Domino electrocyclization/azide-capture/Schmidt rearrangement of dienones: One-step synthesis of dihydropyridones from simple building blocks

Article abstract of DOI:10.1021/ja071041z

Simple 1,4-dien-3-ones undergo Lewis acid-catalyzed Nazarov electrocyclization and intermolecular trapping by various azides to furnish 3,4-dihydropyridin-2-ones in moderate to good yields. The reaction is proposed to proceed via nucleophilic trapping of

Full text of DOI:10.1021/ja071041z

Published on Web 09/08/2007
Domino Electrocyclization/Azide-Capture/Schmidt
Rearrangement of Dienones: One-Step Synthesis of
Dihydropyridones from Simple Building Blocks
Dong Song, Ali Rostami, and F. G. West*
Department of Chemistry, UniVersity of Alberta, E3-43 Gunning-Lemieux Chemistry Centre,
Edmonton, Alberta, Canada T6G 2G2
Received February 13, 2007; E-mail: frederick.west@ualberta.ca
Abstract: Simple 1,4-dien-3-ones undergo Lewis acid-catalyzed Nazarov electrocyclization and intermo-
lecular trapping by various azides to furnish 3,4-dihydropyridin-2-ones in moderate to good yields. The
reaction is proposed to proceed via nucleophilic trapping of the 2-oxidocyclopentenyl intermediate, followed
by Schmidt-type rearrangement to give a transient 1,4-dipole. In unsymmetrical examples, complete
regioselectivity in favor of attack on the less substituted side was observed. The 1,4-dipole intermediate
then rearranges to the observed dihydropyridone, via either proton transfer or 1,5-hydride shift.
ions8 all could be intercepted with azide groups in either inter-
or intramolecular fashion.
Introduction
The Nazarov cyclization of cross-conjugated dienones pro-
vides a convenient method for accessing cyclopentanoid prod-
ucts.1 As a result of its unique mechanistic features (conrotatory
pentadienyl f cyclopentenyl electrocyclization), the Nazarov
reaction has recently attracted considerable attention as a tool
for initiating domino processes2 that result in complex, poly-
cyclic products.3 Common trapping modes include [4 + 3]
cycloaddition with 1,3-dienes or nucleophilic capture by carbon
π-nucleophiles. However, silyl hydride4 or simple amines3c have
also been shown to efficiently trap the Nazarov intermediate in
intermolecular processes.
Initial studies focused on intramolecular trapping using
dienone substrates containing azide-terminated side chains
(Scheme 1).9 In the event, efficient electrocyclization and
reaction of the resulting cyclopentenyl cation with the pendent
azide was observed. However, this work revealed an unexpected
oxidative pathway leading to peroxy-bridged piperidones as the
major or exclusive products. These products were presumed to
arise via intermediate cyclic 1,4-dipoles resulting from nucleo-
philic attack and ring expansion with loss of dinitrogen. Trace
amounts of molecular oxygen could then trap the reactive dipole
intermediate by an electron-transfer chain process. Carrying the
reaction out with rigorous exclusion of air led to the exclusive
formation of the corresponding indolizidinone lacking the
peroxide bridge, a product which had been observed in only
trace quantities under the normal conditions.
Although this process results in a major skeletal reorganiza-
tion and furnishes a potentially useful bicyclic product, its
synthetic appeal was attenuated somewhat by the sensitivity of
the products and the multistep route required for the synthesis
of the azidodienone substrates. Moreover, although the peroxy
group found in the major products provided an additional
functionality handle, we were interested in accessing the
nonoxygenated dihydropyridone products without resorting to
extraordinary efforts at oxygen exclusion. Here we describe the
intermolecular version of this reaction, offering a surprisingly
efficient and general method for the convergent synthesis of
dihydropyridones from simple dienone and azide partners.
Organic azides can react as 1,3-dipoles with various π-sys-
tems and are also well-known to act as nucleophiles in the
presence of carbocations or other electron-deficient species.5
With this in mind, we envisioned a possible trapping process
involving simple azides and the Nazarov intermediate. Prior
work indicated that simple allyl cations,6 an acyclic 2-oxidoallyl
cation,7 or photochemically generated 2-oxidopentadienyl cat-
(1) Reviews: (a) Habermas, K. L.; Denmark, S. E.; Jones, T. K. Org. React.
(N.Y.) 1994, 45, 1-158. (b) Pellisier, H. Tetrahedron 2005, 61, 6479-
6517. (c) Frontier, A. J.; Collison, C. Tetrahedron 2005, 61, 7577-7606.
(2) (a) Tietze, L. F. Chem. ReV. 1996, 96, 115-136. (b) Tietze, L. F. Domino
Reactions In Organic Synthesis; John Wiley: New York, 2006.
(3) Recent examples: (a) White, T. D.; West, F. G. Tetrahedron Lett. 2005,
46, 5629-5632. (b) Giese, S.; Mazzola, R. D., Jr.; Amann, C. M.; Arif, A.
M.; West, F. G. Angew. Chem., Int. Ed. 2005, 44, 6546-6549. (c) Dhoro,
F.; Tius, M. A. J. Am. Chem., Soc. 2005, 127, 12472-12473. (d) Janka,
M.; He, W.; Haedicke, I. E.; Fronczek, F. R.; Frontier, A. J.; Eisenberg, R.
J. Am. Chem. Soc. 2006, 128, 5312-5313. (e) Grant, T. N.; West, F. G. J.
Am. Chem. Soc. 2006, 128, 9348-9349. (f) Mahmoud, B.; West, F. G.
Tetrahedron Lett. 2007, 48, 5091-5094. (g) Review: Tius, M. A. Eur. J.
Org. Chem. 2005, 2193-2206.
Results and Discussion
(4) Giese, S.; West, F. G. Tetrahedron 2000, 56, 10221-10228.
(5) For recent reviews concerning the reaction of azides with electrophiles,
see: (a) Bra¨se, S.; Gil, C.; Knepper, K.; Zimmermann, V. Angew. Chem.,
Int. Ed. 2005, 44, 5188-5240. (b) Lang, S.; Murphy, J. A. Chem. Soc.
ReV. 2006, 35, 146-156.
Initial Trapping Studies. Dibenzylidenepentan-3-one 1a was
employed for the initial experiments, given its exceptional
(8) Schultz, A. G.; Macielag, M.; Plummer, M. J. Org. Chem. 1988, 53, 391-
(6) Pearson, W. H.; Fang, W.; Kampf, J. W. J. Org. Chem. 1994, 59, 2682-
395.
2684.
(9) Rostami, A.; Wang, Y.; Arif, A. M.; McDonald, R.; West, F. G. Org. Lett.
2007, 9, 703-706.
(7) Aube´, J.; Desai, P. Org. Lett. 2000, 2, 1657-1659.
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J. AM. CHEM. SOC. 2007, 129, 12019-12022
12019

A R T I C L E S
Song et al.
Scheme 1. Intramolecular Azide Trapping of the Nazarov
Intermediate with Oxygen Incorporation
Scheme 3. Optimized Intramolecular Trapping To Form
Dihydropyridones
Scheme 2. Initial Intermolecular Trapping Experiments
formation of 4a and 5a. Instead, we propose a proton-transfer
process involving an as-yet unidentified base.12
The effect of reaction time and temperature on the products
was examined. In the event, it was found that longer reaction
times at low temperature resulted in an alternative pair of
products, 6a and 7a (1:1), in 71% yield (Scheme 3), with none
of the previously observed 4a and 5a. In contrast to the earlier
result, these products contained a tetrasubstituted, endocyclic
alkene and were assigned as diastereomeric dihydropyridones.
Further experimentation revealed optimal conditions for the
formation of these products to be relatively short reaction at
-78 °C, followed by an immediate aqueous quench and workup,
giving an 82% yield of 6a and 7a in a 2:1 ratio.
Generalization of Optimized Conditions to Other Sub-
strates. The modified conditions were then applied to all
combinations of dienones 1a-1d13 and azides 2a-2c (Table
1), in all cases furnishing dihydropyridone adducts 6 and 7.
Notably, unsymmetrical substrates reacted with complete regi-
oselectivity in favor of initial nucleophilic attack by azide on
the less hindered end of the intermediate 2-oxidocyclopentenyl
cation (entries 4-12). Moreover, substrates 1b and 1c furnished
the trans isomer exclusively with all azides. Higher temperatures
were required to consume dienones 1c and 1d (entries 7-12).
