Reactions of Benzocyclic β-Keto Esters with Tosyl and 4-Nitrophenyl Azide. Structural Influence of Dicarbonyl Substrate and Azide Reagent on Distribution of Diazo, Azide and Ring-Contraction Products

Article abstract of DOI:10.1021/jo980223w

The reactions of β-keto esters derived from 1- and 2-indanone, 1- and 2-tetralone, and benzosuberone with toluene-4-sulfonyl- (tosyl) and 4-nitrobenzenesulfonyl azide (PNBSA) in the presence of Et₃N have been investigated in order to evaluate the influence of both dicarbonyl substrate and azide reagent on the product distribution. With tosyl azide the keto esters derived from both 2-benzocycloalkanones exhibit deacylating diazo transfer, but those derived from the 1-benzocycloalkanones undergo additional azido transfer to a significant or even exclusive extent. The finding is mainly explained in terms of the lesser reactivity of the conjugate aryl ketone than alkyl ketone moiety. This would discourage cyclization of the initial sulfonyltriazenyl anion-the presumable azide precursor-to the triazoline adduct, in turn envisaged as the diazo progenitor. With PNBSA both indanones smoothly undergo diazo transfer, whereas their higher homologues lead to ring-contraction products ascribable to corresponding triazolines that curiously prefer to suffer Favorskiitype ring fragmentation. Evidence has been obtained that tosyl azide acts as a azide-transfer reagent superior to PNBSA. A possible explanation of this fact is discussed. An X-ray crystal structure analysis of the phthalazine compound 18 (Ar = 4-Me-C₆H₄) has been performed.

Full text of DOI:10.1021/jo980223w

J . Org. Chem. 1998, 63, 4679-4684
4679
Rea ction s of Ben zocyclic â-Keto Ester s w ith Tosyl a n d
4-Nitr op h en yl Azid e. Str u ctu r a l In flu en ce of Dica r bon yl Su bstr a te
a n d Azid e Rea gen t on Distr ibu tion of Dia zo, Azid e a n d
Rin g-Con tr a ction P r od u cts†
Luisa Benati,*,‡ Gianluca Calestani,§ Daniele Nanni,‡ and Piero Spagnolo‡
Dipartimento di Chimica Organica “A. Mangini”, Universita` di Bologna, Viale Risorgimento 4,
I-40136 Bologna, Italy, and Dipartimento di Chimica Generale ed Inorganica, Analitica e Chimica Fisica,
Viale delle Scienze 78, I-43100 Parma, Italy
Received February 6, 1998
The reactions of â-keto esters derived from 1- and 2-indanone, 1- and 2-tetralone, and benzosuberone
with toluene-4-sulfonyl- (tosyl) and 4-nitrobenzenesulfonyl azide (PNBSA) in the presence of Et3N
have been investigated in order to evaluate the influence of both dicarbonyl substrate and azide
reagent on the product distribution. With tosyl azide the keto esters derived from both
2-benzocycloalkanones exhibit deacylating diazo transfer, but those derived from the 1-benzocy-
cloalkanones undergo additional azido transfer to a significant or even exclusive extent. The finding
is mainly explained in terms of the lesser reactivity of the conjugate aryl ketone than alkyl ketone
moiety. This would discourage cyclization of the initial sulfonyltriazenyl anionsthe presumable
azide precursorsto the triazoline adduct, in turn envisaged as the diazo progenitor. With PNBSA
both indanones smoothly undergo diazo transfer, whereas their higher homologues lead to ring-
contraction products ascribable to corresponding triazolines that curiously prefer to suffer Favorskii-
type ring fragmentation. Evidence has been obtained that tosyl azide acts as a azide-transfer
reagent superior to PNBSA. A possible explanation of this fact is discussed. An X-ray crystal
structure analysis of the phthalazine compound 18 (Ar ) 4-Me-C6H4) has been performed.
In tr od u ction
substrate may discourage a deacylating diazo-transfer
process in favor of an alternative azido transfer, which
is only encountered in special cases with resonance-
stabilized enolates.4 To gain a further insight into the
effect of cyclic keto ester structure, we were led to study
the behavior of the available benzocyclic keto esters 1a -c
and 2a ,b, derived from 1- and 2-benzocycloalkanones,
respectively (Figure 1). Since we were also interested
in ascertaining the effect of sulfonyl azide reagent, the
reactivity of the above compounds 1a -c and 2a ,b toward
more electrophilic 4-nitrobenzenesulfonyl azide (PNBSA)
was additionally examined. Very recently,5 PNBSA has
found an advantageous use in promoting deacylating
diazo transfer to acyclic benzoyl-activated esters and
ketones, though PNBSA was originally reported to be
inferior to tosyl azide as a diazo-transfer reagent.6
Herein, we report the results obtained from the present
work.
Diazo-group transfer from a sulfonyl azide to the active
methylene of a â-dicarbonyl compound is a valuable
method for the production of R-diazocarbonyl com-
pounds.1 With simple ketones or esters the diazo transfer
can be normally accomplished through prior acylation
and subsequent elimination of the activating acyl group
in the course of the actual diazo transfer.1 In previous
work2 we have observed that toluene-4-sulfonyl (tosyl)
azide can smoothly transform 2-substituted indan-1,3-
diones into ring-opened o-N-tosylcarbamoyl-substituted
R-diazoacetophenones, thus providing the first instances
of deacylating diazo transfer with cyclic â-diones. We
have next examined a similar process upon several
monocyclic â-keto esters.3 The five- to seven-membered-
ring compounds cleanly led to diazo amido esters, whereas
other derivatives exhibited significant or even preferen-
tial occurrence of the azidation product. It has been
therefore inferred that structural features of the cyclic
Resu lts a n d Discu ssion
†Dedicated to the memory of Professor Antonino Fava (deceased
on December 19, 1997), Professore Emerito of the University of
Bologna.
Following a procedure analogous to that previously
reported for the monocyclic examples,3 2-ethoxycarbonyl-
1-indanone 1a was reacted with tosyl azide and triethy-
lamine at room temperature in anhydrous tetrahydro-
furan for ca. 6 days. Column chromatography of the
‡ Universita` di Bologna.
§ Universita` di Parma e Centro di Studio per la Strutturistica
Diffrattometrica del CNR.
(1) Ye, T.; McKervey, M. A. Chem. Rev. 1994, 94, 1091. Regitz, M.;
Maas, G. Diazo Compounds: Properties and Synthesis; Academic
Press: New York, 1986, ch. 13. Scriven, E. F. V.; Turnbull, K Chem.
Rev. 1988, 88, 298.
(2) (a) Benati, L.; Montevecchi, P. C.; Spagnolo, P.; Foresti, E. J .
Chem. Soc., Perkin Trans. 1 1992, 2845. (b) Benati, L.; Calestani, G.;
Montevecchi, P. C.; Spagnolo, P. J . Chem. Soc., Perkin Trans. 1 1994,
2637. (c) Benati, L.; Calestani, G.; Montevecchi, P. C.; Spagnolo, P. J .
Chem. Soc., Perkin Trans. 1 1995, 1381.
(3) Benati, L.; Nanni, D.; Spagnolo, P. J . Chem. Soc., Perkin Trans.
1 1997, 457.
(4) Mataka, S.; Koga, G.; Anselme, J .-P.; Weininger, S. J .; Kohen,
S. J . Org. Chem. 1974, 39, 1591. Wasserman, H. H.; Hlasta, D. J . J .
Am. Chem. Soc. 1978, 100, 6780. Hakimelahi, G. H.; J ust, G. Synth.
Commun. 1980, 10, 429.
(5) Taber, D. F.; You, K.; Song, Y. J . Org. Chem. 1995, 60, 1093.
Taber, D. F.; Gleave, D. M.; Herr, R. J .; Moody, K.; Hennessy, M. J . J .
Org. Chem. 1995, 60, 2283.
(6) Hendrickson, J . B.; Wolf, W. A. J . Org. Chem. 1968, 33, 3610.
S0022-3263(98)00223-0 CCC: $15.00 © 1998 American Chemical Society
Published on Web 06/12/1998

4680 J . Org. Chem., Vol. 63, No. 14, 1998
Benati et al.
Ta ble 1. Yield s (%)a of Dia zo-Tr a n sfer , Azid o-Tr a n sfer , a n d Rin g-Con tr a ction P r od u cts fr om th e Rea ction s of
Ben zocyclic Keto Ester s 1a -c, 2a ,b w ith Tosyl Azid e a n d P NBSAb
keto
ester
diazo-transfer
product(s) (% yield)
azido-transfer
product (% yield)
ring-contraction
product (% yield)
entry
azide
time
1
2
3
4
5
6
7
8
9
1a
1b
1c
2a
2b
1a
2a
1b
2b
1c
TsN3
TsN3
TsN3
TsN3
6 d
4 d
5 d
12 h
12 h
2 h
1 h
20 h
1 h
3a (55), 6 (25)
3b (traces)
3c (51), 8 (15)
17a /b (84)c
9b (51)d
5a (16)
5b (75)
5c (31)
TsN3
PNBSA
PNBSA
PNBSA
PNBSA
PNBSA
7 (94)e
13 (45), 17a /b (10)f
5b (21)
14a (R ) Et) (47)
14a (R ) Me) (37)g
14b (R ) Et) (75)
16 (8)
10
4 h
a
b
Yields isolated by column chromatography. Reactions were normally carried out in THF at rt in the presence of Et3N. c 17a or 17b
(Ar ) 4-Me-C6H4). 30 min at 0 °C, then 12 h at rt; the aminated tetralone 11 was also produced in 20% yield. e 30 min at 0 °C, then 2
d
h at rt; the triethylammonium salt of 4a was obtained in 94% yield. By chromatography, 4a furnished 7. f 10 min at 0 °C, then 1 h at
g
rt; 17a or 17b (Ar ) 4-NO2-C6H4). The aminated tetralone 12 was also produced in 28% yield.
F igu r e 2. The X-ray molecular structure of methyl 4-({[(4-
methylphenyl)sulfonyl]amino}carbonyl)-1-phthalazinecarboxy-
late 18 (Ar ) 4-Me-C6H4) showing the atom-numbering
scheme.
cantly enhanced (Table 1, entry 3). Moreover, 2-ethoxy-
carbonyl-1-tetralone 1b surprisingly furnished a fairly
high yield of azide 5b and only trace amounts of the
expected diazo butanoate 3b (Table 1, entry 2).
