Facile allylation of N-Boc and N-Cbz imines with allyltrichlorosilane promoted by DMF

Article abstract of DOI:10.1080/00397910701860422

Facile allylation of various N-Boc and N-Cbz imines with allyltrichlorosilane has been effected using N,N-dimethylformamide (DMF) as the activator. The N-Boc and N-Cbz homoallylic amines were obtained in good to high yields under mild conditions. Copyrigh

Full text of DOI:10.1080/00397910701860422

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Facile Allylation of N‐Boc and N‐Cbz Imines
with Allyltrichlorosilane promoted by DMF
Pengcheng Wu a b c & Jian Sun a
a Natural Products Research Center, Chengdu Institute of Biology, Chinese
Academy of Sciences , Chengdu, China
b Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences ,
Chengdu, China
c Graduate School of Chinese Academy of Sciences , Beijing, China
Published online: 12 Mar 2008.
To cite this article: Pengcheng Wu & Jian Sun (2008) Facile Allylation of N‐Boc and N‐Cbz Imines with
Allyltrichlorosilane promoted by DMF, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 38:7, 1003-1010, DOI: 10.1080/00397910701860422
To link to this article: http://dx.doi.org/10.1080/00397910701860422
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Synthetic Communicationsw, 38: 1003–1010, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701860422
Facile Allylation of N-Boc and N-Cbz Imines
with Allyltrichlorosilane promoted by DMF
Pengcheng Wu1,2,3 and Jian Sun1
1Natural Products Research Center, Chengdu Institute of Biology,
Chinese Academy of Sciences, Chengdu, China
2Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences,
Chengdu, China
3Graduate School of Chinese Academy of Sciences, Beijing, China
Abstract: Facile allylation of various N-Boc and N-Cbz imines with allyltrichlorosi-
lane has been effected using N,N-dimethylformamide (DMF) as the activator. The
N-Boc and N-Cbz homoallylic amines were obtained in good to high yields under
mild conditions.
Keywords: Allylation, allyltrichlorosilane, N-Boc imines, N-Cbz imines, DMF
INTRODUCTION
Homoallylic amines are important precursors to versatile nitrogen-containing
compounds of biological importance, and hence continuous efforts have been
devoted to the development of methods for the preparation of these
compounds.[1–4] The allylation of imines has been widely recognized as a
direct and efficient method for the synthesis of homoallylic amines.[2] Among
various allylic reagents used for the allylation of imines, allyltrichlorosilane is
a preferable choice because of its easy availability and low toxicity, and it has
been extensively used in the allylation of aldehydes.[3] Kobayashi first reported
that when N,N-dimethylformamide (DMF) or hexamethylphosphoramide
(HMPA) was used as activator, imine equivalents N-acylhydrazones were
Address correspondence to Jian Sun, Natural Products Research Center, Chengdu
Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China.
E-mail: sunjian@cib.ac.cn
1003

