Sequential retro-ene arylation reaction of N-alkoxyenamides for the synthesis of tert -alkylamines

Article abstract of DOI:10.1021/ol4014238

A sequential retro-ene arylation reaction has been developed for the conversion of N-alkoxyenamides to the corresponding tert-alkylamines in good yields via the nucleophilic addition of a triarylaluminum reagent to an in situ generated N-acylketimine. The reaction is tolerant of a range of functional groups and provides facile access to a series of tert-alkylamines that would be otherwise difficult to access using conventional procedures.

Full text of DOI:10.1021/ol4014238

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Sequential Retro-Ene Arylation Reaction
of N‑Alkoxyenamides for the Synthesis
of tert-Alkylamines
Tetsuya Miyoshi, Syota Matsuya, Mikako Tsugawa, Shohei Sato, Masafumi Ueda, and
Okiko Miyata*
Kobe Pharmaceutical University, Motoyamakita, Higashinada, Kobe 658-8558, Japan
miyata@kobepharma-u.ac.jp
Received May 20, 2013
ABSTRACT
A sequential retro-ene arylation reaction has been developed for the conversion of N-alkoxyenamides to the corresponding tert-alkylamines in
good yields via the nucleophilic addition of a triarylaluminum reagent to an in situ generated N-acylketimine. The reaction is tolerant of a range of
functional groups and provides facile access to a series of tert-alkylamines that would be otherwise difficult to access using conventional
procedures.
Biologically active small molecules bearing N-substituted
quaternary carbon atoms (i.e., tert-alkylamines) are ubi-
quitous in natural products and pharmaceuticals.1 Com-
pounds of this type are usually prepared using the Ritter
reaction, where tertiary alcohols or substituted alkenes
capable of generating stable carbocations are treated with
a nitrile-containing species under acidic conditions to give
the corresponding amides, which can then be hydrolyzed
to give the amines.2 These compounds can also be gener-
ated via the reduction of tert-alkyl azides3 or nucleophilic
addition to nitriles.4 Nucleophilic addition to ketimine deri-
vatives also represents a powerful method for the con-
struction of tert-alkylamine derivatives. Unfortunately,
however, N-alkyl and N-arylketimines are limited in
terms of the scope of their reactivity and can only react
successfully with a narrow range of nucleophilic reagents.
In contrast, N-acylketimines are particularly attractive
substrates for the preparation of tert-alkylamine deriva-
tives using the nucleophilic addition reaction because of
their higher electrophilicity, which enables them to over-
come the poor reactivity observed using N-alkyl or
N-arylimines.5 N-Acylketimines 4 have been prepared in
a number of ways, including (1) the reaction of N-silyli-
mines 1 with acyl chlorides;6 (2) the dehydration of
Scheme 1. Methods for the Formation of N-Acylketimines and
Their Nucleophilic Addition Reaction
(1) (a) Kang, S. H.; Kang, S. Y.; Lee, H.-S.; Buglass, A. J. Chem. Rev.
2005, 105, 4537. (b) Funabashi, K.; Ratni, H.; Kanai, M.; Shibasaki, M.
J. Am. Chem. Soc. 2001, 123, 10784. (c) Sarges, R.; Howard, H. R.;
Kelbaugh, P. R. J. Org. Chem. 1982, 47, 4081.
(2) (a) Ritter, J. J.; Minieri, P. P. J. Am. Chem. Soc. 1948, 70, 4045. (b)
Ritter, J. J.; Kalish, J. J. Am. Chem. Soc. 1948, 70, 4048. (c) Jirgensons,
A.; Kauss, V.; Kalvinsh, I.; Gold, M. R. Synthesis 2000, 1709.
(3) (a) Koziara, A.; Osowska-Parewicka, K.; Zawadzki, S.; Zwierzak,
A. Synthesis 1987, 487. (b) Koziara, A.; Zwierzak, A. Tetrahedron Lett.
1987, 28, 6513. (c) Balderman, D.; Kalir, A. Synthesis 1978, 24.
