Enantioselective synthesis of polycyclic nitrogen heterocycles by Rh-catalyzed alkene hydroacylation: Constructing six-membered rings in the absence of chelation assistance

Article abstract of DOI:10.1021/ol501869s

Catalytic, enantioselective hydroacylations of N-allylindole-2- carboxaldehydes and N-allylpyrrole-2-carboxaldehydes are reported. In contrast to many alkene hydroacylations that form six-membered rings, these annulative processes occur in the absence of

Full text of DOI:10.1021/ol501869s

Letter
pubs.acs.org/OrgLett
Enantioselective Synthesis of Polycyclic Nitrogen Heterocycles by
Rh-Catalyzed Alkene Hydroacylation: Constructing Six-Membered
Rings in the Absence of Chelation Assistance
Xiang-Wei Du, Avipsa Ghosh, and Levi M. Stanley*
Department of Chemistry, Iowa State University, 1605 Gilman Hall, Ames, Iowa 50014, United States
S
* Supporting Information
ABSTRACT: Catalytic, enantioselective hydroacylations of N-
allylindole-2-carboxaldehydes and N-allylpyrrole-2-carboxaldehydes
are reported. In contrast to many alkene hydroacylations that form
six-membered rings, these annulative processes occur in the absence
of ancillary functionality to stabilize the acylrhodium(III) hydride
intermediate. The intramolecular hydroacylation reactions generate
7,8-dihydropyrido[1,2-a]indol-9(6H)ones and 6,7-dihydroindolizin-8(5H)-ones in moderate to high yields with excellent
enantioselectivities.
he hydroacylation of alkenes in the presence of a
Ttransition metal catalyst has been extensively investigated
as a direct route to ketones from simple starting materials.1
Despite the importance of ketones as synthetic building blocks
and their potential as entry points to an array of chemical
architectures, the hydroacylation of alkenes remains under-
developed and underutilized relative to other metal-catalyzed
hydrofunctionalizations of alkenes.2
Intramolecular hydroacylations to generate five-membered
carbocycles are the most established class of alkene hydro-
acylations,3 and many enantioselective hydroacylations of
substituted 4-pentenals and 2-vinylbenzaldehydes form chiral,
nonracemic cyclopentanones and dihydroindenones.4 Recent
strategies also enable the synthesis of six-, seven-, and eight-
membered carbocycles and heterocycles through intramolecular
alkene hydroacylation reactions.5 Despite these achievements,
intramolecular alkene hydroacylations to generate nitrogen
heterocycles remain rare,5a−c,6 and hydroacylation reactions to
by transient generation of a 2-aminopicoline-based aldimine
that stabilizes the acylrhodium hydride intermediate. However,
this approach to chelation assistance requires a complex
mixture of catalyst precursors and additives, and highly
enantioselective hydroacylations involving 2-aminopicoline-
based aldimines have not been reported.
form rings of greater than five atoms are often driven by strain
release5c,e,h or rely on heteroatom functionality contained at
specific sites within the substrate molecules to stabilize
acylrhodium(III) hydride intermediates and prevent catalyst
decomposition.5b,d,g,6b
We now report catalytic, enantioselective hydroacylations of
N-allylindole-2-carboxaldehyes and N-allylpyrrole-2-carboxalde-
hydes (eq 2). These hydroacylations occur to form
dihydropyridoindolones and dihydroindolizinones in moderate
to high yields and represent the first examples of highly
enantioselective, transition metal-catalyzed hydroacylation to
form six-membered rings in the absence of chelation assistance.
To test whether intramolecular hydroacylations would occur
to generate six-membered rings in the absence of chelation
assistance, we studied the reaction of 1-(2-methylallyl)-1H-
The potential to develop alkene hydroacylation as a platform
for synthesis of medicinally important nitrogen heterocycles led
us to study hydroacylations of indole- and pyrrole-2-
carboxaldehydes containing N-vinyl and N-allyl substitution.
