Radical Chain Reactions of α-Azido-β-keto Esters with Tributyltin Hydride. a Novel Entry to Amides and Lactams through Regiospecific Nitrogen Insertion

Article abstract of DOI:10.1021/jo990837g

A variety of acyclic and carbocyclic α-azido-β-keto esters have been readily prepared from the parent dicarbonyl compounds, and their radical chain reactions with tributyltin hydride have been investigated. These reactions normally result in efficient production of alkoxycarbonyl-substituted amides and lactams and thence provide a new, useful method for regiospecific nitrogen insertion of keto ester compounds. The likely mechanism entails initial addition of tributylstannyl radical to the azido moiety to give a stannylaminyl radical, which readily undergoes intramolecular three-membered cyclization onto the ketone group to form an alkoxyl radical. The alkoxyl radical then undergoes regiospecific β-scission to form a stable ring-opened radical that is eventually reduced by tributyltin hydride to propagate the chain. With certain substrates, concomitant deazidation occurs to an important extent. This process, which is unusually observed in radical reactions of alkyl azides, is ascribed to addition of the stannyl radical to the terminal azido nitrogen; subsequent fragmentation of the ensuing 1,3-triazenyl adduct gives stannyl azide and a deazidated alkyl radical, resonance-stabilized by the adjacent carbonyl groups. The radical reactions of 2-azido-2-(ethoxycarbonyl)-1-tetralone with allyltributylstannane and allyltriphenylstannane have also been investigated with the (missed) aim to achieve nitrogen insertion and concomitant allylation.

Full text of DOI:10.1021/jo990837g

7
836
J . Org. Chem. 1999, 64, 7836-7841
Ra d ica l Ch a in Rea ction s of r-Azid o-â-k eto Ester s w ith Tr ibu tyltin
Hyd r id e. A Novel En tr y to Am id es a n d La cta m s th r ou gh
Regiosp ecific Nitr ogen In ser tion
Luisa Benati,* Daniele Nanni, Corrado Sangiorgi, and Piero Spagnolo
Dipartimento di Chimica Organica “A. Mangini”, Universit a` di Bologna, Viale Risorgimento 4,
I-40136 Bologna, Italy
Received May 21, 1999
A variety of acyclic and carbocyclic R-azido-â-keto esters have been readily prepared from the parent
dicarbonyl compounds, and their radical chain reactions with tributyltin hydride have been
investigated. These reactions normally result in efficient production of alkoxycarbonyl-substituted
amides and lactams and thence provide a new, useful method for regiospecific nitrogen insertion
of keto ester compounds. The likely mechanism entails initial addition of tributylstannyl radical
to the azido moiety to give a stannylaminyl radical, which readily undergoes intramolecular three-
membered cyclization onto the ketone group to form an alkoxyl radical. The alkoxyl radical then
undergoes regiospecific â-scission to form a stable ring-opened radical that is eventually reduced
by tributyltin hydride to propagate the chain. With certain substrates, concomitant deazidation
occurs to an important extent. This process, which is unusually observed in radical reactions of
alkyl azides, is ascribed to addition of the stannyl radical to the terminal azido nitrogen; subsequent
fragmentation of the ensuing 1,3-triazenyl adduct gives stannyl azide and a deazidated alkyl radical,
resonance-stabilized by the adjacent carbonyl groups. The radical reactions of 2-azido-2-(ethoxy-
carbonyl)-l-tetralone with allyltributylstannane and allyltriphenylstannane have also been inves-
tigated with the (missed) aim to achieve nitrogen insertion and concomitant allylation.
In tr od u ction
Organic azides are important intermediates that have
Sch em e 1
found extensive use in the production of a great variety
of acyclic and, especially, heterocyclic nitrogen-containing
compounds. The utility of these versatile intermediates
stands from their fair capability of reacting with both
electrophilic and nucleophilic species, additionally acting
as 1,3-dipoles in cycloaddition reactions as well as
affording reactive nitrenes under thermal and photo-
chemical conditions.1 Synthetic applications of azides
under radical conditions are much less documented;
though, since the pioneering reports by Horner and Bauer
The reported studies have revealed that carbon-
centered radicals normally exhibit a modest reactivity
towards azides and thence their intermolecular reactions
have so far attracted only limited interest. However,
2
3
in 1966 and Leffler and Gibson in 1968, it has been
demonstrated that the azido moiety can act, to a varying
degree, as a radical acceptor toward carbon- and het-
eroatom-centered species. The azido group, in fact, can
6
7
recent intramolecular additions of aryl, thiocarbonyl,
8
9
alkyl, and vinyl radicals to alkyl and/or aryl azides were
found to give smoothly cyclic aminyl radicals and there-
fore these reactions show good promise for the synthesis
of N-heterocycles. As far as heteroatom-centered radicals,
silyl and, especially, stannyl radicals are virtually the
only species hitherto investigated. Triorganosilyl radicals
were originally reported in 197910 to react with a variety
of azides and display EPR spectra best ascribable to 1,3-
triazenyl adducts, but the synthetic potential of these
radical reactions has since remained unexplored. More
recently, tributylstannyl radicals were found to add
a
undergo homolytic addition at either the inner (N ) or
c
the terminal (N ) nitrogen, to give a 3,3-triazenyl radical
1
or a 1,3-triazenyl radical 2, respectively; however, it is
often not clear to which end addition occurs because
aminyl radicals 3, which are often subsequently formed
by loss of nitrogen, might plausibly arise from either
4
,5
initial triazenyl adduct (Scheme 1).
(1) For leading information concerning the chemistry of azides and
nitrenes, see (a) The Chemistry of The Azido Group; Patai, S., Ed.;
Wiley Interscience: New York, 1971. (b) Azides and Nitrenes-Reactivity
and Utility; Scriven, E. F. V., Ed.; Academic Press: New York, 1984.
(6) Benati, L.; Montevecchi, P. C.; Spagnolo, P. Tetrahedron Lett.
1978, 815.
(c) Scriven, E. F. V.; Turnbull, K. Chem. Rev. 1988, 88, 297.
(
2) Homer, L.; Bauer, G. Tetrahedron Lett. 1966, 3573.
(7) Benati, L.; Montevecchi, P. C. J . Org. Chem. 1981, 46, 4570.
(8) Kim, S.; J oe, G. H.; Do, J . Y. J . Am. Chem. Soc. 1994, 116, 5521.
(9) Montevecchi, P. C.; Navacchia, M. L.; Spagnolo, P. Eur. J . Org.
Chem. 1998, 1219.
(10) Roberts, B. P.; Winter, J . N. J . Chem. Soc., Perkin Trans. 2
1979, 1353.
(3) Leffler, J . E.; Gibson, H. H., J r. J . Am. Chem. Soc. 1968, 90,
4
1
117.
(
(
4) Abramovitch, R. A.; Kyba, E. P. in ref la, Ch. 5.
5) Roberts, B. P.; Dang, H.-S. J . Chem. Soc., Perkin Trans. 1 1996,
493.
1
0.1021/jo990837g CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/23/1999

Radical Chain Reactions of R-Azido-â-keto Esters
J . Org. Chem., Vol. 64, No. 21, 1999 7837
Sch em e 2
readily to alkyl and acyl azides to give the corresponding
N-stannylaminyl radicals, which could usefully be re-
duced to amines1 or rearranged imines. Similar addi-
tions of triorganostannyl radicals to arenesulfonyl azides
also proved to be synthetically appealing, since they could
provide a novel entry to N-allylarenesulfonamides through
allylation of the derived N-stannylsulfonamidyl radicals.5
A further important application of the reactivity of azides
with stannyl radicals has been uncovered by the very
recent work of Kim and co-workers.13 These authors first
found that (tributylstannyl)aminyl radicals, generated
from appropriate azido aldehydes and azido ketones, are
highly capable of performing intramolecular five- and six-
membered cyclization onto the carbonyl group to give
amides by â-fragmentation of ensuing alkoxyl radicals.
Such findings allowed to devise a ready access to rather
inaccessible medium-sized lactams using available ethyl
and propyl azides tethered to cyclic ketones and keto
esters (Scheme 2).
In the course of our previous study of diazo and azido
transfer reactions of sulfonyl azides with carbocyclic
â-keto esters14 we realized that the R-azido derivatives
of â-keto esters, though in principle readily available,
were surprisingly scarcely explored. Our joint interest
in the chemistry of azido and radical species6,7,9,14-16 thus
led us to undertake a study of the radical chain reactions
of that type of aliphatic azide with tributyltin hydride.
In light of the previously mentioned findings of Kim,13
we aimed at developing a new method for regiospecific
nitrogen insertion of â-keto ester compounds. Herein we
report our results with the acyclic and carbocyclic keto
ester azides shown in Figure 1.
1
12
F igu r e 1.
produced from the hydroxynaphthoate 10. Neverthe-
less, this method was not practicable for the production
of the bicyclic azide 13 from the camphor derivative 12
since in this case the obtained 2-endo-bromide proved
highly reluctant to undergo displacement by azide ion.
However, the azide 13, which had been previously
prepared in low yield by direct azidation of 12 with tosyl
azide in tetrahydrofuran,1 was presently obtained in
satisfactory yield by using 2,4,6-tri-iso-propylbenzene-
sulfonyl (trisyl) azide in acetonitrile. Trisyl azide is in
fact superior to tosyl and other sulfonyl congeners in
performing azidation of cyclic keto esters at the expense
of diazotization.1
All reactions between our azides and tributyltin hy-
dride (1.1 equiv) were carried out in refluxing benzene,
under a nitrogen atmosphere, and were initiated by
thermal decomposition of 2,2′-azobis(2-methylpropio-
nitrile) (AIBN, 0.1 equiv). The reactions were normally
prolonged for ca. 2-6 h, and the crude mixtures were
then directly subjected to column chromatography (Fig-
ure 2 and Table 1).
4a
4c
Resu lts a n d Discu ssion
The monocyclic azides 5a -d , as well as the benzocyclic
ones 7a -c, were easily produced through R-bromination
of the parent compounds 4a -d and 6a -c and subsequent
displacement of halide with azide ion, by using a proce-
dure analogous to that we had previously employed to
prepare the azidopropionates 8a ,9a from the propionates
The monocyclic five-, six-, and eight-membered com-
pounds 5a ,b,d , as well as the bicyclic one 13, yielded the
aimed ring-expanded lactams 14a ,b,d and 15, respec-
tively, as the only identifiable products, whereas the
seven-membered analog 5c, besides lactam 14c, also
afforded a significant amount of the corresponding amine
(Figure 2 and Table 1, entries 1-5). The azonin-2-one
l4c
8
b,9b. The azido-2-tetralone 11 was also similarly
(11) Redlich, H.; Roy, W. Liebigs Ann. Chem. 1981, 1215. Samano,
M. C.; Robins, M. J . Tetrahedron Lett. 1991, 32, 6293. Poopeiko, N.
E.; Pricota, T. I.; Mikhailopulo, I. A. Synlett 1991, 342. Hays, S. D.;
Fu, G. C. J . Org. Chem. 1998, 63, 2796.
(
(
12) Kim, S.; Do, J . Y. J . Chem. Soc., Chem. Commun. 1995, 1607.
13) (13) Kim, S.; J oe, G. H.; Do, J . Y. J . Am. Chem. Soc. 1993, 115,
1
4d was obtained as an equilibrium mixture of (Z)- and
3
5
328; Kim, S.; Yoon, K. S.; Kim, S. S.; Seo, H. S. Tetrahedron 1995,
1, 8437.
1
7
(
E)-amides in a 1:1 ratio at room temperature. This was
1
3
(14) (a) Benati, L.; Nanni, D.; Spagnolo, P. J . Chem. Soc., Perkin
particularly apparent in the C NMR spectrum, which
exhibited a duplicate set of signals. The 3-azalactam 15
was obtained as a mixture of the 2-endo and 2-exo
Trans. 1 1997, 457. (b) Benati, L.; Calestani, G.; Nanni, D.; Spagnolo,
P. J Org. Chem. 1998, 63, 4679. (c) Benati, L.; Nanni, D.; Spagnolo, P.
J . Org. Chem. 1999, 64, 5132.
