Intramolecular cyclopropanation of bromodiazoacetates

Article abstract of DOI:10.1055/s-0033-1340170

A series of allylic diazoacetates were prepared from the corresponding allylic alcohols and bromoacetyl bromide. When the allylic diazoacetates were treated with 1,8-diazabicyclo[5.4.0]undec-7-ene and N-bromosuccinimide, a rapid full conversion to the corresponding allylic bromodiazoacetates occurred. Exposure of the allylic bromodiazoacetates to rhodium(II) catalysts induced an intramolecular cyclopropanation and gave cyclopropyl bromolactones in yields that were low to good, depending on the substitution pattern. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1340170

LETTER
▌221
lIenttetr ramolecular Cyclopropanation of Bromodiazoacetates
Intramolecular Cyclopropanation of Bromodiazoacetates
Marianne Bolsønes, Hanne Therese Bonge-Hansen, Tore Bonge-Hansen*
University of Oslo, Department of Chemistry, Sem Sælands vei 26, 0315 Oslo, Norway
Fax +47(228)55441; E-mail: tore.bonge-hansen@kjemi.uio.no
Received: 13.09.2013; Accepted after revision: 08.10.2013
version into the corresponding halogenated analogue in
less than five minutes. We previously investigated the use
of the resulting halodiazoacetates in rhodium(II)-cata-
lyzed intermolecular cyclopropanation,3 C–H insertion,
Abstract: A series of allylic diazoacetates were prepared from the
corresponding allylic alcohols and bromoacetyl bromide. When the
allylic diazoacetates were treated with 1,8-diazabicyclo[5.4.0]un-
dec-7-ene and N-bromosuccinimide, a rapid full conversion to the
corresponding allylic bromodiazoacetates occurred. Exposure of and Si–H insertion reactions.4 The mechanisms of the in-
termolecular cyclopropanation reactions5 and the inter-
the allylic bromodiazoacetates to rhodium(II) catalysts induced an
intramolecular cyclopropanation and gave cyclopropyl bromolac-
molecular C–H insertion reactions6 have also been
tones in yields that were low to good, depending on the substitution
investigated by density functional theory calculations.
pattern.
The use of halodiazoacetates in carbenoid reactions repre-
Key words: cyclization, diazo compounds, fused ring system,
rhodium, catalysis, carbenoids
sents a novel approach to the selective introduction of hal-
ogens.7 Whereas intermolecular reactions with
halodiazoacetates have been well studied, there are no
published reports of any systematic investigation of the
Electrophilic rhodium(II) carbenoids are useful and versa-
intramolecular cyclopropanation reactions of halodiazo-
tile intermediates in organic synthesis. These highly reac-
acetates. However, there is one report of an intramolecular
tive species participate in a wide range of carbon–carbon
cyclopropanation of a chlorodiazoacetate that demon-
and carbon–heteroatom bond-forming reactions.1 The
strates the usefulness of this intramolecular reaction.
most frequently encountered rhodium(II) carbenoid pre-
Zhang and Tang used electrophilic chlorination to pro-
cursors are diazo compounds. Diazoacetates are the most
duce an indole-derived chlorodiazoacetate that underwent
widely studied class of diazo compounds and are widely
subsequent intramolecular cyclopropanation as a key step
used in organic synthesis.2 We previously developed a
in their total synthesis of the cyclohexanone core of the
novel and highly efficient procedure for the synthesis of
biologically very interesting welwitindolinone C series
halogenated analogues of ethyl diazoacetate (Scheme 1).3
of compounds (Scheme 2).8
Here we describe a systematic study of the synthesis of a
range of allylic bromodiazoacetates and their subsequent
intramolecular cyclopropanation reactions in the presence
of rhodium(II) catalysts.
DBU
NCS, NBS or NIS
EtO2C
H
EtO2C
X
CH2Cl2
0 °C, 5 min
N2
N2
X = Cl, Br, I
Various ways of synthesizing diazo compounds have re-
cently been reviewed.9 In the search for an efficient syn-
thesis of allylic diazoacetates from allylic alcohols, we
screened several of the known methods, and we found the
procedure developed by Toma and co-workers10 to be the
best for our purposes. We chose to optimize the reaction
conditions by using cinnamyl alcohol as the substrate
(Scheme 3).
Scheme 1 Preparation of halogenated analogues of ethyl diazoace-
tate
Treatment of commercially available ethyl diazoacetate
with a small excess of 1,8-diazabicyclo[5.4.0]undec-7-
ene and an N-halosuccinimide results in quantitative con-
Cl
O
O
O
Cl
O
N2
N2
NCS
DBU
O
O
Rh(II)
Cl
TIPSO
O
N
N
N
N
Boc
Boc
Boc
Boc
Scheme 2 Zhang and Tang’s electrophilic α-diazoacetate chlorination and subsequent intramolecular cyclopropanation8
SYNLETT 2014, 25, 0221–0224
Advanced online publication: 02.12.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1340170; Art ID: ST-2013-D0877-L
© Georg Thieme Verlag Stuttgart · New York

222
M. Bolsønes et al.
LETTER
O
Table 1 Yields of Allylic Diazoacetates from Allylic Alcohols and
Bromoacetyl Bromide
O
Br
Br
Br
K3PO4
Allylic diazoacetate
Yielda (%)
99
O
OH
CH2Cl2
0 °C, 2 h
O
THF TsNHNHTs
0 ºC, 1 h DBU
O
O
N2
H
O
O
O
N2
82
N2
Scheme 3 Synthesis of cinnamyl diazoacetate
O
We modified the literature procedure slightly, and found
that the yield increased substantially when we changed the
base from potassium carbonate to potassium phosphate
and extended the reaction time from ten minutes to two
hours. Furthermore, excess N,N′-ditosylhydrazine, pres-
ent after the workup, co-eluted with the product during
column chromatography. This problem in purifying the
product was solved by washing the organic phase with
0.1 M aqueous sodium hydroxide before performing the chro-
matographic purification. By using the optimized reaction
conditions, we synthesized a series of allylic diazoacetates
from commercially available allylic alcohols (Table 1).
76
75
65
60
O
N2
O
N2
O
O
O
N2
O
O
With primary and secondary allylic alcohols, the yields
were generally high; however, the reaction became more
sluggish and gave a lower yield when a tertiary allylic
alcohol was used as the substrate.
N2
O
58
36
O
We used cinnamyl diazoacetate as a substrate to optimize
the reaction conditions for the synthesis of the desired
allylic bromodiazoacetates and for the subsequent intra-
molecular cyclopropanation reaction (Scheme 4).
N2
O
O
N2
O
We began by using our previously developed procedure
for the bromination of ethyl diazoacetate (Scheme 1).3
The halogenated analogues of ethyl diazoacetate are un-
stable when neat and handled at room temperature, but
they can be conveniently handled in solution at 0 °C. We
therefore expected that cinnamyl bromodiazoacetate
would have similar thermal stability. The cinnamyl bromo-
diazoacetate was kept in solution at 0 °C during workup
and purification, and the solution was used directly in the
next step. The yield was measured over two steps for the
isolated cyclopropyl bromolactone. We varied several of
the reaction conditions, such as the catalyst, temperature,
addition rate, order of addition, and concentration to opti-
mize the reaction conditions, and we used an aqueous so-
dium thiosulfate (Na2S2O3) workup instead of silica gel
plug filtration. The highest isolated yield in the catalyst-
screening process was 62%, obtained with tetrakis(1-{[4-
a Isolated yield after silica gel chromatography.
alkyl(C11–C13)phenyl]sulfonyl}-(2S)-pyrrolidinecarbox-
ylate)dirhodium(II) [Rh2(S-DOSP)4], which gave an aver-
age 80% yield for the bromination and intramolecular
cyclopropanation steps. However, the enantioselectivity
of the bromocyclopropane was only 4%, which made us
choose the best nonchiral catalyst, bis{rhodium[3,3'-(1,3-
phenylene)bis(2,2-dimethylpropanoic
acid)]}
[Rh2(esp)2],11 for our systematic study. This was also
found to be the best catalyst in Zhang and Tang’s study.8
In a control experiment, we exposed cinnamyl diazoace-
tate to Rh2(esp)2, under otherwise identical conditions to
those used for cinnamyl bromodiazoacetate, and we ob-
served rapid decomposition of the diazo compound; how-
ever, the crude product mixture did not contain any
O
O
O
Br
DBU
NBS
Br
Rh(II)
H
O
O
O
N2
N2
Scheme 4 Synthesis of cinnamyl bromodiazoacetate
Synlett 2014, 25, 221–224
© Georg Thieme Verlag Stuttgart · New York

