Sequential reactions promoted by manganese: Completely stereoselective synthesis of (E)-α,β-unsaturated amides, ketones, aldehydes, and carboxylic acids

Article abstract of DOI:10.1021/jo701417z

(Chemical Equation Presented) A complete E-selective synthesis of α,β-unsaturated amides through a sequential reaction of a range of dichloroamides with a variety of aldehydes promoted by Rieke manganese (Mn*) is reported. A mechanism based on a sequential aldol-type reaction and a completely stereoselective β-elimination is proposed to explain these results. The unsaturated amides obtained are readily and efficiently transformed into α,β-unsaturated ketones, aldehydes, or carboxylic acids without loss of the diastereoisomeric purity of the C-C double bond.

Full text of DOI:10.1021/jo701417z

Sequential Reactions Promoted by Manganese: Completely
Stereoselective Synthesis of (E)-r,â-Unsaturated Amides, Ketones,
Aldehydes, and Carboxylic Acids‡
Jose´ M. Concello´n,* Humberto Rodr´ıguez-Solla, and Pamela D´ıaz
Departamento de Qu´ımica Orga´nica e Inorga´nica, UniVersidad de OViedo, Julia´n ClaVer´ıa 8,
33071 OViedo, Spain
jmcg@unioVi.es
ReceiVed June 29, 2007
A complete E-selective synthesis of R,â-unsaturated amides through a sequential reaction of a range of
dichloroamides with a variety of aldehydes promoted by Rieke manganese (Mn*) is reported. A mechanism
based on a sequential aldol-type reaction and a completely stereoselective â-elimination is proposed to
explain these results. The unsaturated amides obtained are readily and efficiently transformed into R,â-
unsaturated ketones, aldehydes, or carboxylic acids without loss of the diastereoisomeric purity of the
C-C double bond.
Introduction
experimental procedure was very straightforward and easy,
demonstrating that this sequential reaction mediated by Mn* is
an improvement to our previously described sequential synthesis
of R,â-unsaturated esters mediated by SmI2,1 and constitutes a
valuable alternative to obtain R,â-unsaturated esters.
These previous results prompted us to test the application of
a Mn*-promoted sequential reaction toward the synthesis of
other unsaturated compounds such as R,â-unsaturated amides,
since these compounds belong to an important class of natural
products which show both biological and insecticide properties.7
In addition, from a synthetic point of view, R,â-unsaturated
amides are useful building blocks in organic synthesis8 and have
In an ideal organic synthesis, the starting materials should
be cheap and readily available, the number of steps should be
minimized, and the desired target compounds should be prepared
in both high yields and with complete selectivity. In general,
the two first requirements are achievable by sequential processes
and consequently, in recent years, these methodologies have
shown a great deal of development. In this context, we recently
reported the SmI2-mediated synthesis of a range of unsaturated
compounds such as R,â-unsaturated esters,1 carboxylic acids,2
or ketones3 through a sequential process (an aldolic/elimination
reaction). However, these methods present a drawback in the
relatively high cost of the SmI2. For this reason an alternative
method to form the fore-mentioned unsaturated compounds by
using a reagent cheaper than samarium diiodide would be
desirable. To this end, we have published very recently a
sequential synthesis of R,â-unsaturated esters by reaction of
dihaloesters with aldehydes, promoted by cheap4 active man-
ganese5 (Mn*). This synthesis is the first example of a sequential
reaction mediated by manganese,6 which afforded R,â-unsatur-
ated esters in high yields, with complete E-selectivity. The
(4) Aldrich Catalogue (2007-2008): manganese (325 mesh): 250 g,
37.00 euros; samarium (40 mesh): 50 g, 357.50 euros; 1 mmol SmI2
(prepared by the method described in: Concello´n, J. M.; Rodr´ıguez-Solla,
H.; Bardales, E.; Huerta, M. Eur. J. Org. Chem. 2003, 1775-1778),1.2
euros; 1 mmol Mn* (prepared by the method herein described), 0.30 euros.
(5) For see some synthetic applications of manganese see: (a) Kakiya,
H.; Nishimae, S.; Shinokubo, H.; Oshima, K. Tetrahedron 2001, 57, 8807-
8815. (b) Kim, S.-H.; Rieke, R. D. J. Org. Chem. 2000, 65, 2322-2330.
(c) Guijarro, A.; Go´mez, C.; Yus, M. Trends Org. Chem. 2000, 8, 65-91.
(d) Cahiez, G.; Mart´ın, A.; Delacroix, T. Tetrahedron Lett. 1999, 40, 6407-
6410. (e) Kim, S.-H.; Rieke, R. D. Synth. Commun. 1998, 28, 1065-1072.
(f) Kim, S.-H.; Rieke, R. D. J. Org. Chem. 1998, 63, 6766-6767. (g) Tang,
J.; Shinokubo, H.; Oshima, K. Synlett 1998, 1075-1076. (h) Rieke, R. D.;
Kim, S.-H. J. Org. Chem. 1998, 63, 5235-5239. (i) Kim, S.-H.; Rieke, R.
D. Tetrahedron Lett. 1997, 38, 993-996. (j) Suh, Y.; Rieke, R. D.
Tetrahedron Lett. 2004, 45, 1807-1809.
‡ Dedicated to the memory of Prof. Lorenzo Pueyo Casaus.
(1) Concello´n, J. M.; Concello´n, C.; Me´jica, C. J. Org. Chem. 2005, 70,
6111-6113.
(2) Concello´n, J. M.; Concello´n, C. J. Org. Chem. 2006, 71, 1728-
1731.
(3) Concello´n, J. M.; Rodr´ıguez-Solla, H.; Concello´n, C.; D´ıaz, P. Synlett
2006, 837-840.
(6) Concello´n, J. M.; Rodr´ıguez-Solla, H.; D´ıaz, P.; Llavona, R. J. Org.
Chem. 2007, 72, 4396-4400.
10.1021/jo701417z CCC: $37.00 © 2007 American Chemical Society
Published on Web 09/21/2007
7974
J. Org. Chem. 2007, 72, 7974-7979

Sequential Reactions Promoted by Manganese
been used as starting materials to obtain many natural products.9
However, compared to the synthesis of other R,â-unsaturated
acid derivatives such as esters, the preparation of R,â-unsaturated
amides has been scarcely reported and the development of
effective general methods for their stereoselective synthesis is
of significant value. The previously reported preparations of
R,â-unsaturated amides are generally achieved by CdC bond
formation by Horner-Wadsworth-Emmons10 or by Peterson11
reactions, from acetylenic compounds,9,12 by carbonylation
processes13 or by using 2,2-difluorovinyllithium.14 Previously,
our group reported the synthesis of R,â-unsaturated amides with
complete or high E-selectivity and in good yields, from 2-chloro-
3-hydroxyamides15 or R,â-epoxyamides,16 the process being
promoted, in both cases, by SmI2.
Herein, we describe a new and easy route to (E)-R,â-un-
saturated amides with total stereoselectivity and in high yield,
via a sequential reaction using readily available dichloroamides
and a variety of aldehydes. Moreover, the interesting transfor-
mation of amides into various unsaturated compounds without
loss of the diastereoisomeric purity of the C-C double bond
previously generated is reported. A mechanism to explain the
E-stereoselectivity is also proposed.
SCHEME 1. Synthesis of (E)-r,â-Unsaturated Amides 3
TABLE 1. Synthesis of r,â-Unsaturated Amides 3
3
entry
3
R1
R2
NR2
yield (%)a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
n-C7H15
n-C7H15
s-Bu
i-Bu
i-Bu
CH2dCH(CH2)8
CH2dCH(CH2)8
Cy
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
PhCH2
PhCH2
NEt2
b
NEt2
NEt2
b
87
84
78
84
83
81
80
85
85
77
82
71
79
82
83
80
75
73
77
78
76
71
73
NEt2
b
NEt2
Ni-Pr2
NEt2
NEt2
NEt2
b
NEt2
Ni-Pr2
NEt2
NEt2
b
NEt2
NEt2
b
NEt2
NEt2
Cy
PhCH(Me)
PhCH2CH2
Ph
Ph
p-MeOC6H4
p-MeOC6H4
p-ClC6H4
n-C7H15
s-Bu
i-Bu
PhCH2CH2
Ph
(7) (a) Nieman, J. A.; Coleman, J. E.; Wallace, D. J.; Piers, E.; Lim, L.
Y.; Roberge, M.; Anderson, R. J. J. Nat. Prod. 2003, 66, 183-199. (b)
Shealy, Y. F.; Riordan, J. M.; Frye, J. L.; Simpson-Herren, L.; Sani, B. P.;
Hill, D. L. J. Med. Chem. 2003, 46, 1931-1939. (c) Marrano, C.; de
Macedo, P.; Keillor, J. W. Bioorg. Med. Chem. 2001, 9, 1923-1928. (d)
Choo, H. Y. P.; Peak, K. H.; Park, J.; Kim, D. H.; Chung, H. S. J. Med.
Chem. 2000, 35, 643-648. (e) Meinke, P. T.; Ayer, M. B.; Colletti, S. L.;
Li, C.; Lim, J.; Ok, D.; Salva, S.; Schmatz, D. M.; Shih, T. L; Shoop, W.
L.; Warmke, L. M.; Wyvratt, M. J.; Zakson-Aiken, M.; Fisher, M. H. Bioorg.
Med. Chem. Lett. 2000, 10, 2371-2374. (f) Takami, H.; Koshimura, H.;
Kishibayashi, N.; Ishii, A.; Nonaka, H.; Aoyama, S.; Kase, H.; Kumazawa,
T. J. Med. Chem. 1996, 39, 5047-5052.
3t
3u
3v
3w
n-C7H15
CH2)CH(CH2)8
a
Yields of the isolated products after column chromatography based
on aldehydes 1; in all cases a single diastereoisomer was observed the
diastereoisomeric ratio (>98%/2) being determined from the crude reaction
1
product by GC-MS and/or H NMR (300 MHz). b From morpholine.
(8) (a) Fortin, S.; Duppont, F.; Deslongchamps, P. J. Org. Chem. 2002,
67, 5437-5439. (b) Kojima, S.; Inai, H.; Hidaka, T.; Ohkata, K. Chem.
Commun. 2000, 1795-1796. (c) Caramella, P.; Reami, D.; Falzoni, M.;
Quadrelli, P. Tetrahedron 1999, 55, 7027-7044. (d) Gothelf, R. F.;
Jorgensen, K. A. Chem. ReV. 1998, 98, 863-909. (e) Jurczak, J.; Bauer,
T.; Chapuis C. In StereoselectiVe Synthesis (Houben-Weyl); Helmchen, G.,
Hoffmann, R. W., Mulzer, J., Schaumann, E., Eds.; Thieme Verlag:
Stuttgart, Germany, 1995; Vol. E 21c, p 2735.
(9) (a) Hu, Y.; Floss, H. G. J. Am. Chem. Soc. 2004, 126, 3837-3844.
(b) Leibold, T.; Sasse, F.; Reichenbach, H.; Ho¨fle, G. Eur. J. Org. Chem.
2004, 431-435. (c) Han, B.; McPhail, K. L.; Ligresti, A.; Di Marzo, V.;
Gerwick, W. H. J. Nat. Prod. 2003, 66, 1364-1368. (d) Andrus, M. B.;
Meredith, E. L.; Hicken, E. J.; Simmons, B. L.; Glancey, R. R.; Ma, W. J.
Org. Chem. 2003, 68, 8162-8169. (e) Chen, J.; Forsyth, C. J. J. Am. Chem.
Soc. 2003, 125, 8734-8735.
Results and Discussion
Synthesis of R,â-Unsaturated Amides 3. The active man-
ganese was readily prepared by using the method described by
Cahiez.5d Thus, treatment of Li2MnCl4 (or MnCl2.2LiCl) (13
mmol) with 26 mmol of lithium in the presence of catalytic
amounts of 2-phenylpyridine (4 mmol) at room temperature for
3 h afforded active manganese cheaply as a black slurry.
Our first attempts were performed with n-octanal 1a and N,N-
diethyldichloroacetamide, as starting materials, at room tem-
perature and under a variety of reaction conditions. The reaction
did not proceeded to completion and long reaction times were
required. The reaction was hence carried out at reflux in THF,
and the best results were obtained by treating a solution of a
range of aldehydes 1 (1 equiv.) and the corresponding dichlo-
roacetamide 2 (1.2 equiv) in THF at reflux with active
manganese (5 equiv) for 5 h (Scheme 1).
The corresponding disubstituted (E)-R,â-unsaturated amides
3a-p were obtained with total E-stereoselectivity and high
yields after hydrolysis (Scheme 1, Table 1). Taking into account
that the highly stereoselective preparation of trisubstituted
alkenes is one of the most challenging problems in organic
chemistry,17 we have also applied this methodology for syn-
thesizing R,â-unsaturated amides in which the CdC bond is
trisubstituted (Table 1, entries 17-23). To this end, 2,2-
dichloropropanamide (R2 ) Me) or 2,2-dichloro-3-phenylpro-
panamide (R2 ) PhCH2) was employed, using the above-
mentioned reaction conditions.
(10) (a) Herna´ndez-Ferna´ndez, E.; Ferna´ndez-Zertuche, M.; Garc´ıa-
Barradas, O.; Mun˜oz-Mun˜iz, O.; Ordon˜ez, M. Synlett 2006, 440-444. (b)
Kojima, S.; Hidaka, T.; Ohba, Y. Heteroatom Chem. 2004, 15, 515-523.
(c) Kojima, S.; Hidaka, T.; Ohba, Y.; Ohkata, K. Phosphorus, Sulfur, Silicon
Related Elements 2002, 177, 729-732. (d) Ando, K. Synlett 2001, 1272-
1274. (e) Petrova, J.; Momchilova, S.; Vassilev, N. G. Phosphorus, Sulfur,
Silicon Related Elements 2000, 164, 87-94. (f) Janecki, T.; Bodalski, R.;
Wieczorek, M.; Bujacz, G. Tetrahedron 1995, 51, 1721-1740. (g) Tay,
M. K.; About-Jaudet, E.; Collignon, N.; Savignac, P. Tetrahedron 1989,
45, 4415-4430, and ref 8a.
