A direct aldol addition of simple thioesters employing soft enolization

Article abstract of DOI:10.1055/s-2006-958959

Simple thioesters undergo direct aldol addition to aldehydes in the presence of magnesium bromide-diethyl ether and N,N-diisopropylethylamine using untreated, reagent grade dichloromethane under atmospheric conditions. The reactions proceed extremely rapi

Full text of DOI:10.1055/s-2006-958959

4
78
PRACTICAL SYNTHETIC PROCEDURES
A Direct Aldol Addition of Simple Thioesters Employing Soft Enolization
A
G
D
irect Aldol
A
d
u
dition of Sim
o
ple
T
hioeste
q
rs Employing
i
Soft
E
a
nolizationng Zhou, Julianne M. Yost, Don M. Coltart*
Department of Chemistry and the Center for Chemical Biology, Duke University, Durham,
NC 27708, USA
Fax +1(919)6685483; E-mail: don.coltart@duke.edu
PSP
Received 6 September 2006
No76
Abstract: Simple thioesters undergo direct aldol addition to aldehydes in the presence of magnesium bromide–diethyl ether and N,N-diiso-
propylethylamine using untreated, reagent grade dichloromethane under atmospheric conditions. The reactions proceed extremely rapidly
and in excellent yield.
Key words: direct aldol reaction, ester, magnesium, thioester, thiol
O
PhCHO, MgX2,
i-Pr2NEt, CH2Cl2
OH
O
SBn
Ph
SBn
1
2
Entry MgX2 Time Yield
1
2
3
MgCl2 24 h 32%
MgBr2 24 h 83%
MgI2 25 min 95%
O
PhCHO, MgI2,
OH
O
i-Pr2NEt, CH2Cl2
OBn
Ph
OBn
2
0 h; 46%
3
4
2
+
Scheme 1 Mg -promoted direct aldol reactions of thioester 1 and O,O-ester 3 with benzaldehyde
The aldol reaction is one of the most powerful tools avail- sive, commercially available thiols and carboxylic acids
able for carbon–carbon bond formation. Much of the con- via standard coupling procedures, or are themselves com-
trol that is possible for the aldol reaction derives from the mercially available. They are also stable and easily han-
1
use of preformed enolates. However, the general desire to dled, yet undergo a number of important transformations
develop milder and operationally simplified chemical under very mild conditions including reduction, hydroly-
methods has spawned a renewed interest in the direct al- sis, direct amidation, and conversion into ketones.
1
a
dol reaction, without reliance on such prior manipula-
tions. While only a limited number of reports have
appeared, initial investigations into these in situ eno-
lization approaches clearly establish their potential.
To explore the possibility of using simple thioesters to de-
velop a direct aldol addition reaction, we investigated the
reaction of S-benzyl thioacetate (1) with benzaldehyde
1
a,2
5
under a variety of conditions using different metal salts.
Given the pervasiveness of thioesters in biological car- To do so, the metal salt was added to a mixture of 1 and
bon–carbon bond formation, we became interested in benzaldehyde in dichloromethane, followed by addition
studying them in the context of the direct aldol addition.3 of N,N-diisopropylethylamine. The reaction was tried us-
Nature’s choice to use thioesters rather than O,O-esters ing magnesium bromide, zinc(II) chloride, copper(II) ac-
for these processes is undoubtedly a deliberate one, that is etate, and nickel(II) bromide. Only in the case of the Mg2
likely connected to the increased acidity of the thioester a- salt was the desired b-hydroxy thioester 2 obtained, albeit
+
4
proton, compared to that of the corresponding O,O-ester. in low yield (32%), after 24 hours (Scheme 1). Nonethe-
From a practical point of view, the use of simple thioesters less, the formation of aldol product encouraged us to try
in a direct aldol addition is desirable for a number of rea- other magnesium salts. Thus, magnesium bromide and io-
sons. First, the increased acidity of their a-protons, rela- dide were examined under the same conditions and gave
tive to those of other simple carboxylate derivatives, 2 in 83% and 95% isolated yield, respectively. Interesting-
makes them better suited to soft enolization processes. In ly, the reaction with magnesium iodide required only 25
addition, thioesters are readily accessible from inexpen- minutes to go to completion, whereas the magnesium bro-
mide reaction took 24 hours. A control experiment was
carried out in which 1 and benzaldehyde were combined
SYNTHESIS 2007, No. 3, pp 0478–0482
x
x
.