(
15) Montevecchi, P. C.; Navacchia, M. L.; Spagnolo, P. J . Org.
Chem. 1997, 62, 5846.
16) Leardini, R.; Nanni, D.; Pareschi, P.; Tundo, A.; Zanardi, G. J .
isomers in a 60:40 ratio. Stereochemical assignment to
these isomers was based on 1H NMR analysis, which
(
Org. Chem. 1997, 62, 8394. Camaggi, C. M.; Leardini, R.; Nanni, D.;
Zanardi, G. Tetrahedron 1998, 54, 5587. Leardini, R.; McNab, H.;
Nanni, D.; Parsons, S.; Reed, D.; Tenan, A. G. J . Chem. Soc., Perkin
Trans. 1 1998, 1833.
(17) Evans, P. A.; Holmes, A. B.; McGeary, R. P.; Nadin, A.; Russell,
K.; O’Hanlon, P. J .; Pearson, N. D. J . Chem. Soc., Perkin Trans. 1 1996,
123.

7
838 J . Org. Chem., Vol. 64, No. 21, 1999
Benati et al.
Sch em e 3
F igu r e 2.
Ta ble 1. Yield of P r od u cts fr om th e Ra d ica l Ch a in
Rea ction s of â-Keto Ester Azid es 5a -d , 7a -c, 8a , 9a , 11,
a
a n d 13 w ith Bu 3Sn H
yield (%)b
keto ester
azide
deazidated
keto ester
entry
amide
amine
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
13
7a
7b
7c
14a (70)
14b (81)
14c (65)
14d (72)
5c, R ) NH2 (18)
7a , R ) NH2 (34)
c
Finally, the acyclic azidopropionates 8a ,9a , similar to
their monocyclic and bicyclic counterparts, were ef-
ficiently converted into the amides 18,19, which could
be isolated in fairly high yield. The azidopropionate 9a ,
however, also suffered minor deazidation to give 9b
(Figure 2 and Table 1, entries 11, 12).
d
15 (72)
16a (46)
16b (68)
16c (20)
16c (28)
17 (15)
6b (27)
6c (12)
6e (12)
10 (55)
7c, R ) NH2 (23)
7c, R ) NH2 (28)
11, N3 ) NH2 (7)
e
7c
1
1
1
0
1
2
11
8a
9a
18 (80)
19 (75)
Our overall results, summarized in Table 1, indicate
that the radical chain reactions of Bu SnH with the
3
9b (17)
a
Reactions were normally carried out in refluxing benzene by
treating each azide with Bu3SnH (1.1 equiv) in the presence of
AIBN (0.1 equiv). Isolated by column chromatography. Mixture
of cis and trans isomers in ca. 1:1 ratio in CDCl3. Mixture of the
endo and exo isomers in ca. 60:40 ratio. Slow treatment with
Bu3SnH using a syringe pump.
R-azides of â-keto esters can offer a practicable tool for
the regiospecific production of alkoxycarbonyl-substituted
amides and lactams. The successful outcome of these
nitrogen compounds is reasonably explained on the basis
of the mechanism outlined in Scheme 3, which is related
b
c
d
e
1
3
to that previously suggested by Kim and co-workers to
explain their radical production of medium-ring lactams
(Scheme 2). The proposed mechanism entails intramo-
lecular 3-exo cyclization of derived (tributylstannyl)-
aminyl radical A onto the adjacent ketone group to yield
an alkoxyl radical B. The alkoxyl radical undergoes a
regiospecific â-scission to give the ring-opened radical C,
revealed the minor component to exhibit a relative
deshielding of both bridgehead methyl groups, plausibly
due to anisotropic deshielding effect of the 2-exo meth-
oxycarbonyl substituent.
The benzocyclic 1-tetralone azide 7b similarly fur-
nished a satisfactory yield of the desired benzo-fused
lactam 16b, but it concomitantly furnished the deazi-
dated tetralone 6b to an important extent (Figure 2 and
Table 1, entry 7). However, the l-indanone azide 7a and,
particularly, the l-benzosuberone and dehydro-2-tetralone
azides 7c and 11 were less rewarding. The azide 7a , in
fact, exhibited a rather modest, though still useful, yield
of the corresponding benzocyclic lactam 16a because of
remarkable reduction to amine (Figure 2 and Table 1,
entry 6). Moreover, the azides 7c and 11 hardly yielded
their lactam products 16c and 17 since they preferred
to undergo reduction to amine and/or deazidation to the
parent compounds 6c or 10 (Figure 2 and Table 1, entries
3
which is eventually reduced by Bu SnH to perpetuate the
chain. The driving force of the regiospecific â-fragmenta-
tion process is ascribable to resonance stabilization of the
amide group formed and, additionally, to the formation
of a stable radical such as the captodative radical C. In
the cases examined the produced stannylaminyl radical
A was normally highly prone to cyclize onto the ketone
moiety, but the radical derived from the monocyclic azide
5c and those derived from the benzocyclic ones 7a ,c
showed a peculiar propensity for undergoing concomitant
hydrogen abstraction to give the reduced amine. We
consider that aminyl radicals 5Ac and 7Aa ,c, owing to
possible conformational restraints, are discouraged to
8
, 10).

Radical Chain Reactions of R-Azido-â-keto Esters
J . Org. Chem., Vol. 64, No. 21, 1999 7839
afford their cyclized adducts 5Bc and 7Ba ,c and thence
entitled to undergo alternative H-abstraction reaction.
In an attempt to depress the occurrence of the amine in
favor of the competing lactam, the reaction of the azide
Sch em e 4
7
3
c was repeated by performing slow addition of Bu SnH
by syringe pump over 3 h. However, even under these
conditions, the relative proportion of the amine and
lactam products remained almost unchanged (Table 1,
entries 9 and 8). This finding suggests that at least the
reduction of the transient aminyl radical 7Ac is primarily
due to some intramolecular H-transfer process rather
than to the expected H-abstraction from the hydride.5
The noticeable occurrence of deazidation process, en-
countered in the reactions of the azides 7b,c, 9, and
especially 11, plausibly arose from addition of the stannyl
radical to the terminal azido nitrogen, followed by
fragmentation of the resulting 1,3-triazenyl radical to
give stannyl azide (detected) and a resonance-stabilized
alkyl radical D (Scheme 3). Similar deazidation processes
have very recently been observed in reactions of stannyl
5
radicals with sulfonyl azides, but to our knowledge no
documented instance of deazidation has been so far
reported for parallel reactions of alkyl azides. Our present
findings seem to suggest that deazidation of an alkyl
azide by stannyl radical can be feasible, provided that a
suitably stabilized alkyl radical might arise. Accordingly,
tributylstannyl radical could especially perform deazi-
dation of the dehydrotetralone 11, owing to consequent
occurrence of an aromatized naphthoxyl radical. How-
ever, other subtle factors probably play some additional
role considering that such deazidation process was not
generally encountered with our azide reactions.
of either stannane, presumably because of its fair stabil-
ity and poor electrophilicity. Consequently, under both
circumstances, the radical 7Cb underwent exclusive
trapping by the 2-cyano-2-propyl radical (CPR) arising
from fragmentation of AIBN. On this basis, it may be
concluded that a direct access to allylated amides or
lactams would not be feasible with our keto ester azides,
at least when ATBS or ATPS are used as the allylating
agents. Despite such a frustrating conclusion, our allyl-
stannane reactions were, however, rewarding since they
led to two points of some interest: (i) triphenylstannyl
radical proved to be much more prone than the tributyl-
stannyl analog to perform deazidation of the tetralone
7bsthis fact might suggest a higher propensity of the
bulkier triphenylstannyl radical for adding to the less-
hindered terminal nitrogen of the azido moiety; and (ii)
the electrophilic deazidated radical 7Db proved to be
much more prone to add to the allyl group of ATPS than
ATBS. Indeed, in the presence of ATBS, the radical 7Db
curiously underwent reduction rather than allylation
reaction (Scheme 4).
In the present work we also briefly investigated the
radical reactions of the tetralone azide 7b with allyl-
tributylstannane (ATBS) and allyltriphenylstannane
(ATPS) in the presence of AIBN initiator. In the light of
the successful findings with Bu SnH, we were interested
3
in examining the potential utility of our azides for the
direct construction of allylated lactams and amides that
might form through allylation of the intermediate ring-
opened radical C by allylstannane. Allylstannanes are
well-known allylating agents of carbon and nitrogen
compounds in radical chain reactions of considerable use
in organic synthesis.5
,18
In these reactions, the key
propagation involves homolytic addition to the terminal
carbon of the allyl group followed by â-scission of the
adduct radical to give a stannyl radical.
In refluxing benzene, in the presence of 2 equiv of
ATBS and 0.1 equiv of AIBN, the azide 7b remained
largely unchanged, but, upon addition of up to 0.8 equiv
of AIBN, it was essentially consumed. Subsequent col-
umn chromatography separated the alkylated lactam 20
in 48% yield, along with minor amounts (22%) of the
tetralone 6b and small amounts (5%) of the allylated
derivative 21 (Scheme 4). Under analogous conditions,
the corresponding reaction with ATPS furnished the
lactam 20 in poor yield (14%) and instead the allylated
compound 21 in fairly high yield (63%). In either case
there was no evidence at all for any occurrence of the
aimed allylated lactam 22 (Scheme 4).
In conclusion, we have shown that the chain reaction
of Bu SnH with R-azido-â-keto esters can efficiently
3
afford amides and lactams as a result of ready 3-exo
cyclization of a transient (tributylstannyl)aminyl radical
onto the ketone moiety and prompt regiospecific â-scis-
sion of the derived alkoxyl radical. These reactions, which
are normally applicable to acyclic, monocyclic, benzo-
cyclic, and bicyclic substrates, provide a new protocol for
regiospecific nitrogen insertion of â-keto ester compounds
using the easily accessible R-azides, and thence enlarge
the synthetic utility of the radical chemistry of azides.
The present protocol offers a useful alternative to the
known ionic methods, including the Beckmann and
Schmidt reactions,19 which require (strongly) acid condi-
tions and may result in nitrogen insertion with poor or
These results clearly suggest that the ring-expanded
radical 7Cb is highly reluctant to add to the allyl group
(
18) Curran, D. P. Synthesis 1988, 489. Motherwell, W. B.; Crich,
(19) (a) March, J . Advanced Organic Chemistry, 4th ed.; Wiley-
Interscience: New York, 1992; pp 1093-1097. (b) Krow, G. R.
Tetrahedron 1981, 37, 1283. (c) Grunewald, G. L.; Dahanukar, V. H.
J . Heterocycl. Chem. 1994, 31, 1609.
D. Free Radical Chain Reactions in Organic Synthesis; Academic
Press: London, 1992; pp 202-207. Roberts, B. P.; Dang, H.-S. J . Chem.
Soc., Perkin Trans. 1 1996, 769.

7
840 J . Org. Chem., Vol. 64, No. 21, 1999
Benati et al.
undesired regioselectivity. A similar radical procedure,
using ATBS or ATPS in place of Bu SnH, appears,
however, of no utility for performing nitrogen insertion
45.48, 51.97, 53.78, 57.96, 64.51, 168.49, 208.35; MS m/ z (rel
+
23
inten) 290 and 288 (M , 4), 260 (16), 83 (100). This bromo
compound remained virtually unchanged upon prolonged
treatment with sodium azide in DMSO at 50 °C.
3
and concomitant allylation of â-keto ester.
