Switching the reactivity of dihydrothiopyran-4-one with aldehydes by aqueous organocatalysis: Baylis-Hillman, aldol, or aldol condensation reactions

Article abstract of DOI:10.1021/ol202145w

An aqueous medium containing catalytic amounts of a tertiary amine was employed to direct the chemoselectivity of the reaction of aldehydes with 1a. With DBU, 2 was formed at room temperature as a rare exemplary of Baylis-Hillman reactions in heterocyclic

Full text of DOI:10.1021/ol202145w

ORGANIC
LETTERS
2011
Vol. 13, No. 19
5282–5285
Switching the Reactivity of
Dihydrothiopyran-4-one with Aldehydes
by Aqueous Organocatalysis:
BaylisÀHillman, Aldol, or Aldol
Condensation Reactions†
M. Saeed Abaee,*,§ Mohammad M. Mojtahedi,*,§ Ghasem F. Pasha,§
Elahe Akbarzadeh, Abbas Shockravi, A. Wahid Mesbah,§ and Werner Massa^
Department of Organic Chemistry, Chemistry & Chemical Engineering Research Center
of Iran, P.O. Box 14335-186, Tehran, Iran, Department of Chemistry, Tarbiat Moallem
University, 49, Mofatteh Avenue 1571914911, Tehran, Iran, and Fachbereich Chemie der
Philipps-Universitaet Marburg, Hans-Meerwein-Strasse, D-35032 Marburg, Germany
abaee@ccerci.ac.ir; mojtahedi@ccerci.ac.ir
Received August 8, 2011
ABSTRACT
An aqueous medium containing catalytic amounts of a tertiary amine was employed to direct the chemoselectivity of the reaction of aldehydes
with 1a. With DBU, 2 was formed at room temperature as a rare exemplary of BaylisÀHillman reactions in heterocyclic enones. DABCO alternated
the pathway toward an aldol reaction to form syn/anti mixtures of 3 with the syn isomers being the major products. With Et3N, aldol condensation
dominated.
Since its discovery in the early 1970s, the BaylisÀ
Hillman (BH) reaction1 has received significant attention
from organic chemists due to the ability to produce densely
functionalized molecules from relatively simple starting
materials via an atom-economic one-pot procedure.2 The
BH adducts have found many applications in the synthesis
of natural products,3 bioactive molecules,4 and various
heterocyclic5 and carbocyclic compounds.6 Extensive ef-
forts have been devoted in recent years to overcoming the
(3) (a) Mandal, S. K.; Paira, M.; Roy, S. C. J. Org. Chem. 2008, 73,
3823. (b) Lee, S.; Il.; Hwang, G.-S.; Shin, S. C.; Lee, T. G.; Jo, R. H.;
Ryu, D. H. Org. Lett. 2007, 9, 5087.
(4) (a) Madhavan, S.; Shanmugam, P. Org. Lett. 2011, 13, 1590. (b)
Trost, B. M.; Thiel, O. R.; Tsui, H.-C. J. Am. Chem. Soc. 2002, 124,
11616.
(5) (a) O’Dell, D. K.; Nicholas, K. M. J. Org. Chem. 2003, 68, 6427.
(b) Krishna, P. R.; Kannan, V.; Sharma, G. V. M. J. Org. Chem. 2004,
69, 6467. (c) Kinoshita, H.; Osamura, T.; Kinoshita, S.; Iwamura, T.;
Watanabe, S.-I.; Kataoka, T.; Tanabe, G.; Muraoka, O. J. Org. Chem.
2003, 68, 7532. (d) Back, T. G.; Rankic, D. A.; Sorbetti, J. M.; Wulff,
J. E. Org. Lett. 2005, 7, 2377.
(6) (a) Krafft, M. E.; Haxell, T. F. N.; Seibert, K. A.; Abboud, K. A.
J. Am. Chem. Soc. 2006, 128, 4174. (b) Teng, W.-D.; Huang, R.; Kwong,
C. K.-W.; Shi, M.; Toy, P. H. J. Org. Chem. 2006, 71, 368. (c) Deng,
H.-P.; Wei, Y.; Shi, M. Org. Lett. 2011, 13, 3348.