x
x
.2
0
0
6
in dichloromethane in the presence of N,N-diisopropyl-
Advanced online publication: 21.12.2006
DOI: 10.1055/s-2006-958959; Art ID: Z18206SS
Georg Thieme Verlag Stuttgart · New York
ethylamine, but in the absence of any Mg2+ salt, and gave
©

PRACTICAL SYNTHETIC PROCEDURES Direct Aldol Addition of Simple Thioesters Employing Soft Enolization 479
only starting material after two days. The addition reac-
tion was also attempted in the presence of magnesium io-
dide, but without any base added, with no product
detected after two days.
O
O
PhCHO, MgI2,
i-Pr2NEt, CH2Cl2
OH
OH
OH
O
O
O
OBn
+
SBn
SBn
SBn
Ph
Ph
Ph
SBn
SBn
SBn
30 min; 93%
3
1
2
2
2
O
O
PhCHO, MgI2,
i-Pr2NEt, CH2Cl2
Using magnesium iodide as the promoter, we next set out
to evaluate our hypothesis regarding the beneficial reac-
tivity of thioesters, as compared to other simple carboxy-
late derivatives. We began this by conducting the reaction
using 3, the O,O-ester analogue of 1, which gave only
NHBn
+
3
0 min; 91%
5
1
O
O
PhCHO, MgI2,
i-Pr2NEt, CH2Cl2
NMeBn +
4
6% yield of the b-hydroxy ester 4 after 20 hours (see
3
0 min; 96%
6
1
Scheme 1). We next carried out a series of competition
experiments between thioester 1 and either ester 3, amide
Scheme 2 Competition experiments to establish superior reactivity
5
, or amide 6 (Scheme 2). Thus, equimolar amounts of the of thioester 1 over ester 3 and amides 5 and 6.
competing species were combined under the standard
conditions and allowed to react for 30 min. In each case,
only the b-hydroxy thioester 2 was obtained, and in the
usual excellent yield, thus confirming the superior reactiv-
ity of thioesters in this reaction.
periments involving 7, 8, and 9 with benzaldehyde
showed a slight preference for the formation of 12 over 13
and 14. On this basis, and the fact that it is commercially
available, 7 was chosen for subsequent studies.
We next investigated the effect of the thiol component of
the thioester on its reactivity. Thus, thioesters 7–11
Given the extremely rapid nature of the reaction with
thioester 7, we wondered about the possibility of substi-
tuting magnesium bromide–diethyl ether for magnesium
iodide. This compound is commercially available and
very inexpensive and, like magnesium iodide, generates
no toxic byproducts on aqueous workup. While the reac-
tion with magnesium bromide–diethyl ether would be ex-
pected to be slower, we hoped that this would be more
(
Table 1) were subjected to the conditions described
above. Remarkably, thioesters 7, 8, and 9 provided the
corresponding aldol products 12, 13, and 14 nearly quan-
titatively within only 20 minutes. Given the extremely
rapid nature of the reaction in the case of 7, 8, and 9, we
were unable to establish a clear preference for either
thioester in the aldol addition. However, competition ex-
Table 1 Investigation of the Effect of the Thiol on Thioester Reactivity in the Magnesium Iodide Promoted Direct Aldol Reactiona
Entry
1
Thioester
b-Hydroxy thioester
Time (min)
25
Isolated yield (%)
95
AcSBn
OH
OH
O
O
1
Ph
SBn
SPh
2
2
3
AcSPh
20
20
94
98
7
Ph
1
2
OMe
OMe
OH
OH
O
O
AcS
Ph
S
S
8
13
4
20
96
AcS
Ph
OMe
OMe
9
14
5
6
NO2
NO2
60
30
92
96
OH
OH
O
O
AcS
Ph
S
S
1
0
15
O
AcS
O
Ph
1
1
1
6
a
Conducted under argon by combining thioester (1 equiv), benzaldehyde (1.2 equiv) and MgI (1.2 equiv), CH Cl (concn 0.2 M), followed by
2
2
2
addition of i-Pr NEt (1.3 equiv).
