Selective bromocyclization of 2-geranylphenols promoted by phosphite-urea cooperative catalysts

Article abstract of DOI:10.1002/chir.22297

Nucleophilic phosphite-urea cooperative catalysts are highly efficient for the bromonium-induced cyclization of 2-geranylphenols. Phosphite-N,N'- dimethylurea catalysts also show moderate activity, probably due to the steric effect of their bent conformat

Full text of DOI:10.1002/chir.22297

CHIRALITY 26:356–360 (2014)
Selective Bromocyclization of 2-Geranylphenols Promoted by
Phosphite–Urea Cooperative Catalysts
4
1,3
YASUHIRO SAWAMURA,1 HIDEFUMI NAKATSUJI,1 MATSUJIRO AKAKURA,2,3 AKIRA SAKAKURA, AND KAZUAKI ISHIHARA
*
*
1Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa, Nagoya, Japan
2Department of Chemistry, Aichi University of Education, Igaya-cho, Kariya, Aichi, Japan
3JST-CREST, Furo-cho, Chikusa, Nagoya, Japan
4Graduate School of Natural Science and Technology, Okayama University, Tsushima-naka, Kita-ku, Okayama, Japan
ABSTRACT
Nucleophilic phosphite–urea cooperative catalysts are highly efficient for the
bromonium-induced cyclization of 2-geranylphenols. Phosphite–N,N’-dimethylurea catalysts also
show moderate activity, probably due to the steric effect of their bent conformation. Chirality
26:356–360, 2014. © 2014 Wiley Periodicals, Inc.
KEY WORDS: bromocyclization; bromophosphonium salt; N,N’-dimethylurea; 2-geranylphenol;
phosphite; steric effect; urea
INTRODUCTION
RESULTS AND DISCUSSION
The biosynthesis of bromine-containing polycyclic
terpenoids appears to include the regio- and enantioselective
bromination of a carbon–carbon double bond followed by
We first examined the catalytic activities of nucleophilic phos-
phites 1 and 2 for the bromocyclization of 4-homogeranyltoluene
(3). The reaction of 3 was conducted with NBS (1.1 equiv) in
the presence of 1 or 2 (30 mol%) in toluene at À40°C for 6 h
(Table 1). As we described in the previous report, the reaction
diastereoselectively gave the desired trans-fused AB-ring prod-
uct 4 together with endo- and exo-isomeric A-ring products 5
and undesired dibromide 6. Dibromide 6 was generated via de-
composition of the bromophosphonium active species.23 The
ratio of 4, endo-5 and exo-5 in each reaction was ca. 1:1:1, and
the crude products did not include the cis-fused isomer of 4
or the tetrasubstituted isomer of 5. Since A-ring products 5
could be quantitatively converted to AB-ring product 4 by treat-
ment with SnCl4 and trifluoroacetic acid, the combined yield of
diastereoselective
π–cation
cyclization.1–3
Biomimetic
bromonium-induced polyene cyclizations (π–cation cyclization)
should be powerful tools for the construction of complex poly-
cyclic structures of these bromine-containing natural products.
Hence, much attention has been devoted to the development of
biomimetic bromonium-induced polyene cyclizations. How-
ever, conventional methods that use a standard electrophilic
brominating reagent such as Br2, N-bromosuccinimide (NBS)
or 2,4,4,6-tetrabromocyclohexa-2,5-dienone (TABCO) are
generally less reactive and generate significant amounts of
byproducts.4–15 Only a few efficient methods have been
developed thus far for bromonium-induced polyene cycliza-
tions.16–20 In 2009, Snyder and colleagues reported that
Et2SBr•SbCl5Br (BDSB) is a highly reactive electrophilic bro-
mination reagent and gives the bromocyclization products in
good to high yields.21,22
We recently reported nucleophilic phosphite–urea coopera-
tive catalysts 1b and 2b (Scheme 1), which had high turnover
rates for the highly selective bromocyclization of
homogeranylarenes.23–28 Only 0.5 mol% of 2b successfully
catalyzes the bromocyclization of 4-homogeranyltoluene
(3) to give the corresponding bromocyclization product in
94% yield (Scheme 1). The nucleophilic phosphite group
catalytically activates a brominating reagent such as NBS
and 1,3-dibromo-5,5-dimethylhydantoin (DBH) to generate
the corresponding bromophosphonium ion as an active
species. The urea group probably interacts with the succinimide
anion via hydrogen bonding to inhibit decomposition of the cata-
lyst and the generation of byproducts. In the same report, we de-
scribed that phosphite–N,N’-dimethylurea catalyst 1c showed
unexpectedly good activity for the bromocyclization of 3 (84%
yield), although 1c did not have any acidic protons to interact
with the succinimide anion. Since we were interested in the abil-
ity of the N,N’-dimethylurea group to promote bromocyclization,
we reinvestigated the catalytic activity of nucleophilic phosphite
catalysts 1 and 2 for the bromocyclization of 3 in detail. We re-
port here the results of our reinvestigation of the catalytic activity
of phosphite–urea catalysts and an investigation of the
bromocyclization of 2-geranylphenols.
1
4 and 5 was evaluated by H nuclear magnetic resonance
(NMR) analysis of the crude products. As a result of the
reexamination, phosphite–urea catalysts 1b and 2b gave the
best results: the desired products 4 and 5 were obtained in
almost quantitative yields and the generation of dibromide 6
was successfully suppressed (entries 3 and 4), as we noted in
the previous report. On the other hand, the reaction did not
proceed without a catalyst.
However, the use of phosphite–N,N’-dimethylurea catalyst
1c gave 4 and 5 in only 43% yield (entry 5), although our
previous report23 stated that 1c showed unexpectedly good
activity (4 + 5: 84% yield). The rather high activity of 1c in
our previous report might have been due to some impurities
(acidic materials such as 4-CF3C6H4OH) in the sample of
1c. The data in entry 4 were reproducible, and the purity of
1
1c was >99% based by H NMR analysis. Sterically bulky
phosphite–N,N’-dimethylurea catalyst 2c showed slightly
higher activity than 1a and 1c (53% yield, entry 6). However,
the activity of 2c was almost the same as that of 2a (52%,
entry 2). These results suggested that the N,N’-dimethylurea
*Correspondence to: K. Ishihara, Graduate School of Engineering, Nagoya
University, Furo-cho, Chikusa, Nagoya 464–8603, Japan. E-mail: ishihara@cc.
nagoya-u.ac.jp or A. Sakakura, Graduate School of Natural Science and Technol-
ogy, Okayama University, Tsushima-naka, Kita-ku, Okayama 700–8530, Japan.
E-mail: sakakura@okayama-u.ac.jp
Received for publication 31 October 2013; Accepted 11 December 2013
DOI: 10.1002/chir.22297
Published online 7 February 2014 in Wiley Online Library
(wileyonlinelibrary.com).
© 2014 Wiley Periodicals, Inc.

