Stereospecific formal [3+2] dipolar cycloaddition of cyclopropanes with nitrosoarenes: An approach to isoxazolidines

Article abstract of DOI:10.1002/anie.201400885

The MgBr₂-catalyzed formal [3+2] cycloaddition of donor-acceptor activated cyclopropanes with nitrosoarenes offers a novel approach to various structurally diverse isoxazolidines. The reactions, which are experimentally easy to conduct, occur with complete stereospecificity and perfect control of regioselectivity. Product isoxazolidines can be readily transformed into α-amino lactones by reductive or decarboxylative N-O cleavage and subsequent lactonisation, and the N-aryl bond cleavage is also possible under oxidative conditions. Stereospecific and regioselective: The MgBr ₂-catalyzed formal [3+2] cycloaddition of donor-acceptor-activated cyclopropanes with nitrosoarenes offers a novel approach to structurally diverse isoxazolidines. The reactions, which are experimentally easy to conduct, occur with complete stereospecificity and perfect control of regioselectivity.

Full text of DOI:10.1002/anie.201400885

Angewandte
Chemie
DOI: 10.1002/anie.201400885
Heterocycles
Stereospecific Formal [3+2] Dipolar Cycloaddition of Cyclopropanes
with Nitrosoarenes: An Approach to Isoxazolidines**
Shyamal Chakrabarty, Indranil Chatterjee, Birgit Wibbeling, Constantin Gabriel Daniliuc, and
Armido Studer*
Abstract: The MgBr2-catalyzed formal [3+2] cycloaddition of
donor–acceptor activated cyclopropanes with nitrosoarenes
offers a novel approach to various structurally diverse
isoxazolidines. The reactions, which are experimentally easy
to conduct, occur with complete stereospecificity and perfect
control of regioselectivity. Product isoxazolidines can be
readily transformed into a-amino lactones by reductive or
cycloaddition with nitrosoarenes. Donor–acceptor (DA)
cyclopropanes have gained much attention to the synthetic
community because of their synthetic utility and ease of
preparation.[6] In the presence of a Lewis acid (LA), DA-
cyclopropanes undergo a ring opening to form a 1,3 dipole
equivalent that has been used for [3+n] annulation reac-
tions.[7–9] Work by Johnson, Kerr, and other research groups
showed that cyclopropanes react with various 2p components,
such as aldehydes, imines, nitriles, olefins, and other systems,
À
decarboxylative N O cleavage and subsequent lactonisation,
and the N-aryl bond cleavage is also possible under oxidative
conditions.
to afford
a variety of carbocycles and heterocycles
(Scheme 2).[8,9]
C
ycloaddition reactions that involve nitroso compounds as
2p components offer an efficient approach to numerous
structurally diverse heterocycles, which are commonly used as
intermediates for the synthesis of natural products.[1] Cleav-
À
age of the labile N O bond of the corresponding cycloadducts
affords synthetically useful amino alcohols. In the past, many
research groups have investigated the [4+2] and [2+2]
cycloaddition of nitroso compounds with various dienes and
alkenes.[2,3] However, the use of nitroso compounds as cou-
pling partners in [3+2] cycloadditions has not been well
explored to date. Along these lines, we recently reported the
Cu-catalyzed formal [3+2] cycloaddition reaction of allyl-
stannes with 2-nitroso pyridine, in which allylstannes are used
as formal 1,3 dipoles (Scheme 1).[4]
Scheme 2. [3+2] cycloaddition of cyclopropane with different 2p com-
ponents.
Scheme 1. Formal [3+2] cycloaddition of 2-nitroso pyridine with allyl
tributyl tin.
Moreover, the [3+2] cycloaddition with nitrosylchloride
was reported to afford isoxazolines.[10] However, the reaction
of DA-cyclopropanes with nitrosoarenes is to our knowledge
currently unknown.[11] Herein, we wish to present the formal
[3+2] cycloaddition reaction of cyclopropanes with nitroso-
arenes to give isoxazolidines.
We first investigated the reaction of readily available
cyclopropane 1a (1 equiv) with nitrosobenzene 2a (1.5 equiv)
to afford isoxazolidine 3a (Table 1). The initial experiment
was conducted with Cu(OTf)2 (20 mol%) as LA in CH2Cl2 at
room temperature. Pleasingly, the targeted isoxazolidine 3a
was formed, showing that the concept is working. The
structure of 3a was unambiguously assigned by X-ray analysis
(see below). However, the yield of the isolated product was
low (25%, Table 1, entry 1). Other Lewis acids that are
frequently used for the activation of DA-cyclopropanes, such
as Sc(OTf)3, Sn(OTf)2, and InBr3 in either CH2Cl2 or
Inspired by this work and the continuation of the
development of nitrosoarene chemistry,[2i,j,5] and considering
the importance of isoxazolidines as valuable heterocycles, we
decided to explore other potential 1,3 dipoles in the [3+2]
[*] S. Chakrabarty, Dr. I. Chatterjee, B. Wibbeling, Dr. C. G. Daniliuc,
Prof. Dr. A. Studer
NRW Graduate School of Chemistry, Organisch-Chemisches Insti-
tut, Westfꢀlische Wilhelms-Universitꢀt
Corrensstraße 40, 48149 Mꢁnster (Germany)
E-mail: studer@uni-muenster.de
[**] We thank the DFG for supporting our work.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201400885.
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Table 1: Reaction of 1a with 2a under different conditions.
Entry
Lewis acid
LA [mol%]
T [8C]
Solvent
Yield [%]
1
2
3
4
5
6
7
8
Cu(OTf)2
Sc(OTf)3
Sn(OTf)2
InBr3
FeCl3
MgCl2
MgI2
20
20
15
20
20
20
20
20
20
20
20
20
10
20
20
20
20
20
20
20
20
20
20
90
20
20
90
90
20
20
CH2Cl2
CH2Cl2
ClCH2CH2Cl
CH2Cl2
ClCH2CH2Cl
CH2Cl2
25
10
20
<10
40
40
40
60
20
50
CH2Cl2
MgI2
MgI2
ClCH2CH2Cl
ClCH2CH2Cl
CH2Cl2
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
CCl4
9
10
11
12
13
14
15
MgBr2
MgBr2
MgBr2
MgBr2
MgBr2
MgBr2
70
92
50
10
THF
40
The entry in bold marks optimized reaction conditions.
ClCH2CH2Cl provided only 10%, 20%, and trace amounts of
3a, respectively (Table 1, entries 2–4).
Disappointingly, Lewis acids such as Mg(ClO4)2, AlCl3,
GaCl3, Cu(SbF6)2, and Ni(ClO4)2·6H2O did not deliver any
product (not shown). The use of FeCl3 as a catalyst improved
the yield to 40%, and a similar result was also obtained with
MgCl2 in CH2Cl2 (Table 1, entries 5 and 6). The product was
isolated with the same yield in the MgI2-catalyzed reaction
(Table 1, entry 7). A further improvement was achieved with
MgI2 upon changing the solvent from CH2Cl2 to ClCH2CH2Cl
(60%; Table 1, entry 8). However, increasing the temperature
to 908C resulted in a significantly lower yield (20%; Table 1,
entry 9). Switching the catalyst from MgI2 to MgBr2 in CH2Cl2
at room temperature led to 3a in 50% yield, which was then
further improved to 70% when ClCH2CH2Cl was used as
a solvent (Table 1, entries 10 and 11). Pleasingly, we found
that the yield was further increased to 92% at an elevated
temperature (908C; Table 1, entry 12). Varying the solvent
(CCl4 and THF; Table 1, entries 14 and 15) as well as lowering
the catalyst loading to 10 mol% (Table 1, entry 13) provided
worse results.
Using the optimized reaction conditions (see Table 1,
entry 12), the scope and limitations of the [3+2] cycloaddition
were studied (Figure 1). Various ester groups at the DA-
cyclopropanes were tested with 2a as the reaction partner.
These studies were conducted using racemic cyclopropane
derivatives. As expected, the methyl ester gave 3b in good
yield (82%). A slightly lower yield was achieved with the allyl
ester (see 3d), and the bulkier tert-butoxycarbonyl cyclo-
propane gave the corresponding isoxazolidine 3c, albeit in
slightly lower yield (51%). Note that for this substrate the
phenyl substituent at the cyclopropane moiety was also
substituted by a p-tolyl group.
Figure 1. Products of the cycloaddition of various DA-cyclopropanes
with various nitrosoarenes.
thoxycarbonyl cyclopropanes were studied first, investigating
electronic effects exerted by substituents at the aryl group.
Electron-rich p-acetoxy- and p-methoxy-substituted arylcy-
clopropanes gave isoxazolidines 3e and 3 f in 70% and 75%
yield, respectively. However, cycloadditions with substrates
that bear aryl substituents with electron-withdrawing groups,
such as p-cyano and p-trifluoromethyl, proceeded less effi-
ciently and 3g and 3h were isolated in 45% and 50% yield,
respectively. Steric effects seem to be less important, as the
reaction with the ortho-tolyl cyclopropane gave 3i in 70%
yield. The naphthyl derivative worked well (3j) and the
furanyl substituent was tolerated, but the product (3k) was
obtained in a significantly lower yield. Notably, a cyclopro-
pane derived from indane worked very well and 3l was
isolated in 82% yield as a single diastereoisomer.
We next explored the generality of the reaction by
switching to non-aromatic donor substituents at the DA-
cyclopropane moiety. The vinylcyclopropane derivative gave
the isoxazolidine 3n in high yield (82%); the corresponding
We then explored the compatibility of various donor
groups of the DA-cyclopropanes. Aryl-substituted bisme-
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isomeric 7-membered heterocycle (an 1,2-oxazepane deriva-
tive) resulting from reaction at the terminal vinyl position was
not identified. Pleasingly, we found that the less activated n-
butyl derivative gave 3m in 65% yield, showing that an
activating p-donor substituent is not mandatory for this
transformation. Also the N-phthaloyl-substituted isoxazoli-
dine 3o could be obtained in very good yield, showing that the
method is not restricted to C-substituted DA-cyclopropanes.
The structure of 3o was assigned by X-ray analysis (see the
Supporting Information).[12] A lower yield was obtained with
the acetoxy-substituted cyclopropane derivative (see 3p).
The scope of the reaction was further tested with respect
to the nitrosoarene component. We found that electron-
deficient nitrosoarenes that bear either p or s acceptors at the
para position delivered the corresponding cycloadducts in
excellent yield (3r–u). Notably, a quantitative yield was
obtained using p-nitro nitrosobenzene (3u). The reaction
worked with p-nitrosotoluene; however, 3q was isolated in
a lower yield, showing that cycloadditions work far more
efficiently with electron-deficient nitrosoarenes. Indeed, with
electron-rich congeners such as o-methoxy and p-methoxy
nitrosobenzene (not shown in the figure), the reaction with 1a
under the optimized conditions did not work. However, the
cycloaddition occurred smoothly with the p-trifluoromethoxy
nitrosobenzene and 3v was isolated in 78% yield.
Scheme 4. Proposed catalytic cycle.
We next explored the stereospecificity of the [3+2]
cycloaddition using the enantiopure phenyl cyclopropane
(S)-1a.[9d] Nitrosobenzene reacted with (S)-1a with complete
stereospecificity, providing (S)-3a in 90% yield (Scheme 3,
Mg atom of enolate B, to give magnesiated hydroxylamine C.
The Mg–O interaction in D explains the observed regiose-
lectivity of the enolate amination. Note that the regioisomeric
isoxazolidine was not identified in the experiment. Inter-
mediate C eventually cyclizes through an intramolecular SN2
substitution to close the catalytic cycle, providing (S)-3a with
net retention at the stereogenic center with respect to the
starting cyclopropane (S)-1a. The experimentally observed
higher reactivity of the electron-deficient nitrosoarenes can
be explained by their intrinsic higher electrophilicity and
hence more efficient reaction with enolate B. The lower Lewis
basicity at the O atom of the electron-deficient nitrosoarenes
obviously plays a less important role in the enolate amination.
To document the potential of the isoxazolidines 3 as
building blocks in synthesis, we further investigated follow-up
Scheme 3. Testing stereospecificity of the cycloaddition of nitrosoben-
zene with enantiopure cyclopropane (S)-1a.
