A new method for generation of non-stabilized α-amino-substituted carbanions by the reaction of magnesium carbenoids with N-lithio arylamines: their reactivity and a new synthesis of α-amino acid derivatives

Article abstract of DOI:10.1016/j.tet.2006.05.052

Magnesium carbenoids were generated from aryl 1-chloroalkyl sulfoxides with i-PrMgCl in THF at low temperature in quantitative yields. The magnesium carbenoids were found to be reactive with N-lithio alkylamines to afford an olefin, which was derived from dimerization of the magnesium carbenoid, in moderate yield. On the other hand, reaction of the magnesium carbenoids with N-substituted N-lithio arylamines gave non-stabilized α-amino-substituted carbanions in good yields. Reactivity of the α-amino-substituted carbanions with some electrophiles was investigated and it was found that ethyl chloroformate reacted to give α-amino acid derivatives in good yields. As a whole, a new method for one-pot, three-component combined synthesis of α-amino acid derivatives from aryl 1-chloroalkyl sulfoxides was realized.

Full text of DOI:10.1016/j.tet.2006.05.052

Tetrahedron 62 (2006) 7892–7901
A new method for generation of non-stabilized
a-amino-substituted carbanions by the reaction of
magnesium carbenoids with N-lithio arylamines: their
reactivity and a new synthesis of a-amino acid derivatives
*
Tsuyoshi Satoh, Atsushi Osawa, Tohru Ohbayashi and Atsushi Kondo
Department of Chemistry, Faculty of Science, Tokyo University of Science, Ichigaya-funagawara-machi 12,
Shinjuku-ku, Tokyo 162-0826, Japan
Received 25 April 2006; accepted 16 May 2006
Available online 15 June 2006
Abstract—Magnesium carbenoids were generated from aryl 1-chloroalkyl sulfoxides with i-PrMgCl in THF at low temperature in quanti-
tative yields. The magnesium carbenoids were found to be reactive with N-lithio alkylamines to afford an olefin, which was derived from
dimerization of the magnesium carbenoid, in moderate yield. On the other hand, reaction of the magnesium carbenoids with N-substituted
N-lithio arylamines gave non-stabilized a-amino-substituted carbanions in good yields. Reactivity of the a-amino-substituted carbanions
with some electrophiles was investigated and it was found that ethyl chloroformate reacted to give a-amino acid derivatives in good yields.
As a whole, a new method for one-pot, three-component combined synthesis of a-amino acid derivatives from aryl 1-chloroalkyl sulfoxides
was realized.
Ó 2006 Elsevier Ltd. All rights reserved.
R1
R1
1. Introduction
N
R2
1
Y
N
R2
2
Metal
a-Amino-substituted carbanions 2 are quite interesting reac-
tive intermediates in the synthesis of amines and a-amino
acid derivatives. They are classified into two categories:
1
–4
1
,2
stabilized a-amino-substituted carbanions 2a and non-
stabilized a-amino-substituted carbanions 2b. The substit-
Y=H, Bu3Sn, etc
Metal=Li, MgX
α-Amino-substituted carbanion
3
,4
1
uent R of the stabilized a-amino-substituted carbanions 2a
is usually an alkyl-, alkenyl-, or aryl group and the substit-
1
2
2
a
b
Stabilized: R and/or R =Carbanion stabilizing group
Non-stabilized: R1 and R =Carbanion non-stabilizing group
2
2
2
uent R is generally a tert-butoxycarbonyl (Boc) group.
Generation of 2a is carried out by hydrogen–lithium
Scheme 1.
(
exchange reaction from the corresponding 1.
H–Li) exchange reaction or by tin–lithium (Bu Sn–Li)
3
5
intermediates in organic synthesis. Recently, we have been
interested in the generation of magnesium carbenoids from
a-halo sulfoxides via sulfoxide–magnesium exchange re-
On the other hand, non-stabilized a-amino-substituted carb-
anions 2b are generated from 1 with Bu Sn–Li exchange
6
3
4
action and applications of the generated magnesium carbe-
noids to new methods for organic synthesis. In continuation
7
reaction and fewer examples are reported. Only lithium is
reported so far as the metal of the a-amino-substituted
carbanions 2 (Scheme 1).
of our interest in the chemistry of the magnesium carbe-
noids, we recently studied the generation of simple magne-
sium carbenoids 4 from aryl 1-chloroalkyl sulfoxides 3
with isopropylmagnesium chloride and the reaction of mag-
nesium carbenoids 4 with nitrogen nucleophiles (Scheme 2).
Carbenes and carbenoids have been well known as a highly
reactive carbon species and are recognized as useful
Interestingly, the reaction of magnesium carbenoid 4 with
N-lithio alkylamine gave an olefin 5 (dimerized product of
the carbenoid). In sharp contrast to this result, the reaction
of 4 with several N-lithio N-substituted arylamines afforded
Keywords: Sulfoxide–magnesium exchange; Magnesium carbenoid; Dimer-
ization; a-Amino-substituted carbanion; a-Amino acid.
*
Corresponding author. Tel.: +81 3 5228 8272; fax: +81 3 5261 4631;
e-mail: tsatoh@ch.kagu.tus.ac.jp
0
040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.05.052

T. Satoh et al. / Tetrahedron 62 (2006) 7892–7901
7893
O
N-lithio piperidine (generated from piperidine and n-BuLi)
through a cannula and the temperature of the reaction mix-
ture was slowly allowed to warm to ꢀ40 C for 1 h.
2
3
i-PrMgX
R R NLi
R-CH2SAr
R-CHSAr
Cl
R-CHMgX
Cl
R-CH=CH-R
ꢁ
5
3
4
R=Alkyl
We anticipated the reaction of the carbenoid 4a with N-lithio
piperidine would give the N-alkylated product; however,
unexpectedly, an olefin 5a (dimer of the carbenoid 4a) was
obtained in 55% yield. The produced olefin 5a was found
R4
ArNLi
Ar=Ph, Tol
R=Alkyl, H
R4
R4
R-CH-NAr
COOEt
10
to be a mixture of two geometrical isomers (E/Z¼5:1).
ClCOOEt
R-CH-NAr
MgX
Quite interestingly, olefin 5a was not obtained at all from
carbenoid 4a in the absence of N-lithio piperidine. Obvi-
ously, N-lithio piperidine is essential in this olefin formation
6
7
(
Scheme 3).
R=Alkyl, H
R =CH3, CH2Ph
4
The reaction of the generated magnesium carbenoid 4a with
lithium diisopropylamide and lithium tert-butylamide gave
also olefin 5a in 37% and 46% yield, respectively (see the
table in Scheme 3). Again, the product 5a was a mixture
of two geometrical isomers and the ratio of the two isomers
was found to be variable by the used lithium amide.
Scheme 2.
the non-stabilized a-amino-substituted carbanions 6. We in-
vestigated the reactivity of the a-amino-substituted carban-
ions 6 with several electrophiles and found that the
reaction with ethyl chloroformate gave a-amino acid deriv-
8
atives 7 in good yields (Scheme 2).
A plausible mechanism for the formation of the olefin 5a
is proposed in Scheme 3. Thus, magnesium carbenoid 4a
reacted with N-lithio piperidine to give the a-amino-substi-
tuted carbanion 8 (metal was magnesium or lithium), which
reacted again with carbenoid 4a to give 9. b-Elimination of
N-magnesio (or lithio) piperidine from 9 afforded olefin 5a.
Herein we report in detail the generation of non-stabilized
a-amino-substituted carbanions 6 from magnesium carbe-
noids 4 with N-lithio N-substituted arylamines and a study
of their reactivity with some electrophiles. A new one-pot,
three-component combined synthesis of a-amino acid deriv-
atives 7 from 3, including glycine derivatives, is described.
