Synthesis of primary amines by the electrophilic amination of Grignard reagents with 1,3-dioxolan-2-one O-sulfonyloxime

Article abstract of DOI:10.1021/ol0479951

(Chemical equation presented) Primary amines are prepared by the electrophilic amination of Grignard reagents with 4,4,5,5-tetramethyl-1,3- dioxolan-2-one O-phenylsulfonyloxime and the acidic hydrolysis of the resulting imines.

Full text of DOI:10.1021/ol0479951

ORGANIC
LETTERS
2004
Vol. 6, No. 24
4619-4621
Synthesis of Primary Amines by the
Electrophilic Amination of Grignard
Reagents with 1,3-Dioxolan-2-one
O-Sulfonyloxime
Mitsuru Kitamura, Takahiro Suga, Shunsuke Chiba, and Koichi Narasaka*
Department of Chemistry, Graduate School of Science, The UniVersity of Tokyo,
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
narasaka@chem.s.u-tokyo.ac.jp
Received October 1, 2004
ABSTRACT
Primary amines are prepared by the electrophilic amination of Grignard reagents with 4,4,5,5-tetramethyl-1,3-dioxolan-2-one O-phenylsulfonyloxime
and the acidic hydrolysis of the resulting imines.
Primary amines are an important class of compounds in
organic synthesis, which provide various nitrogen-containing
biologically active substances and fine chemicals. Generally,
primary amines are prepared by the alkylation of nucleophilic
amination reagents such as potassium phthalimidate1 or the
reduction of nitrogen-containing compounds having a nitro
or cyano group.2 Recently, transition-metal-mediated ami-
nation methods have been developed3 and are also applied
for the synthesis of primary amines.4 While the reaction of
organometallic reagents with electrophilic nitrogen reagents
such as hydroxylamine derivatives has also been developed
(electrophilic amination),5 the method is less common
compared with the former methods.
Previously, we found that the intramolecular nucleophilic
substitution on the sp2 nitrogen of oximes occurred easily
in an SN2 manner.6,7 Based on this finding, we expected to
prepare primary amines by the intermolecular substitution
on oximes with organometallic reagents because the resulting
N-alkylimines A would be easily hydrolyzed to give primary
amines (Scheme 1).
Although some aminations with oxime derivatives for the
synthesis of primary amines have been reported, these
(1) (a) Gabriel, S. Ber. Dtsch. Chem. Ges. 1887, 20, 2224. (b) Gibson,
M. S.; Bradshaw, R. W. Angew. Chem., Int. Ed. Engl. 1968, 7, 919. (c)
Johnstone, R. A. W.; Payling, D. W.; Thomas, C. J. Chem. Soc. C 1969,
2223. (d) Ragnarsson, U.; Grehn, L. Acc. Chem. Res. 1991, 24, 285.
(2) (a) House, H. O. Modern Synthetic Reactions, 2nd ed.; W. A.
Benjamin: Reading, MA, 1972. (b) Kabalka, G. W. In ComprehensiVe
Organic Synthesis; Trost, B. M., Ed.; Pergamon: Oxford, 1991; Vol. 8, p
363. (c) Hutchins, R. O.; Hutchins, M. K. In ComprehensiVe Organic
Synthesis; Trost, B. M., Ed.; Pergamon: Oxford, 1991; Vol. 8, p 25. (d)
Mitsunobu, O. In ComprehensiVe Organic Synthesis; Trost, B. M., Ed.;
Pergamon: Oxford, 1991; Vol. 6, p 65.
(3) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Acc. Chem.
Res. 1998, 31, 805. Hartwig, J. F. Acc. Chem. Res. 1998, 31, 852. Hartwig,
J. F. Angew. Chem., Int. Ed. 1998, 37, 2046.
(4) Wolfe, J. P.; A° hman, J.; Sadighi, J. P.; Singer, R. A.; Buchwald, S.
