Modulation of selectivity in a fluorocarbene cyclopropanation reaction: a catalytic role for bromide ion

Article abstract of DOI:10.1016/j.tetlet.2006.03.066

Phenylfluorocarbene is diverted to phenylfluorobromomethide carbanion (PhCFBr^-) by adding bromide ion. The carbanion adds to acrylonitrile leading, after expulsion of bromide, to 1-fluoro-1-phenyl-2-cyanocyclopropane.

Full text of DOI:10.1016/j.tetlet.2006.03.066

Tetrahedron Letters 47 (2006) 3419–3421
Modulation of selectivity in a fluorocarbene
cyclopropanation reaction: a catalytic role for bromide ion
Robert A. Moss* and Jingzhi Tian
Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, New Brunswick, NJ 08903, USA
Received 25 January 2006; revised 9 March 2006; accepted 10 March 2006
Available online 31 March 2006
Abstract—Phenylfluorocarbene is diverted to phenylfluorobromomethide carbanion (PhCFBrꢀ) by adding bromide ion. The carb-
anion adds to acrylonitrile leading, after expulsion of bromide, to 1-fluoro-1-phenyl-2-cyanocyclopropane.
ꢀ 2006 Elsevier Ltd. All rights reserved.
At the heart of Hine’s classic mechanism for the hydro-
lysis of chloroform is a carbene–carbanion equilibrium
(Eq. 1).1 Similar equilibria govern the capture of CCl2
by other halide ions, affording trihalomethide carba-
nions and thence, by protonation, ‘mixed’ haloforms;
for example, CHCl2Y.1b,d Trihalomethide carbanions
are also central to various methods for the generation
of dihalocarbenes, including the reaction of NaI with
PhHgCCl2Br,2 and the phase transfer catalytic genera-
tion of CCl2,3 CBr2,4 CBrCl,4 and CBrI.5 In these latter
cases, carbene–carbanion equilibria play important
roles.4,5
reactivity of acrylonitrile (ACN), an electron-poor ole-
fin, versus trimethylethylene (TME), an electron-rich
olefin, is 0.0677c as determined by classical product-
based competitive cyclopropanations8 of the paired
substrates with PhCF generated photochemically from
3-phenyl-3-fluorodiazirine.7b,9
However, the apparent selectivity of PhCF smoothly
changes in response to the addition of bromide ion in
the form of tetrabutylammonium bromide (TBABr).
Thus, binary mixtures of 0.5 M TME and 0.5 M ACN
in 1 M MeCN–THF solvent, containing varying quanti-
ties of added TBABr, were allowed to compete for
PhCF generated by the photolysis (k > 300 nm, A =
2.5 at 369 nm) of phenylfluorodiazirine. The products
were cyclopropanes 1 and 2 from the additions of PhCF
to (respectively) ACN and TME, as well as a-bromo-
a-fluorotoluene (3). The latter, identified by GC–MS,
arose by proton abstraction from the solvent by phenyl-
fluorobromomethide carbanion (see below). The yield of
3 reached 13% at the highest concentration of bromide
(0.49 M). Cyclopropanes 1 and 2, each a mixture of
syn and anti isomers, comprised the bulk of the product
mixture, and were identified by GC and GC–MS com-
parisons with authentic samples. It is crucial to note that
only PhCF adducts 1 and 2 were formed; adducts of
PhCBr were absent. The mechanistic implications of this
observation are discussed below.
ꢀCCl3 ꢀ :CCl2 þ Clꢀ
ð1Þ
We recently showed that the deliberate manipulation of
carbene–carbanion equilibria analogous to 1 permits the
effective modulation of selectivity during carbene/alkene
cyclopropanation reactions.6 Thus, the addition of chlo-
ride or bromide ions allows the concurrent cyclopropa-
nation of electron-poor alkenes by an equilibrating
mixture of phenylhalocarbenes and phenyldihalometh-
ide carbanions, enabling a smooth variation of selectiv-
ity between electron-rich and electron-poor olefins.6
Here, we extend this methodology to a fluorocarbene,
demonstrating that bromide ion functions as an ‘umpo-
lung catalyst’ in the cyclopropanation of an electron-
poor olefinic substrate.
Phenylfluorocarbene (PhCF) is known to be a moderate
electrophile in addition to alkenes.7 Indeed, the relative
Ph
F
Ph
F
CN
Me
PhCHFBr
Me Me
*
Corresponding author. Tel.: +1 732 445 2606; fax: +1 732 445
5312; e-mail: moss@rutchem.rutgers.edu
3
1
2
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.03.066

