Rhodium-catalyzed reaction of diazoacetates, thiols and azodicarboxylates: An unusual 1,2-aza shift from a sulfonium ylide

Article abstract of DOI:10.1055/s-2007-977454

A one-pot reaction of diazoacetates, thiols and azodicarboxylates in the presence of a dirhodium acetate catalyst gave N,S-ketals in good yields. This reaction proceeded via an unusual 1,2-aza shift from a sulfonium ylide intermediate. Georg Thieme Verlag

Full text of DOI:10.1055/s-2007-977454

1314
LETTER
Rhodium-Catalyzed Reaction of Diazoacetates, Thiols and Azodicarboxylates:
An Unusual 1,2-Aza Shift from a Sulfonium Ylide
R
eactionof Diazoa
a
cetates,
T
h
o
iols and
A
zo
x
dicarboxylat
i
es Huang,a,b,c Wenhao Hu*a
a
Department of Chemistry, East China Normal University, Shanghai 200062, P. R. of China
Fax +86(21)62233176; E-mail: whu@chem.ecnu.edu.cn
b
c
Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, P. R. of China
Graduate School of Chinese Academy of Sciences, Beijing 100039, P. R. of China
Received 18 January 2007
PhHN
EtO2C
EtO2C
Abstract: A one-pot reaction of diazoacetates, thiols and azodicar-
boxylates in the presence of a dirhodium acetate catalyst gave N,S-
ketals in good yields. This reaction proceeded via an unusual 1,2-
aza shift from a sulfonium ylide intermediate.
CO2Et
HN CO2Et
Rh2(OAc)4
N
N2
CO2Et +
+
PhNH2
N
N
CH2Cl2
75%
CO2Et
Key words: one-pot reaction, diazo compounds, sulfonium ylides,
N,S-ketals, rearrangement reaction
Scheme 1 The rhodium-catalyzed reaction of EDA, aniline and
DEAD
To our surprise, under similar reaction conditions, using
thiophenol instead of aniline gave unexpected results.
There was no three-component product formed from the
reaction of EDA, diethyl azodicarboxylate, and thio-
phenol catalyzed by dirhodium acetate. Instead, we main-
ly obtained the adduct 6, which was generated from the
direct addition of thiophenol to DEAD (Scheme 2).
Ylides as reactive intermediates have been known to un-
dergo synthetically useful transformations.1 The reaction
of carbenes with sulfur compounds represents a useful ap-
proach to generate sulfonium ylides. The sulfonium ylides
have been extensively reported to undergo rearrangement
reactions such as 1,2-Stevens2 and 2,3-sigmatropic rear-
rangements.3 Sulfonium ylides have been also useful in-
termediates in synthetic chemistry.4 For example, the
sulfonium ylides were utilized in the Corey–Chaykovsky
reaction for oxirane formation.5 In contrast, the reaction of
carbonyl-stabilized sulfonium ylides with electrophiles
was scarcely reported despite the potential usefulness in
constructing complex sulfur-containing molecules. Oku’s
group recently reported that dirhodium(II) acetate cata-
lyzed intramolecular reaction of diazoketones bearing a
sulfide group with a Lewis acid activated aldehyde to give
a carbon–carbon-bonded cyclic product.6 However, the
intermolecular reaction of carbonyl-stabilized sulfonium
ylides with electrophiles is unknown.
R3O2C
CO2R
Rh2(OAc)4
N
R2SH
+
+
R1
N2
N
CH2Cl2, reflux
CO2R3
1
2
3
R, R1
R2
R3
Et, H (1a)
Ph (2a)
Et (3a)
Me, Ph (1b)
Ph (2a)
Et (3a)
R1
CO2R3
R2S
CO2R
CO2R3
R2S
CO2R
4 : 5 : 6
R3O2C
+
N
+
N
N
SR2
<1 : <1 : >98
R3O2C
N
R1
5
H
H
>98 : <1 : <1
4
6
We have recently unveiled a new type of three-component
ylide trapping process, in which in situ generated ammo-
nium and oxonium ylides were trapped by electrophiles
such as imines, aldehydes, and azodicarboxylates.7 For
example, nucleophilic addition of an ammonium ylide
generated from ethyl diazoacetate (EDA) and aniline to
diethyl azodicarboxylate gave an aminal in good yield
(Scheme 1).7e
Scheme 2 The rhodium-catalyzed reaction of diazoacetate, thiols,
and azodicarboxylates
Control experiment indicated that product 6 could be
formed in 85% yield in the absence of the rhodium cata-
lyst. In addition, the two-component reaction of EDA with
benzenethiol gave the S–H insertion product in the pres-
ence of the rhodium catalyst9 (Scheme 3).
We anticipated that this strategy would be applicable sim-
ilarly to sulfonium ylide to afford N,S-acetal compounds.
N,S-Acetal analogues were useful intermediates in the
synthesis of natural and biomedicinal molecules, such as
gliotoxin and HIV-protease inhibitors.8
Interestingly, different results were observed when using
methyl phenyldiazoacetate instead of EDA. Hence, reac-
tion of methyl phenyldiazoacetate, thiophenol and DEAD
Rh2(OAc)4
N2
CO2Et
1a
PhSH
+
PhS
CO2Et
CH2Cl2
reflux
SYNLETT 2007, No. 8, pp 1314–1316
1
6.
0
5.
2
0
0
7
2a
5
Advanced online publication: 08.05.2007
DOI: 10.1055/s-2007-977454; Art ID: W01207ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 3 S–H Insertion of EDA with thiophenol