L. Tetrahedron Lett., 1997, 38, 6367. Mann, G.; Hartwig, J. F.; Driver, M.
S.; Ferna´ndez-Rivas, C. J. Am. Chem. Soc. 1998, 120, 827.
(5) (a) Casarini, A.; Dembech, P.; Lazzari, D.; Marini, E.; Reginato, G.;
Ricci, A.; Seconi, G. J. Org. Chem. 1993, 58, 5620. (b) Greck, C.; Geneˆt,
J. P. Synlett 1997, 741. (c) Erdik E.; Ay, M. Chem. ReV. 1989, 89, 1947.
(d) Dembech, P.; Seconi, G.; Ricci, A. Chem. Eur. J. 2000, 6, 1281.
(6) Mori, S.; Uchiyama, K.; Hayashi, Y.; Narasaka, K.; Nakamura, E.
Chem. Lett. 1998, 111.
(7) Kusama, H.; Yamashita, Y.; Narasaka, K. Chem. Lett. 1995, 5.
Kusama, H.; Uchiyama, K.; Yamashita, Y.; Narasaka, K. Chem. Lett. 1995,
715. Kusama, H.; Yamashita, Y.; Uchiyama, K.; Narasaka, K. Bull. Chem.
Soc. Jpn. 1997, 70, 965. Uchiyama, K.; Yoshida, M.; Hayashi, Y.; Narasaka,
K. Chem. Lett. 1998, 607. Yoshida, M.; Uchiyama, K.; Narasaka, K.
Heterocycles 2000, 52, 681. Kitamura, M.; Yoshida, M.; Kikuchi, T.;
Narasaka, K. Synthesis 2003, 2415. Tanaka, K.; Mori, Y.; Narasaka, K.
Chem. Lett. 2004, 33, 26.
10.1021/ol0479951 CCC: $27.50
© 2004 American Chemical Society
Published on Web 10/27/2004

The amination of p-tolyl Grignard reagent prepared in Et2O
was examined with O-phenylsulfonyloxime 3a in various
solvents (Table 1).11 The Grignard reagent reacted with
Scheme 1. Electrophilic Amination with Oximes
Table 1. Reaction of O-Phenylsulfonyloxime 3a with
p-Tolylmagnesium Bromidea
methods still remain practical due to the use of an excess
amount of organometallic reagents, overalkylation, and low
product yield.8 We also examined the electrophilic amination
of Grignard reagents with oxime derivatives such as bis-
[3,5-bis(trifluoromethyl)phenyl]ketone O-tosyloxime (1)9 and
1,3-dimethyl-2-imidazolidinone O-tosyloxime (2).10 While
primary amines are prepared in high yield with wide
generality, it was desired to modify these oximes to realize
more efficient synthetic processes. For example, bulky
substituents of 1 like 3,5-bis(trifluoromethyl)phenyl groups
are not appropriate for atom economy, and the hydrolysis
of the resulting imines derived from 2 requires harsh basic
conditions (CsOH, ethylene glycol, 150 °C).
run
solvent
CH2Cl2
PhCl
PhCl
toluene
1,4-dioxane
THF
conditions
yield/%
1
2
3b
4
5
6
0 °C, 30 min
0 °C, 30 min
rt, 1 h
rt, 40 min
rt, 6 h
90
97
90
86
85
c
Recently, we found that 4,4,5,5-tetramethyl-1,3-dioxolan-
2-one O-phenylsulfonyloxime (3a) is definitely suitable for
the amination of Grignard reagents. In this letter, we wish
to describe the electrophilic amination with 3a.
rt, 6 h
a 3a: p-TolMgBr ) 1:1.1. b p-TolMgBr in THF was used. c After the
reaction of 3a with p-TolMgBr, 5b was obtained in 39% yield and 56% of
3a was recovered. Further hydrolysis was not examined.
