Kinetics and regioselectivity of ring opening of 1-bicyclo[3.1.0] hexanylmethyl radical

Article abstract of DOI:10.1021/jo702010v

(Chemical Equation Presented) Rate constants for the rearrangement of 1-bicyclo[3.1.0]-hexanylmethyl radical (2) to 3-methylenecyclohexenyl radical (3) and 2-methylenecyclopentyl-1-methyl radical (1) were measured using the PTOC-thiol competition method. The ring-expansion pathway is described by the rate equation, log(k/s^-1) = (12.5 ± 0.1) - (4.9 ± 0.1)/θ; the non-expansion pathway is described by log(k/s^-1) = (11.9 ± 0.6) - (6.9 ± 0.8)/θ. Employing the slower trapping agent, tri-n-butylstannane, favors methylenecyclohexane over 2-methyl-methylenecyclopentane by more than 120:1 at ambient or lower temperatures.

Full text of DOI:10.1021/jo702010v

Fragmentation of the cyclopropylcarbinyl radical system is
of particular interest and has been thoroughly studied by many
groups. The prototype system holds a prominent place in radical
kinetic investigations and has been accurately characterized3
across a temperature range spanning more than 250 °C with a
fragmentation rate of 9.4 × 107 s-1 at 298 K. A wide breadth
of substituted derivatives has also been studied and has provided
much insight into the influence of substitution, resonance, and
stereoelectronic effects.4 Unsymmetrically substituted derivatives
have a bifurcated reaction pathway available and permit rate
comparisons between the two modes of fragmentation. Some
aryl-substituted analogues have been shown4d,5 to be exception-
ally fast with unimolecular fragmentation rates exceeding 1011
Kinetics and Regioselectivity of Ring Opening of
1-Bicyclo[3.1.0]hexanylmethyl Radical
Eric J. Kantorowski,* Daniel D. Le, Caleb J. Hunt,
Keegan Q. Barry-Holson, Jessica P. Lee, and
Lauren N. Ross
Department of Chemistry and Biochemistry, California
Polytechnic State UniVersity, San Luis Obispo, California 93407
ekantoro@calpoly.edu
ReceiVed September 12, 2007
s-1
.
An accurate study of fragmentation rates has necessitated the
use of a variety of techniques. These include, for example, the
use of spectroscopy (e.g., ESR), competition methods employing
a reducing agent (e.g., Bu3SnH, PhSH, PhSeH), and laser flash
photolysis. Of these, stannane and thiol reagents have been
useful as indirect methods for probing a wide range of radical
reactions. More recently, laser flash photolysis and the use of
PhSeH have proven useful for the upper end of the time scale
(>1011 s-1).6 Accurate rate expressions for the reaction of these
reducing agents with carbon-centered radicals have been
established and cross-calibrated with each other using several
radical reactions.3a,4g,7
In the present study, the effect of angularly fusing a
cyclopentyl ring onto the cyclopropylcarbinyl radical moiety
was investigated (Scheme 1). The unsymmetrically substituted
strained ring system gives rise to two fragmentation pathways.
Fission along the shared (endo) bond of the bicyclic structure
(2) realizes a ring-expansion event, providing methylenecyclo-
hexane (6) after reduction. Alternatively, fission of the bond
exo to the cyclopentyl group leads to 2-methyl-methylenecy-
clopentane (4).
Rate constants for the rearrangement of 1-bicyclo[3.1.0]-
hexanylmethyl radical (2) to 3-methylenecyclohexenyl radi-
cal (3) and 2-methylenecyclopentyl-1-methyl radical (1) were
measured using the PTOC-thiol competition method. The
ring-expansion pathway is described by the rate equation,
log(k/s-1) ) (12.5 ( 0.1) - (4.9 ( 0.1)/θ; the non-expansion
pathway is described by log(k/s-1) ) (11.9 ( 0.6) - (6.9 (
0.8)/θ. Employing the slower trapping agent, tri-n-butylstan-
nane, favors methylenecyclohexane over 2-methyl-methyl-
enecyclopentane by more than 120:1 at ambient or lower
temperatures.
Carbon-centered radicals have become valuable players in
synthetic strategy. This is due in no small part to the growing
catalogue of kinetic data available on a wide variety of radical
reactions. This information is especially critical in cases where
tandem events are planned.1 Additionally, radicals have proven
highly useful for annulations, intermolecular additions, realizing
quaternary centers, ring expansions, and combinations thereof.2
Their tolerance of a wide range of functional groups also permits
radicals to be utilized without the need to incorporate protecting
groups throughout other portions of a molecule.
The cyclopropylcarbinyl radical 2 framework played an early
role in demonstrating the importance that stereoelectronic factors
(3) (a) Newcomb, M.; Glenn, A. G. J. Am. Chem. Soc. 1989, 111, 275.
(b) Beckwith, A. L. J.; Bowry, V. W.; Moad, G. J. Org. Chem. 1988, 53,
1632. (c) Mathew, L.; Warkentin, J. J. Am. Chem. Soc. 1986, 108, 7981.
(d) Beckwith, A. L. J.; Moad, G. J. Chem. Soc., Perkin Trans. 2 1980,
1473. (e) Kinney, R. J.; Jones, W. D.; Bergman, R. G. J. Am. Chem. Soc.
1978, 100, 7902. (f) Maillard, B.; Forrest, D.; Ingold, K. U. J. Am. Chem.
Soc. 1976, 98, 7024.
(4) (a) Takekawa, Y.; Shishido, K. J. Org. Chem. 2001, 66, 8490. (b)
Lee, P. H.; Lee, B.; Lee, J.; Park, S. K. Tetrahedron Lett. 1999, 40, 3427.
(c) Kantorowski, E. J.; Eisenberg, S. W. E.; Fink, W. H.; Kurth, M. J. J.
Org. Chem. 1999, 64, 570. (d) Choi, S.-Y.; Newcomb, M. Tetrahedron
1995, 51, 657. (e) Batey, R. A.; Grice, P.; Harling, J. D.; Motherwell, W.
B.; Rzepa, H. S. J. Chem. Soc., Chem. Commun. 1992, 942. (f) Bowry, V.
W.; Lusztyk, J.; Ingold, K. U. J. Am. Chem. Soc. 1991, 113, 5687. (g)
Newcomb, M.; Glenn, A. G.; Williams, W. G. J. Org. Chem. 1989, 54,
2675. (h) Beckwith, A. L. J.; Phillipou, G. Chem. Commun. 1971, 658. (i)
Cristol, S. J.; Barbour, R. V. J. Am. Chem. Soc. 1968, 90, 2832.
(5) (a) Choi, S.-Y.; Toy, P. H.; Newcomb, M. J. Org. Chem. 1998, 63,
8609. (b) Martin-Esker, A. A.; Johnson, C. C.; Horner, J. H.; Newcomb,
M. J. Am. Chem. Soc. 1994, 116, 9174. (c) Newcomb, M.; Johnson, C. C.;
Manek, M. B.; Varick, T. R. J. Am. Chem. Soc. 1992, 114, 10915.
(6) (a) Newcomb, M.; Choi, S.-Y.; Horner, J. H. J. Org. Chem. 1999,
64, 1225. (b) Horner, J. H.; Tanaka, N.; Newcomb, M. J. Am. Chem. Soc.
1998, 120, 10379.
(1) (a) Booker-Milburn, K. I.; Jenkins, H.; Charmant, J. P. H.; Mohr, P.
Org. Lett. 2003, 5, 3309. (b) Zhou, S.; Bommezizijn, S.; Murphy, J. A.
Org. Lett. 2002, 4, 443. (c) Njardarson, J. T.; McDonald, I. M.; Spiegel, D.
A.; Inoue, M.; Wood, J. L. Org. Lett. 2001, 3, 2435. (d) Lee, H.-Y.; Kim,
B. G. Org. Lett. 2000, 2, 1951. (e) Zoretic, P. A.; Fang, H. J. Org. Chem.
1998, 63, 7213. (f) Parker, K. A.; Fokas, D. J. Am. Chem. Soc. 1992, 114,
9688. (g) Curran, D. P.; Rakiewicz, D. M. J. Am. Chem. Soc. 1985, 107,
1448.
