Regioselective synthesis of 2,3-dihydrobenzodioxepinones from epoxides and 2-bromophenols via palladium-catalyzed carbonylation

Article abstract of DOI:10.1039/c3cc48490d

A highly regioselective cascade synthesis of 2,3-dihydrobenzodioxepinone from 2-bromophenols and epoxides has been developed. The reactions go through nucleophilic ring-opening of epoxides and subsequent palladium-catalyzed intramolecular alkoxylcarbonylation. The Royal Society of Chemistry.

Full text of DOI:10.1039/c3cc48490d

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Regioselective synthesis of 2,3-dihydrobenzo-
dioxepinones from epoxides and 2-bromophenols
via palladium-catalyzed carbonylation†
Cite this: Chem. Commun., 2014,
50, 2114
Received 6th November 2013,
Accepted 19th December 2013
Haoquan Li, Anke Spannenberg, Helfried Neumann, Matthias Beller* and
Xiao-Feng Wu*
DOI: 10.1039/c3cc48490d
www.rsc.org/chemcomm
A highly regioselective cascade synthesis of 2,3-dihydrobenzo- until now.5 Due to our continual interest in palladium-catalyzed
dioxepinone from 2-bromophenols and epoxides has been developed. carbonylative synthesis of heterocycles, we report herein our
The reactions go through nucleophilic ring-opening of epoxides and recent results on the synthesis of benzodioxepinones which
subsequent palladium-catalyzed intramolecular alkoxylcarbonylation. are valuable analogues of seven-membered lactones.6 The
reaction started from commercially available 2-bromophenols
Palladium-catalyzed carbonylation reactions are of broad interest and epoxides via the cascade ring-opening reaction and
in both academic research and pharmaceutical applications. Ever palladium-catalyzed carbonylative transformation. The desired
since the pioneering work from Heck and co-workers in 1974,1 products were produced in a highly selective manner in high
palladium-catalyzed carbonylations have experienced impressive yields.
progress and have already become one of the most efficient tools
The first test of the reaction was carried out with 2-bromo-
in modern organic synthesis.2 The most obvious advantages of phenol (0.5 mmol), styrene oxide (0.55 mmol), 2 mol% Pd(OAc)2,
carbonylative transformation are two but not least: (1) carbon 3 mol% dppf, in MeCN (2 mL) under 15 bar of CO, 7% yield of
monoxide is an inexpensive and easily available C1 building 3a was observed at 100 1C. 3a0 which originated from the
block; (2) carbonyl containing molecules such as aldehydes, nucleophilic attack at the benzylic position, was observed as
amides, esters, ketones, alkynones etc. can be obtained efficiently well, and the ratio between 3a and 3a0 was 68 : 32 (Table 1,
by varying the coupling partners, which are valuable compounds entry 1). At this point, we found carbonylation to be the rate-
themselves and ready for further modification as well.
determining step for this reaction as 2-bromophenoxy-phenyl-
Epoxides are widely available compounds, generally obtained from ethanol was observed as the main by-product. Then different
an intramolecular SN2 substitution reaction or epoxidation of olefins.3 ligands were tested to promote the carbonylation step; no desired
Additionally, epoxides are an important class of chemicals with broad product was formed with monodentate ligands (6 mol%) such as
applications in organic synthesis and advanced materials.4 Notably, a BuPAd2 and PPh3. To our delight, 27% yield of 3a was observed
chiral center can be easily introduced into the parent molecules by with binap as the ligand and which was chosen for further
applying chiral epoxides as substrates, which are readily available by optimizations (Table 1, entry 2). In solvent testing, moderate
asymmetric epoxidation of the corresponding alkenes. Among all the yields of the target molecule can be obtained in DMF or DMSO
types of reactions, the ring-opening reaction of epoxides is one of the (40% and 34% respectively, with 3a : 3a0 as 85 : 15 and 86 : 14
most straightforward routes for the utilization of epoxides. In general, respectively; Table 1, entries 9 and 10). In toluene, tBuOH and
it undergoes the SN1 type reaction under acidic conditions and water, low or no reactivity was observed (Table 1, entries 11–14).
nucleophilic attack takes place at the more substituted position, while The pressure of CO was varied as well, but no effects were
nucleophiles attack occurs at the less hindered carbon under the SN2 observed for this transformation (Table 1, entry 15). In the end,
type mechanism under basic conditions.
