Cationic bromonium complex: NBS/P(OPh)3 as an efficient catalyst for Nazarov cyclization

Article abstract of DOI:10.1016/j.tet.2012.06.107

A general, catalytic method for Nazarov cyclization of dihydropyran derivatives has been developed. Cationic bromonium complex: NBS/P(OPh) ₃ was identified as an efficient catalyst for the synthesis of a number of different cyclopentenones in high yields with an excellent level of diastereocontrol.

Full text of DOI:10.1016/j.tet.2012.06.107

Tetrahedron 68 (2012) 8367e8370
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Cationic bromonium complex: NBS/P(OPh)3 as an efficient catalyst for Nazarov
cyclization
,
a
a
a
b,
*
Fenglou Guo a, Limin Wang a , Song Mao , Chi Zhang , Jianjun Yu , Jianwei Han
*
a Shanghai Key Laboratory of Functional Materials Chemistry and Institute of Fine Chemicals, East China University of Science and Technology, 130 Meilong Road,
Shanghai 200237, PR China
b Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry, The Chinese Academy of Sciences, 345 Ling Ling Road,
Shanghai 200032, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 May 2012
Received in revised form 14 June 2012
Accepted 26 June 2012
Available online 20 July 2012
A general, catalytic method for Nazarov cyclization of dihydropyran derivatives has been developed.
Cationic bromonium complex: NBS/P(OPh)3 was identified as an efficient catalyst for the synthesis of
a number of different cyclopentenones in high yields with an excellent level of diastereocontrol.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Cationic bromonium
N-bromosuccinimide
Triphenyl phosphate
Nazarov cyclization
Dihydropyran
1. Introduction
Lewis acids are considered to be the most popular species for
the development of catalytic processes in the broad variety of
transformations.1 Due to a large potential in this research field, we
have disclosed some new rare earth salts as Lewis acid catalysts in
organic synthesis.2 Apart from a number of metal complexes,
compounds containing carbenium, silyl or phosphonium cations
can also act as metal free Lewis acids, which incorporate a Lewis
acidic cation or a hypervalent center.3 It is well known that the use
of N-bromosuccinimide (NBS) and triphenyl phosphine as a halide
source yielded alkyl bromides from alcohols (Type I, Fig. 1).4 Re-
cently, Ishihara group and others reported that the nucleophilic
promoters can activate NBS to form cationic bromonium (‘Brþ’) as
the reagent in electrophilic halocyclization reaction.5 Very recently,
a new concept of Lewis base catalysis by thiourea: NBS mediated
oxidation of alcohols was presented (Type II, Fig. 1).6 Therefore,
from the point of mechanism view, the cationic halonium is gen-
erated from N-halosuccinimide with nucleophilic promoters, which
can display a Lewis acid catalytic activity. We became interested in
the chemistry of cationic bromonium as Lewis acid catalyst in the
organic synthesis.
Fig. 1. The formation of cationic bromonium.
The Nazarov cyclization reaction,7 a highly effective method for
the generation of five-membered rings, has been successfully uti-
lized in the synthesis of many complex molecules, including many
biologically-active natural products. As a result, the Nazarov cycli-
zation has received tremendous attention in the past decades, and
the viability of the substoichiometric catalytic process promoted by
strong Lewis or Brønsted acids has been revealed.8 However, as far
as we know, cationic bromonium as Lewis acid catalyst induced
Nazarov cyclization has not been reported.
2. Results and discussion
Herein, we describe a successful catalytic Nazarov cyclization of
dihydropyran substrates catalyzed by a combination of NBS and
P(OPh)3, in which, bromonium ion was activated by Lewis base.
* Corresponding authors. E-mail address: wanglimin@ecust.edu.cn (L. Wang).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.06.107

8368
F. Guo et al. / Tetrahedron 68 (2012) 8367e8370
Table 2
Our investigations began with the optimization of the reaction
conditions for the model reaction shown in Scheme 1. A catalyst
Survey of reaction conditionsa
Entry
Solvent
Temp./Time
Yield(%)b
1
2
3
4
MeCN
EtOH
THF
Toluene
DCM
MeCN
MeCN
10 ꢀC/10 min
10 ꢀC/12 h
10 ꢀC/24 h
10 ꢀC/12 h
10 ꢀC/12 h
10 ꢀC/40 min
10 ꢀC/6 h
99
Trace
Trace
18
33
99
5
6c
7d
10
a
Scheme 1. Nazarov cyclization catalyzed by bromonium ioneLewis base.
Reaction conditions: 1a (0.1 mmol), NBS (10 mol %), P(OPh)3 (10 mol %).
Isolated yield by silica gel column chromatography; dr value was not
b
determined.
c
5 mol % NBS, 5 mol % P(OPh)3.
1 mol % NBS, 1 mol % P(OPh)3.
loading of 30 mol % N-bromosuccinimide (NBS) in the presence of
different phosphorus species was studied. To our delight, the tri-
phenyl phosphine as Lewis base afforded the desired product 2a in
99% yield within 4.5 h at room temperature (Table 1 entry 1). Only
d
Table 3
Survey of bromonium sourcesa
Table 1
Survey of Lewis basesa
Entry
Lewis base
Time
Yield (%)b
1c
2
3
4
5
PPh3
d
4.5 h
10 h
<1 min
13 min
5 h
99
Trace
99
99
99
P(OPh)3
Tri(2-furyl)phosphine
Tri(4-fluorophenyl) phsophine
Entry
Bromonium source
Lewis base
Time
Yield (%)b
6
Tris(4-methoxyphenyl) phosphine
6 h
60
7
8
9
10
11
12
Tricyclohexyl phosphine
POPh3
PO(PhO)3
HMPA
DMAP
20 h
20 h
20 h
20 h
20 h
20 h
Trace
n.r.
n.r.
n.r.
n.r.
n.r.
1
2
3
4
5
6
3
4
Br2
3
4
P(OPh)3
P(OPh)3
P(OPh)3
d
25 min
11 min
2 h
17 h
17 h
8 h
18 h
17 h
12 h
99
99
99
n.r.
n.r.
80
90
n.r.
36
d
DABCO
Br2
I2
d
7c
8d
9
d
a
Reaction conditions: 1a (0.1 mmol), NBS (10 mol %), Lewis base (10 mol %),
d
P(OPh)3
P(OPh)3
MeCN (0.5 mL), rt.
5
b
Isolated yield by silica gel column chromatography; dr value was not
a
determined.
Reaction conditions: 1a (0.1 mmol), bromonium source (10 mol %) or and Lewis
c
30 mol % PPh3, 25 ꢀC.
base (10 mol %), MeCN (0.5 mL), 10 ꢀC.
b
Isolated yield by silica gel column chromatography; dr value was not
determined.
c
30 mol % Br2 or I2, 25 ꢀC.
30 mol % P(OPh)3, 50 ꢀC.
d
a trace amount of product was observed in the absence of triphe-
nylphospine (Table 1, entry 2). When the PPh3 was switched to
P(OPh)3, reaction went into completion in less than 1 min, thus
suggesting that more nucleophilic the triphenyl phosphite is better
for the reaction to proceed efficiently (Table 1, entry 3). Different
substituted phosphines could promote this reaction with moderate
to excellent yield except tricyclohexyl phosphine (Table 1, entries
4e7) under this condition. The NBS combined with triphenyl
phosphate or triphenyl phosphorus oxide displayed non-catalytic
activity. As expected, no cyclized product was observed under
this catalytic system when the base additives, such as DABCO or
DMAP was employed, this finding possibly points toward the in-
activation cationic bromonium Lewis acid species by N-Lewis bases.
In order to indicate the exact reaction time, the reaction tem-
perature was decreased to 10 ꢀC, the reaction catalyzed by NBS and
P(OPh)3 proceeds smoothly to give the desired product in high
yields after 10 min (Table 2, entry 1). Additional studies showed
that solvents have dramatic effects on the reaction yield, and ace-
tonitrile was found as an optimal solvent for this reaction (Table 2,
entries 2e5). With 5 mol % catalyst， the reaction were finished
after 40 min indicated by TLC to give 99% yield of the desired
product (Table 2, entry 6), however, with 1 mol % catalyst loading,
only 10% 2a was isolated after 6 h (Table 2, entry 7).
achieved in the presence of Br2, or I2, which demonstrated that
iodine is emerged as an effective Lewis acid catalyst for Nazarov
cyclization. As far as we know, this reaction has never been
reported by employing any of halogen catalyst systems. No cycli-
zation product was observed in the presence of triphenyl phosphite
without halide source (Table 3, entry 8). To prove that an oxidation
state of Iþ is the source of catalytic species, 5 was further in-
vestigated with P(OPh)3, the cyclization was conducted, but with
a significant loss in the catalytic efficiency (Table 3, entry 9).
Having established that NBS/P(OPh)3 in MeCN was the optimal
system to promote the reaction, a number of dialkenyl ketones of 1
was subjected to cyclization and the results are showed in Table 4. It
is apparent that the electron-donating group of the substituent
gave the corresponding products in excellent isolated yield with
moderate to high levels of diastereocontrol (Table 4, entries 2, 3).
The desired products were also obtained in excellent yields with
better stereoinduction for substrates 1d-1j, which have an
electron-withdrawing group, such as a halogen, nitro, cyano or
trifluoromethyl group on the phenyl ring (Table 4, entries 4e10).
The reaction of 1f proceeded at a considerably slower rate than 1e
(Table 4, entry 5 vs 6). On the other hand, reactions using substrates
1k, 1l gave decreased yields with excellent diastereocontrol (Table
4, entries 11,12). When the R group of 1 was 9-anthracenyl, styryl or
2-furyl, the cyclization proceeded efficiently as well as the model
reaction (Table 4, entries 13e15).
As shown in Table 3, alternative bromonium sources, such as 3,
4, or Br2 showed excellent catalytic activity in the presence of tri-
phenyl phosphite (Table 3, entries 1e3). Once again, by using
30 mol % of either 3 or 4 (Table 3, entries 4, 5), no reaction occurred
even after 17 h. In contrast, 80% conversion of 1a to 2a were

