Evaluating the Baylis-Hillman reaction of cyclic enones using surfactants in water

Article abstract of DOI:10.1055/s-2005-921890

Conjugated cyclic enones react smoothly in water with a variety of aldehydes (Baylis-Hillman reaction) in the presence of surfactants above their critical micelle concentrations (CMC). Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-921890

LETTER
2923
Evaluating the Baylis–Hillman Reaction of Cyclic Enones Using Surfactants in
Water
B
aylis–HillmanR
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eactionof
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yclic
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none
i
s
U
sing
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urfactants inWater Porzelle, Craig M. Williams,* Brett D. Schwartz, Ian R. Gentle
School of Molecular and Microbial Sciences, University of Queensland, Brisbane, 4072, Queensland, Australia
Fax +61(7)33654299; E-mail: c.williams3@uq.edu.au
Received 24 August 2005
prenyl (1)] would reside in the hydrophobic region of the
Abstract: Conjugated cyclic enones react smoothly in water with a
variety of aldehydes (Baylis–Hillman reaction) in the presence of
surfactants above their critical micelle concentrations (CMC).
surfactant allowing the enone portion of cyclohexenone 1
(Scheme 1) to reside in the water phase. Furthermore,
additional stabilization of the reaction intermediates could
be provided by the polar head group of the surfactant,
whether it be anionic or cationic (Figure 1). In order to test
this hypothesis one example of an anionic [sodium
dodecyl sulfate (SDS)], cationic [cetyl trimethyl ammoni-
um bromide (CTAB)] and neutral [a-octyl-glucoside
(Oct-Glc)]13 surfactant was investigated using the con-
version of 1 to 2 as a model system (Table 1).
Key words: Baylis–Hillman reaction, cyclic enones, surfactant,
green chemistry, aldehydes, aqueous media
Organic reactions that can be performed in water offer
many environmental and economical benefits, not to
mention reactivity enhancement in some cases.1 However,
a failing of water as a solvent is the inability to solubilize
many organic reactants and reagents. To circumvent this
problem surfactants have been employed, most common-
ly in the form of micellar dispersions,2 and as such have
been utilized in organic synthesis, although sparingly.3 In
the course of synthesizing the core of vibsanin E,4 we
utilized the El Gaïed5 Baylis–Hillman6 protocol to access
cyclohexenone 2 (Scheme 1, Table 1). Even though this
protocol was superior to other methods7–9 yields were less
than satisfactory.10 Considering, however, that compound
2 was required for other investigations,11 we initiated a
study into improving Baylis–Hillman conditions in the
hope of a broad application.
O
O
base
OH
H2O, CH2O
surfactant
r.t., 16 h
1
2
Scheme 1
The test system conditions further differed from the orig-
inal system4 in that only water was used as solvent and
reactions were only conducted at room temperature. For
each surfactant the concentration was chosen to be above
the critical micelle concentration (CMC) but below the
point where phases other than spherical micellar may
become possible, or where phase separation at the purifi-
cation stage may become problematic.14
As expected the absence of a surfactant gave only trace
amounts of 2 (entry 1), whereas SDS (entry 2), CTAB
(entry 3) and Oct-Glc (entry 4) gave 85%, 39% and 70%
yield, respectively, on small scale (Table 1). Increasing
the scale showed that both the anionic and neutral surfac-
tants were behaving similarly. For comparative purposes
imidazole in sodium hydrogencarbonate solution was
investigated (entries 5–8, Table 1). In this instance yields
were generally lower and reaction times much longer, but
interestingly, the cationic surfactant (CTAB) gave the best
results, most likely due to the counterion exchange of
bromide for hydrogencarbonate.
Figure 1
Due to the zwitterionic nature of Baylis–Hillman reaction
intermediates12 and the lipophilic properties of cyclohex-
enone 1, we surmised that a surfactant in water may well
provide the ideal reaction medium to satisfy both
requirements. For example, it could be imagined that the
lipophilic cyclohexyl ring and/or side chains [i.e. homo-
In the view that SDS offers zwitterionic charge stabiliza-
tion (Figure 1) and is readily available, we applied the
newly discovered conditions (i.e. SDS, H2O, DMAP) to a
range of cyclic enones (Table 2 and Table 3, Scheme 2).
