Metal-free tandem cyclization/hydrosilylation to construct tetrahydroquinoxalines

Article abstract of DOI:10.1039/c7gc03095a

A one-pot tandem procedure involving cyclization and sequential hydrosilylation of imines and amides under the catalysis of B(C₆F₅)₃ has been developed for the step-economical construction of 1,2,3,4-tetrahydroquinoxalines directly from readily available 1,2-diaminobenzenes, α-ketoesters and low-cost, safe polymethylhydrosiloxane (PMHS). This metal-free approach provides various products in good to excellent yields, and displays a wide range of substrate scope and a high degree of functional group tolerance even to reduction-sensitive moieties. The choice of hydrosilanes is critical to the catalysis, and PMHS has proved to be optimal. Decreasing the amount of PMHS could enable the reaction to stop at the 3,4-dihydroquinoxalin-2(1H)-one stage. The procedure is convenient and scalable, and neither a dried solvent nor an inert atmosphere is required. Moreover, the enantioselective construction of these products was explored, and promising results were achieved.

Full text of DOI:10.1039/c7gc03095a

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PAPER
Metal-free Tandem Cyclization/Hydrosilylation to Construct
Tetrahydroquinoxalines
Yixiao Pan,a Changjun Chen,a Xin Xu,a Haoqiang Zhao,a Jiahong Han,a Huanrong Li,a Lijin Xu,a*
Qinghua Fanb* and Jianliang Xiaoc*
Received 00th January 20xx,
Accepted 00th January 20xx
A one-pot tandem procedure involving cyclization and sequential hydrosilylation of imines and amides under the catalysis
of B(C6F5)3 has been developed for the step-economical construction of 1,2,3,4-tetrahydroquinoxalines directly from
readily available 1,2-diaminobenzenes and α-ketoesters and cheap, safe polymethylhydrosiloxane (PMHS). This metal-free
approach provides various products in good to excellent yields, and displays a wide range of substrate scope and high
degree of functional group tolerance even to reduction-sensitive moieties. The choice of hydrosilanes is critical to the
catalysis, and PMHS proved to be optimal. Decreasing the amount of PMHS could enable the reaction to stop at 3,4-
dihydroquinoxalin-2(1H)-one stage. The procedure is convenient and scalable, and neither a dried solvent nor an inert
atmosphere is required. Moreover, the enantioselective construction of these products were explored, and promising
results were achieved.
DOI: 10.1039/x0xx00000x
www.rsc.org/
has been less studied. In 2013, Beller et al. disclosed a tandem
process consisting of cyclization of phenylglyoxal and 1,2-
phenylenediamine and catalytic asymmetric hydrogenation of the in
Introduction
situ generated 2-phenylquinoxaline to provide 2-phenyl
tetrahydroquinoxaline in high yields and enantioselectivities
(Scheme 1b).7q Shortly after, Shi and co-workers reported an
asymmetric organocatalytic tandem reaction of cyclization/transfer
hydrogenation for the step-economical construction of various
chiral 2-aryl tetrahydroquinoxalines from aryl glyoxals and 1,2-
phenylenediamines (Scheme 1b).9j
Tetrahydroquinoxalines constitute the core structures of numerous
bioactive natural products and synthetic compounds.1,2 Accordingly,
the development of efficient protocols for the synthesis of these
heterocycles has received considerable interest in the past several
decades, and remains to be of great appeal today.3 Among these
known methods, the direct reduction of quinoxalines represents
one of the most frequently adopted strategies for the preparation
of tetrahydroquinoxalines.4 In the past several decades,
tremendous progress has been made towards the selective
reduction of quinoxalines into tetrahydroquinoxalines with cheap
molecular hydrogen in the presence of homogeneous or
heterogeneous transition-metal catalysts (Scheme 1a).5-8
Meanwhile, catalytic reduction of quinoxalines with formates,9a-h
Hantzsch esters,9i,j hydrosilanes,9k water9l.m and ammonia borane9n
as hydrogen donors has also been successfully achieved (Scheme
1a). Despite these impressive achievements, it should be pointed
out that most of these known reports necessitated the prior
preparation and purification of quinoxaline substrates, and the
step-economic synthesis of tetrahydroquinoxalines via in situ
generation of quinoxalines from readily available starting materials
Previous works
a)
: catalytic reduction of quinoxalines
H
N
N
[cat.]
R
R'
R
R'
[H]
N
N
H
[cat.]: Au, Co, Fe, Ir, Mo, Pd, Rh, Ru, B, Bronsted acid
[H]: H2, hydrosilane, formate, Hantzsch ester, H2O, BH3.NH3
Previous works
b)
: step-econmical synthesis of 2-aryl tetrahydroquinoxalines
H
N
[Fe]
R
O
H2
NH2
N
N
N
H
Ar
Ar
OR'
OR'
R
Ar
+
R
NH2
H
Ar
N
phosphoric acid
Hantzsch ester
R
N
H
c) This work: step-econmical synthesis of 2-substituted tetrahydroquinoxalines
H
O
NH2
NH2
N
PMHS, cat. B(C6F5
one-pot tandem process
(R' = alkyl, aryl and alkenyl)
)
3
OR''
R
R
R'
+
N
H
R'
O
deoxygentive
hydrosilylation
of amides
cyclization
PMHS,
cat. B(C6F5)3
H
H
O
O
N
N
N
PMHS, cat. B(C6F5)3
hydrosilylation of imines
R
R
N
H
R'
R'
Scheme 1. Catalytic synthesis of 1,2,3,4-tetrahydroquinoxalines.
Deoxygenative reduction of the amide moiety of 3,4-
dihydroquinoxalin-2(1H)-ones represents another useful route to
1,2,3,4-tetrahydroquinoxalines,10 but this transformation has been
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almost completely overlooked most likely due to the lack of efficient
Our investigations started with the reaction of 1,2-
and practical catalytic methods for amide reduction. Although diaminobenzene (1a) and ethyl 2-oxopropanoate (2a) in the
catalytic hydrogenation is an ideal choice for selective reduction of
amides into amines, it is still in its infancy.11 In contrast, the
operationally simple catalytic hydrosilylation of amides has been
subjected to intensive studies, and a variety of catalytic systems
based on Rh,14a-e Ru,14f-i Ir,14j Mo,14k-m Pt,14n,o In,15a,b Zn,15c-e Cu,15f
presence of catalytic amount of B(C6F5)3 at 110 °C (Table 1; also see
Supporting Information for more details). With THF as the solvent
and PhSiH3 as the reductant, the first reaction gave the target
product 2-methyl-1,2,3,4-tetrahydroquinoxaline (3aa) in 67% yield
together with 3-methyl-3,4-dihydroquinoxalin-2(1H)-one (4aa)
(25%) and a small amount of 3-methylquinoxalin-2(1H)-one (5aa)
(Table 1, entry 1). Clearly, the cyclization of 1a with 2a to produce
5aa and the following hydrosilyation of 5aa into 4aa proceeded well
under the current conditions, but the efficiency of the
deoxygenative reduction of the amide group of 4aa needed to be
improved. Considering that the choice of hydrosilanes could affect
the reaction efficiency, the performance of different hydrosilanes
was then examined. Although Ph2SiH2, Et3SiH, (EtO)3SiH, EtMe2SiH
and TMDS (tetramethyldisilazane) all exhibited reductive reactivity
(Table 1, entries 2-7), the inexpensive and non-toxic PMHS provided
the best 3aa yield of 80% (Table 1, entry 8). Subsequently a brief
screening of various solvents revealed that replacing THF with
nBu2O, toluene or MTBE led to better yields of 3aa (Table 1, entries
10-12), but the use of 1,4-dioxane, CH3CN or DMF as the solvent
was detrimental (Table 1, entries 9, 13, 14). Toluene furnished the
highest 3aa yield (94%) with minimal amount of side products, and
was thus selected as the choice of solvent for further studies (Table
1, entry 11). When the catalyst loading, reaction temperature or the
amount of PMHS was lowered, the yield of 3aa decreased as well
(Table 1, entries 15-17). Notably, BPh3 and bis(2-
chlorophenyl)(hydroxy)borane, which have been reported to
efficiently catalyse hydrosilylation of amides,18c,d turned out to be
ineffective in the current reaction (Table 1, entries 18 and 19).
Finally a control experiment showed that B(C6F5)3 catalyst was
indispensable for this transformation (Table 1, entry 20). It should
be stressed that the reaction is operationally simple, and neither a
dried solvent nor an inert atmosphere is required.
Co,15g Fe,16 B17 and even the simple bases have been developed
18
for the efficient reduction of amides into amines. In particular,
B(C6F5)3 and its analogues, which exhibited remarkable catalytic
performance in the metal-free reduction of aldehydes, ketones,
imines, olefins, alkynes, ethers and N-heteroarenes with
hydrosilanes as the reductants via frustrated Lewis pairs,19.20 has
proved to be quite effective to catalyze hydrosilylation of various
primary, secondary and tertiary amides into the corresponding
amines.21 Moreover, Fu and co-workers revealed that B(C6F5)3 could
efficiently catalyze N-alkylation of amines with readily available
carboxylic acids and PMHS, and the transformation is believed to
proceed through the in situ generation of an amide intermediate
followed by a catalytic reduction of the amide to the amine with
PMHS.22a Ingleson and co-workers reported that B(C6F5)3 could
perform well in wet solvent to catalyze the reductive amination of
aldehydes and ketones with amines using Me2PhSiH as the
reductant.22b,c Very recently, Otte et al. described the tandem
Meinwald rearrangement-reductive amination of epoxides with
anilines and silanes under B(C6F5)3 catalysis.22d
Since B(C6F5)3 is known to be capable of catalysing the reduction
of both the in situ formed amides and imines with hydrosilanes, we
envisaged that it would be possible to enable the one-pot tandem
construction of 1,2,3,4-tetrahydroquinoxalines directly from the
easily accessible 1,2-diaminobenzenes and α-ketoesters by using
B(C6F5)3 as the catalyst. This would involve the initial cyclization
reaction of the amine with the ketoester to in situ generate
quinoxalin-2(1H)-ones followed by the sequential catalytic
hydrosilylation of the resulting imine and amide moieties of
quinoxalin-2(1H)-ones. Following our previous studies on catalytic
reduction of N-heteroaryl compounds,7g,7m,9c,9f,23 herein we would
like to report the development of such a one-pot tandem process
for the step-economical synthesis of 1,2,3,4-tetrahydroquinoxalines,
which combines cyclization with subsequent sequential
hydrosilylation of imines and amides with PMHS under the catalysis
of B(C6F5)3 (Scheme 1c). This metal-free protocol features high
yields, broad substrate scope, wide functional group tolerance and
simple operational procedure. Moreover, the reaction could be
halted at the 3,4-dihydroquinoxalin-2(1H)-one stage by decreasing
the amount of PMHS. Finally, promising initial results for the
enantioselective construction of these products have been
accomplished.
Table 1. Optimization of the reaction conditions.a
Entry
1
2
3
4
5
6
7
8
Solvent
THF
THF
THF
THF
THF
THF
THF
THF
dioxane
nBu2O
toluene
MTBE
CH3CN
DMF
toluene
toluene
toluene
Hydrosilane
PhH3Si
Ph2H2Si
Et3HSi
(EtO)3HSi
EtMe2HSi
PhMe2HSi
TMDS
PMHS
PMHS
PMHS
PMHS
PMHS
PMHS
PMHS
PMHS
PMHS
PMHS
3aa (%)b
67
73
68
62
71
73
42
80
78
88
94 (91)
83
62
4
88
86
4aa (%)b
25
20
20
27
23
22
50
13
12
10
3
10
25
3
9
12
13
5aa (%)b
3
4
8
10
4
2
3
2
8
<1
<1
4
10
85
<1
<1
<1
9
10
11
12
13
14
15c
16d
17e
Results and discussion
83
2 | J. Name., 2012, 00, 1-3
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18f
19g
20h
toluene
toluene
toluene
PMHS
PMHS
PMHS
<1
7
nd
<1
41
nd
95
50
98
Furthermore, the biomass-derived acetyl ketene (2x) and levulinic
acid (2y) also worked well, giving rise to the seven- and eight-
Reaction conditions: 1a (0.25 mmol), 2a (0.275 mmol), B(C6F5)3 (5.0 mol%), membered products 3ax24and 3ay in 74% and 54% yields,
a
PMHS (1.0 mmol), solvent (1.5 mL) at 110 °C for 16 h. nd: not detected. Yield of
respectively (Scheme 2a). Interestingly, the current catalytic system
could also catalyse the reaction of 1a with pyruvic acid (2z) to afford
3aa in 90% yield (Scheme 2b).
isolated product was given in parenthesis. b Yield determined by 1H NMR with
c
CH2Br2 as an internal standard. B(C6F5)3 (4.0 mol%) was employed. d Reaction
e
f
temperature 80 °C. PMHS (0.75 mmol) was used. BPh3 (5.0 mol%) was
employed. g Bis(2-chlorophenyl)(hydroxy)borane (5.0 mol%) was employed. h No
B(C6F5)3.
O
H
O
H
N
N
O
2x
CO2H
NH2
NH2
2y
(a)
(b)
B(C6F5)3, PMHS,
B(C6F5 3, PMHS,
)
N
H
N
H
toluene, 110 oC, 16 h
toluene, 110 oC, 16 h
With the optimized reaction conditions in hand, the scope of this
3ax
1a
3ay, 54%
, 74%
1a
reaction with respect to α-ketoester
in Table 2, the reaction of a wide range of α-alkyl substituted α-
ketoesters 2b 2j proceeded smoothly, furnishing the
corresponding products (3ab 3aj) in good to excellent yields. Both
2 was first explored. As shown
H
N
O
NH2
B(C6F5
)
3
OH
+
PMHS, toluene
110 oC, 16 h
NH2
N
H
O
(
- )
2z
3aa
, 89%
-
Scheme 2. Reactions of acetyl ketene (2x), levulinic acid (2y) and pyruvic acid (2z).
linear and branched alkyl groups were found to be compatible with
the reaction conditions, but the presence of bulky alkyl groups
We next turned our attention to the reactions of different 1,2-
diaminobenzenes
1
with 2a under the optimized reaction
1i
resulted in lower reactivity due to the steric hindrance (3ad
3ag 3ai). Ethyl 3,3,3-trifluoro-2-oxopropanoate (2k) reacted in a
similar fashion to give 3ak in 71% yield. Likewise, α-aryl substituted
α-ketoesters (2l 2u) proved to be viable reaction partners to
provide the desired products (3al 3au) in high yields with good
, 3af,
conditions. A range of 4-substituted 1,2-diaminobenzenes (1b
-
)
,
containing electron-donating and electron-withdrawing substituents
underwent smooth reaction with 2a to generate mixture of
-
separable C6- and C7-substituted regioisomers (3ba1-3ia1,3ba2-3ia2)
-
in favour of the latter in 66-90% yields. The electron-rich 4-
substituted 1,2-diaminobenzenes generally exhibited better
reactivity. Importantly, the reaction was tolerant of a variety of
valuable functional groups such as OMe, CF3, F, Cl, Br, and even the
reducible CN and CO2Me groups. The symmetrical 1,2-
tolerance of functional groups regardless of the nature of the
substituents on the aryl ring. It is notable that the synthetically
valuable halide substituents including F (3ap), Cl (3aq) and Br (3ar
)
remained untouched during the reaction process, thus offering the
opportunity for further elaboration. When ethyl 2-(naphthalen-1-
yl)-2-oxoacetate (2v) was employed, the product 3av was obtained
in 77% yield. It is worth noting that the protocol was applicable to
ethyl (E)-2-oxo-4-phenylbut-3-enoate (2w) to deliver the target
product 3aw in 84% yield with the sensitive C=C bond kept intact
throughout the reaction. To showcase the scalability of this
methodology, a gram-scale reaction of 1a (10.0 mmol) and 2a (11.0
mmol) was performed, and 3aa was isolated in 90% yield under the
standard conditions.
