Aromatic Claisen Rearrangements of Benzyl Ketene Acetals: Conversion of Benzylic Alcohols to (ortho-Tolyl)acetates

Article abstract of DOI:10.1002/ejoc.201601354

Claisen rearrangements of benzyl vinyl ethers are much less facile than those of aliphatic allyl vinyl ethers, and their synthetic utility has remained relatively unexplored. A one-pot procedure is reported for the generation and Claisen rearrangement of benzyl vinyl ethers that contain an activating α-alkoxy substituent on the vinyl group. A [3,3]-sigmatropic mechanism was supported by trapping of the intermediate isotoluene in an intramolecular Alder–ene reaction.

Full text of DOI:10.1002/ejoc.201601354

A Journal of
Accepted Article
Title: Aromatic Claisen Rearrangements of Benzyl Ketene Acetals:
Conversion of Benzylic Alcohols to (ortho-Tolyl)Acetates
Authors: Jed M Burns, Elizabeth H Krenske, and Ross Peter McGeary
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Aromatic Claisen Rearrangements of Benzyl Ketene Acetals:
Conversion of Benzylic Alcohols to (ortho-Tolyl)Acetates
Jed M. Burns, Elizabeth H. Krenske and Ross P. McGeary*
Aliphatic Claisen rearrangement (allyl vinyl ethers)
(a)
Abstract: Claisen rearrangements of benzyl vinyl ethers are much
less facile than those of aliphatic allyl vinyl ethers, and their synthetic
utility has remained relatively unexplored. A one-pot procedure is
reported for the generation and Claisen rearrangement of benzyl
vinyl ethers that contain an activating -alkoxy substituent on the
vinyl group. A [3,3]-sigmatropic mechanism is supported by trapping
of the intermediate isotoluene in an intramolecular Alder-ene
reaction.
R = OSiR3
R
R
Ireland-Claisen
R = OR
O
O
Johnson-Claisen
R = NMe2
Eschenmoser-Claisen
2
1
Aromatic Claisen rearrangement (allyl phenyl ethers)
O
O
OH
Introduction
4
5
3
The Claisen rearrangement of allyl vinyl ethers to ɣ,δ-
unsaturated carbonyl compounds (Scheme 1a), first reported in
1912,[1] is a fundamentally important organic transformation.[2]
The wide utility of the Claisen rearrangement and its variants,
including the Ireland–Claisen,[3] Johnson–Claisen[4] and
Eschenmoser–Claisen[5] rearrangements, has led to many
applications in natural products synthesis.[2, 6]
Aromatic Claisen rearrangement (benzyl vinyl ethers)
R
R
R
O
O
O
6
7
8
Claisen rearrangements of aliphatic allyl vinyl ethers 1 are
well known, as are the “aromatic” Claisen rearrangements of
allyl phenyl ethers 3.[2] Much less is known about the
rearrangements of benzyl vinyl ethers 6, which in principle
represents a “missing” substrate class. For benzyl vinyl ethers,
the high energy of the intermediate isotoluene 7 disfavors the
Claisen rearrangement relative to other thermal reactions such
(b)
O
OBn
O
OBn
O
distillation
150 °C
OBn
9
11
(46%)
10
7]
as [1,3]-sigmatropic rearrangement and polymerization.[5,
McElvain’s conversion of 9 to 11 (Scheme 1b) upon distillation at
150 °C is one of the few reported examples of a Claisen
rearrangement of a benzyl vinyl ether derivative.[8] Until now, no
broadly applicable solution-phase methodology for the
rearrangement of this class of substrates has been identified.[9]
Scheme 1. (a) Claisen Rearrangements. (b) McElvain’s Rearrangement of a
Benzyl Ketene Acetal.[8]
.
Results and Discussion
Herein we report the development of methodology for
aromatic Claisen rearrangements of benzyl vinyl ethers which
utilizes the activating effect of an α-alkoxy substituent on the
vinyl group (i.e., benzyl ketene acetals). We describe the
substrate scope and regioselectivity of the process, which may
be conveniently conducted in one pot starting from the α-
bromoacetal. We report trapping studies that provide evidence
for a concerted [3,3]-sigmatropic mechanism.
Quantum mechanical computations reveal the extent to
which the Claisen rearrangement of a benzyl vinyl ether is
disfavored with respect to that of an aliphatic analogue (Figure
1). The barrier (G‡) for rearrangement of benzyl vinyl ether 6a,
computed with CBS-QB3, is 40.1 kcal/mol, which is about 10
kcal/mol higher than the barrier for rearrangement of allyl vinyl
[11]
ether 1a (29.8 kcal/mol).[10]
Isotoluene intermediate 7a is 13
kcal/mol higher in energy than 6a, but subsequent
rearomatization to 8a is favorable and the overall conversion of
6a to 8a has G = –20 kcal/mol. We surmised that, similar to the
Johnson–Claisen rearrangement,[12] an -alkoxy substituent on
the vinyl group would activate a benzyl vinyl ether toward
rearrangement. Computations supported this idea, predicting
that the barrier for rearrangement of methoxy-substituted benzyl
ketene acetal 6b is 29.9 kcal/mol, almost the same as the barrier
for allyl vinyl ether 1a. Furthermore, the alkoxy substituent
renders isotoluene intermediate 7b 5 kcal/mol more stable than
reactant 6b.
[a]
School of Chemistry and Molecular Biosciences,
The University of Queensland,
St Lucia, Brisbane, QLD, 4072, Australia
E-mail: r.mcgeary@uq.edu.au.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201601354
European Journal of Organic Chemistry
COMMUNICATION
suppressed and the [3,3]-sigmatropic rearrangement could be
promoted by performing the reaction in anhydrous DMF.[17] Thus,
heating 14a in DMF at reflux for 15 h provided rearranged
product 15a in 48% yield after purification by column
chromatography, with no homolysis products detectable by
GCMS. Diglyme was also found to be a permissible solvent.
Table 1. Synthesis of Bromoacetals 13.
entry
12
R
R1
H
H
H
H
H
H
H
H
yield 13 (%)
89,[a] 96[b]
61,[a] 99[b]
96[b]
1
2
3
4
5
6
7
8
12a
12b
12c
12d
12e
12f
H
4-Me
4-C6H5
4-Cl
65[a]
Figure 1. Free Energy Profiles for Claisen Rearrangements of 1a, 6a, and 6b,
Computed with CBS-QB3 (∆G in kcal/mol).
4-Br
4-OMe
4-SMe
64[b]
64[a]
12g
12h
71[b]
Accordingly, we focused our attention on the
rearrangements of benzyl ketene acetals (general structure 14,
Scheme 2). The synthesis of 14 required access to -
bromoacetals 13, which were prepared by two routes (Table 1).
Bromoacetalization[13] utilizing ethyl vinyl ether (EVE) and N-
bromosuccinimide (NBS) in DCM proved to be operationally
simple, but gave only moderate yields of 13 (~60%).[14]
Alternatively, bromination with Br2/DIPEA provided 13 in superior
yields (64–99%).[15]
(CH)4
94[b]
(1-naphthyl)
9
12i
(CH)4
(2-naphthyl)
H
72[b]
10
11
12
13
14
15
16
17
18
19
20
21
22
12j
H
Me
40, [a] 99[b]
23, [a] 90[b]
40, [a] 82[b]
54, [a] 92[b]
43[a]
12k
12l
4-F
H
3-OMe
3-Br
H
12m
12n
12o
12p
12q
12r
12s
12t
H
H
(CH2)3CH=CH2
H
(CH2)4CH=CH2
53[a]
4-NMe2
4-SO2Me
4-COOBn
4-NO2
4-CN
4-CF3
H
H
87[b]
H
80[b]
Scheme 2. Synthetic Routes to Benzyl Ketene Acetals 14.
H
85[b]
H
55[a]
Bromoacetal 13a was converted to ketene acetal 14a[8, 14, 16]
by treatment with KOtBu in THF (1 M), typically under reflux to
drive the elimination of HBr to completion (Table 2, Method A).
The crude ketene acetal 14a could be isolated by diluting the
reaction mixture with hexanes, filtering off the inorganic salts,
and evaporating the filtrate, as per the procedure of Middleton
and Simpkins.[14] Due to instability toward hydrolysis, the ketene
acetals were generally carried forward without further purification.
H
60[a]
12u
12v
H
68[b]
Me2
58[b]
[a] NBS used as the brominating agent. [b] Br2/DIPEA used as the
brominating agent.
Rather than isolating ketene acetals 14 prior to conducting
their Claisen rearrangements, we found that the procedure could
be simplified by combining the elimination of HBr from
bromoacetal 13 and the rearrangement of ketene acetal 14 into
a one-pot operation (Table 2, Method B). Such procedures are
commonplace in the Ireland variant of the Claisen
rearrangement. Results of the elimination/rearrangement
sequence involving a range of bromoacetals are given in Table
2. Purification of the arylacetate esters 15 by column
chromatography proved tedious, due to the presence of benzyl
acetates (hydrolytic side products of ketene acetals 14).
With ketene acetals 14 in hand, conditions for the Claisen
rearrangement to arylacetates 15 were explored (Table 2). Initial
experiments employed xylenes as a non-polar, high boiling point
solvent. Heating a solution of 14a (R = R1 = H) in xylenes at
reflux for 15 h led to the formation of a complex mixture which
did not contain any of the expected Claisen rearrangement
product 15a. Among the components identified by GCMS
analysis were diethyl succinate, bibenzyl and ethyl 3-
phenylpropionate, which are thought to be products of radical
fission/recombination reactions of 14a.
A solvent screen
revealed that these undesired homolytic processes could be
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10.1002/ejoc.201601354
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However, saponification of the crude reaction mixtures with
ethanolic KOH allowed ready isolation of the corresponding
carboxylic acids 16 (Table 2) in pure form.
para-NMe2, NO2, CN, CO2Bn, SO2Me and CF3 derivatives all
decomposed under the reaction conditions. However, the fluoro-
substituted substrate 13k did provide a 28% yield of rearranged
product. The failure to obtain rearranged products from ketene
acetals bearing strong donor or acceptor groups is not
necessarily due to a higher rearrangement barrier, but more
likely reflects the incompatibility of such substrates towards the
conditions of the elimination/rearrangement protocol.
Table 2. Synthesis and Claisen Rearrangements of Benzyl Ketene Acetals 14
The rearrangements of meta-substituted benzyl ketene
acetals were found to be moderately regioselective (Scheme 3).
For the meta-methoxy and meta-bromo substituted ketene
acetals 14l and 14m, products 15/16-ortho were favored over
15/16-para with a selectivity of 3:2–4:1. The preference for the
more sterically crowded regioisomer is surprising, and is not
observed in normal aromatic Claisen rearrangements of allyl
phenyl ethers.[18] However, comparable regioselectivity has
previously been noted in rearrangements of fused aromatic
systems similar to 14i.[19]
Scheme 3. Regioselective Claisen Rearrangements of meta-Substituted
Benzyl Vinyl Ethers.
[a] Method A, DMF [b] Method B, DMF [c] Method B, diglyme.
Trapping studies were conducted to probe the mechanism of
the benzyl ketene acetal Claisen rearrangement. Based on the
known reactivity of isotoluenes[20] and dearomatized furans[21]
towards Alder-ene reactions, we designed ketene acetal 14n
(Scheme 4), for which the isotoluene intermediate 17n could
undergo either tautomerization to 15n or an intramolecular
Alder-ene reaction with the tethered alkene (red arrows) giving
18n. Rearrangement of 14n under the standard reaction
conditions was found to give Alder-ene product 18n and regular
product 15n in a ratio of 2:1 (41% yield), supporting the
proposed involvement of isotoluene 17n. As expected,[22] the
length of the tether was crucial to the Alder-ene reaction. With
an additional methylene group in the tether, none of the
cyclohexyl homologue of 18n was detected, and only the regular
tautomerization product was obtained (see the Supporting
Information).
The elimination/Claisen rearrangement protocol was
compatible with a range of electron-neutral and donor groups on
the aromatic ring. Thus, the para-Me, Ph, Cl, Br, OMe and SMe
derivatives 13b–g gave arylacetates 16b–g, respectively, in
yields of 27–58% for three steps in the one pot (Table 2),
comparable to the yield obtained with the unsubstituted system
13a (50%). Replacement of the benzyl group by 1- or 2-naphthyl
(13h and 13i) or by a secondary benzylic group (13j) was also
tolerated.
However,
while
elimination/Claisen
rearrangement/saponification of the 1-naphthyl-bromoacetal 13h
gave 16h as the sole product, analogous reactions of the 2-
naphthyl-bromoacetal 13i gave mainly 16i, accompanied by 3-
(naphthalene-2-yl)propionic acid, the product of
sigmatropic shift (See Supporting Information). Powerful donor
or acceptor groups were not compatible with the transformation;
a [1,3]-
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10.1002/ejoc.201601354
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We thank the Australian Research Council (FT120100632 to
E.H.K.) for financial support. Computational resources were
provided by the National Computational Infrastructure National
Facility (Australia) and The University of Queensland Research
Computing Centre.
Keywords: Claisen rearrangement • Benzyl-Claisen • Ketene
acetal • Density Functional Theory • Alder-ene
[1]
[2]
[3]
L. Claisen, Ber. Dtsch. Chem. Ges. 1912, 45, 3157-3166.
A. M. Martín Castro, Chem. Rev. 2004, 104, 2939-3002.
a) R. E. Ireland, R. H. Mueller, J. Am. Chem. Soc. 1972, 94, 5897-
5898; b) R. E. Ireland, R. H. Mueller, A. K. Willard, J. Am. Chem. Soc.
1976, 98, 2868-2877.
Scheme 4. Tandem Claisen Rearrangement/Alder-Ene Reaction of 14n
Showing Evidence for Formation of Isotoluene Intermediate 17n. Conditions
are Method B, DMF (see Table 2).
[4]
[5]
W. S. Johnson, L. Werthemann, W. R. Bartlett, T. J. Brocksom, T.-T. Li,
D. J. Faulkner, M. R. Petersen, J. Am. Chem. Soc. 1970, 92, 741-743.
a) A. E. Wick, D. Felix, K. Steen, A. Eschenmoser, Helv. Chim. Acta
1964, 47, 2425-2429; b) D. Felix, K. Gschwend-Steen, A. E. Wick, A.
Eschenmoser, Helv. Chim. Acta 1969, 52, 1030-1042.
Conclusions
We have demonstrated the successful implementation of
Claisen rearrangements involving benzyl vinyl ether derivatives.
These substrates are intrinsically much less prone to Claisen
rearrangements than are allyl vinyl ethers 1 or allyl phenyl ethers
3, but we have shown that their rearrangements are promoted
by an α-alkoxy substituent on the vinyl group, similar to the
Johnson–Claisen rearrangement. These results expand the
applicability of Claisen rearrangements to a challenging and
previously little-studied substrate class. Studies of the
mechanism of the rearrangement will be reported in due course.
[6]
[7]
a) F. E. Ziegler, Chem. Rev. 1988, 88, 1423-1452; b) M. Hiersemann, U.
Nubbemeyer, Eds, The Claisen Rearrangement, Wiley-VCH Verlag
GmbH & Co. KGaA, Weinheim, Germany, 2007.
a) A. W. Burgstahler, L. K. Gibbons, I. C. Nordin, J. Chem. Soc. 1963,
4986-4989; b) I. Shiina, H. Nagasue, Tetrahedron Lett. 2002, 43, 5837-
5840; c) S. Raucher, A. S. T. Lui, J. Am. Chem. Soc. 1978, 100, 4902-
4903; d) W. J. le Noble, P. J. Crean, J. Am. Chem. Soc. 1964, 86,
1649-1650; e) V. Valerio, C. Madelaine, N. Maulide, Chem. Eur. J.
2011, 17, 4742-4745.
[8]
[9]
S. M. McElvain, H. I. Anthes, S. H. Shapiro, J. Am. Chem. Soc. 1942,
64, 2525-2531.
For Claisen rearrangements of benzyl propargyl ethers, see Tudjarian,
A. A.; Minehan, T. G. J. Org. Chem. 2011, 76, 3576–3581.
Experimental Section
[10] For previous CBS-QB3 calculations on the Claisen rearrangements of
1a and 3, see: S. Osuna, S. Kim, G. Bollot, K. N. Houk, Eur. J. Org.
Chem. 2013, 2013, 2823-2831.
Typical procedure for the synthesis of bromoacetals 13: To a round-
bottom flask (under argon and cooled in an ice bath) was added 50 mL
DCM and 0.5 mL (9.4 mmol) bromine (dissolved in approximately 4 mL
DCM). Ethyl vinyl ether (1.00 mL, 10.3 mmol) was then added dropwise,
the mixture changed from red-brown to clear (indicating complete
consumption of bromine). The mixture was left to stir at 0 oC for 5
minutes before DIPEA (1.8 mL, 10.3 mmol) was added in one portion
followed by the requisite alcohol 12 (6.3 mmol) dropwise. Once addition
was complete, the reaction flask was removed from the ice bath and
allowed to stir at room temperature under argon. After stirring overnight,
the mixture was washed with 30 mL saturated NaHCO3 solution then 30
mL brine. The organic phase was dried with Na2SO4, filtered and
evaporated in vacuo to a brown oil. Products were purified by silica gel
chromatography.
[11] Several previous computational studies of the aromatic Claisen
rearrangement of 3 have proposed that the tautomerization step (45)
may be rate limiting in certain media. See (a) Yamabe, S.; Okumoto, S.;
Hayashi, T. J. Org. Chem. 1996, 61, 6218; (b) Zheng, Y.; Zhang, J. J.
Phys. Chem. A 2010, 114, 4325; (c) Ghadari, R.; Shaabani, A.; J. Mol.
Model. 2012, 18, 319.
[12] For previous theoretical studies of substituent effects on the Claisen
rearrangement, see: (a) Yoo, H. Y.; Houk, K. N. J. Am. Chem. Soc.
1997, 119, 2877. (b) Aviyente, V.; Yoo, H. Y.; Houk, K. N. J. Org. Chem.
1997, 62, 6121–6128. (c) Aviyente, V.; Houk, K. N. J. Phys. Chem. A
2001, 105, 383–391.
[13] a) Y. Ueno, O. Moriya, K. Chino, M. Watanabe, M. Okawara, J. Chem.
Soc., Perkin Trans. 1 1986, 1351-1356; b) G. Stork, P. M. Sher, H. L.
Chen, J. Am. Chem. Soc. 1986, 108, 6384-6385.
