Mild Metal-Free Hydrosilylation of Secondary Amides to Amines

Article abstract of DOI:10.1021/acs.joc.6b00572

The combination of amide activation by Tf₂O with B(C₆F₅)₃-catalyzed hydrosilylation with TMDS constitutes a method for the one-pot reduction of secondary amides to amines under mild conditions. The method displays a broad applicability for the reduction of many types of substrates, and shows good compatibility and excellent chemoselectivity for many sensitive functional groups. Reductions of a multifunctionalized α,β-unsaturated amide obtained from another synthetic methodology, and a C-H functionalization product produced the corresponding amines in good to excellent yield. Chemoselective reduction of enantiomeric pure (ee >99%) tetrahydro-5-oxo-2-furaneamides yielded 5-(aminomethyl)dihydrofuran-2(3H)-ones in a racemization-free manner. The latter were converted in one pot to N-protected 5-hydroxypiperidin-2-ones, which are building blocks for the synthesis of many natural products. Further elaboration of an intermediate led to a concise four-step synthesis of -epi-pseudoconhydrine.

Full text of DOI:10.1021/acs.joc.6b00572

Article
pubs.acs.org/joc
Mild Metal-Free Hydrosilylation of Secondary Amides to Amines
Pei-Qiang Huang,* Qi-Wei Lang, and Yan-Rong Wang
Department of Chemistry, Fujian Provincial Key Laboratory of Chemical Biology, iChEM (Collaborative Innovation Center of
Chemistry for Energy Materials), College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian 361005, PR
China
S
* Supporting Information
ABSTRACT: The combination of amide activation by Tf2O with
B(C6F5)3-catalyzed hydrosilylation with TMDS constitutes a method for
the one-pot reduction of secondary amides to amines under mild conditions.
The method displays a broad applicability for the reduction of many types of
substrates, and shows good compatibility and excellent chemoselectivity for
many sensitive functional groups. Reductions of a multifunctionalized α,β-
unsaturated amide obtained from another synthetic methodology, and a C−
H functionalization product produced the corresponding amines in good to
excellent yield. Chemoselective reduction of enantiomeric pure (ee >99%)
tetrahydro-5-oxo-2-furaneamides yielded 5-(aminomethyl)dihydrofuran-
2(3H)-ones in a racemization-free manner. The latter were converted in one pot to N-protected 5-hydroxypiperidin-2-ones,
which are building blocks for the synthesis of many natural products. Further elaboration of an intermediate led to a concise four-
step synthesis of (−)-epi-pseudoconhydrine.
synthesis, which require an extra step to convert an amide to a
thioamide2d or an imide.5
INTRODUCTION
■
The secondary amine is a structural motif found in numerous
medicinal agents and bioactive alkaloids. In the list of top 200
brand-name drugs by total US prescriptions in 2012, 43 of
those pharmaceuticals contain a secondary amino functional
group,1 from which, 19 are N-methyl, N-isopropyl, or N-tert-
butylamines (cf. Figure 1). Because of the easy availability2 and
In recent years, much efforts have been devoted to the direct
reduction of secondary amide to amines, which cumulated in
several chemoselective methods.6 Those methods comprised
(1) the metal-catalyzed hydrosilylation (Nagashima:7 Ru and
Pt; Beller:8 Zn, Cu; Brookhart:9 Ir; Reeves/Senanayake:10 Ru;
Sakai:11 InI3); (2) the metal-catalyzed hydrogenation (Breit:12
Pd or Pt/Re/graphite; Luo:13 Mg-TiCl4); (3) the metal-free
orgonocatalytic hydrosilylation {Beller:14 boronic acid;
Zhang,15 Cantat16 and Adronov:17 tris(pentafluorophenyl)
boron [B(C6F5)3]}, and (4) the in situ triflic anhydride
(Tf2O)-activated reduction [Huang:18 NaBH4; Charette:19
Hantzsch ester hydride (HEH)]. Among them, the B(C6F5)3-
catalyzed hydrosilylation with 1,1,3,3-tetramethyldisiloxane
(TMDS)16,17 is attractive because this system combines
B(C6F5)3,20 a powerful Lewis acid with water, air, and
functional group tolerance, with nontoxic, cheap, and easy-to-
handle TMDS. Moreover, in Piers’s seminal work on the
B(C6F5)3-catalyzed hydrosilylation of carbonyl compounds21a,b
and imines,21c a Frustrated Lewis Pair (FLP)22 consisted of
silyliminium cation and a hydridoborate counterion has been
postulated.23 The FLP catalysis is a rapidly expanding field.22
However, this class of metal-free organocatalysis, while
powerful, is still at its infancy, much chemistry needs to be
explored. Thus, development of complementary methods16,17
that allow running the reduction reactions under milder
conditions, display broader functional group tolerance, and
suitable for more types of substrates, is highly desirable.
Figure 1. Selected examples of pharmaceuticals containing a secondary
amino functional group (taken from the list of top 200 brand-name
drugs by total US prescriptions in 2012).
high stability of amides, their reduction constitutes an
important entrance to amines.3 The classical methods utilizing
aluminum and boron-based strong reducing reagents4 such as
LiAlH4, borane, and DIBAL-H present several drawbacks such
as low functional group tolerance, production of large amounts
of alumino residue and/or formation of borane-amine adducts.
In fact, stepwise methods are being routinely used in organic
Received: March 18, 2016
© XXXX American Chemical Society
A
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In a program of these laboratories aimed at the development
of methods for the direct transformations of amides,24 several
reducing agents/systems including Et3SiH,24a−d LiAlH4,24e,g
price of B(C6F5)3, efforts have been devoted to reduce catalyst
loading. For this purpose, a two-stage one-pot protocol was
investigated first at 5 mol % catalyst loading. Thus, amide 1a
was activated with Tf2O (1.1 equiv, 0 °C, 20 min), partially
reduced with TMDS (1.2 equiv, 0 °C, 30 min, rt, 3 h). At this
stage, B(C6F5)3 (5 mol %) was introduced at 0 °C, and the
reaction was run at rt for 2−3 h. Similar to the results obtained
via the protocol A, in the absence of 2-F-Pyr. or use of a lower
amount of 2-F-Pyr. (0.6 equiv), amine 2a was obtained in lower
but respectable yield of 76% (entry 5) and 88% (entry 6),
respectively. Further optimization by using 1.2 equiv of 2-F-Pyr.
led to an improved yield to 94% (entry 7). The impact of
amount of TMDS was next surveyed (entries 8 and 9), which
showed that the use of 1.2 equiv of TMDS to be optimal (entry
7). After screening those reaction parameters, we were in a
position to examine the feasibility to reduce the catalyst
loading. To our satisfaction, when only 2 mol % of B(C6F5)3
was used, amine 2a was produced in 94% yield (entry 10).
Further reducing the catalyst loading to 1 mol % resulted in a
lower yield (83%, entry 11). On the basis of these results, the
optimized conditions for Protocols A and B turned out to be
those shown in entries 3 and 10 (Table 1), respectively.
After optimizing the reaction conditions, we turned our
attention to examine the scope of the reaction by Protocol B
(using 2 mol % catalyst loading). A series of benzamide
derivatives bearing either electron-donating groups (Me, OMe,
Table 2, entries 2 and 3) or electron-withdrawing groups (Br,
CF3, NO2, CO2Me, OAc, and CN, Table 2, entries 4−9)
reacted smoothly to give the corresponding secondary amines
2b−i in good to excellent yields (86−98%). Naphthane-2-
carboxamide 1j and heteroaromatic amide thiophene-2-
carboxamide 1k reacted similarly to give the corresponding
amines 2j and 2k in 98% (entry 10) and 88% yield (entry 11),
respectively.