3420
R. A. Moss, J. Tian / Tetrahedron Letters 47 (2006) 3419–3421
mediating the cyclopropanation of the electron-poor
y = 2.726x + 0.110 r = 0.996
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0
substrate. The key to this phenomenon is the exclusive
expulsion of Brꢀ rather than Fꢀ in the ring closure of
carbanion 5 (as evidenced by the formation of cyclopro-
pane 1 and the absence of cyclopropane 6). Of course,
bromide is the superior leaving group; fluoride is not
generally subject to nucleophilic displacement. Note that
in the related closure of carbanion 7, formed by the
addition of PhCClBrꢀ to ACN, Clꢀ and Brꢀ are com-
petitively expelled in a ratio of 1:1.5, leading to a mix-
ture of cyclopropanes 6 and 8.6
CN
Ph
Br
Ph
Cl
_
CN
CN
Ph
Cl
Br
6
7
8
0.0
0.1
0.2
0.3
0.4
0.5
Laser flash photolysis (LFP) enables us to visualize
PhCF and PhCFBrꢀ (cf., Scheme 1). LFP of phenylfluo-
rodiazirine in MeCN–THF gives an absorption for
PhCF at 290 nm.13 In the presence of 0.2 M added
TBABr, we also observe PhCFBrꢀ at 500 nm; see Figure
2.14
[TBABr], [M]
Figure 1. Product ratio (1/2) versus added TBABr (M) for the addition
of PhCF to ACN/TME.
A correlation of the molar product ratio (1/2)10 versus
the concentration of added TBABr for the addition of
PhCF to ACN/TME appears in Figure 1. We observe
that (1/2) smoothly increases from 0.080 in the absence
of TBABr11 to 1.40 in the presence of 0.494 M TBABr, a
17.5-fold increase. The change in product ratio seems
to imply a change in the selectivity of PhCF from elec-
trophilic to nucleophilic caused by the addition of
bromide.
Carbanion 4, monitored at 500 nm, is quenched by
added ACN with kq = 4.25 · 106 Mꢀ1 sꢀ1, which we take
as equivalent to k4 in Scheme 1. Similarly, we measure
k1 = 2.46 · 107 Mꢀ1 sꢀ1 for the quenching of PhCF by
TBABr (monitored at 300 nm); k2 = 4.20 · 107 Mꢀ1 sꢀ1
for the quenching of PhCF by TME; and k3 = 2.23 ·
106 Mꢀ1 sꢀ1 for the direct addition of PhCF to ACN.
With these absolute rate constants, and the slope (2.73)
of the correlation in Figure 1, it is possible to estimate
k
ꢀ1 = 9.12 · 105 sꢀ1, so that k1/kꢀ1 = Keq ꢁ 27 Mꢀ1 for
Mechanistically, these results can be understood in
terms of Scheme 1. Here, PhCF generated by the photo-
lysis of the diazirine is reversibly captured by bromide
ion (k1/kꢀ1), affording the phenylfluorobromomethide
carbanion (4). Michael addition of 4 to ACN (which is
probably reversible)12 generates new carbanion 5,
whence rapid ring closure with loss of bromide (not fluo-
ride) gives cyclopropane 1 (overall rate constant k4).
Product 1 also forms directly by the addition of PhCF
to ACN (k3). However, carbanion 4 does not readily
add to the electron-rich TME; cyclopropane 2 comes
only from the addition of PhCF to TME (k2).
the equilibrium between (PhCF + Brꢀ) and PhCFBrꢀ
(see Scheme 1). However, this value is specific to the
1 M MeCN–THF solvent, and is likely to be solvent
dependent. Moreover, the estimate ignores the probable
solvent dependent aggregation of TBABr, as well as the
reversibility of the addition of carbanion 4 to ACN.
Therefore our estimates of k and Keq must be viewed
ꢀ1
with caution.
In conclusion, added bromide diverts PhCF to the phe-
nylfluorobromomethide carbanion (4) which undergoes
Michael addition to ACN leading, after closure of carb-
anion 5 with the release of bromide, to cyclopropane 1,
the PhCF adduct of ACN. The action of bromide ion is
functionally equivalent to catalytic umpolung of the
normally electrophilic carbene, thus mediating the
nucleophilic cyclopropanation of an electron-poor
olefin. We are extending these studies to other fluoro-
carbenes and other substrates.
As we increase the concentration of bromide, the equi-
librium between PhCF and PhCFBrꢀ shifts to the right,
augmenting the formation of cyclopropane 1 via carban-
ion 4, relative to the formation of cyclopropane 2 via
PhCF. Therefore, the apparent selectivity for ACN in-
creases, relative to TME, as illustrated in Figure 1. Bro-
mide ion therefore functions as an ‘umpolung catalyst’
CN
Ph
N
N
Ph
k1
ACN
h
ν
C: + Br-
Ph
PhCFBr
4
5
F
-N2
F
k-1
F
Br
k4
fast -Br-
k3
ACN
k2 TME
2
1
Scheme 1.

