Nazarov reactions of vinyl cyclopropylamines: An approach to the imino-nazarov problem

Article abstract of DOI:10.1021/ol4012663

Dichlorocyclopropanation of 2-amino-1,3-dienes affords 1-alkenyl-1-amino-2, 2-dichlorocyclopropanes which undergo silver-assisted 2-π electrocyclic opening to furnish 3-aminopentadienyl cations. Nazarov-type cyclization of these intermediates leads to cyclopentenone iminium salts, which provide allylic amines upon reduction. This process, the imino version of the traditional Nazarov reaction, can also be combined with an interrupted Nazarov domino process to give polycyclic amines.

Full text of DOI:10.1021/ol4012663

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Nazarov Reactions of Vinyl
Cyclopropylamines: An Approach
to the Imino-Nazarov Problem
Sara A. Bonderoff,† Tina N. Grant,† F. G. West,*,† and Martin Tremblay‡
Department of Chemistry, University of Alberta, E3-43 Gunning-Lemieux Chemistry
Centre, Edmonton, Alberta, Canada, T6G 2G2, and Boehringer Ingelheim (Canada),
ꢀ
Ltd., 2100 rue Cunard, Laval, Quebec, Canada, H7S 2G5
frederick.west@ualberta.ca
Received May 7, 2013
ABSTRACT
Dichlorocyclopropanation of 2-amino-1,3-dienes affords 1-alkenyl-1-amino-2,2-dichlorocyclopropanes which undergo silver-assisted 2-π
electrocyclic opening to furnish 3-aminopentadienyl cations. Nazarov-type cyclization of these intermediates leads to cyclopentenone
iminium salts, which provide allylic amines upon reduction. This process, the imino version of the traditional Nazarov reaction, can also be
combined with an interrupted Nazarov domino process to give polycyclic amines.
In its traditional form, the Nazarov reaction entails the
electrophilic activation of a cross-conjugated dienone and
the electrocyclic closure of the resulting 3-oxygenated
pentadienyl cation.1 The resulting cyclopentenyl cation
can undergo elimination to furnish a cyclopentenone or
can be trapped with various functionalities to generate
additional strategic bonds.2 In contrast to these examples,
there are relatively few cases of the analogous process
employing a nitrogen in place of oxygen, termed the
imino-Nazarov reaction (Scheme 1). The lack of general
methods for the construction of the required divinyl
imines, especially those with non-hydrogen substituents
at C-2 and C-4, is one likely reason for the dearth of
examples. Moreover, calculations by Smith and Ulmer
have suggested that replacement of oxygen with nitrogen
has a deleterious effect on the energetics of the process due
to resonance stabilization of the 3-aminopentadienyl ca-
tion precursor to electrocyclization3 (though it should be
noted that these calculations were for the unsubstituted
example).
Several successful approaches to the imino-Nazarov
reaction have been described. Tius and co-workers re-
ported the formation of 2-aminocyclopent-2-enones from
the addition of an allenyllithium reagent to an unsaturated
nitrile, presumably via an allenyl vinyl imine.4a Gonzalez
ꢀ
and co-workers obtained N-tosylcyclopentenone imines
from treatment of propargyl tosylates with catalytic gold-
(I) and a tosyl imine and proposed an N-tosyldivinyl
imine as the precursor.4b More recently, gold(I) was also
used as a catalyst in the imino-Nazarov reaction of
R-arylallenamides.4c The Tius group was able to effect
Nazarov cyclization of enediones via activation by an
enantioenriched diamine, with the likely involvement of a
† University of Alberta.
‡ Boehringer Ingelheim (Canada), Ltd.
(1) (a) Vaidya, T.; Eisenberg, R.; Frontier, A. J. ChemCatChem 2011,
3, 1. (b) Shimada, V.; Stewart, C.; Tius, M. A. Tetrahedron 2011, 67,
5851. (c) Nakanishi, W.; West, F. G. Curr. Opin. Drug Discovery Dev.
2009, 12. (d) Grant, T. N.; Rieder, C. J.; West, F. G. Chem. Commun.
2009, 5676. (e) Frontier, A. J.; Collison, C. Tetrahedron 2005, 61, 7577.
(f) Pellissier, H. Tetrahedron 2005, 61, 6479. (g) Habermas, K. L.;
Denmark, S.; Jones, T. K. Org. React. 1994, 45, 1.
(3) Smith, D. A.; Ulmer, C. W., II. J. Org. Chem. 1997, 62, 5110–
5115.
(4) (a) Tius, M. A.; Chu, C. C.; Nieves-Colberg, R. Tetrahedron Lett.
ꢀ
ꢀ
2001, 42, 2419–2422. (b) Suarez-Pantiga, S.; Rubio, E.; Alvarez-Rua, C.;
ꢀ
Gonzalez, J. M. Org. Lett. 2009, 11, 13–16. (c) Ma, Z.-X.; He, S.; Song,
(2) Grant, T. N.; Rieder, C. J.; West, F. G. Chem. Commun. 2009,
5676–5688.
W.; Hsung, R. P. Org. Lett. 2012, 14, 5736–5739. (d) Bow, W. F.; Basak,
A. K.; Jolit, A.; Vicic, D. A.; Tius, M. A. Org. Lett. 2010, 12, 440–443.
r
10.1021/ol4012663
XXXX American Chemical Society