On the other hand, similar to the amides [(i-Pr (1a−k)]
bearing a secondary N-alkyl group, N-cyclohexylamides (1l)
and 1m were reduced to give 2l and 2m in excellent yields
(95%, entry 12; 96%, entry 13). The reductions of β-branched
N-alkyl amide 1n and δ-branched N-alkyl amide 1o also gave
the corresponding amines 2n and 2o in similar excellent yields
(94% and 97%, entries 14 and 15), and unbranched N-alkyl and
N-alkynyl amides 1p and 1q produced amines 2p and 2q in
87% and 88% yields (entries 16 and 17). As two exceptions, the
reduction reactions of N-cyclopropyl and N-allyl amides 1r and
1s are less efficient giving the corresponding amines 2r and 2s
in 76% (entry 18) and 73% yield (entry 19), respectively. The
lowest yield (34%) was obtained with the least hindered N-
methylbenzamide 1t, which was improved to 58% by
performing the amide activation at −78 °C (entry 20).
Interestingly, N-tert-butyl benzamide reacted to give amine 2u
in 58% yield along with 14% of benzonitrile. The yield of amine
2u was improved to 74% with the use of 2.0 equiv of TMDS
and 10 mol % of B(C6F5)3 (entry 21).
10% Pd/C/H2,24f Bu3SnH,24g HEH,24g 20% Pd(OH)2/ H2,24g
18,24g
and NaBH4
have been employed. In particular, we have
developed versatile and mild methods for the reduction of both
tertiary and secondary amides with Tf2O-NaBH4 system,18 and
secondary lactams with Cp2ZrHCl-NaBH4 system, respective-
ly.18b The former method employed Tf2O25 as an amide
activating reagent and NaBH4 as a reductant. With the aim to
develop a mild and metal-free reduction of secondary amides,
we opted for merging the Tf2O activation with B(C6F5)3 (cat.)/
TMDS reduction (Scheme 1), and the results are reported
herein.
Scheme 1
RESULTS AND DISCUSSION
At the outset of our investigation, a one-stage protocol
(Protocol A, Table 1) was first examined. In the event, N-i-
■
Table 1. Optimization of the Reduction Reaction
c
entry TMDS (equiv) 2-F-Pyr. (equiv) B(C6F5)3 (mol %) yield (%)
a
a
a
a
b
b
b
b
b
d
1
2
3
4
5
6
7
8
9
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.1
1.5
1.2
1.2
0
5
5
5
2
5
5
5
5
5
2
1
61 (15)
d
0.6
1.2
1.2
0
86 (6)
93
87
76
88
94
91
93
94
83
0.6
1.2
1.2
1.2
1.2
1.2
b
10
b
11
a
Protocol A: Tf2O (1.1 equiv), 2-F-Pyr. (1.2 equiv), DCM, 0 °C, 20
min; TMDS (m equiv), 10 min; B(C6F5)3 (n mol %), 0 °C to rt, 3 h.
b
Protocol B: Tf2O (1.1 equiv), 2-F-Pyr. (1.2 equiv), DCM, 0 °C, 20
min; TMDS (m equiv), rt, 3 h; B(C6F5)3 (n mol %), rt, 2−3 h.
c
d
Isolated yield. Recovered starting material.
propyl benzamide 1a was treated successively with Tf2O (1.1
equiv, 0 °C, 20 min), TMDS (1.2 equiv) and B(C6F5)3 (5 mol
%). To our delight, after been reacted at rt for 3 h, secondary
amine 2a was formed in 61% yield, along with 15% of the
recovered starting material (Table 1, entry 1). To improve the
yield of the reaction, 0.6 equiv of 2-fluoropyridine (2-F-Pyr.)
was introduced as a base additive.26 In this manner, the yield of
2a was improved to 86%, and recovered starting material
diminished to 6% (Table 1, entry 2). Increasing the amount of
2-F-Pyr. to 1.2 equiv led to an improved yield of 93% (entry 3).
Lowering the catalyst loading from 5 mol % to 2 mol % resulted
in a decrease of yield (87%) (entry 4). Considering the high
Besides aromatic and heteroaromatic amides, reactions of
aliphatic amides were examined. The reduction of cyclo-
hexanecarboxamide 1v gave amine 2v in excellent yield (90%,
entry 22), while less hindered 2-methylpropanamide 1w and
acetamide 1x produced amines 2w and 2x in only 74% and 58%
yield, respectively (entries 23 and 24). Reduction of α,β-
unsaturated amide 1y by protocol A produced the fully reduced
saturated amine 2y−a as the major product (56%), while by
employing protocol B, allylic amine 2y and saturated amine
B
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a
Table 2. Scope of the Reduction Reaction
a
b
c
d
Protocol B was used unless otherwise specified. Isolated yield. Protocol B, amide activation was undertaken at −78 °C for 40 min. Amide
activation was undertaken at −78 °C for 40 min, TMDS (2.0 equiv) was added and stirred for 10 min at −78 °C, and then B(C6F5)3 (10 mol %) was
added, the mixture was warmed up to rt slowly, and stirred for another 3 h.
2y−a were obtained in 31% and 37% yield, respectively
(Scheme 2, eq 1).
elaboration were envisioned (Scheme 3). 5-Hydroxypiperidin-
2-one is a structural feature found in peptidal nucleoside
antibiotics streptothricins,28 and has been converted into the 5-
amino-4-hydroxypentanoic acid, a molecule possessing anx-
iolytic and sedative activities.27a In addition, several protected
forms of 5-hydroxypiperidin-2-one have served as intermediates
in the synthesis of several drugs and alkaloids, which include
immunosuppressant agents tofacitinib (CP-690,550)29a and
FR901483 (9),29b xestocyclamine A,29c fasicularin,29d
(−)-deoxoprosophylline, (+)-cis-195A,29e streptolutine stereo-
isomers,29f (2R,5R)-5-chloropipecolic acid,29g and (2S,5S)-5-
hydroxypipecolic acids.29h Thus, chemoselective reduction of
the known amido lactones 3a and 3b, easily available in two
steps from (S) or (R)-glutamic acid,29b were investigated.
Reduction of (S)-3a by protocol A produced 4a in 69% yield
(Scheme 3). HPLC analysis of the resultant amino lactone 4a
on a chiral stationary phase30 showed that its enantiomeric
Because amides are products of a number of synthetic
methodologies,2 their further transformation is, in most case,
imperative. In this context, Jiang and co-workers have
developed a method for the synthesis of multifunctionalized
secondary amides such as 1z.2a Subjection of this amide to our
reduction produced 2z in 93% yield (Scheme 2, eq 2).
Interestingly, reduction of C−H functionalization product
1aa2c afforded amine 2aa in a respectable yield of 78%
(Scheme 2, eq 3). Comparing this result with that obtained
from amide 1t which lacks an o-butyl group (2t, yield: 58%)
allowed confirming the beneficial effect of steric hindrance for
the reaction.
To further demonstrate the synthetic utility of the method,
the synthesis of amino lactones 4a and 4b,27 protected forms of
5-hydroxypiperidin-2-one (6a and 6b), as well as their further
C
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Mechanistic Considerations. Plausible mechanisms for
the reduction of secondary amides by two protocols are
depicted in Scheme 4, which differ from each other only in the
Scheme 2
Scheme 4. Plausible Mechanisms for the Reduction of
Secondary Amides by Protocols A and B
Scheme 3
step b. Thus, for both protocols A and B, the first step involves
amide activation with Tf2O to generate the iminium triflate A,
which upon treatment with 2-F-Pyr. generates the nitrilium ion
intermediate B and 2-F-Pyr. triflic acid salt.24a−c,32 Movassaghi
has detected nitrilium ion B by IR.26 Previously we have
observed that the amide activation-based C−C bond forming
reaction failed with secondary lactams, which also implicated
the intermediacy of a nitrilium ion intermediate.32
For Protocol B, the nitrilium ion B is reduced by TMDS to
give, after protonation, the iminium ion C (step b, path a). The
latter was further reduced by the Piers’ intermediate (step c), in
situ generated from B(C6F5)3 (cat.) and TMDS, to produce,
after basic workup, a free amine. For the reduction employing
Protocol A, nitrilium ion intermediate B was reduced by the
Piers’ intermediate (Piers’ hydride) to give intermediates C
(the regeneration of B(C6F5)3 not shown in the Scheme 4),
that is further reduced by the Piers’ hydride (step c) to give an
amine.
excess is >99% (cf. SI). Treatment of amino lactone 4a with
NaH in THF at 60 °C yielded the ring expanded
hydroxylactam 5a, which was O-benzylated in situ with BnBr
to give directly lactam 6a in 91% yield. Employing the method
developed from these laboratories,24g one-pot reductive
alkylation of (R)-6a produced 7 and diastereomer 8 in a 13:1
ratio with a combined yield of 76%. The stereochemistry of the
major diastereomer 7 was deduced from the final product
(−)-epi-pseudoconhydrine31 hydrochloride salt (10), which
was obtained in 97% yield via catalytic hydrogenolysis. Thus,
starting from the known 3a, (−)-epi-pseudoconhydrine·HCl
(10) was synthesized in four steps with an overall yield of 43%.