1004
P. Wu and J. Sun
smoothly allylated with allyltrichlorosilane to afford homoallylic amines in high
yield undermildreaction conditions.[4] However, simple imines failed to undergo
the same reaction, on the basis of which imines were once believed to be resistant
to allyltrichorosilane.[4] Later, the same research group found that smooth allyla-
tion could occur with N-(o-hydroxylphenyl)imines using DMF, HMPA, or
pyridine N-oxide as activator.[5] The adjacent hydroxy group of these imines
proved to be indispensable for the high reactivity. Thus, the apparent limitation
of the current imine allylation method using allyltrichlorosilane was the special
requirements of the N-substituent of imines, which undoubtedly thwart the use-
fulness of this because removal of these substituents is not trivial. Herein, we
report the first facile allylation of N-Boc and N-Cbz imines[6] with allyltrichoro-
silane as the allylating agent and DMF as the activator.
RESULTS AND DISCUSSION
The tert-butoxycarbonyl group (Boc) is a favorite protection group for amines. It
is easy to install and remove and is quite stable under nonacidic conditions.
Aldimines derived fromN-Boc amines and aldehydes (N-Boc aldimines) are pre-
ferable substrates for nucleophilic additions from the viewpoint of practical
application. Thus, in this study, N-Boc imines were first examined as substrates
for the allylation with allyltrichlorosilane. Initially, 1a was subjected to the ally-
lation with DMF as solvent at 0 8C using 1.5 equiv. of allyltrichlorosilane. To our
delight, the reaction proceeded to give the desired product N-Boc allylamine 2a
in 53% yield in 8 h (entry 1, Table 1). Interestingly, a mixed solvent system of
DMF–CH2Cl2 was found to be favorable to the reaction (entries 2–4), and the
yield varied with different ratios of DMF–CH2Cl2. The highest yield of 80%
was obtained at a DMF–CH2Cl2 ratio of 1:4 (entry 3). In the absence of DMF,
the reaction failed to proceed (entries 5 and 6).
We also examined the effects of several other potential organic activators
on the allylation of N-Boc aldimines (entries 7–10). Surprisingly, although
DMSO, HMPA, and triphenylphosphine were all shown to be effective activa-
tors for the allylation of N-acylhydrazones,[4] none of them exhibited detect-
able activity in the allylation of 1a (entries 7–9); neither did triethylamine
(entry 10). DMF thus seems to be unique as an effective organic activator
for the allylations of N-Boc aldimines. Some other solvents were also
surveyed for the allylation of 1a in the presence of DMF (entries 11–14,
Table 1). Although dichloroethane, toluene, and THF all afforded much
lower yields than CH2Cl2, acetonitrile (CH3CN) gave a slightly better yield
than CH2Cl2 (entry 11 vs. 3) and is hence a suitable solvent.
We next carried out the allylation of various N-Boc aldimines with ally-
trichlorosilane at 0 8C using a mixed solvent of DMF–CH3CN (1:4). As
shown in Table 2, the selected electron-rich and electron-deficient aromatic
imines 1a–l all reacted well to give the desired products 2a–l in good to
excellent yields (entries 1–12).

Allylation of N-Boc and N-Cbz Imines
1005
Table 1. Allylation of N-Boc aldimine with allyltrichlorosilanea
Entry
Activator/solvent
DMF/DMF
DMF/CH2Cl2 (v/v ¼ 1/1)
DMF/CH2Cl2 (v/v ¼ 1/4)
DMF/CH2Cl2 (v/v ¼ 1/9)
-/CH2Cl2
Yield (%)b
1
2
53
62
80
31
0
3
4
5
6
-/CH3CN
0
7
DMSO/CH2Cl2 (v/v ¼ 1/4)
HMPA/CH2Cl2 (v/v ¼ 1/4)
Ph3P ¼ O/CH2Cl2 (2.6 M)
TEA/CH2Cl2 (v/v ¼ 1/4)
DMF/CH3CN (v/v ¼ 1/4)
DMF/Toluene (v/v ¼ 1/4)
DMF/ClCH2CH2Cl (v/v ¼ 1/4)
DMF/THF (v/v ¼ 1/4)
,5
0
8
9
0
10
11
12
13
14
0
84
30
47
,5
aReaction condition: C ¼ 0.2 M: reaction time: 8 h.
bIsolated yield based on imine.
Becasue the N-Cbz group, another well-known useful protection group, is
structurally and electronically similar to the N-Boc group, we also examined
the allylation of N-Cbz aldimines under optimal conditions. As expected,
imines 3a–d also underwent smooth allylation to afford products 4a–d in
good yields (Table 2, entries 13–16).
Notably, when either the aliphatic N-Boc or N-Cbz imine 5 was subjected
to the same reaction conditions, the major product obtained was not the
desired allylation product 6 but a self-condensation product 7 (Scheme 1).[7]
The crotylation of 1a with (E)-crotyltrichlorosilanes was also tested under
similar conditions. As illustrated in Scheme 2, the desired product 8 was
obtained as a syn/anti mixture in good yield at 220 8C. The syn/anti ratio
1
was determined by H NMR analysis. Becasue of severe side reactions, a
much lower yield was achieved at 08C. The poor diastereoselectivity, in
contrast to the high diastereoselectivities observed in the crotylation of
N-acylhydrazones and N-(o-hydroxylphenyl)imines,[3,4] seems to imply that
this reaction proceeds through an open acyclic transition state.
We propose that N-Boc and N-Cbz imines be allylated with allyltrichlor-
osilane through a similar pathway as N-acylhydrazones (Scheme 3).[3] DMF
behaves as a Lewis basic activator. As for the transition state, while the one

