Intramolecular Diels-Alder Reaction of N-Alkyl-2-cyano-1-azadienes: A Study of the Eschenmoser Cycloreversion of Dihydrooxazines as a Route to N-Alkyl-2-cyano-1-azadienes

Article abstract of DOI:10.1021/jo9614046

In connection with the development of the intramolecular Diels-Alder reaction (IMDA) of 1-azadienes, the 5,6-dihydro-4H-1,2-oxazine 12 has been evaluated as a synthon equivalent of the 2-cyano-1-azadiene system. It was found that the dihydrooxazonium salt 27, generated in situ from the cyclic hydroxamic acid derivative 26, is converted directly to azadiene 4a via tautomerization to the corresponding enamine and a particularly facile Eschenmoser type cycloreversion process. Conditions were subsequently found for the preparation of synthon 12. N-Alkylation of this intermediate with alkyl bromides in the presence of Ag⁺ ion also resulted in direct formation of the 2-cyano-1-azadiene products 38a-d and 4a. Microwave irradiation of a benzene solution of azadiene 4a proved to be a convenient means to effect its IMDA conversion to indolizidine 5a. To avoid decomposition of azadiene 38c, its intramolecular cycloaddition giving 40 (60%) was achieved by flash vacuum thermolysis.

Full text of DOI:10.1021/jo9614046

2098
J . Org. Chem. 1997, 62, 2098-2105
In tr a m olecu la r Diels-Ald er Rea ction of
N-Alk yl-2-cya n o-1-a za d ien es: A Stu d y of th e Esch en m oser
Cyclor ever sion of Dih yd r ooxa zin es a s a Rou te to
N-Alk yl-2-cya n o-1-a za d ien es
Irina A. Motorina, Frank W. Fowler,*,† and David S. Grierson*,‡
Institut de Chimie des Substances Naturelles, 91198 Gif-sur Yvette, France, and Department of
Chemistry, State University of New York at Stony Brook, Stony Brook, New York 11794
Received J uly 23, 1996X
In connection with the development of the intramolecular Diels-Alder reaction (IMDA) of
1-azadienes, the 5,6-dihydro-4H-1,2-oxazine 12 has been evaluated as a synthon equivalent of the
2-cyano-1-azadiene system. It was found that the dihydrooxazonium salt 27, generated in situ
from the cyclic hydroxamic acid derivative 26, is converted directly to azadiene 4a via tautomer-
ization to the corresponding enamine and a particularly facile Eschenmoser type cycloreversion
process. Conditions were subsequently found for the preparation of synthon 12. N-Alkylation of
this intermediate with alkyl bromides in the presence of Ag+ ion also resulted in direct formation
of the 2-cyano-1-azadiene products 38a -d and 4a . Microwave irradiation of a benzene solution of
azadiene 4a proved to be a convenient means to effect its IMDA conversion to indolizidine 5a . To
avoid decomposition of azadiene 38c, its intramolecular cycloaddition giving 40 (60%) was achieved
by flash vacuum thermolysis.
Sch em e 1
The Diels-Alder reaction has proven to be an excep-
tionally powerful method for carbon-carbon bond forma-
tion in the synthesis of natural products and novel
structures of both fundamental and applied interest.
Indeed, in this process the simultaneous creation of two
new C-C bonds is coupled with the possibility for regio-
and stereocontrol at up to four carbon centers in the
newly formed six-membered ring. Over the past decade
considerable effort has also gone into the development
of the Diels-Alder reaction of 1-azadienes 1.1 In par-
ticular, strategies have evolved to surmount the inherent
problems associated with the lack of reactivity of these
dienes in both the inter- and intramolecular Diels-Alder
reactions. These include reinforcing the inverse electron
demand nature of the azadiene system in LUMOdiene
-
controlled cycloadditions through N-SO2AR and N-COR
substitution and, alternatively, reversing the normal
electrophilic character of these heterodienes by introduc-
tion of electron-donating N,N-dialkylamino groups onto
nitrogen.2-5
In a continuation of our work on the [4 + 2] cycload-
dition chemistry of 1-azadienes,6 it was found that the
intramolecular Diels-Alder (IMDA) reactions of the
2-cyano-substituted N-alkyl azadienes 4a ,b occur under
mild conditions to give the fused bicyclic nitrogen het-
erocycles 5a ,b in up to 90% yield (Scheme 1).7,8 These
results indicate that a C-2 cyano substituent alone can
serve to both accentuate the Diels-Alder reactivity of the
1-azadiene system and render the process efficient through
stabilization of the starting diene and the derived ∆2-
piperideine product. Of greater synthetic interest, the
† State University of New York at Stony Brook.
‡ Institut de Chimie des Substances Naturelles.
X Abstract published in Advance ACS Abstracts, March 1, 1997.
(1) For a general discussion of the Diels-Alder reaction of 1-aza-
dienes, see: Boger, D. L.; Weinreb, S. M. Hetero Diels-Alder Methodol-
ogy in Organic Synthesis; Academic Press; San Diego, 1987; Chapter
9.
(2) (a) Boger, D. L.; Kasper, A. M. J . Am. Chem. Soc. 1989, 111,
1517. (b) Boger D. L.; Corbett, W. L.; Wiggins, J . M. J . Org. Chem.
1990, 55, 2999. (c) Boger, D. L.; Curran, T. T. J . Org. Chem. 1990, 55,
5439. (d) Boger, D. L.; Corbett, W. L.; Curran, T. T.; Kasper, A. M. J .
Am. Chem. Soc. 1991, 113, 1713.
(3) (a) Hwang, Y. C.; Fowler, F. W. J . Org. Chem. 1985, 50, 2719.
(b) Cheng, T.-S.; Lupo, A. T.; Fowler, F. W. J . Am. Chem. Soc. 1983,
105, 7696.
(4) (a) Serckx-Poncin, B.; Hesbain-Frisque, A.-M.; Ghosez, L. Tet-
rahedron Lett. 1982, 23, 3261. (b) Ghosez, L.; Serckx-Poncin, B.; Rivera,
M.; Bayard, P.; Sainte, F.; Demoulin, A.; Hesbain-Frisque, A.-M.;
Mockel, A.; Munoz, L.; Bernard-Henriet, C. J . Heterocycl. Chem. 1985,
22 (Suppl. Issue Lect. Heterocycl. Chem., 8), 69.
(6) (a) Teng, M.; Fowler, F. W. Tetrahedron Lett. 1989, 30, 2481.
(b) Teng, M.; Fowler, F. W. J . Org. Chem. 1990, 55, 5646. (c) Sisti, N.
J .; Fowler, F. W.; Grierson, D. S. Synlett 1991, 816. (d) Trione, C.;
Toledo, L. M.; Kuduk, S.; Fowler, F. W.; Grierson, D. S. J . Org. Chem.
1993, 58, 2075. (e) Sisti, N. J .; Motorina, I. A.; Tran Huu Dau, M.-E.;
Claude, R.; Fowler, F. W.; Grierson, D. S. J . Org. Chem. 1996, 61, 3715.
(7) Dufour, B.; Motorina, I.; Fowler, F. W.; Grierson, D. S. Hetero-
cycles 1994, 37, 1455.
(5) Boger, D. L.; Corbett, W. L.; Allcock, S. J .; Gilchrist, T. L.;
Shattleworth, S. J . Tetrahedron 1991, 48, 10053. See also ref 3a.
(8) Sisti, N. J .; Zeller, E.; Grierson, D. S.; Fowler, F. W. J . Org. Chem.
1997, 62, 2093.
S0022-3263(96)01404-1 CCC: $14.00 © 1997 American Chemical Society

Eschenmoser Cycloreversion of Dihydrooxazines
J . Org. Chem., Vol. 62, No. 7, 1997 2099
Sch em e 2
Sch em e 3
ther work by other groups has shown that the dihydroox-
azonium salts 8 where R1 ) H or Ph can also be formed
by N-alkylation of the corresponding dihydro-1,2-oxazines
11 with alkyl iodides and Meerwein reagents.12 However,
lacking suitable activation, the simple 1-azadienes ob-
tained via the Eschenmoser retro Diels-Alder route have
not found application as dienes in inter- or intramolecular
Diels-Alder reactions.
We have undertaken a project to evaluate the reactivity
and use of the dihydro-1,2-oxazine 12 functionalized at
C-3 by a cyano group as a synthon equivalent of 2-cyano-
1-azadiene. The initial objectives in this work have been
to develop conditions for the preparation and N-alkyla-
tion of synthon 12, as well as to demonstrate that the
retro Diels-Alder reaction of the corresponding enamine
tautomer 9 efficiently reveals the 2-cyano-1-azadiene
system in 13.
Resu lts a n d Discu ssion
Two principal methods for the preparation of 5,6-
dihydro-4H-1,2-oxazines include the cyclization of γ-halo
oximes such as 1413 and the Diels-Alder reaction of
nitrosoethylene derivatives 16, generated from R-chloro-
(bromo)methyl oximes such as 15, with nucleophilic
olefins (Scheme 2).14 In view of the close parallel between
the latter approach and Eschenmoser’s work on R-chlo-
ronitrones 6, we initially pursued this route to prepare
3-cyano-substituted dihydro-1,2-oxazines.
results suggest that the IMDA reaction of 2-cyano-1-
azadienes can be integrated with confidence into strate-
gies for the multistep synthesis of structurally complex
heterocycles.
In this context, coordination of the timing and mode
of construction of the azadiene component in the syn-
thetic intermediate which is engaged in the intramolecu-
lar cycloaddition reaction is important. For the unfunc-
tionalized compounds 4, this was achieved by elaboration
of the stable amides 3 followed by their reaction with
triflic anhydride/LiCN.6e,9 However, for more complicated
target molecules the situation may well arise where the
reaction conditions, and the linear type of approach taken
to access 4, are not applicable. Alternatives are thus
required. A more convergent strategy is to construct the
2-cyano-1-azadiene and dienophile components sepa-
rately and connect them only immediately prior to the
programmed cycloaddition step. Anticipating the insta-
bility of 2-cyano-1-azadiene itself,10 we have sought to
develop this IMDA approach through the use of more
stable 1-azadiene equivalents from which, ideally, the
2-cyano-1-azadiene unit can be generated in situ under
the thermal conditions of the Diels-Alder reaction.
As demonstrated in elegant experiments conducted by
Eschenmoser et al. in the early 1970s, dihydro-1,2-
oxazines possess this potential.11 It was observed that
5,6-dihydro-4H-1,2-oxazonium salts 8, formed in the
Diels-Alder reaction of transient vinylnitrosonium in-
termediates 7, readily tautomerize in the presence of base
producing the isomeric dihydrooxazines 9. On gentle
heating (50 °C) these intermediates undergo a very clean
cycloreversion to give 1-azadienes 10 (Scheme 2). Fur-
Ogloblin et al. showed that the starting cyano-substi-
tuted R-chloro oxime 17 could be prepared by reaction of
nitrosyl chloride with acrylonitrile in ether/HCl.15 How-
ever, under the reported conditions we found that product
isolation was complicated due to concomitant formation
of significant amounts of 2-chloropropionitrile through
conjugate addition of HCl. Fortunately, by carrying out
the reaction in the presence of catalytic quantities of
AlCl3, compound 17 was formed exclusively and isolated
in 76% yield. Concerning the reactivity of this chlo-
rooxime, Viehe et al. demonstrated that it reacts with
cyclopentadiene in the presence of carbonate base to give
the expected Diels-Alder product.16 Furthermore, Gil-
christ found that the related vinylnitroso intermediate
16 (R1 ) CO2Et) reacts successfully with R-methylsty-
rene, but not with unactivated olefins such as ethylene.14
For this reason we opted to prepare dihydrooxazine 18
by reaction of 17 with K2CO3 in CH2Cl2 containing 2
equiv of R-methylstyrene (20 °C, 15 h) (Scheme 3). This
produced a separable mixture (1:1.2) of the desired
(12) (a) Goldberg, I.; Saad, D.; Shalom, E.; Shatzmiller, S. J . Org.
Chem. 1982, 47, 2192.; (b) Shatzmiller, S.; Shalom, E. Liebigs Ann.
Chem. 1983, 897. (c) Hardegger, B.; Shatzmiller, S. Helv. Chim. Acta
1976, 59, 2765.
(9) For the preparation of LiCN, see: Livinghouse, T. Org. Synth.
1981, 60, 126.
(10) De Corte, B.; Denis, J .-M.; De Kimpe, N. J . Org. Chem. 1987,
52, 1147.
(11) (a) Gygax, P.; Das Gupta, T. K.; Eschenmoser, A. Helv. Chim.
Acta 1972, 55, 2205. b) Kempe, U. M.; Das Gupta, T. K.; Blatt, P.;
Gygax, P.; Felix, D.; Eschenmoser, A. Helv. Chim. Acta 1972, 55, 2187.
(13) Comprehensive Heterocyclic Chemistry; Katritsky, A., Rees, C.
W., Eds.; Pergamon: New York, 1984; Vol. 3, Chapter 2-27.
(14) Gilchrist, T. L. J . Chem. Soc. Rev. 1983, 1, 53.
(15) Ogloblin, K. A.; Semenov, V. P. Z. Organich. Himii SSSR 1965,
1, 1361, Chem. Abstr. 1966, 64, 588a.
(16) Francotte, E.; Mere´nyi, R.; Vandenbulcke-Coyette, B.; Viehe,
H.-G. Helv. Chim. Acta 1981, 64, 1208.

2100 J . Org. Chem., Vol. 62, No. 7, 1997
Motorina et al.
Sch em e 4
Sch em e 5
Diels-Alder adduct 18 (40%) and the more polar nitrone
19, whose structure was confirmed by X-ray crystal-
lography.17
presence of K2CO3 (Scheme 4). Cyclization of 21 (Hal )
Cl) was complicated by competing formation of 22;
however, compound 23 was obtained in 75% yield from
the corresponding bromide derivative of 21 (Hal ) Br).
Somewhat suprizingly, different attempts to transform
23 to synthon 12 produced a mixture of unidentifiable
products, leading us to focus all subsequent attention
upon the preparation of N-alkylated hydroxamic acid 26
by ring closure of the bromo compound 25. Compound
25 was itself prepared by reaction of bromobutyryl
chloride with the hydroxylamine derivative 24, which
was in turn obtained by cyanoborohydride reduction of
oxime 2a .20 Under typical solution reaction conditions
(CH2Cl2, NaOH), cyclization of 25 was capricious, but by
carrying out the reaction on alumina impregnated with
KF in the absence of solvent,21 a high-yield transforma-
tion to compound 26 was achieved (90%).
In subsequent attempts to N-alkylate or N-acylate
dihydrooxazine 18, it was found that it does not react
even with alkyl triflates or Meerwein’s reagent. Indeed,
1
by H NMR it was revealed that, at best, a 2-5% yield
of the desired N-alkylated enamine tautomer, or the
azadiene resulting from retrocondensation, was formed
in the case where 18 was treated with an excess of
4-pentenyl triflate and triethyloxonium tetrafluoroborate
at temperatures up to 80 °C. In earlier work by Lee and
Woodward,18 similar difficulties were encountered to
N-alkylate 3-carbethoxy-substituted dihydrooxazines. How-
ever, in the present case this problem is most probably
aggravated by the sterically crowded neopentyl environ-
ment of the oxime ether nitrogen.
Several different options were thus considered at this
point for the preparation of the unsubstituted 3-cyano-
dihydrooxazine 12 and the subsequent study of its
N-alkylation/cycloreversion. Wade19 previously showed
that this synthon can be accessed by cyclization of the
nitro-substituted halo oxime 14 (R1 ) NO2), followed by
displacement of the nitro group in the derived dihydroox-
azine product by cyanide ion. This route is direct, but
in terms of our objectives the approach illustrated in
Scheme 4 potentially offered greater flexibility, since the
Tf2O/LiCN conditions used to convert 3 f 4 could be
employed to prepare 12 and/or the dihydrooxazonium salt
27 from the cyclic hydroxamic acid derivatives 23 and
26.
