Highly efficient formation of halodiazoacetates and their use in stereoselective synthesis of halocyclopropanes

Article abstract of DOI:10.1039/b814374a

Halogenated analogues of ethyl diazoacetate are synthesised by a novel and highly efficient procedure and give halocyclopropanes in good to excellent yields when exposed to a Rh(ii) catalyst in the presence of alkenes. The Royal Society of Chemistry 2008.

Full text of DOI:10.1039/b814374a

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Highly efficient formation of halodiazoacetates and their use in stereoselective
synthesis of halocyclopropanes†
Hanne Therese Bonge, Benjamin Pintea and Tore Hansen*
Received 18th August 2008, Accepted 20th August 2008
First published as an Advance Article on the web 10th September 2008
DOI: 10.1039/b814374a
Halogenated analogues of ethyl diazoacetate are synthesised
by a novel and highly efficient procedure and give halocyclo-
propanes in good to excellent yields when exposed to a Rh(II)
catalyst in the presence of alkenes.
The introduction of rhodium(II) catalysts has since the mid
1970’s allowed tremendous progress within the field of carbene
chemistry, greatly improving the synthetic use of carbene reactions
through increased chemo-, regio- and stereoselectivity. The new
advances in both carbene chemistry and the synthesis of diazo
compounds prompted us to go back and revisit the synthesis of
halodiazoacetates and explore their reactivity in metal catalysed
cyclopropanation reactions.
Because of the toxicity and environmental hazards associ-
ated with mercury chemistry, and the explosive nature of ethyl
silverdiazoaceate,7 we wanted to pursue a new way of synthesising
a-halodiazoacetates. We started our investigations by searching
for a mild base that would be strong enough to deprotonate
EDA, as the use of strong bases such as LDA and n-BuLi
typically requires low reaction temperatures. DBU, recently used
to promote aldol and Mannich reactions with EDA,13 proved to be
a good choice. N-Halosuccinimides were selected as electrophilic
halogenation reagents. In our first attempt to synthesise ethyl
diazobromoacetate (1) from EDA we used DBU and NBS in
dichloromethane at 0 ◦C (Scheme 1).
Halogenated molecules are widely distributed in the biosphere;1,2
more than 4500 halogenated natural products are currently
known, many of them chiral. Several halogenated natural products
have therapeutic interest,3 and new examples are continuously
discovered. The frequent utilisation of chlorine and fluorine
substituents in drug design further illustrates the ability of
halogens to modulate selectivity, enzymatic stability and/or
affinity of pharmaceutically active compounds. Within the field of
organic chemistry, halogenation reactions are not only among the
most historically significant reactions, but also of great practical
importance. Alkyl halides can serve as precursors in numerous
useful reactions, including the synthesis of carbon–carbon bonds
and introduction of a wide range of functional groups. The
desirable biological as well as chemical properties of halogenated
molecules have spurred renewed effort in the synthetic community
to develop methodologies that will allow selective introduction of
halogen atoms. The most recent noticeable advances have been
made in the area of a-halogenation,4 a current example being the
asymmetric, organocatalytic introduction of F, Cl and Br in the
a-position to aldehydes and ketones.5
Diazo compounds undergo a variety of useful synthetic
transformations, such as cyclopropanation and C–H inser-
tion reactions.6 We started looking into the synthesis of a-
halodiazoacetates for utilisation in the selective formation of a-
halocyclopropanecarboxylates, as a complementary approach to
the already developed methodologies for selective introduction of
halogens. The first syntheses of a-halodiazoacetates were reported
in the literature around 1970.7–12 These syntheses were based
on mercury or silver chemistry. Diethyl mercurybisdiazoacetate
was generated from ethyl diazoacetate (EDA) by treatment with
mercury oxide, whereas ethyl silverdiazoacetate was synthesised
by treatment of EDA with silver(I) oxide. Either of these were then
treated with an electrophilic halogen source to give the desired
halodiazoacetates. Decomposition, thermally or by irradiation,
gave low to moderate yields and poor stereocontrol in cyclopropa-
nation and C–H insertion reactions.
Scheme 1 Formation of halogenated EDA-analogues.
These reaction conditions gave quantitative conversion of EDA
to 1 in less than 5 min. After some screening, we were able to
obtain quantitative yields of 1, 2 and 3 using 1.4–1.6 equiv. of
DBU and 1.3–1.5 equiv. of NBS, NCS, NIS or I2. Triethylamine
could also be used as a base, but the reaction was much slower,
and it was difficult to reach full conversion of EDA.
One potential problem with diazo compounds is their thermal
instability and decomposition when exposed to heat and light.
Commercially available EDA itself is relatively stable when neat
and can be stored in the fridge for months. The halogenated EDA-
analogues are less stable, and decompose within hours at room
temperature, both as neat compounds and in solution. However,
all three halogenated EDA-analogues can be conveniently handled
in solution at 0 ◦C.9
After having established an efficient procedure for the synthesis
of the halogenated EDA-analogues, we turned to the use of these
diazo compounds in the cyclopropanation of alkenes. Styrene
was selected as the alkene in our initial attempts to make 1-
bromocyclopropanecarboxylates 4 (Scheme 2). Selected results
from experiments with different reaction conditions are shown in
University of Oslo, Department of Chemistry, Sem Sælands vei 26, 0315 Oslo,
Norway. E-mail: torehans@kjemi.uio.no; Fax: +47 22855386; Tel: +47
22855441
† Electronic supplementary information (ESI) available: Experimental
and spectroscopic data for all compounds; experimental protocol for
experiments in Table 3. See DOI: 10.1039/b814374a
3670 | Org. Biomol. Chem., 2008, 6, 3670–3672
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Table 1 Cyclopropanation of styrene with 1. Screening of reaction conditions
Entry
Catalyst loading (mol%)
Solvent
Additive
Yield of 4 (%)a
Diastereomeric ratio (4a : 4b)f
c
c
c
c
d
e
1
2
3
4
5
6
7
8
9
5
1
1
1
1
1
1
1
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
—
17
11
25
24
33
20
58
86b
91b
90
81
6 : 1
6 : 1
7 : 1
6 : 1
6 : 1
ND
7 : 1
9 : 1
9 : 1
7 : 1
7 : 1
15 mol% Na2S2O3
15 mol% Cu
1 equiv. Cu
15 mol% Cu
15 mol% Cu
15 mol% Cu
15 mol% Cu
—
d
Dry CH2Cl2
Dry toluened
Dry toluened
Dry toluened
Dry toluened
1
0.5
0.1
10
11
—
—
a Measured by internal standard (2-naphthaldehyde) in 1H NMR analysis of crude reaction mixture. b Isolated yield. c Dropwise addition of dilute solution
of 1 to styrene and Rh2esp2 in DCM over 3 h at rt; total reaction volume ca. 50 mL; stirring for additional 15 min. d Bulk addition of solution of Rh2(esp)2
to dissolved 1 and styrene at rt; stirring for 15 min. e Bulk addition of solution of Rh2(esp)2 to dissolved 1 and styrene at 0 ◦C, stirring for 15 min.
f Measured by 1H NMR analysis of crude reaction mixture.
toluene as solvent. This solvent effect was observed in our case
as well; switching from dichloromethane to toluene gave another
large improvement in yield (entry 8). Only traces of the carbene
dimerisation products could be detected. Eliminating the copper
Scheme 2 Synthesis of ethyl 1-bromo-2-phenylcyclopropanecarboxylate.
additive took the yield of 4 from 86% to 91% (entry 9), and it
was also shown that lower catalyst loadings could be used with
satisfactory results (entries 10 and 11).
The diastereomeric ratio of the products from the cyclo-
propanation reaction was persistently in the area 6 : 1–9 : 1,
which is consistent with cyclopropanation reactions with diazo
compounds bearing two electron withdrawing groups.6 The major
diastereomer, mirroring the results of cyclopropanation with
EDA, was the diastereomer with the phenyl group and the ester
function in a trans relationship (4a).