(11) Kojima, S.; Inai, H.; Hidaka, T.; Fukuzaki, T.; Ohkata, K. J. Org.
Chem. 2002, 67, 4093-4099, and ref 8b.
(12) (a) Matsuda, I.; Takeuchi, K.; Itoh, K. Tetrahedron Lett. 1999, 40,
2553-2556. (b) Kazmaier, U. Chem. Commun. 1997, 1795-1796.
(13) (a) Park, J. H.; Kim, S. Y.; Kim, S. M.; Chung, Y. K. Org. Lett.
2007, 9, 2465-2468. (b) Xu, J.; Burton, D. J. J. Org. Chem. 2005, 70,
4346-4353. (c) El Ali, B.; Tijani, J.; El-Ghanam, A. M. Appl. Organomet.
Chem. 2002, 16, 369-376.
(14) Tellier, F.; Sauveˆtre, R. Tetrahedron Lett. 1993, 34, 5433-1681.
(15) Concello´n, J. M.; Pe´rez-Andre´s, J. A.; Rodr´ıguez-Solla, H. Chem.
Eur. J. 2001, 7, 3062-3068.
(16) (a) Concello´n, J. M.; Bardales, E. J. Org. Chem. 2003, 68, 9492-
9495. (b) Concello´n, J. M.; Bardales, E. Eur. J. Org. Chem. 2004, 1523-
1526.
(17) Kelly, S. E. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, U.K., 1991; Vol. 1, p 730.
J. Org. Chem, Vol. 72, No. 21, 2007 7975

Concello´n et al.
SCHEME 2. Proposed Mechanism
Attempts to synthesize tetrasubstituted amides from ketones
and 2,2-dichloroamides failed, however. After studying several
sets of conditions, a mixture of products without synthetic value
was obtained.
3q16b by comparison of its NMR spectra with those previously
described in the literature for the same unsaturated amide. The
E-stereochemistry of compounds 3s and 3w was assigned by
analogy.
This synthesis of R,â-unsaturated amides via a sequential
reaction of aldehydes 1 with the corresponding dichloroamide
2 is general. Thus, unsaturated amides are obtained from
aliphatic (linear, branched, or cyclic) aldehydes in high
yields and as a single diastereoisomer. The synthesis of aromatic
(E)-R,â-unsaturated amides has been performed with aldehydes
having donor and withdrawing substituents. Interestingly, the
selectivity and yield of these reactions were unaffected when
the reaction was carried out from dichloroamides derived from
different amines (Table 1, entries 1/2, 4/5, 6/7, 8/9, 12/13, and
14/15). Therefore, it was possible to synthesize amides such as
those derived from morpholine (Table 1, entries 2, 5, 7, 13, 18,
and 21), which can be easily transformed into other synthetically
valuable compounds (see below). In addition, unsaturated amides
3 were also obtained by using an aldehyde with high proclivity
to enolize (Table 1, entry 10) and from some functionalized
aldehydes, the reported transformation being compatible with
the presence of a C-C double bond (Table 1, entries 6, 7, and
23), an alkoxy (Table 1, entries 14 and 15), or a chlorine atom
(Table 1, entry 16) in the molecule.
The synthesis described herein of R,â-unsaturated amides
constitutes an improvement of our previous syntheses of R,â-
15,16
unsaturated amides promoted by SmI2
since the starting
materials are readily available, the experimental procedure is
very simple, and the unsaturated amides are obtained in higher
overall yields, based on the starting aldehyde and with complete
stereoselectivity (unsaturated amides were obtained by using
SmI2 with a E/Z ratio ranging between 81/19 and >98/2).15,16
To rationalize the synthesis of amides 3, we proposed a
similar mechanism to that previously used to explain the
preparation of R,â-unsaturated esters through a sequential
reaction promoted by Mn*.6 Thus, an aldolic reaction initially
takes place between the enolate generated by metalation of the
dichloroamide and the aldehyde affording the Reformatsky
adducts 4. A second metalation of 4 by Mn* affords the
intermediate 5, which undergoes a spontaneous â-elimination
reaction to give amides 3. The complete E-selectivity of the
elimination reaction can be explained by assuming a cyclic six-
membered transition state I, as a consequence of the coordina-
tion between the manganese and the oxygen. The R1 group
occupies an equatorial position in this transition state to reduce
the 1,3-steric hindrance. The elimination through this transition
state I generates a C-C double bond with an E-relative
configuration as that shown by products 3 (Scheme 2).
Synthesis of R,â-Unsaturated Ketones 6, Aldehydes 7, and
Carboxylic Acids 8. To demonstrate the synthetic applications
of the obtained amides 3, selected examples were readily
transformed into various unsaturated compounds, such as
ketones 6, aldehydes 7, or carboxylic acids 8 (Scheme 3).
The preparation of R,â-unsaturated ketones 6 was carried out
starting from various R,â-unsaturated amides derived from
morpholine. Thus, the reaction of different R,â-unsaturated
amides with the corresponding organolithium compound at -78
°C for 30 min afforded the corresponding unsaturated ketone
in very high yields (>83%) (Scheme 3, Table 2).23
The diastereoisomeric ratio of the R,â-unsaturated amides 3
1
was determined based on the crude reaction products by H
NMR spectroscopy (300 MHz) and GC-MS. In all cases, the
(E)-stereoisomer was isolated as the only isomer and other
isomers were not detected in the crude reaction.18
The E stereochemistry in the CdC bond was assigned on
1
the basis of the value of H NMR coupling constant between
the olefinic protons of compounds 319 in the case of compounds
3a-p, and by comparison of the NMR spectra for compounds
3a,15,20 3d,20 3e,21 3i,16b 3j,15 3l,15,16a and 3n16a with those
described in the literature for the same unsaturated amides. In
the case of trisubstituted amides 3q-w, the total stereoselectivity
was again observed and ascertained as above. The relative
configuration of compounds 3r, 3t, and 3v was assigned by
NOESY experiments, or in the case of compounds 3u22 and
The transformation seems to be general and a range of
morpholine-based unsaturated amides and organolithium com-
pounds can be used. It is noteworthy that the integrity of the
C-C double bond was unaffected by this transformation, with
the ketone being obtained as a single E-stereoisomer. The
(18) When the minor diastereoisomer was not observed the E/Z ratio
was assigned >98/2.
(19) The coupling constant between the olefinic protons of compounds
3 ranging between J ) 14.9 and 15.4 Hz were in accordance with the
average literature values: Silverstein, R. M.; Bassler, G. C.; Morrill T. C.
In Spectrometric Identification of Organic Compounds; John Wiley and
Sons: New York, 1991; Chapter 4, Appendix F, p 221.
(20) Huang, Y.-Z.; Chen, C.; Shen, Y. J. Organomet. Chem. 1989, 366,
87-93.
(22) Harrington, P. E.; Murai, T.; Chu, C.; Tius, M. A. J. Am. Chem.
Soc. 2002, 124, 10091-10100.
(23) Mart´ın, R.; Romea, P.; Tey, C.; Urp´ı, F.; Vilarrasa, J. Synlett 1997,
1414-1416.
(21) Janecki, T.; Boldaski, R.; Wieczorek, M.; Bujacz, G. Tetrahedron
1995, 51, 1721-1740.
7976 J. Org. Chem., Vol. 72, No. 21, 2007

Sequential Reactions Promoted by Manganese
SCHEME 3. Synthesis of r,â-Unsaturated Ketones 6,
or 8, respectively. Thus, unsaturated ketones 6 were obtained
from the corresponding aldehydes in an overall yield ranging
between 61% and 82%, aldehydes 7 in an overall yield of 71%
or 72%, and finally, in the case of carboxylic acids 8, the yields
ranged between 74% and 77%.
Aldehydes 7, and Carboxylic Acids 8a
Conclusions
We have described a complete E-selective synthesis of R,â-
unsaturated amides through a sequential reaction of a range of
dichloroamides with a variety of aldehydes promoted by Rieke
manganese (Mn*). This synthetic method is an advantageous
alternative to other methods of synthesis of (E)-a,â-unsaturated
amides, because (a) the reaction takes place with complete
E-selectivity, (b) high yields are obtained, (c) an easy experi-
mental procedure is utilized, and (d) the requisite starting
materials are very cheap. Moreover, it has been shown that the
obtained unsaturated amides could be readily transformed into
R,â-unsaturated ketones, aldehydes, or carboxylic acids with
very high yields and without losing diastereoisomeric purity of
the C-C double bond. A mechanism based on a successive
aldol-type reaction and a â-elimination is proposed to explain
these results. Further studies directed toward the development
of the synthetic applications of this method are currently under
investigation in our laboratory.
a Reagents and conditions: (i) R4Li, -78 °C, THF, 30 min; (ii) H3O+;
(iii) LiAlH4, -78 °C, THF, 12 h; (iv) t-BuOK, H2O, THF, reflux, 12 h.
TABLE 2. Synthesis of r,â-Unsaturated Ketones 6
entry
6
R1
R2
R4
yield (%)a
1
2
3
4
6a
6b
6c
6d
i-Bu
n-C7H15
s-Bu
H
H
Me
Me
Ph
Me
n-Bu
CH2Cl
94
98
89
83
s-Bu
a Yields of the isolated products after column chromatography based on
the unsaturated amides 3.
synthesis of alkyl alk-1-enyl ketones, such as 6b,c, by other
alternative methods would present special difficulty.24 In addi-
tion it is worthy to mention that in the synthesis of the
chlorinated ketone 6d, chloromethyllithium was generated in
situ.25 Remarkably, the use of morpholine amides as starting
materials, to transform R,â-unsaturated amides into ketones, is
more advantageous than the corresponding Weinreb derivatives
since the morpholine derivatives are cheaper.
The R,â-unsaturated aldehydes 7a-c can be obtained by
reduction of unsaturated morpholine-based amides 3, with
lithium aluminum hydride at low temperature (-78 °C).26
Compounds 7 were obtained in high yield (>85%) and as a
single E-diastereoisomer (Scheme 3). No important differences
in the yields of the obtained aldehydes were observed when
different morpholine amides 3 were employed as starting
compounds.
Finally, unsaturated carboxylic acids 8 were also obtained
from amides 3, as is shown in Scheme 3. Thus, the treatment
of the morpholine amide 3b or 3u with t-BuOK/H2O/THF27 at
reflux afforded the corresponding (E)-R,â-unsaturated carboxylic
acid 8a and 8b in very high yield (92% and 97% yield,
respectively) and without loss of stereochemistry. This trans-
formation also could be carried out with the N,N-diethyl amides
instead of the N-morpholine amide. So, the treatment of N,N-
diethylcinnamamide 3l under the same reaction conditions
afforded the cinnamic acid 8c in very high yields (95%).
Therefore the reported synthesis of R,â-unsaturated amides
combined with their transformation into different unsaturated
carbonyl compounds constitutes an easy and efficient access to
R,â-unsaturated ketones, aldehydes, or carboxylic acids 6, 7,
Experimental Section
General Procedure. Reactions requiring an inert atmosphere
were conducted under dry nitrogen, and the glassware was oven
dried (120 °C). THF was distilled from sodium/benzophenone ketyl
immediately prior to use. All reagents were purchased in the highest
1
quality available and were used without further purification. H
NMR spectra were recorded at 300 or 400 MHz. 13C NMR spectra
and DEPT experiments were recorded at 75 or 100 MHz. GC-MS
spectra were measured at 70 eV.
Preparation of Starting Dichloroamides 2. A mixture of
diethylamine, diisopropylamine, or morpholine (40 mmol) and
dichloroacetyl chloride (1.9 mL, 20 mmol) in dry CH2Cl2 (54 mL)
was refluxed for 5 h. After that time, the mixture was quenched
with aqueous HCl (1.0 M) and extracted with dichloromethane.
The combined extracts were dried over Na2SO4 and the solvent
was removed in vacuuo to afford N,N-diethyldichloroacetamide,
N,N-diisopropyldichloroacetamide, or N-dichloroacetylmorpholine.
2,2-Dichloropropionamides were prepared by alkylation of the
corresponding dichloroacetamides as is described in the following
procedure: A solution of lithium diisopropylamide [prepared from
MeLi (36 mmol, 14.4 mL, 2.5 M solution in hexane) and
diisopropylamine (40 mmol, 5.8 mL) in THF (20 mL) at -78 °C]
was added dropwise to a stirred solution of the dichloroacetamide
(28 mmol) in dry THF (2 mL) at -78 °C and the mixture was
stirred for 15 min. After that time a solution of MeI or BnBr
(28 mmol) in THF (5 mL) was added dropwise and stirring
was continued for 15 min. The mixture was warmed to room
temperature and then quenched with an aqueous saturated solution
of NH4Cl (20 mL) followed by extraction with diethyl ether (3 ×
20 mL). The usual workup provided crude products, which were
purified by flash column chromatography on silica gel (hexane:
EtOAc 10:1).
N,N-Diethyldichloroacetamide: yellow oil (95% yield); 1H
NMR (300 MHz, CDCl3) δ 6.21 (s, 1 H), 3.45 (q, J ) 7.1 Hz, 2
H), 3.38 (q, J ) 7.1 Hz, 2 H), 1.24 (t, J ) 7.1 Hz, 3 H), 1.13 (t,
J ) 7.1 Hz, 3 H); 13C NMR (75 MHz, CDCl3) δ 162.8 (C), 64.9
(CH), 42.3 (CH2), 41.2 (CH2), 14.1 (CH3), 12.1 (CH3).
(24) (a) Duncan, A. P.; Leighton, J. L. Org. Lett. 2004, 6, 4117-4119.
(b) Huddleston, R. R.; Krische, M. J. Org. Lett. 2003, 5, 1143-1146.
(25) Barluenga, J.; Baragan˜a, B.; Alonso, A.; Concello´n, J. M. J. Chem.
Soc., Chem. Commun. 1994, 969-970.