We recently reported Rh-catalyzed hydroacylation of N-
vinylindole-2-carboxaldehydes to form dihydro-
pyrroloindolones in high yields with excellent enantioselectiv-
ities.7 Hydroacylations of N-allylindole-2-carboxaldehydes have
proven more challenging because these processes involve the
formation of a six-membered ring instead of a five-membered
ring. During our studies, Douglas reported the first example of
alkene hydroacylation involving N-allylindole-2-carboxalde-
hydes (eq 1).5a These hydroacylation reactions are enabled
Received: June 27, 2014
© XXXX American Chemical Society
A
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Organic Letters
Letter
indole-2-carboxaldehyde 1a catalyzed by complexes prepared in
situ from [Rh(COD)Cl]2, (R)-BINAP L1, and a variety of silver
salts (Table 1).8 We found the hydroacylation of 1a did not
favored; the formation of a five-membered ketone product was
not observed.10
The absolute configuration of 2a was determined after
bromination of 2a with N-bromosuccinimide to generate 3 in
nearly quantitative yield (Scheme 1). The absolute config-
uration of 3 was determined to be (S) by X-ray crystallographic
analysis.
Table 1. Identification of Catalysts for Hydroacylation of 1-
(2-Methylallyl)-1H-indole-2-carboxaldehyde 1a
Scheme 1. Absolute Stereochemistry and Structure of 3
a
b
c
entry
ligand
AgX
conv (%)
yield 2a (%)
ee (%)
1
2
3
4
5
6
7
8
L1
L1
L1
L1
L1
L1
L2
L3
L2
−
5
0
−
−
Table 2 summarizes the results of hydroacylations with 1-(2-
methylallyl)-indole-2-carboxaldehydes containing substitution
AgOMs
AgOTf
AgPF6
AgBF4
AgSbF6
AgBF4
AgBF4
−
2
0
18
69
99
82
99
99
98
17 (12)
69 (63)
86 (83)
82 (79)
99 (94)
99 (97)
93 (90)
94
96
95
96
97
87
96
Table 2. Rh-Catalyzed Enantioselective Hydroacylation of 1-
(2-Methylallyl)-indole-2-carboxaldehydes 1b−j
d
9
a
b
Conversion of 1a determined by 1H NMR spectroscopy. Yield of 2a
determined by 1H NMR spectroscopy. Isolated yield of 2a is shown in
c
d
parentheses. Determined by chiral HPLC analysis. Reaction
performed with 5 mol % [Rh(COD)2]BF4 as a catalyst precursor.
a
b
entry
1
R1
R2
2
yield 2 (%)
ee (%)
1
2
3
4
5
6
7
8
9
1b
1c
1d
1e
1f
H
H
H
H
H
H
H
H
Et
4-MeO
5-MeO
6-MeO
4,7-(MeO)2
5-Cl
2b
2c
2d
2e
2f
96
95
84
53
92
83
89
65
93
97
99
97
95
98
96
96
95
93
occur in the presence of rhodium catalysts with chloride or
mesylate counterions (entries 1 and 2) and formed dihydro-
pyridoindolone 2a in low yield when the catalyst contained a
triflate counterion (entry 3).
1g
1h
1i
6-Cl
2g
2h
2i
5-NO2
6-CF3
H
The intramolecular hydroacylation of 1a occurred in higher
yields and formed 2a with higher enantioselectivities when the
rhodium catalyst contained a weakly coordinating counterion.9
The reaction of 1a generated 2a in 63−83% yield with 95−96%
enantiomeric excess in the presence of rhodium complexes with
hexafluorophosphate, tetrafluoroborate, and hexafluoro-
antimonate counterions (entries 4−6). The identity of the
counterion had minimal effect on the enantioselectivity of the
hydroacylations. However, catalysts containing tetrafluorobo-
rate and hexafluorantimonate counterions led to significantly
higher yields of 2a.
To improve the yield and selectivity of our model reaction,
we studied the impact of catalysts prepared from additional
BINAP derivatives on the reaction of 1a. The rhodium(I)
complexes of (R)-Tol-BINAP L2 and (R)-Xyl-BINAP L3
catalyze the hydroacylation of 1a to form 2a in higher yields
(94% and 97% yield) than the Rh complex of the parent ligand
L1 (compare entries 7 and 8 with entry 5). However, the
hydroacylation of 1a occurred with the highest enantioselec-
tivity when the reaction was conducted with the Rh complex of
(R)-Tol-BINAP. The hydroacylation of 1a occurs with similar
enantioselectivity and forms 2a in 90% yield when the reaction
is performed with a catalyst generated from [Rh(COD)2]BF4
and (R)-Tol-BINAP (entry 9), suggesting the role of the Ag(I)
salt is limited to anion exchange to generate the active catalyst.