Differently from the above keto esters 1a -c, their more
acidic congeners 2a ,b reacted fairly rapidly with tosyl
azide and, additionally, failed to afford any azidation
product. 1-Methoxycarbonyl-2-indanone 2a , in fact, in-
terestingly furnished a high yield of a single compound
whose spectral data strongly suggested that it had a
dihydrophthalazine (17a , Ar ) 4-Me-C6H4) structure or
was its tautomer (17b, Ar ) 4-Me-C6H4). Upon treat-
ment with o-chloranil in refluxing benzene this compound
was rapidly converted to the aromatic phthalazine 18 (Ar
) 4-Me-C6H4), whose structure was fully established by
X-ray crystallographic analysis (Figure 2).7
The observed production of a dihydrophthalazine com-
pound, 17a or 17b (Ar ) 4-Me-C6H4), clearly points to
the primary intervention of the intermediate diazo
acetate 9a that, under the basic reaction conditions,
F igu r e 1.
crude mixture separated the rather unstable diazo pro-
panoate 3a and the formal carbene decomposition
productsthe cyclized isoquinolinone 6 (see the Experi-
mental Section)sin 80% overall yield, together with
minor amounts of the azidation product 5a (Table 1,
entry 1).
would readily undergo intramolecular cyclization onto the
adjacent carbamoyl enolate (Table 1, entry 4 and Scheme
1). 1-Methoxycarbonyl-2-tetralone 2b gave instead the
isolable diazo acetate 9b, but in moderate yield, together
with the tosylamino-substituted tetralone 11 to a minor
extent (Table 1, entry 5).
A somewhat comparable finding was provided by
2-ethoxycarbonyl-1-benzosuberone 1c, but in such case
the proportion of the corresponding azide 5c to the overall
diazo-transfer productssthe diazo pentanoate 3c and the
â-hydride-elimination carbene product 83swas signifi-
(7) Listings of atomic coordinates, thermal parameters, bond lengths,
and bond angles have been deposited at the Cambridge Crystal-
lographic Data Centre. The data can be obtained, on request, from the
Director, the Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge, CB2, 1EZ, UK.

Influence of Dicarbonyl Substrate and Azide Reagent
J . Org. Chem., Vol. 63, No. 14, 1998 4681
Sch em e 1a
Triazoline 2Bb additionally furnishes the amino-substi-
tuted tetralone 11 through a minor decomposition mode
probably entailing ring-cleavage isomerization of a tran-
sient aziridine (Scheme 2).2a
Instead, in the case of keto esters 1a -c, the ensuing
triazenyl adducts 1Aa -c are evidently encouraged to
fragment into toluene-4-sulfinate and azides 5a -c at the
expense of the competing cyclization to the diazo precur-
sors 1Ba -c (Scheme 3).
Consequently, the different behavior of 1a -c and 2a ,b
is primarily ascribable to the lesser reactivity of the
conjugated aryl ketone moiety versus the alkyl one.
However, it is likely that unfavorable conformational
restraints also play a significant role, at least in limiting
diazo transfer to 1b.
Our subsequent study of the reactions of the benzocy-
clic keto esters 1a -c and 2a ,b with PNBSA proved that
the use of this azide reagent, while generally resulting
in sizable reaction-rate enhancement as well as essential
azido transfer suppression, was of limited advantage for
diazo transfer production. In fact, both indanones 1a and
2a were rapidly consumed by PNBSA to afford the
respective diazo amide esters 4a and 10a . The diazo
compound 4a was obtained in high yield as its triethy-
lammonium salt, but on attempted chromatographic
purification, it was totally converted into the cyclized
isoquinolin-1-one 7 (Table 1, entry 6). The isomeric diazo
ester 10a was decomposed under the reaction conditions
to give predominantly the isoquinolin-3-one 13 and only
modest amounts of dihydrophthalazine compound 17a or
17b (Ar ) 4-NO2-C6H4), in contrast to the diazo analogue
9a (Table 1, entry 7). The poor capability of the diazo
compound 10a to cyclize to phthalazine presumably
resulted from higher acidity of its carbamoyl nitrogen,
which largely prevented possible production of the adja-
cent enolate (Scheme 1). Instead, the higher tetralone
homologues 1b and 2b underwent no virtual diazo-
transfer reaction with PNBSA. Compound 1b gave the
indan derivative 14a (R ) Et) in addition to minor
amounts of azide 5b (Table 1, entry 8). Compound 2b
preferentially led to the analogous indan 14a (R ) Me).
This product was accompanied by the aminated tetralone
12 and, to a little extent, the benzazepine 16, which
probably arose from spontaneous cyclization of some
produced diazo ester 10b (Table 1, entry 9). Similarly,
no evidence for any occurrence of diazo (or azido) transfer
from provided by the benzosuberone 1c, which only led
to a corresponding tetralin derivative 14b (R ) Et) in
fairly good yield (Table 1, entry 10). The ring-contracted
compounds 14a (R ) Et, Me) and 14b (R ) Et) were most
likely due to Favorskii-type rearrangements of the re-
spective triazoline adducts 1Bb, 2Bb, and 1Bc (Ar )
4-NO2-C6H4), which possibly proceeded through transient
diazonium betaines (Scheme 4). However, the underlying
reasons why these triazolines would prefer to exhibit the
Favorskii-type rearrangement rather than the expected
fragmentation to diazo compounds are not clear at
present. It is worth noting that such a rearrangement
has never been encountered in the reported examples of
diazo transfer from PNBSA to benzoylated esters and
ketones.5
a
Reagents: (i) o-chloranil, benzene, 80 °C.
Sch em e 2a
a
Reagents: (i) TsN3, Et3N, 20 °C.
Sch em e 3a
a
Reagents: (i) TsN3, Et3N, 20 °C.
The present findings therefore revealed that the keto
esters 2a ,b are fairly prone to undergo diazo transfer
from tosyl azide, in contrast with the analogues 1a -c,
which show a marked tendency to exhibit azido transfer.
This fact can be explained on the basis of the likely
mechanism outlined in Schemes 2 and 3 for compounds
2a ,b and 1a -c, respectively. This would involve the
initial intervention of a triazenyl anion A and thence a
cyclized triazoline B.2,3 The keto esters 2a ,b, like the
monocyclic counterparts,3 smoothly lead to intermediate
triazolines 2Ba ,b, whose usual fragmentations subse-
quently furnish the corresponding diazo esters 9a ,b.
