Catalytic, formal homo-Nazarov-type cyclizations of alkylidene cyclopropane-1,1-ketoesters: Access to functionalized arenes and heteroaromatics

Article abstract of DOI:10.1021/ol501676q

A catalytic, formal homo-Nazarov-type cyclization of alkylidene cyclopropanes (ACPs) to give functionalized arenes and heteroaromatics is reported. In the presence of a Lewis acid catalyst, the ACP 1,1-ketoesters undergo distal bond cleavage to afford an allyl cation intermediate. Adjacent π-attack on the allyl cation then provides a six-membered ring that undergoes rapid aromatization. In these cases, benzenoid products are formed in up to 98% yield. Strategic choice of the substitution about the ACP allows for the generation of other useful isomeric products in good yields.

Full text of DOI:10.1021/ol501676q

Letter
pubs.acs.org/OrgLett
Catalytic, Formal Homo-Nazarov-Type Cyclizations of Alkylidene
Cyclopropane-1,1-Ketoesters: Access to Functionalized Arenes and
Heteroaromatics
Joel Aponte-Guzman, J. Evans Taylor, Jr., Elayna Tillman, and Stefan France*
́
School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia 30332, United States
S
* Supporting Information
ABSTRACT: A catalytic, formal homo-Nazarov-type cycliza-
tion of alkylidene cyclopropanes (ACPs) to give functionalized
arenes and heteroaromatics is reported. In the presence of
a Lewis acid catalyst, the ACP 1,1-ketoesters undergo distal
bond cleavage to afford an allyl cation intermediate. Adjacent
π-attack on the allyl cation then provides a six-membered ring
that undergoes rapid aromatization. In these cases, benzenoid
products are formed in up to 98% yield. Strategic choice of the
substitution about the ACP allows for the generation of other useful isomeric products in good yields.
lkylidene cyclopropanes (ACPs) serve as versatile building
blocks in organic synthesis due to their interesting
demonstrated the first intramolecular Friedel−Crafts-type alkyla-
A
tion initiated by distal cleavage of alkylidene cyclopropane-1,1-
diesters to afford indenes or dihydronaphthalene derivatives.6
Oshima similarly demonstrated the efficient synthesis of indene
from the tetrasubstituted benzylidenecyclopropane using Wang’s
protocol.7
reactivity.1 These substrates can readily participate in alkene
addition reactions, including H-Nuc additions, hydrometalations,
dimetalations, and cycloadditions.2 Furthermore, due to their
inherent ring strain,3 they undergo a variety of ring-opening
reactions in the presence of nucleophiles, transition metal
catalysts, and acids.1 The most intriguing ring-opening pathways
are acid-promoted and are categorized into two general patterns:
heterolytic cleavage of the C(1)/C(3) distal bond and heterolytic
breakage of the C(2)/C(3) proximal bond (Figure 1A). Due to
this distinct reactivity, within the past decade, ACPs have been
the subject of several focused and comprehensive reviews.1,2
Over the past several years, we have exploited intramolecular
ring-opening cyclizations of strained carbocycles to generate
functionalized (hetero)arenes.8 For example, we published
examples of catalytic, formal homo-Nazarov cyclizations of
alkenyl8a and heteroaryl8b cyclopropyl ketones to form
functionalized six-membered rings. Inspired by these successes,
we sought to explore the compatibility of ACP-1,1-dicarbonyls
within our mechanistic regime. Here, we disclose the catalytic,
formal homo-Nazarov-type intramolecular ring-opening cycli-
zations of ACP-1,1-ketoesters (Scheme 1). Mechanistically, the
Scheme 1. Formal Homo-Nazarov-Type Cyclizations of ACPs
Figure 1. Heterolytic reactivity of alkylidene cyclopropanes (ACPs).
