Morita-Baylis-Hillman alkylation of unsaturated thioesters

Article abstract of DOI:10.1055/s-0030-1258777

The Morita-Baylis-Hillman alkylation reaction with unsaturated thioesters is described. Five- and six-membered rings are formed with ease and in excellent yields. The method is high yielding with either stoichiometric or catalytic amounts of tributylphosp

Full text of DOI:10.1055/s-0030-1258777

LETTER
2583
Morita–Baylis–Hillman Alkylation of Unsaturated Thioesters
Morita–Baylis–Hillma
a
n
A
lkylatio
r
n of Uns
i
aturate
e
d Thioesters E. Krafft,* Kimberly A. Seibert, Thomas F. N. Haxell
Department of Chemistry and Biochemistry, Florida State University, Tallahassee, Fl 32306-4390, USA
Fax +1(850)6447409; E-mail: mek@chem.fsu.edu
Received 19 July 2010
ester 1 was treated with tributylphosphine in t-BuOH fol-
lowed by the addition of KOH with BnEt3NCl in CH2Cl2/
H2O and resulted in recovery of starting material only
(Equation 2). Employing trimethylphosphine, tribu-
tylphosphine or tricyclohexylphosphine as the nucleo-
phile also failed to promote cyclization of ester 1.
Conversion into the more activated iodide unfortunately
did not improve the reactivity.
Abstract: The Morita–Baylis–Hillman alkylation reaction with un-
saturated thioesters is described. Five- and six-membered rings are
formed with ease and in excellent yields. The method is high yield-
ing with either stoichiometric or catalytic amounts of tributylphos-
phine.
Key words: cyclization, alkylation, thioesters, organocatalysis,
Morita–Baylis–Hillman reaction
O
O
Activated alkenes now utilized in the Morita–Baylis–
Hillman (MBH) reaction1 include acrylates, vinyl nitriles,
vinyl sulfones, allenic esters and acrolein. Recently the
list of viable activated alkenes has been expanded to in-
clude thioesters,2 which undergo a variety of important
transformations under mild conditions including hydroly-
sis, reduction and direct amidation.3 Commercially avail-
able themselves or readily accessible from commercially
available thiols, thioesters are an attractive functional
group. Mimicking nature, which prefers thioesters over
oxoesters, thioesters seemed an intriguing target for use in
the Baylis–Hillman reaction due to their stability and ease
in handling.4 Keck employed oxoesters and thioesters
containing enolizable aldehydes in the intramolecular
Morita–Baylis–Hillman reaction and observed slow cy-
clization when treating unsaturated oxoesters with a cata-
lytic amount of trimethylphosphine.5 However, treatment
of unsaturated thioesters under the same conditions pro-
vided efficient cyclization giving rise to both cyclohexene
and cyclopentene derivatives in good yields. In addition,
Krische examined thioesters with vinylsulfones as the
electrophilic partner.6 Using catalytic amounts of tribu-
tylphosphine, five- and six-membered-ring cross-Michael
cycloisomerization products were obtained in excellent
yields.
organic nucleophilic
catalyst
Br
R
R
X
X
X = S, O
n
Equation 1
O
X
Hoveyda–Grubbs
catalyst
Br
CH2Cl2, reflux
X = MeO, EtS, n-BuS, t-BuS
O
X
Br
1, X = MeO, 85%
2, X = EtS, 44%
3, X = n-BuS, 69%
4, X = t-BuS, 51%
Scheme 1
O
recovered
starting
material
R3P
t-BuOH
X
MeO
1
X = Br, I
R = Me, Bu, Cy
Equation 2
With this in mind we set out to investigate various activat-
ed enones in the intramolecular Morita–Baylis–Hillman
alkylation reaction (Equation 1). A series of unsaturated
oxoesters and thioesters were synthesized (Scheme 1), via
cross metathesis of acrylates with 5-bromo-1-pentene us-
ing the Hoveyda–Grubbs catalyst, in order to probe the
tolerance of alternative activated alkenes in the MBH
alkylation reaction.
These results suggested that modification of the oxoester
to the thioester would be beneficial. Reaction of unsatur-
ated thioester 2 with one equivalent of trimethylphosphine
in t-BuOH followed by the addition of KOH and
BnEt3NCl in CH2Cl2/H2O (1:1) provided none of the de-
sired product (Equation 3).7 However, recognizing the
variability from our earlier work on MBH alkylation of
enones7–9 regarding which trialkylphosphine nucleophile
Using the reaction conditions that were successful in the is optimal for which substrate, MBH alkylation of
MBH alkylation reactions of enones,7,8 unsaturated oxo- thioester 2 was attempted using tributylphosphine. Treat-
ment of thioester 2 in t-BuOH with tributylphosphine fol-
lowed by addition of base under phase-transfer conditions
SYNLETT 2010, No. 17, pp 2583–2588
Advanced online publication: 30.09.2010
DOI: 10.1055/s-0030-1258777; Art ID: S04210ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
1
0
provided 99% of the desired cyclized enone 5
(Equation 3). The MBH alkylation of unsaturated ketones
is a two-step process involving nucleophilic addition and

2584
M. E. Krafft et al.
LETTER
cyclization in the first step and a base-catalyzed elimina- ment of thioester 8 in t-BuOH with trimethylphosphine
tion of the phosphine in a second distinct step.9 Building followed by the addition of base under phase-transfer con-
on these promising initial results, the impact of steric bulk ditions yielded 21% of the desired product (entry 2). In-
on the thioester alkyl group was investigated.
creasing the concentration of the solvent from 0.5 M to 1
M provided only a slight increase in the yield of the de-
sired product. Lastly, addition of two equivalents of trim-
ethylphosphine following the same procedure gave 47%
of the desired product 9 as well as some decomposition of
starting material (Table 2, entry 4).
1) PMe3, t-BuOH
recovered
starting
material
2) KOH, BnEt3NCl,
CH2Cl2/H2O (1:1)
O
Br
EtS
Table 2 Synthesis of the Precursors to Six-Membered Rings
2
O
1) PBu3, t-BuOH
O
Br
O
1) nucleophile (X equiv)
Y M t-BuOH
2) KOH, BnEt3NCl,
CH2Cl2/H2O (1:1)
99%
EtS
EtS
EtS
2) KOH, BnEt3NCl
CH2Cl2/H2O (1:1)
5
8
9
Equation 3
Entry
Nucleophile
X
1
1
2
2
1
1
Y
Yield (%)
Treatment of n-butyl thioester 3 with tributylphosphine in
t-BuOH followed by addition of KOH and BnEt3NCl in
CH2Cl2/H2O (1:1) afforded the desired product, 6, in 95%
yield. Unfortunately treatment of tert-butyl thioester 4
with tributylphosphine in t-BuOH followed by addition of
base under phase-transfer conditions provided none of the
desired product, leaving only starting material. It was
speculated the steric hindrance of the more bulky tert-
butyl thioester group might be slowing down nucleophilic
addition to the unsaturated thioester thus minimizing the
concentration of zwitterion available for cyclization. With
this in mind, thioester 4 in t-BuOH was treated with tri-
methylphosphine followed by addition of base under
phase-transfer conditions giving 60% of the desired prod-
uct 7.
1
2
3
4
5
6
Bu3P
Me3P
Bu3P
Me3P
Bu3P
Me3P
0.5
0.5
0.5
0.5
1
0
21
0
47
0
1
29
Recognizing the difficulty in the formation of six-mem-
bered rings may be avoided by adding substitution on the
tether to provide Thorpe–Ingold assistance, enones substi-
tuted on the tether were synthesized. Treatment of 10 with
tributylphosphine in t-BuOH followed by the addition of
KOH under phase-transfer conditions, afforded six-mem-
bered-ring product 11 in 92% yield (Table 3, entry 5). As
expected, and building on this excellent result, reaction of
thioesters 12 and 14 with tributylphosphine in t-BuOH
followed by the addition of base under phase-transfer con-
ditions provided the products, 13 and 15, in 91% and 82%
yield, respectively (Table 3).
Table 1 Conversion of Thioesters into the Corresponding Cyclic
Enones
Entry
Thioester
Product
Yield (%)
O
O
Br
RS
RS
To extend the scope of the above reaction, additional
enoates with different substitution patterns were exam-
ined under the optimized conditions. Unsaturated
thioester 16 was synthesized and cyclizations were at-
tempted under a variety of conditions. Regardless of
whether tributylphosphine or trimethylphosphine were
used for the cyclization, none of the desired cyclic enone
was isolated. Speculating the substitution at the g position
may be hindering addition of the nucleophile to the acti-
vated alkene, excess phosphine was used, however neither
five nor ten equivalents of either phosphine promoted the
desired process. Hoping to use a more rigid conformation
to assist in the cyclization of substituted enoates, a cis-
fused bicycle was targeted where substitution at the g po-
sition was still present. Treatment of thioester 18 with
tributylphosphine in t-BuOH followed by addition of
1
2
3
2
3
4
R = Et
5
6
7
99
R = n-Bu
R = t-Bu
95
60a
a Using 1 equiv of Me3P.
To probe further, precursors to generate six-membered
rings were synthesized. Treatment of thioester 8 in t-
BuOH with one equivalent of tributylphosphine followed
by the addition of KOH and BnEt3NCl in CH2Cl2/t-BuOH
(1:1) did not afford the desired product (Table 2, entry 1).
Increasing the concentration of the solvent yielded none
of the desired product. Likewise treatment of thioester 8
with two equivalents of tributylphosphine failed to pro-
vide the desired product leaving mainly starting material
along with some decomposition (entry 3). However, treat-
Synlett 2010, No. 17, 2583–2588 © Thieme Stuttgart · New York

LETTER
Morita–Baylis–Hillman Alkylation of Unsaturated Thioesters
2585
the next step to improve the reaction was to employ cata-
lytic amounts of the trialkylphosphine nucleophile. In our
previous work on the MBH alkylation of enones we
showed that only 20 mol% of tributylphosphine was nec-
essary to provide five- and six-membered rings with little
to no reduction in yields when compared to the reaction
efficiency with stoichiometric amounts of trialkylphos-
phine.10 With this in mind, we set out to improve the un-
saturated thioester alkylation reaction by decreasing the
amount of phosphine nucleophile needed to promote cy-
clization. The choice of trialkylphosphine and its percent
loading as well as the concentration of the organic layer
were expected to be important factors in the success of the
catalytic MBH alkylation of unsaturated thioesters. To as-
sess the feasibility of this reaction, thioester 2 was tested
for its compatibility with all the reagents in a one-pot sto-
ichiometric reaction. Tributylphosphine (100 mol%) was
added to a solution of thioester 2 with 100 mol% KOH and
10 mol% BnEt3NCl in 0.5 M t-BuOH and 0.2 M CH2Cl2/
H2O providing 99% of the desired product 5.
Table 3 Stoichiometric Morita–Baylis–Hillman Alkylation of Un-
saturated Thioesters
O
O
1) Bu3P (1 equiv)
t-BuOH
Br
RS
RS
2) KOH, BnEt3NCl,
CH2Cl2/H2O (1:1)
n
n
Entry Thioester
Product
Yield
(%)
O
O
Br
1
2
3
4
8
5
6
7
9
99
EtS
EtS
O
O
Br
2
95
BuS
BuS
O
O
Br
3
4
60a
47b
S
S
With the compatibility of the reagents confirmed,
thioester 2 was then subjected to the optimized conditions
used when alkyl enones were employed as the activated
alkene component. Thus, thioester 2 with 10 mol%
BnEt3NCl and 0.2 M KOH (aq) solution, in 0.5 M
CH2Cl2–t-BuOH was treated with 20 mol% tributylphos-
phine, and as expected, thioester 5 was obtained in 97%
yield as compared to 99% obtained in reactions with stoi-
chiometric amounts of tributylphosphine (Equation 4).
O
Br
O
EtS
EtS
EtS
EtS
O
O
Br
O
5c
6d
7d
10
12
14
11 92
13 91
15 82
E
E
E
E
Br
O
PBu3 (20 mol%)
BnEt3NCl (10 mol%),
0.2 M KOH(aq)
O
O
BuS
BuS
Br
E'
E'
EtS
EtS
0.5 M CH2Cl2/t-BuOH (1:1)
97%
E'
Br
E'
2
5
O
O
Equation 4
S
S
E'
E'
E'
E'
Continuation with these promising results, the generality
of this catalytic reaction is summarized in Table 4. Upon
treatment of thioester 3 with 20 mol% tributylphosphine,
the desired product 6 was isolated with no reduction in
yield (Table 4, entry 2). The bulky thioester 4 was not in-
vestigated in the catalytic reaction due to the fact that the
reaction failed to provide products when stoichiometric
tributylphosphine was employed (Table 3, entry 3) and
the use of trimethylphosphine in the catalytic reaction
proved futile due to its volatility. Formation of six-mem-
bered-ring adducts proceeded with ease in the catalytic re-
action. Thioesters 10, 12, and 14 all furnished the cyclized
product in 90%, 83% and 79% yield, respectively, exhib-
iting a slight reduction of yield (Table 3, entries 5–7).
Lastly, thioester 18 failed to form products when treated
with 20 mol% of tributylphosphine in a 0.5 M organic so-
lution. However when thioester 18 was subjected to reac-
tion with 20 mol% of tributylphosphine in 1.0 M CH2Cl2
cyclization proceeded to give 85% yield of the desired
product 19 (Table 4, entry 4).
O
O
Br
EtS
8
9
16
18
17 0
EtS
O
O
19 85
SEt
SEt
Br
a Using 1 equiv of Me3P.
b Using 2 equiv of Me3P.
c E = CO2Et.
d E¢ = CO2Me.
KOH and BnEt3NCl in CH2Cl2/H2O (1:1), afforded cis-
fused bicycle 19 in 85% yield (Table 3, entry 9).
Having shown unsaturated thioesters work well in the sto-
ichiometric Morita–Baylis–Hillman alkylation reaction,
Synlett 2010, No. 17, 2583–2588 © Thieme Stuttgart · New York

2586
M. E. Krafft et al.
LETTER
Table 4 Catalytic MBH Alkylation of Unsaturated Thioesters
O
O
Bu3P, BnEt3NCl,
0.2 M KOH(aq)
Br
RS
RS
0.5 M CH2Cl2/t-BuOH (1:1)
n
n
Entry
Thioester
Product
Yield (%)
O
O
1
2
3
2, R = Et
3, R = Bu
4, R = t-Bu
5
6
7
97
96
–
Br
RS
RS
O
O
4
18
19
85b
SEt
Br
SEt
O
Br
O
5c
6c
7c
10, R = Et
12, R = Bu
14, R = t-Bu
11
13
15
90
83
79
RS
RS
E
E
E
E
O
Br
O
8
8
9
–
EtS
EtS
a 10,11 E = CO2Et; 12,13,14,15 E = CO2Me.
b Under catalytic conditions a 1.0 M organic phase was used. Reaction times varied from 1 h to 6 h.
c E = CO2Et.
(3) (a) Black, G. P.; Dinon, F.; Fratucello, S.; Murphy, P. J.;
Nielsen, M.; Williams, H. L.; Walshe, N. D. A. Tetrahedron
Lett. 1997, 38, 8561. (b) Dinon, F.; Richards, E.; Murphy,
P. J.; Hibbs, D. E.; Hursthouse, M. B.; Malic, K. M. A.
Tetrahedron Lett. 1999, 40, 3279. (c) Richards, E. L.;
Murphy, P. J.; Dinon, F.; Fratucello, S.; Brown, P. M.;
Gelbrich, T.; Hursthouse, M. B. Tetrahedron 2001, 57,
7771. (d) Des Mazery, R.; Pullez, M.; Lopéz, F.;
Harutyunyan, S. R.; Minnaare, A. J.; Feringa, B. L. J. Am.
Chem. Soc. 2005, 127, 9966.
(4) Yost, J. M.; Zhou, G.; Coltart, D. M. Org. Lett. 2006, 8,
1503.
(5) Keck, G. E.; Welch, D. S. Org. Lett. 2002, 4, 3687.
(6) Agapiou, K.; Krische, M. J. Org. Lett. 2003, 5, 1737.
(7) Krafft, M. E.; Seibert, K. A.; Haxell, T. F. N.; Hirosawa, C.
Chem. Commun. 2005, 5772.
We have expanded the Morita–Baylis–Hillman alkylation
reaction to include thioesters as a viable alternative acti-
vated alkene. Five- and six-membered rings were formed
with ease and in excellent yields. This method tolerates
substitution on the tether and the Thorpe–Ingold assis-
tance provided by the diesters played a vital role in facili-
tating the formation of six-membered rings. Additionally,
thioesters have been shown to form products in the pres-
ence of a catalytic amount of tributylphosphine with little
to no reduction in yield compared to the stoichiometric
process. Five- and six-membered rings were furnished in
excellent yields. Substitution on the tether of five-mem-
bered-ring precursors was shown to have no detrimental
effects on the cyclization when substoichiometric
amounts of phosphine were employed.11
(8) Krafft, M. E.; Haxell, T. F. N. J. Am. Chem. Soc. 2005, 127,
10168.
(9) Krafft, M. E.; Haxell, T. F. N.; Seibert, K. A.; Abboud, K. A.
J. Am. Chem. Soc. 2006, 128, 4174.
Acknowledgment
(10) Krafft, M. E.; Seibert, K. A. Synlett 2006, 3334.
(11) (a) Compound 2: 1H NMR (500 MHz, CDCl3): d = 6.83 (td,
J = 7.0, 15.5 Hz, 1 H), 6.16 (td, J = 1.3, 15.5 Hz, 1 H), 3.41
(t, J = 6.6 Hz, 2 H), 2.95 (q, J = 7.5 Hz, 2 H), 2.38 (ddt, J =
1.3, 7.0, 7.0 Hz, 2 H), 2.03 (tt, J = 6.6, 7.0 Hz, 2 H), 1.28 (t,
J = 7.1 Hz, 3 H). 13C NMR (75 MHz, CDCl3): d = 189.6,
142.4, 129.5, 32.4, 30.6, 30.2, 23.0, 14.6. HRMS (FAB+):
m/z [M + Na] calcd for C8H13BrOSNa: 259.9766; found:
258.9768. FTIR (neat): 2965, 2960, 2872, 1667, 1633, 1436,
1265, 1026, 970 cm–1. Anal. Calcd for C8H13OBrS: C, 40.52;
H, 5.53. Found: C, 40.13; H, 5.53. (b) Compound 3: 1H
NMR (500 MHz, CDCl3): d = 6.83 (td, J = 7.1, 15.4 Hz, 1
H), 6.16 (td, J = 1.3, 5.4 Hz, 1 H), 3.41 (t, J = 6.7 Hz, 2 H),
2.95 (t, J = 7.3 Hz, 2 H), 2.37 (ddt, J = 1.3, 7.1, 7.1 Hz, 2 H),
2.03 (tt, J = 6.7, 7.1 Hz, 2 H), 1.59 (tt, J = 7.3, 7.3 Hz, 2 H),
We are grateful for support from the NSF and MDS Research Foun-
dation.
References and Notes
(1) (a) Singh, V.; Batra, S. Tetrahedron 2008, 64, 4511.
(b) Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. Rev.
2003, 103, 81.
(2) (a) Kaaoka, T.; Iwama, H.; Kinoshita, H.; Tsujiyama, Y.;
Iwamura, T.; Watanabe, S. Synlett 1999, 197. (b) Kataoka,
T.; Kinoshita, H.; Iwama, T.; Tsujiyama, S.-I.; Iwamura, T.;
Watanabe, S.-I.; Muraoka, O.; Tanabe, G. Tetrahedron
2000, 56, 4725.
Synlett 2010, No. 17, 2583–2588 © Thieme Stuttgart · New York

LETTER
Morita–Baylis–Hillman Alkylation of Unsaturated Thioesters
2587
1.41 (qt, J = 7.3, 7.3 Hz, 2 H), 0.92 (t, J = 7.3 Hz, 3 H). 13
C
Hz, 2 H), 1.26 (t, J = 7.4 Hz, 3 H), 1.25 (t, J = 7.1 Hz, 6 H).
NMR (75 MHz, CDCl3): d = 189.4, 142.2, 129.5, 32.3, 31.4,
30.6, 30.1, 28.2, 21.7, 13.4. HRMS (FAB+): m/z [M + Na]
calcd for C10H17OBrNa: 287.00813; found: 287.00812.
FTIR (neat): 2959, 2930, 2872, 1671, 1632 cm–1. Anal.
Calcd for C10H17OBr: C, 45.29; H, 6.46. Found: C, 45.57; H,
6.57. (c) Compound 4: 1H NMR (500 MHz, CDCl3): d =
6.75 (td, J = 7.1, 15.5 Hz, 1 H), 6.06 (td, J = 1.3, 15.5 Hz, 1
H), 3.41 (t, J = 6.6 Hz, 2 H), 2.34 (tdd, J = 1.3, 7.1, 7.1 Hz,
2 H), 2.01 (tt, J = 6.6, 7.1 Hz, 2 H), 1.50 (s, 9 H). 13C NMR
(75 MHz, CDCl3): d = 190.4, 141.4, 130.3, 47.9, 32.5, 30.7,
30.2, 29.8. HRMS (FAB+): m/z [M + Na] calcd for
C10H17OBrSNa: 287.00825; found: 287.00812. FTIR (neat):
2962, 1667, 1630, 1454, 1363, 968 cm–1. Anal. Calcd for
C10H17OBrS: C, 45.29; H, 6.46. Found: C, 45.54; H, 6.50.
(d) Compound 5: Treatment of bromide 2 (237 mg, 1 mmol),
with tributylphosphine (0.23 mL, 1 mmol) in t-BuOH (2 mL)
followed by addition of KOH (56 mg, 1 mmol) and
13C NMR (75 MHz, CDCl3): d = 192.0, 170.7, 137.0, 134.2,
61.5, 52.4, 30.9, 27.0, 22.9, 21.2, 14.7, 13.9. HRMS (CI+):
m/z [M + H] calcd for C15H23O5S: 315.1262; found:
315.1266. FTIR (neat): 2957, 2930, 2871, 1655, 1156 cm–1.
Anal. Calcd for C15H22O5S: C, 57.30; H, 7.05. Found: C,
57.34; H, 7.07. (k) Compound 12: 1H NMR (500 MHz,
CDCl3): d = 6.67 (td, J = 7.6, 15.3 Hz, 1 H), 6.15 (br d, J =
15.3 Hz, 1 H), 3.76 (s, 6 H), 3.35 (t, J = 8.2 Hz, 2 H), 2.94 (t,
J = 7.3 Hz, 2 H), 2.78 (dd, J = 1.1, 7.6 Hz, 2 H), 2.46 (t, J =
8.2 Hz, 2 H), 1.58 (tt, J = 7.3, 7.3 Hz, 2 H), 1.40 (qt, J = 7.3,
7.3 Hz, 2 H), 0.92 (t, J = 7.3 Hz, 3 H). 13C NMR (75 MHz,
CDCl3): d = 189.2, 169.9, 137.0, 132.2, 57.3, 52.8, 36.6,
36.2, 31.4, 28.4, 26.5, 21.8, 13.5. HRMS (FAB+): m/z [M +
Na] calcd for C15H23O5BrSNa: 417.03409; found:
417.03472. FTIR (neat): 2956, 1734, 1670, 1437, 1264 cm–1.
Anal. Calcd for C15H23O5BrS: C, 45.57; H, 5.86. Found: C,
45.57; H, 6.17. (l) Compound 13: 1H NMR (500 MHz,
CDCl3): d = 6.91 (tt, J = 1.5, 4.0 Hz, 1 H), 3.73 (s, 6 H), 2.90
(t, J = 7.3 Hz, 2 H), 2.78 (td, J = 2.2, 4.0 Hz, 2 H), 2.38 (dtt,
J = 1.5, 2.2, 6.4 Hz, 2 H), 2.19 (t, J = 6.4 Hz, 2 H), 1.56 (tt,
J = 7.3, 7.4 Hz, 2 H), 1.39 (tq, J = 7.4, 7.4 Hz, 2 H), 0.92 (t,
J = 7.4 Hz, 3 H). 13C NMR (75 MHz, CDCl3): d = 192.1,
171.2, 137.2, 134.0, 52.8, 52.5, 31.6, 31.1, 28.3, 27.2, 22.0,
21.3, 13.6. HRMS (CI+): m/z [M + H] calcd for C15H23O5S:
315.12677; found: 315.12662. FTIR (neat): 2955, 2872,
1736, 1651, 1257 cm–1. Anal. Calcd for C15H22O5S: C,
57.30; H, 7.05. Found: C, 57.16; H, 7.20. (m) Compound
14: 1H NMR (500 MHz, CDCl3): d = 6.59 (td, J = 7.6, 15.3
Hz, 1 H), 6.06 (td, J = 1.2, 15.3 Hz, 1 H), 3.76 (s, 6 H), 3.35
(t, J = 8.1 Hz, 2 H), 2.76 (dd, J = 1.2, 7.6 Hz, 2 H), 2.45 (t,
J = 8.1 Hz, 2 H), 1.49 (s, 9 H). 13C NMR (75 MHz, CDCl3):
d = 189.7, 170.0, 136.0, 133.0, 57.3, 52.9, 48.2, 36.6, 36.1,
29.7, 26.6. HRMS (FAB+): m/z [M + Na] calcd for
C15H23O5BrSNa: 417.03471; found: 417.02472. FTIR
(neat): 2956, 1734, 1667, 1631, 1435, 1264 cm–1. Anal.
Calcd for C15H23O5BrS: C, 45.57; H, 5.86. Found: C, 45.47;
H, 5.95. (n) Compound 15: 1H NMR (500 MHz, CDCl3): d
= 6.86 (tt, J = 2.0, 4.4 Hz, 1 H), 3.73 (s, 6 H), 2.73 (td, J =
2.2, 4.0 Hz, 2 H), 2.32 (dtt, J = 2.2, 2.2, 6.4 Hz, 2 H), 2.16 (t,
J = 6.4 Hz, 2 H), 1.47 (s, 9 H). 13C NMR (75 MHz, CDCl3):
d = 193.0, 171.3, 138.0, 133.2, 52.9, 52.5, 47.6, 31.1, 29.9,
28.3, 27.3, 21.6. HRMS (CI+): m/z [M+] calcd for
C15H22O5S: 315.12718; found: 315.12662. FTIR (neat):
2954, 1735, 1645, 1257 cm–1. Anal. Calcd for C15H22O5S: C,
57.30; H, 7.05. Found: C, 57.66; H, 7.21. (o) Compound
16: 1H NMR (500 MHz, CDCl3): d = 6.70 (dd, J = 8.2, 15.7
Hz, 1 H), 6.13 (dd, J = 1.0, 15.7 Hz, 1 H), 3.40 (ABt, J = 9.7,
6.5 Hz, 1 H), 3.33 (ABt, J = 9.7, 6.5 Hz, 1 H), 2.95 (q, J =
7.4 Hz, 2 H), 2.57 (m, 1 H), 1.94 (ABdt, J = 14.0, 7.0, 7.0
Hz, 1 H), 1.91 (ABdt, J = 14.0, 7.0, 7.0 Hz, 1 H), 1.28 (t, J =
7.4 Hz, 3 H), 1.10 (d, J = 6.8 Hz, 3 H). 13C NMR (75 MHz,
CDCl3): d = 189.6, 147.5, 127.9, 43.9, 38.2, 34.7, 30.9, 26.6,
25.8, 23.2, 22.9, 18.8, 14.6, 14.5, 14.4. HRMS (FAB+): m/z
[M + Na] calcd for C9H15OBrNaS: 272.99276; found:
272.99247. FTIR (neat): 2965, 1670, 1631, 1453 cm–1. Anal.
Calcd for C9H15OBrS: C, 43.03; H, 6.02. Found: C, 43.29; H,
6.23. (p) Compound 18: 1H NMR (500 MHz, CDCl3): d =
6.98 (dd, J = 9.2, 15.5 Hz, 1 H), 6.23 (dd, J = 0.7, 15.5 Hz, 1
H), 3.25 (dd, J = 7.1, 10.0 Hz, 1 H), 3.14 (dd, J = 8.2, 10.0
Hz, 1 H), 2.96 (ABq, J = 15.0, 7.5 Hz, 1 H), 2.96 (ABq, J =
15.0, 7.5 Hz, 1 H), 2.78 (dddd, J = 4.0, 4.0, 8.0, 9.1 Hz, 1 H),
1.98 (ddddd, J = 4.0, 4.0, 7.1, 8.2, 10.8 Hz, 1 H), 1.3–1.75
(m, 7 H), 1.29 (t, J = 7.5 Hz, 3 H). 13C NMR (75 MHz,
CDCl3): d = 189.7, 143.1, 130.0, 42.6, 40.1, 36.6, 30.2, 27.2,
24.8, 23.1, 21.6, 14.7. HRMS (FAB+): m/z [M + Na] calcd
for C12H19OBrSNa: 313.02361; found: 313.02377. FTIR
BnEt3NCl (23 mg, 0.1 mmol) in CH2Cl2–H2O (10 mL, 1:1)
yielded enone 5 in 99% yield (155 mg). 1H NMR (500 MHz,
CDCl3): d = 6.79 (tt, J = 2.2, 2.4 Hz, 1 H), 2.93 (q, J = 7.4
Hz, 2 H), 2.62 (dtt, J = 2.2, 2.3, 7.6 Hz, 2 H), 2.51 (tdt, J =
2.3, 2.4, 7.6 Hz, 2 H), 1.96 (tt, J = 7.6, 7.6 Hz, 2 H), 1.27 (t,
J = 7.4 Hz, 3 H). 13C NMR (75 MHz, CDCl3): d = 188.9,
144.0, 141.4, 33.2, 31.0, 22.8, 22.7, 13.4. HRMS (CI+): m/z
[M + H] calcd for C8H13OS: 157.06899; found: 157.06872.
FTIR (neat): 2957, 2871, 1655, 1459, 1154 cm–1. Anal.
Calcd for C8H12OS: C, 61.50; H, 7.74. Found: C, 61.03; H,
7.65. (e) Compound 6: 1H NMR (500 MHz, CDCl3): d =
6.80 (tt, J = 2.1, 2.3 Hz, 1 H), 2.93 (t, J = 7.4 Hz, 2 H), 2.62
(dtt, J = 2.1, 2.2, 7.6 Hz, 2 H) 2.51 (tdt, J = 2.2, 2.3, 7.6 Hz,
2 H), 1.96 (tt, J = 7.6, 7.6 Hz, 2 H), 1.58 (m, 2 H), 1.41 (tq,
J = 7.4, 7.4 Hz, 2 H), 0.94 (t, J = 7.4 Hz, 3 H). 13C NMR (75
MHz, CDCl3): d = 189.1, 144.1, 141.5, 33.4, 31.7, 31.2,
28.1, 22.9, 22.0, 13.6. HRMS (CI+): m/z [M+] calcd for
C10H16OS: 185.0999; found: 185.1000. FTIR (neat): 2958,
2930, 1655, 1613, 1156 cm–1. Anal. Calcd for C10H16OS: C,
65.17; H, 8.75. Found: C, 64.82; H, 8.87. (f) Compound 7:
Kishimoto, N.; Fujimoto, T.; Yamamoto, I. J. Org. Chem.
