Intermolecular [3 + 3]-cycloadditions of azides with the Nazarov intermediate

Article abstract of DOI:10.1021/ol102651k

Tetrasubstituted 1,4-dien-3-ones undergo Nazarov cyclization at low temperature, followed by reaction with organic azides via an apparent [3 + 3]-cycloaddition to give bridged bicyclic triazenes. These products do not appear to be intermediates in the pre

Full text of DOI:10.1021/ol102651k

ORGANIC
LETTERS
2011
Vol. 13, No. 1
114-117
Intermolecular [3 + 3]-Cycloadditions of
Azides with the Nazarov Intermediate
Owen Scadeng, Michael J. Ferguson,† and F. G. West*
Department of Chemistry, UniVersity of Alberta, E3-43 Gunning-Lemieux Chemistry
Centre, Edmonton, AB, T6G 2G2, Canada
frederick.west@ualberta.ca
Received November 1, 2010
ABSTRACT
Tetrasubstituted 1,4-dien-3-ones undergo Nazarov cyclization at low temperature, followed by reaction with organic azides via an apparent [3
+ 3]-cycloaddition to give bridged bicyclic triazenes. These products do not appear to be intermediates in the previously described Schmidt-
type process to furnish dihydropyridones. The reaction typically occurs with high diastereoselectivity.
The Nazarov cyclization provides convenient access to
cyclopentanoid products from acyclic precursors,1 and has
been shown to be an efficient tool in tandem and domino
processes.2 The initial electrocyclization process results in
an oxyallyl cation subject to a variety of trapping modalities.
Dienes3 and electron rich olefins4 have been shown to react
in [4 + 3] and [3 + 2] cycloadditions, while aromatic
systems5 can trap the intermediate via Friedel-Crafts alky-
lations. Organic azides can capture the oxyallyl cation with
subsequent Schmidt rearrangement to form dihydropyri-
dones6 or peroxy bridged indolizidinones.7 This reactivity
contrasts with the findings of Aube´ and Desai,8 who noted
that azides participated in apparent [3 + 3]-cycloadditions
with a simple oxyallyl cation to furnish a labile tetrahydro-
triazine-5-one which then underwent rearrangement to a
diazoketone or azepinone. Intramolecular [3 + 3] trapping
of a more elaborate, photochemically generated oxyallyl
zwitterion was reported by Schultz and co-workers.9
The synthetic value of the dihydropyridones obtained from
Schmidt-type reactivity in the case of azide trapping of
Nazarov intermediates was clear; however, a mechanistic
rationale for the failure to observe [3 + 3]-adducts or
products clearly arising from them was elusive. Conceivably,
the nitrogen-insertion products 1 seen in these cases could
arise from initially formed [3 + 3]-adducts 3, followed by
C-N bond cleavage and ring enlargement by a Schmidt-
type mechanism (Scheme 1). The alternative N-N cleavage
in analogy to the Aube´ example might be suppressed in these
cases due to the greater rigidity of bridged bicyclic cycload-
ducts 3. However, if this were the case, isolation of at least
† X-ray Crystallographic Lab, Department of Chemistry, University of
Alberta.
(1) (a) Pellissier, H. Tetrahedron 2005, 61, 6479–6517. (b) Frontier,
A. J.; Collison, C. Tetrahedron 2005, 61, 7577–7606. (c) Tius, M. A. Eur.
J. Org. Chem. 2005, 2193–2206. (d) Nakanishi, W.; West, F. G. Curr. Opin.
Drug. DicoVery DeV. 2009, 12, 732–751.
(2) Grant, T. N.; Rieder, C. J.; West, F. G. Chem. Commun. 2009, 5676–
5688.
(3) (a) Wang, Y.; Schill, B.; West, F. G. Org. Lett. 2003, 5, 2747–
2750. (b) Wang, Y.; Arif, A. M.; West, F. G. J. Am. Chem. Soc. 1999, 121,
876–877.
(4) (a) Mahmoud, B.; West, F. G. Tetrahedron Lett. 2007, 48, 5091–
5094. (b) Giese, G.; Kastrup, L.; Stiens, D.; West, F. G. Angew. Chem.,
Int. Ed. 2000, 39, 1970–1973.
(6) Song, D.; Rostami, A.; West, F. G. J. Am. Chem. Soc. 2007, 129,
12019–12022.
(7) Rostami, A.; Wang, Y.; Arif, A. M.; McDonald, R.; West, F. G.
Org. Lett. 2007, 9, 703–706.
(5) (a) Rieder, C. J.; Fradette, R. J.; West, F. G. Heterocycles 2010, 80,
1413–1427. (b) Rieder, C. J.; Fradette, R. J.; West, F. G. Chem. Commun.
2008, 13, 1572–1574. (c) Grant, T. N.; West, F. G. Org. Lett. 2007, 9,
3789–3792. (d) Browder, C. C.; Marmsa¨ter, F. P.; West, F. G. Can. J. Chem.
2004, 82, 375–385. (e) Browder, C. C.; Marmsa¨ter, F. P.; West, F. G. Org.
Lett. 2001, 3, 3033–3035.
(8) (a) Aube´, J.; Desai, P. Org. Lett. 2000, 2, 1657–1659. (b) Grecian,
S.; Desai, P.; Mossman, C.; Poutsma, J. L.; Aube´, J. J. Org. Chem. 2007,
72, 9439–9447.
(9) Schultz, A. G.; Macielag, M.; Plummer, M. J. Org. Chem. 1988,
53, 391–395.
10.1021/ol102651k  2011 American Chemical Society
Published on Web 12/03/2010

returned unchanged after stirring with trifluoroacetic acid,
first at -78 °C and then at 0 °C. On the other hand,
p-toluenesulfonic acid furnished an intractable mixture of
products after 0.5 h at -78 °C. Although we were unable to
detect any of the desired adduct after treatment with TsOH,
the efficient consumption of starting materials at low
temperature was promising, and other strong acids were
examined. Bis(trifluoromethane)sulfonimide was found to
consume starting materials to provide one main product, an
apparent adduct of some sort, though clearly not the expected
dihydropyridone. Instead, it seemed to be the elusive [3 +
3]-cycloadduct (3a), formed as a single diasteromer in 57%
yield. A crystalline solid, 3a was analyzed by single crystal
X-ray diffraction analysis, which confirmed the initial
structural assignment. Finally, trifluoromethanesulfonic acid
was found to give 3a in 78% yield after only 5 min at -78
°C, and these conditions were then used to examine the
generality of this process with other substrates.10
Scheme 1
The scope of this unexpected cycloaddition process was
probed using a variety of dienone substrates 5a-f, both
symmetrically and unsymmetrically substituted, along with
azides 4a-c. Previously unreported dienones 5b-d were
prepared from enones 6b-d via aldol addition to the
appropriate aldehydes and elimination of a suitably activated
form of the ꢀ-hydroxyl group (Scheme 2).
minor amounts of the putative intermediate would be
expected, yet cycloadducts 3 were never observed. Here we
describe the effective trapping of the Nazarov intermediate
by simple azides through Brønsted acid activation to provide
access to remarkably stable bridged triazene cycloadducts.
Brønsted acid activation of the azide-interrupted Nazarov
reaction was initially investigated as part of an effort to
intercept the zwitterionic intermediate 2 presumed to form
during ring-expansion. No trapping of this 1,4-dipole by
intra- or intermolecular processes could be seen using the
optimized BF3·OEt2 conditions described in the original
study,6 furnishing only the usual dihydropyridone products
1. Using benzyl azide 4a and prototypical dienone 5a, several
protic acids were examined in order to determine whether
interrupted Nazarov reaction could be effected under these
alternative conditions (Table 1). Starting materials were
Scheme 2
Table 1. Evaluation of Brønsted Acids in Azide Trapping of the
Nazarov Intermediatea
Symmetrical dienones 5a,b reacted cleanly with azides
4a,b to provide in each case a single [3 + 3]-cycloadduct 3
(Table 2). The stereochemical assignments for adducts 3b-d
were made based upon their close spectral analogy to the
crystallographically characterized 3a. Next, unsymmetrical
dienone 5c was examined (entries 5,6). This substrate
required somewhat higher reaction temperature (-40 °C) to
effect the initial Nazarov electrocyclization, presumably a
result of the steric demand of the t-butyl substituent.
Notwithstanding the higher temperature, reaction with 4a and
4b furnished in each case a single cycloadduct (3e,f) in
moderate to good yield, indicating complete regio- and
entry
1
conditions
yield 3a (%)b
trifluoroacetic acid, CH2Cl2,
-78 °C, 2 h; then 0 °C, 2 h
p-toluenesulfonic acid,
CH2Cl2, -78 °C, 0.5 h
bis(trifluoromethane)sulfonimide,
CH2Cl2, -78 °C, 0.25 h
trifluoromethanesulfonic acid,
CH2Cl2, -78 °C, 5 min
no conversion
2
3
4
intractable mixture
57
78
a 4a (2 equiv) and 5a were stirred with 2.2 equiv of Brønsted acid in
CH2Cl2 at the indicated temperature. b Yields are given for isolated products
after chromatographic purification.
(10) Use of less than 2 equiv of acid led to diminished yields and
incomplete consumption of starting materials.
Org. Lett., Vol. 13, No. 1, 2011
115