2
Synthesis 2007, No. 3, 478–482 © Thieme Stuttgart · New York

4
80
G. Zhou et al.
PRACTICAL SYNTHETIC PROCEDURES
than compensated for, not only by the low cost of the re- isopropylethylamine was found to be the best of those
agent, but also by allowing us to conduct the reactions tried, giving clean and high-yielding (>90%) conversion
open to the atmosphere using untreated, reagent grade sol- into 13 after only 30 minutes. Triethylamine gave a some-
vent.
what lower yield (75%) after one hour of reaction, and the
formation of the bis-alkylated byproduct 17 (Figure 1)
was also evident. With pyridine and 5-methoxybenzimi-
dazole, no desired product was detected, even after 24
hours. 2,6-Lutidine, 1,8-diazabicyclo[5.4.0]undec-7-ene,
To test this, compound 7 was combined with benzalde-
hyde, N,N-diisopropylethylamine, and magnesium bro-
mide–diethyl ether in untreated, reagent grade
6
dichloromethane, under atmospheric conditions. For this
1
,5-diazabicyclo[4.3.0]non-5-ene, and Barton’s base (2-
experiment, the relative molar amount of all components
used was the same as that for the magnesium iodide pro-
moted reactions shown in Table 1. In this case, however,
a slightly lower yield (88%) of b-hydroxy thioester 12 was
tert-butyl-1,1,3,3-tetramethylguanidine) all gave <50%
conversion after one hour, with byproducts developing
over extended periods of time.
obtained than when magnesium iodide was used (95%). Having confirmed the reaction conditions for the magne-
Thus, we did a cursory investigation of the effect of in- sium bromide–diethyl ether promoted process, we inves-
creasing the amount of each reactant, relative to the tigated the scope of the reaction with 7 and a variety of
thioester component. No improvement in yield was ob- aldehydes (Table 2). In all cases, reaction times were
served when the amount of benzaldehyde was increased, short and yields were excellent. Notably, the reaction
but increasing the amount of either magnesium bromide– could be conducted using an aldehyde having a single a-
diethyl ether or N,N-diisopropylethylamine gave both a proton 24 (entry 8) with only a small amount (<4%) of the
slightly faster reaction and a higher conversion. We even- self-addition product produced. In this case, best results
tually settled on the following conditions: 7 (1.0 equiv), were obtained when the thioester was used in a 1.5-fold
benzaldehyde (1.2 equiv), magnesium bromide–diethyl excess, relative to the aldehyde.
ether (1.4 equiv), and N,N-diisopropylethylamine (2.0
equiv) in dichloromethane (concn 0.2 M). Under these
conditions, 12 was obtained in 96% yield in only 30 min-
In conclusion, we have developed a mild and efficient di-
rect aldol reaction using simple thioesters. The reaction is
conducted using inexpensive magnesium bromide–dieth-
utes. No increase in yield or decrease in reaction time was
yl ether in untreated, reagent grade solvent under atmo-
observed when the reaction was conducted using anhy-
spheric conditions, and produces innocuous byproducts
drous dichloromethane under an argon atmosphere. In
on workup. The superior reactivity of thioesters over O,O-
contrast, when magnesium iodide was used in this man-
esters in this reaction was established via competition ex-
ner, reaction yields were lower than when anhydrous con-
periments and is fundamental to the facility of this proce-
ditions were employed.
