A kinetically controlled direct aldol addition of α-chloro thioesters via soft enolization

Article abstract of DOI:10.1016/j.tetlet.2016.11.010

Herein we report that simple α-chloro thioesters undergo soft enolization and direct aldol addition to aldehydes in the presence of MgBr₂·OEt₂and i-Pr₂NEt. At ?78?°C the reaction proceeds in a kinetically controlled manner

Full text of DOI:10.1016/j.tetlet.2016.11.010

Accepted Manuscript
A Kinetically Controlled Direct Aldol Addition of α-Chloro Thioesters via Soft
Enolization
Rachel J. Alfie, Ngoc Truong, Julianne M. Yost, Don M. Coltart
PII:
S0040-4039(16)31466-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.11.010
TETL 48296
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Accepted Date:
15 October 2016
2 November 2016
Please cite this article as: Alfie, R.J., Truong, N., Yost, J.M., Coltart, D.M., A Kinetically Controlled Direct Aldol
Addition of α-Chloro Thioesters via Soft Enolization, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/
j.tetlet.2016.11.010
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Graphical Abstract
A Kinetically Controlled Direct Aldol
Addition of -Chloro Thioesters via Soft
Enolization
Leave this area blank for abstract info.
Rachel J. Alfie, Ngoc Truong, Julianne M. Yost and Don M. Coltart

1
Tetrahedron Letters
A Kinetically Controlled Direct Aldol Addition of -Chloro Thioesters via Soft
Enolization
Rachel J. Alfiea, Ngoc Truonga, Julianne M. Yostb and Don M. Coltarta,*
a Department of Chemistry, University of Houston, Houston, Texas 77204, U.S.A.
b Department of Chemistry, Rice University, Houston, Texas 77251, U.S.A.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Herein we report that simple -chloro thioesters undergo soft enolization and direct aldol
addition to aldehydes in the presence of MgBr2·OEt2 and i-Pr2NEt. At –78 ºC the reaction
proceeds in a kinetically controlled manner giving good diastereoselectivity. Significantly, the
transformation is applicable to both enolizable and nonenolizable aldehydes. Moreover,
excellent stereoselectivity results when a chiral nonracemic -hydroxy aldehyde derivative is
used. To our knowledge, this is the first report of a kinetically controlled soft enolization-based
Available online
Keywords:
aldol addition
.
Direct aldol addition
Soft enolization
Thioester
2009 Elsevier Ltd. All rights reserved.
Kinetic control
-Halo--hydroxy thioester
-Halo--hydroxy carboxylic acid derivatives are useful
synthetic intermediates that are typically prepared by the aldol
addition of
a
pre-formed enolate and an aldehyde.1
Notwithstanding the effectiveness of this approach, the step-wise
procedures required to generate the enolates are time consuming,
especially if trapping is involved. The -halo enolates may be
generated via hard enolization using a strong base such as LDA
and then trapped with a silylating agent if needed to give the
corresponding silyl ketene acetal or related species. In another
approach -halo silyl ketene acetals and their boronyl analogs
may be generated via soft enolization. Here, a relatively weakly
basic amine is used in combination with a silylating or
boronylating agent to induce deprotonation. Given the sensitivity
of the above approaches to water, all manipulations must be
conducted under anhydrous conditions and, when strong bases
are used, at low temperature (Scheme 1a). Soft enolization may
also be conducted in a direct manner2,3 thereby circumventing
these stepwise procedures. In this case the enolate precursor (-
halo ester, -halo thioester, etc.) and aldehyde are combined and
then treated with a amine base and a Lewis acid in such a way
that the enolate precursor is chemoselectively converted to its
corresponding enolate (Scheme 1b). This then adds to the
aldehyde giving the desired -halo--hydroxy carboxylate
product. A further advantage of this direct approach is that it
may often be carried out under non-anhydrous conditions. We
have been exploring this approach to enolization with thioesters
in the development of direct versions of certain key carbon–
carbon bond-forming reactions.4 We recently extended this
strategy to the synthesis of -halo--hydroxy thioesters via a
thermodynamically controlled process that gave modest
diastereoselectivity.5 In what follows, we describe the further
development of this MgBr2OEt2-promoted direct aldol addition
Scheme 1 Hard and soft enolization-based aldol additions.