Table 2. [3 + 3] Cycloadditions of Using Optimized Conditionsa
entry
dienone
R1
R2
R3
R4
azide
R5
CH2Ph
CH2CH2Ph
CH2Ph
CH2CH2Ph
CH2Ph
CH2CH2Ph
CH2Ph
product(s) (yield (%))b
1
2
3
4
5
6
7
8
5a
5a
5b
5b
5c
5c
5d
5d
5e
5f
Ph
Me
Me
Ph
4a
4b
4a
4b
4a
4b
4a
4b
4a
4a
4c
3a (78)
3b (70)
3c (81)
(4-MeO)C6H4
Me
Me
Me
Me
Me
Me
(4-MeO)C6H4
3d (64)
Ph
Ph
Me
t-Bu
Ph
H
3e (75)c
3f (62)c
n-Pr
3g/7g (81, 1:2.2)
3h/7h (61, 1:2.1)
8 (52)c
CH2CH2Ph
CH2Ph
CH2Ph
9
10
11
Ph
H
(CH2)3
Me
(CH2)3
Ph
9 (57)c
5a
Ph
CH2CHdCHPh
3k/10 (56, 1:1.58)
a General Procedure: TfOH (2.2 equiv) was added dropwise to a solution of 5 and 4 (2.0 equiv) in DCM at -78 °C. The reaction mixture was stirred
at -78 °C and monitored for the disappearance of starting material by TLC analysis (5-30 min). The reaction was then quenched by addition of saturated
NaHCO3 solution and warmed to room temperature. b Yields are given for isolated products after chromatographic purification. c Reactions of dienones 5c,
5e, and 5f were carried out at -40 °C, 0 °C and rt, respectively.
diastereoselectivity in the approach of the azide moiety to
the unsymmetrical 2-hydroxycyclopentenyl cation intermedi-
ate. The indicated regiochemistry, assigned based upon
HMBC correlations, is the result of approach of the azide
with the alkyl substituent distal to the bulky t-butyl group.
In contrast to 5c, reaction of 5d with 4a,b was only
marginally regioselective (entries 7,8), with a slight prefer-
ence for approach of the azide with the alkyl group adjacent
to the propyl chain rather than the methyl (ca. 2:1 3g,h:7g,h).
However, in both cases, each regioisomer was formed as a
single diastereomer.
Two other previously described dienones were studied.
Lightly substituted dienone 5e had previously been shown
to undergo Nazarov cyclization in the presence of BF3·OEt2
followed by efficient and completely regioselective azide
trapping via the Schmidt pathway to yield dihydropyridones.6
In contrast, under the TfOH conditions 5e reacted with benzyl
azide to afford aziridine 8 (entry 9). Higher temperatures
are required to achieve electrocyclization with less substituted
dienones such as 5e, and apparently a competing aziridina-
tion11 occurs competitively at these temperatures.12 Dicy-
clopentenyl ketone 5f also failed to produce any of the
expected [3 + 3]-adduct, instead furnishing enaminone 9 in
moderate yield.13 Again, the higher reaction temperature
required for Nazarov cyclization of 5f4a,b allows for alterna-
tive pathways involving 4a and the starting dienone to
intervene. Given the premature reaction with 4a seen in the
case of these two dienones, other azides were not examined.
Trapping by cinnamyl azide 4c was also explored using
dienone 5a (entry 11). These reactants afford the usual
dihydropyridone under Lewis acid conditions, and were
expected to furnish [3 + 3]-adduct 3k. While this product
was indeed observed to be the primary component of the
crude reaction mixture, attempted purification by silica gel
chromatography resulted in a ca. 1:1.6 mixture of 3k and a
second product containing two exchangeable protons and
with an apparent molecular formula indicating loss of N2
and addition of water. The structure of this product was
tentatively assigned as 2-hydroxy-5-aminocyclopentanone 10.
Trituration with hexane and recrystallization ultimately
furnished crystalline material suitable for X-ray diffraction,
which confirmed the assigned connectivity and established
a trans relative stereochemistry between the two heteroatom
substituents flanking the carbonyl. A similar hydrolysis
product was reported by Schultz and co-workers for one of
their intramolecular [3 + 3]-photocycloadducts,9 apparently
upon extended storage. Notably, we have not observed
analogous hydrolysis behavior with any of the other [3 +
3]-adducts 3a-h or 7g,h, nor did pure 3k seem to degrade
during storage.
The complete diastereoselectivity observed in the forma-
tion of 10 suggests a possible internal delivery mechanism
(Scheme 3). Ionic fragmentation of the triazene bridge of
(11) (a) Mahoney, J. M.; Smith, C. R.; Johnston, J. N. J. Am. Chem.
Soc. 2005, 127, 1354–1355. (b) Li, J.; Fu, Y.; Guo, Q.-X. Tetrahedron
2008, 64, 11167–11174.
(12) The intermediacy of a triazoline [3 + 2]-cycloadduct in the
formation of 8 cannot be ruled out, as Johnston has shown that acid-mediated
extrusion of N2 from triazolines to provide the aziridine can occur at
temperatures as low as 0 °C: Hong, K. B.; Donahue, M. G.; Johnston, J. N.
J. Am. Chem. Soc. 2007, 129, 2323–2328.
(13) (a) Milligan, G. L.; Mossman, C. J.; Aube´, J. J. Am. Chem. Soc.
1995, 117, 10449–10459. (b) Molander, G. A.; Bibeau, C. T. Tetrahedron
Lett. 2002, 43, 5385–5388. (c) Reddy, D. S.; Judd, W. R.; Aube´, J. Org.
Lett. 2003, 5, 3899–3902.
116
Org. Lett., Vol. 13, No. 1, 2011