1,3-Dioxolan-2-one O-sulfonyloximes 3a-d were pre-
pared as shown in Scheme 2. Commercially available
oxime 3a smoothly in dichloromethane at 0 °C within 30
min (run 1). The obtained crude imine 5b was successfully
hydrolyzed to p-toluidine in high yield under HCl-acidic
conditions by the contrast to the case of 2-imidazolidinone-
oxime 2.12 Reaction of the Grignard reagent in chlorobenzene
also proceeded efficiently to give 7b in 97% yield after acid
hydrolysis (run 2). Grignard reagent prepared in THF was
less reactive to 3a, and the amination was completed after 1
h at room temperature (run 3). Although 3a was barely
dissolved in toluene, the amination proceeded at room
temperature (run 4). In polar solvents such as 1,4-dioxane
and THF, the reaction became much slower (runs 5 and 6).
Several 1,3-dioxolan-2-one oximes 3b-d were examined
for amination with p-tolyl Grignard reagent ((i) 3, p-TolMgBr
in Et2O, CH2Cl2; (ii) 1 M HCl in Et2O, MeOH). Although
the amination with O-tosyl oxime 3b and O-mesitylsulfonyl
oxime 3c proceeded smoothly, the yields of 7b were slightly
decreased (90% and 80%, respectively). O-Methylsulfonyl
oxime 3d is hygroscopic and the amination was not
reproducible, though freshly prepared one gave toluidine in
86% yield. In addition, 1,3-dioxolan-2-one O-tosyloxime (8),8
having no methyl groups on the 1,3-dioxolane ring, was very
moisture sensitive and was difficult to use as a common
amination reagent. Tetramethyl groups are indispensable
Scheme 2. Preparation of 1,3-dioxolan-2-one O-sulfonyloximes
3a-d
phenylcarbonimidic dichloride (4) was treated with pinacol
and NaH to give 2-phenylimino-1,3-dioxolane 5a in 87%
yield, which was transformed to 1,3-dioxolane oxime 6 with
hydroxylamine in 90%. O-Sulfonylation of oxime 6 pro-
ceeded smoothly under the standard procedure to afford
O-sulfonyloximes 3a-d in high yields.
(8) (a) Hagopian, R. A.; Therien, M. J.; Murdoch, J. R. J. Am. Chem.
Soc. 1984, 106, 5753. (b) Erdik, E.; Ay, M. Synth. React. Inorg. Met.-Org.
Chem. 1989, 19, 663. (c) Wu¨rthwein, E.-U.; Weigmann, R. Angew. Chem.,
Int. Ed. Engl. 1987, 26, 923. (d) Erdik, E.; Daskapan, T. Synth. Commun.
1999, 29, 3989. (e) Erdik, E.; Daskapan, T. J. Chem. Soc., Perkin Trans. 1
1999, 3139.
(9) (a) Tsutsui, H.; Hayashi, Y.; Narasaka, K. Chem. Lett. 1997, 317.
(b) Tsutsui, H.; Ichikawa, T.; Narasaka, K. Bull. Chem. Soc. Jpn. 1999, 72,
1869.
(11) Although 3a reacted with various organometalic reagents such as
PhZnCl, Ph2Zn, PhCu, and Ph2Cu, the yields of amination products were
low.
(12) Prior to study amination with oxime 3, the hydrolysis of 2-phen-
ylimino-1,3-dioxolane 5a was examined to check the difficulty of the
hydrolysis of the aminated compounds and was found to be easily
hydrolyzed under acidic conditions (1 M HCl in Et2O, MeOH, rt) to give
aniline hydrochloride in 96% yield. 1 M HCl in Et2O was purchased from
Aldrich.
(10) Kitamura, M.; Chiba, S.; Narasaka, K. Bull. Chem. Soc. Jpn. 2003,
76, 1063.