LETTER
Intramolecular Cyclopropanation of Bromodiazoacetates
223
bicyclic lactone formed by intramolecular cyclopropana- olefins gave moderate yields. The yields for the chlorina-
tion.
tion and subsequent intramolecular cyclopropanation re-
ported in Zhang and Tangs’s study8 were 50–60% and
correspond well with those obtained in our study.
We then exposed the allylic diazoacetates listed in Table
1 to N-bromosuccinimide and 1,8-diazabicyclo[5.4.0]un-
dec-7-ene in dichloromethane at 0 °C. When bromination In summary, we have developed an efficient synthetic
was complete (about 5 min), we changed the solvent to protocol12 for the synthesis of allylic bromodiazoacetates
toluene and we used Rh2(esp)2 as the catalyst for the intra- and cyclopropyl bromolactones. The allylic bromodiazo-
molecular cyclopropanation step, keeping the temperature acetates are thermally unstable at room temperature, but
at 0 °C. The Rh2(esp)2-catalyzed decomposition of the can be conveniently handled in solution at 0 °C. Exposure
bromodiazoacetates was complete within a few seconds. of the allylic bromodiazoacetates to birhodium(II) cata-
The results from our systematic study are shown in Table lysts induced a very rapid intramolecular cyclopropana-
2. The reported yields are for both the bromination and the tion. The yields for the Rh2(esp)2-catalyzed
intramolecular cyclopropanation steps; combined yields intramolecular cyclopropanation of the allylic bromodia-
of up to 68% were obtained for the best substrates.
zoacetates varied from low to good, but were considerably
lower than those for intermolecular cyclopropanation of
styrene with halogenated analogues of ethyl diazoace-
tate.3 It is apparent that there is an unexplored potential for
further development of the catalyst with respect to both
the yield and enantiomeric induction in the intramolecular
cyclopropanation reaction. Further studies on the reactiv-
ity and stability of halodiazoacetates, halodiazoamides,
and halodiazophosphonates are in progress and will be re-
ported in due course.
Table 2 Yields of Bicyclic Bromolactones
Bicyclic bromolactone
Yielda
68
O
Br
O
O
Br
64
44b
44
O
Acknowledgment
Br
Financial support by the Chemistry Department, University of Oslo
is gratefully acknowledged. We would like to thank Mr. Osamu
Sekiguchi for his assistance with mass spectrometric analyses.
O
O
O
Br
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
O
r
t
iornat
Br
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29c
18
O
O
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DBU (1.3 equiv) and NBS (1.2 equiv) were added
sequentially to a solution of the allylic diazoacetate (1.0
equiv) in CH2Cl2 (5.0 mL/mmol diazo substrate) at 0 °C, and
the solution was stirred for 15 min. The solution was then
washed with 20% aq Na2S2O3 (6 × 6 mL/mmol diazo
substrate), and the aqueous phases were extracted with
CH2Cl2 (6.0 ml/mmol diazo substrate) at 0 °C. The organic
The general trend with respect to the yield appears to fol-
low the substitution pattern on the olefin. Substrates with
a terminal olefin group gave the lowest yields, the sub-
strate with a terminal gem-disubstituted olefin group gave
the highest yield (68%), and substrates with disubstituted
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 221–224

224
M. Bolsønes et al.
LETTER
1-Bromo-6-phenyl-3-oxabicyclo[3.1.0]hexane-2-one
phases were combined, dried (MgSO4), and filtered through
a plug of silica gel, with elution by CH2Cl2 cooled to 0 °C.
The filtered soln was diluted with toluene (10 mL/mmol
diazo substrate) and the CH2Cl2 was removed in vacuo at
0 °C. To the rapidly stirred toluene solution of the resulting
allylic bromodiazoacetate at 0 °C under N2 was added a
solution of Rh2(esp)2 (1 mol%) in toluene (2 mL/mmol diazo
substrate), and the resulting mixture was stirred for 15–25
min. The solvent was removed in vacuo, and the crude
product was purified by flash chromatography (silica gel).
White solid; 96.6 mg (44% yield); mp 117–118 °C; Rf = 0.33
(20% EtOAc–hexane). 1H NMR (300 MHz, CDCl3): δ =
2.58 (d, J = 5.1 Hz, 1 H), 2.87 (ddd, J = 0.6, 4.7, 5.1 Hz, 1
H), 4.39 (dd, J = 0.6, 9.6 Hz, 1 H), 4.59 (dd, J = 4.7, 9.6 Hz,
1 H), 7.17–7.40 (m, 5 H). 13C NMR (75 MHz, CDCl3): δ =
29.6, 34.2, 35.8, 68.5, 128.1, 128.5, 128.7, 132.9, 172.1. MS
(EI): m/z (%) = 254/252 (0.5/0.5) [M+], 174 (25), 173 (100),
145 (34), 128 (30), 115/117 (85/85), 91 (37). HRMS: m/z
calcd for C11H9O2Br: 251.9779; found 251.9786 (Δ 2.5
ppm).
Synlett 2014, 25, 221–224
© Georg Thieme Verlag Stuttgart · New York

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