Table 1. Freshly prepared 1 was used in all the experiments since
formation of 1 from EDA was quantitative within 5 min reaction
time. The dichloromethane solution of 1 was washed with aq.
Na2S2O3 and passed quickly through a plug of silica gel before
the cyclopropanation reaction was initiated. Our earlier positive
experiences14,15 with commercially available Rh2(esp)2,16 a robust
Rh(II) catalyst with bidentate ligands, made this catalyst a natural
choice.
Our starting point was the common procedure for cyclopropa-
nation with EDA and many other diazo compounds,6 dropwise
addition (3 h) of a cold, diluted dichloromethane solution of
the diazo compound to alkene and catalyst (entry 1). We were
delighted to find that formation of 4 had taken place. However, the
yield was low, and products from carbene dimerisation abundant.
Copper powder or Na2S2O3, both additives known to stabilise
alkyl halides, were added to the reaction mixture in attempts
to prevent any undesired decomposition of the diazo compound
(entries 2–8). Whereas Na2S2O3 gave a slight reduction in yield, the
copper powder had a minor positive effect. The main reason for
doing a dropwise addition of the diazo compound to the catalyst
solution is to prevent dimer formation. In a simplification of the
experimental procedure, the time consuming dropwise addition
of the diazo compound was proved unnecessary. Addition of the
dissolved catalyst to a solution of diazo compound and styrene,
followed by stirring for 15 minutes at room temperature, was just
as effective. Addition of the catalyst at room temperature (entry 5)
was more advantageous than addition at 0 ◦C (entry 6). The yields
were not significantly improved, however, demonstrating that the
main competing reaction, the carbene dimerisation, happened
quickly in the reaction mixture and not in the dichloromethane
solution of 1 during the slow addition.
Cyclopropanation of styrene with the chlorinated and iodinated
EDA-analogues 2 and 3 also worked very well, giving cyclo-
propanes analogous to 4, with yields and diastereomeric ratios
comparable to the results observed in the reactions with 1. Table 2
shows the results from cyclopropanation using the conditions
described in Table 1, entry 9.
The scope of the cyclopropanation reaction was examined by
reaction between 1 and a range of alkenes with varying electronic
and steric properties, using the same reaction conditions (Table 3).
Table 2 Cyclopropanation of styrene with compounds 1–3
Entry
Diazo compound
Yield (%)a
Dr (a : b)b
1
2
3
Ethyl diazobromoacetate (1)
Ethyl diazochloroacetate (2)
Ethyl diazoiodoacetate (3)
91
87
85
9 : 1
7 : 1
9 : 1
Performing the reaction under dry conditions drastically im-
proved yields (entry 7). As Kim et al. have noted,17 the efficiency
of Rh2(esp)2 may in certain cases be improved by the use of
1
a Isolated yield after silica gel chromatography. b Measured by H NMR
analysis of crude reaction mixture.
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two chiral Rh(II) catalysts, Rh2(DOSP)4 and Rh2(PTTL)4.19 Both
catalysts gave good yields of 4, but the asymmetric induction was
below 10% ee.
Table 3 Scope of cyclopropanation reaction with 1
Entry
Alkene
Yield (%)a
Dr (a : b)b
In summary, we have developed a novel procedure for the
synthesis of halogenated analogues of EDA, employing EDA,
DBU and a mild halogenating agent. Ethyl diazobromoacetate (1),
-chloroacetate (2) and -iodoacetate (3) are generated quantitatively
from EDA in only 5 minutes. The halogenated diazo compounds
have been used in Rh(II) catalysed cyclopropanation of a range
of olefins. The experimental procedure for the cyclopropanation
is quick and simple, with no need for dropwise addition of
the diazo compound, and the reaction gives good to excellent
yields and a diastereomeric ratio of up to 20 : 1 with electron-
rich, sterically unencumbered alkenes. This new synthesis of
1-halocyclopropanecarboxylates represents a novel method for
stereoselective introduction of halogens and broadens the range
of easily accessible a-halo carbonyl compounds.