SELECTIVE BROMOCYCLIZATION OF 2-GERANYLPHENOLS
357
TABLE 1. Catalytic activities of phosphite–urea catalysts for
the bromocyclization of 4-homogeranyltoluene (3)
Yield (%)a
Entry
Catalyst
4 + 5
6
1
2
3
4b
5
6
7
1a
2a
39
52
96
99
43
53
0
22
15
0
1b
2b
0
1c
12
14
0
2c
no catalyst
aYields were evaluated by 1H NMR analysis.
bThe reaction was conducted with 5 mol% of 2b.
The activity of less-hindered phosphite 1a was very poor
(9% yield, entry 1) since 1a easily decomposed to form inert
phosphonium salt under the reaction conditions.23 The 1a-
catalyzed reaction of 7a gave significant amounts of B-ring
product 10a (7%) and dibromides 11a and 12a (24%) as
byproducts. The absence of a urea group would increase
the reactivity of the internal carbon–carbon double bond of
7a via the generation of phenoxide 13 (Scheme 2) to in-
crease the yield of 10a. The generation of phenoxide 13
may also have promoted phosphorylation of the phenolic hy-
droxyl group of 7a by the bromophosphonium active species
(Scheme 2). The phosphorylation generated bromide ion
and gave dibromide 12a.23 Sterically hindered phosphite
2a showed almost the same activity as 1a (12% yield, entry
3). The addition of N-[3,5-bis(trifluoromethyl)phenyl]-N’-
phenylurea (30 mol%) to the 1a- and 2a-catalyzed reaction
improved the reactivity and gave the desired products in
respective yields of 38 and 36% (entries 2 and 4). However,
the yield of 10a was also increased (20 and 17%). These
results suggested that the introduction of the phosphite
group and the urea group to the same molecule was critical
for the selective promotion of bromocyclization.
Interestingly, phosphite–N,N’-dimethylurea catalysts 1c
and 2c showed higher activities than the corresponding phos-
phites 1a and 2a (entries 7 and 8). These results suggested
that the N,N’-dimethylurea group in 1c and 2c promoted
the bromocyclization of 7a. This positive effect might be
ascribed to a steric effect of the N,N’-dimethylurea group.
Density Functional Theory (DFT) calculations29 of
bromophosphonium salts 14, which would be derived from
phosphite–N,N’-dimethylurea catalyst 1c and NBS, indicated
Chirality DOI 10.1002/chir
Scheme 1. Nucleophilic phosphite catalysts 1 and 2, and 2b-catalyzed
bromocyclization of 4-homogeranyltoluene (3).
group in 1c and 2c did not promote the bromocyclization of
3, and steric hindrance around the phosphite moiety slightly
improved the catalytic activity probably due to inhibition of
the decomposition of the catalyst to the phosphonium salt.23
We next examined the bromocyclization of 2-geranylphenol
(7a) catalyzed by phosphite–urea catalysts 1 and 2 under the
same conditions as the reaction of 3 (Table 2). The
bromocyclization of 7a generates a core structure of bro-
mine-containing natural products such as 4-isocymobarbatol.
The bromocyclization of 7a gave the desired trans-fused
AB-ring product 8a together with endo- and exo-isomeric A-ring
products 9a and undesired dibromide 11a. In contrast to the
reaction of 3, the A-ring products seemed to include
tetrasubstituted isomer (endo:exo:tetrasubstituted = ca. 4:6:1).
As in the reaction of 4-homogeranyltoluene (3), phosphite–
urea catalysts 1b and 2b showed high activities to give the
desired products 8a and 9a in yields of 85–89% (entries 5
and 6). The use of 1b or 2b successfully suppressed the
generation of dibromides 11a and 12a. However, the reac-
tion also gave B-ring product 10a. Since the reaction of the
internal carbon–carbon double bond was not observed at all
in the bromocyclization of 3, the reactivity of the internal
carbon–carbon double bond of 7a is thought to be much
higher than that of 3, probably due to the more nucleophilic
hydroxy group.

