Mitsunobu Reaction of Unbiased Cyclic Allylic Alcohols

Article abstract of DOI:10.1021/jo9615155

The stereochemical inversion of unbiased allylic alcohols using triphenylphosphine, diethyl azodicarboxylate, and benzoic acid, commonly known as the Mitsunobu reaction, was studied in three different solvents with specific attention toward the product composition. The results generated for the Mitsunobu reaction of (R)-3-deuterio-2-cyclohexen-1-ol and the cis and trans isomers of 1-deuterio-5-methyl-2-cyclohexen-1-ol, 1-deuterio-5-tert-butyl-2-cyclohexen-1-ol, and optically active cis and trans 5-isopropyl-2-methyl-2-cyclohexen-1-ol all gave similar product distributions with respect to inversion and retention at the carbinol center as well-as syn and anti S_n2′ type addition when THF or benzene was used as the solvent (CH₂Cl₂ gave less selective product distributions). Interestingly, it was found that the quasi-equatorial and quasi-axial nature of the starting allylic alcohol does not appear to affect the product distribution for this reaction, nor does methyl substitution at the central carbon of the allylic alcohol. In all cases, significant amounts (8-28%) of non-S_N2 type products were detected for these sterically unbiased allylic alcohols; only 72-77% of the product was from S_N2 type reaction when sterically undemanding (R)-S-deuterio-2-cyclohexen-1-ol was subjected to Mitsunobu conditions.

Full text of DOI:10.1021/jo9615155

8294
J . Org. Chem. 1997, 62, 8294-8303
Articles
Mitsu n obu Rea ction of Un bia sed Cyclic Allylic Alcoh ols
Brian K. Shull,*,† Takashi Sakai,‡ J effrey B. Nichols,§ and Masato Koreeda*,
Department of Chemistry, The University of Michigan, Ann Arbor, Michigan 48109-1055
Received August 5, 1996 (Revised Manuscript Received September 3, 1997X)
The stereochemical inversion of unbiased allylic alcohols using triphenylphosphine, diethyl
azodicarboxylate, and benzoic acid, commonly known as the Mitsunobu reaction, was studied in
three different solvents with specific attention toward the product composition. The results
generated for the Mitsunobu reaction of (R)-3-deuterio-2-cyclohexen-1-ol and the cis and trans
isomers of 1-deuterio-5-methyl-2-cyclohexen-1-ol, 1-deuterio-5-tert-butyl-2-cyclohexen-1-ol, and
optically active cis and trans 5-isopropyl-2-methyl-2-cyclohexen-1-ol all gave similar product
distributions with respect to inversion and retention at the carbinol center as well-as syn and anti
SN2′ type addition when THF or benzene was used as the solvent (CH2Cl2 gave less selective product
distributions). Interestingly, it was found that the quasi-equatorial and quasi-axial nature of the
starting allylic alcohol does not appear to affect the product distribution for this reaction, nor does
methyl substitution at the central carbon of the allylic alcohol. In all cases, significant amounts
(8-28%) of non-SN2 type products were detected for these sterically unbiased allylic alcohols; only
72-77% of the product was from SN2 type reaction when sterically undemanding (R)-3-deuterio-
2-cyclohexen-1-ol was subjected to Mitsunobu conditions.
In tr od u ction
irreversible4 formation of a betaine (1),5 which in the
presence of alcohols and phenols form dioxytriphenylphos-
phoranes 2,6 intermediates detectable only when the acid
is added last.7 In the presence of a carboxylic acid, the
dioxytriphenylphosphorane is in equilibrium with an
alkoxyphosphonium carboxylate salt8 and this equilibri-
um (as well as the resultant yield of the reaction)9 is
extremely sensitive to the acidity of the reaction mixture
as well as the nature of the solvent. However, if the
betaine (1) is treated with the acid before introduction
of the alcohol, the acid phosphonium salt 4 is formed.10
Introduction of the alcohol then allows for the slow
formation of alkoxyphosphonium carboxylate salt 3. It
was reported that alkoxyphosphonium carboxylate salt
3 can also be generated by treating triphenylphosphine
first with benzoyl peroxide, forming a mixture of bis-
(acyloxy)triphenylphosphorane 5 in equilibrium with its
conjgate salt, (acyloxy)triphenylphosphonium carboxylate
6. Subsequent addition of an alcohol then produces
alkoxyphosphonium carboxylate salt 3 (Scheme 1).
Of the various methods available1 for the stereochem-
ical inversion of hydroxyl groups, the Mitsunobu reac-
tion,2 utilizing triphenylphosphine, diethyl azodicarbox-
ylate (DEAD), or diisopropyl azodicarboxylate (DIAD)
and an acid component (usually a carboxylic acid, phenol,
or phthalimide), is undoubtedly one of the most utilized
and studied. The mechanism of this reaction has been
the subject of much scrutiny and debate, and recently
free radicals have been implicated.3 The initial interac-
tion between triphenylphosphine and DEAD leads to the
† Current address: Glycosyn, Inc., 620 Hutton St., Ste. 104, Raleigh,
NC 27606. Tel/fax: 1-919-836-8655. E-mail: shull@glycosyn.com.
‡ On leave from the School of Engineering, Okayama University,
J apan.
§ Deceased December 1993.
Tel/fax: 1-313-764-7371. E-mail: koreeda@UMich.Edu.
X Abstract published in Advance ACS Abstracts, October 15, 1997.
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S0022-3263(96)01515-0 CCC: $14.00 © 1997 American Chemical Society

Mitsunobu Reaction of Unbiased Alcohols
J . Org. Chem., Vol. 62, No. 24, 1997 8295
Sch em e 1
Sch em e 2
study on the Mitsunobu reaction of several unbiased
cyclic allylic alcohols.
Resu lts a n d Discu ssion
The first system we were interested in studying was
the bicyclo[3.3.0]oct-2-en-1-ol system, in connection with
the work toward the synthesis of pentalenolactone E
methyl ester and a related study of the [2,3]-Wittig
rearrangement on this cyclic skeleton. The required
cyclic allylic alcohols were synthesized starting with
commercially available bicyclooctene (7) (Scheme 2).
Oxidation (m-CPBA) followed by treatment of the result-
ing epoxide with Et2NLi provided allylic alcohol 8 in 40%
overall yield. Oxidation to the enone followed by Luche17
reduction for the introduction of the deuterium label
provided deuterated allylic alcohol 10 in 80% yield for
the two steps (32% overall from 7). This allylic alcohol
was accompanied with 3% of its diastereomer, easily
separable by silica gel chromatography. Unexpectedly,
the extent of deuterium incorporation was relatively
lowsonly 85% as judged by both 1H and 2H NMR
analysis. The origin of this low incorporation of deute-
rium remains puzzling since the deuteride (98% D) is not
likely exchanged under the Luche conditions.
Although the protocol for the Mitsunobu reaction has
been extensively utilized for saturated alcohols and the
mechanism well studied and defined, there exists con-
siderable ambiguity as to the factors that govern the
course of this reaction when allylic or benzylic alcohols
are employed.11 When allylic or benzylic alcohols are
used, a dramatic rate enhancement is observed and the
yields are greatly improved. However, this comes at the
expense of the amount of inversion vs retention of
configuration, and allylic migration12 or loss in optical
purity13 has been reported in many cases. There have
been several reports of this reaction on unbiased acyclic14
and cyclic15 systems but only one, that of a tricyclic
cyclopentenol, that was systematically studied and dif-
ferentiated between each of the four possible products
from the reaction.16 Herein we report the results of the
With the requisite allylic alcohol in hand, the Mit-
sunobu reaction was performed using three different
solvents typically used for the reaction: THF, benzene,
and CH2Cl2. The product benzoates obtained from the
Mitsunobu inversion reaction were compared to those
obtained directly from allylic alcohols 8 and nondeuter-
ated 10 wtih benzoyl chloride. The diagnostic carbinol
protons could not be completely resolved from the olefinic
(11) For examples of very similar systems with significantly different
results, see: (a) Dyong, I.; Weigand, J .; Thiem, J . J ustus Liebigs Ann.
Chem. 1986, 577. (b) Dyong, I.; Merten, H.; Thiem, J . J ustus Liebigs
Ann. Chem. 1986, 600. (c) Schulte, G.; Meyer, W.; Starkloff, A.; Dyong,
I. Chem. Ber. 1981, 114, 1809. (d) Gauchet, F.; J ulia, M.; Mestdagh,
H.; Rolando, C. Bull. Soc. Chim. Fr. 1987, 1036. (e) Fiaud, J . C.; Aribi-
Zouioueche, L. Tetrahedron Lett. 1982, 23, 5279. (f) Whitesell, J . K.;
Fisher, M.; J ardine, P. D. S. J . Org. Chem. 1983, 48, 1556 and the
results of ref 15 and this study. (g) J ohnson, C. R.; Ple´, P. A.; Adams,
J . P. J . Chem. Soc., Chem. Commun. 1991, 1006. (h) Pingli, L.;
Vandewalle, M. Tetrahedron 1994, 50, 7061. (i) Mereyala, H. B.;
Gaddam, B. R. J . Chem Soc., Perkin Trans. 1 1994, 2187.
(12) For some representative examples, see: (a) Danishefsky, S.;
Berman, E. M.; Ciufolini, M.; Etheredge, A. J .; Segmuller, B. E. J . Am.
Chem. Soc. 1985, 107, 3891. (b) Rao, A. V. R.; Yadav, J . S.; Reddy, K.
B.; Mehendale, A. R. J . Chem. Soc., Chem. Commun. 1984, 453.
(13) (a) Rao, A. V. R.; Yadav, J . S.; Reddy, K. B.; Mehendale, A. R.
J . Chem. Soc., Chem. Commun. 1984, 453; (b) Tetrahedron 1984, 40,
4643. (c) Guindon, Y.; Delorme, D. Can. J . Chem. 1987, 65, 1438. (d)
Guindon, Y.; Delorme, D.; Lau, C. K.; Zamboni, R. J . Org. Chem. 1988,
53, 267.
(14) Grynkiewicz, G.; Burzynska, H. Tetrahedron 1976, 32, 2109.
(15) (a) Trost, B. M.; Edstrom, E. D. Angew. Chem., Int. Ed. Engl.
1990, 29, 520. (b) Castedo, L.; Mascarenas, J . L.; Mourino, A.
Tetrahedron Lett. 1987, 28, 2099. (c) J ohnson, B. M.; Vollhardt, K. P.
C. Synlett 1990, 209. (d) Fleming, I.; Higgins, D.; Lawrence, N. J .;
Thomas, A. P. J . Chem. Soc., Perkin Trans. 1 1992, 3331. (e) Carda,
M.; Marco, J . A. Tetrahedron 1992, 48, 9789. (f) Suemune, H.; Matsuno,
K.; Uchida, M.; Sakai, K. Tetrahedron: Asymmetry 1992, 3, 297. (g)
Balan, A.; Ziffer, H. J . Chem. Soc., Chem. Commun. 1990, 175 and ref
30.
1
ones in the H NMR spectra, and thus it was necessary
to hydrolyze the product esters with LAH in order to
better assess the product composition.
Examination of the product allylic alcohols revealed
that all four possible products (Scheme 3) were present
in the mixture. The amount of allylic alcohol that
corresponds to the inversion of stereochemistry of the
hydroxyl (i.e., 11) was shown to be high (Table 1) but
not complete. However, the amount of such apparent
inversion product was not as high as one would expect
given the majority of the reports of inversion in cyclo-
pentenol systems.18 The choice of solvent, at least among
(17) Luche, J .; Gemal, A. L. J . Am. Chem. Soc. 1981, 103, 5454.
(18) The only exceptions found: (a) Danda, H.; Nagatomi, T.;
Maehara, A.; Umemura, T. Tetrahedron 1991, 47, 8701. (b) Takano,
S.; Suzuki, M.; Ogasawara, K. Tetrahedron: Assymmetry 1993, 4, 1043.
(c) Wachtmeister, J .; Classon, B.; Samuelsson, B. Tetrahedron 1995,
51, 2029 and ref 15.
(16) Farina, V. Tetrahedron Lett. 1989, 30, 6645.

8296 J . Org. Chem., Vol. 62, No. 24, 1997
Shull et al.
Sch em e 3
Ta ble 1. Mitsu n obu In ver sion of (()-2r-Deu ter io-2â-
h yd r oxy-1r,5r-bicyclo[3.3.0]oct-3-en e (10)
Sch em e 4
product distribution, %
%
%
%
solvent yielda inversion retention
11
12
10
13
THF
benzene
CH2Cl2
80
90
80
93
93
91
7
7
9
79
83
65
15
10
26
1
1
4
5
6
5
a
Yield of the benzoates.
Ta ble 2. Mitsu n obu In ver sion of (()-2â-Deu ter io-2r-
h yd r oxy-1r,5r-bicyclo[3.3.0]oct-3-en e (11)
product distribution, %b
%
%
%
solvent yielda inversion retention
10
13
11
12
THF
benzene
CH2Cl2
80
90
87
65
55
50
35
45
50
44
46
32
27
14
23
6
21
17
23
19
28
Ta ble 3. Mitsu n obu Rea ction of
(R)-3-Deu ter io-2-cycloh exen -1-ol (14)
a
b
Yield of the benzenes. Percentages corrected for the starting
9:1 mixture of 10/11.
% product distributionb
17 18 19 20
72 18
solvent
% yielda
15:16
the three solvents examined, does not seem to alter the
product distribution for this reaction, although CH2Cl2
does give a somewhat less selective product distribution.
The yields for the formation of the benzoates were also
in the range of what was expected. A 9:1 mixture of exo
alcohol 11 and 12 was subjected to Mitsunobu conditions,
and as before, the resultant benzoates had to be hydro-
lyzed in order to best determine the product ratios. The
allylic alcohols isolated from the above sequence showed
the deuterium label to be extensively scrambled, with the
product with the inverted stereochemistry of the hydroxyl
group accounting for less than 50% of the product (Table
2). The results obtained for this system are in accord
with those reported by Farina.15
The next system studied, 3-deuterio-2-cyclohexen-1-ol,
was made optically active in order to differentiate
between retention vs inversion or allylic migration with
syn vs anti addition. Deuterated 2-cyclohexen-1-one was
prepared by LAD reduction19 of 3-ethoxycyclohex-2-en-
1-one, followed by acidic workup. Optically active 3-deu-
terio-2-cyclohexen-1-ol (14) was prepared by using the
method of Terashima;20 i.e. LAH reduction in the pres-
ence of N-methylephedrine and 2-ethylaminopyridine.
The amount of chiral induction was determined by
THF
benzene
CH2Cl2
82
81
77
77:23
78:22
75:25
1
0
0
9
9
7
77
74
14
19
a
Yield of the isolated, chromatographically pure benzoates 15
and 16. Percentages corrected for the optical purity of (R)-3-
deuterio-cyclohex-2-en- ol used (70% ee).
b
that reported by Terashima, the 70% ee obtained in the
present study was sufficient for our purposes.
The Mitsunobu reaction of the deuterated, optically
active 2-cyclohexen-1-ol was again performed in three
different solvents, THF, benzene, and CH2Cl2. The
product benzoates from this reaction were isolated and
compared to the benzoates prepared directly from 2-cy-
clohexen-1-ol and benzoyl chloride, and the amount of
1
allylic migration was determined by H NMR spectros-
copy. However, to fully assess the ratio of the products
it was necessary to hydrolyze the inseparable mixture
of benzoates 15 and 16 and convert the resulting alcohols
into their (-)-MTPA esters (Scheme 4). This mixture was
1
then analyzed by 360 and 500 MHz H as well as 55.3
2
MHz H NMR spectroscopy (Table 3) and compared to
that prepared with (-)-MTPA-Cl and 2-cyclohexen-1-ol
14. As can be seen by the yields as well as the product
distribution (adjusted to take into account the 70% ee of
the starting 3-deuterio-2-cyclohexen-1-ol), there is es-
sentially no solvent effect for this reaction for the solvents
1
2
analyzing both the H and H NMR spectra of the (-)-
MTPA ester of the product 2-cyclohexen-1-ol. Although
the extent of chiral induction was not as significant as
1
tried. On the basis of the H NMR analysis of the initial
benzoates obtained, one-fourth of the product was pro-
duced through allylic migration and subsequent analysis
of its MTPA ester derivatives indicated the virtual
absence of the retention product 17. Interestingly, of the
(19) (a) Kantner, S. S.; Humski, K.; Georing, H. L. J . Am. Chem.
Soc. 1982, 104, 1693. (b) Georing, H. L.; Paisley, S. D.; J . Org. Chem.
1987, 52, 943.
(20) Kawasaki, M.; Suzuki, Y.; Terashima, S. Chem. Pharm. Bull.
1985, 33, 52.

Mitsunobu Reaction of Unbiased Alcohols
J . Org. Chem., Vol. 62, No. 24, 1997 8297
Sch em e 5
two products resulting from allylic migration, the one
from syn addition was predominant over the anti addition
product by a ratio of approximately 2:1. To ensure that
the loss in stereo- and regiochemistry was due to the
nature of the reaction and not from the acid present in
the reaction medium, both the product benzoates and
starting allylic alcohol were exposed to benzoic acid in
THF and the mixture was stirred for the same period of
time. No change in the starting alcohol nor in the
benzoates was observed. Since cyclohex-2-en-1-ol and
1-methoxycyclohex-2-ene adopt a conformation in which
the hydroxyl or methoxy group is in a pseudoaxial
position,21 it is probable that the conformation of the
alkoxytriphenylphosphonium carboxylate salt of 2-cyclo-
hexene-1-ol is that in which the O-+PPh3 group22 is in a
pseudoaxial position. This group may direct the addition
of the benzoate group from the same face, thus providing
the allylic benzoate resulting from allylic migration, syn
addition. This is not entirely unprecedented for SN2′
reactions,23 for there are several reports where allylic
carbamates direct addition from the same face for cuprate
additions.24
deuterium label by LAD reduction of keto enol ether 22.
This reduction proceeded smoothly in 75% yield and
essentially 100% D incorporation. Reduction of enone 25
using the protocol of Wharton26 provided 26 as the major
product, along with three other inseparable contaminants
(Scheme 5). Although its 1H NMR spectrum indicated
an 11:1 mixture of isomers 26:24, 2H NMR spectrum
showed that during the reaction sequence a small amount
of allylic migration occurred. It should be emphasized
here that the product was never exposed to acid during
the reaction and isolation; it was always handled under
slightly basic conditions.
