Iron-catalyzed synthesis of cyclopropanes by in situ generation and decomposition of electronically diversified diazo compounds

Article abstract of DOI:10.1039/C8CC07060A

The modular synthesis of a variety of trans 1,2-disubstituted cyclopropanes in a safe and user-friendly one-pot iron-catalyzed cyclopropanation reaction is described. Easily synthesized N-nosylhydrazones are used as diazo precursors, allowing the in situ generation of electron-rich diazo compounds under mild reaction conditions and their direct participation in the cyclopropanation reaction.

Full text of DOI:10.1039/C8CC07060A

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Iron-catalyzed synthesis of cyclopropanes by
in situ generation and decomposition of
electronically diversified diazo compounds†
Cite this: Chem. Commun., 2018,
54, 13256
Received 31st August 2018,
Accepted 26th October 2018
Emmanuelle M. D. Allouche, Afnan Al-Saleh and Andre B. Charette
*
´
DOI: 10.1039/c8cc07060a
rsc.li/chemcomm
The modular synthesis of a variety of trans 1,2-disubstituted cyclo-
propanes in a safe and user-friendly one-pot iron-catalyzed cyclo-
propanation reaction is described. Easily synthesized N-nosylhydrazones
are used as diazo precursors, allowing the in situ generation of electron-
rich diazo compounds under mild reaction conditions and their direct
participation in the cyclopropanation reaction.
The cyclopropane core has been ranked as the 10th most commonly
used cyclic scaffold for the elaboration of new drugs1 and is present
in a large number of bioactive compounds.2 Among all the possible
substitution patterns, trans 1,2-diarylcyclopropanes moieties
are of particular interest, being a motif often screened during
the development of biologically relevant molecules.3 These trans
1,2-disubstituted cyclopropanes are generally obtained by reactions
between toxic and unstable aryldiazomethanes4 (or their corres-
ponding metal carbenes) and styrene derivatives. For obvious
safety reasons, many efforts have been invested to develop safer
generation and utilization protocols of those electron-rich entities.
Recently, continuous flow strategies have been described by us and
others in order to produce and use right away streams of various
aryl diazo compounds without the need to handle them directly.5
Scheme 1 (a) First in situ process developed by Aggarwal and co-workers.10a
(b) Silver-catalyzed cyclopropenation16c and cyclopropanation16d of 1,2
disubstituted alkenes using N-nosylhydrazones as diazo surrogates. (c) This
work: modular synthesis of cyclopropanes via iron catalysis.
Alternatively, classical batch methodologies allowing the in situ derived from benzaldehyde as precursors (Scheme 1a).10a This
generation and consumption of those reagents have also been cyclopropanation methodology was then applied to substrates
described: the Aggarwal group was the first to report the use varying from styrene derivatives,10a to dehydroaminoacids,10b
of N-tosylhydrazones to that effect, taking advantage of the proving its compatibility with a wide array of alkenes. The
Bamford–Stevens reaction6 to generate the wanted diazo compounds limiting point was however the modulation of the hydrazone
and subsequently engaging them in various metal-catalyzed reac- component: in all examples, very few electronically enriched or
tions such as epoxidations,7a aziridinations,7b olefinations,7c C–H8 impoverished phenyldiazomethane precursors were described or
and X–H insertions9 or cyclopropanations7b,10 in the same pot.11 For successfully used. This lack of results may be explained by the
example, 1,2-diphenylcyclopropane 2a has been synthesized in 73% high temperature that is often needed to trigger the decomposition
yield with a 91 : 9 trans/cis ratio after 48 hours at 40 1C via iron of the tosylsulfonylhydrazones, which can be incompatible with the
