Direct chemoselective allylation of inert amide carbonyls

Article abstract of DOI:10.1021/ol3000316

Direct allylation of inert amide carbonyls utilizing the Schwartz reagent afforded either substituted tertiary or secondary amines. A preactivation step was successfully avoided, which is generally a requisite to increase the electrophilicity of amides. The reaction exhibited remarkable functional group tolerance and proceeded even in the presence of methyl esters and nitro groups.

Full text of DOI:10.1021/ol3000316

ORGANIC
LETTERS
2012
Vol. 14, No. 3
950–953
Direct Chemoselective Allylation of Inert
Amide Carbonyls
Yukiko Oda, Takaaki Sato,* and Noritaka Chida*
Department of Applied Chemistry, Faculty of Science and Technology, Keio University,
3-14-1, Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan
takaakis@applc.keio.ac.jp; chida@applc.keio.ac.jp
Received January 6, 2012
ABSTRACT
Direct allylation of inert amide carbonyls utilizing the Schwartz reagent afforded either substituted tertiary or secondary amines. A preactivation
step was successfully avoided, which is generally a requisite to increase the electrophilicity of amides. The reaction exhibited remarkable
functional group tolerance and proceeded even in the presence of methyl esters and nitro groups.
Nucleophilic addition to carbonyl groups, such as ke-
tones and esters, is one of the most fundamental transfor-
mations in organic synthesis.1 However, the reaction with
amide carbonyls remains a formidable challenge because
of their high stability caused by the resonance effect of the
nitrogen atom. Assuming a high yielding access to amide
groups,2 direct chemoselective nucleophilic addition to
the amide carbonyls would undoubtedly offer an opportu-
nity for widespread applications in the synthesis of natural
products and pharmaceuticals. However, direct nucleophi-
lic addition to amide carbonyls requires harsh reaction
conditions, which limits the substrate scope. Acyclic amides
are especially challenging substrates because the intermedi-
ates readily undergo hydrolysis.3 Thus, general approaches
for the functionalization of acyclic amides currently rely on
a preactivation step of the inert amide carbonyl (Scheme 1,
1f2∼4) and use of reactive nucleophiles such as DIBAL,
Grignard reagents, and organolithium reagents (2∼4f5).
A preactivation step increases the electrophilicity by redu-
cing the resonance effect of the amide nitrogen via imide 2
(DeNinno4 and Suh5) or thioamide 3 (Murai6). Recently,
Belanger7c,f and Huang7d,e reported a practical one-pot
ꢀ
(4) (a) DeNinno, M. P.; Eller, C. Tetrahedron Lett. 1997, 38, 6545–
6548. (b) DeNinno, M. P.; Eller, C.; Etienne, J. B. J. Org. Chem. 2001, 66,
6988–6993.
(5) (a) Suh, Y.-G.; Shin, D.-Y.; Jung, J.-K.; Kim, S.-H. Chem.
Commun. 2002, 1064–1065. (b) Suh, Y.-G.; Kim, S.-H.; Jung, J.-K.;
Shin, D.-Y. Tetrahedron Lett. 2002, 43, 3165–3167. (c) Jung, J.-W.; Shin,
D.-Y.; Seo, S.-Y.; Kim, S.-H.; Paek, S.-M.; Jung, J.-K.; Suh, Y.-G.
Tetrahedron Lett. 2005, 46, 573–575.
(6) (a) Murai, T.; Mutoh, Y.; Ohta, Y.; Murakami, M. J. Am. Chem.
Soc. 2004, 126, 5968–5969. (b) Murai, T.; Asai, F. J. Am. Chem. Soc.
2007, 129, 780–781. For other selected examples on nucleophilic
additions to acyclic thioamides, see: (c) Tamaru, Y.; Harada, T.; Nishi,
S.; Yoshida, Z. Tetrahedron Lett. 1982, 23, 2383–2386. (d) Ishida, A.;
Nakamura, T.; Irie, K.; Oh-ishi, T. Chem. Pharm. Bull. 1985, 33, 3237–
3249. (e) Tominaga, Y.; Kohra, S.; Hosomi, A. Tetrahedron Lett. 1987,
28, 1529–1532. (f) Tominaga, Y.; Matsuoka, Y.; Hayashida, H.; Kohra,
S.; Hosomi, A. Tetrahedron Lett. 1988, 29, 5771–5774.