Typical procedure for one-pot elimination-Claisen rearrangement:
To a round-bottom flask, equipped with a reflux condenser, under argon
was placed the requisite bromoacetal 13 and DMF (to form a 0.5 M
solution). To this was added 1.1 eq KOtBu. The reaction mixture became
warm and a cloudy precipitate formed.[23] The mixture was allowed to stir
at RT for 30 minutes before being heated at 155 oC (oil bath
temperature) overnight. The reaction mixture was then poured into 20 mL
distilled water and extracted with 5 × 20 mL hexanes. The organic layer
was washed with 2 × 20 mL distilled water and 20 mL brine, then dried
(Na2SO4), filtered and evaporated in vacuo to give the crude product.
Hydrolysis of the crude product with ethanolic KOH yielded the product
acid 16.
[14] D. S. Middleton, N. S. Simpkins, Synth. Commun. 1989, 19, 21-29.
[15] P. Magnus, N. Sane, B. P. Fauber, V. Lynch, J. Am. Chem. Soc. 2009,
131, 16045-16047.
[16] a) W. J. Bailey, L.-L. Zhou, Tetrahedron Lett. 1991, 32, 1539-1540; b)
Q.-H. Zheng, J. Su, Synth. Commun. 1999, 29, 3467-3476.
[17] Eschenmoser has noted
a
similar effect when applying the
Eschenmoser-Claisen rearrangement to benzyl alcohol. See: Felix, D.;
Gschwend-Steen, K.; Wick, A. E.; Eschenmoser, A. Helv. Chim. Acta
1969, 52, 1030.
[18] a) F. C. Gozzo, S. A. Fernandes, D. C. Rodrigues, M. N. Eberlin, A. J.
Marsaioli, J. Org. Chem. 2003, 68, 5493-5499; b) W. N. White, C. D.
Slater, J. Org. Chem. 1961, 26, 3631-3638.
[19] 2-Naphthylmethanol 12i leads to 19 as the sole product when
submitted to Eschenmoser-Claisen conditions. See: Felix, D.;
Acknowledgements
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10.1002/ejoc.201601354
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Gschwend-Steen, K.; Wick, A. E.; Eschenmoser, A. Helv. Chim. Acta
1969, 52, 1030.
[21] W. H. Miles, E. A. Dethoff, H. H. Tuson, G. Ulas, J. Org. Chem. 2005,
70, 2862-2865.
[22] W. Oppolzer, V. Snieckus, Angew. Chem., Int. Ed. Engl. 1978, 17, 476-
486.
[23] The cloudy precipitate (KBr) is also observed when the reaction is run
in diglyme.
[20] a) J. J. Gajewski, A. M. Gortva, J. Am. Chem. Soc. 1982, 104, 334-335;
b) J. J. Gajewski, A. M. Gortva, J. Org. Chem. 1989, 54, 373-378; c) W.
D. Graham, J. G. Green, W. A. Pryor, J. Org. Chem. 1979, 44, 907-914.
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Benzylic Claisen rearrangements*
Jed M. Burns, Elizabeth H. Krenske and
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Aromatic Claisen Rearrangements of
Benzyl Ketene Acetals: Conversion of
Benzylic Alcohols to (Ortho-
Tolyl)Acetates
A one-pot procedure is reported for the generation and Claisen rearrangement of
benzyl vinyl ethers that contain an activating -alkoxy substituent on the vinyl
group. A [3,3]-sigmatropic mechanism is supported by trapping of the intermediate
isotoluene in an intramolecular Alder-ene reaction.
*one or two words that highlight the emphasis of the paper or the field of the study
[1]
[2]
[3]
L. Claisen, Ber. Dtsch. Chem. Ges. 1912, 45, 3157-3166.
A. M. Martín Castro, Chem. Rev. 2004, 104, 2939-3002.
a) R. E. Ireland, R. H. Mueller, J. Am. Chem. Soc. 1972, 94, 5897-5898; b) R. E. Ireland, R. H.
Mueller, A. K. Willard, J. Am. Chem. Soc. 1976, 98, 2868-2877.
[4]
[5]
[6]
W. S. Johnson, L. Werthemann, W. R. Bartlett, T. J. Brocksom, T.-T. Li, D. J. Faulkner, M. R.
Petersen, J. Am. Chem. Soc. 1970, 92, 741-743.
a) A. E. Wick, D. Felix, K. Steen, A. Eschenmoser, Helv. Chim. Acta 1964, 47, 2425-2429; b) D.
Felix, K. Gschwend-Steen, A. E. Wick, A. Eschenmoser, Helv. Chim. Acta 1969, 52, 1030-1042.
a) F. E. Ziegler, Chem. Rev. 1988, 88, 1423-1452; b) M. Hiersemann, U. Nubbemeyer, Eds, The
Claisen Rearrangement, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007.
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10.1002/ejoc.201601354
European Journal of Organic Chemistry
COMMUNICATION
[7]
a) A. W. Burgstahler, L. K. Gibbons, I. C. Nordin, J. Chem. Soc. 1963, 4986-4989; b) I. Shiina,
H. Nagasue, Tetrahedron Lett. 2002, 43, 5837-5840; c) S. Raucher, A. S. T. Lui, J. Am. Chem.
Soc. 1978, 100, 4902-4903; d) W. J. le Noble, P. J. Crean, J. Am. Chem. Soc. 1964, 86, 1649-
1650; e) V. Valerio, C. Madelaine, N. Maulide, Chem. Eur. J. 2011, 17, 4742-4745.
S. M. McElvain, H. I. Anthes, S. H. Shapiro, J. Am. Chem. Soc. 1942, 64, 2525-2531.
For Claisen rearrangements of benzyl propargyl ethers, see Tudjarian, A. A.; Minehan, T. G. J.
Org. Chem. 2011, 76, 3576–3581.
[8]
[9]
[10] S. Osuna, S. Kim, G. Bollot, K. N. Houk, Eur. J. Org. Chem. 2013, 2013, 2823-2831.
[11] The proton transfer step of the aromatic Claisen rearrangement is proposed to be rate limiting.
See (a) Yamabe, S.; Okumoto, S.; Hayashi, T. J. Org. Chem. 1996, 61, 6218; (b) Zheng, Y.;
Zhang, J. The Journal of Physical Chemistry A 2010, 114, 4325.
[12] Previous theoretical studies of substituent effects on the Claisen rearrangement: (a) Yoo, H. Y.;
Houk, K. N. J. Am. Chem. Soc. 1997, 119, 2877–2884. (b) Aviyente, V.; Yoo, H. Y.; Houk, K.
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[14] D. S. Middleton, N. S. Simpkins, Synth. Commun. 1989, 19, 21-29.
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[17] Eschenmoser has noted a similar effect when applying the Eschenmoser-Claisen rearrangement
to benzyl alcohol. See: Felix, D.; Gschwend-Steen, K.; Wick, A. E.; Eschenmoser, A. Helv.
Chim. Acta 1969, 52, 1030.
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[19] 2-naphthyl methanol 13m leads to 22 as the sole product when submitted to Eschenmoser-
Claisen conditions. See: Felix, D.; Gschwend-Steen, K.; Wick, A. E.; Eschenmoser, A. Helv.
Chim. Acta 1969, 52, 1030.
[20] a) J. J. Gajewski, A. M. Gortva, J. Am. Chem. Soc. 1982, 104, 334-335; b) J. J. Gajewski, A. M.
Gortva, J. Org. Chem. 1989, 54, 373-378; c) W. D. Graham, J. G. Green, W. A. Pryor, J. Org.
Chem. 1979, 44, 907-914.
[21] W. H. Miles, E. A. Dethoff, H. H. Tuson, G. Ulas, J. Org. Chem. 2005, 70, 2862-2865.
[22] W. Oppolzer, V. Snieckus, Angew. Chem., Int. Ed. Engl. 1978, 17, 476-486.
[23] The cloudy precipitate (KBr) is also observed when the reaction is run in diglyme.
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