Bromination and iodination of donor-acceptor cyclopropanes. Evidence for an ET mechanism

Article abstract of DOI:10.1016/S0040-4039(02)01966-4

Ethyl 2,2-dimethoxycyclopropanecarboxylates 1a-d react easily with Br₂ and I₂ in CCl₄ or CH₂Cl₂ leading, in high yields, to 1-ethyl-4-methyl 2-halobutanedioates 2 and 3, respectively. Bromination in the presence of pyridine, NBS, trimethyl phosphate, and iodination with ICl and ICl/pyridine has been also performed. A common SET mechanism may be proposed for both halogenations; depending on the reaction conditions, bromination can also occur via acid-catalysed or S_E2 routes. The reaction of the 2-ethoxyanalogues cis-12 and trans-12 with the same halogens proceeds in a similar manner, giving 3-formyl-2-haloesters along with the corresponding diethylacetals as main products. Iodination of 12 with the catalytic system NaI/m-CPBA/18-crown-6 has also been investigated.

Full text of DOI:10.1016/S0040-4039(02)01966-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8067–8070
Bromination and iodination of donor–acceptor cyclopropanes.
Evidence for an ET mechanism
Vincenzo Piccialli,* M. Liliana Graziano,* M. Rosaria Iesce and Flavio Cermola
Dipartimento di Chimica Organica e Biochimica, Universita` degli Studi di Napoli ‘Federico II’, Via Cynthia 4, 80126 Napoli,
Italy
Received 29 July 2002; revised 10 September 2002; accepted 11 September 2002
Abstract—Ethyl 2,2-dimethoxycyclopropanecarboxylates 1a–d react easily with Br2 and I2 in CCl4 or CH2Cl2 leading, in high
yields, to 1-ethyl-4-methyl 2-halobutanedioates 2 and 3, respectively. Bromination in the presence of pyridine, NBS, trimethyl
phosphate, and iodination with ICl and ICl/pyridine has been also performed. A common SET mechanism may be proposed for
both halogenations; depending on the reaction conditions, bromination can also occur via acid-catalysed or SE2 routes. The
reaction of the 2-ethoxyanalogues cis-12 and trans-12 with the same halogens proceeds in a similar manner, giving 3-formyl-2-
haloesters along with the corresponding diethylacetals as main products. Iodination of 12 with the catalytic system NaI/m-CPBA/
18-crown-6 has also been investigated. © 2002 Elsevier Science Ltd. All rights reserved.
Vicinally substituted donor–acceptor cyclopropanes are
versatile building blocks in organic synthesis.1 Our
group has long been involved in the study of the
reactivity of ethyl 2,2-dimethoxycyclopropanecarboxyl-
ates. In particular, we have recently shown that these
compounds react easily with saturated electrophiles
such as sulfenyl2a and benzeneselenenyl2b chlorides and
with oxidising reagents such as RuO4,3a Pb(OAc)4,3b
and m-CPBA,3c leading to synthetically useful com-
pounds via regioselective ring-opening at the C1ꢀC2
bond.
Scheme 1 depicts the results for cyclopropanes 1a–d. As
shown, C-2 bromosuccinates 2 and C-2 iodoanalogues
3 were the only reaction products except for the brom-
ination of unsubstituted cyclopropane 1a which also led
to the isomeric C-3 bromocompound 4 and, in a minor
amount, to the C-2,C-3-dibromoderivative 5. Note that
almost equimolecular amounts of syn- and anti-2b,c
and 3b,c were formed in the reactions of C-3 monoalkyl-
ated cyclopropanes 1b and 1c.
Since both isomers within the diastereomeric pairs 2b,
2c, 3b, and 3c exhibited the same value of the vicinal
coupling constant, assignment of the configuration of
compounds composing each pair was carried out on the
We now report that ethyl 2,2-dimethoxycyclopropane-
carboxylates 1a–d, and structurally related ethyl 2-
ethoxyanalogues cis- and trans-12, react easily with Br2
and I2 leading, via scission of the reactive C1ꢀC2 bond,
to haloderivatives, generally in good yields.
1
basis of the straightforward comparison of H NMR
spectral data with those exhibited by the corresponding
thio- and seleno-analogues.2 In particular, as reported
for the latter,2 the syn-isomers all show the singlet
resonance due to CO2Me upshifted by about 0.05 ppm
compared with that for the corresponding anti-isomers.
The configuration of compounds composing the pair 2b
was also chemically confirmed by stereoselective con-
version of syn- and anti-2b into anti- and syn-1-ethyl
4-methyl 2-phenylsulphenylbutandioate,2a respectively,
via the well-known5 SN2 reaction with PhSNa in
dioxane.
In a typical experiment, to the cyclopropane (2.5 mmol)
dissolved in CCl4 or CH2Cl2 (1 mL) was added Br2 (2.5
mmol) or a solution of I2 dissolved in the same solvent.
The reaction was complete within a few minutes with
disappearance of the halogen colour. Removal of the
solvent followed by HPLC (hexane/EtOAc, 96:4) gave
pure reaction products.4
Keywords: halogenation; ethyl 2,2-dimethoxycyclopropanecarboxyl-
ates; ethyl 2-ethoxycyclopropanecarboxylates; 2-halosuccinates; 3-for-
myl-2-haloesters; electron transfer.
* Corresponding authors. Tel.: 39-81-674111; fax: 39-81-674393;
e-mail: vinpicci@unina.it
The results obtained for 1a–d might be explained in
terms of the two classical competitive corner and edge
attacks of an electrophile at the cyclopropane ring as
shown in Scheme 2 for trans-1b,c.6 The SE2 corner
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01966-4

8068
V. Piccialli et al. / Tetrahedron Letters 43 (2002) 8067–8070
Scheme 1.
Scheme 2.
attack gives inversion of configuration at the C-1 cen-
tre, delivering the syn-isomer, while the edge mode
proceeds with retention at C-1 and formation of the
anti isomer, via the stabilised cations 6 and 7.
the corner attack is generally predominant,2 and the
direct attack of the halogen, especially of iodine, should
be subject to steric hindrance. An electron transfer (ET)
mechanism appears to be more plausible. In particular,
as depicted in Scheme 3, the transfer of an electron
from the C1ꢀC2 bond of the cyclopropane to the
halogen would generate the well-stabilised cation radi-
cal 8. The radical centre, that is likely to be planar,7
would undergo halogenation from both sides of the
plane, leading to an equimolecular mixture of the C-2
The obtention of almost equal amounts of the syn- and
anti-2b,c and 3b,c could be explained assuming that
both above routes are operating with a very similar
rate. Though in principle possible, this seems to be,
however, not plausible in that for cyclopropanes 1a–d
Scheme 3.

V. Piccialli et al. / Tetrahedron Letters 43 (2002) 8067–8070
8069
Scheme 4.
cal inhibitor,14 did not affect the course of the bromina-
tion, suggesting no radical involvement.
diastereomeric compounds 2 or 3 via 6, 7. It is to be
noted that I2 and mixed halogens such as ICl, may
iodinate activated aromatic compounds via an ET
mechanism,8 and that similar routes have been pro-
posed in the bromination of some bicyclobutanes9a and
bicyclohexane9b derivatives. Moreover, donor-substi-
tuted cyclopropanes can give radical cations.10
The same trend was observed for trans-1c. Interest-
ingly, the unsubstituted cyclopropane 1a did not afford
the C-3 bromoderivative 4 under all three HBr-free
conditions, confirming the role of the acid catalysis in
its formation. Compound 5, instead, was obtained
under all the brominating conditions. Its formation can
be rationalised assuming bromine addition to the
alkene 11 (Scheme 5) formed through HBr loss from
6a, an intermediate species common to all the proposed
mechanistic routes.
The presence of HBr in Br2 could, however, promote a
competitive mechanism for bromination, as shown in
Scheme 4. Thus, compounds 2 would be formed via the
acid-catalysed ring opening to the enols 9 followed by
bromine addition on both faces of the double bond and
MeBr loss. This route also explains the obtention of
almost equimolecular amount of syn- and anti-isomers
2b,c. Support for this path is provided by formation of
4 which should originate from bromine addition to the
alkene 10 in turn derived from the easy acid-catalysed
isomerisation2 of 1a, as shown in Scheme 4.
Bromination and iodination of related ethyl 2-ethoxy-
cyclopropanecarboxylates cis- and trans-12 (Scheme 6)
led to mixtures of the 3-formyl-2-haloesters 13 and the
diethylacetals 14 in addition to variable amounts of the
conjugated product 15 (50–60% total yield).4 The latter
likely derives from 13 by HX loss occurring during the
process or subsequent work-up. Mass balance for this
reaction indicated a loss of material. Attempts to opti-
mise the process by varying the halogen concentration
or using other solvents gave scarcely significative
results. On the assumption that the loss of material
could be due to the volatility of the products, a less
volatile derivative of cis-12 was synthesised from it by
In order to gain further insight into the mechanism of
the above processes, the halogenation of 1a–d was
carried out under different conditions. Table 1 lists the
results obtained for cyclopropane 1b. As shown, iodina-
tion with ICl alone or in the presence of pyridine
(entries 7 and 8), able to trap possible acid traces, gave
results similar to those obtained with I2. On the other
hand, also bromination with Br2 in trimethyl phosphate
(HBr-free bromine)11 (entry 5) afforded the same results
obtained with Br2. These evidence confirm that indeed
an ET mechanism could be operating for both pro-
cesses (Scheme 3). In contrast, the ratio of the
diastereomers dramatically changes from 1/1 to 5/1 or
6/1 using Br2 in the presence of pyridine or NBS,
respectively, (entries 2 and 3). Besides the HBr-trapping
ability, these additives are able, particularly pyridine, to
generate complexes with Br2 which are considered the
effective brominating agents.12 Due to their reduced
redox potential, it is difficult for these complexes to
undergo ET reactions. Therefore, a direct ring attack of
these complexes would occur in a manner similar to
that shown in Scheme 2, with a preference for the
corner mode, which leads to syn-2b. Control experi-
ments showed that the same result was obtained by
using the preformed complex pyridine–bromine (i.e.
pyridinium perbromide).13 Finally, the presence of
2,4,6-tri-tert-butylphenol (TTBP) (entry 4), a free radi-
Table 1. Reactions of cyclopropane 1b under different
halogenating conditions
Entry
Conditiona
Br2
Solventb
Product (%)c
syn/antid
1
2
3
4
5
6
7
8
CCl4
2b (80)
2b (80)
2b (90)
2b (78)
2b (70)
3b (98)
3b (94)
3b (93)
1/1
5/1
6/1
1/1
1/1
1/1
1/1
1/1
e
Py-Br2
CH2Cl2
CH2Cl2
CCl4
e
NBS-Br2
Br2-TTBPf
g
HBr-free Br2 CCl4
I2
CH2Cl2
CH2Cl2
CH2Cl2
ICl
Py-ICle
a Equimolecular amount of halogenating agent.
b 0.2 M solution except for entry 6 (0.02 M).
c Isolated (HPLC) yield.
d Evaluated by 1H NMR.
e 1b:Py (or NBS)=1:1.
f 1b:TTBP=3:1.
g 1 M solution of Br2 in trimethyl phosphate.

8070
V. Piccialli et al. / Tetrahedron Letters 43 (2002) 8067–8070
Scheme 5.
Scheme 6.
References
alkaline hydrolysis (K2CO3/MeOH–H2O (95:5), reflux,
48 h) followed by esterification with tetradecanol (1
equiv.) in the presence of DMAP(cat.)/DCC (1.2 equiv.)
in CH2Cl2. Unfortunately, halogenation of this sub-
stance also gave only a slightly higher mass recovery.
Finally, iodination of cis-12 was carried out using the
catalytic system NaI (5 equiv.)/m-CPBA (2 equiv.)/18-
crown-6 (0.1 equiv.) in CH2Cl2 at rt. Only a modest
5–10% higher mass recovery was obtained in this case
as well, while yields for 13 and 14 appeared to be
essentially unaffected.
1. For a review, see: Reißig, H.-U. Top. Curr. Chem. 1988,
144, 73–135.
2. (a) Graziano, M. L.; Iesce, M. R.; Cermola, F. Synthesis
1999, 1944–1950; (b) Graziano, M. L.; Iesce, M. R.;
Cermola, F.; Caputo, G.; De Lorenzo, F. J. Chem. Soc.,
Perkin Trans. 1 2002, 664–668.
3. (a) Graziano, M. L.; Lasalvia, M.; Piccialli, V.; Sica, D.
Tetrahedron Lett. 1996, 4, 527–530; (b) Graziano, M. L.;
Piccialli, V. Tetrahedron Lett. 1999, 40, 8469–8470; (c)
Piccialli, V.; Graziano, M. L. Tetrahedron Lett. 2001, 42,
93–95.
It is likely that routes similar to those invoked for
compounds 1a–d could be involved in the formation of
halocompounds 13 while it remains an intriguing ques-
tion how could the acetal species 14 be formed. The
presence of two OEt goups at C-3 (acetal function)
suggests that two molecules of cyclopropane are
required for each molecule of 14 to be formed but how
incorporation of the second OEt group in the acetal
function could occur is still unclear.
4. All products gave satisfactory spectral data. Yields are
referred to isolated products (HPLC).
5. Trost, B. M. Chem. Rev. 1978, 78, 363–382 and references
cited therein.
6. (a) Lambert, J. B.; Chelius, E. C.; Schulz, W. J., Jr.;
Carpenter, N. E. J. Am. Chem. Soc. 1990, 112, 3156–3162;
(b) Coxon, J. M.; Steel, P. J.; Wittington, B. I. J. Org.
Chem. 1990, 55, 4136–4144.
7. Curran, D. P.; Porter, N. A.; Giese, B. Stereochemistry of
Radical Reactions; VCH: Weinheim, 1996.
8. (a) Eberson, L.; Hartshorn, M. P.; Radner, F.; Persson, O.
J. Chem. Soc., Perkin Trans. 2 1998, 59–70; (b) Fabbrini,
M.; Galli, C.; Gentili, P.; Macchitella, D.; Petride, H. J.
Chem. Soc., Perkin Trans. 2 2001, 1516–1521.
9. (a) Hoz, S.; Livneh, M.; Cohen, D. J. Am. Chem. Soc. 1987,
109, 5149–5156; (b) Graziano, M. L.; Iesce, M. R.;
Cermola, F.; Ialongo, G. J. Chem. Soc., Perkin Trans. 1
1997, 2155–2160.
In conclusion, the uncatalysed ring-opening of donor–
acceptor cyclopropanes by halogens proceeds at the
C1ꢀC2 bond regio- but not stereoselectively; however,
the stereochemical course of bromination can be
addressed under suitable conditions. The reaction prod-
ucts appear to be prone to further synthetic manipula-
tions that would deserve further attention. It is to be
noted that continuous attention is devoted to bromina-
tion of cyclopropanes;15 while, on the contrary, iodina-
tion has been performed in very few cases and in the
presence of catalysts,16a and has generally been limited
to derivatives where the cyclopropane ring is part of a
highly strained molecular framework.16b
10. Oku, A.; Abe, M.; Iwamoto, M. J. Org. Chem. 1994, 59,
7445–7452 and references cited therein.
11. Pearson, D. E.; Frazer, M. G.; Frazer, V. S.; Washburn,
L. C. Synthesis 1976, 621–623.
12. Heasley, V. L.; Louie, T. J.; Luttrull, D. K.; Millar, M. D.;
Moore, H. B.; Nogales, D. F.; Sauerbrey, A. M.; Shevel,
A. B.; Shibuya, T. Y.; Stanley, M. S.; Shellhamer, D. F.;
Heasley, G. E. J. Org. Chem. 1988, 53, 2199–2204.
13. Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis;
Wiley: New York, 1967; pp. 966–967.
Acknowledgements
14. Dastan, A.; Demir, U.; Balci, M. J. Org. Chem. 1994, 59,
6534–6538.
15. Coxon, J. M.; Smith, W. B. J. Org. Chem. 2000, 65,
2192–2194.
16. (a) Barluenga, J.; Martinez-Gallo, J. M.; Najera, C.; Yus,
M. Synthesis 1987, 582–584; (b) Suits, J. Z.; Applequist, D.
E.; Swart, D. J. J. Org. Chem. 1983, 48, 5120–5123.
We are grateful to MIUR (L488/92 Cluster C-11) for
the use of 500 MHz NMR spectrometer and GC–MS
instruments (Laboratorio INCA, Napoli). Thanks are
also due to the ‘Centro di Metodologie Chimico-Fisiche
dell’Universita` di Napoli Federico II’ for NMR
facilities.