(1) For a review on functionalization of carbonyl groups in ketones,
esters, and amides, see: Seebach, D. Angew. Chem., Int. Ed. 2011, 50,
96–101.
(2) For selected recent reviews on amide bond formation, see:
(a) Humphrey, J. M.; Chamberlin, A. R. Chem. Rev. 1997, 97, 2243–
ꢀ
2266. (b) Albericio, F.; Chinchilla, R.; Dodsworth, D. J.; Najera, C. Org.
Prep. Proced. Int. 2001, 33, 203–313. (c) Han, S.-Y.; Kim, Y.-A.
Tetrahedron 2004, 60, 2447–2467. (d) Montalbetti, C. A. G. N.; Falque,
V. Tetrahedron 2005, 61, 10827–10852. (e) Valeur, E.; Bradley, M. Chem.
Soc. Rev. 2009, 38, 606–631.
(7) For selected examples on nucleophilic addition to acyclic amides
via iminium triflates, see: (a) Magnus, P.; Payne, A. H.; Hobson, L.
Tetrahedron Lett. 2000, 41, 2077–2081. (b) Magnus, P.; Gazzard, L.;
Hobson, L.; Payne, A. H.; Rainey, T. J.; Westlund, N.; Lynch, V.
Tetrahedron 2002, 58, 3423–3443. (c) Larouche-Gauthier, R.;
(3) For selected examples on direct conversion of acyclic amides to R,
R-dimethylamines, see: (a) Kuffner, F.; Polke, E. Monatsh 1951, 82
€
330–335. (b) Schiess, M. Diss. ETH Nr. 7935, ETH: Zurich, 1986. (c)
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Calderwood, D. J.; Davies, R. V.; Rafferty, P.; Twigger, H. L.; Whelan, H. M.
Tetrahedron Lett. 1997, 38, 1241–1244. (d) Denton, S. M.; Wood, A.
Synlett 1999, 55–56. (e) Tomashenko, O.; Sokolov, V.; Tomashevskiy,
A.; Buchholz, H. A.; Welz-Biermann, U.; Chaplinski, V.; de Meijere, A.
Eur. J. Org. Chem. 2008, 5107–5111.
Belanger, G. Org. Lett. 2008, 10, 4501–4504. (d) Xiao, K.-J.; Luo,
J.-M.; Ye, K.-Y.; Wang, Y.; Huang, P.-Q. Angew. Chem., Int. Ed. 2010,
49, 3037–3040. (e) Xiao, K.-J.; Wang, Y.; Ye, K.-Y.; Huang, P.-Q. Chem.;
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Eur. J. 2010, 16, 12792–12796. (f) Belanger, G.; O’Brien, G.; Larouche-
Gauthier, R. Org. Lett. 2011, 13, 4268–4271.
r
10.1021/ol3000316
Published on Web 01/19/2012
2012 American Chemical Society

nucleophilic addition via iminium triflate 4.7 Although the
preactivation step enhances the electrophilicity of the amide
carbonyls, it costs an extra operation and still requires re-
active nucleophiles, which renders the reaction conditions
incompatible with sensitive functional groups.
imine 11.13 We expected that imine 11 would be amenable to
one-pot allylation, providing the secondary amine 12. The
reaction conditions we developed were found to be highly
chemoselective, enabling the direct allylation of either tertiary
or secondary amides in the presence of sensitive functional
groups.
Scheme 1. Nucleophilic Addition to Amide Carbonyl Groups
via the Preactivation Step
Scheme 2. (A) Direct Allylation of Tertiary Amides without the
Preactivation Step; (B) Direct Allylation of Secondary Amides
without the Preactivation Step.
As part of our ongoing studies aimed at exploring direct
functionalization of inert amide carbonyls, our group8a and
that of Vincent/Kouklovsky8b independently reported the
novel sequential nucleophilic addition to N-alkoxyamides via
a five-membered chelated intermediate.8 In this methodol-
ogy, exclusion of the preactivation step was achieved with
assistance of the N-alkoxy group. In this paper, we descri
be the development of a direct chemoselective allylation9
of inert amide carbonyls using the Schwartz reagent
(Cp2ZrHCl),10,11 which enables us to functionalize amide
groups directly without supporting functional groups
(Scheme 2). When tertiary amides such as 1 are exposed to
the Schwartz reagent at room temperature, they are known
to produce the zirconacycle intermediate 6, which affords
the corresponding aldehyde 7 after workup.12 We predicted
that addition of an acid to 6 in one pot would initiate the
generation of iminium ion 8 instead of aldehyde 7. The
resulting iminium ion 8 could undergo subsequent allylation
to give substituted tertiary amine 9 in a single step. On the
other hand, reduction of the secondary amide 10 mech-
anistically requires 2 equiv of the Schwartz reagent, providing
Our direct allylation of tertiary amides was first evalu-
ated with N-benzyl-N-methylbenzamide 1a (Table 1).14
Treatment of 1a in (CH2Cl)2 with Schwartz reagent, which
was freshly prepared from Red-Al and Cp2ZrCl2 in
THF,10b quickly gave zirconacycle 6a. The subsequent
allylation withallyltributylstannane, inthe absenceofacid,
provided the desired product 9a in 9% yield, along with
a significant amount of benzaldehyde 7a (Table 1, entry 1).
This result indicated that iminium ion 8a (shown in
Scheme 2) was not efficiently formed without an acid. We
then investigated the effect of different acids, which could
potentially mediate the formation of both iminium ion 8a
and aldehyde 7a from the common zirconacycle 6a. In-
deed, the allylation with Sc(OTf)3 produced tertiary amine
9a in 36% yield and secondary alcohol 13a in 34% yield
(Table 1, entry 2). The selectivity depended greatly on the
(8) (a) Shirokane, K.; Kurosaki, Y.; Sato, T.; Chida, N. Angew.
Chem., Int. Ed. 2010, 49, 6369–6372. (b) Vincent, G.; Guillot, R.;
Kouklovsky, C. Angew. Chem., Int. Ed. 2011, 50, 1350–1353. Kibayashi
reported pioneering work involving Grignard addition and subsequent
hydride reduction to six-membered N-alkoxylactams; see: Iida, H.;
Watanabe, Y.; Kibayashi, C. J. Am. Chem. Soc. 1985, 107, 5534–5535.
(9) For selected reviews on allylation to iminium intermediates, see:
(a) Yamamoto, Y.; Asao, N. Chem. Rev. 1993, 93, 2207–2293.
(b) Puentes, C. O.; Kouznetsov, V. J. Heterocycl. Chem. 2002, 39, 595–
614.
nature of the acid. When BF3 Et2O was utilized, both yield
3
and selectivity were improved to produce 9a in 58% yield,
along with 13a in 9% yield (Table 1, entry 3). After an
extensive survey of Lewis acids and Brønsted acids, TFA
proved to be the best acid with 9a isolated in 75% yield
(10) (a) Wailes, P. C.; Weigold, H. J. Organomet. Chem. 1970, 24,
405–411. (b) Hart, D. W.; Schwartz, J. J. Am. Chem. Soc. 1974, 96, 8115–
8116.
(11) For selected reviews on the Schwartz reagent, see: (a) Negishi, E.;
Takahashi, T. Synthesis 1988, 1–19. (b) Hoveyda, A. H.; Morken, J. P.
Angew. Chem., Int. Ed. 1996, 35, 1262–1284. (c) Wipf, P.; Jahn, H.
Tetrahedron 1996, 52, 12853–12910. (d) Wipf, P.; Nunes, R. L. Tetra-
hedron 2004, 60, 1269–1279.
(14) As a control experiment, tertiary amide 1a was reduced with
DIBAL (1.3 equiv) at À78 °C, and subsequent treatment with Sc(OTf)3
(1.3 equiv) and allyltributylstannane (3 equiv) at room temperature
afforded 9a in 21% yield, along with overreduced byproduct 14 in 32%
yield. These results indicated that the N,O-acetal after DIBAL reduction
was quickly converted to the iminium ion, which underwent extra
DIBAL reduction to provide 14.
(12) (a) White, J. M.; Tunoori, A. R.; Georg, G. I. J. Am. Chem. Soc.
2000, 122, 11995–11996. (b) Spletstoser, J. T.; White, J. M.; Tunoori,
A. R.; Georg, G. I. J. Am. Chem. Soc. 2007, 129, 3408–3419.
(13) (a) Schedler, D. J. A.; Godfrey, A. G.; Ganem, B. Tetrahedron
Lett. 1993, 34, 5035–5038. (b) Schedler, D. J. A.; Li, J.; Ganem, B. J. Org.
Chem. 1996, 61, 4115–4119.
Org. Lett., Vol. 14, No. 3, 2012
951

(Table 1, entry 4). Addition of MeCN prior to the allyla-
tion gave a slightly better yield (Table 1, entry 5).
nature of the allylation reagents was found to be critical in
determining the selectivity between the secondary
amine 12a and secondary alcohol 13a. While the use
of allylboronicacid pinacol ester gave 13a exclusively,
allylindium bromide afforded secondary amide 12a as
the major product (Table 3, entries 1 and 2). We found
that the best result in terms of both selectivity and
yield was obtained when using allylzinc bromide
(Table 3, entry 3: method A). As alternative conditions,
TMSOTf-mediated allylation using allyltributylstan-
nane showed complete selectivity and good yield
(Table 3, entry 4: method B).
Table 1. Optimization of the Reaction Conditions in the Direct
Allylation of Tertiary Amides 1aa
yield (%)b
entry
acid
none
additive
9a
13a
Table 2. Substrate Scope in the Direct Allylation of Tertiary
Amide 1a
1
2
3
4
5
none
none
none
none
MeCN
9
0
Sc(OTf)3
36
56
75
77
34
9
BF3 Et2O
3
TFA
TFA
15
6
a Conditions: 1a (150 μmol), Cp2ZrHCl (1.8 equiv in THF),
(CH2Cl)2, rt, 15 min, then CH2dCHCH2SnBu3 (3.0 equiv), acid (1.5
equiv), additive, rt, overnight. b Yield of isolated product after purifica-
tion by column chromatography on silica gel.
The scope of the direct allylation with various acyclic
tertiary amides revealed remarkable functional group tol-
erance (Table 2).15 We succeeded in chemoselective allyla-
tion of the inert amide carbonyls without affecting the more
electrophilic methyl ester to afford 9b in 72% yield (Table 2,
entry 1). The reaction was also compatible with 1c bearing
the sensitive nitro group (Table 2, entry 2). Electron-rich
4-methoxybenzamide 1d and sterically hindered amide 1e
led to a decrease in product yield with the corresponding
benzyl alcohols isolated as byproduct (24% and 17%,
respectively), likely because zirconacycle 6 was not stable
during the reduction, and over-reduction to aldehyde 7
took place (Table 2, entries 3 and 4). The reaction of aliphatic
amides gave rise to better results than aromatic amides.
Allylation of aliphatic amides with, or without, the methyl
ester proceeded in good yield (Table 2, entries 5 and 6).