Regiocontrol of ring opening poses a unique opportunity
for ACP utility. By altering the substitution pattern about the
cyclopropane and by choosing appropriate metal reagents or
catalysts, ring-opening selectivity can be achieved. For example,
distal cleavage (C(1)/C(3) cleavage) is preferentially observed
when ACPs are substituted with acceptors on C(1) of the
cyclopropyl ring (Figure 1B).
Despite the growing interest in the reactivity of 1-acceptor-
substituted ACPs, examples of their intramolecular ring-opening
cyclization reactions have only recently begun to surface.
Surprisingly, only a handful of examples of this reaction class
have been reported, starting with a seminal contribution by Ma
in 2003.4 Lautens et al. explored Lewis acid catalyzed cyclo-
isomerizations to form cyclic diazadienes.5 Wang et al. later
reaction involves Lewis acid catayzed heterolytic distal cleavage
of the ACP to afford a 1,3-dipole containing an allyl cation.
Intramolecular π-attack can occur at either end of the
delocalized allyl cation (pathways a and b) to afford a six-
membered ring. Proton loss and alkene isomerization provide
Received: June 10, 2014
Published: July 8, 2014
© 2014 American Chemical Society
3788
dx.doi.org/10.1021/ol501676q | Org. Lett. 2014, 16, 3788−3791

Organic Letters
Letter
two isomeric o-phenolic ester derivatives A and B, whose ratios
are dependent upon the nature of R1. In most cases, product A,
arising from the thermodynamically preferred pathway a, is
expected to be the major product formed.
To evaluate our hypothesis, alkylidene cyclopropanes were
prepared9 in one of two ways using the Rh(II)-catalyzed cyclo-
propanation of allenes with α-diazo dicarbonyl compounds as a
benchmark (Scheme 2).10
along with ∼40% unreacted starting material (entry 7). When
the reaction was run at reflux, the reaction went to completion
in ∼12 h and the product yield increased to 91% (entry 8).
Similar yield improvements were obtained for the other Lewis
acids in CH2Cl2 at reflux (entries 9−12); however, none of
the catalysts gave higher yields than Yb(OTf)3. When the
Yb(OTf)3 loading was changed to either 20 and 10 mol %,
the yields decreased to 74% and 81%, respectively (entries 13
and 14).12 Therefore, 15 mol % Yb(OTf)3 in CH2Cl2 at reflux
was chosen as the conditions for the examination of substrate
scope.13
Scheme 2. Preparation of ACPs
Next, the effects of the alkylidene substituents were examined
(Table 2). When the alkylidene was substituted with a
Table 2. Alkylidene Substituent Effects
Due to the commercial availability of cyclohexyl allene 3a
and the large amount of the corresponding α-diazo compound
on hand, 3-furyl ACP 5a was chosen as the model system for
reaction optimization (Table 1). Various metal triflates were
Table 1. Reaction Optimization
a
loading
(mol %)
temp
(°C)
time
(h)
Reactions run with Lewis acid (15 mol %), cyclopropane 5, and 4 Å
a
b
c
b
entry
Lewis acid
% yield
6a:6a
molecular sieves in CH2Cl2 (0.1 M) at 40 °C. Isolated yield after
c
1
In(OTf)3
Sc(OTf)3
Al(OTf)3
Ga(OTf)3
Cu(OTf)2
Zn(OTf)2
Yb(OTf)3
Yb(OTf)3
In(OTf)3
Sc(OTf)3
Al(OTf)3
Ga(OTf)3
Yb(OTf)3
Yb(OTf)3
15
15
15
15
15
15
15
15
15
15
15
15
20
10
rt
8
66
68
74
70
20
98:2
98:2
98:2
99:1
99:1
99:1
98:2
95:5
99:1
99:1
99:1
99:1
97:3
97:3
column chromatography. Combined isolated yield of 6 and 6′.
d
e
2
rt
8
Reactions performed in 1,2-dichloroethane at reflux. Product ratios
1
3
rt
20
9
determined by H NMR of isolated mixture.
