An intramolecular Heck reaction that prefers a 5-endo- to a 6-exo-trig cyclization pathway

Article abstract of DOI:10.1055/s-2006-951504

A regioselective aromatic Claisen rearrangement was used to prepare 17a, the precursor of triflate 17e. The intramolecular Heck reaction of 17e is promoted only by bidentate phosphine ligands, giving exclusively and in excellent yield 20, the product of a 5-endo-trig cyclization, despite the possibility for a 6-exo-trig pathway. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-951504

3140
LETTER
An Intramolecular Heck Reaction that Prefers a 5-endo- to a 6-exo-trig
Cyclization Pathway
I
ntramolecular
a
H
eck
R
eac
u
tion lo Vital, Per-Ola Norrby, David Tanner*
Department of Chemistry, Technical University of Denmark, Building 201, Kemitorvet, 2800 Kgs. Lyngby, Denmark
Fax +4545933968; E-mail: dt@kemi.dtu.dk
Received 27 March 2006
ert their biological activity by mimicking 1,2-diacyl-
glycerols in the activation of protein kinase C (PKC).5a
Since activation of PKC is a crucial step in the regulation
of several essential cellular processes, the teleocidins B
Abstract: A regioselective aromatic Claisen rearrangement was
used to prepare 17a, the precursor of triflate 17e. The intramolecu-
lar Heck reaction of 17e is promoted only by bidentate phosphine
ligands, giving exclusively and in excellent yield 20, the product of
a 5-endo-trig cyclization, despite the possibility for a 6-exo-trig constitute a leading target in pharmaceutical research.5
pathway.
As part of ongoing studies towards the total synthesis of
the teleocidins B, we envisioned that the quaternary car-
bon center at C14 could be stereoselectively installed via
Key words: intramolecular Heck reaction, 5-endo-trig cyclization,
regioselective Claisen rearrangement
an intramolecular asymmetric Heck reaction (IAHR;
Scheme 1).6 In this reaction, best results are usually ob-
‘Teleocidin B’, first isolated in 1960 by Takashima and
Sakai from the mycelia of Streptomyces mediocidicus,1 is
comprised of four diastereomeric compounds, teleocidins
B-1 to B-4 (1a–d).2 The teleocidins B are related to other
natural products, namely lyngbyatoxin A (2a; aka teleoci-
din A-1) and (–)-indolactam V (2b), but are structurally
more complex in that they possess two quaternary carbon
centers embedded within a 6-membered cyclic framework
bridging the 6- and 7-positions of the indole nucleus
(Figure 1).3,4
tained with conditions that promote the formation of cat-
ionic intermediates, where the chiral ligand is believed to
remain fully chelated therefore maximizing the possibility
for asymmetric induction. Typically, this is accomplished
by combining a bidentate chiral ligand with triflates as
electrophiles.6–8 With respect to the regioselectivity in the
cyclization step (4 to 3), we expected that, in accordance
with the Baldwin rules9a,b and in line with what is usually
observed in metal-catalyzed cross-coupling reactions,9c,d
the desired 6-exo-trig cyclization to C14 would be favored
over the alternative 5-end-trig to C19.
H
12
N
IAHR
N
OH
9
4
O
1a: teleocidin B-1 (14S,17R)
1b: teleocidin B-2 (14R,17S)
1c: teleocidin B-3 (14S,17S)
1d: teleocidin B-4 (14R,17R)
3
6-exo-trig
cyclization
6
N
TfO
14
H
N
H
1
7
14
17
14
17
19
4
3
Scheme 1 Key step for formation of the carbocyclic framework of
the teleocidins B.
H
N
N
OH
O
2a: R =
2b: R = H
To test the feasibility of this approach we started by inves-
tigating how the severe steric bulk, derived from the
neighboring quaternary carbon center at C17, would af-
fect the formation of the six-membered carbocycle skele-
ton. To this end, we turned our attention to a simplified
model target, indole 5. A simplified retrosynthetic analy-
sis of 5 is shown in Scheme 2. As before, the carbocyclic
moiety in indole 5 was envisioned to be formed via an in-
tramolecular Heck reaction (IHR) of 6 (as the correspond-
ing triflate).6 Indole 6 can be prepared by an aromatic
Claisen rearrangement of 7,10,11 which in turn could be ob-
tained via a Hemetsberger–Knittel reaction12 of the corre-
sponding azidocinnamate (not shown) prepared from
ethyl azidoacetate (8), 4-hydroxybenzaldehyde (9) and
geranyl bromide (10).10
N
H
R
Figure 1 Structures of teleocidins B (1a–d), lyngbyatoxin A (2a)
and indolactam V (2b).