catalysis using styrene and the sodium salt of the tosylhydrazone sensitive diazo compound that is generated and the subsequent
cyclopropanation. We therefore decided to attempt the develop-
ment of smoother conditions for a modular cyclopropanation
Centre in Green Chemistry and Catalysis, Department of Chemistry,
reaction in which a wide variety of electronically and sterically
´
´
´
Universite de Montreal, P.O. Box 6128, Station Downtown, Montreal, Quebec,
H3C 3J7, Canada. E-mail: andre.charette@umontreal.ca
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c8cc07060a
modified aryl diazo compounds would be generated in situ.12
Concerning the cyclopropanation step by itself, we decided
to focus on iron chemistry using the well-known ClFeIII(TPP)
13256 | Chem. Commun., 2018, 54, 13256--13259
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(TPP = tetraphenylporphyrin) catalyst, as this metal is one of the that the metal carbene could react with an equivalent of diazo
most abundant on earth.13,14
to deliver this product of formal dimerization. Finally, the
In order to achieve our goal, we needed to find a way to N-nosylhydrazone gave the more promising result, the desired
decompose our hydrazones at lower temperature. In the literature, product being observed in 65% yield and displaying an excellent
two main strategies have been described in this optic. First, it is diastereoselectivity (Table 1, entry 4). Despite an extensive initial
possible to increase the steric bulk of the aromatic ring sitting on screening of solvents and bases, dichloromethane and sodium
the sulfonylhydrazone. By doing so, the steric decompression hydride proved to be the best for this reaction.17 Lowering the
during the diazo formation renders this step more favourable, temperature of the deprotonation step to 0 1C instead of room
as illustrated by the use of 2,4,6-triisopropylphenyl (Trip)15 temperature allowed us to minimize the formation of stilbene
or mesityl (Mes)5e sulfonylhydrazones. Alternatively, electronic and to obtain a slightly higher 75% yield (Table 2, entry 2).
effects can be used instead of steric ones.16 For example Additionally, a higher dilution of 0.05 M allowed us to observe
2-nosylhydrazones have been shown to decompose into the the desired product in 85% yield after 19 hours (Table 2, entry 3)
corresponding diazo compounds at room temperature once and in a quantitative yield after 24 hours (Table 2, entry 4).17 This
deprotonated by sodium hydride and are compatible with silver compound 2a was isolated in a slightly lower 92% yield due to its
catalyzed cyclopropenation16c and cyclopropanation16d reactions. volatility.
Another important aspect of those N-nosylhydrazones is that the
Those conditions in hand, the scope of the reaction was
diazo compound is slowly generated over time:16c therefore, there investigated using styrene and various nosylhydrazones at first
would be no diazo accumulation, risk of dimerization or degrada- (Scheme 2). p-Chloro-, p-bromo- and o-fluoro-phenylhydrazones
tion, as it would be consumed right away in the subsequent reaction. were successfully used under our reaction conditions, the
We began our studies by screening those different phenyl- corresponding products 2b, 2c and 2d being isolated in 87,
sulfonylhydrazones in an iron-catalyzed cyclopropanation reac- 85 and 81% respective yields with good diastereoselectivities.
tion of styrene: after a one-hour deprotonation step using The product 2e bearing a trifluoromethyl group in the para
sodium hydride in dichloromethane, an excess of the alkene position was also isolated in an excellent 97% yield with a 91 : 9
was added along with 10 mol% of the commercially available trans/cis ratio, showing that hydrazones bearing electron-
ClFeIII(TPP) catalyst, and the reaction was stirred overnight at withdrawing substituents are well tolerated in this reaction.