4
rt
4-methoxyphenyl group (as in 5b), the expected benzofuran 6b
was formed in 53% as the only product (entry 1). In contrast,
when the substituent is phenyl (as in 5c), a 2.2:1 mixture of 6c
and its isomer 6c′ was obtained in 71% combined yield (entry 2).
A similar result was observed with ACP 5d (bearing a
4-chlorophenyl group) as a 53% yield of a 2.0:1 mixture of
6d:6d′ was formed (entry 3). These observations suggest activa-
tion barriers that are closer in energy for the intramolecular
cyclization at either terminus of the allyl cation as compared to
ACP 5b.14
5
rt
48
48
19
12
4
d
6
rt
−
7
rt
57
91
77
74
80
77
74
81
8
40
40
40
40
40
40
40
9
10
11
12
13
14
4
8
4
10
14
a
When the alkylidene substituent was an electron-withdrawing
group, an alternative reaction outcome was observed. For
instance, when the alkylidene substituent was an ester group,
the 2,3′-bifuran derivative 7 was generated in 69% yield and none
of the benzofuran product(s) were seen (Table 2, entry 4).15
Bifuran 7 arises from an intramolecular attack of the enolate
oxygen on the alkylidene cyclopropane to form a transient
dihydrofuran intermediate that undergoes aromatization to the
furan (Scheme 3). The regiochemical outcome suggests that
Reactions run with Lewis acid, cyclopropane 5a, and 4 Å molecular
b
sieves in CH2Cl2 (0.1 M) at the indicated temperature. Combined
c
yield of 6a and 6a′ after column chromatography. Product ratios
d
determined by 1H NMR of isolated mixture. ∼15% conversion
1
observed as determined by crude H NMR.
examined at 15 mol % in CH2Cl2 (Table 1). For ACP 5a, the
reactions proved to be regioselective for the favored benzofuran
6a (>88:12 in all cases). For In(OTf)3, Sc(OTf)3, Al(OTf)3,
and Ga(OTf)3, each reaction went to completion and afforded
6a in 66−74% yield (entries 1−4). In contrast, Cu(OTf)2
and Zn(OTf)2 proved to be inefficient catalysts for the trans-
formation as low yields/conversions (<20%) of 6a were
obtained (entries 5 and 6).
Scheme 3. Formation of 2,3′-Bifuran 7
Interestingly, although the reaction with Yb(OTf)3 did not
reach completion,11 benzofuran 6a was obtained in 57% yield
3789
dx.doi.org/10.1021/ol501676q | Org. Lett. 2014, 16, 3788−3791

Organic Letters
Letter
the allyl cation is not formed which is in agreement with the
destabilizing effect of an electron-withdrawing substituent on an
allyl cation.
Table 3. Aryl Groups as the Intramolecular π-Nucleophiles
In hopes of generating more functionalized/functionalizable
products, ACPs bearing a second substituent on the alkylidene
were employed (Scheme 4). In one example, the ACP (5f) had
Scheme 4. Effects of Alkylidene Disubstitution
two methyl alkylidene substituents and gave the 4-oxo-4,7-
dihydrobenzofuran derivative 9 in 63% yield (Scheme 4A).
9 contains both a quaternary center and an alkylidene β-ketoester
moiety, which can serve as a site for further reactivity.16
In another example, the alkylidene was substituted with a methyl
and a trimethylsilyl group (Scheme 4B). 10 was formed in 68%
yield and presumably arises via formation of a silyl-stabilized17
methyl allyl cation II followed by Friedel−Crafts-type cycliza-
tion and subsequent aromatization. This approach offers potential
for functionalization, as the proper choice of silyl group would
allow for facile C−C18 and C−O19 bond formation.
a
Reactions run with Yb(OTf)3 (15 mol %), ACP (15b, 17b, or
19a−c), and 4 Å molecular sieves in CH2Cl2 (0.1 M) at 40 °C.
b
c
Isolated yield after column chromatography. Combined yield of 20c
d
and 20c′. Product ratios determined by 1H NMR of isolated mixture.
e
Reaction performed in 1,2-dichloroethane at reflux.
This outcome is seemingly the result of a combination of
electronic and steric effects in the transition state for cyclization.
To assess the steric influence on the regiooutcome, ACP 19a
(bearing the cyclohexyl alkylidene substituent) was prepared. As
anticipated, the only observed product was naphthalene
derivative 20a′ in 39% yield (entry 5). Thus, sterics directly
influence the cyclization pathways and product outcomes.
Next, the ACP π-nucleophilic moiety was changed to alkenyl
groups and evaluated for performance (Table 4).8a,20a,23 For the
To further explore the reaction scope, the reactive π-systems
on the ACP were modified in three different ways and the result-
ing reactivities were cataloged. First, other heteroaryl π-systems
were employed under the reaction conditions (eq 1).8b,20 The
Table 4. Performance of Alkenyl Ketone Substituents
2-benzofuryl ACP 11b (bearing an 4-methoxyphenyl alkylidene
substituent) gave the corresponding dibenzofuran product 12b
in 78% yield. Similarly, 2-indolyl ACP 13b smoothly afforded
carbazole 14b in 69% yield.
Next, the effect of employing aryl groups21 as the intra-
molecular π-nucleophile for the ring-opening cyclization was
examined (Table 3). When the ACP was substituted with a
3-methoxyphenyl group as the π-donor and a 4-methoxyphenyl
group on the alkylidene (as in 15b), the expected regioisomeric
naphthalene product 16b was formed in 77% yield (entry 1). If
the π-nucleophile is a 2-naphthyl group, two regioisomeric
products are possible via Friedel−Crafts-type alkylation at C(1)
or C(3) of the naphthalene. The preferred reactivity is expected
to occur at C(1) given the relative stability of the resulting
Wheland intermediate.22 Indeed, the only observed cyclization
product is phenanthrene 18b, resulting from C(1) attack, in
44% yield (entry 2). When 3,5-dimethoxyphenyl was the
π-donor, regiochemical outcomes were found to be dependent
upon the alkylidene substituent. For instance, a 4-methoxyphenyl
substituent gives the favored naphthalene product 20b in 80%
yield (entry 3), whereas a phenyl group gives a 1.8:1 preference for
the less energetically favorable 20c′ over 20c (98% yield, entry 4).
a
Reactions run with Yb(OTf)3 (15 mol %), ACP (21a−c, 23b, or 25b),
b
and 4 Å molecular sieves in CH2Cl2 (0.1 M) at 40 °C. Isolated yield
after column chromatography. Reactions performed with 30 mol %
c
d
Yb(OTf)3. Reaction performed in 1,2-dichloroethane at reflux.
e
f
Combined yield of 22c and 22c′. Product ratios determined by
NMR of isolated mixture.
3790
dx.doi.org/10.1021/ol501676q | Org. Lett. 2014, 16, 3788−3791

Organic Letters
Letter
(2) (a) Nakamura, I.; Yamamoto, Y. Adv. Synth. Catal. 2002, 344,
111. (b) Brandi, A.; Cicchi, S.; Cordero, F. M.; Goti, A. Chem. Rev.
2003, 103, 1213. (c) Rubin, M.; Rubina, M.; Gevorgyan, V. Chem. Rev.
2007, 107, 3117. (d) Masarwa, A.; Marek, I. Chem.Eur. J. 2010, 16,
9712. (e) Yu, L.; Guo, R. Org. Prep. Proced. Int. 2011, 43, 209. (f) Shi,
M.; Lu, J.-M.; Wei, Y.; Shao, L.-X. Acc. Chem. Res. 2012, 45, 641.
(3) Laurie, V. W.; Stigliani, W. M. J. Am. Chem. Soc. 1970, 92, 1485.
(4) Ma, S.; Zhang, J. Angew. Chem., Int. Ed. 2003, 42, 183.
(5) Scott, M. E.; Bethuel, Y.; Lautens, M. J. Am. Chem. Soc. 2007, 129,
1482.
(6) Hu, B.; Xing, S.; Wang, Z. Org. Lett. 2008, 10, 5481.
(7) Fujino, D.; Yorimitsu, H.; Oshima, K. J. Am. Chem. Soc. 2011,
133, 9682.
(8) (a) Patil, D. V.; Phun, L. H.; France, S. Org. Lett. 2010, 12, 5684.
(b) Phun, L. H.; Patil, D. V.; Cavitt, M. A.; France, S. Org. Lett. 2011,
13, 1952. (c) Patil, D. V.; Cavitt, M. A.; Grzybowski, P.; France, S.
Chem. Commun. 2011, 47, 10278. (d) Phun, L. H.; Aponte-Guzman, J.;
France, S. Angew. Chem., Int. Ed. 2012, 51, 3198.
isopropenyl π-donor, similar reactivity trends were observed for
ACPs bearing either a cyclohexyl (21a)24 or a 4-methoxyphenyl
(21b) alkylidene substituent, as phenols 22a and 22b were
formed in 66% and 49% yield, respectively (entries 1 and 2).
For 21c, bearing the phenyl group, an unsurprising 2.7:1
mixture of phenols 22c and 22c′ was observed in 59% yield
(entry 3). With dihydropyran as the π-nucleophile, phenol 24b
was obtained in 26% yield (entry 4). The conformation and
steric impact of the pyranyl ring are implicated in the decreased
reaction efficiency. To examine that premise, the ACP 25b,
containing an ethoxy vinyl subtituent, was prepared. 25b, having
less destabilizing steric and conformational influences, should
perform more effectively. Indeed, 25b smoothly afforded phenol
26b in 51% yield (entry 5).
Finally, to understand the regioselectivity of the reaction
of ACPs derived from 1,3-disubstituted allenes, we prepared
21h from 3-methyl-1-(4-methoxyphenyl)allene 3h. Under the
standard reaction conditions, 21h afforded the expected phenol
22h in 58% yield (eq 2).
(9) For a review on recent synthetic approaches to alkylidene
cyclopropanes, see: Audran, G.; Pellissier, H. Adv. Synth. Catal. 2010,
352, 575.
(10) For representative examples of the formation of alkylidene
cyclopropanes from Rh(II)-catalyzed cyclopropanation of allenes and
α-diazocompounds, see: (a) Cheng, C.; Shimo, T.; Domekawa, K.;
Baba, M. Tetrahedron 1998, 54, 2031. (b) Huval, C. C.; Singleton, D.
A. J. Org. Chem. 1994, 59, 2020. (c) Gregg, T. M.; Farrugia, M. K.;
Frost, J. R. Org. Lett. 2009, 11, 4434.
1
(11) Conversions were determined by both TLC and H NMR for
In conclusion, we have disclosed a Lewis acid catalyzed, formal
homo-Nazarov-type cyclization of alkylidene-1,1-ketoesters to
form functionalized arenes and heteroarenes in up to 98% yield.
Of the two possible regioisomeric outcomes, the major product
arises from intramolecular π-attack on the most energetically
favorable allylic cationic intermediate, unless steric constraints
prevent such an attack. The choice of the alkylidene substituent
also affects reaction outcomes. The reaction is amenable to
alkenyl, aryl, and heteroaryl intramolecular π-nucleophiles.
Application of the methodology in both natural product and
materials synthesis is underway, and the results will be reported
in due course.
the consumption of ACP 5a. See Supporting Information.
(12) Changing the solvent (i.e., CH3CN, 1,2-DCE, toluene) afforded
reduced yields or poor conversion. See Supporting Information.
(13) We also examined Al(OTf)3 as the catalyst (higher selectivity),
but it proved to be less effective for the substrate scope studies.
(14) Hanna, S. Y.; Khalil, S. M.; Shandala, M. Y. Z. Naturforsch., A
2004, 59, 971.
(15) Wang reported the formation of an alkylidene-2,3-dihydrofuran
that is similar to intermediate 8 from a benzylidene cyclopropane 1,1-
ketoester (see ref 6). For representative examples of the formation of
2,3-dihydrofurans from donor−acceptor cyclopropanes, see:
(a) Yadav, V. K.; Balamurugan, R. Org. Lett. 2001, 3, 2717.
(b) Bowman, R. K.; Johnson, J. S. Org. Lett. 2006, 8, 573.
(c) Schneider, T. F.; Kaschel, J.; Dittrich, B.; Werz, D. B. Org. Lett.
2009, 11, 2317.
ASSOCIATED CONTENT
* Supporting Information
■
S
(16) Schotes, C.; Mezzetti, A. ACS Catal. 2012, 2, 528.
(17) Duttwyler, S.; Zhang, Y.; Linden, A.; Reed, C. A.; Baldridge, K.
K.; Siegel, J. S. Angew. Chem., Int. Ed. 2009, 48, 3787.
Experimental procedures, spectral and analytical data for all
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(18) For representative examples of Hiyama coupling reactions:
(a) Hiyama, T. J. Organomet. Chem. 2002, 653, 58. (b) Hachiya, H.;
Hirano, K.; Satoh, T.; Miura, M. Angew. Chem., Int. Ed. 2010, 49, 2202.
(19) For the seminal contribution by Fleming (Fleming oxidation),
see: Fleming, I.; Sanderson, P. E. J. Tetrahedron Lett. 1987, 28, 4229.
(20) For examples of heteroaryl π-nucleophiles in the formal homo-
Nazarov reaction, see: (a) Greiner-Bechert, L.; Sprang, T.; Otto, H.-H.
Monatsh. Chem. 2005, 136, 635. (b) Yadav, V. K.; Kumar, N. V. Chem.
Commun. 2008, 3774. (c) De Simone, F.; Andres, J.; Torosantucci, R.;
Waser, J. Org. Lett. 2009, 11, 1023.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: stefan.france@chemistry.gatech.edu.
Notes
The authors declare no competing financial interest.
(21) For formal homo-Nazarov literature using an aryl group as π-
nucleophiles: (a) Murphy, W. S.; Wattanasin, S. J. Chem. Soc., Perkin
Trans. 1 1982, 271. (b) Yoshida, E.; Nishida, K.; Toriyabe, K.;
Taguchi, R.; Motoyoshiya, J.; Nishii, Y. Chem. Lett. 2010, 39, 194.
(22) (a) Wheland, G. W. J. Am. Chem. Soc. 1942, 64, 900.
(b) Dowdy, D.; Gore, P. H.; Waters, D. N. J. Chem. Soc., Perkin Trans.
2 1991, 1149.
(23) For the seminal example of a formal homo-Nazarov cyclizations
using alkenyl π-nucleophiles, see: Tsuge, O.; Kanemasa, S.; Otsuka, T.;
Suzuki, T. Bull. Chem. Soc. Jpn. 1988, 61, 2897.
ACKNOWLEDGMENTS
■
S.F. gratefully acknowledges financial support from the
National Science Foundation (CAREER Award CHE-
1056687) and Georgia Tech for a Blanchard Assistant Professor
Fellowship. J.A.-G. thanks the National Science Foundation for
a graduate research fellowship (DGE-1148903) and Georgia
Tech for a Presidential Fellowship. E.T. acknowledges Georgia
Tech and the National Science Foundation for a summer REU
(NSF REU 1156657).
(24) We observed that there is no measurable effect on reaction
efficiencies (i.e., yield, conversion, reaction time) by switching between
methyl or ethyl esters.
REFERENCES
(1) Pellissier, H. Tetrahedron 2010, 66, 8341.
■
3791
dx.doi.org/10.1021/ol501676q | Org. Lett. 2014, 16, 3788−3791