Dynamic kinetic asymmetric transfer hydrogenation of racemic 2,4-diaryl-2,3-dihydrobenzo[b][1,4]diazepines catalyzed by chiral phosphoric acids

Article abstract of DOI:10.1016/j.bmcl.2009.05.039

Dynamic kinetic Transfer hydrogenation reaction of 2-methyl-2,4-diaryl-2,3-dihydrobenzo[b][1,4]diazepines, using phosphoric acids as catalysts and Hantzsch ester as hydride source, has been studied. A 3,3′-H8-binol derived phosphoric acid has been identif

Full text of DOI:10.1016/j.bmcl.2009.05.039

Bioorganic & Medicinal Chemistry Letters 19 (2009) 3729–3732
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Dynamic kinetic asymmetric transfer hydrogenation of racemic
2,4-diaryl-2,3-dihydrobenzo[b][1,4]diazepines catalyzed by chiral phosphoric
acids
*
Zhi-Yong Han, Han Xiao, Liu-Zhu Gong
Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Dynamic kinetic Transfer hydrogenation reaction of 2-methyl-2,4-diaryl-2,3-dihydrobenzo[b][1,4]diaze-
pines, using phosphoric acids as catalysts and Hantzsch ester as hydride source, has been studied. A 3,30-
H8-binol derived phosphoric acid has been identified the optimal chiral catalyst for this transformation,
affording 1,3-diamine derivatives with up to 8/1 dr, 86% ee and 94% ee for the major and minor diaste-
reomers, respectively.
Received 28 March 2009
Revised 11 May 2009
Accepted 12 May 2009
Available online 18 May 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Dynamic kinetic transfer hydrogenation
Phosphoric acid
1,3-Diamines
Asymmetric organocatalysis
Chiral 1,3-diamines constitute core structural motifs present in
natural products and bioactive substrates and serve as chiral build-
ing blocks commonly used in organic synthesis.1,2 Moreover, chiral
1,3-diamines have found wide applications in asymmetric synthe-
sis either as chiral auxiliaries or ligands.3 Synthetic approaches
readily available to access these molecules include asymmetric
synthesis starting with optically pure 1,3-diols,4 b-amino nitriles,5
and b-amino cyanides6, and other transformations such as stereo-
selective ring opening of special aziridines and epoxides,7 kinetic
resolution of racemic 1,3-diamines,8 and diastereoselective Man-
nich reactions as well.9 Asymmetric catalytic synthesis of chiral
1,3-diamines has been focused on 1,3-dipolar cycloaddition of
hydrazones to olefins and enantioselective addition of enamides
to imines.10
Despite the presence of these synthetic methods, new catalytic
asymmetric transformations to access optically pure 1,3-diamines
are still in great demand. 2-Methyl-2,4-diaryl-2,3-dihydro-
benzo[b][1,4]diazepines can be conveniently obtained from a Man-
nich-type reaction of o-phenylenediamines and ketones using
Yb(OTf)3 as a catalyst.11 Enantioselective reduction of these com-
pounds would be an attractive approach to access 1,3-diamine
derivatives. We found that 2-methyl-2,4-diphenyl-2,3-dihydro-
benzo[b][1,4]diazepine (1a) and its starting materials, acetophe-
none and o-phenylenediamine, could rapidly and reversely
transform into each other as 1a reacted with p-nitroacetophenone
to furnish 2-methyl-2,4-bis(4-nitroiphenyl)-2,3-dihydrobenzo [b]
[1,4]diazepine (1b) and acetophenone in 80% conversion in the pres-
ence of 20 mol % of phosphoric acid 2a (Eq. 1). This finding prompted
us to envision if it would be possible to initiate a dynamic kinetic
asymmetric hydrogenation of 2-methyl-2,4-diaryl-2,3-dihydro-
benzo[b][1,4]diazepines (1), allowing a facile synthesis of chiral
1,3-diamines bearing a quaternary stereogenic center.
Asymmetric transfer hydrogenation of prochiral imines has
emerged as a valuable biomimetic method for the generation of
optically active amines, which was pioneered by List, Rueping,
and MacMillan, independently.12 List and co-workers recently de-
scribed an asymmetric reductive amination of
a-branched alde-
hydes, which proceeded with a dynamic kinetic resolution.13
However, the application of the biomimetic procedure to the
reduction of 2,4-diaryl-2,3-dihydrobenzo[b][1,4]diazepines has
not been reported. Herein, we will present our effort on the dy-
namic kinetic transfer hydrogenation of 2-methyl-2,4-diaryl-2,3-
dihydrobenzo[b][1,4]diazepines 1 using phosphoric acids 2 and 3
as chiral catalysts,14 leading to the formation of 1,3-diamines 5
in high yields with good to high stereoselectivity (Fig. 1).
At the outset of this study, we evaluated structurally different
chiral phosphoric acids for the transfer hydrogenation of 2-
methyl-2,4-diphenyl-2,3-dihydrobenzo[b][1,4]diazepine 1a con-
ducted in chloroform at 0 °C using ethyl Hantzsch ester 4a as a hy-
dride source (Table 1). The phosphoric acids examined all showed
high catalytic activity, each of which afforded the model reaction in
high conversion, but provided different enantioselectivity for both
5a and the diastereomer 5a0 (entries 1–5). However, the diastereo-
* Corresponding author.
E-mail address: gonglz@ustc.edu.cn (L.-Z. Gong).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.05.039