the yield of 3a was successfully increased to 80% with a ratio
To the best of our knowledge, no example was reported between 3a and 3a0 of 85 : 15 by increasing the amount of
for the carbonylative cross-coupling reaction with epoxides styrene oxide to 1.5 equiv. (Table 1, entry 16). Among all the
tested bases, NaOAc and organic base such as Et3N and DBU
gave only trace amounts of the product; moderate yield (72%)
¨
Leibniz-Institut fur Katalyse e.V., Albert Einstein Straße, 29a, 18059 Rostock,
was produced with the use of 1.1 equiv. of KOH, and the best
result was obtained with K3PO4 as the base (90%, 3a : 3a0 =
90 : 10; Table 1, entries 16–21). Interestingly, the selectivity
was reversed by adding 30 mol% of ZnBr2 as the Lewis acid
Germany. E-mail: xiao-feng.wu@catalysis.de; Tel: +49-381-1281-343
† Electronic supplementary information (ESI) available: NMR data and spectrum.
CCDC 968227. For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c3cc48490d
2114 | Chem. Commun., 2014, 50, 2114--2116
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Table 1 Benzodioxepinone synthesis: optimizationa
Entry
2 : 1
Ligand
Base
Solvent
Yieldb
3a : 3a0
1
2
3
4
5
6
7
8
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.5
1.5
1.5
1.5
1.5
1.5
1.5
dppf
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
NaOAc
K3PO4
KOH
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DMF
DMSO
Dioxane
Toluene
tBuOH
H2O
DMF
DMF
DMF
DMF
DMF
DMF
DMF
H2O
7
27
N.R
17
18
24
N.R
13
40
34
N.R
9
68 : 32
74 : 26
—
76 : 24
72 : 28
74 : 26
—
81 : 19
85 : 15
86 : 14
—
40 : 60
—
binap
xantphos
dppe
dppp
dppb
dpppe
DPEPhos
binap
binap
binap
binap
binap
binap
binap
binap
binap
binap
binap
binap
binap
binap
9
10
11
12
13
14
15c
16c
17c
18c
19c,d
20c
21c
22c,e
N.R
N.R
47
Scheme 1 Proposed reaction mechanism.
—
84 : 16
85 : 15
—
90 : 10
91 : 9
—
80
o5
addition of the Ar–Br bond to the Pd(0) center, and the benzoyl
palladium complex was produced as the key intermediate after
the subsequent coordination and insertion of CO. Finally,
by the intramolecular nucleophilic attack of the hydroxyl group,
the seven-membered ring was eliminated as the final product
and palladium(0) was regenerated under assistance of base.
With the optimized reaction conditions in hand [2 mol%
Pd(OAc)2, 3 mol% binap, 0.5 mmol of 2-bromophenol, 0.75 mmol
of epoxide, in DMF as the solvent, with 3 equiv. of K3PO4 as the
base, under 5 bar of CO, at 100 1C for 16 hours], we carried out
the generality testing (Table 2).
90
72
Et3N
DBU
K3PO4
o5
o5
50
—
15 : 85
a
Pd(OAc)2 (2 mol%), ligand (3 mol%), 1 (0.5 mmol, 1 equiv.), 2 (0.75 mmol,
b
1.5 equiv.), base (2 equiv.) CO (15 bar), at 100 1C, 20 hours. Yield was
c
determined by GC with hexadecane as the internal standard. CO (5 bar).
d
e
KOH (1.1 equiv.). ZnBr2 (30 mol%). dppf = 1,10-bis(diphenylphosphino)-
ferrocene, binap = 1,10-binaphthalene-2,20-diyl)bis(diphenylphosphine,
xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, dppe =
ethylenebis(diphenylphosphine), dppp = 1,3-bis(diphenylphosphino)-
propane, dppb = 1,4-bis(diphenylphosphino)butane, dpppe = 1,5-bis-
(diphenylphosphino)pentane, DPEPhos
= (oxydi-2,1-phenylene)bis-
Initially, different epoxides were examined with 2-bromophenol
as the model substrate. Firstly, 4-chloro-styreneoxide was tested,
4,5-dihydrobenzo[c]oxepinone was obtained with a ratio between
3-substituted (3c) and 4-substitued (3c0) compounds of 90 : 10
and 3c was isolated in 85% yield (Table 2, entry 2). Epoxides
with aliphatic chains, 2-butyloxirane and 2-octyloxirane were
subjected to the optimized conditions, moderate yields (respec-
tively 79% and 79%) were obtained with better regioselectivity
(95 : 5; Table 2, entries 3 and 4). With cyclopentene oxide as the
starting substrate, the reaction also proceeded well and 3e
was isolated as a single diastereoisomer in 70% yield (Table 2,
entry 5). However, when using cyclohexene oxide as the starting
substrate, the product was isolated as a mixture of diastereo-
isomers in a diastereoisomeric ratio of 75: 25 which might be
explained by the co-existence of SN1 and SN2 mechanisms as the
presence of palladium acetate as the Lewis acid and K3PO4 as
base (Table 2, entry 6). With these results in hand, we then tested
different glycidyl ethers under our best conditions (Table 2,
entries 7–12). Notably, glycidyl ethers are another important
class of epoxides and have become commercially available since
the late 1940s, which are used as components of epoxy resins.