With the requisite labeled allylic alcohols prepared, the
Mitsunobu reaction was again conducted in three sol-
vents, THF, benzene, and CH2Cl2, with the results
outlined in Table 4. As was the case for 3-deuterio-2-
cyclohexen-1-ol, the predominant product was that of
direct SN2 inversion and essentially no product from
retention at the carbinol center was detected for either
the cis or trans isomer. In addition, as in the case of
3-deuterio-2-cyclohexen-1-ol, little solvent effect was
discerned with the exception that CH2Cl2 gives a less
A focus was next directed toward an effort to discern
whether a preferred quasiaxial or equatorial orientation
of the O-+PPh3 group of the allylic alcohol-phosphonium
intermediate could be manifested in the relative energies
of the transition states for the formation of the SN2 and
SN2′ products. To this end, the product distribution of
the Mitsunobu reaction was investigated using deuter-
ated cis- and trans-5-alkyl-2-cyclohex-1-ols. 5-Methyl-2-
cyclohexen-1-ol was chosen as the first substrate because
of the ease of synthesis and because it is intermediate
between 2-cyclohexen-1-ol and possibly the best substrate
for this study, 5-tert-butyl-2-cyclohexen-1-ol.
(21) (a) Senda, Y.; Imaizumi, S. Tetrahedron 1974, 30, 3813. (b)
Lessard, J .; Tan, P. V. N.; Martino, R.; Saunders, J . K. Can. J . Chem.
1977, 55, 1015. (c) Ouedraogo, A.; Viet, M. T. P.; Saunders, J . K.;
Lessard, J . Can. J . Chem. 1987, 65, 1761.
(22) The A value is not expected to be much greater than that of a
methoxy group. For A values of similar substituents, see: Eliel, E. L.;
Wilen, S. L. Stereochemistry of Organic Compounds; J ohn Wiley &
Sons: New York, 1994; pp 690-700 (cyclohexanes) and pp 726-730
(cyclohexenes) and references cited within.
(23) The existence of a synchronous SN2′ reaction mechansim has
been the subject of much debate: (a) Bordwell, F. G. Acc. Chem. Res.
1970, 281. (b) Bordwell, F. G.; Mecca, T. G. J . Am. Chem. Soc. 1972,
94, 5825, 5829. (c) Yates, R. L.; Epiotis, N. D.; Bernardi, F. J . Am.
Chem. Soc. 1975, 97, 6615. For a discussion of the preference of SN2′
syn addition over anti addition, see (d) Magid, R. M. Tetrahedron 1980,
36, 1901.
(24) (a) Gallina, C.; Ciattini, P. G. J . Am. Chem. Soc. 1979, 101,
1035. (b) Goering, H. L.; Kantner, S. S. J . Org. Chem. 1981, 46, 2144.
(c) Gallina, C. Tetrahedron Lett. 1982, 23, 3093. (d) Goering, H. L.;
Kantner, S. S.; Tseng, C. C. J . Org. Chem. 1983, 48, 715. (e) Goering,
H. L.; Tseng, C. C. J . Org. Chem. 1985, 50, 1597. (f) Fleming, I.;
Thomas, A. P. J . Chem. Soc., Chem. Commun. 1986, 1456. (g)
Underiner, T. L.; Goering, H. L. J . Org. Chem. 1989, 54, 3239.
However, a majority of the copper-assisted SN2′ reactions are in favor
of anti attack: (h) Wipf, P.; Fritch, P. C. J . Org. Chem. 1994, 59, 4875.
(i) Marshal, J . A. Chem Rev. 1989, 89, 1503. (j) Corey, E. J .; Boaz, N.
W. Tetrahedron 1984, 25, 3063. (k) Denmark, S. E.; Marble, L. K. J .
Org. Chem. 1990, 55, 1984.
Commercially available dione 21 was readily converted
into enone 23 via the keto enol ether 22 in good overall
yield. Luche25 reduction of 23 afforded deuterium-labeled
allylic alcohol 24 in 80% yield. However, this product
was accompanied with 3.3% of isomer 26, which proved
to be inseparable by silica gel chromatography. Ad-
ditionally, the extent of D incorporation was again only
1
2
88% as judged by H and H NMR spectroscopy. Inter-
estingly, when the reduction was conducted in MeOD the
D incorporation into 24 increased to 92%. To obtain
diastereomer 26, it was necessary to introduce the
(25) See ref 17.
(26) Wharton, P. S.; Bohlen, D. H. J . Org. Chem. 1961, 26, 3615.

8298 J . Org. Chem., Vol. 62, No. 24, 1997
Ta ble 4. Mitsu n obu Rea ction of cis- a n d tr a n s-5-Alk yl-2-cycloh exen -1-ol
Shull et al.
allylic alcohol
R
R1
R2
solvent
yield
product distribution, %a
(()-cis-5-Alkyl-2-cyclohexen-1-ol (quasi equatorial OH)
35
36
91
93
77
40
78
78
66
37
0
2
8
41
6
38
7
5
12
42
9
10
22
24
24
24
Me
Me
Me
OH
OH
OH
D
D
D
THF
benzene
CH2Cl2
80
75
69
2
0
3
39
7
5
32
32
32
t-Bu
t-Bu
t-Bu
OH
OH
OH
D
D
D
THF
benzene
CH2Cl2
93
88
70
6
8
4
(()-trans-5-Alkyl-2-cyclohexen-1-ol (quasi axial OH)
35
36
0
0
6
40
3
37
13
12
16
41
12
11
11
38
8
9
5
42
5
26
26
26
Me
Me
Me
D
D
D
OH
OH
OH
THF
benzene
CH2Cl2
82
92
93
79
79
73
39
80
80
75
34
34
34
t-Bu
t-Bu
t-Bu
D
D
D
OH
OH
OH
THF
benzene
CH2Cl2
80
72
42
3
10
6
4
a
Corrected for pure starting allylic alcohol.
favorable product mixture with respect to the direct
inversion product. However, unlike the case of 3-deute-
rio-2-cyclohexen-1-ol, the anti addition adduct dominated
over the syn addition adduct on average by a ratio of 2:1
in the product from allylic migration. Furthermore, there
also seems to be a slight difference between the product
distribution of the cis versus trans isomer, with the cis
isomer giving a higher percentage of direct inversion
product.
To ensure that the alkoxyphosphonium intermediate
adopts the half-chair cyclohexene conformation with the
5-alkyl group in an equatorial orientation, the tert-butyl
analogues 32 and 34 were prepared in the same manner
as 5-methyl-2-cyclohexen-1-ol from 5-tert-butyl-1,3-cyclo-
hexadione.27 The cis deuterated allylic alcohol made had
90% D incorporation as well as 4.6% of the inseparable
diastereomer 34. The diastereomer 34 was prepared
with complete D incorporation but was contaminated
with 9% of the other isomer 32.
The Mitsunobu reaction was performed upon the
deuterium-labeled tert-butyl allylic alcohols under the
same conditions used for their unsubstituted and methyl
analogues, and the results are also summarized in Table
4. The yields for the reaction were good, except for the
inversion of the trans isomer in CH2Cl2. The data
obtained for the trans tert-butyl isomer (quasi axial OH)
are essentially identical with those of its corresponding
methyl analogue. This was not unexpected since the
hydroxyl (or phosphonium salt) is more stable in the axial
conformation, as previously discussed and thus both
trans-5-methyl-2-cyclohexen-1-ol (26) and trans-5-tert-
butyl-2-cyclohexen-1-ol (34) are likely to exist exclusively
in a half-chair conformation with the alkyl group in an
equatorial position and the hydroxyl or phosphonium salt
in an axial position. In contrast, a comparison of the data
from the cis-5-tert-butyl-2-cyclohexen-1-ol (32) (quasi
equatorial OH) with its methyl analogue 24 shows a
slight loss of selectivity when the tert-butyl group is used
in an attempt to lock the conformation of the cyclohexene
ring. Interestingly, inspection of the results given in
Table 4 suggests that the orientation of the alcohol does
not play an important role in this reaction. trans-5-Alkyl-
2-cyclohexen-1-ol would be expected to provide more
product from allylic rearrangement since the half-chair
cyclohexene conformation provides the phosphonium
leaving group in a quasi-axial position with maximum
orbital overlap with the π-bond system, usually a re-
quirement for SN2′-type addition. In contrast, cis-5-alkyl-
2-cyclohexen-1-ol would have to proceed through a twist
boat-like transition state in order to accommodate SN2′
addition.23d At the same time, this conformation having
the pseudoaxially oriented leaving group should lead to
the favorable transition state for the SN2 process as well.
However, there was little difference observed in the
product distribution between the cis- and trans-5-alkyl-
2-cyclohexen-1-ols.
To further investigate what role substituents might
play in this reaction, the Mitsunobu reaction of another
unbiased 2-cyclohexenol, dihydrocarvol, was investigated.
The required allylic alcohol substrates29 were synthesized
in optically active form starting from (R)-(-)-carvone,
and thus the use of a deuterium label was not necessary.
As for the case of 3-deuterio-2-cyclohexen-1-ol, the prod-
uct benzoates from the Mitsunobu inversion of the two
allylic alcohols, 44 and 45, of which the 300 and 360 MHz
1H NMR spectra in CDCl3 could distinguish the facial
selectivity (cis versus trans), had to be converted into
their MTPA esters in order to ascertain the extent of
allylic migration (Scheme 6). The results from these
(28) Reference deleted.
(29) (a) Grandi, R.; Pagnori, U. M.; Trave, R.; Granti, L. Tetrahedron
1974, 30, 4037. For the intermediates, see: (b) Birch, A. J .; Walker,
K. A. M. J . Chem. Soc. C 1966, 1894. (c) Klein, E.; Ohloff, G.
Tetrahedron 1963, 1091. (d) Tadwalker, V. R.; Narayanaswamy, M.;
Rao, A. S. Indian J . Chem. 1971, 1223. (e) Dale, J . A.; Dull, D. L.;
Mosher, H. S. J . Org. Chem. 1969, 34, 2543.