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Z.-Y. Han et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3729–3732
O
O
20 mol% 2a
CHCl3, 50 ºC
4.5 days
N
NH
N
NH
+
+
(eq 1)
NO2
80% conversion
O2N
NO2
1a
1b
Ar
Ph
acteristic of the substituent (entries 1–4), but was influenced by
the position of the same substituent in comparison of reactions
involving 1d and 1f with those involving 1k and 1l (entries 2 and
4 vs entries 9–10). The minor diastereomers were always isolated
with higher enantioselectivity (79–94% ee) than the major ones
(63–86% ee).
The absolute configuration of the products was assigned by X-
ray analysis.15 The X-ray structure of 5d indicated the S configura-
tion at C2 and the R configuration at C4 (Fig. 2).
2a, Ar = Ph
O
P
O
O
O
O
2b, Ar = 4-NO2C6H4
2c, Ar = 4-Biphenyl
2d, Ar = 2-naphthyl
2e, Ar = 9-phenanthryl
OH
P
OH
O
Ar
Ph
3
2
Figure 1. Chiral phosphoric acids evaluated in this study.
The dynamic kinetic transfer hydrogenation could be best ex-
plained by the reaction pathway shown in Scheme 1. We proposed
that the (S)-enantiomer among racemic 1a underwent a fast trans-
fer hydrogenation under catalysis of the Brønsted acid such as 3,
diastereo- and enantioselectively furnishing (2S,4R)-5a and
(2S,4S)-5a0, respectively, while meanwhile the (R)-1a participated
in a slow transfer hydrogenation and the unhydrogenated (R)-1a
rapidly racemized via the sequential retro-Mannich and Mannich
reactions. The racemization was confirmed by a finding that the
starting material was recovered as racemates.16 The racemic 1a
from the racemization of (R)-1a again underwent the dynamic ki-
netic transfer hydrogenation following the reaction procedure as
shown in Scheme 1.
In conclusion, we have disclosed a dynamic kinetic transfer hydro-
genation of 2-methyl-2,4-diaryl-2,3-dihydrobenzo[b][1,4] diaze-
pines using phosphoric acids as catalysts. This reaction provided a
synthetic approach to access 1,3-diamines in high yields with good
to high ee for the major diastereomers and high to excellent ee for
minor diastereomers. Our next study will be focused on the improve-
ment of the stereoselectivity.
meric ratio of 5a/5a0 was seemingly independent of the catalyst
structure. Interestingly, the minor diastereomer 5a0 was obtained
in higher ee than the major diastereomer 5a. The substituent on
the Hantzsch ester also had impact on the stereoselectivity as indi-
cated by the transfer hydrogenation of 1a catalyzed by 2e with var-
ious Hantzsch esters (entries 5–8). In terms of enantioselectivity
for 5a, allyl Hantzsch ester 4b turned out to be the optimal hydride
source for the transfer hydrogenation (entry 6). Under the opti-
mized conditions, the H8-binol derived phosphoric acid 3 provided
the best results for the major diastereomer (entry 9).
The generality of the optimal reaction conditions was examined
for the dynamic kinetic transfer hydrogenation of various 2-
methyl-2,4-diaryl-2,3-dihydrobenzo[b][1,4]diazepines (Table 2).
In general, the electronically poor aryl substituent of 1 was benefi-
cial to diastereoselectivity (entries 1–4 vs 5–6). Accordingly, the
highest diastereomeric ratio of 8/1 was obtained for 1c possessing
a trifluoromethyl substituent (entry 1) while only 2/1 dr was ob-
served for para-methyl substituted substrate 1g (entry 5). On the
contrary, the enantioselectivity did not rely on the electronic char-
Table 1
Evaluation of phosphoric acids and Hantzsch estersa
RO2C
CO2R
N
NH
HN
NH
HN
NH
10 mol% 2 or 3
CHCl3, 0 ºC
+
+
N
H
4
1a
5a'
5a
Entry
Catalyst
R (4)
Time (day)
Conv.b (%)
dr (syn/anti)c
eed (%)
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2e
2e
2a
3
Et (4a)
Et (4a)
Et (4a)
Et (4a)
3
2
3
3
3
3
3
2
93
93
96
91
97
85
87
93
90
2/1
3/1
3/1
2/1
2/1
2/1
2/1
3/1
2/1
50 (65)
50 (59)
60 (72)
60 (77)
63 (77)
64 (69)
57 (85)
66 (73)
80 (78)e
Et (4a)
Allyl (4b)
i-Pr (4c)
Allyl (4b)
Allyl (4b)
5.5
a
Unless indicated otherwise, the reaction of 1a (0.1 mmol) with a Hantzsch ester (0.23 mmol) was carried out at 0 °C.
Determined by 1H NMR and calculated on the basis of 1a.
b
c
syn/anti refers to 5a/5a0 and was determined by 1H NMR.
d
e
The ee was determined by HPLC and that in parentheses is for 5a0.
The reaction was carried out at ꢀ10 °C with 1.3 equiv 4b.

