Synthesis of some new tertiary amines and their application as co-catalysts in combination with l-proline in enantioselective Baylis-Hillman reaction between o-nitrobenzaldehyde and methyl vinyl ketone

Article abstract of DOI:10.1016/j.tetlet.2006.06.023

A chiral benzodiazepine derivative 1 was synthesized starting from o-nitrobenzoyl chloride and methyl l-prolinate hydrochloride. Diastereomeric (1R,2R,1′S)-(+)-2-[N-methyl-N-(α-phenylethyl)amino]cyclohexanol 3a and (1S,2S,1′S)-(+)-2-[N-methyl-N-(α-phenylethyl)amino]cyclohexanol 3b were synthesized starting from (S)-α-phenylethylamine and cyclohexene oxide via ring-opening, diastereomer separation and N-methylation. (S,S)-octahydrodipyrrolo[1,2-a:1′,2′-d]pyrazin 5 was synthesized from methyl l-prolinate. Chiral tertiary amines 1, 3a, 3b and 5 almost cannot catalyze the Baylis-Hillman reaction between o-nitrobenzaldehyde and methyl vinyl ketone (MVK). However, they functioned as efficient catalysts for this reaction in the presence of l-proline. The corresponding adducts were obtained in good yields with enantioselectivity of 83% ee, 81% ee, 51% ee and 66% ee, respectively.

Full text of DOI:10.1016/j.tetlet.2006.06.023

Tetrahedron Letters 47 (2006) 5717–5721
Synthesis of some new tertiary amines and their application as
co-catalysts in combination with L-proline in enantioselective
Baylis–Hillman reaction between o-nitrobenzaldehyde
and methyl vinyl ketone
Hongying Tang, Guofeng Zhao,* Zhenghong Zhou,* Qilin Zhou and Chuchi Tang
State Key Laboratory of Elemento-Organic Chemistry, Institute of Elemento-Organic Chemistry, Nankai University,
Tianjin 300071, PR China
Received 20 March 2006; revised 1 June 2006; accepted 2 June 2006
Available online 23 June 2006
Abstract—A chiral benzodiazepine derivative 1 was synthesized starting from o-nitrobenzoyl chloride and methyl L-prolinate hydro-
chloride. Diastereomeric (1R,2R,10S)-(+)-2-[N-methyl-N-(a-phenylethyl)amino]cyclohexanol 3a and (1S,2S,10S)-(+)-2-[N-methyl-
N-(a-phenylethyl)amino]cyclohexanol 3b were synthesized starting from (S)-a-phenylethylamine and cyclohexene oxide via ring-
opening, diastereomer separation and N-methylation. (S,S)-octahydrodipyrrolo[1,2-a:10,20-d]pyrazin 5 was synthesized from methyl
L-prolinate. Chiral tertiary amines 1, 3a, 3b and 5 almost cannot catalyze the Baylis–Hillman reaction between o-nitrobenzaldehyde
and methyl vinyl ketone (MVK). However, they functioned as efficient catalysts for this reaction in the presence of L-proline. The
corresponding adducts were obtained in good yields with enantioselectivity of 83% ee, 81% ee, 51% ee and 66% ee, respectively.
Ó 2006 Elsevier Ltd. All rights reserved.