Scheme 1. Nazarov and Imino-Nazarov Cyclization
Scheme 2. Dichlorocyclopropane Nazarov Substrates
divinyl iminium salt.4d In each of these examples, a unique
structural feature can be invoked to explain successful
cyclization. The involvement of allenes in the Nazarov
cyclization is thought to provide additional conjugative
stabilization of the cyclized product,5 and in those cases a
subsequent irreversible loss of a MOM group occurred,
preventing back-reaction.4a The N-tosyl imines in the
gold(I)-catalyzed examples are likely to have greatly re-
duced ability to stabilize the acyclic pentadienyl cation.
Finally, the diamine adducts of enediones possess a
2,3-dinitrogen substitution on the pentadienyl framework,
leading to resonance stabilization by one of the nitrogen
atoms in both cyclized and uncyclized forms.
Table 1. Preparation of Aminocyclopropane Substratesa
yield
(%)b
We have previously shown that 1-alkenyl-2,2-dichloro-
1-siloxycyclopropanes serve as unconventional Nazarov
substrates; these structures undergo sequential silver-
assisted dehalogenative electrocyclic opening of the cyclo-
propane followed by 4π electrocyclization of the resulting
3-siloxypentadienyl cation (Scheme 2).6 We speculated
that a similar approach in which an amine was substituted
for the siloxy group could provide direct access to 3-ami-
nopentadienyl cations bearing a variety of substituents,
allowing us to probe the generality of the imino-Nazarov
reaction in the absence of the structural quirks that may
have biased the previous examples. Here we describe the
preparation of a series of aminocyclopropane substrates
and their successful conversion to amine-substituted cy-
clopentanoid products via an imino-Nazarov process.
The requisite cyclopropanes could be obtained from the
corresponding 2-dialkylamino-1,3-butadienes by standard
dichlorocyclopropanation chemistry. We employed an
aminomercuration/demercuration strategy with conju-
gated enynes,7,8 modified by use of mercury(II) fluoride
in place of mercury(II) acetate, and at elevated tempera-
tures (Table 1).9 The resulting dienes were found to be
very labile, requiring immediate use in the subsequent
cyclopropanation step without subjection to purification
in most cases. The latter reaction was carried out under
entry
R1
R2
R3
R4
product
1
Ph
Ph
Ph
H
Me
Me
Me
Me
Bn
Me
1a
1b
1c
1d
1e
1f
42
46
14
34
44
38
37
26
2
C2H4OC2H4
Ph Me
3
4
C2H4OC2H4
C2H4OC2H4
C2H4OC2H4
5
(CH2)4
6c
7c
8c
Ar1(CH2)2
Ar1(CH2)2
Ar2(CH2)2
Me
Me
Me
Bn
Me
1g
1h
C2H4OC2H4
a See Supporting Information for detailed procedures. b Overall
yields for two steps, given for isolated 1 after chromatographic purifica-
tion. Yields are unoptimized. c Ar1 = 3-MeOC6H4; Ar2 = 4-MeOC6H4.
standard phase-transfer conditions.10 Complications asso-
ciated with the aminodienes undoubtedly contributed to
the modest two-step yields obtained in this process.
However, this deficiency was mitigated by the simplicity
of the reactants (simple enynes, secondary amines, and
chloroform).
With substrates 1aꢀh in hand, we were now ready to test
the key question: will the 3-aminopentadienyl cations
generated from these cyclopropane precursors undergo
Nazarov cyclization despite the ground-state stabilization
afforded by the 3-amino substituent? Using 1a as a test
case, we subjected it to 1 equiv of AgNTf2 in acetonitrile at
reflux (Scheme 3). The starting material was consumed
after several hours, and two new polar products were
formed, identified as the two iminium ion geometrical
isomers 2a and 2a0 resulting from imino-Nazarov cycliza-
tion and elimination. Although the isomers were insepar-
able, it was possible to assign related protons and carbons
from each isomer in the NMR spectra, whose chemical
(5) Marx, V. M.; Burnell, D. J. J. Am. Chem. Soc. 2010, 132, 1695–
1689.
(6) (a) Grant, T. N.; West, F. G. J. Am. Chem. Soc. 2006, 128, 9348–
9349. (b) Grant, T. N.; West, F. G. Org. Lett. 2007, 9, 3789–3792.
(7) (a) Barluenga, J.; Aznar, F.; Liz, R.; Cabal, M.-P. J. Chem. Soc.,
ꢀ
Chem. Commun. 1985, 1375–1376. (b) Barluenga, J.; Aznar, F.; Valdes,
C.; Cabal, M.-P. J. Org. Chem. 1991, 56, 6166–6171.
(8) BuchwaldꢀHartwig-type amination of 2-chlorodienes has also
been reported, though not with nonhydrogen substituents at C-3:
ꢀ
Barluenga, J.; Fernandez, M. A.; Aznar, F.; Valdes, C. Chem. Commun.
ꢀ
2004, 1400–1401.
(9) Catalytic amounts of AlCl3 were added to promote redistribution
of mercury ligands: Calingaert, G.; Soroos, H.; Hnizda, V. J. Am. Chem.
Soc. 1940, 62, 1107–1110.
(10) (a) Makosza, M.; Wawrzyniewicz, M. Tetrahedron Lett. 1969,
4659–4662. (b) Futugawa, T.; Mishiyama, N.; Tai, A.; Okuyama, T.;
Sugimura, T. Tetrahedron 2002, 58, 9279–9287.
B
Org. Lett., Vol. XX, No. XX, XXXX