LETTER
Reaction of Diazoacetates, Thiols and Azodicarboxylates
1315
proceeded well to give the N,S-acetal 4a in 70% yield, and
the two-component side product 6 and the S–H insertion
product 5 were insignificant in the reaction mixture.
Table 2 Reaction of Diazoacetate 1 with Azodicarboxylates 3 and
Thiophenol (2a)a
Entry R1 (R = Me)
R3
Yield of 4 Ratio of
(%)b
4:5c
A variety of thiols were employed into the reaction. As
can be seen from Table 1, excellent selectivity of the
three-component products to the S–H-insertion products
(4:5 > 99:1) was observed regardless of the electronic
property of the substituents on the phenyl ring (Table 1,
entries 1–3). When aliphatic thiols were used in the reac-
tion, the ratio of 4:5 decreased significantly (Table 1, en-
tries 4–6). In addition, decreased yield of 4 was obtained
with the thiol bearing a b-ester functionality (Table 1,
entry 7). There was no reaction occurring by using di-
methylsulfide (Table 1, entry 8).
1
2
3
4
5
p-MeOC6H4 (1c)
Et (3a)
Et (3a)
Et (3a)
t-Bu (3b)
Et (3a)
80 (4h)
70 (4a)
50 (4i)
50 (4j)
67 (4k)
>99:1
>99:1
>99:1
83:17
>99:1
Ph (1b)
p-NO2C6H4 (1d)
Ph (1b)
CO2Me (1e)
a All reaction were carried out in refluxing CH2Cl2 in the presence of
Rh2(OAc)4 (1 mol%) with 1:2a:3 = 1.0:1.1:1.2 mmol.
b Isolated yields after chromatography.
c Determined by 1H NMR of crude reaction mixtures.
Table 1 Reaction of Methyl Phenyldiazoacetate (1b) with DEAD
(3a) and Thiols 2a
Entry
2
Yield of 4 (%)b
70 (4a)
60 (4b)
45 (4c)
68 (4d)
63 (4e)
55 (4f)
Ratio of 4:5c
>99:1
>99:1
>99:1
84:16
76:24
68:32
55:45
–
1
2
3
4
5
6
7
8
PhSH
p-NO2PhSH
p-MeOPhSH
EtSH
n-PrSH
BnSH
HSCH2CO2Et
Me2S
35 (4g)
NRd
a All reactions were carried out in refluxing CH2Cl2 in the presence of
Rh2(OAc)4 (1 mol%) with 1b:2:3a = 1.0:1.1:1.2 mmol.
b Isolated yields after chromatography.
c Determined by 1H NMR analysis of the crude reaction mixture.
d No diazo decomposition occurred in refluxing CH2Cl2.
Figure 1 X-ray structure of compound 4h
methyl phenyldiazoacetate 1b did give 4a in 85% isolated
yield (Scheme 4).
The scope of the reaction was further expanded to other
diazoacetates and azodicarboxylates with thiophenol. The
three-component reaction was found to be quite versatile
to give the desired products 4 in moderate to good yields
and consistently high ratio of 4:5 (Table 2). Lower ratio of
4:5 was observed when sterically hindered di-tert-butyl
azodicarboxylate was used (Table 2, entry 4). The reac-
tion was not limited to phenyldiazoacetates, we were
pleased to find that the similar results were obtained when
dimethyl diazomalonate was used (Table 2, entry 5). The
structure of 4h was conformed by single-crystal X-ray
analysis (Figure 1).10
Ph
CO2Et
CO2Me
Rh2(OAc)4 (1 mol%)
CH2Cl2
SPh
PhS
CO2Me
CO2Et
+
EtO2C
N
N
N
Ph
N2
EtO2C
N
H
reflux
85%
H
1b
6
4a
Scheme 4 Reaction of methyl phenyldiazoacetate (1b) with 6
A mechanism for this reaction is proposed in Scheme 5.
There are two competitive reaction pathways involved in
the reaction: (A) The adduct 6 is trapped by a carbenoid
intermediate 8 to form a ylide 9, the N,S-acetal 4 is formed
by an unusual [1,2]-aza shift of 9. A similar aza shift was
reported in a ring-expanding reaction.11 (B) The carbenoid
intermediate 8 react directly with thiol 2 to give ylide 7,
which then undergoes a [1,2]-H shift to give an S–H-in-
sertion product 5. The ratio of 4:5 was much related to the
relative concentration of 6:2 in the reaction mixture.12
The major reaction pathway to form the N,S acetals 4 was
found to be quite different from the ylide-trapping process
proposed previously.7 In the present study, addition of
thiol to azodicarboxylate was a rapid process. We found
that significant amount of 6 was formed at the time of
additon of the diazo compounds. It was suspected that the
formation of 4 resulted from the reaction of the diazo
compounds 1 with the adduct 6. To prove this possibility,
pure 6 was prepared and isolated. Reaction of 6 with
Synlett 2007, No. 8, 1314–1316 © Thieme Stuttgart · New York