Reaction of 12 (3 mmol) with trisyl azide (6 mmol) and
triethylamine (3 mmol) in anhydrous acetonitrile (7.5 mL) for
10 d at rt gave, after aqueous workup and chromatography of
Exp er im en ta l Section
l4c
the crude, unreacted 12 (1.38 mmol, 46%), the title azide
All solvents were distilled before use. All melting points
(0.99 mmol, 61% based on reacted 12), identical in all respects
1
13
14a
(
Kofler melting point apparatus) are uncorrected. H and
C
to an authentic specimen,
and, probably, methyl [2,2,3-
NMR spectra were carried out in CDCl solutions, using
3
trimethyl-3-(N-trisylcarbamoyl)cyclopentyl]diazoacetate (0.32
-
1
tetramethylsilane as the internal standard. Mass spectra were
determined by the electron impact method (70 eV). IR spectra
were recorded in chloroform solutions. Column chromatogra-
phy was performed on ICN silica gel (63-200, 60 Å) by gradual
elution with light petroleum (bp ) 40-70 °C)/diethyl ether
mixtures and final elution with ethyl acetate and dichloro-
methane.
mmol, 20% based on reacted 12); IR νmax (cm ) 3400 (NH),
+
2080 (CN ), 1680 (CO); MS m/ z (rel inten) 491 (M - 28, 7),
2
384 (97), 203 (100).1
4a
Gen er a l P r oced u r e for Rea ction s of â-Keto Ester
Azid es w ith Tr ibu tyltin Hyd r id e. A benzene (20 mL)
solution containing the keto ester azide (1 mmol), the tin
hydride (1.1 mmol), and AIBN (0.1 mmol) was refluxed under
a nitrogen atmosphere for 2-6 h, until TLC monitored the
virtual disappearance of the starting azide. In the case of azide
7c, alternative treatment with the hydride by syringe pump
over ca. 3 h was also performed. The solvent was removed
under reduced pressure, and the resultant residue was directly
subjected to column chromatography. Yields of the isolated
products are given in Table 1. In all of the reactions affording
the deazidated product (Table 1, entries 7-10 and 12) tri-
butylstannyl azide was either separated by column chroma-
tography (Table 1, entry 10) or directly identified by IR
l4b
14a
Ma ter ia ls. The keto esters 6a -c
and 12
azide as well as the keto ester azides 8a l4c and 9a
prepared according to literature methods. Methyl 2-hydroxy-
-naphthoate (10) was prepared by methylation of the com-
mercially available carboxylic acid with methyl iodide and
and trisyl
2
0
14c
were
1
2
1
showed the expected spectral properties. The monocyclic keto
esters 4a-d, tributyltin hydride, allyltributylstannane (ATBS),
and allyltriphenylstannane (ATPS) were commercially avail-
able and were used as received. AIBN (Fluka) was recrystal-
3 3
lized from CHCl /CH OH.
-
l
Syn th esis of th e Keto Ester Azid es 5a -d , 7a -c, a n d
1. These compounds were prepared through bromination of
analysis of the reaction crude (ν 2060 cm ).
1
Rea ction of Azid e 5a . Chromatography gave methyl 6-oxo-
2-piperidinecarboxylate (14a ), whose spectral properties were
fully consistent with those recently reported.24
the corresponding parent compounds 4a -d , 6a -c, and 10 with
N-bromosuccinimide (NBS, 1 equiv) in tetrachloromethane and
subsequent reaction of the crude bromide with sodium azide
Rea ction of Azid e 5b. Chromatography gave ethyl 7-oxo-
2-azepanecarboxylate (14b);2 H NMR (200 MHz) δ 1.29 (3H,
t, J ) 7.1 Hz), 1.53-2.57 (8H, m), 4.00-4.12 (1H, m), 4.24 (2H,
5 1
(1 equiv) in dimethyl sulfoxide (DMSO), by following the same
procedure previously described for the preparation of the azide
1
4c
13
analogs 8a , 9a . Overall yields amounted to 50-70%. The
q, J ) 7.1 Hz), 6.42 (1H, br s, NH); C NMR (50 MHz) δ 14.45,
1
4a
14b
already known azides 5d
and 7a -c
had spectral data
23.23, 29.92, 34.07, 37.32, 56.20, 62.42, 171.76, 176.71.
consistent with those previously reported. The newly prepared
Rea ction of Azid e 5c. Chromatography gave methyl 8-oxo-
-
1
azides 5a -c and 11 were as follows: methyl 1-azido-2-
2-azocanecarboxylate (14c) [mp ) 80-82 °C; IR ν
max
(cm )
-
1
1
oxocyclopentanecarboxylate (5a ) was an oil [IR νmax (cm
)
3440 (NH), 1750 (CO), 1660 (CO); H NMR (200 MHz) δ 1.35-
2.15 (8H, m), 2.31-2.51 (2H, m), 3.79 (3H, s), 4.21-4.42 (1H,
1
2
2
5
3
110 (N ), 1760 (CO), 1740 (CO); H NMR (200 MHz) δ 1.94-
+
13
.59 (6H, m), 3.88 (3H, s); MS m/ z (rel inten) 155 (M - 28,
m), 6.13 (1H, br d, NH); C NMR (50 MHz) δ 24.66, 26.56,
0), 96 (60), 68 (100)]; ethyl l-azido-2-oxocyclohexanecarbox-
28.40, 34.02, 36.67, 53.19, 55.38, 172.53, 175.83; MS m/ z (rel
-
1
+
ylate (5b) was an oil [IR νmax (cm ) 2110 (N
3
), 1740 (br, CO);
inten) 185 (M , 20), 126 (100), 98 (33). Anal. Calcd for C H15-
9
1
H NMR (200 MHz) δ 1.35 (3H, t, J ) 7.2 Hz), 1.61-2.06 (5H,
NO : C, 58.36; H, 8.16; N, 7.56. Found: C, 58.25; H, 8.10; N,
3
m), 2.32-2.71 (3H, m), 4.32 (2H, q, J ) 7.2 Hz); MS m/ z (rel
7.65.] and methyl 1-amino-2-oxocycloheptanecarboxylate (5c,
+
-1
inten) 183 (M - 28, 0.2), 82 (100), 55 (79)]; methyl 1-azido-
R ) NH ) as an oil [IR ν
(cm ) 3380-3300 (br, NH ), 1750
2
max
2
-
1
1
2
2
2
2
2
-oxocycloheptanecarboxylate (5c) was an oil [IR νmax (cm
)
(CO), 1740 (CO); H NMR (200 MHz) δ 1.53-1.98 (7H, m),
1
110 (N
3
), 1760 (CO), 1730 (CO); H NMR (200 MHz) δ 1.41-
2.10-2.27 (1H, m), 2.43 (2H, br s, NH ), 2.49-2.55 (1H, m),
2
2.82-2.98 (1H, m), 3.73 (3H, s); 13C NMR (50 MHz) δ 23.97,
.08 (7H, m), 2.14-2.29 (1H, m), 2.60-2.75 (1H, m), 2.81-
.98 (1H, m), 3.81 (3H, s); 13C NMR (50 MHz) δ 24.02, 26.03,
26.64, 30.18, 36.12, 41.44, 52.84, 69.91, 173.65, 209.35; MS
+
9.81, 33.68, 41.68, 53.32, 75.95, 168.95, 205.87; MS m/ z (rel
m/ z (rel inten) 185 (M , 6), 114 (56), 98 (100). Anal. Calcd for
+
inten) 183 (M - 28, 1), 124 (80), 96 (100)]; methyl 1-azido-
-oxo-1,2-dihydro-1-naphthalenecarboxylate (11) was a solid
C H NO : C, 58.36; H, 8.16; N, 7.56. Found: C, 58.40; H, 8.15;
9
15
3
2
[
(
N, 7.60.].
