An efficient and rapid chalcogenide-Morita-Baylis-Hillman process promoted by TBDMSOTf and a thiolane

Article abstract of DOI:10.1016/j.tetlet.2006.03.070

The ability of the combination of sulfide/TBDMSOTf to promote a chalcogenide-Morita-Baylis-Hillman reaction is reported. The original Michael-Mukaiyama-retroaldol sequence took place and furnished the MBH adducts from the corresponding enones and acetals.

Full text of DOI:10.1016/j.tetlet.2006.03.070

Tetrahedron Letters 47 (2006) 3553–3556
An efficient and rapid chalcogenide-Morita–Baylis–Hillman
process promoted by TBDMSOTf and a thiolane
a
a,
*
`
Jamjanam Srivardhana Rao, Jean-Franc¸ois Briere,
Patrick Metznera,* and Deevi Basavaiahb
aLaboratoire de Chimie Mole´culaire et Thio-organique (UMR CNRS 6507), ENSICaen-Universite´,
6 Boulevard du Mare´chal Juin, F-14050 Caen, France
bSchool of Chemistry, University of Hyderabad, Hyderabad 500 046, India
Received 15 February 2006; revised 8 March 2006; accepted 10 March 2006
Available online 5 April 2006
Abstract—The ability of the combination of sulfide/TBDMSOTf to promote a chalcogenide-Morita–Baylis–Hillman reaction is
reported. The original Michael–Mukaiyama-retroaldol sequence took place and furnished the MBH adducts from the correspond-
ing enones and acetals. This one step process could be performed smoothly at low temperatures (À20 to À50 ꢀC) and is rapidly com-
pleted within a few hours.
ꢁ 2006 Elsevier Ltd. All rights reserved.
The nucleophilic addition of an activated alkene to a
carbonyl group (1 to 2) promoted by either an amine
or a phosphine, namely the Morita–Baylis–Hillman
reaction (MBH), paved the way for a steadily increasing
amount of researches since its discovery.1 A myriad of
papers have been dealing with the chemistry of the ob-
tained a-methylene-b-hydroxycarbonyl compounds as
versatile,2 and chiral synthetic intermediates.3 In that
context, Kataoka and co-workers pioneered research
into the use of both a sulfide and TiCl4, as promoters
of the so-called chalcogenide-MBH.4 This effective dual
Lewis acid–base activation, studied by several groups,5
leads to improved reaction rates under mild conditions.6
This combination takes advantage of weak interactions
between a hard Lewis acid and a soft chalcogenide
Lewis base,7 and can overcome the sluggishness of the
processes often met under regular conditions.8 More-
over, the use of chiral sulfides, engaged in an asymmetric
process, has been envisaged and led to promising
results.9 Nevertheless, the discovery of novel and
improved conditions leading to an effective MBH reac-
tion is still an ongoing endeavour.
We would like to report herein on a domino Michael–
Mukaiyama-retroaldol process,10 promoted by the com-
bination of TBDMSOTf/sulfide as described in Scheme
1. This system provides a formally chalcogenide-MBH
reaction in which every chemical step could be studied
separately.5,11 Indeed, Noyori first demonstrated the
conjugated addition of a silyl selenide to an enone (1
to 3), catalyzed by TMSOTf, to form a silyl enolether
of type 3b. This intermediate was then successfully en-
gaged in the following Mukaiyama-retroaldol reactions
O
O
OMe
Ph
S
1
2
TBDMSOTf
R3N
OTBDMS
O
OMe
Ph
MeO OMe
S
S
OTf
OTf
H
Ph
3a
4
Keywords:
Chalcogenide-Morita–Baylis–Hillman;
TBDMSOTf;
N
SePh
3b
NEt2
3c
SPh
3d
Sulfide; Enone; Acetal.
3e
*
Corresponding authors. Tel.: +33 231 452 886; fax: +33 231 452
877; e-mail addresses: jean-francois.briere@ensicaen.fr; patrick.
metzner@ensicaen.fr
Scheme 1. Chalcogenide-MBH.
0040-4039/$ - see front matter ꢁ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.03.070

3554
J. S. Rao et al. / Tetrahedron Letters 47 (2006) 3553–3556
with acetals (3 to 2).12 Such a process was also proven by
means of silyl amines (via 3c), silyl sulfides (via 3d) and
pyridine (via 3e).13
Although the yield is not quantitative, the 1H NMR
spectrum of the crude product was clean after workup.
(4) Almost an equal amount of the enone and the alde-
hyde was used. This last point is noteworthy as, in most
cases, the MBH reaction requires an excess of either the
aldehyde or the polymerisable enone.2,3 We then varied
the nature of the amine and found that the non-nucleo-
philic 2,6-lutidine gave poor yields in this reaction (entry
6). This base is likely not basic enough to promote the b-
elimination step. On the other hand, by increasing the
However, only one example, published by Kim and co-
workers, stated the ability to carry out the three chemi-
cal steps (1 to 2) with sulfides and the help of both
TBDMSOTf and TMSOTf.14 Unfortunately, in the
aforementioned studies, a sequential addition of re-
agents was usually performed after each step. Further-
more, a nucleophilic base such as DBU, or an
oxidative treatment of the sulfide or selenide intermedi-
ates was required to realise the b-elimination process.
We reasoned that the softness of a sulfide would facili-
tate the addition–elimination steps (1 to 3 and 4 to 2).
Therefore, we undertook this study in order to allow a
domino Michael–Mukaiyama-retroaldol sequence,
using an enone, an acetal and a suitable amine base.
In such an original single-step method, the sulfide pro-
moter would be recycled in situ, and a catalytic and
asymmetric process with chiral sulfides could be
envisaged.9
amount of Hunig’s base and using a somewhat lower
¨
temperature, the yield remained similar after 6 h of reac-
tion (entries 7 and 8). The presence of the base prevents
any residual triflic acid in the reaction media, which
could decompose the crude product, as we observed
sometimes. Moreover, the temperature of the reaction
medium is a crucial point (entry 5). We witnessed a
smooth and complete transformation at À20 ꢀC within
30 min (entry 9). This result proved the fastness of the
three chemical steps and the nice compatibility of all
the components (Scheme 1). The yield of 2 decreased
dramatically at 0 ꢀC (entry 10). A complete conversion
was observed, but the 1H spectrum of the crude product
revealed a complex mixture. With this protocol in hand,
we then sought a process with a catalytic amount of sul-
fide. Using an excess of base (entry 11) or a sterically
more hindered amine (entry 12) did not furnish any
turnover. Although moderate yields were obtained at
À40 ꢀC, the catalytic cycle was demonstrated with
In order to validate the chalcogenide-MBH described in
Scheme 1, we simply mixed all reagents together in one
pot. We also chose a sterically hindered amine such as
the Hunig’s base (Table 1).15 Although a sluggish reac-
¨
tion took place in THF, a smooth process occurred in
more polar acetonitrile (entries 1 and 2). We checked
that the amine did not lead to any reaction in the ab-
sence of sulfide (entry 3). The best results were obtained
in CH2Cl2, affording 2 with 76% yield in only 6 h at
À40 ꢀC (entry 4). So, we have in hand an original chal-
cogenide-MBH process, involving a single-step opera-
0.2 equiv of sulfide and 1 equiv of Hunig’s base (entry
¨
13).