Following the same two-step sequence described for the
transformation of (S)-3a, the known amido lactone (R)-3b was
converted into 5-benzyloxypiperidin-2-one (R)-6b in an overall
yield of 57%. 6b has served as the key chiral building block in
the total synthesis of the potent immunosuppressant agent
FR901483 (9) where it was prepared from (R)-3b by a four-
step procedure.29b
CONCLUSIONS
■
In conclusion, we have demonstrated that by in situ activation
with Tf2O/2-F-Pyr., secondary amides can be efficiently
reduced to amines by the B(C6F5)3 (2 mol %)−TMDS
combination under very mild conditions. The reaction displays
a broad applicability for many types of substrates, including
those been excluded by other methods such as N-alkyl (in
particular N-methyl, N-isopropyl, N-c-hexylCH2, N-tert-butyl,
and N-allyl) amides. The reaction also shows good functional
group tolerance and excellent chemoselectivity for several
functional groups including MeO, CF3, Br, NO2, CO2Me, AcO,
CN, alkenyl, alkynyl, cyclopropyl, and OTBDPS groups. The
mildness, chemoselectivity, and synthetic utility of the method
were further demonstrated by the smooth reduction of the
Jiang’s multifunctionalized α,β-unsaturated secondary amide 1z,
the C−H activation product 1aa, and enantiomeric amido
D
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(CDCl3, 125 MHz) δ 21.0, 22.8 (2C), 47.9, 51.3, 128.0 (2C), 129.0
(2C), 136.3, 137.6 ppm; MS (ESI, m/z) 164 (M + H+).
lactones 3a and 3b. The latter were directly transformed to
lactams (S)-6a and (R)-6b, respectively, which are building
blocks for the synthesis several natural products such as the
potent immunosuppressant agent FR901483 (9). Moreover,
direct reductive alkylation of (S)-6a resulted in a concise four-
step synthesis of (−)-epi-pseudoconhydrine·HCl (10) from the
known 3a with an overall yield of 43%.
N-(4-Methoxybenzyl)isopropylamine (2c). Following the gen-
eral procedure (Protocol B), the reduction of amide 1c (193 mg, 1.0
mmol) gave, after flash column chromatography on silica gel (eluent:
EtOAc/Hexane/Et3N = 1/1/0.01), the known amine 2c18b (169 mg,
yield: 94%) as a colorless oil. IR (film) νmax 3316, 2962, 2930, 2835,
1612, 1585, 1512, 1465, 1379, 1300, 1247, 1172, 1070, 1037, 823, 750,
1
701 cm−1; H NMR (CDCl3, 500 MHz) δ 1.09 (d, J = 6.3 Hz, 6H),
1.50 (br s, 1H), 2.84 (septet, J = 6.3 Hz, 1H), 3.71 (s, 2H), 3.78 (s,
3H), 6.83−6.87 (m, 2H), 7.21−7.25 (m, 2H); 13C NMR (CDCl3, 125
MHz) δ 22.8 (2C), 47.9, 50.9, 55.2, 113.7 (2C), 129.2 (2C), 132.8,
158.5 ppm; MS (ESI, m/z) 180 (M + H+).
EXPERIMENTAL SECTION
■
For general experimental methods, see refs 24b, g.
General Procedure for Reduction of Secondary Amides 1 to
Secondary Amines 2. Protocol A. Into a dry 10 mL round-bottom
flask equipped with a stirring bar were added successively an amide
(1.0 mmol), 4 mL of anhydrous dichloromethane and 2-fluoropyridine
(117 mg, 103 μL, 1.2 mmol). After being cooled to 0 °C,
trifluoromethanesulfonic anhydride (Tf2O) (310 mg, 185 μL, 1.1
mmol) was added dropwise via a syringe at 0 °C and the mixture was
stirred for 20 min. To the resulting mixture, 1,1,3,3-tetramethyldisilox-
ane (TMDS) (161 mg, 212 μL, 1.2 mmol) was added dropwise at 0
°C and the resulting mixture was stirred for 10 min. A solution of
B(C6F5)3 (25.6 mg, 5 mol %) in 1 mL of dichloromethane was added
at 0 °C and allowed to warm-up to room temperature slowly, then
stirred at room temperature for 3 h. The reaction was quenched by
addition of 5 mL of a saturated aqueous solution of sodium
bicarbonate (NaHCO3) at 0 °C and diluted with 30 mL of
dichloromethane. The aqueous layer was extracted with dichloro-
methane (2 × 5 mL). The combined organic layers were dried over
anhydrous sodium sulfate (Na2SO4), filtered and concentrated under
reduced pressure, the residue was purified by flash chromatography on
silica gel (300−400 mesh) to give the corresponding amine.
N-(4-Bromobenzyl)isopropylamine (2d). Following the general
procedure (Protocol B), the reduction of amide 1d (242 mg, 1.0
mmol) gave, after flash column chromatography on silica gel (eluent:
EtOAc/Hexane/Et3N = 1/2/0.01), amine 2d (215 mg, yield: 94%) as
a colorless oil. IR (film) νmax 3315, 2963, 2928, 2867, 2829, 1591,
1487, 1469, 1403, 1380, 1367, 1337, 1173, 1125, 1070, 1012, 812, 800,
1
739 cm−1; H NMR (CDCl3, 500 MHz) δ 1.08 (d, J = 6.3 Hz, 6H),
1.36 (br s, 1H,), 2.82 (septet, J = 6.3 Hz, 1H), 3.72 (s, 2H), 7.19 (d, J
= 8.2 Hz, 2H), 7.43 (d, J = 8.2 Hz, 2H); 13C NMR (CDCl3, 125 MHz)
δ 22.9 (2C), 48.0, 50.8, 120.5, 129.7 (2C), 131.4 (2C), 139.8 ppm;
HRMS-ESI calcd for [C10H14BrN + H]+ (M + H)+ 228.0382, found
228.0380.
N-[4-(Trifluoromethyl)benzyl]isopropylamine (2e). Following
the general procedure (Protocol B), the reduction of amide 1e (231
mg, 1.0 mmol) gave, after flash column chromatography on silica gel
(eluent: EtOAc/Hexane/Et3N = 1/2/0.01), the known amine 2e33
(188 mg, yield: 86%) as a pale yellow oil. IR (film) νmax 3311, 2966,
2930, 2866, 1620, 1469, 1418, 1382, 1326, 1165, 1126, 1066, 1019,
1
829, 757, 720 cm−1; H NMR (CDCl3, 500 MHz) δ 1.11 (d, J = 6.3
Protocol B. Into a dry 10 mL round-bottom flask equipped with a
stirring bar were added successively an amide (1.0 mmol), 4 mL of
anhydrous dichloromethane and 2-fluoropyridine (117 mg, 103 μL,
1.2 mmol). After being cooled to 0 °C, trifluoromethanesulfonic
anhydride (Tf2O) (310 mg, 185 μL, 1.1 mmol) was added dropwise
via a syringe at 0 °C and the reaction was stirred for 20 min. To the
resulting mixture, 1,1,3,3-tetramethyldisiloxane (TMDS) (161 mg, 212
μL, 1.2 mmol) was added dropwise at 0 °C and the mixture was stirred
for 10 min. The mixture was allowed to warm-up to room temperature
and stirred for 3 h before addition of a solution of B(C6F5)3 (10.2 mg,
2 mol %) in 1 mL of dichloromethane at 0 °C. The resulting mixture
was stirred at room temperature for 2−3 h. The reaction was
quenched with 5 mL of a saturated aqueous solution of sodium
bicarbonate (NaHCO3) at 0 °C, and mixture diluted with 30 mL of
dichloromethane. The aqueous layer was extracted with dichloro-
methane (2 × 5 mL). The organic layers were dried over anhydrous
sodium sulfate (Na2SO4), filtered and concentrated under reduced
pressure, the residue was purified by flash chromatography on silica gel
(300−400 mesh) to give the corresponding amine.