§ Chemistry & Chemical Engineering Research Center of Iran.
Tarbiat Moallem University.
^ Fachbereich Chemie der Philipps-Universitaet Marburg.
† A version of this work was published in Organic Letters and was
retracted, since it was submitted without the knowledge or permission of
M. Saeed Abaee, who directed the research for this project. See DOI:
10.1021/ol102683j.
(1) (a) Baylis, A. B.; Hillman, M. E. D. Ger. Offen. 2 155 113, 1972;
Chem. Abstr. 1972, 77, 34174. (b) Hillman, M. E. D.; Baylis, A. B. U.S.
Patent 3743669, 1963.
(2) For reviews on BH reactions, see: (a) Singh, V.; Batra, S. Tetra-
hedron 2008, 64, 4511. (b) Basavaiah, D.; Rao, K. V.; Reddy, R. J. Chem.
Soc. Rev. 2007, 36, 1581. (c) Basavaiah, D.; Reddy, B. S.; Badsara, S. S.
Chem. Rev. 2010, 110, 5447. (d) Shi, Y.-L.; Shi, M. Eur. J. Org. Chem.
2007, 2905. (e) Declerck, V.; Martinez, J.; Lamaty, F. Chem. Rev. 2009,
109, 1. (f) Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. Rev. 2003,
103, 811.
(7) Hayashi, Y.; Okado, K.; Ashimine, I.; Shoji, M. Tetrahedron Lett.
2002, 43, 8683.
r
10.1021/ol202145w
Published on Web 09/07/2011
2011 American Chemical Society

inherent low reactivity of enones in BH reactions by the use
of high pressure systems,7 microwave irradiation,8 ultra-
sonic waves,9 nonamine nucleophiles,10 solid-supported
reagents,11 ionic liquids,12 Lewis acids,13 and organo-
catalysts.14 A particular improvement in BH reactions is
gained by employment of aqueous media,15 the conditions
known to boost the selectivity and reactivity of many syn-
thetic organic transformations.16
Another limitation to BH reactions is the parallel com-
petition of aldol reaction/condensation in the case of
substrateswithacidicR hydrogens.17 Moreover, utilization
of heterocyclic enones with an electron-donating nature in
BH reactions has still remained a challenge.2 Because of
our experience on thiopyran heterocyclic systems,18 we
envisaged that enone 1a would be an appropriate probe to
tackle these limitations.19 As a result of our studies, we
hereby disclose the potential of an aqueous organocataly-
tic system that can direct the reaction of 1a with aldehydes
to selectively undergo either BH or aldol reactions. To the
best of our knowledge, this is the first report on BH and
aldol reactions in the dihydrothiopyran-4-one system
(Scheme 1).
A variety of conditions were examined to optimize the
addition of 1a20 to benzaldehyde using different amines
and solvents. The best results were obtained when DBU
was added to an aqueous mixture of the reactants without
organic solvents (Table 1). Under these conditions, cata-
lytic quantities of DBU were effective to obtain 2a within 8
h (entry 1). When other aldehydes bearing electron-with-
drawing groups were used, products 2bÀf were obtained
within the same time period (entries 2À6).
Table 1. BH Reactions of 1a with Aldehydes
entry
Ar
C6H5
product
time (h)
yield (%)a
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
8
4
4
7
6
6
4
2
1
68
73
70
67
72
68
62
60
52
3-FC6H4
4-FC6H4
3-ClC6H4
4-ClC6H4
3-BrC6H4
2-thienyl
2-NO2C6H4
4-CF3C6H4
Scheme 1. Competition of BH and Aldol Reactions in 1a:
Possibilities and Potentials
2g
2h
2i
a Yields of isolated products.