(26) Douat, C.; Heitz, A.; Martinez, J.; Fehrentz, J.-A. Tetrahedron Lett.
2000, 41, 37-40.
(27) Gassman, P. G.; Hodgson, P. K. G.; Balchunis, R. J. J. Am. Chem.
Soc. 1976, 98, 1275-1276.
N,N-Diisopropyldichloroacetamide: yellow oil (90% yield); 1H
NMR (200 MHz, CDCl3) δ 5.97 (s, 1 H), 4.05 (m, 1 H), 3.26 (m,
1 H), 1.14 (d, J ) 6.5 Hz, 6 H), 1.02 (d, J ) 6.5 Hz, 1 H); 13C
J. Org. Chem, Vol. 72, No. 21, 2007 7977

Concello´n et al.
NMR (50 MHz, CDCl3) δ 161.5 (C), 66.8 (CH), 49.1 (CH), 46.5
(CH), 19.9 (2 × CH3), 19.3 (2 × CH3).
6.19 (dt, J ) 15.0, 1.5 Hz, 1 H), 5.87-5.77 (m, 1 H), 5.02-4.91
(m, 2 H), 3.43 (q, J ) 7.1 Hz, 2 H), 3.38 (q, J ) 7.1 Hz, 2 H),
2.21 (q, J ) 7.1 Hz, 2 H), 2.08-2.02 (m, 2 H), 1.47-1.25 (m, 12
H), 1.20 (t, J ) 7.1 Hz, 3 H), 1.15 (t, J ) 7.1 Hz, 3 H); 13C NMR
(100 MHz, CDCl3) δ 165.9 (C), 146.2 (CH), 139.1 (CH), 120.2
(CH), 114.0 (CH2), 42.0 (CH2), 40.7 (CH2), 33.7 (CH2), 32.4 (CH2),
29.3 (CH2), 29.1 (CH2), 29.0 (2 × CH2), 28.8 (CH2), 28.3 (CH2),
14.7 (CH3), 13.1 (CH3); MS (70 eV, EI) m/z (%) 265 [M+, 9], 154
(19), 126 (100), 55 (25); HRMS (70 eV) calcd for C17H31NO
265.2406, found 265.2412; IR (neat) 3412, 2927, 1660, 1619, 1431
cm-1; Rf 0.28 (hexane:EtOAc 3:1).
N-Dichloroacetylmorpholine: white solid (92% yield); 1H NMR
(300 MHz, CDCl3) δ 6.19 (s, 1 H), 3.71-3.68 (m, 4 H), 3.61-
3.59 (m, 4 H); 13C NMR (75 MHz, CDCl3) δ 161.9 (C), 66.3 (CH2),
65.9 (CH2), 65.3 (CH), 46.8 (CH2), 43.2 (CH2).
2,2-Dichloro-N,N-Diethylpropionamide: yellow oil (80% yield);
1H NMR (300 MHz, CDCl3) δ 3.25 (q, J ) 7.0 Hz, 2 H), 3.18 (q,
J ) 7.0 Hz, 2 H), 2.40 (s, 3 H), 1.14 (t, J ) 7.0 Hz, 3 H), 1.01 (t,
J ) 7.0 Hz, 3 H); 13C NMR (75 MHz, CDCl3) δ 163.7 (C), 80.3
(C), 43.1 (CH2), 42.3 (CH2), 14.8 (CH3), 12.9 (CH3).
N-[(E)-Tridec-2,12-dienoyl]morpholine (3g): colorless oil; 1H
NMR (300 MHz, CDCl3) δ 6.91 (dt, J ) 15.0, 6.9 Hz, 1 H), 6.19
(dt, J ) 15.0, 1.5 Hz, 1 H), 5.88-5.74 (m, 1 H), 5.03-4.91 (m, 2
H), 3.69-3.49 (m, 8 H), 2.34-2.27 (m, 1 H), 2.20 (dq, J ) 6.9,
1.3 Hz, 1 H), 2.03 (apparent q, J ) 6.9 Hz, 2 H), 1.48-1.26 (m,
12 H); 13C NMR (100 MHz, CDCl3) δ 165.8 (C), 147.4 (CH), 139.1
(CH), 119.2 (CH), 114.1 (CH2), 66.7 (2 × CH2), 45.6 (CH2), 41.5
(CH2), 33.7 (CH2), 32.5 (CH2), 29.4 (CH2), 29.3 (CH2), 29.3 (CH2),
28.9 (CH2), 28.8 (CH2), 28.2 (CH2); MS (70 eV, EI) m/z (%) 279
[M+, 52], 168 (69), 140 (100), 129 (30), 69 (79); HRMS (70 eV)
calcd for C17H29NO2 279.2198, found 279.2188; IR (neat) 2930,
1665, 1267, 907 cm-1; Rf 0.12 (hexane:EtOAc 3:1).
N-(2,2-Dichloropropionyl)morpholine: yellow oil (72% yield);
1H NMR (300 MHz, CDCl3) δ 3.78-3.76 (m, 4 H), 3.51-3.49
(m, 4 H), 2.08 (S, 3 H); 13C NMR (75 MHz, CDCl3) δ 163.4 (C),
79.7 (C), 66.1 (2 × CH2), 48.3 (CH2), 43.8 (CH2), 35.9 (CH3).
2,2-Dichloro-N,N-diethyl-3-phenylpropionamide: yellow oil
1
(71% yield); H NMR (300 MHz, CDCl3) δ 7.48-7.33 (m, 5 H),
3.84 (q, J ) 6.9 Hz, 2 H), 3.77 (s, 2 H), 3.41 (q, J ) 6.9 Hz, 2 H),
1.27 (t, J ) 6.9 Hz, 3 H), 1.20 (t, J ) 6.9 Hz, 3 H); 13C NMR (75
MHz, CDCl3) δ 164.4 (C), 134.4 (C), 132.3 (2 × CH), 127.5 (2 ×
CH), 127.3 (CH), 83.4 (C), 50.5 (CH2), 43.1 (CH2), 41.9(CH2),
13.1 (CH3), 11.9 (CH3).
Preparation of Highly Active Manganese (Mn*). A mixture
of lithium (26 mmol) and 2-phenylpyridine (4 mmol) in THF (20
mL) under a nitrogen atmosphere was stirred for 1 h. In a separate
flask a solution of the Li2MnCl4 complex was prepared by stirring
a suspension of anhydrous MnCl2 (13 mmol) and LiCl (26 mmol)
in THF (20 mL) for 30 min. Then, this yellow solution was added
at room temperature with a syringe to the 2-phenylpyridine/lithium
solution previously prepared and was stirred, under a nitrogen
atmosphere, at room temperature for 1 h. The black slurry was
allowed to stir at room temperature for 3 h.
