Asymmetric Morita-Baylis-Hillman reaction catalyzed by simple amino alcohol derived thioureas

Article abstract of DOI:10.1055/s-2007-984882

Thioureas straightforwardly derived from commercially available enantiopure amino alcohols have been found to promote the asymmetric Morita-Baylis-Hillman reaction of 2-cyclohexen-1-one and different aldehydes in the presence of triethylamine under solven

Full text of DOI:10.1055/s-2007-984882

2106
LETTER
Asymmetric Morita–Baylis–Hillman Reaction Catalyzed by Simple Amino
Alcohol Derived Thioureas
A
symmetric Morit
l
a–Bayl
e
is–Hillma
n
s
Reaction
s
Catalyzed
a
by Simple
n
Thioureas dra Lattanzi*
Dipartimento di Chimica, Università di Salerno, Via Ponte don Melillo, 84084, Fisciano, Italy
Fax +39(089)969603; E-mail: lattanzi@unisa.it
Received 19 May 2007
shown to be a successful strategy for the development of
Abstract: Thioureas straightforwardly derived from commercially
available enantiopure amino alcohols have been found to promote
the asymmetric Morita–Baylis–Hillman reaction of 2-cyclohexen-
1-one and different aldehydes in the presence of triethylamine under
solvent-free conditions. The corresponding allylic alcohols were
obtained in good to high yields and up to 88% ee.
more efficient catalysts.10,12
Thus, we speculated that chiral 1,2-amino alcohols could
have been a suitable platform to access novel monothio-
ureas capable of promoting asymmetric MBH reaction.
Herein, we report our findings that simple amino alcohol
derived thioureas in the presence of triethyl amine can
satisfactorily promote the asymmetric MBH reaction of
2-cyclohexen-1-one with aldehydes.
Key words: Morita–Baylis–Hillman reaction, chiral thioureas,
asymmetric organocatalysis, amino alcohols
It has been well-documented that the most active thio-
ureas are those having the 3,5-bistrifluoromethyl phenyl
residue which makes them better H-bond donors.13 Some
commercially available enantiopure amino alcohols were
then treated with the corresponding isothiocyanate in
CH2Cl2 to give thioureas 1a–h in almost quantitative
yields (Scheme 1).14 Compounds 1b and 1c were recently
reported as promoters in the asymmetric Friedel–Crafts
alkylation of indoles with nitroalkenes.15
The Morita–Baylis–Hillman reaction (MBH) is an impor-
tant synthetic tool for C–C bond formation.1 The coupling
of aldehydes with a,b-unsaturated carbonyl compounds,
in the presence of a Lewis base such as DABCO or alkyl
and aryl phosphines, affords a variety of densely function-
alized allylic alcohols. In the asymmetric version of this
reaction, enantioenriched allylic alcohols are obtained as
valuable synthetic intermediates2 and relatively few high-
ly enantioselective and efficient protocols have been dis-
covered up to now. A growing interest in this context has
been recently directed to the development of catalytic
versions3 and the organocatalyzed protocols widen the op-
portunity to improve the reaction. Quinine-derived chiral
bases,4 BINOL-derived Brønsted acids,5 amino acids,6
and chiral diamines7 derived from L-proline were success-
fully developed, affording MBH products in moderate
to high yields and ee values. Enantiopure bisthioureas
coupled with DABCO or DMAP have been proved
valuable systems.8 Both thiourea groups were found to be
necessary for the activity and the asymmetric induction.8a
An efficient bifunctional organocatalyst was developed
by Wang and co-workers, who designed a binaphthyl-
derived amine thiourea, which incorporated both Lewis
base and acidic thiourea groups in the chiral scaffold.9
Functionalized monothioureas have been used as organo-
catalysts in the aza-Baylis–Hillman reaction affording
high enantioselectivity.10
CF3
R2
CF3
OH
R1
R
R3
HN
R2
F3C
N C S
OH
R1
R
R3
F3C
N
CH2Cl2, 0 °C to r.t.
