Intermolecular Electrophilic Bromoesterification and Bromoetherification of Unactivated Cyclopropanes

Article abstract of DOI:10.1002/adsc.201901665

1,3-difunctionalization of cyclopropane is an useful organic transformation. The corresponding 1,3-difunctionalized products are synthetic synthons and building blocks in many organic syntheses. Many existing ring-opening difunctionalization methodologies rely primarily on the use of donor?acceptor cyclopropanes, while the difunctionalization of unactivated cyclopropanes is less exploited. In this research, 1,3-bromoesterification and 1,3-bromoetherification of unactivated cyclopropanes were successfully achieved using N-bromosuccinimide as the brominating agent with high yields and regioselectivity. (Figure presented.).

Full text of DOI:10.1002/adsc.201901665

Title: Intermolecular Electrophilic Bromoesterification and
Bromoetherification of Unactivated Cyclopropanes
Authors: Vincent Ming-Yau Leung, Matthew H. Gieuw, Zhihai Ke, and
Ying-Yeung Yeung
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10.1002/adsc.201901665
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Intermolecular Electrophilic Bromoesterification and
Bromoetherification of Unactivated Cyclopropanes
Vincent Ming-Yau Leung,† Matthew H. Gieuw,† Zhihai Ke,* Ying-Yeung Yeung*
Department of Chemistry and State Key Laboratory of Synthetic Chemistry, The Chinese University of Hong Kong,
Shatin, NT, Hong Kong (China)
[E-mail: chmkz@cuhk.edu.hk; yyyeung@cuhk.edu.hk]
† These authors contributed equally in this project.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. 1,3-difunctionalization of cyclopropane is a useful
organic
transformation.
The
corresponding
1,3-
Keywords: Cyclopropane; Haloether; Haloester;
Halogenation; Mechanism
difunctionalized products are synthetic synthons and
building
Many
blocks
in
many
organic
syntheses.
existing
ring-opening
difunctionalization
methodologies rely primarily on the use of donor–acceptor
cyclopropanes, while the difunctionalization of unactivated
cyclopropanes is less exploited. In this research, 1,3-
bromoesterification
and
1,3-bromoetherification
of
unactivated cyclopropanes were successfully achieved using
N-bromosuccinimide as the brominating agent with high
yields and regioselectivity.
cyclopropanes 1 using KICl2 as the stoichiometric
halogenating agent, giving a mixture of 1,3-
halogenated products 2a and 2b (Scheme 1).[11]
Recently, Hennecke et al. described a catalyst-free
halocyclization of cyclopropyl substrates 2 to give a
range of halo-heterocyclic compounds 3.[12]
Mechanistically relevant reactions that involve the
use of hypervalent iodine species in the oxidative 1,3-
difunctionalization of unactivated cyclopropanes
have also been reported by Szabó[13] and Jacobsen.[14]
Our research group also reported Lewis basic
chalcogen-catalyzed halocyclization of cyclopropyl
amides 4 to give oxazines 5.[15] A similar system was
found to be applicable to the halocyclization of
Introduction
Electrophilic halogenation of olefins in the
difunctionalization of unsaturated carbon-carbon
bonds appears in many organic transformations. It is
an extremely useful methodology whereas halogen
and another functionality can be introduced in a
vicinal relationship simultaneously with good stereo-
and regioselectivity.[1] The halogen handles in the
products can readily be manipulated using
conventional methods. Both intramolecular and
intermolecular electrophilic halogenation of olefins
have been extensively studied.[2,3]
The complementary 1,3-difuntionization reactions
that involve highly ring-strained cyclopropanes also
cyclopropylmethyl
carboxylic
acids.[16]
Diastereoselective halocyclization of cyclopropyl
place great importance in synthetic organic chemistry. diester compounds was also achieved with N-
Cyclopropanes pose -character -bonds and their
reactivity resembles that of olefins in many
situations.[4] Most existing literature examples of
ring-opening 1,3-difuntionalization of cyclopropanes
rely on the use of activated cyclopropanes such as
donor–acceptor cyclopropanes[5] and transition metal
mediated radical reactions.[6-8] However, many
cyclopropanes are unactivated.[9,10]
bromosuccinimide (NBS) as the halogen source.[17] In
addition, recently we reported a Lewis base-promoted
1,3-dioxygenation of unactivated cyclopropanes
using hypervalent iodine reagents.[18] Nonetheless, the
difunctionalization of unactivated cyclopropanes via
electrophilic halogenation remains less exploited and
has been an attractive research area. Particularly, the
intermolecular electrophilic halofunctionalization of
unactivated cyclopropanes remain underexploited.
Based on our previous experience on the electrophilic
halogenation of unactivated olefins,[19] we anticipated
that unactivated cyclopropanes could undergo
Electrophilic
halogenation
of
unactivated
cyclopropanes opens a new opportunity to construct
1,3-halofunctionalized molecules. Zyk et al. reported
a seminal work on the 1,3-dihalogenation of
1
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10.1002/adsc.201901665
Advanced Synthesis & Catalysis
intermolecular halogenation under mild conditions.
were also examined. Higher reaction yields were
obtained using 1,3-dibromo-5,5-dimethylhydantoin
(DBH) (entries 8 and 10). The reactions with N-
bromophthalimide (NBP) resulted in lower yields
(entries 9 and 11). However, the reactions using DBH
and NBP gave significant amount of aromatic
brominated side-products. Water was found to be
crucial in which no desired product was detected
when the reaction was carried out under anhydrous
condition (entry 2 vs 3).
Herein,
we
describe
an
intermolecular
halofunctionalization of unactivated cyclopropanes 8
with N,N-dimethylformamide (DMF) and alcohols to
give 1,3-haloesters
respectively.
9
and 1,3-haloethers 10,
Table 1. Reaction Optimization.[a]
entry
Br source
solvent
yield (%)[b]
1
2
NBS
NBS
NBS
NBS
NBS
NBS
NBS
DBH
NBP
DBH
NBP
DMF
55
77
0
61
63
CH2Cl2/DMF (1:1)
CH2Cl2/DMF (1:1)
CHCl3/DMF (1:1)
(CHCl)2/DMF (1:1)
THF/DMF (1:1)
MeCN/DMF (1:1)
CH2Cl2/DMF (1:1)
CH2Cl2/DMF (1:1)
CHCl3/DMF (1:1)
CHCl3/DMF (1:1)
3[c]
4
5
6
7
8
9
10
11
53
51[d,e]
86[e]
35[e]
85[e]
73[e]
[a]
Reactions were carried out with cyclopropylbenzene 8a
(0.2 mmol), bromination source (0.4 mmol) and water (0.2
mmol) in various solvents (1.0 mL) at room temperature
[b]
(except specified) in the absence of light for 48 h.
[c]
[d]
Isolated yield.
Water was not added.
Yield was
Aromatic brominated product
1
[e]
measured by H NMR.
was observed in the NMR study on the crude product
mixture and was inseparable by column chromatography.
Scheme 1. Comparison of The Previous and Present
Studies.
With the optimized reaction conditions in hand, the
substrate scope of the bromoesterification reaction
was investigated (Table 2). Good conversion and
regioselectivity were generally observed. The
reaction (exemplified with 9a) was found to be
readily scalable with comparable performance. The
reactions were also found to be compatible with
substrates bearing various electron-withdrawing (9b-
9e) and electron-donating (9f-9h) substituents. Apart
from monosubstituted cyclopropanes, we also
extended the substrate scope to a 1,1-disubstituted
cyclopropane, (1-methylcyclopropyl)benzene (8i),
giving 9i in moderate yield.[21] Instead of DMF, the
use of N,N-dimethylbutyramide yielded the
corresponding butyl ester product 9j thought the
efficiency was moderate. The 1,2-disubstituted
substrate cis-1,2-diphenylcyclopropane (8k) was also
converted into 3-bromo-1,3-diphenylpropyl formate
(9k) with a good diastereoselectivity.
Results and Discussion
At
the
beginning
of
experimentation,
cyclopropylbenzene 8a and NBS were used as the
substrate and the halogen source, respectively. 1,3-
halo-formyloxylation reaction was subjected to the
investigation using DMF and water as the
nucleophilic partners.[20] To our delight, 8a was
converted to -haloformate 9a in 55% yield and
excellent regioselectivity (Markovnikov product) at
room temperature in the absence of any external
promoter (Table 1, entry 1). Various reaction
conditions were evaluated in order to optimize the
reaction (Table 1). The choice of solvent and the
composition of DMF were firstly investigated. The
introduction of chlorinated solvents (dichloromethane,
chloroform and 1,2-dichloroethane) gave higher
yields (entries 2, 4-5). In contrast, using a solvent
blend of DMF with THF (entry 6) or acetonitrile
(entry 7) returned inferior reaction performance. Next,
the brominating reagent and the reaction temperature
2
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10.1002/adsc.201901665
Advanced Synthesis & Catalysis
Table
2.
Bromoesterification
of
Unactivated
On the other hand, in the presence of NBS in
methanol, 8a was smoothly converted into
bromoether 10a (75%) at room temperature with high
regioselectivity (Table 3). Substrates with various
substituents were also compatible with the protocol to
Cyclopropanes.[a]
Table
3.
Bromoetherification
of
Unactivated
Cyclopropanes.[a]
[a]
Reactions were carried out with aromatic substituted
cyclopropylbenzene 8 (0.2 mmol), NBS (0.4 mmol) and
water (0.2 mmol) in CH2Cl2/DMF (1:1 v/v, 1.0 mL) at 23
oC in the absence of light for 48 h. The yields are isolated
yields.
bromoesterification
[b]
Isolated yield of 9i for
2
steps:
[c]
and
hydrolysis.
N,N-
dimethylbutyramide/CH2Cl2 (1:1 v/v, 1 mL) was used.
The bromoester product 9a was transformed into
2-phenyloxetane
11
(63%)
using
diisobutylaluminium hydride (DIBAL-H) followed
by the addition of potassium tert-butoxide (Scheme
2). This approach can be considered as an oxygen-
insertion/ring-expansion of cyclopropane 8a in the
synthesis of oxetane 11.
[a]
Reactions were carried out with aromatic substituted
cyclopropylbenzene 8 (0.2 mmol) and NBS (0.3 mmol) in
o
MeOH (1.0 mL) at 23 C in the absence of light for 48 h.
The yields are isolated yields. [b] Ethylene glycol was used
[c]
instead of MeOH. NBS (0.2 mmol) was used. Aromatic
bromination side-product was detected when more NBS
was used.
Scheme 2. Transformation of Bromoester into
Oxetane.
3
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10.1002/adsc.201901665
Advanced Synthesis & Catalysis
give 10b-10f in good yields. Similar to the
bromoesterification, bromoethers 10g, 10h and 10i
were obtained smoothly using the corresponding
disubstituted substrates. When ethylene glycol was
used in place of methanol in the bromoetherification
of 8a, 10j was obtained in 95% yield and no
dimerized product was observed. 8k was transformed
into 1,3-dimethoxy-1,3-diphenylpropane (10k), and
attack species A via SN1 or SN2 mechanism to give
the Markovnikov adduct B. Finally, species B might
be hydrolyzed by water to give the desired product 9.
For the bromoetherification, a similar mechanism
might be adopted whereas the alcohol might attack
intermediate A to give the bromoether 10.
(2,2-dimethylcyclopropyl)benzene
converted into
(8m)
was
(1,3-dimethoxy-3-
methylbutyl)benzene (10m), presumably obtained
from the substitution of the secondary benzyl/tertiary
alkyl bromide intermediate by MeOH. Spiro substrate
8n was also found to be compatible to the reaction,
giving 10n in moderate yield. For other cyclopropane
substrates derived from cinnamates (8o), trans--
nitrostyrene (8p), acrylates (8q), both electrophilic
bromoesterification and bromoetherification were
found to be sluggish.
Isotopic labeling experiments were conducted in
order to probe the reaction mechanism. Under
optimized conditions, 8a was subjected to the
18
16
reaction using H2 O instead of H2 O as the
nucleophilic partner (Scheme 3, eq. 1). The
corresponding oxygen-labelled product 9a-I, which
was characterized by NMR and MS, was obtained in
70% yield with 90% deuterium purity. When the
reaction
was
conducted
using
N,N-
dimethylformamide-d7, the resultant deuterium-
labelled product 9a-II was obtained smoothly in 54%
yield (Scheme 3, eq. 2). These results indicate that
the carbonyl oxygen in the product 9 was contributed
by water while the remaining ester moiety was
originated from the DMF molecule.
Scheme 4. Plausible Reaction Mechanism.
Scheme 3. Isotopic Labelling Experiments.
A plausible mechanism is depicted in Scheme 4.
Based on the previous studies,[11,12,15-17] we believe
that the -character -bonds in the cyclopropane
substrates 8 might interact with the electrophilic
brominating agent NBS to give the corresponding
bromiranium-like intermediate A, which might exist
in equilibrium with the open-chain carbocation
species. Subsequently, the oxygen of DMF might
Scheme 5. 1H NMR Experiment of NBS and DMF.
4
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10.1002/adsc.201901665
Advanced Synthesis & Catalysis
Experimental Section
Since the reaction proceeded smoothly without an
external promoter, we suspected that the solvent
might be involved in activating NBS. Indeed, it is
known that DMF could activate NBS for aromatic
halogenation.[22] 1H NMR experiment on a mixture of
NBS (2.92 ppm) and DMF in CD2Cl2 was conducted
(Scheme 5). It was found that the signals of
succinimide’s protons shifted up-field upon the
addition of DMF. A possible explanation is that the
Lewis basic DMF might coordinate to the Br of NBS
to give activated brominating species C, which may
increase the anionic character of the succinimide. We
General procedure for the 1,3-bromo-formyloxylation
reaction of cyclopropane 8.
To a solution of cyclopropane 8 (0.2 mmol) in
dichloromethane (0.5 mL) and N,N-dimethylformamide
(0.5 mL) was added water (3.6 µL, 0.2 mmol) and N-
bromosuccinimide (71.2 mg, 0.4 mmol) into a vial. The
reaction was shielded from light and then stirred at 23 °C
for 48 h. The reaction was quenched with saturated
aqueous Na2SO3 (0.5 mL) and H2O (2 mL), and was then
extracted with diethyl ether (3 × 5 mL). The combined
organic extract was washed with brine (5 mL), dried over
anhydrous MgSO4, filtered, and concentrated under
reduced pressure with a rotary evaporator. The residue was
purified by flash column chromatography to yield the
desired methanoate 9.
1
also performed a H NMR experiment of NBS in
CD3OD. However, it appears that no adduct such as
CD3OBr was formed because no succinimide was
detected (see SI for details). Thus, we suspect that the
polar protic alcohol solvent might facilitate the
reaction by stabilizing the charged species A.
Acknowledgements
When other nucleophiles such as pyrrolidine
(secondary amine) or n-butylamine (primary amine)
was used instead of methanol or DMF, no desired
product was detected (Scheme 6, eq. 1). We also
conducted the reaction in the absence of nucleophile
and water in the hope of generating species A so that
the succinimide might act as the nucleophile to attack
the cationic species (Scheme 6, eq. 2). However, no
reaction was observed and cyclopropylbenzene (8a)
was recovered quantitatively.
We thank the financial support from RGC General Research
Fund of HKSAR (CUHK 14305219), The Chinese University of
Hong Kong Direct Grant (4053321) and Innovation and
Technology Commission to the State Key Laboratory of Synthetic
Chemistry (GHP/004/16GD). Equipment was partially supported
by the Faculty Strategic Fund for Research from the Faculty of
Science of the Chinese University of Hong Kong, China.
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Conclusion
In summary, mild, efficient, and regioselective
bromoesterification and bromoetherification of
unactivated cyclopropanes have been developed. The
methodology features advantages including broad
substrate scope and products being possible 1,3-
difunctionalized synthons to other biologically
essential organic molecules.
5
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10.1002/adsc.201901665
Advanced Synthesis & Catalysis
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6
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10.1002/adsc.201901665
Advanced Synthesis & Catalysis
FULL PAPER
Intermolecular Electrophilic Bromoesterification
and Bromoetherification of Unactivated
Cyclopropanes
Adv. Synth. Catal. 2020, Volume, Page – Page
Vincent Ming-Yau Leung, Matthew H. Gieuw,
Zhihai Ke*, Ying-Yeung Yeung*
7
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