Type 2 intramolecular nitroso Diels-Alder reaction. Synthesis and structure of bridgehead oxazinolactams.

Article abstract of DOI:10.1021/ol005811m

[reaction--see text] The type 2 intramolecular Diels-Alder cycloaddition utilizing N-acylnitroso dienophiles provides an efficient entry into bridged oxazinolactams. In contrast to the bimolecular counterpart, the reaction is completely regioselective. Structural characterization of the cycloadducts allows for evaluation of the olefin distortion and the degree of pyramidalization of the bridgehead oxazinolactam.

Full text of DOI:10.1021/ol005811m

ORGANIC
LETTERS
2
000
Vol. 2, No. 10
473-1475
Type 2 Intramolecular Nitroso
Diels−Alder Reaction. Synthesis and
Structure of Bridgehead Oxazinolactams
Steven M. Sparks, Jesse D. Vargas, and Kenneth J. Shea*
1
Department of Chemistry, 516 Rowland Hall, UniVersity of California, IrVine,
IrVine, California 92697-2025
kjshea@uci.edu
Received March 14, 2000
ABSTRACT
The type 2 intramolecular Diels−Alder cycloaddition utilizing N-acylnitroso dienophiles provides an efficient entry into bridged oxazinolactams.
In contrast to the bimolecular counterpart, the reaction is completely regioselective. Structural characterization of the cycloadducts allows for
evaluation of the olefin distortion and the degree of pyramidalization of the bridgehead oxazinolactam.
Diels-Alder reactions with heterodienophiles have provided
entry into a number of important ring systems. The early
studies of Kirby established that the use of N-acylnitroso
dienophiles offer an efficient entry into the 3,6-dihydro-1,2-
1). We now report the first examples of a type 2 intramo-
lecular N-acylnitroso Diels-Alder reaction for the synthesis
of bridged oxazinolactams.
1
oxazine ring system. These adducts have been elaborated
into pyrrolidines, piperidines, and tropanes as well as a
number of amino alcohol derivatives. The extension of this
methodology to include the intramolecular N-acylnitroso
Diels-Alder reaction has been used as a key step in the
synthesis of a number of alkaloid natural products including
members of the pyrrolizidine and indolizidine families.
The utility of oxazinolactams as key intermediates in the
synthesis of heterocycles has prompted our study of the type
Our strategy for the synthesis of [n.3.1] bridgehead olefin/
oxazinolactams anticipated a Diels-Alder cycloadduct 1 that
would arise from the corresponding 2-substituted-N-acylni-
troso-1,3-diene 2 which in turn would be generated in situ
by oxidation of the requisite hydroxamic acid 3 (Scheme
2
2
variant of the intramolecular nitroso Diels-Alder reaction.
Type 2 intramolecularity provides an opportunity to control
the regiochemistry of the cycloaddition, a factor that has
restricted applications of this reaction in more complex
settings. Attachment of the hydroxamic acid to the two
position of the diene would allow for the synthesis of bridged
oxazinolactams, which, after the appropriate manipulations,
could be elaborated to medium ring amines or lactams (eq
Scheme 1
(
1) Kirby, G. W.; Chem. Soc. ReV. 1977, 6, 1-24.
(
2) For reviews of nitroso Diels-Alder reactions, see: (a) Vogt, P. F.;
Miller, M. J. Tetrahedron 1998, 54, 1317-1348. (b) Kibayashi, C.; Aoyagi,
S. Synlett 1995, 873-879. (c) Streith, J.; Defoin, A. Synthesis 1994, 1107-
1
117. (d) Boger, D. L.; Weinreb, S. M. Hetereo Diels-Alder Methodology
in Organic Synthesis; Pergamon: Oxford, 1987. (e) Weinreb, S. M.; Staib,
R. R. Tetrahedron 1982, 38, 3087-3128.
(3) Shea, K. J.; Pham, P. Q. Tetrahedron Lett. 1983, 24, 1003.
1
0.1021/ol005811m CCC: $19.00 © 2000 American Chemical Society
Published on Web 04/27/2000

1
). The hydroxamic acid can be derived from a carboxylic
The X-ray structures verify the regiochemistry of the
cycloaddition. In addition, the structures reveal the bridge-
head double bond and bridgehead oxazinolactam are sig-
acid that would ultimately come from nitrile 4.
The diene nitriles 6a,b needed for the synthesis of the
Diels-Alder precursors were prepared by coupling the
5
nificantly distorted from planarity (Figure 1). The extent
iodonitriles 5a,b with chloroprene Grignard in the presence
3
2
of Li CuCl
4
(Scheme 2). Basic hydrolysis of the resulting
Scheme 2
Figure 1. ORTEP plot of 9 and 10 at the 50% probability level.
of the distortions can be quantified by the torsion angle τ
between the p-orbitals of the double bond and nitrogen-
carbonyl π systems and the pyramidalization angles ø of the
constituent atoms of the two functional groups. The method
used to measure the distortions observed in unsymmetrically
nitriles afforded the carboxylic acids 7a,b. The acids were
converted to the corresponding hydroxamic acids 8a,b by
treatment with oxalyl chloride followed by addition of
hydroxylamine hydrochloride under biphasic conditions.
The bridgehead olefin/oxazinolactams were prepared by
the type 2 intramolecular nitroso Diels-Alder cycloaddition
of hydroxamic acids 8a and 8b (Scheme 3). The Diels-
6
deformed π systems is shown in Figure 2.
Scheme 3
Figure 2. Definitions of distortional parameters ø and τ.
The view along the C
represented by 12 (Figure 2). Rotation of C
1
-C
2
axis of π system 11 is
relative to C
1
2
produces a misalignment of the π bond p-orbitals. This
deformation causes the two atoms of the π-system to
rehybridize independently. The torsional deformation is
quantified by the angle τ between the axes of the two
p-orbitals. The torsion angle τ is not directly measurable but
may be determined by summing the four atom torsion angles
Alder precursors were treated with Et
4 4 3
NIO in CHCl at 0
°
C under dilute conditions (0.01 M) to afford the corre-
sponding cycloadducts 9 and 10 in 75 and 80% yield,
respectively. Each Diels-Alder reaction gave a single
product. The reactions occurred with complete regiochemical
control to provide the 1,3-bridged cycloadducts exclusively.
The intermediacy of the N-acylnitroso compounds is inferred
from the structure of the cycloadducts, and no attempt was
made to observe the intermediates. Compounds 9 and 10
were crystalline and were analyzed by X-ray crystal-
YC
1
2
C W (Φ
1
) and ZC
1
C
2
X (Φ
2
) and dividing the result by
2
(τ ) (Φ
1
+ Φ
2
)/2). The p-orbital alignment is presumed
to be optimal for a double bond with τ ) 0.0 °.
(5) For similar studies of bridgehead olefins, see: (a) Lease, T. G.; Shea,
K. J. In AdVances in Theoretically Interesting Molecules; Thummel, R. P.,
Ed.; JAI: Greenwich, CT, 1992; Vol. 2, pp 79-112. (b) Lease, T. G.; Shea,
K. J. J. Am. Chem. Soc. 1993, 115, 2248-2260. (c) Shea, K. J.; Lease, T.
G.; Ziller, J. W. J. Am. Chem. Soc. 1990, 112, 8627-8629.
4
lography.
(4) Experimental details of the X-ray crystallography can be found in
the Supporting Information.
(6) Winkler, F. K.; Dunitz, J. D. J. Mol. Biol. 1971, 59, 169-182.
1474
Org. Lett., Vol. 2, No. 10, 2000