In contrast to aromatic amides, a variation in steric bulk
on the amine side was possible without a loss in yield
(Table 2, entries 7 and 8). While the reaction with 1h provided
a 1.2:1 mixture of diastereomers in 80% yield, proline-
derived amide 1i gave the product in 77% yield as a single
diastereomer.16
Our next challenge was direct access to secondary amines
from the corresponding secondary amides (Table 3). Be-
cause the reduction of secondary amides with the Schwartz
reagent proceeds in a different manner from that of tertiary
amides as shown in Scheme 2, we needed to develop
different optimized conditions. We first investigated the re-
action using N-benzylbenzamide 10a. After treatment of
10a with the Schwartz reagent, a variety of allylation re-
agents were added tothe resulting imine 11a in one pot. The
a Conditions: 1, Cp2ZrHCl in THF, (CH2Cl)2, rt, 15 min, then
CH2dCHCH2SnBu3, TFA, MeCN, rt, overnight. b Yield of isolated
product after purification by column chromatography on silica gel.
As summarized in Table 4, two useful methods were
applied to each of the secondary amides 10. The high func-
tional selectivity was also observed for secondary amides
bearing the methyl ester and nitro groups (Table 4, entries 1
and 2). In these situations, allyltributylstannane (method B)
was superior to allylzinc bromide (method A) because of its
(15) Calderwood reported R-dimethylation of primary amides in the
presence of a nitrile group; see: ref 3c.
(16) Although 9i was obtained as a single diastereomer, the relative
stereochemistry of 9i was not determined.
952
Org. Lett., Vol. 14, No. 3, 2012

Table 3. Optimization of the Reaction Conditions in the Direct
Allylation of Secondary Amides 10aa
Table 4. Substrate Scope in the Direct Allylation of Secondary
Amides 10a
yield (%)b
entry
M
acid
none
temp (°C)
12a
13a
1
2
3
4
B(pinacol)
InBr
none
0
73
7
none
À78 to rt
0 to rt
rt
56
81
74
ZnBr
none
0
SnBu3
TMSOTf
0
a Conditions: 10a (150 μmol), Cp2ZrHCl (2.6 equiv in THF),
CH2Cl2, rt, 15 min, then CH2dCHCH2M (2.0 equiv), acid (2.0 equiv),
rt, overnight. b Yield of isolated product after purification by column
chromatography on silica gel.
milder nucleophilicity. Method A was found to be more
effective on electron-rich p-methoxybenzamide 10d and
sterically hindered amide 10e (Table 4, entries 3 and 4).
In contrast to the tertiary amides shown in Table 2,
aliphatic secondary amides tended to give relatively
lower yields than aromatic secondary amides (Table 4,
entries 5 and 6). Method A was preferable for aliphatic
amide 10f (Table 4, entry 5). Variation in the steric bulk
on the amine side was possible without detrimental
effects on yield (Table 4, entry 6).
a Conditions: 10, Cp2ZrHCl in THF, CH2Cl2, À20 °C to rt, 4 h, then
<method A> CH2dCHCH2ZnBr, THF, 0 °C to rt, overnight or <meth-
od B> CH2dCHCH2SnBu3, TMSOTf, rt, overnight. b Yield of isolated
product after purification by column chromatography on silica gel.
In conclusion, we have developed a direct allylation re-
action of inert amide carbonyls by taking advantage of the
properties of the Schwartz reagent. The methodology af-
forded either substituted tertiary amines or secondary amines
from the corresponding amides without a preactivation step,
which is generally required to increase the electrophilicity of
amide carbonyls. A conspicuous feature of the direct allyla-
tion was its high chemoselectivity. The reaction conditions
allowed us to perform functionalization of inert amides even
in the presence of more electrophilic esters or sensitive nitro
groups. Studies in which a carbon nucleophile is introduced
in the first step, instead of the hydride, as well as the intro-
duction of a variety of nucleophiles in the second step, will be
forthcoming.
Acknowledgment. This research was supported by a
Grant-in-Aid for Young Scientists (B) from MEXT
(21750049), and the Otsuka Pharmaceutical Co. Award in
Synthetic Organic Chemistry, Japan. We thank Dr. Takeshi
Noda and Takuya Shimogaki, Kanagawa Institute of Tech-
nology, for their assistance with mass spectrometric analysis.
Supporting Information Available. Experimental pro-
cedures; copies of 1H and 13C NMR spectra of new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 3, 2012
953