Under the same conditions, aldehydes with a more
electron-deficient nature disappeared faster. However,
they gave lower yields of their respective BH adducts
2hÀi (entries 8À9), due to the effective competition of an
aldolcondensation reaction to giveproductsof type4. This
encouraged us to find the optimized conditions for the
synthesis of 4 as well. Consequently, when we substituted
DBU withDMAP (10%), highyields ofvarious products4
were obtained at room temperature within relatively short
time periods (Table 2). In this case, electron-rich aldehydes
such as 4-MeOC6H4CHO reacted sluggishly giving low
yields of aldol products (entry 12).
(8) Kundu, M. K.; Mukherjee, S. B.; Balu, N.; Padmakumar, R.;
Bhat, S. V. Synlett 1994, 444.
(9) Coelho, F.; Diaz, G.; Abella, C. A. M.; Almeida, W. P. Synlett
2006, 435.
(10) (a) Pereira, S. I.; Adrio, J.; Silva, A. M. S.; Carretero, J. C. J. Org.
Chem. 2005, 70, 10175. (b) Cho, C.-W.; Kong, J.-R.; Krische, M. J. Org.
Lett. 2004, 6, 1337. (c) Zhong, F.; Wang, Y.; Han, X.; Huang, K.-W.; Lu,
Y. Org. Lett. 2011, 13, 1310. (d) del Villar, I. S.; Gradillas, A.;
With these results in hand, we were encouraged to
investigate the feasibility of halting the aldol process before
the dehydration step occurs. The experiments carried out
with other amines in water showed that the use of DABCO
ꢀ
Domınguez, G.; Perez-Castells, J. Org. Lett. 2011, 12, 2418.
´
(11) (a) Zhao, L.-J.; Kwong, C. K.-W.; Shia, M.; Toy, P. H. Tetra-
hedron 2005, 61, 12026. (b) Sheng, S. R.; Wang, Q.; Wang, Q. Y.; Guo,
L.; Liu, X. L.; Huang, X. Synlett 2006, 1887.
(12) (a) Mi, X.; Luo, S.; Xu, H.; Zhanga, L.; Cheng, J.-P. Tetrahedron
2006, 62, 2537. (b) Yunkyung, Y.; Ryu, J.-S. J. Org. Chem. 2010, 75,
4183.
(13) (a) Lee, S. I.; Hwang, G. S.; Ryu, D. H. Synlett 2007, 59. (b) Pan,
W.; Dong, D. W.; Sun, S. G.; Liu, Q. Synlett 2006, 1090. (c) Patel, C.;
Sunoj, R. B. J. Org. Chem. 2010, 75, 359. (d) Bugarin, B.; Connell, B. T.
J. Org. Chem. 2009, 74, 4638.
(14) (a) Kawahara, S.; Nakano, A.; Esumi, T.; Iwabuchi, Y.;
Hatakeyama, S. Org. Lett. 2003, 5, 3103. (b) Wadhwa, K.; Chintareddy,
V. R.; Verkade, J. G. J. Org. Chem. 2009, 74, 6681. (c) Guan, X.-Y.; Wei,
Y.; Shi, M. J. Org. Chem. 2009, 74, 6343. (d) Wang, J.; Li, H.; Yu, X.; Zu,
L.; Wang, W. Org. Lett. 2005, 7, 4293. (e) Berkessel, A.; Roland, K.;
Neudorfl, J. M. Org. Lett. 2006, 8, 4195.
(16) (a) Butler, R. N.; Coyne, A. G. Chem. Rev. 2010, 110, 6302. (b)
Chanda, A.; Fokin, V. V. Chem. Rev. 2009, 109, 725.
(17) Basavaiah, D.; Sreenivasulu, B.; Rao, A. J. J. Org. Chem. 2003,
68, 5983.
(18) (a) Abaee, M. S.; Mojtahedi, M. M.; Zahedi, M. M.; Sharifi, R.;
Khavasi, H. Synthesis 2007, 3339. (b) Abaee, M. S.; Mojtahedi, M. M.;
Zahedi, M. M. Synlett 2005, 2317. (c) Abaee, M. S.; Mojtahedi, M. M.;
Akbari, M.; Mehraki, E.; Mesbah, A. W.; Harms, K. J. Heterocycl.