S
H
H2N
94–99%
1
H
HO
Ph
S
H
H
H
N
Ar
N
N
Ar
HN
Ph
Ph
OH
Ph
Ar
N
N
H
H
S
S
OH
1a
Ph
1b
1c
HO
Ph
S
S
R = Me 1d
R = i-Pr 1e
R = Ph
R = Bn
Ph
H
H
Ar
Ar
N
H
N
N
N
1f
1g
H
H
H
Me
R
1h
Scheme 1 Thioureas screened in the MBH reaction
Polar protic solvents as methanol and water are known to
accelerate MBH reaction likely through hydrogen-bond- A preliminary study was carried out by reacting cyclo-
ing stabilization of the enolate intermediate and/or activa- hexancarboxaldehyde and 2-cyclohexen-1-one under sol-
tion of the aldehyde.11 Activation using basic and protic vent-free conditions at room temperature in the presence
centers of variable range of acidity strength has been of 20 mol% of thioureas 1a–h and 20 mol% of DABCO
(Table 1).
Catalyst 1a afforded 4a in modest yield and in almost
racemic form (entry 1). Catalysts 1b and 1c having two
chiral centers in flexible and rigid spatial arrangements
slightly improved the enantioselectivity (entries 2 and 3).
SYNLETT 2007, No. 13, pp 2106–2110
Advanced online publication: 12.07.2007
DOI: 10.1055/s-2007-984882; Art ID: G15307ST
© Georg Thieme Verlag Stuttgart · New York
1
3
.0
8
.2
0
0
7

LETTER
Asymmetric Morita–Baylis–Hillman Reaction Catalyzed by Simple Thioureas
2107
a much slower conversion to 4a was achieved while the
enantioselectivity improved. These results confirmed the
positive effect of the hydroxyl group of catalyst 1d in
accelerating the reaction, which was more pronounced
than when using an external alcohol as hydrogen-bonding
donor. Furthermore, it has been pointed out for the first
time, that unfunctionalized monothioureas derived from
simple chiral amines can catalyze the MBH reaction with
reasonable level of asymmetric induction.
Table 1 MBH Reaction of 2 with 3 Catalyzed by 20 mol% of 1a–h
and DABCO Under Solvent-Free Conditionsa
1 (20 mol%)
O
OH
O
O
DABCO (20 mol%)
neat, r.t.
+
H
2
3a
4a
Entry
1
Time (h)
48
Yield (%)b ee (%)c
Reactions carried out with catalyst 1f and DABCO at 20
mol% loading and room temperature in different solvents
were very sluggish and only traces of the product were
detected after 5 days.17
1
2
1a
1b
1c
1d
1e
1f
32
31
20
56
15
50
40
31
46
27
9
30
31
46
45
63
53
60
47
55
48
3
46
Given the importance of the nucleophilic base nature on
the outcome of the MBH reaction,18 its influence was in-
vestigated employing catalysts 1d,f under solvent-free
conditions (Table 2).
4
65
5
50
6
88
When using catalyst 1d and DMAP, 4a was recovered in
better yield and improved ee (entry 1). A stronger base
like DBU afforded the product in satisfactory yield after
shorter reaction time, but with low ee (entry 2). N-Methyl
imidazole did not furnish any trace of 4a (entry 3). Trieth-
ylamine was slightly less efficient than DMAP (entry 4),
7
1g
1h
1h
1h
66
8
65
9d
10e
65
65
a Conditions: 3a (0.2 mmol), 2 (0.4 mmol), 1 (0.04 mmol), DABCO
(0.04 mmol).
b Isolated yields after flash chromatography.
Table 2 MBH Reaction of 2 with 3a Catalyzed by 1d,f and
Different Lewis Bases at Room Temperature Under Solvent-Free
Conditionsa
c Determined by HPLC analysis using Chiralpak AS-H column.
Absolute configuration of the major enantiomer was determined to be
S by comparison of optical rotation with that reported in the literature.
d The reaction was carried out adding 0.2 equiv of MeOH.
e The reaction was carried out adding 0.2 equiv of (–)-TADDOL.