(4) Tomashenko, O.; Sokolov, V.; Tomashevskiy, A.; de Meijere, A.
Synlett 2007, 652.
(5) For reviews, see: (a) Maryanoff, B. E.; Zhang, H.-C.; Cohen,
J. H.; Turchi, I. J.; Maryanoff, C. A. Chem. Rev. 2004, 104, 1431. (b)
Petrini, M.; Torregiani, E. Synthesis 2007, 159.
r
10.1021/ol4014238
XXXX American Chemical Society

hemiaminals 2;7 and (3) the aza-Wittig reaction of ketones
3 with iminophosphoranes (Scheme 1).8 The scope of the
addition reaction of nucleophiles to N-acylketimines is
limited, however, to the use of nontautomerizable N-acyl-
ketimines because tautomerizable N-acylketimines can
readily tautomerize to give the corresponding enamides,
which are more stable.9 For this reason, tautomerizable
N-acylketimines have not been well-utilized for nucleo-
philic addition reactions.10
the addition reaction to give the corresponding tert-alkyl-
amines 10.
Table 1. Optimization of the Retro-Ene Arylation Reaction
yield (%)
Scheme 2. Retro-Ene Arylation Reaction of N-Alkoxyenamides
entry
substrate
R
temp (°C)
12a
13
1
11a
11a
11a
11b
11c
11d
H
rt
À
À
34
À
2
H
50
90
50
50
50
58
50
72
68
30
3b
4
H
Ph
53
67
25
5
4-CF3C6H4
4-MeOC6H4
6
It was envisaged that nucleophilic addition to a tauto-
merizable N-acylketimine could be achieved via the in situ
generation of an N-acylketimine in the presence of a
suitable nucleophile. Herein, we describe the development
of a novel preparative method for the synthesis of
N-acylketimines 8 bearing R-protons via the retro-ene
reaction of the corresponding N-alkoxyenamides 7 and
their subsequent reaction withtriarylaluminum reagents to
afford the tert-alkylamides 9 (Scheme 2). The presence of
the strongly electron-withdrawing trifluoroacetyl group
effectively enhanced the electrophilicity of the imine in this
system, and the group could be readily removed following
a PMP: p-methoxyphenyl. b (CH2Cl)2 was used instead of CH2Cl2.
The reaction of N-methoxyenamide 11a11 with 2.5 equiv
of tris(4-methoxyphenyl)aluminum, which was prepared
from the reaction of trichloroaluminum with 4-methoxy-
phenylmagnesium bromide, was initially selected as a
model reaction to optimize the reaction conditions.12
When the reaction was conducted at ambient temperature,
it did not provide any of the desired product, and only the
starting material was recovered (Table 1, entry 1). Pleasingly,
however, when the reaction was conducted at a tempera-
ture of 50 °C, the tert-alkylamide 12a and 4-methoxy-
benzylalcohol (13a) were obtained in 58 and 34% yields,
respectively (Table 1, entry 2). A further increase in the
reaction temperature to 90 °C led to a minor reduction in
the yield of the reaction (Table 1, entry 3). When we
used 4-methoxyphenylmagnesium bromide instead of tris-
(4-methoxyphenyl)aluminum, a complex mixture was
obtained.
€
(6) (a) Kupfer, R.; Meier, S.; Wurthwein, E.-U. Synthesis 1984, 688.
ꢀ
(b) Vidal, J.; Guy, L.; Sterin, S.; Collet, A. J. Org. Chem. 1993, 58, 4791.
€
(7) (a) Koppen, J.; Matthies, D.; Schweim, H. Liebigs Ann. Chem.
1985, 2383. (b) Osipov, S. N.; Golubev, A. S.; Sewald, N.; Michel, T.;
Kolomiets, A. F.; Fokin, A. V.; Burger, K. J. Org. Chem. 1996, 61, 7521.
(c) Moroni, M.; Koksch, B.; Osipov, S. N.; Crucianelli, M.; Frigerio, M.;
Bravo, P.; Burger, K. J. Org. Chem. 2001, 66, 130. (d) Osipov, S. N.;
Tsouker, P.; Hennig, L.; Burger, K. Tetrahedron 2004, 60, 271. (e)
Skarpos, H.; Vorob’eva, D. V.; Osipov, S. N.; Odinets, I. L.; Breuer,
€
E.; Roschenthaler, G.-V. Org. Biomol. Chem. 2006, 4, 3669. (f) Smits, R.;
The N-alkoxyenamides 11bÀd were used to investigate
the substituent effects ofthe different alkoxy groups. When
N-benzyloxyenamide 11b was used as the substrate, the
reaction proceeded smoothly to afford 12a and 13b in 72
and 53% yields, respectively (Table 1, entry 4). The applica-
tion of the same reaction conditions to substrate 11c
bearing an electron-withdrawing 4-trifluoromethylbenzyl-
oxy group provided similar results (Table 1, entry 5).
In contrast, the application of the reaction conditions to
substrate 11d bearing an electron-donating 4-methoxy-
benzyloxy group resulted in lower levels of reactivity and
a poorer yield (Table 1, entry 6).
Cadicamo, C. D.; Burger, K.; Koksch, B. Chem. Soc. Rev. 2008, 37,
1727. (g) Maisch, D.; Wadhwani, P.; Afonin, S.; Bottcher, C.; Koksch,
B.; Ulrich, A. S. J. Am. Chem. Soc. 2009, 131, 15596.
€
(8) (a) Versleijen, J. P.; Hovens, M. S. S.; Vanhommerig, S. A.;
Vekemans, J. A.; Meijer, E. M. Tetrahedron 1993, 49, 7793. (b) Bravo,
P.; Fustero, S.; Guidetti, M.; Volonterio, A.; Zanda, M. J. Org. Chem.
1999, 64, 8731. (c) Armstrong, A.; Jones, L. H.; Knight, J. D.; Kelsey,
R. D. Org. Lett. 2005, 7, 713. (d) Yan, W.; Wang, D.; Feng, J.; Li, P.;
Zhao, D.; Wang, R. Org. Lett. 2012, 14, 2512.
(9) (a) Sato, M. J. Org. Chem. 1961, 26, 770. (b) Colvin, D. M.; Uff,
B. C. Tetrahedron Lett. 1966, 7, 6079. (c) Mecozzi, T.; Petrini, M. Synlett
2000, 73. (d) Matsubara, R.; Vital, P.; Nakamura, Y.; Kiyohara, H.;
Kobayashi, S. Tetrahedron 2004, 60, 9769.
(10) Nucleophilic addition reaction to N-acylaldimines are known:
(a) Pesenti, C.; Bravo, P.; Corradi, E.; Frigerio, M.; Meille, S. V.;
Panzeri, W.; Viani, F.; Zanda, M. J. Org. Chem. 2001, 66, 5637. (b)
ꢀ
Palomo, C.; Oiarbide, M.; Landa, A.; Gonzalez-Rego, M. C.; Garcia,
(11) Preparation of N-alkoxyenamides 11a: To a solution of cyclo-
hexanone O-methyl oxime (551 mg, 4.3 mmol) in CH2Cl2 (20 mL) was
added TFAA (1.2 mL, 8.6 mmol) dropwise at 0 °C. After stirring for 4 h,
the reaction mixture was concentrated under reduced pressure. The
crude product was purified by flash column chromatography (hexane/
AcOEt = 50/1) to give 11a (921 mg, 96%).
(12) Triarylaluminum reagents were prepared the same as in our
previous work. See: (a) Miyoshi, T.; Miyakawa, T.; Ueda, M.; Miyata,
O. Angew. Chem., Int. Ed. 2011, 50, 928. (b) Miyoshi, T.; Sato, S.;
Tanaka, H.; Hasegawa, C.; Ueda, M.; Miyata, O. Tetrahedron Lett.
2012, 53, 4188.
ꢀ
J. M.; Gonzalez, A.; Odarizola, J. M.; Martin-Pastor, M.; Linden, A. J.
Am. Chem. Soc. 2002, 124, 8637. (c) Ballini, R.; Petrini, M. Tetrahedron
2004, 60, 1017. (d) Pesenti, C.; Arnone, A.; Arosio, P.; Frigerio, M.;
Meille, S. V.; Panzeri, W.; Viani, F.; Zanda, M. Tetrahedron Lett. 2004,
ꢀ
45, 5125. (e) Palomo, C.; Oiarbide, M.; Laso, A.; Lopez, R. J. Am. Chem.
Soc. 2005, 127, 17622. (f) Bernardi, L.; Fini, F.; Herrera, R. P.; Ricci, A.;
Sgarzani, V. Tetrahedron 2006, 62, 375. (g) Enders, D.; Vrettou, M.
Synthesis 2006, 2155. (h) Matsuo, J.-i.; Tanaki, Y.; Ishibashi, H. Org.
Lett. 2006, 8, 4371. (i) Yin, B.; Zhang, Y.; Xu, L.-W. Synthesis 2010,
3583. (j) Suh, Y.-G.; Jang, J.; Yun, H.; Han, S. M.; Shin, D.; Jung, J.-K.;
Jung, J.-W. Org. Lett. 2011, 13, 5920.
B
Org. Lett., Vol. XX, No. XX, XXXX

that the magnesium salt played an important role in this
reaction. The tris(p-tolyl)aluminum and tris(4-fluoro-
phenyl)aluminum reagents also performed well under the
optimized conditions to give the desired amides 12c and
12d in relatively good yields (Table 2, entries 3 and 4,
respectively).
Table 2. Sequential Retro-Ene Arylation Reactions of a Variety
of Different N-Alkoxyenamides
Various cyclic and acyclic N-alkoxyenamides were then
investigated under the optimized reaction conditions to
further expand the scope of the reaction (Table 2, entries
5À11). To evaluate the impact of the ring size of cyclic
enamides, a substrate bearing a cyclopentenyl group 11e
and a substrate bearing a cycloheptenyl group 11f were
subjected to the optimized reaction conditions (Table 2,
entries 5 and 6, respectively). When the substrate bearing a
cyclopentenyl group was subjected to the reaction condi-
tions, the desired product was obtained in a 45% yield
following an extended reaction time of 15 h (Table 2,
entry 5). In contrast, the substrate bearing a cycloheptenyl
group gave the corresponding amide in 70% yield follow-
ing a reaction time of only 3 h (Table 2, entry 6). The
reactions of the enamides 11gÀi, which contained sub-
stituents on their cyclohexene rings, were also examined
(Table 2, entries 7À9). The results revealed that certain
functional groups were well-tolerated under the optimized
reaction conditions, such as an ethyl ester and an acetal.
Compared with 11b, the linear benzyloxyenamides 11j and
11k required extended reaction times to afford the desired
amides in moderate yields (Table 2, entries 10 and 11).
a Reaction was carried out with commercially available Ph3Al.
b Starting material 11b was recovered in 41% yield. c Commercially
available Ph3Al with MgBr2 improved the yield of product to 50%.
With an optimized procedure in hand, we proceeded to
examine the scope of the reaction by reacting 11b with a
range of different triarylaluminum reagents (Table 2,
entries 1À4). The use of the triphenylaluminum prepared
in situ gave similar results to those observed above for
the tris(4-methoxyphenyl)aluminum reagent (Table 2,
entry 1). In contrast, the use of the commercially available
triphenylaluminum reagent led to a significant reduction
in the yield of amide 12b (Table 2, entry 2). The commer-
cially available triphenylaluminum reagent with MgBr2
gave the product in 50% yield. These results demonstrated
Various reaction conditions were also examined in an
attempt to develop a deeper understanding of the reaction
and elucidate the mechanism of the reaction. When the
alkoxyenamide 11b was treated with magnesium bromide
at 50 °C, the NÀO bond was cleaved to give enamide 14
and benzaldehyde (15) in 68 and 35% yields, respectively
(eq 1). When the reaction was conducted in the absence of
magnesium bromide, the enamide 14 was obtained in a
much lower yield of only 7%, with 68% of the starting
material also being recovered. These results demonstrated
Org. Lett., Vol. XX, No. XX, XXXX
C

that the magnesium salt was critical to the retro-ene step of
the reaction, and that the enamide 14 could be an inter-
mediate in this reaction. Interestingly, however, when the
enamide 14 was subjected to the optimized conditions, no
reaction was observed (eq 2). Deuterium labeling experi-
ments were also conducted to investigate the mechanism of
this transformation. The deuterated alkoxyenamide 16 was
treated with tris(4-methoxyphenyl)aluminum that had
been generated in situ at 50 °C and gave the β-deuterated
amide 17 in a 50% yield (eq 3).
To complete this work, we proceeded to investigate the
removal of the trifluoroacetyl group to afford the corre-
sponding tert-alkylamine 21. When the trifluoroacetamide
12b was treated with NaOH in methanol, the tert-alkyl-
amine 21 was obtained in 91% yield (Scheme 4). The
cleavage conditions were also successfully applied to
trifluoroacetamide 12h, whichcontainedanacetal-protect-
ing group, to give the desired tert-alkylamine product 22 in
good yield.
Scheme 4. Removal of the Trifluoroacetyl Group
Scheme 3. Plausible Reaction Pathway
In conclusion, we have successfully developed a new
retro-ene reaction for the conversion of N-alkoxyenamides
to tautomerizable N-acylketimines. The resulting N-acyl-
ketimines were immediately arylated withtriarylaluminum
reagents to afford the corresponding tert-alkylamides
following the removal of the trifluoroacetyl group. This
reaction represents a new procedure for accessing
N-acylketimines. Further applications for this in situ gen-
erated N-acylimine are currently being investigated in our
laboratory.
On the basis of these results, we have proposed a
plausible reaction mechanism, as shown in Scheme 3.
Although the role of the magnesium salt remains unclear,
it is envisaged that the magnesium would coordinate with
the oxygen atoms of the carbonyl and alkoxy groups to
inhibit the free rotation of alkoxy groups and effectively fix
the conformation in a way that way favors the retro-ene
reaction. The NÀO bond would then be cleaved, fol-
lowed by a 1,5-hydrogen shift to give the N-acylimine
19 and benzaldehyde (15). The retro-ene reaction with
concomitant NÀO bond cleavage would proceed
smoothly because of the formation of a strong CdO
bond at the expense of the energy required to break the
weak NÀO bond.13 The aryl groups would then add to
the N-acylimine immediately before the occurrence of
any tautomerization to the corresponding enamide.
The benzaldehyde (15) also reacted with triarylalumi-
num to give the alcohol 13.
Acknowledgment. We are grateful for a Grant-in-Aid
for Young Scientists (B) from the Japan Society for the
Promotion of Science and the MEXT-Supported Pro-
gram for the Strategic Research Foundation at Private
Universities.
Supporting Information Available. Experimental meth-
ods and NMR spectra of products. This material is
available free of charge via the Internet at http://pubs.
acs.org.
(13) (a) Kleier, D. A.; Pilgram, K. H. J. Heterocycl. Chem. 1987, 24,
1643. (b) Saczewski, J.; Brzozowski, Z.; Gdaniec, M. Tetrahedron 2005,
61, 5303.
)
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX