Highly enantioselective aza-Morita-Baylis-Hillman reaction with a bisphenol-based bifunctional organocatalyst

Article abstract of DOI:10.1016/j.tetlet.2007.06.158

Newly developed phosphino-bisphenol 1c was found to be an efficient organocatalyst for the aza-Morita-Baylis-Hillman reaction. High enantioselectivity up to 96% ee was obtained with catalyst loading of 1 mol %.

Full text of DOI:10.1016/j.tetlet.2007.06.158

Tetrahedron Letters 48 (2007) 6147–6149
Highly enantioselective aza-Morita–Baylis–Hillman reaction
with a bisphenol-based bifunctional organocatalyst
Katsuji Ito,* Kanako Nishida and Takashi Gotanda
Department of Chemistry, Fukuoka University of Education, Akama, Munakata, Fukuoka 811-4192, Japan
Received 12 June 2007; revised 25 June 2007; accepted 26 June 2007
Available online 4 July 2007
Abstract—Newly developed phosphino-bisphenol 1c was found to be an efficient organocatalyst for the aza-Morita–Baylis–Hillman
reaction. High enantioselectivity up to 96% ee was obtained with catalyst loading of 1 mol %.
Ó 2007 Elsevier Ltd. All rights reserved.
Chiral Lewis acid-catalyzed reactions are one of the
most effective methods for synthesizing optically active
compounds. The typical reaction involves the enantiose-
lective addition of a nucleophile to carbonyl compounds
in the presence of a chiral Lewis acid.1 The carbonyl
compound is activated through coordination of car-
bonyl oxygen atom to the Lewis acid and undergoes
enantioselective nucleophilic addition. On the other
hand, many biologic syntheses also include nucleophilic
addition to carbonyl groups, however, the addition reac-
tions are mostly non-metal catalyzed processes in which
hydrogen bonding plays a pivotal role. Therefore, much
effort has been directed toward the development of new
organocatalysts bearing hydrogen-bond donor(s).2 It
has been demonstrated that appropriately oriented
hydrogen-bond donors sufficiently activate carbonyl
compounds through double or multiple hydrogen bond-
ing.2,3 Of the various organocatalysts reported to date,
thiourea-based chiral organocatalysts have been the
most successfully used for the activation of carbonyl,
imine, and nitro groups through double hydrogen bond-
ing.3 It is well known that a phenolic hydroxy group also
functions as a hydrogen-bond donor in some enzymes,
such as L-fuculose 1-phosphate aldolase.4 Although
the successful application of chiral organocatalysts bear-
ing phenolic hydroxy group(s) as a hydrogen-bond
donor to enantioselective reactions is limited, it has been
reported that the enantioselective aza-Morita–Baylis–
Hillman (aza-MBH) reaction that affords functionalized
allylic amines in a single step can be promoted by this
type of organocatalysts.5,6 For example, quinidine deriv-
atives,6a,c,d,g
phosphinophenols,6b,f,h
3-substituted
BINOLs,6e,j,k and thiourea Schiff bases6i have been
developed to serve as the catalyst. Quite recently, Shi
et al. reported that the chiral phosphine Lewis bases
bearing multiple phenolic hydroxy groups were efficient
catalysts for aza-MBH reactions.6l Although these reac-
tions exhibited high enantioselectivities due to a sophis-
ticated hydrogen bonding system (Fig. 1), relatively high
catalyst loading (10 mol %) was required to obtain
O
O
n
O
H
H
H
O
O
HO
OH
Ph
P
O
PPh2
Ph
1a: n=0
1b: n=1
1c: n=2
1d: n=3
Figure 1. A hydrogen bonding structure proposed for the intermediate of aza-MBH reaction by Shi et al.
Keywords: Organocatalyst; Allyl amine; Aza-Morita–Baylis–Hillman reaction; Hydrogen bonding.