(E)-3-Cyclohexyl-N,N-diethylacrylamide (3h): yellow oil; 1H
NMR (300 MHz, CDCl3) δ 6.84 (dd, J ) 15.1, 7.0 Hz, 1 H), 6.12
(d, J ) 15.1 Hz, 1 H), 3.44-3.32 (m, 4 H), 3.11-2.02 (m, 1 H),
1.76-1.61 (m, 4 H), 1.30-1.10 (m, 12 H); 13C NMR (75 MHz,
CDCl3) δ 166.0 (C), 151.0 (CH), 117.8 (CH), 41.9 (CH2), 40.7
(CH2), 40.5 (CH), 31.9 (2 × CH2), 25.8 (CH2), 25.6 (2 × CH2),
14.6 (CH3), 12.9 (CH3); MS (70 eV, EI) m/z (%) 209 [M+, 21],
137 (36), 126 (100), 55 (49); HRMS (70 eV) calcd for C13H23NO
209.1780, found 209.1785; IR (neat) 2926, 1657, 1614, 980 cm-1
;
Rf 0.22 (hexane:EtOAc 3:1).
General Procedure for the Synthesis of R,â-Unsaturated
Amides 3. The slurry of Mn* (2.5 mmol, 8.5 mL) in THF was
added to a stirred solution of 1,1-dichloroacetamide (0.6 mmol)
and the corresponding aldehyde (0.5 mmol) in THF (2 mL) under
inert atmosphere. The mixture was heated at reflux for 5 h before
it was quenched with HCl (3 M). The organic material was extracted
with diethyl ether (3 × 20 mL), and the combined organic extracts
were washed sequentially with HCl (3 M; 2 × 10 mL), saturated
NaHCO3 (2 × 20 mL), saturated Na2S2O3 (2 × 20 mL), and brine
(2 × 20 mL) and dried over Na2SO4. Solvents were removed in
vacuuo. Purification by flash column chromatography on silica gel
(hexane:EtOAc 3:1) provided pure compounds 3.
(E)-N,N-Diethyl-5-phenylpent-2-enamide (3k): orange oil; 1H
NMR (300 MHz, CDCl3) δ 7.39-7.25 (m, 5 H), 7.00 (dt, J )
15.1, 6.9 Hz, 1 H), 6.24 (dt, J ) 15.1, 1.6 Hz, 1 H), 3.49 (q, J )
7.0 Hz, 2 H), 3.37 (q, J ) 7.0 Hz, 2 H), 2.86 (t, J ) 8.2 Hz, 2 H),
2.65-2.57 (m, 2 H), 1.21 (t, J ) 7.0 Hz, 6 H); 13C NMR (75 MHz,
CDCl3) δ 165.7 (C), 144.5 (CH), 141.1 (C), 128.3 (4 × CH), 125.9
(CH), 121.2 (CH), 42.0 (CH2), 40.6 (CH2), 34.6 (CH2), 34.0 (CH2),
14.7 (CH3), 13.0 (CH3); MS (70 eV, EI) m/z (%) 231 [M+, 18],
159 (46), 126 (69), 91 (100), 72 (17); HRMS (70 eV) calcd for
C15H21NO 231.1623, found 231.1600; IR (neat) 2932, 1659, 1616,
670 cm-1; Rf 0.15 (hexane:EtOAc 3:1).
Compounds 3a, 3d,e, 3i,j, 3l, 3n, 3q, and 3u displayed analytical
N-Cinnamoylmorpholine (3m): white solid; 1H NMR (300
MHz, CDCl3) δ 7.72 (d, J ) 15.5 Hz, 1 H), 7.56-7.37 (m, 5 H),
6.86 (d, J ) 15.5 1 H), 3.75 (apparent s, 8 H); 13C NMR (100
MHz, CDCl3) δ 165.0 (C), 143.1 (CH), 134.2 (C), 129.7 (CH),
128.6 (2 × CH), 127.6 (2 × CH), 115.3 (CH), 66.6 (CH2), 66.5
(CH2), 45.6 (CH2), 41.9 (CH2); HRMS (70 eV) calcd for
C13H15NO2 217.1103, found 217.1093; IR (neat) 3426, 1649, 1265,
909, 739 cm-1; Rf 0.52 (EtOAc).
(E)-N,N-Diisopropyl-3-(4-methoxyphenyl)acrylamide (3o): yel-
low oil; 1H NMR (400 MHz, CDCl3) δ 7.57 (d, J ) 15.2 Hz, 1 H),
7.49 (d, J ) 8.8 Hz, 2 H), 6.89 (d, J ) 8.8 Hz, 2 H), 6.77 (d, J )
15.2 Hz, 1 H), 4.30-4.27 (m, 1 H), 3.83 (s, 3 H), 3.47-3.42 (m,
1 H), 1.45 (d, J ) 6.6 Hz, 6 H), 1.23 (d, J ) 6.3 Hz, 6 H); 13C
NMR (100 MHz, CDCl3) δ 166.0 (C), 159.9 (C), 140.6 (CH), 128.9
(2 × CH), 127.5 (C), 116.9 (CH), 113.6 (2 × CH), 55.1 (CH3),
45.7 (2 × CH), 20.2 (4 × CH3); MS (70 eV, EI) m/z (%) 261 [M+,
12], 161 (100), 134 (14), 77 (4); HRMS (70 eV) calcd for
C16H23NO2 261.1729, found 261.1701; IR (neat) 3452, 2966, 1643,
1641, 1511, 825 cm-1; Rf 0.22 (hexane:EtOAc 3:1).
data in accordance with the published values.15,16,20-22
N-[(E)-Dec-2-enoyl]morpholine (3b): yellow oil; 1H NMR (300
MHz, CDCl3) δ 6.78 (dt, J ) 15.0, 7.1 Hz, 1 H), 6.07 (dt, J )
15.0, 1.4 Hz, 1 H), 3.56-3.41 (m, 8 H), 2.07 (apparent q, J ) 7.05
Hz, 2 H), 1.35-1.30 (m, 2 H), 1.19-1.14 (m, 8 H), 0.75 (t, J )
8.1 Hz, 3 H); 13C NMR (75 MHz, CDCl3) δ 165.3 (C), 148.0 (CH),
118.2 (CH), 66.4 (CH2), 66.3 (CH2), 45.4 (CH2), 41.5 (CH2), 32.5
(CH2), 31.6 (CH2), 29.3 (CH2), 29.0 (CH2), 27.8 (CH2), 22.5 (CH2),
14.1 (CH3); MS (70 eV, EI) m/z (%) 239 [M+, <1], 168 (100),
140 (17), 81 (35); HRMS (70 eV) calcd for C14H25NO2 239.1885,
found 239.1853; IR (neat) 3440, 2924, 1654, 1653, 1116 cm-1; Rf
0.44 (hexane:EtOAc 1:1).
1
(E)-N,N-Diethyl-4-methylhex-2-enamide (3c): yellow oil; H
NMR (300 MHz, CDCl3) δ 6.79 (dd, J ) 14.9, 7.9 Hz, 1 H), 6.14
(d, J ) 14.9 Hz, 1 H), 3.46-3.34 (m, 4 H), 2.21 (apparent q, J )
6.7 Hz, 3 H), 1.27-1.10 (m, 6 H), 1.04 (d, J ) 6.6 Hz, 3 H),
0.95-0.86 (m, 3 H); 13C NMR (75 MHz, CDCl3) δ 165.9 (C),
151.1 (CH), 118.7 (CH), 42.0 (CH2), 40.7 (CH2), 38.3 (CH), 28.9
(CH2), 19.2 (CH3), 14.7 (CH3), 13.0 (CH3), 11.5 (CH3); MS (70
eV, EI) m/z (%) 183 [M+, 12], 126 (100), 111 (79), 55 (43); HRMS
(70 eV) calcd for C11H21NO 183.1623, found 183.1624; IR (neat)
2965, 1657, 1608, 983 cm-1; Rf 0.27 (hexane:EtOAc 3:1).
(E)-3-(4-Chlorophenyl)-N,N-diethylpropenamide (3p): pale
orange oil; 1H NMR (400 MHz, CDCl3) δ 7.59 (d, J ) 15.4 Hz, 1
H), 7.43-7.09 (m, 4 H), 6.71 (d, J ) 15.4 Hz, 1 H), 3.39-3.36
(m, 4 H), 1.16 (t, J ) 7.0 Hz, 3 H), 1.08 (t, J ) 7.0 Hz, 3 H); 13
C
(E)-N,N-Diethyltrideca-2,12-dienamide (3f): pale orange oil;
NMR (75 MHz, CDCl3) δ 165.7 (C), 142.2 (CH), 129.3 (C), 128.6
1H NMR (400 MHz, CDCl3) δ 6.94 (dt, J ) 15.1, 7.1 Hz, 1 H),
(2 × CH), 127.7 (2 × CH), 126.9 (C), 117.6 (CH), 42.2 (CH2),
7978 J. Org. Chem., Vol. 72, No. 21, 2007

Sequential Reactions Promoted by Manganese
41.0 (CH2), 14.9 (CH3), 13.1 (CH3); MS (70 eV, EI) m/z (%) 203
[M+ - Cl, 16], 131 (100), 103 (56), 77 (45); HRMS (70 eV) calcd
for C13H16NO 203.1310, found 203.1298; IR (neat) 3387, 1649,
1601, 1454 cm-1; Rf 0.17 (hexane:EtOAc 3:1).
provided crude products 6, which were purified by flash column
chromatography on silica gel (hexane:EtOAc 10:1).
Compounds 6a and 6b displayed analytical data in accordance
with the published values.28
1
N-[(E)-2,4-Dimethylhex-2-enoyl]morpholine (3r): yellow oil;
1H NMR (400 MHz, CDCl3) δ 5.17 (d, J ) 9.7 Hz, 1 H), 3.61-
3.50 (m, 4 H), 3.48-3.44 (m, 4 H), 2.28-2.16 (m, 1 H), 1.71 (s,
3 H), 1.32-1.23 (m, 1 H), 1.21-1.11 (m, 1 H), 0.85 (d, J ) 6.63
Hz, 3 H), 0.74 (t, J ) 7.4 Hz, 3 H); 13C NMR (100 MHz, CDCl3)
δ 172.3 (C), 137.3 (CH), 128.4 (C), 66.6 (CH2), 66.4 (CH2), 47.1
(CH2), 41.2 (CH2), 33.6 (CH), 29.5 (CH2), 20.2 (CH3), 14.5 (CH3),
12.3 (CH3); HRMS (70 eV) calcd for C12H21NO2 211.1572, found
211.1568; IR (neat) 3440, 1619, 1460, 1266, 909, 739 cm-1; Rf
0.22 (hexane:EtOAc 1:1).
(E)-6,8-Dimethyldec-6-en-5-one (6c): colorless oil; H NMR
(300 MHz, CDCl3) δ 6.24 (d, J ) 9.6 Hz, 1 H), 2.53 (t, J ) 7.3
Hz, 2 H), 2.41-2.29 (m, 1 H), 1.66 (s, 3 H), 1.51-1.38 (m, 2 H),
1.29-1.14 (m, 4 H), 0.90 (d, J ) 6.8 Hz, 3 H), 0.80 (t, J ) 7.2
Hz, 3 H), 0.75 (t, J ) 7.6 Hz, 3 H); 13C NMR (75 MHz, CDCl3)
δ 202.6 (C), 147.9 (CH), 135.8 (C), 36.9 (CH2), 35.1 (CH), 29.7
(CH2), 27.2 (CH2), 22.4 (CH2), 19.6 (CH3), 13.9 (CH3), 11.8 (CH3),
11.5 (CH3); HRMS (70 eV) calcd for C12H22O 182.1671, found
182.1676; IR (neat) 2960, 1670, 1459, 1056 cm-1; Rf 0.52 (hexane:
EtOAc 10:1).
(E)-1-Chloro-3,5-dimethylhept-3-en-2-one (6d): yellow oil; 1H
NMR (200 MHz, CDCl3) δ 6.39 (dd, J ) 9.7, 1.1 Hz, 1 H), 4.45
(s, 2 H), 2.58-2.48 (m, 1 H), 1.85 (s, 3 H), 1.53-1.37 (m, 2 H),
1.05 (d, J ) 6.6 Hz, 3 H), 0.89 (t, J ) 6.5 Hz, 3 H); 13C NMR (75
MHz, CDCl3) δ 192.8 (C), 150.5 (CH), 133.8 (C), 45.0 (CH2), 33.4
(CH), 31.5 (CH2), 19.5 (CH3), 14.0 (CH3), 11.8 (CH3); HRMS (70
eV) calcd for C9H15ClO 174.0811, found 178.0815; IR (neat) 3406,
1443, 1266, 739 cm-1; Rf 0.30 (hexane:EtOAc 20:1).
General Procedure for the Synthesis of Aldehydes 7. A
solution of LiAlH4 (1.0 mmol, 1.5 M in THF) was added dropwise
to a mixture of the corresponding morpholine amide 3 (1 mmol)
in THF (4 mL) at -78 °C. Then the mixture was stirred for 12 h
and quenched with an ice/water mixture (10 mL), followed by
extraction with diethyl ether (2 × 10 mL). Usual workup provided
crude products, which were purified by flash column chromatog-
raphy on silica gel (hexane:EtOAc 10:1).
Compounds 7a,29 7b,30 and 7c30 displayed analytical data in
accordance with the published values or with those of the
commercial sample.
General Procedure for the Synthesis of Carboxylic Acids 8.
A slurry of potassium tert-butoxide (3.0 mmol), water (1.0 mmol),
and the corresponding amide 3 (0.5 mmol) in THF (4 mL) was
stirred vigorously at reflux for 12 h. After that time, the reaction
mixture was cooled with an ice bath and a mixture of ice/water
(10 mL) was added. The organic layer was separated and the
aqueous layer was extracted with diethyl ether (2 × 10 mL). Usual
workup provided crude products, which were purified by flash
column chromatography on silica gel (hexane:EtOAc 1:1).
Compounds 8a,2 8b,30 and 8c30displayed analytical data in
accordance with the published values or with those of the
commercial sample.