For 1d, this may reflect a higher barrier for the initial
electrocyclization due to the fusion of a second ring,14 whereas
the absence of a C-4 alkyl group in 1c is the probable
explanation for its sluggish reactivity.1a Lower yields in the case
of 1c could result from a greater propensity for side reactions
by the starting dienone or the 2-oxidocyclopentenyl intermediate.
Mechanistic and Stereochemical Considerations. It is
notable that, for unsymmetrically substituted dienones 1b-1d,
complete regioselectivity was observed (entries 4-12). The
products isolated result from cyclic 1,4-dipoles 3d-3l, which
derive from selective attack by azides 2a-2c on the less
hindered terminus of the cyclopentenyl cation formed during
reactivity toward electrocyclic closure even at low temperatures.4
Treatment of 1a with BF3‚OEt2 at -78 °C in the presence of 2
equiv of benzyl azide 2a, followed by warming to 0 °C and
aqueous workup, yielded two new products, 4a and 5a, as a
1:1 ratio in 72% yield (Scheme 2). Spectral analysis indicated
that these compounds were diastereomeric, containing three
adjacent methine centers and an exocyclic methylene group.
Product 4a was assigned as the all-trans isomer on the basis of
large vicinal coupling constants for the methine protons, while
5a was tentatively assigned to be epimeric at C-3. Analogous
to earlier work, we presume that both products arise from
the 1,4-dipole 3a resulting from addition of azide followed
by Schmidt-type rearrangement. Formation of the exocyclic
methylene moiety and both epimers at C-3 may then occur from
3 via proton transfer.
We were surprised to find no evidence of endoperoxide
products resulting from oxygen trapping, a process that was
extremely efficient in examples involving intramolecular azide
trapping.8,10 Equally unexpected was the isolation of products
possessing an exocyclic alkene resulting from apparent proton-
transfer processes, as opposed to the 3,4-dihydropyridone
product seen in the earlier intramolecular case when oxygen
was scrupulously excluded. Other examples of transiently
formed 1,4-dipoles analogous to 3 have typically rearranged to
give endocyclic alkenes, a process postulated to occur via a
concerted 1,5-hydrogen shift.11 Given the geometrical constraints
prohibiting continuous orbital overlap between C-3 and the
methyl C-H bond, this mechanism is unlikely to apply in the
(11) For examples of 1,5-hydrogen shifts by cyclic 1,4-dipoles, see: (a) Lenz,
G. R. Synthesis 1978, 489-518. (b) Ninomiya, I.; Naito, T. Heterocycles
1981, 15, 1433-1462. (c) Potts, K. T.; Rochanapruk, T.; Padwa, A.; Coats,
S. J.; Hadjiarapoglou, L. J. Org. Chem. 1995, 60, 3795-3805. (d) Padwa,
A.; Flick, A. C.; Lee, H. I. Org. Lett. 2005, 7, 2925-2928.
(12) Potts and Padwa proposed a 1,5-shift mechanism for enamide products in
which the new CdC bond was exocyclic to the original 6-membered ring
of the 1,4-dipole (see ref 11c); however, these cases involved highly rigid,
tricyclic systems which might permit a concerted suprafacial rearrangement.
(13) Dienones 1b-1d were prepared by addition of CH2dC(Me)MgBr or CH2d
CHMgBr to the corresponding unsaturated aldehydes, followed by oxidation
of the resulting dienols with BaMnO4. See Supporting Information for
details.
(10) No peroxy-bridged products were observed even when the reaction was
carried out under an atmosphere of O2.
(14) Wang, Y.; Schill, B. D.; Arif, A. M.; West, F. G. Org. Lett. 2003, 5, 2747-
2750.
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12020 J. AM. CHEM. SOC. VOL. 129, NO. 39, 2007

One-Step Synthesis of Dihydropyridones
A R T I C L E S
Table 1. Intermolecular Azide Trapping of Dienones 1a-1da
Scheme 5. Stereochemical Implications of 1,5-Hydrogen Shift vs
Proton-Transfer Mechanism
entry
dienone
azide
conditions
products (% yield; ratio)b
1
2
3
4
5
6
7
8
1a
1a
1a
1b
1b
1b
1c
1c
1c
1d
1d
1d
2a
2b
2c
2a
2b
2c
2a
2b
2c
2a
2b
2c
-78 °C/10 min
-78 °C/10 min
-78 °C/10 min
-78 °C/0.5 h
-78 °C/0.5 h
-78 °C/0.5 h
0 °C/1 h
0 °C/1 h
0 °C/1 h
0 °C/0.5 h
0 °C/0.5 h
6a + 7a (82; 2:1)
6b + 7b (78; 2.3:1)
6c + 7c (85; 2:1)
6d (75)
6e (80)
6f (72)
6g (62)
6h (40)
6i (43)
9
10
11
12
6j + 7j (80; 2:1)
6k + 7k (70; 3:1)
6l + 7l (73; 2.5:1)
0 °C/0.5 h
a See Experimental Section for standard procedure. b All yields given
are based on isolated material after chromatographic purification.
Scheme 4. Regioselective Azide Trapping of Unsymmetrical
Cyclopentenyl Cation Intermediates
features lead to these divergent reactivity paths? When taken
in sum, it is the facile oxygenation seen in the intramolecular
examples that is the most surprising. Conformational restrictions
on the bicyclic 1,4-dipoles formed in those cases may diminish
the rate of proton transfer or 1,5-hydrogen shift processes as
compared with the simpler systems reported in this study.
However, it should be noted that bicyclic zwitterions derived
from dienone 1d (entries 10-12) also show no evidence for
oxygen incorporation. The relatively short reaction times and
modified quenching conditions (vide infra) may also be
responsible for the preferred formation of the dihydropyridone
products.
electrocyclization (Scheme 4, path a). No evidence for the
alternative regioisomer 3′ (via path b) was seen in any of these
examples. Regioselective attack at the less substituted terminus
(as in entries 7-9) was also seen in intermolecular 3 + 2
trapping of the Nazarov intermediate by allyl silanes,15 and
selectivity for nucleophilic trapping adjacent to the less substi-
tuted carbon (as in entries 4-12) was recently described for
vinyl sulfide trapping processes.3f
In all cases examined, trans diastereomer 6 was formed
predominantly or exclusively. In the cases employing dienone
1a (Table 1, entries 1-3), the trans relative stereochemistry is
consistent with suprafacial 1,5-hydrogen shift by the C-5
hydrogen (Scheme 5); however, this rationale does not account
for the significant amounts of cis diastereomer 7. Possible in
situ epimerization of 6 to 7 was considered, but preliminary
control experiments with 6a indicate that this scenario is
unlikely.16 Instead, proton transfer with diastereoselective enolate
protonation seems most likely and is also consistent with the
Once zwitterions 3 were formed, a rapid rearrangement to
dihydropyridones apparently ensued. As noted above, this result
stands in contrast to the earlier intermolecular studies. What
(16) Subjection of pure 6a to the reaction conditions did not result in any
epimerization to 7a. Extended stirring in the presence of DBU also failed
to effect epimerization.
(15) Giese, S.; Kastrup, L.; Stiens, D.; West, F. G. Angew. Chem., Int. Ed. 2000,
39, 1970-1973.
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A R T I C L E S
Song et al.
Experimental Section
earlier observation of products 4a and 5a, whose formation is
most readily explained by this mechanism. Moreover, the low-
temperature aqueous quench used in the optimized conditions
introduces an abundance of proton donors and acceptors to the
reaction mixture. The complete trans diastereoselectivity seen
using dienones 1b and 1c, which lack nonhydrogen substituents
at what will become C-5 of the eventual dihydropyridone
(entries 4-9), is notable. The conformational preferences of
enolates 8 arising from deprotonation of 3d-3i provide one
possible explanation. In these cases, the C-4 phenyl group may
well sit in a quasi-equatorial orientation, in which enolate
protonation is subject to product development control (avoidance
of developing eclipsing interaction between the C-3 methyl and
the C-4 phenyl groups by proton delivery syn to the C-4 phenyl).
In the cases employing 1a (entries 1-3), enolates 8a-8c may
adopt conformations in which the C-4 phenyl group assumes a
quasi-axial position to avoid allylic strain with the neighboring
C-5 phenyl, leading to erosion of the facial selectivity for
protonation. The factors leading to lower selectivity in bicyclic
examples (entries 10-12) are less clear and merit further study.