N-Benzyl-isopropylamine (2a). Following the general procedure
(Protocol B), the reduction of amide 1a (163 mg, 1.0 mmol) gave,
after flash column chromatography on silica gel (eluent: EtOAc/
Hexane/Et3N = 1/2/0.01), the known amine 2a18b (140 mg, yield:
94%) as a colorless oil. IR (film) νmax 3448, 2934, 2856, 1615, 1470,
1367, 1113, 707 cm−1; 1H NMR (CDCl3, 500 MHz) δ 1.09 (d, J = 6.3
Hz, 6H), 1.86 (br s, 1H), 2.85 (septet, J = 6.3 Hz, 1H), 3.77 (s, 2H),
7.20−7.26 (m, 1H), 7.28−7.34 (m, 4H); 13C NMR (CDCl3, 125
MHz) δ 22.7 (2C), 48.0, 51.5, 126.8, 128.0 (2C), 128.3 (2C), 140.4
ppm; MS (ESI, m/z) 150 (M + H+).
Hz, 6H), 1.41 (br s, 1H), 2.84 (septet, J = 6.3 Hz, 1H), 3.84 (s, 2H),
7.44 (d, J = 8.1 Hz, 2H), 7.57 (d, J = 8.1 Hz, 2H); 13C NMR (CDCl3,
125 MHz) δ 22.9 (2C), 48.2, 51.0, 124.2 (q, JC,F = 272.2 Hz), 125.2
(q, JC,F = 3.7 Hz, 2C), 128.2 (2C), 129.1 (q, JC,F = 32.1 Hz), 145.0
ppm; MS (ESI, m/z) 218 (M + H+).
N-(4-Nitrobenzyl)isopropylamine (2f). Following the general
procedure (Protocol B), the reduction of amide 1f (208 mg, 1.0
mmol) gave, after flash column chromatography on silica gel (eluent:
EtOAc/Hexane/Et3N = 1/2/0.01), the known amine 2f18b (186 mg,
yield: 96%) as a pale yellow oil. IR (film) νmax 3321, 3103, 3078, 2964,
2929, 2867, 1604, 1519, 1468, 1380, 1347, 1174, 1126, 1109, 1080,
1015, 854, 799, 737 cm−1; 1H NMR (CDCl3, 500 MHz) δ 1.11(d, J =
6.3 Hz, 6H), 1.48 (br s, 1H), 2.85 (septet, J = 6.3 Hz, 1H), 3.90 (s,
2H), 7.51 (d, J = 8.7 Hz, 2H), 8.17 (d, J = 8.7 Hz, 2H); 13C NMR
(CDCl3, 125 MHz) δ 22.9 (2C), 48.4, 50.7, 123.5 (2C), 128.5 (2C),
146.8, 148.7 ppm; MS (ESI, m/z) 195 (M + H+).
Methyl 4-[(isopropylamino)methyl]benzoate (2g). Following
the general procedure (Protocol B), the reduction of amide 1g (221
mg, 1.0 mmol) gave, after flash column chromatography on silica gel
(eluent: EtOAc/Hexane/Et3N = 1/1/0.01), the known amine 2g18b
(203 mg, yield: 98%) as a pale yellow oil. IR (film) νmax 3322, 2962,
2920, 2866, 1722, 1611, 1435, 1380, 1278, 1176, 1109, 1020, 967, 848,
1
754 cm−1; H NMR (CDCl3, 500 MHz) δ 1.10 (d, J = 6.3 Hz, 6H),
1.53 (br s, 1H), 2.84 (septet, J = 6.3 Hz, 1H), 3.84 (s, 2H), 3.90 (s,
3H), 7.40 (d, J = 8.1 Hz, 2H), 7.99 (d, J = 8.1 Hz, 2H); 13C NMR
(CDCl3, 125 MHz) δ 22.8 (2C), 48.2, 51.2, 51.9, 127.9 (2C), 128.7,
129.7 (2C), 146.1, 167.0 ppm; MS (ESI, m/z) 208 (M + H+).
4-[(Isopropylamino)methyl]phenyl acetate (2h). Following
the general procedure (Protocol B), the reduction of amide 1h (221
mg, 1.0 mmol) gave, after flash column chromatography on silica gel
(eluent: EtOAc/Hexane/Et3N = 1/1/0.01), amine 2h (180 mg, yield:
87%) as a pale yellow oil. IR (film) νmax 3298, 2964, 2921, 2850, 1762,
1610, 1560, 1507, 1467, 1370, 1216, 1195, 1165, 1017, 911, 834 cm−1;
1H NMR (CDCl3, 500 MHz) δ 1.09 (d, J = 6.3 Hz, 6H), 1.61 (br s,
1H), 2.29 (s, 3H), 2.85 (septet, J = 6.3 Hz, 1H), 3.77 (s, 2H), 7.01−
7.05 (m, 2H), 7.31−7.35 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ
21.1, 22.8 (2C), 48.1, 50.9, 121.4 (2C), 129.1 (2C), 138.3, 149.5,
N-(4-Methylbenzyl)isopropylamine (2b). Following the general
procedure (Protocol B), the reduction of amide 1b (177 mg, 1.0
mmol) gave, after flash column chromatography on silica gel (eluent:
EtOAc/Hexane/Et3N = 1/2/0.01), the known amine 2b18b (147 mg,
yield: 90%) as a colorless oil. IR (film) νmax 3326, 2963, 2920, 2850,
1577, 1541, 1515, 1467, 1383, 1337, 1259, 1174, 1121, 1073, 1021,
1
805, 725 cm−1; H NMR (CDCl3, 500 MHz) δ 1.09 (d, J = 6.3 Hz,
6H), 1.40 (br s, 1H), 2.32 (s, 3H), 2.84 (septet, J = 6.3 Hz, 1H), 3.73
(s, 2H), 7.12 (d, J = 7.8 Hz, 2H), 7.20 (d, J = 7.8 Hz, 2H); 13C NMR
E
DOI: 10.1021/acs.joc.6b00572
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The Journal of Organic Chemistry
Article
169.6 ppm; HRMS-ESI calcd for [C12H17NO2 + H]+ (M + H)+
208.1332, found 208.1337.
7.26 (m, 1H), 7.28−7.35 (m, 4H); 13C NMR (CDCl3, 125 MHz) δ
26.0 (2C), 26.7, 31.4 (2C), 38.0, 54.1, 56.2, 126.7, 128.0 (2C), 128.3
(2C), 140.7 ppm; MS (ESI, m/z) 204 (M + H+).
4-[(Isopropylamino)methyl]benzonitrile (2i). Following the
general procedure (Protocol B), the reduction of amide 1i (188 mg,
1.0 mmol) gave, after flash column chromatography on silica gel
(eluent: EtOAc/Hexane/Et3N = 1/2/0.01), the known amine 2i18b
(153 mg, yield: 88%) as a pale yellow oil. IR (film) νmax 3318, 3055,
2964, 2929, 2869, 2834, 2227, 1608, 1504, 1467, 1412, 1380, 1337,
1174, 1127, 1078, 1220, 824, 755 cm−1; 1H NMR (CDCl3, 500 MHz)
δ 1.10 (d, J = 6.3 Hz, 6H), 1.36 (br s, 1H), 2.84 (septet, J = 6.3 Hz,
1H), 3.85 (s, 2H), 7.45 (d, J = 8.0 Hz, 2H), 7.60 (d, J = 8.1 Hz, 2H);
13C NMR (CDCl3, 125 MHz) δ 22.8 (2C), 48.3, 51.0, 110.5, 118.9,
128.5 (2C), 132.1 (2C), 146.5 ppm; MS (ESI, m/z) 175 (M + H+).