2.2. Reaction of the generated magnesium carbenoids
with N-lithio arylamines
2
. Results and discussion
We next investigated the reaction of magnesium carbenoid
4a with N-lithio arylamines (Scheme 4). In contrast to the
reaction of 4a with N-lithio alkylamines, the reaction
with N-lithio aniline gave N-alkylaniline 10 in 67% yield.
In order to know if the intermediate of this reaction was
a-amino-substituted carbanion 12, the reaction mixture
was quenched with excess CD OD; however, no deuterium
3
was incorporated on the a-carbon in the N-alkylaniline 10.
Next, magnesium carbenoid 4a was treated with 5 equiv of
2.1. Generation of the magnesium carbenoid and the
reaction with N-lithio alkylamines
At first, 1-chloro-3-(4-methoxyphenyl)propyl phenyl sulf-
oxide 3a was synthesized from 3-(4-methoxyphenyl)propyl
9
phenyl sulfide and it was treated with 2.5 equiv of i-PrMgCl
at ꢀ70 C in THF to give cleanly magnesium carbenoid 4a
ꢁ
in a quantitative yield. To this solution was added 5 equiv of
9
O
2.5 eq.
i-PrMgCl
5
eq.
NLi
CH3O
CH2CH2CHSPh
Cl
ArCH CH CHMgCl
2 2 2 2
ArCH CH CH=CHCH CH Ar
2
2
THF, -70 °C
-70 °C, 10 min
then -70 ~ -40 °C for 1 h
5%
Cl
10 min
5a (E/Z=5/1)
3a
5
4a
ArCH2CH2CHMgCl
Cl
NLi
N
N
4a
4a
ArCH2CH2CHMgCl
or Li)
2 2 2 2
ArCH CH CH-CHCH CH Ar
(
8
MgCl
or Li)
9
(
ArCH2CH2CH=CHCH2CH2Ar
5a
NMgCl
or Li)
Lithium amide
5a
(
Yield / %
37
i-Pr2NLi
E/Z=4/1
E/Z=2/1
t-BuNHLi
46
Scheme 3. Treatment of magnesium carbenoid 4a with N-lithio alkylamines to give olefin 5a and a plausible mechanism for the formation of the olefin.

7894
T. Satoh et al. / Tetrahedron 62 (2006) 7892–7901
1
2
) 5 eq.
NHLi
67%
CH3O
CH2CH2CHMgCl
Cl
ArCH2CH2CH2NH
) CD3OD
10
4a
1
2
) 5 eq.
NCH3Li
77%
CH3
4a
ArCH2CH2CHN
D
) CD3OD
1
1a (D-content, 91%)
LiHN
H
H
CD3OD
ArCH2CH2CH2NHPh
ArCH2CH2CHMgCl
Cl
ArCH2CH2CHNPh
ArCH2CH2CHNPh
MgCl
MgCl
10
4a
12
13
NCH3Li
CH3
CH3
CD3OD
ArCH2CH2CHNPh
D
4a
ArCH2CH2CHNPh
MgCl
14
11a
Scheme 4. Treatment of magnesium carbenoid 4a with N-lithio aniline and N-lithio N-methylaniline, and a plausible mechanism for the formation of N-alkyl-
aniline 10 and N-(1-deuterated alkyl)-N-methylaniline 11a.
N-lithio N-methylaniline under the same conditions as
above, and the reaction mixture was quenched with excess
good result (entries 5 and 6). We decided to use THF as a
solvent without any additive throughout this study.
CD OD. We obtained the N,N-dialkylaniline 11a in 77%
3
yield and the product was deuterated on the a-carbon and
the deuterium incorporation was found to be 91% judging
from its H NMR spectra. A plausible mechanism of this
interesting reaction is shown in Scheme 4.
Next, we investigated trapping the generated non-stabilized
a-amino carbanion 14 with electrophiles other than deute-
rium (Scheme 5). After the generation of carbanion 14
1
ꢁ
at ꢀ70 to ꢀ40 C, 5 equiv of aldehydes (benzaldehyde and
propionaldehyde), acetophenone, benzoyl chloride, or pro-
pionyl chloride were added. Carbanion 14 proved to show
quite low reactivity and all these reactions gave only a rather
complex mixture with the protonated product 11b.
The reaction of the magnesium carbenoid with N-lithio
aniline gave the desired a-amino-substituted carbanion 12.
As carbanion 12 has an acidic hydrogen on the nitrogen, the
carbanion quickly picks up this acidic hydrogen to give 13.
So, as described above, on quenching this reaction with
CD OD no deuterium was incorporated on the a-carbon.
3
Table 1. Reaction of magnesium carbenoid 4a with N-lithio N-methyl-
aniline in several solvents
In contrast to this, the reaction of 4a with N-lithio N-methyl-
aniline provided the a-amino-substituted carbanion 14,
which has no acidic hydrogen on the nitrogen, to give the
product 11a deuterated at the a-position.
1)
NCH3Li
5 eq)
(
-70 ~ -40 °C
Solvent
CH3
4a
ArCH2CH2CH2NPh
Generation of the non-stabilized a-amino-substituted carb-
anions is well recognized to be quite difficult from unacti-
vated amines. The results obtained in this study are highly
notable as a new method for generation of non-stabilized
2) H2O
11b
Entry
Solvent
11b
3
,4
a-amino carbanions.
Yield/%
1
2
3
4
5
6
THF
THF+DME (6 equiv)
THF+HMPA (6 equiv)
Toluene
Toluene+DME (6 equiv)
Diethyl ether+THF (4:1)
77
79
78
47
56
49
We investigated the best conditions for the reaction of 4awith
N-lithio N-methylaniline and the results are summarized
in Table 1. As shown in Table 1, DME or HMPA as
additive gave almost the same results (entries 2 and 3). Tolu-
ene as a solvent gave much lower yield (entry 4). A mixture
of toluene–DME and diethyl ether–THF did not show any
a
a
a
a
Corresponding to 4a.
Li
NCH3
CH3
CH3
(
5 eq or 3.5 eq)
ClCOOEt
3%
CH3O
CH2CH2CHMgCl
Cl
2 2
ArCH CH CHN
ArCH2CH2CHNPh
MgCl
7
COOEt
7a
4a
14
Scheme 5. Treatment of magnesium carbenoid 4a with N-lithio N-methylaniline followed by ethyl chloroformate to give a-amino acid derivative 7a.

T. Satoh et al. / Tetrahedron 62 (2006) 7892–7901
7895
Fortunately, addition of 5 equiv of ethyl chloroformate gave
a clean reaction mixture and the desired ethoxycarbonylated
2.3. Investigation for generality of the new synthetic
method of a-deuterio amines and a-amino acid ethyl
esters
product, a-amino acid ester, 7a was obtained in 73% yield
(
Scheme 5). After some further investigation for improve-
ment of this reaction, reducing of N-lithio N-methylaniline
to 3.5 equiv was found to be enough to give the same yield.
We used 3.5 equiv of N-lithio N-substituted arylamines and
5 equiv of ethyl chloroformate in this new method for the
synthesis of a-amino acid derivatives 7 (vide infra).
Generality of the above-mentioned reaction was investi-
gated using four kinds of 1-chloroalkyl phenyl sulfoxides
3 and N-methyl-p-anisidine, N-benzyl-p-anisidine, and
N-methyl-p-chloroaniline. The results are summarized in
Table 2.
Table 2. Synthesis of a-deuterio N,N-dialkyl arylamines and a-amino acid esters from magnesium carbenoids 4 by the reaction with N-lithio N-substituted
arylamines followed by methanol-d or ethyl chloroformate
4
R1
1) 3.5 eq. ArNLi
2) Electrophile
O
2.5 eq.
i-PrMgCl
R1
RCHSPh
Cl 3
RCHMgCl
RCHN-Ar
THF, -70 °C
Cl
E
4
15
1
Entry
3
Ar
R
Electrophile
E
15
R
Yield/%
CH3O
CH2CH2
a
1
CH3O
CH
3
CD
3
OD
D
15a 81%
3a
2
3
4
5
6
3a
CH O
CH
CH
CH
3
3
3
ClCOOEt
CD OD
COOEt
D
15b 74%
3
a
3a
3a
3a
3a
Cl
3
15c 79%
15d 73%
Cl
ClCOOEt
CD OD
ClCOOEt
COOEt
D
b
CH O
3
PhCH
2
2
3
15e 69%
CH O
3
PhCH
COOEt
15f 67%
CH2CH2
CH3O
c
7
8
9
PhCH
2
2
CD
3
OD
D
15g 73%
3
b
3b
CH O
PhCH
ClCOOEt
COOEt
D
15h 71%
3
CH2
CH3O
b
CH
3
CD
3
OD
15i 70%
3
c
10
11
12
3c
CH O
CH
CH
CH
3
3
3
ClCOOEt
CD OD
ClCOOEt
COOEt
D
15j 68%
15k 72%
15l 68%
3
c
3c
3c
Cl
3
Cl
COOEt
CH3O
d
13
CH
3
CD
3
OD
D
15m 48%
3d
14
15
16
3d
3d
3d
CH O
CH
CH
CH
3
3
3
ClCOOEt
CD OD
COOEt
D
15n 48%
3
b
Cl
3
15o 42%
Cl
ClCOOEt
COOEt
15p 41%
a
b
c
d
D-content 90%.
D-content 97%.
D-content 95%.
D-content 99%.

7896
T. Satoh et al. / Tetrahedron 62 (2006) 7892–7901
Entries 1–6 show that the reaction of the magnesium carbe-
noid generated from 3a with three kinds of arylamines,
N-methyl-p-anisidine, N-methyl-p-chloroaniline, and N-
benzyl-p-anisidine, gave equally good yields (67–81%) of
the a-deuterio amines or a-amino acid derivatives. The reac-
tion starting from the sulfoxide having a 2-phenylethyl
group as R (3b) gave similar results (entries 7 and 8). Entries
3e in THF was added to a solution of i-PrMgCl (2.5 equiv)
in THF at ꢀ78 C and after 10 min a solution of N-lithio
ꢁ
N-benzyl-p-anisidine was added to the reaction mixture.
The temperature of the reaction mixture was slowly allowed
to warm to ꢀ40 C. We obtained the desired 16; however, the
ꢁ
yield was only 23% (entry 1).
9
–12 show the reaction starting from sulfoxide 3c having
After some investigation, as we found that the generated
carbenoid 4e was fairly unstable, it was immediately treated
with N-lithio N-benzyl-p-anisidine to give better yield
(entry 2). Finally, the conditions shown in entry 3 were found
to be the choice for this reaction. We further investigated
other conditions shown in entries 4–6; however, all the trials
were ineffective.
a cyclohexylmethyl group as 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 (3d) showed markedly diminished yield of the
a-deuterio amines and a-amino acid derivatives (entries
1
3–16). Steric hindrance or the stability of the generated
magnesium carbenoid is thought to be the reason for the
lowering of the yield.
Next, magnesium carbenoid 4e was treated with N-lithio
amines and the generated a-amino-substituted carbanions
17 were treated with water or methanol-d (Table 4). The
2
.4. Synthesis of glycine derivatives
1
reaction of 4e with N-lithio N-benzyl-p-anisidine followed
by CH OD gave the deuterated amine 19a with 96% deute-
rium incorporation (entry 2). The reaction with N-lithio
N-methyl-p-anisidine gave the desired amine 18b or deuter-
ated amine 19b; however, the yield was not satisfactory
We further investigated the generation of magnesium
methylidene 4e from chloromethyl p-tolyl sulfoxide 3e
with i-PrMgCl at ꢀ78 C and trapping of the carbenoid with
3
ꢁ
N-lithio N-benzyl-p-anisidine (Table 3). Thus, a solution of
(entries 3 and 4). Interestingly the reaction of the magnesium
methylidene 4e with N-lithio alkylamine (dibenzylamine)
gave 18c and 19c in 31% yield.
Table 3. Generation of magnesium carbenoid 4e from chloromethyl p-tolyl
sulfxoide 3e with Grignard reagent and the trapping of 4e with N-lithio
N-benzyl-p-anisidine
Finally, we studied the reaction for the synthesis of glycine
derivatives by the trapping of the generated a-amino-sub-
stituted carbanions 17 with ethyl chloroformate (Table 5).
The reaction of magnesium carbenoid 4e with N-lithio
N-benzyl-p-anisidine followed by ethyl chloroformate gave
the desired a-amino acid ester 20a in 58% yield. Although
the yield of the corresponding amine 18b was 35%, the
glycine derivative 20b was obtained in moderate yield
Li
CH3O
NCH2Ph
O
2.5 eq.
RMgCl
(3.5 eq)
H2CSTol
Cl
CH MgCl
CH3O
NCH2Ph
CH3
2
Solvent,
-78 °C
Cl
3e
4e
16
Entry
Solvent
RMgCl
Temperature
16
(entry 2). The reaction using N-methyl-p-chloroaniline and
Yield/%
N-methylaniline gave the desired amino acid ethyl ester 20c
and 20d; however, the yields were low (entries 3 and 4). As
shown in entry 5, although the yield was low, N,N-dibenzyl-
glycine ethyl ester 20e could be synthesized by this method.
ꢁ
ꢁ
a
b
b
b
b
b
1
2
3
4
5
6
THF
THF
THF
THF
THF
Toluene
i-PrMgCl
i-PrMgCl
i-PrMgCl
i-PrMgBr
EtMgCl
ꢀ78 to ꢀ40 C
23
36
65
32
15
20
ꢀ78 to ꢀ70 C
ꢁ
ꢀ78 to ꢀ40 C
ꢁ
ꢀ78 to ꢀ40 C
ꢁ
ꢀ78 to ꢀ40 C
ꢁ
i-PrMgCl
ꢀ78 to ꢀ40 C
In conclusion, we have found a novel and versatile method
for generation of non-stabilized a-amino-substituted carb-
anions by the reaction of magnesium carbenoids with
N-lithio N-alkyl arylamines. Trapping the non-stabilized
a
N-Lithio arylamine was added after 10 min.
N-Lithio arylamine was added immediately after generation of mag-
nesium carbenoid 4e.
b
Table 4. Generation of magnesium carbenoid 4e from chloromethyl p-tolyl sulfxoide 3e with Grignard reagent and the trapping of 4e with N-lithio amines
followed by water or methanol-d
1
O
2.5 eq.
i-PrMgCl
Li
CH2Y
R1 N R2
18 Y=H
R1 N R2
(3.5 eq)
CH2MgCl H O or CH OD
2
3
H2CSTol
Cl
4e
R1 N R2
17
THF, -78 °C
-78 ~ -40 °C
3e
19 Y=D
Entry
Amine
Electrophile
16, 18 or 19
(D content/%)
1
R
2
R
Yield/%
1
2
H
CH
2
O
16
19a
65
65 (96)
H3CO
H3CO
CH2
CH2
3
OD
3
4
H
CH
2
O
18b
19b
35
35 (99)
CH3
3
OD
5
6
H
CH
2
O
18c
19c
31
31 (99)
CH2
3
OD

T. Satoh et al. / Tetrahedron 62 (2006) 7892–7901
7897
ꢁ
Table 5. Synthesis of glycine derivatives 20 from magnesium carbenoid 4e
with N-lithio amines followed by ethyl chloroformate
cooled to ꢀ70 C] through a cannula with stirring. The reac-
ꢁ
and the reaction mixture was quenched with satd aq NH Cl.
tion mixture was slowly allowed to warm to ꢀ40 C for 1 h
Li
4
CH2COOEt
R1 N R2
R1 N R2
(3.5 eq)
2
CH MgCl
R1 N R2
17
ClCOOEt
The whole was extracted with CHCl and the organic layer
3
was washed with satd aq NH Cl and dried over MgSO .
4
4e
-78 ~ -40 °C
4
20
The product was purified by silica gel column chromato-
graphy to afford 5a (33 mg; 55%) as a colorless oil (a mix-
ture of two geometrical isomers; the ratio is about E/Z¼5:1).
Entry
Amine
20
1
R
2
R
Yield/%
ꢀ1 1
IR (neat) 3010, 2933, 1611, 1510, 1245, 1037, 757 cm ; H
NMR d 2.24–2.26 (4H, m), 2.52 (0.7H, t, J¼7.8 Hz), 2.59
1
2
3
4
5
6
H CO
CH2
20a 58
20b 61
20c 30
20d 23
20e 25
0
3
(
3.3H, t, J¼7.8 Hz), 3.78 (6H, s), 5.40 (0.3H, t, J¼4.7 Hz),
5
.46 (1.7H, t, J¼3.7 Hz), 6.81 (4H, d, J¼8.5 Hz), 7.07
3
H CO
CH
CH
CH
3
3
3
(4H, d, J¼8.5 Hz). MS m/z (%) 296 (M , 15), 121 (100).
Calcd for C H O : M, 296.1774. Found: m/z 296.1774.
+
2
0 24 2
Cl
3.1.2. Ethyl 4-(4-methoxyphenyl)-2-(N-methyl-N-phenyl-
amino)butyrate (7a). To a solution of i-PrMgCl (0.5 mmol)
ꢁ
argon atmosphere was added a solution of 3a (62 mg;
in 0.5 mL of dry THF in a flame-dried flask at ꢀ70 C under
CH2
CH2
0
.2 mmol) in 0.4 mL of dry THF dropwise with stirring.
ꢁ
The reaction mixture was stirred at ꢀ70 C for 10 min. To
a solution of the generated magnesium carbenoid 4a was
added a solution of N-lithio N-methylaniline [prepared from
N-methylaniline (1 mmol) and n-BuLi (1.2 mmol) in 2 mL
ꢁ
ꢁ
of THF at 0 C and the solution was cooled to ꢀ70 C]
through a cannula with stirring. The reaction mixture was
slowly allowed to warm to ꢀ40 C for 1 h. To a solution
ꢁ
of the a-amino-substituted carbanion 14 was added ethyl
a-amino-substituted carbanions with deuterated methanol
gave amines having the alkyl group deuterated at the a-posi-
tion. Trapping the carbanions with ethyl chloroformate gave
a-amino acid ethyl esters. As a whole, a novel method for the
synthesis of a-amino acid derivatives from three compo-
nents, aryl 1-chloroalkyl sulfoxide, N-alkyl arylamines,
and ethyl chloroformate, in one flask was realized.
ꢁ
chloroformate (1 mmol) dropwise at ꢀ40 C with stirring.
After 20 min, the reaction mixture was quenched with satd
aq NH Cl. The whole was extracted with CHCl and the
organic layer was washed with satd aq NH Cl and dried
4
3
4
over MgSO . The product was purified by silica gel column
4
chromatography to afford 7a (48 mg; 73%) as colorless oil;
IR (neat) 2955, 1731 (CO), 1600, 1512, 1301, 1247, 1179,
ꢀ
1 1
3
. Experimental
1036, 751, 693 cm ; H NMR d 1.21 (3H, t, J¼7.0 Hz),
.11–2.18 (1H, m), 2.20–2.28 (1H, m), 2.53–2.59 (1H, m),
2.64–2.70 (1H, m), 2.93 (3H, s), 3.78 (3H, s), 4.09–4.17
2
3
.1. General
(
2H, m), 4.31 (1H, dd, J¼9.3, 5.5 Hz), 6.75 (3H, m), 6.80
1
H NMR spectra were measured in a CDCl solution with
3
(2H, d, J¼8.6 Hz), 7.05 (2H, d, J¼8.6 Hz), 7.22 (2H, m).
+
JOEL JNM-LA 500 spectrometer. Electron-impact mass
spectra (MS) were obtained at 70 eV by direct insertion.
Silica gel 60 (Merck) containing 0.5% fluorescence reagent
MS m/z (%) 327 (M , 20), 254 (75), 132 (9), 121 (100),
91 (9). Calcd for C H NO : M, 327.1835. Found:
m/z 327.1838.
2
0
25
3
2
54 and a quartz column were used for column chromato-
graphy and the products having UVabsorption were detected
by UV irradiation. In experiments requiring a dry reagent
and solvent, THF was distilled from diphenylketyl. Piperi-
dine, diisopropylamine, tert-butylamine, and toluene were
dried over CaH and distilled before use. HMPA were dried
3.1.3. N-[3-(4-Methoxyphenyl)propyl]aniline (10). To
a solution of i-PrMgCl (0.5 mmol) in 0.5 mL of dry THF
ꢁ
in a flame-dried flask at ꢀ70 C under argon atmosphere
was added a solution of 3a (62 mg; 0.2 mmol) in 0.4 mL
of dry THF dropwise with stirring. The reaction mixture was
ꢁ
over CaSO and distilled before use. 1-Chloroalkyl phenyl
4
stirred at ꢀ70 C for 10 min. To a solution of the generated
sulfoxides 3a–d were synthesized from the corresponding
alcohols (or halides) via the sulfides in the same way as
described before.
magnesium carbenoid 4a was added a solution of N-lithio
aniline [prepared from aniline (1 mmol) and n-BuLi
9
,12
ꢁ
(1.2 mmol) in 2 mL of THF at 0 C and the solution was
ꢁ
cooled to ꢀ70 C] through a cannula with stirring. The reac-
ꢁ
The reaction mixture was quenched with excess CD OD.
3.1.1. 1,6-Di(4-methoxyphenyl)-3-hexene (5a). To a solu-
tion of i-PrMgCl (0.5 mmol) in 0.5 mL of dry THF in a
tion mixture was slowly allowed to warm to ꢀ40 C for 1 h.
3
ꢁ
added a solution of 3a (62 mg; 0.2 mmol) in 0.4 mL of
flame-dried flask at ꢀ70 C under argon atmosphere was
The whole was extracted with CHCl . The organic layer
3
9
was washed satd aq NH Cl and dried over MgSO . The prod-
4
4
dry THF dropwise with stirring. The reaction mixture was
stirred at ꢀ70 C for 10 min. To a solution of the generated
uct was purified by silica gel column chromatography to
afford 10 (32 mg; 67%) as colorless oil; IR (neat) 3404,
ꢁ
magnesium carbenoid 4a was added a solution of N-lithio
ꢀ
1
2933, 2835, 1604, 1512, 1246, 1178, 1035, 750, 693 cm ;
H NMR d 1.91 (2H, quintet, J¼7.3 Hz), 2.67 (2H, t,
J¼7.3 Hz), 3.12 (2H, t, J¼7.3 Hz), 3.59 (1H, s), 3.79 (3H,
1
piperidine [prepared from piperidine (1 mmol) and n-BuLi
ꢁ
(
1.2 mmol) in 2 mL of THF at 0 C and the solution was

7898
T. Satoh et al. / Tetrahedron 62 (2006) 7892–7901
+
s), 6.57 (2H, d, J¼8.8 Hz), 6.68 (1H, t, J¼7.3 Hz), 6.83 (2H,
d, J¼8.6 Hz), 7.11 (2H, d, J¼8.3 Hz), 7.16 (2H, m). MS
J¼7.5 Hz). MS m/z (%) 361 (M , 20), 290 (20), 288 (55),
122 (10), 121 (100). Calcd for C H ClNO : M,
24
2
0
3
+
m/z (%) 241 (M , 50), 148 (37), 121 (13), 106 (100), 93
361.1443. Found: m/z 361.1442.
(
m/z 241.1463.
11), 77 (16). Calcd for C H NO: M, 241.1465. Found:
16 19
3.1.10. N-Benzyl-N-[1-deuterio-3-(4-methoxyphenyl)-
propyl]-p-anisidine (15e). Colorless oil; IR (neat) 2933,
ꢀ1 1
3.1.4. N-[1-Deuterio-3-(4-methoxyphenyl)propyl]-N-
methylaniline (11a). Colorless oil; IR (neat) 2934, 1600,
1611, 1510, 1452, 1242, 1178, 1037, 814 cm ; H NMR
d 1.89 (2H, q, J¼7.6 Hz), 2.57 (2H, t, J¼7.6 Hz), 3.29
(1H, t, J¼7.6 Hz), 3.72 (3H, s), 3.78 (3H, s), 4.42 (2H, s),
6.61 (2H, d, J¼9.2 Hz), 6.76 (2H, d, J¼9.2 Hz), 6.81 (2H,
d, J¼8.6 Hz), 7.06 (2H, d, J¼8.6 Hz), 7.20–7.24 (3H, m),
ꢀ
1 1
1
511, 1300, 1245, 1177, 1035, 748, 692 cm ; H NMR
d 1.89 (2H, q, J¼7.7 Hz), 2.59 (2H, t, J¼7.7 Hz), 2.91
(
(
7
3H, s), 3.30 (1H, t, J¼7.7 Hz), 3.79 (3H, s), 6.63–6.69
+
3H, m), 6.83 (2H, d, J¼8.6 Hz), 7.10 (2H, d, J¼8.6 Hz),
7.27–7.30 (2H, m). MS m/z (%) 362 (M , 60), 227 (70),
+
.18–7.22 (2H, m). MS m/z (%) 256 (M , 25), 121 (100),
07 (15), 77 (12). Calcd for C H DNO: M, 256.1685.
137 (15), 121 (20), 91 (100). Calcd for C H DNO : M,
2
4
26
2
1
Found: m/z 256.1687.
362.2102. Found: m/z 362.2096.
1
7 20
3.1.11. Ethyl 2-[benzyl(4-methoxyphenyl)amino]-4-
(4-methoxyphenyl)butyrate (15f). Colorless oil; IR (neat)
2935, 1732 (CO), 1612, 1512, 1454, 1300, 1246, 1178,
3
(
.1.5. N-Methyl-N-[3-(4-methoxyphenyl)propyl]aniline
11b). Colorless oil; IR (neat) 2935, 1600, 1511, 1371,
ꢀ
1
1
ꢀ1
1
1
246, 1178, 1035, 749, 693 cm ; H NMR d 1.87 (2H,
1039, 819, 755 cm ; H NMR d 1.22 (3H, t, J¼7.0 Hz),
2.04–2.12 (1H, m), 2.20–2.26 (1H, m), 2.60–2.73 (2H, m),
3.72 (3H, s), 3.78 (3H, s), 4.12 (2H, q, J¼7.0 Hz), 4.25
(1H, t, J¼7.2 Hz), 4.51 (1H, d, J¼17.1 Hz), 4.57 (1H, d,
J¼17.1 Hz), 6.73 (4H, s), 6.78 (2H, d, J¼8.6 Hz), 6.97
(2H, d, J¼8.6 Hz), 7.19–7.21 (1H, m), 7.27–7.32 (4H, m).
quintet, J¼7.6 Hz), 2.59 (2H, t, J¼7.6 Hz), 2.91 (3H, s),
3
6
.32 (2H, t, J¼7.6 Hz), 3.79 (3H, s), 6.64–6.69 (3H, m),
.82 (2H, d, J¼8.6 Hz), 7.10 (2H, d, J¼8.6 Hz), 7.18–7.22
+
(
2H, m). MS m/z (%) 255 (M , 30), 120 (100), 107 (13),
7
2
7 (11). Calcd for C H NO: M, 255.1623. Found: m/z
17 21
55.1616.
+
MS m/z (%) 433 (M , 35), 360 (100), 212 (18), 147 (8),
1
433.2253. Found: m/z 433.2260.
21 (80), 91 (55), 77 (8). Calcd for C H NO : M,
27 31 4
3.1.6. N-[1-Deuterio-3-(4-methoxyphenyl)propyl]-N-
methyl-p-anisidine (15a). Colorless oil; IR (neat) 2932,
ꢀ
1 1
1
611, 1508, 1243, 1037, 814 cm ; H NMR d 1.83 (2H,
3.1.12. N-Benzyl-N-(1-deuterio-3-phenylpropyl)-p-anisi-
dine (15g). Colorless oil; IR (neat) 2935, 1512, 1453,
1242, 1044, 814, 699 cm ; H NMR d 1.93 (2H, q,
q, J¼7.6 Hz), 2.57 (2H, t, J¼7.6 Hz), 2.84 (3H, s), 3.21
ꢀ1
1
(
1H, t, J¼7.5 Hz), 3.75 (3H, s), 3.79 (3H, s), 6.66 (2H, d,
J¼9.2 Hz), 6.79–6.84 (4H, m), 7.09 (2H, d, J¼8.6 Hz).
J¼7.6 Hz), 2.62 (2H, t, J¼7.6 Hz), 3.31 (1H, t, J¼7.6 Hz),
3.72 (3H, s), 4.43 (2H, s), 6.61 (2H, d, J¼8.9 Hz), 6.76
+
MS m/z (%) 286 (M , 40), 151 (100), 137 (13), 121 (20).
Calcd for C H DNO : M, 286.1791. Found: m/z 286.1796.
(2H, d, J¼8.9 Hz), 7.15–7.18 (3H, m), 7.21–7.23 (3H, m),
1
8
22
2
+
7
.26–7.30 (4H, m). MS m/z (%) 332 (M , 50), 269 (10),
3.1.7. Ethyl 4-(4-methoxyphenyl)-2-[N-(4-methoxy-
phenyl)-N-methylamino]butyrate (15b). Colorless oil; IR
227 (70), 137 (10), 91 (100). Calcd for C H DNO: M,
23 24
332.1996. Found: m/z 332.1995.
(
neat) 2936, 1729 (CO), 1612, 1511, 1464, 1299, 1245,
ꢀ1 1
1
2
2
4
179, 1037, 818 cm ; H NMR d 1.19 (3H, t, J¼7.3 Hz),
.08–2.23 (2H, m), 2.55–2.61 (1H, m), 2.65–2.71 (1H, m),
.88 (3H, s), 3.76 (3H, s), 3.79 (3H, s), 4.08–4.11 (2H, m),
3.1.13. Ethyl 2-[benzyl(4-methoxyphenyl)amino]-4-
phenylbutyrate (15h). Colorless oil; IR (neat) 2935, 1732
(CO), 1604, 1512, 1453, 1244, 1179, 1040, 818, 737,
ꢀ
1 1
.14–417 (1H, m), 6.74 (2H, d, J¼8.9 Hz), 6.79–6.82 (4H,
700 cm ; H NMR d 1.22 (3H, t, J¼7.0 Hz), 2.08–2.16
(1H, m), 2.23–2.30 (1H, m), 2.66–2.71 (1H, m), 2.73–2.79
(1H, m), 3.72 (3H, s), 4.13 (2H, q, J¼7.0 Hz), 4.27 (1H,
t, J¼7.2 Hz), 4.52 (1H, d, J¼17.1 Hz), 4.57 (1H, d,
J¼17.1 Hz), 6.72–6.76 (4H, m), 7.07 (2H, d, J¼7.7 Hz),
7.16–7.22 (2H, m), 7.23–7.25 (2H, m), 7.28–7.33 (4H, m).