We then investigated the scope and limitations of this
original chalcogenide-MBH protocol with various ace-
tals (Table 2).18 We firstly tested enone derivatives (en-
tries 1–3). Both five- and six-membered rings led to
smooth reactions in only 1 h at À20 ꢀC. Even the highly
polymerisable methyl vinyl ketone afforded the corre-
sponding adduct, in a moderate yield, but without using
excess of enone. The aromatic dimethylacetals bearing
alkyl or halogen groups at the 4-position, turned out
to be good substrates for the chalcogenide-MBH reac-
tion with cyclohexenone (entries 4–6). Acetal acceptors
displaying strongly electron-withdrawing (entries 7 and
tion, with
a resident acetal and a
base,4b and
promoted by TBDMSOTf.16 Moreover, the cascade
reactions proceed in very mild conditions.8 We verified
that the reaction did not take place at lower temperature
(entry 5). At this early stage of optimisation, several
observations have to be pointed out: (1) No reaction
took place with benzaldehyde. More reactive acetals,
as oxonium precursors, are required to react with the
enol silylether 3a.17 (2) The base has to be the last re-
agent added for the success of the procedure. (3)
Table 1. Optimisation of the chalcogenide-MBH reaction to give 2 according to Scheme 1a
Entry
R3N (equiv)
Thiolane (equiv)
Time (h)
Solvent, T (ꢀC)
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
i-Pr2EtN (1)
i-Pr2EtN (1)
i-Pr2EtN (1)
i-Pr2EtN (1)
i-Pr2EtN (1)
2,6-Lutidine (1)
i-Pr2EtN (1.5)
i-Pr2EtN (1.5)
i-Pr2EtN (1.5)
i-Pr2EtN (1.5)
i-Pr2EtN (1.5)
Cy2EtN (1)
1.1
1.1
—
6
6
6
6
6
6
6
1
0.5
0.5
1
6
6
THF, À40
Traces
66
—
76
—
37
71
25
81
37
21
Traces
42
MeCN, À40
MeCN, À40
CH2Cl2, À40
CH2Cl2, À78
CH2Cl2, À40
CH2Cl2, À50
CH2Cl2, À50
CH2Cl2, À20
CH2Cl2, 0
1.1
1.1
1.1
1.1
1.1
1.1
1.1
0.2
0.2
0.2
CH2Cl2, À20
CH2Cl2, À40
CH2Cl2, À40
i-Pr2EtN (1)
a Reaction conditions: 2-cyclohexen-1-one (0.5 mmol), PhCH(OMe)2 (1.1 equiv), thiolane, TBDMSOTf (1.4 equiv), R3N, solvent (2 mL).
b Isolated yield based on the cyclohexenone.

J. S. Rao et al. / Tetrahedron Letters 47 (2006) 3553–3556
Table 2. The chalcogeno MBH reaction with various substratesa
3555
on an acetal, in the presence of TMSOTf, to form a sul-
fonium of type 6 (Scheme 2).20 To monitor the possible
formation of such intermediates, we carried out the fol-
lowing NMR experiments. First of all, we mixed cycloh-
exenone (1 equiv), TBDMSOTf (1.4 equiv) and thiolane
(1.1 equiv) in CD2Cl2 and recorded the 1H NMR at
À50 ꢀC (solution A). Indeed, the cyclohexenone 1 was
rapidly equilibrated with the corresponding sulfonium
salt 3a to afford a ratio of 39:61 (1:3a).21 We warmed
up the NMR tube and observed that only traces of the
sulfonium salt 3a remained at À20 ꢀC. This stressed that
the aldolisation step gives a rapid formation of 4 at
À20 ꢀC (vs À50 ꢀC), and consumes intermediate 3a,
which is present at low concentration.21 These condi-
tions provide indeed very short reaction times (Table
2; entries 1–6). However, with more shielded or less reac-
tive acetals (Table 2; entries 7–14), it seems desirable to
have a higher concentration of the enol intermediate 3a
at À50 ꢀC. We also mixed, in a NMR tube, the dimethyl-
acetal of benzaldehyde and thiolane in the presence of
TBDMSOTf (Scheme 2). The sulfonium salt 6 was rap-
idly and completely formed at À50 ꢀC (solution B). The
cyclohexenone was subsequently added to 6 in solution
B. In a parallel experiment, we added the dimethyl acetal
of benzaldehyde to intermediate 3a in solution A at
À50 ꢀC. In both cases, we obtained the same NMR spec-
trum, which was compatible with the aldol adduct 4.
The exact interpretation of the numerous signals, likely
due to a mixture of diastereoisomers, was not straight-
forward. Nevertheless, these experiments show that a
sulfonium salt 6 could be involved either directly, or
as a precursor of the oxonium 7, in such a process.
O
O
OMe
R3
S
(1 equiv)
MeO OMe
R1
R2
R1
R2
H
R3
TBDMSOTf, i-Pr2EtN
CH2Cl2 -20 °C, 1 h
,
Entry
Enone (R1; R2)
Acetal (R3)
Yield (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
(CH2)2
(CH2)
Ph
Ph
Ph
80
71
55
66
66
83
Me; H
(CH2)2
(CH2)2
(CH2)2
(CH2)2
(CH2)2
(CH2)2
(CH2)2
(CH2)2
(CH2)2
(CH2)2
(CH2)2
4-MeC6H4
4-ClC6H4
4-FC6H4
4-CF3C6H4
4-CF3C6H4
4-MeOC6H4
4-MeOC6H4
2-MeC6H4
2-MeOC6H4
PhCH@CH
PhCH2CH2
33
65c
26
39c
45c
21c
64c
—
a Reaction conditions: enone (0.5 mmol), acetal (1.1 equiv), thiolane
(1.1 equiv), TBDMSOTf (1.4 equiv), i-Pr3EtN (1.5 equiv), CH2Cl2
(2 mL), À20 ꢀC, 1 h.
b Isolated yield.
c This reaction has been performed at À50 ꢀC for 6 h.
8) or donating groups (entries 9 and 10) gave better re-
sults at À50 ꢀC. This reaction is also sensitive to steric
hindrance as 2-substituted acetals tended to give lower
yields (entries 11 and 12). Although a complex mixture
was obtained at À20 ꢀC, we were pleased to find that
the acetal of the (E)-cinnamaldehyde afforded the corre-
sponding bis-allylic ether at À50 ꢀC (entry 13). Unfortu-
nately, the aliphatic acetals did not undergo any
chalcogenide-MBH reaction with these conditions (en-
try 14).
In summary, we have reported on an alternative chalco-
genide-Morita–Baylis–Hillman reaction requiring an
equal amount of both an enone and an acetal. This pro-
cess proceeds via a rapid Michael–Mukaiyama-retro-
aldol sequence, conveniently promoted by mixing a
sulfide, TBDMSOTf in the presence of the Hunig’s base.
¨
We wondered about the nature of the intermediates
going on in this process. It has been shown by Kim14
and others19 that the dimethyl sulfonium salt of type
3a, resulting from the addition of dimethyl sulfide to
cyclohexenone in the presence of TBDMSOTf, is rapidly
formed at À78 ꢀC (Scheme 1). This salt would slowly re-
verse to cyclohexenone between À45 and À20 ꢀC. In our
conditions, we did not obtain any product between the
silyl enolether 3a and benzaldehyde regardless of the
temperature. So, one could think that the more reactive
oxonium species 7 (Scheme 2), resulting from the resi-
dent acetal and the excess of TBDMSOTf, would be in-
volved in the Mukaiyama aldolisation step (3a to 4;
Scheme 1). The lack of reactivity of the hindered silyl-
enolether 3a would also explain the absence of reaction
at À78 ꢀC. On the other hand, a sulfide is capable to add
These conditions furnished the products in very mild
conditions (À20 to À50 ꢀC) and reasonably short times
(30 min to 6 h). Studies are in progress to render this
original process practically catalytic in sulfide and even-
tually asymmetric.
Acknowledgements
We gratefully acknowledge financial support from the
`
‘Ministere de la Recherche’, CNRS (Centre National
´
de la Recherche Scientifique), the ‘Region Basse-Nor-
mandie’ and the European Union (FEDER funding).
We also thank CEFISO/IFCOS (France–India network)
for support. We are grateful for CNRS who provided a
grant.
OMe
OMe
Ph
MeO OMe
Ph
References and notes
CD2Cl2,-50 ºC
?
OTf
S
Ph
H
S
1.4 TBDMSOTf
- MeOTBS
OTf
1. (a) Morita, K.; Suzuki, Z.; Hirose, H. Bull. Chem. Soc.
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German Patent 2155113, 1972; Chem. Abstr. 1972, 77,
34174q.
1.1 equiv
5
6
7
Scheme 2. Intermediates in the chalcogenide-MBH.

3556
J. S. Rao et al. / Tetrahedron Letters 47 (2006) 3553–3556
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5. For a recent exhaustive review covering this field of
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15. A typical procedure for the preparation of the 2-[meth-
oxy(phenyl)methyl]-2-cyclohexen-1-one (2): In a 10 mL
Schlenk flask, 2-cyclohexen-1-one 1 (50 lL, 0.50 mmol),
benzaldehyde dimethyl acetal (83 lL, 0.55 mmol,
1.1 equiv), tetrahydrothiophene (48 lL, 0.55 mmol,
1.1 equiv) and TBDMSOTf (161 lL, 0.7 mmol, 1.4 equiv)
were added to dry CH2Cl2 (2 mL) at À20 ꢀC under N2
atmosphere. Subsequently, a freshly distilled i-Pr2NEt
(131 lL, 0.75 mmol, 1.5 equiv) was added to the mixture.
