A practical synthesis of b-keto thioesters by direct crossed-claisen coupling of thioesters and N-acylbenzotriazoles

Article abstract of DOI:10.1055/s-0029-1216971

Thioesters undergo chemoselective soft enolization and acylation with N-acylbenzotriazoles on treatment with MgBr2?OEt2 and i-Pr2NEt to give b-keto thioesters. Prior enolate formation is not required and the reaction is conducted using untreated dichlorom

Full text of DOI:10.1055/s-0029-1216971

3350
PRACTICAL SYNTHETIC PROCEDURES
A Practical Synthesis of b-Keto Thioesters by Direct Crossed-Claisen Coupling
of Thioesters and N-Acylbenzotriazoles
Practical
S
ynthesis
u
of
b
-Keto
T
o
hioesters qiang Zhou, Daniel Lim, Fang Fang, Don M. Coltart*
Department of Chemistry, Duke University, Durham, NC 27708, USA
Fax +1(919)6601605; E-mail: don.coltart@duke.edu
PSP
Received 13 June 2009
No169
Abstract: Thioesters undergo chemoselective soft enolization and acylation with N-acylbenzotriazoles on treatment with MgBr2·OEt2 and
i-Pr2NEt to give b-keto thioesters. Prior enolate formation is not required and the reaction is conducted using untreated dichloromethane
open to the air.
Key words: soft enolization, crossed-Claisen condensation, acylation, thioester, C–C coupling reaction
MgBr2⋅OEt2, i-Pr2NEt
O
O
O
O
O
CH2Cl2 (untreated)
r.t., open to air
+
+
SPh
SPh
Bt
Bt
SPh
12 h, 78%
OBn
OBn
1
2
3
MgBr2⋅OEt2, i-Pr2NEt
CH2Cl2 (untreated)
r.t., open to air
O
O
O
TBSO
TBSO
SPh
6 h, 64%
Ph
Bt
Ph
4
5
6
MgBr2⋅OEt2, i-Pr2NEt
MeO2C
O
O
MeO2C
O
O
CH2Cl2 (untreated)
r.t., open to air
O
O
SPh
SPh
O
+
48 h, 80%
7
8
9
O
Scheme 1 Direct thioester crossed-Claisen reaction via soft enolization
The crossed-Claisen coupling reaction is an essential does not require prior enolate formation and is conducted
carbon–carbon bond-forming method.1 The b-keto ester using untreated, reagent-grade solvent open to the air, thus
moiety produced is found in countless natural products, providing a remarkably simple approach to this important
pharmaceuticals, and other compounds in either its native transformation.
or derivatized form. In situations where both components
The underlying premise for chemoselectivity in this trans-
of the coupling reaction possess a-protons, chemoselec-
tivity is controlled by prior enolate formation.1 While ef-
fective, the step-wise procedures required for enolate
formation are time consuming, particularly if trapping is
involved, and require that all manipulations be conducted
under anhydrous conditions and, when strong bases are
used, at low temperature. Moreover, a large excess of eno-
late ( acylating agent) is required for high conversion,
making these transformations inherently inefficient.1,2
Herein, we report an efficient and operationally-simple di-
rect crossed-Claisen coupling of thioesters and N-acyl-
benzotriazoles based on chemoselective soft enolization3
that addresses these limitations (Scheme 1). The process
formation derives from our earlier observations4 that, like
ketones, thioesters are particularly well suited to soft eno-
lization, whereas N-acylbenzotriazoles5 are relatively less
susceptible to this form of enolization. Consequently,
combination of a thioester and an N-acylbenzotriazole un-
der conditions that promote soft enolization should result
in a controlled crossed-Claisen reaction, with the thioester
serving as the enolate precursor and the N-acylbenzotria-
zole as the acylating agent (Scheme 2).4e
O
O
O
O
MgBr2⋅OEt2, i-Pr2NEt
soft enolization
Bt
SPh
SPh
+
R1
R2
R1
R2