R. A. Moss, J. Tian / Tetrahedron Letters 47 (2006) 3419–3421
3421
(d) Hine, J. Divalent Carbon; Ronald Press: New York,
1964; pp 36f.
2. Seyferth, D.; Gordon, M. E.; Mui, J. Y.-P.; Burlitch, J. E.
J. Am. Chem. Soc. 1967, 89, 959.
3. (a) Dehmlow, E. V. Annalen 1972, 148; (b) Dehmlow, E.
V.; Slopianka, M. Annalen 1979, 1465.
4. Dehmlow, E. V.; Lissel, M.; Heider, J. Tetrahedron 1977,
33, 363.
5. Dehmlow, E. V.; Broda, W. Chem. Ber. 1982, 115,
3894.
6. Moss, R. A.; Tian, J. J. Am. Chem. Soc. 2005, 127,
8960.
7. (a) Moss, R. A. Acc. Chem. Res. 1989, 22, 15; (b) Moss, R.
A.; Lawrynowicz, W. J. Org. Chem. 1984, 49, 3828; (c)
Moss, R. A.; Lawrynowicz, W.; Hadel, L. M.; Hacker, N.
P.; Turro, N. J.; Gould, I. R.; Cha, Y. Tetrahedron Lett.
1986, 27, 4125.
0.007
0.006
0.005
0.004
0.003
0.002
0.001
0.000
-0.001
200
300
400
500
600
700
8. Moss, R. A.. In Carbenes; Jones, M., Jr., Moss, R. A.,
Eds.; Wiley, 1973; Vol. 1, pp 153f.
wavelength, nm
9. Cox, D. P.; Moss, R. A.; Terpinksi, J. J. Am. Chem. Soc.
1983, 105, 6513.
10. Product ratios were determined by capillary GC; the flame
ionization detector was calibrated for differential response
with known blends of 1 and 2.
Figure 2. LFP–UV spectra of PhCF (290 nm) and PhCFBrꢀ (500 nm)
in 1 M MeCN–THF.
11. With equimolar TME and ACN, this value (0.080) is equal
to the relative reactivity of ACN/TME. We attribute the
slight increase, relative to the literature value (0.0677c), to
the polar MeCN–THF solvent used in the present case.
12. Bernasconi, C. F. Tetrahedron 1989, 45, 4017.
13. In a 3-methylpentane matrix at 77 K, PhCF is reported to
absorb at 270 nm: Gould, I. R.; Turro, N. J.; Butcher, J.,
Jr.; Doubleday, C., Jr.; Hacker, N. P.; Lehr, G. F.; Moss,
R. A.; Cox, D. P.; Guo, W.; Munjal, R. C.; Perez, L. A.;
Fedorynski, M. Tetrahedron 1985,ꢀ41, 1587.
Acknowledgements
We are grateful to Professor Ronald R. Sauers, for help-
ful discussions, and to the National Science Foundation,
for financial support.
References and notes
ꢀ
1. (a) Hine, J. J. Am. Chem. Soc. 1950, 72, 2438; (b) Hine, J.;
Dowell, A. M., Jr. J. Am. Chem. Soc. 1954, 76, 2688; (c)
Hine, J.; Ehrenson, S. J. J. Am. Chem. Soc. 1958, 80, 824;
14. Absorption maxima of PhCCl2 and PhCBr2 are
observed at 410 and 430 nm, respectively, in MeCN–
THF.6