358
SAWAMURA ET AL.
TABLE 2. Catalytic activities of phosphite–urea catalysts for
the bromocyclization of 2-geranylphenol (7a)
Scheme 2. Proposed mechanism of the generation of phenoxide 13 and
dibromide 12a.
Yield (%)a
Especially, 2-geranylphenols 7 bearing electron-withdrawing
substituents were converted to the corresponding products
8 with high diastereoselectivities (entries 1–3, 6 and 7). On
the other hand, the bromocyclization of 2-geranylphenols 7
bearing electron-donating substituents gave 8 with slightly
low diastereoselectivities (entries 4, 5, and 8). Since the first
bromination step did not give any cis-fused isomers of 8, it
was conceivable that the second acid-promoted B-ring cycliza-
tion step kinetically favored the cis-cyclization, and that the elec-
tron-rich hydroxyphenyl groups increased the ratio of cis-fused
isomers of 8. When the bromocyclization of 2-geranylphenols
Entry
Catalyst
8a + 9a
10a
11a + 12a
1
1a
1a
2a
2a
1b
2b
1c
2c
9
7
20
2
17
12
10
6
24
25
4
13
2
0
22
12
2b
3
38
12
36
85
89
17
50
4b
5
6c
7
8
9
aYields were evaluated by 1H NMR analysis.
bThe reaction was conducted in the presence of N-[3,5-bis(trifluoromethyl)
phenyl]-N’-phenylurea (30 mol%).
cThe reaction was conducted with 5 mol% of 2b.
that in the optimized conformation, the N,N’-dimethylurea
group of 14 was folded (Fig. 1).30 The bromophosphonium
moiety was surrounded by three electron-deficient aryl
groups, and one of the fluorine atoms of the 3,5-bis
(trifluoromethyl)phenyl groups seemed to interact with a pro-
ton of the 4-trifluoromethylphenyl group. The steric effect of
these aryl groups might inhibit decomposition of the catalyst
to improve the catalytic activity.
Since phosphite–urea catalyst 2b showed high activity for
the bromocyclization of 7a, we investigated the
bromocyclization of 2-geranylphenols 7 with various substitu-
ents on the phenol ring to explore the scope and limitation of
the present bromocyclization. The reaction of 7 was
conducted with NBS (1.1 equiv) in the presence of 2b
(5 mol%) in toluene at À40 °C for 6 h (Table 3). The isolated
yields of the corresponding AB-ring products 8 were evalu-
ated after subsequent treatment with TfOH in i-PrNO2 at
À78 °C. As shown in Table 3, a variety of 2-geranylphenols
7 were smoothly cyclized to give the desired trans-fused
AB-ring products 8 in good to high yields along with small
amounts of cis-diastereomers and B-ring products 10.
Chirality DOI 10.1002/chir
Fig. 1. B3LYP/6-31G* optimized geometry of bromophosphonium ions
14, which would be derived from phosphite–N,N’-dimethylurea catalysts 1c
and NBS.

SELECTIVE BROMOCYCLIZATION OF 2-GERANYLPHENOLS
359
TABLE 3. 2b-Catalyzed bromocyclization of 2-geranylphenols 7
ACKNOWLEDGMENT
This project was supported in part by grants from JSPS.
KAKENHI (23350039 and 24245020) and the Program for
Leading Graduate Schools “Integrative Graduate Education
and Research in Green Natural Sciences,” MEXT, JAPAN.
SUPPORTING INFORMATION
Additional supporting information may be found in the
online version of this article at the publisher’s web-site.
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