Synthesis of functionalized enamines: A facile and efficient protocol toward N-protected α,β-dehydroamino acid derivatives

Article abstract of DOI:10.1055/s-2008-1042901

α,β-Dehydroamino acid derivatives were synthesized in good yields from α-bromoketones or α-bromoesters and hydroxamates via a sequential procedure involving displacement of bromide by hydroxamate anion, followed by a base-induced elimination-isomerization reaction. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1042901

LETTER
861
Synthesis of Functionalized Enamines: A Facile and Efficient Protocol toward
N-Protected a,b-Dehydroamino Acid Derivatives
S
ynthesis of Funct
u
ionalized En
n
amines Sun,a Xiaozhao Wang,a,b Xiufang Zheng,a Kang Zhao*a
a
Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology,
Tianjin University, Tianjin 300072, P. R. of China
Fax +86(22)27890968; E-mail: kangzhao@tju.edu.cn
Evans Chemical Laboratories, The Ohio State University, Columbus, OH 43210, USA
b
Received 4 December 2007
The required starting materials 1 and 2 for this approach
were conveniently prepared from commercial materials in
high yields according to a reported process.9 Initially, we
started research with the model reaction starting from 1a
and 2a (Table 1). The conversion was explored by inves-
tigating the use of different bases (KOt-Bu, NaH, DBU,
Et3N, K2CO3, and Cs2CO3) and different solvent systems
(DMF, MeCN, THF, CH2Cl2, and PhMe).
Abstract: a,b-Dehydroamino acid derivatives were synthesized in
good yields from a-bromoketones or a-bromoesters and hydroxam-
ates via a sequential procedure involving displacement of bromide
by hydroxamate anion, followed by a base-induced elimination-
isomerization reaction.
Key words: a,b-dehydroamino acid derivatives, functionalized
enamines, substitution, elimination, electron-withdrawing group
In these solvent studies, we found that polar aprotic sol-
vents benefited not only the first step reaction but also the
second. The order of reactivity for different solvents was
found to be in the sequence as DMF > MeCN > THF >
CH2Cl2 > PhMe. Comparing the effect of the solvent on
the two-step reaction, MeCN was the most suitable one.
We found that Cs2CO3 should be used as the proper base
for the first-step reaction instead of stronger bases to
avoid the unwanted self-elimination of a-bromo carbonyl
compounds. The self-elimination would produce conju-
gated a,b-unsaturated ketones or esters, especially for a-
bromoketones and a-bromoesters with an aromatic group
at the b-position, which could be confirmed by compari-
son with the same products prepared by a known meth-
od.10 Furthermore, hydroxamates could not be consumed
completely if the intramolecular elimination reaction pro-
ceeded faster than the substitution reaction. If R2 was an
aromatic group, the intermediate 3 could be converted
into the desired products using Cs2CO3 at an elevated tem-
perature (entry 14). A stronger base was preferable in the
second step when R2 was an aliphatic group because of the
prolonged reaction time and unsatisfactory yield. From
these studies, we arrived at a set of conditions which were
attempted in a general procedure: compound 1a was add-
ed to the mixture of Cs2CO3 and 2a in dry acetonitrile at
40 °C (entry 12) and the resulting mixture was cooled to
room temperature when the starting material 2a was total-
ly consumed, and then DBU was added dropwise. It was
noteworthy that the reaction should be heated to reflux in
the second step to facilitate the conversion of aliphatic a-
bromoketones.
Functionalized enamines have long served as useful
building blocks in the synthesis of a variety of different
structures which possess biological and medicinal impor-
tance.1 As members of this family, a-ketoenamines (also
referred to as a,b-dehydroamino acid derivatives2) occur
as frequent subunits in natural products and biologically
active compounds and thus play important roles in organic
synthesis.3 They are useful synthons not only in electro-
philic and nucleophilic chemistry, but also in photochem-
istry and electrocyclic reactions, especially for the
synthesis of heterocyclic compounds.4
In virtue of the wide application of a-ketoenamines in or-
ganic chemistry, there is still a need to develop facile and
practical synthetic methods for their preparation although
some methods for the synthesis of this useful class of
compounds have been well documented in literature.
These methods can be mainly exemplified as follows: (1)
the Claisen–Schmidt condensation reaction;5 (2) the pho-
tooxidation of 2-morpholino cyclopropanols;6 (3) the
elimination of molecular nitrogen from a-azidoketones;7
(4) the ring opening of trans-1,3-dibenzoyl-2-phenylazir-
idine in the presence of a base;8 (5) the aminohalogenation
reaction of a,b-unsaturated ketones followed by treatment
with specific bases.2
Herein we disclose a new one-pot, two-step synthetic
strategy for the preparation of a-ketoenamines through the
reactions of a-bromoketones or a-bromoesters 1 with hy-
droxamates 2, namely, (1) initial displacement of bromide
by hydroxamate anion to give the intermediate 3 and (2)
base-induced elimination of benzyl alcohol with the sub-
sequent generation of the a,b-double bond. The two steps
were then combined into an efficient standard procedure.
These optimized conditions were subsequently applied to
the reactions of diverse a-bromoketones or a-bromoesters
1 with different hydroxamates 2 (Table 2).
SYNLETT 2008, No. 6, pp 0861–0866
x
x.
x
x.
2
0
0
8
Advanced online publication: 11.03.2008
DOI: 10.1055/s-2008-1042901; Art ID: W20907ST
© Georg Thieme Verlag Stuttgart · New York

862
Y. Sun et al.
LETTER
Table 1 Optimizing Conditions for the Synthesis of a,b-Dehydroamino Acid Derivativesa
Step 2
Step 1
O
O
O
(2a)
base
BnO NHTs
Ar1
BnO
Ar2
Ar1
Ar2
Ar1
Ar2
solvent, temp
base, solvent, temp
N
HN
Br
Ts
Ts
1a
3a
4a
Ar1 = 4-MeC6H4
Ar2 = 4-MeOC6H4
Entry
Base
Solvent
Temp (°C)
Time (h)
Yield (%)b
Yield of 2a (%)c
3a
4a
47
56
73
trace
5
1
2
KOt-Bu
NaH
DMF
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
40
60
80
80
80
0.1
0.5
0
0
0
0
DMF
3
DBU
DMF
1.0
0
12
76
0
4
Et3N
DMF
24.0
2.0
16
90
91
91
97
19
24
0
5
K2CO3
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
DMF
6
MeCN
DMF
18.0
1.0
3
0
7
5
0
8
MeCN
THF
1.5
trace
37
36
0
0
9
72.0
72.0
6.0
0
10
11
12
13
14
15
16
CH2Cl2
PhMe
MeCN
MeCN
MeCN
THF
8
96
0
1.0
97
0
trace
72
76
47
44
18.0
4.0
0
0
0
5.0
0
0
CH2Cl2
11.0
0
0
a Reaction conditions: 1a (2.2 mmol), 2a (2.0 mmol), base (4.2 mmol) in 20 mL solvent.
b Isolated yields.
c Starting material 2a recovered from the reaction mixture.
Table 2 Synthesis of a,b-Dehydroamino Acid Derivatives13–17
O
O
O
H
3 (2)
DBU
BnO
N
R
R1
R2
R1
BnO
R2
R3
R1
R2
MeCN, r.t. or reflux
HN
Cs2CO3, MeCN, 40 °C
N
R3
Br
1
3
4
Entry
1
Starting material 1
Hydroxamate 2
Product 4
Time (h)
Yield (%)
78a
R1 = 4-MeC6H4, R2 = 4-MeOC6H4
(1a)
R3 = Ts
(2a)
4a
4.0
2.0
1.5
3.0
2
3
4
1a
1a
1a
R3 = 4-ClC6H4SO2
(2b)
4b
4c
4d
73a
59a
61a
R3 = 4-O2NC6H4SO2
(2c)
R3 = Ms
(2d)
Synlett 2008, No. 6, 861–866 © Thieme Stuttgart · New York

LETTER
Synthesis of Functionalized Enamines
863
Table 2 Synthesis of a,b-Dehydroamino Acid Derivatives13–17 (continued)
O
O
O
H
3 (2)
DBU
BnO
N
R
R1
R2
R1
BnO
R2
R3
R1
R2
MeCN, r.t. or reflux
HN
Cs2CO3, MeCN, 40 °C
N
R3
Br
1
3
4
Entry
5
Starting material 1
Hydroxamate 2
Product 4
Time (h)
10.0
Yield (%)
1a
R3 = EtO2C
(2e)
4e
88b
87b
70b
53b
74a
6
7
8
9
1a
1a
1a
R3 = Boc
(2f)
4f
4g
4h
4i
10.0
5.0
R3 = Et(O)C
(2g)
R3 = (CH2)5N(O)C
(2h)
12.0
4.0
R1 = 4-MeOC6H4, R2 = Me
2a
(1b)
10
11
12
13
14
15
16
17
1b
1b
1b
1b
1b
1b
1b
2b
2c
2d
2e
2f
4j
1.5
2.0
78a
52a
51a
90b
85b
68b
67b
92b
4k
4l
5.0
4m
4n
4o
4p
4q
16.0
15.0
5.0
2g
2h
2e
29.0
14.0
R1 = 4-MeOC6H4, R2 = (CH2)3Me
(1c)
18
19
20
R1 = naphth-2-yl, R2 = Ph
(1d)
2e
2e
2e
4r
4s
9.0
9.0
93b
86b
65c
R1 = Ph, R2 = naphth-2-yl
(1e)
40.0
CO2Me
CO2Me
HN
O
Br
1f
OEt
4t
21
2e
2a
11.0
24.0
78b
61b
CO2Me
CO2Me
O
Br
HN
1g
OEt
4u
4v
22
R1 = t-Bu, R2 = 4-MeOC6H4
(1h)
a Purified by neutral Al2O3 chromatography.
b Isolated yields after silica gel chromatography.
c Recovery (18%) of 2e.