2
Tetrahedron
reaction between -halo thioesters and aldehydes that utilizes
soft enolization. In particular we show that when the
Table 1 Effect of the thioester and temperature on
diastereoselectivity.
transformation is conducted at –78 °C it proceeds under kinetic
control and gives significantly improved diastereoselectivity. To
our knowledge this is the first report of a kinetically controlled
soft enolization-based aldol reaction. Moreover, we show that
excellent stereoselectivity results when a chiral nonracemic -
hydroxy aldehyde derivative is used.
entry
thioester
product temp time syn:anti conversion (%)
The possibility of competing Darzens reaction6 to produce the
corresponding -epoxy thioesters (Scheme 2a) is a practical
concern associated with the proposed transformation. However,
our previous experiences led us to believe that the magnesium
aldolate intermediate formed upon addition of the enolate and
aldehyde would be sufficiently stable under the reaction
conditions to prevent epoxide formation.7 This was confirmed in
our initial studies5 by conducting the aldol addition with aldehyde
10 and -bromo thioester 11 under soft enolization conditions
(Scheme 2b). The desired -bromo--hydroxy thioester (12) was
formed rapidly and in excellent yield from this reaction with no
epoxide formation.
(°C) (h)
1
2
13 R1 = Ph
14 R1 =
17
18
24 0.5 1.2:1
24 0.5 2.5:1
98
97
3
4
15 R1 =
19
20
24 0.5 5.2:1
97
90
16 R1 =
24
1
4.5:1
5
6
7
13
14
15
16
16
15
15
17
18
19
20
20
19
19
–78
–78
–78 12
–78 12
–78 12
5
5
1.9:1
8.2:1
11:1
17:1
9:1
72
65
85
60
87
85
85
8
9b
10
11
–40 12 5.3:1
–60 12 9:1
a1 molar equiv of 10, 1.2 molar equiv of thioester, and 1.4 molar equiv of
MgBr2·OEt2 (concn 0.2 M), followed by addition of 2.0 molar equiv of i-
Pr2Net. b2 molar equiv of thioester used.
Scheme 2 a) Possible reaction pathways. b) MgBr2OEt2-
promoted direct aldol reaction of 10 and 11.
depleted to 9:1. The reaction was also tried at –40 and –60 ºC
(entries 10 and 11) but was found to be less effective than at –78
ºC. Thus, we used thioester 15 at –78 ºC for our subsequent
studies.
In our previous work we had investigated the effect of the
halogen of the -halo thioester on the reaction and found the
chloro species to be preferred.5 Moreover, we established that
the 2,4,6-triisopropylphenyl thioester gave the best outcome in
terms of both diastereoselectivity and yield at room temperature
(Table 1, entries 1-4). With this as a starting point we further
investigated the effect of temperature on the diastereoselectivity
of the reaction. While we suspected that lower reaction
Table 2 Varying bases in the MgBr2·OEt2-Promoted Aldol
Addition Reaction.
temperatures
might
well
correlate
with
improved
diastereoselectivity, we were concerned that they might
significantly hinder the reaction rate making the transformation
impractical. However, in the event the overall reaction times
were slowed, but not to an extent that was unmanageable. As can
be seen in Table 1, while at room temperature S-phenyl -
chlorothioacetate (13) failed to exhibit any appreciable
diastereoselectivity, at –78 ºC a syn:anti ratio of 1.9:1 was
observed (entry 5). The dr increased to 8.2:1 when the S-(2,6-
dimethyl)phenyl thioester 14 was used in the reaction at –78 ºC
(entry 6). The greatest effect on the dr was due to the use of
b
entry
base
time(h) syn:anti
conver-
sion (%)
98
87
16
3
10
85
39
pKa
1
2
3
4
5
6
7
8
9
i-Pr2NEt
NEt3
piperidine
pyridine
pyrrolidine
n-Bu3N
DABCO
0.5
4
5.2:1
3:1
11.44
10.75
11.22
5.21
11.27
10.89
8.9
24
24
24
7
22
21
4
1.5:1
2:1
1.6:1
1.7:1
1.9:1
3.2:1
1.2:1
2,4,6-triisopropylphenyl -chloro thioacetate (15), with
a
syn:anti ratio of 11:1 at –78 ºC. While the trend pointed to the
bulkier thioesters giving aldol products with higher syn:anti
ratios, we found a discrepancy when using 2,4,6-tri-tert-
butylphenyl thioacetate 16. Initial trials with the usual 1.2
equivalents of this thioester resulted in a 17:1 syn:anti ratio, but
with only 60% conversion after 14 h. By using two equivalents
of the thioester (16), the conversion increased, but the dr was
2,6-lutidene
2,2,6,6-tetramethyl-
piperidine
22
86
6.75
10.89
a1 molar equiv of 10, 1.2 molar equiv of thioester, and 1.4 molar equiv of
MgBr2·OEt2 (concn 0.2 M), followed by addition of 2.0 molar equiv of i-
Pr2Net. bOf conjugate acid of base.