F. Guo et al. / Tetrahedron 68 (2012) 8367e8370
8369
Table 4
a catalytic cycle is proposed, which involves an intermediacy of
a highly electrophilic, phosphine-bound bromonium ion A or B of
Lewis base-NBS complex BrP*. The BrP* mediates the pentadienyl
cation (D). Subsequent a conrotatory closure proceeds to form an
oxyallyl cation (E), which was deprotonated by the anion of suc-
cinimide to give F. Protonation of G afford the Nazarov product with
concomitant ejection of the catalytic complex BrP*.
a
Scope of the Nazarov cyclization catalyzed by NBSeP(OPh)3
Asymmetric Nazarov cyclization was also investigated by using
NBS with chiral binaphthyl derivative phosphine 6 or phosphites 7
and 8 as promoters. However, as shown in Fig. 3, only racemic
products were obtained although in high levels of reaction effi-
ciency, which implied the PPh3eNBS complex formed though the
possible route A in the proposed catalytic cycle.
Entry
Substrate (R)
Time
Yield(%)b
trans:cisc
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
Ph
10 min
<1 min
9 min
2 h
2 h
2 h
3 h
3 h
2 h
4 h
22 h
22 h
3 h
5 min
<5 min
99
99
99
99
92
60
82
88
99
89
60
50
90
99
99
17:1
12:1
15:1
15:1
17:1
20:1
20:1
17:1
15:1
17:1
>99:1
>99:1
>99:1
10:1
20:1
4-MeOeC6H4
4-MeeC6H4
4-CleC6H4
4-BreC6H4
2-BreC6H4
4eNO2eC6H4
3eNO2eC6H4
4eCNeC6H4
4eCF3eC6H4
c-Hexyl
9
10
11
12
13
14
15
i-Pr
9-Anthracenyl
Styryl
2-Furyl
a
Reaction conditions: 1 (0.1 mmol), NBS (10 mol %), P(OPh)3 (10 mol %), MeCN
(0.5 mL), 10 ꢀC.
b
c
Isolated yield by silica gel column chromatography.
The ratio was determined by 400 MHz 1H NMR.
Although the mechanism of the reaction is not clear, on the basis
of the reports concerning the reaction of NBS with good electron
donors, such as triphenyl phosphine, it is assumed that charge-
transfer complexes of the type [Ph3PeBr]þX- is formed. Therefore,
Fig. 3. Asymmetric Nazarov cyclization.
31P NMR study was performed with PPh3 and PPh3eNBS complex,
3. Conclusion
a
respectively. The parent signal (ꢁ7.02 ppm) of PPh3 was replaced by
a new signal (25.57 ppm) of PPh3eNBS adduct (the spectrogram
was provided in Supplementary data). This evidence revealed that
there was a coordination between NBS and PPh3. However, there
are two possible ways to form the complexes as shown in Fig. 2.
(Route I or Route II), thus, based on Denmark’s pioneer work,9
In summary, we have developed the first bromonium cation
catalyzed Nazarov reaction, in which, bromonium ion could be
activated by phosphorus (III) species as a Lewis acid catalyst. The
reaction was effectively catalyzed by 10 mol % NBSeP(OPh)3 com-
plex and the desired products were obtained in good to excellent
yields with excellent diastereocontrol. Further studies of the re-
action mechanism and asymmetric catalysis are ongoing in our lab
and will be reported in due course.
4. Experimental section
4.1. General
4.1.1. Nazarov cyclization of 2a catalyzed by NBSeP(OPh)3. To a flask
equipped with a stir bar was added the NBS (0.01 mmol, 1.8 mg),
then the P(OPh)3 (0.1 mmol, 3.1 mg) in MeCN (0.5 mL) was added.
After stirring at 10 ꢀC for 10 min, 1a (0.1 mmol, 29 mg) was added in
one portion. After completion of the reaction, as indicated by TLC,
the reaction mixture was concentrated under reduced pressure,
and the crude compound was purified by flash chromatography
(Ethyl acetate/Petroleum ether: 1/20 to 1/4) to afford the desired
Nazarov product 2a as a yellow solid; yield: 28.7 mg (99%). 1H NMR
(400 MHz, CDCl3)
d
7.41e7.29 (m, 3H), 7.15 (d, J¼7.0 Hz, 2H),
4.31e4.11 (m, 5H), 3.32 (d, J¼2.0 Hz, 1H), 2.24 (dt, J¼12.2, 5.9 Hz,
1H), 2.11 (dt, J¼19.1, 6.1 Hz, 1H), 1.96 (m, 2H), 1.30 (t, J¼7.1 Hz, 3H).
13C NMR (100 MHz, CDCl3)
d 193.13, 168.37, 149.87, 147.40, 139.95,
129.18, 127.67, 127.39, 67.09, 61.88, 59.36, 47.72, 22.25, 21.31, 14.18.
HRMS-EI (m/z): [M]þcalcd for C17H18O4, 286.1205; found, 286.1203.
Acknowledgements
This research was financially supported by the National Nature
Fig. 2. Proposed catalytic cycle.
Science Foundation of China (20672035), the Fundamental