According to the experimental results, there are three as- thermore, it is noteworthy that only one isomer was pre-
pects that should be highlighted: (1) this method is appli- dominately generated as determined by NMR analysis
cable to the preparation of not only a-ketoenamines, but under the specified conditions described above. The ge-
also a,b-dehydroamino acid esters (entries 20, 21). Fur- ometry of the products has been confirmed as Z-configu-
Synlett 2008, No. 6, 861–866 © Thieme Stuttgart · New York

864
Y. Sun et al.
LETTER
ration by single-crystal X-ray analysis, NOE experiment, sent a doable and effective approach toward a variety of
and comparison to the literature.2,5,11 For instance, irradi- a,b-dehydroamino acid derivatives.
ation of the vinyl proton of compound 4v resulted in no
NOE enhancement of the sulfonamide N–H signal, which
Acknowledgment
was consistent with Z-olefin geometry.12 The structure of
We acknowledge the Tianjin Municipal Science and Technology
Commission (043186011), the Basic Research Project
(#2003AA223151) of the MOST for financial support.
compound 4v was further proved to be in Z-configuration
by single-crystal X-ray analysis (Figure 1); (2) the reac-
tivity of aromatic a-bromoketones with an aromatic group
at the b-position is higher than those with aliphatic groups
at the same position and both of them are better than ali-
phatic a-bromoketones. In particular, the competition be-
tween conjugated self-elimination of a-bromoesters or
aliphatic a-bromoketones and the nucleophilic attack of
hydroxamates becomes more obvious under basic condi-
tions.
References and Notes
(1) (a) Meyers, A. I.; Beverung, W. N. J. Chem. Soc., Chem.
Commun. 1968, 877. (b) Nakatsuka, S.; Tanino, H.; Kishi,
Y. J. Am. Chem. Soc. 1975, 97, 5008. (c) Nicolaou, K. C.;
Zak, M.; Rahimipour, S.; Estrada, A. A.; Lee, S. H.; O’Brate,
A.; Giannakakou, P.; Ghadiri, M. R. J. Am. Chem. Soc. 2005,
127, 15042. (d) Armstrong, R. W.; Moran, E. J. J. Am.
Chem. Soc. 1992, 114, 371.
(2) Chen, D. J.; Guo, L.; Liu, J. Y.; Kirtane, S.; Cannon, J. F.;
Li, G. G. Org. Lett. 2005, 7, 921.
(3) (a) Harburn, J. J.; Lofius, G. C.; Marples, B. A. Tetrahedron
1998, 54, 11907. (b) Chang, L. C.; Bhat, K. P. L.; Pisha, E.;
Kennelly, E. J.; Fong, H. H. S.; Pezzuto, J. M.; Kinghorn, A.
D. J. Nat. Prod. 1998, 61, 1257. (c) Kohno, J.; Nishio, M.;
Kawano, K.; Nakanishi, N.; Suzuki, S. I.; Uchida, T.;
Komatsubara, S. J. Antibiot. 1996, 49, 1212.
(4) Eervinka, O. In The Chemistry of Enamines, Part 1, Vol. 1;
Rappoport, Z., Ed.; Wiley: New York, 1994.
(5) (a) Srinivasan, M.; Perumal, S.; Selvaraj, S. ARKIVOC
2006, (x), 21. (b) Liu, J. B.; Li, L. C.; Dai, H.; Liu, Z.; Fang,
J. X. J. Organomet. Chem. 2006, 691, 2686.
(6) Weigel, W.; Henning, H.-G. Chem. Commun. 1997, 19,
Figure 1 X-ray crystal structure obtained for compound 4v
1893.
(7) Van Sant, K.; South, M. S. Tetrahedron Lett. 1987, 28, 6019.
(8) Padwa, A.; Eisenhardt, W. J. Org. Chem. 1970, 35, 2472.
(9) (a) Schumann, E. L.; Heinzelman, R. V.; Greig, M. E.;
Veldkamp, W. J. Med. Chem. 1964, 7, 329. (b) Pégurier,
C.; Morellato, L.; Chahed, E.; Andrieux, J.; Nicolas, J.-P.;
Boutin, J. A.; Bennejean, C.; Delagrange, P.; Langlois, M.;
Mathé-Allainmat, M. Bioorg. Med. Chem. 2003, 11, 789.