1006
P. Wu and J. Sun
Table 2. Allylation of various N-Boc and N-Cbz aldimines with allyltrichlorsilanea
Entry
1
Imine
Product
Yield (%)b
84
2
3
4
93
86
96
5
6
7
8
87
74
66
75
(continued)

Allylation of N-Boc and N-Cbz Imines
Table 2. Continued
1007
Entry
9
Imine
Product
Yield (%)b
78
10
62
11
12
64
68
13
14
15
16
80
65
56
78
aReaction condition: C ¼ 0.2 M.
bIsolated yield based on imine.

1008
P. Wu and J. Sun
Scheme 1.
Scheme 2. 0 8C: yield 37%, syn:anti (5:6); 220 8C: yield 78%, syn:anti (4:6).
proposed for the allylation of N-acylhydrazones is a closed six-membered
cycle,[1c,3] the allylation of N-Boc and N-Cbz imines most likely adopts an
open acyclic transition state given the observed poor stereoselectivity and
the slim possibility of coordination of the nitrogen atom of such imine with
the silicon atom becasue of the strong electron-withdrawing effects of the
Boc and Cbz groups.
In summary, facile allylation of various N-Boc and N-Cbz imines with
allyltrichlorosilane has been effected using DMF as the activator. The
N-Boc and N-Cbz homoallylic amines were obtained in good to high
yields under mild conditions. The asymmetric version of this reaction using
chiral DMF analogs as catalyst[8] is currently under investigation in this
laboratory.
Scheme 3.

Allylation of N-Boc and N-Cbz Imines
1009
EXPERIMENTAL
Typical Experimental Procedure for the Allylation of N-Boc and
N-Cbz Aldimines
Aldimine (0.2 mmol) was dissolved in 0.2 mL of DMF and 0.8 mL of CH3CN.
Allyltrichlorosilane (0.3 mmol) was added dropwise at 0 8C. The reaction was
stirred at 08C overnight and was then quenched with a saturated aqueous
NaHCO3 solution (2 mL) and extracted with ether. The oganic phase was
combined, washed with water and brine, dried over MgSO4, and concentrated
under reduced pressure. The residue was purified by flash-column chromato-
graphy on silica to give the pure product.
ACKNOWLEDGMENT
We are grateful for financial support from the National Natural Science
Foundation of China (Projects 20402014 and 20672107).
REFERENCES
1. For general reviews, see (a) Enders, R. D.; Reinhold, U. Asymmetric synthesis of
amines by nucleophilic 1,2-addition of organometallic reagents to the CN-double
bond. Tetrahedron: Asymmetry 1997, 8, 1895; (b) Bloch, R. Addition of organo-
metallic reagents to C55N bonds: Reactivity and selectivity. Chem. Rev. 1998,
98, 1407; (c) Kobayashi, S.; Sugiura, M.; Ogawa, C. Neutral coordinate-organoca-
talysts in organic synthesis: Allylation of acylhydrazones with allyltrichlorosi-
lanes. Adv. Synth. Catal. 2004, 346, 1023; (d) Ding, H.; Friestad, K. G.
Asymmetric addition of allylic nucleophiles to imino compounds. Synthesis
2005, 17, 2815.
2. For selected recent examples of allylation of imines, see (a) Deng, D.-S.; Liu, P.;
Cai, J.-W. Regio- and diastereoselective three-component syntheses of homo-
allylic amines in aqueous media catalyzed by Brønsted acids. Eur. J. Org.
Chem. 2007, 1594; (b) Das, B.; Laxminarayana, K.; Ravikanth, B.; Ramarao, B.
Efficient synthesis of homoallylic alcohols and amines using 2,4,6-trichloro-
1,3,5-triazine. Tetrahedron Lett. 2006, 51, 9103; (c) Zhao, G.; Li, G.-L. Three-
component synthesis of homoallylic amines promoted by carboxylic acids.
Synthesis 2006, 19, 3189; (d) Smitha, G.; Miriyala, B.; Williamson, J. S. Phospho-
molybodic acid–catalyzed efficient three-component reaction: A facile synthesis
of protected homoallylic amines. Synlett 2005, 839; (e) Ella-Menye, J.-R.;
Dobbs, W.; Billet, M.; Klotz, P.; Mann, A. Unexpected 1,2 syn diastereoselectivity
in the three-component “aza Sakurai–Hosomi” reaction. Tetrahderon Lett. 2005,
46, 1897; (f) Phukan, P. Iodine as a very powerful catalyst for three-component
synthesis of protected homoallylic amines. J. Org. Chem. 2004, 69, 4005;
(g) Yamasaki, S.; Fuji, K.; Wada, R.; Kanai, M.; Shibassaki, M. A general
catalytic allylation using allyltrimethoxysilane. J. Am. Chem. Soc. 2002, 124,
6536.

1010
P. Wu and J. Sun
3. Demark, S. E.; Fu, J. P. Catalytic enantioselective addition of allylic organometal-
lic reagents to aldehydes and ketones. Chem. Rev. 2003, 103, 2763.
4. Sugiura, M.; Robvieux, F.; Kobayashi, S. The first allylation of imines with ally-
trichlorosilanes using neutral coordinate organocatalysts. Synlett 2003, 1748.
5. (a) Kobayashi, S.; Hirabayashi, R. Highly stereoselective synthesis of homoallylic
amines based on addition of allyltrichlorosilanes to benzoyhydrazones under
neutral conditions. J. Am. Chem. Soc. 1999, 121, 6942; (b) Hirabayashi, R.;
Ogawa, C.; Sugiura, M.; Kobayashi, S. Highly stereoselective synthesis of homo-
allylic amines based on addition of allyltrichlorosilanes to benzoylhydrazones.
J. Am. Chem. Soc. 2001, 123, 9493; (c) Ogawa, C.; Sugiura, M.; Kobayashi, S.
Stereoselective synthesis of both syn- and anti-N-tert-alkylamines using highly
stereospecific crotylation of ketone-derived acylhydrazones with crotyltrichlorosi-
lanes. J. Org. Chem. 2002, 67, 5359.
6. Kanazawa, A. M.; Denis, J.; Greene, A. E. Highly stereocontrolled and efficient
preparation of the protected, esterification-ready docetaxel (Taxotere) side chain.
J. Org. Chem. 1994, 59, 1238N-Boc and N-Cbz aldimines were prepared
acoording to the following reference.
7. An analogous self-condensation has been previously observed under Lewis acidic
Sc(OTf)3-catalyzed conditions; see Kobayashi, S.; Gustafsson, T.; Shimizu, Y.;
Kiyohara, H.; Matsubara, R. Enecarbamates as imine surrogates: Nucleophilic
addition of 1,3-dicarbonyl compounds to enecarbamates. Org. Lett. 2006, 8, 4923.
8. For chiral DMF analogs we previously developed for asymmetric reduction of
ketimines by trichlorosilane, see (a) Wang, Z.; Ye, X.; Wei, S.; Wu, P.;
Zhang, A.; Sun, J. A highly enantioselective Lewis basic organocatalyst for
reduction of N-aryl mines with unprecedented substrate spectrum. Org. Lett.
2006, 8, 999; (b) Wang, Z.; Cheng, M.; Wu, P.; Wei, S.; Sun, J. L-Piperazine-2-
carboxylic acid derived N-formamide as a highly enantioselective Lewis basic
catalyst for hydrosilylation of N-aryl imines with an unprecedented substrate
profile. Org. Lett. 2006, 8, 3045.