Chem. 2011in press.
(19) For other synthetic utilities of thiopyran 1a, see: (a) Beye, G. E.;
Ward, D. E. J. Am. Chem. Soc. 2010, 132, 7210. (b) Rosiak, A.; Frey, W.;
Christoffers, J. Eur. J. Org. Chem. 2006, 4044.
(15) (a) Patra, A.; Roy, A. K.; Batra, S.; Bhaduri, A. P. Synlett 2002,
1819. (b) Yu, C.; Liu, B.; Hu, L. J. Org. Chem. 2001, 66, 5413. (c) Luo, S.;
Wang, P. G.; Cheng, J.-P. J. Org. Chem. 2004, 69, 555.
(20) Compound 1a was synthesized according to an available proce-
dure. For details, see: Chen, C. H.; Reynolds, G. A.; Van Allen, J. A.
J. Org. Chem. 1977, 42, 2777.
Org. Lett., Vol. 13, No. 19, 2011
5283

Table 2. Aldol Condensations of 1a with Aldehydes
entry
Ar
product
time (h)
yield (%)a
1
2-thienyl
4g
4h
4i
9
4
87
80
85
62
92
84
75
85
89
82
86
10
2
2-NO2C6H4
4-CF3C6H4
3-NO2C6H4
PhCHdCH
2-furyl
Figure 1. Structure of syn 3s in the crystal. Displacement ellip-
soids at the 50% probability level. Disorder in the thiopyran
ring with alternative conformation (occupation 5.2(4)%) drawn
transparent.
3
4
4
4j
2
5
4k
4l
8
6
8
7
2-ClC6H4
4m
4n
4o
4p
4q
4r
8
8
2,3-Cl2C6H3
2,4-Cl2C6H3
2,6-Cl2C6H3
3-NCC6H4
4-MeOC6H4
8
9
5
10
11
12
8
8
12
a Yields of isolated products.
Table 3. Aldol Reactions of 1a with Aldehydes
yield (%)a
(syn/anti)b
Figure 2. Suggested mechanism: nucleophilicity versus basicity
in enones with R acidic hydrogens.
entry
Ar
product
time (h)
1
2
3
4
5
6
7
8
9
3-ClC6H4
3d
3e
3h
3j
8
4
75 (2:1)
80 (2:1)
85c (4:1)
83 (2:1)
85 (5:1)
80 (3:1)
80 (2:1)
À
4-ClC6H4
2-NO2C6H4
3-NO2C6H4
2,4-Cl2C6H3
4-NO2C6H4
3-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4
In the case of 3t, the minor anti isomer was also separated
and characterized by spectroscopic methods. Under the
same conditions, more electron-rich aldehydes remained
intact (entry 8) or, at elevated temperatures, gave 4(entry9).
To rationalize these observations, two different path-
ways can be envisaged for the reaction of an amine with an
enone like 1a. The amine can either add to the conjugated
CdC site as a Michael donor, a step which is accepted to
occur initially in BH reactions,3,21 or remove the R hydro-
gen of the carbonyl group to trigger the aldol process
(Figure 2). Therefore, it is not surprising if the more
nucleophilic amines end up with the BH adducts, as we
observed for DBU catalyzed reactions. At the other ex-
treme, a bulkier amine such as DABCO could be expected
to show more basicity and would prefer the aldol route.22
4
3o
3s
3t
À
3
4
3
12
10
4r
35d
a Yields of isolated products. b Only the structure of the major syn
stereoisomers is shown here. c 5% DABCO was used. d 50 ꢀC.
directs the process toward selective removal of the proton
of the R methylene group in 1a. Hence, the addition of
electron-deficient aldehydes to enone 1a occurred to give
good to high yields of syn/anti mixtures of 3 (Table 3). 1H
NMR analysis of the mixtures showed preferential forma-
tion of the syn stereoisomers over the anti counterparts in a
ratio ranging from 5:1 to 2:1. It appears from the results
that the stereoselectivity values correspond to the electron
density of the starting aldehydes and grow as the electron
deficiency increases. The syn stereochemistry for the major
products was assigned based on their 1H NMR spectra and
verified by X-ray crystallography of product 3s (Figure 1).
