A mild and convenient synthesis of N-carbobenzyloxy ketimines

Article abstract of DOI:10.1039/b605882e

N-Carbobenzyloxy (Cbz) ketimines were prepared conveniently from N-Cbz amines by oxidation with N-tert-butylbenzenesulfinimidoyl chloride. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b605882e

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A mild and convenient synthesis of N-carbobenzyloxy ketimines{
Jun-ichi Matsuo,* Yumi Tanaki, Aimi Kido and Hiroyuki Ishibashi*
Received (in Cambridge, UK) 25th April 2006, Accepted 16th May 2006
First published as an Advance Article on the web 1st June 2006
DOI: 10.1039/b605882e
temperature for 10 days. The scope and limitations of the present
1-mediated oxidation were investigated for the reaction of various
N-Cbz protected amines 2 giving N-Cbz aryl alkyl ketimines 3
(Table 1). N-Cbz phenyl ethyl ketimine 3b, N-Cbz phenyl propyl
ketimine 3c, and N-Cbz phenyl isopropyl ketimine 3d were isolated
in high yields regardless of the steric hindrance. It was found that
yields of N-Cbz aryl ketimines 3 depended strongly on the
substituents on the phenyl ring. In the presence of an electron-
attracting group, such as chloride, ketimine 3g was isolated in 96%
yield as the sole product, while a mixture of ketimine and ene
carbamate was obtained in the presence of electron-donating
substituents such as methyl and methoxy groups (Entries 6 and 8).
It was thought that protonation of the nitrogen atom of the
ketimine took place more easily when electron-donating groups
were attached to the phenyl ring. In the oxidation of 2i, having a
3-pyridyl group as an aryl group, ketimine 3i was obtained along
with an ene carbamate 3i9 in 87% combined yield (3i:3i9 = 79:21).
The two compounds 3i and 3i9 were separated by thin-layer
chromatography on silica gel. It should be noted that only one
isomer of ketimine was obtained by the present procedure. We
speculated that anti-N-Cbz ketimines were selectively formed,
judging from 13C NMR chemical shift differences14 between the
a-carbons of N-Cbz ketimines and the corresponding ketones.15
When the oxidation of N-Cbz cyclohexylamine (4a) was carried
out by the above-mentioned procedure, only the starting material
4a was recovered. Elevating the reaction temperature to room
temperature gave ene carbamate 5a9 in 60% yield, and many by-
products were detected by TLC analysis (Scheme 1). Since the
N-Carbobenzyloxy (Cbz) ketimines were prepared conveniently
from N-Cbz amines by oxidation with N-tert-butylbenzenesul-
finimidoyl chloride.
N-Carboalkoxy aldimines are often used as nitrogen-containing
electrophiles for carbon–carbon bond forming reactions, especially
for highly enantioselective reactions such as the Mannich type
reaction1 and the aza-Henry reaction.2,3 N-Carboalkoxy amines
having a chiral tertiary carbon center are stereoselectively
constructed by these reactions. Given this, N-carboalkoxy
ketimines should be attractive electrophilic targets for creating
chiral quaternary carbon centers; however, only
a few
N-carboalkoxy ketimines have been prepared4–11 and most did
not have acidic a-protons. Preparation of N-carboalkoxy keti-
mines is more difficult than preparation of N-carboalkoxy
aldimines4 because of the lower reactivity of ketones and the
tendency of N-carboalkoxy ketimines to tautomerize into the
corresponding ene carbamates. Hoch reported that N-carboethoxy
ketimines were prepared from diethyl ketals and NH2CO2Et in the
presence of a trace amount of PhNH3Cl at 90–100 uC,5 but it was
later found that N-carboethoxy ketimines obtained by Hoch’s
method included ene carbamate.6,7 N-Carboalkoxy ketimines are
also prepared from NH ketimines8,9 or N-silyl ketimines,10 though
available NH ketimines and N-silyl ketimines have been limited to
non-enolizable ones; i.e., diaryl and aryl tert-butyl ketimines.11
We have found that N-tert-butylbenzenesulfinimidoyl chloride
(1){ oxidized various organic compounds under very mild reaction
conditions.12 We expected that the above-mentioned labile N-
carboalkoxy ketimines would be synthesized under mild conditions
by 1-mediated oxidation of the corresponding N-carboalkoxy
Table 1 Oxidation of various N-Cbz amines 2a–i to N-Cbz ketimines
3a–i
amines. We describe here the oxidation of
a variety of
N-carbobenzyloxy (Cbz) amines to N-Cbz ketimines using 1.
First, oxidation of N-Cbz-1-phenylethylamine (2a) to the
corresponding N-Cbz ketimine 3a was tried using the following
procedure: 2a was treated with n-BuLi in THF at 278 uC and then
1 was added at the same temperature. As expected, the 1-mediated
oxidation of 2a proceeded rapidly at 278 uC and the desired
product 3a was obtained in 97% yield after chromatography on
silica gel. It was noted that ene carbamate 3a9 13 was not obtained
by this procedure. The crystalline product 3a was stable in a
refrigerator for several months, while a part of 3a tautomerized to
3a9 after keeping the solution of 3a in chloroform at room
Entry N-Cbz amine R1
R2
Product Yield (%)
1
2
3
4
5
6
7
8
9
a
2a
2b
2c
2d
2e
2f
2g
2h
2i
Ph
Ph
Ph
Ph
Me
Et
n-Pr 3c
i-Pr 3d
Me
Me
Me
3a
3b
97
90
92
94
1-Naph
p-MeC6H4
p-ClC6H4
p-MeOC6H4 Me
3-Py Me
3e
3f
3g
3h
3i
89
95a
96
Division of Pharmaceutical Sciences, Graduate School of Natural
Science and Technology, Kanazawa University, Kakuma-machi,
Kanazawa 920-1192, Japan. E-mail: jimatsuo@p.kanazawa-u.ac.jp;
Fax: (+81) 76-234-4439; Tel: (+81) 76-234-4439
{ Electronic supplementary information (ESI) available: Typical experi-
mental procedures and spectral data for all new compounds. See DOI:
10.1039/b605882e
89b
87c
b
A mixture of 3f and 3f9 (3f:3f9 = 61:39). A mixture of 3h and 3h9
c
(3h:3h9 = 75:25). A mixture of 3i and 3i9 (3i:3i9 = 79:21).
2896 | Chem. Commun., 2006, 2896–2898
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Scheme 1 Oxidation of 4a with 1 at room temperature.
Scheme 3 Formation of ene carbamate 5a9 from 7a.
yellow color of 1 immediately disappeared after the addition of 1
at 278 uC, it was thought that 1 reacted smoothly with the lithium
anion of 4a at 278 uC to form an oxidation intermediate 6a, and
that 5a would be formed during warming to room temperature
(Scheme 2). Therefore, we tried to trap the N-Cbz ketimine 5a with
MeOH16 before isomerization of 5a to 5a9. In fact, the expected
MeOH-addition product 7a was obtained in 80% yield by
generating 5a in the presence of MeOH (Table 2, Entry 1). This
result suggested that dialkyl ketimine 5a was also formed
effectively by the present oxidation. Other cyclic and acyclic
dialkyl ketimines were generated by this method and MeOH-
addition products were obtained in good to high yields by trapping
ketimines with MeOH (Table 2, Entries 2–4).
using the oxidizing agent 1; relatively stable N-Cbz aryl ketimines
were isolated in high yields and labile N-Cbz dialkyl ketimines
were trapped with MeOH in situ. Since a variety of N-Cbz
ketimines are now available and anti-isomers of ketimines were
selectively formed by the present oxidation, it is expected that the
N-Cbz ketimines would be useful synthetic intermediates in
organic synthesis and we are now studying carbon–carbon bond
forming reactions using them."
Notes and references
{ Commercially available from Tokyo Chemical Industry.
§ Typical procedure (Table 1, entry 1): to a stirred solution of 2a (100 mg,
0.39 mmol) in dry THF (2 mL) was added a solution of n-BuLi (1.59 N in
hexane, 0.27 mL, 0.43 mmol) at 278 uC under an argon atmosphere. After
the resulting pale yellow solution was stirred for 15 min at the same
temperature, a solution of 1 (129 mg, 0.60 mmol) in THF (1 mL) was
added at 278 uC and the mixture was stirred for 30 min. The reaction
was then quenched by adding saturated NaHCO3 (5 mL) and the mixture
was extracted with EtOAc (three times). The combined organic extracts
were washed with brine, dried over anhydrous Na2SO4, filtered, and
concentrated. The crude product was purified by thin layer chromato-
graphy (silica gel, hexane–AcOEt 5:1) to afford 3a (96 mg, 97%) as a
colorless powder.
Kugelrohr distillation (290 uC/0.9 mmHg) of 7a gave ene
carbamate 5a917 as a sole product (Scheme 3). Therefore, oxidation
of N-Cbz amine with 1, followed by addition of MeOH and
successive distillation would give a useful method for preparation
of ene carbamates.
Thus, we have established a new method for the preparation of
a variety of N-Cbz ketimines.§ Oxidation of N-Cbz amines to the
corresponding N-Cbz ketimines proceeded smoothly at 278 uC
" The authors thank for the financial support, the Novartis Foundation
(Japan) for the Promotion of Science, and this work was partially
supported by a Grant-in-Aid for Scientific Research from the Ministry of
Education, Culture, Sports, Science, and Technology of Japan.
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Scheme 2 Mechanism for formation of 5a9.
4 They have been easily prepared by the condensation of alkyl carbamate
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Table 2 Oxidation of N-Cbz amines 4a–d to N-Cbz ketimines 5a–d,
and successive addition of MeOH to give 7a–d
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Entry
N-Cbz amine
R1
R2
Product
Yield (%)a
1
2
3
4
a
4a
4b
4c
4d
–(CH2)5–
–(CH2)4–
Me
Et
7a
7b
7c
7d
80
75
77
91
Me
Et
Isolated yield.
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15 The 13C chemical shifts of alkyl a-carbons of N-Cbz ketimines 3 were
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and Y. Aizawa, Tetrahedron Lett., 2005, 46, 407–410; J.-i. Matsuo and
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shifted to higher field, except for 3d. The stereochemistry of 3d was
ambiguous.
13 R. Matsubara, P. Vital, Y. Nakamura, H. Kiyohara and S. Kobayashi,
Tetrahedron, 2004, 60, 9769–9784.
14 C. A. Bunnell and P. L. Fuchs, J. Org. Chem., 1977, 42,
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16 Y. H. Suen and H. B. Kagan, Bull. Soc. Chim. Fr., 1965, 1460–1463.
17 Compound 5a9 was prepared via the isocyanate. See: S. Machida and
I. Tanaka, Kyoto Kogei Sen’i Daigaku Sen’igakubu Gakujutsu Hokoku,
1975, 7, 423 (Chem. Abs., 84, 122382) and ref. 6 and 13.
2898 | Chem. Commun., 2006, 2896–2898
This journal is ß The Royal Society of Chemistry 2006