dure. Given the operational simplicity of the reaction and
In our initial survey of metal salts to promote the direct al- the accessibility of thioesters, we expect that this method
dol addition of simple thioesters, we noted a pronounced will meet with wide application.
difference in reactivity between magnesium chloride, bro-
mide, and iodide, which is most likely attributable to sol-
ubility issues. As such, we decided to screen a variety of
standard solvents for their effect on the outcome of the below) and under a slight static pressure of argon (pre-purified qual-
Unless stated to the contrary, where applicable, the following con-
ditions apply: Reactions were carried out using dried solvents (see
magnesium bromide–diethyl ether reaction. Thus, the re- ity) that had been passed through a column (5 × 20 cm) of Drierite.
Glassware was dried in an oven at 120 °C for at least 12 h prior to
use and then either cooled in a desiccator cabinet over Drierite or as-
sembled quickly while hot, sealed with rubber septa, and allowed to
cool under a stream of argon. Reactions were stirred magnetically
using Teflon-coated magnetic stirring bars. Teflon-coated magnetic
stirring bars and syringe needles were dried in an oven at 120 °C for
action between 7 and benzaldehyde was conducted in the
presence of magnesium bromide–diethyl ether and N,N-
diisopropylethylamine, but using either tetrahydrofuran,
diethyl ether, N,N-dimethylformamide, ethyl acetate, ben-
zene, or toluene in place of dichloromethane. However, in
no case was there an improvement over the initial results at least 12 h prior to use and then cooled in a desiccator cabinet over
obtained with dichloromethane.
Drierite. Hamilton microsyringes were dried in an oven at 60 °C for
at least 24 h prior to use and cooled in the same manner. Commer-
cially available Norm-Ject disposable syringes were used. Anhyd
benzene, toluene, Et O, CH Cl , THF, MeCN, and DME were ob-
OMe
OH
O
2
2
2
tained using an Innovative Technologies solvent purification sys-
tem. All other solvents were of anhydrous quality purchased from
Aldrich. Commercial grade solvents were used for routine purposes
without further purification. Et N, pyridine, i-Pr NEt, 2,6-lutidine,
Ph
S
Ph
OH
17
3
2
Figure 1 Bis-alkylated byproduct
i-Pr
2
NH, and TMEDA were distilled from CaH under a N atmo-
2 2
sphere prior to use. Flash column chromatography was performed
1
13
on silica gel 60 (230–400 mesh). H and C NMR were recorded on
We also explored the effect of the base in the context of
the magnesium bromide–diethyl ether promoted reaction
1
a Varian Mercury 300 MHz spectrometer at r.t. All H chemical
13
shifts are reported relative to TMS; C shifts are reported relative
using, in this case, thioester 8 and benzaldehyde. N,N-Di- to the corresponding NMR solvent.
Synthesis 2007, No. 3, 478–482 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES Direct Aldol Addition of Simple Thioesters Employing Soft Enolization 481
Table 2 Magnesium Bromide–Diethyl Ether Promoted Direct Aldol Addition between 7 and Various Aldehydes Using Untreated Solvent
a
under Atmospheric Conditions
Entry
1
Aldehyde
b-Hydroxy thioester
Time (min)
30
Isolated yield (%)
96
PhCHO
OH
O
SPh
1
2
2
3
CHO
OH
O
30
30
97
96
SPh
MeO
1
8
MeO
2
5
CHO
OH
O
SPh
OMe
1
9
OMe
2
6
4
5
CHO
OH
O
60
60
94
95
SPh
O2N
O2N
2
0
2
7
Cl
CHO
OH
O
Cl
SPh
2
1
2
8
6
7
CHO
OH
O
60
60
92
94
Ph
2
2
Ph
SPh
2
9
0
CHO
OH
O
SPh
O
2
3
3
8
CHO
OH
60
82
SPh
2
4
3
1
a
Conducted under atmospheric conditions by combining 7 (1 equiv), aldehyde (1.2 equiv), MgBr ·OEt (1.4 equiv) in untreated, reagent grade
2
2
CH Cl (concn 0.2 M), followed by addition of i-Pr NEt (2.0 equiv).
2
2
2
S-Benzyl 3-Hydroxy-3-phenylpropanethioate (2); Typical Pro-
cedure
give a light-yellow solid. Flash chromatography (silica gel, EtOAc–
hexanes, 10:90) gave 2 (0.1294 g, 95%) as a pure, colorless solid.
MgI (0.167 g, 0.6 mmol) was added to a stirred soln of S-benzyl
1
2
H NMR (300 MHz, CDCl ): d = 7.42–7.18 (m, 10 H), 5.20 (X of
3
thioacetate (1; 0.083 g, 0.5 mmol) and benzaldehyde (61 mL, 0.6
an ABX system, apparent td, J = 3.6, 8.7 Hz, 1 H), 4.17 and 4.15
mmol) in CH Cl (2.5 mL), followed by the addition of i-Pr NEt
2
2
2
(
AB q, DnAB = 6.6 Hz, J = 13.8 Hz, 2 H), 3.08–2.88 [m, 3 H, includ-
ing A of an ABX system, apparent dd, at d = 3.02 (J = 9.0, 15.9 Hz,
H) and B of an ABX system, apparent dd, at d = 2.93 (J = 3.9, 15.9
Hz, 1 H)].
(
0.11 mL, 0.65 mmol). Stirring was continued for 25 min and
EtOAc (2.5 mL) and 10% (v/v) aq HCl (2.5 mL) were added. Stir-
ring was continued for 15 min and the mixture was partitioned be-
1
tween EtOAc (15 mL) and H O (2 mL). The aqueous phase was
2
1
3
C NMR (300 MHz, CDCl ): d = 198.2, 142.4, 137.2, 129.0,
extracted with EtOAc (3 × 5 mL) and the combined organic extracts
3
1
28.82, 128.75, 128.1, 127.5, 125.8, 71.0, 52.4, 33.4.
were washed with sat. aq NaCl, dried (MgSO ), and evaporated to
4
ESI-MS: m/z calcd for C H NaO S: 295.1; found: 294.9.
1
6
16
2
Synthesis 2007, No. 3, 478–482 © Thieme Stuttgart · New York

4
82
G. Zhou et al.
PRACTICAL SYNTHETIC PROCEDURES
1
3
S-2-Methoxyphenyl Thioacetate (9); Typical Procedure
C NMR (300 MHz, CDCl ): d = 197.1, 136.4, 134.6, 131.2, 129.8,
3
Ac O (1.86 mL, 19.68 mmol) was added via syringe to a stirred soln
129.6, 129.4, 128.7, 128.0, 127.2, 126.7, 69.5, 50.3.
2
of 2-methoxythiophenol (2.00 mL, 16.43 mmol), DMAP (0.0464 g,
ESI-MS: m/z calcd for C H NaO S: 307.1; found: 306.9.
1
7
16
2
0
.38 mmol), pyridine (1 mL), and CH Cl (19 mL). The mixture
2 2
was allowed to stir for 12 h and then partitioned between EtOAc and
sat. aq NaHCO . The organic phase was washed with H O, sat. aq
3
2
Acknowledgment
NaCl, dried (MgSO ), and evaporated to give a light-yellow oil.
4
We thank Dr. Anna Gromova and Drew Schwartz for their assi-
stance in conducting certain experiments.
Flash chromatography (silica gel, EtOAc–hexanes, 6:94) gave 9
(2.7551 g, 92%) as a pure, colorless liquid.
1
H NMR (300 MHz, CDCl ): d = 7.48–7.34 (m, 2 H), 7.04–6.92 (m,
3
2
H), 3.86 (s, 3 H), 2.41 (s, 3 H).