Generally, different glycidyl ethers bearing aliphatic and aro-
matic glycidyl ethers gave moderate to good yields (66–88%).
Moreover, the regioselectivity of the ring-opening reaction of
glycidyl ethers are proved to be better than other aliphatic and
aromatic substituted epoxides in which the selectivity is more
(diphenylphosphine), DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene.
in H2O (Table 1, entry 22). From those primary results, we
found that the properties of base and solvent were the two main
factors which influenced the regioselectivity between 3a and 3a0
and the yield.
In order to confirm the molecule structure, one of the
products has been analyzed using X-ray diffraction (Fig. 1).
Considering the reaction pathway for this cascade reaction, the
most plausible mechanism for this transformation has been
given in Scheme 1. Under basic conditions, the SN2 type nucleo-
philic attack at the less hindered site of the epoxide and
generation of the corresponding 2-(2-bromophenoxy)ethan-
1-ol was the initial step. This was followed by the oxidative
Fig. 1 Molecular structure of 3m. Displacement ellipsoids are drawn at
the 50% probability level.
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Table 2 Scope of the reaction under optimized conditionsa
As the achievements in asymmetric epoxidation of alkenes
have been acknowledged by the Nobel Prize in 2001 and several
name reactions, asymmetric epoxides are becoming readily
available. It will be highly interesting if we can keep the chiral
centre of the epoxide in the final products under our condi-
tions. To our delight, when S-(–)-benzyl glycidyl ether was
subjected to the optimized conditions, 98% of ee was obtained
in the final products. Moreover, the substrate scope could also
be extended to 3-bromonaphthalen-2-ol under the same condi-
tions, which also yields the corresponding product in 85% yield
(Table 2, entry 13).
In summary, a highly regioselective cascade synthesis of
2,3-dihydrobenzodioxepinone from 2-bromophenols and epoxides
has been developed. Starting from commercially available sub-
strates, moderate to good yields of versatile desired products are
obtained in a regioselective manner (major product > 90%) under
mild conditions.
Entry
1
2
Product
Yieldb (3 : 30)c
1
1a
90 (90 : 10)
2
3
4
5
1a
1a
1a
1a
85 (90 : 10)
79 (95 : 5)
79 (95 : 5)
70
(dr > 99 : 1)d
The authors thank the state of Mecklenburg-Vorpommern,
the Bundesministerium fu¨r Bildung und Forschung (BMBF) for
financial support. We also thank Dr W. Baumann, Dr C. Fischer,
Ms S. Schareina and Mr S. Buchholz (All LIKAT) for analytical
support.
77
6
7
1a
1a
(dr: 75 : 25)d
66 (>99 : 1)
Notes and references
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8
1a
1a
1a
88 (>99 : 1)
66 (98 : 2)
79 (>99 : 1)
85 (98 : 2)
9
10
11
12
1a
1a
98% eee
13
85 (90 : 10)
a
General conditions: Pd(OAc)2 (2 mol%), binap (3 mol%), 1 (0.5 mmol,
1 equiv.), 2 (0.75 mmol, 1.5 equiv.), K3PO4 (1.5 mmol, 3 equiv.), in DMF (2 mL),
CO (5 bar), at 100 1C for 16 hours. b Isolated yield of 3a–m. c Determined by
GC. d Analyzed using NMR of the purified compound. e Analyzed using gas
chromatography equipped with a chiral column of the crude product.
than 98 : 2. Remarkably, this catalytic system is proven to be
tolerable towards the allyl group as 79% of 3j was isolated
by using allyl glycidyl ether as the starting material (Table 2,
entry 10). In the cases of 9-oxabicyclo[6.1.0]nonane and
ethyl 3-phenyloxirane-2-carboxylate, no desired products were
detected.
2116 | Chem. Commun., 2014, 50, 2114--2116
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