+
m), 7.06 (2H, d, J¼8.6 Hz). MS m/z (%) 357 (M , 35),
2
3
84 (80), 122 (10), 121 (100). Calcd for C H NO : M,
21 27 4
57.1938. Found: m/z 357.1936.
3.1.8. N-[1-Deuterio-3-(4-methoxyphenyl)propyl]-N-
methyl-4-chloroaniline (15c). Colorless oil; IR (neat)
+
MS m/z (%) 403 (M , 20), 330 (100), 285 (18), 134 (10),
91 (80). Calcd for C H NO : M, 403.2146. Found: m/z
403.2160.
ꢀ
1 1
2
934, 1596, 1505, 1245, 809 cm ; H NMR d 1.84 (2H,
2
6
29
3
q, J¼7.6 Hz), 2.58 (2H, t, J¼7.6 Hz), 2.88 (3H, s), 3.26
(
6
1H, t, J¼7.6 Hz), 3.79 (3H, s), 6.53 (2H, d, J¼9.2 Hz),
.83 (2H, d, J¼8.5 Hz), 7.08–7.13 (4H, m). MS m/z (%)
3.1.14. N-(1-Deuterio-2-cyclohexylethyl)-N-methyl-p-
anisidine (15i). Colorless oil; IR (neat) 2922, 2851, 1515,
+
290 (M , 40), 155 (100), 141 (20), 121 (10). Calcd for
C H DClNO: M, 290.1294. Found: m/z 290.1292.
ꢀ
1 1
1448, 1244, 1042, 813 cm ; H NMR d 0.87–0.98 (2H,
m), 1.11–1.27 (4H, m), 1.40 (2H, t, J¼7.6 Hz), 1.64–1.74
(5H, m), 2.83 (3H, s), 3.22 (1H, t, J¼7.6 Hz), 3.76 (3H, s),
6.69 (2H, d, J¼9.2 Hz), 6.83 (2H, d, J¼9.2 Hz). MS m/z
1
7 19
3.1.9. Ethyl 2-[N-(4-chlorophenyl)-N-methylamino]-4-(4-
methoxyphenyl)butyrate (15d). Colorless oil; IR (neat)
+
2
1
2
2
956, 1732 (CO), 1597, 1513, 1301, 1247, 1179, 1102,
(%) 248 (M , 30), 151 (100), 136 (10), 121 (8). Calcd for
ꢀ1 1
036, 812 cm ; H NMR d 1.20 (3H, t, J¼7.5 Hz), 2.10–
.17 (1H, m), 2.20–2.27 (1H, m), 2.51–2.57 (1H, m),
.64–2.69 (1H, m), 2.90 (3H, s), 3.79 (3H, s), 4.11–4.17
C H DNO: M, 248.1997. Found: m/z 248.2007.
16 24
3.1.15. Ethyl 3-cyclohexyl-2-[N-(4-methoxyphenyl)-N-
methylamino]propionate (15j). Colorless oil; IR (neat)
2924, 2852, 1732 (CO), 1514, 1448, 1247, 1182, 1040,
(
(
2H, m), 4.20–4.23 (1H, m), 6.64 (2H, d, J¼7.5 Hz), 6.80
2H, d, J¼6.0 Hz), 7.03 (2H, d, J¼6.0 Hz), 7.14 (2H, d,

T. Satoh et al. / Tetrahedron 62 (2006) 7892–7901
7899
ꢀ
1
1
+
8
17 cm ; H NMR d 0.87–1.02 (2H, m), 1.11–1.16 (2H,
m), 1.19 (3H, t, J¼7.3 Hz), 1.29–1.38 (1H, m), 1.58–1.78
8H, m), 2.84 (3H, s), 3.76 (3H, s), 4.07–4.14 (2H, m),
7.15 (2H, d, J¼8.9 Hz). MS m/z (%) 309 (M , 18), 236
(100), 226 (23), 198 (13), 154 (40), 138 (8). Calcd for
C H ClNO : M, 309.1494. Found: m/z 309.1498.
(
1
7
24
2
4
.30 (1H, t, J¼7.6 Hz), 6.77–6.83 (4H, m). MS m/z (%)
+
319 (M , 15), 246 (100), 164 (8), 55 (8). Calcd for
C H NO : M, 319.2145. Found: m/z 319.2143.
3.1.22. N-Benzyl-N-methyl-p-anisidine (16). To a solution
of i-PrMgCl (0.5 mmol) in 0.5 mL of dry THF in a flame-
1
9
29
3
ꢁ
dried flask at ꢀ78 C under argon atmosphere was added
3.1.16. N-(1-Deuterio-2-cyclohexylethyl)-N-methyl-4-
chloroaniline (15k). Colorless oil; IR (neat) 2923, 2852,
a solution of 3e (38 mg; 0.2 mmol) in 0.4 mL of dry THF
dropwise with stirring. Immediately, to a solution of the
generated magnesium carbenoid 4e was added a solution
of N-lithio N-benzyl-p-anisidine [prepared from N-benzyl-
p-anisidine (0.7 mmol) and n-BuLi (0.77 mmol) in 2 mL
ꢀ1 1
1
0
1
6
597, 1505, 1448, 1216, 808, 760 cm ; H NMR d 0.90–
.99 (2H, m), 1.13–1.27 (4H, m), 1.41 (2H, t, J¼7.3 Hz),
.64–1.73 (5H, m), 2.87 (3H, s), 3.27 (1H, t, J¼7.3 Hz),
ꢁ
ꢁ
.57 (2H, d, J¼8.9 Hz), 7.13 (2H, d, J¼8.9 Hz). MS m/z
of THF at 0 C and the solution was cooled to ꢀ78 C]
+
(%) 252 (M , 20), 155 (100), 140 (10). Calcd for
C H DClN: M, 252.1502. Found: m/z 252.1505.
through a cannula with stirring. The reaction mixture was
slowly allowed to warm to ꢀ40 C for 1 h. The reaction mix-
ꢁ
ture was quenched with satd aq NH Cl. The whole was ex-
1
5 21
4
3.1.17. Ethyl 2-[N-(4-chlorophenyl)-N-methylamino]-3-
cyclohexylpropionate (15l). Colorless oil; IR (neat) 2925,
tracted with CHCl and the organic layer was washed with
3
satd aq NH Cl and dried over MgSO . The product was
4
4
2
8
852, 1733 (CO), 1598, 1499, 1188, 1140, 1104,
11 cm ; H NMR d 0.87–1.02 (2H, m), 1.14–1.16 (2H,
purified by silica gel column chromatography to afford 16
(30 mg; 65%) as a colorless oil.
ꢀ
1
1
11
m), 1.21 (3H, t, J¼7.3 Hz), 1.26–1.31 (1H, m), 1.56–1.69
(
6H, m), 1.77 (2H, t, J¼7.3 Hz), 2.87 (3H, s), 4.09–4.16
3.1.23. N,N-Dimethyl-p-anisidine (18b). Colorless oil; IR
(neat) 2933, 1515, 1245, 1038, 817 cm ; H NMR d 2.86
(6H, s), 3.76 (3H, s), 6.75 (2H, d, J¼8.9 Hz), 6.84 (2H, d,
ꢀ
1 1
(
7
2H, m), 4.37 (1H, t, J¼7.3 Hz), 6.71 (2H, d, J¼8.3 Hz),
+
.17 (2H, d, J¼8.3 Hz). MS m/z (%) 323 (M , 10), 250
+
(
M, 323.1650. Found: m/z 323.1648.
100), 168 (15), 154 (20), 55 (17). Calcd for C H ClNO :
1
J¼8.9 Hz). MS m/z (%) 151 (M , 65), 136 (100), 108 (12),
8
26
2
65 (8). Calcd for C H NO: M, 151.0996. Found: m/z
13
9
151.0998.