3
In a further attempt to improve the transformation, a variety of
amine bases was tested for their effect on diastereoselectivity and
conversion (Table 2). Of the amines tried i-Pr2NEt gave the
highest syn:anti ratio (5.2:1) in the reaction of 2-napthaldehyde
and thioester 15 at room temperature, as well as the greatest
conversion (98%) (entry 1). The sp3-hybridized bases i-Pr2NEt,
NEt3, and n-Bu3N gave consistently high conversions (entries 1,
2 and 6). Interestingly, 2,2,6,6-tetramethylpiperidine also gave a
high conversion (86%) to the aldol product, whereas piperidine
failed to give a similar result (entries 3 and 9).
The scope of the reaction was explored next using thioester 15
and a variety of aldehydes (Table 3). The transformation
proceeded efficiently with aromatic aldehydes and also worked
well with the highly sterically-hindered aldehyde 18. Notably,
when the reaction was carried out with enolizable aldehydes
possessing a single -proton (19 and 20, entry 4 and 5), the aldol
product was produced in good yield. Encouraged by this result
aldehydes 21 and 22 were tested in the addition reaction.
Unfortunately, while the desired products (27 and 28,
respectively) did form, they were obtained in a somewhat lower
yield due to competing aldehyde self addition.
Scheme 3 Kinetic/thermodynamic control studies.
under thermodynamic control and thus reversible, while at –78
ºC it was under kinetic control and irreversibly formed the syn
isomer in excess. If the reaction was reversible at room
temperature, then by placing the pure aldol product 17 in the
standard reaction conditions of 1.4 equiv of MgBr2·OEt2 and 2.0
equiv of i-Pr2NEt in CH2Cl2 without starting thioester and
aldehyde present, then when p-tolualdehyde (29) was introduced
to the system the initial aldol product 17, as well as the newly
formed 30 should both be observed after 30 min (Scheme 3a).
Indeed, when this experiment was conducted, a 3:1 ratio of 17 to
aldol product 30 resulted. A similar control experiment was
performed at –78 ºC for 12 h (Scheme 3b) and resulted in the re
isolation of only 17 with no crossover product 30 detected,
indicative of an irreversible reaction.
Table 3 Scope of the MgBr2OEt2-promoted aldol addition
using thioester 15 and various aldehydes.
a)
15, MgBr2·OEt2
i-Pr2NEt, CH2Cl2
–78 ºC, 12 h
OH
O
O
entry
1
aldehyde
product
17
syn:anti
11:1
yield (%)
80
SAr
10 R1 =
24%
Cl
32
TBSO
Ar = 2,4,6-(i-Pr)3C6H2
31
single stereoisomer
2
14 R1 =
23
9:1
77
NaBH4, i-PrOH
OH
O
CH2Cl2; 69%
OH OH
SAr
18 R1 =
19 R1 =
24
25
6:1
3:1
81
87
Cl
26
3
4
TBSO
Cl
33
5
6
7
20 R1 =
21 R1 =
22 R1 =
26
27
28
3:1
2:1
3:1
96
40
52
X-ray crystal structure of 31
b)
15, MgBr2·OEt2
i-Pr2NEt, CH2Cl2
24 ºC, 1 h
OH
O
O
SAr
63%
TBSO
Cl
TBSO
31
32
a1 molar equiv of aldehyde, 1.2 molar equiv of thioester, and 1.4 molar equiv
of MgBr2·OEt2 (concn 0.2 M), followed by addition of 2.0 molar equiv of i-
Pr2Net.
single stereoisomer
Scheme 4 Aldol addition to chiral nonracemic aldehyde 28.
Having discovered that the diastereoselectivity varied with
reaction temperature, we examined whether the reaction was
operating under thermodynamic or kinetic control at rt and –78
ºC. We speculated that at room temperature the reaction was
We next tested the use of a chiral, nonracemic aldehyde (31)
in a cursory investigation of broader asymmetric induction.
Remarkably, when 15 and 31 were combined under the aldol

4
Tetrahedron
reaction conditions, the desired addition product (32) was
obtained as a single diastereomer, albeit in low (24%) yield.
Interestingly, a byproduct was also formed to a small extent that
was identified to be 26 (syn:anti = 2:1). 26 is formally the aldol
addition product of 15 and isobutyraldehyde, however, there was
no trace of isobutyraldehyde contamination in any of the reagents
or solvents used. It appears that some form of decarbonylation
may be occurring in the reaction mixture that ultimately gives
rise to 26. In an effort to improve the reaction yield, the aldol
addition was carried out at room temperature. We were very
pleased to find that not only did the yield of the desired product
increase, but it was still obtained as a single stereoisomer.
Byproduct 26 was also formed in this reaction.
In conclusion, we have developed a kinetically-controlled
aldol addition of -chloro thioesters and aldehydes. The reaction
proceeds at –78 ºC in very good yield, and with good syn-
diastereoselectivity. Significantly, it is also amenable to the use
of enolizable aldehydes, albeit with somewhat poorer yields.
Very interestingly, when conducted using chiral, nonracemic
aldehyde 31 at room temperature, a single stereoisomeric product
(32) was obtained in 63% yield. Further studies of this promising
transformation employing chiral nonracemic aldehydes are
underway and will be reported in due course.
Acknowledgments
We thank James Korp (University of Houston) for X-ray
structure determination and the University of Houston for
financial support.
References and notes
1.
(a) Nebot, J.; Romea, P.; Urpi, F. J. Org. Chem. 2009, 74, 7518;
(b) Kiyooka, S.-I.; Shahid, K. A. Tetrahedron-Asymm. 2000, 11,
1537; (c) Wang, Y.-C.; Su, D.-W.; Lin, C.-M.; Tseng, H.-L.; Li,
C.-L.; Yan, T.-H. Tetrahedron Lett. 1999, 40, 3577; (d) Corey, E.
J.; Choi, S. Tetrahedron Lett. 1991, 32, 2857; (e) Evans, D. A.;
Sjogren, E. B.; Weber, A. E.; Conn, R. E. Tetrahedron Lett. 1987,
28, 39.
2.
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.
3.
4.
Lim, D.; Zhou, G.; Livanos, A. E.; Fang, F.; Coltart, D. M.
Synthesis 2008, 2148.
See, for example: (a) Zhou, G.; Lim, D.; Coltart, D. M. Org. Lett.
2008, 10, 3809; (b) Yost, J. M.; Garnsey, M. R.; Kohler, M. C.;
Coltart, D. M. Synthesis 2009, 56; (c) Lim, D.; Fang, F.; Zhou, G.;
Coltart, D. M. Org. Lett. 2007, 9, 4139; (d) Yost, J. M.; Zhou, G.;
Coltart, D. M. Org. Lett. 2006, 8, 1503.
5.
6.
Yost, J. M.; Alfie, R. J.; Tarsis, E. T.; Coltart, D. M. Chem.
Commun. 2011, 47, 571.
(a) Rosen, T. In Comprehensive Organic Synthesis, Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol. 2, 409–
439. (b) Ghosh, A. K.; Kim, J.-H. Org. Lett. 2004, 6, 2725; (c)
Pridgen, L. N.; Abdel-Magid, A. F.; Lantos, I.; Shilcrat, S.;
Eggleston, D. S. J. Org. Chem. 1993, 58, 5107; (d) Abdel-Magid,
A.; Pridgen, L. N.; Eggleston, D. S.; Lantos, I. J. Am. Chem. Soc.
1986, 108, 4595.
7.
(a) Sauer, S. J.; Garnsey, M. R.; Coltart, D. M. J. Am. Chem. Soc.
2010, 132, 13997; (b) Sano, S.; Miyamoto, M.; Mitani, T.; Nagao,
Y. Heterocycles 2006, 68, 459.
Supplementary Material
Supplementary data associated with this article can be found,
in the online version, at X.

5
Highlights




Direct aldol additon
Soft enolization
Syn-selective aldol
Kinetically controlled soft enolization
process