(c) Romine, J. L.; Martin, S. W.; Meanwell, N. A.; Epperson,
J. R. Synthesis 1994, 846.
(10) (a) Sivakumar, P. M.; Seenivasan, S. P.; Kumar, V.; Doble,
M. Bioorg. Med. Chem. Lett. 2007, 17, 1695. (b) Tan, E.
W.; Chan, B.; Blackman, A. G. J. Am. Chem. Soc. 2002, 124,
2078.
In order to obtain the desired products, strong nucleo-
philes leading to fast substitution reactions are needed,
therefore, preventing competitive self-elimination of a-
bromoketones or a-bromoesters; (3) hydroxamates with a
strong electron-withdrawing group at the nitrogen atom,
such as a sulfonyl group, would further enhance not only
the reactivity of the nucleophilic attack and elimination of
the alcohol, but also the a-hydrogen acidity of the benzyl-
oxy group. Upon treatment with base, both the desired
product 4 and the byproduct 5 could be detected
(Scheme 1). Not surprisingly, when less nucleophilic N-
substituted hydroxamates were used, this drawback could
be overcome while the rate of the conversion into the cor-
responding products was lower.
(11) (a) Alexander, P. A.; Marsden, S. P.; Muñoz Subtil, D. M.;
Reader, J. C. Org. Lett. 2005, 7, 5433. (b) Sai, H.; Ogiku,
T.; Ohmizu, H. Synthesis 2003, 201. (c) Srinivasan, A.;
Stephenson, R. W.; Olsen, R. K. J. Org. Chem. 1977, 42,
2256.
(12) (a) Shimohigashi, Y.; Nitz, T. J.; Stammer, C. H.; Unubushi,
T. Tetrahedron Lett. 1982, 23, 3235. (b) Trost, B. M.; Dake,
G. R. J. Am. Chem. Soc. 1997, 119, 7595.
In summary, we have described a practical and efficient
procedure, which offers advantages in easy availability of
reagents and good yields. Since the protocol is simple to
carry out, this new synthetic methodology should repre-
(13) General Procedure for the Synthesis of a,b-
Dehydroamino Acid Derivatives 4a–u
O
Ha
O
O
O
CHO
R1
R3
R2
R1
R2
R1
R2
R3
R1
R2
R3
DBU
– Ha
DBU
– Hb
+
N
HN
N
HN
O
R3
Ph
Hb
5
3
4
Scheme 1
Synlett 2008, No. 6, 861–866 © Thieme Stuttgart · New York

LETTER
To a mixture of hydroxamate 2 (2.0 mmol) and Cs2CO3 (2.2
Synthesis of Functionalized Enamines
865
55.39, 114.36, 125.17, 129.20, 129.65, 130.01, 132.63,
mmol) in anhyd MeCN (20 mL) was added a-bromoketone
or a-bromoester 1 (2.2 mmol) in one portion under stirring at
40 °C. When the starting material 2 was totally consumed,
the resulting mixture was cooled to r.t. and DBU (2.0 mmol)
was added dropwise. When the intermediate 3 was not
detected via TLC analysis any more, the solvent was
evaporated under reduced pressure and the residue was
purified by neutral Al2O3 chromatography or silica gel
chromatography to afford the desired products 4a–u.
(14) General Procedure for the Synthesis of a,b-
Dehydroamino Acid Derivative 4v
134.48, 138.89, 143.35, 161.42, 194.19. HRMS: m/z calcd
for C18H18NO4S- [M – H]-: 344.0962; found: 344.0970.
Compound 4e: yellow solid, mp 112–114 °C. 1H NMR (500
MHz, CDCl3): d = 1.20 (br, 3 H), 2.42 (s, 3 H), 3.83 (s, 3 H),
4.11 (br, 2 H), 6.71 (br s, 2 H), 6.90 (d, J = 8.5 Hz, 2 H), 7.25
(d, J = 7.5 Hz, 2 H), 7.49 (d, J = 8.5 Hz, 2 H), 7.75 (d, J = 8.0
Hz, 2 H). 13C NMR (125 MHz, CDCl3): d = 14.64, 21.89,
55.57, 62.10, 114.46, 126.61, 129.21, 129.90, 130.65,
131.15, 131.54, 134.76, 143.18, 154.35, 160.58, 193.63.
HRMS: m/z calcd for C20H21NNaO4+ [M + Na]+: 362.1363;
found: 362.1361.
