Enantioselective hydroacylation of N-vinylindole-2-carboxaldehydes

Article abstract of DOI:10.1039/c4cc00210e

We report catalytic, enantioselective intramolecular hydroacylation of N-vinylindole-2-carboxaldehydes. These hydroacylation reactions occur in the presence of a readily accessible rhodium catalyst and form chiral, non-racemic 2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-ones in high yields with excellent enantioselectivities.

Full text of DOI:10.1039/c4cc00210e

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Enantioselective hydroacylation of
N-vinylindole-2-carboxaldehydes†
Cite this: Chem. Commun., 2014,
50, 2765
Avipsa Ghosh and Levi M. Stanley*
Received 9th January 2014,
Accepted 24th January 2014
DOI: 10.1039/c4cc00210e
www.rsc.org/chemcomm
We report catalytic, enantioselective intramolecular hydroacylation form nitrogen heterocycles by alkene hydroacylations that occur (1)
of N-vinylindole-2-carboxaldehydes. These hydroacylation reac- with high enantioselectivity and (2) without the need for strategies to
tions occur in the presence of a readily accessible rhodium catalyst stabilize the acylrhodium(III) hydride intermediate.
and form chiral, non-racemic 2,3-dihydro-1H-pyrrolo[1,2-a]indol-
1-ones in high yields with excellent enantioselectivities.
Intramolecular hydroacylation of alkenes in the presence of
transition metal catalysts is a well-known process that couples
C–H bond activation with carbon–carbon bond formation to
form synthetically valuable ketone products.1 Hydroacylations
of substituted 4-pentenals and 2-vinylbenzaldehydes to form
cyclopentanones are common2 and occur with high enantio-
selectivities in the presence of chiral, non-racemic catalysts.3 Recent
reports have also shown that six-, seven- and eight-membered
carbocycles and heterocycles are accessible from intramolecular
alkene hydroacylation reactions.4 However, alkene hydroacylations
to generate nitrogen-containing heterocycles are rare.4e,5,6
Bendorf and co-workers reported amine-directed, intramolecular
hydroacylation of 2-(homoallylamino)benzaldehydes.5a These amine-
directed hydroacylation reactions occur in the presence of 10 mol%
of Wilkinson’s catalyst, and the efficiency of the reactions is greatly
influenced by the identity of the substituents on the nitrogen atom.
Recently, Douglas reported hydroacylation of N-allylindole-2-
carboxaldehydes and N-allylpyrrole-2-carboxaldehydes.5b These
hydroacylation reactions involve in situ formation of imines to install
chelating functionality to stabilize the resulting iminorhodium(III)
hydride intermediate.2j,7 The heterocyclic ketone products are formed
in good yields, but the requirement for chelation assistance leads to
poor atom economy and efforts to develop a highly enantioselective
catalyst were unsuccessful. Although reports by Bendorf and Douglas
provide an entry into practical alkene hydroacylation reactions to
generate nitrogen containing heterocycles, the opportunity exists to
(1)
The potential for enantioselective intramolecular hydroacylation
to create a rapid entry into dihydropyrroloindoles led us to study Rh-
catalyzed hydroacylation of N-vinylindole-2-carboxaldehydes (eqn (1)).
Dihydropyrroloindoles are core structures of a variety of indole
alkaloids including yuremamine8,9 and antimalarial bis-indoles from
the Flindersia species, such as the isoborreverines (Fig. 1).10 Thus, we
report the synthesis of highly enantioenriched 2,3-dihydro-1H-
pyrrolo[1,2-a]indolones by intramolecular hydroacylation of
N-vinylindole-2-carboxaldehydes in the presence of a rhodium
catalyst prepared in situ from commercially available precursors.
Initial studies to develop catalytic, enantioselective hydro-
acylations of N-vinylindole-2-carboxaldehydes were guided by
Department of Chemistry, Iowa State University, Ames, Iowa 50011, USA.
E-mail: lstanley@iastate.edu
† Electronic supplementary information (ESI) available: Experimental procedures,
characterization data for new compounds, and crystallographic data (CIF) for
compound 3. CCDC 976167. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c4cc00210e
Fig. 1 Dihydropyrroloindoles as core elements of indole alkaloids.
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Table 1 Identification of catalysts for Rh-catalyzed hydroacylation of
1-(1-phenylvinyl)-1H-indole-2-carboxaldehyde 1aa
Table 2 Rhodium-catalyzed enantioselective hydroacylation of N-vinylindole-
2-carboxaldehydes 1a–ha
Entry
R1 (1)
2
Yieldb (%)
eec (%)
1
2
3
Ph (1a)
2a
2b
2c
2d
2d
2e
2f
2g
2h
2h
90
99
68
30
70
92
82
99
20
45
99
99
98
99
99
98
99
99
97
95
4-MeO-C6H4 (1b)
4-Cl-C6H4 (1c)
4-F3C-C6H4 (1d)
4-F3C-C6H4 (1d)
3-MeO-C6H4 (1e)
3,4,5-(MeO)3-C6H2 (1f)
Me (1g)
4
5d
6
7
8
Entry
AgX
Ligand
Conversionb (%)
Yieldc (%)
eed (%)
9
Cyclohexyl (1h)
Cyclohexyl (1h)
10e
1
2
3
4
5
6
7
8
—
3
3
3
3
3
3
3
4
5
6
7
0
0
0
—
—
—
10
54
49
61
75
35
63
90
—
—
—
ND
94
91
95
96
98
97
99
AgNO3
AgOMs
AgClO4
AgBF4
AgPF6
AgSbF6
AgBF4
AgBF4
AgBF4
AgBF4
a
b
c
For detailed reaction conditions, see ESI. Isolated yield of 2. Deter-
d
96
75
72
99
95
42
80
95
mined by chiral HPLC analysis. Reaction run in the presence of
10 mol% catalyst. Reaction run at 100 1C in 1,4-dioxane.
e
(Table 1, entries 5, 8–11). The rhodium(I) complex of (R)-Tol-
BINAP 4 catalyzes the hydroacylation of 1a to form 2a in higher
yield than the rhodium complex of the parent (R)-BINAP ligand,
while the rhodium(I) complex of (R)-Xyl-BINAP catalyzes the
formation of 2a in lower yield (compare entries 8 and 9 with
entry 5). Rhodium complexes of both (R)-Tol-BINAP and (R)-Xyl-
BINAP catalyze the formation of 2a with higher enantioselectivity.
The reaction of 1a occurred with the best combination of yield
9
10
11
a
b
For detailed reaction conditions, see ESI. Determined by 1H NMR
spectroscopy using 1,3,5-trimethoxybenzene as the internal standard.
c
d
Isolated yield of 2a. Determined by chiral HPLC analysis.
hydroacylations of 2-vinylbenzaldehydes catalyzed by a rhodium(I)– and enantioselectivity in the presence of rhodium complexes
BINAP complex. To test whether hydroacylation of N-vinylindole-2- of (S)-Me-BIPHEP and (S)-MeO-BIPHEP (entries 10 and 11).
carboxaldehydes could occur with similar catalysts, we studied the The hydroacylation of 1a catalyzed by rhodium(I) complex of
reaction of 1-(1-phenylvinyl)-1H-indole-2-carboxaldehyde 1a cata- (S)-MeO-BIPHEP formed 2a in 90% yield with 99% ee (entry 11).
lyzed by complexes prepared in situ from [Rh(COD)Cl]2, (R)-BINAP
The results of intramolecular hydroacylations of N-vinylindole-
3, and a variety of silver salts (Table 1, entries 1–7). We found that 2-carboxaldehydes containing a range of substituted vinyl units
the hydroacylation of 1a did not occur in THF at 60 1C when the are shown in Table 2. The hydroacylations of N-vinylindole-2-
rhodium(I) catalysts contained coordinating counteranions, such as carboxaldehydes containing electron-neutral or electron-rich
chloride, nitrate, and mesylate (entries 1–3). However, the hydro- aryl groups at the 1-position of the N-vinyl moiety gave the
acylation of 1a formed dihydropyrroloindolone 2a in low to modest corresponding dihydropyrroloindolones 2a (R1 = Ph) and 2b
yield when the rhodium catalyst contained a weakly coordinating (R1 = 4-MeO-C6H4) in high yields (90–99%) with 99% enantiomeric
counteranion. The hydroacylation of 1a catalyzed by a rhodium excess (entries 1 and 2). The hydroacylation of N-vinylindole-2-
catalyst with a perchlorate counterion occurred to high conversion, carboxaldehydes substituted with electron-deficient aryl groups at
but formed 2a in low yield (entry 4). In contrast, the reaction of the 1-position of the vinyl group formed dihydropyrroloindolones
1a generated dihydropyrroloindolone 2a in 49–61% yield in the 2c (R1 = 4-Cl-C6H4) and 2d (R1 = 4-F3C-C6H4) in lower yield (68%
presence of rhodium complexes with tetrafluoroborate, hexa- and 30%, entries 3 and 4). However, these hydroacylations
fluorophosphate, and hexafluoroantimonate counteranions occurred with excellent enantioselectivity (98–99% ee), and
(entries 5–7). Although the catalyst containing a hexafluoro- the yield of 2d improved to 70% when the reaction was run
antimonate counterion led to the highest yield of 2a, this in the presence of 10 mol% rhodium catalyst (entry 5).
catalyst also promoted decomposition of 1a. We chose to
N-Vinylindole-2-carboxaldehydes containing meta-substituted
continue our study with rhodium catalysts containing a tetra- aryl groups at the 1-position of the N-vinyl moiety are also
fluoroborate counterion since we observed less decomposition excellent substrates for these intramolecular hydroacylations.
of 1a with this catalyst system.
N-Vinylindole-2-carboxaldehydes 1e (R1 = 3-MeO-C6H4) and 1f
To improve the yield and selectivity of our model reaction, (R1 = 3,4,5-(MeO)3-C6H2) reacted to form dihydropyrroloindolones
we studied the hydroacylation of 1a in the presence of catalysts 2e and 2f in 82–92% yield with 98–99% ee (entries 6 and 7). We
prepared from [Rh(COD)Cl]2, AgBF4, and a selection of aromatic were unable to generate data on hydroacylations of N-vinylindole-
bisphosphine ligands 3–7 containing axial chiral backbones 2-carboxaldehydes containing ortho-substituted aryl groups at the
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1-position of the N-vinyl moiety because Ullmann-type coupling
of appropriately substituted indoles and a-halogenated styrenes
were unproductive in our hands.
Reactions of N-vinylindole-2-carboxaldehydes containing alkyl
groups at the 1-position of the N-vinyl moiety also occurred with
high enantioselectivity. The reaction of 1g (R1 = Me) formed 2g in
nearly quantitative yield and nearly perfect enantioselectivity
(entry 8). The reaction of N-vinylindole-2-carboxaldehyde 1h
bearing a bulky cyclohexyl group formed dihydropyrroloindole
2h with 97% enantiomeric excess (entry 9). However, the yield of
2h was low when the reaction was run under our standard
conditions. The yield of 2h improved to 45% with a modest
decrease in enantioselectivity when the reaction was performed
in 1,4-dioxane at 100 1C (entry 10).
Scheme 1 summarizes the results of hydroacylations with
N-vinylindole-2-carboxaldehydes containing substitution at the
3-, 4-, 5-, and 6-positions on the indole moiety. A variety of
N-vinylindole-2-carboxaldehydes containing electron-donating
and electron-withdrawing substituents, as well as halogens,
were excellent substrates for the intramolecular alkene hydro-
acylation. Alkyl substitution at the 3-position of the indole
ring was well tolerated, and the hydroacylation of 3-ethyl-1-
(1-phenylvinyl)-1H-indole-2-carboxaldehyde 1i (R2 = Et, R3 = H)
formed product 2i in 89% yield with 98% ee. Hydroacylations of
4-MeO, 5-MeO, and 5-F substituted N-vinylindole-2-carboxalde-
hydes 1j–l occurred with excellent enantioselectivity (98–99%),
Scheme 2 Impact of catalyst loading on the enantioselective hydroacyl-
ation of N-vinylindole-2-carboxaldehyde 1a.
and dihydropyrroloindolones 2j–l were isolated in 90–97% yield.
Intramolecular hydroacylations of 6-chloro- and 6-trifluoromethyl-
1-(1-phenylvinyl)-1H-indole-2-carboxaldehydes (1m and 1n) formed
2m and 2n in slightly lower yield (81–82%), but the enantio-
selectivity remained high (98–99% ee).
Although reactions of N-vinylindole-2-carboxaldehydes to
establish the scope of these hydroacylations are conducted in
the presence of 5 mol% of the rhodium catalyst, this relatively
high catalyst loading is not a requirement to achieve high
isolated yields and enantioselectivities (Scheme 2). The hydro-
acylation of 1-(1-phenylvinyl)-1H-indole-2-carboxaldehyde 1a
performed in the presence of 1 mol% of the rhodium catalyst
at 100 1C in 1,4-dioxane generates dihydropyrroloindolone 2a
in 95% yield with 98% ee. Decreasing the catalyst loading to
0.2 mol% led to a lower yield (79%) of dihydropyrroloindolone
2a, but this heterocyclic ketone was still formed with excellent
enantioselectivity (98% ee).
The absolute configuration of dihydropyrroloindolone 2a
was determined after bromination (Scheme 3). Treatment of
2a with N-bromosuccinimide occurred to form 3 in 88% yield.
The absolute configuration of 9-bromo-3-phenyl-2,3-dihydro-
1H-pyrrolo[1,2-a]indol-1-one 3 was determined to be (3S) by
X-ray crystallographic analysis. Thus, the catalyst generated
from (S)-MeO-BIPHEP 7 leads to the formation of (S)-3.
In conclusion, we have established a method for highly
enantioselective intramolecular hydroacylation of N-vinylindole-
2-carboxaldehydes in the presence of a rhodium catalyst prepared
in situ from commercially available precursors. These reactions
encompass a broad range of N-vinylindole-2-carboxaldehydes
bearing a variety of aryl and alkyl substituents on the olefin
Scheme 1 Rhodium-catalyzed enantioselective hydroacylation of N-vinyl-
indole-2-carboxaldehydes 1i–n.
Scheme 3 Absolute stereochemistry and structure of 3 based on X-ray
diffraction data.
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E. Sakamoto, M. Takahashi, Y. Eto-Kato, X. M. Wu, K. Funakoshi,
K. Sakai and H. Suemune, J. Org. Chem., 2000, 65, 5806; (g) P. Marce,
Y. Diaz, M. I. Matheu and S. Castillon, Org. Lett., 2008, 10, 4735;
(h) K. Kunda, J. V. McCullagh and A. T. Morehead, Jr., J. Am. Chem.
Soc., 2005, 127, 16042; (i) T. J. Hoffman and E. M. Carreira, Angew.
Chem., Int. Ed., 2011, 50, 10670.
4 For selected examples, see: (a) Y. Sato, Y. Oonishi and M. Mori,
Angew. Chem., Int. Ed., 2002, 41, 1218; (b) A. D. Aloise, M. E. Layton
and M. D. Shair, J. Am. Chem. Soc., 2000, 122, 12610; (c) M. M.
Coulter, P. K. Dornan and V. M. Dong, J. Am. Chem. Soc., 2009,
moiety and substitution throughout the indole core. The enantio-
enriched dihydropyrroloindolone products are generated with
consistently high enantioselectivity (95–99% ee) even at low
catalyst loadings. The use of this reaction to complete the first
total synthesis of yuremamine is currently under investigation
in our laboratory.
We thank Iowa State University and the ISU Institute for
Physical Research and Technology for financial support of this
work. We thank Dr Arkady Ellern and the Molecular Structure
Laboratory (Iowa State University) for X-ray diffraction data
collection and structure determination. We thank Professor
Emeritus Richard Larock (Iowa State University) for instrumen-
tation and chemicals.
¨
131, 6932; (d) C. Aıssa and A. Fu¨rstner, J. Am. Chem. Soc., 2007,
´
¨
129, 14836; (e) D. Crepin, J. Dawick and C. Aıssa, Angew. Chem.,
Int. Ed., 2010, 49, 620.
5 (a) H. D. Bendorf, K. E. Ruhl, A. J. Shurer, J. B. Shaffer, T. O. Duffin,
T. L. LaBarte, M. L. Maddock and O. W. Wheeler, Tetrahedron Lett.,
2012, 53, 1275; (b) E. V. Beletskiy, C. Sudheer and C. J. Douglas,
J. Org. Chem., 2012, 77, 5884.
6 Willis and co-workers recently reported a two-step sequence invol-
ving hydroacylation of alkynes with 2-aminobenzaldehydes to form
2-aminoaryl enones and subsequent intramolecular 1,4-addition of
the amine to the enone to generate dihydroquinolones: M. Castaing,
S. L. Wason, B. Estepa, J. F. Hooper and M. C. Willis, Angew. Chem.,
Int. Ed., 2013, 52, 13280.
7 For reviews, see ref. 1b and c. For selected examples, see: (a) J.-W.
Park, J.-H. Park and C.-H. Jun, J. Org. Chem., 2008, 73, 5598;
(b) E.-A. Jo, J.-H. Lee and C.-H. Jun, Chem. Commun., 2008, 5779;
(c) E.-A. Jo and C.-H. Jun, Eur. J. Org. Chem., 2006, 2504; (d) D.-W.
Kim, S.-G. Lim and C.-H. Jun, Org. Lett., 2006, 8, 2937; (e) D.-H.
Chang, D.-Y. Lee, B.-S. Hong, J.-H. Choi and C. H. Jun, J. Am. Chem.
Soc., 2004, 126, 424; ( f ) D.-Y. Lee, I.-J. Kim and C.-H. Jun, Angew.
Chem., Int. Ed., 2002, 41, 3031; (g) D.-Y. Lee, C. W. Moon and
C.-H. Jun, J. Org. Chem., 2002, 67, 3945; (h) C.-H. Jun, D.-Y. Lee,
H. Lee and J.-B. Hong, Angew. Chem., Int. Ed., 2000, 39, 3070.
8 J. J. Vepsalainen, S. Auriola, M. Tukiainen, N. Ropponen and J. C.
Callaway, Planta Med., 2005, 71, 1053.
9 For synthetic efforts towards yuremamine, see: (a) M. B. Johansen
and M. A. Kerr, Org. Lett., 2008, 10, 3497; (b) W. B. Liu, X. Zhang,
L. X. Dai and S. L. You, Angew. Chem., Int. Ed., 2012, 51, 5183.
10 (a) J. Pousset, A. Cave, A. Chiaroni and C. Riche, J. Chem. Soc., Chem.
Commun., 1977, 261; (b) F. Tillequin and M. Koch, J. Chem. Soc.,
Chem. Commun., 1978, 826; (c) L. S. Fernandez, M. F. Jobling, K. T.
Andrews and V. M. Avery, Phytother. Res., 2008, 22, 1409; (d) L. S.
Fernandez, M. S. Buchanan, A. R. Carroll, Y. J. Feng, R. Quinn and
V. M. Avery, Org. Lett., 2009, 11, 329; (e) R. Vallakati and J. A. May,
J. Am. Chem. Soc., 2012, 134, 6936; D. H. Dethe, R. D. Erande and
A. Ranjan, J. Org. Chem., 2013, 78, 10106.
Notes and references
1 For selected reviews, see: (a) M. C. Willis, Chem. Rev., 2010, 110, 725;
(b) Y. J. Park, J.-W. Park and C.-H. Jun, Acc. Chem. Res., 2008, 41, 222;
(c) C.-H. Jun, E.-A. Jo and J.-W. Park, Eur. J. Org. Chem., 2007, 1869.
2 For selected examples, see: (a) C. F. Lochow and R. G. Miller, J. Am.
Chem. Soc., 1976, 98, 1281; (b) R. C. Larock, K. Oertle and G. F.
Potter, J. Am. Chem. Soc., 1980, 102, 190; (c) M. G. Vinogradov,
A. B. Tuzikov, G. I. Nikishin, B. N. Shelimov and V. B. Kazansky,
J. Organomet. Chem., 1988, 348, 123; (d) D. P. Fairlie and B. Bosnich,
Organometallics, 1988, 7, 936; (e) K. Sakai, Y. Ishiguro, K. Funakoshi,
K. Ueno and H. A. Suemune, Tetrahedron Lett., 1984, 25, 961;
( f ) Y. Taura, M. Tanaka, K. Funakoshi and K. Sakai, Tetrahedron Lett.,
1989, 30, 6349; (g) Y. Taura, M. Tanaka, X. M. Wu, K. Funakoshi and
K. Sakai, Tetrahedron, 1991, 47, 4879; (h) M. Rolandsgard, S. Baldawi,
D. Sirbu, V. Bjørnstad, C. Rømming and K. Undheim, Tetrahedron,
2005, 61, 4129; (i) Y. Oonishi, J. Ogura and Y. Sato, Tetrahedron Lett.,
2007, 48, 7505; ( j) N. R. Vautravers, D. D. Regent and B. Breit, Chem.
Commun., 2011, 47, 6635; (k) R. Okamoto and K. Tanaka, Org. Lett.,
2013, 15, 2112.
3 For selected examples, see: (a) X.-M. Wu, K. Funakoshi and K. Sakai,
Tetrahedron Lett., 1992, 33, 6331; (b) X.-M. Wu, K. Funakoshi and
K. Sakai, Tetrahedron Lett., 1993, 34, 5927; (c) R. W. Barnhart,
X. Q. Wang, P. Noheda, S. H. Bergens, J. Whelan and B. Bosnich,
J. Am. Chem. Soc., 1994, 116, 1821; (d) R. W. Barnhart, X. Q. Wang,
P. Noheda, S. H. Bergens, J. Whelan and B. Bosnich, Tetrahedron,
1994, 50, 4335; (e) R. W. Barnhart, D. A. McMorran and B. Bosnich,
Chem. Commun., 1997, 589; ( f ) M. Tanaka, M. Imai, M. Fujio,
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