An efficient, overall [4+1] cycloadditon of 1,3-dienes and nitrene precursors

Article abstract of DOI:10.1002/chem.201101630

Intermolecular cycloadditions of conjugated dienes and nitrene precursors usually produce aziridines. A generally useful method was lacking to directly provide the [4+1] cycloadducts, 3-pyrrolines. We have realized this transformation by using an uniquely active catalyst, copper(II) 1,1,1,5,5,5-hexafluoroacetylacetonate ([Cu(hfacac)₂]). The method is applicable to a wide array of dienes with good yields. When 1,4-disubsituted dienes are used as substrates, good-to-excellent cis or trans selectivity can be obtained. Interestingly, the cis or trans preference depends on the nature of the substituents, rather than diene geometry. Mechanistic studies reveal that the [4+1] cycloaddition proceeds through diene aziridination and subsequent ring expansion. Among common copper catalysts, only [Cu(hfacac)₂] can efficiently catalyze both steps, which explains the unique efficiency of the catalyst.

Full text of DOI:10.1002/chem.201101630

FULL PAPER
DOI: 10.1002/chem.201101630
An Efficient, Overall [4+1] Cycloadditon of 1,3-Dienes and Nitrene
Precursors
Qiong Wu,[b] Jian Hu,[a] Xinfeng Ren,[a] and Jianrong (Steve) Zhou*[a]
Abstract: Intermolecular cycloaddi-
tions of conjugated dienes and nitrene
precursors usually produce aziridines.
A generally useful method was lacking
to directly provide the [4+1] cycload-
ducts, 3-pyrrolines. We have realized
this transformation by using an
uniquely active catalyst, copper(II)
1,1,1,5,5,5-hexafluoroacetylacetonate
ble to a wide array of dienes with good
yields. When 1,4-disubsituted dienes
are used as substrates, good-to-excel-
lent cis or trans selectivity can be ob-
tained. Interestingly, the cis or trans
preference depends on the nature of
the substituents, rather than diene ge-
ometry. Mechanistic studies reveal that
the [4+1] cycloaddition proceeds
through diene aziridination and subse-
quent ring expansion. Among common
copper catalysts, only [CuACTHNUTRGNEG(NU hfacac)2] can
Keywords: aziridination · copper ·
cycloaddition · nitrenes · ring ex-
pansion
efficiently catalyze both steps, which
explains the unique efficiency of the
catalyst.
([CuACHTUNGTRENNUNG(hfacac)2]). The method is applica-
Introduction
Substituted pyrrolidines are frequently present in many nat-
ural products and therapeutic agents. Due to their important
biological activities, a wide variety of methods have been
developed to prepare these compounds, often with defined
stereochemistry.[1] We are particularly interested in intermo-
lecular cycloadditions for the construction of azacycles due
to material convergence and catalytic control of the stereo-
chemical outcome. Typical examples are [3+2] cycloaddi-
tions of olefins/alkynes with azomethine ylides[2]/aziridines[3]
and [3+2] cycloadditions of imines with allenes,[4] trimethy-
lenemethanes,[5] or cyclopropanes.[6] However, these reac-
tions usually require activation of the reactants (alkenes, al-
kynes, allenes, and cyclopropanes) with electron-withdraw-
ing groups.
Scheme 1. Intermolecular [4+1] cycloaddition of conjugated dienes and
nitrene equivalents to access 3-pyrrolines.
olefin groups of which can be readily transformed into other
functionalities. For example, olefine dihydroxylation can
lead to stereoselective synthesis of 3,4-dihydroxypyrroli-
dines,[7] which are core structures in many bioactive com-
pounds.[8]
Formal intramolecular [4+1] cycloadditions have been ex-
tensively studied by Hudlicky[9] and Pearson[10] via thermoly-
sis of 1,3-dienyl azides, which proceeds via triazoline inter-
mediates.[11] However, these reactions are often accompa-
nied by side reactions and low yields of the [4+1] cycload-
ducts. Furthermore, 2- and 3-pyrroline isomers are pro-
duced, dependent on the substitution of the dienes.
Intermolecular cycloadditions of stabilized nitrenes with
1,3-dienes usually lead to aziridines[12] and a generally useful
method to directly produce [4+1] cycloadducts was lack-
ing.[13] Thus, a separate step is needed to convert preformed
vinylazirdines[14] into pyrrolines.[15] Herein, we report an effi-
cient, intermolecular overall [4+1] cycloaddition of
1,3-dienes and nitrene precursors.
We envision intermolecular [4+1] cycloaddition of conju-
gated dienes and nitrene equivalents as an alternative gener-
al approach to access pyrrolidines (Scheme 1). Besides the
attributes of convergence and catalytic control of the stereo-
chemistry, the [4+1] cycloaddition produces 3-pyrrolines, the
[a] Dr. J. Hu, Dr. X. Ren, Prof. Dr. J. Zhou
Division of Chemistry and Biological Chemistry
School of Physical and Mathematical Sciences
Nanyang Technological University
637371 (Singapore)
Fax : (+65)67911961
E-mail: jrzhou@ntu.edu.sg
[b] Q. Wu
Results and Discussion
Department of Medicinal Natural Products
West China School of Pharmacy
Sichuan University
For the model reaction (Table1), we selected an ester-con-
taining 1,3-butadiene and a common nitrene precursor,
(N-p-tosylimino)phenyliodinane (PhI=Ts).[16] After exten-
sive research, we found that copper(II) 1,1,1,5,5,5-hexa-
Chengdu, 610041 (P. R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201101630.
Chem. Eur. J. 2011, 17, 11553 – 11558
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11553

Table 1. Optimization of the reaction parameters for [4+1] cycloaddition
of a 1,3-diene with PhI=NTs.
Entry
Modification of
GC yield
[%]
reaction conditions[a]
1
2
3
[Cu
[Cu
[Cu
N
89
20
13
4
Cu
G
14
5
6
7
8
CuI, CuOAc, or Cu
G
<10
68
83
83
30
27
89
48
86
5% [Cu(L1)2] in PhCl
5% [Cu(L1)2] in PhCF3
2% [Cu(L1)2] in PhCF3
5% [Cu(L2)2] in PhCl
5% [Cu(L2)2] in PhCF3
chlorobenzene
toluene
benzene
a,a,a-trifluorotoluene
9
10
11
12
13
14
76
[a] Initial conditions (entries 1 and 11): [CuACTHNUTRGEN(UNG hfacac)2] (5 mol%), PhI=
NTs, PhCl, 1008C, 24h.
Scheme 2. Scope of the [4+1] cycloaddition of dienes (d.r.=diastereo-
meric ratio).
fluoroacetylacetonate ([CuACHTNUTRGENNG(U hfacac)2]) can catalyze the for-
mation of the desired [4+1] cycloadducts in good yield at
1008C. When 1.0 equivalent of the diene was used, the yield
dropped to 63%. The results of our studies of the catalyst
and solvent effects are summarized in Table 1. The two CF3
EWGs on the hfacac ligand proved to be essential for the
high catalytic activity, in comparison with copper(II)
Notably, presence of the alkyl groups in isoprene and 2,3-di-
methyl-1,3-butadiene allows the reactions to proceed at
room temperature in high yields. The method is tolerant of
ester groups at both the terminal and internal positions of
the dienes. Also, cyclic diene, 1,3-cyclooctadiene, and a cy-
clopropyl-substituted diene gave acceptable yields of the re-
spective cycloadducts. In the latter case, no cyclopropyl ring-
opened byproducts were detected.[20]
When 1,4-disubstituted dienes are used, formation of cis
and trans isomers of the 3-pyrrolines is possible. In our reac-
tions, good-to-excellent cis/trans selectivity can be obtained,
depending on the nature of the substituents, rather than the
diene geometry. If both substituents are alkyl groups, the
formation of trans-pyrrolines is favored; if one or both sub-
stituents are aryl groups, the cis isomers are the major prod-
ucts. For example, trans,trans-1,4-diphenyl-1,3-butadiene fur-
nishes the cis isomer almost exclusively (Scheme 2). A
1,6-disubstituted triene also selectively provided cis-pyrro-
lines. Interestingly, the triene also gave <10% of the [6+1]
cycloadduct. The configuration of the 2,5-disubstituted pyr-
rolines was determined by X-ray crystallography.[18]
1,1,1-trifluoroacetylacetonate ([Cu
acetylacetonate ([Cu(acac)2]) (Table 1, entries 2 and 3).