Our present observation that PNBSA is less prone than
tosyl azide to promote azido transfer substantiates recent,
unexplained evidence furnished by related reactions of
both sulfonyl azides with (acyclic) imide and ester eno-

4682 J . Org. Chem., Vol. 63, No. 14, 1998
Benati et al.
TION: like all sulfonyl azide derivatives, PNBSA and espe-
cially tosyl azide are potentially explosive; these compounds
have been recently subjected to risk evaluation.16] All solvents
were distilled before use. THF was distilled from sodium-
benzophenone and dichloromethane from calcium hydride. All
melting points (Kofler melting point apparatus) are uncor-
rected. 1H and 13C NMR spectra were normally recorded in
CDCl3 solutions, using tetramethylsilane as internal standard,
unless otherwise stated. Mass spectra were determined by
the electron impact method (70 eV). IR spectra were recorded
in chloroform solutions. Column chromatography was per-
formed on ICN silica gel (63-200, 60 Å) by gradual elution
with light petroleum (bp ) 40-70 °C)/diethyl ether and final
elution with ethyl acetate and dichloromethane.
F igu r e 3.
Sch em e 4
Rea ction of Ar ylsu lfon yl Azid e w ith Keto Ester s 1a -c
a n d 2a ,b: Gen er a l P r oced u r e. A solution of arylsulfonyl
azide (8 mmol) and the appropriate keto ester 1a -c or 2a ,b
(8 mmol) in THF (10 mL) was treated with freshly distilled
triethylamine (8 mmol). The resulting mixture was stirred
at rt until disappearance of the starting reagents (monitored
by TLC or IR) and quenched by addition of water (30 mL) to
pH ∼7. The solution was extracted with diethyl ether (3 ×
20 mL), and the combined organic layers were dried over
anhydrous sodium sulfate and concentrated in vacuo, and the
residue (crude 1) was chromatographed. The aqueous solution
was acidified with concentrated HCl (pH ∼2) and extracted
three times with diethyl ether, and the combined extracts were
dried over sodium sulfate and concentrated in vacuo (crude
2). Approximate reaction times and isolated product yields
are given in Table 1.
lates.8 For unknown stereoelectronic reasons the nitro
substituent might strongly encourage the initial occur-
rence of Z- rather than E-triazenyl anions, thus favoring
the subsequent cyclization to triazoline (Figure 3). Al-
ternatively, more reactive PNBSA would normally react
with our keto ester enolates to give directly triazoline
adducts via a 1,3-dipolar cycloaddition process.
Rea ction of Tosyl Azid e w ith Eth yl 1-Oxo-2-in d a n ca r -
boxyla te (1a ). Column chromatography of crude 1 gave ethyl
2-azido-1-oxo-2-indancarboxylate 5a [mp ) 53-55 °C; 1H NMR
(200 MHz) δ 1.28 (3H, t), 3.22 (1H, d, J ) 17 Hz), 3.72 (1H, d,
J ) 17 Hz), 4.32 (2H, q), 7.47-7.94 (4H, m); 13C NMR (50 MHz)
14.49, 38.98, 63.43, 70.61 (q), 126.08, 126.91, 128.88, 136.92,
135.50 (q), 152.60 (q), 168.95 (q), 198.00 (q). Anal. Calcd for
Con clu sion s
Our present and previous findings have proved that
the reactions of enolates derived from carbocyclic â-keto
esters with tosyl azide and PNBSA are strongly sensitive
to both the dicarbonyl substrate and the azide reagent
structures. With the five-, six- and seven-membered
mono- and benzocyclic keto esters, the tosyl azide reaction
normally results in successful deacylating diazo transfer,
but with those benzocyclic compounds bearing a conju-
gated aryl ketone moiety, competing azido transfer can
represent a serious drawback. Replacement of tosyl azide
with PNBSA normally results in suppression of the
azidation process. The diazo transfer may be however
accompanied or even prevented by the preferential oc-
currence of novel ring-contraction rearrangements. Fi-
nally, we wish to conclude that our deacylating diazo
transfer with cyclic keto esters (and diones) is an ap-
pealing process, owing to the availability of the starting
substrates and the synthetic potential of the ensuing
carbamoyl-substituted diazocarbonyl compounds.2,3 In
the present work, the usefulness of our diazocarbonyl
compounds has been further documented by the ready
cyclization of the diazo esters 3a , 4a , and 10a to the
isoquinolinones 6, 7, and 13 and of the higher homologues
9b and 10b to the benzazepinones 15 and 16 (see the
Experimental Section), as well as by the novel entry to
the phthalazine ring system provided by the diazo acetate
9a .
C
12H11N3O3: C, 58.77; H, 4.52; N, 17.14. Found: C, 58.65; H,
4.50; N, 17.17.] and ethyl 2-[(4-methylphenyl)sulfonyl]-1-oxo-
1,2,3,4-tetrahydro-3-isoquinolinecarboxylate 6 [mp ) 134-135
1
°C; H NMR (300 MHz) δ 1.00 (3H, t, J ) 6.7 Hz), 2.43 (3H,
s), 3.45 (1H, dd, J 1 ) 3.0 Hz, J 2 ) 16.8 Hz), 3.56 (1H, dd, J 1
)
7.5 Hz, J 2 ) 16.8 Hz), 4.02 (2H, m, becoming an AB system, J
) 10.5 Hz, upon irradiation at δ ) 1.0), 5.59 (1H, dd, J 1 ) 3.0
Hz, J 2 ) 7.5 Hz), 7.16-7.99 (4H, m), 7.36 (2H, d, J ) 8.1 Hz),
8.06 (2H, d, J ) 8.1 Hz); 13C NMR (50 MHz) 14.30, 22.18, 32.54,
57.29, 62.62, 128.04, 128.34, 128.55 (q), 128.81 (q), 129.39,
129.57, 130.08, 134.12, 136.21 (q), 145.42 (q), 163.09 (q), 170.08
(q). Anal. Calcd for C19H19NO5S: C, 61.11; H, 5.13; N, 3.75;
S, 8.59. Found: C, 61.20; H, 5.12; N, 3.76; S, 8.62.].
