Protocol for the synthesis of heteroaromatic ring-Fused cyclohexanones

Article abstract of DOI:10.1021/ol200305n

A general protocol for the catalytic homo-Nazarov cyclization of cyclopropyl heteroaryl ketones has been developed,which employs indiumtriflate as the promoter. A range of heteroaromatic ring-fused cyclohexanones was synthesized in 56-91% yield using this

Full text of DOI:10.1021/ol200305n

ORGANIC
LETTERS
2011
Vol. 13, No. 8
1952–1955
A Catalytic Homo-Nazarov Cyclization
Protocol for the Synthesis of
Heteroaromatic Ring-Fused
Cyclohexanones
Lien H. Phun, Dadasaheb V. Patil, Marchello A. Cavitt, and Stefan France*
School of Chemistry and Biochemistry, Georgia Institute of Technology, 901 Atlantic
Drive, Atlanta, Georgia 30332, United States
stefan.france@chemistry.gatech.edu
Received January 31, 2011
ABSTRACT
A generalprotocolfor the catalytic homo-Nazarov cyclizationofcyclopropylheteroarylketoneshasbeendeveloped, which employsindiumtriflateas
the promoter. A range of heteroaromatic ring-fused cyclohexanones was synthesized in 56ꢀ91% yield using this protocol. An example of a tandem
cyclopropanation/homo-Nazarov cyclization is also reported in which the one-pot yield is greater than the overall yield of the two individual steps.
Heteroaromatic compounds fused to cyclohexyl rings
are present in the core of many natural products and
medicinally active molecules.1 Furthermore, these ring-
fused systems often serve as building blocks for complex
chemical synthesis.2 Given this utility, organic chemists
have steadily explored the development of efficient meth-
ods for their synthesis.3 One such method that has been
relatively underexplored is the heteroaromatic homo-
Nazarov cyclization,4 an acid-promoted ring closure of a
cyclopropyl heteroaryl ketone.5
Recently, we reported that In(OTf)3 can effectively
catalyze the homo-Nazarov cyclizations of alkenyl cyclo-
propyl ketones, furnishing cyclohexenones and methylene
cyclohexanols under mild conditions.6 The use of do-
norꢀacceptor cyclopropanes bearing a secondary electron
acceptor (an ester group) was central to the observed
reactivity because it allows for milder conditions for
(1) For some recent examples of naturally occurring or biologically
active heteroaromatic ring-fused cyclohexyl rings: (a) Qu, Y.; Xu, F.;
Nakamura, S.; Matsuda, H.; Pongpiriyadacha, Y.; Wu, L.; Yoshikawa,
M. J. Nat. Med. 2009, 63, 102. (b) Wildeboer, K. M.; Zheng, L.; Choo,
K. S.; Stevens, K. E. Brain Res. 2009, 1300, 41. (c) Barta, T. E.; Veal,
J. M.; Rice, J. W.; Partridge, J. M.; Fadden, R. P.; Ma, W.; Jenks, M.;
Geng, L.; Hanson, G. J.; Huang, K. H.; Barabasz, A. F.; Foley, B. E.;
Otto, J.; Hall, S. E. Bioorg. Med. Chem. Lett. 2008, 18, 3517. (d) Ishiuchi,
K. i.; Kubota, T.; Mikami, Y.; Obara, Y.; Nakahata, N.; Kobayashi, J. I.
Bioorg. Med. Chem. 2007, 15, 413. (e) Li, X.; Vince, R. Bioorg. Med.
Chem. 2006, 14, 2942. (f) Romeo, G.; Materia, L.; Pittala, V.; Modica,
M.; Salerno, L.; Siracusa, M.; Russo, F.; Minneman, K. P. Bioorg. Med.
Chem. 2006, 14, 5211.
(2) For representative examples as chemical building blocks: (a)
Ohta, K.; Kobayashi, T.; Tanabe, G.; Muraoka, O.; Yoshimatsu, M.
Chem. Pharm. Bull. 2010, 58, 1180. (b) Cadierno, V.; Diez, J.; Gimeno,
J.; Nebra, N. J. Org. Chem. 2008, 73, 5852. (c) Martin, A. E.; Prasad,
K. J. R. Synth. Commun. 2008, 38, 1778.
(4) For the earliest examples of an aromatic homo-Nazarov cycliza-
tion: (a) Murphy, W. S.; Wattanasin, S. J. Chem. Soc., Perkin Trans. 1
1982, 271. (b) Murphy, W. S.; Wattanasin, S. J. Chem. Soc., Perkin
Trans. 1 1982, 1029.
(5) For early usage of the term ‘homo-Nazarov cyclization’, see:
Tsuge, O.; Kanemasa, S.; Otsuka, T.; Suzuki, T. Bull. Chem. Soc. Jpn.
1988, 61, 2897.
(3) For representative approaches to heteroaryl ring-fused cyclohex-
anones: (a) Albrecht, L.; Ransborg, L. K.; Gschwend, B.; Jorgensen,
K. A. J. Am. Chem. Soc. 2010, 132, 17886. (b) Bunce, R. A.; Nammalwar,
B. J. Heterocycl. Chem. 2009, 46, 172. (c) Sridharan, M.; Beagle, L. K.;
Zeller, M.; Prasad, K. J. R. J. Chem. Res. 2008, 572. (d) Yadav, P. P.;
Gupta, P.; Chaturvedi, A. K.; Shukla, P. K.; Maurya, R. Bioorg. Med.
Chem. 2005, 13, 1497. (e) Amat, M.; Perez, M.; Llor, N.; Martinelli, M.;
Molins, E.; Bosch, J. Chem. Commun. 2004, 1602.
(6) Patil, D. V.; Phun, L. H.; France, S. Org. Lett. 2010, 12, 5684.
r
10.1021/ol200305n
Published on Web 03/18/2011
2011 American Chemical Society

cyclopropyl ring-opening.7 Furthermore, a catalytic
amount of Lewis acid was sufficient to promote the
reaction.
Scheme 2. Substrate Synthesis
With this concept in mind, we envisioned employing
these donorꢀacceptorꢀacceptor (DꢀAꢀA) cyclopro-
panes with heteroaromatics as reactive π-systems in order
to generate heteroaryl ring-fused cyclohexanones.8 This
communication describes the development of a catalytic
procedure for their synthesis using the homo-Nazarov
cyclization of cyclopropyl heteroaryl ketones (Scheme 1).
Scheme 1. Heteroaromatic Homo-Nazarov Cyclization of
DonorꢀAcceptorꢀAcceptor (DꢀAꢀA) Cyclopropanes
Rh2esp2 (dirhodium R,R,R0,R0-tetramethyl-1,3-benzene
dipropanoate)11 in the presence of the requisite alkene pro-
vided cyclopropanes 3 as the homo-Nazarov precursors.
Given thiophene’s stability in the presence of Lewis
acids,12 it was chosen as the first heteroaromatic moiety
examined for optimizing our protocol. The 2-substituted
thienyl cyclopropane 3a was synthesized and used as the
substrate for catalyst screening (Table 1).13 Influenced by
To date, there have only been two examples of hetero-
aromatic homo-Nazarov cyclizations reported in the lit-
erature. In the earliest report, Yadav9 reported the
synthesis of 4-silylmethyl/hydroxymethyl-substituted 2,3-
heteroaromatic ring-fused cyclohexanones. Although
Yadav’s method offers good to high yields (70ꢀ90%)
and broad substrate scope, there are some key drawbacks,
including the use of stoichiometric amounts of SnCl4 (4
equiv), elevated temperatures (80 °C), and long reaction
times (12 h) which were necessary for the cyclization to
occur. Along the same line, Waser10 recently reported a
catalytic homo-Nazarov cyclization of activated cyclopro-
panes using p-TsOH. Despite this innovation, the success-
ful cyclization of only one heteroaryl substrate was shown.
