Bleach/Acetic Acid-Promoted Chlorinative Ring Expansion of [2.2.1]- and [2.2.2]-Bicycles

Article abstract of DOI:10.1021/ol0267331

(Matrix Presented) Treatment of vinyl-substituted [2.2.1]- and [2.2.2]-bicyclocarbinols with NaOCI and AcOH provides [3.2.1]- and [3.2.2]-β-chloro-bicycloketones, respectively. For [2.2.2]-bicycles, these chlorinative ring expansions are particularly efficient and selective.

Full text of DOI:10.1021/ol0267331

ORGANIC
LETTERS
2002
Vol. 4, No. 22
3899-3902
Bleach/Acetic Acid-Promoted
Chlorinative Ring Expansion of [2.2.1]-
and [2.2.2]-Bicycles
Erik L. Ruggles and Robert E. Maleczka, Jr.*
Department of Chemistry, Michigan State UniVersity, East Lansing, Michigan 48824
maleczka@cem.msu.edu
Received August 14, 2002
ABSTRACT
Treatment of vinyl-substituted [2.2.1]- and [2.2.2]-bicyclocarbinols with NaOCl and AcOH provides [3.2.1]- and [3.2.2]-â-chloro-bicycloketones,
respectively. For [2.2.2]-bicycles, these chlorinative ring expansions are particularly efficient and selective.
Nearly 30 years ago, Johnson1 described the chlorinative ring
homologation of simple cyclobutanes, -pentanes, and -hex-
Scheme 1
anes and isopropenyl [2.2.1]-heptanol (1). As reported,
treatment of a warm, dark solution of 1 with t-BuOCl
afforded a mixture of [3.2.1]-â-chloroketones (Scheme 1,
conditions a). Despite the relatively mild nature of this
chlorinative rearrangement, to the best of our knowledge,
its use in the expansion of bicyclic molecules beyond the
isopropenyl-containing [2.2.1] framework of 1 has not been
studied.2
Due in part to our interest in the ring expansions of bicyclic
ketones,3 we wanted to learn more about the regio-, chemo-,
and stereoselectivity of this process. Of particlular interest
was the reaction of [2.2.2]-bicyclic carbinols substituted with
different vinyl groups. We also wanted to explore alternative
conditions to obviate both the use of potentially explosive
t-BuOCl4 and the reported need to perform these reactions
in the dark.
At the start of this investigation, we deemed it prudent to
and NOE NMR methods unavailable at the time of Johnson’s
original report. Furthermore, as we sought a preparative way
to chlorinatively ring-expand bicyclic molecules, the isolated
yields of 2-5 needed to be determined.5 Isopropenyl [2.2.1]-
heptanol 1 was obtained by simple Grignard addition to
norcamphor (a 50:1 mixture of diastereomeric carbinols
confirm the structural assignments of 2-5 using high-field
(1) (a) Johnson, C. R.; Herr, R. W. J. Org. Chem. 1973, 38, 3153-
3159. (b) see also Johnson, C. R.; Cheer, C. J.; Goldsmith, D. J. J. Org.
Chem. 1964, 29, 3320-3323.
(2) For a review of one-carbon ring expansions of bridged bicyclic
ketones, see: Krow, G. R. Tetrahedron 1987, 43, 3-38.
(3) Mi, B.; Maleczka, R. E., Jr. Tetrahedron Lett. 1999, 40, 2053-2056.
(4) Simpkins, N. S. In Encyclopedia of Reagents for Organic Synthesis;
Paquette, L. A., Ed.; Wiley: New York, 1995; Vol. 2, 889-891.
(5) Johnson and Herr (ref 1a) reported GC yields.
10.1021/ol0267331 CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/03/2002

resulted). Subjecting 1 to t-BuOCl as described by Johnson
yielded the expected chloroketones, though complete conver-
sion took 12 h instead of 8 h and a small amount (2%) of
dichloroketone 66 was also observed. 1H NMR data, includ-
ing those from one-dimensional NOE experiments, were in
good agreement with the original stereo- and regiochemical
assignments.7
Scheme 2a
With the foundation for our study secure, we began to
experiment with the aim of replacing t-BuOCl with NaOCl.
These experiments revealed that a combination of ∼1.2 equiv
of NaOCl8 and ∼2 equiv AcOH in a 1:1 mixture of water
and CCl4 at 0 °C efficiently afford ring-expanded products
2-5 (Scheme 1, conditions b).9 Though the yields of 2-5
were similar to those realized with t-BuOCl, the NaOCl/
HOAc expansions were slightly faster and afforded an
intrusive amount of chlorinated starting material (7).
With these conditions in hand, we set out to evaluate
NaOCl/HOAc-promoted ring expansions outside the realm
of a [2.2.1] to [3.2.1] conversion. Relative to the [2.2.1]
systems,1,2,10 there is little literature on cationic rearrange-
ments of vinyl-substituted [2.2.2]-bicyclic molecules. To
more fully appreciate the selectivity, scope, and mechanism
of this chlorinative rearrangement, a series of carvone-derived
“vinyl” [2.2.2]-bicyclocarbinols would be subjected to NaOCl
and HOAc.
a Reagents and conditions: (a) NBS, CH2Cl2, MeOH (3:1), 0
°C, 1.5 h, rt for 10 h (quant). (b) t-BuOK, t-BuOH, THF, 0 °C, 10
min, rt 18 h (40% 8a; 28% 8b). (c) CH2dC(Me)MgBr, THF, 0
°C, 30 min, 80 °C, 3 h (81%; 4:1 9a/b). (d) DHPLi, THF, -78 °C,
15 min, 0 °C, 45 min, -78 °C, 5 h (75%; 10:1 10a/b). (e)
CH2dCHMgBr, THF, 0 °C, 30 min, 80 °C, 3 h (87%; 4:1 12a/b).
(f) DHFLi, THF, -78 °C, 15 min, 0 °C, 45 min, -78 °C, 5 h
(60%; 2.5:1 11a/b).
Following the intramolecular alkylation procedure of
Srikrishna (Scheme 2), bicyclic ketones 8a and 8b were
prepared.11 Various vinyl nucleophiles were then introduced
as described in Scheme 2. The resultant allylic alcohols (9-
12)12 were then subjected to the bleach and acetic acid
chlorinative ring expansion conditions (Table 1).
Rearrangement of isopropenyl [2.2.2] adducts 9a and 9b
(entries 1 and 2, Table 1) occurred in high isolated yields
and proved to be much more selective than those of [2.2.1]-
bicycle 1. For both substrates, the bridgehead carbon
migrated exclusively. The new stereogenic center was also
formed stereospecifically with NOE experiments indicating
that 9a and 9b afforded 13 and 14 in 20:1 and 1:12 ratios,
respectively.12 These levels of stereocontrol greatly exceeded
the ∼1.3:1 ratio observed during the expansion of 1.
Paquette had shown proton-mediated expansions of dihy-
drofuranyl (DHF)-derived [2.2.1]-carbinols to be particularly
effective.10c Thus, we examined substrates 10 and 11 to form
the chlorofunctionalized [3.2.2] products12 (entries 3 and 4,
Table 1). For the pyranyl derivative (10a), rearrangement
proceeded in 90% yield with excellent selectivity. Again only
the bridgehead carbon migrated. Like the isopropenyl case,
the carbinol with the OH exo to the alkene bridge migrated
to place the chlorocarbon exo to that bridge. Furthermore,
the stereochemistry of that chlorocarbon was such that the
chloro group was positioned syn to the ketone.12 Though
rearrangement of the furnayl derivative (11a) was less
efficient (56%), the regio- and stereocontrol R to the newly
formed carbonyl remained total and in accordance with the
direction established in entries 1-3.12
(6) Johnson’s GLC analysis indicted four major and two unidentified
minor peaks. It is likely that one of these unidentified products was 6.
(7) This analysis also supports Johnson’s conclusion of a preferred CH2-
Cl rotomer present in [3.2.1]-ketone 3. The methyl substituent appears as
a doublet (J ) 0.6 Hz), resultant from W-coupling with the CH2Cl protons
making two conformers possible. Johnson used aromatic solvent-induced
shifts of 3 to deduce the preferred conformer shown below. NOE data are
consistent with this model. (For aromatic solvent-induced shifts, see:
Bhacca, N. S.; Williams, D. H. In Applications of NMR Spectroscopy in
Organic Chemistry; Holden-Day: San Francisco, 1964; Chapter 7.)
(8) (a) Galvin, J. M.; Jacobsen, E. N. In Encyclopedia of Reagents for
Organic Synthesis; Paquette, L. A., Ed.; Wiley: New York, 1995; Vol. 7,
4580-4585. (b) This work was carried out with “regular” Clorox, which
is ∼0.75 M in NaOCl. This product is being replaced by “ultra” Clorox,
which is more alkaline and concentrated (∼0.83 M).
(9) Typical Procedure. After a solution of bicyclocarbinol (1.00 equiv)
in CCl4 (0.6 M) was cooled to 0 °C, AcOH (1.95 equiv) was added rapidly.
After 5 min at 0 °C, this solution was added rapidly to a 0 °C solution of
NaOCl (0.75 M, 1.19 equiv) in H2O (same volume as CCl4). The biphasic
reaction was vigorously stirred for 6 h at 0 °C. The reaction was poured
into a cold solution of 3% K2CO3 in water and then partitioned with room-
temperature CH2Cl2. The organic layer was washed three times with a cold
solution of 3% K2CO3 in water. The combined aqueous washes were back-
extracted three times with CH2Cl2. The combined organics were then dried
over MgSO4, filtered, and concentrated. The residual was purified via flash
chromatography (10 g of SiO2/1 g of compound) with EtOAc/hexane as
the eluent. See Supporting Information for additional details.
Finally, simple vinyl derivatives were examined. Substrates
12a and 12b mimicked the isopropenyl adducts in both
(10) For examples, see: (a) Filippini, M. H.; Rodriguez, J. Chem. ReV.
1999, 99, 27-76. (b) Djuardi, E.; Bovonsombat, P.; McNelis, E. Tetra-
hedron 1994, 50, 11793-11802. (c) Paquette, L. A.; Andrews, J. F. P.;
Vanucci, C.; Lawhorn, D. E.; Negri, J. T.; Rogers, R. D. J. Org. Chem.
1992, 57, 3956-3965.
(11) Srikrishna, A.; Sharma, G. V. R.; Danieldoss, S.; Hemamalini, P.
J. Chem. Soc., Perkin Trans. 1 1996, 1305-1311.
(12) The structure assigned to each new compound is in accordance with
its infrared, 300 or 500 MHz 1H NMR, and 75 or 125 MHz 13C NMR
spectral data, as well as appropriate ion identification by high-resolution
mass spectrometry. Stereochemical assignments were supported by NOE
NMR experiments. See Supporting Information for details.
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Org. Lett., Vol. 4, No. 22, 2002

(BHT). Given these observations and earlier works,1,7,10,13
these ring expansions appear to be best described as cationic.
Capture of Cl+ by the vinylic portion of the molecule
followed by a Wagner-Meerwein shift of the more nucleo-
philic bridgehead carbon2 and loss of a proton would afford
the observed products (Figure 1).
Table 1. NaOCl/HOAc-Promoted Ring Expansion Resultsa
Figure 1.
As for stereocontrol, the [2.2.1] and [2.2.2] systems behave
differently. For rearrangement of the [2.2.1] molecule (1),
the conformer that places the alkene and the hydroxyl in
opposing directions appears to be slightly preferred. Johnson
argued that this is the result of a steric bias with the reacting
conformer being the lowest energy rotomer (Figure 1, eq
1).
a Conditions: NaOCl, HOAc, 6 h, 0 °C, H2O/CCl4 (1:1); for experimental
details, see ref 9 and Supporting Information.
Data on the rearrangements of 9-12 suggest that, in
contrast to 1, the [2.2.2]-bicycles rearrange via conformers
that place the olefin and the hydroxyl syn to each other.
Paquette has described a similar relationship during proton-
mediated ring expansions of dihydrofuran-substituted [2.2.1]-
carbinols,10c pointing to a preferred anti relationship between
the ring oxygen and the hydroxyl (Figure 1, eq 2). However,
entries 1, 2, 5, and 6 suggest that, in our reactions, the
heteroatom may not be the primary stereocontrol element.
Furthermore, the resultant stereochemistry of the chlorine
bearing carbons in 15 and 16 indicates that the same
conformer undergoes both chlorination and ring expansion.
These observations, in combination with the lack of reactivity
at the bridging olefin (vide infra), open up the possibility of
regioselectivity and stereospecificity (entries 5 and 6, Table
1). The exo-carbinol (relative to the alkene bridge) again
produced the exo-chloroketone, while the endo-carbinol
yielded the endo-chloroketone.12 A key difference in the
rearrangement of these substrates was that the â-chloroketone
products were quick to eliminate HCl as can be seen from
enone production. Such an elimination is in itself useful
because it represents a direct way of carrying out a ring
expansion/exo-olefin insertion process on bicyclic ketones.
Further studies on the generality of this sequence will be
reported in due course.
Whether these reactions are carried out in the light or in
the dark, the product composition is not affected by the
addition of radical scavenger di-tert-butylhydroxytoluene
(13) Anbar, M.; Ginsburg, D. Chem. ReV. 1954, 54, 925-958.
Org. Lett., Vol. 4, No. 22, 2002
3901

and loss of a proton can be drawn.16 However, data suggest
that here there may be some radical involvement because
the reaction is somewhat hindered by BHT (45% yield with
BHT vs 60% yield without BHT). Furthermore, the stereo-
chemistry about the methyl group R to the ketone goes from
a 2:1 to a 1.2:1 mixture when the reaction is run dark. Thus,
the exact mechanism of this rearrangement remains under
investigation.
Scheme 3
In summary, bleach and acetic acid are effective promoters
of chlorinative one-carbon ring expansions of [2.2.1]- and
[2.2.2]-bicyclic molecules. Rearrangement of vinyl-, iso-
propenyl-, DHF-, and DHP-substituted [2.2.2]-bicyclo-
carbinols are chemo-, regio-, and stereoselective, affording
â-chloro-[3.2.2]-bicycloketones17 in respectable yields. The
selectivity of these rearrangements appears to be derived from
reaction of a preferred conformer in which the hydroxyl and
the reacting vinyl groups are in a syn orientation. In addition,
nonvinylic [2.2.2]-bicyclocarbinols undergo their own unique
chlorinative rearrangements upon exposure to NaOCl/HOAc.
a concerted mechanism (Figure 1, eq 3), which Johnson
ruled1 out for 1. It is also possible that in contrast to the
rearrangement of 1,1 the [2.2.2] systems are converted to
their hypochlorites prior to rearrangement (Figure 1, eq 4).
However, when hypohalites are reacted in light, at least trace
amounts of oxy-radical-derived products14,15 are expected.
We saw none. Furthermore, attempts to purposely prepare
hypohalites of 12 by alternative methods never afforded 18
(or other halo analogues) or 19.
In terms of chemoselectivity, ether oxygens did not
interfere with the expansion. Moreover, no reaction with the
bridging olefin was observed during the rearrangement of
the vinyl carbinols. This is not to say that such olefins are
completely inert to the reaction conditions. Reaction of
[2.2.2] secondary alcohols (21a/b) gave γ-chloro[3.2.1]-
ketones 22a/b12 in good yield and in a ratio of 2:1 (Scheme
3). A putative cationic mechanism involving reaction of Cl+
with the internal olefin, bond migration, 1,2-deuterium shift,
Acknowledgment. We thank the NIH (HL-58114), the
Yamanouchi USA Foundation, and the MSU Department of
Chemistry for generous support. Special thanks go to Dr.
Art Bates, Dr. Long Le, and Mr. Kermit Johnson of the Max
T. Rogers NMR facility and Ms. Beverly Chambers of
MSU’s Mass Spectrometry facility for their efforts and
assistance.
Supporting Information Available: Spectral data for all
new compounds pictured, as well as general experimental
procedures. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL0267331
(14) (a) Greene, F. D.; Savitz, M. L.; Osterholtz, F. D.; Lau, H. H.; Smith,
W. N.; Zanet, P. M. J. Org. Chem. 1963, 28, 55-64. (b) Walling, C.; Thaler,
W. J. Am. Chem. Soc. 1961, 83, 3877-3884. (c) Walling, C.; Clark, R, T.
J. Am. Chem. Soc. 1974, 96, 4530-4534.
(15) Galatsis, P.; Millan, S. D.; Faber, T. J. Org. Chem. 1993, 58, 1215-
1220.
(16) (a) Kwart, H.; Irvine, J. L. J. Am. Chem. Soc. 1969, 91, 5541-
5546. (b) Smith, W. B. J. Org. Chem. 2001, 66, 376-380.
(17) For examples of â-chloroketones in organic synthesis, see: (a)
Zoretic, P. A.; Bendiksen, B.; Branchaud, B. J. Org. Chem. 1976, 41, 3767.
(b) Krause, H.-J. DE Patent 29 25 521, 1981. (c) Miller, J. A.; Ullah, G.
M.; Welsh, G. M.; Mallon, P. Tetrahedron Lett. 2001, 42, 2729-2731.
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