Remarkable stereoelectronic control in the lewis base assisted [2,3]-rearrangement of cyclopropenylmethyl phosphinites

Article abstract of DOI:10.1021/ol702473s

A novel 2,3-rearrangement of cyclopropenylmethyl phosphinites to methylenecyclopropylphosphine oxides was demonstrated. It was found that, in striking contrast to the analogous rearrangement known for nonstrained allylic systems, this reaction does not proceed at all upon thermal activation; however, it can be efficiently mediated by Lewis bases. Unique stereoelectronic effects control the diastereoselectivity of this transformation, leading to predominant formation of the more sterically hindered products.

Full text of DOI:10.1021/ol702473s

ORGANIC
LETTERS
2007
Vol. 9, No. 26
5501-5504
Remarkable Stereoelectronic Control in
the Lewis Base Assisted
[2,3]-Rearrangement of
Cyclopropenylmethyl Phosphinites
Marina Rubina, Eric W. Woodward, and Michael Rubin*
Department of Chemistry, UniVersity of Kansas and Center for EnVironmentally
Beneficial Catalysis, 1251 Wescoe Hall DriVe, Lawrence, Kansas 66045-7582
mrubin@ku.edu
Received October 10, 2007
ABSTRACT
A novel 2,3-rearrangement of cyclopropenylmethyl phosphinites to methylenecyclopropylphosphine oxides was demonstrated. It was found
that, in striking contrast to the analogous rearrangement known for nonstrained allylic systems, this reaction does not proceed at all upon
thermal activation; however, it can be efficiently mediated by Lewis bases. Unique stereoelectronic effects control the diastereoselectivity of
this transformation, leading to predominant formation of the more sterically hindered products.
Recent impressive progress in the development of synthetic
approaches toward stereodefined cyclopropenes1 has signifi-
cantly broadened the scope of useful transformations involv-
ing these unique synthons.2 The extremely reactive double
bond of the cyclopropene allows for efficient and selective
functionalization of the three-membered ring providing
densely substituted cyclopropane derivatives unavailable by
alternative cyclization methodologies. Two main approaches
of such functionalization include the direct addition of
various entities to the cyclopropene double bond (eq 1) and
the electrophilic or nucleophilic substitution reactions of
cyclopropenes involving a strain-driven shift of the double
bond to the exocyclic position (eq 2). While the former
approach has been broadly exploited,2 the second route,
leading to valuable methylenecyclopropane (MCP) deriva-
tives,3 has attracted little attention to date. Most of the known
examples of such isomerization involve intermolecular
addition of a new entity, and only a few syntheses of optically
active methylenecyclopropanes via this method have been
demonstrated.4
(1) (a) Doyle, M. P.; Winchester, W. P.; Hoorn, J. A. A.; Lynch, V.;
Simonsen, S. H.; Ghosh, R. J. Am. Chem. Soc. 1993, 115, 9968. (b) Doyle,
M. P.; Protopopova, M.; Mu¨ller, P.; Ene, D.; Shapiro, E. A. J. Am. Chem.
Soc. 1994, 116, 8492. (c) Davies, H. M. L.; Lee, G. H. Org. Lett. 2004, 6,
1233. (d) Liao, L. A.; Zhang, F.; Dmitrenko, O.; Bach, R. D.; Fox, J. M.
J. Am. Chem. Soc. 2004, 126, 4490. (e) Lou, Y.; Horikawa, M.; Kloster, R.
A.; Hawryluk, N. A.; Corey, E. J. J. Am. Chem. Soc. 2004, 126, 8916.
(2) For recent reviews, see, for example: (a) Rubin, M.; Rubina, M.;
Gevorgyan, V. Chem. ReV. 2007, 107, 3117. (b) Rubin, M.; Rubina, M.;
Gevorgyan, V. Synthesis 2006, 1221. (c) Fox, J. M.; Yan, N. Curr. Org.
Chem. 2005, 9, 719.
(3) For recent reviews on MCPs, see: (a) Brandi, A.; Goti, A. Chem.
ReV. 1998, 98, 589. (b) Nakamura, I.; Yamamoto, Y. AdV. Synth. Catal.
2002, 344, 111. (c) Nakamura, E.; Yamago, S. Acc. Chem. Res. 2002, 35,
867. See also ref 2a.
(4) (a) Yang, Z.; Xie, X.; Fox, J. M. Angew. Chem. 2006, 118, 4064;
Angew. Chem., Int. Ed. 2006, 45, 3960. (b) Weatherhead-Kloster, R. A.;
Corey, E. J. Org. Lett. 2006, 8, 171. (c) Simaan, S.; Masarwa, A.; Bertus,
P.; Marek, I. Angew. Chem., Int. Ed. 2006, 45, 3963.
10.1021/ol702473s CCC: $37.00
© 2007 American Chemical Society
Published on Web 11/17/2007

