Chiral bifunctional organocatalysts bearing a 1,3-propanediamine unit for the aza-MBH reaction

Article abstract of DOI:10.1016/j.tetasy.2013.08.005

The introduction of a 1,3-propanediamine unit at the 3-position of (S)-BINOL using a methylene spacer led to the formation of a chiral bifunctional organocatalyst for the aza-Morita-Baylis-Hillman (aza-MBH) reaction. The organocatalyst 1k mediated aza-MBH

Full text of DOI:10.1016/j.tetasy.2013.08.005

Tetrahedron: Asymmetry 24 (2013) 1189–1192
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Chiral bifunctional organocatalysts bearing a 1,3-propanediamine
unit for the aza-MBH reaction
Shuichi Hirata, Kouichi Tanaka, Katsuya Matsui, Fernando Arteaga Arteaga, Yasushi Yoshida,
⇑
⇑
Shinobu Takizawa , Hiroaki Sasai
The Institute of Scientific and Industrial Research (ISIR), Osaka University, Mihogaoka, Ibaraki, Osaka 567-0047, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 July 2013
Accepted 6 August 2013
The introduction of a 1,3-propanediamine unit at the 3-position of (S)-BINOL using a methylene spacer
led to the formation of
a chiral bifunctional organocatalyst for the aza-Morita–Baylis–Hillman
(aza-MBH) reaction. The organocatalyst 1k mediated aza-MBH transformations with high chemical yields
and with up to 82% ee.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
Lewis base units
The design and development of chiral organocatalysts possess-
ing two or more reaction-promoting functionalities have attracted
much attention in the field of asymmetric catalysis.1 In bi- and
multifunctional organocatalysis, acid–base moieties can activate
substrates and control the stereochemistry of reactions to afford
significant chiral induction.2 The balance and appropriate location
of acid and base units in a catalyst are important for the efficient
activation of substrates. Herein we report that (S)-BINOL substi-
tuted at the 3-position with appropriate 1,3-propanediamine
derivatives using a methylene spacer works as an effective chiral
bifunctional organocatalyst. The organocatalyst 1k (Fig. 1) medi-
ates aza-Morita–Baylis–Hillman (aza-MBH) transformations in
high chemical yields and with up to 82% ee.
Bn
N
N
3
OH
OH
Brønsted acid units
1k
Figure 1. Chiral bifunctional organocatalyst 1k bearing a 1,3-propanediamine unit
for the aza-MBH reaction.
introduce a tertiary diamine7 (a strong Lewis base unit) at the
3-position of BINOL (a chiral Brønsted acid) using a spacer. A
tertiary diamine moiety could be used to easily adjust Lewis basi-
city via the introduction of substituents onto the nitrogen atom
and the distance between the acid–base units with an alkyl chain
of appropriate length. As a step toward the development of such
a bifunctional organocatalyst, 1,2-ethanediamine 1a,b, 1,3-pro-
panediamine 1c,d, 1,4-butanediamine 1e, 1,5-pentanediamine 1f,
and 1,6-hexanediamine 1g were introduced at the 3-position of
(S)-BINOL using a methylene or ethylene spacer. Next, the reaction
of methyl vinyl ketone 2a and 4-bromophenyl N-tosyl aldimine 3a
as prototypical substrates was attempted using the above
organocatalysts 1 (Table 1). The aza-MBH adduct 4a was isolated
in 48% yield with 61% ee when using 1,3-propanediamine deriva-
tive 1c with a methylene linker (entry 3). The analogous catalysts
1b and 1d bearing an ethylene spacer were then prepared and
applied to the reaction. These catalysts also promoted the reaction
but at lower rates with lower enantioselectivities (entries 2 and 4)
compared with those obtained using catalyst 1c with the
2. Results and discussion
The aza-MBH reaction is recognized as one of the most useful
and atom-economical carbon–carbon bond forming reactions
between the
a-position of enones and the carbonyl group of
imines, and is catalyzed by nucleophilic amines or phosphines.3
The products of the aza-MBH reaction are highly functionalized
allylic amines that have proven to be valuable building blocks for
biologically important compounds and natural products.4 Obtain-
ing efficient catalysts for the aza-MBH reaction however, has been
a challenge in organic synthesis.5
We envisioned locating both an acidic and a basic unit on one
chiral binaphthyl skeleton, thereby facilitating synergistic cooper-
ation in the aza-MBH reaction.5b,k,6 To that end, it was proposed to
⇑
Corresponding authors. Tel.: +81 6 6879 8466; fax: +81 6 6879 8469.
E-mail address: taki@sanken.osaka-u.ac.jp (S. Takizawa).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.08.005

1190
S. Hirata et al. / Tetrahedron: Asymmetry 24 (2013) 1189–1192
Table 1
Table 2
Enantioselective aza-MBH reaction of 2a with 3a using organocatalysts 1a
Effect of reaction conditions using the organocatalyst 1ca
p-TsN
O
NHp-Ts
(S)-1c (10 mol%)
O
2a + 3a
(R)-4a
Yieldb (%)
1
(S)- (10 mol%)
25 o
C
+
H
Me
Me
CHCl3
Entry
Solvent
Concd of 3a (M)
Time (d)
eec (%)
25 oC, 1 d
Br
Br
2a
3a
Catalyst
4a
(R)-
1
2
3
4
5
6
7
8
9
MeOH
H2O
Toluene
THF
CH2Cl2
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
0.5
0.5
0.5
0.5
0.5
0.5
0.1
0.25
0.5
1.0
1
1
1
1
1
1
3
3
3
3
6
16
18
18
23
48
Trace
33
85
74
2
6
Entry
Yieldb (%)
eec (%)
42
49
54
61
—
56
64
42
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
16
6
48
16
8
4
11
61
47
7
7
1
10
1g
Trace
—
a
b
c
3 Equiv of 2a.
Isolated yield of product 4a.
Determined by HPLC (Daicel Chiralpak AD-H).
a
b
c
0.5 M (substrate concentration of 3a) and 3 equiv of 2a.
Isolated yield of product 4a.
Determined by HPLC (Daicel Chiralpak AD-H).
Table 3
Effect of the N-substituents in the bifunctional organocatalysts 1a
methylene spacer. Alkyldiamines with various chain lengths (C2
and C4–C6 for 1a and 1e–g, respectively) were then incorporated
using a methylene spacer, and the resulting compounds were used
as organocatalysts. In these cases, low or no catalytic activity was
observed (entries 1 and 5–7). These results indicate that the exact
positioning of the acid and base units on the catalyst dramatically
affects the efficiency of bifunctional enantioselective catalysis.
Entry
Catalyst (10 mol %)
Time (d)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
1c
1h
1i
1j
1k
1l
3
4
3
4
3
2
2
2
85
73
86
65
86
64 (R)
58 (R)
63 (R)
70 (R)
70 (R)
12 (S)
—
65
1m
1n
NRd
NRd
Me
N
Me
N
—
Me
a
b
c
N
N
Me
0.5 M (substrate concentration of 3a) and 3 equiv of 2a.
Isolated yield of product 4a.
Determined by HPLC (Daicel Chiralpak AD-H).
No reaction.
Me
Me
OH
OH
OH
OH
d
1a
1b
The most efficient process was observed with organocatalyst
1k8 (R = Bn) bearing a terminal pyrrolidine unit and a concentra-
tion of 3a <0.5 M (Table 3, entry 5). When BINOL derivatives 1m
and 1n were applied in the reaction, no activity was observed
probably owing to the steric hindrance of the terminal Lewis base
unit or electronic influence of the oxygen atom on the morpholine
to the terminal nitrogen-Lewis base region.
Me
N
Me
N
Me
Me
N
N
Me
Me
OH
OH
OH
OH
1c
1d
Me
N
Me
Me
N
R
N
Me
N
R
N
Me
N
N
N
Me
Me
Me
OH
OH
OH
OH
OH
OH
OH
OH
1e
1f
1h (R = H)
1i (R = Bn)
1j (R = Me)
1k (R = Bn)
Me
N
Me
N
Me
N
N
N
Me
OH
OH
OH
OH
1g
1l
Encouraged by these results, the effects of solvent and concen-
tration on the reaction of 2a with 3a (Table 2) were then investi-
gated. In terms of enantioselectivity, CHCl3 (entry 6), toluene
(entry 3), THF (entry 4), and CH2Cl2 (entry 5) gave good results
compared with those obtained with protic solvents (entries 1
and 2). The appropriate concentration of 3a was also important
for promoting the reaction in high yields with good enantioselec-
tivity (entry 9).