Rea ction of Azid e 5d . Chromatography gave ethyl 9-oxo-
-azonanecarboxylate (14d ) as a 1:1 mixture of the (Z)- and
-
1
3
mp ) 100-101 °C; IR νmax (cm ) 2120 (N ), 1760 (CO), 1670
1
CO); H NMR (200 MHz) δ 3.71 (3H, s), 6.27 (1H, d, J ) 8.9
2
1
3
Hz), 7.39-7.50 (4H, m), 7.57 (1H, d, J ) 8.9 Hz); C NMR (50
MHz) δ 54.24, 70.90, 123.89, 128.77, 129.61, 130.32, 130.52,
-1
(
1
E)-amides [IR νmax (cm ) 3440 (NH), 3380 (NH), 1730 (CO),
1
660 (CO); H NMR (300 MHz) δ 1.28 (3H, m), 1.44-2.44 (12H,
1
31.43, 135.61, 147.26, 167.82, 193.59; MS m/ z (rel inten) 215
m), 4.20 (2H, m), 4.25-4.36 (0.5H, m), 4.60-4.70 (0.5H, m),
5
22.35, 23.15, 24.56, 26.41, 26.53, 27.76, 30.12, 33.01, 34.58,
+
(M , 30), 156 (35), 129 (100)].
13
.90 (1H, br s, NH); C NMR (50 MHz) δ 14.62 (2 × CH
3
),
Syn th esis of Meth yl 2-Azid o-4,7,7-tr im eth yl-3-oxobi-
cyclo[2.2.1]h ep ta n e-2-ca r boxyla te (13). Usual bromination
of methyl 4,7,7-trimethyl-3-oxobicyclo[2.2.1]heptane-2-car-
boxylate (12) with NBS gave, in virtually quantitative yield,
34.83, 38.83, 53.51 (CH), 56.50 (CH), 61.91 (OCH ), 62.28
2
(OCH ), 172.27 (CO), 173.07 (CO), 175.44 (CO), 176.48 (CO);
2
HRMS calcd for C H NO 213.1365, found 213.1363.
1
1
19
3
2
2
the corresponding 2-endo-bromide: mp ) 125-126 °C (lit.
Rea ction of Azid e 7a . Chromatography gave ethyl 1-oxo-
1,2,3,4-tetrahydro-3-isoquinolinecarboxylate (16a ) as an oil [IR
-
1
1
mp ) 67 °C); IR νmax (cm ) 1760 (CO), 1740 (CO); H NMR
-
1
1
(
(
(
200 MHz) δ 0.80 (3H, s), 1.00 (3H, s), 1.10 (3H, s), 1.48-1.78
νmax (cm ) 3400 (NH), 1740 (CO), 1660 (CO); H NMR (200
MHz) δ 1.30 (3H, t, J ) 6.9 Hz), 3.09-3.43 (2H, m collapsing
to AB dd, J ) 15 Hz, upon irradiation at δ 4.38), 4.24 (2H, q,
2H, m), 1.94-2.28 (2H, m), 2.88 (1H, br d, J ) 1.9 Hz), 3.80
1
3
3H, s); C NMR (50 MHz) δ 10.02, 20.87, 20.92, 24.84, 31.06,
(
20) Harmon, R. E.; Wellman, G.; Gupta, S. K. J . Org. Chem. 1973,
(23) Structural assignment to the 2-endo-bromo derivative of the
keto ester 12 was fully supported by X-ray crystallographic analysis.
(24) Davies, C. E.; Heightman, T. D.; Hermitage, S. A. Synth.
Commun. 1996, 26, 687.
3
8, 11.
(
(
21) (21) Kurian, O. P. Austr. J . Chem. 1976, 29, 1393.
22) Antkowiak, R.; Antkowiak, W. Z. Bull. Acad. Polon. Sci., Ser.
Sci. Chim. 1975, 23, 723 (Chem. Abstr. 1976, 84, 105797c).
(25) Shechter, H.; Kirk, J . C. J . Am. Chem. Soc. 1951, 73, 3087.

Radical Chain Reactions of R-Azido-â-keto Esters
J . Org. Chem., Vol. 64, No. 21, 1999 7841
J ) 6.9 Hz), 4.33-4.46 (1H, m), 6.52 (1H, br s, NH), 7.24-
13C NMR (50 MHz) δ 53.52, 57.86, 126.79, 126.99, 129.24,
7
.63 (3H, m), 8.02 (1H, d, J ) 8 Hz); MS m/ z (rel inten) 219
130.30, 130.56, 134.96, 136.58, 138.31, 167.60, 170.26; MS m/ z
+
+
(
M , 7), 146 (100), 91 (31). Anal. Calcd for C12
H
13NO
3
: C, 65.74;
(rel inten) 217 (M , 3), 158 (100). Anal. Calcd for C12
H
11NO
3
:
H, 5.98; N, 6.39. Found: C, 65.65; H, 5.95; N, 6.40] and ethyl
C, 66.35; H, 5.10; N, 6.45. Found: C, 66.20; H, 5.15; N, 6.50]
2
-amino-1-oxoindanecarboxylate (7a , R ) NH
2
) as an oil [IR
and methyl 1-amino-2-oxo-1,2-dihydro-1-naphthalenecarbox-
-
1
1
1
ν
max (cm ) 3440 and 3320 (NH
NMR (200 MHz) δ 1.17 (3H, t, J ) 6.9 Hz), 2.01 (2H, br s, NH
2
), 1740 (CO), 1660 (CO); H
),
ylate (11, N
δ 2.67 (2H, br s, NH
Hz), 7.37-7.63 (4H, m), 7.56 (1H, d, J ) 10.10); C NMR (50
MHz) δ 53.37, 66.69, 123.69, 127.00, 128.89, 129.18, 129.83,
130.72, 139.50, 146.42, 171.39, 197.44. Anal. Calcd for C12
NO : C, 66.35; H, 5.10; N, 6.45. Found: C, 66.55; H, 5.05; N,
6.45.
3
) NH
2
) [mp ) 148-150 °C; H NMR (200 MHz)
2
2
), 3.65 (3H, s), 6.30 (1H, d, J ) 10.10
1
3
3
.06 (1H, d, J ) 16.4 Hz), 3.70 (1H, d, J ) 16.4 Hz), 4.15 (2H,
q, J ) 6.9 Hz), 7.41-7.72 (3H, m), 7.79 (1H, d, J ) 8.0 Hz);
MS m/ z (rel inten) 219 (M , 12), 146 (74). Anal. Calcd for
C
5
+
11
H -
12
H
13NO
3
: C, 65.74; H, 5.98; N, 6.39. Found: C, 65.85; H,
3
.95; N, 6.45].
Rea ction of Azid e 7b. Chromatography gave the keto ester
b and ethyl 1-oxo-2,3,4,5-tetrahydro-lH-2-benzazepine-3-car-
Rea ction of Azid e 13. Chromatography gave methyl 5,8,8-
trimethyl-4-oxo-3-azabicyclo[3.2.1]octane-2-carboxylate (15) as
6
-1
boxylate (16b), whose spectral properties were fully consistent
a 60:40 mixture of the 2-endo- and 2-exo-isomer [IR ν
max
(cm )
l9c
1
with those previously reported.
3460 (NH) and 3420 (NH); H NMR (200 MHz) δ 0.82 (1.8H,
s), 0.88 (1.8H, s), 0.94 (1.2H, s), 1.00 (1.2H, s), 1.04 (1.8H, s),
1.06 (1.2H, s), 1.28-2.24 (4H, m), 2.28-2.34 (0.4H, m), 2.56-
2.64 (0.6H, m), 3.72 (1.8H, s), 3.74 (1.2H, s), 3.78 (0.6H, br d),
4.20 (0.4H, br d), 5.94 (0.4H, br s, NH), 6.12 (0.6H, br s, NH);
Rea ction of Azid e 7c. Chromatography gave the keto ester
6
c, ethyl 1-oxo-1,2,3,4,5,6-hexahydro-2-benzazocine-3-carbox-
-1
ylate (16c) [mp ) 108-110 °C; IR νmax (cm ) 3380 (NH), 1730
1
(
CO), 1640 (CO); H NMR (200 MHz) δ 1.25 (3H, t, J ) 6.9
1
3
Hz), 1.58-1.81 (2H, m), 2.06-2.34 (2H, m), 2.83-2.91 (2H,
m). 3.80 (1H, br t), 4.18 (2H, q, J ) 6.9 Hz), 6.60 (1H, br d,
C NMR (50 MHz) δ 13.56, 13.78, 19.58, 19.87, 23.52, 23.63,
23.74, 29.13, 29.23, 36.98, 37.34, 43.10, 43.88, 45.66, 46.66,
52.45, 52.86, 52.91, 58.03, 60.95, 172.24, 172.45, 178.04,
1
3
NH), 7.17-7.49 (4H, m); C NMR (50 MHz) δ 14.52, 27.92,
+
3
1
1
2.48, 34.69, 55.90, 62.46, 127.25, 128.30, 130.19, 131.54,
178.17; MS m/ z (rel inten) 225 (M , 4), 166 (100). Anal. Calcd
+
34.23, 140.51, 172.08, 172.30; MS m/ z (rel inten) 247 (M ,
for C H NO : C, 63.98; H, 8.50; N, 6.22. Found: C, 64.05;
1
2
19
3
8), 146 (84), 131 (100). Anal. Calcd for C14
H
17NO
3
: C, 68.00;
H, 8.45; N, 6.15.
H, 6.93; N, 5.66. Found: C, 68.15; H, 6.90; N, 5.65] and ethyl
Rea ction of Azid e 7b w ith Allyltr ibu tylsta n n a n e. A
refluxing solution of the azide (1 mmol) and the stannane (2
mmol) in benzene (3 mL) was slowly treated with AIBN (0.8
mmol) under an atmosphere of nitrogen and then further
refluxed for 4.5 h. Cooling of the reaction mixture to room
temperature separated a white solid. This was filtered off and
shown to be ethyl 3-(1-cyano- 1-methylethyl)-1-oxo-2,3,4,5-
6
-amino-5-oxo- 6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene-6-
-
1
carboxylate (7c, R ) NH ) as an oil [IR νmax (cm ) 3400 and
2
1
3
(
2
2
340 (NH ), 1740 (CO), 1680 (CO); H NMR (200 MHz) δ 1.14
3H, t, J ) 7.1 Hz), 1.72-2.16 (3H, m), 2.20 (2H, br s, NH
2
),
.25-2.45 (1H, m), 2.80-3.11 (2H, m), 4.10 (2H, q, J ) 7.1
1
3
Hz), 7.10-7.45 (4H, m); C NMR (50 MHz) δ 14.35, 22.59,
3
1
1
2.89, 33.80, 62.18, 69.03, 127.01, 129.01, 129.43, 132.15,
tetrahydro-1H-2-benzazepine-3-carboxylate (20) (30%): mp )
+
39.13, 139.52, 173.64, 206.71; MS m/ z (rel inten) 247 (M ,
-1
2
1
(
03-204 °C; IR νmax (cm ) 3400 (NH), 2230 (CN), 1730 (CO),
4), 174 (44), 128 (100). Anal. Calcd for C14
H
17NO
3
: C, 68.00;
1
660 (CO); H NMR (200 MHz) δ 1.08 (3H, t, J ) 7.1 Hz), 1.42
3H, s), 1.48 (3H, s), 2.42 (1H, m), 2.77 (1H, m), 3.10 (2H, q, J
H, 6.93; N, 5.66. Found: C, 68.25; H, 6.95; N, 5.60].
Reaction of Azide 8a. Chromatography gave ethyl 2-(acetyl-
)
7.1 Hz), 3.60 (1H, m), 3.87 (1H, m), 6.73 (1H, br s, NH),
.15 (1H, m), 7.27-7.40 (2H, m), 7.71 (1H, m); C NMR (50
2
6
-1
amino)propanoate (18); IR νmax (cm ) 3426 (NH), 1730 (CO),
13
7
1
1
(
(
665 (CO); H NMR (200 MHz) δ 1.25 (3H, t, J ) 7.0 Hz), 1.36
MHz) δ 14.23, 23.36, 23.84, 30.30, 37.92, 41.24, 62.97, 66.75,
3H, d, J ) 7.0 Hz), 1.98 (3H, s), 4.17 (2H, q, J ) 7.0 Hz), 4.54
1
1
9
22.21, 127.72, 129.06, 130.08, 132.34, 134.19, 138.70, 170.18,
72.73. Anal. Calcd for C17 : C, 67.98; H, 6.71; N,
.33: Found: C, 68.15; H, 6.70; N, 9.40.
1H, m collapsing to q, J ) 7.0 Hz, upon irradiation at δ 6.18
20 3 3
H N O
1
3
and to br d upon irradiation at δ 1.36), 6.3 (1H, br s, NH);
C
NMR (50 MHz) δ 13.61, 14.11, 23.18, 48.10, 61.51, 169.53,
Chromatography of the evaporated filtrate gave further 20
1
73.22.
(
18%), the keto ester 6b (22%), and ethyl 2-allyl-1-oxo-1,2,3,4-
Rea ction of Azid e 9a . Chromatography gave the keto ester
1
tetrahydro-2-naphthalenecarboxylate (21) (5%) as an oil:
H
2
7
-1
9
3
(
7
7
6
b and ethyl 2-(benzoylamino)propanoate (19); IR νmax (cm )
1
NMR (200 MHz) δ 1.17 (3H, t, J ) 6.9 Hz), 2.09-2.28 (1H,
m), 2.48-2.67 (1H, m), 2.72-3.22 (4H, m), 4.17 (2H, q, J )
440 (NH), 1740 (CO), 1660 (CO); H NMR (200 MHz) δ 1.30
3H, t, J ) 7.0 Hz), 1.52 (3H, d, J ) 7.0 Hz), 4.24 (2H, q, J )
6
.9 Hz), 5.11-5.26 (2H, m), 5.78-6.02 (1H, m), 7.22-7.61 (3H,
.0 Hz), 4.78 (1H, m), 6.78 (1H, br d, NH), 7.22-7.52 (3H, m),
.70-7.80 (2H, m); 13C NMR (50 MHz) δ 14.75, 19.28, 49.17,
2.22, 127.64, 129.16, 132.28, 134.6, 167.42, 173.86.
m), 8.13 (1H, d, J ) 8.0 Hz). Anal. Calcd for C16
H, 7.02. Found: 74.50; H, 6.95.
18 3
H O : C, 74.39;
R ea ct ion of Azid e 7b w it h Allylt r ip h en ylst a n n a n e.
This was carried out for 4 h following the same procedure as
described above for the reaction with ATBS. Chromatography
gave 20 (14%) and 21 (63%).
Rea ction of Azid e 11. Chromatography gave the naph-
thoate 10, methyl 3-oxo-2,3- dihydro-lH-2-benzazepine-1-car-
-
1
boxylate (17) [mp ) 212-213 °C; IR νmax (cm ) 3380 (NH),
1
1
(
6
1
7
740 (CO), 1650 (CO); H NMR (200 MHz) δ 3.83 (3H, s), 5.02
1H, d, J ) 6.25, collapsing to s upon irradiation at δ 6.83),
Ack n ow led gm en t. The authors gratefully acknowl-
edge financial support from MURST (1998-1999 Grant
for “Free Radicals and Radical Ions in Chemical and
Biological Processes”) and the University of Bologna
(1997-1999 Funds for Selected Research Topics).
.27 (1H, dd, J
1
) 12.5 Hz, J ) 2 Hz, collapsing to d, J )
2
2.5 Hz, upon irradiation at δ 6.83), 6.83 (1H, br s, NH), 7.00-
.08 (1H, m), 7.12 (1H, d, J ) 12.5 Hz), 7.33-7.41 (3H, m);
(
26) Pereira, W.; Close, V.; Patton, W.; Halfern, B. J . Org. Chem.
969, 34, 2032.
27) Elliott, I. W. J . Org. Chem. 1962, 27, 3302.
1
(
J O990837G