Thus, a need remains for a general heteroaromatic homo-
Nazarov method that will generate heteroaromatic ring-
fused cyclohexanones rapidly and under mild conditions.
This prompted us to disclose a protocol we have developed
for a facile catalytic homo-Nazarov cyclization of hetero-
aromatic compounds.
Table 1. Effects of Catalyst Loading
loading
(mol %)
time
(h)
entry
Lewis acid
% yield
1
2
3
4
ln(OTf)3
ln(OTf)3
ln(OTf)3
InCl3
30
5
2.5
5
88%
86%
77%
78%
1
6.5
4.5
5
our earlier report, we began by screening In(OTf)3. When
subjected to 30 mol % catalyst, 3a successfully cyclized to
give the heteroaromatic 2,3-ring fused cyclohexanone 4a in
88% yield in less than 3 h (entry 1). Next, the effects of
lowering the amount of catalyst were examined. Starting
from 30 mol %, the loading was gradually decreased to 1
mol %. As the catalyst loading was decreased, unsurpris-
ingly, the reaction time increased. Ultimately, a loading of
5 mol % In(OTf)3 provided the homo-Nazarov product in
86% yield (entry 2), which was highly comparable to the
results with 30 mol % catalyst. It is notable that 1 mol %
In(OTf)3 can also be used to catalyze the reaction, albeit
with a lower yield (entry 3). Similarly, InCl3 catalyzes the
The homo-Nazarov substrates 3 were synthesized ac-
cording to Scheme 2. Addition of the enolate of methyl
acetate to the appropriate 2- or 3-substituted heteroaro-
matic acid chloride provided β-ketoesters 1. Diazo transfer
then provided R-diazo esters 2. Finally, treatment of 2 with
(7) (a) Rubin, M.; Rubia, M.; Gevorgyan, V. Chem. Rev. 2007, 107,
3117. (b) Yu, M.; Pagenkopf, B. L. Tetrahedron 2005, 61, 321. (c)
Reissig, H.-U.; Zimmer, R. Chem. Rev. 2003, 103, 1151.
(8) For representative examples of polarizing the classic heteroaro-
matic Nazarov cyclization: (a) He, W.; Herrick, I. R.; Atesin, T. A.;
Caruana, P. A.; Kellenberger, C. A.; Frontier, A. J. J. Am. Chem. Soc.
2008, 130, 1003. (b) For heteroaromatic: Malona, J. A.; Colbourne,
J. M.; Frontier, A. J. Org. Lett. 2006, 8, 5661.
(9) Yadav, V. K.; Kumar, N. V. Chem. Commun. 2008, 3774.
(10) (a) De Simone, F.; Andres, J.; Torosantucci, R.; Waser, J. Org.
Lett. 2009, 11, 1023. (b) De Simone, F.; Gertsch, J.; Waser, J. Angew.
Chem., Int. Ed. 2010, 49, 5767.
(12) Katritzky, A. R. Advances in Heterocyclic Chemistry, Vol. 78;
Academic Press: San Diego, 2001.
(13) Electron-donating groups on the phenyl ring promote efficient
homo-Nazarov cyclization due to their ability to stabilize the benzylic
carbocation. To facilitate cyclopropane ring opening, a 4-methoxyphe-
nyl substituent was employed.
ꢀ
(11) Gonzalez-Bobes, F.; Fenster, M. D. B.; Kiau, S.; Kolla, L.;
Kolotuchin, S.; Soumeillant, M. Adv. Synth. Catal. 2008, 350, 813.
Org. Lett., Vol. 13, No. 8, 2011
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cyclization in comparable time to In(OTf)3, but with a
significant decrease in yield (entry 4). Inspired by its
successful use in Sc(OTf)3- and In(OTf)3-catalyzed Frie-
delꢀCrafts acylations14 and Nazarov cyclizations,8 Li-
ClO4 was explored as an additive. However, when 1
equiv of LiClO4 was used with either In3þ salt, very low
conversion was observed. Thus, In(OTf)3 at 5 mol %
loading in dichloromethane at room temperature was
chosen as the final protocol.
Table 2. Heteroaromatic Homo-Nazarov Cyclizationsa
With optimized conditions for the cyclization in hand, a
diverse set of heteroaryl substrates was examined to de-
termine the reaction scope and limitations (Table 2). In
direct comparison to the 2-thienyl cyclopropane 3a which
afforded 4a in 86% yield (entry 1), the 3-thienyl substrate
3c provided cyclohexanone 4c in 73% yield (entry 3). In
contrast, the 3-furanyl substrate 3d (entry 4) provided its
product 4d in a higher yield (73% vs 67%) than that of
2-substituted counterpart 3b15 (entry 2). The 2-indolyl
cyclopropane 3e afforded the cyclized product 4e in 63%
yield (entry 5), and the 3-indole 3f gave product 4f in 91%
yield (entry 7). Similarly, the 2-benzofuran 3g cleanly
cyclized to give 4g in 61% yield (entry 6) and the 3-benzo-
furan 3h afforded the desired product 4h in 71% yield
(entry 8). This is noteworthy because benzofuran had been
unsuccessful as a homo-Nazarov substrate due to issues
with competing polymerization.10
To date, only 2,3-ring-fused heteroaromatics had been
synthesized using homo-Nazarov cyclizations. As an ex-
pansion of the scope of this reaction, we were interested in
trying to synthesize 3,4-ring-fused compounds as well. We
envisioned employing a 3-substituted substrate with the
2-position blocked, as in the 2-bromo thienyl cyclopropane
3i. With the 2-position unavailable, the only site for electro-
philic attack would be the 4-position. Thus, cyclization of 3i
should produce the 3,4-fused heteroaryl cyclohexanone 4i.
As anticipated, when subjected to the reaction conditions, 3i
generated the desired product 4i in 56% yield (entry 9).
Next, other donor substituents about the cyclopropane
were examined (Table 3). Phenyl derivatives 3j and 3k
provided the desired ring-fused cyclohexanones 4j and 4k
in 81% and 83% yield, respectively (entry 1).16 When R-
methyl styrene was used to generate cyclopropane 3l,
product 4l was obtained in 71% yield (entry 3). Similarly,
the indanyl substrate 3m gave tetracycle 4m in 87% yield
(entry 4). Inspired by Yadav’s report, silyl derivative 3n
was synthesized and cyclized to afford 4n in 72% yield
(entry 5). When the donor group on the cyclopropane was
changed to an oxygen donor (as in 3p, derived from
dihydropyran), no cyclization was observed (entry 7).
Even at higher catalyst loading or elevated temperatures,
a Reactions run with 1 equiv of substrate 3 and 5 mol % In(OTf)3 in
CH2Cl2 at 25 °C and complete within 6 h. b Isolated yields after column
chromatography. c Diastereoselectivities as determined by crude 1H
NMR. d Reaction performed in 1,2-dichloroethane at 80 °C. e 2:1
Mixture of keto and enol forms.
only startingmaterialwas recovered. Thislackofreactivity
can be rationalized if no chelation event was occurring at
the two carbonyls. To support this hypothesis, we looked
at the lowest energy conformers of 3o based on MMFF
calculations.17 In each of these conformers, the two carbo-
nyl oxygens are anti to one another, thus eliminating the
ability to generate the requisite six-membered chelate.
Without this activation, cyclopropane ring-opening does
not occur. Furthermore, this effect seems to arise from the
stereoelectronic influence of the methyl ester on the con-
formation of the fused pyran ring.18 This effect can
1
arguably be seen in the H NMR spectrum of 3o where
the hydrogen at the fused ring junction adjacent to the
oxygen is located at 6.5 ppm, which represents a ∼3 ppm
downfield shift from the analogous pyranyl derivative
without the ester.9,19 This downfield shift suggests the
strong influence of the electron-withdrawing ester on
the conformation of the fused ring. This hypothesis
was further supported when the acyclic ether 3p (derived
from ethyl vinyl ether) was subjected to the standard
reaction conditions and the substituted benzothiophene 5
was obtained in 51% yield (entry 8). This product
(14) (a) Chapman, C. J.; Frost, C. G.; Hartley, J. P.; Whittle, A. J.
Tetrahedron Lett. 2001, 42, 773. (b) Kawada, A.; Mitamura, S.;
Kobayashi, S. Chem. Commun. 1996, 183. (c) Hachiya, I.; Moriwaki,
M.; Kobayashi, S. Tetrahedron Lett. 1995, 36, 409.
(15) The 2-furanyl derivative 3c readily cyclized at room tempera-
ture, but the yields (∼28%) were fairly low due to byproduct formation.
To circumvent this issue, 3c was refluxed in DCE. No byproduct
formation was observed.
(17) MMFF calculations were run using Trident software available
from Wave function, Inc.
(18) It has been previously shown that cyclization readily occurs for
the analogous pyran derivative without the methyl ester (see ref 9).
(19) See Supporting Information.
(16) We have observed that heating is required to achieve efficient
cyclization for phenyl rings without substitution and those substituted
with electron-withrawing groups.
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Org. Lett., Vol. 13, No. 8, 2011

In(OTf)3 (5 mol %) was established by monitoring a
stirring mixture of the two components. Next, the stability
of the alkene (4-methoxy styrene) was examined in the
presence of both Rh2esp2 and In(OTf)3. To achieve an
active indium catalyst loading of ∼20 mol %, 1 mol % of
Rh2esp2 and 0.2 mol % of In(OTf)3 in dichloromethane at
0 °C were employed as the initial reaction conditions. We
werepleasedtofindthatsubjectingR-diazoester2dtothese
conditions provided the desired ring-fused cyclohexanone
4d in 56% yield, which is higher than the yield for the
two-step process and equates to an average of about 75%
yield for each individual step.
Table 3. Effects of Cyclopropyl Substituentsa
Scheme 3. Tandem Cyclopropanation/Homo-Nazarov Cycli-
zation
a Reactions run with 1 equiv of substrate 3 and 5 mol % In(OTf)3 in
CH2Cl2 at 25 °C and complete within 6 h. b Isolated yields after column
chromatography. c Diastereoselectivities as determined by crude 1H
NMR. d Reaction performed in 1,2-dichloroethane at 80 °C. e Only
one diastereomer visible by 1H NMR.
In summary, a general protocol for the heteroaromatic
homo-Nazarov cyclization has been reported. Further stu-
dies are underway to expand this method to other hetero-
aromatics, such as pyrrole and pyridine. Other activities
include optimization and generalization of both the one-pot
reaction as well as the aromatization reaction. Reactions
examining the transfer of absolute chirality during the cycli-
zation of a chiral cyclopropane are being conducted.20 The
results of each of these studies will be reported in due course.
seemingly arises from a rapid aromatization of the tran-
sient homo-Nazarov cyclization product through an in-
dium-promoted elimination of EtOH.
Given that both the cyclopropanation and homo-
Nazarov cyclization steps readily occurred in dichlorometh-
ane at room temperature, we envisioned the development
of a one-pot procedure that would occur in the presence of
both the rhodium (for cyclopropanation) and indium (for
cyclization) catalysts (Scheme 3). To test the feasibility of
this procedure, two key control reactions were conducted.
First, the stability of R-diazoester 2d in the presence of
Acknowledgment. S.F. thanks the NSF FACES Pro-
gram for a Career Initiation Grant and ORAU for the
Ralph E. Powe Junior Faculty Enhancement Award.
Supporting Information Available. Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(20) Preliminary studies have shown some transfer of chirality upon
cyclization which suggests some degree of intimate ion pairing.
Org. Lett., Vol. 13, No. 8, 2011
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