Practical synthesis and highly diastereoselective diels-alder reactions of 1-alkylthio-3-silyloxybutadienes

Article abstract of DOI:10.1021/jo901347u

(Chemical Equation Presented) An efficient acid-catalyzed method for the synthesis of vinylogous thioesters was developed. 1-Alkylthio-3- silyloxybutadienes were then produced in high yields from the corresponding vinylogous thioesters. These dienes were

Full text of DOI:10.1021/jo901347u

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We were intrigued by the possibility of using an alkylthio
Practical Synthesis and Highly Diastereoselective
Diels-Alder Reactions of 1-Alkylthio-3-
silyloxybutadienes
substituent instead of the alkoxy or dialkylamino group.
Specifically, we were interested in determining their stabi-
lity, reactivity, and selectivity in Diels-Alder reactions.
Although many sulfur-containing dienes have been re-
ported,4 the properties of 1-alkylthio-3-silyloxybutadienes
analogous to Danishefsky’s and Rawal’s dienes have not yet
been investigated.5 In this paper, we describe the conditions
required for the efficient preparation of 1-alkylthio-3-silyl-
oxybutadienes in high yields and discuss their behavior in the
Diels-Alder reaction.
To access 1-alkylthio-3-silyloxybutadienes, we needed an
efficient method for vinylogous thioester synthesis. In con-
trast to the straightforward preparation of vinylogous
amides,3a simple mixing of 4-methoxy-3-buten-2-one (1)
with butanethiol in dichloromethane at room temperature
did not result in any reaction. Thus, the synthesis of the
desired vinylogous thioester through a direct addition-
elimination reaction was attempted by using basic conditions
(Scheme 1). We were encouraged by the isolation of the
conjugate addition product (2a), although no vinylogous
thioester (3a) was detected. Subjection of adduct 2a to acidic
conditions resulted in the elimination of the methoxy group,
producing the desired vinylogous thioester 3a.
Janice M. Holmes, Andrea L. Albert, and Michel Gravel*
Department of Chemistry, University of Saskatchewan,
110 Science Place, Saskatoon, SK, S7N 5C9, Canada
michel.gravel@usask.ca
Received June 24, 2009
An efficient acid-catalyzed method for the synthesis of
vinylogous thioesters was developed. 1-Alkylthio-3-silyl-
oxybutadienes were then produced in high yields from
the corresponding vinylogous thioesters. These dienes
were highly reactive in Diels-Alder reactions, affording
the cycloadducts in high endo selectivity under mild
conditions.
The successful elimination of the methoxy group under
acidic conditions prompted an attempt to directly convert
1 into 3a by using acid catalysis. In the presence of catalytic
p-toluenesulfonic acid, 3a was obtained in a single step with a
good E:Z ratio (Table 1, entry 1). Substitution of dichloro-
methane with toluene resulted in a small improvement in
E:Z ratio and a significant improvement in yield (entry 2).
Decreasing the temperature of the reaction resulted in an
excellent E:Z ratio (entry 3).
The generality of this method for vinylogous thioester
synthesis was then assessed for various thiols. The products
3a-c derived from alkylthiols were produced with high
E selectivity and isolated in good yields (entries 3-5). On
the other hand, product 3d derived from benzenethiol was
obtained in a much reduced E:Z ratio (entry 6). In addition,
the reaction leading to 3d resulted in an incomplete conver-
sion and the desired product could not be conveniently
separated from the conjugate addition intermediate (2d) by
distillation or chromatography. The minor Z isomer present
in 3a-c could be removed through column chromatography,
affording geometrically pure (E)-3 (>95:5 E:Z). Although
we have found the vinylogous thioesters 3 to isomerize at
ambient temperature, they could be stored for several weeks
at -20 °C without any significant change in the E:Z ratio.
Formation of a silyl dienol ether from the vinylogous
thioester with use of Ward’s conditions produced the desired
The stereocontrolled production of a carbocycle has made
the Diels-Alder cycloaddition a greatly valued reaction in
organic synthesis.1 Electron donating groups on the diene
serve to enhance both the rate and regioselectivity of
the reaction. Among the vast number of dienes developed
for Diels-Alder and hetero-Diels-Alder reactions,
Danishefsky’s2 and Rawal’s3 silyloxydienes stand out as
being particularly reactive. As shown in Figure 1, the former
diene bears an additional methoxy substituent, whereas the
latter contains a dimethylamino group.