In all cases, the formation of six-membered ketone 2a was
1j
2j
a
b
Isolated yield of 2. Determined by chiral HPLC analysis.
at the 3-, 4-, 5-, 6-, and 7-positions on the indole core. In
general, hydroacylations of 1-(2-methylallyl)-indole-2-carbox-
aldehydes containing electron-donating substituents, electron-
withdrawing substituents, and halogens at the 4-, 5-, 6-, and 7-
positions occur with excellent enantioselectivity (entries 1−8).
Hydroacylations of 4-MeO-, 5-MeO-, and 6-MeO-substituted
1b−d formed 2b−d in high yields (84−96%) with excellent
enantioselectivities (97−99% ee, entries 1−3). The hydro-
acylation of 4,7-dimethoxy-substituted 1-(2-methylallyl)-indole-
2-carboxaldehyde 1e occurred with high enantioselectivity, but
the corresponding dihydropyridoindole 2e was isolated in 53%
yield (entry 4).11 Hydroacylations of 1f−i containing halogens
or electron-withdrawing groups at the 5- and 6-positions
occurred with excellent enantioselectivities (95−98% ee), and
2f−i were isolated in 65−92% yields (entries 5−8). A 3-
substituted 1-(2-methylallyl)-indole-2-carboxaldehyde 1j was
also an excellent substrate for hydroacylation. The reaction of
1j formed 2j in 93% yield with 93% ee (entry 9).
The results of intramolecular hydroacylations of N-allyl-
indole-2-carboxaldehydes containing a range of 2-substituted
B
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Organic Letters
Letter
allyl units, are shown in Table 3. Hydroacylations of 1k−q
containing alkyl, benzyl, aryl, and ester substituents at the
catalyst. However, the reaction of 4d formed 5d in 52% yield
with 92% enantiomeric excess when the reaction was run in the
presence of 10 mol % rhodium catalyst (entry 4).
In general, the N-allylpyrrole-2-carboxaldehydes are less
prone to decarbonylation than the related N-allylindole-2-
carboxaldehydes. These results are particularly evident for
pyrroles 4e−g with aryl substitution at the central carbon of the
allyl unit. The hydroacylations of 4e−g (R = Ph, 4-Me-C6H4,
and 4-Cl-C6H4) occurred with excellent enantioselectivities
(95−97% ee), and the heterocyclic ketone products 5e−g were
isolated in 85−96% yields (entries 5−7). These results contrast
hydroacylations of N-allylindole-2-carboxaldehydes with aryl
substitution at the central carbon of the allyl unit (compare
entries 4−6 in Table 3 with entries 5−7 in Table 4). Reactions
of indoles 1n−p require 10 mol % catalyst to reach high
coversion due to competing decarbonylation, while reactions of
the analogous pyrroles 4e−g require only 5 mol % catalyst to
reach full conversion and decarbonlyation side products are not
observed.12 The hydroacylation of pyrrole 4h containing an
electron-withdrawing group at the central carbon of the allyl
unit (R = CO2Et) generated 5h in 98% yield with 98% ee
(entry 8).
Table 3. Enantioselective Hydroacylation of N-Allylindole-2-
carboxaldehydes 1k−q
a
b
c
entry
R (1)
Et (1k)
2
conv (%)
yield 2 (%)
ee (%)
d
1
2k
2l
80
73
82
72
71
83
53 (75)
42 (61)
45 (55)
37 (64)
31 (63)
56 (66)
23 (56)
97
96
97
97
96
95
96
d
2
n-hexyl (1l)
CH2Ph (1m)
Ph (1n)
3
4
5
6
7
2m
2n
2o
2p
2q
4-Me-C6H4 (1o)
4-Cl-C6H4 (1p)
CO2Et (1q)
65
a
b
1
Conversion of 1 determined by H NMR spectroscopy. Isolated
c
yield of 2. NMR yield of 2 is listed in parentheses. Determined by
chiral HPLC analysis. AgBF4 was used in place of AgSbF6.
d
The synthetic utility of our enantioselective hydroacylation
reactions has been demonstrated through a rapid asymmetric
synthesis of the nonsteroidal aromatase inhibitor MR 20492
(Scheme 2).13 Enantioselective hydroacylation of N-allylindole-
central carbon of the allyl unit occurred with excellent
enantioselectivities (95−97% ee), but these reactions formed
dihydropyridoindoles 2k−q in modest yields (55−75% NMR
yields, 23−56% isolated yields). The relatively low isolated
yields of 2k−q result from a combination of competitive
decarbonylation of 1k−q and challenging product purifications
from reaction mixtures containing unreacted 1k−q and
decarbonylation products. Yields of decarbonylation products
ranged from 5% to 15%.
Scheme 2. Enantioselective Synthesis of (S,Z)-MR 20492
The ability to form dihydropyridoindoles by enantioselective
hydroacylations of N-allylindole-2-carboxaldehydes led us to
investigate analogous hydroacylations of N-allylpyrrole-2-
carboxaldehydes containing a range of substituted allyl units
(Table 4). The hydroacylations of N-allylpyrrole-2-carbox-
aldehydes 4a−c containing alkyl substitution at the central
carbon of the allyl unit formed dihydroindolizinones 5a−c in
modest-to-good yields (51−79%) with 94−97% enantiomeric
excess (entries 1−3). The hydroacylation of 4d (R = CH2Ph)
did not occur to high conversion in the presence of 5 mol %
2-carboxaldehyde 4g formed dihydroindolizinone 5g in 85%
yield with 95% ee (Table 4, entry 7). Aldol condensation of 5g
with pyridine-4-carboxaldehyde generated (S,Z)-MR 20492 in
57% yield.
In summary, we have developed catalytic, enantioselective
hydroacylations of N-allylindole- and N-allylpyrrole-2-carbox-
aldehydes. These hydroacylation reactions are catalyzed by a
readily available Rh complex, occur in the absence of chelation
assistance, and form six-membered heterocyclic ketones in
moderate-to-excellent yields from a variety of indole and
pyrrole substrates. The utility of our method is demonstrated in
a straightforward asymmetric synthesis of the nonsteroidal
aromatase inhibitor MR 20492. Studies to expand the scope of
transition-metal-catalyzed hydroacylation reactions that occur
in the absence of chelation assistance and to extend these
methods to additional carbocyclic and heterocyclic scaffolds are
ongoing in our laboratory.
Table 4. Enantioselective Hydroacylation of N-Allylpyrrole-
2-carboxaldehydes 4a−h
a
b
entry
R (4)
Me (4a)
5
yield 5 (%)
ee (%)
c
1
5a
5b
5c
5d
5e
5f
79
70
51
52
96
86
85
98
97
96
94
92
97
97
95
98
2
3
Et (4b)
n-hexyl (4c)
CH2Ph (4d)
Ph (4e)
d
4
5
6
7
4-Me-C6H4 (4f)
4-Cl-C6H4 (4g)
CO2Et (4h)
ASSOCIATED CONTENT
■
5g
5h
S
* Supporting Information
d
8
Experimental procedures, characterization for all new com-
pounds, and crystallographic data for compound 3. This
material is available free of charge via the Internet at http://
pubs.acs.org.
a
b
c
Isolated yield of 5. Determined by chiral HPLC analysis. Reaction
d
run at 100 °C using AgBF4 in place of AgSbF6. Reaction run in the
presence of 10 mol % catalyst.
C
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Organic Letters
Letter
(12) Reactions of substrates 1n and 4e occur in the presence of 5 mol
% catalyst to approximately 50% conversion in 1.5 h suggesting the
reactivity of indole and pyrrole substrates are similar in the absence of
catalyst deactivation.
(13) (a) Dallemagne, P.; Sonnet, P.; Enguehard, C.; Rault, S. J.
Heterocycl. Chem. 1996, 33, 1689. (b) Sonnet, P.; Enguehard, J. G.;
Dallemagne, P.; Rault, R. B. Bioorg. Med. Chem. Lett. 1998, 8, 1041.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: lstanley@iastate.edu.
Notes
The authors declare no competing financial interest.
́
(c) Auvray, P.; Sourdaine, P.; Moslemi, S.; Seralini, G. E.; Sonnet, P.;
Enguehard, C.; Guillon, J.; Dallemagne, P.; Bureau, R.; Rault, S. J.
Steroid. Biochem. Mol. Biol. 1999, 70, 59. (d) Sonnet, P.; Dallemagne,
P.; Guillon, J.; Enguehard, C.; Stiebing, S.; Tanguy, J.; Bureau, R.;
ACKNOWLEDGMENTS
■
We thank ISU, the ISU Institute for Physical Research, and the
NSF (CAREER 1353819) for financial support of this work.
L.S. thanks the NIH for a Pathways to Independence Award
(GM95697). We thank Dr. Arkady Ellern (ISU) for X-ray
diffraction data collection and structure determination.
́
Rault, S.; Auvray, P.; Moslemi, S.; Sourdaine, P.; Seralini, G. Bioorg.
Med. Chem. 2000, 8, 945.
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D
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