Chiral phosphinothiourea organocatalyst in the enantioselective Morita-Baylis-Hillman reactions of aromatic aldehydes with methyl vinyl ketone

Article abstract of DOI:10.1016/j.tetlet.2008.08.042

A new class of chiral phosphinothioureas has been developed as efficient organocatalyst for the enantioselective Morita-Baylis-Hillman reaction of aromatic aldehydes with methyl vinyl ketone. The reaction proceeds under very mild conditions to afford the

Full text of DOI:10.1016/j.tetlet.2008.08.042

Tetrahedron Letters 49 (2008) 6262–6264
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Chiral phosphinothiourea organocatalyst in the enantioselective Morita–
Baylis–Hillman reactions of aromatic aldehydes with methyl vinyl ketone
*
Kui Yuan, Lei Zhang, Hong-Liang Song, Yinjun Hu, Xin-Yan Wu
Lab for Advanced Materials and Institute of Fine Chemicals, East China University of Science and Technology, Shanghai 200237, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A new class of chiral phosphinothioureas has been developed as efficient organocatalyst for the enantio-
selective Morita–Baylis–Hillman reaction of aromatic aldehydes with methyl vinyl ketone. The reaction
proceeds under very mild conditions to afford the desired product in a short time period in good to excel-
lent yields with up to 94% ee.
Received 1 August 2008
Accepted 8 August 2008
Available online 14 August 2008
Ó 2008 Elsevier Ltd. All rights reserved.
The Morita–Baylis–Hillman (MBH) reaction is a powerful tool
for the atom-economic construction of densely functionlized
a
-
methylene-b-hydroxycarbonyl derivatives which serve as valuable
building blocks in organic synthesis.1 The development of a suit-
able asymmetric version of this reaction has attracted considerable
interest in recent years.2 Various chiral organocatalysts including
quinidine-derived b-isocupreidine,3 BINOL-derived Brønsted acid,4
and bifunctional aminothiourea5 have been notably developed for
the asymmetric MBH reaction to achieve high enantiomeric ex-
cesses. Bis(thio)ureas derived from chiral trans-1,2-diaminocyclo-
hexane, isophorone-diamine (IPDA), and H8-BINAM were also
proven to be efficient organocatalysts for the asymmetric MBH
reactions of various aldehydes with 2-cyclohexen-1-one as de-
scribed by Nagasawa, Berkessel and Shi, respectively.6 However,
Morita–Baylis–Hillman reactions involving methyl vinyl ketone
(MVK) as reaction partner usually afforded the corresponding
products in moderate enantioselectivities.2,7 To the best of our
knowledge, the highest enantioselectivity of this kind of MBH reac-
tion was 83% ee using chiral tertiary amine/proline cocatalysts.7d
Cyclohexane-based aminothiourea has been extensively stud-
ied in recent years as a bifunctional organocatalyst for asymmetric
catalysis.8 In 2004, Yudin and co-workers reported cyclohexane-
based iminophosphines derived from the ring-opening of aziridine
for transition metal catalysis.9 Due to the structural analogy be-
tween aminothiourea and iminophosphine, we envisioned that
the overlapped structure, that is, phosphinothiourea (Fig. 1), could
serve as a new class of bifunctional organocatalysts for enantiose-
lective catalysis. As tertiary phosphines are effective catalysts for
the MBH reaction, it is conceivable that the phosphinothiourea
could catalyze this reaction in an enantioselective fashion.
S
S
N
OH
X
N
N
N
N
H
H
H
H
PPh2
PR2
phosphinothiourea
NMe2
aminothiourea
iminophosphine
Figure 1. Overlap approach to design new catalyst.
presence of carboxylic acid as co-catalyst for the asymmetric
aza-Morita–Baylis–Hillman reaction. However, the reaction
usually takes a long time. Herein, we report a new class of
phosphinothiourea organocatalysts, derived from trans-2-amino-
1-(diphenylphosphino)cyclohexane (1),11 which are fairly effective
bifunctional organocatalysts for the enantioselective MBH reaction
of arylaldehydes with MVK to give the corresponding adducts in up
to 94% ee and good to excellent yields.
The organocatalysts 2a–f12 are easily prepared by condensation
of (R,R)-2-amino-1-(diphenylphosphino)cyclohexane (1) with
1.1 equiv of the corresponding iso(thio)cyanate or isocyanate
under mild conditions (Fig. 2, see Supplementary data).
We initially chose the reaction of MVK with p-nitrobenzalde-
hyde to screen the phosphinothioureas as bifunctional organocat-
alysts for the MBH reaction. To our delight, when using CH2Cl2 as
solvent, the reaction completed in 45 min with catalyst 2a to pro-
vide the desired MBH product in 71% yield and 85% ee (Table 1,
entry 3). Longer reaction time afforded lower chemical yield due
X
The bifunctional phosphinothiourea was not documented be-
fore for asymmetric catalysis until recently Shi and Shi10 reported
the BINOL-derived phosphinothioureas as organocatalysts in the
2a: X = S, R = C6H5
2b: X = O, R = C6H5
2c: X = S, R = 3,5-(CF3)2C6H3
2d: X = S, R = 4-ClC6H4
2e: X = S, R = 4-MeOC6H4
2f: X = S, R = c-Hexyl
NH2
HN
N
H
R
RNCX
PPh2
PPh2
1
* Corresponding author. Tel.: +86 21 64252011; fax: +86 21 64252758.
E-mail address: xinyanwu@ecust.edu.cn (X.-Y. Wu).
Figure 2. New class of phosphinothiourea catalysts.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.08.042