To a mixture of hydroxamate 2a (2.0 mmol) and Cs2CO3 (2.2
mmol) in anhyd MeCN (20 mL) was added a-bromoketone
1h (2.4 mmol) in one portion under stirring at 40 °C. When
the starting material 2a had disappeared, DBU (2.0 mmol)
was added dropwise and the temperature was raised to
reflux. When the intermediate 3v was not detected via TLC
analysis any more, the solvent was evaporated under reduced
pressure and the residue was purified by silica gel
Compound 4f: yellow solid, mp 130–132 °C. 1H NMR (500
MHz, CDCl3): d = 1.39–1.46 (br, 9 H), 2.42 (s, 3 H), 3.83 (s,
3 H), 6.58–6.67 (br, 2 H), 6.91 (d, J = 8.5 Hz, 2 H), 7.26 (d,
J = 8.0 Hz, 2 H), 7.50 (d, J = 8.5 Hz, 2 H), 7.77 (d, J = 8.0
Hz, 2 H). 13C NMR (125 MHz, CDCl3): d = 21.88, 28.30,
55.57, 81.19, 114.40, 126.82, 129.16, 129.28, 129.88,
130.08, 131.53, 134.83, 143.08, 153.24, 160.44, 193.72.
HRMS: m/z calcd for C22H25NNaO4+ [M + Na]+: 390.1676;
found: 390.1680.
chromatography to afford the desired products 4v.
(15) All melting points were determined on a Kofler hot-plate
Compound 4g: yellow solid, mp 179–181 °C. 1H NMR (500
MHz, CDCl3): d = 1.21 (t, J = 7.0 Hz, 3 H), 2.39–2.42 (m, 5
H), 3.83 (s, 3 H), 6.75 (s, 1 H), 6.90 (d, J = 8.5 Hz, 2 H), 7.25
(d, J = 8.0 Hz, 2 H), 7.41 (d, J = 8.0 Hz, 2 H), 7.45 (br s, 1
H), 7.75 (d, J = 8.0 Hz, 2 H). 13C NMR (125 MHz, CDCl3):
d = 9.62, 21.88, 29.81, 55.56, 114.39, 126.67, 129.13,
130.05, 131.44, 131.50, 131.85, 134.67, 143.19, 160.55,
172.54, 193.96. HRMS: m/z calcd for C20H21NNaO3+ [M +
Na]+: 346.1414; found: 346.1410.
microscope apparatus and were uncorrected. 1H NMR, 13
C
NMR, and NOE spectra were recorded on a Varian Inova
500 MHz instrument. High-resolution electrospray
ionization mass spectra (HR-ESI-MS) were obtained using
an IonSpec Ultima 7.0T FTICR ESI mass spectrometer.
(16) Compound 4v: crystallized in triclinic, space group P1 with
cell parameters: a = 0.951 (3) nm, b = 0.104 (3) nm,
c = 0.109 (3) nm, a = 110.184 (4)°, b = 93.423 (5)°,
g = 98.428 (4)°, V = 0.999 (5) nm3, Dc = 1.287 g/cm3, Z = 2;
CCDC 672176.
Compound 4h: yellow solid, mp 156–158 °C. 1H NMR (500
MHz, CDCl3): d = 1.61–1.66 (m, 6 H), 2.42 (s, 3 H), 3.46 (t,
J = 5.0 Hz, 3 H), 3.83 (s, 3 H), 6.64 (s, 1 H), 6.68 (br s, 1 H),
6.89 (d, J = 8.5 Hz, 2 H), 7.24 (d, J = 7.5 Hz, 2 H), 7.44 (d,
J = 9.0 Hz, 2 H), 7.77 (d, J = 8.0 Hz, 2 H). 13C NMR (125
MHz, CDCl3): d = 21.85, 24.71, 26.13, 45.68, 55.53, 114.35,
127.32, 128.98, 129.42, 130.20, 131.19, 133.47, 134.87,
142.88, 154.99, 160.16, 194.81. HRMS: m/z calcd for
C23H26N2NaO3+ [M + Na]+: 401.1836; found: 401.1836.
Compound 4i: white solid, mp 131–133 °C. 1H NMR (500
MHz, CDCl3): d = 2.14 (d, J = 7.0 Hz, 2 H), 2.28 (s, 3 H),
3.85 (s, 3 H), 6.54 (q, J = 7.5 Hz, 1 H), 6.84–6.86 (m, 3 H),
7.17 (d, J = 8.0 Hz, 2 H), 7.40 (d, J = 9.0 Hz, 2 H), 7.70 (d,
J = 8.5 Hz, 2 H). 13C NMR (125 MHz, CDCl3): d = 15.61,
21.70, 55.71, 113.71, 127.63, 128.58, 129.74, 131.61,
134.05, 136.38, 142.24, 144.14, 163.25, 191.73. HRMS:
m/z calcd for C18H19NNaO4S+ [M + Na]+: 368.0927; found:
368.0926.
