Formation of halogenated cyclopent-2-enone derivatives by interrupted Nazarov cyclizations

Article abstract of DOI:10.1016/j.tetlet.2009.10.052

Allenyl vinyl ketones were exposed to titanium and indium halides in order to carry out Nazarov cyclizations. Whereas TiI₄ and InX₃ (X = Cl, Br, and I) led to cyclopentenones in which a halogen was trapped highly regioselectively, th

Full text of DOI:10.1016/j.tetlet.2009.10.052

Tetrahedron Letters 50 (2009) 7213–7216
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Formation of halogenated cyclopent-2-enone derivatives by interrupted
Nazarov cyclizations
*
Vanessa M. Marx, T. Stanley Cameron, D. Jean Burnell
Department of Chemistry, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4J3
a r t i c l e i n f o
a b s t r a c t
Article history:
Allenyl vinyl ketones were exposed to titanium and indium halides in order to carry out Nazarov cycli-
zations. Whereas TiI4 and InX3 (X = Cl, Br, and I) led to cyclopentenones in which a halogen was trapped
highly regioselectively, the reactions mediated by TiBr4 gave mixtures of brominated isomers. When the
allenyl vinyl ketones were treated first with Br2 and then with TiBr4, doubly brominated cyclopentenones
resulted, and treatment with I2 followed by TFA gave cyclopentenones bearing both hydroxyl and iodo
groups.
Received 25 July 2009
Revised 8 October 2009
Accepted 11 October 2009
Available online 29 October 2009
Ó 2009 Elsevier Ltd. All rights reserved.
O
There are examples in which the cyclized, cationic intermediate
of a Nazarov cyclization1 was intercepted, or ‘interrupted,’ by a
nucleophile.2–4 In the presence of protic or Lewis acids, allenyl vi-
nyl ketones (AVK’s) undergo Nazarov cyclizations particularly eas-
ily,5–7 and work by Tius and co-workers8 and ourselves9 suggests
that these substrates may be well suited for intermolecularly inter-
cepted Nazarov cyclizations. The cationic intermediates (2a–g)
from AVK’s 1a–g have two unencumbered positions (a and b) to
which a nucleophile might add (Scheme 1). Our previous work in-
volved mainly the trapping of 2a–g by an oxygen function, and the
products that were isolated (3a–g) had been intercepted only at
position a.9 A reaction of AVK 1d in which AuCl3 was used as the
acid provided 4, in which chloride had interrupted the Nazarov
process at position a. The yield of 4 was only 32%, but prompted
by this result, we explored whether halogens from other sources
might intercept cationic intermediates 2a–g more efficiently and
whether a halogen might be captured at position b.
OH
O
a
1. acid,
CH2Cl2
HO
.
2. Al2O3,
CH3OH
b
R
R
R
1a R = H
1b R = Me
R = i-Pr
2a−g
3a
R = H
3b R = Me
3c R = i-Pr
3d R = Ph
1c
1d R = Ph
1e R = Ph-p-OMe
R = Ph-p-OMe
3e
R = Ph-p-CF3
1f
1g
3f R = Ph-p-CF3
3g R = 2-furyl
R = 2-furyl
Scheme 1. Interrupted Nazarov cyclization of AVK’s 1a–g with trifluoroacetic acid
(TFA).8
O
Initially, we noted that treatment of 1d with HCl yielded mainly
products of Michael addition of chloride to the allene. White and
West3 had observed an interrupted Nazarov cyclization in which
chloride was incorporated when a Lewis acid, TiCl4, was used,
but when we added TiCl4 to 1d the AVK was rapidly consumed
and only intractable material was obtained.9 However, retesting
AVK 1d with 5 M equiv10 of TiBr4 gave the brominated cyclopente-
none 5d in 80% yield. This was again the result of addition of bro-
mide to position a of 2d. The relative stereochemistry of 5d and of
subsequent Nazarov products was consistent with coupling con-
stants in the 1H NMR spectrum. This encouraging result led us to
test AVK’s 1a–g with TiBr4 (Scheme 2), but this TiBr4 was from a
different batch from the same commercial source. With this sam-
Cl
Ph
4
ple of TiBr4 AVK’s 1a–d afforded modest yields of the brominated
cyclopentenones 5a–d and 6a–d as 1:1 mixtures of compounds
resulting from indiscriminate addition of bromide to positions a
and b of intermediates 2a–d. AVK’s 1e–g gave intractable material
only. Purification of the TiBr4 by sublimation led to frustrating re-
sults. With AVK 1d as the substrate, the purer, pale yellow subli-
mate mediated the formation of the 1:1 mixture of 5d and 6d,
but the impure, orange–brown residue elicited the highly regiose-
lective process that yielded 5d only.
* Corresponding author. Tel.: +1 902 494 1664; fax: +1 902 494 1310.
E-mail address: jean.burnell@dal.ca (D.J. Burnell).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.10.052

7214
V. M. Marx et al. / Tetrahedron Letters 50 (2009) 7213–7216
O
O
O
O
Br
TiI4 (5 equiv), CH2Cl2
TiBr4
+
1d
.
78 oC to rt, 48 h
−
CH2Cl2,
R
78 oC to rt
−
R
R
Br
(90%)
Ph
1a
5a R = H
6a (1:1, 32%)
R = H
10
1b R = Me
1c R = i-Pr
5b R = Me 6b (1:1, 38%)
O
5c
6c
R = i-Pr
(1:1, 36%)
( , 80%)
1d
5d R = Ph 6d 5d
R = Ph
TiI4 (5 equiv), CH2Cl2
Scheme 2. Exposure of AVK’s 1a–d to TiBr4.
1b,e,f
78 oC to rt, 48 h
−
R
12b R = Me (28%)
12e R = Ph-p-OMe (27%)
12f R = Ph-p-CF3 (14%)
I
It was not clear what the impurity was that led to the regiose-
lective reaction, but the color of the residue suggested that it might
have been molecular bromine. Dibromide 7 was formed when 1d
was treated with Br2 at À78 °C. Exposure of 7 to TiBr4 led first to
the isomerized dibromide 812 and then to the doubly brominated
cyclopentenone 9d in good overall yield (Scheme 3). It seems plau-
sible that 9d was the result of Nazarov cyclization of 8, addition of
bromide to the cyclic cationic intermediate, and then elimination
of HBr to generate the conjugated double bond. It should be noted
that neither 5d nor 6d was detected in the product mixture. Addi-
tion of Br2 and then TiBr4 to AVK’s 1b,e,f afforded the doubly bro-
minated Nazarov products 9b,e,f. Addition of TFA to 7 also gave the
isomerized dibromide 8, but 8 did not then undergo a Nazarov
cyclization in the presence of TFA.
O
I
TiI4 (5 equiv), CH2Cl2
1c
o
−
78 C to rt, 48 h
(10%)
i-Pr
I
13
Scheme 4. Exposure of AVK’s 1b–f to TiI4.
O
AVK’s 1a–g were mixed with 5 M equiv of TiI4, and the result
with 1d was different from that with the other AVK’s (Scheme 4).
AVK 1d was the only substrate that cyclized in high yield. Cyclo-
pentenone 10 was the only product isolated, but this represented
not only a Nazarov cyclization but also a reduction. In light of
the TiI4 products from the other AVK’s, it seemed likely that 10
was derived from an iodinated cyclopentenone by de-iodination,
a process for which there is precedence in work by West.3 AVK
1a reacted only by Michael addition of iodide, and 1g was de-
stroyed. Reaction of TiI4 with 1b,c,e,f led to complex mixtures of
uncyclized, poly-iodinated Michael-addition products and di-
iodinated compounds analogous to 11, but, in addition, small
amounts of iodinated cyclopentenones were isolated from the
reaction mixtures. AVK’s 1b,e,f yielded 12b,e,f, and 1c gave the
di-iodo compound 13.
Ph
I
I
11
Addition of I2 to 1d provided 1112 directly, but subsequent addi-
tion of TiI4 or TiBr4 gave complex mixtures of products. However,
in contrast with 8, TFA did mediate the Nazarov cyclization of 11
to give the iodo-alcohol 14d, following hydrolysis of an intermedi-
ate trifluoroacetate with silica gel. Then, the sequential treatment
of 1a–c,e first with I2, then with TFA, and then with silica gel pro-
vided 14a–c,e (Scheme 5) in low to modest yield.
InCl3 has been shown to be similar to TiCl4 in Lewis acidity,13
but more recently it has been determined to be unlike TiCl4 in
the reactions that it preferentially mediates.14 In addition, InCl3
is much less soluble in the reaction medium, dichloromethane,
than the titanium(IV) halides. In contrast with TiCl4, cyclized prod-
ucts were obtained from AVK’s 1a–f, but the yields were generally
low (Scheme 6). Nevertheless, in contrast with the reactions
involving TiBr4, the only cyclopentenones isolated, 15a–d,f, were
the result of addition of chloride to position b of intermediates
2a–d,f. The product derived from 1e was very different, and its
structure, 16, was confirmed by X-ray crystallography (Fig. 1).15
This compound must have arisen by initial Nazarov cyclization,
but then the intermediate carbocation 2e underwent a regioselec-
tive, facially selective, and endo-selective cyclization with another
O
O
Br2, CH2Cl2
acid
Br
Br
1d
o
−
78 C, 15 min
Ph
Ph
Br
7
Br
8
O
Br
TiBr4 (5 equiv), CH2Cl2
8
o
−
78 C to rt
Ph
Br
9d
O
(79% from 1d)
1. I2, CH2Cl2,
O
HO
o
−
78 C, 1 h
1a−e
1. Br2, CH2Cl2,
Br
2. TFA (5 equiv),
o
−
78 C, 15 min
78 oC to rt, 48 h
3. SiO2, 1 h
−
R
I
1b,e,f
2. TiBr4 (5 equiv), CH2Cl2,
14a R = H (18%)
o
R
Br
R = Me (22%)
9e R = Ph-p-OMe (70%)
9f
−
78 C to rt
14b
R = Me (trans/cis 3:1, 40%)
9b
14c R = i-Pr (45%)
14d R = Ph (61%)
R = Ph-p-CF3 (65%)
14e
R = Ph-p-OMe (32%)
Scheme 3. Exposure of AVK’s 1b,d–f to Br2 and then to TiBr4.
Scheme 5. Exposure of AVK’s 1a–e to I2 and then to TFA.