With intermediate 26 in hand, its reaction with triflic
anhydride and LiCN at -60 °C was examined. Following
our established protocol6c in which diisopropylethylamine
is present in the reaction medium from the outset, only
starting material was recovered. Recognizing that the
amine base may tautomerize the initially formed O-triflyl
imidate salt 28 to the N,O-triflyl ketene acetal 31
(Scheme 5), which is simply hydrolyzed upon reaction
workup, the experimental procedure was modified such
that the Hunig’s base and LiCN are simultaneously
added in equivalent amounts after the triflic anhydride.
Under these new conditions two products were formed,
and varying amounts of the starting hydroxylamine
derivative were again recovered (up to 30%). Quite
suprizingly, the major less polar reaction component
(44%) corresponded to azadiene 4a and not to the
expected cyano enamine intermediate 29. Indeed, direct
conversion of amide 26 to this azadiene, presumably via
the dihydrooxazonium salt 27 and its tautomer 29, was
shown by TLC to occur during the period in which the
The acyclic hydroxamic acid 21 was easily prepared
in 95% yield by reaction of chloro- or bromobutyryl
chloride 20 with hydroxylamine hydrochloride in the
(17) The authors have deposited atomic coordinates for compound
19 with the Cambridge Crystallographic Data Centre. The coordinates
can be obtained, on request, from the Director, Cambridge Crystal-
lographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK.
(18) Lee, V. J .; Woodward, R. B. J . Org. Chem. 1979, 44, 2487.
(19) Wade, P. J . Org. Chem. 1978, 43, 2020.
(20) House, H. O.; Lee, L. F. J . Org. Chem. 1976, 41, 863.
(21) Bergbreiter, D. E. J . Org. Chem. 1987, 52, 1601.

Eschenmoser Cycloreversion of Dihydrooxazines
J . Org. Chem., Vol. 62, No. 7, 1997 2101
Sch em e 6
reaction was brought to room temperature. This result
indicates that the dihydrooxazine isomer 29 bearing the
electron-withdrawing cyano substituent at C-3 is remark-
ably prone to undergo the retro Diels-Alder process
described by Eschenmoser, precluding therefore its isola-
tion as a discrete product. The other more polar product
(8%) of this reaction, also isolated by silica gel flash
column chromatography, corresponded to the dicyano
addition product 30. Compound 30 most likely arises
through competing reaction of the initially formed cyano
imidate 27 with CN- ion. In agreement with this
mechanism was the observation that when 26 was
treated with Tf2O and LiCN in the absence of amine base
azadiene 4a was not produced, and the yield of the
dicyano product 30 increased accordingly to 35%. Vary-
ing the reaction temperature and other parameters did
not permit us to suppress completely the formation of
the dicyano product 30, or the process leading back to
starting material, indicating that there is a very fine
balance between the three different reaction pathways.
Having shown that the dihydrooxazonium salt 27 can
be generated from hydroxamic acid 26, and further that
this intermediate transforms directly to azadiene 4a , we
returned to the preparation of synthon 12 in order to
determine whether it could be successfully N-alkylated.
A new route to this compound was devised based upon
both the reported use of Pb(OAc)4 to oxidize tetrahy-
drooxazine to the parent dihydro system 33 (11; R1 ) H)22
and our own experience in the conversion of R-aminoni-
triles to imodyl cyanides using the same oxidant.7 Thus,
5,6-dihydro-4H-1,2-oxazine (33) was synthesized in high
overall yield by reaction of N-hydroxyurethane 32 with
dibromobutane followed by ester hydrolysis-decarboxy-
lation and Pb(OAc)4 oxidation (Scheme 6).23 By subse-
quent reaction of this sensitive intermediate with
TMSCN, the stable aminonitrile 34 was obtained (84%).
Finally, treatment of 34 with Pb(OAc)4 provided a very
convenient method to obtain gram quantities of 12.
In marked contrast to 18, synthon 12 reacted rapidly
with triethyloxonium tetrafluoroborate, followed by Et3N,
to give directly the volatile N-ethyl-2-cyano-1-azadiene
(38a ) (71%) (Scheme 6). The same product was also
formed, albeit in lower yield (29%), on reaction of 12 with
EtBr in the presence of AgBF4. In a similar way the
reaction of 12 with benzyl bromide and silver ion gave
the expected N-benzyl azadiene product 38b in 72%
isolated yield. Building upon this result, it was also
found that reaction of 12 with the benzyl bromide
derivative 37 was efficient, leading directly to formation
of azadiene 38c in 67% yield (along with 4% of the cyclic
amide related to 26 produced by hydrolysis of the initially
formed intermediate of type 35/36). However, for reasons
which have not been firmly established,24 the correspond-
ing Ag+-promoted N-alkylation of 12 with 4-pentenyl
bromide and 2-bromohex-5-ene produced the desired
azadienes 38d and 4a in only 6-8% yields. Likewise,
treatment of 12 with 4-pentenyl triflate did not result in
formation of appreciable amounts of cyano enamine 36
or azadiene 38d .
remained to effect the IMDA reaction of azadienes 4a and
38c. Although the conversion of 4a to indolizidine 5a
(mixture of diastereomers) had already been achieved by
heating in benzene overnight in a sealed tube at 110 °C,8
it was found that reaction time could be reduced to a
mere 14 min when this Diels-Alder reaction was carried
out in a microwave oven (650 W). On the other hand,
independent of the mode employed, heating 38c in
benzene solution did not result in its intramolecular
cycloaddition to the indolizidine derivative 40. NMR
examination of the major isolable reaction components
revealed that in several instances cleavage of the
N-C(benzyl) bond in 38c occurred, producing, among
other things, compounds possessing a styrene type double
bond. To suppress decomposition of this apparently
sensitive azadiene via polar reaction pathways, its in-
tramolecular cycloaddition reaction was subsequently
examined under flash vacuum thermolysis conditions.25
Indeed, by using the technique where the azadiene is
brought into the gas phase by cosublimation with ben-
zene, a very clean conversion to the desired Diels-Alder
product 40 (mixture of 3,8a-cis/trans isomers) was ob-
served at 470 °C. Note, however, that at slightly lower
temperature (400 °C) the reaction took a different course,
producing 2-azadiene 39. Formation of this more highly
conjugated azadiene results from a [1,5]-hydrogen shift,
which is most likely reversible at the higher temperature
at which conversion to cycloadduct 40 is observed.
In conclusion, it has been shown that dihydrooxazine
12 can be alkylated successfully using benzyl halides in
To finalize this preliminary study of the use of dihy-
drooxazine 12 as a 2-cyano-1-azadiene equivalent, it
(22) Norman, R. O. C.; Purchase, R.; Thomas, C. B. J . Chem. Soc.,
Perkin Trans. 1 1972, 1701.
(23) King, H. J . Chem. Soc 1942, 432.
(24) The lower yields observed for the formation of azadienes 38d
and 4a may be the consequence of competing reactions of nonstabilized
carbocation type intermediates formed on complexation of RBr with
Ag+ ion.
(25) Magrath, J .; Fowler, F. W. Tetrahedron Lett. 1988, 29, 2171.

2102 J . Org. Chem., Vol. 62, No. 7, 1997
Motorina et al.
combination with Ag+ ion and that the resultant dihy-
drooxazonium salts undergo rearrangement to the cor-
responding enamine and very facile retro Diels-Alder
reaction to give 2-cyano-1-azadienes. Further work to
develop compound 12 as a stable 2-cyano-1-azadiene
equivalent in IMDA reactions is in progress.
dropwise to a stirred solution of hydroxylamine hydrochloride
(6.0 g, 0.086 mol) in H2O-ether (4:1; 250 mL) at a rate such
that reflux was maintained. Stirring was then continued at
room temperature for an additional 3 h. The ether layer was
separated, and the aqueous layer was filtered to remove
insoluble material. The water layer was extracted successively
with CH2Cl2 and CH2Cl2-acetone. The combined organic
layers were dried over Na2SO4 and concentrated, and the
residue was silica gel flash column chromatographed (hep-
tane-EtOAc, 1:3, followed by CH2Cl2, and CH2Cl2-acetone,
1:1). 4-Bromobutyrohydroxamic acid (21) (13.76 g, 88%) was
obtained as a yellow oil, which slowly transformed to 1,2-
oxazin-3-one (23) and decomposition products at room tem-
perature and/or on prolonged contact with silica gel: 1H NMR
(CDCl3) δ 2.18 (m, 2H), 2.58 (t, J ) 7.1 Hz, 2H), 3.49 (t, J )
6.3 Hz, 2H), 8.4-9.2 (br, 2H); 13C NMR (CDCl3) δ 27.53, 32.26,
32.53, 178.29; IR (neat) 1175, 1438, 1713, 1734, 2975, 3156
cm-1; MS (CI, isobutane, 170 °C) 102 ([M - HBr] + H)+, 87,
86.