diaminobenzenes
(1j
-1n
)
also successfully engaged in the
transformation, affording the corresponding products (3ja-3na) in
high yields. The N1-substituted benzene-1,2-diamines
(
1o-
1q)
participated well in this reaction, and the desired products (3oa
-
3qa) were isolated in 75-78% yields. It is noteworthy that the
reducible allyl moiety in substrate 1q remained intact during the
reaction.
Table 3 Synthesis of tetrahydroquinoxalines from 1,2-diaminobenzenes and 2a.a,b
R'
R'
N
Table 2 Synthesis of tetrahydroquinoxalines from 1a and α-ketoesters.a,b
NH
O
OEt
B(C6F5)3 (5.0 mol%)
PMHS, toluene,110 oC, 16 h
R
+
R
H
N
O
NH2
N
H
NH2
NH2
O
B(C6F5)3 (5.0 mol%)
PMHS, toluene,110 oC, 16 h
OEt
+
R
1
2a
3
O
N
H
R
H
N
H
H
N
H
N
H
N
6
N
2
3
6
1a
6
6
6
Cl
F
F3C
Me
MeO
7
7
7
7
7
N
H
N
H
N
H
N
H
N
H
H
N
H
N
H
N
H
N
3ba
1(6), 43%
3ca
1(6), 42%
3da
3ea
3fa
1(6), 42%
1(6), 35%
1(6), 37%
3ba2(7), 44%
3ca2(7), 46%
3da2(7), 45%,
3ea2(7), 50%,
3fa2(7), 46%
R1
N
H
N
H
N
H
N
H
H
H
N
H
N
H
N
R2
N
6
R
6
6
3ja
, R = Me, 89%
, R1 = Me, 90%c
3al
2
3av
, 77%
3at, 74%
3aa
, R = H, 88%
MeO2C
Br
NC
3ka, R = Cl, 83%
3la
3ab, R1 = Et, 94%
7
7
, R2 = Me, 86%
7
3am
N
H
N
R
N
H
, R = Br, 77%
N
H
, R1 = nPr, 92%
3an, R2 = OMe, 85%
H
3ac
3ma
H
N
, R = OMe,
H
N
3ha
3ia
1(6), 25%
3ia
2(7), 41%,
3ga
,
1(6), 30%
3ad, R1 = iPr, 89%
, R2 = Ph, 78%
3ap, R2 = F, 79%
1(6) 35%
3ao
85%
3ha
2(7), 41%
, R1 = nBu, 93%
3ga2(7), 42%
3ae
, R1 = iBu, 89%
3aq
N
H
Ph
, R2 = Cl, 83%
N
H
3af
H
N
R'
N
3ag, R1 = tBu, 84%
, R2 = Br, 84%
3ar
3oa
3pa
3qa
, R' = Me, 78%
, R' = Bn, 75%
, R' = CH2-CH=CH2, 78%
3au
3aw
, 84%
, 79%
, R1 = nC6H13, 87% 3as
3ai, R1 = Cy, 73%
, R2 = CF3, 81%
3ah
N
H
N
H
, R1 = Bn, 88%
3na, 83%
3aj
a Reaction conditions: 1a (0.25 mmol), 2 (0.275 mmol), B(C6F5)3 (5.0 mol%), PMHS
a Reaction conditions: 1 (0.25 mmol), 2a (0.275 mmol), B(C6F5)3 (5.0 mol%), PMHS
(1.0 mmol), toluene (1.5 mL) at 110 °C for 16 h. b Isolated Yield.
b
(1.0 mmol), toluene (1.5 mL) at 110 °C for 16 h. Isolated Yield. c 1a (10.0 mmol)
was employed.
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Furthermore, the reaction of 2a with 2,3-diaminomaleonitrile (1r
Journal Name
)
mol% B(C6F5)3 (Scheme 4a). Still further, when the separately
and 2-aminophenol (1s) led to the formation of 3ra and 3sa in 69% synthesized 5aa and 4aa were treated with PMHS under the
and 53% yields (Scheme 3), respectively, thus further demonstrating standard conditions, the target product 3aa was isolated in
the power of the current catalytic system.
excellent yields (Scheme 4b,c). These results clearly suggest that the
role of B(C6F5)3 in the current transformation is to catalyze the
reduction of 5aa and 4aa with PMHS.
H
N
O
NC
NC
NH2
NH2
NC
NC
OEt
OEt
B(C6F5) (5.0 mol%)
3
PMHS, toluene,110 oC, 16 h
(a)
(b)
+
+
N
H
O
1r
H
N
H
N
2a
3ra, 69%
H
N
O
NH2
NH2
O
O
O
B(C6F5
) (5.0 mol%)
3
OH
O
OMe
+
+
+
B(C6F5
) (5.0 mol%)
3
PMHS, toluene
110 oC, 16 h
N
H
3aa
N
H
4aa
N
PMHS, toluene,110 oC, 16 h
O
NH2
N
H
, 53%
O
1a
5aa
2a
1s
2a
3sa
Scheme 3. Reactions of 2,3-diaminomaleonitrile (1r) and 2-aminophenol (1s).
Considering that the reaction involves the intermediary of an
amide, the potential of this catalytic system for the preparation of
3,4-dihydroquinoxalin-2(1H)-ones was also investigated. It was
found that the reaction of 1a with 2a could deliver 4aa as the sole
product in 93% yield when the amount of PMHS was reduced to 1.5
equivalents (Table 4). Similarly, other 2-substituted 3,4-
dihydroquinoxalin-2(1H)-ones
(4ab,4ac,4aj,4al,4aw,4ja) could be
obtained in good to excellent yields. Notably, acetyl ketene (2x) also
underwent ready reaction with 1a to provide the corresponding
product 4ax in 88% yield, and 2,3-diaminomaleonitrile (1r) and 2-
aminophenol (1s) could be used, affording the corresponding
products 4ra and 4sa in 82% and 88% yields, respectively.
Fig. 1 Kinetic profile for the reaction of 1a with 2a under standard reaction
conditions. Yields were determined by 1H NMR with CH2Br2 as an internal
standard.
Table 4 Synthesis of 3,4-dihydroquinoxalin-2(1H)-ones.a,b
H
O
NH2
NH2
N
O
OEt
toluene
+
(a)
110 oC, 1 h
O
H
N
N
NH2
NH2
O
O
OEt
B(C6F5)3 (5.0 mol%)
PMHS, toluene,110 oC, 3 h
5aa,
1a
with B(C6F5)3,
95%
2a
R
R'
+
R
w/o B(C6F5)3, 5aa, 94%
O
N
H
R'
H
N
H
N
4
1
2
O
B(C6F5)3 ( 5.0 mol%)
PMHS, toluene, 110 oC, 16 h
H
H
N
H
H
N
H
(b)
(c)
O
O
O
O
N
O
N
N
N
H
N
5aa
3aa
3aa
, 93%
N
H
Et
N
H
Bn
N
H
nPr
N
H
N
H
, 86%
Ph
H
N
H
N
O
4aa
, 93%
4ab, 92%
4ac
4aj
4al
B(C6F5)3 ( 5.0 mol%)
PMHS, toluene, 110 oC, 16 h
, 93%
, 94%
H
N
O
H
N
H
N
H
N
H
4aa
N
H
O
O
O
O
NC
NC
O
N
, 95%
N
H
N
H
Ph
N
H
N
H
N
H
Scheme 4. Mechanistic studies.
4ja
, 95%
4aw, 89%
4ax, 85%
4ra
, 82%
4sa
, 88%
a
Based on the above mechanistic studies and the previous
reports,19-22 a reaction pathway is proposed. As shown in Scheme 5,
Reaction conditions: 1 (0.25 mmol), 2 (0.275 mmol), B(C6F5)3 (5.0 mol%), PMHS
(0.375 mmol), toluene (1.5 mL) at 110 °C for 3 h. b Isolated Yield.
the starting materials
the quinoxalinone . Meanwhile, B(C6F5)3 abstracts a hydride from
the hydrosilane to give the borane-silane complex A. The transfer of
silylium cation of to leads to the formation of intermediate
possessing a borohydride anion. The following hydride attack gives
rise to the silylated amine is protonated by water to afford the
3,4-dihydroquinoxalin-2(1H)-one and the hydroxysilane. The
silylium cation of then activates the C=O bond of to generate
the intermediate D 21
which is subsequently attacked by a hydride
to form the corresponding O-silylated N,O-acetal . Reduction of
by , presumably via the intermediary of an iminium species , the
affords the product
1 and 2 initially undergo cyclization to form
With an aim to shed light on the reaction mechanism, the kinetic
profile of the reaction between 1a and 2a was monitored. As shown
in Figure 1, 1a was completely transformed into 5aa within 1 h. The
following hydrosilylation of 5aa into 4aa started before the total
consumption of 1a. Finally deoxygenative reduction of the amide
moiety of 4aa led to the formation product 3aa. Obviously, 4aa and
5aa are the intermediates of the reaction. HRMS analysis of the
reaction system of 1a and 2a under standard conditions confirmed
the generation of 4aa and 5aa during the reaction. Furthermore,
formation of propane-1,2-diol or ethyl 2-hydroxypropanoate was
not observed by HRMS analysis, indicating that the reduction of 2a
by PMHS did not occur. Additional studies revealed that the
reaction of 1a and 2a in the absence of B(C6F5)3 and PMHS gave
almost identical yield of 5aa to that obtained in the presence of 5.0
5
A
5
B
C. C
4
A
4
,
E
E
A
F
3
.
4 | J. Name., 2012, 00, 1-3
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ARTICLE
are tolerated. The choice of hydrosilane is shown to be crucial for a
high catalytic activity and selectivity. Moreover, 3-substituted-3,4-
dihydroquinoxalin-2(1H)-ones could be efficiently prepared simply
by reducing the amount of PMHS. The enantioselective version of
this transformation has also been demonstrated. This operationally
simple protocol offers a practical and environmentally friendly
alternative to the currently known methods for the reduction of
qinoxalines and quinoxalin-2(1H)-ones.
Scheme 5. Proposed reaction pathway
Experimental
a preliminary exploration of the
Finally we carried out
enantioselective synthesis of these heterocycles. Inspired by the
recent reports from the group of Du on the application of chiral
General
borane catalysts generated by the in situ hydroboration of chiral All experiments were carried out in air, and all commercially
available chemicals including organic solvents were used as
dienes with HB(C6F5)2 for symmetric reduction of imines and
quinoxalines with hydrosilanes and hydrogen,7r,25 we examined the
reaction of 1a and 2a under similar catalysis, with the catalyst
formed in situ from the hydroboration of chiral dienes. After a brief
screening of the reaction conditions (Table S7 in Supporting
Information), it was found that 3aa could be obtained in 87% yield
with 47% ee under the optimal reaction conditions (Scheme 6a).