(27) (a) Dominianni, S. J .; Ryan, C. W.; DeArmitt, C. W. J . Org.
Chem. 1977, 42, 344. (b) Sardina, F. J .; J ohnston, A. D.; Mourino, A.;
Okamura, W. J . Org. Chem. 1982, 47, 1576.

Mitsunobu Reaction of Unbiased Alcohols
J . Org. Chem., Vol. 62, No. 24, 1997 8299
10 and 25% of the product. As in Farina’s case,15 even
when the face for direct SN2 displacement is greatly
favored over the face for retention/allylic migration-syn
addition, modes other than simple SN2 displacement still
occur. In the cases of 5-methyl- and 5-tert-butyl-2-
cyclohexen-1-ol, and 5-isopropyl-2-methyl-2-cyclohexen-
1-ol, the cis/trans relationship of the hydroxyl (thus
predisposing the hydroxyl to quasi-axial or quasi-equato-
rial orientations) borders on irrelevant for the makeup
of the product distribution, which is constant throughout
this study.
Sch em e 6
With regard to the corresponding SN2′ type product
distribution, in the cases of 5-methyl- and 5-tert-butyl-
2-cyclohexen-1-ols and 5-isopropyl-2-methyl-2-cyclohexen-
1-ol, the preference of allylic migration with anti addition
over syn addition has theoretical precedent,31 in which
ab initio and semiempirical molecular orbital calculations
led to a postulate that neutral nucleophiles would attack
in a syn fashion but the approach of anionic nucleophiles
(such as benzoate) would be anti. However, the observed
preference for allylic migration with syn addition over
that with anti addition in the case of deuterated 2-cy-
clohexen-1-ol is surprising, and a rationale as to why this
case does not follow the pattern of the other cases
remains to be sought.
Su m m a r y a n d Con clu sion s
Ta ble 5. Mitsu n obu Rea ction of (+)-cis- (43) a n d
(-)-tr a n s-5-Isop r op yl-2-m eth yl-2-cycloh exen -1-ol (44)
The Mitsunobu reaction of unbiased cyclic allylic
alcohols usually provides the inverted allylic alcohol in
75-90% purity, unless the face for SN2 attack is sterically
crowded, as in 2â-deuterio-2R-hydroxy-1R,5R-bicyclo-
[3.3.0]oct-3-ene (11), in which case the product distribu-
tion approaches a statistical one. This range in product
distribution is small for the variety of substrates chosen
and dependent on the choice of solvent and on olefin
substitution. When SN2 attack is appreciably sterically
less favored than attack from the same face (as for 11),
or when CH2Cl2 is used as a solvent, products from
retention at the carbinol center are observed. Even for
sterically undemanding (R)-3-deuterio-2-cyclohexen-1-ol,
only 72-77% SN2 type product was obtained. Most
interestingly, for 2-cyclohexen-1-ols, there is virtually no
difference in the product distribution when the alcohol
is constrained to a quasi-axial or quasi-equatorial posi-
tion, as in the case of cis- or trans-5-tert-butyl-2-cyclo-
hexen-1-ol. Benzene appears to be the most useful
solvent for this reaction, with product yields and purity
slightly better than those in THF. Generally, CH2Cl2 was
found to be a poor solvent for this reaction.
product distribution, %
allylic
alcohol solvent cis/transa yielda
45
46
47
48
(+)-cis-5-Isopropyl-2-methyl-2-cyclohexen-1-ol
(quasi-equatorial OH)
43
43
43
THF
benzene
CH2Cl2
9/91
5/95
15/85
96
95
25
6
2
14
82
85
66
9
10
19
3
3
1
(-)-trans-5-Isopropyl-2-methyl-2-cyclohexen-1-ol
(quasi-axial OH)
44
44
44
THF
benzene
CH2Cl2
93/7
94/6
91/9
83
95
14
3
11
16
4
4
4
3
2
5
90
83
75
a
Ratio and yield of the isolated, chromatographically pure
benzoates.
analyses of the Mitsunobu reactions of allylic alcohols 43
and 44 are presented in Table 5.
Inspection of these results reveals a dramatic solvent
effect with respect to yield, and to a lesser extent
selectivity; clearly, CH2Cl2 is not a suitable solvent for
this reaction. The overall selectivities for this reaction
are consistent with the loss of optical purity reported for
this reaction on (+)-carvol30 and are also quite similar
to those for cis- and trans-1-deuterio-5-tert-butyl-2-cyclo-
hexen-1-ol, and thus show little difference in the results
between the quasi-axial and quasi-equatorial alcohols.
Additionally, preference for anti over syn addition in the
product from allylic migration increased to greater than
3:1.
The data obtained from these studies seem to suggest
several features about the reaction. In all of these
relatively unbiased cyclic allylic alcohols, the direct
inversion is always accompanied with a certain amount
of allylic migration product, which tends to be between
Exp er im en ta l Section
Gen er a l Meth od s. 1H NMR spectra were recorded at
either 300 or 360 MHz and 13C NMR at 75.47 or 90.56 MHz
in CDCl3 unless otherwise stated. Fourier transform infrared
spectra (IR) were obtained as neat films on NaCl plates
(liquids) or as KBr pellets (solids). Elemental analyses were
performed by Spang Microanalytical laboratory, Eagle Harbor,
MI, or by the Microanalytical Laboratory, Department of
Chemistry, The University of Michigan, Ann Arbor, MI.
Column chromatographic separation was performed with the
method of flash column chromatography with Merck 230-400
mesh silica gel.32 Reactions were monitored by thin-layer
(30) (a) Takano, S.; Inomata, K.; Ogasawara, K. Chem. Lett. 1992,
443. (b) Mori, M.; Saitoh, F.; Uesaka, N.; Shibasaki, M. Chem. Lett.
1993, 213. (c) Uesaka, N.; Saitoh, F.; Mori, M.; Shibasaki, M.;
Okamura, K.; Date, T. J . Org. Chem. 1994, 59, 5633.
(31) (a) Epiotis, N. D.; Cherry, W. R.; Shaik, S.; Yates, R. L.;
Bernardi, F. Top. Curr. Chem. 1977, 70, 1. See also ref 22c.
(32) Still, W. C.; Kahn, M.; Mitra, A. J . J . Org. Chem. 1978, 43,
2923.

8300 J . Org. Chem., Vol. 62, No. 24, 1997
Shull et al.
chromatography (TLC) with Analtech 250 plates with fluo-
rescent indicator. Spots were detected by ultraviolet light (254
nm) and iodine vapor or ceric ammonium sulfate-sulfuric acid.
All reagents and starting materials were purchased from
Aldrich Chemical Co. Tetrahydrofuran (THF) and ether were
distilled from sodium benzophenone ketyl. Methylene chloride
and pyridine were distilled from calcium hydride. Benzene
was distilled from sodium metal and stored under nitrogen.
Nondeuterated benzoates and MTPA esters were prepared
from nondeuterated cyclic allylic alcohols (obtained in the same
manner as the deuterated ones described below with the
appropriate substitution of nondeuterated reagents) in order
to establish their spectral properties. All product ratios were
determined by integration of the carbinol and olefinic peaks
in the 1H and 2H NMR spectra.
(()-2â,3â-Ep oxy-1r,2â,3â,5r-bicyclo[3.3.0]oct-2-en eox-
ir a n e. In a three-necked, round-bottomed flask fitted with a
reflux condenser, dropping funnel, and a vent for nitrogen was
added 5.00 g (46.2 mmol) of bicyclo[3.3.0]oct-2-ene (7) in 100
mL of chloroform. A solution of 10.0 g (57.9 mmol) of 3-chloro-
perbenzoic acid in 100 mL of chloroform was added dropwise.
After the addition was complete, the reaction mixture was
refluxed for 2 h. The solution was cooled with an ice bath and
the resultant precipitate removed by filtration. The filtrate
was washed once with 100 mL of 1 N aqueous sodium bisulfate
and then twice with 100-mL portions of saturated aqueous
sodium bicarbonate. The organic layer was dried over anhy-
drous magnesuim sulfate, and the solvent was removed under
reduced pressure. The residue was purified by flash chroma-
tography with hexanes/ethyl acetate (97.5:2.5) to give 3.02 g
(53%) of the exo epoxide as a colorless liquid: 1H NMR (300
MHz) δ 1.25-1.73 (m, 7H), 2.24 (dd, 1H, J ) 8.9, 14.4 Hz),
2.30-2.40 (m, 1 H), 2.61 to 2.68 (m, 1H), 3.31 (d, 1H, J ) 2.4
Hz), 3.47 (d, 1H, J ) 2.4 Hz); 13C NMR (75.47 MHz) δ 25.54
(t), 27.58 (t), 33.46 (t), 35.22 (t), 40.20 (d), 45.93 (d), 59.26 (d),
61.71 (d); IR (neat) 3015, 2951, 2865, 1417, 1450. 1398, 1270,
1222, 1008, 837 cm-1. Anal. Calcd for C8H12O: C, 77.38; H,
9.74. Found: C, 77.46; H, 9.76.
(()-2r-Hyd r oxy-1r,5r-bicyclo[3.3.0]oct-2-en e (8). In a
250 mL, three-necked, round-bottomed flask fitted with a
dropping funnel, reflux condenser and a vent for nitrogen was
added 2.10 mL (20.3 mmol) of diethylamine in 50 mL of ethyl
ether. The solution was cooled to 0 °C and then treated with
9.40 mL of 1.45 M n-butyllithium in hexanes. The mixture
was stirred for 20 min, and then 1.00 g (8.05 mmol) of the exo
epoxide obtained above in 50 mL of diethyl ether was added
dropwise. The reaction mixture was stirred at room temper-
ature for 2 days and then refluxed for 8 h. After cooling to rt,
50 mL of saturated aqueous ammonuim chloride was added.
The reaction mixture was extracted twice with 50-mL portions
of ethyl acetate, and the combined organic layers were washed
once with 50 mL of brine and dried over MgSO4. The solvent
was removed under reduced pressure, and the residue was
purified by silica gel column chromatography with a hexanes/
ethyl acetate gradient (97.5:2.5 to 90:10) to give 0.321 g (39%)
of exo alcohol 8 as a colorless liquid and 0.173 g of unchanged
exo epoxide: 1H NMR (300 MHz) δ 1.20-1.70 (m, 7H), 2.39-
2.69 (m, 1H), 3.28-3.36 (m, 1H), 4.45 (br s, 1H), 5.72 (ddd,
1H, J ) 2.0, 2.1, 5.6 Hz), 5.79 (dd, 1H, J ) 2.2, 5.6 Hz); 13C
NMR (75.47 MHz) δ 24.79 (t), 30.72 (t), 32.42 (t), 49.44 (d),
51.65 (d), 85.50 (d), 132.13 (d), 139.89 (d); IR (neat) 3325, 2945,
2903, 1034, 1012 cm-1. Anal. Calcd for C8H12O: C, 77.38; H,
9.74. Found: C, 77.13; H, 9.70.
(()-1r,5r-Bicyclo[3.3.0]oct-3-en -2-on e (9). In a 250-mL,
three-necked, round-bottomed flask fitted with a dropping
funnel, mechanical stirrer, and a vent for nitrogen were placed
3.50 g (16.2 mmol) of pyridinium chlorochromate, 3.50 g of
Celite, and 100 mL of methylene chloride. The slurry was
stirred while a solution of 2.00 g (16.1 mmol) of allylic alcohol
8 in 50 mL of methylene chloride was added dropwise. After
the solution was stirred for 4 h, 75 mL of diethyl ether was
added. The reaction mixture was stirred overnight and the
resultant precipitate removed by filtration. The precipitate
was washed with ether and the filtrate concentrated under
reduced pressure. The residue was passed through Florisil
with ether as the eluent. The solvent was removed under
reduced pressure and the residue purified by silica gel column
chromatography with hexanes/ethyl acetate (10:1) to give 1.89
g (95%) of (()-1R,5R-bicyclo[3.3.0]oct-3-en-2-one (9) as a color-
less liquid: 1H NMR (300 MHz) δ 1.56-1.79 (m, 5 H), 1.88-
1.94 (m, 1H), 2.69 (dd, 1H, J )5.4, 9.8 Hz), 3.32-3.39 (m, 1H),
6.145 (dd, 1H, J ) 1.4, 5.6 Hz), 7.53 (dd, 1H, J ) 2.8, 5.6 Hz);
13C NMR (75.47 MHz) δ 23.25 (t), 29.06 (t), 29.70 (t), 46.23 (t),
49.21 (d), 133.95 (d), 166.82 (d), 212.56 (s); IR (neat) 2952,
2948, 2940, 1705, 1584, 1347, 1189 cm-1
. Anal. Calcd for
C8H10O: C, 78.65; H, 8.25. Found: C, 78.53; H, 8.34.
(()-2â-Hyd r oxy-1r,5r-bicyclo[3.3.0]oct-2-en e (10). In a
50-mL round-bottomed flask were placed 0.100 g (0.818 mmol)
of enone 9, 0.302 g (0.818 mmol) of cerium trichloride hep-
tahydrate, and 20 mL of methanol. The solution was cooled
to 0 °C, and 31 mg (0.818 mmol) of sodium borohydride was
added in several portions. The reaction mixture was stirred
at 0 °C for 4 h. The solvent was removed under reduced
pressure and the residue purified by silica gel column chro-
matography with hexanes/ethyl acetate (10:1) as the eluent
to give 94 mg (92%) of allylic alcohol 10 as a colorless liquid:
1H NMR (300 MHz) δ 1.35-1.89 (m, 6H), 2.71-2.81 (m, 1H),
3.06-3.11 (m, 1H), 4.84 (d, 1H, J ) 8.1 Hz), 5.65 (dd, 1H, J )
1.9, 5.6 Hz), 5.72 (dd, 1H, J ) 2.1, 5.6 Hz); 13C NMR (75.47
MHz) δ 26.35 (t), 26.65 (t), 32.39 (t), 45.10 (d), 50.62 (d), 78.19
(d), 133.14 (d), 137.36 (d); IR (neat) 3342, 3336, 2946, 2863,
1007 cm-1
. Anal. Calcd for C8H12O: C, 77.38; H, 9.74.
Found: C, 77.15; H, 9.75.
Gen er a l P r oced u r e for th e Mitsu n obu Rea ction of (()-
2-Deu ter io-2-h yd r oxy-1r,5r-bicyclo[3.3.0]oct-3-en e. en-
do- or exo-2-Deuterio-2-hydroxy-1R,5R-bicyclo[3.3.0]oct-3-ene
(0.120 g, 0.96 mmol) (10 or 11, respectively) was dissolved in
2 mL of solvent (THF, benzene, or CH2Cl2) with triphen-
ylphosphine (0.300 g, 1.14 mmol, 1.2 equiv) and added to a
solution of DEAD (0.200 g, 1.15 mmol, 1.2 equiv) and benzoic
acid (0.140 g, 1.14 mmol, 1.2 equiv) in 2 mL of solvent at 0 °C.
The resultant solution was stirred for 1 h at this temperature,
and then the solvent was removed under reduced pressure,
10 mL of 2:1 hexanes/ethyl acetate was added, the solution
was filtered, the solvent was removed under reduced pressure,
and the crude product was purified by silica gel chromatog-
raphy (petroleum ether). The purified benzoate mixture was
then hydrolyzed by addition of 5 mL of 5% NaOH/methanol
and the resulting mixture stirred for 3 h. The solvent was
removed under reduced pressure, and the crude mixture was
dissolved in 10 mL of ether, washed once with 5 mL of water
and 5 mL of brine, dried over Na2SO4, filtered, and concen-
trated to provide the crude product alcohols 10-13 which could
1
be analyzed by H NMR spectroscopy.
(()-2â-Hydr oxy-1r,5r-bicyclo[3.3.0]oct-3-en yl Ben zoate.
(()-2â-Hydroxy-1R,5R-bicyclo[3.3.0]oct-3-ene (10) (0.100 g, 0.80
mmol) was added to a solution of 0.126 g (0.88 mmol, 1.1 equiv)
of benzoyl chloride and 0.254 g (3.22 mmol, 4 equiv) of pyridine
in 3 mL of THF, and the resulting solution was stirred
overnight. The reaction mixture was then poured into 50 mL
of water and the resulting mixture extracted with 25 mL of
ether. The organic layer was washed with 25 mL of saturated
aqueous CuSO4 and 10 mL of brine, dried over MgSO4, filtered,
and concentrated. The crude product was then purified by
silica gel chromatography (10% ethyl acetate/hexane) to give
a colorless oil (0.145 g, 79%): 1H NMR (300 MHz) δ 1.42-
1.64 (m, 4 H), 1.66-1.75 (m, 2 H), 3.06 (m, 1 H), 3.20 (br dd,
1 H, J ) 7.1, 8.2 Hz), 5.74 (ddd, 1 H, J ) 1.9, 1.9, 5.6 Hz), 5.90
(ddd, 1 H, J ) 1.7, 2.0, 5.6 Hz), 5.94 (dd, 1 H, J ) 1.4, 8.3 Hz),
7.44 (br dd, 2 H, J ) 7.4, 7.6 Hz), 7.55 (br dd, 1 H, J ) 7.4, 7.4
Hz), 8.05 (br d, 2 H, J ) 7.6 Hz); 13C NMR (75.47 MHz) δ 26.19
(t), 27.56 (t), 31.96 (t), 43.93 (d), 50.34 (d), 81.02 (d), 128.33
(d, 2 C), 128.99 (d), 129.57 (d, 2 C), 130.71 (s), 132.77 (d), 139.31
(d), 166.31 (s); IR (neat) 1713, 1176, 1113 cm-1; high-resolution
MS (EI) calcd for C15H16O2 (M)+ m/z 228.1150, found m/z
228.1141.
(()-2r-Hydr oxy-1r,5r-bicyclo[3.3.0]oct-3-en yl Ben zoate.
(()-2R-Hydroxy-1R,5R-bicyclo[3.3.0]oct-3-ene (8) (0.100 g, 0.80
mmol) was added to a solution of 0.126 g (0.88 mmol, 1.1 equiv)
of benzoyl chloride and 0.254 g (3.22 mmol, 4 equiv) of pyridine
in 3 mL of THF and the resulting mixture stirred overnight.
The solution was then poured into 50 mL of water and the

Mitsunobu Reaction of Unbiased Alcohols
J . Org. Chem., Vol. 62, No. 24, 1997 8301
resulting mixture extracted with 25 mL of ether. The organic
layer was washed with saturated aqueous (25 mL) CuSO4 and
10 mL of brine, dried over MgSO4, filtered, and concentrated.