Herein, we wish to report a novel Lewis base assisted 2,3-
rearrangement of 1-cyclopropenylmethyl phosphinites lead-
ing to densely substituted cyclopropylphosphine deriva-
tives.5,6 This methodology represents a valuable alternative
to the existing approaches to phosphorylated cyclopropanes,
involving trapping of a cyclopropylmetal species with a
phosphorus electrophile, which are highly sensitive to steric
factors. The discovered unusual promoting effect of the
Lewis base additive and unique stereoelectronic control of
the selectivity by a very remote substituent are remarkable
and set this reaction apart from the majority of the previously
reported diastereoselective transformations of cyclopropenes,
which are governed by steric or directing effects.
Scheme 1
[2,3]-Sigmatropic rearrangements of both allylphosphites7
and allylphosphinites8 5 are well-known; they proceed
thermally (at 80-110 °C)9 via a concerted transition state
(TS1)11 to provide allylphosphine oxide 6 (Scheme 1, eq 3).
We hypothesized that the analogous transformation of
cyclopropenylphosphinite 7 into MCP 8 should proceed
under much milder conditions, urged forward by the sig-
nificant strain release10 accompanying migration of the
double bond (eq 4). Indeed, DFT computations11 of a putative
rearrangement of 7 into 8 suggested the reaction is highly
thermodynamically favorable (∆G ) -34 kcal/mol). How-
ever, the activation barrier for the rearrangement of cyclic
phosphinite 7 was unexpectedly high, comparable to that for
the reaction with acyclic substrate 5 (∆Gq ) 25 and 31 kcal/
mol, respectively).12 Geometry analysis of the transition state
TS2 (Scheme 1) suggested that the rather large ∆Gq value
for the transformation 7f8 is primarily associated with
severe distortion of the sp2-hybridized carbon rendering the
angle θ between the small cycle plane and the methylene
group abnormally small (137°). Introduction of substituents
at C-3 of cyclopropene led to further increase of the
activation barrier for the concerted reaction (eq 5). Thus,
∆Gq values for the rearrangement of the methyl- and phenyl-
substituted phosphinites 9a and 9b were higher than for the
parent system by 5 and 12 kcal/mol, respectively. The results
of theoretical modeling indicated that the thermal 2,3-
rearrangement of substituted cyclopropenylphosphinites would,
most likely, require heating to temperatures not compatible
with preservation of the fragile three-membered carbocycle.
Indeed, our attempts to perform thermal rearrangement of
phosphinite 11a were unsuccessful: prolonged refluxing in
toluene did not provide the expected phosphine oxide and
resulted in slow decomposition of the starting material (eq
6).
(5) For employment of cyclopropylphosphine derivatives in synthesis,
see, for example: (a) Molander, G.; Burke, J. P.; Carroll, P. J. J. Org.
Chem. 2004, 69, 8062. (b) Imamoto, T.; Oshiki, T.; Onozawa, T.; Kusumoto,
T.; Sato, K. J. Am. Chem. Soc. 1990, 112, 5244. (c) Meijs, G. P.; Eichinger,
P. C. H. Tetrahedron Lett. 1987, 28, 5559.
(6) For biological studies on phosphorous-containing methylenecyclo-
propanes, see: (a) Zhou, S.; Brietenbach, J. M.; Borysko, K. Z.; Drach, J.
C.; Kern, E. R.; Gullen, E.; Cheng, Y.-C.; Zemlicka, J. J. Med. Chem. 2004,
47, 566. (b) Yan, Z.; Zhou, S.; Kern, E. R.; Zemlicka, J. Tetrahedron 2006,
62, 2608. (c) Devreux, V.; Wiesner, J.; Goeman, J. L.; van der Eycken, J.;
Jomaa, H.; van Calenbergh, S. J. Med. Chem. 2006, 49, 2656.
(7) (a) Lemper, A. L.; Tieckelmann, H. Tetrahedron Lett. 1964, 3053.
(b) Lu, X.; Zhu, J. J. Organomet. Chem. 1986, 304, 239. (c) Janecki, T.;
Bodalski, R. Synthesis 1990, 9, 799. (d) Muthiah, C.; Kumar, K. S.; Vittal,
J. J.; Swamy, K. C. K. Synlett 2002, 1787.
(8) (a) Liron, F.; Knochel, P. Chem. Commun. 2004, 304. (b) Demay,
S.; Volant, F.; Knochel, P. Angew. Chem. 2001, 113, 1272; Angew. Chem.,
Int. Ed. 2001, 40, 1235.
Surprisingly, during preparation of phosphinite 11a from
the corresponding cyclopropenylmethanol 12a and chlo-
rodiphenylphosphine, we detected formation of small amounts
of isomeric methylenecyclopropylphosphine oxides 13a and
14a (eq 7). Thus, when the reaction was carried out in the
(9) Typical reaction times for this process are 3-12 h. See ref 8a.
(10) Bach, R. D.; Dmitrienko, O. J. Am. Chem. Soc. 2004, 126, 4444.
(11) B3LYP/6-31G(d): Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.;
Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.;
Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.;
Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.;
Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda,
R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai,
H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken,
V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.;
Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.;
Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski,
V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D.
K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui,
Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith,
T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.;
Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople,
J. A. Gaussian 03, revision C.02; Gaussian, Inc.: Wallingford, CT, 2004.
(12) See Supporting Information for details.
presence of triethylamine and DMAP at room temperature,
it initially resulted in the rapid formation of phosphinite 11a.
However, when allowed to react overnight, phosphinite 11a
was slowly transformed into phosphinoxides 13a and 14a
(eq 7). These results clearly indicated the amine plays an
important role in assisting the rearrangement of 11 into 13
and 14 and also demonstrated the viability of the direct one-
5502
Org. Lett., Vol. 9, No. 26, 2007