1,2-Oxa zin a n -3-on e (23) a n d 1-Hyd r oxyp yr r olid in -2-
on e (22). NaH [527 mg (60% suspension in mineral oil), 13.2
mmol] was added in portions to a solution of 4-bromobutyro-
hydroxamic acid (21) (2.00 g, 11 mmol) in dry THF (30 mL) at
0 °C under nitrogen, and stirring was continued for an
additional 1 h at room temperature. H2O (10 mL) was then
added (ice bath), the organic layer was separated, and the
aqueous layer was washed with CH2Cl2. The combined organic
fractions were dried over Na2SO4 and concentrated without
heating, and the residue was silica gel flash column chromato-
graphed (heptane). 1,2-Oxazinan-3-one (23) was obtained as
a colorless liquid (0.83 g, 75%) along with 3-5% of 1-hydroxy-
pyrrolidin-2-one (22).
Exp er im en ta l Section
Ch lor o Oxim e 17. P r oced u r e 1. Cold ether (150 mL)
(dry ice bath) was transferred to NOCl (24.8 g, 0.38 mol)
(prepared in 95% yield according to ref 26 and kept in a septum
sealed flask at -73 °C), followed by acrylonitrile (24.8 g, 0.468
mol) and concd HCl (12 mL, 0.14 mol). The reaction vessel
was then tightly sealed with a glass stopper, very slowly
brought to room temperature, and stirred for 2 days (solution
color fades and pressure drops to normal). Taking care to work
in a well-ventillated fume hood, the reaction mixture was
washed with water, and the aqueous layers were back-
extracted with CH2Cl2. The combined organic layers were
dried over MgSO4 and concentrated. Distillation of the liquid
residue in vacuo (bp 77-79 °C/1 mmHg) gave oxime 17 (14.91
g, 33%).
P r oced u r e 2. To solution of NOCl (11.80 g, 0.18 mol) in
Et2O (80 mL) at -73 °C was added acrylonitrile (23.7 mL, 0.36
mol) and AlCl3 (1.2 g, 0.009 mol). After the flask was tightly
sealed, the reaction mixture was stirred at -20 °C for 2 h and
then at room temperature for an additional 18 h. Taking care
to work in a well-ventillated fume hood, the solvent volume
was diminished to about 30 mL, and the residual liquid was
washed with aqueous HCl (0.5 N) and water. The aqueous
fractions were then back-extracted with CH2Cl2, and the
combined organic phases were dried over MgSO4 and concen-
trated. Distillation of the liquid residue in vacuo (bp 76-
85°C/1 mmHg) gave chloro oxime 17 as a pale yellow liquid
(16.18 g; 76%): Rf 0.58 (heptane-EtOAc, 3:1); 1H NMR (CDCl3)
δ 4.34 (s, 2H), 10.20 (br s, 1H); 13C NMR (CDCl3) δ 33.47 and
40.32, 108.50 and 112.83, 129.86 and 135.38; IR (neat) 1688,
Com p ou n d 23: Rf ) 0.88 (heptane); 1H NMR (CDCl3) δ
2.18 (dt, J ) 7.2, 7.4 Hz, 2H), 2.63 (t, J ) 7.8 Hz, 2H), 4.37 (t,
J ) 6.8 Hz, 2H), 9.08 (br s, 1H); 13C NMR (CDCl3) δ 23.70,
26.12, 72.13, 160.41; IR (neat) 3480, 3367, 1771, 1645, 1377,
1173 cm-1; MS (CI, isobutane, 170 °C) 102 (M + H), 87.
Com p ou n d 22: Rf ) 0.17 (heptane-EtOAc, 3:1); 13C NMR
(CDCl3) δ 15.62, 23.58, 25.99, 165.42.
2250, 3331 cm-1
.
Hex-5-en -2-on e oxim e.20 Hydroxylamine hydrochloride
(10.4 g, 15 mmol) and NaOAc (12.3 g, 15 mmol) were added to
a solution of hex-5-en-2-one (4.9 g, 5 mmol) in H2O (50 mL)-
EtOH (3 mL), and the reaction mixture was stirred at reflux
for 46 h. The mixture was then extracted with CH2Cl2, and
the combined organic layers were washed with saturated
aqueous NaHCO3, dried over Na2SO4, and concentrated.
Oxime was obtained as a colorless liquid (4.73 g, 84%) by
vacuum distillation: bp 59°C/2 mmHg; Rf 0.66 and 0.76
(heptane-EtOAc, 1:1); 1H NMR (CDCl3) δ 1.88 and 1.90 (s,
3H), 2.30 (s, 4H), 5.02 (m, 2H), 5.82 (m, 1H), 9.48 (br s, 1H);
13C NMR (CDCl3) δ anti (major) 13.67, 28.04, 35.28, 115.41,
137.32, 157.92; syn (minor) 20.01, 29.52, 30.44, 115.26, 137.56,
6-Meth yl-6-p h en yl-5,6-d ih yd r o-4H-1,2-oxa zin e-3-ca r bo-
n itr ile (18) a n d 2-Cya n o-5-m eth yl-5-p h en yl-1-p yr r olin e
1-oxid e (19). Chloro oxime 17 (510 mg, 4.3 mmol) in CH2Cl2
(10 mL) was added dropwise over 2 h to a stirred mixture of
R-methylstyrene (1.016 g, 8.6 mmmol) in CH2Cl2 (20 mL)
containing K2CO3 (0.912 g, 8.6 mmol). Stirring under nitrogen
at room temperature was continued overnight, the solids were
then removed by filtration, and the filtrate was concentrated
under reduced pressure. Compound 18, a colorless solid (215
mg; 25%), was obtained after silica gel column chromatography
(gradient elution: heptane-EtOAc, 30:1 to 2:1).
In a separate experiment in which 3.56 g (30 mmol) of oxime
17 was engaged, Na2CO3 was employed as the base, and the
reaction mixture was stirred at room temperature for 6 days,
compound 18 (847 mg; 14%) and 2-cyano-5-methyl-5-phenyl-
1-pyrroline 1-oxide (19) (1.00 g; 17%) were isolated by silica
gel column chromatography (gradient elution: heptane-
EtOAc, 30:1 to 1:1).
158.30; IR (neat) 1649 and 1663, 3243 cm-1
.
N-(1-Meth ylpen t-4-en yl)h ydr oxyla m in e (24). In a modi-
fication of literature procedure,20 a solution of MeOH-HCl (12
N) (8 mL; 1:1 v/v) was added dropwise over 30 min with
stirring to a cooled (-20 °C) mixture of hex-5-en-2-one oxime
(3.40 g, 30 mmol) and NaBH3CN (2.31 g, 33 mmol) in MeOH
(30 mL) containing bromophenol blue (3 mg) (nitrogen atmo-
sphere). The rate of addition was controlled such that the color
of the reaction mixture remained yellow-yellow-green (pH
3-4). The reaction was then brought slowly to room temper-
ature, and stirring under nitrogen was continued for an
additional 1 h. After basification by the addition of aqueous
KOH (until pH ) 9), the reaction mixture was extracted
successively with Et2O and CH2Cl2. The combined organic
phases were deoxygenated (N2 bubbling) to prevent cycliza-
tion,26 dried over Na2SO4, and concentrated in vacuo, affording
hydroxylamine 24 (3.43 g, 99%) as a white solid in sufficiently
pure form to be employed directly in the next operation. For
analytical purposes the product was column chromatographed
(silica gel; heptane-EtOAc, 1:3; 3.07 g, 89%): Rf 0.34 (hep-
tane-EtOAc, 1:1); mp 39-40 (CH2Cl2-ether); 1H NMR (CDCl3)
Dih yd r ooxa zin e 18: Rf ) 0.46 (heptane-EtOAc, 3:1); mp
1
73-74 °C (heptane-EtOAc); H NMR (CDCl3) δ 1.58 (s, 3H),
1.99 (m, 2H), 2.23-2.54 (m, 2H), 7.31 (m, 5H); 13C NMR
(CDCl3) δ 22.60, 27.73, 29.31, 81.92, 114.3, 124.60, 128.07,
129.15, 136.51, 141.86; IR (neat) 2231, 1575 cm-1; MS (EI, 100
°C) 200 (M•+, 100), 183 (44), 168 (23), 156 (9), 154 (10), 131
(40), 118 (36); HRMS cald for C12H12N2O m/ z 200.0949, found
200.0946. Anal. Calcd for C12H12N2O: C, 71.98; H, 6.04; N,
13.99. Found: C, 71.32; H, 6.07; N, 13.67.
1-P yr r olin e 1-oxid e 19: Rf ) 0.21 (heptane-EtOAc, 3:1);
1
mp 63 °C; Rf 0.21 (hexane-EtOAc, 3:1); H NMR (CDCl3) δ
1.82 (s, 3H), 2.48 (m, 1H), 2.70 (m, 1H), 2.81 (m, 2H), 7.31 (m,
5H); 13C NMR (CDCl3) δ 25.47, 25.74, 35.95, 82.21, 112.04,
125.08, 128.49, 129.01, 139.74; IR (neat) 2219, 1538 cm-1. Anal.
Cald for C12H12N2O: C, 71.98; H, 6.04; N, 13.99. Found: C,
71.85; H, 6.07; N, 13.76.
4-Br om obu tyr oh yd r oxa m ic Acid (21). 4-Bromobutyryl
chloride (10.0 mL, 0.086 mol) in Et2O (50 mL) was added
(26) Doyle, M. P.; Bosch, R. J .; Seites, P. G. J . Org. Chem. 1978, 43,
4120.

Eschenmoser Cycloreversion of Dihydrooxazines
J . Org. Chem., Vol. 62, No. 7, 1997 2103
δ 1.45 (d, J ) 7.5 Hz, 3H), 1.76 (m, 1H), 2.16 (m, 3H), 3.53 (m,
1H), 5.06 (m, 2H), 5.77 (m, 1H), 9.52 (br, 1H); 13C NMR (CDCl3)
δ 14.45, 29.53, 29.67, 57.31, 116.10, 136.53; IR (neat) 2526,
3402 cm-1; MS (EI, 160 °C) 115 (M+, 35.9), 114 (6.4), 101 (100),
83 (5.1), 70 (15.4); HRMS calcd for C6H13NO m/ z 115.0997,
found 115.1007.
6.5 Hz, 3H), 1.52 (m, 1H), 1.76-2.09 (m, 3H), 2.14 (dd, J )
7.3, 14.4 Hz, 2H), 2.44 (m, 2H), 3.38 (m, 1H), 3.94 (dt, J ) 3.2,
10.3 Hz, 1H), 4.07 (dt, J ) 4.0, 11.2 Hz, 1H), 5.00 (d, J ) 7.6
Hz, 1H), 5.08 (dd, J ) 1.6, 17.0 Hz, 1H), 5.81 (m, 1H); 13C NMR
(CDCl3) δ 13.96, 21.33, 30.55, 33.76, 36.68, 54.06, 59.75, 70.37,
113.18, 115.29, 137.96; IR (neat) 2238, 1438 cm-1; MS (CI,
isobutane, 180 °C) 220 (M + H (1.4)), 193 (100), 166 (8.6), 136
(20.7), 84 (5.7); HRMS calcd for C12H18N3O m/ z 220.1451,
found 220.1432. Anal. Calcd for C12H17N3O: C, 65.73; H, 7.81;
N, 19.16. Found: C, 65.26; H, 7.75; N, 18.54.
1-(1-Met h ylp en t -4-en yl)-2-cya n o-1-a za -1,3-b u t a d ien e
(4a ). Triflic anhydride (447 mg, 1.59 mmol) was added
dropwise over 10 min to a cold (-60 °C) solution of (1-
methylpent-4-enyl)-1,2-oxazinan-3-one (26) (223 mg, 1.22 mmol)
in anhydrous CH2Cl2 (10 mL), and the resulting mixture was
stirred for 2 h under nitrogen. A suspension of LiCN (242 mg,
6 equiv) in anhydrous THF (10 mL) containing 12-crown-4 (21
mg, 0.12 mmol) and diisopropylethylamine (410 mg, 3.18
mmol) was then added dropwise over 20 min, and stirring was
continued at -60 °C for 1 h. The reaction mixture was
subsequently warmed to -20 °C over 15 min and stopped by
the addition of H2O (20 mL). The organic layer was removed,
and the aqueous phase was extracted with CH2Cl2. The
combined organic layers were washed with H2O, dried over
Na2SO4, and concentrated without heating. The resulting oil
was flash column chromatographed on silica gel (pentane-
Et2O, 9:1). The less polar component in the product mixture
corresponded to azadiene 4a (colorless volatile liquid; 86 mg;
44%), and the more polar component to oxazinane 30 (20 mg;
8%): Rf 0.70 (heptane-EtOAc, 3:1). Spectral characteristics
of compound 4a are identical to those published earlier (ref
8).
3-Met h yl-1,2,3,7,8,8a -h exa h yd r oin d olizin e-5-ca r b on i-
tr ile (5a ). A solution of azadiene 4a (54 mg, 0.33 mmol) in
2.5 mL of dry degassed toluene in a 10-mL capacity thick-
walled glass tube, equipped with a Rotoflo tap and a magnetic
stirring bar was placed in a beaker filled with vermiculite and
irradiated in a microwave oven for 6 + 8 min (650 W, Philips
microwave oven 900 W).29 After cooling, the solvent was
evaporated and the residue was flash column chromato-
graphed (silica gel; hexane-Et2O, 4:1). Compound 5a was
isolated as an inseparable mixture of diastereoisomers (1:2.2)
(38 mg, 70%):30 Rf 0.73 (heptane-EtOAc, 3:1). Spectral
characteristics of compound 5a are identical to those published
earlier (ref 8).
4-Br om o-N-h yd r oxy-N-(1-m et h ylp en t -4-en yl)b u t yr a -
m id e (25). To hydroxylamine 24 (3.16 g, 27.48 mmol) and
Na2CO3 (8.75 g, 82.5 mmol, 3 equiv) in Et2O-CH2Cl2 (150 mL;
1:1 v/v) was added a solution of 4-bromobutyryl chloride (3.18
mL, 5.10 g, 27.50 mmol) in CH2Cl2 (10 mL) with stirring under
nitrogen at 0 °C. After further stirring for 1 h at room
temperature, the mixture was filtered, and the filtrate was
concentrated under reduced pressure. The residue was column
chromatographed on silica gel (heptane-EtOAc, 1:1). Com-
pound 25 was obtained as a colorless oil (6.56 g, 90%): Rf 0.58
1
(heptane-EtOAc, 1:1); H NMR (CDCl3)28 δ 1.15 (d, J ) 6.4
Hz), 1.29 (d, J ) 6.5 Hz), 1.41 (d, J ) 6.6 Hz), 1.47-1.75 (m,
1H), 1.96-2.22 (m, 5H), 2.49 and 2.67 (m, 2H), 3.47 (t, J )
6.3 Hz), and 3.40-3.84 (m, 2H), 3.99 and 4.38 and 4.56
(m, 1H), 4.98 (m, 2H), 5.76 (m, 1H); 13C NMR (CDCl3) δ 14.38,
17.07, 17.56, 17.76, 18.63, 22.09-33.84 (19 peaks), 50.99,
54.14, 57.95, 59.64, 61.68, 61.89, 79.55 and 80.46, 114.76,
115.59, 116.02, 116.16, 116.32, 136.49, 136.67, 137.00, 137.52,
138.37, 165.75, 173.00, 178.56; IR (neat) 3144, 1631 and 1681,
1444 cm-1; MS (CI, CH4, 180 °C) 266 and 264 (31.3, 65.7), 264
and 262 (65.7, 32.8), 184 (16.4), 178 and 176 (6.7 (6.7)), 168
(25.4), 116 (10.4), 114 and 112 (35.8 (23.9)), 98 and 96 (100
(85.1)); HRMS calcd for C10H19NO2Br m/ z 264.0600, found
264.0613.
2-(1-Meth ylp en t-4-en yl)-1,2-oxa zin a n -3-on e (26). Com-
pound 25 (3.58 g, 13.6 mmol) in CH2Cl2 (20 mL) was adsorbed
onto 15 g of KF/Al2O3,21 and the solvent was removed under
reduced pressure without heating. The resultant mixture was
stirred for 5 h at room temperature. After the adsorbant was
copiously washed with CH2Cl2, the combined washings were
concentrated, giving a colorless volatile oil (2.24 g). Compound
26, a colorless oil (1.57 g; 63%), was obtained after silica gel
flash chromatography (pentane-Et2O gradient): Rf 0.16 (hep-
tane-EtOAc, 3:1); 1H NMR (CDCl3) δ 1.19 (d, J ) 6.7 Hz, 3H),
1.53 (m, 1H), 1.75 (m, 1H), 2.06 (m, 4H), 2.47 (d, J ) 7.3 Hz),
4.02 (m, 2H), 4.57 (m, 1H), 4.96 (ddd, J ) 10.1, 1.7, 1.2 Hz,
1H), 5.02 (ddd, J ) 17.1, 1.7, 1.5 Hz, 1H), 5.81 (m, 1H); 13C
NMR (CDCl3) δ 17.67, 22.52, 28.66, 30.80, 32.75, 50.56, 69.66,
115.00, 138.01, 170.15; IR (neat) 1413, 1450, 1644 cm-1; MS
(CI, isobutane, 170 °C) 184 (M + H (100)), 168 (18.2), 154 (2.8),
116 (21.0), 114 (29.4), 98 (46.2); HRMS calcd for C10H18NO2
m/ z 184.1338, found 184.1342.
1,2-Oxa zin a n e-3-ca r bon itr ile (34). To 5,6-dihydro-4H-
1,2-oxazine (33) (240 mg, 2.8 mmol)22,23 were added TMSCN
(307 mg, 3.1 mmol) and anhydrous ZnBr2 (16 mg, 0.07 mmol),
and the resultant mixture was stirred under nitrogen at room
temperature for 3 h. The reaction was then stopped by the
addition of H2O and extracted with CH2Cl2. The combined
organic phases were dried over Na2SO4 and concentrated. The
residue was column chromatographed on silica gel (heptane-
EtOAc, 3:1). Compound 34 was obtained as a colorless oil (260
mg, 84%): Rf ) 0.17 (heptane-EtOAc, 3:1); 1H NMR (CDCl3)
2-(1-Met h ylp en t -4-en yl)-1,2-oxa zin a n e-3,3-d ica r b on i-
tr ile (30). Triflic anhydride (171 µL, 1.5 equiv) was added
dropwise over 10 min to a cold (-60 °C) solution of 2-(1-
methylpent-4-enyl)-1,2-oxazinan-3-one (26) (124 mg, 0.68 mmol)
in anhydrous CH2Cl2 (5 mL), and the resulting mixture was
stirred for 1.5 h (nitrogen atmosphere). A suspension of LiCN
(112 mg, 5 equiv; predried for 2 h at 80 °C in vacuo) in
anhydrous THF (3 mL) containing 12-crown-4 (12 mg, 11 µL,
0.1 equiv) was then added, and stirring was continued at -60
°C for 1 h. After this period diisopropylethylamine (355 µl,
2.04 mmol, 3 equiv) was added, and the reaction was subse-
quently warmed to -20 °C over 15 min before the addition of
H2O (5 mL). The organic layer was removed and the aqueous
phase extracted with CH2Cl2. The combined organic layers
were washed with H2O, dried over Na2SO4, and concentrated.
Oxazinane 30 was obtained as a yellow oil (52 mg, 35%) after
silica gel flash column purification (pentane-Et2O, 4:1): Rf
δ 2.06 (m, 4H), 3.90 (m, 1H), 4.03 (m, 2H), 5.06 (br s, 1H); 13
C
NMR (CDCl3) δ 22.03, 26.53, 48.55, 70.28, 118.71; IR (neat)
3297, 2938, 2235, 1680, 1638, 1441 cm-1; MS (EI, 150 °C) 112
(M•+, 100), 111 (5.0), 100 (3.9), 97 (11.1), 86 (19.0), 81 (12.4),
80 (32.0); HRMS calcd for C5H8N2O m/ z 112.0637, found
112.0632. Anal. Calcd for C5H8N2O: C, 53.56; H, 7.19; N,
24.98. Found: C, 53.41; H, 6.93; N, 24.99.
5,6-Dih yd r o-4H-1,2-oxa zin e-3-ca r bon itr ile (12). To a
solution of 1,2-oxazinane-3-carbonitrile (34) (230 mg, 2.05
mmol) in CH2Cl2 (10 mL) was added a solution of Pb(OAc)4
(1.00 g, 2.25 mmol) in CH2Cl2 (10 mL). The mixture was
stirred for 1 h at room temperature, pentane (30 mL) was
added, and the mixture was filtered through a short Celite
pad. The solvent was evaporated, and the oily residue was
1
0.56 (heptane-EtOAc, 3:1); H NMR (CDCl3) δ 1.31 (d, J )
(27) In the presence of air, hydroxylamine 24 readily cyclizes to 2,5-
dimethyl-N-hydroxypyrrolidine; see ref 20 and the following: (a)
Oppolzer, W.; Siles, S.; Snowden, L.; Baker, B. H.; Petrzilka, M.
Tetrahedron, 1985, 41, 3497. (b) House, H. O.; Manning, D. T.; Mellio,
D. G.; Lee, L. F.; Haynes, O. R.; Wilkes, B. E. J . Org. Chem. 1976, 41,
855.
(28) Note that multiple signals are observed for the same hydrogens/
carbons in the 1H/13C NMR spectra for compound 25. This is ascribed
to both amide rotamers and the presence of H-bonded species in the
sample analyzed.
(29) CAUTION: As the internal pressure increases in the closed
tube upon heating, the cycloaddition reaction should be carried out in
an isolated fume cupboard and behind a protective screen. Open only
after cooling the tube to room temperature.
(30) Separation of the diastereoisomers may be achieved by HPLC.
For conditions, see ref 8.

2104 J . Org. Chem., Vol. 62, No. 7, 1997
Motorina et al.
flash chromatographed on silica gel (pentane-Et2O, 4:1). 5,6-
Dihydro-4H-1,2-oxazine-3-carbonitrile (12) was isolated as a
colorless oil (158 mg, 70%): Rf ) 0.55 (heptane-EtOAc, 1:1);
1H NMR (CDCl3) δ 2.04 (m, 2H), 2.42 (t, J ) 6.7 Hz, 2H), 4.18
(t, J ) 5.3 Hz, 2H); 13C NMR (CDCl3) δ 17.17, 23.17, 67.90,
114.49, 137.00; IR (neat) 2945, 1882, 2235, 1567, 1448, 1173,
1026 cm-1; MS (EI, 150 °C) 110 (M•+, 31.4), 101 (3.3), 97 (9.2),
80 (21.6), 69 (22.5), 65 (13.1), 57 (22.2), 55 (19.6), 53 (100);
HRMS calcd for C5H6N2O m/ z 110.0480, found 110.0484.
Anal. Calcd for C5H6N2O: C, 54.54; H, 5.49. Found: C, 54.31;
H, 5.57.
cm-1. Anal. Calcd for C11H13Br: C, 58.69; H, 5.82. Found:
C, 58.64; H, 5.81.
1-Eth yl-2-cya n o-1-a za -1,3-bu ta d ien e (38a ). P r oced u r e
1. To a solution of 12 (58 mg, 0.53 mmol) in dry CH2Cl2 (5
mL) at -60 °C under nitrogen was added triethyloxonium
tetrafluoroborate (200 mg, 1.06 mmol). The mixture was
brought to room temperature and stirred for 2 h before
recooling to -60 °C and addition of Et3N (107 mg, 1.06 mmol).
The solution was then concentrated without heating, and the
residue was flash column chromatographed on silica gel
(pentane). Azadiene 38a was obtained as a colorless volatile
liquid (41 mg, 71%), which quickly decomposed at room
temperature (1-2 h).
P r oced u r e 2. To a solution of 12 (68 mg, 0.62 mmol) in
dry CH2Cl2 (2 mL) at room temperature under nitrogen were
added ethyl bromide (202 mg, 1.85 mmol) and AgBF4 (360 mg,
1.85 mmol). The mixture was stirred for 10 min at room
temperature and at 40 °C for an additional 5 min. The
reaction mixture was then cooled to -60 °C, and Et3N (187
mg, 1.85 mmol) was added. The mixture was concentrated
without heating, and subsequent flash column chromatogra-
phy on silica gel (pentane-Et2O, 4:1) provided azadiene 38a
(19 mg, 29%) plus recovered 12 (34 mg, 50%).
(1-Br om o-p en t-4-en yl)ben zen e (37). Potassium hydride
(6.7 g, 30% suspension in mineral oil, 50 mmol), in a round
bottom flask flushed with nitrogen, was washed with dry THF
(3 × 40 mL). THF (100 mL) was then added, followed, after
cooling to 0 °C, by slow addition of acetophenone (5.71 g, 47.6
mmol in 20 mL of THF). The mixture was stirred for 20 min
at room temperature before addition of triethylborane (59.5
mL of 1 M solution in THF; 59.5 mmol) in several portions.
After the mixture was stirred for a further 20 min, allyl
bromide (8.64 g, 71.4 mmol) was added, and the mixture was
stirred for 4 h. A 1:1 mixture of 30% H2O2 and 30% NaOH
(50 mL) was then added dropwise with cooling in an ice bath.
The reaction mixture was diluted with H2O, and the organic
fraction was separated and washed with water. The aqueous
fractions were subsequently extracted with CH2Cl2, and the
combined organic fractions were dried over Na2SO4, concen-
trated, and distilled in vacuo. 1-Phenylpent-4-en-1-one31 (6.03
g, 79%) was obtained as a colorless liquid: bp 65-78 °C/2
mmHg; Rf 0.76 (heptane-ethyl acetate, 3:1); 1H NMR (CDCl3)
δ 2.50 (dd, J ) 7.0, 14.3 Hz, 2H), 3.08 (t, J ) 7.4 Hz, 2H), 5.01
(dd, J ) 1.2, 10.1 Hz, 1H), 5.09 (dd, J ) 1.6, 17.2 Hz, 1H),
5.91 (m, 1H), 7.46 (t, J ) 7.8 Hz, 2H), 7.56 (t, J ) 7.3 Hz, 1H),
7.97 (d, J ) 7.1 Hz, 2H); 13C NMR (CDCl3) δ 28.14, 37.72,
115.26, 128.01, 128.28, 128.58, 132.98, 137.30, 199.35; IR
(neat): 3529, 3353, 3072, 2924, 1688, 1645, 1588, 1448, 1363,
1265, 1209 cm-1; MS (CI, isobutane, 180 °C) 161 (M + H), 145,
121, 105. Anal. Calcd for C11H12O: C, 82.46; H, 7.55.
Found: C, 82.21; H, 7.81.
Com p ou n d 38a : Rf ) 0.74 (heptane-EtOAc, 1:1); 1H NMR
(CDCl3) δ 1.35 (t, J ) 7.3 Hz, 3H), 3.89 (q, J ) 7.3 Hz, 2H),
5.99 (d, J ) 10.5 Hz, 1H), 6.17 (d, J ) 17.6 Hz, 1H), 6.58 (dd,
J ) 10.5, 17.6 Hz, 1H); 13C NMR (CDCl3) δ 15.45, 53.39,
127.84, 134.92, 142.31; IR (neat) 2931, 2225, 1631, 1456, 1375
cm-1
.
1-Ben zyl-2-cya n o-1-a za -1,3-bu ta d ien e (38b). To a solu-
tion of 12 (46 mg, 0.42 mmol) in dry CH2Cl2 (5 mL) at room
temperature under nitrogen were added benzyl bromide (79
mg, 0.46 mmol) and AgBF4 (90 mg, 0.46 mmol). The mixture
was stirred for 2 h at room temperature and then for an
additional 5 min at 40 °C before cooling to -60 °C and addition
of Et3N (46 mg, 0.46 mmol). The reaction mixture was
concentrated without heating, and the residue was flash
column chromatographed on silica gel (pentane-Et2O, 4:1).
1-Benzyl-2-cyano-1-aza-1,3-butadiene (38b) was obtained as
a colorless liquid (51 mg, 72%): Rf ) 0.73 (heptane-EtOAc,
1:1); 1H NMR (CDCl3) δ 5.02 (s, 2H), 6.01 (d, J ) 10.5 Hz,
1H), 6.22 (d, J ) 17.6 Hz, 1H), 6.63 (dd, J ) 10.5, 17.6 Hz,
1H); 13C NMR (CDCl3) δ 62.60, 108.87, 127.80, 128.24, 128.66,
128.89, 134.92, 137.24, 143.07; IR (neat) 2225, 1625, 1588,
1494, 1456 cm-1; MS (EI, <150 °C) 170 (M•+), 169, 155, 142,
115, 107, 104, 92, 91, 77; HRMS calcd for C11H10N2 m/ z
170.0844, found 170.0835.
To a solution of 1-phenylpent-4-en-1-one (4.00 g, 25 mmol)
in methanol (50 mL) at 0 °C under nitrogen was added NaBH4
(1.43 g, 37.5 mmol) in portions over 30 min. The reaction
mixture was stirred for an additional 1 h at 0 °C and 3 h at
room temperature. The mixture was then cooled to 0 °C, and
the excess reducing agent was destroyed by slowly adding
water (30 mL). Following extraction with ether and CH2Cl2,
the combined organic fractions were dried over Na2SO4 and
concentrated. 1-Phenylpent-4-en-1-ol (2.90 g, 72%) was ob-
tained as a colorless liquid after column chromatography on
silica (heptane-ethyl acetate, 5:1): Rf 0.53 (heptane-ethyl
1-(1-P h en ylp en t -4-en yl)-2-cya n o-1-a za -1,3-b u t a d ien e
(38c) a n d 2-(1-P h en ylp en t-4-en yl)-1,2-oxa zin a n -3-on e. To
a solution of 12 (108 mg, 0.98 mmol) in dry CH2Cl2 (5 mL) at
room temperature under nitrogen was added (1-bromopent-
4-enyl)benzene (37) (265 mg, 1.18 mmol) and AgBF4 (230 mg,
1.18 mmol). The mixture was stirred for 0.5 h at room
temperature and then for an additional 3-5 min at 40 °C
before cooling to -60 °C and addition of Et3N (119 mg, 1.18
mmol). The solution was concentrated without heating and
the resulting azadiene separated by flash column chromatog-
raphy on silica gel (gradient pentane f pentane:ether, 1:1).
1-(1-Phenylpent-4-enyl)-2-cyano-1-aza-1,3-butadiene (38c) (146
mg, 67%) was obtained as a pale yellow liquid along with 2-(1-
phenylpent-4-enyl)-1,2-oxazinan-3-one (9 mg, 4%).
1
acetate, 3:1); H NMR (CDCl3) δ 1.83 (m, 2H), 2.12 (m, 2H),
2.23 (d, J ) 3.0 Hz, 1H), 4.64 (dt, J ) 2.8, 6.5 Hz, 1H), 5.01
(m, 2H), 5.82 (m, 1H), 7.31 (m, 5H); 13C NMR (CDCl3) δ 26.99,
38.11, 74.02, 114.99, 125.96, 127.59, 128.50, 138.25, 144.71;
IR (neat) 3374, 2938, 1638, 1497, 1462, 1061, 913 cm-1; MS
(CI, isobutane, 170 °C) 163, 147, 145, 130; HRMS (CI,
isobutane, 170 °C) calcd for C11H15O (M + H) m/ z 163.1123,
found 163.1097.
PPh3 (3.90 g, 14.9 mmol) was added in portions over 10 min
to a solution of CBr4 (4.93 g, 14.9 mmol) and 1-phenylpent-4-
en-1-ol (2.19 g, 13.5 mmol) in dry ether (50 mL) at 0 °C under
nitrogen.32 The mixture was stirred for 20 min at 0 °C and
for an additional 0.5 h at room temperature. The mixture was
then diluted with pentane (100 mL), the white precipitate was
filtered off, and the solution was concentrated under reduced
pressure without heating. (1-Bromopent-4-enyl)benzene (37)
(2.91 g, 96%) was obtained as a colorless liquid after distillation
in vacuo: bp 47 °C/2 mmHg; Rf 0.70 (heptane-ethyl acetate,
3:1); 1H NMR (CDCl3) δ 2.10-2.24 (m, 3H), 2.36 (m, 1H), 4.95
(dd, J ) 6.0, 8.2 Hz, 1H), 5.01 (d, J ) 1.7 Hz, 1H, 5.06 (dd, J
) 1.2, 10.3 Hz, 1H), 5.77 (m, 1H), 7.26-7.41 (m, 5H); 13C NMR
(CDCl3) δ 32.25, 39.01, 54.86, 116.05, 127.39, 128.42, 128.78,
136.72, 142.07; IR (neat): 3072, 2938, 1638, 1497, 1455, 920
1
Com p ou n d 38c: Rf 0.83 (heptane-ethyl acetate, 3:1); H
NMR (CDCl3) δ 2.03 (m, 4H), 4.87 (t, J ) 5.6 Hz, 1H), 4.98 (s,
1H), 5.05 (d, J ) 7.0 Hz, 1H), 5.81 (m, 1H), 5.98 (d, J ) 10.5
Hz, 1H), 6.25 (d, J ) 17.5 Hz, 1H), 6.62 (dd, J ) 10.5, 17.6
Hz, 1H), 7.25-7.42 (m, 5H); 13C NMR (CDCl3) δ (major isomer)
30.44, 37.49, 72.52, 108.96, 115.56, 127.35, 127.87, 128.23,
128.83, 134.99, 137.38, 141.81, 141.52; (minor isomer) 29.80,
35.52, 75.59, 115.32, 126.63, 126.78, 128.55, 141.51; IR
(neat): 3072, 2924, 2221, 1736, 1645, 1588, 1455, 1251 cm-1
;
MS (CI, isobutane, 170 °C) 225 (M + H), 145; HRMS (CI,
isobutane, 170 °C) calcd for C15H17N2 (M + H) m/ z 225.1392,
found 225.1378.
2-(1-P h en ylp en t-4-en yl)-1,2-oxa zin a n -3-on e: yellow liq-
1
uid; Rf 0.38 (heptane-ethyl acetate, 1:1); H NMR (CDCl3) δ
(31) Negishi, E. Tetrahedron Lett. 1979, N10, 845.
(32) Hooz, J .; Gilani, S. S. H. Can. J . Chem. 1968, 46, 86.
2.07 (m, 6H), 2.48 (m, 2H), 3.68 (m, 1H), 3.87 (m, 1H), 5.03

Eschenmoser Cycloreversion of Dihydrooxazines
J . Org. Chem., Vol. 62, No. 7, 1997 2105
(m, 1H), 5.56 (m, 1H), 5.84 (m, 1H), 7.28-7.41 (m, 5H); 13C
NMR (CDCl3) δ 22.34, 28.69, 30.15, 30.75, 57.44, 69.70, 115.41,
127.85, 127.98, 128.52, 137.60, 139.27, 170.23; IR (neat) 2931,
1666, 1406 cm-1; MS (CI, isobutane, 170 °C) 246 (M + H), 216,
176; HRMS (CI, isobutane, 170 °C) calcd for C15H20NO2 (M +
H) m/ z 246.1494, found 246.1486.
mg, 30%) was separated from residual starting material and
decomposition products by preparative layer chromatography
on silica gel (heptane-EtOAc, 3:1): Rf 0.60 (heptane-AcOEt,
3:1); 1H NMR (CDCl3) δ 1.74 (d, J ) 7.3 Hz, 3H), 2.29 (m, 2H),
2.87 (m, 2H), 5.03 (m, 2H), 5.81 (m, 1H), 6.03 (q, J ) 7.1 Hz,
1H), 7.37 (m, 4H), 7.86 (m, 1H); IR (neat) 2931, 2225, 1644,
1606, 1450, 1413 cm-1; MS (CI, isobutane, 160 °C: 225, 216,
161, 145, 73.
3-P h en yl-1,2,3,7,8,8a -h exa h yd r oin d olizid in e-5-ca r b o-
n itr ile (40). 1-(1-Phenyl-pent-4-enyl)-2-cyano-1-aza-1,3-buta-
diene (38c) (10 mg, 0.04 mmol) in frozen benzene (0.5 mL) was
flash vacuum thermolyzed at 470 °C according to ref 25.
3-Phenyl-1,2,3,7,8,8a-hexahydroindolizidine-5-carbonitrile (40)
(6 mg, 60%) was obtained as a yellow oil after preparative TLC
on silica gel (heptane-EtOAc, 3:1) (3:1 mixture of dia-
stereomeres): Rf 0.59 (heptane-AcOEt, 3:1); 1H NMR (CDCl3),
δ: 1.68-2.42 (m, 8H), 2.70 and 3.18 (m, 1H), 4.57 and 4.77
(m, 1H), 5.01 (m, 1H), 7.29 (m, 5H); 13C NMR (CDCl3) δ 26.24,
27.38, 29.84, 30.82, 34.41, 34.83, 37.43, 57.97, 72.67, 115.51,
126.38, 127.25, 127.77, 128.56, 128.77, 137.49; IR (neat) 2925,
2219, 1613, 1450, 1269 cm-1; MS (CI, isobutane, 160 °C) 225,
145, 73.
1-P en t-4-en yl-2-cya n o-1-a za -1,3-bu ta d ien e (38d ). To a
solution of 5,6-dihydro-4H-1,2-oxazine-3-carbonitrile (12) (68
mg, 0.62 mmol) in dry CH2Cl2 (5 mL) at room temperature
under nitrogen was added 1-bromopent-4-ene (101 mg, 0.68
mmol) and AgBF4 (132 mg, 0.68 mmol). The mixture was
stirred for 3.5 h at room temperature and then for an
additional 10 min at 40 °C. The reaction mixture was then
cooled to -50 °C, and triethylamine (69 mg, 0.68 mmol) was
added. The solvent was evaporated under reduced pressure
without heating, and the residue was flash column chromato-
graphed on silica gel (pentane-Et2O, 4:1). Compound 38d was
obtained as a volatile colorless liquid (6 mg, 6%, recovered
starting material 48 mg, 71%): 1H NMR (CDCl3) δ 1.60-1.91
(m, 2H), 2.14 (m, 2H), 3.86 (t, J ) 6.9 Hz, 1H), 4.18 (m, 1H),
5.12 (m, 2H), 5.84 (m, 1H), 5.99 (dd, J ) 2.2, 10.5 Hz, 1H),
6.18 (dd, J ) 4.2, 17.6 Hz, 1H), 6.58 (ddd, J ) 4.9, 10.5, 17.5
Hz, 1H); IR (neat) 2931, 2221, 1659, 1462 cm-1; MS (CI,
isobutane, 150 °C): 149 (M + H), 122; HRMS (CI, isobutane,
170 °C) calcd for C9H13N2 (M + H) m/ z 149.1079, found
149.1072.
1-(1-Met h ylp en t -4-en yl)-2-cya n o-1-a za -1,3-b u t a d ien e
(4a ). As described for 38a , alkylation of 5,6-dihydro-4H-1,2-
oxazine-3-carbonitrile (12) with 2-bromohex-5-ene (rt, 3 h)
produced azadiene 4a (8%) plus recovered starting material
(68%).
1-P h en yl-1-bu t-3-en yl-3-cyan o-2-aza-1,3-pen tadien e (39).
1-(1-Phenylpent-4-enyl)-2-cyano-1-aza-1,3-butadiene (38c) (6
mg, 0.03 mmol) in frozen benzene (0.5 mL) was flash vacuum
thermolyzed at 400 °C according to ref 25. 2-Azadiene 39 (2
Ack n ow led gm en t. A Postdoctoral fellowship from
the Ministe`re de la Recherche et de la Technologie for
Dr. Motorina is gratefully acknowledged.
Su p p or tin g In for m a tion Ava ila ble: NMR spectral data
(56 pages). ORTEP drawing and X-ray experimental data for
19 (5 pages; see ref 17). This material is contained in libraries
on microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
J O9614046