The crude product was then purified by silica gel chromatog-
raphy (10% ethyl acetate/hexane) to give a colorless oil (0.140
g, 76%): 1H NMR (300 MHz) δ 1.35-1.68 (m, 4 H), 1.70-1.83
(m, 2 H), 2.68 (ddd, 1 H, J ) 1.5, 7.3, 10.9 Hz), 3.39 (ddd, 1 H,
J ) 2.5, 6.1, 7.3 Hz), 5.58 (d, 1 H, J ) 1.8 Hz), 5.81 (ddd, 1 H,
J ) 2.1, 2.1, 5.5 Hz), 5.96 (dd, 1 H, J ) 2.1, 5.5 Hz), 7.42 (br
dd, 2 H, J ) 7.4, 7.6 Hz), 7.54 (br dd, 1 H, J ) 7.4, 7.4 Hz),
8.04 (br d, 2 H, J ) 7.6 Hz); 13C NMR (75.47 MHz) δ 24.77 (t),
30.77 (t), 32.25 (t), 48.30 (d), 49.59 (d), 88.44 (d), 128.14 (d, 2
C), 128.35 (d), 129.47 (d, 2 C), 130.71 (s), 123.58 (d), 142.15
(d), 166.48 (s); IR (neat) 1713, 1176, 1113 cm-1; high-resolution
MS (EI) calcd for C15H16O2 (M)+ m/z 228.1150, found m/z
228.1145.
MgSO4 and filtered, and the solvent was removed under
reduced pressure. The crude product was then dissolved in
100 mL of ether and the solution cooled to 0 °C, and 40 mL of
1 M LiAlH4 (or LiAlD4 for the preparation of 25) in ether was
added dropwise. The reaction mixture was stirred for 1 h and
then carefully neutralized by the addition of 50 mL of water
and then 50 mL of 10% aqueous HCl. The organic layer was
separated, and the aqueous layer was extracted once with 100
mL of ether. The combined organic layers were then washed
with 50 mL of saturated NaHCO3 and 50 mL of brine, dried
over Na2SO4, and filtered, and the solvent was removed under
reduced pressure. The crude oil was then purified by silica
gel chromatography with 10% ethyl acetate in hexanes as the
eluent to afford 3.06 g (70%) of 5-methyl-2-cyclohexenone as
a colorless oil whose spectral properties matched those previ-
ously reported.34
cis-1-Deu ter io-5-m eth yl-2-cycloh exen -1-ol (24). In a 50-
mL round-bottomed flask were placed 1.00 g (9.08 mmol) of
enone 23, 3.35 g (9.08 mmol) of cerium trichloride heptahy-
drate, and 100 mL of methanol. The solution was cooled to 0
°C, and 0.381 g (9.078 mmol) of sodium borodeuteride (or 0.344
g sodium borohydride for the preparation of nondeuterated 24)
was added in several portions. The reaction mixture was
stirred at 0 °C for 4 h. The solvent was removed under reduced
pressure and the residue purified directly by silica gel column
chromatography with hexanes/ethyl acetate (10:1) as the
eluent to give 0.822 g (80%) of allylic alcohol 24 as a colorless
liquid accompanied with 3.3% of diasteriomer 26 as an
inseparable impurity. Spectral properties of nondeuterated
(R)-3-Deu ter io-2-cycloh exen -1-ol (14) was prepared by
the asymmetric reduction of 3-deuterio-2-cyclohexen-1-one33
by the method reported by Terashima et al.33 (LiAlH4, 2-ethyl-
aminopyridine, and N-methylephedrine in ether). Optical
purity was determined as 70.0% on the basis of 1H and 2H
NMR analysis after conversion to its corresponding MTPA
ester as described below.
Gen er a l P r oced u r e for t h e P r ep a r a t ion of MTP A
Ester s. The following is a slight modification of Mosher’s
method. A solution of 0.100 mmol of the cyclic allylic alcohol,
118 mg (1.5 mmol) of pyridine in 1 mL of CCl4 was cooled to
0 °C, and 38 mg (0.150 mmol) of (-)-R-methoxy-R-(trifluoro-
methyl)phenylacetyl (MTPA) chloride in 0.5 mL of CCl4 was
added, and the solution was allowed to slowly warm to rt and
stirred overnight. The reaction mixture was then poured into
15 mL of ether and washed successively with 5 mL of 5% HCl,
5 mL of aqueous saturated CuSO4, 5 mL of aqueous saturated
NaHCO3, and 5 mL of brine. The organic layer was then dried
over Na2SO4 and filtered and the solvent removed. The
residue was purified by preparative TLC (20:1 hexanes/ether)
to give the MTPA ester in 85-90% yield.
1
24 matched those reported previously.35 Its H NMR indicated
88% D incorporation and 2H NMR failed to detect the other
two isomers, 27 and 28.
tr a n s-1-Deu ter io-5-m eth yl-2-cycloh exen -1-ol (26). At
0 °C, 2.00 g (18.0 mmol) of 3-deuterio-5-methyl-2-cyclohex-
enone (25) (or 5-methyl-2-cyclohexenone (23) for the prepara-
tion of nondeuterated 26) and 21 mL (10 equiv) of 30%
hydrogen peroxide were combined in 25 mL of methanol, and
one drop of concentrated aqueous NaOH was added. The
reaction was stirred at this temperature for 1 h and then
allowed to slowly warm to rt and stirred overnight. Ether (100
mL) was then added and the resulting mixture washed three
times with 100 mL of water each and once with 50 mL of brine.
The organic layer was then dried over Na2SO4, filtered, and
concentrated under reduced pressure, and the crude oil was
dissolved in 25 mL of methanol and the solution cooled to 0
°C. Hydrazine monohydrate (9.00 g, 10 equiv) followed by one
drop of concentrated aqueous NaOH was then added and the
reaction mixture was allowed to stir for 1 h at 0 °C and 1 h at
rt. Ether (100 mL) was then added to the reaction mixture,
and the organic layer was washed with 100 mL of water three
times each and once with 50 mL of brine. The organic layer
was then dried over Na2SO4 and filtered and the solvent
removed under reduced pressure. The crude product was
purified by silica gel chromatography to afford 0.977 g (48%)
of trans-1-deuterio-5-methyl-2-cyclohexen-1-ol (26) as a color-
less oil accompanied by a small amount of inseparable cis-1-
deuterio-5-methyl-2-cyclohexen-1-ol (24) (8%), cis-3-deuterio-
5-methyl-2-cyclohexen-1-ol (27) (1%), and trans-3-deuterio-5-
methyl-2-cyclohexen-1-ol (28) (1%) as judged by 1H and 2H
NMR analysis.
(R)-3-Deu ter io-2-cycloh exen -1-yl MTP A ester (17): 1H
NMR (300 MHz) δ 1.57-2.16 (m, 6H), 3.56 (s, 3H), 5.50 (m,
1H), 5.72 (s, 0.850 H), 5.81 (s, 0.150 H), 7.37-7.41 (m, 3H),
7.47-7.59 (m, 2H).
tr a n s-(1R,5S)-5-Isop r op yl-2-m eth yl-2-cycloh exen -1-yl
MTP A ester : 1H NMR (300 MHz, benzene-d6) δ 0.71 (d, 3H,
J ) 6.7 Hz), 0.72 (d, 3H, J ) 6.7 Hz), 1.07-1.25 (m, 2H), 1.27-
1.46 (m, 2H), 1.51 (s, 3H), 1.73 (m, 1H), 1.95 (m, 1H), 3.49 (s,
3H), 5.38 (m, 1H), 5.44 (m, 1H), 7.01-7.12 (m, 3H), 7.74-7.76
(m, 2H).
cis-(1R ,5R )-5-Isop r op yl-2-m e t h yl-2-cycloh e xe n -1-yl
MTP A ester : 1H NMR (300 MHz, benzene-d6) δ 0.67 (d, 3H,
J ) 3.8 Hz), 0.71 (d, 3H, J ) 6.4 Hz), 1.17-1.39 (m, 3H), 1.46
(s, 3H), 1.49 (m, 1H), 1.66 (m, 1H), 2.20 (m, 1H), 3.47 (s, 3H),
5.53 (m, 1H), 5.69 (m, 1H), 7.00-7.11 (m, 3H), 7.73-7.75 (m,
2H).
tr a n s-(1S,5R)-5-Isop r op yl-2-m eth yl-2-cycloh exen -1-yl
MTP A ester : 1H NMR (300 MHz, benzene-d6) δ 0.64 (d, 3H,
J ) 6.7 Hz), 0.65 (d, 3H, J ) 6.7 Hz), 1.02-1.38 (m, 4H), 1.61
(s, 3H), 1.70 (m, 1H), 1.88 (m, 1H), 3.47 (s, 3H), 5.43 (m, 2H),
7.03-7.10 (m, 3H), 7.70-7.73 (m, 2H).
cis-(1S ,5S )-5-Isop r op yl-2-m e t h yl-2-cycloh e xe n -1-yl
MTP A ester : 1H NMR (300 MHz, benzene-d6) δ 0.66 (d, 3H,
J ) 6.4 Hz), 0.69 (d, 3H, J ) 6.4 Hz), 1.13-1.49 (m, 4H), 1.64
(s, 3H), 2.21 (m, 1H), 3.43 (s, 3H), 5.33 (m, 1H), 5.65 (m, 1H),
7.01-7.11 (m, 3H), 7.72-7.74 (m, 2H).
5-Meth yl-2-cycloh exen on e (23). In a three-necked flask
fitted with a Dean-Stark trap were heated 90 mL of isobutyl
alcohol, 0.100 g of p-toluenesulfonic acid, 100 mL of benzene,
and 5 g of 5-methyl-1,3-cyclohexanedione to reflux overnight.