Me
N
Et
N
Me
N
O
N
Et
OH
OH
OH
OH
1m
1n

S. Hirata et al. / Tetrahedron: Asymmetry 24 (2013) 1189–1192
1191
Table 4
Substrate scopea
O
O
NHR3
R2
NR3
(S)-1k (10 mol%)
+
R1
R1
CHCl3
H
R2
2
3
(R)-4
Entry
2
3
Temp (°C)
Time (d)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
2a, R1 = Me
2a
2a
2a
2a
2a
2a
2a
3a, R2 = p-Br–C6H4, R3 = p-Ts
3b, R2 = o-Br–C6H4, R3 = p-Ts
3c, R2 = p-Cl–C6H4, R3 = p-Ts
3d, R2 = p-Cl–C6H4, R3 = m-Ts
3e, R2 = p-Cl–C6H4, R3 = o-Ts
3f, R2 = p-Cl–C6H4, R3 = SO2Ph
3g, R2 = p-CN–C6H4, R3 = p-Ts
3h, R2 = p-NO2–C6H4, R3 = p-Ts
3i, R2 = m-NO2–C6H4, R3 = p-Ts
3j, R2 = p-F–C6H4, R3 = p-Ts
3k, R2 = p-Et–C6H4, R3 = p-Ts
3l, R2 = p-MeO–C6H4, R3 = p-Ts
3h
25
25
25
25
25
25
0
0
-25
5
3
3
3
3
3
3
1.5
1.5
2
2
5
8
7
4a, 86
4b, 83
4c, 51 (85)d
4d, 44
4e, 51
4f, 44
4g, 88
4h, 92
4i, 97
4j, 83
4k, 88
4l, 78
4m, 77
70
39f
74 (74)d
55
20
69
67
64
60
71
72
82
9
2a
2a
2a
2a
10
11e
12
13
25
25
5
2b, R1 = 2-naphthoxy
0
a
0.5 M (substrate concentration of 3) and 3 equiv of 2.
b
c
d
e
f
Isolated yield.
Determined by HPLC (Daicel Chiralpak AD-H for 4a–k; Daicel Chiralcel OD-H for 4l; Daicel Chiralpak IB for 4m; Daicel Chiralcel OD-3 for 4n; Daicel Chiralpak IA for 4o).
For 5 days.
20 mol % of 1k was used.
(S)-Configuration product was obtained.
Me
NBoc
O
1k
(S)- (10 mol%)
2a
+
NHBoc
O
(1)
O
CHCl3, 5 oC, 4d
N
Bn
N
3m
Bn
4n
90%, 71% ee
NHp-Ts
2a
O
NHp-Ts
SO2Ph
+
(S)-1k (10 mol%)
(2)
Me
Me
CHCl3, 5 oC, 4 d
Me
3n
4o
19%, 50% ee
Scheme 1. aza-MBH reaction of 2a with ketimine 3m, or aliphatic aldimine generated from 3n in situ.