1999, 64, 5988. (g) Compound 8: 1H NMR (500 MHz,
CDCl3): d = 6.86 (td, J = 6.9, 15.4 Hz, 1 H), 6.12 (td, J = 1.5,
15.4 Hz, 1 H), 3.41 (t, J = 6.6 Hz, 2 H), 2.95 (q, J = 7.3 Hz,
2 H), 2.23 (dtd, J = 1.5, 7.1, 7.1 Hz, 2 H), 1.89 (tt, J = 6.6,
7.1 Hz, 2 H), 1.64 (tt, J = 7.1, 7.1 Hz, 2 H), 1.28 (t, J = 7.3
Hz, 3 H). 13C NMR (75 MHz, CDCl3): d = 189.7, 143.9,
129.0, 33.0, 31.9, 31.0, 26.3, 22.9, 14.7. HRMS (FAB+):
m/z [M + Na] calcd for C9H15OBrSNa: 272.9927; found:
272.9925. FTIR (neat): 2930, 1670, 1632, 1451, 1265, 969
cm–1. Anal. Calcd for C9H15OBrS: C, 43.03; H, 6.02. Found:
C, 43.36; H, 5.98. (h) Compound 9: Schaumann, E.;
Mergardt, B. J. Chem. Soc., Perkin Trans. 1: Organic and
Bioorganic Chem. 1989, 1361. (i) Compound 10: 1H NMR
(500 MHz, CDCl3): d = 6.70 (td, J = 7.8, 15.4 Hz, 1 H), 6.15
(td, J = 1.2, 15.4 Hz, 1 H), 4.23 (ABq, J = 7.1, 7.1 Hz, 2 H),
4.22 (ABq, J = 7.1, 7.1 Hz, 2 H), 3.36 (t, J = 8.2 Hz, 2 H),
2.94 (q, J = 7.4 Hz, 2 H) 2.77 (dd, J = 1.2, 7.8 Hz, 2 H), 2.45
(t, J = 8.2 Hz, 2 H), 1.28 (t, J = 7.4 Hz, 3 H), 1.27 (t, J = 7.1
Hz, 6 H). 13C NMR (75 MHz, CDCl3): d = 189.3, 169.5,
137.5, 132.2, 61.9, 57.2, 36.7, 36.2, 26.6, 23.1, 14.6, 13.9.
HRMS (FAB+): m/z [M + Na] calcd for C15H23O5BrSNa:
417.0340; found: 417.0347. FTIR (neat): 2980, 2934, 1730,
1671, 1633, 1443, 1261 cm–1. Anal. Calcd for C15H23O5BrS:
C, 45.57; H, 5.86. Found: C, 45.47; H, 5.95. (j) Compound
11: 1H NMR (500 MHz, CDCl3): d = 6.89 (tt, J = 1.8, 4.0 Hz,
1 H), 4.19 (ABq, J = 7.1, 7.1 Hz, 2 H), 4.19 (ABq, J = 7.1,
7.1 Hz, 2 H), 2.91 (q, J = 7.4 Hz, 2 H), 2.76 (td, J = 2.4, 4.0
Hz, 2 H), 2.39 (dtt, J = 1.8, 2.4, 6.4 Hz, 2 H), 2.18 (t, J = 6.4
Synlett 2010, No. 17, 2583–2588 © Thieme Stuttgart · New York

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M. E. Krafft et al.
LETTER
(neat): 2930, 2856, 1670, 1628, 1449 cm–1. Anal. Calcd for
C12H19OBrS: C, 49.49; H, 6.58. Found: C, 49.70; H, 6.53.
(q) Compound 19: HRMS (CI+): m/z [M + Na] calcd for
C12H18OS: 211.1152; found: 211.1157. Anal. Calcd for
C12H18OS: C, 68.52; H, 8.63. Found: C, 68.27; H, 8.67.
(r) Catalysis of Reactions of a,b-Unsaturated Thioesters
in the MBH Reaction: General Procedure of the
(1:1; 2 mL, 0.5 M), and H2O (10 mL, 0.1 M) with BnEt3NCl
(23 mg, 0.1 mmol) and KOH (56 mg, 1 mmol) was treated
with tributylphosphine (0.45 mL, 0.2 mmol). The reaction
was stirred in a resealable tube until complete consumption
of starting material as indicated by TLC. The organic layer
was then extracted with CH2Cl2, dried over anhyd Na2SO4
and concentrated in vacuo. Purification via column chroma-
tography gave the desired product 5 (152 mg, 97%).
Catalytic MBH Alkylation Reaction of Thioesters: A
solution of thioester 2 (237 mg, 1 mmol) in CH2Cl2–t-BuOH
Synlett 2010, No. 17, 2583–2588 © Thieme Stuttgart · New York

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