N-(Naphthalen-2-ylmethyl)isopropylamine (2j). Following the
general procedure (Protocol B), the reduction of amide1j (213 mg, 1.0
mmol) gave, after flash column chromatography on silica gel (eluent:
EtOAc/Hexane/Et3N = 1/1/0.01), amine 2j (196 mg, yield: 98%) as a
pale yellow oil. IR (film) νmax 3313, 3054, 2963, 2928, 2868, 2821,
1601, 1508, 1467, 1379, 1363, 1325, 1173, 1124, 1067, 949, 891, 855,
N-Benzyl-2-[(t-butyldiphenylsilyl)oxy]ethylamine (2o). Fol-
lowing the general procedure (Protocol B), the reduction of amide
1o (404 mg, 1.0 mmol) gave, after flash column chromatography on
silica gel (eluent: EtOAc/Hexane/Et3N = 1/6/0.01), amine 2o (376
mg, yield: 97%) as a colorless oil. IR (film) νmax 3324, 3069, 3045,
3027, 2929, 2857, 1661, 1494, 1471, 1453, 1428, 1390, 1361, 1259,
1
1190, 1111, 1028, 938, 823, 737, 701 cm−1; H NMR (CDCl3, 500
MHz) δ 1.05 (s, 9H), 1.87 (br s, 1H), 2.77 (t, J = 5.2 Hz, 2H), 3.78−
3.82 (m, 4H), 7.22−7.27 (m, 1H), 7.28−7.33 (m, 4H), 7.34−7.38 (m,
4H), 7.39−7.43 (m, 2H), 7.63−7.69 (m, 4H); 13C NMR (CDCl3, 125
MHz) δ 19.2, 26.8, 50.9, 53.6, 63.1, 126.8, 127.7, 128.0, 128.4, 129.6,
133.6, 135.5, 140.5 ppm; HRMS-ESI calcd for [C25H31NOSi + H]+
(M + H)+ 390.2248, found 390.2247.
N-Benzyl-n-butylamine (2p). Following the general procedure
(Protocol B), the reduction of amide 1p (177 mg, 1.0 mmol) gave,
after flash column chromatography on silica gel (eluent: EtOAc/
Hexane/Et3N = 1/2/0.01), the known amine 2p18b (142 mg, yield:
87%) as a colorless oil. IR (film) νmax 3309, 3085, 3063, 3027, 2957,
2927, 2871, 2812, 1604, 1495, 1454, 1377, 1359, 1260, 1200, 1122,
1075, 1028, 905, 732, 698 cm−1; 1H NMR (CDCl3, 500 MHz) δ 0.91
(t, J = 7.3 Hz, 3H), 1.30−1.39 (m, 2H), 1.46−1.54 (m, 3H), 2.63 (t, J
= 7.3 Hz, 2H), 3.78 (s, 2H), 7.21−7.27 (m, 1H), 7.29−7.34 (m, 4H);
13C NMR (CDCl3, 125 MHz) δ 14.0, 20.4, 32.2, 49.1, 54.1, 126.8,
128.1 (2C), 128.3 (2C), 140.5 ppm; MS (ESI, m/z) 164 (M + H+).
N-Benzylpent-4-yn-1-ylamine (2q). Following the general
procedure (Protocol B), the reduction of amide 1q (187 mg, 1.0
mmol) gave, after flash column chromatography on silica gel (eluent:
EtOAc/Hexane/Et3N = 1/2/0.01), the known amine 2q36 (152 mg,
yield: 88%) as a pale yellow oil. IR (film) νmax 3299, 3084, 3062, 3027,
2932, 2820, 2116, 1603, 1495, 1453, 1354, 1259, 1121, 1073, 1028,
1
815, 745 cm−1; H NMR (CDCl3, 500 MHz) δ 1.11 (d, J = 6.3 Hz,
6H), 1.47 (br s, 1H), 2.88 (septet, J = 6.3 Hz, 1H), 3.93 (s, 2H), 7.39−
7.46 (m, 3H), 7.74 (s, 1H), 7.77−7.82 (m, 3H); 13C NMR (CDCl3,
125 MHz) δ 22.9 (2C), 48.1, 51.7, 125.4, 125.9, 126.3, 126.6, 127.6
(2C), 128.0, 132.5, 133.4, 138.2 ppm; HRMS-ESI calcd for [C14H17N
+ H]+ (M + H)+ 200.1434, found 200.1438.
N-(Thiophen-2-ylmethyl)isopropylamine (2k). Following the
general procedure (Protocol B), the reduction of amide 1k (169 mg,
1.0 mmol) gave, after flash column chromatography on silica gel
(eluent: EtOAc/Hexane/Et3N = 1/2/0.01), the known amine 2k34
(137 mg, yield: 88%) as a colorless oil. IR (film) νmax 3312, 3070,
2963, 2930, 2869, 2826, 1467, 1440, 1380, 1338, 1309, 1259, 1220,
1
1175, 1123, 1069, 1039, 854, 824, 696 cm−1; H NMR (CDCl3, 500
MHz) δ 1.09 (d, J = 6.3 Hz, 6H), 1.42 (br s, 1H), 2.89 (septet, J = 6.3
Hz, 1H), 3.98 (s, 2H), 6.90−6.96 (m, 2H), 7.19 (dd, J = 5.0, 0.9 Hz,
1H); 13C NMR (CDCl3, 125 MHz) δ 22.8 (2C), 45.9, 47.6, 124.1,
124.6, 126.5, 144.4 ppm; MS (ESI, m/z) 156 (M + H+).
1
906, 806, 735, 699 cm−1; H NMR (CDCl3, 500 MHz) δ 1.43 (br s,
1H), 1.73 (quintet, J = 7.1 Hz, 2H), 1.94 (t, J = 2.6 Hz, 1H), 2.27 (td, J
= 7.1, 2.6 Hz, 2H), 2.74 (t, J = 7.0 Hz, 2H), 3.79 (s, 2H), 7.22−7.27
(m, 1H), 7.29−7.35 (m, 4H); 13C NMR (CDCl3, 125 MHz) δ 16.3,
28.7, 48.1, 53.9, 68.5, 84.1, 126.9, 128.0 (2C), 128.3 (2C), 140.4 ppm;
MS (ESI, m/z) 174 (M + H+).
N-Benzyl-cyclopropylamine (2r). Following the general proce-
dure (Protocol B), the reduction of amide 1r (161 mg, 1.0 mmol)
gave, after flash column chromatography on silica gel (eluent: EtOAc/
Hexane/Et3N = 1/5/0.01), the known amine 2r37 (111 mg, yield:
76%) as a pale yellow oil. IR (film) νmax 3320, 3085, 3063, 3026, 3006,
2923, 2850, 2819, 1604, 1495, 1452, 1373, 1347, 1213, 1160, 1089,
1014, 928, 827, 730, 697 cm−1; 1H NMR (CDCl3, 500 MHz) δ 0.36−
0.41 (m, 2H), 0.42−0.46 (m, 2H), 1.80 (br s, 1H), 2.13−2.18 (m,
1H), 3.83 (s, 2H), 7.22−7.27 (m, 1H), 7.29−7.35 (m, 4H); 13C NMR
(CDCl3, 125 MHz) δ 6.4 (2C), 30.0, 53.7, 126.8, 128.2 (2C), 128.3
(2C), 140.6 ppm; MS (ESI, m/z) 148 (M + H+).