(21) (a) Santos, L. S.; Pavam, C. H.; Almeida, W. P.; Coelho, F.;
Eberlin, M. N. Angew. Chem., Int. Ed. 2004, 43, 4330. (b) Cantillo, D.;
Kappe, C. O. J. Org. Chem. 2010, 75, 8615. (c) Price, K. E.; Broadwater,
S. J.; Jung, H. M.; McQuade, D. T. Org. Lett. 2005, 7, 147.
(22) For a similar analogy on the basicity vs nucleophilicity issue (for
DMAP and DABCO), see: Faltin, C.; Fleming, E. M.; Connon, S. J.
J. Org. Chem. 2004, 69, 6496.
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Org. Lett., Vol. 13, No. 19, 2011

Table 4. BH Reactions of 1b with Aldehydes
Scheme 2. Tandem BH-Aldol Synthesis of 5b and 5x
entry
R
product
time (h)
yield (%)a
only for electron-deficient aryl aldehydes (entries 1À6) but
also for electron-rich aromatic (entry 7) and aliphatic
substrates (entries 8À9).
1
2
3
4
5
6
7
8
9
C6H5
6a
6b
6c
6e
6f
24
18
15
15
15
24
24
15
18
78
75
80
82
75
79
68
80
82
3-FC6H4
4-FC6H4
4-ClC6H4
3-BrC6H4
2-thienyl
4-MeC6H4
Me(CH2)2
Me2CH
In conclusion, by using a nucleophilic amine in an aqu-
eous environment, we accomplished a rare BH reaction
in heterocyclic enone systems, which presumably due to a
lower affinity for conjugate addition have been less prone so
far to undergo BH reactions. To divert the process toward
the alternative aldol pathway, we suppressed the conjugate
addition (the BH route) by choosing a relatively bulkier
amine which shows better basicity, which is required to
initiate the aldol process. Currently, we are extending the
methodology to the synthesis of products of type 5, two of
which are presented in Scheme 2. The application of the
results in similar heterocyclic systems (1; X = NR, O) is
under study and will be reported in due course.
6g
6u
6v
6w
a Yields of isolated products.
If the proposed analogy is valid, one would expect that for
enones with X = CH2 (e.g., 1b, Table 4) the aldol pathway
becomes less important because the stabilizing homoaro-
maticity effect cannot exist for 1b (incontrastto 1a as shown
with A; X = S)23 and thus the enone is expected to be a
relatively better Michael acceptor. Indeed, the spontaneous
rearrangement of the CdC to the endocyclic position in the
aldol condensation products could also be attributed to the
aromaticity of 4 (as depicted for B).
Acknowledgment. The authors would like to thank the
Iran National Science Foundation (INSF-88002449) for
financial support of this work. Dedicated to the late
Professor H. Pirelahi.
To support this idea, BH reactions of cyclohexenone 1b
were evaluated under similar conditions. In the presence of
DBU, DABCO, DMAP, or Et3N the major observed
process was the formation of the BH adducts 6. In this
case, Et3N gave better results and therefore the reactions
were carried out using this amine. This was the case not
Supporting Information Available. Crystallographic
data (excluding structure factors) for 3s have been de-
posited with the Cambridge Crystallographic Data Cen-
tre, CCDC No.841408. Copies of the data can be
obtained free of charge via the Internet at http://www.
ccdc.cam.ac.uk/conts/retrieving.html. Experimental pro-
cedures and spectral data of new compounds available
free of charge via the Internet at http://pubs.acs.org.
(23) Homoaromaticity in the thiopyran system has been pointed out
before: Vessally, E.; Kavian, H.; Arshadi, S.; Pirelahi, H. J. Mol. Struct.
2004, 678, 171.
Org. Lett., Vol. 13, No. 19, 2011
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