(17) Compound 4a: yellow solid, mp 167–168 °C. 1H NMR (500
MHz, CDCl3): d = 2.29 (s, 3 H), 2.41 (s, 3 H), 3.84 (s, 3 H),
6.89 (d, J = 9.0 Hz, 2 H), 6.94 (br s, 1 H), 7.08 (s, 1 H), 7.16
(d, J = 8.0 Hz, 2 H), 7.20 (d, J = 8.0 Hz, 2 H), 7.39 (d, J = 8.0
Hz, 2 H), 7.71 (d, J = 8.5 Hz, 2 H), 7.90 (d, J = 8.5 Hz, 2 H).
13C NMR (125 MHz, CDCl3): d = 21.50, 21.58, 55.36,
113.99, 125.44, 127.62, 128.95, 129.09, 129.12, 129.46,
133.43, 133.80, 136.15, 140.95, 142.72, 143.97, 161.71,
193.47. HRMS: m/z calcd for C24H23NNaO4S+ [M + Na]+:
444.1240; found: 444.1235.
Compound 4b: yellow solid, mp 142–144 °C. 1H NMR (500
MHz, CDCl3): d = 2.41 (s, 3 H), 3.84 (s, 3 H), 6.89 (d,
J = 8.5 Hz, 2 H), 6.97 (br s, 1 H), 7.13 (s, 1 H), 7.22 (d,
J = 8.0 Hz, 2 H), 7.33 (d, J = 8.5 Hz, 2 H), 7.42 (d, J = 8.0
Hz, 2 H), 7.76 (d, J = 8.5 Hz, 2 H), 7.87 (d, J = 9.0 Hz, 2 H).
13C NMR (125 MHz, CDCl3): d = 21.86, 55.64, 114.32,
125.45, 128.88, 129.31, 129.33, 129.35, 129.36, 133.64,
133.95, 137.93, 139.86, 141.62, 143.25, 162.06, 193.58.
HRMS: m/z calcd for C23H20ClNNaO4S+ [M + Na]+:
464.0694; found: 464.0691.
Compound 4j: white solid, mp 125–126 °C. 1H NMR (500
MHz, CDCl3): d = 2.15 (d, J = 7.0 Hz, 2 H), 3.86 (s, 3 H),
6.61 (q, J = 7.0 Hz, 1 H), 6.86–6.89 (m, 3 H), 7.35 (d, J = 8.5
Hz, 2 H), 7.43 (d, J = 9.0 Hz, 2 H), 7.76 (d, J = 8.5 Hz, 2 H).
13C NMR (125 MHz, CDCl3): d = 15.62, 55.73, 113.88,
128.45, 129.07, 129.40, 131.62, 133.66, 137.95, 139.79,
142.77, 163.44, 191.51. HRMS: m/z calcd for
Compound 4c: yellow solid, mp 197–198 °C. 1H NMR (500
MHz, CDCl3): d = 2.42 (s, 3 H), 3.85 (s, 3 H), 6.91 (d,
J = 9.0 Hz, 2 H), 7.01 (br s, 1 H), 7.20 (s, 1 H), 7.23 (d,
J = 7.5 Hz, 2 H), 7.44 (d, J = 8.0 Hz, 2 H), 7.86 (d, J = 8.5
Hz, 2 H), 8.01 (d, J = 8.5 Hz, 2 H), 8.19 (d, J = 9.0 Hz, 2 H).
13C NMR (125 MHz, CDCl3): d = 21.86, 29.93, 55.66,
114.46, 124.21, 125.19, 128.30, 129.10, 129.39, 129.47,
133.83, 142.37, 143.61, 145.24, 150.33, 162.24, 193.37.
HRMS: m/z calcd for C23H20N2NaO6S+ [M + Na]+:
475.0934; found: 475.0930.
C17H16ClNNaO4S+ [M + Na]+: 388.0381; found: 388.0382.
Compound 4k: white solid, mp 170–171 °C. 1H NMR (500
MHz, CDCl3): d = 2.18 (d, J = 7.0 Hz, 2 H), 3.85 (s, 3 H),
6.70 (q, J = 7.0 Hz, 1 H), 6.86–6.89 (m, 3 H), 7.43–7.46 (m,
2 H), 8.00–8.04 (m, 2 H), 8.21–8.23 (m, 2 H). 13C NMR (125
MHz, CDCl3): d = 15.77, 55.76, 114.02, 124.31, 128.21,
128.92, 131.60, 133.13, 143.92, 145.22, 150.36, 163.65,
191.11. HRMS: m/z calcd for C17H15N2O6S- [M – H]–:
375.0656; found: 375.0650.
