Stereoselective ultrasonically induced reductive monosilylation of geminal dibromonorcaranes. Steric effects

Article abstract of DOI:10.1016/S0022-328X(99)00146-1

Sonochemical reductive silylation of 1-R-7,7-dibromonorcaranes (R=H, Me, Et, i-Pr) by magnesium produces in each case two 7-bromo-7-trialkylsilylnorcaranes (alkyl=methyl or ethyl). The major isomer is exo (the trialkylsilyl group is cis to the R substituent), but the stereoselectivity of silylation decreases as the alkyl group size at C-1 increases. 1-Phenyl-7,7-dibromonorcarane produced a mixture of phenylcycloheptadienes and monobromonorcaranes.

Full text of DOI:10.1016/S0022-328X(99)00146-1

www.elsevier.nl/locate/jorganchem
Journal of Organometallic Chemistry 584 (1999) 230–234
Stereoselective ultrasonically induced reductive monosilylation of
geminal dibromonorcaranes. Steric effects
Brian C. Raimundo a, Albert J. Fry b,*
a Tularik Incorporated, 2 Corporate Dri6e, South San Francisco, CA, 94080, USA
b Department of Chemistry, Wesleyan Uni6ersity, Middletown, CT 06459, USA
Received 7 December 1998
Abstract
Sonochemical reductive silylation of 1-R-7,7-dibromonorcaranes (R=H, Me, Et, i-Pr) by magnesium produces in each case
two 7-bromo-7-trialkylsilylnorcaranes (alkyl=methyl or ethyl). The major isomer is exo (the trialkylsilyl group is cis to the R
substituent), but the stereoselectivity of silylation decreases as the alkyl group size at C-1 increases. 1-Phenyl-7,7-dibromonor-
carane produced a mixture of phenylcycloheptadienes and monobromonorcaranes. © 1999 Elsevier Science S.A. All rights
reserved.
Keywords: Grignard; Magnesium; Norcarane; Silylation; Silylcyclopropane; Ultrasound
addition of TMS–Cl, had previously been shown to
afford the complementary endo-trimethylsilyl isomer 3.
[13]
1. Introduction
Halocyclopropanes are useful synthetic intermediates
[1–6] and have a long-established use as substrates for
testing the stereochemical features of reaction mecha-
nisms [7–9]. Recently silylcyclopropanes have emerged
as versatile synthetic intermediates [10], particularly
since many of their reactions occur with strictly defined
stereochemistry [7–9,11]. A synthetic route to 1-halo-1-
trialkylsilylcyclopropanes, incorporating both halogen
and silane functionalities, would be of interest, but only
if it proceeded in such a way as to place the two groups
in well defined stereochemical relationship to other
groups on the cyclopropane ring. In a recent study of
the electrochemical reduction of several dibromocyclo-
propanes (1) in the presence of trimethylchlorosilane
(TMS–Cl), we found that the substances 1 are con-
verted to bromotrimethylsilylcyclopropanes (2 and 3) in
fair-to-good yields (Scheme 1) [12]. The reactions were
found to proceed with modest stereoselectivity. The
major stereoisomer in the electrochemical reaction was
found to be that in which the silyl group is in the
exo-position (2), whereas a sequence involving metalla-
tion of the dihalide at low temperature, followed by
This discovery was potentially useful in its own right.
However, our interest was piqued by the incidental
observation in the course of that study that dihalides 1
react readily with magnesium and trimethylchlorosilane
(TMS–Cl) in a non-electrochemical reaction if the reac-
tion vessel is subjected to ultrasonic irradiation during
reaction. [14–16] The regioselectivity of the sonochemi-
cal reaction appeared to be superior to the electrochem-
ical process [12]. The present study was carried out to
further define the stereochemical course of the sono-
chemical reaction and to examine methods for improv-
ing its stereoselectivity.
2. Results and discussion
The 1-substituted-7,7-dibromonorcaranes (4a–e),
prepared by addition of dibromocarbene to the corre-
sponding cyclohexene [16], were chosen because they
present an increasing degree of steric hindrance in the
vicinity of the reaction site. A mixture of the dibromide
and 1.2 molar equivalents of chlorotrimethylsilane (5a)
was sonicated in dry THF containing a slight excess of
* Corresponding author.
0022-328X/99/$ - see front matter © 1999 Elsevier Science S.A. All rights reserved.
PII: S0022-328X(99)00146-1

B.C. Raimundo, A.J. Fry / Journal of Organometallic Chemistry 584 (1999) 230–234
231
a sufficient quantity could be isolated) was isolated by
preparative GC for subsequent spectral analysis. Dibro-
mides 4a and 4b were also reacted with triethylchlorosi-
lane (5b) to afford the corresponding bromotrialkyl-
silylcyclopropanes 10 and 11. Reduction of 1-phenyl-
7,7-dibromonorcarane (4e) under the usual silylation
conditions afforded neither 6 nor 7. Instead, a mixture
of four compounds consisting of dienes (12 [20] and 13
[21]) and two stereoisomeric monobromides (9e) was
produced. The (inseparable) mixture of 12 and 13 was
isolated by preparative GC and identified by mass and
1H-NMR spectroscopy (four multiplets in the region d
5.9, 6.1, 6.2 and 6.4, four multiplets at 2.1, 2.4, 2.5 and
2.8, and an aromatic multiplet from 7.2 to 7.5).
Scheme 1.
magnesium powder. Although longer irradiation was
sometimes necessary, most reactions were complete in
0.5–3 h at 25°C (Scheme 2). Sonication is known to
accelerate the reaction between alkyl halides and metals
[14,15,17]. In control experiments, we found that only a
few percent of the dihalide is consumed after several
days when the suspension is stirred magnetically,
whereas the dihalide is usually completely consumed
within hours when the reaction vessel is immersed in an
ultrasonic bath. Exact placement of the reaction flask
within the ultrasonic bath is important to obtain repro-
ducible results [12,18,19]. The bromosilanes 6 and 7
constitute the principal products from 4a–d under these
conditions; significantly for possible synthetic applica-
tions, little disilyl compound 8 is produced. This was of
course insured by the use of less than two equivalents
of magnesium, but in point of fact, monobromides 6
and 7 react with magnesium much more slowly than do
the starting dibromides 4 [12]. Small amounts of the
corresponding monobromonorcaranes (9) were also
formed in each reaction (Table 1). After analysis of the
mixture by gas chromatography (GC) and work-up, the
major bromosilyl product (and the minor isomer when
2.1. NMR measurements
The dibromocyclopropanes and the major bromosi-
lane isomer from each sonochemical reaction were sub-
jected to careful analysis by a number of NMR
techniques. The stereochemistry of the trialkylsilyl
group was assigned as follows. Proton spin–lattice (T1)
relaxation times were first measured by the inversion-re-
covery method [22]. The bridgehead cyclopropyl pro-
ton(s) could be assigned because they have the largest
T1 of any protons in the molecule as a consequence of
the rigidity of the cyclopropane ring. Spin decoupling
experiments and the chemical shift of the cyclopropyl
proton (at ca. l 1 in the exo-trimethylsilyl isomers 6
and ca. l 1.9 in the exo-bromo isomers 7) supported
the T1 assignments. Nuclear Overhauser enhancement
(n.o.e.) experiments were then carried out, irradiating
the trialkylsilyl protons. Exo-trimethylsilyl compounds
6 exhibit a n.o.e. of the cyclopropyl bridge proton and
the bridgehead alkyl group; endo-trimethylsilyl com-
pounds 7 exhibit enhancement of two or more of the
cyclohexyl ring resonances (those protons syn to the
Scheme 2.

232
B.C. Raimundo, A.J. Fry / Journal of Organometallic Chemistry 584 (1999) 230–234
Table 1
Product composition from the sonochemical reduction of geminal dibromocyclopropanes bymagnesium in the presence of chlorotrimethylsilane
Run Dibromide Silylating agent Unreacted
dibromide, 4 (%)
Product mixture composition (%)
Bromosilanes 6 plus 7 or 10 plus 11 (%)
(exo:endo ratio)
Disilane, 8 (%) Monobromide 9
(%)
1
2
3
4
5
6
4a
4a
4b
4b
4c
4d
5a
5b
5a
5b
5a
5a
22
20
9
15
17
5
61 (94:6)
66 (87:13)
73 (91:9)
75 (89:11)
78 (81:19)
85 (68:32)
B1
0
0
1
0
17
14
10
10
5
1
9
magnesium species (13), formed by reduction of the
radical, may invert more or less rapidly; this is sug-
gested by run c2, in which the exo:endo stereoselectiv-
ity increases as the steric bulk of the silyl halide
increases. A bulky silane is less likely to react from the
endo face of 13. By the same token, increased steric
bulk on the exo face of 13 as the size of the R group
increases will favor silylation from the endo direction.
trialkylsilyl group) [12]. Our assignments substantiate
an earlier postulate [13] that exo-trimethylsilyl protons
resonate at higher field than do those of the endo
isomer.
Sonochemical reductive silylation clearly comple-
ments the two-step metallation–silylation sequence [13]
for synthesis of 7-bromo-7-silylnorcaranes, since the
latter reaction produces the endo-silyl isomer as the
major product (Scheme 1), whereas the exo-silyl isomer
is the predominant product from the sonochemical
reaction. The sonochemical reaction is carried out at
room temperature, proceeds in fair-to-good yields, and
shows little or no tendency to proceed further to the
corresponding disilyl compound. On the other hand,
the tendency to form the exo-silyl isomer 6 decreases as
the size of the bridgehead alkyl group increases.
There is general agreement that the reaction of alkyl
halides with magnesium involves transient radicals
which are coordinated to magnesium and more or less
quickly reduced to carbanions [23–26]. Our results
require that at least one intermediate in the overall
process be capable of losing its stereochemical configu-
ration. Cyclopropyl radicals are generally believed to
invert relatively rapidly [7,27,28]. Cyclopropyl carban-
ions and the corresponding lithium compounds have
been traditionally understood to maintain their stereo-
chemical configuration [29,30] However, 7-lithio-7-
bromonorcaranes, although configurationally stable at
−78°C, lose configuration at temperatures closer to
room temperature [9,31]. It is likely that the first step in
the sonochemical reaction of dibromides 4 with magne-
sium is a single electron transfer to form a rapidly
interconverting bromocyclopropyl radical (12). It is not
possible therefore to determine whether the two
bromine atoms of 4 are attacked selectively or with
more or less equal facility. However, we showed earlier
that electron transfer from an electrode surface occurs
preferentially to the more sterically accessible halogen
of a bicyclic geminal halide [32]. We favor a similar
interpretation here, i.e. that the more readily accessible
exo bromine atom of 4 is more reactive. The organo-
(3)
The initially formed bromonorcarane radicals 12 ap-
parently have a finite lifetime under our conditions,
since bromides presumably 9 arise by hydrogen abstrac-
tion by 12 from the solvent THF, a good hydrogen
atom donor [33,34]. Our recent study of electrochemical
reductive silylations [12] showed that such monobro-
mides are formed even in scrupulously dried solvents,
so it is unlikely that they arise by protonation of a
carbanion or Grignard species 13. The conversion of
1-phenyl-7,7-dibromonorcarane (4e) to dienes 10 and
11 provides further evidence for radical intermediates in
these reactions. We propose that these dienes arise by
intramolecular hydrogen atom abstraction and subse-
quent ring opening (Scheme 3). Conversion of rear-
ranged radicals 14 and 15 to 10 and 11 could proceed
by loss of bromine atom or by reduction to a carbanion
by magnesium, followed by loss of bromide ion.
3. Experimental
1H-NMR spectra were measured at 400 MHz in
CDCl3 on a Varian XL-400 spectrometer. GC-MS spec-
trometry was carried out using a Hewlett–Packard
5890/59988A GC-MS. Preparative GC was carried out
on a Varian model 3300 GC using a 2×1/8%% 5%
OV-101 on Chromosorb GHP column.