The degree of pyramidalization of each atom is quantified
by the pyramidalization angle ø, defined as the acute angle
formed by the projection of one substituent (Z) across the
4 4 3
hydroxamic acid to a 0 °C solution of Et NIO in CHCl
led to a 1:1 mixture of inseparable regioisomers. The
1
diagnostic peaks in the H NMR of the mixture included
2.00
atom onto the geminal substituent (Y). For an sp atom, ø
two vinyl proton resonances at 5.68 and 5.64 ppm. The
identity of the 1,3-substituted isomer was verified by its
independent synthesis via a type 2 nitroso Diels-Alder
0.0°, while, for an sp3 atom, ø ) 60.0°.
.00
)
At the bridgehead C-C double bond, the torsion angles
C4-C5 are 6.83(9)° for 9 and 3.53(9)° for 10. The pyrami-
9
τ
reaction containing a cleavable tether. Diels-Alder precur-
dalization angle of the bridgehead carbons øC5 is 20.3° for 9
and 13.5° for 10 whereas øC4 is 9.0° for 9 and 6.0° for 10.
The CdC bond distances, 1.3331(18) Å for 9 and 1.3323-
sor 15 was prepared from 3-methylene-4-penten-1-ol by
condensation with carbonyldiimidazole followed by displace-
ment with hydroxylamine. Oxidation of 15 with NaIO in
4
(
14) Å for 10 are within error of the value for cyclohexene
water led to cycloadduct 16. Tether cleavage with ethanolic
potassium hydroxide afforded the ethyl carbamate which was
hydrolyzed with potassium hydroxide in water/dioxane.
Acylation with acetyl chloride provided isomerically pure
13 in 55% along with 11% of acetate 18. Conformation of
7
(1.335(3) Å) and reveal the bond distance is not a sensitive
function of the olefin distortions.
A soft bending potential at nitrogen and a weak torsion
potential about the C-N bond result in a more extensive
distortion of the bridgehead oxazinolactam. Pyramidalization
of the bridgehead nitrogen is essentially complete: øN1
)
54.8° for 9 and 52.6° for 10. This is in contrast to the
Scheme 5
carbonyl carbons which undergo almost no pyramidiliza-
tion: øC7 ) 0.4° for 9 and 1.5° for 10. The torsion angle
τ
N1-C9 is 3.53(10)° for 9 and τN1-C10 is 10.35(8)° for 10. It
is interesting to note that the torsion angle of the bridgehead
oxazinolactam 10 is greater than that of cycloadduct 9. This
may be a consequence of relief of transannular interactions
in cycloadduct 10 that could result in a greater distortion of
the bridgehead oxazinolactam. The crystal structure of 10
reveals two close contacts between hydrogens at C-7 and
C-9 with the syn hydrogen at C-11. Only one such contact
is observed in 9.
Scheme 4
1
the structure of 13 was verified by correlation of the H NMR
spectra to the regioisomeric mixture. The vinyl proton
resonance at 5.68 ppm for the 1,3-regioisomer 13 matched
that seen in the spectra of the mixture of regioisomers.
In summary, the type 2 nitroso Diels-Alder reaction has
been developed for the synthesis of bridged oxazinolactams.
The reaction provides complete control over the regiochem-
istry of the cycloaddition to furnish the 1,3-substituted
regioisomer exclusively. Structural characterization of the
bridged compounds has allowed for quantification of the
distortions of the bridgehead double bond and oxazinolactam
functional groups. Bridgehead oxazinolactams are currently
being developed for the stereoselective synthesis of medium
ring amides and amines.
In addition to providing access to novel bridged bicyclic
oxazinolactams, type 2 intramolecularity provides a strong
regiochemical bias for formation of the meta or 1,3-
regioisomer. To establish the unencumbered regiochemical
preference of the corresponding intermolecular reaction, the
Diels-Alder reaction of 3-methylene-4-penten-1-ol with
Acknowledgment. This research was supported in part
by a grant from the NIH. S.M.S. was supported by a graduate
fellowship sponsored by Pharmacia & Upjohn and would
also like to thank Hoffmann-La Roche Inc. for financial
support. J.D.V. is a recipient of a UROP fellowship from
UCI. We are grateful to Dr. Joseph Ziller for his assistance
with the X-ray crystallography.
8
acetohydroxamic acid was carried out. Addition of aceto-
(
7) Determined by electron diffraction: Chiang, J. F.; Bauer, S. H. J.
Am. Chem. Soc. 1969, 91, 1898-1901.
8) For earlier studies of the regiochemistry of intermolecular acyl nitroso
(
Diels-Alder reactions, see: (a) Aoyagi, S.; Tanaka, R.; Naruse, M.;
Kibayashi, C. J. Org. Chem. 1998, 63, 8397. (b) Boger, D. L.; Patel, M. J.
Org. Chem. 1984, 49, 4098. (c) Boger, D. L.; Patel, M.; Takusagawa, F. J.
Org. Chem. 1985, 50, 1911.
Supporting Information Available: Crystallographic
data for compounds 9 and 10. This material is available free
of charge via the Internet at http://pubs.acs.org.
(
9) Davies, G.; Russel, A. T.; Sanderson, A. J.; Simpson, S. J.
Tetrahedron Lett. 1999, 40, 4391.
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