Z.-Y. Han et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3729–3732
3731
Table 2
Asymmetric reduction of 2-methyl-2,4-diaryl-2,3-dihydrobenzo[b][1,4]diazepines 1 catalyzed by phosphoric acid 3a
AllylO2C
CO2Allyl
10 mol% 3
CHCl3, -10 ºC, Na2SO4
5.5 days
HN
Ar
NH
Ar
HN
Ar
NH
Ar
N
NH
Ar
+
+
N
H
4b
Ar
1
5
5'
Entry
1
Ar
Yieldb (%)
dr (syn/anti)c
eed (%)
1
2
3
4
5
6
7
8
9
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
4-CF3C6H4
4-BrC6H4
4-ClC6H4
4-FC6H4
4-MeC6H4
3-MeOC6H4
4-PhC6H4
2-Naphthyl
3-FC6H4
92
81
83
89
63
87
95
97
84
87
8/1
5/1
5/1
5/1
2/1
3/1
4/1
3/1
4/1
6/1
82 (85)
81 (87)
83 (86)
82 (85)
84 (87)
74 (75)
85 (94)
86 (92)
73 (81)
63 (89)
10
3-BrC6H4
a
Unless indicated otherwise, the reaction of 1 (0.1 mmol) with a Hantzsch ester (0.13 mmol) was carried out at 0 °C.
Isolated overall yield of 5 and 50.
b
c
syn/anti refers to 5/50 and was determined by 1H NMR.
d
The ee was determined by HPLC and that in parentheses is for 50.
Br
Br
H
4
2
(S) (R)
HN
NH
5d
Figure 2. X-ray structure of 5d.
Kinetic Resolution Catalyzed by 3
10 mol% 3
HEH 4b (1.3 equiv)
N
NH
Ph
HN
Ph
(2S, 4R)-5a
NH
HN
Ph
(2S, 4S)-5a'
NH
+
Fast reaction
Ph
Ph
Ph
(S)-1a
+
10 mol% 3
HEH 4b (1.3 equiv)
N
NH
Ph
HN
Ph
(2R, 4S)-5a
NH
HN
Ph
(2R, 4R)-5a'
NH
+
Slow reaction
Ph
Ph
Ph
(R)-1a
Racemization of Enantiomerically Enriched Starting Material from Kinetic Resolution
Bronsted Acid
Mannich Reaction
N
NH
Ph
N
NH
HN
Ph
N
Retro-Mannich
(R)
Ph
Ph
Ph
Ph
Me
I
(R)-1a
rac-1a
Scheme 1. Explanation of the dynamic kinetic transfer hydrogenation.

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Z.-Y. Han et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3729–3732
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www.ccdc.cam.ac.uk/conts/retrieving.html
(or
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Crystallographic Data Centre, 12 Union Road, Cambridge CB21EZ, UK; fax:
(+44) 1223-336-033; or deposit@ccdc.cam.ac.uk).
16. The recovered 1a from the hydrogenation reaction of 1a with ethyl Hantzsch
ester (4a) in 93% conversion using catalyst 2a was determined to be racemic
while 5a was isolated with 43% ee.
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