Highly Stereoselective Metal-Free Hydrogenations of Pyrrolo[1,2- a]quinoxalines

Article abstract of DOI:10.1021/acs.orglett.8b02364

A metal-free hydrogenation of pyrrolo[1,2-a]quinoxalines has been successfully realized by using the combination of B(C₆F₅)₃ and tris(4-methoxyphenyl)phosphine to furnish the corresponding 1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinoxalines in 59-99% yields. For 4-aryl-substituted pyrrolo[1,2-a]quinoxalines, high cis selectivities were obtained, but trans-selectivities were achieved for the 4-methyl-substituted substrates.

Full text of DOI:10.1021/acs.orglett.8b02364

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Highly Stereoselective Metal-Free Hydrogenations of
Pyrrolo[1,2‑a]quinoxalines
Xiaoqin Liu,†,‡ Ting Liu,†,‡ Wei Meng,*,†,‡ and Haifeng Du*,†,‡
†Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular Recognition and Function, CAS
Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing
100190, China
‡School of Chemical Science, University of Chinese Academy of Sciences, Beijing 100049, China
S
* Supporting Information
ABSTRACT: A metal-free hydrogenation of pyrrolo[1,2-a]quinoxalines has
been successfully realized by using the combination of B(C6F5)3 and tris(4-
methoxyphenyl)phosphine to furnish the corresponding 1,2,3,3a,4,5-
hexahydropyrrolo[1,2-a]quinoxalines in 59−99% yields. For 4-aryl-substituted
pyrrolo[1,2-a]quinoxalines, high cis selectivities were obtained, but trans-
selectivities were achieved for the 4-methyl-substituted substrates.
liphatic polyfused heterocycles, which are the core
been developed for the synthesis of dihydropyrrolo[1,2-
Aframeworks of numerous natural or synthetic molecules a]quinoxalines, including the Mannich reaction,7 1,3-dipolar
cycloaddition reaction,8 visible-light-induced photoredox cat-
with diverse biological or medicinal activities, have attracted
alysis,9 modified Pictet−Spengler reaction,10 reduction/cycli-
intensive interest, and considerable efforts have been devoted
zation,11 and Pd-catalyzed intramolecular N-arylations.12
However, there is still a lack of efficient methods for the
construction of hexahydropyrrolo[1,2-a]quinoxalines. The
direct catalytic hydrogenation of pyrrolo[1,2-a]quinoxalines
seems to be an effective approach to access these compounds.
Unfortunately, such a transformation has rarely been reported.
As part of our ongoing interest in the FLP catalysis, we have
successfully realized the hydrogenation of several types of
aromatic N-heterocycles, such as pyridines, quinolines,
quinoxalines, 1,8-naphthyridines, and pyridazines.13 Herein,
we report our preliminary results for the FLP-catalyzed highly
stereoselective hydrogenation of pyrrolo[1,2-a]quinoxalines.
The metal-free hydrogenation of pyrrolo[1,2-a]quinoxaline
4a was initially investigated by using 10 mol % of B(C6F5)3
(5a)14 as catalyst under H2 (40 bar) at 80 °C in toluene
(Scheme 1). We were pleased to find that this reaction went
smoothly to give the hexahydropyrrolo[1,2-a]quinoxaline 6a in
a quantitative conversion with a good cis selectivity. In
contrast, Lewis acid 5b with relatively weaker acidity generated
in situ by the hydroboration of pentafluorostyrene with
HB(C6F5)2, gave partially reduced product 7a in a quantitative
conversion instead of 6a.
to constructing these structures.1 Catalytic hydrogenations of
aromatic heterocycles have become an efficient and straightfor-
ward approach for their synthesis.2 In comparison with the
success of transition-metal catalysis, metal-free hydrogenations
have not achieved substantial progress until the advent of
frustrated Lewis pairs (FLPs).3 A number of unsaturated
compounds proved to be effective substrates for the FLP
catalysis.4 Notably, the metal-free hydrogenation of aromatic
heterocycles as well as its asymmetric version has made an
important advance in recent several years.5 However, to the
best of our knowledge, catalytic hydrogenations of aromatic
polyfused heterocycles with FLPs have seldom been reported.
Hexahydropyrrolo[1,2-a]quinoxalines are important moi-
eties present in a variety of biologically active molecules; for
example, compounds 1−3 (Figure 1) exhibit some promising
activities, such as antimicrobial, antitumor, anxiolytic,
analgesic, and antiallergic, and act as candidates for diuretics,
glucagon receptors antagonists, etc.6 Several protocols have
The B(C6F5)3-catalyzed hydrogenation of pyrrolo[1,2-a]-
quinoxaline 4a was further optimized. When the reaction
temperature was lowered to 70 °C, the stereoselectivity was
significantly improved to >99/1 but with a dramatic loss of
Received: July 26, 2018
Figure 1. Representative biologically active molecules.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02364
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Initial Studies on Hydrogenations of Pyrrolo[1,2-
a]quinoxaline 4a
Table 2. Hydrogenations of Aryl-Substituted Pyrrolo[1,2-
a]quinoxalines 4
a
reactivity (Table 1, entries 1 vs 2). Solvents had a large
influence on both reactivity and stereoselectivity (Table 1,
a
Table 1. Optimization of Reaction Conditions
b
time
(h)
conv
(%)
c
entry
1
2
solvent
phosphine 8
dr
toluene
toluene
n-hexane
o-xylene
DCM
6
12
6
6
6
6
6
6
6
>99
50
50
43
22
trace
>99
>99
38
>99
>99
87/13
>99/1
>99/1
87/13
nd
d
3
4
5
6
7
8
9
THF
nd
toluene
toluene
toluene
toluene
toluene
Ph3P (8a)
(4-FPh)3P (8b)
(4-MeOPh)3P (8c)
(4-MeOPh)3P (8c)
(4-MeOPh)3P (8c)
91/9
85/15
>99/1
>99/1
>99/1
e
10
11
10
12
f
a
All of the reactions were carried out with pyrrolo[1,2-a]quinoxaline
4a (0.10 mmol), B(C6F5)3 (5a) (0.01 mmol), phosphine 8 (0.01
mmol), and H2 (40 bar) in a solvent (0.5 mL) at 80 °C unless
b
c
1
otherwise noted. Determined by crude H NMR. Determined by
d
e
crude 1H NMR. At 70 °C. 2 mol % of tris(4-methoxyphenyl)-
f
phosphine 5c was added. 1 mol % of 8c and 5 mol % of 5a was used.
entries 3−6). Additional Lewis bases were next subjected to
the hydrogenation. The combination of 10 mol % of B(C6F5)3
(5a) and triphenylphosphine (8a) or tris(4-fluorophenyl)-
phosphine (8b) gave similar cis selectivities without loss of
reactivities (Table 1, entries 1 vs 7 and 8). When tris(4-
methoxyphenyl)phosphine (8c) was used, >99/1 dr was
obtained, but the reaction was slowed sharply (Table 1,
entry 9). Reducing the loading amount of 8c from 10 to 2 mol
% resulted in a quantitative conversion with >99/1 dr (Table
1, entry 10). Further treating the obtained product (>99/1 dr)
with 10 mol % of B(C6F5)3 (5a) at 80 °C without addition of
8c led a partial isomerization (87/13 dr), which indicates the
major role of phosphine Lewis base is likely to inhibit the
isomerization instead of forming a frustrated Lewis pair with
B(C6F5)3. When a combination of 5 mol % of B(C6F5)3 (5a)
and 1 mol % of phosphine 8c was used, the high reactivity and
cis selectivity could be well maintained (Table 1, entry 11).
With the optimal reaction conditions in hand, a variety of 4-
aryl-substituted pyrrolo[1,2-a]quinoxaline derivatives 4a−l
were subjected to this metal-free hydrogenation. As shown in
Table 2, all the reactions proceeded smoothly with high
stereoselectivities to give the desired cis-hexahydropyrrolo[1,2-
a]quinoxalines 6a−l in 59−99% yields. A gram-scale hydro-
genation of pyrrolo[1,2-a]quinoxaline 4a was successfully
realized to afford cis-6a as a sole product in 87% yield
a
All of the reactions were carried out with pyrrolo[1,2-a]quinoxaline
4 (0.30 mmol), B(C6F5)3 5a (0.015 mmol), and 8c (0.003 mmol)
under H2 (40 bar) in toluene (1.5 mL) at 80 °C for 12 h unless
b
c
otherwise noted. Isolated yield for cis-isomer. Determined by crude
d
e
f
1H NMR. 100 °C for 18 h. 100 °C for 12 h. 140 °C for 20 h.
(Scheme 2). The relative configuration was determined
according to the X-ray structure of compound 6a (Figure 2).
Interestingly, when 4-methyl-substituted pyrrolo[1,2-a]-
quinoxalines 4m−p were employed as substrates for this
hydrogenation, good to high trans-selectivities were afforded,
and the trans-products 6m−p were obtained in 70−96% yields
(Scheme 3). The relative configuration was determined
according to the X-ray structure of compound 6m (Figure
Scheme 2. Gram-Scale Hydrogenation of 4a
B
DOI: 10.1021/acs.orglett.8b02364
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02364.
Experimental procedures for metal-free hydrogenation,
characterization of substrates and products, and NMR
spectra (PDF)
Figure 2. X-ray structures of compounds 6a and 6m
Accession Codes
Scheme 3. Metal-Free Hydrogenation of 4-
Methylpyrrolo[1,2-a]quinoxalines
CCDC 1850822 and 1853614 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: mengwei@iccas.ac.cn.
*E-mail: haifengdu@iccas.ac.cn.
ORCID
Wei Meng: 0000-0002-1555-3738
Haifeng Du: 0000-0003-0122-3735
Notes
2). Moreover, with the use of in situ generated borane Lewis
acid 5b, the partial hydrogenation of pyrrolo[1,2-a]-
quinoxalines 4 was realized to furnish the corresponding
dihydro products 7a−e in 50−95% yields (Scheme 4).
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for generous financial support from the
National Natural Science Foundation of China (21572231 and
21521002).
Scheme 4. Partial Reductions of Pyrrolo[1,2-a]quinoxalines
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DOI: 10.1021/acs.orglett.8b02364
Org. Lett. XXXX, XXX, XXX−XXX