1
received without further purification. H NMR and 13C NMR spectra
were recorded on a Bruker Model Avance DMX 400 Spectrometer
(1H 400 MHz and 13C 100.6 MHz, respectively). Chemical shifts (δ)
are given in ppm and are referenced to residual solvent peaks, and
coupling constants (J) were reported in Hertz.
General procedure for the synthesis of tetrahydroquinoxalines
To an oven-dried screw-capped pressure tube were sequentially
Likewise, the reactions of 1a with 2b, 2c, 2j and 2l provided the
added 1,2-diaminobenzene
1 (0.25 mmol), α-ketoester 2 (0.275
corresponding products in 83-90% yields with 47-76% ee values.
Further investigations showed that decreasing the amount of the
reducing agent Ph2H2Si to 1.5 equivalents and lowering the reaction
temperature to 45 °C resulted in the formation of 3,4-
dihydroquinoxalin-2(1H)-ones in high yields with moderate to good
mmol), B(C6F5)3 (6.4 mg, 5.0 mol%), PMHS (0.06 mL, 1.0 mmol) and
toluene (1.5 mL). Then the reaction mixture was stirred at 110 °C for
16 h. After cooling to room temperature, the mixture was diluted
with EtOAc (5.0 mL). Then water (5.0 mL) was added to the reaction
mixture, which was extracted with EtOAc three times (5.0 mL each).
The combined organic phases were dried over Na2SO4, then filtered
and evaporated under reduced pressure. After the removal of
volatile materials by rotary evaporation, the resultant mixture was
purified by silica gel column chromatography using a mixture of
EtOAc and hexane to give the corresponding pure product.
ee values (Scheme 6b). The lower ee values of 3 may result from the
higher temperature used for the reduction of amide moiety.
General procedure for the synthesis of 3,4-dihydroquinoxalin-
2(1
To an oven-dried screw-capped pressure tube were sequentially
added 1,2-diaminobenzene (0.25 mmol), α-ketoester (0.275
H)-ones
1
2
mmol), B(C6F5)3 (6.4 mg, 5.0 mol%), PMHS (22.5 μL, 0.375 mmol)
and toluene (1.5 mL). Then the reaction mixture was stirred at 110
°C for 3 h. After cooling to room temperature, the mixture was
diluted with EtOAc (5.0 mL). Then water (5.0 mL) was added to the
reaction mixture, which was then extracted with EtOAc three times
(5.0 mL each). The combined organic phases were dried over
Na2SO4, then filtered and evaporated under reduced pressure. After
the removal of volatile materials by rotary evaporation, the
resultant mixture was purified by silica gel column chromatography
using a mixture of EtOAc and hexane to give the corresponding pure
product.
Scheme 6. Asymmetric synthesis of 1,2,3,4-tetrahydroquinoxalines and 3,4-
dihydroquinoxalin-2(1H)-ones.
Conclusions
In conclusion, we have developed a new and efficient one-pot
tandem protocol for the step-economic synthesis of 2-substituted
1,2,3,4-tetrahydroqinoxalines directly from readily available 1,2-
diaminobenzenes and α-ketoesters under B(C6F5)3 catalysis with
Acknowledgments
cheap, safe PMHS as the reductant. The reaction scope is broad, We are grateful for financial support from the NSFC (No. 21372258),
the Fundamental Research Funds for the Central Universities, and
and a number of functional groups including the reducible moieties
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J. Name., 2013, 00, 1-3 | 5
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Journal Name
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DOI: 10.1039/C7GC03095A
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Green Chemistry
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DOI: 10.1039/C7GC03095A
Graphical Abstract:
Metal-free Tandem Cyclization/Hydrosilylation to Construct
Tetrahydroquinoxalines
Yixiao Pan, Changjun Chen, Xin Xu, Haoqiang Zhao, Jiahong Han, Huanrong Li,
Lijin Xu,* Qinghua Fan* and Jianliang Xiao*
B(C6F5)3-catalyzed tandem cyclization/hydrosilylation for the step-economical construction of
1,2,3,4-tetrahydroquinoxalines from readily available starting materials has been developed.