form 1a from 5a + 4a (eq 1).6 In the event, 3a remained
unconsumed, even after warming to rt.15 In light of this result,
we believe that nitrogen insertion products 1 arise from direct
nucleophilic attack of the intermediate 2-oxidocyclopentenyl
cations without the intermediacy of [3 + 3]-adducts 3. The
dramatically different outcomes in azide trapping seen under
Lewis vs Brønsted acid conditions is intriguing. This
difference may result from a greater propensity of the
2-hydroxycyclopentenyl cation to undergo a concerted cy-
cloaddition process with azide in preference to nucleophilic
trapping, or a greater rate of ring-expansion with expulsion
of dinitrogen by the zwitterionic BF3 complex following
nucleophilic attack by azide.
Scheme 3
We have found that treatment of a variety of dienones
with organoazides in the presence of TfOH results in a new
type of interrupted Nazarov reaction, furnishing bridged
bicyclic triazenes via an apparent [3 + 3]-cycloaddition
between the 2-hydroxycyclopentenyl cation that results from
Nazarov electrocyclization and the azide 1,3-dipole. The
reaction is remarkably stereoselective, and displays modest
to high regioselectivity in unsymmetrical cases. An unusual
and facile hydrolysis process was observed for one of the [3
+ 3]-cycloadducts. Applications of this domino process and
additional study of the origins of the high selectivity will be
described in due course.
3k to zwitterion 11 could permit equilibration with aziridine
12,14 which could then undergo epoxide formation to 13 with
inversion at the diazonium-substituted center. 13 would be
expected to suffer facile hydrolysis to 10. Alternatively,
hydrate formation from 11 would allow for internal displace-
ment of N2 to give 14, which should readily rearrange to
10. Attempts to fully convert the crude product to 10 via
exposure to water or extended stirring with silica gel were
unsuccessful. Given the variable ratios obtained in this
capricious reaction, we did not examine the reaction of azide
4c with other dienones. However, this unusual result and
the reason for its limitation to the cinammyl-substituted case
merit further study.
Acknowledgment. We thank NSERC for support of this
work, and Dr. Robert McDonald (U. of Alberta X-ray
Crystallography Lab) for obtaining the X-ray crystal structure
of 10. O.S. thanks the University of Alberta for the generous
award of a Queen Elizabeth II Scholarship.
Supporting Information Available: Experimental pro-
cedures, physical data and NMR spectra for all compounds
and synthetic intermediates, and X-ray crystallographic data
for 3a, 3c and 10. This material is available free of charge
via the Internet at http://pubs.acs.org.
Finally, to address the question of whether [3 + 3]-adducts
such as 3 are intermediates in the formation of 1,4-dipoles
2 and dihydropyridones 1 (see Scheme 1), we subjected a
sample of 3a to the conditions (BF3·OEt2, -78 °C) used to
OL102651K
(14) Intermediates related to 11 and 12 have previously been proposed
by Aube´,13c Molander,13b and Sha: Sha, C.-K.; Ouyang, S.-L.; Hsieh, D.-
Y.; Chang, R.-C.; Chang, S.-C. J. Org. Chem. 1986, 51, 1490–1494.
(15) Under the standard conditions, 4a and 5a are converted to 1a in
ca. 10 min.
Org. Lett., Vol. 13, No. 1, 2011
117