V. M. Marx et al. / Tetrahedron Letters 50 (2009) 7213–7216
7215
O
O
InCl3 (5 equiv), CH2Cl2
InI3 (5 equiv), CH2Cl2
1a−f
1a−d,f
78 oC to rt, 3 to 5 h
o
−
−
78 C to rt, 1 to 3 h
R
Cl
R = H (31%)
R
I
15a
12a
R = H (34%)
15b R = Me (20%)
15c R = i-Pr (21%)
12b R = Me (9%)
12c R = i-Pr (9%)
15d
R = Ph (35%)
15f R = Ph-p-CF3 (23%)
12d
R = Ph (32%)
12e R = Ph-O-Me (26%)
12f R = Ph-p-CF3 (13%)
MeO
Scheme 7. Exposure of AVK’s 1a–f to InI3.
O
InCl3 (5 equiv), CH2Cl2
H
OMe
1e
low yield. With this reagent even 1e gave the cyclopentenone
(12e) instead of the dimerized product (Scheme 7).
78 oC to rt, 3 h
(83%)
−
H
In summary, we have ascertained that AVK’s can undergo Naz-
arov cyclizations in which the intermediate carbocation can be
trapped by a halogen at either position a or position b in the cat-
ionic intermediate 2. However, the efficiency of this process is very
highly dependent on the Lewis acid and the substituent on the al-
kene, with yields ranging from very good to essentially zero. The
AVK bearing a simple phenyl substituent (1d) is generally the best
substrate. We observed the first instance of a formal [3+2] cycload-
dition involving a carbocation intermediate being captured by
unreacted substrate to generate the dimeric product.
H
O
.
16
O
InBr3 (5 equiv), CH2Cl2
1d
78 oC to rt, 2 h
(29%)
−
Ph
Br
6d
Acknowledgments
Scheme 6. Exposure of AVK’s 1a–f to InCl3 and InBr3.
We thank Dr. L. Turculet for the sublimation of TiBr4. We are
grateful to the Natural Sciences and Engineering Research Council
of Canada and the Killam Trust for financial support.
Supplementary data
Supplementary data (experimental details and characterization
data for all identified products are available) associated with this
article can be found, in the online version, at doi:10.1016/
j.tetlet.2009.10.052.
References and notes
1. Reviews: (a) Habermas, K. L.; Denmark, S. E.; Jones, T. K. Org. React. 1994, 45, 1–
158; (b) Pellissier, H. Tetrahedron 2005, 61, 6479–6517; (c) Frontier, A. J.;
Collison, C. Tetrahedron 2005, 61, 7577–7606; (d) Tius, M. A. Eur. J. Org. Chem.
2005, 2193–2206.
2. Most of the work on interrupted Nazarov cyclizations has been accomplished
by West and co-workers. Some recent examples: (a) Rostami, A.; Wang, Y.; Arif,
A. M.; McDonald, R.; West, F. G. Org. Lett. 2007, 9, 703–706; (b) Mahmoud, B.;
West, F. G. Tetrahedron Lett. 2007, 48, 5091–5094; (c) Grant, T. G.; West, F. G.
Org. Lett. 2007, 9, 3789–3792; (d) Rieder, C. J.; Fradette, R. J.; West, F. G. Chem.
Commun. 2008, 1572–1574. See also Refs. 3 and 10.
Figure 1. X-ray crystal structure of 16.
3. White, T. D.; West, F. G. Tetrahedron Lett. 2005, 46, 5629–5632.
4. Recent review on interrupted Nazarov cyclizations: Grant, T. N.; Rieder, C. J.;
West, F. G. Chem. Commun. 2009, 5676–5688.
5. (a) Tius, M. A.; Kwok, C.-K.; Gu, X.; Zhao, C. Synth. Commun. 1994, 24, 871–885;
(b) Tius, M. A. Acc. Chem. Res. 2003, 36, 284–290; (c) delos Santos, D. B.; Banaag,
A. R.; Tius, M. A. Org. Lett. 2006, 8, 2579–2582; (d) Banaag, A. R.; Tius, M. A. J.
Am. Chem. Soc. 2007, 129, 5328–5329; (e) Banaag, A. R.; Tius, M. A. J. Org. Chem.
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K.; Tius, M. A. Org. Lett. 2008, 10, 4073–4076.
9. Marx, V. M.; Burnell, D. J. Org. Lett. 2009, 11, 1229–1231.
10. Preliminary experiments with 1d had shown that 1 and 2 equiv of Lewis acid
resulted in lower yields of cyclized products.
molecule of 1e. It is remarkable to note that even at a concentra-
tion of 0.01 M this reaction took place in good yield. Also, it seemed
that electron donation by the para-methoxybenzyl substituent was
crucial for this reaction to proceed because a re-examination of the
1H NMR spectra of the crude reaction products from 1a–d,f re-
vealed no hint of any product resembling 16. West2b,11 had re-
ported
a
cationic intermediate of
a
Nazarov cyclization
undergoing formal [3+2] cycloaddition with electron-rich alkenes,
but, to the best of our knowledge, 16 represented the first example
of a dimerization as part of a domino process involving a Nazarov
cyclization. InBr3 was tested with AVK 1d only, but the result par-
alleled that with InCl3. Brominated cyclopentenone 6d was isolated
in only 29% yield. AVK’s 1a–f reacted with InI3 as they had in the
presence of InCl3 to afford the iodo-cyclopentenones 12a–f in
11. Giese, S.; Kastrup, L.; Stiens, D.; West, F. G. Angew. Chem., Int. Ed. 2000, 40,
1970–1973.

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V. M. Marx et al. / Tetrahedron Letters 50 (2009) 7213–7216
12. Addition of 2 equiv of Br2 to 1d gave the tetrabrominated compound below.
The geometry of its double-bond was determined by X-ray crystallography,15
and this geometry was then assumed for the structures of 8 and 11.
13. Deters, J. F.; McCusker, P. A.; Pilger, R. C., Jr. J. Am. Chem. Soc. 1968, 90, 4583–
4585.
14. Kobayashi, S.; Busujima, T.; Nagayama, S. Chem. Eur. J. 2000, 6, 3491–3494.
15. Crystallographic data (excluding structure factors) for the structures in this
Letter have been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication nos. CCDC 741824 and CCDC 741825. Copies of the
data can be obtained, free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK (fax: +44 (0)1223 336033 or e-mail:
deposit@ccdc.cam.ac.uk).
Br
O
Br
Br
Br