3.1.18. N-[Cyclohexyl(deuterio)methyl]-N-methyl-p-ani-
sidine (15m). Colorless oil; IR (neat) 2923, 2851, 1513,
3.1.24. N-Methyldibenzylamine (18c). Colorless oil; IR
(neat) 3028, 2786, 1495, 1453, 1366, 1024, 736,
ꢀ
1
1
1448, 1245, 1181, 1121, 1042, 811, 757, 692 cm ; H
NMR d 0.86–0.95 (2H, m), 1.11–1.26 (3H, m), 1.64–1.75
ꢀ1 1
698 cm ; H NMR d 2.18 (3H, s), 3.52 (4H, s), 7.21–7.25
(2H, m), 7.29–7.33 (4H, m), 7.35–7.37 (4H, m). MS m/z
(%) 211 (M , 40), 134 (40), 120 (20), 91 (100). Calcd for
(
6H, m), 2.88 (3H, s), 3.00 (1H, d, J¼6.7 Hz), 3.75 (3H,
+
s), 6.63 (2H, d, J¼8.9 Hz), 6.82 (2H, d, J¼8.9 Hz). MS
+
m/z (%) 234 (M , 25), 151 (100), 136 (10). Calcd for
C H DNO: M, 234.1841. Found: m/z 234.1844.
C H N: M, 211.1360. Found: m/z 211.1364.
15 17
1
5 22
3.1.25. N-Benzyl-N-deuteriomethyl-p-anisidine (19a).
Colorless oil; IR (neat) 2932, 2831, 1509, 1451, 1241,
3.1.19. Ethyl cyclohexyl[N-(4-methoxyphenyl)-N-methyl-
amino]acetate (15n). Colorless oil; IR (neat) 2929, 2852,
ꢀ1 1
1040, 813 cm ; H NMR d 2.89 (2H, t, J¼1.5 Hz), 3.75
(3H, s), 4.42 (2H, s), 6.73 (2H, d, J¼8.9 Hz), 6.82 (2H, d,
1
8
731 (CO), 1512, 1449, 1279, 1246, 1176, 1039,
18 cm ; H NMR d 0.85–0.93 (1H, m), 0.98–1.06 (1H,
ꢀ
1
1
+
J¼8.9 Hz), 7.22–7.32 (5H, m). MS m/z (%) 228 (M , 100),
m), 1.15–1.34 (3H, m), 1.19 (3H, t, J¼7.3 Hz), 1.62–1.81
5H, m), 1.94–2.02 (1H, m), 2.85 (3H, s), 3.75 (3H, s),
.86 (1H, d, J¼10.7 Hz), 4.10 (2H, q, J¼7.3 Hz), 6.81
213 (10), 151 (20), 137 (95), 91 (65). Calcd for
C H DNO: M, 228.1372. Found: m/z 228.1375.
(
1
5 16
3
+
(
4H, s). MS m/z (%) 305 (M , 20), 232 (100), 222 (30),
3.1.26. N-Deuteriomethyl-N-methyl-p-anisidine (19b).
Colorless oil; IR (neat) 2951, 2832, 1512, 1244, 1038,
1
Found: m/z 305.1980.
94 (12), 150 (15). Calcd for C H NO : M, 305.1989.
1
8
27
3
ꢀ1 1
817 cm ; H NMR d 2.84 (2H, t, J¼1.8 Hz), 2.86 (3H, s),
3
.76 (3H, s), 6.75 (2H, d, J¼9.2 Hz), 6.84 (2H, d,
+
3.1.20. N-[Cyclohexyl(deuterio)methyl]-N-methyl-4-
chloroaniline (15o). Colorless oil; IR (neat) 2924, 2852,
J¼9.2 Hz). MS m/z (%) 152 (M , 70), 137 (100), 109 (10),
65 (10). Calcd for C H DNO: M, 152.1060. Found: m/z
12
9
ꢀ
1 1
1
(
598, 1505, 1448, 1331, 807 cm ; H NMR d 0.88–0.95
2H, m), 1.12–1.25 (3H, m), 1.65–1.73 (6H, m), 2.92 (3H,
s), 3.07 (1H, d, J¼6.7 Hz), 6.55 (2H, d, J¼9.2 Hz), 7.13
152.1062.
3.1.27. N-Deuteriomethyldibenzylamine (19c). Colorless
oil; IR (neat) 3063, 3028, 2794, 1603, 1495, 1454, 1367,
+
(
1
2
2H, d, J¼9.2 Hz). MS m/z (%) 238 (M , 15), 155 (100),
ꢀ
1
1
40 (8). Calcd for C H DClN: M, 238.1346. Found: m/z
1
1028, 735, 698 cm ; H NMR d 2.16 (2H, br s), 3.52
(4H, s), 7.22–7.26 (2H, m), 7.29–7.37 (8H, m). MS m/z
4 19
38.1346.
+
(
%) 212 (M , 40), 135 (40), 121 (20), 91 (100), 65 (14).
3.1.21. Ethyl [N-(4-chlorophenyl)-N-methylamino]cyclo-
hexylacetate (15p). Colorless oil; IR (neat) 2928, 2853,
Calcd for C H DN: M, 212.1423. Found: m/z 212.1425.
15 16
1
7
732 (CO), 1597, 1499, 1449, 1176, 1105, 1027, 810,
57 cm ; H NMR d 0.81–0.96 (1H, m), 0.99–1.08 (1H,
3.1.28. Ethyl [benzyl(4-methoxyphenyl)amino]acetate
(20a). To a solution of i-PrMgCl (0.5 mmol) in 0.5 mL of
dry THF in a flame-dried flask at ꢀ78 C under argon atmo-
ꢀ
1 1
ꢁ
sphere was added a solution of 3e (38 mg; 0.2 mmol) in
0.4 mL of dry THF dropwise with stirring. Immediately,
m), 1.14–1.36 (3H, m), 1.21 (3H, t, J¼7.3 Hz), 1.63–1.78
5H, m), 1.97–2.04 (1H, m), 2.89 (3H, s), 3.92 (1H, d,
J¼10.7 Hz), 4.08–4.16 (2H, m), 6.75 (2H, d, J¼8.9 Hz),
(

7900
T. Satoh et al. / Tetrahedron 62 (2006) 7892–7901
to a solution of the generated magnesium carbenoid 4e
was added a solution of N-lithio N-benzyl-p-anisidine [pre-
pared from N-benzyl-p-anisidine (0.7 mmol) and n-BuLi
References and notes
1. Reviews concerning the stabilized a-amino-substituted carban-
ions: (a) Beak, P.; Zajdel, W. J. Chem. Rev. 1984, 84, 471; (b)
Meyers, A. I. Aldrichimica Acta 1985, 18, 59.
ꢁ
(
0.77 mmol) in 2 mL of THF at 0 C and the solution was
ꢁ
cooled to ꢀ78 C] through a cannula with stirring. The reac-
ꢁ
To a solution of the a-amino-substituted carbanion 17 was
tion mixture was slowly allowed to warm to ꢀ40 C for 1 h.
2. Some recent papers concerning generation and chemistry of
stabilized a-amino-substituted carbanions: (a) Beak, P.; Yum,
E. K. J. Org. Chem. 1993, 58, 823; (b) Beak, P.; Lee, W. K.
J. Org. Chem. 1993, 58, 1109; (c) Gawley, R. E.; Zhang, Q.
Tetrahedron 1994, 50, 6077; (d) Elworthy, T. R.; Meyers,
A. I. Tetrahedron 1994, 50, 6089; (e) Dieter, R. K.; Li, S. J.
Tetrahedron Lett. 1995, 36, 3613; (f) Voyer, N.; Roby, J.
Tetrahedron Lett. 1995, 36, 6627; (g) Dieter, R. K.; Dieter,
J. W.; Alexander, C. W.; Bhinderwala, N. S. J. Org. Chem.
1996, 61, 2930; (h) Sieburth, S. M.; Somers, J. J.; O’Hare,
H. K. Tetrahedron 1996, 52, 5669; (i) Sieburth, S. M.;
Somers, J. J. Tetrahedron 1996, 52, 5683; (j) Park, Y. S.;
Beak, P. Tetrahedron 1996, 52, 12333; (k) Park, Y. S.; Boys,
M. L.; Beak, P. J. Am. Chem. Soc. 1996, 118, 3757; (l)
Dieter, R. K.; Velu, S. J. Org. Chem. 1997, 62, 3798; (m)
Faibish, N. C.; Park, Y. S.; Lee, S.; Beak, P. J. Am. Chem.
Soc. 1997, 119, 11561; (n) Tomoyasu, T.; Tomooka, K.;
Nakai, T. Synlett 1998, 1147; (o) Serino, C.; Stehle, N.; Park,
Y. S.; Florio, S.; Beak, P. J. Org. Chem. 1999, 64, 1160; (p)
Kim, B. J.; Park, Y. S.; Beak, P. J. Org. Chem. 1999, 64,
1705; (q) Tomoyasu, T.; Tomooka, K.; Nakai, T. Tetrahedron
Lett. 2000, 41, 345.
ꢁ
with stirring. After 20 min, the reaction mixture was
added ethyl chloroformate (1 mmol) dropwise at ꢀ40 C
quenched with satd aq NH Cl. The whole was extracted
4
with CHCl . The organic layer was washed with satd aq
3
NH Cl and dried over MgSO . The product was purified
4
4
by silica gel column chromatography to afford 20a
(
(
35 mg; 58%) as a colorless oil; IR (neat) 2935, 1745
CO), 1514, 1244, 1187, 1029, 815, 739, 698 cm , H
ꢀ
1 1
NMR d 1.24 (3H, t, J¼7.0 Hz), 3.73 (3H, s), 4.01 (2H, s),
4
.18 (2H, q, J¼7.0 Hz), 4.58 (2H, s), 6.66 (2H, d,
J¼8.9 Hz), 6.79 (2H, d, J¼8.9 Hz), 7.23–7.35 (5H, m).
+
MS m/z (%) 299 (M , 47), 226 (75), 195 (40), 120 (10),
91 (100). Calcd for C H NO : M, 299.1520. Found:
18 21 3
m/z 299.1519.
3
.1.29. Ethyl [N-(4-methoxyphenyl)-N-methylamino]-
acetate (20b). Colorless oil; IR (neat) 2937, 1747 (CO),
ꢀ1 1
1
515, 1245, 1188, 1118, 1038, 948, 816 cm . H NMR
d 1.23 (3H, t, J¼7.0 Hz), 3.01 (3H, s), 3.75 (3H, s), 3.99
2H, s), 4.16 (2H, q, J¼7.0 Hz), 6.68 (2H, d, J¼8.9 Hz),
(
6
+
.82 (2H, d, J¼8.9 Hz). MS m/z (%) 223 (M , 28), 150
3. Some recent reviews concerning generation and reaction of
non-stabilized a-amino carbanions: (a) Kessar, S. V.; Singh,
P. Chem. Rev. 1997, 97, 721; (b) Katritzky, A. R.; Qi, M.
Tetrahedron 1998, 54, 2647; (c) Pearson, W. H.; Stoy, P.
Synlett 2003, 903.
(
100), 135 (15), 120 (10). Calcd for C H NO : M,
17
1
2
3
2
23.1207. Found: m/z 223.1208.
3.1.30. Ethyl [N-(4-chlorophenyl)-N-methylamino]-
acetate (20c). Colorless oil; IR (neat) 2982, 1747 (CO),
4. 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, 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, 1569; (k) Pearson, W. H.; Mans, D. M.; Kampf, J. W.
Org. Lett. 2002, 4, 3099.
ꢀ
1 1
1
598, 1504, 1370, 1192, 1119, 1029, 811 cm . H NMR
d 1.24 (3H, t, J¼7.0 Hz), 3.04 (3H, s), 4.03 (2H, s), 4.17
(
2H, q, J¼7.0 Hz), 6.60 (2H, d, J¼9.2 Hz), 7.17 (2H, d,
+
J¼9.2 Hz). MS m/z (%) 227 (M , 20), 154 (100), 139 (10).
Calcd for C H ClNO : M, 227.0712. Found m/z 227.0711.
1
1
14
2
3.1.31. Ethyl (N-methyl-N-phenylamino)acetate (20d).
Colorless oil; IR (neat) 2931, 1748 (CO), 1602, 1508,
ꢀ
1 1
1
369, 1191, 1029, 749, 691 cm . H NMR d 1.24 (3H, t,
J¼7.0 Hz), 3.07 (3H, s), 4.05 (2H, s), 4.17 (2H, q, J¼
7
7
.0 Hz), 6.69 (2H, d, J¼7.9 Hz), 6.75 (1H, t, J¼7.3 Hz),
+
.23 (2H, m). MS m/z (%) 193 (M , 29), 120 (100), 105
(7), 77 (10). Calcd for C H NO : M, 193.1102. Found
11 15 2
m/z 193.1096.
3.1.32. Ethyl (dibenzylamino)acetate (20e). Colorless oil;
IR (neat) 2854, 1729 (CO), 1455, 1190, 1029, 746,
5. (a) Kirmse, W. Carbene Chemistry; Academic: New York, NY,
1971; (b) Stang, P. J. Chem. Rev. 1978, 78, 383; (c) Oku, A.;
Harada, T. J. Synth. Org. Chem. Jpn. 1986, 44, 736; (d) Oku,
A. J. Synth. Org. Chem. Jpn. 1990, 48, 710; (e) Dorwald,
F. Z. Metal Carbenes in Organic Synthesis; Wiley-VCH:
Weinheim, 1999.
6. (a) Satoh, T. J. Synth. Org. Chem. Jpn. 1996, 54, 481; (b) Satoh,
T. J. Synth. Org. Chem. Jpn. 2003, 61, 98; (c) Satoh, T. Chem.
Rec. 2004, 3, 329.
ꢀ1 1
6
3
7
98 cm . H NMR d 1.26 (3H, t, J¼7.0 Hz), 3.28 (2H, s),
.81 (4H, s), 4.15 (2H, q, J¼7.0 Hz), 7.22–7.26 (2H, m),
.29–7.32 (4H, m), 7.37–7.41 (4H, m). MS m/z (%) 283
+
(M , 4), 210 (98), 192 (10), 91 (100). Calcd for
C H NO : M, 283.1571. Found m/z 283.1575.
1
8
21
2
Acknowledgements
7
. (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. Tetrahedron 1998, 54,
5557; (c) Satoh, T.; Kurihara, T.; Fujita, K. Tetrahedron
2001, 57, 5369; (d) Satoh, T.; Sakamoto, T.; Watanabe, M.
This work was supported by a grant from the Ministry of
Education, Culture, Sports, Science and Technology of
Japan to promote multi-disciplinary research project, which
is gratefully acknowledged.

T. Satoh et al. / Tetrahedron 62 (2006) 7892–7901
7901
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.
. Preliminary results of this study were reported as a communica-
tion: Satoh, T.; Osawa, A.; Kondo, A. Tetrahedron Lett. 2004,
10. (a) Silverstein, R. M.; Bassler, G. C.; Morrill, T. C.
Spectroscopic Identification of Organic Compounds, 4th ed.;
Wiley: New York, NY, 1981; pp 227–228; (b) Satoh, T.;
Hanaki, N.; Yamada, N.; Asano, T. Tetrahedron 2000, 56, 6223.
11. Jung, Y. J.; Bae, J. W.; Park, E. S.; Chang, Y. M.; Yoon, C. M.
Tetrahedron 2003, 59, 10331.
8
9
4
5, 6703.
. Satoh, T.; Kondo, A.; Musashi, J. Tetrahedron 2004, 60,
453.
12. Satoh, T.; Kaneko, Y.; Izawa, T.; Sakata, K.; Yamakawa, K.
Bull. Chem. Soc. Jpn. 1985, 58, 1983.
5