Boronate urea activation of nitrocyclopropane carboxylates

Article abstract of DOI:10.1021/ol202873d

Boronate ureas operate as catalysts for the activation of nitrocyclopropane carboxylates in nucleophilic ring-opening reactions. A variety of amines were found to open the urea-activated nitrocyclopropane carboxylates, generating highly useful nitro ester

Full text of DOI:10.1021/ol202873d

ORGANIC
LETTERS
2012
Vol. 14, No. 2
444–447
Boronate Urea Activation of
Nitrocyclopropane Carboxylates
Sonia S. So, Tyler J. Auvil, Victoria J. Garza, and Anita E. Mattson*
Department of Chemistry, The Ohio State University, 100 W. 18th Avenue, Columbus,
Ohio 43210, United States
mattson@chemistry.ohio-state.edu
Received October 24, 2011
ABSTRACT
Boronate ureas operate as catalysts for the activation of nitrocyclopropane carboxylates in nucleophilic ring-opening reactions. A variety of
amines were found to open the urea-activated nitrocyclopropane carboxylates, generating highly useful nitro ester building blocks in good yields.
Standard manipulations allow access to a wide range of valuable compounds from the ring-opened products with direct applications in bioactive
target synthesis.
Hydrogen bond donors (HBDs) operate as impres-
sive catalysts for the activation of electrophiles.1 Suitable
ureas, for example, effectively enhance the reactivity of
β-nitrostyrenes and R,β-unsaturated imides toward the
1,4-addition of nucleophiles (1).2 The activation of
imines and carbonyl compounds for 1,2-nucleophilic
addition reactions provides additional evidence of the
power of urea catalysis (2).3 While the collection of
reactions catalyzed through hydrogen bonding with
ureas has grown tremendously in the past ten years,
the realization of the full potential of urea catalysis
requires the continued development of catalysts with
improved activity and the exploration of new activation
modes. A research program in our laboratory is geared
toward the design of enhanced urea catalysts, along
with the study of their application toward the develop-
ment of unique reactivity patterns for the synthesis of
bioactive target molecules. Herein we report our initial
success with boronate urea catalyzed activation of
strained rings (3).
Figure 1. Proposed urea activation of strained systems.
Recently, we reported that fluoroboronate urea cata-
lysts offer improved reactivity over conventional urea
catalysts in the conjugate addition reactions of indoles to
nitroalkenes, possibly due to enhanced acidity of the NÀH
protons resulting from internal coordination of the urea
carbonyl to the strategically placed boron.4À6 We were
interested in taking advantage of these enhanced HBDs in
(1) For recent reviews, see: (a) Pihko, P. M. Hydrogen Bonding in
Organic Synthesis, 1st ed.; Wiley-VCH: Weinheim, 2009. (b) Doyle, A. G.;
Jacobsen, E. N. Chem. Rev. 2007, 107, 5713. (c) Akiyama, T. Chem. Rev.
2007, 107, 5744.
(2) (a) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X. N.; Takemoto,
Y. J. Am. Chem. Soc. 2005, 127, 119. (b) Herrera, R. P.; Sgarzani, V.;
Bernardi, L.; Ricci, A. Angew. Chem., Int. Ed. 2005, 44, 6576. (c) Hoashi,
Y.; Okino, T.; Takemoto, Y. Angew. Chem., Int. Ed. 2005, 44, 4032.
(3) (a) Wenzel, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124,
12964. (b) Kavanagh, S. A.; Piccinini, A.; Fleming, E. M.; Connon, S. J.
Org. Biomol. Chem. 2008, 6, 1339. (c) Fuerst, D. E.; Jacobsen, E. N.
J. Am. Chem. Soc. 2005, 127, 8964.
(4) So, S. S; Burkett, J. A.; Mattson, A. E. Org. Lett. 2011, 13, 716.
(5) For pioneering work using boronate ureas in anion recognition,
see: (a) Hughes, M. P.; Shang, M. Y.; Smith, B. D. J. Org. Chem. 1996,
61, 4510. (b) Hughes, M. P.; Smith, B. D. J. Org. Chem. 1997, 62, 4492.
r
10.1021/ol202873d
Published on Web 12/30/2011
2011 American Chemical Society