room temperature. When the tosylhydrazone derivative was The presence of a cyano group at the para position proved to be
used in these conditions (Table 1, entry 1), by 1H NMR we were more problematic: neither the desired cyclopropane 2f nor
able to observe only 27% of the desired product along with the the dimerization product were observed, although a complete
rest of the starting material untouched. This corroborates the consumption of the starting hydrazone. We hypothesized that
hypothesis that stronger conditions are needed to degrade such the diazo compound was successfully generated but did not
hydrazones. Although delivering the desired cyclopropane proceed to the carbene formation. Running the reaction at
in the same range of yields, the corresponding triisopropyl- 40 1C instead of room temperature after the introduction of the
phenylhydrazone and mesitylhydrazone experiments showed no alkene and the catalyst, we were pleased to isolate the desired
more hydrazone left but stilbene generated (Table 1, entries 2 product 2f in 95% yield, displaying a satisfactory 85 : 15 trans/cis
and 3). This suggested that the diazo compound was generated too ratio. Concerning hydrazones bearing electron-donating
quickly for the cyclopropanation reaction in those experiments, and effects, we also observed only little amounts of products when
the reactions were run at room temperature (Scheme 2, entries
2g, 2h, 2i, 2j). For these examples, the starting hydrazones were
recovered in the end, meaning that the diazo formation was the
Table 1 Screening of N-arylsulfonyl hydrazones as diazo surrogates
issue with electron rich hydrazones. Once again, heating the
reaction at 40 1C was beneficial as the desired products were
obtained in yields above 80% and displaying good diastereo-
selectivities. However, steric hindrance was detrimental to the
reaction, as shown by compound 2k, isolated with a moderate
Entry
Ar
Yielda,b (%)
drc
Mass balance
yield and a low diastereoselectivity even at 40 1C. We were
pleased to see that heteroaryldiazoalkanes can also be success-
fully generated and cyclopropanated in our conditions (com-
pounds 2l, 2m and 2n). A low 44% NMR yield was however
observed for product 2n as those types of alkoxy-substituted
cyclopropanes are generally prone to ring opening. We hence
failed to obtain any isolated yield after flash column chromato-
graphy, even using deactivated silica gel.18 Hydrazones derived
from a,b-unsaturated aldehydes were also effectively fragmented
into the corresponding diazo compounds, the cyclopropanation
products 2o and 2p being isolated in moderate to good yields
with good diastereoselectivities. We then investigated the alkene
1
2
3
4
Tolyl
Trip
Mes
o-Nitroaryl
27
24
17
65
—
92 : 8
—
Hydrazone recovered
Dimerization
Dimerization
92 : 8
Dimerization
a
Determined by 1H NMR (Ph3CH used as internal standard). b Combined
1H NMR yields of both diastereomers. dr trans/cis, trans diastereomer as
major.
c
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Table 2 Overview of the reaction optimization
Entry
Variation from the above conditions
Yielda,b (%)
drc
1
2
3
4
None
65
75
92 : 8
91 : 9
92 : 8
91 : 9
Deprotonation at 0 1C
Deprotonation at 0 1C + concentration of [0.05 M] (19 h)
Deprotonation at 0 1C + concentration of [0.05 M] (24 h)
85
99 (92)d
a
b
1
c
Determined by 1H NMR (trimethoxybenzene used as internal standard). Combined H NMR yields of both diastereomers. dr trans/cis, trans
d
diastereomer as major. Isolated yield (volatile compound).
p-Fluoro- and p-bromostyrenes are also viable substrates, as the
corresponding products 3b and 3c were isolated in good yields,
albeit a bit lower than the model substrate. Positioning the
bromine atom on the ortho position caused a drop of the isolated
yield, although still at an acceptable 76% and good diastereo-
selectivity (compound 3d). Interestingly, t-butyl acrylate successfully
undergoes the cyclopropanation reaction, although the desired
product 3e was isolated in a modest 48% yield and a mediocre
diastereoselectivity. 1,1-Diphenyl ethylene proved to be also
compatible with our conditions: the desired cyclopropane 3f
being isolated in 94% yield. Replacing one phenyl ring on this
substrate by a methyl group required to heat the reaction at 40 1C
to provide compound 3g that was isolated in 87% yield. Similarly,
a-bromostyrene was successfully cyclopropanated at 40 1C, the
product 3h being isolated in an 82% yield although with poor
diastereoselectivity. Product 3i and 3j were only isolated in low
28% and 37% yields respectively using 2,3-dimethyl-1,3-butadiene
and indene, showing limitations concerning the substitution and
the geometry of the starting alkene. It is worthy to note that the
compounds 2c and 3c are identical and similar yields and diastereo-
selectivities were obtained starting from either the p-bromophenyl
N-nosylhydrazone or the p-bromostyrene. As the styrene derivatives
are often very unstable and expensive, this methodology offers the
possibility to use relatively cheap and stable aldehydes instead to
access to the same moieties.
We then attempted an intramolecular example using compound
1q (Scheme 3a). We were glad to isolate compound 2q in 89% yield,
with a diastereoselectivity of 96 : 4. As the minor diastereoisomer
observed here could only result from the inversion of the
alkene’s geometry, we think that this reaction goes through a
stepwise radical mechanism described before as metalloradical
catalysis (MRC) by the Zhang group.10f Finally, we decided to
use our methodology for the synthesis of intermediate 3h
(Scheme 3b), that was used during the development of hepatitis
C virus inhibitors.3a In the original patent, this compound
Scheme 2 Scope of the reaction on 0.5 mmol scale. Yields on the isolated
was synthetized using Shi’s carbenoid in a Simmons–Smith
mixture of both combined diastereomers. Diastereomeric ratio determined
by 1H NMR on the isolated mixture. For each compound, the temperature of reaction of trans-stilbene followed by a bromination using NBS,
1
giving an overall yield lower than 40% (Scheme 3b).3a Using our
the reaction is specified in brackets. * H NMR yield on the crude mixture.
methodology, we synthesized efficiently 3h in a 80% overall
component of our reaction using the phenyl N-nosylhydrazone. yield starting from the cheap and commercially available
p-t-Butylstyrene worked well, the compound 3a being isolated 4-bromobenzaldehyde and nosylhydrazide, and this, without
in an almost quantitative yield with a good diastereoselectivity. the use of pyrophoric reagents.
13258 | Chem. Commun., 2018, 54, 13256--13259
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Scheme 3 (a) Intramolecular example. 0.5 mmol scale. Diastereomeric
ratio determined by 1H NMR on the crude mixture. (b) Application of the
methodology developed. 0.5 mmol scale. Diastereomeric ratio deter-
mined by 1H NMR on the isolated mixture.
9 For a recent example, see: E.-H. Wang, Y.-J. Ping, Z.-R. Li, H. Qin,
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In summary, we developed a safe and easy-to-handle protocol
for the in situ generation of electronically diversified compounds
and their implication in an iron-catalyzed cyclopro-panation
reaction in the same pot. The use of nosylhydrazones allowed
us to broaden the scope accessible of diazo compounds by
avoiding side reactions, therefore permitting an efficient, safe
and modular synthesis of cyclopropanes bearing a multitude of
substituents with various electronics properties for the first time
in a one-pot methodology.
This work was supported through funding from the Natural
Science and Engineering Research Council of Canada (NSERC)
Discovery Grant RGPIN-06438, the Canada Foundation for
Innovation Leaders Opportunity Funds 227346, the Canada
Research Chair Program CRC-227346, the FRQNT Centre in Green
Chemistry and Catalysis (CGCC) Strategic Cluster RS-171310, and
´
J. Org. Chem., 2005, 1479–1492; (b) J. Barluenga and C. Valdes,
Angew. Chem., Int. Ed., 2011, 50, 7486–7500; (c) Z. Shao and
H. Zhang, Chem. Soc. Rev., 2012, 41, 560–572; (d) Q. Xiao,
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12 For selected examples of in situ generation and cyclopropanation of
other types of diazo compounds, see: (a) R. P. Wurz and A. B. Charette,
Org. Lett., 2002, 4, 4531–4533; (b) B. Morandi and E. M. Carreira, Angew.
Chem., Int. Ed., 2010, 49, 938–941; (c) B. Morandi and E. M. Carreira,
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R. M. Koenigs, Green Chem., 2017, 19, 2118–2122.
´
´
´
Universite de Montreal. E. M. D. A. is grateful to Universite de
´
Montreal for postgraduate scholarship.
Conflicts of interest
13 For a short screening of other catalysts, see ESI†.
14 For a study on iron(II)-catalyzed cyclopropanation of phenyldiazo-
methane, see: C. G. Hamaker, G. A. Mirafzal and L. K. Woo,
Organometallics, 2001, 20, 5171–5176.
There are no conflicts to declare.
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Notes and references
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17 See ESI† for more details.
Bittner, C. J. Sinz, J. Chang, R. M. Kim, J. W. Mirc, E. R. Parmee and 18 Et3N was used to deactivate the silica.
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