‘Teleocidin B’ has a strong irritating and vesicatory action
on human skin1 and is also a potent tumor promoter.2a
Like the other indolactam alkaloids, the teleocidins B ex-
SYNLETT 2006, No. 18, pp 3140–3144
Advanced online publication: 25.10.2006
DOI: 10.1055/s-2006-951504; Art ID: S05306ST
© Georg Thieme Verlag Stuttgart · New York
0
3
.1
1
.2
0
0
6

LETTER
Intramolecular Heck Reaction
3141
IHR
CO2Et
CHO
OR
N3
6
8, NaOEt
O
EtOH, –15 °C
N
H
8
HO
N
CO2R
7
H
76%
11
10, K2CO3
acetone, reflux
quant.
12
9: R = H
11: R = geranyl
5
6
aromatic
Claisen
PhMe, reflux
quant. (crude)
N3
CO2R
8
CHO
N
CO2R
O
H
N
CO2Et
O
products
shown below
H
HO
see
Table 1
Hemetsberger–
Knittel
9
13
Br
7
10
N
H
CO2Et
N
H
HO
CO2Et
HO
Scheme 2 Retrosynthetic analysis for model indole 5.
Following a literature procedure, etherification of 4-hy-
droxybenzaldehyde (9) with geranyl bromide (10) and
K2CO3 was accomplished in refluxing acetone in quanti-
tative yield (Scheme 3).13 Subsequent NaOEt-promoted
condensation of 11 with ethyl azidoacetate (8) at low tem-
perature afforded azide 12 in good yield. Thermolysis of
12 in refluxing toluene gave the known indole 13 in excel-
lent yield and high purity.10
15
14
R1O
N
R2
CO2Et
N
CO2Et
O
11
Ac
17a: R1 = R2 = H
17b: R1 = R2 = Ac
17c: R1 = Ac, R2 = H
17d: R1 = TMS, R2 = H
16
When this substrate was subjected to the usual conditions
for the aromatic Claisen rearrangement (refluxing in di-
methylaniline, entry 1, Table 1), only an equimolar in-
separable mixture of 14 and 15 was obtained, presumably
formed through further rearrangements of the expected in-
dole 17a. These so-called abnormal aromatic Claisen
rearrangements14 can in principle be avoided by trapping
the phenolic oxygen in 17a. Traditionally this has been ac-
complished by in situ conversion to the corresponding ac-
Scheme 3 Preparation and product distribution in the Claisen rear-
rangement of indole 13 (see Table 1).
Table 1 Conditions Investigated for the Aromatic Claisen Rear-
rangement of Indole 13
etate.15a,b Using the conditions developed by Kishi Entry
Reaction conditionsa
Dimethylaniline
Product distributionb
(NaOAc in refluxing Ac2O),15a we hoped to obtain the re-
1
55% of 14 and 15
(1:1 inseparable mixture)
arranged indole as the corresponding N,O-diacetate 17b.
The desired rearranged product was indeed produced, but
2
NaOAc (1.5 equiv) in Ac2O, 45% of 16
as the O-acetate 17c and only in poor yield. The main
product was instead the N-acylated compound 16 (entry
2). Performing the reaction in a refluxing mixture of Ac2O
and dimethylaniline inverted the previous ratio, delivering
the known 17c as the main product together with a small
amount of the N-acylated by-product 16 (entry 3).10 The
highest selectivity for the desired product was obtained
using the conditions developed by Fukuyama, reflux in a
mixture of HMDS and dimethylaniline,15c thus trapping
17a as the corresponding TMS ether 17d. Subsequent in
situ acidic hydrolysis yielded 17a (entry 4) in 88% over
the two steps.16
170 °C
33% of 17c
5% of 13
3
Ac2O in dimethylaniline
(1:1, v/v)
<5% of 16
61% of 17c
4c
i) HMDS (10 equiv) in
dimethylaniline
ii) aq HCl–EtOH (0 °C)
88% of 17a
a Unless stated otherwise, all reactions were performed at 195 °C in a
closed vessel.
b Isolated yields.
c See ref. 16 for experimental details.
As previously noticed by others, notably Moody and co-
workers, the Claisen rearrangement is completely regiose-
lective for the 7-position of the indole nucleus.10,17 We
have calculated the relative energies for 18 and 19
Synlett 2006, No. 18, 3140–3144 © Thieme Stuttgart · New York

3142
P. Vital et al.
LETTER
(Figure 2), simplified versions of the two possible inter-
mediates in the Claisen rearrangement at C7 and C5, re-
spectively. In accordance with the Bell–Evans–Polanyi
principle18 the relative energies of high-energy intermedi-
ates should correlate well with the relative barriers for the
two possible rearrangements. We found a difference of 40
kJ mol–1 in favor of 18, in good agreement with the ob-
served selectivity.19 The reason for the high energy differ-
ence between superficially similar intermediates is that
only 18 preserves an aromatic pyrrole moiety in its struc-
ture.
N
CO2Et
13
H
N
CO2Et
RO
H
see
Table 2
8
8
13
20
Tf2O, pyridine
CH2Cl2, –30 °C to 0 °C
75%
17a: R = H
17e: R = Tf
Scheme 4 Formation of cyclopentadieno-indole (20) via a 5-endo-
trig intramolecular Heck reaction.
Table 2 Ligands Screened for the IHR of Indole 17e
O
N
H
Conditionsa,b
Resultsc
O
N
Entry
H
1
2
3
4
5
6
7
Pd(OAc)2, rac-Binap, 3.5 h
Pd(OAc)2, PPh3, TEA, 28 h
Pd(OAc)2, PPh3, LiCl, TEA, 28 h
Pd(PPh3)4, LiCl, Et3N, 28 h
Pd2(dba)3, AsPh3, 30 h
88% of 20
18
19
–
Figure 2 Simplified versions of the two possible intermediates in
the Claisen rearrangement.
–
–
Having installed the C11 quaternary carbon we proceeded
by converting 17a into the corresponding triflate 17e. This
was accomplished in good yield by treating 17a with Tf2O
in the presence of pyridine at low temperature
(Scheme 4).
Traces of 20d
Traces of 20d
Traces of 20d
Pd(OAc)2, P(t-Bu)3, 30 h
Pd(OAc)2, biphenyl dicyclohexyl
phosphine, 43 h
For the cyclization of 17e we started by investigating the
use of rac-BINAP (entry 1, Table 2). To our surprise, the
product was not the expected cyclohexadieno-indole 5.
Instead, NMR analysis indicated the cyclopentadieno-in-
dole 20, presumably obtained via what is normally con-
sidered to be a disfavored 5-endo-trig cyclization mode.
Whereas 5-endo-type products in IHR are not unprece-
dented they are rare, being confined to special substrates
such as N-vinyl-2-haloarylamines20, aryl/alkenyl halides
containing an appropriate a,b-unsaturated carbonyl
group21 or 1,1-difluoro-1-alkenes.22 Furthermore, their
formation can frequently be rationalized by alternative
mechanisms other than a direct 5-endo cyclization.23 Ad-
ditionally, when this cyclization mode operates, it typical-
ly requires harsher conditions and often produces only
low yields of the products,24 whereas in our case indole 20
was obtained in high yield and the reaction was complete
in about 3.5 h.
8
9
Pd(OAc)2, dppf, 3.5 h
Pd(OAc)2, dppb, 3.5 h
Pd(OAc)2, dppp, 2.5 h
Pd(OAc)2, dppe, 2.5 h
Pd(OAc)2, dppbz, 24 h
88% of 20
85% of 20
88% of 20
94% of 20
10
11
12
20:17ee
2.6:1
13
Pd(OAc)2, triphos, 24 h
20:17ee
1:1.8
a All reactions were performed in refluxing THF and unless stated
otherwise, K2CO3 was used as the base.
b For experimental details, see ref.25,
c Isolated yields; ‘–’ stands for only starting material 17e recovered.
d As judged by TLC.
e Ratio based on crude 1H NMR.
In order to obtain a better understanding of this process,
and in particular if the regioselectivity of the cyclization
could be reversed into the desired 6-exo mode, we
screened several readily available ligands (Table 2). We
started by investigating the use of the classic PPh3 [with
and without LiCl as additive, entries 2 and 3, respectively,
and in the form of Pd(PPh3)4, entry 4], AsPh3 (entry 5) and
then moved on to bulkier ligands such as P(t-Bu)3 (entry
6) and biphenyl dicyclohexyl phosphine (entry 7). How-
ever, all of these monodentate ligands failed to deliver
product and only starting material was recovered. This
suggests that for this system, and in line with the generally
accepted mechanism for the cationic pathway in the Heck
reaction, a bidentate ligand is required for the stability of
the active catalyst.
Hence we subsequently investigated bidentate ligands
other than rac-BINAP. In contrast to the monodentate
ligands, all the bidentate phosphines screened succeeded
in promoting the cyclization reaction, but again only the
5-endo product 20 was obtained (entries 8–13). The in-
complete conversion, even after long reaction times, ob-
served when dppbz and triphos were used (entries 12 and
13, respectively) together with the fact that a slightly fast-
er reaction was observed for dppe and dppp (entries 10
Synlett 2006, No. 18, 3140–3144 © Thieme Stuttgart · New York

LETTER
Intramolecular Heck Reaction
3143
(4) For selected synthesis of the teleocidins B, see: (a) Okabe,
K.; Muratake, H.; Natsume, M. Tetrahedron 1991, 47,
8559. (b) Nakatsuka, S.; Masuda, T.; Goto, T. Tetrahedron
Lett. 1987, 28, 3671. (c) For a recent and interesting
approach towards the core of the teleocidins B, see:
(d) Dangel, B. D.; Godula, K.; Youn, S. W.; Sezen, B.;
Sames, D. J. Am. Chem. Soc. 2002, 124, 11856.
(5) (a) Kishi, Y.; Rando, R. R. Acc. Chem. Res. 1998, 31, 163.
(b) Newton, A. C. Chem. Rev. 2001, 101, 2353.
(c) Hinterding, K.; Alonso-Díaz, D.; Waldmann, H. Angew.
Chem. Int. Ed. 1998, 37, 688. (d) Meseguer, B.; Alonzo-
Díaz, D.; Griebenow, N.; Herget, T.; Waldmann, H. Chem.
Eur. J. 2000, 6, 3943.
(6) For some reviews, see: (a) De Meijere, A.; Bräse, S. In
Handbook of Organopalladium Chemistry for Organic
Synthesis; Negishi, E., Ed.; John Wiley and Sons: New
York, 2002, 1223. (b) Shibasaki, M.; Vogl, E. M. J.
Organomet. Chem. 1999, 576, 1. (c) Link, J. T. Org. React.
2002, 60, 157.
(7) (a) Ozawa, F.; Kubo, A.; Hayashi, T. J. Am. Chem. Soc.
1991, 113, 1417. (b) Cabri, W.; Candiani, I.; DeBernardinis,
S.; Francalanci, F.; Penco, S. J. Org. Chem. 1991, 56, 5796.
(c) Fristrup, P.; Le Quement, S.; Tanner, D.; Norrby, P.-O.
Organometallics 2004, 23, 6160.
(8) (a) Addition of silver salts to the reaction mixture often
allows the use of aryl and vinyl halides in AIHR, see ref. 6.
(b) For a notorious example of IAHR where the ‘neutral’
pathway affords higher enantioselectivity than the
corresponding ‘cationic’, see: Overman, L. E.; Poon, D. J.
Angew. Chem., Int. Ed. Engl. 1997, 36, 518.
and 11, respectively) suggests that ideally the ligand bite
angle should be slightly less than 90°.
To the best of our knowledge, this is the first example
where, having available the possibility for a 6-exo-trig
path, the IHR occurs exclusively to afford high yields (up
to 94%) of the 5-endo-trig cyclized product. This result is
likely to be a consequence of two factors: i) the steric bulk
of the neighboring quaternary carbon, which positions and
eventually locks the C12–C13 double bond of 17e in the
proximity of the oxidatively added Pd; and ii) in the mi-
gratory insertion step, occurring in the coordination
sphere of Pd, the bond formation is initiated at a long C–
C distance, and can thus occur in geometries that are dis-
tinctly different from those allowed in systems for which
the Baldwin rules were originally developed.9a,b
Finally, it is noted that this serendipitous finding could po-
tentially be used as an entry to natural products such as the
trekentrins [e.g., cis-trekentrin A (21)]26 and the herbin-
doles [e.g., herbindole B (22)]27 (Figure 3), taking full ad-
vantage of the regioselective Claisen rearrangement–5-
endo-trig Heck cyclization sequence.
N
H
N
(9) (a) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976,
734. (b) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976,
736. (c) Grigg, R.; Sridharan, V.; Stevenson, P.;
Sukirthalingam, S.; Worakun, T. Tetrahedron 1990, 46,
4003. (d) See ref. 6.
(10) Indole 7 (which for R = Et is indole 13) has previously been
used in synthetic studies towards Lyngbyatoxin A, see:
Moody, C. J. J. Chem. Soc., Chem. Commun. 1983, 1129.
(11) For selected reviews on the Claisen rearrangement, see:
(a) Bennett, G. B. Synthesis 1977, 589. (b) Lutz, R. P.
Chem. Rev. 1984, 84, 205. (c) Ito, H.; Taguchi, T. Chem.
Soc. Rev. 1999, 28, 43.
H
cis-trikentrin A (21)
herbindole B (22)
Figure 3 Examples of natural products containing a 6,7-cyclopen-
tena-indole core.
Acknowledgment
The Portuguese Foundation for Science and Technology is grateful-
ly acknowledged for providing the financial support for this work.
Professor Robert Madsen is acknowledged for kindly providing
some of the ligands used in the Heck reaction screening.
(12) Hemetsberger, H.; Knittel, D.; Weidmann, H. Monatsh.
Chem. 1970, 101, 161.
(13) Shinmon, N.; Cava, M. J. Chem. Soc., Chem. Commun.
1980, 1020.
References and Notes
(14) Scheinmann, F.; Barner, R.; Schmid, H. Helv. Chim. Acta
1968, 51, 1603.
(15) (a) Karanewsky, D. S.; Kishi, Y. J. Org. Chem. 1976, 41,
3026. (b) Falling, S. N.; Rapoport, H. J. Org. Chem. 1980,
45, 1260. (c) Fukuyama, T.; Tangqing, L.; Peng, G.
Tetrahedron Lett. 1994, 35, 2145.
(1) (a) Takashima, M.; Sakai, H. Bull. Agric. Chem. Soc. Jpn.
1960, 24, 647. (b) Takashima, M.; Sakai, H. Bull. Agric.
Chem. Soc. Jpn. 1960, 24, 652. (c) Takashima, M.; Sakai,
H.; Arima, K. Agric. Biol. Chem. 1962, 26, 660.
(d) Takashima, M.; Sakai, H.; Arima, K. Agric. Biol. Chem.
1962, 26, 669.
(16) Procedure for the Preparation of 17a.
A solution of indole 13 (1.42 g, 4.16 mmol, 1.0 equiv),
HMDS (8.7 mL, 41.8 mmol, 10 equiv) and dimethylaniline
(30 mL) in a closed, thick-wall glass container was inserted
in a salt bath (53% KNO3, 40% NaNO2 and 7% NaNO3, by
weight) at 195 °C until TLC showed no more starting
material (aprox. 6–7 h). After reaching r.t., the reaction
mixture was partitioned between Et2O (150 mL) and 3 M aq
HCl (150 mL); the organic layer was further washed with
3 M aq HCl (100 mL), aq NaHCO3 (two portions of 120
mL), brine (50 mL) and dried (Na2SO4). The solvent was
removed under reduced pressure to afford a tan-colored oil,
which was dissolved in EtOH (20 mL). The resulting
solution was cooled to ice-bath temperature and treated with
3 M aq HCl (2.5 mL). After approx. 10 min, the reaction
(2) (a) Fujiki, H.; Sugimura, T. Cancer Surv. 1983, 2, 539.
(b) Hitotsuyanagi, Y.; Fujiki, H.; Suganuma, M.; Aimi, N.;
Sakai, S.; Endo, Y.; Sugimura, T. Chem. Pharm. Bull. 1984,
32, 4233. (c) Sakai, S.; Aimi, N.; Yamaguchi, K.; Watanabe,
C.; Hitotsuyanagi, Y.; Shudo, K.; Itai, A. Chem. Pharm.
Bull. 1984, 32, 354.
(3) The numbering system of teleocidins is defined in the
following order of preference: the indole ring, the nine-
membered lactam ring, and the other substituents.
Synlett 2006, No. 18, 3140–3144 © Thieme Stuttgart · New York

3144
P. Vital et al.
LETTER
(21) O’Connor, B.; Zhang, Y.; Negishi, E. Tetrahedron Lett.
