Reaction of magnesium carbenoids with N-lithio arylamines: A novel method for generation of non-stabilized α-amino-substituted carbanions and a new synthesis of α-amino acid derivatives

Article abstract of DOI:10.1016/j.tetlet.2004.07.069

Treatment of 1-chloroalkyl phenyl sulfoxides with a Grignard reagent at low temperature afforded magnesium carbenoids in quantitative yields. The magnesium carbenoids were found to be reactive with N-lithio alkylamines and N-lithio arylamines. The reaction with N-lithio alkylamines afforded an olefin, which was derived from dimerization of the magnesium carbenoid, in moderate yield. The reaction with N-lithio arylamines gave the adducts, α-amino-substituted carbanions, in good yields. From these intermediates, a novel synthesis of α-amino acid derivatives and N,N-dialkyl arylamines having a deuterium at the α-position was realized.

Full text of DOI:10.1016/j.tetlet.2004.07.069

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6703–6707
Reaction of magnesium carbenoids with N-lithio arylamines: a
novel method for generation of non-stabilized a-amino-substituted
carbanions and a new synthesis of a-amino acid derivatives
Tsuyoshi Satoh,* Atsushi Osawa and Atsushi Kondo
Department of Chemistry, Faculty of Science, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
Received 10 June 2004; revised 9 July 2004; accepted 16 July 2004
Abstract—Treatment of 1-chloroalkyl phenyl sulfoxides with a Grignard reagent at low temperature afforded magnesium carbenoids
in quantitative yields. The magnesium carbenoids were found to be reactive with N-lithio alkylamines and N-lithio arylamines. The
reaction with N-lithio alkylamines afforded an olefin, which was derived from dimerization of the magnesium carbenoid, in moderate
yield. The reaction with N-lithio arylamines gave the adducts, a-amino-substituted carbanions, in good yields. From these interme-
diates, a novel synthesis of a-amino acid derivatives and N,N-dialkyl arylamines having a deuterium at the a-position was realized.
Ó 2004 Published by Elsevier Ltd.
Carbenes and carbenoids have been well known as a
highly reactive carbon species and are recognized as use-
ful intermediates in organic synthesis.1 Generation of
carbenes and carbenoids has mainly been carried out
in two ways: (a) photolysis, pyrolysis, and metal-cata-
lyzed decomposition of diazo compounds,2 (b) base-in-
duced a-elimination.1,3
tions of the generated magnesium carbenoids to new
methods for organic synthesis.5 In continuation of our
investigation of the chemistry of the magnesium carbe-
noids, we recently studied the generation of simple
magnesium carbenoids 3 from 1-chloroalkyl phenyl sulf-
oxides 2 with Grignard reagents and reaction of 3 with
nitrogen nucleophiles (Scheme 1).
In this decade, we have been interested in the generation
of magnesium carbenoids from a-halo sulfoxides via
sulfoxide–magnesium exchange reaction4 and applica-
Interestingly, the reaction of the magnesium carbenoid 3
with N-lithio dialkylamine gave no aminated product
but dimeric product 4. In sharpcontrast to this result,
O
R1MgX
R2R3NLi
R-CH2SPh
R-CHMgX
R-CH=CH-R
R-CHSPh
Cl
Cl
1
4
2
3
R4
ArNLi
R4
R4
ClCOOEt
R-CH-NAr
R-CH-NAr
Li
COOEt
5
6
Scheme 1.
Keywords: Sulfoxide–magnesium exchange; Magnesium carbenoid; Dimerization; a-Amino-substituted carbanion; a-Amino acid.
*
Corresponding author. Tel.: +81 3 5228 8272; fax: +81 3 3235 2214; e-mail: tsatoh@ch.kagu.tus.ac.jp
0040-4039/$ - see front matter Ó 2004 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2004.07.069

6704
T. Satoh et al. / Tetrahedron Letters 45 (2004) 6703–6707
the reaction of 3 with several N-lithio arylamines af-
forded the adduct, a-amino-substituted carbanions 5.