Compound 4d: white solid, mp 103–104 °C. 1H NMR (500
MHz, CDCl3): d = 2.44 (s, 3 H), 3.10 (s, 3 H), 3.83 (s, 3 H),
6.45 (br s, 1 H), 6.93 (d, J = 9.0 Hz, 2 H), 7.05 (s, 1 H), 7.29
(d, J = 8.0 Hz, 2 H), 7.70 (d, J = 8.0 Hz, 2 H), 7.77 (d, J = 8.5
Hz, 2 H). 13C NMR (125 MHz, CDCl3): d = 21.66, 42.00,
Compound 4l: white solid, mp 101–102 °C. 1H NMR (500
MHz, CDCl3): d = 2.11 (d, J = 7.0 Hz, 2 H), 3.00 (s, 3 H),
3.89 (s, 3 H), 6.35 (br s, 1 H), 6.63 (q, J = 7.0 Hz, 1 H), 6.95–
Synlett 2008, No. 6, 861–866 © Thieme Stuttgart · New York

866
Y. Sun et al.
LETTER
136.59, 154.42, 163.27, 192.26. HRMS: m/z calcd for
6.98 (m, 2 H), 7.72–7.75 (m, 2 H). 13C NMR (125 MHz,
CDCl3): d = 15.32, 41.32, 55.77, 114.06, 129.26, 131.99,
134.29, 141.63, 163.62, 192.41. HRMS: m/z calcd for
C12H15NNaO4S+ [M + Na]+: 292.0614; found: 292.0612.
Compound 4m: white solid, mp 98–99 °C. 1H NMR (500
MHz, CDCl3): d = 1.25 (t, J = 7.0 Hz, 3 H), 1.88 (d, J = 7.0
Hz, 3 H), 3.87 (s, 3 H), 4.15 (q, J = 7.0 Hz, 2 H), 6.14 (q,
J = 6.5 Hz, 1 H), 6.63 (br s, 1 H), 6.93 (d, J = 9.0 Hz, 2 H),
7.78 (d, J = 8.5 Hz, 2 H). 13C NMR (125 MHz, CDCl3):
d = 14.33, 14.65, 55.66, 61.77, 113.71, 129.63, 131.86,
132.01, 134.98, 154.24, 163.24, 192.17. HRMS: m/z calcd
for C14H17NNaO4+ [M + Na]+: 286.1050; found: 286.1056.
Compound 4n: white solid, mp 158–160 °C. 1H NMR (500
MHz, CDCl3): d = 1.42 (s, 9 H), 1.86 (d, J = 7.5 Hz, 3 H),
3.86 (s, 3 H), 6.05 (br s, 1 H), 6.46 (br s, 1 H), 6.92 (d,
J = 8.5 Hz, 2 H), 7.80 (d, J = 8.5 Hz, 2 H). 13C NMR (125
MHz, CDCl3): d = 14.11, 28.34, 55.66, 80.87, 113.67,
114.02, 129.79, 131.84, 132.02, 135.44, 153.26, 163.21,
192.19. HRMS: m/z calcd for C16H21NNaO4+ [M + Na]+:
314.1363; found: 314.1357.
C17H23NNaO4+ [M + Na]+: 328.1519; found: 328.1522.
Compound 4r: white solid, mp 160–162 °C. 1H NMR (500
MHz, CDCl3): d = 1.19 (br, 3 H), 4.10–4.12 (m, 2 H), 6.71
(s, 2 H), 7.35–7.43 (m, 3 H), 7. 52–7.62 (m, 4 H), 7.89–7.98
(m, 4 H), 8.42 (s, 1 H). 13C NMR (125 MHz, CDCl3):
d = 14.61, 62.28, 125.68, 127.04, 128.07, 128.57, 128.60,
129.14, 129.29, 129.47, 129.68, 129.70, 131.37, 132.54,
133.57, 134.03, 134.44, 135.57, 154.32, 193.59. HRMS:
m/z calcd for C22H19NNaO3+ [M + Na]+: 368.1257; found:
368.1252.
Compound 4s: white solid, mp 115–117 °C. 1H NMR (500
MHz, CDCl3): d = 1.18 (br, 3 H), 4.11 (br, 2 H), 6.81 (br s,
1 H), 6.86 (s, 1 H), 7.47–7.53 (m, 4 H), 7.57–7.60 (m, 1 H),
7.66–7.68 (m, 1 H), 7.81–7.85 (m, 3 H), 7.90–7.92 (m, 3 H).
13C NMR (125 MHz, CDCl3): d = 14.64, 62.27, 126.25,
126.90, 127.38, 127.98, 128.40, 128.66, 129.50, 129.81,
130.12, 130.20, 131.63, 132.73, 133.37, 133.44, 133.63,
137.25, 154.11, 193.76. HRMS: m/z calcd for
C22H19NNaO3+ [M + Na]+: 368.1257; found: 368.1260.
Compound 4t: white solid, mp 84–86 °C. 1H NMR (500
MHz, CDCl3): d = 1.20 (br, 3 H), 3.86 (s, 3 H), 4.13 (q,
J = 7.0 Hz, 2 H), 6.26 (br s, 1 H), 7.31–7.39 (m, 4 H), 7.53
(d, J = 7.5 Hz, 2 H). 13C NMR (125 MHz, CDCl3):
d = 14.63, 52.89, 62.04, 124.68, 128.82, 129.61, 129.92,
131.56, 134.00, 154.33, 166.11. HRMS: m/z calcd for
C13H15NNaO4+ [M + Na]+: 272.0893; found: 272.0899.
Compound 4u: oil. 1H NMR (500 MHz, CDCl3): d = 1.06 (d,
J = 6.5 Hz, 6 H), 1.27 (t, J = 7.0 Hz, 3 H), 2.68–2.76 (m, 1
H), 3.78 (s, 3 H), 4.18 (q, J = 7.0 Hz, 2 H), 5.94 (br s, 1 H),
6.46 (d, J = 8.5 Hz, 1 H). 13C NMR (125 MHz, CDCl3):
d = 14.66, 21.83, 27.80, 52.51, 61.75, 123.73, 145.09,
155.01, 165.72. HRMS: m/z calcd for C10H17NNaO4+ [M +
Na]+: 238.1050; found: 238.1046.
Compound 4o: white solid, mp 83–85 °C. 1H NMR (500
MHz, CDCl3): d = 1.22 (t, J = 2.5 Hz, 3 H), 1.85 (d, J = 7.0
Hz, 3 H), 2.40 (q, J = 7.5 Hz, 2 H), 3.86 (s, 3 H), 6.24 (q,
J = 7.0 Hz, 2 H), 6.92 (d, J = 9.0 Hz, 2 H), 7.48 (br s, 1 H),
7.78 (d, J = 8.5 Hz, 2 H). 13C NMR (125 MHz, CDCl3):
d = 9.68, 14.85, 29.76, 55.47, 113.53, 129.30, 131.94,
133.39, 134.40, 163.11, 171.93, 192.35. HRMS: m/z calcd
for C14H17NNaO3+ [M + Na]+: 270.1101; found: 270.1107.
Compound 4p: white solid, mp 128–130 °C. 1H NMR (500
MHz, CDCl3): d = 1.60–1.62 (m, 6 H), 1.85 (d, J = 8.5 Hz, 3
H), 3.45–3.47 (m, 4 H), 3.86 (s, 3 H), 6.11 (q, J = 7.0 Hz, 1
H), 6.59 (br s, 1 H), 6.92 (d, J = 9.0 Hz, 2 H), 7.79 (d, J = 9.0
Hz, 2 H). 13C NMR (125 MHz, CDCl3): d = 14.57, 24.66,
25.91, 45.54, 55.65, 113.60, 129.81, 130.60, 132.24, 136.33,
155.09, 163.12, 193.32. HRMS: m/z calcd for
Compound 4v: white solid, mp 152–154 °C. 1H NMR (500
MHz, CDCl3): d = 1.14 (s, 9 H), 2.39 (s, 3 H), 3.85 (s, 3 H),
6.87 (br s, 1 H), 6.90 (d, J = 9.0 Hz, 2 H), 7.20 (s, 1 H), 7.23
(d, J = 8.5 Hz, 2 H), 7.65 (d, J = 8.0 Hz, 2 H), 7.82 (d, J = 9.0
Hz, 2 H). 13C NMR (125 MHz, CDCl3): d = 21.72, 29.08,
43.08, 55.58, 114.21, 125.66, 127.62, 128.13, 129.50,
133.28, 136.11, 136.13, 144.07, 161.50, 203.59. HRMS:
m/z calcd for C21H25NNaO4S+ [M + Na]+: 410.1397; found:
410.1398.
C17H22N2NaO3+ [M + Na]+: 325.1523; found: 325.1516.
Compound 4q: white solid, mp 67–69 °C. 1H NMR (500
MHz, CDCl3): d = 0.90 (t, J = 7.0 Hz, 3 H), 1.24 (t, J = 7.5
Hz, 3 H), 1.45–1.31 (m, 4 H), 2.29 (q, J = 7.5 Hz, 2 H), 3.87
(s, 3 H), 4.14 (q, J = 7.0 Hz, 2 H), 5.98 (t, J = 7.0 Hz, 1 H),
6.55 (br s, 1 H), 6.93 (d, J = 8.5 Hz, 2 H), 7.79 (d, J = 9.0 Hz,
2 H). 13C NMR (125 MHz, CDCl3): d = 14.07, 14.63, 22.73,
28.19, 30.86, 55.65, 61.77, 113.71, 129.72, 132.08, 133.74,
Synlett 2008, No. 6, 861–866 © Thieme Stuttgart · New York