Crude
2
gave ethyl 2-diazo-3-[2-({[(4-methylphenyl)-
sulfonyl]amino}carbonyl)phenyl]propanoate 3a as an oil; 1H
NMR (200 MHz) δ 1.22 (3H, t), 2.44 (3H, s), 3.67 (2H, s), 4.22
(2H, q), 7.25-8.11 (8H, m). Compound 3a furnished quanti-
tatively isoquinolinone 6 after 8 days at rt in chloroform
solution; the decomposition of 3a to 6 was virtually immediate
in the presence of silica gel.
Rea ction of Tosyl Azid e w ith Eth yl 1-Oxo-1,2,3,4-
tetr ah ydr o-2-n aph th alen ecar boxylate (1b). Without aque-
ous workup, column chromatography of the crude product
obtained by evaporation of the solvent gave ethyl 2-azido-1-
oxo-1,2,3,4-tetrahydro-2-naphthalenecarboxylate 5b [mp )
31-33 °C; 1H NMR (200 MHz) δ 1.28 (3H, t, J ) 6.9 Hz), 2.08-
2.25 (1H, m), 2.51-2.70 (1H, m), 2.83-3.23 (2H, m), 4.29 (2H,
q, J ) 6.9 Hz), 7.21-8.08 (4H, m); 13C NMR (50 MHz) 14.07,
24.81, 31.40, 62.71, 70.89 (q), 127.27, 128.50, 129.91, 129.96
Exp er im en ta l Section
Gen er a l P r oced u r es. The starting keto esters 1a ,9 1b,10
1c,11 2a ,12 2b,13 as well as tosyl14 and 4-nitrobenzenesulfonyl15
azide, were prepared following known procedures. [CAU-
(11) Anderson, A. G., J r.; Greef, H. F. J . Am. Chem. Soc. 1952, 74,
5203.
(8) Evans, D. A.; Britton, T. C.; Ellman, J . A.; Dorow, R. L. J . Am.
Chem. Soc. 1990, 112, 4011.
(9) Sartori, G.; Bigi, F.; Maggi, R.; Bernardi, G. L. Tetrahedron Lett.
1993, 34, 7339.
(12) Harmata, M.; Murray, T. J . Org. Chem. 1989, 54, 3761.
(13) Oommen, P. K. Aust. J . Chem. 1976, 29, 1393.
(14) Regitz, M.; Hocker, J .; Liedhegeum, A. Org. Synth. 1968, 48,
36.
(10) Bachmann, W. E.; Wendler, N. L. J . Am. Chem. Soc. 1946, 68,
2580.
(15) Reagan, M. T.; Nickon, A. J . Am. Chem. Soc. 1968, 90, 4102.
(16) Bollinger, F. W.; Tuma, L. D. Synlett. 1996, 407.

Influence of Dicarbonyl Substrate and Azide Reagent
(q), 134.70, 143.57 (q), 168.58 (q), 189.51 (q). Anal. Calcd for
J . Org. Chem., Vol. 63, No. 14, 1998 4683
tate 9b [yellow solid, mp ) 56-58 °C (dec); 1H NMR (200 MHz)
δ 2.33-2.56 (2H, m), 2.44 (3H, s), 2.71-3.02 (2H, m), 3.87 (3H,
s), 7.02-7.35 (6H, m), 7.83 (2H, d, J ) 8.1 Hz)]. In benzene
solution, compound 9b was quantitatively converted (slowly
at rt, in 10 min at 80 °C) into methyl 2-[(4-methylphenyl)sul-
fonyl]-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-1-carboxy-
C
13H13N3O3: C, 60.23; H, 5.05; N, 16.21. Found: C, 60.32; H,
5.07; N, 16.17.] and trace amounts of ethyl 2-diazo-4-[2-({[(4-
methylphenyl)sulfonyl]amino}carbonyl)phenyl]butanoate 3b
as a yellow oil.
Rea ction of Tosyl Azid e w ith Eth yl 5-Oxo-6,7,8,9-
tetr a h yd r o-5H-ben zo[a ]cycloh ep ten e-6-ca r boxyla te (1c).