Entry
1
Base
Time
(h)
Yield
(%)b
ee
(%)c
1
2
1d
1d
1d
1d
1d
1d
1f
DMAP
DBU
64
46
65
60
–
52
15
–
Catalysts with only one chiral center, but having a steri-
cally demanding diphenyl carbinol moiety were then
checked. Suitable activation by the gem-diphenyl carbinol
group has been suggested by our recent findings on
nucleophilic asymmetric epoxidation of a,b-enones
promoted by diaryl 2-pyrrolidinemethanols in the pres-
ence of tert-butyl hydroperoxide as oxidant.16 The conver-
sion to 4a showed to be affected by the nature of the R
group in organocatalysts 1d–g and pleasingly a significant
improvement of the enantioselectivity was achieved using
compound 1f which furnished the product in 50% yield
and 63% ee (entry 6).
3
N-Methyl imidazole
Et3N
70
4
70
52
–
54
–
5
PPh3
92
6
Et3P
78
50
24
61
67
75
87
0
7
DMAP
Et3N
70
46
79
84
80
84
8d
9e
10f
11f
1f
93
1f
Et3N
122
116
94
1f
DABCO
Et3N
In order to prove the involvement of the hydroxyl group
in the process, the reaction was performed using organo-
catalyst 1h, which was identical to the most active com-
pound 1d devoid of the hydroxyl group (entry 8). After a
comparable reaction time, the product was isolated in sub-
stantially lower yield, although an improved ee was ob-
served (compare with entry 4). The reaction was then
performed under the same conditions but adding 20 mol%
of MeOH as external hydrogen-bonding donor (entry 9).
The same level of asymmetric induction and a smaller
conversion to 4a was achieved when compared to the
employment of catalyst 1d (entry 4). Finally, 20 mol% of
optically pure (–)-TADDOL was added to catalyst 1h as
external hydrogen-bonding donor (entry 10). In this case,
1f
a Conditions: 3a (0.2 mmol), 2 (0.4 mmol), 1 (0.04 mmol), base (0.04
mmol).
b Isolated yields after flash chromatography.
c Determined by HPLC analysis using Chiralpak AS-H column.6
Absolute configuration of the major enantiomer was determined to be
S by comparison of the optical rotation with that reported in the
literature.
d The reaction was carried out using 0.2 equiv of 1f and Et3N and
4 equiv of 2.
e The reaction was carried out at 4 °C using 0.2 equiv of 1f and Et3N
and 4 equiv of 2.
f The reaction was carried out at 4 °C using 0.3 equiv of 1f and base
and 4 equiv of 2.
Synlett 2007, No. 13, 2106–2110 © Thieme Stuttgart · New York

2108
A. Lattanzi
LETTER
while phosphines proved to be ineffective for the reaction Table 3 Solvent-Free MBH Reaction of 2 with 3 Promoted by 1f
and Triethylamine at 4 °Ca
(entries 5 and 6). Then, the best candidate DMAP was
checked with catalyst 1f (entry 7), but no improvement
O
OH
O
O
1f, Et3N
was observed. Triethylamine was found to be the base of
choice when used with promoter 1f, in fact, the product
was obtained in satisfactory yield and 79% ee (entry 8).
When the temperature was decreased to 4 °C the product
was isolated in good yield a higher ee (entry 9). A com-
parison was then made using catalyst 1f at 30 mol% load-
ing with DABCO (entry 10) and triethylamine (entry 11)
at 4 °C with 4 equivalents of 2. These experiments ascer-
tained that triethylamine worked as a better base than
DABCO. The scope of the MBH reaction was then evalu-
ated reacting 2 with different aldehydes employing 20
mol% of 1f and triethylamine at 4 °C under solvent-free
conditions and the results are reported in Table 3.19
+
R
R
H
4 °C
2
3
4
Entry Aldehyde
Time
(h)
Yield
(%)b
ee
(%, config)c,d
O
122
147
67
61
84 (S)
1
2
H
88e
O
139
120
67
45
76 (S)
81e
H
Cyclic aldehydes were converted into the corresponding
allylic alcohols in good yields and fairly good enantio-
selectivities (entries 1 and 2). A significant decrease of the
enantioselectivity and reactivity was observed when using
aliphatic aldehydes of decresing steric hindrance (entries
3 and 4).20 Interestingly, unsaturated trans-cinnamalde-
hyde furnished the product in high yield (entry 5), when
compared to the saturated compound (entry 4), but with
lower ee.