Scheme 2. Mechanistic Rationale for the Amine-Assisted Rearrangement
pot transformation of alcohol 12 into phosphinoxides 13 and
selectivity toward formation of 13 improved with an increase
of electron density on the phosphorus atom (entries 1-3).
However, phosphinites 11d,e obtained from very bulky
[(iPr)2N]2PCl and (t-Bu)2PCl failed to undergo rearrangement
under these conditions, potentially due to overwhelming
steric clashes between the phosphinite moiety and the
substituents at C-3 (entries 4 and 5). Second, and very
surprisingly, the electronic nature of the para substituent on
the aryl ring of cyclopropene has a significant effect on the
diastereoselectivity of this rearrangement. Thus, in a series
of 3-aryl-substituted cyclopropenes, the diastereoselectivity
degraded from the more electron-rich toward the more
electron-poor aryl group and finally reversed in the case of
the p-CF3 analogue producing phosphine oxide 13i as a major
product (entries 1 and 6-9). Reactions of ester- and
acetyloxymethyl-substituted cyclopropenylmethanols 12j,k
followed the general trend predominantly affording more
hindered product 13 (entries 10 and 11).
14 without isolation of the sensitive phosphinite 11. Encour-
aged by this finding and intrigued by the fact that the
“thermally improbable”, more hindered diastereomer 13 was
also observed in notable amounts, we performed systematic
screening of a series of different amines.11 It was found that
a number of tertiary amines enabled the phosphinite-to-
phosphine oxide rearrangement; however, DBU13 was par-
ticularly efficient in selectively catalyzing the formation of
the sterically more hindered phosphine oxide 13 (Table 1).
Table 1. Sequential Phosphinylation/2,3-Rearrangement into
Methylenecyclopropylphosphine Oxides
yield,
%
The following mechanism was proposed for this rear-
rangement (Scheme 2). Initially, addition of an amine to the
cyclopropene double bond14 produces zwitterionic intermedi-
ate 15, thereby releasing the strain and making the phos-
phinite moiety flexible enough to undergo intramolecular
nucleophilic ring closure to form oxophospholanium zwit-
terion 16. The latter, upon rapid five-membered ring cleav-
age, provides phosphine oxide 13. Minor product 14 is
obtained in a similar manner, after initial nucleophilic attack
of the amine from the more hindered face, via intermediates
17 and 18 (Scheme 2). The unusual stereoelectronic effects
observed in this reaction can be rationalized as follows.
According to the Curtin-Hammett principle, rapid thermo-
dynamic equilibrium between 15 and 1715 should play a
negligible role in stereodifferentiation, which should be rather
a
no.
Ar
R1
R2
product
13/14b
1
2
3
4
5
6
7
8
9
p-MeC6H4 CH2OMOM Ph
13a, 14a 86
13b, 14b 74c
2.7:1
4.0:1
p-MeC6H4 CH2OMOM i-Pr
p-MeC6H4 CH2OMOM Cy
p-MeC6H4 CH2OMOM t-Bu
p-MeC6H4 CH2OMOM (i-Pr)2N 11e
p-MeOC6H4 CH2OMOM Ph
13c, 14c 90c,d 5.2:1
11d
-
-
-
-
3.5:1
1.5:1
1.1:1
13f, 14f 90
13g, 14g 96
13h, 14h 83e
13i, 14i 91
p-FC6H4
Ph
CH2OMOM Ph
CH2OMOM Ph
p-CF3C6H4 CH2OMOM Ph
1:1.3
10 Ph
11 Ph
12 p-CF3C6H4 CH2OH
CO2Me
CH2OAc
Ph
Ph
Ph
13j, 14j 47c,f 2.4:1
13k, 14k 83
2.8:1
-
-
0g
a Combined isolated yields of 13 and 14. b Crude 1H NMR ratios.
c Inseparable mixture of 13 and 14. d Reaction ran at 50 °C. e Enantiomeri-
cally enriched substrate was used; optical yield of 100%. f Reaction ran at
rt. g Complex mixture of products.
(14) For addition of nitrogen nucleophiles to the cyclopropene double
bond, see: (a) Franck-Newmann, M.; Miesch, M.; Kempf, H. Tetrahedron
1988, 44, 2933. (b) Gritsenko, E. I.; Khaliullin, R. R.; Plemenkov, V. V.;
Faizullin, E. M. Zh. Obshch. Khim. 1988, 58, 2733.
(15) The difference in activation energies for steps 11 / 15 and 11 /
17 was found to be ca. 3 kcal/mol (B3LYP/6-31G(d)) and was shown to
only insignificantly depend on the electronic nature of the aryl substituent.11
Two aspects of this transformation are noteworthy. First,
employment of different chlorophosphines revealed that the
(13) DBU ) 1,8-diazabicyclo[5.4.0]undec-7-ene.
Org. Lett., Vol. 9, No. 26, 2007
5503

C3-C2-P) ) 125° which does not permit proper alignment
of the interacting orbitals. However, such resonance is
possible for the sterically more hindered transition state 19,
where the torsion angle (again, due to the ring strain) is close
to 0°. This mechanistic rationale involving zwitterionic
transition states is strongly supported by the observed
dependence of the diastereoselectivity on the σ+-Hammet
constants of para substituents in the aryl ring at C-3 (Figure
1).11
In conclusion, a novel [2,3]-rearrangement of cyclopro-
penylmethylphosphinites to methylenecyclopropylphosphine
oxides is demonstrated. Having been found thermally impos-
sible due to insurmountable ring strain, this transformation
can, however, be efficiently assisted by Lewis bases, which
alter the geometry of the transition state via reversible
addition to the strained double bond of cyclopropene. Unique
stereoelectronic effects of this reaction result in preferential
formation of the more sterically hindered products. The
described methodology allows for easy introduction of a very
important phosphorus functionality into the rigid and densely
substituted cyclopropyl scaffold and can be easily amended
to the synthesis of optically active 2-phosphorylated meth-
ylenecyclopropanes bearing a quaternary chiral center.
Figure 1. Hammett analysis of diastereoselectivity of the [2,3]-
phosphinite-to-phosphine oxide rearrangement.
controlled kinetically on the first irreversible step (15f16
vs 17f18). The latter represents an SN2-type process
proceeding via concerted transition states 19 and 21,
respectively. We rationalize that M+-substituents in the aryl
ring can contribute to the resonance stabilization of transition
state 19 via mesomeric form 20, making it more favorable
than 21. Remarkably, in contrast to the analogous classical
stereoelectronic effects observed in five- and six-membered
rings, where maximum orbital overlap is realized for trans
substituents at a torsion angle of θ ) 180°, in the strained
cyclopropane system 21, the corresponding angle θ (Ar-
Acknowledgment. The support of the National Science
Foundation (EEC-0310689) and the University of Kansas
REU program (E.W.W.) is gratefully acknowledged.
Supporting Information Available: Full experimental
details. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL702473S
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Org. Lett., Vol. 9, No. 26, 2007