Synthesis of 2-(phenoxymethyl)oxirane derivatives through unexpected rearrangement of oxiran-2-ylmethyl benzenesulfonates

Article abstract of DOI:10.1080/00397911.2016.1258579

The synthesis of 2-(phenoxymethyl)oxirane derivatives from oxiran-2-ylmethyl benzenesulfonates was developed through a base promoted rearrangement. A new C-O bond was formed along with the unexpected cleavage of C-S bond via this process. This unusual reaction was characterized with mild reaction conditions, high efficiency, and excellent functional group tolerance. A plausible reaction mechanism was proposed on the basis of experimental results and control experiments.

Full text of DOI:10.1080/00397911.2016.1258579

Synthesis of 2-(Phenoxymethyl)Oxirane Derivatives through Unexpected
Rearrangement of Oxiran-2-Ylmethyl Benzenesulfonates
Chuang Shen1, Xiang Guo1, Jun Yu1, Xian-Guo Zeng1, Li Peng1, Chuan-Meng Zhao1,
Fu-Li Zhang1
1China State Key Laboratory Of New Drug and Pharmaceutical Process, Shanghai
Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry,
Shanghai
Corresponding author Fu-Li Zhang E-mail: zhangfuli1@sinopharm.com
Abstract
The synthesis of 2-(phenoxymethyl)oxirane derivatives from oxiran-2-ylmethyl
benzenesulfonates was developed through a base promoted rearrangement . A new C-O
bond was formed along with the unexpected cleavage of C-S bond via this process. This
unusual reaction was characterized with mild reaction conditions, high efficiency and
excellent functional group tolerance. A plausible reaction mechanism was proposed on
the basis of experimental results and control experiments.
Graphical Abstract
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KEYWORDS: 2-(phenoxymethyl)oxirane; potassium hydroxide; rearrangement; C–S
cleavage; oxiran-2-ylmethyl benzenesulfonate
INTRODUCTION
Epoxides serving as powerful intermediates in organic synthesis could be easily
converted to various biologically active compounds through ring opening [1]. For example,
β-amino alcohols including metoprolol[2], propranolol[3], atenolol[4] which are easily
obtained through ring opening of 2-(phenoxymethyl)oxirane derivatives represent as a
class of drugs used primarily in cardiovascular diseases. The recent medicinal chemistry
applications include synthesis of delamanid [5], an anti-tuberculosis drug approved by
EMA (European Medicines Agency) in 2014 (Figure 1). Furthermore, a simple and
efficient method for the synthesis of cyclic carbonates from epoxides and CO2 was
reported recently [6].Thus, the development of effective methods for the synthesis of
2-(phenoxymethyl)oxirane derivatives remain as an important task in organic synthesis
and medicinal chemistry.
The classical methods utilized for the synthesis of 2-(phenoxymethyl)oxirane derivatives
involve the reaction between substituted phenols and oxiran-2-ylmethyl
benzenesulfonates (eq 1, Scheme 1). Non-nucleophilic strong base was commonly
employed to avoid the ring opening of epoxides, thus the reaction with substituted
phenols occurs at the carbon atom connecting to the leaving group rather than ring
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opening [7]. Although this protocol provided the corresponding epoxides in good to
excellent yield, electron-withdrawing group substituted phenols often suffer from
relatively low yield and harsh conditions [8]. Herein we report an effective method for the
synthesis of electron-withdrawing groups substituted 2-(phenoxymethyl)oxirane
derivatives through the base promoted rearrangement of oxiran-2-ylmethyl
benzenesulfonates, which could be easily prepared from substituted benzene sulfonic
chloride and glycidol [9]
.
RESULTS AND DISCUSSION
As part of our studies toward the process research of delamanid,
(R)-(2-methyloxiran-2-yl)methyl 4-nitrobenzenesulfonate 1a was treated with
4-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)phenol for the preparation of
2-(phenoxymethyl)oxirane derivatives , while a side product 2a was observed when
sodium hydroxide was used as base. The byproduct 2a turned out to be
2-methyl-2-((4-nitrophenoxy)methyl)oxirane which might be generated through the
rearrangement of 1a. This unexpected result provided a new approach for the synthesis of
2-(phenoxymethyl)oxirane derivatives. Therefore, further investigations were conducted
to optimize the reaction conditions and explore the plausible mechanism.
To our delight, the product 2a was isolated in 42% yield when NaOH (1.0 equiv) was
added to the solution of 1a in THF at room temperature (Table 1, entry 1). In order to
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improve the conversion rate of raw materials, the reaction was conducted at elevated
temperature and the desired product was isolated in 65% yield at 60 oC (entries 2−3).
Further optimization work indicated that the KOH was more appropriate compared with
NaOH and LiOH (entries 3−5). Interestingly, no reaction was observed when
non-nucleophilic base was employed (Table 1, entry 6-8). Other solvents included 1,
4-dioxane, toluene and DMF were also tested, and THF proved to be the most effective
medium (Table 1, entry 9-11). Besides, increasing or decreasing the equivalent of base
both led to the decrease in yield (Table 1, entry 12-13). Thus, the optimum conditions for
this base-promoted rearrangement are as follows: 1 equiv of KOH as base in THF at 60
oC for 24 h in the air.
With the optimized reaction conditions in hand, the scope and generality were explored.
Various oxiran-2-ylmethyl benzenesulfonates that were synthesized from substituted
benzene sulfonic chloride and glycidol were subjected to this reaction and the results
were summarized in Table 2. (R)-(2-methyloxiran-2-yl)methyl 4-nitrobenzenesulfonate
1a and its corresponding isomer 1b worked efficiently to furnish the corresponding
products in excellent yields with high enantioselectivity (Table 2, entries 1-2).
Nitro–substituted oxiran-2-ylmethyl benzenesulfonates all underwent the rearrangement
reaction smoothly with good to excellent yield (58%-74%), while p-substituted substrate
afforded the product with a higher yield compared with ortho- or meta- analogues (Table
2, entries 3-5). Halo substituents including F, Cl and Br are compatible with the reaction
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conditions, providing the target products with moderate yield (Table 2, entries 6-10).
Other substrates bearing different electron-withdrawing groups (CN, CF3) all efficiently
delivered the products with a yield ranging from 56% to 81% (Table 2, entries 11-13).
While oxiran-2-ylmethyl benzenesulfonate and Methyl substituted substrates gave the
product with poor yield even under higher reaction temperature and pressure (Table 2,
entries 14-15). Electronic effect of substituents on the aromatic ring was found to be
significant; substrates with electron-withdrawing groups usually gave a better result. On
the other hand, p-substituted substrate generally worked more efficiency as a result of
less steric hindrance and stronger electron withdrawing ability.
On the basis of the above experimental results and recent work on C-S functionalization
owing to the its relative weak bond energy[10], we assumed that the reaction might go
through the epoxide ring opening of the substrate, intramolecular aromatic nucleophilic
substitution, carbon-sulfur bond cleavage and formation of a new epoxide compound
(Scheme 2). To test this hypothesis, compound 3 was subjected to the standard reaction
conditions, the desired product 2c could be obtained smoothly in 70% yield (Scheme 3).
In conclusion, an efficient novel approach to obtain 2-(phenoxymethyl)oxirane
derivatives via the rearrangement of oxiran-2-ylmethyl benzenesulfonate has been
developed. The highlights of this work include the mild reaction conditions, good
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functional group tolerance and the metal-free feature. Further studies concerning its
appliance in the field of drug synthesis are currently underway in our laboratory.
EXPERIMENTAL
General Infrared spectra were recorded with a FTIR spectrometer. NMR spectra were
recorded for 1H NMR at 400 MHz or 500 MHz, and 13C NMR at 100 MHz or 125 MHz
using TMS as internal standard. The following abbreviations were used to describe peak
patterns where appropriate: singlet (s), doublet (d), doublet of doublets (dd), triplet (t),
quartet (q), multiplet (m), broad resonances (br). Mass spectroscopy data of the products
were collected on an HRMS-EI-TOF instrument or a low-resolution MS instrument using
EI or ESI ionization.
Preparation of 2-(phenoxymethyl)oxirane derivatives 2 : A mixture of
oxiran-2-ylmethyl benzenesulfonate 1 (0.5 mmol), KOH(0.5mmol, powder) in THF (2
mL) was stirred at 60 oC under air for 24 h. Afterward, the mixture was cooled to room
temperature, filtered through a pad of celite and the filtrate was concentrated. The crude
product was dissolved in Et2O (20 mL), washed with water (2×20 mL), brine (20 mL),
then dried over Na2SO4. The solvent was evaporated with rotary evaporator, and the
residue was subjected to flash column chromatography to obtain the desired product 2.
SUPPORTING INFORMATION
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Full experimental details, 1H and 13C NMR spectra, HPLC traces. This material can be
found via the “Supplementary Content” section of this article’s webpage.
ACKNOWLEDGMENT
Financial support from China State Institute of Pharmaceutical Industry is gratefully
acknowledged.
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TABLE 1. Optimization of Reaction Conditions a
Entry base(equiv) solvent T(oC) yield(%)b
1
NaOH(1.0) THF
NaOH(1.0) THF
NaOH(1.0) THF
RT
40
60
60
60
60
60
60
42
57
65
73
44
NR
NR
NR
61
46
18
55
62
2
3
4
KOH(1.0)
LiOH(1.0)
NaH(1.0)
THF
THF
THF
5
6
7
K2CO3(1.0) THF
Cs2CO3(1.0) THF
8
9
KOH(1.0)
KOH(1.0)
KOH(1.0)
KOH(0.5)
KOH(1.5)
dioxane 60
toluene 60
10
11
12
13
DMF
THF
THF
60
60
60
a All reactions were carried out with (2-methyloxiran-2-yl)methyl
4-nitrobenzenesulfonate (0.3 mmol), solvent (2 mL), 24 h.
b Isolated yields.
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Table 2. Synthesis of Various 2-(phenoxymethyl)oxirane a
Entry substrate
product Yield (%)b
R1=
R2=
1
1a(S)c 4-NO2 CH3
1b(R) c 4-NO2 CH3
73c
2a(R)
2
71c
2b(S)
3
4-NO2
2-NO2
3-NO2
4-F
H
H
H
H
H
H
H
H
H
H
H
H
H
74
66
1c
1d
1e
1f
2c
2d
2e
2f
4
5
58
66
54
63
61
52
70
56
81
36
21
6
7
2-F
1g
1h
1i
2g
2h
2i
8
4-Cl
9
4-Br
10
11
12
13
14d
15d
2-Br
1j
2j
4-CN
2-CN
4-CF3
H
1k
1l
2k
2l
1m
1n
1o
2m
2n
2o
4-CH3
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a Reaction conditions: 1 (0.5 mmol), KOH (0.5mmol), THF (2 ml), 60 oC, 24 h
b Isolated yields.
c ee=98%
d 80 oC, sealed tube
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Scheme 1. Comparison of previous work with this work
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Scheme 2. Possible reaction mechanism
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Scheme 3. Control experiment
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Figure 1. Examples of biologically compounds synthesized from epoxides.
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