Column chromatography of crude 1 gave ethyl 6-azido-5-oxo-
6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene-6-carboxylate 5c
as an oil [1H NMR (200 MHz) δ 1.22 (3H, t, J ) 6.9 Hz), 1.71-
2.37 (4H, m), 2.73-3.10 (2H, m), 4.24 (2H, m), 7.14-7.57 (4H,
m); 13C NMR (50 MHz) 14.40, 21.90, 31.25, 32.35, 63.05, 74.14
(q), 127.42, 129.25, 129.61, 133.06, 138.42 (q), 139.15 (q),
169.30 (q), 202.20 (q). Anal. Calcd for C14H15N3O3: C, 61.53;
H, 5.53; N, 15.38. Found: C, 61.65; H, 5.50; N, 15.42.] and a
3:2 E/Z mixture of ethyl 5-[2-({[(4-methylphenyl)-sulfonyl]-
amino}carbonyl)phenyl]-2-pentenoate 8 [E-isomer: 1H NMR
(200 MHz) δ 1.30 (3H, t, J ) 6.9 Hz), 2.17-2.41 (2H, m), 2.48
(3H, s), 2.78 (2H, bt, J ) 8 Hz), 4.26 (2H, q, J ) 6.9 Hz), 5.74
(1H, d, J ) 16 Hz), 6.89 (1H, dt, J d ) 16 Hz, J t ) 6.8 Hz),
7.17-8.17 (8H, m); Z-isomer: 1H NMR (200 MHz) δ 1.22 (3H,
t, J ) 6.9 Hz), 2.48 (3H, s), 2.87-3.09 (2H, m), 3.37-3.61 (2H,
m), 4.13 (2H, q, J ) 6.9 Hz), 5.78 (1H, d, J ) 12 Hz), 6.17 (1H,
dt, J d ) 12 Hz, J t ) 7.6 Hz), 7.17-8.08 (8H, m)].
1
late 15: mp ) 186-187 °C (from 2-propanol); H NMR (200
MHz) δ 2.47 (3H, s), 2.55-2.94 (2H, m), 2.96-3.13 (2H, m),
3.81 (3H, s), 6.55 (1H, s), 7.23-7.61 (6H, m), 7.97 (2H, d, J )
8.4 Hz); 13C NMR (50 MHz) 22.16, 28.56, 36.79, 54.16, 62.42,
127.47, 129.59 (b, 2C), 129.77, 130.77, 132.55 (q), 132.66,
136.22 (q), 137.48 (q), 145.29 (q), 170.95 (q), 172.66 (q). Anal.
Calcd for C19H19NO5S: C, 61.11; H, 5.13; N, 3.75; S, 8.59.
Found: C, 61.15; H, 5.14; N, 3.75; S, 8.62.
Rea ction of P NBSA w ith 1a . This reaction was carried
out at 0 °C for 30 min and then at rt for 2 h. Without aqueous
workup, the solvent was evaporated and the oily yellow residue
was washed several times with diethyl ether. 1H NMR
analysis of this crude product (94% yield) was consistent with
the triethylammonium salt of ethyl 2-diazo-3-[2-({[(4-nitro-
phenyl)sulfonyl]amino}carbonyl)phenyl]propanoate (4a ): 1H
NMR (200 MHz) δ 1.27 (3H, t, J ) 7.2 Hz), 1.31 (9H, t, J )
7.4 Hz), 3.18 (6H, q, J ) 7.4 Hz), 3.91 (2H, s), 4.17 (2H, q, J )
7.2 Hz), 7.13-7.35 (3H, m), 7.77 (1H, bd), 8.17 (2H, d, J ) 8.8
Hz), 8.26 (2H, d, J ) 8.8 Hz). By column chromatography,
the triethylammonium salt of 4a quantitatively gave ethyl
2-[(4-nitrophenyl)sulfonyl]-1-oxo-1,2,3,4-tetrahydro-3-isoquino-
The crude 2 gave ethyl 2-diazo-5-[2-({[(4-methylphenyl)-
sulfonyl]amino}carbonyl)phenyl]pentanoate 3c as a yellow oil.
Compound 3c gave quantitatively alkene 8 (E/Z mixture) after
10 days in chloroform solution.
1
linecarboxylate 7: mp ) 178-180 °C; H NMR (200 MHz) δ
1.07 (3H, t), 3.42-3.71 (2H, m), 4.00-4.20 (2H, m), 5.56-5.64
(1H, m), 7.20-7.58 (3H, m), 7.96 (1H, bd), 8.40 (4H, bs); 13C
NMR (50 MHz) 14.43, 32.45, 57.47, 63.00, 123.99, 127.82 (q),
128.15, 128.66, 129.01, 131.79, 134.70, 136.24 (q), 144.57 (q),
151.09 (q), 163.13 (q), 169.94 (q). Anal. Calcd for
Rea ction of Tosyl Azid e w ith Meth yl 2-Oxo-1-in d a n -
ca r boxyla te (2a ). Without aqueous workup, flash column
chromatography (ethyl acetate/ethanol) of the crude material
obtained by evaporation of the solvent gave a product that was
suspended in water and acidified with concentrated HCl.
Extraction with diethyl ether afforded methyl 4-({[(4-methyl-
phenyl)sulfonyl]amino}carbonyl)-3,4-dihydro-1-phthalazine-
carboxylate 17a (Ar ) 4-Me-C6H4) or methyl 4-({[(4-methyl-
phenyl)sulfonyl]amino}carbonyl)-1,2-dihydro-1-phthalazine-
carboxylate 17b (Ar ) 4-Me-C6H4); mp ) 181-183 °C (from
toluene); 1H NMR (200 MHz, THF-d8) δ 2.37 (3H, s), 3.72 (3H,
s), 4.98 (1H, s), 7.00 (1H, m), 7.21-7.34 (4H, m), 7.82 (2H, d,
J ) 8.4 Hz), 8.17 (1H, m), 8.47 (1H, bs); 13C NMR (50 MHz,
DMSO-d6) 21.20, 51.81, 57.15, 123.36 (q), 124.32, 125.98 (q),
126.76, 127.71, 129.32, 129.83, 130.60, 130.70 (q), 135.80 (q),
145.09 (q), 164.07 (q), 169.14 (q). Anal. Calcd for
C
18H16N2O7S: C, 53.46; H, 3.99; N, 6.93; S, 7.93. Found: C,
53.50; H, 4.00; N, 6.95; S, 7.96.