mixture was diluted with Et2O (90 mL), washed with aq
NaHCO3 (two portions of 40 mL), brine (20 mL) and dried
(Na2SO4). The resulting solution was concentrated under
vacuum to approx. 1/5 of its original volume and eluted/
filtered through a short column of silica gel using hexane–
Et2O (2:1). Rearranged indole 17a (1.25 g, 88%) was
obtained as a thick, light-tan-colored oil. 1H NMR (300
MHz, CDCl3): d = 9.38 (br s, 1 H), 7.41 (d, J = 8.5 Hz, 1 H),
7.11 (d, J = 2.1 Hz, 1 H), 6.67 (d, J = 8.5 Hz, 1 H), 6.57 (dd,
J = 17.8, 10.8 Hz, 1 H), 5.63 (s, 1 H), 5.43 (d, J = 17.8 Hz, 1
H), 5.41 (d, J = 10.8 Hz, 1 H), 5.07 (m, 1 H), 4.37 (q, J = 7.1
Hz, 2 H), 2.18–1.76 (m, 4 H), 1.70 (s, 3 H), 1.62 (s, 3 H),
1.44 (s, 3 H), 1.40 (t, J = 7.1 Hz, 3 H). 13C NMR (75 MHz,
CDCl3): d = 162.2, 153.0, 148.7, 137.3, 131.9, 126.1, 124.5,
123.8, 122.1, 114.5, 113.3, 113.1, 108.7, 61.0, 45.5, 39.9,
25.9, 25.6, 24.0, 17.4, 14.7.
1988, 29, 3903.
(22) Sakoda, K.; Mihara, J.; Ichikawa, J. Chem. Commun. 2005,
4684.
(23) Grigg, R.; Savic, V. J. Chem. Soc., Chem. Commun. 2000,
871.
(24) (a) Wiedenau, P.; Monse, B.; Blechert, S. Tetrahedron 1995,
51, 1167; in particular Scheme 7. (b) Gaudin, J.-M.
Tetrahedron Lett. 1991, 32, 6113.
(25) Typical Procedure for the Preparation of 20.
A mixture of indole 17e (50 mg, 0.1 mmol, 1.0 equiv),
Pd(OAc)2 (2.5 mg, 0.01 mmol, 10 mol%), K2CO3 (44 mg,
0.3 mmol, 3.0 equiv), and the ligand (0.03 mmol, 30 mol%)
in degassed THF (2.1 mL) was refluxed for the time shown
in Table 2. After cooling to r.t., H2O (2 mL) was added and
the mixture was partitioned between Et2O (15 mL) and H2O
(10 mL). The organic layer was washed with brine (5 mL),
dried (MgSO4) and concentrated under vacuum. The
obtained residue was purified by flash chromatography
(hexane–ether, 2:1) to afford cyclopentadieno-indole 20 as a
faint yellow oil. 1H NMR (300 MHz, CDCl3): d = 8.63 (br s,
1 H), 7.58 (dd, J = 0.75, 8.1 Hz, 1 H), 7.29 (d, J = 2.0 Hz, 1
H), 7.19 (d, J = 8.1 Hz, 1 H), 6.78 (d, J = 5.4 Hz, 1 H), 6.39
(d, J = 5.4 Hz, 1 H), 4.94 (m, 1 H), 4.43 (q, J = 7.1 Hz, 2 H),
2.10–1.59 (m, 4 H), 1.55 (br s, 3 H), 1.44 (s, 3 H), 1.43 (t,
J = 7.1 Hz, 3 H), 1.36 (br s, 3 H).). 13C NMR (75 MHz,
CDCl3): d = 162.5, 144.7, 141.4, 134.1, 132.7, 131.9, 130.1,
127.6, 126.7, 124.4, 121.4, 116.1, 109.9, 61.2, 54.1, 38.0,
25.8, 23.9, 22.8, 17.7, 14.7.
(17) For selected applications in synthesis, see: (a) Martin, T.;
Moody, C. J. J. Chem. Soc., Chem. Commun. 1985, 1391.
(b) MacKenzie, A. R.; Moody, C. J.; Rees, C. W.
Tetrahedron 1986, 42, 3259.
(18) For a discussion, see: Jensen, F. Introduction to
Computational Chemistry; Wiley: Chichester, 1999.
(19) The structures were optimized at the B3LYP/6-31G* level
of theory in Jaguar v. 4.2 from Scrödinger Inc.,
www.schrodinger.com. The conformations were chosen to
represent the immediate product from a chair transition state,
as expected for a Claisen rearrangement.
(20) For representative examples, see: (a) Ackermann, L.;
Kaspar, L. T.; Gschrei, C. J. Chem. Commun. 2004, 2824.
(b) Watanabe, T.; Arai, S.; Nishida, A. Synlett 2004, 907.
(c) Chen, C.; Lieberman, D. R.; Larsen, R. D.; Verhoeven,
T. R.; Reider, P. J. J. Org. Chem. 1997, 62, 2676.
(26) Capon, R. J.; MacLeod, J. K.; Scammells, P. J. Tetrahedron
1986, 42, 6545.
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