With the optimized conditions in hand, the reaction scope was
(Table 4, entry 13) and the aliphatic aldimine generated in situ
from 3n (Scheme 1, Eq. 2) were not appropriate for this
system.5c,e,y
explored.9 As can be seen in Table 4, when N-p-tosyl aldimines 3,
prepared from the corresponding p- and m-substituted
arylaldehydes, were applied as substrates (entries 1, 3, and
7–12), organocatalyst 1k efficiently promoted the reaction with
2a to give adducts 4 in high yields and with good enantioselectiv-
ities. The reaction of 2a and 3l with organocatalyst 1k proceeded
with the highest ee (82%) (entry 12). It should be noted that while
Furthermore, it was confirmed that a diamine unit is essential
for promoting the transformation; the monoamine derivatives 5
and 6 failed to undergo the reaction (Scheme 2). Given these re-
sults and considering our previously proposed transition state for
the aza-MBH reaction catalyzed by (S)-3-(N-isopropyl-N-3-pyrid-
inylaminomethyl)-1,10-bi(2-naphthol),5b,6a,b it was thought that
one acid–base pair (the 2-hydroxy group and the nitrogen atom
on the benzylic position) fixed the conformation of the organocat-
alyst via hydrogen bonding, while the other acid–base unit acti-
vates substrate 2a (Fig. 2). Notably, the 1H NMR (400 MHz,
CDCl3) studies showed that in the reaction mixture consisting of
the ketimine 3m derived from a cyclic a-keto amide was found to
be a suitable substrate (Scheme 1, Eq. 1),5w 2-naphthyl acrylate 2b
(S)-1m, 1n, 5 or 6 (10 mol%)
2a + 3a
No reaction
CHCl3, 25 o
C
Me
N
Bn
N
Me
N
Me
H
Me
O
OH
OH
OH
OH
N
O H
O
5
6
Me
Scheme 2. Catalyst screening of compounds 5 and 6.
Figure 2. Our proposed intermediate.

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S. Hirata et al. / Tetrahedron: Asymmetry 24 (2013) 1189–1192
3. (a) Morita, K.; Suzuki, Z.; Hirose, H. Bull. Chem. Soc. Jpn. 1968, 41, 2815; (b) Baylis,
A. B.; Hillman, M. E. D. German Patent 2,155,113, 1972. [Chem. Abstr. 1972, 77,
34174q].
4. For recent reviews on applications of MBH adducts to bioactive molecules, see:
(a) Declerck, V.; Martinez, J.; Lamaty, F. Chem. Rev. 2009, 109, 1; (b) Basavaiah,
D.; Reddy, B. S.; Badsara, S. S. Chem. Rev. 2010, 110, 5447; (c) Lima–Junior, C. G.;
Vasconcellos, M. L. A. A. Bioorg. Med. Chem. 2012, 20, 3954.
catalyst 1c and enone 2a, the peak for the Me group of 2a at d 2.26
(3H, s) shifted to d 2.07 (3H, s), and the peaks for the two phenolic
hydroxy groups at d 4.12 (1H, s) and d 4.00 (1H, s) in catalyst 1c
also shifted to 3.96 (2H, br s) due to the formation of the corre-
sponding ammonium enolates. A chiral bifunctional organocatalyst
bearing a 1,3-propanediamine unit would provide a flexible chiral
pocket resulting in the formation of the aza-MBH adducts with
moderate to good enantioselectivities.
5. For selected recent reviews and reports on the enantioselective MBH reaction,
see: (a) Masson, G.; Housseman, C.; Zhu, J. Angew. Chem., Int. Ed. 2007, 46, 4614;
(b) Takizawa, S.; Matsui, K.; Sasai, H. J. Synth. Org. Chem. Jpn. 2007, 65, 1089; (c)
Abermil, N.; Masson, G.; Zhu, J. J. Am. Chem. Soc. 2008, 130, 12596; (d) Abermil,
N.; Masson, G.; Zhu, J. Org. Lett. 2009, 11, 4648; (e) Abermil, N.; Masson, G.; Zhu,
J. Adv. Synth. Catal. 2010, 352, 656; (f) Wang, X.; Chen, Y.-F.; Niu, L.-F.; Xu, P. F.
Org. Lett. 2009, 11, 3310; (g) Wei, Y.; Shi, M. Acc. Chem. Res. 2010, 43, 1005; (h)
Takizawa, S.; Inoue, N.; Hirata, S.; Sasai, H. Angew. Chem., Int. Ed. 2010, 49, 9725;
(i) Liu, Y.-L.; Wang, B.-L.; Cao, J.-J.; Chen, L.; Zhang, Y.-X.; Wang, C.; Zhou, J. J. Am.
Chem. Soc. 2010, 132, 15176; (j) Guan, X.-Y.; Wei, Y.; Shi, M. Eur. J. Org. Chem.
2010, 4098; (k) Takizawa, S.; Horii, A.; Sasai, H. Tetrahedron: Asymmetry 2010,
21, 891; (l) Anstiss, C.; Liu, F. Tetrahedron 2010, 66, 5486; (m) Oh, K.; Li, J.-Y.;
Ryu, J. Org. Biomol. Chem. 2010, 8, 3015; (n) Wang, S.-X.; Han, X.; Zhong, F.;
Wang, Y.; Lu, Y. Synlett 2011, 2766; (o) Takizawa, S.; Inoue, N.; Sasai, H.
Tetrahedron Lett. 2011, 52, 377; (p) Takizawa, S.; Kiriyama, K.; Ieki, K.; Sasai, H.
Chem. Commun. 2011, 9227; (q) Han, X.; Wang, Y.; Zhong, F.; Lu, Y. Org. Biomol.
Chem. 2011, 9, 6734; (r) Cihalova, S.; Dziedzic, P.; Cordova, A.; Vesely, J. Adv.
Synth. Catal. 2011, 353, 1096; (s) Zhong, F.; Wang, Y.; Han, X.; Huang, K.-W.; Lu,
Y. Org. Lett. 2011, 13, 1310; (t) Zhong, F.; Chen, G.-Y.; Lu, Y. Org. Lett. 2011, 13, 82;
(u) Yang, Y.-L.; Wei, Y.; Shi, M. Org. Biomol. Chem. 2012, 10, 7429; (v) Kitagaki, S.;
Ohta, Y.; Takahashi, R.; Komizu, M.; Mukai, C. Tetrahedron Lett. 2013, 54, 384;
(w) Hu, F.-L.; Wei, Y.; Shi, M.; Pindi, S.; Li, G. Org. Biomol. Chem. 2013, 11, 1921;
(x) Duan, Z.; Zhang, Z.; Qian, P.; Han, J.; Pan, Y. RSC Adv. 2013, 3, 10127; (y)
Rémond, E.; Bayardon, J.; Takizawa, S.; Rousselin, Y.; Sasai, H.; Jugé, S. Org. Lett.
2013, 15, 1870; (z) Yao, Y.; Li, J.-L.; Zhou, Q.-Q.; Dong, L.; Chen, Y.-C. Chem. Eur. J.
2013, 19, 9447.
3. Conclusion
In conclusion, the chiral bifunctional catalyst 1k was found to
accelerate the aza-MBH reaction to afford the desired adducts in
high yields with up to 82% ee. The realization that BINOL as a
Brønsted acid unit is compatible with a range of 1,3-propanedi-
amine derivatives as Lewis base units has allowed the develop-
ment of bifunctional catalysts for the aza-MBH reaction. Further
studies aimed for elucidating the detailed activation mechanism
are currently in progress.
Acknowledgments
This study was supported by the CREST project of the Japan
Science and Technology Corporation (JST), Grant-in-Aid for
Scientific Research on Innovative Areas ‘Advanced Molecular
Transformations by Organocatalysts’ from The Ministry of Educa-
tion, Culture, Sports, Science and Technology (MEXT), Japan and
JST, Advanced Catalytic Transformation Program for Carbon Utili-
zation (ACT-C). Y.Y. thanks JSPS Research Fellowships for Young
Scientists. We acknowledge the technical staff of the Comprehen-
sive Analysis Center of ISIR, Osaka University (Japan).
6. (a) Matsui, K.; Takizawa, S.; Sasai, H. J. Am. Chem. Soc. 2005, 127, 3680; (b)
Matsui, K.; Tanaka, K.; Horii, A.; Takizawa, S.; Sasai, H. Tetrahedron: Asymmetry
2006, 17, 578; (c) Matsui, K.; Takizawa, S.; Sasai, H. Synlett 2006, 761.
7. Lee, K. Y.; GowriSankar, S.; Kim, J. N. Tetrahedron Lett. 2004, 45, 5485.
8. Analytical data for (S)-1k: ½a 2D0 (cmꢁ1) 3056,
¼ ꢁ30:6 (c 0.59, CHCl3); IR (neat) m
ꢀ
2928, 2821, 2346, 1736, 1620, 1596, 1509, 1431, 1342, 1244, 1211, 1148, 1107;
1H NMR (400 MHz, CDCl3): d 7.90 (d, J = 8.9 Hz, 1H), 7.85 (d, J = 7.6 Hz, 1H), 7.79
(d, J = 8.2 Hz, 1H), 7.70 (s, 1H), 7.37 (d, J = 8.9 Hz, 1H), 7.33–7.12 (m, 11H), 4.10
(d, J = 13.0 Hz, 1H), 4.02 (d, J = 13.7 Hz, 1H), 3.79 (d, J = 13.7 Hz, 1H), 3.65 (d,
J = 13.0 Hz, 1H), 2.66–2.55 (m, 2H), 2.40–2.27 (m, 6H), 1.80–1.74 (m, 2H), 1.71–
1.67 (m, 4H); 13C NMR (100 MHz, CDCl3): d 154.8, 151.6, 136.2, 133.8, 133.7,
129.7, 129.6, 129.2, 129.1, 128.6, 128.4, 128.2, 127.7 ꢂ 2, 126.8, 126.3, 125.1,
125.0, 124.5, 123.6, 123.1, 117.8, 115.3, 113.1, 58.5, 58.4, 54.1, 54.0, 51.4, 25.5,
23.3; HRMS (ESI) calcd for C35H37N2O2, m/z = 517.2855 [(M+H)+]; found, m/
z = 517.2849.
References
1. For recent reviews on enantioselective multifunctional organocatalysis, see:
(a) Sohtome, Y.; Nagasawa, K. Chem. Commun. 2012, 7777; (b) Lu, L.-Q.; An, X-L.;
Chen, J.-R.; Xiao, W.-J. Synlett 2012, 490; (c) Briere, J. F.; Oudeyer, S.; Dalla, V.;
Levacher, V. Chem. Soc. Rev. 2012, 41, 1696; (d) Chauhan, P.; Chimni, S. S. RSC
Adv. 2012, 2, 737.
2. For selected recent reports on enantioselective multifunctional organocatalysis,
see: (a) Wakchaure, V. N.; List, B. Angew. Chem., Int. Ed. 2010, 49, 4136;
(b) Sakakura, A.; Sakuma, M.; Ishihara, K. Org. Lett. 2011, 13, 3130; (c)
Momiyama, N.; Konno, T.; Furiya, Y.; Iwamoto, T.; Terada, M. J. Am. Chem. Soc.
2011, 133, 19294; (d) Takizawa, S.; Nguyen, T. M. N.; Grossmann, A.; Enders, D.;
Sasai, H. Angew. Chem., Int. Ed. 2012, 51, 5423; (e) Uraguchi, D.; Yoshioka, K.;
Ueki, Y.; Ooi, T. J. Am. Chem. Soc. 2012, 134, 19370; (f) Inokuma, T.; Furukawa,
M.; Suzuki, Y.; Kimachi, T.; Kobayashi, Y.; Takemoto, Y. ChemCatChem 2012, 4,
983; (g) Takizawa, S.; Nguyen, T. M. N.; Grossmann, A.; Suzuki, M.; Enders, D.;
Sasai, H. Tetrahedron 2013, 69, 1202; (h) Mori, K.; Ichikawa, Y.; Kobayashi, M.;
Shibata, Y.; Yamanaka, M.; Akiyama, T. J. Am. Chem. Soc. 2013, 135, 3964.
9. General procedure for the enantioselective aza-MBH reaction catalyzed by (S)-1k
(Table 4): To a solution of organocatalyst 1k (2.5 mg, 0.005 mmol) in CHCl3
(0.3 mL) were added 2 (0.15 mmol) and imine 3 (0.05 mmol). The mixture was
stirred until the reaction reached completion as determined by TLC analysis. The
mixture was directly purified by flash column chromatography (SiO2,
hexane:EtOAc = 3/1) to give the corresponding adduct 4 as a white solid. All
adducts were characterized by 1H, 13C NMR, MS, and IR spectroscopy, and were
identical in all respects with the reported data.5,6 The absolute configurations of
4 were determined by comparing the specific rotation assignments with those
in the literature.5,6