N-Benzyl-allylamine (2s). Following the general procedure
(Protocol B), the reduction of amide 1s (161 mg, 1.0 mmol) gave,
after flash column chromatography on silica gel (eluent: EtOAc/
Hexane/Et3N = 1/3/0.01), the known amine 2s38 (107 mg, yield:
73%) as a colorless oil. IR (film) νmax 3332, 3084, 3062, 3026, 2920,
2850, 2805, 1601, 1494, 1450, 1358, 1260, 1201, 1124, 1073, 1028,
977, 893, 843, 733, 697 cm−1; 1H NMR (CDCl3, 500 MHz) δ 1.54 (br
s, 1H), 3.27 (d, J = 6.0 Hz, 2H), 3.79 (s, 2H), 5.09−5.13 (m, 1H),
5.16−5.23 (m, 1H), 5.88−5.98 (m, 1H), 7.22−7.27 (m, 1H), 7.30−
7.35 (m, 4H); 13C NMR (CDCl3, 125 MHz) δ 51.7, 53.2, 116.0,
126.9, 128.1 (2C), 128.3 (2C), 136.7, 140.2 ppm; MS (ESI, m/z) 148
(M + H+).
N-Benzyl-cyclohexylamine (2l). Following the general procedure
(Protocol B), the reduction of amide 1l (203 mg, 1.0 mmol) gave,
after flash column chromatography on silica gel (eluent: EtOAc/
Hexane/Et3N = 1/2/0.01), the known amine 2l18b (180 mg, yield:
95%) as a colorless oil. IR (film) νmax 3311, 3084, 3062, 3026, 2926,
2852, 1601, 1495, 1451, 1361, 1259, 1124, 1074, 1028, 889, 733, 698
cm−1; 1H NMR (CDCl3, 500 MHz) δ 1.06−1.31 (m, 5H), 1.36 (br s,
1H), 1.57−1.65 (m, 1H), 1.69−1.77 (m, 2H), 1.88−1.95 (m, 2H),
2.44−2.52 (m, 1H), 3.80 (s, 2H), 7.20−7.26 (m, 1H), 7.30−7.32 (m,
4H); 13C NMR (CDCl3, 125 MHz) δ 24.9 (2C), 26.1, 33.5 (2C), 51.0,
56.1, 126.7, 128.0 (2C), 128.3 (2C), 140.9 ppm; MS (ESI, m/z) 190
(M + H+).
N-Benzyl-2,3-dihydro-1H-inden-2-amine (2m). Following the
general procedure (Protocol B), the reduction of amide 1m (237 mg,
1.0 mmol) gave, after flash column chromatography on silica gel
(eluent: EtOAc/Hexane/Et3N = 1/5/0.01), the known amine 2m35
(215 mg, yield: 96%) as a colorless oil. IR (film) νmax 3307, 3063,
3023, 2934, 2897, 2836, 1604, 1584, 1494, 1483, 1457, 1343, 1253,
1
1216, 1194, 1126, 1026, 972, 907, 741, 698 cm−1; H NMR (CDCl3,
500 MHz) δ 1.59 (br s, 1H), 2.81 (dd, J = 15.6, 7.0 Hz, 2H), 3.17 (dd,
J = 15.6, 7.0 Hz, 2H), 3.67 (quintet, J = 6.8 Hz, 1H), 3.85 (s, 2H),
7.10−715 (m, 2H), 7.16−7.20 (m, 2H), 7.21−7.26 (m, 1H), 7.28−
7.36 (m, 4H); 13C NMR (CDCl3, 125 MHz) δ 40.0 (2C), 52.3, 58.9,
124.6 (2C), 126.4 (2C), 126.9, 128.2 (2C), 128.4 (2C), 140.3, 141.7
(2C) ppm; MS (ESI, m/z) 224 (M + H+).
N-(Cyclohexylmethyl)benzylamine (2n/ 2v). Following the
general procedure (Protocol B), the reduction of amides 1n/1v
(217 mg, 1.0 mmol) and gave, after flash column chromatography on
silica gel (eluent: EtOAc/Hexane/Et3N = 1/4/0.01), the known amine
2n35 (191 mg, yield: 94%)/ 2v (183 mg, yield: 90%) as a colorless oil.
IR (film) νmax 3333, 3062, 3026, 2920, 2850, 2805, 1494, 1449, 1357,
1258, 1200, 1124, 1072, 1031, 973, 733, 697 cm−1; 1H NMR (CDCl3,
500 MHz) δ 0.85−0.96 (m, 2H), 1.09−1.30 (m, 3H), 1.40−1.54 (m,
2H), 1.63−1.78 (m, 5H), 2.46 (d, J = 6.7 Hz, 2H), 3.77 (s, 2H), 7.20−
N-Benzyl-methylamine (2t). Following the general procedure
(Protocol B, activation at −78 °C), the reduction of amide 1t (135 mg,
1.0 mmol) gave, after flash column chromatography on silica gel
(eluent: EtOAc/Hexane/Et3N = 1/1/0.01), the commercially available
amine 2t (70 mg, yield: 58%) as a colorless oil. IR (film) νmax 3311,
3058, 3026, 2920, 2844, 2789, 1601, 1494, 1452, 1382, 1263, 1027,
1
736, 698 cm−1; H NMR (CDCl3, 500 MHz) δ 1.43 (br s, 1H), 2.45
(s, 3H), 3.74 (s, 2H), 7.22−7.35 (m, 5H); 13C NMR (CDCl3, 125
F
DOI: 10.1021/acs.joc.6b00572
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The Journal of Organic Chemistry
Article
MHz) δ 36.0, 56.0, 126.9, 128.1 (2C), 128.3 (2C), 140.1 ppm; MS
(ESI, m/z) 122 (M + H+).
N-(2-Butylbenzyl)methylamine (2aa). Following the general
procedure (Protocol B, activation at −78 °C), the reduction of amide
1aa2c (96 mg, 0.5 mmol) gave, after flash column chromatography on
silica gel (eluent: EtOAc/Hexane/Et3N = 2/1/0.01), amine 2aa (69
mg, yield: 78%) as a colorless oil. IR (film) νmax 3324, 2956, 2930,
N-Benzyl-t-butylamine (2u). Following the general procedure
[Protocol A, activation at −78 °C, TMDS (2.0 equiv), B(C6F5)3 (10
mol %)], the reduction of amide 1u (177 mg, 1.0 mmol) gave, after
flash column chromatography on silica gel (eluent: EtOAc/Hexane/
Et3N = 1/4/0.01), the known amine 2u38 (121 mg, yield: 74%) as a
colorless oil. IR (film) νmax 3309, 3086, 3063, 3027, 2964, 2901, 2861,
1605, 1495, 1478, 1452, 1387, 1361, 1230, 1214, 1095, 1073, 1027,
1
2871, 2788, 1604, 1450, 1378, 1353, 1131, 1103, 750 cm−1; H NMR
(CDCl3, 500 MHz) δ 0.95 (t, J = 7.3 Hz, 3H), 1.36−1.43 (m, 2H),
1.45 (br s, 1H), 1.53−1.61 (m, 2H), 2.50 (s, 3H), 2.66 (t, J = 8.0 Hz,
2H), 3.75 (s, 2H), 7.13−7.22 (m, 3H), 7.28−7.32 (m, 1H); 13C NMR
(CDCl3, 125 MHz) δ 14.0, 22.8, 32.1, 33.5, 36.4, 53.1, 125.8, 127.0,
128.7, 129.3, 137.6, 141.0 ppm; HRMS-ESI calcd for [C12H19N + H]+
(M + H)+ 178.1590, found 178.1593.
1
902, 697 cm−1; H NMR (CDCl3, 500 MHz) δ 1.18 (s, 9H), 3.72 (s,
2H), 7.20−7.25 (m, 1H), 7.28−7.35 (m, 4H); 13C NMR (CDCl3, 125
MHz) δ 29.1 (3C), 47.2, 50.6, 126.7, 128.2 (2C), 128.4 (2C), 141.4
ppm; MS (ESI, m/z) 164 (M + H+).
(S)-5-[(Benzylamino)methyl]dihydrofuran-2(3H)-one (4a).
Following the general procedure [Protocol A, activation at −78 °C,
TMDS (1.1 equiv), B(C6F5)3 (5 mol %)], the reduction of amide
3a29b (219 mg, 1.0 mmol) gave, after flash column chromatography on
silica gel (eluent: MeOH/CH2Cl2 = 1/30), amine 4a (141 mg, yield:
N-Benzyl-isobutylamine (2w). Following the general procedure
(Protocol B), the reduction of amide 1w (177 mg, 1.0 mmol) gave,
after flash column chromatography on silica gel (eluent: EtOAc/
Hexane/Et3N = 1/2/0.01), the known amine 2w39 (121 mg, yield:
74%) as a colorless oil. IR (film) νmax 3334, 3085, 3063, 3027, 2954,
2920, 2870, 2809, 1604, 1494, 1454, 1385, 1365, 1207, 1116, 1075,
20
69%) as a colorless oil. [α]D = +27.7 (c 1.0, CHCl3). IR (film) νmax
3332, 3027, 2921, 2850, 1770, 1453, 1352, 1261, 1181, 1026, 915, 801,
738, 699 cm−1; 1H NMR (CDCl3, 500 MHz) δ 1.68 (br s, 1H), 1.96−
2.06 (m, 1H), 2.22−2.32 (m, 1H), 2.48−2.62 (m, 2H), 2.78 (dd, J =
12.9, 6.8 Hz, 1H), 2.89 (dd, J = 12.9, 3.5 Hz, 1H), 3.82 (d, J = 13.4 Hz,
1H), 3.84 (d, J = 13.4 Hz, 1H), 4.62−4.69 (m, 1H), 7.23−7.28 (m,
1H), 7.29−7.35 (m, 4H); 13C NMR (CDCl3, 125 MHz) δ 25.2, 28.6,
52.8, 53.8, 80.2, 127.1, 128.0 (2C), 128.4 (2C), 139.7, 177.1 ppm;
HRMS-ESI calcd for [C12H15NO2 + Na]+ (M + Na)+ 228.0995, found
228.0996.
1
1028, 977, 903, 800, 735, 698 cm−1; H NMR (CDCl3, 500 MHz) δ
0.91 (d, J = 6.7 Hz, 6H), 1.41 (br s, 1H), 1.72−1.83 (m, 1H), 2.44 (d,
J = 6.8 Hz, 2H), 3.78 (s, 2H), 7.21−7.26 (m, 1H), 7.27−7.35 (m, 4H);
13C NMR (CDCl3, 125 MHz) δ 20.6 (2C), 28.3, 54.1, 57.5, 126.8,
128.0 (2C), 128.3 (2C), 140.7 ppm; MS (ESI, m/z) 164 (M + H+).
N-Benzyl-n-propylamine (2x). Following the general procedure
(Protocol B), the reduction of amide 1x (163 mg, 1.0 mmol) gave,
after flash column chromatography on silica gel (eluent: EtOAc/
Hexane/Et3N = 1/1/0.01), the known amine 2x40 (86 mg, yield: 58%)
as a colorless oil. IR (film) νmax 3305, 3085, 3063, 3027, 2958, 2930,
2873, 2812, 1601, 1494, 1454, 1378, 1198, 1122, 1074, 1028, 970, 906,
(S)-5-[(Allylamino)methyl]dihydrofuran-2(3H)-one (4b). Fol-
lowing the general procedure [Protocol A, activation at −78 °C,
TMDS (1.1 equiv), B(C6F5)3 (5 mol %)], the reduction of amide
3b29b (169 mg, 1.0 mmol) gave, after flash column chromatography on
silica gel (eluent: MeOH/CH2Cl2 = 1/30), amine 4b (98 mg, yield:
1
820, 733, 698 cm−1; H NMR (CDCl3, 500 MHz) δ 0.92 (t, J = 7.4
Hz, 3H), 1.49−1.57 (m, 3H), 2.60 (t, J = 7.3 Hz, 2H), 3.78 (s, 2H),
7.22−7.27 (m, 1H), 7.29−7.36 (m, 4H); 13C NMR (CDCl3, 125
MHz) δ 11.7, 23.2, 51.3, 54.0, 126.8, 128.1 (2C), 128.3 (2C), 140.5
ppm; MS (ESI, m/z) 150 (M + H+).
20
63%) as a colorless oil. [α]D = −36.8 (c 1.0, CHCl3). IR (film) νmax
3324, 3078, 2923, 2850, 1775, 1643, 1461, 1261, 1184, 1020, 916, 802
cm−1; 1H NMR (CDCl3, 500 MHz) δ 1.71 (br s, 1H), 1.96−2.06 (m,
1H), 2.27−2.34 (m, 1H), 2.52−1.61 (m, 2H), 2.79 (dd, J = 12.9, 7.2
Hz, 1H), 2.88 (dd, J = 12.9, 3.6 Hz, 1H), 3.29 (d, J = 6.2 Hz, 2H), 4.66
(ddd, J = 10.8, 7.2, 3.6 Hz, 1H), 5.12 (dq, J = 10.2, 1.4 Hz, 1H), 5.19
(dq, J = 17.1, 1.6 Hz, 1H), 5.87 (ddt, J = 17.1, 10.2, 6.0 Hz, 1H); 13C
NMR (CDCl3, 125 MHz) δ 25.3, 28.6, 52.3, 52.9, 80.1, 116.4, 136.2,
177.1 ppm; HRMS-ESI calcd for [C8H13NO2 + Na]+ (M + Na)+
178.0839, found 178.0839.
(E)-N-(3-Phenylprop-2-en-1-yl)isopropylamine (2y) and N-
(3-Phenylpropyl)isopropylamine (2y−a). Following the general
procedure (Protocol B), the reduction of amide 1y (177 mg, 1.0
mmol) gave, after flash column chromatography on silica gel (eluent:
EtOAc/Hexane/Et3N = 1/2/0.01), the inseparable known amine
2y18b and 2y−a18b (120 mg, combined yield: 68%, 2y:2y−a = 1:1.2,
1
determined by H NMR of crude product) as a pale yellow oil. 2y
(S)-1-Benzyl-5-(benzyloxy)piperidin-2-one (6a). To a suspen-
sion of NaH (60% dispersion in mineral oil, 272 mg, 6.8 mmol) in
THF (20 mL) was added a solution of 4a (700 mg, 3.4 mmol) in THF
(4 mL) at room temperature and the reaction mixture was heated to
the 60 °C and stirred for 4 h. Benzyl bromide was added dropwise and
the reaction stirred at 60 °C for 15 h. The reaction was quenched by
addition of H2O at 0 °C and extracted with Et2O (3 × 30 mL). The
combined organic extracts were dried over anhydrous Na2SO4 and
concentrated under reduced pressure. The residue was purified by
flash column chromatography on silica gel (eluent: EtOAc/hexane =
1/1) to give the known compound 6a41 (914 mg, yield: 91%) as a
1
(data read from the spectrum of the mixture): H NMR (CDCl3, 500
MHz) δ 1.09 (d, J = 6.3 Hz, 6H), 2.89 (septet, J = 6.3 Hz, 1H), 3.41
(d, J = 6.4 Hz, 2H), 6.31 (dt, J = 15.8, 6.4 Hz, 1H), 6.52 (d, J = 15.8
Hz, 1H), 7.15−7.38 (m, 5H); 13C NMR (CDCl3, 125 MHz) δ 22.9
(2C), 48.1, 49.5, 126.2 (2C), 127.2, 128.5 (2C), 128.7, 131.0, 137.1
ppm; MS (ESI, m/z) 176 (M + H+). 2y−a (data read from the
spectrum of the mixture): 1H NMR (CDCl3, 500 MHz) δ 1.04 (d, J =
6.3 Hz, 6H), 1.77−1.85 (m, 2H), 2.60−2.68 (m, 4H), 2.77 (septet, J =
6.3 Hz, 1H), 7.18−7.38 (m, 5H); 13C NMR (CDCl3, 125 MHz) δ
22.9 (2C), 32.0, 33.8, 47.0, 48.6, 125.7, 128.30 (2C), 128.25 (2C),
142.1 ppm; MS (ESI, m/z) 178 (M + H+).
(Z)-3-Chloro-N-isopropyl-3-phenyl-2-[(tetrahydrofuran-2-
yl)methyl)]prop-2-en-1-ylamine (2z). Following the general
procedure (Protocol B, activation at −78 °C), the reduction of
amide 1z2a (46 mg, 0.15 mmol) gave, after flash column
chromatography on silica gel (eluent: EtOAc/Hexane/Et3N = 1/3/
0.01), amine 2z (41 mg, yield: 93%) as a colorless oil. IR (film) νmax
3324, 3056, 2964, 2927, 2867, 1640, 1597, 1489, 1467, 1444, 1379,
1336, 1261, 1228, 1173, 1063, 1016, 920, 890, 810, 761, 699 cm−1; 1H
NMR (CDCl3, 500 MHz) δ 1.12 (d, J = 6.3 Hz, 6H), 1.28−1.36 (m,
1H), 1.70−1.81 (m, 3H), 1.83−1.91 (m, 1H), 2.34 (d, J = 6.5 Hz,
2H), 2.85 (septet, J = 6.3 Hz, 1H), 3.59 (d, J = 12.8 Hz, 1H), 3.65 (d, J
= 12.8 Hz, 1H), 3.68 (dd, J = 14.4, 7.4 Hz, 1H), 3.74 (dd, J = 14.4, 7.4
Hz, 1H), 3.91−3.98 (m, 1H), 7.28−7.36 (m, 5H); 13C NMR (CDCl3,
125 MHz) δ 22.9, 23.0, 25.4, 31.3, 37.5, 48.3, 48.4, 67.7, 77.9, 128.1,
128.2 (2C), 129.2 (2C), 129.8, 135.0, 139.1 ppm; HRMS-ESI calcd for
[C17H24ClNO + H]+ (M + H)+ 294.1619, found 294.1617.
colorless oil. [α]D = +22.1 (c 1.0, CHCl3) {lit.41 [α]D = +29.8 (c
1.68, CH2Cl2)}. IR (film) νmax 3029, 2922, 1644, 1495, 1453, 1416,
20
25
1359, 1265, 1205, 1181, 1089, 737, 697 cm−1; H NMR (CDCl3, 500
1
MHz) δ 1.90−2.00 (m, 1H), 2.01−2.09 (m, 1H), 2.44 (dt, J = 17.7,
5.8 Hz, 1H), 2.71 (ddd, J = 17.7, 9.5, 6.3 Hz, 1H), 3.26−3.35 (m, 2H),
3.77−3.82 (m, 1H), 4.41 (d, J = 11.8 Hz, 1H), 4.48 (d, J = 11.8 Hz,
1H), 4.52 (d, J = 14.8 Hz, 1H), 4.64 (d, J = 14.8 Hz, 1H), 7.22−7.35
(m, 10H); 13C NMR (CDCl3, 125 MHz) δ 25.8, 28.1, 49.8, 50.6, 70.2,
70.4, 127.30, 127.34 (2C), 127.7, 127.9 (2C), 128.4 (2C), 128.5 (2C),
136.8, 137.9, 169.3 ppm; HRMS-ESI calcd for [C19H21NO2 + Na]+
(M + Na)+ 318.1465, found 318.1464.
(R)-1-Allyl-5-(benzyloxy)piperidin-2-one (6b). To a suspension
of NaH (60% dispersion in mineral oil, 186 mg, 4.6 mmol) in THF
(10 mL) was added a solution of 4b (360 mg, 2.3 mmol) in THF (2
mL) at room temperature and the reaction mixture was heated to the
60 °C and stirred for 4 h. Benzyl bromide was added dropwise and the
reaction stirred at 60 °C for 15 h. The reaction was quenched by
G
DOI: 10.1021/acs.joc.6b00572
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
addition of H2O at 0 °C and extracted with Et2O (3 × 15 mL). The
combined organic extracts were dried over anhydrous Na2SO4, filtered
and concentrated under reduced pressure. The residue was purified by
flash column chromatography on silica gel (eluent: EtOAc/hexane =
2/1) to give compound 6b (508 mg, yield: 90%) as a colorless oil.
[α]D20 = −10.6 (c 1.0, CHCl3) {lit.29b [α]D20 = −6.4 (c 1.0, CHCl3)}.
IR (film) νmax 3029, 2919, 1641, 1490, 1454, 1415, 1359, 1270, 1193,
1099, 924, 738, 698 cm−1; 1H NMR (500 MHz, CDCl3) δ 1.90−2.09
(m, 2H), 2.37 (dt, J = 17.6, 5.9 Hz, 1H), 2.63 (ddd, J = 17.6, 9.4, 6.3
Hz, 1H), 3.33 (dd, J = 12.7, 4.6 Hz, 1H), 3.37 (dd, J = 12.7, 4.1 Hz,
1H), 3.80−3.86 (m, 1H), 3.94 (dd, J = 15.2, 5.8 Hz, 1H), 4.01 (dd, J =
15.2, 5.8 Hz, 1H), 4.54 (d, J = 11.9 Hz, 1H), 4.59 (d, J = 11.9 Hz, 1H),
5.14−5.16 (m, 1H), 5.17−5.20 (m, 1H), 5.74 (ddt, J = 17.6, 9.8, 5.9
Hz, 1H), 7.27−7.39 (m, 5H); 13C NMR (125 MHz, CDCl3) δ 25.7,
28.1, 49.1, 50.9, 70.3, 70.5, 117.3, 127.4 (2C), 127.7, 128.4 (2C),
132.5, 137.9, 169.0; MS (ESI, m/z) 268 (M + Na+).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are grateful for financial support from the National
Natural Science Foundation of China (21332007) and the
Program for Changjiang Scholars and Innovative Research
Team in University of Ministry of Education, China.
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(2R,5S)-1-Benzyl-5-(benzyloxy)-2-propylpiperidine (7). Tf2O
(217 mg, 130 uL, 1.1 equiv) was added dropwise to a cooled (−78 °C)
solution of 6a (207 mg, 1.0 equiv) and DTBMP (172 mg, 1.2 equiv)
in CH2Cl2 (10 mL) and stirred at −78 °C for 2 h. A solution of n-
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(eluent: EtOAc/hexane = 1/20) to give pure compound 7 and its
diastereomeric mixture with 8 (172 mg in total, yield: 76%) as a
colorless oil (dr = 13:1, determined by 1H NMR of a crude product).
20
[α]D = +1.7 (c 1.0, CHCl3). IR (film) νmax 3028, 2931, 2869, 1494,
1453, 1368, 1096, 1028, 734, 697 cm−1; 1H NMR (CDCl3, 500 MHz)
δ 0.90 (t, J = 7.3 Hz, 3H), 1.15−1.27 (m, 1H), 1.28−1.40 (m, 1H),
1.46−1.83 (m, 6H), 2.52−2.60 (m, 3H), 3.45−3.53 (m, 1H), 3.57 (d, J
= 13.6 Hz, 1H), 3.75 (d, J = 13.6 Hz, 1H), 4.46 (s, 2H), 7.20−7.35 (m,
10H); 13C NMR (CDCl3, 125 MHz) δ 14.4, 19.9, 25.7, 26.7, 28.4,
51.6, 57.5, 58.2, 70.0, 73.6, 126.7, 127.3, 127.5 (2C), 128.1 (2C), 128.2
(2C), 128.6 (2C), 138.9, 139.9 ppm; HRMS-ESI calcd for [C22H29NO
+ H]+ (M + H)+ 324.2322, found 324.2321.
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20
20
1
1258, 1087, 1038, 983 cm; H NMR (D2O, 500 MHz) δ 0. 81 (t, J =
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ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.6b00572.
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HPLC chromatograms of ( )-3a/4a and (S)-3a/4a; H
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AUTHOR INFORMATION
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Corresponding Author
*E-mail: pqhuang@xmu.edu.cn.
H
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