In the case of reaction with formaldehyde (Table 2) cyclo-
hexenone (entry 1) gave comparable or slightly lower
yields to those reported.5,7,9,17 However, the reaction rate
SYNLETT 2005, No. 19, pp 2923–2926
Advanced online publication: 27.10.2005
DOI: 10.1055/s-2005-921890; Art ID: D25505ST
© Georg Thieme Verlag Stuttgart · New York
0
1
.1
2
.2
0
0
5

2924
A. Porzelle et al.
LETTER
As expected 3-methylcyclohexenone did not react, but for
reasons unknown cyclopentenone and cycloheptenone
resulted in complete consumption of starting material
with very little or no product formation.
Table 1 Evaluating the Baylis–Hillman Reaction of 1 with Formal-
dehyde Using Surfactants under Various Conditions15
Entry Base
(1 equiv)
Solvent
Surfactant Temp Yield
(10 mol%)a
(%)b
1
2
DMAP
DMAP
H2O
H2O
None
r.t
r.t
Trace
O
OH
R1
O
O
85c (70),d
(63)e
a
SDS
n
n
R1
H
R
R
R
R
3
4
5
6
7
8
DMAP
DMAP
H2O
H2O
CTAB
Oct-Glc
None
r.t
r.t
r.t
r.t
r.t
r.t
39c (53)d
70c (67)d
Trace
40c
5a R1 = 4-NMe2-Ph
5b R1 = 4-OMe-Ph
5c R1 = 4-Br-Ph
5d R1 = 4-NO2-Ph
5e R1 = C6H11
5f R1 = CH=CHPh
6a R = H, R1 = 4-NMe2-Ph
6b R = H, R1 = 4-OMe-Ph
6c R = H, R1 = 4-Br-Ph
6d R = H, R1 = 4-NO2-Ph
6e R = H, R1 = C6H11
6f R = H, R1 = CH=CHPh
6g R = CH3, R1 = CH=CHPh
6h R = H, n-1, R1 = 4-NO2-Ph
3a R = H
3c R = CH3
3d R = H, n-1
f
f
f
f
Imidazole 1 M NaHCO3
Imidazole 1 M NaHCO3
Imidazole 1 M NaHCO3
Imidazole 1 M NaHCO3
SDS
CTAB
Oct-Glc
65c
55c
Scheme 2 Reagents and conditions: a) ratio enone/aldehyde =
1:1.1, DMAP (1 equiv), SDS (0.1 equiv), H2O, r.t., 16 h, 20–78%.
a Total surfactant concentration 0.05 M.
b Isolated yield.
c 40-mg scale.
Table 3 Baylis–Hillman Reaction of Cyclic Enones with Various
d 100-mg scale.
Aldehydes18,19
e 1-g scale.
f NaHCO3/formalin (1:1, v/v).
Entry
Enone
3a
Aldehyde Product
Yield (%)a
0
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
6a
6b
6c
6d
6e
6f
increase was quite significant. For example, in our case
(the applied standard conditions are 10 mol% of surfac-
tant, 1 equiv of base, ratio of enone/aldehyde is approxi-
mately 1:14) reaction was over in less than 1 hour as
compared to multiple hours or more commonly days.
Decreasing the amount of N,N-dimethylaminopyridine
(DMAP, entry 3) to 50 mol% gave a slight reduction in
yield and the use of imidazole instead of DMAP lowered
the yield considerably.
3a
43,b 20
3a
71,b,c 27c
61,b 68, (69)b9
78,b 31
3a
3a
3a
73,b 78
3b
5f
6g
6h
44,b 39
Table 2 Baylis–Hillman Reaction of Cyclohexenones with
3c
5d
65,b 54
Formaldehyde16
48–909,20
Entry
1
Enone
Product
Yield (%)a
a Isolated yield.
b Enone (3 equiv).
c SDS (25 mol%).
65
O
OH
OH
OH
O
58b
63c
Other than 4-N,N-dimethylaminobenzaldehyde (entry 1),
4-methoxy- (entry 2), 4-bromo- (entry 3) and 4-nitrobenz-
aldehydes reacted smoothly, as did cyclohexyl- (entry 5)
and cinnamylaldehyde (entry 6) (Table 3). It was found in
some cases (entries 3 and 5), however, that isolated yields
could be more than doubled if three equivalents of enone
were used (Table 3).
4a
3a
2
3
0a
O
O
3b
4b
70a
68c
45d
O
O
In conclusion we have demonstrated that the use of
surfactants allows the Baylis–Hillman reaction to be
performed without the use of organic co-solvents and at
room temperature with observable reaction rate increases.
This procedure is more likely to be applicable to enones
that have high lipophilicity and as such could be utilized
at later stages of target orientated synthesis.
3c
4c
a Isolated yield.
b DMAP (50 mol%).
c Oct-Glc (10 mol%).
d Imidazole (1 equiv), 72 h.
Synlett 2005, No. 19, 2923–2926 © Thieme Stuttgart · New York

LETTER
Baylis–Hillman Reaction of Cyclic Enones Using Surfactants in Water
2925
quenched with brine (1 mL) and extracted with EtOAc (2 × 3
mL). The combined organic layers were dried (MgSO4) and
concentrated in vacuo. Then the residue was purified by
column chromatography (PE–EtOAc 2:1, Rf = 0.33) to give
2 (39 mg, 85%) as a colorless liquid.
Acknowledgment
The authors thank The University of Queensland for financial sup-
port.
B) Representative Procedure for Reactions with
Formalin and Imidazole.
References
To a mixture of 1 M NaHCO3 (200 mL) and 1 (40 mg, 0.208
mmol) were added CTAB (8 mg, 0.02 mmol) and imidazole
(14 mg, 0.2 mmol). After stirring for 15 min formalin (200
mL) was added and stirred for 16 h at r.t. The mixture was
then quenched with brine (1 mL) and extracted with EtOAc
(2 × 3 mL). The combined organic layers were dried
(MgSO4) and concentrated in vacuo. The residue was
purified by column chromatography (PE–EtOAc 2:1,
Rf = 0.33) to give 2 (30 mg, 65%) as a colorless liquid.
(16) Representative Procedure for Reactions with Formalin
and DMAP.
To a mixture of H2O (3 mL) and of dimethylcyclohexenone
(372 mg, 3 mmol) were added SDS (80 mg, 0.3 mmol) and
DMAP (366 mg, 3 mmol). After stirring for 15 min formalin
(3 mL) was added and stirred for 45 min at r.t. The mixture
was then quenched with brine (5 mL) and extracted with
EtOAc (2 × 10 mL). The combined organic layers were
dried (MgSO4) and concentrated in vacuo. The residue was
purified by column chromatography (PE–EtOAc 2:1,
Rf = 0.36) to give 2-(hydroxymethyl)-4,4-dimethylcyclo-
hex-2-enone (4c, 305 mg, 67%) as a colorless liquid.
(17) We were unable to obtain the reported yield (99%, ref. 8).
(18) Representative Procedure for Reactions with Various
Aldehydes in Water.
(1) (a) Organic Syntheses in Water; Grieco, P. A., Ed.; Blackie
Academic and Professional: London, 1998. (b) Li, C.-J.;
Chan, T.-H. Organic Reactions in Aqueous Media; John
Wiley and Sons: New York, 1997. (c) Klijn, J. E.; Engberts,
J. B. F. N. Nature (London) 2005, 435, 746.
(2) (a) Barnes, G. T.; Gentle, I. R. Interfacial Science: An
Introduction; Oxford University Press: Oxford, 2005.
(b) Fendler, J. H.; Fendler, E. J. Catalysis in Micellar and
Macromolecular Systems; Academic Press: London, 1975.
(3) See for example: (a) Manabe, K.; Mori, Y.; Wakabayashi,
T.; Nagayama, S.; Kobayashi, S. J. Am. Chem. Soc. 2000,
122, 7202; and references therein. (b) Tian, H.-Y.; Li, H.-J.;
Chen, Y.-J.; Wang, D.; Li, C.-J. Ind. Eng. Chem. Res. 2002,
41, 4523; and references therein.
(4) Heim, R.; Wiedemann, S.; Williams, C. M.; Bernhardt, P. V.
Org. Lett. 2005, 7, 1327.
(5) Rezgui, F.; El Gaïed, M. M. Tetrahedron Lett. 1998, 39,
5965.
(6) (a) Baylis, A. B.; Hillman, M. E. D. German Patent
2,155,113, 1972; Chem. Abstr. 1972, 77, 341174q.
(b) Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. Rev.
2003, 103, 811.
(7) Gatri, R.; El Gaïed, M. M. Tetrahedron Lett. 2002, 43, 7835.
(8) Aggarwal, V. K.; Dean, D. K.; Mereu, A.; Williams, R. J.
Org. Chem. 2002, 67, 510.
To a mixture of H2O (6 mL) and cyclohexenone (300 mg, 3
mmol) were added SDS (80 mg, 0.3 mmol) and DMAP (366
mg, 3 mmol). After stirring for 15 min, p-nitrobenzaldehyde
(538 mg, 3.6 mmol) was added and stirring continued for 16
h at r.t. The mixture was then quenched with brine (5 mL)
and extracted with EtOAc (2 × 10 mL). The combined
organic layers were dried (MgSO4) and concentrated in
vacuo. The residue was purified by column chromatography
(PE–EtOAc 2:1, Rf = 0.36) to give 2-[(4-nitrophenyl)(hy-
droxy)methyl]cyclohex-2-enone (6d, 500 mg, 68%) as a
yellow syrup.
(9) Luo, S.; Wang, P. G.; Cheng, J.-P. J. Org. Chem. 2004, 69,
555.
(10) Isolated yield 32%. Yield based on starting material
recovery, 43%.
(11) Tilly, D. P.; Williams, C. M.; Bernhardt, P. V. Org. Lett.,
accepted.
(12) Santos, L. S.; Pavam, C. H.; Almeida, W. P.; Coelho, F.;
Eberlin, M. N. Angew. Chem. Int. Ed. 2004, 43, 4330.
(13) Experimental Procedure.
To a solution of glucose (3.6 g, 20 mmol) in 1-octanol (200
mL) was added TMSCl (20 mL) and the reaction mixture
stirred for 3 d at r.t. The mixture was then diluted with
CH2Cl2 (200 mL) and extracted with brine (2 × 100 mL).
The combined organic layers were then evaporated (CH2Cl2)
and concentrated under high vacuum. The residue was
further purified by column chromatography (CHCl3–MeOH
5:1, Rf = 0.3) to yield a-octylglucoside (3 g, 50%) as a white
solid (ratio a/b = 6:1). 1H NMR (400 MHz, MeOD): d = 4.72
(d, 0.86 H, J = 3.76 Hz, H-a), 4.20 (d, 0.14 H, J = 7.80 Hz,
H-b). Ratio of a/b anomers were determined by 1H NMR. 1H
NMR data matched those in the literature. See:
(a) Straathof, A. J. J.; Romein, J.; van Rontwijk, F.;
Kieboom, A. P. G.; van Beekum, H. Starch/Staerke 1987,
39, 362. (b) Straathof, A. J. J.; van Beekum, H.; Kieboom,
A. P. G. Starch/Staerke 1988, 40, 229. (c) Brown, G. M.;
Dubreuil, P.; Ichhaporia, F. M.; Desnoyers, J. E. Can. J.
Chem. 1970, 48, 2525.
(19) Spectroscopic Data for New Compounds.
Compound 4c: 1H NMR (400 MHz, CDCl3): d = 1.17 (s, 6
H), 1.86 (t, 2 H, J = 6.7 Hz), 2.48 (t, 2 H, J = 6.7 Hz), 3.00
(br s, 1 H), 4.21 (s, 2 H), 6.63 (s, 1 H). 13C NMR: d = 27.7,
32.7, 34.5, 35.8, 61.5, 135.0, 155.8, 200.3. MS (EI):
m/z (%) = 154 (25) [M+], 139 (26), 136 (8), 125 (37), 121
(17), 111 (22), 97 (24), 79 (29), 69 (30), 57 (20), 55 (41), 43
(100). HRMS: m/z calcd for C9H14O2: 154.0994; found:
154.0993.
Compound 6c: 1H NMR (400 MHz, CDCl3): d = 1.93–1.96
(m, 2 H), 2.33–2.41 (m, 4 H), 3.58 (br s, 1 H), 5.45 (s, 1 H),
6.72–6.74 (m, 1 H), 7.18–7.20 (m, 2 H), 7.40–7.42 (m, 2 H).
13C NMR: d = 22.4, 25.7, 38.4, 71.7, 121.2, 128.2, 131.3,
140.7, 140.9, 147.5, 200.2. MS (EI): m/z (%) = 282 (38)
[M+], 281 (58), 280 (42) [M+], 279 (51), 264 (2), 262 (2), 236
(2), 219 (2), 208 (13), 206 (12), 202 (15), 201 (100), 195 (3),
185 (25), 183 (23), 169 (1), 157 (12), 155 (28), 145 (15), 131
(10), 129 (10), 128 (14), 125 (13), 123 (19), 116 (16), 97
(17), 96 (40), 95 (19), 79 (11), 78 (19), 77 (61). HRMS: m/z
calcd for C13H13BrO2: 280.0099; found: 280.0104 for (79Br).
Compound 6f: 1H NMR (400 MHz, CDCl3): d = 1.95–2.01
(m, 2 H), 2.37–2.47 (m, 4 H), 3.40 (br s, 1 H), 5.06 (d, 1 H,
J = 5.9 Hz), 6.29 (dd, 1 H, J = 6.3, 15.9 Hz), 6.62 (d, 1 H,
J = 15.9 Hz), 6.97 (t, 1 H, J = 4.2 Hz), 7.19–7.37 (m, 5 H).
13C NMR: d = 22.5, 25.7, 38.5, 71.6, 126.5, 127.6, 128.6,
(14) Rosen, M. J. Surfactants and Interfacial Phenomena, 3rd ed;
John Wiley and Sons: New York, 2004.
(15) A) Representative Procedure for Reactions with
Formalin and DMAP.
To a mixture of H2O (200 mL) and 1 (40 mg, 0.208 mmol)
were added SDS (6 mg, 0.02 mmol) and DMAP (25 mg, 0.2
mmol). After stirring for 15 min formalin (200 mL) was
added and stirred for 16 h at r.t. The mixture was then
Synlett 2005, No. 19, 2923–2926 © Thieme Stuttgart · New York

2926
A. Porzelle et al.
LETTER
129.6, 130.6, 136.6, 140.2, 147.0, 200.3. MS (EI): m/z (%) =
228 [M+] (43), 210 (12), 200 (10), 182 (5), 172 (11), 167 (5),
153 (5), 137 (17), 131 (12), 128 (15), 124 (19), 123 (18), 115
(23), 105 (18), 104 (17), 103 (18), 96 (100), 95 (21), 91 (37),
77 (37). HRMS: m/z calcd for C15H16O2: 228.1150; found:
228.1151.
15.9 Hz), 6.60 (m, 2 H), 7.38–7.19 (m, 5 H). 13C NMR: d =
27.6, 27.8, 32.9, 34.9, 35.6, 71.7, 126.5, 127.6, 128.5, 129.6,
130.8, 136.6, 136.8, 155.8, 200.2. MS (EI): m/z (%) = 256
[M+] (29), 223 (5), 201 (16), 200(100), 181 (5), 172 (28),
165 (5), 158 (5), 151 (14), 137 (11), 131 (22), 124 (29), 115
(18), 109 (35), 104 (20), 91 (33), 77 (30). HRMS: m/z calcd
for C17H20O2: 256.1463; found: 256.1458.
Compound 6g: 1H NMR (400 MHz, CDCl3): d = 1.17 (s, 6
H), 1.84 (t, 2 H, J = 6.7 Hz), 2.47 (t, 2 H, J = 6.7 Hz), 3.30
(br s, 1 H), 5.00 (d, 1 H, J = 5.9 Hz), 6.26 (dd, 1 H, J = 6.3,
(20) For a non-aqueous comparison, see: You, J.; Xu, J.;
Verkade, J. G. Angew. Chem. Int. Ed. 2003, 42, 5054.
Synlett 2005, No. 19, 2923–2926 © Thieme Stuttgart · New York