 1367, 1249, 1171, 1015, 869, 648.7 cm−1;
HRMS (FAB) calcd for C12H22NO2 [M + H]+ 212.1651, found
212.1652.
(R)-tert-Butyl 1-(methoxy(methyl)amino)-3-methyl-1-oxobu-
(R)-N-(5-Methylhex-1-yn-3-yl)benzamide (3w). Off white
tan-2-ylcarbamate (1u). Colorless oil (1910 mg, 7.3368 mmol,
1
1
powder (198 mg, 0.919 mmol, 79%): mp 72−74 °C; H NMR (300
80%): H NMR (300 MHz, CDCl3) δ 5.14−5.11 (m, 1H), 4.56 (b,
MHz, CDCl3) δ 7.77 (d, J = 7.08 Hz, 2H), 7.50−7.41 (m, 3H), 6.42
(b, 1H), 5.05- 4.99 (m, 1H), 2.30 (d, J = 2.2 Hz, 1H), 1.88−1.84 (m,
1H), 1.65−1.64 (m, 2H), 0.99 (d, J = 6.5 Hz, 6H) ppm; 13C NMR (75
MHz, CDCl3) δ 166.6, 134.3, 131.9, 128.8, 127.2, 83.7, 71.4, 45.1,
40.5, 25.4, 22.9, 22.1 ppm; IR (KBr) ν 3305, 3061, 2870, 1786, 1603,
1531, 1288, 1075, 801, 693 cm−1; HRMS (FAB) calcd for C14H16NO
[M − H]+ 214.1231, found 214.1232.
1H), 3.76 (s, 3H), 3.20 (s, 3H), 2.01−1.92 (m, 1H), 1.43 (s, 9H), 0.95
(d, J = 6.8 Hz; 3H), 0.90 (d, J = 6.8 Hz; 3H) ppm; 13C NMR (75
MHz, CDCl3) δ 172.9, 155.8, 79.3, 61.5, 54.9, 31.8, 31.3, 30.9, 28.3,
19.4, 18.9, 17.5 ppm; [α]28.6 = +9.4 (c, 0.5, CH2Cl2); IR (KBr) ν
D
3325, 2968, 1714, 1660, 1506, 1173, 875 cm−1; HRMS (FAB) calcd
for C12H24N2O4 [M + H]+ 261.1814, found 261.1808.
(R)-tert-Butyl 4-methylpent-1-yn-3-ylcarbamate (2u). Yellow
1
oil (148 mg, 0.385 mmol, 25% (for 2 steps)) ; H NMR (300 MHz,
ASSOCIATED CONTENT
CDCl3) δ 4.7 (b, 1H), 4.31 (b, 1H), 2.24 (s, 1H), 1.93−1.84 (m, 1H),
1.45 (s, 9H), 0.98 (d, J = 6.7 Hz, 6H) ppm; 13C NMR (75 MHz,
CDCl3) δ 155.1, 82.2, 79.8, 77.6, 77.2, 76.8, 71.8, 48.7, 33.1, 28.5, 18.8,
■
S
* Supporting Information
Copies of 1H and 13C NMR spectra for all new compounds and
crystallographic information (CIF file) for compound 6a. This
material is available free of charge via the Internet at http://
pubs.acs.org.
17.6 ppm; [α]28 = +28.3 (c, 0.5, CH2Cl2); IR (KBr) ν 3313, 2967,
D
1694, 1515, 1339, 1172, 865 cm−1; HRMS (FAB) calcd for
C11H19NO2Na [M + Na]+ 220.1313, found 220.1314.
(R)-N-(4-Methylpent-1-yn-3-yl)benzamide (3u). Off white
1
powder (115 mg, 0.571 mmol, 80%): mp 82−84 °C; H NMR (300
MHz, CDCl3) δ 7.77 (d, J = 6.8 Hz, 2H), 7.52−7.42 (m, 3H), 6.24 (b,
1H), 4.90−4.86 (m, 1H), 2.29 (d, J = 2.13 Hz, 2H), 2.11−2.04 (m,
1H), 1.06 (d, J = 6.8 Hz, 6H) ppm; 13C NMR (75 MHz, CDCl3) δ
166.7, 134.4, 131.9, 128.8, 127.2, 81.8, 72.4, 47.8, 32.9, 19.0, 17.8 ppm;
[α]27.0D = −36.7 (c, 0.5, CH2Cl2); IR (KBr) ν 3300, 2964, 2114, 1959,
1638, 1528, 1490, 1308, 1148, 693 cm−1; HRMS (FAB) calcd for
C13H15NO [M + H]+ 202.1232, found 202.1229.
AUTHOR INFORMATION
Corresponding Author
*E-mail: pclin@mail.nsysu.edu.tw.
Notes
■
The authors declare no competing financial interest.
(R)-tert-Butyl 1-(methoxy(methyl)amino)-4-methyl-1-oxo-
ACKNOWLEDGMENTS
■
pentan-2-ylcarbamate (1v). Colorless oil (1100 mg, 4.009 mmol,
1
92.7%): H NMR (300 MHz, CDCl3) δ 5.02 (b, 1H), 4.72−4.69 (b,
This work is supported by grants from National Science
Council (NSC 101-2113-M-110-007-MY2) and National Sun
Yat-sen University (01C030703 and 01A06802). We also thank
the support from National Sun Yat-sen University-Kaohsiung
Medical University Joint Research Center, Kaohsiung, Taiwan.
1H), 3.78 (s, 3H), 3.19 (s, 3H), 1.74−1.67 (m, 1H), 1.55−1.40 (m,
11H), 0.97−0.92 (m, 6H) ppm; 13C NMR (75 MHz, CDCl3) δ
174.13, 155.8, 79.6, 61.7, 49.1, 42.3, 32.3, 28.5, 24.9, 23.5, 21.7 ppm;
[α]28.8D = −23.46 (c, 0.5, CH2Cl2) IR (KBr) ν 3333, 2959, 2871, 1713,
1660, 1170, 876 cm−1; HRMS (FAB) calcd for C13H27N2O4 [M + H]+
275.1971, found 275.1977.
REFERENCES
(R)-tert-Butyl 5-methylhex-1-yn-3-ylcarbamate (2v). Yellow
■
1
oil (430 mg, 1.997 mmol, 51% (2 steps)) ; H NMR (300 MHz,
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1263
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