ring-opening reactions of nitrocyclopropane carboxylates,
typically metal catalysts and/or elevated reaction tempera-
tures are required to generate high yields of product; no
organocatalytic variant has been reported. The most effi-
cient Lewis acid catalyst was found to be nickel perchlo-
rate, while many other Lewis acids caused undesired
rearrangement of the nitrocyclopropane to the isoxazoline
N-oxide.10e Prior work taking advantage of urea activation
of nitroalkenes for conjugate addition reactions did pro-
vide a starting point for the support of our studies, yet at
the onset of our investigations it remained unclear if a
HBD would operate as a strong enough catalyst to activate
a nitrocyclopropane for ring-opening.11 To the best of our
knowledge, this is the first study dedicated toward ring-
opening reactions of activated cyclopropanes using a HBD
catalyst.
Scheme 1
Studies commenced with the treatment of racemic
nitrocyclopropane carboxylate 4a with a catalytic amount
of boronate urea 6 in the presence of aniline (Scheme 1).
Gratifyingly, 5a was isolated in 87% yield as a 1:1 mixture
of diastereomers after 48 h at 23 °C in methylene chloride.
In addition to enhanced activity, boronate ureas are read-
ily prepared from commercially available materials and
benefit from several tunable parameters (e.g., Lewis acid,
ligand) that can be easily altered to facilitate the engineer-
ing of a catalyst with optimal performance for a particular
reaction.4,12,13 A direct comparison of boronate urea 6 to
conventional urea 7 demonstrated the benefit of internal
Lewis acid activation on the activity of the catalyst (87% vs
67% yields). On the basis of literature precedent involving
urea activation of nitroalkenes, it is proposed that the
catalyst may operate through hydrogen bond association
of 6 with the nitro group of 4a to generate intermediate 8,
a species in which the cyclopropane is activated for attack.2,14
With the initial bond-forming process established, the limits
of the reaction with respect to the nitrogen nucleophile
were put to the test (Table 1). The reaction was found to
be tolerant of anilines containing both electron-donating
and electron-withdrawing substituents. 4-Methoxyaniline
as a nucleophile gave rise to 90% 5b with 10 mol % 6
(entry 2). The less electron rich 4-bromoaniline rendered
the reaction more sluggish, affording 58% 5c after 48 h
(entry 3). Nitrogen heterocycles were found to be well
tolerated as nucleophiles in the reaction system. The addi-
tion of morpholine to 4a yielded 95% 5d. Nucleophilic
addition of piperidine was more challenging, although a
78% yield of desired product 5e was obtained (entry 5).
Indoline operated well in the ring-opening of 4a to afford
99% 5f (entry 6). Phenylhydrazine was also well tolerated
in the reaction, affording a near-quantitative yield of 5g
new bond-forming processes and set out to develop bo-
ronate urea catalyzed ring-opening reactions of nitrocy-
clopropanes (3).7 Investigations exploring reactions of
activated cyclopropanes typically focus on the reactivity
of 1,1-diestercyclopropanes.8,9 Reactions of nitro-
cyclopropanes are significantly less studied and warrant
further development due to the value of products contain-
ing the nitro group, as it can be easily converted into useful
nitrogen functionalities often found in bioactive targets.10
Indeed, the highly useful nature of the products obtained
from the ring-opening of nitrocyclopropanes was the basis
of our initial attraction to this area. We envisioned taking
advantage of boronate ureas (6) for the activation of
nitrocyclopropane carboxylates (4) toward attack by an
amine nucleophile to access γ-amino R-nitro ester prod-
ucts (5), valuable building blocks for the construction of
drug targets. In the few existing reports of nucleophilic
(6) For additional recent, interesting examples of alternate strategies
to access hydrogen bond donors with enhanced activity see: (a) Robak,
M. T.; Trincado, M.; Ellman, J. A. J. Am. Chem. Soc. 2007, 129, 15110.
(b) Ganesh, M.; Seidel, D. J. Am. Chem. Soc. 2008, 130, 16464.
(7) For a review on nitrocyclopropanes see: Averina, E. B.; Yashin,
N. V.; Kuznetsova, T. S.; Zefirov, N. S. Russ. Chem. Rev. 2009, 78, 887.
(8) For reviews on the reactivity of activated cyclopropanes, see:
(a) Carson, C. A.; Kerr, M. A. Chem. Soc. Rev. 2009, 38, 3051. (b) Rubina,
M.; Gevorgyan, V. Chem. Rev. 2007, 107, 3117. (c) Yu, M.; Pagenkopf,
B. L. Tetrahedron 2005, 61, 321. (d) Reissig, H. U.; Zimmer, R. Chem. Rev.
2003, 103, 1151. (e) Burrit, A.; Coron, J. M.; Steel, P. J. Trends Org. Chem
1993, 4, 517. (f) Wong, H. N. C.; Hon, M. Y.; Tse, C. W.; Yip, Y. C.;
Tanko, J.; Hudlicky, T. Chem. Rev. 1989, 89, 165. (g) Danishefsky, S. Acc.
Chem. Res. 1979, 12, 66.
(9) For recent examples of Lewis acid catalyzed reactions of
1,1-diestercyclopropanes see: (a) Jackson, S. K.; Karadeolian, A.; Driega,
A. B.; Kerr, M. A. J. Am. Chem. Soc. 2008, 130, 4196. (b) Perreault, C.;
Goudreau, S. R.; Zimmer, L. E.; Charette, A. B. Org. Lett. 2008, 10, 689.
(c) Pohlhaus, P. D.; Johnson, J. S. J. Am. Chem. Soc. 2005, 127, 16014.
(d) Magolan, J.; Kerr, M. A. Org. Lett. 2006, 8, 4561.
(11) For intramolecular H-bond activation of cyclopropanes see:
Emmett, M. R.; Kerr, M. A. Org. Lett. 2011, 13, 4180.
(12) For early work demonstrating that diaryl ureas with trifluoromethyl
substituents have enhanced activity, see: (a) Schreiner, P. R.; Wittkopp, A.
Org. Lett. 2002, 4, 217. (b) Wittkopp, A.; Schreiner, P. R. Chem.;Eur. J.
2003, 9, 407.
(13) A variety of ureas were surveyed as catalysts in this process. See
Supporting Information for more on the catalyst structure.
(14) Participation of the ester in the activation of intermediate 8 has
not been ruled out at this time.
(10) For reports of ring-opening reactions of nitrocyclopropanes see:
(a) Vettiger, T.; Seebach, D. Liebigs Ann. Chem 1990, 195. (b) Seebach,
D.; Haener, R.; Vettiger, T. Helv. Chim. Acta 1987, 70, 1507. (c) Wurz,
R. P.; Charette, A. Org. Lett. 2005, 7, 2313. (d) Budynina, E. M.;
Ivanova, O. A.; Averina, E. B.; Kuznetsova, T. S.; Sefirov, N. S.
Tetrahedron Lett. 2006, 47, 647. (e) Lifchits, O.; Charette, A. B. Org.
Lett. 2008, 10, 2809. (f) Lifchits, O.; Alberico, D.; Zakharian, I.;
Charette, A. B. J. Org. Chem. 2008, 73, 6838.
Org. Lett., Vol. 14, No. 2, 2012
445

after 48 h (entry 7). Under these optimized conditions we
were unable to observe any successful ring-opening of
nitrocyclopropanes with primary amines, such as benzyl
amine. It is noteworthy to mention that the rearrangement
of 4 to the corresponding isoxazoline N-oxide, a problem
encountered under many types of Lewis acidic conditions
(BF3OEt2, AlCl3, and others), was not observed in any
reaction catalyzed by a urea.10e,15
(entry 4). In addition to aromatic rings, alkenes were found to
be viable substituents at the point of substitution on the cyclo-
propane. Nucleophilic addition of aniline to the nitrocyclo-
propane derived from 1,3-butadiene gave rise to 76% 5k
(entry 5). Nitrocyclopropanes prepared from electron-rich
aromatic rings were not examined in this study, as their
rearrangement to the isoxazoline N-oxide occurred upon
purification by column chromatography on silica gel.
Table 1. Substrate Scope with Nitrogen Nucleophilea
Table 2. Substrate Scope with Nitrocyclopropane Carboxylatea
a Reactions performed using 1.5 equiv of aniline at a concentration of
0.5 M. See Supporting Information for detailed experimental proce-
dures. b Isolated as a 1:1 mixture of diastereomers. c Isolated yield.
Pleased with the wide range of products accessible from
boronate urea catalyzed ring-opening of nitrocyclo-
propanes, we became curious about the stereochemical
outcome of the ring-opening of an enantioenriched nitro-
cyclopropane (Scheme 2). The exposure of enantioen-
riched 4a (89% ee) to indoline in otherwise optimized
conditions gave rise to 99% 5f as a 1:1 mixture of diaster-
eomers with complete inversion of stereochemistry
(91% ee for each of the products).10e,16 Taking this result
in combination with previous reports of urea-catalyzed pro-
cesses, a plausible catalytic pathway can be proposed.
Initial coordination of 6 with 4a affords the activated
nitrocyclopropane intermediate I.14 Nucleophilic attack
by the amine causes ring-opening, giving rise to II through
an SN2-type reaction pathway, consistent with the observa-
tion that the product has inverted stereochemistry with
respect to the starting material. This cycle is in contrast to
a Reactions performed using 1.5 equiv of amine at a concentration of
0.5 M. Control experiments result in a 12% yield of product in the
absence of the urea catalyst. See Supporting Information for detailed
experimental procedures. b Isolated as a 1:1 mixture of diastereomers
unless otherwise noted. c Isolated yield. d dr = 1:1.3.
Next we explored the generality of the reaction with
respect to the nitrocyclopropane carboxylate (Table 2).
Product 5h, isolated after the ring-opening of p-Cl styrene-
derived nitrocyclopropane with aniline, was produced
in high yield (77%, entry 2). The naphthyl-derived nitro-
cyclopropane operated well in the addition reaction, afford-
ing a near-quantitative yield of 5i(entry 3). Installation of a
m-CF3 group on the phenyl ring was also fairly well
tolerated in the reaction, generating a 59% yield of 5j
(15) For rearrangements of nitrocyclopropanes to isoxazoline
N-oxides see: Bianchi, L.; Dell’Erba, C.; Gasparrini, F.; Novi, M.;
Petrillo, G.; Sancassan, F.; Tavani, C. ARKIVOC 2002, xi, 142.
(16) For detailed experimental procedures, including evidence for
stereocenter inversion, see the Supporting Information.
446
Org. Lett., Vol. 14, No. 2, 2012

an alternate SN1-like pathway that would likely give rise to a
racemic mixture of 5f, in which ring-opening of the nitro-
cyclopropane occurs prior to nucleophilic attack. After pro-
ton transfer to form III the product is released with simulta-
neous reintroduction of the urea into the catalytic cycle.
the lactam 10 in 97% yield as a single diastereomer, and
our NMR spectroscopic studies suggest a trans orientation
between the nitro group and phenyl ring (eq 2). Chemose-
lective reduction of the nitro group was achieved upon
subjection of 5a to Zn and HCl to yield R-aminoester 11
(92%, eq 3).
The application of the activation of nitrocyclopropanes
toward the synthesis of 16, a CB-1 receptor inverse agonist
recently patented by Eli Lilly, demonstrates potential
applications of boronate urea catalysis in drug discovery
(Scheme 4).17 The addition of 4-(trifluoromethoxy)aniline
(13) to enantioenriched nitrocyclopropane 12 in the pre-
sence of 10 mol % 6 gave rise to nitroester 14 as a 1:1
mixture of diastereomers in 91% yield with 90% ee for
each of the products. Lactamization of 14 using HCl in
methanol enabled isolation of 15 in 97% yield. The
aminolactam was accessed in 92% yield upon reduction
of 15 with Zn and HCl. Condensation of amine with
1-(6-(trifluoromethyl)pyridin-2-yl)ethanone followed by
addition of trimethylaluminum gave rise to the desired
drug candidate 16 in good yield (43% in two steps).
Scheme 2. Ring-Opening of an Enantioenriched Nitrocyclo-
propane and Proposed Catalytic Cycle
Scheme 4. Application to Synthesis of Drug Target 16
Scheme 3. Utility of Nitroester Products
Acknowledgment. Support for this work has been pro-
vided by the OSU Department of Chemistry and the
American Cancer Society (Grant IRG-67-003-47). We
thank the Ohio BioProducts Innovations Center (OBIC)
for helping support our mass spec facility.
A few exemplary manipulations readily carried out on
5a demonstrate some of the utility of the γ-amino R-nitro
ester products prepared from the boronate urea catalyzed
ring-opening of nitrocyclopropanes (Scheme 3). Decarboxy-
lationwas effectedinexcellentyield withlithium hydroxide
in dioxanes, giving rise to amine 9 (88%, eq 1). Straight-
forward subjection of 5a to 1 M HCl in MeOH afforded
Supporting Information Available. Experimental pro-
cedures and spectral data (PDF). This material is
available free of charge via the Internet at http://
pubs.acs.org.
(17) Hu, J. U.S. Patent 0028520 A1, February 3, 2011.
Org. Lett., Vol. 14, No. 2, 2012
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