B.C. Raimundo, A.J. Fry / Journal of Organometallic Chemistry 584 (1999) 230–234
233
up as above when bromosilane formation was com-
plete. The major product was isolated by preparative
GC and analyzed by GC-MS and 1H-NMR spec-
troscopy. Bromosilanes 6a and 7a have been described
previously 12. Structures of minor products were as-
signed from their mass spectra.
3.5. exo-7-Trimethylsilyl-endo-7-bromonorcarane (6a)
1H-NMR (CDCl3): l 0.03 (s, 9H), 1.0 (m, 2H), 1.23
(m, 2H), 1.4 (m, 2H), 1.5 (m, 2H), 2.0 (m, 2H). MS
m/e: 248, 246 [M+], 206, 204, 139, 137 (100), 93.
Scheme 3.
3.1. General procedure for synthesis of
dibromocyclopropanes
3.6. endo-7-Trimethylsilyl-exo-7-bromonorcarane (7a)
A slurry of alkene and three to five equivalents of
potassium t-butoxide was cooled in an ice bath. Three
equivalents of bromoform were added drop-wise and
the mixture was allowed to stir; total addition plus
stirring time ranged from 4 to 7 h. Distilled water was
then added. The aqueous layer was extracted with
hexane; the organic layer was washed with water. The
combined organic layers were dried over MgSO4, sol-
vent was evaporated, and the dibromide purified by
fractional distillation. Dibromocyclopropanes 4a [12],
4b [35], 4d [36] and 4e [20] are known compounds.
1H-NMR (CDCl3): l 0.25 (s, 9H), 1.2 (m, 4H), 1.45
(m, 2H), 1.7 (m, 2H), 1.9 (m, 2H). MS m/e: 248, 246
[M+], 233, 231, 139, 137 (100), 93.
3.7. exo-7-Trimethylsilyl-endo-7-bromo-1-
methylnorcarane (6b)
1H-NMR (CDCl3): l 0.17 (s, 9H), 0.96 (dd, 1H), 1.2
(s, 3H), 1.26 (m, 2H), 1.46 (m, 3H), 1.66 (m, 1H), 1.84
(m, 1H), 2.00 (m, 1H). MS m/e: 262, 260 [M+], 139,
137, 107, 93, 91, 73 (100).
3.2. 1-Ethyl-7,7-dibromonorcarane (4c)
3.8. exo-7-Trimethylsilyl-endo-7-bromo-1-
ethylnorcarane (6c)
1
B.p. 71–73°C/0.2 mm. H-NMR (CDCl3): l 1.08 (t,
3H), 1.46 (dd, 1H), and 1.16–2.01 (m, 10H). MS m/e:
284, 282, 280 [M+], 255, 253, 251 (100), 203, 201, 121.
1H-NMR (CDCl3): l 0.2 (s, 9H), 0.94 (t, 3H), 1.14–
1.6 (m, 9H), 1.76 (t, 1H), 2.0 (m, 1H). MS m/e: 276,
274 [M+], 248, 246, 139, 137, 107, 93, 91, 73 (100).
3.3. 1-Phenyl-7,7-dibromonorcarane20 (4e)
3.9. exo-7-Trimethylsilyl-endo-7-bromo-1-
isopropylnorcarane (6d)
Spectral data appear not to have been reported in the
literature for this compound. B.p. 118°C/0.1 mm. H-
1
NMR (CDCl3): l 1.35 (m, 4H), 1.55 (m, 2H), 1.8 (m,
1H), 2.1–2.3 (m, 2H), 7.3 (m, 4 H), and 7.4 (t, 1H). MS
m/e: 251 (63), 249 (63) [M+ −Br], 169 (100), 141 (81),
91 (45).
1H-NMR (CDCl3): l 0.22 (s, 9H), 0.92 (dd, 1H), 0.96
(d, 3H), 0.97 (d, 3H), 1.2 (m, 2H), 1.4–1.6 (m, 5H),
1.89 (m, 1H), 2.02 (m, 1H). MS m/e: 290, 288 [M+],
247, 245, 139, 137, 93, 91, 73 (100).
3.4. Representati6e procedure for sonochemical
reducti6e silylation
3.10. exo-7-Triethylsilyl-endo-7-bromo-norcarane (10a)
1H-NMR (CDCl3): l 0.6 (q, 6H), 0.97 (t, 9H), 1.05
(dd, 2H), 1.26 (m, 2H), 1.41 (m, 2H), 1.55 (m, 2H), 2.0
(m, 2H). MS m/e: 290, 288 [M+], 233, 231, 167 (100),
165 (100), 139, 137, 93, 91.
Dry THF (25 ml), magnesium powder (0.100 g, 4.1
mmol) dibromide 4a (0.97 g, 3.8 mmol), and chlorosi-
lane 5a (0.51 g, 4.7 mmol) were added to a large
flame-dried test tube which was then sealed with a
rubber septum and flushed with nitrogen. The opaque
gray suspension was immersed in a water-filled Bran-
sonic 2200 ultrasonic bath and sonicated for 3 h, after
which it was a clear yellow solution. Samples were
removed periodically, quenched with aqueous
NaHCO3, extracted with ether and dried. The ether
extract was analyzed by GC. The mixture was worked
3.11. exo-7-Triethylsilyl-endo-7-bromo-1-
methylnorcarane (10b)
1H-NMR (CDCl3): l 0.67 (q, 6H), 0.97 (t, 9H),1.16
(s, 3H), 1.0–2.3 (m, 9 H). MS m/e: 275, 273, 167, 165
(100), 139, 137, 107, 93, 79.

234
B.C. Raimundo, A.J. Fry / Journal of Organometallic Chemistry 584 (1999) 230–234
[16] H.D. Durst, G.W. Gokel, Experimental Organic Chemistry,
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