*
Corresponding author. Tel.: +81 940 35 1367; fax: +81 940 35 1711; e-mail: itokat@fukuoka-edu.ac.jp
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.06.158

6148
K. Ito et al. / Tetrahedron Letters 48 (2007) 6147–6149
Table 1. Enantioselective aza-Morita–Baylis–Hillman reaction using
1a–d as catalystsa
acceptable yields. Thus, the development of a new
organocatalyst with a higher catalytic activity and more
robustness is required. Shi et al. have proposed that
both the naphthol parts take part in the activation of
carbonyl groups, while the asymmetry is mostly induced
by the chirality of the phosphinonaphthol part.6l Based
on this proposal, we hypothesized that the carbonyl
group should be sufficiently activated by two hydrogen
bondings and that the replacement of the binaphthol
unit with a simple phenol unit would facilitate substrate
approach and enhance the catalyst activity. Thus, we
synthesized new bifunctional phosphino-bisphenols 1
differing in the length of the spacer and examined their
effect in the aza-MBH reaction.
NTs
H
TsHN
O
O
1a-d
+
THF
Cl
Cl
Entry Catalyst Catalyst Time Yield % eeb Confign.c
loading
(mol %)
(h)
(%)
1
2
3
4
5
6
7d
1a
1b
1c
1d
1c
1c
1c
10
10
10
10
1
48
2
1.5
1
14
96
48
98
93
100
99
96
95
88
95
95
93
95
95
95
S
S
S
S
S
S
S
Catalysts 1a–d were prepared from phosphinophenol 27
as follows (Scheme 1). Protection of the phenolic hydroxy
group as MOM ether and subsequent MOM group-direc-
ted ortho-formylation gave aldehyde 3. Reduction of the
aldehyde with NaBH4 followed by oxidation with
ureaÆhydrogen peroxide adduct (UHP) afforded alcohol
4. For the synthesis of 1a, alcohol 4 was subjected to a
Mitsunobu reaction8 with mono-protected catechol to
give 5a. The other compounds 5b–d were prepared in a
similar manner to the syntheses of linked BINOL
reported by Shibasaki et al.9 The requisite alcohols 7b–d
were prepared from salicylaldehyde in a conventional
manner. Reduction of the phosphinoyl group with PMHS
0.5
1
100
a All reactions were carried out at 0 °C in THF with molar ratio of
imine/enone = 1:3 unless otherwise mentioned.
b Determined by HPLC analysis using chiral stationary phase column
(Daicel Chiralpak AD-H; hexane/i-PrOH = 80:20).
c Determined by comparison of elution order of HPLC with the
reported value (Ref. 6e).
d Reaction was performed at À15 °C.
With chiral phosphino-bisphenols 1a–d in hand, we first
examined the reaction of p-chlorophenyl N-tosylimine
with methyl vinyl ketone in THF at 0 °C in the presence
of 1a–d (Table 1). The rate and the enantioselectivity of
the reactions depended on the length of spacer in 1. With
1a, the reaction was completed after 48 h, and a good
enantioselectivity of 88% ee was obtained (entry 1).
The reaction rate and enantioselectivity were signifi-
cantly improved when 1b was used as the catalyst (entry
in the presence of Ti(OiPr)4 and deprotection of the
10
MOM group gave the desired phosphino-bisphenols
1a–d. Deprotection of the MOM group in 5b by Amber-
lyst 15 failed due to the instability of 1b under the reaction
conditions. Finally, compound 1b was obtained by using
p-toluenesulfonic acid, albeit in a very low yield.
CHO
OH
1) MsCl, NEt3
1) NaH, MOMCl
1) NaBH4
2) LiBr
OH
OMOM
PPh2
OMOM
PPh2
PPh2 2)
n
DMF
-BuLi, TMEDA
3) 7, NaH
for 5b-d
2) UHP
90%
O
72%
3
MOMO
HO
2
4
DEAD, PPh3
for 5a
1) PMHS, Ti(OiPr)4
O
n
O
n
2) Amberlyst 15, MeOH
OH
PPh2
HO
OMOM MOMO
PPh2
for 1a,c,d
5a: n= 0 (76%)
p
-TsOH•H2O, CH2Cl2/MeOH
for 1b
5b: n= 1 (48%)
5c: n= 2 (50%)
5d: n= 3 (48%)
1a: n= 0 (65%)
1b: n= 1 (6%)
1c: n= 2 (65%)
1d: n= 3 (60%)
O
NaBH4 for 7b
1) MePPh3Br,
n
-BuLi
OH
OMOM
OMOM
2) 9-BBN, NaOH, H2O2
CHO
CHO
MOMCl
iPr2NEt
99%
for 7c
OH
n
1) (EtO)2POCH2CO2Et, NaH
2) H2/Pd-C
3) LAH
7b: n= 1 (99%)
7c: n= 2 (72%)
7d: n= 3 (77%)
6
for 7d
Scheme 1.

K. Ito et al. / Tetrahedron Letters 48 (2007) 6147–6149
6149
Table 2. Enantioselective aza-Morita–Baylis–Hillman reaction using
1c as a catalysta
References and notes
TsHN
R
1. For reviews: (a) Comprehensive Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer: Berlin, 1999; (b) Catalytic Asymmetric Synthesis;
2nd ed.; Ojima, I., Ed., Wiley-VCH: New York, 2000.
2. For reviews: (a) Schreiner, P. R. Chem. Soc. Rev. 2003, 32,
289–296; (b) Pihko, P. M. Angew. Chem., Int. Ed. 2004, 43,
2062–2064; (c) Akiyama, T.; Itoh, J.; Fuchibe, K. Adv.
Synth. Catal. 2006, 348, 999–1010; (d) Taylor, M. S.;
Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 1520–
1543.
3. Examples of bidentate or bifunctional metallic Lewis
acids, see: (a) Maruoka, K. Catal. Today 2001, 66, 33–45;
(b) Maruoka, K. Pure Appl. Chem. 2002, 74, 123–128; (c)
Shibasaki, M.; Kanai, M.; Funabashi, K. Chem. Commun.
2002, 1989–1999, and references cited therein.
4. For reviews: (a) Wong, C.-H.; Halcomb, R. H.; Ichikawa,
Y.; Kajimoto, T. Angew. Chem., Int. Ed. 1995, 34, 412–
432; (b) Machajewski, T. D.; Wong, C.-H. Angew. Chem.,
Int. Ed. 2000, 39, 1352–1374.
5. Reviews for the Morita–Baylis–Hillman reaction, see: (a)
Iwabuchi, Y.; Hatakeyama, S. J. Synth. Org. Chem. Jpn.
2002, 60, 2–14; (b) Basavaiah, D.; Rao, A. J.; Satyanara-
yana, T. Chem. Rev. 2003, 103, 811–892; (c) Masson, G.;
Housseman, C.; Zhu, J. Angew. Chem., Int. Ed. 2007, 46,
4614–4628.
6. (a) Shi, M.; Xu, Y.-M. Angew. Chem., Int. Ed. 2002, 41,
4507–4510; (b) Shi, M.; Chen, L. H. Chem. Commun. 2003,
1310–1311; (c) Kawahara, S.; Nakano, A.; Esumi, T.;
Iwabuchi, Y.; Hatakeyama, S. Org. Lett. 2003, 5, 3103–
3105; (d) Balan, D.; Adolfsson, H. Tetrahedron Lett. 2003,
44, 2521–2524; (e) Matsui, K.; Takizawa, S.; Sasai, H. J.
Am. Chem. Soc. 2005, 127, 3680–3681; (f) Shi, M.; Chen,
L. H.; Li, C.-Q. J. Am. Chem. Soc. 2005, 127, 3790–3800;
(g) Shi, M.; Xu, Y.-M.; Shi, Y.-L. Chem. Eur. J. 2005, 11,
1794–1802; (h) Shi, M.; Li, C.-Q. Tetrahedron: Asymmetry
2005, 16, 1385–1391; (i) Rahhem, I. T.; Jacobsen, E. N.
Adv. Synth. Catal. 2005, 347, 1701–1705; (j) Matsui, K.;
Tanaka, K.; Horii, A.; Takizawa, S.; Sasai, H. Tetra-
hedron: Asymmetry 2006, 17, 578–583; (k) Matsui, K.;
Takizawa, S.; Sasai, H. Synlett 2006, 761–765; (l) Liu,
Y.-H.; Chen, L.-H.; Shi, M. Adv. Synth. Catal. 2006, 348,
973–979.
O
NTs
O
1c (1 mol%)
THF, 0 °C
+
R
H
Entry R in N-tosyl imine Time Yield % eeb Confign.c
(h)
(%)
1
2
3
4
5
6
7
Phenyl
17
17
10
84
100
98
96
95
94
96
95
95
87
S
S
S
S
S
S
S
4-Fluorophenyl
4-Nitrophenyl
4-Methylphenyl
4-Methoxyphenyl
2-Naphthyl
35
99
76
97
17
164
100
71
(E)-Cinnamyl
a All reactions were carried out at 0 °C in THF with molar ratio of
imine/enone/1c = 1:3:0.01.
b Determined by HPLC analysis using chiral stationary phase column
according to the literature (Refs. 6e,f).
c Determined by comparison of elution order of HPLC with the
reported value (Refs. 6e,f).
2). The most optimal result was obtained with 1c, where
the reaction was completed after 1.5 h with a high enantio-
selectivity of 95% ee (entry 3).11 Although 1d exhibited
higher catalytic activity than 1c, the enantioselectivity
was somewhat decreased (entry 4). The high catalytic
activity of 1c allowed the reaction to be carried out at
lower catalyst loading. To our delight, the catalyst load-
ing could be reduced to 1 mol % without diminishing
enantioselectivity (entry 5). The loading could be further
reduced to 0.5 mol %, but the reaction was very slow
(entry 6). Lowering the reaction temperature to À15 °C
considerably retarded the reaction and no enhancement
of the enantioselectivity was observed (entry 7).
Under the optimized conditions, we next examined the
reactions of several other N-tosylimines (Table 2).
Equally high enantioselectivities were obtained irrespec-
tive of the electronic nature of the aryl substituent, while
the reaction rate was found to be dependent on the elec-
tronic nature such that the presence of an electron-
donating group retarded the reaction (entries 4 and 5).
The reaction of cinnamyl N-tosylimine was slow, and
the enantioselectivity was decreased to 87% ee, although
this is still good (entry 7).
7. Uozumi, Y.; Tanahashi, A.; Lee, S. Y.; Hayashi, T. J. Org.
Chem. 1993, 58, 1945–1948.
8. Mitsunobu, O. Synthesis 1981, 1.
9. Matsunaga, S.; Das, J.; Roels, J.; Vogl, E. M.; Yamamoto,
N.; Iida, T.; Yamaguchi, K.; Shibasaki, M. J. Am. Chem.
Soc. 2000, 122, 2252–2260.
10. Coumbe, T.; Lawrence, N. J.; Muhammad, F. Tetrahe-
dron Lett. 1994, 35, 625–628.
In conclusion, we have demonstrated that newly devel-
oped phosphino-bisphenol 1c is an efficient organocata-
lyst for the aza-MBH reaction. To the best of our
knowledge, 1c is the most active organocatalyst so far
developed for the aza-MBH reaction. Further studies on
the scope of the reaction and clarification of the reaction
mechanism are currently under way in our laboratory.
11. Typical experimental procedure is exemplified by aza-
MBH of N-(4-chlorobenzylidene)-4-methylbenzenesulf-
onamide with methyl vinyl ketone (MVK): To a solution
of N-(4-chlorobenzylidene)-4-methylbenzenesulfonamide
(58.8 mg, 0.2 mmol) and 1c (1.2 mg, 2.0 lmol) in THF
(0.4 ml), MVK (48.7 ll, 0.6 mmol) was added at 0 °C.
After stirring for 14 h at 0 °C, the mixture was directly
subjected to silica gel chromatography (hexane/ethyl
acetate = 90:10–70:30), giving the desired product
(70.0 mg, 96%). Enantiomeric excess of the product was
determined to be 95% by HPLC using a chiral stationary
phase column (Ref. 6e).
Acknowledgments
The authors thank Dr. H. Furuno, Institute for
Materials Chemistry and Engineering (IMCE), Kyushu
University for measurement of NMR and HRMS.