SYNTHESIS 2009, No. 19, pp 3350–3352
Advanced online publication: 28.08.2009
x
x.
x
x
.
2
0
0
9
Scheme 2 Direct thioester crossed-Claisen reaction via soft enoliza-
tion
DOI: 10.1055/s-0029-1216971; Art ID: Z12309SS
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Practical Synthesis of b-Keto Thioesters
3351
This idea was tested by combining N-acylbenzotriazole 1
(1.0 equiv) and S-phenyl thioester 10 (1.0 equiv) in
CH2Cl2 (0.25 M) in the presence of MgBr2·OEt2 (3.0
equiv) and Hünig’s base (4.0 equiv) (Table 1, entry 1).
The desired crossed coupling product was obtained in ex-
cellent yield (93%), and neither the self-addition products
nor the other crossed-Claisen product was detected. De-
creasing the amount of MgBr2·OEt2, Hünig’s base, or the
concentration of the reaction resulted in a lower yield and
longer reaction time. Moreover, increasing the relative
amount of the thioester compared to the N-acylbenzotria-
zole gave a slightly lower conversion, along with a small
amount of the thioester self-condensation product.
Table 2 The Direct Crossed-Claisen Coupling of 1 with Various
Thioesters
O
O
O
MgBr2⋅OEt2, i-Pr2NEt
t-Bu
CH2Cl2 (untreated)
1
SPh
SPh
+
r.t., open to air
R
R
Entry
R
Product
Time (h) Yield (%)
1
2
3
4
5
6
Me (5)
24
26
28
3
6
12
12
12
12
12
87
85
88
78
0
Pr (25)
Bn (27)
OBn (2)
The coupling reaction was tried with a variety of acetate-
derived thioesters, as well as with phenyl acetate
(Table 1). Of the thioesters examined, 10 was found to
perform the best in terms of product yield. As expected,
oxoester 22 underwent the transformation much less effi-
ciently, giving only 44% yield of the coupled product after
24 hours.
CH2OBn (29)
CH2OTBS (31)
30
32
0
Table 3 The Direct Crossed-Claisen Coupling of Thioesters with
N-Acylbenzotriazoles
O
O
O
O
MgBr2⋅OEt2, i-Pr2NEt
Table 1 The Direct Crossed-Claisen Coupling of 1 with Various
Thioesters and an Oxoester
CH2Cl2 (untreated)
R1
Bt
SPh
R1
SPh
+
r.t., open to air
R2
R2
MgBr2⋅OEt2
i-Pr2NEt
CH2Cl2
Entry R1
R2
Product Time Yield
(h) (%)
O
O
O
O
t-Bu
+
t-Bu
Bt
Y
Y
1
1
2
3
4
Ph (33)
Me (5)
Me (5)
34
36
38
40
48 91
91
16 76
Entry
Y
Product Time (h) Yield (%)
i-Pr (35)
6
1
2
3
4
5
6
7
SPh (10)
11
13
15
17
19
21
23
4
4
93
84
87
81
83
80
44
(E)-CH=CHPh (37) Me (5)
SC6H4-4-Cl (12)
SC6H4-4-CF3 (14)
SC6H4-4-OMe (16)
SEt (18)
C6H11 (39)
Me (5)
6
90
4
TBSO
5
6
Me (5)
6a
6
64
4
Ph
4
4
SBn (20)
4
Me (5)
Me (5)
42
43
45
120
0
OPh (22)
26
OH
41
One of the compelling features of carbon–carbon bond
formation via soft enolization is the mildness of the reac-
tion conditions. In avoiding the use of strong bases, not
only are low temperature requirements overcome, but so
too is the need for an inert atmosphere and the use of an-
hydrous conditions. To confirm that such conditions
would not be deleterious in the present situation, the reac-
tion between 1 and 10 was repeated, but this time open to
the air using untreated, reagent grade solvent. No change
in the outcome of the reaction was observed using this ex-
tremely simple set of conditions, in comparison to the use
of an inert atmosphere and anhydrous conditions.
7
8
12 87
CO2Me
7
7
24 92
CO2Me
44
O
9
9
48 80
O
CO2Me
7
The scope of the reaction with different a-substituted
thioesters and 1 was investigated (Table 2). The transfor-
mation proved to be compatible with a-alkyl and a-alkoxy
thioesters (entries 1 to 4), however, b-alkoxy and b-silyl-
8
a Control experiments (cf. refs 4c,d) showed that epimerization did not
occur.
Synthesis 2009, No. 19, 3350–3352 © Thieme Stuttgart · New York