The reaction mixture was then cooled to rt and concentrated
under reduced pressure to a volume of approximately 40 mL,
to which 40 mL of ethyl acetate was added. The organic
solution was washed three times with 20 mL portions of 10%
aqueous sodium hydroxide and then with 20 mL of aqueous
saturated sodium chloride. The organic layer was dried over
Gen er a l P r oced u r e for th e Mitsu n obu Rea ction of cis-
a n d tr a n s-1-Deu ter io-5-m eth yl-2-cycloh exen -1-ol. cis- or
trans-allylic alcohol (0.050 g, 0.44 mmol) 24 or 26, respectively,
was dissolved in 1 mL of solvent (THF, benzene, or CH2Cl2)
with triphenylphosphine (0.128 g, 0.49 mmol, 1.1 equiv), and
the mixture was cooled to 0 °C. A solution of DEAD (0.085 g,
0.49 mmol, 1.1 equiv) and benzoic acid (0.060 g, 0.49 mmol,
1.1 equiv) in 1 mL of solvent was added, and the reaction
(34) (a) Cain, D.; Procter, K.; Cassel, R. A. J . Org. Chem. 1984, 49,
2647. (b) Choudary, B. M.; Prasad, A. D.; Swapna, V.; Valli, V. L. K.;
Bhuma, V. Tetrahedron 1992, 48, 953. (c) Gorthey, L. A.; Vairamani,
M.; Djerassi, C. J . Org. Chem. 1985, 50, 4173. (d) Bambridge, K.; Clark,
B. P.; Simpkins, N. S. J . Chem. Soc., Perkin Trans. 1 1995, 2535.
(35) (a) Chamberlain, P.; Roberts, M. L.; Whitham, G. H. J . Chem.
Soc. B 1970, 1374. (b) Adam, W.; Smerz, A. Tetrahedron 1995, 51,
13039.
(33) See ref 19.

8302 J . Org. Chem., Vol. 62, No. 24, 1997
Shull et al.
mixture was allowed to warm to room temperature and stirred
for 2 h. After this time, the solvent was removed under
reduced pressure and 4 mL of 1:1 ether/petroleum ether was
added, the solution was filtered, and the solvent was removed.
Silica gel chromatography (petroleum ether) of the crude
product provided the purified benzoates 35-38.
50 mL round-bottomed flask were placed 2.00 g (13.1 mmol)
of enone 31, 4.85 g (13.1 mmol) of cerium trichloride heptahy-
drate, and 100 mL of methanol. The solution was cooled to 0
°C, and 0.551 g (13.14 mmol) of sodium borodeuteride (or 0.498
g of sodium borohydride for the preparation of nondeuterated
32) was added in several portions. The reaction mixture was
stirred at 0 °C for 4 h. The solvent was removed under reduced
pressure and the residue purified directly by silica gel column
chromatography with hexanes/ethyl acetate (10:1) as the
eluent to give 1.469 g (72%) of allylic alcohol 32 as a colorless
liquid. Spectral properties of nondeuterated 26 matched those
reported previously.35 Its 1H NMR spectrum indicated 90%
cis-5-Meth yl-2-cycloh exen -1-ol Ben zoa te. cis-5-Methyl-
2-cyclohexen-1-ol (0.100 g, 0.89 mmol) was added to 0.140 g
(0.98 mmol, 1.1 equiv) of benzoyl chloride and 0.282 g (3.57
mmol, 4.0 equiv) of pyridine in 3 mL of THF and the resulting
solution stirred overnight. The reaction mixture was then
poured into 25 mL of ether, and the resulting mixture was
washed successively with 25 mL of water, 25 mL of saturated
aqueous CuSO4, and 10 mL of brine, dried over MgSO4, and
filtered, and the solvent was removed under reduced pressure.
The crude product was purified by silica gel chromatography
(10% ethyl acetate/hexane) to give a colorless oil (0.170 g,
88%): 1H NMR (300 MHz) δ 1.03 (d, 3 H, J ) 4.7 Hz), 1.42
(ddd, 1 H, J ) 9.8, 12.1, 12.1 Hz), 1.74 (ddddd, 1 H, J ) 2.9,
2.9, 2.9, 10.3, 19.9 Hz), 1.90 (m, 1 H), 2.16 (m, 2 H), 5.65 (m,
1 H), 5.72 (br d, 1 H, J ) 10.1 Hz), 5.90 (dddd, 1 H, J ) 2.0,
2.0, 4.9, 10.1 Hz), 7.43 (br dd, 2 H, J ) 7.2, 7.6 Hz), 7.55 (dd,
1 H, J ) 7.6, 7.6), 8.05 (br d, 2 H, J ) 7.2 Hz); 13C NMR (90.56
MHz) δ 21.81 (q), 27.87 (d), 33.58 (t), 36.88 (t), 71.30 (d), 126.96
(d), 128.26 (d, 2 C), 129.61 (d, 2 C), 130.65 (d), 130.84 (s), 132.73
(d), 166.33 (s); IR (neat) 1716, 1176, 1137, 1113 cm-1; high-
resolution MS (EI) calcd for C14H16O2 (M)+ m/z 216.1150, found
m/z 216.1147.
2
D incorporation, and its H NMR detected the presence of 4.6%
diasteriomer 34 as an inseparable impurity.
tr a n s-1-Deu ter io-5-ter t-bu tyl-2-cycloh exen -1-ol (34). At
0 °C, 2.00 g (13.1 mmol) of 3-deuterio-5-tert-butyl-2-cyclohex-
enone (33) (or 5-tert-butyl-2-cyclohexenone (31) for the prepa-
ration of nondeuterated 34) and 15 mL (10 equiv) of 30%
hydrogen peroxide were combined in 25 mL of methanol and
one drop of concentrated aqueous NaOH was added. The
reaction was stirred at this temperature for 1 h and then
allowed to slowly warm to rt and stirred overnight. Ether (100
mL) was then added to the reaction mixture, and the solution
was washed three times with 100 mL of water each and once
with 50 mL of brine. The organic layer was then dried over
Na2
SO4, filtered and concentrated under reduced pressure, and
the crude oil was dissolved in 25 mL of methanol and cooled
to 0 °C. Hydrazine monohydrate (6.53 g, 10 equiv) followed
by one drop of concentrated aqueous NaOH was then added,
and the reaction mixture was stirred for 1 h at 0 °C and 1 h
at rt. Ether (100 mL) was then added to the reaction mixture,
and the organic layer was washed with 100 mL of water three
times each and once with 50 mL of brine. The organic layer
was then dried over Na2SO4 and filtered, and the solvent was
removed under reduced pressure. The crude product was
purified by silica gel chromatography to afford 0.507 g (25%)
of a 91:9 mixture of trans-1-deuterio-5-tert-butyl-2-cyclohexen-
1-ol (34) and cis-1-deuterio-5-tert-butyl-2-cyclohexen-1-ol 32 as
tr a n s-5-Meth ylcycloh ex-2-en -1-ol Ben zoa te. trans-5-
Methylcyclohex-2-en-1-ol (0.125 g, 1.11 mmol) was added to
0.160 g (1.14 mmol, 1.03 equiv) of benzoyl chloride and 0.300
g (3.79 mmol, 3.4 equiv) of pyridine in 3 mL of THF, and the
resulting solution was stirred for 12 h. The reaction mixture
was then poured into 15 mL of ether, and the resulting mixture
was washed successively with 25 mL of water, 25 mL of CuSO4,
15 mL of NaHCO3, and brine (10 mL), and dried over MgSO4,
and the solvent was removed under reduced pressure. The
crude product was the then purified by silica gel chromatog-
raphy (10% ethyl acetate/hexane) to give a colorless oil (0.164
g, 68%): 1H NMR (300 MHz) δ 1.02 (d, 3 H, J ) 6.5 Hz), 1.53
(ddd, 1 H, J ) 4.2, 12.5, 14.3 Hz), 1.68 (dddd, 1 H, J ) 2.4,
4.1, 10.2, 17.9 Hz), 1.98 (br d, 1 H, J ) 14.0 Hz), 2.23 (ddd, 1
H, J ) 4.9, 4.9, 17.9 Hz), 5.50 (br s, 1 H), 5.90 (br d, 1 H, J )
9.9 Hz), 6.05 (ddd, 1 H, J ) 2.2, 5.1, 9.9 Hz), 7.42 (br dd, 2 H,
J ) 7.4, 7.7 Hz), 7.54 (br dd, 1 H, J ) 7.4, 7.4 Hz), 8.05 (br d,
2 H, J ) 7.7 Hz); 13C NMR (90.56 MHz) δ 21.57 (q), 24.24 (d),
33.80 (t), 36.63 (t), 68.16 (d), 124.41 (d), 128.28 (d, 2 C), 129.63
(d, 2 C), 130.97 (s), 132.71 (d), 133.56 (d), 166.17 (s); IR (neat)
1
judged by H and 2H NMR analysis.
Gen er a l P r oced u r e for th e Mitsu n obu Rea ction of cis-
a n d tr a n s-1-Deu ter io-5-ter t-bu tyl-2-cycloh exen -1-ol. cis-
or trans-allylic alcohol (0.120 g, 0.77 mmol) 32 or 34, respec-
tively, was dissolved in 5 mL of solvent (THF, benzene, or CH2-
Cl2) with triphenylphosphine (0.243 g, 0.93 mmol, 1.2 equiv)
and added to a solution of DEAD (0.161 g, 0.93 mmol, 1.2
equiv) and benzoic acid (0.113 g, 0.93 mmol, 1.2 equiv) in 5
mL of solvent at 0 °C. The reaction mixture was stirred at
this temperature for 0.5 h and for 3 h at room temperature.