shifts were quite consistent with those reported for a
related unsaturated iminium salt.11 To simplify the isola-
tion and characterization of the cyclization products, we
explored the use of a subsequent reduction step to afford
the neutral amines. On treatment with NaBH4, iminium
salts 2a/2a0 were cleanly converted to amino chlorocyclo-
pentene 3a with complete diastereoselectivity, and in 50%
yield over two steps.12
presence of a Brønsted acid suppresses the opening of the
cyclopropane. When this experiment was carried out in the
presence of the hindered base 2,4,6-tri-tert-butylpyridine,
1b was rapidly consumed, though with no apparent con-
version to Nazarov cyclization products.
Scheme 3. Preliminary Imino-Nazarov Experiment
The effect of electron availability on nitrogen was also
probed using acetamide 1i, which was prepared via di-
chlorocyclopropanation of 2-acetamido diene 6 (Scheme 4).13
Successful Nazarov cyclization in this case would afford
unsaturated N-acylimine 7 or its enamide tautomer, either
of which could be applied to a variety of subsequent
transformations. However, in the event 1i proved to be
inert to the standard conditions, and when the temperature
was increased to 180 °C, an intractable mixture was
obtained. Given this result and the previously noted effect
of the added Brønsted acid, it appears that an electron-rich
amino group is required in the initial electrocyclic opening
of the cyclopropane.
This two-step protocol was applied to the other simple
substrates (1bꢀe), affording cyclopentenes 3bꢀe in mod-
erate yields (Table 2). In some cases, complete consump-
tion of starting material was not possible, leading to
diminished yields (entries 4 and 5). This may be a result
of substrate deactivation via amine protonation by HNTf2
inadvertently formed during the reaction. Evidence for this
can be seenfrom the isolation ofmostlystarting 1bupon its
treatment with 1 equiv of HNTf2, followed by extended
heating with AgNTf2 and aqueous workup (eq 1). Only
small amounts of dienone 4b and cyclopentenone 5b were
isolated, these products coming presumably from hydro-
lysis of the aminopentadienyl cation and the cyclized
iminium salt, respectively. From this, we infer that the
Scheme 4. Acetamidocyclopropane
Finally, substrates 1fꢀh bearing pendent aryl groups
were examined (Scheme 5). We were gratified to find that
morpholino substrate 1f underwent an efficient imino-
Nazarov reaction with subsequent arene trapping, afford-
ing after borohydride reduction the two diastereo-
meric chloroamines 8f and 8f0. The mixture of isomers
results from unselective protonation of the intermediate
Table 2. Combined Imino-Nazarov/Reductiona
(11) Lin, X.; Kavash, R. W.; Mariano, P. S. J. Org. Chem. 1996, 61,
7335–7347.
(12) The syn relative configuration assigned to 3a and analogous
products in Table 2 derives from selective attack by hydride from the
sterically more accessible face and is supported by the observation of
vicinal coupling constants in the range of 7.1ꢀ7.5 Hz.
yield 3
entry
substrate
R1
R2
R3
R4
(%)b
1
1a
1b
1c
1d
1e
Ph
Ph
Ph
H
Me
Me
Me
Me
Bn
Me
50
50
48
22
12
(13) Diene 6 was prepared from the corresponding enone: Burk,
M. J.; Casy, G.; Johnson, N. B. J. Org. Chem. 1998, 63, 6084–6085.
(14) Assignment of the relative stereochemistry for 8f was based on
TROESY correlations, while 8f0 was assigned by single crystal X-ray
diffraction analysis. See Supporting Information for more details.
2
(CH2)2O(CH2)2
Ph Me
3
4
5c
(CH2)2O(CH2)2
(CH2)2O(CH2)2
(CH2)4
ꢀ ꢀ
ꢀ
ꢀ
(15) (a) Kadar, Z.; Molnar, J.; Schneider, G.; Zupko, I.; Frank, E.
Bioorg. Med. Chem. 2112, 20, 1396–1402. (b) Bruno, R. D.; Vasaitis,
T. S.; Gediya, L. K.; Purushottamachar, P.; Godbole, A. M.; Ates-
Alagoz, Z.; Brodie, A. M. H.; Njar, V. C. O. Steroids 2011, 76, 1268–
a See Supporting Information for detailed procedures. Reaction time
varied from 2ꢀ8.5 h. b Overall yields for two steps, given for isolated 3
after chromatographic purification. c Reaction time = 10 min.
ꢀ
1279. (c) Vidma, L.; Cerny, I.; Pouzar, V.; Borovska, J.; Vyklicky, V.;
ꢀ
Vyklicky, L., Jr.; Chodounska, H. Steroids 2011, 76, 1043–1050.
Org. Lett., Vol. XX, No. XX, XXXX
C