1
2
3
4
5
6
7
8
9
Styrene
2-Vinylnaphthalene
Indene
N-Vinylphthalimide
4-MeO-styrene
4-Me-styrene
4-CF3-styrene
1,1-Diphenylethene
4-Cl-styrene
91
99
99c
90
87
84
83
79
77
0
9 : 1
9 : 1
—
> 20 : 1
9 : 1
7 : 1
6 : 1
—
6 : 1
—
—
10
11
cis-Stilbene
trans-Stilbene
0
a Isolated yield after two steps from EDA. Products purified by silica
gel chromatography. b Measured by H NMR analysis of crude reaction
1
mixture. c Isolated as ethyl 2-naphthoate after 3 steps.
The alkenes of entries 1–9 gave good to excellent yields, with
both 2-vinylnapththalene and indene reacting quantitatively. For
indene, the cyclopropane products underwent a further, sponta-
neous reaction (Scheme 3), resulting in ethyl 2-naphthoate.18 The
reaction went to completion after treatment with K2CO3.
Notes and references
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6 M. P. Doyle, M. A. McKervey and T. Ye, Modern catalytic methods for
organic synthesis with diazo compounds: From cyclopropanes to ylides,
Wiley, New York, 1998.
Scheme 3 Further reaction of products formed in cyclopropanation
reaction with indene.
7 U. Scho¨llkopf and N. Rieber, Chem. Ber., 1969, 102, 488–493.
8 F. Gerhart, U. Scho¨llkopf and H. Schumacher, Angew. Chem., Int. Ed.
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9 U. Scho¨llkopf, F. Gerhart, M. Reetz, H. Frasnelli and H. Schumacher,
Justus Liebigs Ann. Chem., 1968, 716, 204–206.
10 U. Scho¨llkopf and M. Reetz, Tetrahedron Lett., 1969, 1541–1544.
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1973, 599–610.
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Justus Liebigs Ann. Chem., 1974, 1767–1783.
13 N. Jiang and J. B. Wang, Tetrahedron Lett., 2002, 43, 1285–1287.
14 H. T. Bonge and T. Hansen, Synlett, 2007, 55–58.
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16 C. G. Espino, K. W. Fiori, M. Kim and J. Du Bois, J. Am. Chem.
Soc., 2004, 126, 15378–15379; Rh2(esp)2 = bis[rhodium(a,a,a¢,a¢-
tetramethyl-1,3-benzenedipropionic acid)].
Five different styrene derivatives with electron-donating or
electron-withdrawing substituents in the 4-position were screened
(entries 5–7, 9). There seemed to be a slight correlation between
the electronic effects of the substituents and the yields, the styrenes
with electron-donating substituents giving somewhat higher yields
than the styrenes with electron-withdrawing substituents. 1,1-
Diphenylethene was a relatively good substrate in the reaction,
but cis-stilbene and trans-stilbene (entries 10 and 11) were
completely unreactive towards cyclopropanation, perhaps due to
the more sterically encumbered double bonds of the latter. The
diastereomeric ratios (dr) of the cyclopropanation products from
all the reactions were between 6 : 1 and 9 : 1, except for the case of
N-vinylphthalimide (entry 4), where the dr was higher than 20 : 1.
The relative stereochemistry of the major diastereomer of 4 was
determined by NOESY experiments. We probed the possibility for
an asymmetric version of this cyclopropanation reaction by using
17 M. Kim, J. V. Mulcahy, C. G. Espino and J. Du Bois, Org. Lett., 2006,
8, 1073–1076.
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Pradhan, Tetrahedron, 1992, 48, 9649–9660.
19 H. M. L. Davies and R. E. J. Beckwith, Chem. Rev., 2003, 103, 2861–
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3672 | Org. Biomol. Chem., 2008, 6, 3670–3672
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©