Asymmetric cycloadditions of palladium-polarized aza-o-xylylenes

Article abstract of DOI:10.1021/ja801742h

Vinyl benzoxazinanones undergo highly enantioselective decarboxylative cycloadditions with electron-deficient olefins in the presence of palladium catalysts. Palladium induces the decarboxylation of the parent benzoxazinanones under mild conditions to produce an intermediate that can be described as a polarized aza-o-xylylene. These intermediates undergo a formal [4 + 2] cycloaddition with good Michael acceptors to produce highly substituted hydroquinolines with excellent regio-, diastereo-, and enantioselectivities. Copyright

Full text of DOI:10.1021/ja801742h

Published on Web 06/06/2008
Asymmetric Cycloadditions of Palladium-Polarized Aza-o-xylylenes
Chao Wang and Jon A. Tunge*
Department of Chemistry, UniVersity of Kansas, 2010 Malott Hall, 1251 Wescoe Hall DriVe, Lawrence, Kansas 66045
Received March 11, 2008; E-mail: tunge@ku.edu
Scheme 2
Thermal decarboxylation of benzoxazinanones under conditions of
flash vacuum pyrolysis at 180 °C generates aza-o-xylylene intermedi-
ates that undergo [4 + 2] cycloaddition in moderate to low yield (eq
1).1
Recently, we have shown that catalytic decarboxylative cyclo-
additions of saturated analogues occur under mild conditions via
zwitterionic π-allyl palladium intermediates (Scheme 1).2 We reasoned
that conjugation of the two charges would allow mild catalytic
generation of aza-o-xylylene intermediates like those used in the above
cycloaddition.3 Such a scenario creates two possibilities. The zwitte-
rionic intermediate (A) can potentially expel Pd(0) to produce a free
aza-o-xylylene. Alternatively, if Pd remains coordinated, then a
polarized aza-o-xylylene intermediately will result.4 Herein we report
that such palladium-polarized aza-o-xylylenes are likely intermediates
in diastereoselective, asymmetric [4 + 2] cycloadditions with electron
deficient olefins.
Next, we turned our attention toward the development of an
asymmetric version of this cycloaddition. A screen of ligands quickly
revealed that the Trost-ligands are superior ligands for the asymmetric
cycloaddition (Table 1).9 While the diphenyldiamine-based ligand (L2)
provided the highest enantioselectivity, the ligand based on the
anthracenyl diamine (L4) provided high enantioselectivity as well as
superior diastereoselectivity. While THF provided the best combination
of ee and dr, the reactions in THF were sluggish, thus CH2Cl2 was
chosen as the optimal solvent. A single recrystallization of the product
provided an 87% yield of highly enantio- and diastereoenriched
hydroquinoline (97% ee, 50:1 dr).
Scheme 1
Next, we briefly explored the effect of electronics on the reaction.
If the benzylidene malononitrile was too electron rich [i.e.,
p-MeOC6H4CHC(CN2)] then the intermolecular cycloaddition did not
compete with the intramolecular cyclization to form dihydroquino-
lines.10 However, if the olefin was sufficiently electron deficient, then
Table 1. Ligand and Solvent Screening Results
To begin, the parent vinyl benzoxazinanone (1a) was prepared and
subjected to Pd(PPh3)4 in CH2Cl2. In contrast to the saturated analogues
which undergo ring contraction to azetidines,2 1a produces the
hydroquinoline 2a in 65% yield (Scheme 2). This product could arise
from either cyclization of the π-allyl intermediate A or via electro-
cyclization of the free aza-o-xylenene.5 Inteterstingly, conducting the
same reaction in toluene solvent produces the 12-membered dimer
exclusively.6 Since it is improbable that such a dimer could arise from
concerted [6 + 6] cycloaddition, it seems likely that Pd-polarized aza-
o-xylylene A is an intermediate in these reactions.
If zwitterionic Pd-π-allyl intermediates are indeed being formed,
then one would also predict that they would undergo [4 + 2]
cycloadditions with electron deficient olefins.7,8 Indeed, upon treatment
of the benzoxazinanone 1a with Pd(PPh3)4 in the presence of one
equivalent of benzylidene malononitrile, cycloaddition occurs to
produce the highly substituted dihydroquinoline 4a with high diaste-
reoselectivity (eq 2).
a This reaction produced 97% ee and 50:1 dr after
recrystallization.
a single
9
8118 J. AM. CHEM. SOC. 2008, 130, 8118–8119
10.1021/ja801742h CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Asymmetric Decarboxylative Cycloadditionsa
Scheme 4
product
X
Y
yield
ee
dr
4bb
4cb
4dc
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
p-OMe
p-Me
H
p-OMe
p-Me
H
p-OMe
p-Me
H
p-OMe
p-Me
H
p-NO2
p-NO2
p-NO2
p-CO2Me
p-CO2Me
p-CO2Me
o-CF3
o-CF3
o-CF3
p-CF3
p-CF3
p-CF3
p-OAc
p-OAc
p-OAc
p-OAc
H
91
90
78
99
97
76
97
85
78
93
88
90
90
73
52
60
92
77
75
99
99
96
92
98
96
86
98
89
84
86
91
80
90
91
87
86
92
87
25:1
>99:1
>99:1
25:1
37:1
25:1
29:1
>99:1
36:1
37:1
56:1
45:1
50:1
70:1
92:1
>99:1
54:1
cyclization.13 Elegant studies have allowed Lloyd-Jones to develop a
model for the binding of Trost ligands to palladium.14 These studies
suggest that the Trost ligand binds to palladium to produce a complex of
C1-symmetry where the ligand bulk is concentrated in the upper right-
hand and lower left-hand quadrants. Superimposing our intermediate onto
Lloyd-Jones’ model gives four potential transition states for cyclization;
three are shown in Scheme 4. The favored transition state results from
placing the benzylidene malononitrile fragment in the least hindered
quadrant and the phenyl group is directed away from the bulky ligand in
back. Such a prediction is confirmed by an X-ray crystal structure of 4a
that is of sufficient quality to allow determination of the relative and
absolute configuration of the product.
In conclusion, we have developed an asymmetric decarboxylative
cycloaddition that proceeds through intermediates that may be viewed
as palladium-polarized aza-ortho-xylylenes. Formal [4 + 2] cyclo-
addition of these intermediates produces enantioenriched hydroquino-
lines with high diastereoselectivity. The implied stabilization of aza-
o-xylylenes by palladium is expected to translate to other reactive
intermediates.
p-OMe
p-Me
H
p-F
p-OMe
p-Me
p-F
H
H
>99:1
87:1
4t
a Run using 1.0 mmol substrate treated with Pd2(dba)3 (0.05 mmol) and
L4 (0.11 mmol) in CH2Cl2 at room temperature for 4-6 h. b Run in
CH2Cl2 at 40 °C for 29 h. c Run in toluene at 80 °C for 6 h.
Scheme 3
Acknowledgment. We thank the National Institute of General
Medical Sciences (Grant 1R01GM079644) for support. We also thank
Victor Day for the X-ray crystallographic analysis.
Supporting Information Available: Experimental procedures, the
X-ray structure of 4a, and characterization data for all new compounds.
This material is available free of charge via the Internet at http://
pubs.acs.org.
the cycloaddition proceeded with both high enantioselectivity and
diastereoselectivity; the ee’s and dr’s of the product dihydroquinolines
before recrystallization are shown in Table 2. Highly electron-deficient
olefins slowed the reaction substantially, presumably because of
favorable binding to the Pd(0) catalyst.11 Thus, in contrast to most
reactions which were facile at room temperature, the nitro-containing
benzylidene malononitrile (entry 4d, Table 2) required 80 °C for the
reaction to proceed. It is noteworthy that the reaction selectivity was
largely unaffected by the increased reaction temperature.
References
(1) Consonni, R.; Dalla Croce, P.; Ferraccioli, R.; La Rosa, C. J. Chem. Soc.,
Perkin Trans. 1 1996, 1809–1814.
(2) Wang, C.; Tunge, J. A. Org. Lett. 2006, 8, 3211–3214.
(3) Wojciechowski, K. Eur. J. Org. Chem. 2001, 3587–3605.
(4) A related palladium-coordinated quinone methide has been proposed: Schultz,
M. J.; Sigman, M. J. Am. Chem. Soc. 2006, 128, 1460–1461.
(5) In analogy to electrocyclizations of quinone methides: Van De Water, R. W.;
Pettus, T. Tetrahedron 2002, 58, 5367–5405.
(6) While the isolated yield of 3b is low, the compound is formed cleanly as
determined by 1H NMR spectroscopy.
The origin of the stereoselectivity in this reaction is not known;
however, the reaction likely proceeds through aza-Michael addition
of intermediate A to the activated olefin (Scheme 3). The resulting
stabilized carbanionic intermediate can then undergo intramolecular
cyclization. The two potential stereochemistry-determining steps in
such a transformation are (1) the aza-Michael addition or (2) the
cyclization. Since it is difficult to imagine that the chirality of the
ligands could effect a highly enantioselective aza-Michael addition,
our working hypothesis is that reversible conjugate addition is followed
by stereochemistry-determining cyclization. This hypothesis is con-
sistent with the pKa values for malononitrile (11.2) and the arylsul-
fonamide (9-10).12
(7) (a) Aoyagi, K.; Nakamura, H.; Yamamoto, Y. J. Org. Chem. 2002, 67,
5977–5980. (b) Sekido, M.; Aoyagi, K.; Nakamura, H.; Kabuto, C.;
Yamamoto, Y. J. Org. Chem. 2001, 66, 7142–7147.
(8) Kuwano, R.; Shige, T. J. Am. Chem. Soc. 2007, 129, 3802–3803.
(9) Trost, B. M.; Van Vranken, D. L.; Bingel, C. J. Am. Chem. Soc. 1992,
114, 9327–9343.
(10) The electrophilicity of p-methoxybenzylidene malononitriles (-10.8) is less
than that of a π-allyl palladium complex (-10.1). (a) Kuhn, O.; Mayr, H.
Angew. Chem., Int. Ed. 1999, 38, 343–346. (b) Lemek, T.; Mayr, H. J.
Org. Chem. 2003, 68, 6880–6886.
(11) Popp, B. V.; Thorman, J. L.; Morales, C. M.; Landis, C. R.; Stahl, S. S.
J. Am. Chem. Soc. 2004, 126, 14832–14842.
(12) Balaban, A. T.; Khadikar, P. V.; Supuran, C. T.; Thakur, A.; Thakur, M.
Bioorg. Med. Chem. Lett. 2005, 3966–3973.
(13) Seeman, J. Chem. ReV. 1983, 83, 83–134.
(14) Lloyd-Jones, G. C.; Stephen, S. C.; Fairlamb, I. J. S.; Martorell, A.; Dominguez,
B.; Tomlin, P. M.; Murray, M.; Fernandez, J. M.; Jeffery, J. C.; Riis-
Johannessen, T.; Guerziz, T. Pure Appl. Chem. 2004, 76, 589–601.
Curtin-Hammett analysis of the resulting kinetic scenario indicates
that the major product of the reaction will result from the most favorable
JA801742H
9
J. AM. CHEM. SOC. VOL. 130, NO. 26, 2008 8119