The solution was stirred for 1 h at À20 ꢀC (until no
cyclohexenone was left as shown on TLC). The resulting
mixture was poured into water (5 mL) and extracted with
CH2Cl2 (2 · 5 mL). The organic layers were combined,
dried over MgSO4 and concentrated in vacuo. The crude
product was purified by column chromatography on silica
gel (AcOEt/pentane: 7/93, Rf = 0.4) to yield 2 (86 mg,
6. For an example of highly effective Chalcogenide-MBH
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Chem., Int. Ed. 2003, 42, 5054.
7. For selected recent examples making use of Lewis acids,
see: (a) Yamada, Y. M. A.; Ikegami, S. Tetrahedron Lett.
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A.; Willams, R. J. Org. Chem. 2002, 67, 510; (c) Li, G.;
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Headley, A. D. Org. Lett. 2003, 5, 329; (d) Yang, K.-S.;
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915; (e) Matsui, K.; Takizawa, S.; Sasai, H. Tetrahedron
Lett. 2005, 46, 1943; (f) Shiina, I.; Yamai, Y.-S.; Shima-
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8. For selected recent examples dealing with the reaction
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Org. Chem. 2003, 68, 692; (b) Maher, D. J.; Connon, S. J.
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1
80%) as a colourless oil. IR (neat): 1670 cmÀ1; H NMR
(250 MHz, CDCl3): 1.85–2.10 (m, 2H), 2.25–2.53 (m, 4H),
3.30 (s, 3H), 5.26 (s, 1H), 7.01 (t, 1H, J = 4.1 Hz), 7.15–
7.40 (m, 5H). 13C NMR (62.5 MHz, CDCl3): 22.59, 25.74,
38.38, 57.00, 78.21, 127.05, 127.45, 128.23, 140.49, 140.54,
145.68, 197.82. HRMS Anal. Calcd for C14H16O2Na:
239.1048. Found: 239.1055.
16. It has been shown that the reaction could be promoted by
TMSOTf or TESOTf in almost the same efficiency. But,
the yields were highly dependent upon the quality of these
air sensitive reagents.
17. For an excellent review discussing the reactivity of acetals
towards silyl enolethers, see: Dilman, A. D.; Loffe, S. L.
Chem. Rev. 2003, 103, 733.
18. The acetals were either commercially available or prepared
following a literature procedure, see: Leonard, N. M.;
Oswald, M. C.; Freiberg, D. A.; Nattier, B. C.; Smith, R.
C.; Mohan, R. S. J. Org. Chem. 2002, 67, 5202.
19. Lee, K.; Kim, H.; Miura, T.; Kiyota, K.; Kusama, H.;
Kim, S.; Iwasawa, N.; Lee, P. H. J. Am. Chem. Soc. 2003,
125, 9682.
9. (a) Kataoka, T.; Iwama, T.; Tsujiyama, S.-I.; Kanematsu,
K.; Iwamura, T.; Watanabe, S.-I. Chem. Lett. 1999, 257;
(b) Walsh, L. M.; Winn, C. L.; Goodman, J. M.
Tetrahedron Lett. 2002, 43, 8219.
10. For recent reviews, see: (a) Tietze, L. F. Chem. Rev. 1996,
96, 115; (b) Pellissier, H. Tetrahedron 2006, 62, 1619, and
references cited therein.
20. Kim, S.; Lee, S.; Park, J. H. Bull. Korean Chem. Soc. 1993,
14, 654.
11. For recent discussions about the mechanism, see: (a)
Santos, L. S.; Pavam, C. H.; Almeida, W. P.; Coelho, F.;
Eberlin, M. N. Angew. Chem., Int. Ed. 2004, 43, 4330; (b)
Aggarwal, V. K.; Fulford, S. Y.; Lloyd-Jones, G. C.
21. This equilibrium is established within minutes and sharply
dependent upon the temperature. For instance, a 23:77
1
ratio of 1 versus 3a was recorded by H NMR at À55 ꢀC,
and 68:32 (1:3a) at À40 ꢀC.