After this time, the reaction mixture was concentrated and
the remaining slurry dissolved in a minimum amount of ether
and then poured into 20 mL of hexane to precipitate out the
triphenylphosphine oxide. This mixture was then filtered, the
solvent was removed under reduced pressure, and the crude
product was purified by silica gel chromatography (10:1
hexanes/ethyl acetate) to give pure benzoates 39-42.
1714, 1176, 1166, 1112 cm-1
.
5-ter t-Bu tyl-2-cycloh exen on e (31). In a three-neck flask
fitted with a Dean-Stark trap were heated 90 mL of isobutyl
alcohol, 0.100 g of toluenesulfonic acid, 100 mL of benzene,
and 6.67 g of 5-tert-butyl-1,3-cyclohexanedione27 to reflux
overnight. The reaction mixture was then cooled to rt and
concentrated under reduced pressure to a volume of ap-
proximately 40 mL, to which 40 mL of ethyl acetate was added.
The organic solution was washed three times with 20 mL
portions of 10% aqueous sodium hydroxide sand then with 20
mL of brine. The organic layer was dried over MgSO4 and
filtered and the solvent removed under reduced pressure. The
crude product was then dissolved in 100 mL of ether and the
solution cooled to 0 °C, and 40 mL of 1 M LiAlH4 (or LiAlD4
for the preparation of 33) in ether was added dropwise. The
reaction was stirred for 1 h and then carefully neutralized by
the addition of 50 mL of water and then 50 mL of 10% aqueous
HCl. The organic layer was separated, and the aqueous layer
was extracted once with 100 mL of ether. The combined
organic layers were then washed with 50 mL of saturated
NaHCO3 and 50 mL of brine, dried over Na2SO4, and filtered,
and the solvent was removed under reduced pressure. The
crude oil thus obtained was then purified by silica gel chro-
matography with 10% ethyl acetate in hexanes as the eluent
to afford 4.726 g (78%) of 5-tert-butyl-2-cyclohexenone as a
colorless oil whose spectral properties matched those previ-
ously reported.
cis-5-ter t-Bu tylcycloh ex-2-en -1-ol Ben zoa te. cis-5-tert-
Butylcyclohex-2-en-1-ol (0.200 g, 1.30 mmol) was added to a
solution of 0.308 g (3.0 equiv) of pyridine and 0.200 g (1.43
mmol, 1.1 equiv) of benzoyl chloride in 3 mL of CH2Cl2, and
the resulting solution was stirred overnight. The reaction
mixture was poured into 20 mL of ether and the resulting
mixture was washed with 20 mL of NaHCO3, 25 mL of
saturated aqueous CuSO4, 25 mL of water, and 10 mL of brine,
dried over Na2SO4, and concentrated. The crude product was
purified by silica gel chromatography (10% ethyl acetate/
hexane) to give a colorless oil (0.271 g, 81%): 1H NMR (300
MHz) δ 0.91 (s, 9 H), 1.40 (dd, 1 H, J ) 11.4, 11.4 Hz), 1.55
(ddd, 1 H, J ) 4.8, 12.0, 12.0 Hz), 1.89 (m, 1 H), 2.09 (br d, 1
H, J ) 17.5 Hz), 2.28 (ddd, 1 H, J ) 1.4, 5.8, 11.4 Hz), 5.66
(m, 1 H), 5.72 (dd, 1 H, J ) 1.2,1, 11.5 Hz), 5.91 (ddd, 1 H, J
) 2.3, 4.8, 11.5 Hz), 7.44 (br dd, 2 H, J ) 7.1, 8.5 Hz), 7.54 (br
dd, 1 H, J ) 7.1, 7.1 Hz), 8.07 (br d, 2 H, J ) 8.5 Hz); 13C
NMR (75.47 MHz) δ 26.76 (t), 27.08 (q, 3 C), 30.32 (t), 32.33
(s), 43.00 (d), 72.77 (d), 127.33 (d), 128.33 (d, 2 C), 129.70 (d,
2 C), 130.98 (s, d, 2 C), 132.79 (d), 166.36 (s); IR (neat) 1717,
cis-1-Deu ter io-5-ter t-bu tyl-2-cycloh exen -1-ol (32). In a
1176, 1160, 1112 cm-1
.

Mitsunobu Reaction of Unbiased Alcohols
J . Org. Chem., Vol. 62, No. 24, 1997 8303
tr a n s-5-ter t-Bu t ylcycloh ex-2-en -1-ol Ben zoa t e. cis-5-
tert-Butylcyclohex-2-en-1-ol (0.180 g, 1.17 mmol) was added
to a solution of 0.278 g (3.0 equiv) of pyridine and 0.180 g (1.28
mmol, 1.1 equiv) of benzoyl chloride in 3 mL of CH2Cl2, and
the resulting solution was stirred overnight. The reaction
mixture was then poured into 20 mL of ether and washed with
20 mL of saturated aqueous NaHCO3, 25 mL of saturated
aqueous CuSO4, 25 mL of water, and 10 mL of brine, dried
over Na2SO4, and concentrated. The crude product was
purified by silica gel chromatography (10% ethyl acetate/
hexane) to give a colorless oil (0.225 g, 75%): bp 157 °C, 0.2
ated by hydrolysis with sodium methoxide in methanol: bp
70-75 °C (3 mmHg); [R]23D -28.3° (c 1.24, methanol) [lit. [R]22
D
-28.21° (c 2.5, methanol)]; 1H NMR (300 MHz) δ 0.88 (d, 3H,
J ) 6.5 Hz), 0.90 (d, 3H, J ) 5.9 Hz), 1.17 (dt, 1H, J ) 10.2,
12.4 Hz), 1.41 (m, 1H), 1.49 (qq, 1H, J ) 6.5, 5.9 Hz), 1.72 (m,
1H), 1.75 (s, 3H), 1.97 (m, 1H), 2.12 (m, 1H), 4.17 (br s, 1H),
5.48 (m, 1H).
tr a n s-(1R,5S)-5-Isop r op yl-2-m eth yl-2-cycloh exen -1-yl
3,5-d in itr oben zoa te: mp 115-116 °C; [R]23D +187.2° (c 1.13,
CHCl3); 1H NMR (300 MHz) δ 0.90 (d, 6H, J ) 6.60 Hz), 1.49-
1.62 (m, 3H), 1.75 (s, 3H), 1.81 (m, 1H), 2.05 (m, 1H), 2.23 (m,
1H), 5.58 (m, 1H), 5.87 (m, 1H), 9.16-9.24 (m, 3H).
1
mmHg; H NMR (300 MHz) δ 0.92 (s, 9 H), 1.47 (ddd, 1 H, J
) 3.9, 13.6, 13.3 Hz), 1.64-1.88 (m, 2 H), 2.10 (ddd, 1 H, J )
1.4, 1.4, 13.6 Hz), 2.19 (dddd, 1 H, J ) 1.5, 4.8, 4.8, 17.4 Hz),
5.53 (br s, 1 H), 5.92 (br dd, 1 H, J ) 9.7 Hz), 6.09 (ddd, 1 H,
J ) 2.0, 4.0, 9.7 Hz), 7.42 (br dd, 2 H, J ) 7.4 Hz), 7.53 (br dd,
1 H, J ) 7.4, 8.5 Hz), 8.04 (br d, 2 H, J ) 8.5 Hz); 13C NMR
(75.47 MHz) δ 26.97 (t), 27.09 (q, 3 C), 29.86 (t), 31.74 (s), 38.86
(d), 68.42 (d), 124.01 (d), 128.12 (d, 2 C), 129.43 (d, 2 C), 130.08
(s), 132.49 (d), 134.27 (d), 165.96 (s); IR (neat) 1714, 1175, 1110
cis-(1S,5S)-5-Isop r op yl-2-m eth yl-2-cycloh exen -1-ol (44)
was prepared in the same manner as trans-(1R,5S)-5-isopro-
pyl-2-methyl-2-cyclohexen-1-ol but from (S)-carvone. 44: [R]23
D
+28.4° (c 1.24, methanol) [lit. [R]22D +28.38° (c 2.3, methanol)].
cis-(1S,5S)-5-Isopropyl-2-methyl-2-cyclohexen-1-yl 3,5-dinitro-
benzoate: [R]23 +32.8° (c 1.07, methanol).
D
cm-1
.
Ack n ow led gm en t. The authors thank the National
Institutes of Health (DK 30025 awarded to M.K.) for
the support of this research.
tr a n s-(1R,5S)-5-Isop r op yl-2-m eth yl-2-cycloh exen -1-ol
(43)36 was prepared from commercially available (Aldrich
Chemical Co.) (R)-carvone, purified as its DNB ester37 by
recrystallization from 3:1 ethanol/ethyl acetate, and regener-
J O9615155
(36) (a) Klein, E.; Ohloff, G. Tetrahedron 1963, 1091. (b) Tadwalker,
V. R.; Narayanaswamy, M.; Rao, A. S. Indian J . Chem. 1971, 1223
and references 29a,b.
(37) (a) Read, J .; Swann, G. J . Chem. Soc. 1937, 239. (b) Mills, J . A.
J . Chem. Soc. 1952, 4976. (c) Schroeter, S. H.; Eliel, E. L. J . Org. Chem.
1965, 30, 1.