> 99% ee as found by HPLC, see the Supporting Informa-
tion). The absolute configuration was unambiguously deter-
mined by X-ray analysis.[12] Hence, cycloaddition occurred
with net retention at the stereogenic center. This is in contrast
to the [3+2] cycloaddition of DA-cyclopropanes with alde-
hydes, which occurs with excellent stereospecificity but with
reversal of stereochemistry.[9d] As an additional example, we
reacted enantiopure (S)-bismethylester with nitrosobenzene
and obtained isoxazolidine (S)-3b in 70% yield with more
than 99% ee (see the Supporting Information).
Our suggested mechanism for the cycloaddition reaction
is depicted in Scheme 4. The catalyst MgBr2 first interacts
with DA-cyclopropane (S)-1a, providing the activated
MgBr2-complexed cyclopropane A. The Br anion then
opens the cyclopropane ring at the benzylic position in an
SN2 reaction, generating enolate B, as previously suggested in
the literature.[13] Enolate B then reacts with the nitrosoben-
zene, likely via the 6-membered transition state D, in which
the O atom of the nitroso compound is bound to the oxophilic
À
chemistry (Scheme 5). Reductive cleavage of the N O bond
was achieved by Zn/AcOH to provide the corresponding 1,3
amino alcohols, which spontaneously undergo cyclization to
afford a-amino g-butyrolactones. Subjecting 3a to reductive
cleavage gave 4 in 70% yield as a 1.3:1 diastereoisomeric
mixture. However, complete diastereoselectivity was
observed when 3l was used for the reductive cleavage, and
the corresponding a-amino lactone 5 was isolated in 55%
yield. The relative configuration was assigned by NMR
spectroscopy. The N-aryl group in 3a was successfully cleaved
under oxidative conditions[14] to provide 6 in 40% yield of
isolated product. It is known that decarboxylation in isoxaz-
olidine 5-carboxylic acids readily occurs by cleavage of the
[15]
À
N O bond. We found that a regioisomer studied herein
showed a similar reactivity. Hence, mild Pd-catalyzed deallyl-
ation[16] of allyl ester 3d provided lactone 7 in 51% yield. Very
little racemization of the product occurred under the applied
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Scheme 5. Follow-up reactions on isoxazolidines 3a, 3d, and 3l
(CAN=ceric ammonium nitrate).
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subsequent decarboxylation to give the corresponding imino
alcohol, which in turn undergoes lactonization. Tautomeriza-
tion of the imine eventually affords 7.
In conclusion, we have reported an unprecedented formal
[3+2] cycloaddition of nitrosoarenes with DA-cyclopropanes
as formal 1,3 dipoles to give valuable isoxazolidines with high
yields and complete regioselectivity. Further examination of
the cycloaddition with an enantiomerically pure cyclopropane
gave the product isoxazolidine with complete stereospecific-
ity. The reaction occurred with retention of stereochemistry at
the stereogenic center. We have also shown that these
isoxazolidine scaffolds can be readily transformed into a-
À
amino lactones by reductive or decarboxylative N O bond
cleavage and subsequent lactonisation, and N-aryl bond
cleavage is also possible under oxidative conditions.
Received: January 27, 2014
Revised: March 10, 2014
Published online: && &&, &&&&
Keywords: cycloadditions · cyclopropanes · heterocycles ·
.
nitrosoarene · stereoselective synthesis
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Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Heterocycles
S. Chakrabarty, I. Chatterjee,
B. Wibbeling, C. G. Daniliuc,
A. Studer*
&&&& — &&&&
Stereospecific Formal [3+2] Dipolar
Cycloaddition of Cyclopropanes with
Nitrosoarenes: An Approach to
Isoxazolidines
Stereospecific and regioselective: The
MgBr2-catalyzed formal [3+2] cycloaddi-
tion of donor–acceptor-activated cyclo-
propanes with nitrosoarenes offers
a novel approach to structurally diverse
isoxazolidines. The reactions, which are
experimentally easy to conduct, occur
with complete stereospecificity and per-
fect control of regioselectivity.
6
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!