(E)-N,N-Diethyl-2,5-dimethylhex-2-enamide (3s): colorless oil;
1H NMR (400 MHz, CDCl3) δ 5.47 (t, J ) 7.1 Hz, 1 H), 3.35 (q,
J ) 6.9 Hz, 2 H), 3.29 (q, J ) 7.1 Hz, 2 H), 1.94-1.90 (m, 2 H),
1.85 (s, 3 H), 1.66-1.59 (m, 1 H), 1.12-1.10 (m, 6 H), 0.85 (d, J
) 6.4 Hz, 6 H); 13C NMR (75 MHz, CDCl3) δ 164.8 (C), 132.4
(C), 128.5 (CH), 42.8 (CH2), 38.5 (CH2), 36.7 (CH2), 28.6 (CH),
22.7 (2 × CH3), 14.9 (CH3), 14.5 (CH3), 12.9 (CH3); MS (70 eV,
EI) m/z (%) 197 [M+, 12], 140 (100), 125 (69), 55 (51); HRMS
(70 eV) calcd for C12H23NO 197.1780, found 197.1782; IR (neat)
2942, 1620, 1615, 1369 cm-1; Rf 0.39 (hexane:EtOAc 3:1).
(E)-N,N-Diethyl-2-methyl-5-phenylpent-2-enamide (3t): yel-
1
low oil; H NMR (400 MHz, CDCl3) δ 7.39-7.21 (m, 5 H), 5.49
(t, J ) 7.4 Hz, 1 H), 3.35 (q, J ) 7.1 Hz, 2 H), 3.13 (q, J ) 7.0
Hz, 2 H), 2.73 (t, J ) 7.6 Hz, 2 H), 2.43 (apparent q, J ) 7.4 Hz,
2 H), 1.76 (s, 3 H), 1.11 (t, J ) 7.1 Hz, 3 H), 1.02 (t, J ) 7.0 Hz,
3 H); 13C NMR (100 MHz, CDCl3) δ 173.1 (C), 141.3 (C), 132.2
(C), 128.2 (2 × CH), 128.1 (2 × CH), 127.8 (CH), 125.8 (CH),
42.3 (CH2), 38.1 (CH2), 34.7 (CH2), 29.1 (CH2), 14.5 (CH3), 14.1
(CH3), 12.5 (CH3); MS (70 eV, EI) m/z (%) 245 [M+, 21], 173
(55), 140 (100), 91 (74); HRMS (70 eV) calcd for C16H23NO
245.1780, found 245.1782; IR (neat) 3441, 2933, 1621, 1454, 700
cm-1; Rf 0.15 (hexane:EtOAc 3:1).
1
(E)-2-Benzyl-N,N-diethyldec-2-enamide (3v): orange oil; H
NMR (400 MHz, CDCl3) δ 7.28-1.67 (m, 5 H), 5.45 (t, J ) 7.2
Hz, 1 H), 3.67 (s, 2 H), 3.26 (q, J ) 6.9 Hz, 2 H), 2.81 (apparent
q, J ) 6.9 Hz, 2 H), 2.27 (q, J ) 6.5 Hz, 2 H), 1.43-1.41 (m, 2
H), 1.31-1.26 (m, 8 H), 0.95 (t, J ) 6.9 Hz, 3 H), 0.87 (t, J ) 6.5
Hz, 3 H), 0.80 (t, J ) 6.9 Hz, 3 H); 13C NMR (100 MHz, CDCl3)
δ 172.2 (C), 138.2 (C), 134.5 (CH), 128.7 (2 × CH), 128.4 (2 ×
CH), 128.3 (C), 126.1 (CH), 41.7 (CH2), 37.9 (CH2), 38.4 (CH2),
31.7 (CH2), 29.2 (3 × CH2), 27.6 (CH2), 22.6 (CH2), 14.2 (CH3),
13.6 (CH3), 11.9 (CH3); MS (70 eV, EI) m/z (%) 315 [M+, 13],
232 (100), 204 (97), 91 (57), 72 (45); HRMS (70 eV) calcd for
C21H33NO 315.2562, found 315.2593; IR (neat) 3402, 2934, 1610,
909 cm-1; Rf 0.39 (hexane:EtOAc 5:1).
Acknowledgment. We thank the Ministerio de Educacio´n
y Ciencia (CTQ2004-1191/BQU) for financial support. J.M.C.
thanks to his wife, Carmen Ferna´ndez-Flo´rez, for her time.
H.R.S. and C.C. thank the Ministerio de Educacio´n y Ciencia
for a Ramo´n y Cajal Contract (Fondo Social Europeo) and a
predoctoral FPI fellowship, respectively. Our thanks to Mr. Euan
C. Goddard (University of Oxford) for his revision of the
English.
(E)-2-Benzyl-N,N-diethyltrideca-2,12-dienamide (3w): yellow
1
oil; H NMR (300 MHz, CDCl3) δ 7.27-7.16 (m, 5 H), 5.89-
5.76 (m, 1 H), 5.49 (t, J ) 7.2 Hz, 1 H), 5.03-4.93 (m, 2 H), 3.67
(s, 2 H), 3.14-2.90 (m, 4 H), 2.27 (q, J ) 7.1 Hz, 1 H), 2.06
(apparent q, J ) 6.9 Hz, 2 H), 1.51-1.28 (m, 13 H), 0.98 (t, J )
7.1 Hz, 6 H); 13C NMR (100 MHz, CDCl3) δ 172.3 (C), 139.1
(CH), 135.2 (C), 129.1 (C), 129.0 (CH), 128.9 (2 × CH), 128.3 (2
× CH), 126.1 (CH), 114.1 (CH2), 41.4 (CH2), 40.4 (CH2), 34.9
(CH2), 33.7 (CH2), 29.5 (CH2), 29.3 (2 × CH2), 29.2 (CH2), 29.0
(CH2), 28.8 (CH2), 27.7 (CH2), 14.0 (CH3), 12.5 (CH3); MS (70
eV, EI) m/z (%) 355 [M+, 36], 216 (100), 130 (28), 91 (16); HRMS
(70 eV) calcd for C24H37NO 355.2875, found 355.2881; IR (neat)
3418, 2927, 1621, 1454, 701 cm-1; Rf 0.30 (hexane:EtOAc 3:1).
General Procedure for the Synthesis of Ketones 6. The
requisite organolithium compound (3.0 mmol) was added dropwise
to the corresponding morpholine amide 3 (1.0 mmol) in THF (4
mL) at -78 °C. After stirring for 30 min the reaction was quenched
with an aqueous saturated solution of NH4Cl (10 mL), followed
by extraction with diethyl ether (3 × 10 mL). Usual workup
Supporting Information Available: General experimental
details and copies of 1H and 13C NMR spectra for all new
compounds 3 and 6. This material is available free of charge via
the Internet at http://pubs.acs.org.
JO701417Z
(28) (a) Compound 6a: Concello´n, J. M.; Rodr´ıguez-Solla, H.; Me´jica,
C. Tetrahedron 2006, 62, 3292-3300. (b) Compound 6b: Trost, B. M.;
Parquette, J. R. J. Org. Chem. 1993, 58, 1579-1581.
(29) Vasil’ev, A.; Engman, L. J. Org. Chem. 2000, 65, 2151-2162.
(30) 1H and 13C NMR spectra of the product obtained were identical
with those of a commercial sample.
J. Org. Chem, Vol. 72, No. 21, 2007 7979