K. Yuan et al. / Tetrahedron Letters 49 (2008) 6262–6264
6263
Table 1
Ph
P
Ph
O
Screening of the catalysts for the reaction of MVK and 4-nitrobenzaldehydea
S
N
N
H
CHO
O
OH
O
10 mol% 2a–f
CH2Cl2,13 ºC
H
H
si-attack
O
Ar
NO2
NO2
Catalyst
Figure 3. Proposed transition state.
Entry
t (min)
Yieldb (%)
eec (%)
1
2
3
2a
2a
2a
2a
2a
2a
2b
2c
2d
2e
2f
15
30
45
60
120
45
45
45
45
45
5
50
66
71
64
53
64
trace
83
64
62
34
83
85
85
85
83
79
n.d.e
4
products in very good yields and excellent enantioselectivities
(90–94% ee, entries 1–5). Both mono- and di-halogen substituted
arylaldehydes are tolerated to generate the products in high
enantioselectivities (87–92% ee) albeit with moderate yields
(entries 6–9). The reactions with non-substituted benzaldehyde
and 2-naphthylaldehyde proceeded slowly to afford the product
in high enantioselecitvity (90% ee), but low yields (entries 10 and
11). As a general trend, the reaction with electron-rich arylalde-
hyde proved to be difficult and complex mixture was observed.
The observed absolute configuration could be explained by the
plausible transition state illustrated in Figure 3. The thiourea moi-
ety forms hydrogen-bond with the aldehyde carbonyl. The cyclo-
hexyl scaffold forces the phosphinoyl associated enolate to attack
4
5
6d
7
8
9
10
11
70
83
80
a
Unless stated otherwise, the reactions were conducted with 10 mol % of
organocatalyst, 5 equiv of MVK in CH2Cl2 (0.2 M) at 13 °C.
b
Isolated yields.
Determined by chiral HPLC.
5 mol % 2a was used.
Not determined.
c
d
e
the activated carbonyl from the si-face to generate the
R
configuration.
In summary, we have developed a highly enantioselective Mori-
ta–Baylis–Hillman reaction involving the addition of MVK to
aromatic aldehydes catalyzed by a phosphinothiourea organocata-
lyst derived from trans-2-amino-1-(diphenylphosphino)cyclohex-
ane. The reaction proceeds under very mild conditions to afford
the desired product in a short time period in good to excellent
yields with generally excellent enantiomeric excesses (87–94%
ee). Further efforts are underway with a focus on improving the
catalyst activity and the scope of substrate as well as the mecha-
nism of the asymmetric MBH reaction.
to the over reaction with MVK (entries 4 and 5 vs 3). The thiourea
moiety proved to be critical for the MBH reaction in terms of both
yield and enantioselectivity. Urea derivative 2b was ineffective un-
der identical conditions (entry 7). Surprisingly, catalyst 2c gave
poor enantioselectivity, albeit with high yield (entry 8). Substitu-
tion at the 4-position of phenyl has no obvious effect on the enanti-
oselectivity (entries 3, 9, and 10). Bearing an alkyl group, the
phosphinothiourea 2f afforded good level of enantioselectivity,
but low yield (entry 11).
Further optimization including various solvents, temperature,
and substrate concentration in the presence of catalyst 2a led to
the optimal reaction conditions (see Supplementary data): using
2a as catalyst, the reaction of 5 equiv of MVK with 0.3 M of p-nitro-
benzaldehyde in CHCl3 completed in 15 min at 13 °C to provide the
desired product in 75% yield and 94% ee.
Acknowledgments
We are grateful for the financial support from National
Natural Science Foundation of China (20402004 and 20772029),
Science and Technology Commission of Shanghai Municipality
(06ZR14028), and the Program for New Century Excellent Talents
in University (NCET-07-0286).
Under the optimized conditions, the substrate scope in terms of
aromatic aldehydes was first investigated. As indicated in Table 2,
reaction of MVK with strong electron-deficient aldehydes usually
proceeded very quickly (within 1 h) to provide the desired
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.08.042.
Table 2
MBH reactions of MVK with aromatic aldehydes catalyzed by 2aa
OH
Ar
O
O
References and notes
10 mol% 2a
ArCHO
CHC l3, 13 ºC
1. For reviews, see: (a) Basavaiah, D.; Rao, P. D.; Hyma, R. S. Tetrahedron 1996, 52,
8001–8062; (b) Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. Rev. 2003, 103,
811–892.
Entry
Ar
t (min)
Yieldb (%)
eec (%)
2. For reviews, see: Organocatalytic Enantioselective Morita–Baylis–Hillman
(MBH) Reactions: (a) Menozzi, C.; Dalko, P. I. In Dalko, P. I., Ed.;
Enantioselective Organocatalysis, Reactions and Experimental Procedures;
Wiley-VCH: Weinheim, 2007; pp 151–187; (b) Masson, G.; Housseman, C.;
Zhu, J. Angew. Chem., Int. Ed. 2007, 46, 4614–4628; (c) Basavaiah, D.; Rao, K. V.;
Reddy, R. J. Chem. Soc. Rev. 2007, 36, 1581–1588.
3. (a) Iwabuchi, Y.; Nakatani, M.; Yodoyama, N.; Hatakeyama, S. J. Am. Chem. Soc.
1999, 121, 10219–10220; (b) Nakano, A.; Kawahara, S.; Morokuma, K.;
Nakatami, M.; Iwabuchi, Y.; Takahashi, K.; Ishihara, J.; Hatakeyama, S.
Tetrahedron 2006, 62, 381–389.
4. (a) McDougal, N. T.; Schaus, S. E. J. Am. Chem. Soc. 2003, 125, 12094–12095; (b)
McDougl, N. T.; Trevellini, W. L.; Rodgen, S. A.; Kliman, L. T.; Schaus, S. E. Adv.
Synth. Catal. 2004, 346, 1231–1240.
5. (a) Wang, J.; Yu, X.; Zu, L.; Wang, W. Org. Lett. 2005, 7, 4293–4296; (b) Lattanzi,
A. Synlett 2007, 2106–2110.
1
2
3
4
5
6
7
8
9
4-NO2C6H4
2-NO2C6H4
3-NO2C6H4
4-CNC6H4
4-CF3C6H4
4-ClC6H4
15
45
20
30
60
120
120
60
90
180
120
75
91
71
63
65
40
62
61
43
48
15
94 (R)
92 (R)
94 (R)
90 (R)
92 (R)
90 (R)
87 (R)
89 (R)
92 (R)
90 (R)
90 (R)
2-ClC6H4
2,4-Cl2C6H3
4-BrC6H4
C6H5
10
11
2-Naphthyl
a
Unless stated otherwise, the reactions were conducted with 10 mol % of
organocatalyst, 5 equiv of MVK in CHCl3 (0.3 M) at 13 °C.
b
Isolated yields.
6. (a) Sohtome, Y.; Tanatani, A.; Hashimoto, Y.; Nagasawa, K. Tetrahedron Lett.
2004, 45, 5589–5592; (b) Berkessel, A.; Roland, K.; Neudörfl, J. M. Org. Lett.
2006, 8, 4195–4198; (c) Shi, M.; Liu, X.-G. Org. Lett. 2008, 10, 1043–1046.
c
The ee was determined by chiral HPLC, and the absolute configuration was
determined by comparison of optical rotation with that of literature report.7c,13

