Thermally induced cycloadditions of donor/acceptor carbenes

Article abstract of DOI:10.1021/ol201628d

The thermal decomposition of aryldiazoacetates and aryldiazoketones in the absence of a catalyst leads to synthetically useful transformations. The thermal reaction of aryldiazoacetates with alkenes generates cyclopropanes in 68-97% yield and with good diastereoselectivity (up to 19:1 dr) when the aryl substituent is electron-rich. The thermal reaction of aryldiazoketones with alkenes generated cyclobutanones in 71-94% yield and with good diastereocontrol (≥9:1 dr).

Full text of DOI:10.1021/ol201628d

ORGANIC
LETTERS
2011
Vol. 13, No. 16
4284–4287
Thermally Induced Cycloadditions of
Donor/Acceptor Carbenes
Stephanie R. Ovalles, Jørn H. Hansen, and Huw M. L. Davies*
Emory University, Department of Chemistry, 1515 Dickey Drive, Atlanta, Georgia
30322, United States
hmdavie@emory.edu
Received June 16, 2011
ABSTRACT
The thermal decomposition of aryldiazoacetates and aryldiazoketones in the absence of a catalyst leads to synthetically useful transformations.
The thermal reaction of aryldiazoacetates with alkenes generates cyclopropanes in 68ꢀ97%yieldandwith good diastereoselectivity(upto19:1dr) when
the aryl substituent is electron-rich. The thermal reaction of aryldiazoketones with alkenes generated cyclobutanones in 71ꢀ94% yield and with
good diastereocontrol (g9:1 dr).
Diazo compounds are widely used precursors for the
generation ofcarbene intermediatesunder metal catalysis.1
They can undergo a variety of useful synthetic transforma-
tions such as cyclopropanation,2 CꢀH insertion,3 and
ylide formation.4 A concern, however, with the use of
diazo compounds is their thermal instability, although
large-scale reactions have been reported.5 We and others
have conducted extensive studies on the metal-catalyzed
reactions of aryldiazoacetates.6 These reactions generate a
class of intermediates, called donor/acceptor carbenoids,
that are more selective than the traditional carbenoids
lacking the donor group.6b This paper describes that,
opposite to conventional wisdom, metal-free, thermal
reactions of aryldiazo esters and aryldiazo ketones are also
capable of highly selective transformations.
The most widely used catalysts for the reactions of
donor/acceptor carbenoids have been dirhodium com-
plexes.7 Although these catalysts are extremely active,5a,8
several other metals have been developed as catalysts for
(1) 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, Inc.: New York, 1998.
(2) (a) Davies, H. M. L.; Antoulinakis, E. G. Org. Reacts. 2001, 57,
1–326. (b) Maas, G. Chem. Soc. Rev. 2004, 33, 183.
(3) (a) Davies, H. M. L.; Beckwith, R. E. J. Chem. Rev. 2003, 103,
2861. (b) Doyle, M. P.; Duffy, R.; Ratnikov, M.; Zhou, L. Chem. Rev.
2010, 110, 704.
(7) (a) Hansen, J.; Davies, H. M. L. Coord. Chem. Rev. 2008, 252, 545.
(b) Doyle, M. P. J. Org. Chem. 2006, 71, 9253.
(8) Davies, H. M. L.; Bruzinski, P. R.; Lake, D. H.; Kong, N.; Fall,
M. J. J. Am. Chem. Soc. 1996, 118, 6897.
(4) (a) Padwa, A.; Weingarten, M. D. Chem. Rev. 1996, 96, 223.
(b) Padwa, A.; Hornbuckle, S. F. Chem. Rev. 1991, 91, 263.
(5) (a) Huang, Y.; Zhang, W.; Zhang, P.; Liu, X. Ind. Eng. Chem. Res.
2010, 49, 12164. (b) Simpson, J. H.; Godfrey, J.; Fox, R.; Kotnis,
A.; Kacsur, D.; Hamm, J.; Totelben, M.; Rosso, V.; Mueller, R.;
Delaney, E.; Deshpande, R. P. Tetrahedron: Asymmetry 2003, 14, 3569.
(c) Saltzmann, T. N.; Ratcliffe, R. W.; Christensen, B. G.; Bouffard,
F. A. J. Am. Chem. Soc. 1980, 102, 6161.
(9) (a) Morilla, M. E.; Diaz-Requejo, M. M.; Belderrain, T. R.;
Nicasio, M. C.; Trofimenko, S.; Perez, P. J. Chem. Commun. 2002,
2998. (b) Yang, M. M.; Wang, X.; Livant, P. J. Org. Chem. 2001, 66,
6729. (c) Mbuvi, H. M.; Klobukowski, E. R.; Roberts, G. M.; Woo,
L. K. J. Porphyr. Phthalocyanines 2010, 14, 284. (d) Del Zotto, A.;
Baratta, W.; Rigo, P. J. Chem. Soc., Perkin Trans. 1 1999, 3079.
(e) Galardon, E.; LeMaux, P.; Simonneaux, G. J. Chem. Soc., Perkin
Trans. 1 1997, 2455. (f) Baumann, L. K.; Mbuvi, H. M.; Du, G.; Woo,
L. K. Organometallics 2007, 26, 3995. (g) Mbuvi, H. M.; Woo, L. K.
Organometallics 2008, 27, 637.
(6) (a) Zhang, Z.; Wang, J. Tetrahedron 2008, 64, 6577. (b) Hansen,
J.; Autschbach, J.; Davies, H. M. L. J. Org. Chem. 2009, 74, 6555.
r
10.1021/ol201628d
Published on Web 07/18/2011
2011 American Chemical Society

this chemistry but they often require reaction conditions
above ambient temperature.9 During exploratory studies
on iron catalysis, we conducted a control experiment in
which methyl phenyldiazoacetate (1a) was heated to reflux
with styrene in trifluorotoluene over 12 h in the absence of
catalyst (Scheme 1). Remarkably, under these conditions,
a clean transformation was observed, generating the cy-
clopropane 2a in 90% yield as a 4:1 E/Z mixture of
diastereomers. Although photochemically induced reac-
tions of aryldiazoacetates have been described in the liter-
ature,10 reports of the thermally induced reactions of such
diazo compounds is sparse.11,12 Herein, we describe a
study of how the nature of the substrate and diazo com-
pound influences the course of thermally induced reactions
of donor/acceptor carbenes.
Table 1. Influence of Diazo Compound Structurea
Scheme 1. Thermal Cyclopropanation of Styrene with 1a
Theoretical studies have shown that the favored electro-
nic structure of carbenes derived from aryldiazoacetates is
dependent on the aryl substituent.10a The singlet ground
state is favored when there is a donor substituent, such as a
p-methoxy group, while the ground state is triplet when
there is an acceptor substituent such as a p-nitro group.10a
The thermal cyclopropanation reaction of a series of
aryldiazoacetates was examined to see what impact the
nature of the substituents would have on the reactivity
(Table 1). The reaction of the aryldiazoacetate in the
presence of 5 equiv of styrene in trifluorotoluene under
reflux for 12 h was used as the standard reaction condi-
tions. The cyclopropanes 2bꢀc, 2fꢀg derived from aryl-
diazoacetates 1bꢀg were obtained in yields ranging from
90 to 97% whereas lower yields (57ꢀ68%) were obtained
with the electron-deficient systems 1h,i. The cyclopropa-
nation reactions were highly diastereoselective (g93:7 dr)
with the most electron-rich substrates 1bꢀc, 1eꢀf, but the
diastereoselectivity was only 56:44 dr for the p-nitro deri-
vative 1h. Many of the reactions proceeded in higher yields
a A dry round-bottom flask was charged with styrene (5.0 equiv) and
dry trifluorotoluene. The reaction mixture was heated to reflux, and then
the diazo compound (1.0 equiv) was added by syringe pump over a
period 3 h. b From 1H NMR of crude reaction mixture.
than the corresponding rhodium-catalyzed reactions,2a
although the diastereoselectivity was inferior and no op-
portunity existsforasymmetricinduction.13 Thereason for
the marked difference in diastereoselectvity may be due to
a change in the reactive electronic state of the carbene or an
inherently more selective reaction by carbenes with a
stronger donor substituent. Thermal reactions of styryl-
diazoacetates were not examined because these carbenoid
precursors undergo thermal electrocyclization to pyrazoles
rather than nitrogen extrusion.14
(10) (a) Geise, C. M.; Wang, Y. H.; Mykhaylova, O.; Frink, B. T.;
Toscano, J. P.; Hadad, C. M. J. Org. Chem. 2002, 67, 3079. (b) Tomioka,
H.; Okuno, H.; Izawa, Y. Tetrahedron Lett. 1982, 23, 1917. (c) Tomioka,
H.; Ozaki, Y.; Izawa, Y. Tetrahedron 1985, 41, 4987. (d) Mizushima, T.;
Ikeda, S.; Murata, S.; Ishii, K.; Hamaguchi, H. Chem. Lett. 2000, 1282.
(11) For examples that are likely to include thermally induced reac-
tions, see: (a) Sharma, A.; Guenee, L.; Naubron, J.-V.; Lacour, J.
Angew. Chem., Int. Ed. 2011, 50, 1. (b) Petrukhina, M. A.; Andreini,
K. W.; Walji, A. M.; Davies, H. M. L. Dalton Trans. 2003, 22, 4221.
(12) Huisgen has conducted extensive studies on the 1,3-dipolar
cycloaddition of diazo compounds with alkenes, and some of the
resulting cycloadducts under forcing conditions extrude nitrogen to
generate cyclopropanes. Typically, the dipolarophiles are electron defi-
cient or strained and the 1,3-dipolar cycloaddition is conducted at
temperatures below the decomposition temperatures of the diazo com-
pounds. For a leading review, see: Huisgen, R. Angew. Chem. 1963, 75,
604.
Studies have shown that the reactivity of metal carbe-
noids is highly dependent on the substituents.15 Therefore,
the thermal reactions of the aryldiazoacetates were com-
pared with those of the other major classes of carbenes, the
(13) See details in the Supporting Information for the results of the
corresponding rhodium-catalyzed reactions.
(14) Davies, H. M. L.; Huby, N. J. S.; Cantrell, W. R., Jr.; Olive, J. L.
J. Am. Chem. Soc. 1993, 115, 9468.
(15) Davies, H. M. L.; Hedges, L. M.; Matasi, J. J.; Hansen, T.;
Stafford, D. G. Tetrahedron Lett. 1998, 39, 4417.
Org. Lett., Vol. 13, No. 16, 2011
4285

acceptor carbenes, and the acceptor/acceptor carbenes
(Scheme 2). The more traditional carbene precursor, ethyl
diazoacetate 3, afforded the cyclopropane 4 in 90% yield
Scheme 2. Thermal Cyclopropanation of Styrene with 3 and 5
and 67:33 dr. Methyl diazomalonate (5) generated the
cyclopropane 6 in only 13% yield after 12 h because the
conversion of 5 was very slow under these conditions.
Having established the thermal cyclopropanation of the
aryldiazoacetates, the reactions of electron-rich aryldia-
zoacetates 1b and 1e were examined with other olefinic
substrates (Figure 1). Highly diastereoselective reactions
were observed with substituted styrenes (7aꢀb dr >91:9).
Butyl vinyl ether afforded 7c in moderate 86:14 dr, but in
good combined yield of 85%. A cyclic vinyl ether, 1,2-
dihydrofuran, afforded the corresponding cyclopropane
7din >95:5 drand 71% yield. Thereactionbetween 1eand
cis-β-methylstyrene affordedcyclopropane 7e in 72% yield
and diastereoselectivity (dr = 92:8). The high stereoselectiv-
ity in this reaction lends support to a mechanism involving
predominantly singlet carbene for the cyclopropanation.16
Even trans-β-methylstyrene readily underwent cyclo-
propanation under these conditions to afford 7f in 62%
yield and >95:5 dr. Cyclopropanation of trans-alkenes
cannot be achieved under rhodium-catalyzed conditions
unless the alkene is very electron-rich.17 Using 1,2-dihy-
dronaphthalene as a substrate afforded 7g in 50% yield
and >95:5 dr. Even cyclopropenation was feasible as the
use of phenylacetylene as a trap afforded cyclopropene 7h
in 44% yield.
Figure 1. Thermal cycloaddition with various substrates.
consistent with the [π2s þ π2a]-mechanism.18b The struc-
ture of the major product (entry 1) was confirmed
unambiguously by X-ray crystallography (see Support-
ing Information).
The synthetic studies conducted above indicated that the
thermal stability of the diazo compounds was structurally
Table 2. Thermal [2 þ 2]-Cycloadditions of Diazoketone 8
Attempts at extending the thermal cyclopropanation to
aryldiazoketones resulted in a totally different reaction.
The resulting carbene preferably underwent a Wolff re-
arrangement to a ketene, whose presence could be identi-
fied by React IR, followed by a much slower thermal [2 þ
2]-cycloaddition with the styrene (Table 2).18 The reaction
of 8 with a series of styrenes proceeded in high yield and
diastereoselectivity. As reported for other ketene cycload-
ditions, the syn-diastereomer was formed preferentially,
compd
Ar
-C6H5
yield (%)a
drb
a
b
c
69
91
94
71
91:9
90:10
90:10
>95:5
-(p-Me)C6H4
-(p-CI)C6H4
-(p-MeO)C6H4
d
a Combined yield of both diastereomers. b From 1H NMR of crude
reaction mixture
(16) (a) Woodworth, R. C.; Skell, P. S. J. Am. Chem. Soc. 1959, 81,
3383. (b) Keating, A. E.; Merrigan, S. R.; Singleton, D. A.; Houk, K. N.
J. Am. Chem. Soc. 1999, 121, 3933.
(17) Ventura, D. L.; Li, Z.; Coleman, M. G.; Davies, H. M. L.
Tetrahedron 2009, 65, 3052.
dependent. This was examined in more detail by conduct-
ing ReactIR studies on the electronically differentiated
aryldiazoacetates 1aꢀb, 1h and ethyl diazoacetate 3. The
disappearance of the diazo compounds was monitored by
(18) Kirmse, W. Eur. J. Org. Chem. 2002, 2193. (b) Brady, W. T.;
Roe, R. J. Am. Chem. Soc. 1971, 93, 1662.
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Org. Lett., Vol. 13, No. 16, 2011

decomposition were very different. The first-order rate
constants were extracted from ln(ΔA) vs time plots and
are reported with error bars from the linear regression
analysis (see Supporting Information). The nature of the
aromatic substituent was profound; the p-methoxy deri-
vative 1b had a half-life of 1.82 min, whereas the p-nitro
derivative 1h had a half-life of ∼5.2 h. Ethyl diazoacetate
(3) displayed a half-life of ∼1.6 h, in between the half-lives
of the unsubstituted aryl derivative 1a (21.7 min) and the
p-nitro derivative 1h. These studies demonstrate that ac-
ceptor groups stabilize diazo compounds.1 Even though
these solution phase thermal reactions proceed very con-
trollably with first-order kinetics, one should always be
cautious when heating diazo compounds, especially on
large scale.
These studies demonstrate that the thermal cyclopro-
panation chemistry of aryldiazoacetates in the absence
of a transition metal catalyst can be a high-yielding
process. Furthermore, when the aryl goup is electron-
rich, the reaction is highly diastereoselective. Decom-
position of aryldiazoketones under similar reaction
conditions results in the formation of cyclobutanones
in high yield and diastereocontrol, via the intermediacy
of ketenes. Kinetic studies of the thermal reactions
show that acceptor groups stabilize diazo compounds.
These studies also suggest that reported catalytic reac-
tions at high temperatures9 may have significant ther-
mal background reactions.
Acknowledgment. Financial support for this work by
the National Science Foundation is gratefully acknowl-
edged (CHE 0750273). We wish to acknowledge Mr. Evan
L. T. Davies from the Gwinnet School of Math, Science &
Technology for his initial studies on iron catalysis, which
were an inspiration for this study.
Figure 2. Kinetic studies on the thermal decomposition of 1aꢀb,
1h, and 3 in the presence of styrene (5 equiv).
tracking the CdN2 stretch frequency (∼2100 cmꢀ1).
Figure 2 shows a conversion plot of the reaction progress
over 1 h for the thermal decomposition in refluxing
trifluorotoluene in the presence of styrene. The diazo com-
pounds decomposed with first-order kinetics, but the rates of
Supporting Information Available. Experimental pro-
cedures, characterization and spectral data for new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 16, 2011
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