1316
H. Huang, W. Hu
LETTER
R3O2C
(7) (a) Wang, Y. H.; Zhu, Y. X.; Chen, Z. Y.; Mi, A.; Hu, W. H.;
Doyle, M. P. Org. Lett. 2003, 5, 3923. (b) Wang, Y. H.;
Zhu, Y. X.; Chen, Z. Y.; Mi, A.; Hu, W. H. Chem. Commun.
2004, 2486. (c) Lu, C. D.; Liu, H.; Chen, Z. Y.; Hu, W. H.;
Mi, A. Org. Lett. 2005, 7, 83. (d) Lu, C. D.; Chen, Z. Y.;
Hu, W. H.; Mi, A. Chem. Commun. 2005, 2624. (e) Huang,
H. X.; Wang, Y. H.; Chen, Z. Y.; Hu, W. H. Adv. Synth.
Catal. 2005, 347, 531. (f) Huang, H. X.; Wang, Y. H.; Chen,
Z. Y.; Hu, W. H. Synlett 2005, 2498.
(8) (a) Aliev, A. E.; Hilton, S. T.; Motherwell, W. B.; Selwood,
D. L. Tetrahedron Lett. 2006, 47, 2387. (b) Hilton, S. T.;
Motherwell, W. B.; Selwood, D. L. Synlett 2004, 2609.
(c) Bjosvik, H.; Bravo, P.; Crucianelli, M.; Volonterio, A.;
Zanda, M. Tetrahedron: Asymmetry 1997, 8, 2817.
(9) For metal-catalyzed S–H insertion, see: (a) Paulissen, R.;
Hayez, E.; Hubert, A. J.; Teyssie, P. Tetrahedron Lett. 1974,
607. (b) Trost, B. M. Chem. Rev. 1978, 78, 363.
CO2R3
HN
N
CO2R
Rh
3
8
N
3
CO2R3
N
CO2
R1
CO2R3
R2
S
R3O2C
N
A
N
H
SR2
CO2R
6
R2SH
2
9
R1
R1
[1,2]-aza shift
B
R2
R1
S
H
CO2R
7
CO2R
R2S
CO2R
CO2R3
[1,2]-H shift
R1
Rh
N
R3O2C
N
S-H insertion
H
8
4
5
Scheme 5 A proposed mechanism of the reaction
In conclusion, we have reported a reaction of diazoace-
tates, thiols, and azodicarboxylates to give sulfur-contain-
ing N,S-acetals in good yield. Although the product type
is similar to that from the previous reported ammonium
ylide trapping process, the current reaction proceeds via
an unusual [1,2]-aza shift of the sulfonium ylides 9.
(c) Mckervey, M. A.; Ratananulul, P. Tetrahedron Lett.
1982, 23, 2509. (d) Moody, C. J.; Taylor, R. J. Tetrahedron
1990, 46, 6501.
(10) Crystal Structure Data for 4h. C22H26N2O7S, Mw = 462.51,
colorless, Triclinic, P1, a = 10.343 (2), b = 10.796 (2),
c = 11.630 (2) Å, a = 106.74 (2)°, b = 102.61 (2)°,
g = 101.02 (2)°, V = 1167.93 (46) Å3, Z = 2, T = 287 (2) K,
r
calcd = 1.315 Mg·m–3, F(000) = 488, l = 0.71073 Å,
m = 0.183 mm–1, GOF = 0.977, R(F) = 0.0435 and
wR(F)2 = 0.1061 for 4930 observed reflections, I > 4s,
1.91° < q < 25.50°. CCDC 299823 contains the
supplementary crystallographic data for this paper. These
data can be obtained free of charge via
Acknowledgment
We are grateful for financial support from the Chinese Academy of
Sciences and National Science Foundation of China (Grant No.
20472080). We thank Prof. Kaibei Yu of Chengdu Institute of
Organic Chemistry for X-ray measurement.
www.ccdc.cam.ac.uk/conts/retrieving.html [or from the
Cambridge Crystallographic Data Centre, 12, Union Road,
Cambridge CB21EZ, UK; fax +44 (1223)336033; or
deposit@ ccdc.cam.ac.uk].
References and Notes