3352
G. Zhou et al.
PRACTICAL SYNTHETIC PROCEDURES
mL), dried (MgSO4), and evaporated to give a light-red oil. Flash
chromatography over silica gel using 5:95 EtOAc–hexanes gave 24
(0.115 g, 87%) as a pure, light-pink oil comprised of a mixture of
the b-keto thioester and tautomeric enol forms in a ratio of 4:1.
1H NMR (400 MHz, CDCl3): d = 13.46 (s, 1 H), 7.52–7.34 (m, 5 H),
3.81 (q, J = 7.2 Hz, 1 H), 2.49 (s, 2 H), 2.24 (s, 2 H), 2.00 (s, 3 H),
1.41 (d, J = 8.0 Hz, 3 H), 1.04 (s, 9 H), 1.03 (s, 9 H).
13C NMR (400 MHz, CDCl3): d = 203.8, 196.0, 194.8, 174.1,
135.5, 134.5, 129.8, 129.6, 129.4, 129.3, 127.7, 127.1, 105.3, 62.7,
53.6, 45.6, 33.3, 31.1, 30.3, 29.7, 13.6, 13.1.
oxy thioesters (entries 5 and 6) were not suitable sub-
strates, due to competing b-elimination.
The scope of the reaction was further explored using a va-
riety of N-acylbenzotriazoles and different thioesters
(Table 3). In general, the transformation proceeded very
well with a range of N-acylbenzotriazoles, including those
possessing ester, acetonide, and a-silyloxy functionality.
It was also effective with an a,b-unsaturated N-acylben-
zotriazole 37. However, the phenolic species 41 failed to
undergo the crossed coupling reaction altogether. Nota-
bly, the direct crossed-Claisen reaction proved to be very
effective in the formation of sterically hindered systems,
as shown in entries 5, 8, and 9.
MS (ESI): m/z [M + Na]+ calcd for C15H20O2S + Na: 287.1; found:
287.1.
Acknowledgment
An additional advantage in using thioesters for the direct
crossed Claisen reaction is that the b-keto thioester prod-
ucts act as stable synthetic equivalents of b-keto acids.
The thioester products can be directly converted into a va-
riety of useful compounds under mild conditions, in addi-
tion to those commonly obtained from b-keto esters.
These include b-keto esters, b-keto amides and b-dike-
tones.4e
G.Z. holds a C. R. Hauser Fellowship from Duke University De-
partment of Chemistry. This work was supported by Duke Univer-
sity, the ACS (PRF 4650-G1), and NCBC (2008-IDG-1010).
References
(1) (a) Smith, M. B.; March, J. March’s Advanced Organic
Chemistry: Reactions, Mechanisms, and Structure, 6th ed.;
Wiley: Hoboken, 2007, Chap. 16. (b) Benetti, S.;
Romagnol, R.; De Risi, C.; Spalluto, G.; Zanirato, V. Chem.
Rev. 1995, 95, 1065.
(2) In a recent modification of the crossed-Claisen reaction, 1:1
mixtures of esters and 2-substituted N-acyl-N-methyl-
imidazolium chlorides were treated with TiCl4 and Bu3N,
lending some efficiency to the coupling. Unfortunately, the
reaction still requires anhydrous conditions and low
temperature, and a large excess (3 equiv) of TiCl4 is needed.
See: Misake, T.; Nagase, R.; Matsumoto, K.; Tanabe, Y.
J. Am. Chem. Soc. 2005, 127, 2854.
(3) For pioneering applications of soft enolization in direct
carbon–carbon bond formation, see: (a) Rathke, M. W.;
Cowan, P. J. J. Org. Chem. 1985, 50, 2622. (b) Rathke, M.
W.; Nowak, M. J. Org. Chem. 1985, 50, 2624. (c) Tirpak,
R. E.; Olsen, R. S.; Rathke, M. W. J. Org. Chem. 1985, 50,
4877.
(4) See, for example: (a) Yost, J. M.; Zhou, G.; Coltart, D. M.
Org. Lett. 2006, 8, 1503. (b) Zhou, G.; Yost, J. M.; Coltart,
D. M. Synthesis 2007, 478. (c) Lim, D.; Fang, F.; Zhou, G.;
Coltart, D. M. Org. Lett. 2007, 9, 4139. (d) Lim, D.; Zhou,
G.; Livanos, A. E.; Fang, F.; Coltart, D. M. Synthesis 2008,
2148. (e) Zhou, G.; Lim, D.; Coltart, D. M. Org. Lett. 2008,
10, 3809.
In conclusion, we have developed an efficient direct
crossed-Claisen reaction between thioesters and N-acyl-
benzotriazoles. The process is efficient, does not require
prior enolate formation, and is conducted using untreated,
reagent-grade solvent open to the air.
Unless stated to the contrary, where applicable, the following con-
ditions apply: Reactions were stirred magnetically using Teflon-
coated magnetic stirring bars. Stirring bars, syringe needles and
glassware were dried in an oven at 120 °C and allowed to cool open
to the air prior to use. Commercially available Norm-Ject dispos-
able syringes were used. Commercial grade solvents were used for
routine purposes without further purification. Flash column chro-
matography was performed on silica gel 60 (230–400 mesh).
S-Phenyl 2,5,5-Trimethyl-3-oxohexanethioate (24); Typical
Procedure
This reaction was conducted using untreated reagent grade CH2Cl2,
open to the atmosphere. Glassware and stirring bars were dried as
described above, but allowed to cool open to the atmosphere.
MgBr2·OEt2 (0.387 g, 1.5 mmol) was added to a stirred solution of
S-phenyl propanethioate (5; 0.083 g, 0.5 mmol) in CH2Cl2 (2 mL),
followed by addition of N-acylbenzotriazole 1 (0.109 g, 0.5 mmol)
and i-Pr2NEt (0.35 mL, 2.0 mmol). Stirring was continued for 6 h
and 10% aq HCl (2 mL) was added. Stirring was continued for 5
min and the mixture was partitioned between EtOAc (30 mL) and
H2O (5 mL). The aqueous phase was extracted with EtOAc (2 × 10
mL) and the combined organic extracts were washed with brine (5
(5) For lead references on N-acylbenzotriazoles see, for
example: (a) Katritzky, A. R.; Wang, Z.; Wang, M.;
Wilkerson, C. R.; Hall, C. D.; Akhmedov, N. G. J. Org.
Chem. 2004, 69, 6617. (b) Katritzky, A. R.; Suzuki, K.;
Wang, Z. Synlett 2005, 1656.
Synthesis 2009, No. 19, 3350–3352 © Thieme Stuttgart · New York