6264
K. Yuan et al. / Tetrahedron Letters 49 (2008) 6262–6264
7. (a) Krishna, P. R.; Kannan, V.; Reddy, P. V. N. Adv. Synth. Catal. 2004, 346, 603–
606; (b) Miller, S. J. Acc. Chem. Res. 2004, 37, 601–610; (c) Vasbinder, M. M.;
Imbriglio, J. E.; Miller, S. J. Tetrahedron 2006, 62, 11450–11459; (d) Tang, H.;
Zhao, G.; Zhou, Z.; Zhou, Q.; Tang, C. Tetrahedron Lett. 2006, 47, 5717–5721.
8. Liu, K.; Cui, H.-F.; Nie, J.; Dong, K.-Y.; Li, X.-J.; Ma, J.-A. Org. Lett. 2007, 9, 923–
925 and references therein.
10. Shi, Y.-L.; Shi, M. Adv. Synth. Catal. 2007, 349, 2129–2135.
11. Caiazzo, A.; Dalili, S.; Yudin, A. K. Org. Lett. 2002, 4, 2597–2600.
12. During the preparation of this manuscript, Jacobsen reported ent-2c and
similar organocatalysts for the asymmetric [3+2] cycloaddition: Fang, Y.-Q.;
Jacobsen, E. N. J. Am. Chem. Soc. 2008, 130, 5660–5661.
13. (a) Imbriglio, J. E.; Vasbinder, M. M.; Miller, S. J. Org. Lett. 2003, 5, 3741–3743;
(b) Hayashi, Y.; Tamura, T.; Shoji, M. Adv. Synth. Catal. 2004, 346, 1106–1110.
9. Dalili, S.; Caiazzo, A.; Yudin, A. K. J. Organomet. Chem. 2004, 689, 3604–3611.