Tetrahydroquinolines and benzazepines through catalytic diastereoselective formal [4 + 2]-cycloaddition reactions between donor-acceptor cyclopropenes and imines

Article abstract of DOI:10.1021/ol401308d

Regio- and diastereoselective Lewis acid catalyzed cycloaddition reactions between imines and donor-acceptor cyclopropenes generated from silyl-protected enoldiazoacetates provide direct access to stable cyclopropane-fused tetrahydroquinolines and, with cyclopropane ring opening under mild conditions, to 1H-benzazipine derivatives.

Full text of DOI:10.1021/ol401308d

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
Tetrahydroquinolines and Benzazepines
through Catalytic Diastereoselective
Formal [4 þ 2]-Cycloaddition Reactions
between DonorꢀAcceptor Cyclopropenes
and Imines
000–000
Phong M. Truong, Michael D. Mandler, Peter Y. Zavalij, and Michael P. Doyle*
Department of Chemistry & Biochemistry, University of Maryland, College Park,
Maryland 20742, United States
mdoyle3@umd.edu
Received May 10, 2013
ABSTRACT
Regio- and diastereoselective Lewis acid catalyzed cycloaddition reactions between imines and donorꢀacceptor cyclopropenes generated from
silyl-protected enoldiazoacetates provide direct access to stable cyclopropane-fused tetrahydroquinolines and, with cyclopropane ring opening
under mild conditions, to 1H-benzazipine derivatives.
3
hypertension (Scheme 1). The preparation of these struc-
c
Access to heterocyclic nitrogen-containing compounds
is of ongoing interest to synthetic and medicinal chemists
because of their abundance in natural products and their
biological activities. Among these heterocycles, tetrahy-
droquinolines and benzazepines represent two important
classes that form the structural motif of many medicinally
2
relevant compounds. As examples, the cyclopropane-
2
,3
tural scaffolds requires multistep syntheses, and this
requirement invites more efficient methodologies for the
1
4
construction of these functionalized structural units.
(
3) (a) Ellis, D.; Kuhen, K. L.; Anaclerio, B.; Wu, B.; Wolff, K.; Yin,
H.; Bursulaya, B.; Caldwell, J.; Karanewsky, D.; He, Y. Bioorg. Med.
Chem. Lett. 2006, 16, 4246–4251. (b) Kondo, K.; Ogawa, H.; Yamashita,
H.; Miyamoto, H.; Tanaka, M.; Nakaya, K.; Kitano, K.; Yamamura,
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Chem. 1999, 7, 1743–1754. (c) Hou, F.; Zhang, X.; Zhang, G.; Xie, D.;
Chen, P.; Zhang, W.; Jiang, J.; Liang, M.; Wang, G.; Liu, Z.; Geng, R.
N. Engl. J. Med. 2006, 354, 131–140.
fused hydroquinoline 1 is an HIV-1 non-nucleoside reverse
transcriptase inhibitor with potency on the nanomolar
3
scale. Benzazepine tolvaptan (2) is an approved drug
a
3
for treatment of hyponatremia, and benazepril (3) is an
b
angiotensin-converting enzyme inhibitor used to treat
(
4) (a) Wang, L.; Huang, J.; Peng, S.; Liu, H.; Jiang, X.; Wang, J.
Angew. Chem., Int. Ed. 2012, 51, 1–6. (b) Jadhav, A. M.; Pagar, V. V.;
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W. B.; Dai, L. X.; You, S. L. Angew. Chem., Int. Ed. 2010, 49, 1496–1499.
(5) (a) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds: From Cyclopro-
panes to Ylides; John Wiley & Sons: New York, 1998. Reviews: (b) Doyle,
M. P.; Duffy, R.; Ratnikov, M. O.; Zhou, L. Chem. Rev. 2010, 110, 704–724.
(c) Merlic, C. A.; Zechman, A. L. Synthesis 2003, 1137–1156. (d) Davies,
H. M. L.; Beckwith, R. E. J. Chem. Rev. 2003, 103, 2861–2904. (e)
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Hodgson, D. M.; Pierard, F. Y. T. M.; Stupple, P. A. Chem. Soc. Rev.
2001, 30, 50–61.
(
1) (a) Joule, J. A.; Mills, K. Heterocyclic Chemistry, 5th ed.; Wiley-
Blackwell: West Sussex, United Kingdom, 2010. (b) Eicher, T.; Hauptmann,
S.; Speicher, A. The Chemistry of Heterocycles: Structure, Reactions,
Syntheses, and Applications, 2nd ed.; Wiley-VCH: Weinheim, Germany,
2
003.
(2) (a) Katritzky, A. R.; Rachwal, S.; Rachwal, B. Tetrahedron 1996,
2, 15031–15070. (b) Renfroe, B.; Harrington, C.; Proctor, G. R.
Heterocyclic Compounds: Azepines; Wiley & Interscience: New York,
984. (c) Kouznetsov, V.; Palma, A.; Ewert, C. Curr. Org. Chem. 2001, 5,
5
1
5
19–551.
1
0.1021/ol401308d r XXXX American Chemical Society

Scheme 1. Examples of Biologically Active Tetrahydroquino-
line and Benzazepine Heterocycles
Table 1. Catalyst Screening and Optimization of Reaction
Conditions
a
catalyst
(mol %)
time
(h)
dr
yield
b
c
entry
(anti/syn)
(%)
1
2
3
4
5
6
7
8
none
Sc(OTf)
12
5
ꢀ
0
3
(5)
(5)
(5)
(5)
>20:1
>20:1
>20:1
>20:1
>20:1
ꢀ
75
50
69
45
56
0
Sn(OTf)
Zn(OTf)
3
5
Metal catalyzed dinitrogen extrusion from diazo com-
pounds through metal carbene intermediates is a versatile
route to access carbocyclic and heterocyclic ring systems.
2
5
Cu(OTf)
2
5
5
TMSOTf (10)
TFA (20)
5
Our group has recently focused on the metal catalyzed
reactions of silyl-protected enoldiazoacetates 4 (Scheme 2)
that generate metal enol carbene intermediates (5) which
5
TfOH (5)
3
>20:1
>20:1
>20:1
60
68
92
d
9
Sc(OTf)
Sc(OTf)
3
(5)
(5)
5
6a,b
6c,d
e
1
0
3
2
are known to undergo cycloaddition, NꢀH insertion,
6
and nucleophilic addition reactions. However, as Davies
e
a
A solution of 4a (0.6 mmol) and 1 mol % Rh (OAc) in 2 mL of
DCM was stirred at 0 °C for 30 min and then for 10 min at rt. Imine 9a
0.5 mmol) and the stated mol % Sc(OTf) were then added to the
2
4
7
and co-workers have shown, if capture of 5 is slow, re-
(
arrangement occurs to form donorꢀacceptor cyclopropenes
b
reaction solution at 0 °C and stirred for the stated time. Diastereos-
electivity was determined by H NMR spectroscopic analyses of the
6
that, for example, have been trapped with cyclopentadiene
1
c
unpurified reaction mixture. Yield of isolated product. Reaction was
d
to form bicyclo[3.2.1]octadiene 7. Although, these interesting
donorꢀacceptor cyclopropenes were discovered almost
two decades ago, their synthetic potential has not yet been
fully explored. We recently discovered that cyclopropenes
e
˚
run with 4 A MS (150 mg). Reaction was carried out at 0 °C. TFA =
trifluoroacetic acid. PMP = p-methoxyphenyl.
6
lowed by rearrangement to form furanones 8 (Scheme 2),
undergo dipolar cycloaddition with nitrile oxides fol-
8
imines and donorꢀacceptor cyclopropenes that are gener-
ated from Rh (OAc) -catalyzed dinitrogen extrusion from
2
4
9
and we now wish to report a Povarov-type reaction between
enoldiazoacetates. This highly regio- and diastereoselec-
tive transformation provides direct access to functiona-
lized cyclopropane-fused tetrahydroquinolines and, with
cyclopropane ring-opening, to benzazepine structural
units.
Scheme 2. Catalytic Dinitrogen Extrusion from Enoldiazoace-
tate 4 and Its Subsequent Reactions
Our investigation began with reactions of enoldiazoace-
tate 4a using 1 mol % of Rh (OAc) to generate the
2
4
donorꢀacceptor cyclopropene intermediate 6 (R = Me)
followed by addition of anisylbenzaldimine 9a.
Tetrahydroquinoline 10a was isolated as a single dia-
stereoisomer in 75% yield following addition of 5.0 mol %
of Sc(OTf) . No reaction occurred between cyclopropene
3
6
and imine 9a in the absence of Sc(OTf) . The stereo-
3
chemistry of 10a with ester and phenyl groups trans was
determinedbysinglecrystal X-ray analysis(see Supporting
Information). Encouraged by this result, we optimized the
reaction conditions by surveying a variety of Lewis and
Brønsted acid catalysts (Table 1, entries 3ꢀ8). However,
none of the surveyed catalysts gave a higher yield of 10a
than did Sc(OTf) , and only Zn(OTf) give a comparable
(
6) (a) Wang, X.; Xu, X.; Zavalij, P. Y.; Doyle, M. P. J. Am. Chem.
Soc. 2011, 133, 16402. (b) Wang, X.; Abrahams, Q. M.; Zavalij, P. Y.;
Doyle, M. P. Angew. Chem., Int. Ed. 2012, 51, 5907. (c) Xu, X.; Zavalij,
P. Y.; Doyle, M. P. Angew. Chem., Int. Ed. 2012, 51, 9829–9833. (d) Xu,
X.; Zavalij, P. Y.; Hu, W.; Doyle, M. P. J. Org. Chem. 2013, 78, 1583. (e)
Valette, D.; Lian, Y.; Haydek, J. P.; Hardcastle, K. I.; Davies, H. M. L.
Angew. Chem., Int. Ed. 2012, 51, 8636.
3
2
yield. Triflic acid gave a moderate yield of product, but
trifluoroacetic acid did not catalyze product formation
even at 20 mol %. Therefore, Sc(OTf) was the catalyst of
3
(
7) Davies, H. M. L.; Houser, J. H.; Thornley, C. J. Org. Chem. 1995,
0, 7529–7534.
8) (a) Xu, X.; Shabashov, D.; Zavalij, P. Y.; Doyle, M. P. Org. Lett.
012, 14, 800–803. (b) Xu, X.; Shabashov, D.; Zavalij, P. Y.; Doyle,
6
(
(9) (a) Povarov, L. S. Russ. Chem. Rev. 1967, 36, 656–670. (b)
Kouznetsov, V. V. Tetrahedron 2009, 65, 2721–2750. (c) Bello, D.;
Ramon, R.; Lavilla, R. Curr. Org. Chem. 2010, 14, 332.
2
M. P. J. Org. Chem. 2012, 77, 5313–5317.
B
Org. Lett., Vol. XX, No. XX, XXXX

˚
choice, and 4 A MS was used as an additive to remove any
Different ester alkyl groups for R also provide Povarov
1
traces of water in the reaction mixture, although without
improving product yield (entry 9). Observing that addition
of Sc(OTf) to the reaction solution at room temperature
products in high yield and diastereoselectivity (entries 17
and 18).
3
caused its color tochange from light yellow toalmost black
within 10 min and immediately caused the temperature of
the reaction flask to increase, the reaction temperature was
lowered to 0 °C. Under these conditions the reaction was
complete in 2 h, and 10a was isolated in 92% yield.
Table 2. Povarov Reaction with in Situ Generated
DonorꢀAcceptor Cyclopropene
a
9
b,10
A stepwise mechanism
for the formation of the
cyclopropane-fused tetrahydroquinolines is outlined in
Scheme 3. Dirhodium(II) catalyzed dinitrogen extrusion
from enoldiazoacetate 4 forms intermediate metal enol
carbene 5 that undergoes intramolecular cyclization to
form donorꢀacceptor cyclopropene 6. Mannich addition
from 6 to the Sc(OTf) activated imine generates the
3
reactive oxonium ion 11 that undergoes intramolecular
electrophilic aromatic addition (11f12) to provide the
cyclopropane-fused tetrahydroquinoline 10. Alternatively,
the cycloadditions between cyclopropene 6 and Sc(OTf)3
activated imines could proceed in a concerted fashion to
1
0c
generate the exo-product 10.
Scheme 3. Proposed Mechanism
a
Reactions were carried out on a 0.5 mmol scale: A solution of 4a
(
for 30 min, then 10 min at rt. Imine 9 (0.5 mmol), and 5 mol % Sc(OTf)
0.6 mmol) and 1 mol % Rh
2 4
(OAc) in 2 mL of DCM was stirred at 0 °C
3
The generality of the Povarov reaction with do-
norꢀacceptor cyclopropenes 4aꢀ6a was evaluated under
these optimized conditions with imines 9aꢀ9p, and the
results are reported in Table 2. The reaction provides
excellent yields and diastereoselectivities toward aromatic
b
was added to the reaction at 0 °C and stirred for 2 h. Diastereoselec-
tivity was determined by H NMR spectroscopic analyses of the
1
unpurified reaction mixture using the proton signal of the propyl group.
Yield of isolated product after chromatography.
c
substitution with aryl groups for R having both electron-
2
Replacing the aryl substituent with a methyl ester
COOMe) group, however, provided 10l in only 45%
donating and moderately electron-withdrawing substitu-
ents, as well as those with ortho-, meta-, and para-halide
substitution (Table 2, entries 2ꢀ8). Furyl and styryl groups
(
isolated yield (entry 12). With the expectation that the
9
b,10
reaction occurs as a stepwise process,
we hypothesized
as R also give Povarov products with high yields (entries
2
that the low yield of 10l is due to coordination of the car-
bonyl group of the ester with the acid catalyst 13, reducing
the nucleophilicity of the nitrogen-activated aromatic ring
toward addition to the oxonium ion 14 (Scheme 4).
Cyclopropenes have enhanced reactivity over unstrained
9
1
ꢀ10). As indicated by the result with R = isobutyl (entry
2
1), an alkyl substituent is only moderately limiting on this
reaction with a slight decrease in yield for 10k and 10:1
diastereoselectivity. Substituentson the N-aryl group (Ar1)
also showed generality in applications (entries 13ꢀ16), and
the p-nitro group had the expected decrease in reactivity
toward cyclization that resulted in lower product yield.
1
1
alkenes in cycloaddition reactions, but this is the first
9
example of their viability for the Povarov reaction. Access to
donorꢀacceptor cyclopropenes, which are available through
(
10) (a) Hermitage, S.; Jay, D. A.; Whiting, A. Tetrahedron Lett.
2
002, 43, 9633–9636. (b) Alves, M. J.; Azoia, N. G.; Fortes, A. G.
(11) (a) Zhu, Z.-B.; Wei, Y.; Shi, M. Chem. Soc. Rev. 2011, 40, 5534–
5563. (b) Fisher, L. A; Smith, N. J.; Fox, J. M. J. Org. Chem. 2013, 78,
3342–3348. (c) Patel, P. R.; Boger, D. L. Org. Lett. 2010, 12, 3540–3543.
Tetrahedron 2007, 63, 727–734. (c) Beifuss, U.; Ledderhose, S. J. Chem.
Soc., Chem. Commun. 1995, 2137–2140.
Org. Lett., Vol. XX, No. XX, XXXX
C

1
0k underwent ring opening when treated with tetrabutyl-
1
4
ammonium fluoride (TBAF) to generate 1H-benzaze-
pine 15k in high yield and diastereoselectivity (Scheme 5).
Scheme 4. Proposed Lewis acid coordinating to 10l
1
H-Benzazepines 15aꢀ15d were obtained in a one-pot
procedure starting with enoldiazoacetate 4a and imines
Table 3). Diastereoselectivity for the formation of 15 was
determined by the protonation of the ester enolate inter-
(
5
a
mediate which forms the more stable trans-products.
Scheme 5. Benzazepine Synthesis
a
Table 3. One-Pot Synthesis of 1H-Benzazepines
In conclusion, we have developed a novel regio- and
diastereoselective Lewis acid catalyzed Povarov reaction
between imines and donorꢀacceptor cyclopropenes that
provides direct access to functionalized cyclopropane-fused
tetrahydroquinoline and 1H-benzazepine derivatives. This
is an efficient, clean, and atom-economic transformation
since the cyclopropenes are catalytically generated in situ
from enoldiazoacetates, and nitrogen gas is the only by-
product. Conversion of 10 to 1H-benzazepine derivatives
occurs in good yield under mild conditions and is linked to
the Povarov process through a one-pot process.
dr
yield
b
c
entry
R
15
(anti/syn)
(%)
1
2
3
4
C
6
H
5
15a
15b
15c
15d
18:1
17:1
13:1
9:1
71
78
75
70
4-MeOC
2-naphthyl
3-BrC
6 4
H
6
H
4
a
Reactions were carried out on a 0.5 mmol scale: A solution of 4a
(OAc)
in 2 mL of DCM was stirred at 0 °C
for 30 min and then for 10 min at rt. Imine 9 (0.5 mmol) and 5 mol %
Sc(OTf)
were added sequentially to the reaction solution at 0 °C and
stirred for 2 h, then TBAF (1.2 equiv) was added, and the resulting
solution was stirred for 2 h. Diastereoselectivity was determined by H
NMR spectroscopic analyses of the unpurified reaction mixture using
the R-hydrogen of the ester group. Yield of isolated product after chroma-
tography. PMP = p-methoxyphenyl. TBAF = tetra-n-butylammonium
fluoride.
(0.6 mmol) and 1 mol % Rh
2
4
3
b
1
Acknowledgment. The authors express their gratitude
to the National Science Foundation (CHE1212446) for
support of this research. M.D.M. thanks the Arnold and
Mabel Beckman Foundation for a Beckman Scholar
Award.
c
dirhodium carboxylate catalyzed reactions with enoldi-
Supporting Information Available. General experimen-
tal procedures, the X-ray crystal structure of 10r, and
spectroscopic data for all new compounds. This material
is available free of charge via the Internet at http://pubs.
acs.org.
12
azoacetates, provides added versatility for these processes.
The product from the Povarov reaction of 4 with imines
contains the tetrahydroquinoline unit that is fused with a
donorꢀacceptor cyclopropane. The donorꢀacceptor cy-
clopropane functionality provides the structural frame-
1
3
work for further transformations. Tetrahydroquinoline
(14) (a) Reissig, H. U.; Hirsch, E. Angew. Chem, Int. Ed. 1980, 19,
13–814. (b) Kundel, E.; Reichelt, I.; Reissig, H. U. Liebigs Ann. Chem.
8
1
984, 4, 802–819.
(
12) Davies, H. M. L.; Hu, B.; Saikali, E.; Bruzinski, P. R. J. Org.
Chem. 1994, 59, 4535–4551.
13) Reissig, H. U.; Zimmer, R. Chem. Rev. 2003, 103, 1151–1196.
(
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX