Lewis acid mediated (3 + 2) cycloadditions of donor-acceptor cyclopropanes with heterocumulenes

Article abstract of DOI:10.1021/ol302494n

Isocyanates, isothiocyanates, and carbodiimides are effective substrates in (3 + 2) cycloadditions with donor-acceptor cyclopropanes for the synthesis of five-membered heterocycles. These reactions exhibit a broad substrate scope, high yields, and well-defined chemoselectivity. Discussed herein are the implications of Lewis acid choice on the stereochemical outcome and the reaction mechanism.

Full text of DOI:10.1021/ol302494n

ORGANIC
LETTERS
2012
Vol. 14, No. 20
5314–5317
Lewis Acid Mediated (3 þ 2)
Cycloadditions of DonorꢀAcceptor
Cyclopropanes with Heterocumulenes
Alexander F. G. Goldberg, Nicholas R. O’Connor,† Robert A. Craig II,† and
Brian M. Stoltz*
The Warren and Katharine Schlinger Laboratory for Chemistry and Chemical
Engineering, Division of Chemistry and Chemical Engineering, California Institute of
Technology, 1200 East California Boulevard, MC 101-20, Pasadena, California 91125,
United States
stoltz@caltech.edu
Received September 10, 2012
ABSTRACT
Isocyanates, isothiocyanates, and carbodiimides are effective substrates in (3 þ 2) cycloadditions with donorꢀacceptor cyclopropanes for the
synthesis of five-membered heterocycles. These reactions exhibit a broad substrate scope, high yields, and well-defined chemoselectivity.
Discussed herein are the implications of Lewis acid choice on the stereochemical outcome and the reaction mechanism.
Donorꢀacceptor cyclopropanes are a useful class of build-
ing blocks for organic synthesis.1 Indeed, (3 þ 2) cycloaddi-
tions of donorꢀacceptor cyclopropanes have proven to be a
powerful strategy for the direct synthesis of five-membered
carbo- and heterocycles, and such methodologies have been
applied toward natural product syntheses.2 Given our own
interest in this field,2e we sought to examine heterocumu-
lenes as potential dipolarophiles in stereoselective (3 þ 2)
cycloadditions to enable access to five-membered hetero-
cycles. At the outset of this project, isocyanates3a,b and
isothiocyanates3c,d had previously been shown to be reac-
tive with alkoxy-substituted donorꢀacceptor cyclopro-
panes in only low to moderate yields, and stereocontrol
of these reactions has relied on existing stereocenters
remote from the site of reactivity. Based on the work of
† These authors contributed equally.
(1) (a) Mel’nikov, M. Y.; Budynina, E. M.; Ivanova, O. A.; Trushkov,
I. V. Mendeleev Commun. 2011, 21, 293–301. (b) Carson, C. A.; Kerr, M. A.
Chem. Soc. Rev. 2009, 36, 3051–3060. (c)DeSimone, F.;Waser, J.Synthesis
2009, 3353–3374. (d) Rubin, M.; Rubina, M.; Gevorgyan, V. Chem. Rev.
2007, 107, 3117–3179. (e) Yu, M.; Pagenkopf, B. L. Tetrahedron 2005, 61,
321–347. (f) Reissig, H.-U.; Zimmer, R. Chem. Rev. 2003, 103, 1151–1196.
(g) Mochalov, S. S.; Gazzaeva, R. A. Chem. Heterocycl. Compd.
2003, 39, 975–988. (h) Reissig, H.-U. Top. Curr. Chem. 1988, 144,
73–135.
(2) Examples include: (a) Karadeolian, A.; Kerr, M. A. Angew.
Chem., Int. Ed. 2010, 49, 1133–1135. (b) Campbell, M. J.; Johnson, J. S.
J. Am. Chem. Soc. 2009, 131, 10370–10371. (c) Zhang, H.; Curran, D. P.
J. Am. Chem. Soc. 2011, 133, 10376–10378. (d) Morales, C. L.; Pagenkopf,
B. L. Org. Lett. 2008, 10, 157–159. (e) Goldberg, A. F. G.; Stoltz, B. M.
Org. Lett. 2011, 13, 4474–4476.
(4) Stereoselective (3 þ 2) reactions of donorꢀacceptor cyclopro-
panes with aldimines: (a) Parsons, A. T.; Smith, A. G.; Neel, A. J.;
Johnson, J. S. J. Am. Chem. Soc. 2010, 132, 9688–9692. Aldehydes: (b)
Parsons, A. T.; Johnson, J. S. J. Am. Chem. Soc. 2009, 131, 3122–3123.
(c) Pohlhaus, P. D.; Sanders, S. D.; Parsons, A. T.; Li, W.; Johnson, J. S.
J. Am. Chem. Soc. 2008, 130, 8642–8650. (d) Pohlhaus, P. D.; Johnson,
J. S. J. Am. Chem. Soc. 2005, 127, 16014–16015. Vinylcyclopropanes
with azlactones: (e) Trost, B. M.; Morris, P. J. Angew. Chem., Int. Ed.
2011, 50, 6167–6170. Alkynes: (f) Lin, M.; Kang, G.-Y.; Guo, Y.-A.;
Yu, Z.-X. J. Am. Chem. Soc. 2012, 134, 398–405.
€
(3) (a) Bruckner, C.; Suchland, B.; Reissig, H.-U. Liebigs Ann. Chem.
1988, 471–473. (b) Graziano, M. L.; Iesce, M. R. J. Chem. Res. (S) 1987,
362–363. (c) Graziano, M. L.; Cimminiello, M. R. J. Chem. Res. (S)
1989, 42–43. (d) Graziano, M. L.; Cimminiello, G. J. Chem. Res. (M)
1989, 446–447.
r
10.1021/ol302494n
Published on Web 10/09/2012
2012 American Chemical Society

Johnson, Kerr, and others, we envisioned that the use of
aryl substituents as the donor component would allow for
an enantiospecific process by means of nucleophilic attack
at the chiral benzylic center.4,5 The products formed could
serve as useful building blocks toward optically active
natural products and pharmaceutically relevant hetero-
cyclic compounds.
We began by examining the reactivity of allyl isothio-
cyanate with aryl-substituted cyclopropanes (1). We found
that a stoichiometric amount of tin(II) triflate enabled full
conversion of the starting materials to thioimidates (2,
Scheme 1). Notably, the chemoselectivity of this reaction is
complementary with respect to the previous studies in
which alkoxy-substituted donorꢀacceptor cyclopropanes
are converted to thioamides.3,6
We found that a variety of substituted aryl groups were
tolerated in this reaction. Thioimidates with electron-rich
aryl substituents (2b, 2c, 2m) were obtained with the shortest
reaction times. Reactions leading to products with ortho or
electron-withdrawing arene substituents (2d, 2h, 2i) were the
slowest. Cyclopropanes were not limited to those with aryl
substituents; a vinyl group could also be used as an electron-
donating substituent, offering 5-vinylthioimidate 2j in quan-
titative yield. In addition, cyclohexyl isothiocyanate was
also compatible under these conditions, providing thioimi-
dates 2k and 2l in 91% and 99% yield respectively.
Under tin(II) triflate mediated conditions, we found aryl
isothiocyanates to be poorly reactive; however, concur-
rent with our studies, Li and co-workers disclosed an
iron(III) chloride mediated (3 þ 2) cycloaddition of aryl
isothiocyanates with donorꢀacceptor cyclopropanes to
form thiolactams (e.g., 4) rather than thioimidates (e.g., 5,
Scheme 2a).7 We suspected that the products reported by
Li may have been misassigned and decided to investigate
this further. Upon comparison of the 13C NMR spectra of
our products (e.g., 2aꢀ2m) to those reported by Li, we
found similar shifts in the carbonyl range for both sets of
spectra. In both cases, three signals are typically ob-
served near 160 ppm: two correspond to the ester
functionalities, and the third is consistent with a thio-
imidate; by contrast, a thioamide CdS 13C NMR signal
is expected at approximately 200 ppm.8 Furthermore,
our IR spectra consistently exhibited CdN stretches
near 1650 cmꢀ1, and CdS signals were not observed.9
Although no IR spectra were included in Li’s report, we
reacted cyclopropane 3 with phenyl isothiocyanate
under similar conditions to those reported by Li and
obtained a compound with NMR spectra matching
those reported (Scheme 2b). The product IR spectrum
contained a CdN stretch at 1638 cmꢀ1, and no CdS
peak was observed. Finally, we found that the 5-mesityl
substituted thioimidate (2h, Scheme 1) was crystalline,
and its structure was confirmed by single crystal X-ray
diffraction (Scheme 2c).10a Combined, the IR, 13C
NMR, and X-ray crystallography data support our
assignment of both the Li group’s and our products
as thioimidates and not thioamides.
Scheme 1. Substrate Scope of Isothiocyanate (3 þ 2) Cycload-
ditiona
Scheme 2. Structural Reassignment of Li’s Aryl Isothiocyanate
(3 þ 2) Products
a Conditions: cyclopropane 1 (0.4 mmol), isothiocyanate (0.8 mmol),
Sn(OTf)2 (0.44 mmol), CH2Cl2 (1.3 mL). b Isolated yields.
(6) Chemoselectivity comparable to that observed in our studies has
been shown in a palladium-catalyzed (3 þ 2) cycloaddition of isothio-
cyanates with aziridines. Baeg, J.-O.; Bensimon, C.; Alper, H. J. Am.
Chem. Soc. 1995, 117, 4700–4701.
(5) Additional examples of stereoselective cycloadditions of donorꢀ
acceptor cyclopropanes can be found in the review articles in ref 1.
Org. Lett., Vol. 14, No. 20, 2012
5315

We then turned our attention to carbodiimide dipolar-
ophiles and observed that, under tin(II) triflate mediated
reaction conditions, the use of diisopropyl carbodiimide
resulted in complete conversion of cyclopropane 3 to ami-
dine 6a in only 80 min and required only 1.1 equiv of the
dipolarophile.10b Electron-rich 5-(4-methoxyphenyl)ami-
dine 6b was formed almost quantitatively in less than 10
min (Scheme 3). Primary amidines (6e and 6f) could also
be accessed using bis(trimethylsilyl)carbodiimide. Nota-
bly, (3 þ 2) reactions were possible with cyclopropanes
that are unreactive with isothiocyanates. For instance, a
sterically congested 5,5-disubstituted amidine 6g could be
generated in 58% yield. In addition, while aryl isothio-
cyanates were poorly reactive in the presence of tin(II)
triflate, use of diphenylcarbodiimide resulted in the for-
mation of the corresponding amidine (6h) in 79% yield.
Overall, the shorter reaction times indicate that carbodii-
mides are considerably more reactive dipolarophiles than
comparable isothiocyanates in these reactions.
mediated reaction conditions. Microwave heating resulted
in shorter reaction times but an array of side products.
Fortunately, we were able to obtain lactams in moderate
yields using iron(III) chloride (Scheme 4).11 A variety of
N-alkyl substituted lactams could be prepared, including
isopropyl (7a), benzyl (7b and 7c), allyl (7d), and n-butyl
(7e). In addition, a secondary lactam (7f) could be synthe-
sized using trimethylsilylisocyanate as a dipolarophile.
In general, these isocyanate reactions were considerably
lower yielding than those with carbodiimides and isothio-
cyanates; nevertheless, they provide a meaningful entry
into the important lactam series.
Scheme 4. Substrate Scope of Isocyanate (3 þ 2) Cycloaddition
Scheme 3. Substrate Scope of Carbodiimide (3 þ 2)
Cycloadditiona
a Conditions: cyclopropane 1 (0.4 mmol), FeCl3 (glovebox, 0.44
mmol), isocyanate (1.2 mmol), CH2Cl2 (1.3 mL). Conditions: cyclo-
propane 1 (0.4 mmol), FeCl3 (benchtop, 0.44 mmol), isocyanate (1.2
b
c
mmol), MS 4 A (50 mg), CH2Cl2 (1.3 mL). Trimethylsilylisocyanate
˚
was used.
Finally, we sought to establish whether stereochemical
information from the starting material is transferred to the
product under the reaction conditions. We prepared en-
antioenriched cyclopropane (S)-3 according to literature
methods and subjected it to our standard reaction condi-
tions (Scheme 5).12 Although treatment of this substrate
with an isocyanate in the presence of iron(III) chloride
resulted in complete racemization of the benzylic stereo-
center (Scheme 5a),13 we observed a transfer of chirality in
the case of tin(II) triflate mediated (3 þ 2) cycloadditions
(Schemes 5b and 5c). Notably substrates that required
longer reaction times resulted in increased erosion of
optical activity.14 We were able to confirm the absolute
stereochemistry of the HBr salt of (R)-6a by single
crystal X-ray diffraction, which revealed an inversion
a Conditions: cyclopropane 1 (0.4 mmol), carbodiimide (0.44 mmol),
Sn(OTf)2 (0.44 mmol), CH2Cl2 (1.3 mL). Isolated yields. Bis-
(trimethylsilyl)carbodiimide was used.
b
c
We also examined isocyanates in (3 þ 2) cycloadditions;
however, they suffered from poor reactivity under tin-
(7) Wang, H.; Yang, W.; Liu, H.; Wang, W.; Li, H. Org. Biomol.
Chem. 2012, 10, 5032–5035.
€
(8) Pretsch, E.; Buhlmann, P.; Badertscher, M. Structure Determina-
tion of Organic Compounds, 4th ed.; Springer-Verlag: Berlin, 2009.
(9) A thioamide CdS IR stretch is expected as a strong band near
1140ꢀ1190 cmꢀ1 8
.
(10) (a) The assignment of Z-stereochemistry for thioimidate 2h was
established via single crystal X-ray diffraction, and other thioimidates in
Scheme 1 were assigned by analogy. (b) The assignment of E-stereo-
chemistry for amidine 6a is based on the crystal structure of its HBr salt
(see below), and other amidines in Scheme 3 were assigned by analogy.
(11) Two methods were used to set up reactions with dry iron(III)
chloride: (a) iron(III) chloride stored in a nitrogen-filled glovebox was
dispensed into a flame-dried flask or (b) iron(III) chloride stored on a
benchtop was dispensed into an oven-dried vial, and used in conjunction
(12) Davies, H. M. L.; Bruzinski, P. R.; Lake, D. H.; Kong, N.; Fall,
M. J. J. Am. Chem. Soc. 1996, 118, 6897–6907.
(13) Treatment of cyclopropane (R)-3 with iron(III) chloride, in the
absence of a dipolarophile, results in racemization of the material.
(14) Prolonged exposure of cyclopropane (R)-3 to Sn(OTf)2 results in
racemization. See ref 4c.
˚
with 4 A molecular sieves. Although (b) is more operationally convenient,
method (a) appears to result in shorter reaction times and higher yields.
(15) Methyl and phenyl hydrogen atoms and the bromide counterion
are omitted for clarity.
5316
Org. Lett., Vol. 14, No. 20, 2012

Scheme 6. Proposed Mechanism for (3 þ 2) Cycloaddition
electron-rich aromatic substituents, are all consistent with
this mechanistic hypothesis.
In conclusion, we have disclosed an effective method
for formation of pyrrolidinones, thioimidates, and amidines
from donorꢀacceptor cyclopropanes. Our data suggest
that, with comparable substituents, carbodiimides are
more reactive than isothiocyanates, which are in turn more
reactive than isocyanates. We have also disclosed a new
mode of reactivity for isothiocyanates with donorꢀacceptor
cyclopropanes. Furthermore, while iron(III) chloride
caused racemization of the cyclopropane and formed race-
mic cycloadducts, tin(II) triflate mediated (3 þ 2) reactions
with isothiocyanates and carbodiimides were shown to
proceed through an enantiospecific pathway, with inversion
of configuration. Efforts to develop conditions catalytic in
Lewis acid, as well as conditions for the enantioselective
reactions of isocyanates with donorꢀacceptor cyclopro-
panes, are currently underway. Applications of these meth-
ods for a range of purposes are also being investigated.
Figure 1. Determination of absolute configuration.15
Scheme 5. Investigations into the Stereochemical Outcome of
the (3 þ 2) Reaction
Acknowledgment. The authors wish to thank NIH-
NIGMS (R01GM080269-01), Amgen, Abbott, Boehringer
Ingelheim, and Caltech for financial support. A.G. grate-
fully acknowledges the Natural Sciences and Engineering
Research Council (NSERC) of Canada for a PGS D
scholarship. Dr. Michael R. Krout (Bucknell University)
and Jonathan R. Gordon (Caltech) are thanked for helpful
discussions. Lawrence Henling (Caltech) is gratefully ac-
knowledged for X-ray crystallographic structural determi-
nation. The Bruker KAPPA APEXII X-ray diffractometer
was purchased via an NSF CRIF:MU award to the Cali-
fornia Institute of Technology, CHE-0639094. The Varian
400 MHz NMR spectrometer was purchased via an NIH
grant (RR027690).
of configuration at the benzylic stereocenter through the
course of the reaction (Figure 1).
We propose that the mechanism of the isothiocyanate
and carbodiimide reactions with tin(II) triflate involves a
stereospecific intimate-ion pair mechanism analogous
to that invoked by Johnson and co-workers for (3 þ 2)
cycloadditions of aldehydes and donorꢀacceptor cyclo-
propanes developed in their laboratories (Scheme 6).4c,d,16
Our observations including stereochemical inversion at
the benzylic position, along with the greater reactivity of
electron-rich dipolarophiles and of cyclopropanes with
Supporting Information Available. Experimental details
and NMR spectra of all intermediates. This material is
available free of charge via the Internet at http://pubs.acs.org.
(16) Related mechanistic investigations were originally performed on
cyclopropane nitrone cycloadditions: (a) Karadeolian, A.; Kerr, M. A.
J. Org. Chem. 2007, 72, 10251–10253. (b) Sapeta, K.; Kerr, M. A. J. Org.
Chem. 2007, 72, 8597–8599. (c) Wanapun, D.; Van Gorp, K. A.; Mosey,
N. J.; Kerr, M. A.; Woo, T. K. Can. J. Chem. 2005, 83, 1752–1767.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 20, 2012
5317