References
1
3
C NMR (300 MHz, CDCl ): d = 193.5, 159.2, 136.8, 131.8, 121.2,
3
(
1) (a) Modern Aldol Reactions; Mahrwald, R., Ed.; Wiley-
VCH: Weinheim, 2004. (b) Carreira, E. M. In Compre-
hensive Asymmetric Catalysis, Vol. 3; Jacobsen, E. N.;
Pfaltz, A.; Yamamoto, H., Eds.; Springer: Heidelberg, 1999.
1
16.2, 111.6, 56.0, 30.1.
ESI-MS: m/z calcd for C H NaO S: 205.0; found: 204.8.
9
10
2
S-Phenyl (E)-3-Hydroxy-5-phenylpent-4-enethioate (29); Typi-
cal Procedure
The following reaction was conducted using untreated CH Cl ,
open to the atmosphere. Glassware and stirring bars were dried as
described above, but allowed to cool open to the atmosphere.
(2) (a) Evans, D. A.; Tedrow, J. S.; Shaw, J. T.; Downey, C. W.
J. Am. Chem. Soc. 2002, 124, 392. (b) Evans, D. A.;
Downey, C. W.; Shaw, J. T.; Tedrow, J. S. Org. Lett. 2002,
4, 1127. (c) Evans, D. A.; Downey, C. W.; Hubbs, J. L. J.
Am. Chem. Soc. 2003, 125, 8706. (d) Lalic, G.; Aloise, A.
D.; Shair, M. D. J. Am. Chem. Soc. 2003, 125, 2852.
2
2
MgBr ·OEt (0.181 g, 0.7 mmol) was added to a stirred soln of S-
2
2
(
e) Magdziak, D.; Lalic, G.; Lee, H. M.; Fortner, K. C.;
Aloise, A. D.; Shair, M. D. J. Am. Chem. Soc. 2005, 127,
284.
3) Yost, J. M.; Zhou, G.; Coltart, D. M. Org. Lett. 2006, 8,
503.
phenyl thioacetate (7; 0.076 g, 0.5 mmol) and trans-cinnamalde-
hyde (22; 76 mL, 0.6 mmol) in CH Cl (2.5 mL), followed by the ad-
dition of i-Pr NEt (0.17 mL, 1.0 mmol). The reaction flask was
capped to prevent evaporation. Stirring was continued for 1 h and
then EtOAc (2.5 mL) and 10% (v/v) aq HCl (2.5 mL) were added.
Stirring was continued for 20 min and the mixture was partitioned
2
2
7
2
(
(
1
4) The pK of the thioester a-proton has been reported to be 2
a
units less than that of a corresponding ester, see: Bordwell,
F. G.; Fried, H. E. J. Org. Chem. 1991, 56, 4218.
5) All thioesters used in this work, with the exception of
commercially available 7, 10, and 11, were prepared via
acylation of the corresponding commercially available
thiols.
between EtOAc (30 mL) and H O (2 mL). The aqueous phase was
2
extracted with EtOAc (3 × 5 mL) and the combined organic extracts
(
were washed with sat. aq NaCl, dried (MgSO ), and evaporated to
4
give a light-yellow solid. Flash chromatography (silica gel, EtOAc–
hexanes, 10:90) gave 29 (0.1307 g, 92% with trace impurities) as a
colorless solid.
(
6) Aldrich ACS reagent grade, ≥99.5%.
1
H NMR (300 MHz, CDCl ): d = 7.46–7.20 (m, 10 H), 6.68 (d,
3
J = 15.8 Hz, 1 H), 6.23 (dd, J = 6.0, 15.8 Hz, 1 H), 4.87–4.76 (m, 1
H), 3.00 (apparent d, J = 6.6 Hz, 2 H), 2.74 (d, J = 4.2 Hz, 1 H).
Synthesis 2007, No. 3, 478–482 © Thieme Stuttgart · New York