Other copper catalysts, such as copper(II) triflate (Cu-
(OTf)2), CuI, and CuOAc, are much less active (Table 1, en-
ACHTUNGTERN(NUNG tfacac)2]) and copper(II)
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
tries 4 and 5). With regards to the choice of solvent, many
aromatic solvents work well, with the exception of toluene
due to benzylic CH amination (Table 1, entries 11–14).[17]
To access more active catalysts, we prepared 1,3-diketo-
nate complexes [Cu(L1)2] and [Cu(L2)2] from CuACHTNUTRGNEUNG(OAc)2
and neutral ligands (see formula in Table 1 for structures).[18]
[Cu(L1)2], which bears n-C7F15 side chains, is more active
than [CuACHTUNGTRENNUNG(hfacac)2] and allows the catalyst loading to be re-
duced to 2 mol% (PhCF3 is used as the solvent for solubility
reasons, Table 1, entry 8). [Cu(L2)2], which bears perfluori-
nated acac ligands, is much less active, probably due to
ligand fragmentation (Table 1, entries 9 and 10).[19]
With regards to the mechanism, we have considered three
possible pathways: 1) a concerted [4+1] cycloaddition be-
tween a copper–nitrene complex and a diene to directly
form the 3-pyrroline (Scheme 3a); 2) a facile, irreversible
aziridination of the diene with the copper–nitrene com-
plex,[21] followed by ring expansion (Scheme 3b); 3) a fast,
reversible aziridination, in coexistence with a slow, irreversi-
Because [CuACHTUNGTRENNUNG(hfacac)2] is highly active and commercially
available, we chose to use this catalyst to study the diene
scope (Scheme 2). A wide range of mono-, di-, and trisubsti-
tuted conjugated dienes gave the target [4+1] cycloadducts.
Common nitrene precursors PhI=NTs and PhI=NNs
(Ns=p-nitrobenzenesulfonyl) both work well in the reaction.
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Cycloaddition of 1,3-Dienes and Nitrene Precursors
FULL PAPER
temperature (368C) so that more mechanistic details
could be revealed (Figure 1). From both dienes, several
vinylaziridine isomers are produced as intermediates,
which isomerize to 3-pyrroline (p) at the same tempera-
ture. Notably, trans,trans-vinylaziridine (tt) is both
formed and isomerized to p much faster than trans,cis-vi-
nylaziridine (tc). In the cycloadditions of both tt and tc,
p is produced with >90:1 d.r. in favor of the cis isomer,
regardless of the diene geometry. In the reaction of the
cis,trans-diene, no isomerization to the trans,trans-diene
was observed at 368C.
Scheme 3. Possible pathways for the catalytic [4+1] cycloaddition.
A close examination of the kinetics in Figure 1 suggests
that, in both cases, tt is concurrently isomerized to both p
and tc. This was confirmed by a separate study, in which
ble [4+1] cycloaddition (Scheme 3c). The following experi-
ments indicate that pathway b is most likely:
pure tt was subjected to [CuACTHNUTRGNE(NUG hfacac)2]-catalyzed ring expan-
1) Cycloaddition of 1,3-cyclooctadiene at 1008C only gave
vinylaziridines, but continued heating of the reaction
mixtures at 1508C provided 3-pyrrolines. This is in agree-
ment with Njardarsonꢁs earlier observation that [Cu-
sion (Figure 2a). In a second experiment (Figure 2b), the
copper-catalyzed ring expansion of pure tc is shown to also
produce p in a cis/trans ratio of 19:1, but the conversion is
much slower than that of tt.
A
Recently, Njardarson et al. reported that [CuACTHGNUTRENNU(G hfacac)2]-
dines requires high-temperature conditions.[15a]
2) Cycloaddition of trans trans-2,4-hexadienes at 258C only
gives a 1.6:1 mixture of two vinylaziridine isomers in
64% yield, with the cis-aziridine as the major product.
When the isolated vinylaziridine isomers are subjected to
copper catalysis at 1008C, they cleanly isomerize to
3-pyrrolines in high yield (Scheme 4).
catalyzed ring expansion of vinylaziridines to 3-pyrrolines
was stereospecific.[22] The active catalyst was proposed to be
a cationic [CuACTHUNTGRNEUNG(hfacac)] species and ring expansion was con-
sidered to proceed via a reactive conformation with all four
carbon atoms of the vinylaziridine in an s-cisoid arrange-
ment.[15a] To account for the stereoselectivity in the overall
[4+1] cycloaddition of 1,4-disubstituted dienes, we have put
forth a mechanistic proposal (Scheme 6). 1,4-Diaryl dienes
Scheme 4. Isomerization of the isolated dimethyl-substituted aziridine.
3) When the isomerization of isolated vinylaziridines was
conducted in the presence of a second diene (10 equiv),
no crossover vinylaziridines or crossover 3-pyrrolines
were detected in either case (Schemes 4 and 5). Thus, the
lack of crossover rules out pathway c.
Scheme 6. Proposed model for the stereoselectivity.
tt and tc, the more stable isomer, can slowly interconvert
under the catalytic conditions.[23] Direct ring expansion of tt
forms the cis-pyrroline, whereas that of tc forms the trans-
pyrroline. However, the latter process is impeded by steric
repulsion when an aryl group is present in the reactive con-
formation of tc. Consequently, tc is slowly converted back to
tt and the cis-pyrroline is formed as the major product in
the overall [4+1] cycloaddition. In contrast, if both of the
terminal substituents are primary alkyl groups,[24] such steric
repulsion in tc’ can be minimized by single-bond rotation.
Thus, the more stable aziridine tc’, which may exist in higher
concentration than tt’, can produce the trans-pyrroline pref-
erentially.
4) Cycloadditions of both trans, trans- and cis,trans-1,4-di-
phenyl-1,3-butadiene were studied separately at a lower
Scheme 5. Isomerization of the isolated diphenyl-substituted aziridine.
Chem. Eur. J. 2011, 17, 11553 – 11558
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J. Zhou et al.
roline (p) in 46% yield
(Table 2, entry 1). Subsequent
heating at 1008C cleanly gener-
ated p in high yield. In con-
trast, other copper catalysts
produced both tc and p in
much lower yields. Because p
is formed after the initial aziri-
dination, the results indicate
that [CuACHTUNTRGEN(UGN hfacac)2] is a much
more active catalyst in both
the aziridination and ring-ex-
pansion steps.
To confirm the superior ac-
tivity of [CuACHTUNGRTENNG(U hfacac)2] in the
ring expansion,[15a] isolated vi-
nylaziridines tt and tc were
subjected to isomerization con-
ditions (Table 3). After heating
at 1008C for 24 h, [Cu-
AHCTUNTGREN(GNNU hfacac)2] gave p in 94% yield
with a high d.r. (21:1), whereas
other copper catalysts provided
very complex mixtures, which
contained <10% yield of p.
Figure 1. Kinetic studies of the overall [4+1] cycloaddition of 1,4-diphenyl-1,3-butadiene isomers.
Table 2. Comparison of the activity of copper catalysts in the overall
[4+1] cycloaddition.
Entry
Catalyst
258C, 24 h
tc [%] p [%]
1008C, 24 h
tc [%] p [%]
1
2
3
4
5
[Cu
[Cu
[Cu
N
36
34
25
0
4 (tc)
12 (tt)
46
3
3
2
0
0
0
0
0
0
72
10
3
4
1
Cu
N
CuI
Table 3. Comparison of the activity of copper catalysts for vinylaziridine
isomerization.
Figure 2. [CuACHTUNGTRENNUNG(hfacac)2]-catalyzed ring expansion of tt and tc.
The overall copper-catalyzed [4+1] cycloaddition occurs
in two steps. We performed the experiment described below
Entry
Catalyst
[Cu(hfacac)2]
[Cu(tfacac)2]
[Cu(acac)2]
Cu(OTf)2
CuI
p [%]
1
2
3
4
5
G
94
7
2
8
1
to compare the activity of [Cu
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
A
tion to other copper catalysts. [Cu
AHCTUNGTRENNUNG
N
addition of trans,trans-1,4-diphenyl-1,3-butadiene at 258C
for 24 h afforded vinylaziridine (tc) in 36% yield and 3-pyr-
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Cycloaddition of 1,3-Dienes and Nitrene Precursors
FULL PAPER
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Conclusion
In summary, we have developed an efficient, intermolecular
overall [4+1] cycloaddition of conjugated dienes and
common nitrene precursors. This method is applicable to a
range of conjugated dienes to provide 3-pyrrolines. When
1,4-disubstituted dienes are used as substrates, good-to-ex-
cellent cis/trans selectivity can be obtained. The cis or trans
preference depends on the nature of the substituents rather
than the geometry of the diene. Mechanistic studies reveal
that the reaction proceeds through diene aziridination and
subsequent ring expansion. Among several copper catalysts,
only [CuACHTUNGTRENNUNG(hfacac)2] displays high activity in both steps. De-
velopment of an asymmetric variant and application to syn-
thesis of bioactive pyrrolidines is underway.
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Experimental Section
In an argon-filled glove box, a dry 25 mL Schlenk tube was charged with
[CuACHTUNGTRENNUNG(hfacac)2] (12 mg, 0.025 mmol), (E)-ethyl 4,6-hepta-dienoate (116 mg,
[11] Other examples of intramolecular, formal [4+1] cycloadditions of
azides: a) A. G. Schultz, J. P. Dittami, S. O. Myong, C. K. Sha, J. Am.
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2242; f) we were unable to detect any [4+1] cycloadduct from the
reaction of 1,3-cyclooctadiene and PhI=NTs using 10 mol% [Cu-
0.75 mmol), and dry chlorobenzene (2.5 mL). 1-Dodecane (10 mL, GC in-
ternal standard), TsN=IPh (187 mg, 0.50 mmol), and dry chlorobenzene
(5.0 mL) were added to this green solution to wash all of the solids into
the tube. The Schlenk tube was capped tightly. After stirring at 258C for
1 h, the mixture was heated with vigorous stirring in a 1008C oil bath for
24 h until no more product was formed (monitored by GC). The reaction
mixture was cooled to 258C and subjected to flash chromatography
(Et3N-treated silica gel; hexane to 5:1 hexane/EtOAc as eluent) to give
the cycloadduct as colorless oil (139 mg, 86%).
The reaction can also be conducted without the use of a glove box. In
air, a dry 25 mL Schlenk tube that contained a magnetic stir bar was
charged with [CuACHTUNGTRENNUNG(hfacac)2] (12 mg, 0.025 mmol) and TsN=IPh (187 mg,
0.50 mmol). After three cycles of evacuation and refilling with argon, the
diene (116 mg, 0.75 mmol) and dry PhCl (7.5 mL) were added by syringe.
After stirring at 258C for 1 h, the mixture was heated with vigorous stir-
ring in a 1008C oil bath for 24 h. The cycloadduct (131 mg, 81%) was iso-
lated by flash chromatography as described above.
ACHUTNRGEN(NUG acac)2] or CuACHUTNGTREN(NUGN OTf)2 at 258C, as reported below. Only the vinylaziri-
dine was produced in 30–50% yield; J. G. Knight, M. P. Muldowney,
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II)), 815943 ([Cu(L1)2] bis[9,9-dihydroperfluoro-8,10-heptadecane-
dionato)copper(II)), 815944 (trans-N-p-Nosyl-2,5-dimethyl-3-pyrro-
Chem. Eur. J. 2011, 17, 11553 – 11558
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J. Zhou et al.
line), 815945 (cis-N-p-Nosyl-2-ethoxycarbonyl-5-phenyl-3-pyrroline),
815946 ((E)-cis-N-p-Nosyl-2-phenyl-5-styryl-3-pyrroline), 815947
(trans-N-p-Tosyl-2,5-dibenzyl-3-methyl-3-pyrroline), 815948 (-N-p-
Nosyl-2,5-diphenyl-3-pyrroline), and 815949 (cis-N-p-Tosyl-2-
methyl-5-phenyl-3-pyrroline) contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
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diene led to low yield of 3-pyrrolines. For example, 1-cyclohexyl-1,3-
butadiene forms the N-Ts-3-pyrroline in 36% yield.
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Received: May 27, 2011
Published online: September 2, 2011
11558
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Chem. Eur. J. 2011, 17, 11553 – 11558