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F. Guo et al. / Tetrahedron 68 (2012) 8367e8370
6. Tripathi, B. C.; Mukherjee, S. J. Org. Chem. 2012, 77, 1592e1598.
7. For recent reviews of Nazarov reaction, see: (a) Pellissier, H. Tetrahedron 2005,
61, 6479e6517; (b) Frontier, A. J.; Collison, C. Tetrahedron 2005, 61,
7577e7606; (c) Vaidya, T.; Eisenberg, R.; Frontier, A. J. ChemCatChem 2011, 3,
1531e1548.
Research Funds for the Central Universities and the Opening
Foundation of Zhejiang Provincial Top Key Discipline.
Supplementary data
8. For selected examples, see: (a) Denmark, S. E.; Jones, T. K. J. Am. Chem. Soc. 1982,
104, 2642e2645; (b) He, W.; Sun, X.; Frontier, A. J. J. Am. Chem. Soc. 2003, 125,
14278e14279; (c) Aggarwal, V. K.; Belfield, A. J. Org. Lett. 2003, 5, 5075e5078;
(d) Janka, M.; He, A.; Frontier, A. J. J. Am. Chem. Soc. 2004, 126, 6864e6865; (e)
Liang, G.; Trauner, D. J. Am. Chem. Soc. 2004, 126, 9544e9545; (f) Dhoro, F.; Tius,
M. A. J. Am. Chem. Soc. 2005, 127, 12472e12473; (g) Janka, M.; He, W.; Haedicke,
I. E.; Fronczek, F. R.; Frontier, A. J.; Eisenberg, R. J. Am. Chem. Soc. 2006, 128,
5312e5313; (h) Rieder, C. J.; Winberg, K. J.; West, F. G. J. Am. Chem. Soc. 2009, 131,
7504e7505; (i) Fujiwara, M.; Kawatsura, M.; Hayase, S.; Nanjo, M.; Itoh, T. Adv.
Synth. Catal. 2009, 351, 123e128; (j) Basak, A. K.; Shimada, N.; Bow, W. F.; Vicic,
D. A.; Tius, M. A. J. Am. Chem. Soc. 2010, 132, 8266e8267; (k) Murugan, K.;
Srimurugan, S.; Chen, C. P. Chem. Commun. 2010, 1127e1129; (l) Cao, P.; Deng, C.;
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Supplementary data related to this article can be found online at
http://dx.doi.org/10.1016/j.tet.2012.06.107.
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