O
3
4
100
142
89
45
61 (S)
55 (S)
H
O
Ph
H
O
This protocol afforded good results even with more chal-
lenging aromatic aldehydes which were converted into
products in high yields and moderate enantioselectivity
(entries 6–8).21 Carrying out the reactions at –8 °C helped
to achieve higher ee (entries 1 and 2), especially for
challenging benzaldehyde (entry 6), whose product was
isolated in respectable 74 yield and 64% ee.22
5
138
91
36 (S)
H
O
O
118
119
92
74
57 (S)
6d
H
H
64e
Although more detailed mechanistic investigation is re-
quired, the catalyst hydroxyl group might be involved in
the proton-transfer step. Indeed, Aggarwal and Lloyd-
Jones have recently proposed that acceleration of MBH
reaction by protic solvents as methanol, occurs through
formal proton transfer from a-keto methine to the alkox-
ide in the zwitterion mediated by the alcohol.12b In our
case, the thiourea moiety might be hydrogen-bonded with
the carbonyl group of the zwitterionic intermediate and
the proton transfer would be accordingly accelerated by
the closely located hydroxyl group giving rise to the
product and regenerating the catalyst through elimination
(Figure 1).
Cl
7
8
119
119
88
86
52 (nd)f
O
56 (S)
H
MeO
a Conditions: 3 (0.2 mmol), 2 (0.8 mmol), 1 (0.04 mmol), Et3N (0.04
mmol).
b Isolated yields after flash chromatography.
c Determined by HPLC analysis using chiral columns.
d Absolute configuration was determined by comparison of optical ro-
tations with those reported in the literature.
e The reaction was carried out at –8 °C using 0.3 equiv of 1f and Et3N.
f Not determined.
R1
Ph
S
Ph
N
Ar
O
N
H
O
H
O
H
H
In summary, structurally simple monothiourea organo-
catalysts, readily obtained in one step and high yields
from commercially available amino alcohols, have been
discovered to promote the asymmetric MBH reaction of
2-cyclohexen-1-one and different aldehydes in the
presence of triethylamine. The allylic alcohols were
isolated in good to high yields and moderate to high
R
N
Figure 1 Plausible transition state for the proton-transfer step
promoted by amino alcohol derived thioureas
Synlett 2007, No. 13, 2106–2110 © Thieme Stuttgart · New York

LETTER
Asymmetric Morita–Baylis–Hillman Reaction Catalyzed by Simple Thioureas
2109
Freese, S.; Kaye, P. T. Synth. Commun. 1988, 18, 495.
enantioselectivity. Given the broad variety of amino
alcohols commercially available or accessible through
asymmetric synthesis, it will be feasible to tune the activ-
ity and the enantioselectivity of amino alcohol derived
thioureas as organocatalysts for the MBH reaction.
Further study to address this issue and the scope of the
MBH reaction are under way.
(e) Aggarwal, V. K.; Dean, D. K.; Mereu, A.; Williams, R.
J. Org. Chem. 2002, 67, 510. (f) Shi, M.; Liu, Y.-H. Org.
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Acknowledgment
MIUR is gratefully acknowledged for financial support. The author
thanks Dr. P. Iannece for MS spectra analyses.
(14) Procedure for the Synthesis of Catalysts 1
References and Notes
To a solution of amino alcohol (0.5 mmol) in CH2Cl2 (2 mL)
was added dropwise 3,5-bis(trifluoromethyl)phenyl
isothiocyanate (92 mL, 0.5 mmol) at 0 °C under N2. After
stirring the reaction mixture for 3–5 h at r.t., the solvent was
removed under reduced pressure and residue was purified by
flash chromatography (PE–Et2O, 90:10) to provide 1.
Spectral data for catalyst 1a: white solid, mp 145–147 °C;
[a]D20 –55.0 (c 0.30, CHCl3). 1H NMR (400 MHz, CDCl3):
d = 8.56 (br s, 1 H), 7.80 (br s, 2 H), 7.67 (s, 1 H), 7.50–7.27
(m, 5 H), 6.91 (br s, 1 H), 5.02 (br s, 1 H), 4.18 (br s, 1 H),
3.65–3.56 (m, 2 H), 3.00 (br s, 1 H). 13C NMR (100.6 MHz,
CDCl3): d = 180.7, 140.5, 138.9, 132.8, 128.9, 128.6, 125.7,
123.8, 119.4, 76.2, 52.1. IR (neat): 3261, 3066, 1538, 1385,
1278, 1133, 700, 682 cm–1. MS (EI): m/z (%) = 271 (100),
213 (37), 202 (58), 163 (30).