From the adduct 5, a novel synthesis of a-amino acid
derivatives 6 was realized (Scheme 1).
piperidine through a canula and the temperature of the
reaction mixture was allowed to warm to À40°C for 1h.
We obtained an olefin 10 (dimer of the carbenoid 9)
in 55% yield. Quite interestingly, this olefin 10 was
not obtained at all from the carbenoid 9 in the absence
of N-lithio piperidine. Obviously, N-lithio piperidine is
essential in this olefin formation.
The representative reactions are reported by using 1-
chloroalkyl phenyl sulfoxide 8, derived from sulfide 7
in high overall yield,6 as an example (Scheme 2). Treat-
ment of 8 in THF with 2.5equiv of i-PrMgCl at À70°C
cleanly gave the magnesium carbenoid 9 in a quantita-
tive yield.6 To this solution was added 5equiv of N-lithio
A plausible mechanism for the formation of the olefin 10
is proposed as shown in Scheme 3. Thus, the magnesium
carbenoid 9 (or 14) reacted with N-lithio piperidine to
2.5 eq.
O
1) MCPBA
2) NCS
i-PrMgCl
ArCH2CH2CHSPh
CH3O
CH2CH2CH2SPh
THF, -70 ˚C
10 min
Cl
7
8
NLi
5 eq.
ArCH2CH2CHMgCl
Cl
ArCH2CH2CH=CHCH2CH2Ar
(E:Z=5:1)
-70 ˚C, 10 min
then -70 - -40 ˚C for 1 h
10
55%
9
1) 5 eq.
NHLi
ArCH2CH2CH2NH
2) CD3OD
11
67%
CH3
1) 5 eq.
NCH3Li
ArCH2CH2CHN
D
2)
CD3OD
77%
(D-content, 91%)
12
CH3
ArCH2CH2CHN
COOEt
1) 5 eq.
NCH3Li
2) ClCOOEt
73%
13
Ar=
CH3O
Scheme 2.
NLi
ArCH2CH2CHMgCl
ArCH2CH2CH: MgCl2
Cl
14
9
N
N
ArCH2CH2CH: MgCl2
ArCH2CH2CHLi
ArCH2CH2CH-CHCH2CH2Ar
15
Li
16
ArCH2CH2CH=CHCH2CH2Ar
NLi
10
Scheme 3. A plausible mechanism for the formation of the dimer 10.

T. Satoh et al. / Tetrahedron Letters 45 (2004) 6703–6707
6705
Li
NHLi
H
ArCH2CH2CH: MgCl2
ArCH2CH2CHNPh
14
17
H
Li
CD3OD
ArCH2CH2CHNPh
ArCH2CH2CH2NHPh
18
11
D CH3
Li
CH3
NCH3Li
CD3OD
ArCH2CH2CHNPh
ArCH2CH2CHNPh
14
12
19
Scheme 4. A plausible mechanism for the formation of the N-alkylaniline 11 and N-(1-deuterated alkyl)-N-methylaniline 12 by the reaction of the
magnesium carbenoid 14 with N-lithio aniline and N-lithio N-methylaniline.
Table 1. Synthesis of N,N-dialkyl arylamine and a-amino acid derivatives 20 from the magnesium carbenoid 3 by the reaction of N-lithio arylamine
followed by electrophiles
R1
2.5 eq.
O
R1
1) 3.5 eq.