Recently, chiral tertiary amines catalyzed asymmetric
Baylis–Hillman (B–H) reaction has attracted much
attention, and significant progress has been witnessed
in this area.1 All the tertiary amines employed as the
catalysts in this reaction can be classified into the
following three categories: (1) Chiral tertiary amine
without free hydroxyl group which functions as a nucleo-
phile to promote the Michael addition on to the acti-
vated alkenes.2 (2) The second class represents chiral
tertiary amine containing a free hydroxyl group. The
existence of suitably positioned hydroxyl group can sta-
bilize the enolate intermediate via a hydrogen-bonding
interaction involving the hydroxyl group and the enolate
formed in the reaction.3 (3) The third type refers to chi-
ral tertiary amine in combination with a Lewis acid or
Brønsted acid which act as co-catalyst in the B–H reac-
tion.4 Only a few examples of tertiary amine without
free hydroxyl groups have been documented because
of their poor enantioselectivities. The best result (75%
ee) in the coupling of methyl vinyl ketone (MVK) with
aromatic aldehyde was obtained by Hayashi et al.2d
The second type of tertiary amine catalysts seems more
important and efficient. Among them, the alkaloids qui-
nine or quinidine and their derivatives demonstrated
good catalytic activity. Hatakeyama and co-workers,
employing a quinidine derivative as the catalyst, at-
tained an enantioselectivity of up to 91% ee. However,
the activated alkene was limited to 1,1,1,3,3,3-hexaflu-
oro-2-propyl acrylate.3f–i Shi and Jiang re-investigated
the same catalyst. The enantioselectivities of 92% ee
and 49% ee were obtained when a-naphthyl acrylate
and MVK were used as the substrate, respectively.3j
Krishna et al. reported L-prolinol catalyzed B–H reac-
tion of MVK with arylaldehydes in which up to 78%
ee was obtained.3k Recently, some examples of the third
type of catalysts were reported. Barret et al. reported
chiral pyrrolizidine catalyzed reaction of ethyl vinyl ke-
tone and aromatic aldehydes. The best enantioselectivity
of 72% ee was observed in the presence of NaBF4.4a
Achiral weak base imidazole and L-proline co-catalyzed
B–H reaction between MVK and arylaldehydes was
examined by Shi et al. Although an obvious rate accel-
eration of the reaction was observed, the enantioselectiv-
ities of the reaction were quite low (5–10% ee).4b Shi
documented Hatakeyama catalyst, in combination with
L- or D-proline, LiOTf, LiClO4, catalyzed reaction
*
Corresponding authors. Fax: +86 22 2350 8939/3438 (Z.Z.); e-mail:
z.h.zhou@nankai.edu.cn
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.023

5718
H. Tang et al. / Tetrahedron Letters 47 (2006) 5717–5721
between MVK and aldehyde. No obvious improvements
in enantioselectivity were achieved compared with the
reaction without the additive.3j Miller and co-workers
developed an efficient co-catalytic system of L-proline
and peptides for the asymmetric B–H reaction of
MVK and aromatic aldehydes. The corresponding
adducts were formed with up to 81% ee. This was the
best result for MVK-based B–H reaction prior to this
report.4c The combination of DABCO (1,4-diaza-bi-
cyclo[2.2.2]octane) and a chiral Lewis acid formed upon
the treatment of D-camphor-derived diimino ligand and
La(OTf)3 provided high enantioselectivity (up to 95%
ee) in acrylate-based B–H reaction.4d Most recently,
Miller and co-workers realized catalytic asymmetric
intramolecular B–H reaction in which ee of up to 84%
was achieved.4e Although only a few examples were doc-
umented for the third type of catalysts, which is sup-
posed to mediate the reaction via dual activation of
the electrophile and the nucleophile,5 it is attracting
more and more attention from organic chemists because
of its efficacy on rate acceleration and enantioselectivity
improvement in asymmetric B–H reactions. Herein, we
wish to report the synthesis of some new chiral tertiary
amines and their application as co-catalysts in combina-
tion with L-proline in enantioselective B–H reaction
between o-nitrobenzaldehyde and methyl vinyl ketone.
Chiral tricyclic benzodiazepine 1 was synthesized start-
ing from o-nitrobenzoic acid and methyl L-prolinate
hydrochloride (Scheme 1). A lot of procedures have been
reported for the synthesis of 2, in which the common
starting material is 2-azidobenzoic6 acid or anthranilic
acid (2-aminobenzoic acid),7 respectively. The use of o-
nitrobenzoic acid as the starting material shortens the ac-
cess to 2. Most importantly, 2 was obtained with good
chemical yield in the key reduction ring-closing step uti-
lizing the cheap and readily available iron filings as the
reductant. Further reduction of 2 provided 1.8,9 This
convenient and practical method may be useful for the
synthesis of chiral benzodiazepine pharmaceuticals.
Diastereomeric (1R,2R,10S)-(+)-2-[N-methyl-N-(a-phen-
ylethyl)amino]cyclohexanol 3a and (1S,2S,10S)-(+)-2-
[N-methyl-N-(a-phenylethyl)amino]cyclohexanol 3b were
synthesized according to the synthetic route outlined in
Scheme 2. Overman and Sugai10 first examined the ring-
opening of cyclohexene oxide with (R)- or (S)-a-phenyl-
ethylamine in the presence of AlMe3. A pair of diastereo-
mer (1:1 molar ratio) was obtained after flash chro-
matography separation. Bianchini and co-workers11
carried out this reaction in an autoclave at high tempera-
ture (160 °C). The separation of diastereomeric amines 4
was accomplished by fractional crystallization of the cor-
responding hydrochloride. According to Juaristic’s and
co-workers procedure,12 the ring-opening of cyclohexene
oxide took place smoothly in the presence of anhydrous
lithium perchlorate. The corresponding diastereomeric
2-aminocyclohexanols 4a (major, 57%) and 4b (minor,
24%) were separated through column chromatography
on silica gel. Further N-methylation of 4a and 4b with
formaldehyde and formic acid afforded 3a and 3b,
respectively.13
O
O
N
i
OMe
Cl
NO2
+
N
73%
H.HCl
NO2
O
MeO
O
O
Following Breitmaier and Zadel’s procedure,14,15 dimer-
ization of methyl L-prolinate and then reduction of the
corresponding cyclic dipeptide gave (S,S)-(+)-octa-
hydrodipyrrolo[1,2-a:10,20-d]pyrazin 5 (Scheme 3).
N
N
iii
80%
ii
68%
N
H
N
H
O
1
2
The catalytic activity of the prepared tertiary amines 1, 3
and 5 was preliminarily examined using the reaction of
o-nitrobenzaldehyde and MVK as a model.16 Chiral
Scheme 1. Reagents and conditions: (i) Et3N/CH2Cl2, 0 °C; (ii) Fe/
AcOH, 110 °C; (iii) LiAlH4/THF, ꢀ10 °C–rt, N2.
OH
R
R
OH
R
iii
Me
R
NH
24%
N
76%
S
S
H
H
Me
Me
)-(+)-3a
S
Ph
Ph
Me
H
i
(1R,2
R,1'
S)-(+)-4a
(1R
,2R
,1'
+
O
H2N
ii
Ph
S
OH
OH
S
57%
iii
Me
S
S
N
S
NH
S
99%
H
Ph
H
Ph
,1'
Me
Me
)-(-)-4b
(1
S,2
S
S
(1S,2S,1'S)-(-)-3b
Scheme 2. Reagents and conditions: (i) LiClO4/MeCN, reflux, 18 h; (ii) Separation of diastereomer via column chromatography; (iii) HCO2H/
HCHO, reflux, 4 h.

H. Tang et al. / Tetrahedron Letters 47 (2006) 5717–5721
5719
O
N
N
iii
72%
i
ii
OMe
OMe
N
N
81%
N
N
72%
H.HCl
H
O
O
O
5
Scheme 3. Reagents and conditions: (i) K2CO3, 0 °C; (ii) 105 °C; (iii) LiAlH4/THF, ꢀ10 °C–rt, N2.
Table 1. Chiral amine/L-proline co-catalyzed B–H reaction between MVK and o-nitrobenzaldehyde
NO2
O
NO2 OH
O
O
Cat./L-Proline
Solvent, 20 oC
+
H
Entry
Catalyst (mol %)
L-Proline (mol %)
Solvent
Time (day)
Yielda (%)
eeb (%)
Configurationc
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1(5)
1(5)
1(5)
1(5)
1(5)
1(30)
1(3)
10
10
10
10
10
60
6
2.5
30
40
30
30
5
THF
MeCN
DMF
5
3
3
5
5
4
5
6
6
4
7
7
5
5.5
80
53
34
82
68
63
71
45
66
84
35
61
79
61
63
75
52
58
83
76
45
53
81
74
54
51
66
47
S
S
S
R
S
S
S
S
S
S
S
S
S
S
CHCl3/THF (v/v, 1:4)
CHCl3/THF (v/v, 4:1)
CHCl3/THF (v/v, 4:1)
CHCl3/THF (v/v, 4:1)
CHCl3/THF (v/v, 4:1)
CHCl3/THF (v/v, 4:1)
CHCl3/THF (v/v, 4:1)
CHCl3/THF (v/v, 4:1)
CHCl3/THF (v/v, 4:1)
CHCl3/THF (v/v, 4:1)
CHCl3/THF (v/v, 4:1)
1(5)
3a(30)
3a(40)
3a(30)
3b(30)
5(5)
5(5)
10
a Isolated yield.
b Determined by HPLC analysis on a chiralcel AD-H column, hexane–2-propanol = 90:10, flow rate 0.7 mL/min, tR = 32.8 and 36.6 min.
c Determined by comparison of the specific rotation value with the literature value.2d
tertiary amine 1 itself exhibited poor catalytic activity
for the reaction when used alone. Almost racemic prod-
uct was obtained with only 10% yield after stirring for 9
days at room temperature. Catalysts 3a, 3b and 5 can
not promote the reaction at all by themselves. No reac-
tion was detected even after stirring for 2 weeks at 20 °C.
However, dramatic improvements on the reaction rate
as well as enantioselectivitiy were observed using chiral
amine 1, 3a, 3b and 5 in combination with L-proline as
the co-catalytic system. The corresponding adduct was
obtained not only in good yield but also with the best
enantioselectivity for MVK-base B–H reaction. The
results are listed in Table 1.
The combination of 5 (5 mol %) and L-proline (5 mol %)
produced the product only with 66% ee (entry 13).
Based on these results, the scope of the aldehydes was
preliminarily investigated. A set of aromatic aldehydes
were employed to the coupling of MVK under the opti-
mized reaction conditions using 1 and L-proline as the
co-catalyst. The results are listed in Table 2. This co-cat-
alyst system was also effective to the tested aldehydes.
The corresponding adducts were obtained in good yields
with moderate enantioselectivities.
Table 2. 1/L-proline co-catalyzed B–H reaction between MVK and
aromatic aldehydes
The influence of solvent, catalyst loading and molar
ratio of catalyst to L-proline on the reaction was systema-
tically investigated. As shown in Table 1, the reaction
conducted best in CHCl3/THF (v/v, 4:1) at 20 °C. The
optimal catalyst loading and molar ratio of catalyst to
L-proline was varied depending on the catalyst em-
ployed. The catalytic system in combination of amine
1 (5 mol %) with L-proline (10 mol %) provided ee value
of 83% (entry 5). The cooperative catalyst consists of
30 mol % of chiral amine 3a and 30 mol % of L-proline
affording enantioselectivity of 81% ee (entry 9). Under
the same condition, diastereomeric 3b provided much
lower selectivity (51% ee, entry 12). This result implies
that 3b and L-proline is a mismatched pair of co-catalyst.
O
OH
O
O
1/L-Proline
+
CHCl3/THF (v/v=4:1)
20 oC
Ar
Ar
H
Entry Ar
Time (days) Yielda (%) eeb (%)
1
2
3
4
5
1-Nitro-2-naphthyl
3-MeO-2-NO2C6H3 10
3-NO2C6H3
4-Cl-2-NO2C6H3
2-F-4-ClC6H3
5
70
66
76
54
66
46
52
59
32
31
4
5
5
a Isolated yield.
b Determined by HPLC analysis on a chiralcel AD-H column.

5720
H. Tang et al. / Tetrahedron Letters 47 (2006) 5717–5721
4. (a) Barrett, A. G. M.; Cook, A. S.; Kamimura, A. Chem.
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In conclusion, an efficient new route for the preparation
of chiral benzodiazepine 1 has been developed starting
from readily available raw materials. Diastereomeric 2-
aminocyclohexanols 3a and 3b were synthesized starting
from (S)-a-phenylethylamine and cyclohexene oxide.
(S,S)-Octahydrodipyrrolo-[1,2-a:10,20-d]pyrazin 5 was
synthesized from methyl L-prolinate. The preliminary
screening of the catalysts 1, 3a, 3b and 5 revealed that
these compounds exhibited almost no catalytic activity
for the reaction of o-nitrobenzaldehyde and MVK with-
out the coexistence of L-proline. However, dramatic
improvements on the reaction rate as well as enantiose-
lectivity were observed with the introduction of L-pro-
line to form a co-catalytic system. The combination of
1 and L-proline gave the product with ee value of 83%.
The L-proline-3a combination provided the product
with an enantioselectivity of 81% ee. At present, these
represent the best result for the MVK-based B–H reac-
tion. The L-Pro-3b and L-Pro-5 combination also affor-
ded the product with selectivity of 51% ee and 66% ee,
respectively. These results revealed that the co-catalytic
function of the tertiary amine and L-proline played an
important role in the reaction. Further extending of this
catalytic system to other aldehydes or activated alkenes
and the exact mechanistic explanation for this reaction
are ongoing in our laboratory.
5. Ma, J. A.; Cahard, D. Angew. Chem., Int. Ed. 2004, 43,
4566.
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E.; Arifuddin, M. Tetrahedron Lett. 2000, 41, 7743; (g)
Kamal, A.; Reddy, K. S.; Prasad, B. R.; Babu, A. H.;
Ramana, A. V. Tetrahedron Lett. 2004, 45, 6517; (h)
Kamal, A.; Ramana, A. V.; Reddy, K. S.; Ramana, K. V.;
Haribabu, A.; Prasad, B. R. Tetrahedron Lett. 2004, 45,
8187; (i) Kamal, A.; Reddy, K. L.; Devaiah, V.; Shanka-
raiah, N. Synlett. 2004, 2533.
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Springer, J. P. Tetrahedron Lett. 1985, 26, 1619; (b)
Nagasaka, T.; Koseki, Y.; Hamaguchi, F. Tetrahedron
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J.; Bremer, M. Zeit. Natur., B Chem. Sci. 1990, 45, 258; (d)
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Acknowledgements
We are grateful to the National Natural Science Foun-
dation of China (No. 20472033) and the Ph.D. Pro-
grams and the Key Science and Technology Project of
Ministry of Education of China for generous financial
support for our programs.
20
9. Experimental data of compound 1: Mp 102–104 °C, ½aꢁD
ꢀ177.7 (c 1.0, CHCl3). Anal. Calcd For C12H16N2: C,
76.60; H, 8.51; N, 14.89. Found: C, 76.57; H, 8.50; N,
14.71. 1H NMR (d, CHCl3, 300 MHz): 1.41–1.54 (m, 1H),
1.75–1.99 (m, 3H), 2.44–2.63 (m, 2H), 2.75 (dd, 1H,
J = 12.6, 9.6 Hz, one proton of NCH2), 3.16 (dt, 1H,
J = 8.4, 2.7 Hz, CH), 3.33 (dd, 1H, J = 12.6, 1.5 Hz, one
proton of NCH2), 3.52 (d, 1H, J = 13.5 Hz, one proton of
PhCH2), 3.83 (d, 1H, J = 13.5 Hz, one proton of PhCH2),
3.86 (br, 1H, NH), 6.72 (dd, 1Harom, J = 7.8 Hz, 0.6 Hz),
6.83 (dt, 1Harom, J = 7.5 Hz, 1.2 Hz), 7.04–7.13 (m,
2Harom).
References and notes
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Rev. 2003, 103, 811; (b) Cai, J. X.; Zhou, Z. H.; Tang, C.
C. Chem. Res. (Chinese) 2001, 12, 54; (c) Langer, P.
Angew. Chem., Int. Ed. 2000, 39, 3049.
2. (a) Oishi, T.; Hirama, M. Tetrahedron Lett. 1992, 33, 639;
(b) Oishi, T.; Oguri, H.; Hirama, M. Tetrahedron: Asym-
metry 1995, 6, 1241; (c) Barrett, A. G. M.; Dozzo, P.;
White, A. J. P.; Williams, D. J. Tetrahedron 2002, 58,
7303; (d) Hayashi, Y.; Tamura, T.; Shoji, M. Adv. Synth.
Catal. 2004, 346, 1106.
3. (a) Drewes, S. E.; Roos, G. H. P. Tetrahedron 1988, 44,
4653; (b) Bailey, M.; Marko, I. E.; Olis, W. D.; Rassmus-
sen, P. R. Tetrahedron Lett. 1990, 31, 4509; (c) Gilbert, A.;
Heritage, T. W.; Isaacs, N. S. Tetrahedron: Asymmetry
1991, 2, 969; (d) Marko, I. E.; Giles, P. R.; Hindley, N. J.
Tetrahedron 1997, 53, 1015; (e) Brzezinski, L. J.; Rafel, S.;
Leaky, J. W. Tetrahedron 1997, 53, 16423; (f) Iwabuchi,
Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J. Am.
Chem. Soc. 1999, 121, 10219; (g) Iwabuchi, Y.; Sugihara,
T.; Esumi, T.; Hatakeyama, S. Tetrahedron Lett. 2001, 42,
7867; (h) Iwabuchi, Y.; Furukawa, M.; Esumi, T.;
Hatakeyama, S. Chem. Commun. 2001, 2030; (i) Iwabuchi,
Y.; Hatakeyama, S. Synth. Org. Chem. Jpn. 2002, 60, 1; (j)
Shi, M.; Jiang, J. K. Tetrahedron: Asymmetry 2002, 13,
1941; (k) Krishna, P. R.; Kannan, V.; Reddy, P. V. N.
Adv. Synth. Catal. 2004, 346, 603.
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11. Barbaro, P.; Bianchini, C.; Sernau, V. Tetrahedron:
Asymmetry 1996, 7, 843.
12. Anaya de Parrodi, C.; Moreno, G. E.; Quintero, L.;
Juaristic, E. Tetrahedron: Asymmetry 1998, 9, 2093.
13. Experimental data of compound 3a and 3b: For 3a, mp
20
72–74 °C, ½aꢁD +45.2 (c 1.0, MeOH). Anal. Calcd for
C15H23NO: C, 77.21; H, 9.93; N, 6.00. Found: C, 77.45; H,
1
9.84; N, 6.07. H NMR (d, CHCl3, 300 MHz): 0.98–1.16
(m, 4H), 1.40 (d, 3H, J = 6.9 Hz), 1.57–1.68 (m, 3H), 2.00–
2.05 (m, 1H), 2.25 (s, 3H), 2.20–2.29 (m, 1H), 3.34 (dt, 1H,
J = 5.2 and 9.9 Hz), 3.72 (q, 1H, J = 6.9 Hz), 3.89 (br,
20
1H), 7.21–7.34 (m, 5Harom); For 3b, oil, ½aꢁD ꢀ68.2 (c 1.0,
MeOH). Anal. Calcd for C15H23NO: C, 77.21; H, 9.93; N,
6.00. Found: C, 77.20; H, 9.90; N, 6.16. 1H NMR (d,
CHCl3, 300 MHz): 1.17–1.27 (m, 4H), 1.36 (d, 3H,
J = 6.9 Hz), 1.57–1.72 (m, 3H), 2.05 (s, 3H), 2.13–2.16
(m, 1H), 2.62–2.70 (m, 1H), 3.41 (dt, 1H, J = 5.2 and
9.9 Hz), 3.69 (q, 1H, J = 6.9 Hz), 3.95 (br, 1H), 7.24–7.34
(m, 5Harom).
14. Zadel, G.; Breitmaier, E. Chem. Ber. 1994, 127, 1323.
20
15. Experimental data of compound 5: mp 48–52 °C, ½aꢁD
+7.2 (c 2.3, CHCl3). 1H NMR (d, CHCl3, 300 MHz):

H. Tang et al. / Tetrahedron Letters 47 (2006) 5717–5721
5721
1.56–1.84 (m, 8H), 2.37–2.48 (m, 4H), 2.55–2.57 (m, 4H),
2.76–2.83 (m, 2Harom).
16. General procedure for the chiral amine/L-proline
mixture was stirred at 20 °C for completion of the
reaction (monitored by TLC). After removal of
solvent, the residue was purified by column chroma-
tography on silica gel (200–300 mesh, gradient eluted
with petroleum ether/ethyl acetate) to afford the
product.
co-catalyzed reaction: To
a solution of aldehyde
(2 mmol), chiral amine and L-proline in 2.5 mL of
solvent was added MVK (6 mmol). Then the resulting