(1) For recent reviews, see: (a) Masson, G.; Housseman, C.;
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Catalyst 1d: white solid, mp 66–68 °C; [a]D19 –53.8 (c 0.34,
CHCl3). 1H NMR (400 MHz, CDCl3): d = 8.5 (br s, 1 H),
7.70–7.20 (m, 14 H), 6.88 (br s, 1 H), 5.64 (br s, 1 H), 2.95
(br s, 1 H), 1.15 (br s, 3 H). 13C NMR (100.6 MHz, CDCl3):
d = 178.8, 144.3, 138.4, 133.0, 128.9, 128.7, 127.7, 127.5,
126.0, 125.7, 125.4, 125.2, 123.5, 119.3, 81.3, 56.7, 14.9. IR
(neat): 3369, 3062, 1528, 1449,1382, 1278, 1176, 1136, 701,
682 cm–1. MS (EI): m/z (%) = 271 (100), 229 (42), 213 (72),
202 (76), 182 (48), 163 (50).
(4) (a) Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.;
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125, 12094. (b) McDougal, N. T.; Trevellini, W. L.;
Rodgen, S. A.; Kliman, L. T.; Schaus, S. E. Adv. Synth.
Catal. 2004, 346, 1231. For bifunctional catalysts in the
aza-MBH reaction, see: (c) Matsui, K.; Takizawa, S.; Sasai,
H. J. Am. Chem. Soc. 2005, 127, 3680. (d) Shi, M.; Chen,
L.-H.; Li, C.-Q. J. Am. Chem. Soc. 2005, 127, 3790.
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42, 127. (b) Imbriglio, J. E.; Vasbinder, M. M.; Miller, S. J.
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E.; Miller, S. J. Tetrahedron 2006, 62, 11450. (d) Aroyan,
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3849.
Catalyst 1e: white solid, mp 66–68 °C; [a]D20 –16.7 (c 0.32,
CHCl3). 1H NMR (400 MHz, CDCl3): d = 8.64 (br s, 1 H),
7.71–7.18 (m, 12 H), 6.92–6.87 (m, 1 H), 5.59 (br s, 1 H),
2.84 (br s, 1 H), 2.04 (br s, 1 H), 1.03 (d, J = 6.8 Hz, 3 H),
0.85 (d, J = 6.8 Hz, 3 H). 13C NMR (100.6 MHz, CDCl3):
d = 180.6, 144.9, 144.4, 138.4, 133.9, 128.5, 128.1, 127.3,
125.6, 125.5, 125.3, 125.1, 123.8, 122.8, 119.3, 83.1, 63.4,
29.7, 23.4, 18.4. IR (neat): 3350, 3063, 2963, 1562, 1449,
1277, 1381, 1176, 1135, 703, 683 cm–1. MS (EI): m/z (%) =
271 (100), 229 (40), 202 (34), 182 (34), 163 (64).
Catalyst 1f: white solid, mp 81–83 °C; [a]D22 –251.7 (c 0.34,
CHCl3). 1H NMR (400 MHz, CDCl3): d = 8.00 (br s, 1 H),
7.68–7.59 (m, 3 H), 7.42–7.26 (m, 5 H), 7.15–7.05 (m, 8 H),
(7) Hayashi, Y.; Tamura, T.; Shoji, M. Adv. Synth. Catal. 2004,
346, 1106.
7.00–6.95 (m, 2 H), 6.46 (br s, 1 H), 2.76 (br s, 1 H). 13
C
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7, 4293.
NMR (100.6 MHz, CDCl3): d = 179.3, 143.6, 143.4, 138.3,
136.3, 133.2, 128.9, 128.7, 128.1, 127.9, 127.3, 125.9,
125.5, 123.7, 119.6, 81.7, 64.7. IR (neat): 3255, 3062, 1518,
1449, 1381, 1278, 1176, 1137, 699, 682 cm–1. MS (EI):
m/z (%) = 271 (100), 213 (34), 202 (28), 163 (42).