(11) A similar ring-expansion N-shift of sulfonium ylide was
reported: Crow, W. D.; Gosney, I.; Ormiston, R. A. J. Chem.
Soc., Chem. Commun. 1983, 643.
(12) Typical Procedure for the Reaction of Diazo Compounds
with Thiols and DEAD
(1) (a) Padwa, A.; Weingarten, M. D. Chem. Rev. 1996, 96,
223. (b) Doyle, M. P.; Mckervey, M. A.; Ye, T. Modern
Catalytic Methods for Organic Synthesis with Diazo
Compounds; John Wiley and Sons: New York, 1998.
(c) Padwa, A.; Hornbuckle, S. F. Chem. Rev. 1991, 91, 263.
(2) For examples of [1,2] Stevens rearrangement of sulfonium
ylides derived from metal carbenoids, see: (a)Kametani,T.;
Yukawa, H.; Honda, T. J. Chem. Soc., Chem. Commun.
1986, 651. (b) Kim, G.; Kang, S.; Kim, S. N. Tetrahedron
Lett. 1993, 34, 7627. (c) Moody, C. J.; Taylor, R. J.
Tetrahedron Lett. 1988, 29, 6005.
(3) For examples of [2,3]-sigmatropic rearrangement of
ammonium ylides derived from metal carbenoids, see:
(a) Ma, M.; Peng, L. L.; Li, C. K.; Zhang, X.; Wang, J. B. J.
Am. Chem. Soc. 2005, 127, 15016. (b) Doyle, M. P.;
Tamblyn, W. H.; Bagbers, V. J. Org. Chem. 1981, 46, 5094.
(c) Vedejs, E.; Hagen, J. P. J. Am. Chem. Soc. 1975, 97,
6878. (d) Doyle, M. P.; Griffin, J. H.; Chinn, M. S.; van
Leusen, D. J. Org. Chem. 1981, 46, 5094.
To a refluxing CH2Cl2 (8 mL) solution of Rh2(OAc)4 (2.7
mg, 1 mol%), benzenethiol 2a (66.0 mg, 0.60 mmol) and
DEAD (143.6 mg, 0.83 mmol) under argon atmosphere was
added methyl phenyl diazoacetate (1b, 96 mg, 0.55 mmol) in
CH2Cl2 (4 mL) over 1 h via a syringe pump. After comple-
tion of the addition, the reaction mixture was cooled to r.t.
Then, the solvent was removed. The crude product was
purified by flash chromatography on silica gel by using 20%
EtOAc–light PE as eluent to give a white solid 4a in 70%
yield.
Methyl 2-(N,N¢-Dicarboethoxyhydrazinyl)-2-phenyl-2-
(phenylthio)acetate (4a)
Rf = 0.22 (30% EtOAc–light PE); mp 126.5–128.4 °C. 1H
NMR (300 MHz, CDCl3): d = 8.08 (d, J = 7.2 Hz, 2 H),
7.20–7.39 (m, 8 H), 6.51 (s, 1 H), 4.27–4.34 (m, 2 H), 3.96–
4.04 (m, 2 H), 3.66 (s, 1 H), 1.04–1.43 (m, 6 H). 13C NMR
(75 MHz, CDCl3): d = 168.5, 156.6, 155.7, 137.9, 137.3,
130.2, 129.3, 128.6, 128.4, 127.9, 127.7, 81.7, 63.1, 62.2,
52.8, 14.5, 13.9. HRMS: m/z calcd for C21H24N2O6S1:
455.1247; found: 455.1237 [M + Na]+.
(4) Huxtable, R. J. Biochemistry of Sulfur; Plenum Press: New
York, 1986.
(5) (a) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1962,
84, 867. (b) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc.
1965, 87, 1353. (c) Li, A. H.; Dai, L. X.; Aggarwal, V. K.
Chem. Rev. 1997, 97, 2341.
(6) Sawada, Y.; Oku, A. J. Org. Chem. 2004, 69, 2899.
Synlett 2007, No. 8, 1314–1316 © Thieme Stuttgart · New York

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