(1) (a) Diels, O.; Alder, K Liebigs Ann. Chem. 1928, 460, 98–122. For
selected reviews, see: (b) Corey, E. J. Angew. Chem., Int. Ed. 2002, 41, 1650–
1667. (c) Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.; Vassilikogiannakis,
G. Angew. Chem., Int. Ed. 2002, 41, 1668–1698.
(2) Danishefsky, S.; Kitahara, T. J. Am. Chem. Soc. 1974, 96, 7807–7808.
(3) (a) Kozmin, S. A.; Rawal, V. H. J. Org. Chem. 1997, 62, 5252–5253.
(b) Kozmin, S. A.; Green, M. T.; Rawal, V. H. J. Org. Chem. 1999, 64, 8045–
8047.
(4) Selected examples of 1-alkylthio- and 1-arylthio-1,3-butadienes: (a)
Cohen, T.; Mura, A. J.; Shull, D. W.; Fogel, E. R.; Ruffner, R. J.; Falck, J. R.
J. Org. Chem. 1976, 41, 3218–3219. (b) Kozikowski, A. P.; Huie, E. J. Am.
Chem. Soc. 1982, 104, 2923–2925. (c) Overman, L. E.; Petty, C. B.; Ban, T.;
Huang, G. T. J. Am. Chem. Soc. 1983, 105, 6335–6337. (d) Grayson, J. I.;
Warren, S.; Zaslona, A. T. J. Chem. Soc., Perkin Trans. 1 1987, 967–976. (e)
Pegram, J. J.; Anderson, C. B. Tetrahedron Lett. 1988, 29, 6719–6720. (f)
(5) Cyclic dienes derived from 2H-thiopyran-4-one were studied pre-
viously: (a) Ward, D. E.; Zoghaib, W. M.; Rhee, C. K. Tetrahedron Lett.
1990, 31, 845–848. (b) Ward, D. E.; Gai, Y. Z.; Zoghaib, W. M. Can. J. Chem.
1991, 69, 1487–1497. (c) Ward, D. E.; Gai, Y. Tetrahedron Lett. 1992, 33,
1851–1854. (d) Ward, D. E.; Gai, Y. Can. J. Chem. 1992, 70, 2627–2634. (e)
Ward, D. E.; Nixey, T. E. Tetrahedron Lett. 1993, 34, 947–950. (f) Ward,
D. E.; Nixey, T. E.; Gai, Y.; Hrapchak, M. J.; Abaee, M. S. Can. J. Chem.
1996, 74, 1418–1436. (g) Ward, D. E.; Gai, Y. Can. J. Chem. 1997, 75, 681–
693.
ꢀ
Skowronska, A.; Dybowski, P.; Koprowski, M.; Krawczyk, E. Tetrahedron
Lett. 1995, 36, 8133–8136. (g) Maddaluno, J.; Gaonac’h, O.; Marcual, A.;
Toupet, L.; Giessner-Prettre, C. J. Org. Chem. 1996, 61, 5290–5306. (h)
Olsen, R. K.; Shao, R.-l. J. Org. Chem. 1996, 61, 5852–5856.
6406 J. Org. Chem. 2009, 74, 6406–6409
Published on Web 07/23/2009
DOI: 10.1021/jo901347u
r
2009 American Chemical Society

Holmes et al.
JOCNote
TABLE 2. Diels-Alder Additions with 1-Benzylthio-3-(tert-butyldimethy-
lsilyloxy)-1,3-butadiene 4ca
FIGURE 1. Reactive silyloxydienes.
SCHEME 1. Two-Step Synthesis of a Vinylogous Thioester
TABLE 1. Single-Step Synthesis of Vinylogous Thioesters
entry
product
T (°C)
solvent
E:Za
yield (%)b
1
2
3
4
5
6
3a
3a
3a
3b
3c
3d
23
23
0
0
0
CH2Cl2
PhMe
PhMe
PhMe
PhMe
CH2Cl2
7:1
8:1
20:1
10:1
25:1
4:1
32
79
70
60
64
n.d.c
0
aRatio determined by H NMR on the crude reaction
1
aReactions in entries 1 and 5 were performed at 80 °C;
b
mixture. Yield of purified E isomer. The yield was not
c
b
reactions in entries 2-4 were performed at 23 °C. Assign-
ment of the endo and exo cycloadducts was based on
determined (see text).
1
comparison of H NMR spectra with related compounds
and through NOESY experiments (see the Support-
c
ing Information). For entries 1-2: yield of pure isolated
SCHEME 2. Synthesis of 1-Alkylthio-3-silyloxybutadienes
silyl enol ether cycloadduct. For entries 3-5: yield of pure
isolated ketone (two-step process of cycloaddition and clea-
vage of the silyl enol ether on the crude cycloadduct).
allowing for the isolation of the cycloadduct in quantitative
yield without the need for purification beyond removal of the
excess methacrolein in vacuo. Doubly activated dienophiles
formed cycloadducts with 4c at ambient temperature with
only one diastereomer detected by 1H NMR analysis (entries
2-4, Table 2). The cycloaddition with maleic anhydride
yields the cycloadduct in its essentially pure form (entry 2).
As isolation of the remainder of the cycloadducts by chro-
matography was unsuccessful, cleavage of the silyl enol ether
was performed on the crude cycloadduct with use of
dienes 4 in high yield (Scheme 2).5a In the presence of
acid or water, the dienes hydrolyze to their vinylogous
thioester precursors. Use of a basic eluent (3% Et3N/
hexanes) in flash column chromatography allows for the
isolation of all the dienes in near-quantitative yield.
Although the dienes can be handled without any particular
precautions, exposure to air results in slow oxidation to the
corresponding sulfoxides.
HF pyridine complex,6 resulting in good yields for the
Dienes 4a-c displayed high endo selectivity in preliminary
Diels-Alder experiments with methacrolein at ambient
temperature (endo:exo > 10:1). Diene 4c showed particular
promise (endo:exo 14:1) and thus was selected for further
investigation. Cycloadditions were performed in the pre-
3
two-step process. (entries 3-5). Not surprisingly, the cy-
cloaddition with dimethyl fumarate was not selective,
with the endo and exo products being obtained in a 1:1 ratio
(entry 5).3a
˚
sence of 4 A molecular sieves to prevent the slow hydrolysis
To determine the relative reactivity of 1-alkylthio-3-silyl-
oxybutadienes, a competition reaction was performed between
diene 4c and a tert-butyl dimethylsilyl version of Danishefsky’s
diene (10). A limiting amount of N-phenylmaleimide was
of the diene. The monoactivated dienophile methacrolein
required heating and a concentrated reaction mixture for the
reaction to proceed at a reasonable rate. Under these condi-
tions, the cycloaddition was highly endo selective (entry 1).
The excess methacrolein served to drive the reaction
to completion prior to the formation of any byproduct,
(6) Lastdrager, B.; Timmer, M. S. M.; van der Marel, G. A.; Overkleeft,
H. S.; Overhand, M. J. Carbohydr. Chem. 2007, 26, 41–59.
J. Org. Chem. Vol. 74, No. 16, 2009 6407

Holmes et al.
JOCNote
SCHEME 3. Competition Reaction between Dienes 4c and 5
Representative Procedure for the Synthesis of Dienes: 1-
Benzylthio-3-(tert-butyldimethylsilyloxy)-1,3-butadiene (4c). A
25-mL round-bottomed flask containing a stir bar and trans-
4-benzylthio-3-buten-2-one (3a) (0.214 g, 1.11 mmol) was
sealed with a septum. The flask was purged with nitrogen, then
CH2Cl2 (10 mL), Et3N (0.466 mL, 3.00 mmol), and tert-butyl-
dimethylsilyltrifluoromethane sulfonate (0.267 mL, 1.16 mmol)
were added sequentially. After 3 h of stirring at room tempera-
ture, the reaction mixture was concentrated in vacuo.
The resulting red mixture was chromatographed rapidly
through a 9ꢀ2.5 cm column of silica gel with 3% Et3N/hexa-
nes as eluent. The title product was obtained as a yellow
oil (0.337 g, 99% yield), and was immediately placed under
an inert atmosphere and stored at -20 °C. 1H NMR (500 MHz,
CDCl3) δ 7.35-7.30 (m, 4H), 7.27-7.25 (m, 1H), 6.51 (d,
J=14.9 Hz, 1H), 6.00 (d, J=14.9 Hz, 1H), 4.17 (s, 1H), 4.15
(s, 1H), 3.99 (s, 2H), 0.97 (s, 9H), 0.14 (s, 6H). 13C NMR (125
MHz, CDCl3) δ 154.4, 137.3, 129.0, 128.8, 127.5, 125.8, 125.0,
93.6, 37.2, 26.0, 18.4, -4.5. FTIR (thin film) νmax 3030, 2956,
2929, 2857, 1681, 1611, 1566, 1494, 1471, 1453, 1361, 1310,
1253 cm-1. HRMS (EIþ) m/z calcd for C17H26OSiS [M]þ
306.1471, found 306.1476.
added to a solution containing equimolar amounts of the
two dienes at room temperature (Scheme 3). After com-
plete consumption of the dienophile (16 h), 1H NMR analysis
of the mixture revealed a product distribution of 3:1 with
the alkoxy cycloadduct (12) being the major product. This
result indicates that 1-alkylthio-3-silyloxybutadienes (4) are
quite reactive dienes, being approximately three times less
reactive than Danishefsky-type dienes (10). In comparison,
Rawal’s diene was found to be >3000 times more
reactive than Danishefsky’s diene 5 in its cycloaddition with
methacrolein.3b
In summary, an efficient two-step method was deve-
loped for the synthesis of 1-alkylthio-3-silyloxybutadienes
in high yield. These new dienes undergo efficient Diels-
Alder reactions with high endo selectivity to produce highly
functionalized cycloadducts. The sulfide moiety present
in the cycloadducts provides a useful functional handle
for further manipulations. For example, Pummerer,
Stevens, and sigmatropic rearrangements on cyclo-
adduct derivatives can be envisaged. Investigations
along those lines are under way and will be reported in
due course.
Diels-Alder Reaction: 2-(Benzylthio)-4-(tert-butyldimethyl-
silyloxy)-1-methylcyclohex-3-enecarbaldehyde (5). A pressure
vessel containing 1-benzylthio-3-(tert-butyldimethylsilyl-
˚
oxy)-1,3-butadiene (4c) (0.640 g, 2.09 mmol) and 4 A mole-
cular sieves (0.1 g) was equipped with a stir bar and septum.
The vessel was purged with nitrogen prior to the addition of
methacrolein (0.516 mL, 6.26 mmol). The septum was re-
placed with a pressure cap prior to heating the reaction
mixture to 85 °C. After 12 h, the reaction mixture was
transferred to a round-bottomed flask and the excess metha-
crolein was removed in vacuo. The resulting mixture was
filtered through a pad of Celite with use of CH2Cl2, then
concentrated in vacuo to yield a yellow oil (0.757 g, 96% yield)
1
as a mixture of endo/exo isomers (7:1). H NMR (500 MHz,
CDCl3, endo isomer) δ 9.59 (s, 1H), 7.33-7.29 (m, 4H), 7.26-
7.22 (m, 1H), 4.82 (d, J=4.9 Hz, 1H), 3.74 (s, 2H), 3.21 (d, J=
3.6 Hz, 1H), 2.12-2.00 (m, 3H), 1.66-1.60 (m, 1H), 1.08
(s, 3H), 0.96 (s, 9H), 0.13 (s, 3H), 0.12 (s, 3H). 13C NMR
(125 MHz, CDCl3) δ 204.1, 151.9, 138.3, 129.1, 128.7, 127.25,
104.4, 48.3, 46.9, 37.3, 26.3, 26.3, 25.8, 19.6, 18.1, -4.3, -4.3.
FTIR (thin film) νmax 3062, 3029, 2929, 2858, 2712, 1725,
1658, 1602, 1495, 1472, 1454, 1390, 1365, 1342, 1253, 1206,
1071, 1006 cm-1. HRMS (CIþ) m/z calcd for C21H33O2SiS
[M þ H]þ 377.1971, found 377.1981.
Experimental Section
Representative Procedure for the Synthesis of Vinylogous
Thioesters: trans-4-Benzylthio-3-buten-2-one (3c). A 250-mL
round-bottomed flask equipped with a stir bar and septum
was purged with nitrogen and placed in an ice bath. The addi-
tion of trans-4-methoxy-3-buten-2-one (2.04 mL, 20.0 mmol)
was followed by the sequential addition of toluene (67 mL),
benzyl mercaptan (2.47 mL, 21.0 mmol), and p-toluenesul-
fonic acid monohydrate (0.380 g, 2.00 mmol). After 165 min,
the reaction was quenched with saturated aqueous sodium
bicarbonate. The organic layer was decanted and the aqueous
layer was extracted with CH2Cl2 (4ꢀ). The combined organic
layers were dried over sodium sulfate and concentrated in
vacuo. The crude yellow oil was purified by flash column
chromatography on silica gel with 5% EtOAc/toluene as eluent.
The title product was obtained as a yellow oil (2.47 g, 64%
yield). 1H NMR (500 MHz, CDCl3) δ 7.61 (d, J = 15.4 Hz, 1H),
7.37-7.34 (m, 4H), 7.32-7.27 (m, 1H), 6.17 (d, J=15.5 Hz, 1H),
4.04 (s, 2H), 2.19 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 194.4,
146.0, 135.4, 129.0, 128.8, 127.9, 124.2, 36.7, 27.4. FTIR (thin
Silyl Enol Ether Cleavage: 7-(Benzylthio)-2-phenyltetrahydro-
2H-isoindole-1,3,6-(6,H)-trione (8). A vial containing the crude
cycloadduct 7 (156 mg, 0.326 mmol) and stir bar was sealed with
a septum and placed under an atmosphere of nitrogen at 0 °C.
THF (1.30 mL), pyridine (0.326 mL), and pyridine hydrofluor-
ide (0.161 mL, 1.79 mmol) were added sequentially. After 3.5 h,
the reaction had ceased to progress by TLC. A 1:1 mixture of
water and Et2O (2 mL) was added to the reaction mixture. The
organic layer was decanted, and the aqueous layer was extracted
with CH2Cl2 (4 ꢀ 2 mL). The organic layers were combined and
dried over sodium sulfate. The orange solution was concen-
trated under reduced pressure. Flash column chromatography
on silica gel (55% EtOAc/hexanes) afforded the title compound
as a white solid (0.100 g, 84% yield). Mp 171-174 °C. 1H NMR
(500 MHz, CDCl3) δ 7.51 (t, J=7.9 Hz, 2H), 7.44 (t, J=7.9 Hz,
1H), 7.35-7.30 (m, 6H), 7.29-7.25 (m, 1H), 3.87 (d, J=13.3 Hz,
1H), 3.82 (d, J=13.6 Hz, 1H), 3.68 (dd, J=8.8, 4.4 Hz, 1H), 3.48
(dd, J=9.8, 5.4 Hz, 1H), 3.41 (dd, J=18.9, 9.5 Hz, 1H), 2.94 (dd,
J=9.1, 1.6 Hz, 2H), 2.56 (dd, J=18.6, 3.8 Hz, 1H), 2.50 (dd, J=
18.3, 4.8 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 205.3, 177.0,
175.1, 136.6, 131.8, 129.5, 129.2, 129.2, 128.9, 127.8, 126.8, 45.1,
44.3, 39.3, 38.2, 37.1, 36.6. FTIR (thin film) νmax 2930, 2858,
film) νmax 3029, 1661, 1548, 1495, 1454, 1356, 1255 cm-1
.
HRMS (EIþ) m/z calcd for C11H12OS [M]þ 192.0609, found
192.0610.
6408 J. Org. Chem. Vol. 74, No. 16, 2009

Holmes et al.
JOCNote
1782, 1657, 1472, 1362, 1255, 1204, 913, 841, 782, 702. HRMS
(EIþ) m/z calcd for C21H19NO3S [M]þ 365.1086, found 365.1096.
for Innovation, and the University of Saskatchewan for
financial support.
Supporting Information Available: Experimental proce-
dures, characterization data, and NMR spectra for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Acknowledgment. We thank the Natural Sciences and
Engineering Research Council of Canada (Discovery Grant
to M.G. and scholarships to J.M.H.), the Canada Foundation
J. Org. Chem. Vol. 74, No. 16, 2009 6409