chromatographic purification in anapparent ratio of 1.2:1,
suggesting selective destruction of the major isomer during
purification. If the cyclization step was followed by hydro-
lysis rather than reduction, chlorocyclopentanones 10g
and 10g0 were obtained in good yields and as a 1.2:1
mixture. Substrate 1h, bearing an isomeric 4-methoxyphe-
nyl trap, underwent Nazarov cyclization, but the sub-
sequent arene trapping did not occur.16 Instead, an un-
expected dehydrohalogenation product 11h was obtained
in moderate yield. The mechanism by which this unusual
product was formed is under study.
Scheme 5. Interrupted Imino-Nazarov Reactions
Silver-assisted electrocyclic opening of 1-amino-1-alkenyl-
2,2-dichlorocyclopropanes provides a convenient route to
the 3-aminopentadienyl cations required for imino-Nazarov
cyclization. Despite concerns about the unfavorability of this
electrocyclization due to preferential stabilization of the
open pentadienyl form, these substrates underwent cycliza-
tion to give unsaturated iminium salts, which could then be
stereoselectively reduced with borohydride. Nitrogen deac-
tivation by protonation or acyl substitution severely inhibits
the reaction, and pendent 3-methoxyphenyl groups permit a
domino process that affords tricyclic products. Further
applications of this new chemistry, including substitution
of the amino group with trapping functionality or stereo-
genic centers, are under current study.
Acknowledgment. We thank NSERC for support of
this research. S.A.B. thanks NSERC for a CGS award,
Alberta Ingenuity for a PhD Graduate Student Scholar-
ship, and Boehringer Ingelheim (Canada) Ltd. for an
Industrial Cooperative Research Award in Synthetic Or-
ganic Chemistry. We thank Dr. Michael Ferguson (U. of
Alberta X-ray Crystallography Lab) for obtaining a crys-
tal structure for 8f0.
chloroenamine, followed by selective hydride delivery
from the side opposite the chloride in each case.14 Steroid
derivatives bearing nitrogen functionality on the D-ring
have shown a variety of promising biological properties,15
including antiproliferative and antitumor activity,15a,b as
well as inhibition of the glutamate-induced response of
NMDA receptors,15c and these products may display
similar activities. Surprisingly, N-benzyl-N-methyl anal-
ogue 1g furnished only one of the cyclized products 8g0 in
moderate yield. However, analysis of the crude mixture
indicated that two diastereomers were present prior to
Supporting Information Available. Experimental pro-
cedures for preparation, and characterization data for the
substrates and products, including X-ray crystallo-
graphic data for 8f0. This material is available free of
charge via the Internet at http://pubs.acs.org.
(16) Similar reactivity issues based upon arene substitution have been
observed in the interrupted Nazarov cyclizations of the related 1,1-
dichloro-2-siloxy-2-vinylcyclopropanes. See ref 6b.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX