An efficient synthesis of hydropyrido[1,2-a]indole-6(7H)-ones via an In(iii)-catalyzed tandem cyclopropane ring-opening/Friedel-Crafts alkylation sequence

Article abstract of DOI:10.1039/c1cc14131g

An efficient Lewis acid-catalyzed cyclopropane ring-opening/Friedel-Crafts alkylation sequence of methyl 1-(1H-indole-carbonyl)-1-cyclopropanecarboxylates is reported. The protocol affords functionalized hydropyrido[1,2-a]indole-6(7H)- ones in up to 99% yield.

Full text of DOI:10.1039/c1cc14131g

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COMMUNICATION
An efficient synthesis of hydropyrido[1,2-a]indole-6(7H)-ones via an
In(III)-catalyzed tandem cyclopropane ring-opening/Friedel–Crafts
alkylation sequencew
Dadasaheb V. Patil, Marchello A. Cavitt, Paul Grzybowski and Stefan France*
Received 9th July 2011, Accepted 28th July 2011
DOI: 10.1039/c1cc14131g
An efficient Lewis acid-catalyzed cyclopropane ring-opening/
Friedel–Crafts alkylation sequence of methyl 1-(1H-indole-
carbonyl)-1-cyclopropanecarboxylates is reported. The protocol
affords functionalized hydropyrido[1,2-a]indole-6(7H)-ones in
up to 99% yield.
The hydropyrido[1,2-a]indole skeleton (1) and, more specifi-
cally, its C(6)-oxidized cogeners (2) are key structural motifs
that appear in the core structures of an impressive number of
naturally-occurring indole alkaloids and pharmaceutically-
Scheme 1 Tandem cyclopropane ring-opening/Friedel–Crafts alkylation.
relevant compounds (Fig. 1).1 Many approaches have been
reported to construct the hydropyrido[1,2-a]indole skeleton.2
Unfortunately, many of these strategies involve extensive
multi-step sequences to construct the N-fused bicyclic ring
system or do not allow for a large range of functionality to be
accessed. Therefore, the development of a more general and
efficient method for the facile construction of this polycyclic
core remains a formidable goal for organic chemists.
In this communication, we describe an efficient and modular
approach to hydropyrido[1,2-a]indole-6(7H)-ones 2 via the
Lewis acid-catalyzed intramolecular cyclizations of methyl
Scheme 2 Modular preparation of cyclization precursors.
1-(1H-indole-carbonyl)-1-cyclopropanecarboxylates (Scheme 1).
and, thus, incorporates a nitrogen atom into the newly formed
ring. This transformation specifically generates the lactam ring
portion of the hydropyrido[1,2-a]indole-6(7H)-ones.
Mechanistically, the protocol involves cyclopropane ring-opening
in the presence of a Lewis acid catalyst, followed by an
intramolecular Friedel–Crafts alkylation3 of the indole.4,5
The cyclization proceeds through the aza-cationic intermediate B
We began our study by outlining a modular sequence for
the preparation of the precursors required for cyclization. Cyclo-
propanes 3 were synthesized in three steps according to Scheme 2.
N-Acylation of an indole with commercially-available methyl
malonyl chloride afforded the 1,3-dicarbonyl compound 5. Next,
diazo transfer provided a-diazoester 6. Lastly, cyclopropanation6
with Rh2esp2 (bis[rhodium(a,a,a0,a0-tetramethyl-1,3-benzenedi-
propionic acid)]) in the presence of a requisite alkene provided
the desired methyl 1-(1H-indole-carbonyl)-1-cyclopropane-
carboxylates 3 with yields up to 70% over the three steps.
With a diverse set of substrates in hand, we first examined
the effects of various donor groups on the cyclopropane by
changing the alkene used during cyclopropanation. Based on
our recent success with In(OTf)3 as an effective catalyst for six
membered-ring formation,7 cyclopropanes 3a–3q (derived
from 3-methyl indole) were treated with 30 mol% In(OTf)3
in either dichloromethane at room temperature or 1,2-dichloro-
ethane at reflux (Table 1).8
Fig. 1 Compounds containing the hydropyrido-[1,2-a]indole core.
School of Chemistry and Biochemistry, Georgia Institute of
Technology, Atlanta, Georgia 30332, USA.
E-mail: stefan.france@chemistry.gatech.edu; Fax: +1 404-894-7452;
Tel: +1 404-385-1796
w Electronic supplementary information (ESI) available: full experi-
mental details and 1H and 13C spectra for all new compounds. See
DOI: 10.1039/c1cc14131g
c
10278 Chem. Commun., 2011, 47, 10278–10280
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Cyclopropane 3a rapidly cyclized to afford the hydropyrido-
[1,2-a]indole based product 4a in near quantitative yield with
2.6 : 1 trans : cis dr (entry 1). Likewise, 2-methoxy phenyl
cyclopropane 3b provided product 4b in 95% with 3.2 : 1 dr
(entry 2). Next, in order to examine the electronic effects of the
para-substituent on the aromatic cyclopropane donor group,
the phenyl, 4-fluorophenyl, 4-chlorophenyl and the 4-nitro-
phenyl cyclopropanes were synthesized. When the phenyl
derivative 3c was subjected to the same reaction conditions,
no reaction occurred (only starting material was recovered). Upon
heating to reflux in 1,2-dichloroethane, 3c gave 52% yield of
the desired hydropyrido[1,2-a]indole 4c with 2.6 : 1 dr (entry 3).
Similarly, for each of the other cyclization precursors bearing
electron-withdrawing groups 3d–3f, no reaction was observed
at room temperature, whereas cyclized products were observed
in 1,2-dichloroethane at reflux. The 4-chlorophenyl and
4-fluorophenyl derivatives furnished cyclized products 4d
and 4e in 48% and 50% yield, respectively (entries 4 and 5).
We were pleased with these results because the aromatic
halogen may serve as a chemical handle for further synthetic
functionalization. However, the 4-nitro derivative 3f only
afforded trace amounts of the desired product 4f as indicated
by crude 1H NMR (entry 6). These observations can be
rationalized based on an increasing cation destabilizing effect
as the substituents are varied from the electron-donating
4-methoxy group to the electron-withdrawing 4-nitro group.
These observations correlate well with known Hammett
substituent values for benzylic cations.9
Table 1 Substrate scopea
Time Yield dr
(h)
(%)b (trans : cis)c
Entry Substrate
Product
Similar reactivity was observed when a heteroaromatic
group was employed as the donor substituent. For example,
with furan as the donor group, cyclized product 4g is readily
obtained in 99% yield with 4.5 : 1 dr (entry 7). This result is
noteworthy in that furyl donor groups of this type have
previously been shown to be prone to polymerization.10a
Placing another cation stabilizing donor substituent on the
cyclopropane, as in 3h (derived from a-methyl styrene),
resulted in a dramatic accelerating effect. This effect can be
seen in that 3h readily cyclizes at room temperature to afford
4h in high yield (94%) with 1.1 : 1 dr (entry 8), whereas 3c does
not cyclize at room temperature. The enhanced reactivity of
3h is presumably attributed to faster ring-opening of the cyclo-
propane due to a release of steric ring strain and the formation of
the more stable 31 benzylic carbocation. This is also important
due to the formation of a quaternary stereocenter.
3a (R1 = H;
1
4a
4b
4c
4d
4e
4f
2.0
99
95
52
48
50
2.6 : 1
3.2 : 1
2.6 : 1
2.6 : 1
1.9 : 1
—
R2 = 4-MeOPh)
3b (R1 = H;
R2 = 2-MeOPh)
3c (R1 = H;
R2 = Ph)
3d (R1 = H;
R2 = 4-F-Ph)
3e (R1 = H;
R2 = 4-Cl-Ph)
3f (R1 = H;
R2 = 4-NO2-Ph)
3g (R1 = H;
R2 = 2-furyl)
3h (R1 = Me;
R2 = Ph)
3i (R1, R2 = Et)
3j (R1, R2 =
–(CH2)4–)
3k (R1, R2 =
–(CH2)5–)
3l (R1 = H;
R2 = CH2TBDPS)
3m (R1 = H;
R2 = NPhth)
3n (R1 = H;
R2 = SPh)
2
3.0
8.0
3d
4d
5d
6d
7
8.0
12.0
20.0 trace
4g
2.0
99
4.5 : 1
8
4h
4i
4j
2.0
6.0
6.0
94
85
88
1.1 : 1e
—
Since tertiary carbocations are very close in energy to
benzylic carbocations11 and a 31 carbocation will be formed
upon cyclopropane ring-opening, we envisioned that cycliza-
tion would occur when two alkyl groups are placed geminally
at the donor position of the cyclopropane. To explore this
premise, 3i (derived from 3-methylene pentane), 3j (derived
from methylene cyclopentane) and 3k (derived from methylene
cyclohexane) were synthesized. When subjected to heating in
DCE with In(OTf)3, each cyclopropane 3i, 3j and 3k provided
their respective hydropyrido[1,2-a]indole products 4i, 4j and
4k in 85, 88 and 79% yield (entries 9–11). These results are
particularly notable for several reasons: (1) spirocyclic com-
pounds (as in 4j and 4k) can be readily accessed from an
appropriate 1,1-disubstituted alkene; (2) the successful use of
alkyl groups as donors has been limited to Tsuge’s seminal
report;10d and (3) a number of hydropyrido[1,2-a]indole
natural products have gem-dialkyl substituents at C(9).
Activated alkyl donor substituents, such as the 2-trialkyl-
silylmethyl group,10b cyclized under similar reaction conditions.
In one representative example, the 2-silylmethyl cyclopropane
3l was synthesized and reacted to give 4l in 82% yield, with only
one observable diastereomer (entry 12). This silyl group not
only stabilizes the carbocation (upon cyclopropane ring-
opening) through the b-silyl effect, but, more importantly, acts
as a point of further functionalization.
9d
10d
—
11d
12d
13d
14d
4k
4l
6.0
16.0
8.0
79
82
55
81
—
f
—
4m
4n
4.8 : 1
6.3 : 1
7.0
f,g
15
16
3o (n = 1)
3p (n = 2)
3q
4o
4p
4q
2.5
2.5
97
93
—
—
f,g
17
2.0
97
7.1 : 1h
a
Reactions run with 1 equiv. substrate 3 and 30 mol% In(OTf)3 in
b
CH2Cl2 at 25 1C. Isolated yields after column chromatography.
Diastereoselectivities determined from 1H NMR of the crude reac-
c
d
tion mixture and represent trans : cis diastereomeric ratios. Reaction
e
performed in 1,2-dichloroethane at 80 1C. Relative configurational
assignment not determined. Only one diastereomer visible by
f
g
h
1H NMR. All-cis diastereomer. Major component is the all-cis
diastereomer, minor component is its C(7) epimer.
Next, the influence of a heteroatom-donating group on the
cyclopropane was examined. In particular, oxygen, sulfur and
c
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Table 2 Varying the indole moietya
construction of hydropyrido[1,2-a]indole based derivatives
in good to excellent yields (48–99%) in four steps from
readily-available indoles and alkenes. The methodology is
highly modular, operationally simple and amenable to a
large variety of functional groups and substitution patterns.
Additional studies towards the application of this method for
the synthesis of complex, biologically-active molecules are
currently underway in our laboratories and will be discussed
in due course.
Time Yield dr
(h)
Entry Substrate
Product
(%)b (trans : cis)c
1
2
3r (R = H)
3s (R =
CH2CH2Br)
3t (R =
CH2CH2NPhth)
3u (R =
CH2CO2Me)
4r
4s
0.75 99
1.1 : 1
2.7 : 1
1.0
2.0
3.0
99
76
88
S. F. thanks the NSF FACES Program for a Career Initiation
Grant and ORAU for the Ralph E. Powe Junior Faculty
Enhancement Award. M. A. C. thanks the Ford Foundation
(Diversity Fellowship), the NSF (Graduate Research Fellowship),
and Georgia Tech (Presidential Fellowship) for generous support.
3
4t
2.8 : 1
2.0 : 1
4
4u
a
Reactions run with 1 equiv substrate 3 and 30 mol% In(OTf)3 in
b
CH2Cl2 at 25 1C. Isolated yields after column chromatography.
c
Diastereoselectivities determined from 1H NMR of the crude reac-
tion mixture and represent trans : cis diastereomeric ratios.
Notes and references
1 For some selected examples, see: (a) D. L. Taylor, P. S. Ahmed,
P. Chambers, A. S. Tyms, J. Bedard, J. Duchaine, G. Falardeau,
J. F. Lavallee, W. Brown, R. F. Rando and T. Bowlin, Antiviral
Chem. Chemother., 1999, 10, 79; (b) X. Li and R. Vince, Bioorg.
Med. Chem., 2006, 14, 294; (c) O. Khdour and E. B. Skibo, J. Org.
Chem., 2007, 72, 8636; (d) J. Magolan, C. A. Carson and
M. A. Kerr, Org. Lett., 2008, 10, 1437; (e) R. A. Bunce and
B. Nammalwar, J. Heterocycl. Chem., 2009, 46, 172.
2 For recent representative syntheses, see: (a) H. Zhu, J. Stockigt,
Y. Yu and H. Zou, Org. Lett., 2011, 13, 2792; (b) M. Mizutani,
F. Inagaki, T. Nakanishi, C. Yanagihara, I. Tamai and C. Mukai,
Org. Lett., 2011, 13, 1796; (c) F. De Simone, J. Gertsch and
J. Waser, Angew. Chem., Int. Ed., 2010, 49, 5767; (d) A. Biechy
and S. Z. Zard, Org. Lett., 2009, 11, 2800; (e) D. Facoetti,
G. Abbiati and E. Rossi, Eur. J. Org. Chem., 2009, 2872.
3 For a recent example of Friedel–Crafts alkylations using donor–
acceptor-acceptor cyclopropanes, see: A. O. Chagarovskiy,
E. M. Budynina, O. A. Ivanova, Y. K. Grishin, I. V. Trushkov
and P. V. Verteletskii, Tetrahedron, 2009, 65, 5385.
nitrogen groups were employed due to their established suc-
cess for donor–acceptor cyclopropanes.2c,10b When a phthal-
imido group was the substituent, the desired cyclized product
4m was obtained in 55% yield and 4.8 : 1 dr (entry 13). Phenyl
thioether 3n provided its cyclization product 4n in 81% yield
with 6.3 : 1 dr (entry 14). Cyclopropanes 3o and 3p (derived
from dihydrofuran or dihydropyran) efficiently cyclized to give
4o and 4p in 97 and 93% yield, respectively (entries 15 and 16).
In both cases, the major diastereomers have the all-cis con-
figuration, as determined by NMR spectroscopy. Likewise, the
Cbz-protected ring-fused piperidinyl cyclopropane 3q afforded
4q in 97% with a 7.1 : 1 dr (entry 17).
To further demonstrate the modular nature of our protocol,
the indole moiety was changed from 3-methyl indole (Table 2).
3r (derived from indole) was used to affirm that a substituent in
the 3-position is not required for cyclization. Cyclization readily
occurred to give 4r in 99% yield with 1.1: 1 dr (entry 1). Next,
the 3-(2-bromoethyl)-1H-indole derived cyclopropane 3s pro-
vided its cyclization product 4s in near quantitative yield with
2.7 : 1 dr (entry 2). The bromide remains intact throughout the
cyclization and, thus, is available for further functionalization.
Similarly, when the phthalimide-protected tryptamine deriva-
tive 3t was subjected to the reaction conditions, hydropyrido-
[1,2-a]indole product 4t was generated in 76% yield with 2.8: 1
dr (entry 3). 4t can then be readily deprotected under standard
conditions to provide the free amine. Lastly, the methyl acetate
substituted indole derivative 3u provided the cyclized product
4u in 88% yield with 2.0 : 1 dr (entry 4).
4 For a mechanistically similar reaction, see: T. Vaidya, G. F. Manbeck,
S. Chen, A. J. Frontier and R. Eisenberg, J. Am. Chem. Soc., 2011,
133, 3300.
5 In the literature, this type of transformation has fallen under the term
‘‘homo-Nazarov’’ cyclization. The term ‘‘homo-Nazarov’’ cyclization
has been used either to describe the type of reaction intermediate
(a six-membered oxyallyl cation) or the type of product formed (a
six-membered ring) in direct comparison to the classic Nazarov cycliza-
tion. Hence, the use of the prefix ‘‘homo’’ to describe the six-membered
ring homo-Nazarov products when compared to the standard Nazarov
products. While we have previously published reports under this name,
however, as one reviewer pointed out, this terminology can be mislead-
ing based on mechanistic considerations, since the Nazarov cyclization
is an electrocyclization, whereas the homo-Nazarov cyclization is not.
To alleviate further confusion, we will refer to our reactions as a tandem
cyclopropane ring-opening/Friedel–Crafts alkylation sequence. For
literature on the homo-Nazarov cyclization, see ref. 10.
This method is also applicable to the direct synthesis of
pyrido[1,2-a]indoles. In one representative example, when
cyclopropane 3v (from a-bromostyrene) was subjected to the
reaction conditions, pyrido[1,2-a]indole 8 was observed in
29% yield (eqn (1)). This product seemingly arises from the
rapid elimination of HBr from the cyclized intermediate 7 to
generate the new aromatic ring.
6 F. Gonzalez-Bobes, M. D. B. Fenster, S. Kiau, L. Kolla, S. Kolotuchin
´
and M. Soumeillant, Adv. Synth. Catal., 2008, 350, 813.
7 (a) D. V. Patil, L. H. Phun and S. France, Org. Lett., 2010,
12, 5684; (b) L. H. Phun, D. V. Patil, M. A. Cavitt and
S. France, Org. Lett., 2011, 13, 1952.
8 Lower catalyst loadings will also catalyze the cyclizations, albeit
with longer reactions and/or less conversion.
9 (a) L. P. Hammett, Chem. Rev., 1935, 17, 125; (b) I. Fernandez and
G. Frenking, J. Org. Chem., 2006, 71, 2251.
10 (a) F. De Simone, J. Andres, R. Torosantucci and J. Waser, Org. Lett.,
2009, 11, 1023; (b) V. K. Yadav and N. V. Kumar, Chem. Commun.,
2008, 3774; (c) L. Greiner-Bechert, T. Sprang and H.-H. Otto, Monatsh.
Chem., 2005, 136, 635; (d) O. Tsuge, S. Kanemasa, T. Otsuka and
T. Suzuki, Bull. Chem. Soc. Jpn., 1988, 61, 2897; (e) W. S. Murphy and
S. Wattanasin, J. Chem. Soc., Perkin Trans. 1, 1982, 1029.
11 R. D. Wieting, R. H. Staley and J. L. Beauchamp, J. Am. Chem.
Soc., 1974, 96, 7552.
ð1Þ
In summary, we report an efficient catalytic cyclopropane
ring-opening/Friedel–Crafts alkylation sequence for the facile
c
10280 Chem. Commun., 2011, 47, 10278–10280
This journal is The Royal Society of Chemistry 2011