Representative Procedure: Formation of Dihydropyridones 6a
and 7a. Trapping of 1a with Benzyl Azide 2a. To a solution of
dienone (100 mg, 0.38 mmol) and benzyl azide 2a (101 mg, 0.76 mmol)
in dichloromethane (5 mL) was added BF3‚OEt2 (53 µL, 0.42 mmol)
in -78 °C (dry ice/acetone bath). The reaction mixture was stirred for
10 min. Saturated NaHCO3 solution (2 mL) was added to quench the
reaction and after warming to rt the resulting mixture was extracted
with CH2Cl2 (20 mL). The organic layer was washed with brine (10
mL) and dried over MgSO4. The solvent was then evaporated under
reduced pressure and the residue purified by column chromatography
(silica gel; hexanes/EtOAc 5:1) to afford the trans isomer 6a (76.7 mg,
55% yield) and cis isomer 7a (37.6 mg, 27% yield) as colorless oils.
6a. Rf 0.36 (5:1 hexanes/EtOAc); IR (microscope) 1667, 1599, 1494,
1
1453 cm-1; H NMR (400 MHz, C6D6) δ 7.36-6.84 (m, 15H), 5.08
(d, 1H, J ) 15.4 Hz), 4.58 (d, 1H, J ) 15.4 Hz), 3.34 (d, 1H, J ) 7.0
Hz), 2.94 (app pentet, 1H, J ) 7.0 Hz), 1.67 (d, 3H, J ) 0.7 Hz), 1.19
(d, 3H, J ) 7.0 Hz); 13C NMR (100 MHz, C6D6) δ 171.6, 141.5, 139.3,
138.1, 132.8, 129.5, 129.2, 128.7, 128.6, 128.5, 128.4, 127.4, 127.2,
126.8, 122.5, 50.7, 45.9, 40.7, 16.8, 13.5; HRMS (EI) calcd for C26H25-
ON 367.1936, found m/z 367.1934. Anal. Calcd for C26H25ON: C,
84.98; H, 6.86; N, 3.81. Found: C, 84.67; H, 7.03; N, 3.72.
Conclusions
The trapping of various 2-oxidocyclopentenyl cation inter-
mediates by added azides has been shown to be efficient and
remarkably regioselective. The product dihyropyridones result
from a Schmidt-type rearrangement, with the overall process
entailing intercalation of the internal azide nitrogen atom
between the dienone carbonyl and the neighboring R carbon.
The sequence is believed to involve a transient 1,4-dipole which
can undergo elimination to form either an exocyclic or an
endocyclic alkene. In a number of cases, complete diastereo-
selectivity for the trans product was observed, consistent with
either a highly stereoselective enolate protonation, or a concerted
1,5-hydrogen shift. In all examples employing unsymmetrically
substituted dienones, complete regioselectivity in favor of attack
on the less hindered end of the cyclopentenyl cation was seen.
Future applications of this new domino process will focus on
more elaborate reaction partners and selective functionalization
of their products, and the application of this chemistry to
polycyclic alkaloid targets.
7a. Rf 0.32 (5:1 hexanes/EtOAc); IR (microscope) 1667, 1599, 1494,
1
1453 cm-1; H NMR (400 MHz, C6D6) δ 7.18-6.91 (m, 15H), 5.16
(d, 1H, J ) 15.7 Hz), 4.46 (d, 1H, J ) 15.7 Hz), 3.33 (s, 1H), 3.02
(dq, 1H, J ) 2.0, 7.3 Hz), 1.65 (d, 3H, J ) 0.5 Hz), 1.37 (d, 3H, J )
7.3 Hz); 13C NMR (100 MHz, CDCl3) δ 172.7, 141.0, 140.5, 138.2,
132.1, 129.1, 128.4, 128.3, 128.1, 127.4, 127.3, 127.0, 126.7, 126.6,
118.1, 50.9, 45.2, 43.9, 17.7, 16.7; HRMS (EI) calcd for C26H25ON
367.1936, found m/z 367.1929.
Acknowledgment. We thank NSERC (Canada) and the
Canadian Institutes for Health Research for support of this work.
Supporting Information Available: Experimental procedures
and spectral data for 1b-1d and spectral data for all azide
adducts 4-7. This material is available free of charge via the
Internet at http://pubs.acs.org.
JA071041Z
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12022 J. AM. CHEM. SOC. VOL. 129, NO. 39, 2007