N,N-Di- and N,N,C-Trialkylation of δ-sulfoximino esters

Article abstract of DOI:10.1246/bcsj.20120195

N,N-Dialkylation of α-sulfoximino esters with Grignard reagents proceeds to give α-N,N-dialkylamino esters. N,N,CTrialkylated product is also obtained via the oxidation and nucleophilic addition reaction of the intermediary enolate.

Full text of DOI:10.1246/bcsj.20120195

Short Articles
Bull. Chem. Soc. Jpn. Vol. 85, No. 11, 1203-1205 (2012) 1203
OSO2R1
2R3MgX
R3 R3
N
Selected Papers
N
R2 CO2Et
R2 CO2Et
N,N-Di- and N,N,C-Trialkylation
of ¡-Sulfoximino Esters
(Z)-1
2
OSO2R1
N
R3 R4
N
1) R3MgX
2) R4MgX
R2 OC2Et
R2 CO2Et
Shingo Hata, Tatsuya Maeda,
and Makoto Shimizu*
(Z)-1
4
Scheme 1. Tandem N,N-dialkylation of ¡-sulfoximino ester.
Table 1. N,N-Diethylation: Examination of Reaction Con-
ditions
Department of Chemistry for Materials, Graduate School
of Engineering, Mie University, Tsu, Mie 514-8507
OSO2R
Et
Et
N
EtMgBr in Et2O (x equiv)
Solvent, Temp, Time
N
Received July 18, 2012
Ph
CO2Et
E-mail: mshimizu@chem.mie-u.ac.jp
Ph
CO2Et
1
2a
Z
EtMgBr Time Temp. 2a
Entry Solv.
R
N,N-Dialkylation of ¡-sulfoximino esters with Grignard
reagents proceeds to give ¡-N,N-dialkylamino esters. N,N,C-
Trialkylated product is also obtained via the oxidation and
nucleophilic addition reaction of the intermediary enolate.
or E /equiv /h /°C
/%a)
1
2
PhMe 2,4-(NO2)2C6H3: 1a
PhMe 2,4-(NO2)2C6H3: 1a
Z
2.0
1.0 ¹78
to rt
0b)
E
2.0
1.0 ¹78
to rt
0
Tertiary and quaternary N,N-dialkylamino acids and alcohols
concern an intriguing field of bioorganic chemistry, since bio-
active molecules such as antiarrhythmic drugs containing these
skeletons show very strong activities.1 Although various ap-
proaches to the synthesis of tertiary and quaternary N,N-dialkyl-
amino acids and alcohols have been reported,2 only limited
examples are available in which N-alkylations are involved.3 We
have recently introduced a useful method for the N-alkylation
of ¡-imino esters, and this methodology has made possible an
integrated 3-component coupling via an umpolung reaction.4 In
these reactions the amination ability of ¡-imino esters for anions
reflects the efficiency of whole transformations. Regarding the
amination of anion species, arylsulfoximines have intrigued us,
since they undergo efficient N-alkylation reactions.5 Using the N-
alkylation of arylsulfoximines coupled with our N-alkylation of
¡-imino esters in an umpolung manner, N,N-dialkylation reaction
was investigated (Scheme 1).
The initial examination was carried out to examine the N,N-
dialkylation of the substrate 1, and Table 1 summarizes the
results. Among the sulfonates examined 4-toluenesulfonyl
derivative gave the best result, and the diethylation reaction
was completed in toluene at 30 °C in 15 min (Entry 15).
Regarding the geometry, the (Z)-isomer effected the desired
diethylation, whereas the (E)-isomer was less reactive and
recovery of the starting material was observed (Entries 4 and 5).
This may be due to the involvement of an SN2 like transition
state as previously reported.5 Among the solvents exmined,
toluene, a relatively less polar solvent gave the best result. Under
the optimum conditions a variety of tosylates6 were subjected to
the dialkylation reaction, and Table 2 summarizes the results.
Ethylation and propylation gave the products in good yields
(Entries 2 and 4), whereas use of sec-alkyl Grignard reagents
gave the dialkylation products in moderate yields (Entries 5 and
6). However, methylation and arylation did not give the desired
products (Entries 1, 9, and 10).
3
4
5
6
PhMe 2,4-Cl2C6H3: 1b
PhMe 4-MeC6H4: 1c
PhMe 4-MeC6H4: 1c
MeCN 4-MeC6H4: 1c
E
Z
E
Z
2.0
2.0
2.0
2.0
1.0 rt
1.0 rt
1.0 rt
5.0 ¹45
to rt
5.0 ¹78
to rt
5.0 ¹78
to rt
5.0 ¹78
to rt
5.0 ¹78
to rt
5.0 ¹78
to rt
1.0 ¹78
to rt
51
79
0
0
7
8
9
EtCN 4-MeC6H4: 1c
Z
Z
Z
Z
Z
Z
2.0
2.0
2.0
2.0
2.0
2.0
0
0
THF
4-MeC6H4: 1c
DME 4-MeC6H4: 1c
0
10 CH2Cl2 4-MeC6H4: 1c
11 PhMe 4-MeC6H4: 1c
12 PhMe 4-MeC6H4: 1c
45
54
79
13 PhMe 4-MeC6H4: 1c
14 PhMe 4-MeC6H4: 1c
15 PhMe 4-MeC6H4: 1c
16 PhMe 4-NO2C6H4: 1d
17 PhMe 4-NO2C6H4: 1d
Z
Z
Z
Z
E
2.0
2.2
2.2
2.0
2.0
1.0 30
1.0 30
0.25 30
1.0 30
1.0 30
83
85
85
0b)
44
a) Isolated yields. b) A complex mixture was obtained.
be controlled to stop at the monoalkylation stage. As shown
in Scheme 2, although the tosyl derivative did not give the
monoethylated product, the addition reaction could be controlled
to some extent using the 4-nitrobenzenesulfonyl counterpart (4-
Ns) 1d, and the ethylated imine 3 was obtained in moderate
yield. It is noteworthy that in contrast to the tosyl derivative
1c, the (E)-nosyl derivative (E)-1d effected the monoethylation
reaction to give the imine 3 at ¹78 °C, although the use of
(Z)-1d did not give the desired imine 3, but a complex mixture
was obtained (see also Table 1, Entries 16 and 17). Using this
particular sulfonate (E)-1d, two different alkyl substituents could
be introduced, albeit in moderate yields (Scheme 2). In these
cases the use of DME as the solvent for the second alkylation
We next investigated the introduction of two different alkyl
groups onto the nitrogen. For this purpose, the reaction should
Published on the web November 1, 2012; doi:10.1246/bcsj.20120195

1204 Bull. Chem. Soc. Jpn. Vol. 85, No. 11 (2012)
Table 2. Dialkylation of the Sulfonate (Z)-1c
© 2012 The Chemical Society of Japan
Table 3. Trialkylation of the Sulfonate (Z)-1c
OTs
OTs
Et
Et
R
R
N
N
RMgX in Et2O (2.2 equiv)
N
N
EtMgBr in Et2O (2.2 equiv)
OEt
OMgBr
Ph
Toluene, 30 °C, 15 min
Ph
CO2Et
Toluene, 30 °C, 15 min
Ph
CO2Et
(Z )-1c
Ph
CO2Et
(Z )-1c
2
Et
Et
Et
Et
N
RMgBr in Et2O (2.0 equiv)
Oxidant (equiv)
EtCN, 30 °C, 15 min
N
Entry RMgX
2/%a) Entry RMgX
2/%a)
30 °C, 15 min
Ph
CO2Et
Ph
CO2Et
R
1
2
3
4
5
MeMgBr
EtMgBr
EtMgBrc) 2a: 70
n-PrMgBr 2b: 65
i-PrMgBr 2c: 32
0b)
2a: 85
6
7
8
c-HexMgBr
2d: 24
2e: 50
0
5
BnMgBr
t-BuMgCl
PhMgBr
Entry
Oxidation reagent (equiv)
BPOb) (1.2)
NBSb) (1.2)
DBDMHb) (0.6)
DBDMH (0.6)
DBDMH (0.6)
DBDMH (0.6)
DBDMH (0.6)
DBDMH (0.6)
DBDMH (0.6)
RMgX
5/%a)
5a: 53
5a: 55
5a: 69
5a: 74
5b: 59
5c: 64
5d: 44
5e: 44
5f: 68
9
0b)
0b)
1
2
3
4
5
6
7
8
9
EtMgBr
EtMgBr
EtMgBr
EtMgBr
MeMgBr
n-PrMgBr
c-PrMgBr
10
4-MeOC6H4MgBr
a) Isolated yields. b) Methylation or arylation of the ester
moiety was observed. c) EtMgBr in THF was used.
OTs
Et
Et
Et
N
N
N
EtMgBr (2.5 equiv)
+
Toluene, -78 °C, 30 min
c-HexMgBr
Ph
CO2Et
Ph
CO2Et
Ph
CO2Et
BnMgBr
(Z )-1c
3
Yield 0%
2a Yield 11%
4-NsO
a) Isolated yields. b) In the presence of BF3¢Et2O (1.0 equiv).
N
EtMgBr (2.5 equiv)
3
+
2a
R1
R2
R1
R2
Toluene, -78 °C, 30 min
OSO2R
OEt
N
N
Ph
N
CO2Et
N
Yield 6%
Yield 51%
OEt
OEt
(E )-1d
Z : E = 89 : 11
R3
O
O
O
4
5
4-NsO
Ph
R
Et
R1MgBr
N
EtMgBr (2.0 equiv)
RMgX (2.0 equiv)
R3MgBr
H2O
Toluene, -78 °C, 30 min
DME, -78 °C to rt, 1 h
b
a
CO2Et
Ph
CO2Et
X-
4
(E )-1d
OSO2R
R1
R2
R1
R2
BrMgR1
N
N
N
OSO2R
OEt
MeMgBr/THF
0%
c-HexMgBr/Et2O 4c: 60%
BnMgCl/THF 4d: 32%
t-BuMgBr/THF 4e: 2%
Oxidation
N
OEt
OMgBr
OEt
n-PrMgBr/Et2O 4a: 49%
i-PrMgBr/Et2O 4b: 34%
O
OEt
O
C
O
B
Mg Br
R1
Scheme 2. Dialkylation of the sulfonate (E)-1d with differ-
ent nucleophiles.
R2
Mg Br
R1
OSO2R
R1
R1
N
N
N
MgBr
R2MgBr
was crucial. This may be due to the enhanced isomerization
ability for the intermediary N-ethyl imine 3 to more reactive
isomer in DME.7
O
OEt
O
OEt
O
OEt
A
The present methodology coupled with the generation of
iminium salts previously discovered8 made possible the intro-
duction of three alkyl groups across the imine function. Thus the
following trialkylations were carried out (Table 3).
Scheme 3. Possible reaction pathways.
In conclusion we have developed an efficient method for
the introduction of alkyl groups onto nitrogen of ¡-imino esters
to synthesize N,N-dialkylated ¡-amino esters in moderate to
good yields.9 Oxidation of an intermediary bromomagnesium
enolate followed by the third alkylation gives N,N,C-trialkylated
quaternary ¡-amino ester. This methodology may provide a
rapid method to tertiary and quaternary N,N-dialkylamino acids
and alcohols which are useful intermediates for the synthesis of
useful bioactive materials such as antiarrhythmic drugs.
Among the oxidation reagents screened, benzoyl peroxide
(BPO) and N-bromosuccinimide (NBS) gave moderate yields
of the triethylated product, whereas use of 1,3-dibromo-5,5-
dimethylhydantoin (DBDMH) afforded a better result, and in
particular, the third ethylation in the absence of BF3¢Et2O
recorded the best yield of 74% (Entry 4). Under the optimum
conditions found for the triethylation raction, a variety of the
third Grignard reagents were subjected to the above reaction. As
can be seen from Table 3, methyl and primary alkyl Grignard
reagents gave good yields of the alkylation products (Entries 5,
6, and 9), whereas, secondary alkyl analogues were less
effective, giving the products in moderate yields (Entries 7 and
8). On the basis of the above results we propose the following
reaction pathways (Scheme 3).
The initial addition of the Grignard reagent gives A via either
an addition-elimination (path a) or an SN2 reaction (path b). The
second alkylation at the nitrogen gives the bromomagnesium
enolate B, which upon hydrolysis affords the dialkylation product
4. On the other hand, oxidation of the intermediary bromomag-
nesium enolate generates the iminium salt C, and the trialkylated
product 5 would be obtained by the subsequent alkylation.
Experimental
General. Infrared spectra were determined on a JASCO FT/
1
IR-460 plus spectrometer. H NMR and 13C NMR spectra were
recorded with a JEOL ECX-400P, or a JEOL A-500 spectrometer
using tetramethylsilane as an internal standard. Mass spectra were
recorded on a JEOL MS-700D spectrometer. Toluene was dried
over calcium chloride, distilled, and stored over Molecular Sieves
4 ¡. Acetonitrile (MeCN) and propionitrile (EtCN) were distilled
from phosphorus pentoxide and then from calcium hydride,
and stored over Molecular Sieves 4 ¡. Tetrahydrofuran (THF)
was distilled from benzophenone ketyl immediately before use.
Dimethoxyethane (DME) was distilled from calcium hydride and
then copper(I) chloride, and stored over sodium. Dichloro-

S. Hata et al.
Bull. Chem. Soc. Jpn. Vol. 85, No. 11 (2012) 1205
methane was distilled from calcium hydride and stored over
Molecular Sieves 4 ¡. Purification of products was performed by
column chromatography on silica gel (Kanto Silica Gel 60N)
and/or preparative TLC on silica gel (Merck Kiesel Gel GF254).
Synthesis of Oximes and ¡-Sulfoxyimino Esters 1a-1d.
See, the Supporting Information.
Purification on silica gel TLC (n-hexane:ethyl acetate:Et3N =
10:1:1 as an eluent) gave the amino ester 5.
Ethyl 2-(Diethylamino)-2-phenylbutanoate (5a):
74%;
1
yellow oil; H NMR (400 MHz, CDCl3): ¤ 0.59 (t, J = 7.3 Hz,
3H), 1.05 (t, J = 7.1 Hz, 6H), 1.30 (t, J = 7.1 Hz, 3H), 1.86 (dq,
J = 7.1, 14.2 Hz, 1H), 2.12 (dq, J = 7.1, 14.2 Hz, 1H), 2.62 (dq,
J = 7.1, 14.2 Hz, 2H), 2.71 (dq, J = 7.1, 14.2 Hz, 2H), 4.23 (dq,
J = 7.1, 10.5 Hz, 1H), 4.28 (dq, J = 7.1, 10.5 Hz, 1H), 7.20-
7.36 (m, 5H); 13C NMR (100 MHz, CDCl3): ¤ 9.2, 14.5, 15.8,
General Procedure for N,N-Dialkylation of ¡-Sulfoximino
Esters (Table 1, Entry 15). Under an argon atmosphere, a
solution of ¡-imino ester (Z)-1c in toluene (0.1 M) was stirred at
30 °C for 10 min, and to it was added Grignard reagent in Et2O
(2.2 equiv). After the mixture was stirred for 15 min at 30 °C,
saturated NH4Cl aq. (5.0 mL) was added to quench the reaction.
The whole mixture was extracted with ethyl acetate (3 © 5.0
mL). The combined organic phases were washed with brine (3 ©
5.0 mL), dried over Na2SO4, and concentrated in vacuo to give a
crude product. Purification on silica gel TLC (n-hexane:ethyl
acetate:Et3N = 10:1:1 as an eluent) gave the amino ester 2.
Ethyl 2-(Diethylamino)-2-phenylacetate (2a): 85%; brown
oil; 1H NMR (400 MHz, CDCl3): ¤ 1.00 (t, J = 7.1 Hz, 6H), 1.23
(t, J = 7.1 Hz, 3H), 2.56-2.69 (m, 4H), 4.15 (dq, J = 7.1,
10.5 Hz, 1H), 4.21 (dq, J = 7.1, 10.5 Hz, 1H), 4.47 (s, 1H), 7.26-
7.34 (m, 3H), 7.43-7.45 (m, 2H); 13C NMR (100 MHz, CDCl3): ¤
11.8, 14.1, 43.6, 60.5, 69.3, 127.8, 128.2, 128.4, 128.7, 137.2,
172.4; IR (neat): 1738, 1454, 1369, 1196, 1155, 1061, 1026, 732,
698 cm¹1; HRMS (EI) Calcd for C14H21NO2 (M)+ 235.1572,
found 235.1565.
31.9, 44.8, 60.1, 75.0, 126.6, 127.4, 127.7, 142.1, 173.3; IR
¹1
(neat): 1721, 1446, 1379, 1215, 1175, 1089, 1027, 701 cm
;
HRMS (EI) Calcd for C13H20N (M ¹ C3H5O2)+ 190.1590,
found 190.1585.
Supporting Information
Synthesis of oximes and ¡-sulfoxyimino esters 1a-1d, and
1H NMR, 13C NMR, and IR spectra of 2b-2e, 3, 4b-4e, and
5b-5f are provided. This material is available free of charge on
the web at http://www.csj.jp/journals/bcsj/.
References
1
D. C. Beshore, N. J. Liverton, C. J. McIntyre, C. F. Claiborne,
B. Libby, J. C. Culberson, J. J. Salata, C. P. Regan, J. J. Lynch, L. Kiss,
R. H. Spencer, S. A. Kane, R. B. White, S. Yeh, G. D. Hartman, C. J.
Dinsmore, Bioorg. Med. Chem. Lett. 2010, 20, 2493, and earlier
references cited therein.
2
For reviews: a) C. Cativiela, M. D. Díaz-de-Villegas,
General Procedure for Dialkylation with Two Different
Tetrahedron: Asymmetry 1998, 9, 3517. b) C. Cativiela, M. D.
Díaz-de-Villegas, Tetrahedron: Asymmetry 2000, 11, 645. c) C.
Cativiela, M. Ordóñez, Tetrahedron: Asymmetry 2009, 20, 1. Asym-
metric Strecker reaction: d) S. Masumoto, H. Usuda, M. Suzuki, M.
Kanai, M. Shibasaki, J. Am. Chem. Soc. 2003, 125, 5634. e) J. Wang,
X. Hu, J. Jiang, S. Gou, X. Huang, X. Liu, X. Feng, Angew. Chem., Int.
Ed. 2007, 46, 8468. Alkylation mediated by phase-transfer catalysts:
f) K. Maruoka, E. Tayama, T. Ooi, Proc. Natl. Acad. Sci. U.S.A. 2004,
101, 5824, and references therein.
Nucleophiles (Scheme 2).
Under an argon atmosphere, a
solution of ¡-imino ester (E)-1d in toluene (0.04 M) was stirred at
¹78 °C for 10 min, and to it was added EtMgBr in Et2O (2.0
equiv). After the mixture was stirred for 30 min at ¹78 °C, DME
(to be at 0.1 M concentration) and RMgX (2.0 equiv) were added
at ¹78 °C. After stiring for 1 h at rt, saturated NaHCO3 aq.
(5.0 mL) was added to quench the reaction. The whole mixture
was extracted with ethyl acetate (3 © 5.0 mL). The combined
organic phases were washed with brine (3 © 5.0 mL), dried over
Na2SO4, and concentrated in vacuo to give a crude product.
Purification on silica gel TLC (n-hexane:ethyl acetate = 6:1 in
the presence of 10% Et3N) gave the amino ester 4.
3
E. Ciganek, Organic Reactions, 2009, Vol. 72, p. 1, and
references therein. doi:10.1002/0471264180.or072.01.
a) M. Shimizu, Y. Niwa, Tetrahedron Lett. 2001, 42, 2829.
4
b) Y. Niwa, M. Shimizu, J. Am. Chem. Soc. 2003, 125, 3720. c) M.
Shimizu, Y. Niwa, T. Nagai, I. Hachiya, Heterocycles 2007, 72, 127.
d) I. Mizota, K. Tanaka, M. Shimizu, Tetrahedron Lett. 2012, 53, 1847.
e) T. Nishi, I. Mizota, M. Shimizu, Pure Appl. Chem. 2012, 84, ASAP
Article. doi:10.1351/PAC-CON-12-01-03.
2-(N-Ethyl-N-propylamino)-2-phenylacetate (4a):
49%;
1
yellow oil; H NMR (500 MHz, CDCl3): ¤ 0.81 (t, J = 7.3 Hz,
3H), 0.98 (t, J = 7.3 Hz, 3H), 1.24 (t, J = 7.3 Hz, 3H), 1.35-1.52
(m, 2H), 2.44-2.55 (m, 2H), 2.63 (q, J = 7.3 Hz, 2H), 4.13-4.25
(m, 2H), 4.51 (s, 1H), 7.25-7.34 (m, 3H), 7.40-7.42 (m, 2H);
13C NMR (126 MHz, CDCl3): ¤ 11.7, 12.3, 14.2, 20.4, 44.3,
52.0, 60.4, 69.1, 127.7, 128.2, 128.7, 137.4, 172.4; IR (neat):
1737, 1453, 1372, 1154, 1067, 1029, 728, 696 cm¹1; HRMS (EI)
Calcd for C12H18N (M ¹ C3H5O2)+ 176.1434, found 176.1434.
General Procedure for Trialkylation of ¡-Sulfoximino
Esters (Table 3). Under an argon atmosphere, a solution of ¡-
imino ester (Z)-1d in toluene (0.10 M) was stirred at 30 °C for
10 min, and to it was added EtMgBr in Et2O (2.2 equiv). After
the mixture was stirred for 15 min at 30 °C, EtCN (to be at
0.10 M concentration) and DBDMH (0.6 equiv) were added at
30 °C. After stirring for 15 min at 30 °C, RMgX in Et2O or THF
(2.0 equiv) was added. After the mixture was stirred for 15 min
at 30 °C, saturated NH4Cl aq. (5.0 mL) was added. The whole
mixture was extracted with ethyl acetate (3 © 5.0 mL). The com-
bined organic phases were washed with brine (3 © 5.0 mL), dried
over Na2SO4, and concentrated in vacuo to give a crude product.
5
a) G. Alvernhe, A. Laurent, Tetrahedron Lett. 1972, 13, 1007.
b) R. A. Hagopian, M. J. Therien, J. R. Murdoch, J. Am. Chem. Soc.
1984, 106, 5753. c) H. Tsutsui, T. Ichikawa, K. Narasaka, Bull. Chem.
Soc. Jpn. 1999, 72, 1869.
6
For determination of the stereochemistry of arylsulfoximines 1:
H. Imoto, E. Imamiya, Y. Momose, Y. Sugiyama, H. Kimura, T. Sohda,
Chem. Pharm. Bull. 2002, 50, 1349.
7
J. E. Johnson, N. M. Morales, A. M. Gorczyca, D. D. Dolliver,
M. A. McAllister, J. Org. Chem. 2001, 66, 7979, and references therein.
a) M. Shimizu, H. Itou, M. Miura, J. Am. Chem. Soc. 2005,
8
127, 3296. b) T. Iwao, M. Shimizu, Heterocycles 2009, 77, 767. c) M.
Shimizu, H. Itou, T. Iwao, Y. Umeda, Chem. Lett. 2009, 38, 732. d) M.
Shimizu, I. Hachiya, I. Mizota, Chem. Commun. 2009, 874. e) M.
Shimizu, T. Kusunoki, M. Yoshida, K. Kondo, I. Mizota, Chem. Lett.
2011, 40, 351. f) S. Hata, H. Koyama, M. Shimizu, J. Org. Chem.
2011, 76, 9670.
9
Similar results have recently been published: Y. Mizutani, H.
Tanimoto, T. Morimoto, Y. Nishiyama, K. Kakiuchi, Tetrahedron Lett.
2012, 53, 5903.