(2) (a) Banwell, M. G.; Kokas, O. J.; Willis, A. C. Org. Lett. 2007, 9,
3503. (b) Ru¨edi, G.; Hansen, H.-J. Tetrahedron Lett. 2004, 45, 5143. (c)
Ogawa, A.; Ogawa, I.; Sonoda, N. J. Org. Chem. 2000, 65, 7682. (d) Ziegler,
F. E.; Petersen, A. K. Tetrahedron Lett. 1996, 37, 809. (e) Boto, A.;
Betancor, C.; Sua´rez, E. Tetrahedron Lett. 1994, 35, 5509. (f) Clive, D. L.
J.; Daigneault, S. J. Org. Chem. 1991, 56, 3801. (g) Dowd, P.; Zhang, W.
J. Am. Chem. Soc. 1991, 113, 9875. (h) Boger, D. L.; Mathvink, R. J. J.
Org. Chem. 1990, 55, 5442. (i) Feldman, K. S.; Romanelli, A. L.; Ruckle,
R. E., Jr.; Miller, R. F. J. Am. Chem. Soc. 1988, 110, 3300. (j) Harling, J.
D.; Motherwell, W. B. J. Chem. Soc., Chem. Commun. 1988, 1380.
(7) (a) Newcomb, M.; Varick, T. R.; Ha, C.; Manek, M. B.; Yue, X. J.
Am. Chem. Soc. 1992, 114, 8158. (b) Beckwith, A. L. J.; Bowry, V. W. J.
Org. Chem. 1989, 54, 2681.
10.1021/jo702010v CCC: $40.75 © 2008 American Chemical Society
Published on Web 01/16/2008
J. Org. Chem. 2008, 73, 1593-1596
1593

SCHEME 1
SCHEME 2. Preparation of Radical Precursor 11
impart on the direction of radical fragmentation. However, in
these examinations it was invariably an embedded portion of a
larger structure (e.g., A-norsteroid derivatives) that conforma-
tionally restricted the orientation of the radical. When liberated
from such larger structures, radical 2 is not subject to the same
rotational restriction, promoting other criteria such as radical
stability and ring strain to greater importance.
TABLE 1. Product Distribution and Rate Constants from
Reduction of 11 with PhSH
relative % yield
T (°C)
[PhSH]m
4
5
6
log k21
log k23
48
35
23
19
19
10
1
-42
-79
0.89
0.89
0.89
0.46
1.62
0.89
0.89
0.89
0.89
1.00
0.83
0.70
0.37
0.51
0.31
0.32
0.21
0.00
6.00
9.29
10.40
5.37
17.62
15.14
14.91
32.82
66.53
93.00
89.88
88.89
94.26
81.88
84.54
84.77
66.97
33.47
7.38
7.06
6.89
6.60
6.77
6.32
6.29
5.51
--
9.24
8.99
8.88
8.90
8.87
8.64
8.61
7.91
6.99
Radical 2 has also appeared as an intermediate in several
rearrangements both as the prototype and substituted derivatives.
Beckwith8 and Stork9 independently studied 5-exo-trig ring
closures of vinyl radicals and noted that 2 was a likely
intermediate en route to the methylenecyclohexane derivative.
The kinetics of the fragmentations were not explored in these
studies. However, the rate of formation of 3 from 1 was
established in Beckwith’s study and pointed to the six-membered
ring as the thermodynamically more stable intermediate in this
reaction manifold. More evidence in support of this was found
by Kilburn who generated several analogues of 2 by a 5-exo-
trig ring closure of a substituted methylenecyclopropyl propyl
radical.10 A ring-expansion event followed (cf., 2 f 3) leading
invariably to substantial yields of the corresponding cyclohexyl
derivatives. More recently, a molecular modeling study correctly
predicted 3 as the kinetically favored intermediate.11 A closely
related unsaturated analogue of 2 has also been invoked in the
biogenesis of the expanded and aromatized D-ring of the nic-1
antifeedant steroid.12 Our present investigation firmly establishes
the rates of these fragmentation pathways and identifies radical
3 as thermodynamically and kinetically favored.13
ethanolic KOH afforded carboxylic acid 10. The carboxylic acid
was converted to PTOC ester radical precursor16 11 with
2-mercaptopyridine-N-oxide and dicyclohexylcarbodiimide.
The competition method using PhSH was employed to
establish fragmentation rates of 2.17 A stock 0.02 M solution
of PTOC 11 in THF was used for all kinetic runs. Thiophenol
was used in >10 equiv to apply steady-state conditions. The
rate of reduction of primary alkyl radicals 1 and 2 by thiophenol
was taken to be equal to the rate of reduction of n-butyl radical
by thiophenol (log kH(prim)/(M-1 s-1) ) 9.41 - 1.74/θ, where θ
) 2.303RT in kcal/mol); the rate of reduction of secondary alkyl
radical 3 by thiophenol was taken to be equal to the rate of
reduction of isopropyl radical by thiophenol (log kH(sec)/(M-1
s-1) ) 9.26 - 1.70/θ).18 As the rate of reduction of alkyl radicals
by PhSH is largely unaffected by the structure of the radical,
the use of these rate functions is sound.19 The product distribu-
tion for hydrocarbon products 4-6 using thiophenol is shown
in Table 1. The rate for rearrangement of 2 f 1 is shown in eq
1; the rate for rearrangement of 2 f 3 is shown in eq 2. Here,
[PhSH]m represents the average thiophenol concentration over
the course of the reaction, and 4/5 and 6/5 represent the ratio
of hydrocarbon products as determined by GC. Analysis across
a temperature range of -79 to -48 °C provided Arrhenius
functions for the two fragmentation pathways (Figure 1).
The preparation of the radical precursor 11 is shown in
Scheme 2. Subjecting cyclopentanone to Wadsworth-Em-
mons14 conditions (triethylphosphonoacetate, NaH) resulted in
exclusive formation of R,â-unsaturated ester 7. The desired â,γ-
unsaturated ester (8) could be obtained by generation of the
extended enolate (LDA, THF) followed by kinetic trapping
(NH4Cl, -78 °C).4c Cyclopropanation15 with diethyl zinc and
diiodomethane and subsequent saponification with 1.0 M
(8) Beckwith, A. L. J.; O’Shea, D. M. Tetrahedron Lett. 1986, 27, 4525.
(9) Stork, G.; Mook, R., Jr. Tetrahedron Lett. 1986, 27, 4529.
(10) (a) Destabel, C.; Kilburn, J. D.; Knight, J. Tetrahedron Lett. 1993,
34, 3151. (b) Destabel, C.; Kilburn, J. D. J. Chem. Soc., Chem. Commun.
1992, 596.
(11) Ardura, D.; Sordo, T. L. J. Org. Chem. 2006, 71, 4803.
(12) Green, S. P.; Whiting, D. A. J. Chem. Soc., Chem. Commun. 1992,
1754.
k21 ) kH(prim)[PhSH]m4/5
k23 ) kH(sec)[PhSH]m6/5
(1)
(2)
(13) When a cyclopentanone derivative of this system was studied, with
the carbonyl adjacent to the cyclopropane ring, it was observed that the
fragmentation preferentially occurs along the exo bond. However, when
the corresponding alcohol was employed, the endo bond fragmentation
dominates and appears to be the kinetically favored route. Ziegler, F. E.;
Petersen, A. K. Tetrahedron Lett. 1996, 37, 809.
(16) Barton, D. H. R.; Crich, D.; Motherwell, W. B. Tetrahedron 1985,
41, 3901.
(17) For a discussion of application of the competition method to probe
the kinetics of the cyclopropylcarbinyl radical and related systems, see:
Newcomb, M. Tetrahedron 1993, 49, 1151.
(18) Franz, J. A.; Bushaw, B. A.; Alnajjar, M. S. J. Am. Chem. Soc.
1989, 111, 268.
(14) Wadsworth, W. S., Jr.; Emmons, W. D. Organic Syntheses; Wiley:
New York, 1963; Collect. Vol. V, p 547.
(15) Takahashi, H.; Yoshioka, M.; Ohno, M.; Kobayashi, S. Tetrahedron
Lett. 1992, 33, 2575.
(19) For a commentary on the reaction rate between PhSH and cyclo-
propylcarbinyl radical see footnote 12 in ref 3a.
1594 J. Org. Chem., Vol. 73, No. 4, 2008

TABLE 2. Product Distribution from Reduction of 11 with
Bu3SnH
T (°C)
[Bu3SnH]m
6/4
T (°C)
[Bu3SnH]m
6/4
50
50
50
19
19
19
0
0.19
0.44
0.66
0.19
0.44
0.66
0.19
0.44
115.6
89.8
93.4
126.7
123.4
124.8
132.4
139.7
0
-41
-41
-41
-78
-78
-78
0.66
0.19
0.44
0.66
0.19
0.44
0.66
144.5
136.4
142.8
162.4
148.0
167.4
189.6
0
FIGURE 1. Arrhenius functions for fragmentation of radical 2 f 1
(∆) and 2 f 3 (O).
From the Arrhenius analysis, fragmentation of the endo bond
leading to ring-expansion (2 f 3) is described by the rate
equation, log(k23/s-1) ) (12.5 ( 0.1) - (4.9 ( 0.1)/θ; the exo
fragmentation leading to non-expansion (2 f 1) is described
by, log(k21/s-1) ) (11.9 ( 0.6) - (6.9 ( 0.8)/θ. At 298 K, the
unimolecular ring-expansion pathway proceeds at a rate of 8.4
× 108 s-1. This rate is surprisingly fast considering that, other
than incipient secondary radical character, 2 is not equipped
with substituents known to enhance the fragmentation rate (e.g.,
carbonyl or aromatic groups). At 298 K, the nonexpansion
pathway (k21) occurs at a rate of 6.9 × 106 s-1. Hence, at 298
K, fission along the shared bond occurs 120 times faster than
along the exo bond.
The ∆Sq term is negative for both fragmentation events.
Cyclopropyl ring opening along the endo bond (∆Sq ) -3.3
eu) or the exo bond (∆Sq ) -6.1 eu) necessitates that ordering
occurs within the system. This can be understood in terms of
the requirement of the methyl radical rotor to align with one of
the σ bonds of the cyclopropyl ring and ultimately become
locked in the nascent methylene unit.
FIGURE 2. Product ratio of 6 to 4 using Bu3SnH.
fies 3 as the thermodynamically favored intermediate (Figure
2). At low temperatures and high concentrations of reducing
agent the pathway leading to radical 3 is further implicated as
kinetically favored in agreement with the Arrhenius analysis.
At elevated temperatures, it is observed that a greater amount
of radical 1 is accessible, although still inferior to the amount
of 3.21 The large disparity between activation energies (6.9 vs
4.9 kcal/mol) for the two pathways makes the equilibrium more
sensitive to temperature changes as reflected in Figure 2.
The behavior of radical 2 was also examined at several
temperatures and concentrations of stannane reducing agent. The
rate at which n-Bu3SnH is able to reduce simple alkyl radicals
(kH, Scheme 1) is significantly slower than for that of PhSH
(∼106 M-1 s-1 vs 108 M-1 s-1) and should therefore permit
identification of the thermodynamic product. The rate of
reduction of primary alkyl radicals 1 and 2 and secondary radical
3 by tri-n-butyltin hydride was taken to be equal to the rate of
reduction of n-butyl radical (log kH(prim)/(M-1 s-1) ) 9.06 -
3.65/θ) and cyclohexyl radical (log kH(sec)/(M-1 s-1) ) 9.24 -
3.97/θ) by tri-n-butyltin hydride, respectively.20 For all runs, 4
and 6 are the only hydrocarbon products observed under these
conditions with no evidence of unopened cyclopropyl 5 even
at -78 °C.
Beckwith established the rate expression for 1 f 3 as part
of his study of vinyl radical ring closures.8 Direct generation
of 1 from the corresponding bromide provided log(k/s-1) ) (10.9
( 0.4) - (8.7 ( 0.9)/θ.22 Thus at 298 K, formation of 3 from
1 occurs at 3.3 × 104 s-1. From the stannane data in the present
study, the rate of the reverse reaction is therefore estimated to
be ∼2 × 102 s-1
.
The ring-expansion pathway available to radical 2 is greatly
favored both kinetically and thermodynamically. The secondary
radical character and methylenecyclohexyl ring system offer an
energetic advantage to the available fragmentation pathways in
favor of the endo cyclopropyl bond. A small entropic advantage
is also realized along this same course. We are presently engaged
in investigating higher homologues in this series to identify the
influence of ring size on the direction and rate of cyclopropyl
fragmentation and as an approach to access medium-sized rings.
In all instances the expansion pathway (2 f 3) is highly
favored (Table 2). This observation is consistent with the greater
stability of secondary radicals over primary radicals as well as
the negligible ring strain associated with methylenecyclohexane.
Extrapolation to lower concentrations of reducing agent identi-
(21) Syringe pump addition of Bu3SnH (in THF) over 1 h to a refluxing
THF solution of PTOC ester 11 provided 6 and 4 in a ratio of 195:1.
(22) When 1 was generated via the vinyl radical precursor, the expression
was found to be log (k/s-1) ) (11.0 ( 0.3) - (8.9 ( 0.5)/θ. See ref 8.
(20) Chatgilialoglu, C.; Ingold, K. U.; Scaiano, J. C. J. Am. Chem. Soc.
1981, 103, 7739.
J. Org. Chem, Vol. 73, No. 4, 2008 1595

Experimental Section
12.1. IR (neat) 3400-2400 (br), 1702 cm-1. HRMS (ESI-TOF)
calcd for C8H12O2Na [M + Na]+ 163.0735, found 163.0729.
General Experimental Methods. Reagents were used as
received. Solvents (THF, CH2Cl2) were anhydrous (over mo-
lecular sieves). All reactions were conducted under a nitrogen
1-[2-(Bicyclo[3.1.0]hexan-1-yl)acetoxy]-2(1H)-pyridineth-
ione (11). Carboxylic acid 10 (0.981 g, 7.00 mmol), 2-mercap-
topyridine-N-oxide (0.890 g, 7.00 mmol), and DMAP (0.086
g, 0.70 mmol) were dissolved in CH2Cl2 (75 mL). The reaction
flask was covered with foil to protect it from light, and DCC
(1.603 g, 7.77 mmol) in CH2Cl2 (25 mL) was added dropwise
over 30 min. The bright-yellow reaction mixture was allowed
to stir at ambient temperature for 20 h. The urea byproduct was
filtered off, and the yellow filtrate was concentrated. Silica gel
chromatography (30% EtOAc in 60-90 ligroin) provided PTOC
ester 11 as a viscous yellow oil which required protection from
1
atmosphere. H NMR and 13C NMR spectra were recorded in
CDCl3 at 300 and 75 MHz, respectively.
Ethyl 2-(1-Cyclopentenyl)acetate (8).23 To a 0 °C solution
of diisopropyl amine (4.371 g, 43.2 mmol) in THF (100 mL)
was slowly added n-butyllithium (28.96 mL, 1.45 M). The
solution was stirred for 30 min and then cooled to -78 °C. A
solution of ethyl 2-cyclopentylideneacetate (7, 6.249 g, 40.0
mmol) in THF (30 mL) was added dropwise over 15 min and
allowed to stir an additional 20 min. Saturated aqueous NH4Cl
(100 mL) was added dropwise over 20 min, and the quenched
reaction was allowed to warm to ambient temperature, poured
into water (200 mL), and extracted with Et2O (2 × 75 mL).
The extracts were dried (Na2SO4), filtered, and concentrated to
afford 3.501 g (22.69 mmol, 53%) of the â,γ-unsaturated ester
as a colorless liquid in high purity. 1H NMR δ 5.54 (1H, br s),
4.15 (2H, q, J ) 7.4 Hz), 3.11 (2H, s), 2.37-2.29 (4H, m),
1.95 - 1.84 (2H, m), 1.26 (3H, t, J ) 7.4 Hz). 13C NMR δ
171.5, 136.6, 128.1, 60.5, 37.1, 35.1, 32.5, 23.4, 14.2. IR (neat)
1
light and oxygen for any extended storage. H NMR δ 7.67
(1H, dd, J ) 8.8, 1.8 Hz), 7.60 (1H, dd, J ) 7.0, 1.5 Hz), 7.21
(1H, m), 6.66 (1H, dt, J ) 7.0, 1.8 Hz), 2.90 (1H, d, J ) 16.5
Hz), 2.83 (1H, d, J ) 16.5 Hz), 1.96-1.58 (5H, m), 1.30-1.16
(2H, m), 0.58 (1H, t, J ) 4.6 Hz), 0.52 (1H, dd, J ) 8.1, 5.5
Hz). 13C NMR δ 175.6, 167.9, 137.6, 137.1, 133.4, 112.5, 38.2,
31.5, 27.3, 24.2, 23.5, 21.2, 12.3. IR (neat) 1803, 1606, 1524,
1445, 1409, 1129 cm-1. HRMS (ESI-TOF) calcd for C13H15-
NO2SNa [M + Na]+ 272.0721, found 272.0715.
Kinetic Runs. A 0.02 M stock solution of PTOC ester 11 in
THF was used for all runs. A 2.0 mL aliquot was transferred to
an N2-flushed test tube capped with a rubber septum. With
stirring, the solution was equilibrated to the desired temperature,
and reducing agent (PhSH or Bu3SnH) was added via syringe.
The sample was irradiated for 60 s with a 200 W tungsten bulb.
TLC analysis confirmed consumption of the PTOC ester, and
for the stannane reactions the yellow color was discharged. The
reaction was immediately analyzed by GC-MS (HP-5MS, 30
m × 0.25 mm × 0.25 µm, 40 °C isothermal; tR ) 5 < 4 < 6).
Authentic samples were prepared to confirm peak identities;
weight response factors were assumed to be equal. Isothermal
reactions were conducted simultaneously.
1736 cm-1
.
Ethyl 2-(Bicyclo[3.1.0]hexan-1-yl)acetate (9). To a -5 °C
solution of Et2Zn (30.0 mL, 1.2 M in hexanes) in CH2Cl2 (130
mL) was added dropwise CH2I2 (19.5 g, 73.14 mmol) over 10
min. The solution became turbid and turned milky white when
the addition was approximately half complete. After an ad-
ditional 10 min, ethyl 2-(1-cyclopentenyl)acetate (8, 3.501 g,
22.69 mmol) in CH2Cl2 (20 mL) was added in one portion, and
the reaction was allowed to stir at room temperature for 12 h
during which time the reaction was a clear liquid with a white
precipitate distributed on the bottom of the flask. The reaction
was quenched by the addition of saturated aqueous NH4Cl (100
mL), extracted with ether (2 × 100 mL), dried (Na2SO4), and
concentrated. The crude material could be used without further
purification. Silica gel chromatography (30% EtOAc in 60-90
ligroin) provided 2.796 g (16.62 mmol, 73%) of 9 as a colorless
liquid. Spectral data was identical to that reported.23
Acknowledgment. This work was supported in part by a
State Faculty Support Grant (California State University) and
a donation from Roche Biosciences. Acknowledgment is made
to the Donors of the American Chemical Society Petroleum
Research Fund for partial support of this research (#46022-GB4).
D.L. is grateful for support through a departmental Frost
scholarship. We thank Dr. Rod W. Schoonover for helpful
discussions. We also thank Vivian Longacre and Tom Feath-
erstone for technical assistance.
2-(Bicyclo[3.1.0]hexan-1-yl)acetic Acid (10). The ester 9 was
refluxed with ethanolic KOH (1.0 M) for 3 h. The reaction was
diluted with water, acidified (1 M HCl), extracted with ether (2
× 50 mL), dried (Na2SO4), and concentrated. Silica gel
chromatography afforded 2.13 g of the pure acid as a colorless
1
oil (67% from 8). H NMR δ 10.1 (1H, br), 2.54 (1H, d, J )
15.4 Hz), 2.42 (1H, d, J ) 15.4 Hz), 1.89-1.54 (5H, m), 1.25-
1.10 (2H, m), 0.49 (1H, t, J ) 4.6 Hz), 0.40 (1H, dd, J ) 8.3,
5.3 Hz). 13C NMR δ 179.4, 40.9, 31.7, 27.4, 24.9, 23.5, 21.4,
Supporting Information Available: Spectral data (1H NMR,
13C NMR, and IR) for compounds 10 and 11. This material is
available free of charge via the Internet at http://pubs.acs.org.
(23) Urabe, H.; Suzuki, K.; Sato, F. J. Am. Chem. Soc. 1997, 119, 10014.
JO702010V
1596 J. Org. Chem., Vol. 73, No. 4, 2008