4620
Org. Lett., Vol. 6, No. 24, 2004

Table 2. Amination of Various Grignard Reagents with Oxime 3aa
first step
second step
run
R
solvent
T/°C
time/h
method
time/h
product
yield/%
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20d,e
Ph
Ph
p-Tol
PhCl
CH2Cl2
PhCl
CH2Cl2
CH2Cl2
PhCl
CH2Cl2
CH2Cl2
CH2Cl2
PhCl
CH2Cl2
PhCl
CH2Cl2
CH2Cl2
CH2Cl2
PhCl
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
0
rt
0
rt
rt
0
rt
rt
rt
0
rt
0
rt
rt
0
0
0
0.5
1
A
A
A
A
A
A
A
A
A
A
A
B
A
B
B
B
B
B
B
B
1.5
1.5
1.5
2
2.5
2.5
2.5
6.5
1.5
0.5
0.5
3
1
3
2
6
6
6
10
10
7a
7a
7b
7c
7d
7e
7e
7f
7g
7h
7h
7i
7j
7k
7l
7m
7m
7n
7o
7p
93
92
97
96
90
96
90
91
90
94
91
90
93
90
92
87
0.5
0.5
0.5
0.5
0.5
1
1
1
1
1
o-MeO-C6H4
m-MeO-C6H4
p-MeO-C6H4
p-MeO-C6H4
2,4-(MeO)2-C6H3
p-F-C6H4
p-CF3-C6H4
p-CF3-C6H4
2,6-Me2-C6H3
1-naphthyl
0.5
0.25
0.5
1
PhCH2CH2
PhCH(CH3)CH2
PhCH2CH(CH3)
PhCH2CH(CH3)
c-hexyl
1-adamantyl
1-norbornyl
1
89
92b (92)c
89
0
0
rt
0.5
0.5
0.2
64
a Oxime 3a: 2.0 mmol; Grignard reagents: 2.2 mmol. b 1H NMR yield (internal standard: anthracene). c Isolated yield of N-benzoyl derivative (PhCOCl,
Et3N, CH2Cl2, rt, 30 min). d Oxime 3a: 1.0 mmol. Grignard reagent: 2.6 mmol. e Grignard reagent in THF-hexane was used.
substituents for oxime 3 as a treatable reagent. The amination
of p-tolyl Grignard reagent proceeded efficiently with
O-phenylsulfonyloxime 3a in CH2Cl2 or chlorobenzene.
The amination with 3a exhibited a wide generality for
amination of various aryl and alkyl Grignard reagents as
listed in Table 2. Regardless of the steric congestion and
the electronic effect of the substituents on the aryl group,
aryl Grignard reagents were smoothly aminated with 3a, and
thus-formed imine 5 was hydrolyzed under acidic conditions
at room temperature giving anilines in high yield (runs
1-13). Alkyl Grignard reagents also reacted with 3a to afford
primary, secondary, and tertiary alkylamines 7 in high yields
(runs 14-20) after the hydrolysis of the resulting N-
alkylimines 5 under reflux in acidic EtOH.
2-Aza-1,3-dienes are used for the synthesis of various
heterocycles and are generally prepared by aza-Wittig
reaction or enolization of N-acyl imines.13 Azadienes 9 could
be prepared by the reaction of alkenyl Grignard reagents such
as styryl and isopropenyl Grignard reagents with 3a in high
yield (Scheme 3).
Acknowledgment. This research was supported by a
Grant-in-Aid for Scientific Research on Priority Areas (A)
“Exploitation of Multi-Element Cyclic Molecules” and a
Grant-in-Aid for The 21st Century COE Program for
Frontiers in Fundamental Chemistry from the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
Scheme 3. Amination of Alkenyl Grignard Reagents with 3a
Supporting Information Available: Typical experimen-
tal procedure, spectral data for new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL0479951
(13) Jayakumar, S.; Ishar, M. P. S.; Mahajan, M. P. Tetrahedron 2002,
58, 379.
Org. Lett., Vol. 6, No. 24, 2004
4621