Organocatalytic enantioselective hetero-Diels-Alder reaction of aldehydes and o-benzoquinone diimide: Synthesis of optically active hydroquinoxalines

Article abstract of DOI:10.1016/j.bmcl.2009.03.013

A highly enantioselective inverse electron demand hetero-Diels-Alder reaction of o-benzoquinone diimide and aldehydes has been developed by secondary amine catalysis, giving a facile protocol to access a variety of chiral hydroquinoxalines under mild cond

Full text of DOI:10.1016/j.bmcl.2009.03.013

Bioorganic & Medicinal Chemistry Letters 19 (2009) 3952–3954
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Organocatalytic enantioselective hetero-Diels–Alder reaction of aldehydes
and o-benzoquinone diimide: Synthesis of optically active hydroquinoxalines
Jun-Long Li a, Bo Han a, Kun Jiang a, Wei Du a, Ying-Chun Chen a,b,
*
a Key laboratory of Drug-Targeting and Drug Deliver System of Education Ministry, Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan University,
Chengdu 610041, China
b State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly enantioselective inverse electron demand hetero-Diels–Alder reaction of o-benzoquinone dii-
mide and aldehydes has been developed by secondary amine catalysis, giving a facile protocol to access
a variety of chiral hydroquinoxalines under mild conditions.
Received 13 February 2009
Revised 3 March 2009
Accepted 4 March 2009
Available online 9 March 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Inverse electron demand
Hetero-Diels–Alder reaction
o-Benzoquinone diimide
Aldehydes
Chiral hydroquinoxalines
Quinoxalines and related compounds represent a prominent
class of pharmaceutical molecules, and the investigation on these
intriguing structures has captured continuing interest of research-
ers worldwide.1 Compounds with quinoxaline cores are used as
HIV antiviral agents,2 antagonists of the selective human A3 aden-
osine receptor,3 antagonists of 5-HT3 receptors,4 growth inhibitors
of Trypanosoma cruzi,5 etc. Moreover, quinoxalines including 3,4-
dihydroquinoxalinone and 1,2,3,4-tetrahydroquinoxaline are also
promising targets for asymmetric synthesis as they show various
types of biological activity such as in blocking or reversing activa-
tion of bradykinin (BK) receptors, in the management of pain and
inflammation, as well as in the treatment of disorders mediated
by BK.6 However, few successful examples of enantioselective syn-
thesis of the functionalized hydroquinoxalines have yet been re-
ported. In 2006, Lectka and co-workers reported an elegant
asymmetric inverse electron demand hetero-Diels–Alder reaction
(HDAR) of acyl chlorides7 and o-benzoquinone diimides to deliver
the chiral quinoxalinones.7c Although perfect ee values were ob-
served by the catalysis of Lewis bases derived from cinchona alka-
loids, the reaction condition was somewhat harsh (À78 °C) and
metal triflates must be used as co-catalysts to activate the electro-
philic o-benzoquinone diimides.7c,d
butadienes8 and aldehydes by employing the small organic mole-
cule as catalyst, which is often nontoxic, environmentally friendly,
and stable under aerobic and aqueous reaction conditions.9
A
diversity of chiral piperidine derivatives and other valuable
compounds could be efficiently prepared from the hemiaminal
cycloadducts.10 Encouraged by the excellent stereoselectivity ob-
served in the reaction, we envisaged that another direct asymmet-
ric HDAR of o-benzoquinone diimides7c and aldehydes could be
carried out through the same catalytic mechanism, giving a facile
strategy to access chiral hydroquinoxalines.
Since the required o-benzoquinone diimide 2a were easily
accessible by benzoylation of commercial available o-phenylenedi-
amine and subsequent oxidation,7c we immediately started our
investigation on the proposed reaction. In the initial screen, we
conducted the HDAR under the previous established conditions:
o-benzoquinone diimide 2a (1.0 equiv), butyraldehyde (2.0 equiv),
benzoic acid (10 mol %), and the catalyst
a,a-diphenylprolinol O-
TMS ether 1 (10 mol %) in a mixture of CH3CN and H2O (10:1) at
room temperature.10 To our delight, this HDAR reaction smoothly
proceeded without the metal-activation of o-benzoquinone dii-
mide 2a. The desired hemiaminal 4a was isolated as a relatively
stable compound with excellent stereoselectivity and good yield
(Table 1, entry 1, dr >99:1, 97% ee). Moreover, we found that water
is also crucial for the transformation efficiency in this HDAR.10 The
expected product could not be obtained when anhydrous acetoni-
trile was employed (entry 2). Encouraged by the promising results,
we undertook more detailed study. It was found that the solvent
Recently, our group has developed an asymmetric inverse elec-
tron demand aza-Diels–Alder reaction of N-sulfonyl-1-aza-1,3-
* Corresponding author. Fax: +86 28 85502609.
E-mail address: ycchenhuaxi@yahoo.com.cn (Y.-C. Chen).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.03.013

J.-L. Li et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3952–3954
3953
Table 1
excellent enantioselectivities were generally obtained (Table 2, en-
tries 1–5). In addition, aldehydes 3f–h with heteroatom bearing
substituents were also employed, and provided the corresponding
quinoxalinone products in good yield and with outstanding optical
purity (entries 6–8). Not surprisingly, poor regioselectivity was ob-
served when unsymmetrical o-benzoquinone diimides 2b and 2c
were employed in the reaction with butyraldehyde 3a, and mix-
tures were isolated.
Optimization of the organocatalytic HDAR of the o-benzoquinone diimide 2a and
butyraldehyde 3aa
Bz
N
Ph
Ph
OTMS (10 mol %)
OH
N
N
Bz
Bz
N
H
CHO
+
1
N
Bz
PhCOOH (10 mol %)
solvent, 25 °C, 12 h
2a
4a
3a
In addition, o-benzoquinone imide 6 instead of o-benzoquinone
diimide 2a was also tested with butyraldehyde 3a under the same
catalytic conditions (Scheme 1). The expected hemiacetal was pro-
duced with good isolated yield and excellent enantioselectivity.
After PCC oxidation, 1,4-benzoxazinone 7, which is another scaf-
Entry
Solvent
Concentration (M)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
MeCN/H2O
MeCN
0.1
0.1
0.1
0.1
0.1
0.1
0.07
0.2
71
<10
83
89
55
49
81
89
97
NDd
>99
>99
98
Diox/H2O
THF/H2O
toleune/H2O
MeOH/H2O
THF/H2O
THF/H2O
fold for biologically active molecules as well as an
a-amino acid
precursor,7b was smoothly obtained without any racemization
(99% ee).
>99
>99
>99
As an illustration of the versatility of this methodology, the
asymmetric HDAR product hemiaminal 4a could be readily con-
verted into other useful chiral hydroquinoxalines. Apart from PCC
oxidation to afford quinoxalinone 5a, the hydroxyl group of 4a
was smoothly removed by reduction with Et3SiH/BF3ÁEt2O at ambi-
ent temperature, affording substituted 1,2,3,4-tetrahydroquinoxa-
line 8 with preserved ee value (Scheme 2, 98% ee, dr >99:1). The
hydroxyl group of 4a was replaced with a cyano group using
TMSCN/BF3ÁEt2O to give compound 9, which could be used for
the synthesis of various 1,2,3,4-tetrahydroquinoxaline-2-carbox-
ylic acid derivatives; while only moderate yield could be obtained
due to the low reaction conversion. Furthermore, 4a could be easily
transformed to chiral 1,2,3,4-tetrahydroquinoxaline-2-acetic acid
ester 10 by successive Wittig reaction-intramolecular aza-Michael
addition; unfortunately, some racemization was detected in the
final product 10 (82% ee, dr >99:1).12,13
a
Reaction conditions: 2 (0.1 mmol), 3 (0.2 mmol), 1 (0.01 mmol), benzoic acid
(0.1 mmol), organic solvent/H2O (10:1), at 25 °C for 12 h.
b
Isolated yield.
Determined by chiral HPLC analysis, dr >99:1.
Not determined.
c
d
had an obvious effect on the outcome of the reaction. While the
high stereoselectivity remained unchanged, lower yields were ob-
tained in toluene and MeOH (entries 3 and 4); nevertheless, more
satisfactory yields could be attained in a mixture of Diox/H2O or
THF/H2O (entries 5 and 6). The reaction concentration also did
not affect the stereoselectivity (entries 7 and 8), but the dilute con-
ditions slightly slowed the rate of the reaction.
Subsequently, the scope of this asymmetric HDAR was evalu-
ated under the optimized reaction condition with o-benzoquinone
diimide 2a. Since the hemiaminal 4 was not stable enough for fur-
ther analysis,11 PCC (pyridinium chlorochromate) oxidation was
employed to give the more stable quinoxalinones 5. As shown in
Table 2, a variety of aldehydes 3a–e bearing simple linear or
In summary, we have developed a highly enantioselective
organocatalytic inverse electron demand hetero-Diels–Alder reac-
tion of o-benzoquinone diimide and aliphatic aldehydes catalyzed
by a chiral secondary amine.14 This reaction was carried out under
branched
a-substituted alkyl groups were well tolerated and
O
O
1) 1 (10% mol)
N
O
Bz
PhCOOH (10% mol)
CHO
+
THF/H2O, 25 °C, 12 h
N
Bz
Table 2
Asymmetric inverse electron demand hetero-Diels–Alder reactions of o-benzoqui-
2) PCC, silica gel
DCM, rt, 8 h
none diimide 2a and aldehyde 3a-ha
6
3a
7 75% yield, 99% ee
Bz
N
1) 1 (10 mol %)
Scheme 1. Synthesis of 1,4-benzoxazinone via asymmetric inverse electron
demand HDAR.
N
Bz
Bz
O
PhCOOH (10 mol %)
R2
CHO
+
THF/H2O, 25 °C, 12 h
R1
N
2a R1 = H
2b R1 = Me
2c R1 = Cl
R1
N
Bz
R2
2) PCC, silica gel
DCM, rt, 8 h
3
5
Bz
N
Entry
R1
R2
Yieldb (%)
eec (%)
Et3SiH/BF3⋅Et2O
1
H
Et (3a)
Me (3b)
i-Pr (3c)
PhCH2 (3d)
n-Pent (3e)
BnO(CH2)2 (3f)
PhSCH2 (3g)
NO2(CH2)2 (3h)
5a—85
5b—82
5c—90
5d—78
5e—92
5f—82
5g—63
5h—79
98
94
99f
99
99
96
95
95
N
2d
3e
4e
5
H
H
H
H
H
H
H
DCM, rt
Bz
8 94% yield, 98% ee
Bz
Bz
N
CN
6d
7d
8d
N
OH
TMSCN/BF3⋅Et2O
DCM, 40 °C
N
N
Bz
a
Bz
Reaction conditions (unless otherwise noted): for HDAR: 2a (0.1 mmol), 3
(0.2 mmol), 1 (0.01 mmol), benzoic acid (0.01 mmol), THF/H2O (10:1, 1 mL), at 25 °C
for 12 h; for PCC oxidation: PCC (3 equiv), silica gel (65 mg), at 25 °C for 8 h.
9 46% yield, 96% ee, dr > 99:1
91% yield based on recovered 4a
4a 98% ee
Bz
OEt
b
Ph3P
Isolated yield for two steps.
1)
N
COOEt
c
O
Determined by chiral HPLC analysis.
d
At 15 °C for 24 h.
N
2) t-BuOK
e
4 equiv of aldehyde was added.
Bz
f
The absolute configuration of 5c was determined by the comparison of the
10 83% yield, 83% ee, dr > 99:1
specific rotation with known compound.7c The other products were assigned by
analogy.
Scheme 2. Synthetic transformations of the chiral hemiaminal 4a.

3954
J.-L. Li et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3952–3954
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mild conditions and a number of enantioenriched hydroquinoxa-
lines could be prepared from the hemiaminal adducts. An optically
pure 1,4-benzoxazinone was also prepared through a similar HDAR
of o-benzoquinone imide and butyraldehyde. We anticipate that
these new HDARs will have great potential in the field of medicinal
chemistry.
6. Su, D. -S.; Bock, M. G. U.S. Patent Appl. 20050020591, 2005.
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Acknowledgments
We are grateful for the financial support from NSFC (20772084)
and Sichuan Province Government (07ZQ026-027).
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14. A plausible catalytic mechanism has been proposed, please see Supplementary
data.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2009.03.013.
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