ArNLi
i-PrMgCl
RCHSPh
RCHMgCl
RCHN-Ar
THF, -70 ˚C
2) Electrophile
Cl
Cl
E
2
20
3
Entry
2
Ar
R1
Electrophile
E
20
R
Yield/%
CH3O
CH3O
CH3O
CH3O
CH3O
CH3O
CH2CH2
CH3O
CH3O
Cl
1
2
CH3
CH3
CD3OD
D
81%a
74%
ClCOOEt
COOEt
CH2CH2
CH2CH2
CH2CH2
CH2CH2
CH2CH2
3
CH3
CD3OD
D
79%a
73%
4
CH3
ClCOOEt
CD3OD
COOEt
D
Cl
5
PhCH2
PhCH2
PhCH2
PhCH2
CH3
69%b
67%
CH3O
CH3O
CH3O
CH3O
CH3O
CH3O
Cl
6
ClCOOEt
CD3OD
COOEt
D
7
73%c
71%
CH2CH2
8
ClCOOEt
CD3OD
COOEt
D
CH2CH2
CH2
9
70%b
68%
10
11
12
13
14
15
16
CH3
ClCOOEt
CD3OD
COOEt
D
CH2
CH3
72%c
68%
CH2
CH3
ClCOOEt
CD3OD
COOEt
D
CH2
Cl
CH3
48%d
48%
CH3O
CH3O
Cl
CH3
ClCOOEt
CD3OD
COOEt
D
CH3
42%b
41%
CH3
ClCOOEt
COOEt
Cl
a D-content 90%.
b D-content 97%.
c D-content 95%.
d D-content 99%.

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T. Satoh et al. / Tetrahedron Letters 45 (2004) 6703–6707
give the adduct 15, which reacted again with the carbe-
noid to give 16. b-Elimination of N-litho piperidine from
16 afforded the olefin 10.
reaction to an asymmetric synthesis of a-amino acid
derivatives is underway in these laboratories.
Acknowledgements
In contrast to the reaction of 9 with N-lithio piperidine,
the reaction with N-lithio aniline gave N-alkylaniline 11
in good yield (Scheme 2). This reaction was quenched
with excess CD3OD; however, no deuterium was incor-
porated in the N-alkylaniline 11. Next, the magnesium
carbenoid 9 was treated with 5equiv of N-lithio N-meth-
ylaniline under the same conditions as above, and the
reaction was quenched with excess CD3OD. We ob-
tained the N,N-dialkylaniline 12 in 73% yield and the
product was deuterated on the a-carbon. The plausible
mechanism of this interesting reaction is shown in
Scheme 4.
This work was supported by a grant from the Ministry
of Education, Culture, Sports, Science and Technology
of Japan, which is gratefully acknowledged.
References and notes
1. (a) Kirmse, W. Carbene Chemistry; Academic: New York,
1971; (b) Stang, P. J. Chem. Rev. 1978, 78, 383; (c) Oku, A.;
Harada, T. J. Syn. Org. Chem. Jpn. 1986, 44, 736; (d) Oku,
A. J. Syn. Org. Chem. Jpn. 1990, 48, 710; (e) Dorwald, F. Z.
Metal Carbenes in Organic Synthesis; Wiley-VCH: Wein-
heim, 1999.
The reaction of the magnesium carbenoid with N-lithio
aniline gave the adduct, N-alkylaniline having carbanion
at the a-position 17. The adduct has an acidic hydrogen
on the nitrogen, and the carbanion quickly picks up this
acidic hydrogen to give 18. So, as described above, on
quenching this reaction with CD3OD no deuterium
was incorporated on the a-carbon. In contrast to this,
the reaction with N-lithio N-methylaniline provided
the adduct 19, which has no acidic hydrogen, to
give the product having the alkyl group deuterated at
the a-position 12. Generation of the a-amino-substi-
tuted carbanions is well recognized to be quite difficult
from unactivated amines.7 The results obtained in this
study are highly notable as a new method for generation
of non-stabilized a-amino carbanions.8
2. Some selected recent papers and reviews in this category: (a)
Adams, J.; Spero, D. M. Tetrahedron 1991, 47, 1765; (b)
Padwa, A.; Krumpe, K. Tetrahedron 1992, 48, 5385; (c)
Padwa, A.; Weingarten, M. D. Chem. Rev. 1996, 96, 223;
(d) Mori, T.; Taniguchi, M.; Suzuki, F.; Doi, H.; Oku, A. J.
Chem. Soc., Perkin Trans. 1 1998, 3623; (e) Sulikowski, G.
A.; Cha, K. L.; Sulikowski, M. M. Tetrahedron: Asymmetry
1998, 9, 3145; (f) Sakai, A.; Aoyama, T.; Shioiri, T.
Tetrahedron Lett. 2000, 41, 6859; (g) Mehta, G.; Muthu-
samy, S. Tetrahedron 2002, 58, 9477.
3. Some selected recent papers and reviews in this category: (a)
Topolsky, M.; Duraisamy, M.; Rachon, J.; Gawronski, J.;
Gawronska, K.; Goedken, V.; Walborsky, H. M. J. Org.
Chem. 1993, 58, 546; (b) Harada, T.; Katsuhira, T.; Hattori,
K.; Oku, A. Tetrahedron 1994, 50, 7987; (c) Taber, D. F.;
Meagley, R. P.; Doren, D. J. J. Org. Chem. 1996, 61, 5723;
(d) Braun, M. Angew. Chem., Int. Ed. 1998, 37, 430; (e)
Kasatkin, A.; Whitby, R. J. J. Am. Chem. Soc. 1999, 121,
7039; (f) Taber, D. F.; Christos, T. E.; Neubert, T. D.;
Batra, D. J. Org. Chem. 1999, 64, 9673; (g) Marek, I.
Tetrahedron 2002, 58, 9463.
In order to synthesize a-amino acid derivatives, we tried
to trapthis carbanion 19 with ethyl chloroformate and,
fortunately, the expected reaction worked to afford the
a-amino acid derivative 13 in 73% yield (see Scheme
2).9 Generality of this reaction was investigated using
four kinds of 1-chloroalkyl phenyl sulfoxides 2 and N-
methyl p-anisidine, N-benzyl p-anisidine, and N-methyl
p-chloroaniline. The results are summarized in Table 1.
4. (a) Satoh, T. J. Syn. Org. Chem. Jpn. 1996, 54, 481; (b)
Satoh, T. J. Syn. Org. Chem. Jpn. 2003, 61, 98; (c) Satoh, T.
Chem. Record 2004, 3, 329.
5. (a) Satoh, T.; Takano, K.; Someya, H.; Matsuda, K.
Tetrahedron Lett. 1995, 36, 7097; (b) Satoh, T.; Takano, K.;
Ota, H.; Someya, H.; Matsuda, K.; Koyama, M. Tetrahe-
dron 1998, 54, 5557; (c) Satoh, T.; Kurihara, T.; Fujita, K.
Tetrahedron 2001, 57, 5369; (d) Satoh, T.; Sakamoto, T.;
Watanabe, M. Tetrahedron Lett. 2002, 43, 2043; (e) Satoh,
T.; Sakamoto, T.; Watanabe, M.; Takano, K. Chem.
Pharm. Bull. 2003, 51, 966; (f) Satoh, T.; Saito, S.
Tetrahedron Lett. 2004, 45, 347.
Entries 1–6 show that the reaction of the magnesium
carbenoid 9 with three kinds of arylamines, N-methyl
p-anisidine, N-methyl p-chloroaniline, and N-benzyl p-
anisidine, gave equally good yields (67–74%) of the a-
amino acid derivatives. The reaction starting from the
sulfoxide having a 2-phenylethyl group as R gave similar
results (entries 7 and 8). Entries 9–12 show the reaction
starting from the sulfoxide 2 having a cyclohexylmethyl
groupas R. The results were shown to be almost equal
to those described above. Interestingly, the reaction
starting from the sulfoxide having a cyclohexyl group
as R showed markedly diminished yield of the a-amino
acid derivatives (entries 13–16). Steric hindrance is
thought to be the reason for the lowering of the yield,
at present.
6. Satoh, T.; Kondo, A.; Musashi, J. Tetrahedron 2004, 60,
5453.
7. Some recent reviews concerning generation and reaction of
non-stabilized a-amino carbanions: (a) Kessar, S. V.; Singh,
P. Chem. Rev. 17997, 97, 721; (b) Katritzky, A. R.; Qi, M.
Tetrahedron 1998, 54, 2647; (c) Pearson, W. H.; Stoy, P.
Synlett 2003, 903.
8. Some recent papers concerning generation and reaction of
non-stabilized a-amino carbanions: (a) Gawley, R. E.;
Zhang, Q. J. Org. Chem. 1995, 60, 5763; (b) Florio, S.;
Capriati, V.; Gallo, A.; Cohen, T. Tetrahedron Lett. 1995,
36, 4463; (c) Coldham, I.; Hufton, R.; Snowden, D. J. J.
Am. Chem. Soc. 1996, 118, 5322; (d) Coldham, I.; Hufton,
R.; Rathmell, R. E. Tetrahedron Lett. 1997, 38, 7617; (e)
Coldham, I.; Lang-Anderson, M. M. S.; Rathmell, R. E.;
Snowden, D. J. Tetrahedron Lett. 1997, 38, 7621; (f)
Katritzky, A. R.; Qi, M.; Feng, D. J. Org. Chem. 1998,
In conclusion, we have found a novel and versatile
method for the formation of non-stabilized a-amino-
substituted carbanions by the reaction of the magnesium
carbenoid and N-lithio N-alkylarylamines. Investigation
of the scope and limitation, and development of this

T. Satoh et al. / Tetrahedron Letters 45 (2004) 6703–6707
6707
63, 6712; (g) Coldham, I.; Fernandez, J.-C.; Snowden, D. J.
Tetrahedron Lett. 1999, 40, 1819; (h) Chambournier, G.;
Gawley, R. E. Org. Lett. 2000, 2, 1561; (i) Azzena, U.; Pilo,
L.; Piras, E. Tetrahedron 2000, 56, 3775; (j) Coldham, I.;
Vennail, G. P. Chem. Commun. 2000, 23, 1569; (k) Pearson,
W. H.; Mans, D. M.; Kampf, J. W. Org. Lett. 2002, 4, 3099.
9. To a solution of i-PrMgCl (0.5mmol) in THF (0.5mL) at
À70°C was added a solution of 8 (62mg; 0.2mmol) in
0.4mL of THF dropwise with stirring. After 10min, a
solution of N-lithio N-methylaniline (prepared from N-
methylaniline (1mmol) and n-BuLi (1.2mmol) in 2mL of
THF at 0°C) was added to a solution of the magnesium
carbenoid 9 through a cannula and the reaction mixture
was slowly allowed to warm to À40°C for 1h. Ethyl
chloroformate (1mmol) was added to the reaction mixture
dropwise with stirring and the solution was stirred at
À40°C for 20min. The reaction was quenched by adding
H2O. The whole mixture was extracted with CHCl3 and the
product was purified by silica gel column chromatography
to give 13 (48mg; 73%) as a colorless oil. IR (neat) 2955,
1
1731 (CO), 1599, 1512, 1300, 1247, 1035cmÀ1; H NMR d
1.20 (3H, t, J = 7.0 Hz), 2.11–2.18 (1H, m), 2.20–2.28 (1H,
m), 2.53–2.59 (1H, m), 2.63–2.70 (1H, m), 2.93 (3H, s), 3.78
(3H, s), 4.13 (2H, m), 4.31 (1H, dd, J = 9.3, 5.5 Hz), 6.75
(3H, m), 6.80 (2H, d, J = 8.6Hz), 7.05 (2H, d, J = 8.6Hz),
7.22 (2H, t, J = 8.3Hz). MS m/z (%) 327 (M+, 15), 254 (75),
121 (100). Calcd for C20H25O3N: M, 327.1838. Found: m/z
327.1835.