Catalyst 1g: white solid, mp 79–82 °C; [a]D21 –75.1 (c 0.33,
CHCl3). 1H NMR (400 MHz, CDCl3): d = 8.03 (br s, 1 H),
7.64–7.15 (m, 15 H), 7.03–7.00 (m, 2 H), 6.78 (s, 1 H), 5.91
(br s, 1 H), 3.17 (br s, 1 H), 2.85–2.78 (m, 2 H). 13C NMR
(100.6 MHz, CDCl3): d = 179.5, 144.2, 138.0, 131.9, 129.5,
128.7, 128.6, 127.5, 127.4, 126.9, 126.4, 125.6, 125.2,
124.0, 122.7, 119.3, 81.8, 60.2, 37.4. IR (neat): 3320, 3063,
1539, 1449, 1383, 1277, 1181, 1135, 701, 681 cm–1.
(10) Raheem, I. T.; Jacobsen, E. N. Adv. Synth. Catal. 2005, 347,
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Synlett 2007, No. 13, 2106–2110 © Thieme Stuttgart · New York

2110
A. Lattanzi
LETTER
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Commun. 1999, 2311. (c) Leadbeater, N. E.; van der Pol, C.
J. J. Chem. Soc., Perkin Trans. 1 2001, 2831. (d)Aggarwal,
V. K.; Emme, I.; Fulford, S. Y. J. Org. Chem. 2003, 68, 692.
(19) Typical Procedure for the MBH Reaction
MS (ESI+): m/z (%) = 575 (70) [M + H+], 557 (100) [M – 17].
Catalyst 1h: white solid, mp 49–51 °C; [a]D21 –8.50 (c 0.30,
CHCl3). 1H NMR (400 MHz, CDCl3): d = 8.08 (br s, 1 H),
7.67 (s, 1 H), 7.33–7.14 (m, 12 H), 5.84 (br s, 1 H), 5.38 (br
s, 1 H), 4.90–4.85 (m, 1 H), 3.93 (d, J = 9.9 Hz, 1 H), 1.21
(d, J = 6.4 Hz, 3 H). 13C NMR (100.6 MHz, CDCl3): d =
179.5, 141.5, 141.1, 138.0, 133.2, 129.0, 128.9, 128.6,
128.3, 128.2, 127.9, 127.2, 127.1, 124.3, 122.7, 119.9, 58.1,
54.2, 19.6. IR (neat): 3063, 1532, 1382, 1279, 1176, 1135,
888, 752, 702 cm–1. MS (ESI+): m/z (%) = 483 (100) [M +
H+].
To a capped vial containing catalyst 1f (22.4 mg, 0.04 mmol)
was added 2-cyclohexen-1-one (78 mL, 0.8 mmol) and Et3N
(4.4 mL, 0.04 mmol). The mixture was stirred for 5 min and
then the aldehyde was added (0.2 mmol). After 100–147 h,
the reaction was directly purified by flash silica gel
chromatography eluting with PE–Et2O mixtures (98:2 to
80:20) to give a clear oil. Spectral data of allylic alcohols
matched those reported in the literature.2,3,5
(15) Herrera, R. P.; Sgarzani, V.; Bernardi, L.; Ricci, A. Angew.
Chem. Int. Ed. 2005, 44, 6576.
(16) (a) Lattanzi, A. Org. Lett. 2005, 7, 2579. (b) Lattanzi, A.
Adv. Synth. Catal. 2006, 348, 339. (c) Lattanzi, A.; Russo,
A. Tetrahedron 2006, 62, 12264.
(17) The following solvents were employed at a concentration of
2 M with respect to the aldehyde: toluene, MeOH, MeCN,
THF, CH2Cl2.
(20) A similar outcome for aliphatic aldehydes was observed in
organocatalyzed MBH reaction, see ref. 5a,b, 8, and 9.
(21) The corresponding products are generally obtained in
moderate yields and ee, see ref. 5a,b, 8, and 9.
(22) The best result achieved up to now for the allylic alcohol
obtained when reacting benzaldehyde and 2-cyclohexen-1-
one is 65% yield and 77% ee, see ref. 8b.
Synlett 2007, No. 13, 2106–2110 © Thieme Stuttgart · New York

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