Rea ction of P NBSA w ith 1b. Column chromatography
of crude 1 gave 5b. Crude 2 was ethyl 1-({[(4-nitrophenyl)-
sulfonyl]amino}carbonyl)-1-indancarboxylate 14a (R ) Et); mp
1
) 130-132 °C (from chloroform); H NMR (200 MHz) δ 1.19
(3H, t, J ) 6.9 Hz), 2.60-2.88 (2H, m), 3.06 (2H, bt), 4.21 (2H,
q, J ) 6.9 Hz), 7.22-7.48 (4H, m), 8.28 (2H, d, J ) 8.5 Hz),
8.42 (2H, d, J ) 8.5 Hz), 9.92 (1H, bs); 13C NMR (50 MHz)
14.27, 31.69, 33.52, 63.44, 66.93 (q), 124.42, 124.52, 126.16,
127.89, 130.11, 130.40, 138.94 (q), 144.10 (q), 145.14 (q), 151.23
(q), 168.48 (q), 171.90 (q). Anal. Calcd for C19H18N2O7S: C,
54.54; H, 4.34; N, 6.70; S, 7.66. Found: C, 54.60; H, 4.33; N,
6.72; S, 7.69.
C
18H17N3O5S: C, 55.81; H, 4.42; N, 10.85; S, 8.28. Found: C,
55.89; H, 4.40; N, 10.90; S, 8.32.]. The dihydrophthalazine
slowly aromatized in solution into methyl 4-({[(4-methyl-
phenyl)sulfonyl]amino}carbonyl)-1-phthalazinecarboxylate 18
Rea ction of P NBSA w ith 1c. A vigorous evolution of
nitrogen was observed. Direct acidification of the reaction
mixture and extraction gave ethyl 1-({[(4-nitro-phenyl)-
sulfonyl]amino}carbonyl)-1,2,3,4-tetrahydro-1-naphthalenecar-
boxylate 14b (R ) Et); mp ) 155-157 °C; 1H NMR (200 MHz)
δ 1.17 (3H, t, J ) 6.9 Hz), 1.59-1.98 (2H, m), 2.25-2.48 (2H,
m), 2.83 (2H, bt), 4.18 (2H, q, J ) 6.9 Hz), 7.07-7.34 (4H, m),
8.15 (2H, d, J ) 8.5 Hz), 8.40 (2H, d, J ) 8.5 Hz), 9.09 (1H,
bs); 13C NMR (50 MHz, acetone-d6) 14.56, 20.63, 29.77, 31.41,
62.40 (q), 62.91, 125.42, 126.95, 129.25, 130.71, 131.04, 131.32,
132.44 (q), 138.89 (q), 145.71 (q), 152.15 (q), 172.22 (q), 172.03
(q). Anal. Calcd for C20H20N2O7S: C, 55.55; H, 4.66; N, 6.48;
S, 7.42. Found: C, 55.60; H, 4.64; N, 6.51; S, 7.45.
Rea ction of P NBSA w ith 2a . This reaction was carried
out at 0 °C for 10 min and then at rt for 1 h. A vigorous
evolution of nitrogen was observed. Direct acidification of the
reaction mixture gave a crude 2 that was washed many times
with diethyl ether, affording methyl 4-({[(4-nitrophenyl)-
sulfonyl]amino}carbonyl)-3,4-dihydro-1-phthalazinecarboxy-
late 17a (Ar ) 4-NO2-C6H4) or methyl 4-({[(4-nitrophenyl)-
sulfonyl]amino}carbonyl)-1,2-dihydro-1-phthalazinecarboxy-
late 17b (Ar ) 4-NO2-C6H4); mp ) 193-195 °C (dec); 1H NMR
(200 MHz, DMSO-d6) δ 3.74 (3H, s), 5.15 (1H, s), 7.30-7.46
(3H, m), 7.90-8.00 (1H, m), 8.09 (2H, d, J ) 8.8 Hz), 8.37 (2H,
d, J ) 8.8 Hz), 9.09 (1H, bs). Anal. Calcd for C17H14N4O7S:
C, 48.80; H, 3.37; N, 13.39; S, 7.66. Found: C, 48.88; H, 3.37;
N, 13.36; S, 7.69. Treatment of this dihydrophthalazine with
o-chloranil in refluxing benzene for 10 min quantitatively
1
(Ar ) 4-Me-C6H4); mp ) 200-202 °C; H NMR (300 MHz) δ
2.44 (3H, s), 4.18 (3H, s), 7.38 (2H, d, J ) 8.2 Hz), 8.03-8.12
(2H, m), 8.15 (2H, d, J ) 8.2 Hz), 8.60-8.70 (1H, m), 9.40-
9.50 (1H, m), 10.80 (1H, bs); 13C NMR (50 MHz) 22.17, 54.19,
126.12, 126.29 (q, 2C, probably C4a and C8a), 126.84, 129.10,
130.17, 134.86, 135.33, 135.93 (q), 145.88 (q), 147.55 (q), 153.23
(q), 161.86 (q), 164.85 (q). Anal. Calcd for C18H15N3O5S: C,
56.10; H, 3.92; N, 10.90; S, 8.32. Found: C, 56.17; H, 3.91; N,
10.94; S, 8.29. The structure of 18 (Ar ) 4-Me-C6H4) was
confirmed by X-ray diffraction (see below). The dihydro-
phthalazine was quantitatively converted into 18 by a 10-min
reflux in benzene solution in the presence of o-chloranil.
Rea ction of Tosyl Azid e w ith Meth yl 2-Oxo-1,2,3,4-
tetr a h yd r o-1-n a p h th a len eca r boxyla te (2b). This reaction
was carried out at 0 °C for 30 min and then at rt for 12 h.
Without aqueous workup, the solvent was evaporated and the
residue chromatographed to give methyl 1-{[(4-methylphenyl-
)sulfonyl]amino}-2-oxo-1,2,3,4-tetrahydro-1-naphthalenecar-
boxylate 11 [mp ) 126-127 °C; 1H NMR (200 MHz) δ 2.35
(3H, s), 2.90-3.52 (4H, m), 3.65 (3H, s), 6.44 (1H, bs), 6.76-
6.90 (2H, m), 7.05 (2H, d, J ) 8.1 Hz), 7.19-7.30 (4H, m); 13
C
NMR (50 MHz) 21.32, 27.93, 38.29, 54.07, 69.00 (q), 127.13,
127.21, 128.86, 129.02, 129.13, 129.48, 132.40 (q), 137.50 (q),
138.50 (q), 142.90 (q), 168.05 (q), 204.00 (q). Anal. Calcd for
C
19H19NO5S: C, 61.11; H, 5.13; N, 3.75; S, 8.59. Found: C,
61.16; H, 5.11; N, 3.74; S, 8.63.] and methyl 2-diazo-2-[2-(3-
{[(4-methylphenyl)sulfonyl]amino}-3-oxopropyl)phenyl]ace-

4684 J . Org. Chem., Vol. 63, No. 14, 1998
Benati et al.
afforded methyl 4-({[(4-nitrophenyl)sulfonyl]amino}carbonyl)-
1-phthalazinecarboxylate 18 (Ar ) 4-NO2-C6H4); mp ) 237-
238 °C (dec); 1H NMR (200 MHz, DMSO-d6) δ 4.11 (3H, s),
8.17-8.36 (4H, m), 8.41 (2H, d, J ) 8.4 Hz), 8.54 (1H, bs),
8.60 (2H, d, J ) 8.4 Hz); 13C NMR (50 MHz, DMSO-d6) 53.83,
124.04 (q), 124.22 (q), 124.81, 125.19, 125.67, 129.57, 134.96,
135.11, 145.47 (q), 150.50 (q), 152.25 (q), 153.24 (q), 164.69
(q), 164.72 (q). Anal. Calcd for C17H12N4O7S: C, 49.04; H,
2.91; N, 13.46; S, 7.70. Found: C, 49.11; H, 2.91; N, 13.42; S,
7.73. Column chromatography of the above ethereal washings
17a or 17b gave methyl 2-[(4-nitrophenyl)sulfonyl]-3-oxo-
1,2,3,4-tetrahydro-1-isoquinolinecarboxylate 13; mp ) 159-
MHz) δ 2.93-3.27 (3H, m), 3.47-3.55 (1H, m), 3.70 (3H, s),
6.70 (1H, bs), 6.80-6.85 (2H, m), 7.17-7.30 (2H, m), 7.50 (2H,
d, J ) 8.5 Hz), 8.10 (2H, d, J ) 8.5 Hz); 13C NMR (50 MHz)
28.50, 39.10, 50.92, 69.65 (q), 124.11, 127.24, 128.44, 128.50,
129.28, 129.57, 132.92 (q), 138.38 (q), 147.44 (q), 149.99 (q),
168.19 (q), 203.67 (q). Anal. Calcd for C18H16N2O7S: C, 53.46;
H, 3.99; N, 6.93; S, 7.93. Found: C, 53.53; H, 3.99; N, 6.91; S,
7.96.], and methyl 1-({[(4-nitrophenyl)sulfonyl]amino}carbonyl)-
1-indancarboxylate 14a (R ) Me) [mp ) 161-162 °C (by
dissolving in dichloromethane and reprecipitating with diethyl
ether); 1H NMR (200 MHz) δ 2.55-2.86 (2H, m), 3.05 (2H, bt,
J ) 7.3 Hz), 3.73 (3H, s), 7.16-7.40 (4H, m), 8.20 (2H, d, J )
8.5 Hz), 8.35 (2H, d, J ) 8.5 Hz), 9.80 (1H, bs); 13C NMR (50
MHz) 31.88, 33.95, 54.40, 66.67 (q), 124.79, 125.10, 126.37,
128.15, 130.39, 130.64, 138.96 (q), 144.23 (q), 146.36 (q), 151.48
(q), 168.73 (q), 172.61 (q). Anal. Calcd for C18H16N2O7S: C,
53.46; H, 3.99; N, 6.93; S, 7.93. Found: C, 53.55; H, 4.01; N,
6.90; S, 7.97.].
1
161 °C; H NMR (200 MHz) δ 3.73 (1H, d, J ) 18 Hz), 3.76
(3H, s), 3.84 (1H, d, J ) 18 Hz), 6.16 (1H, s), 7.07-7.16 (1H,
m), 7.27-7.36 (2H, m), 7.43-7.53 (1H, m), 8.22 (2H, d, J )
8.5 Hz), 8.34 (2H, d, J ) 8.5 Hz); 13C NMR (50 MHz) 39.53,
54.04, 62.27, 124.11, 128.14, 128.23, 128.43, 129.13 (q), 130.15,
131.29 (q), 131.46, 144.04 (q), 151.26 (q), 169.02 (q), 169.39
(q). Anal. Calcd for C17H14N2O7S: C, 52.31; H, 3.61; N, 7.18;
S, 8.21. Found: C, 52.38; H, 3.62; N, 7.14; S, 8.25.
Ack n ow led gm en t. The authors gratefully acknowl-
edge financial support from MURST and CNR (Rome).
The investigation is also supported by the University
of Bologna (funds for selected research topics, A. A.
1995-97).
Rea ction of P NBSA w ith 2b. The IR spectrum of the
reaction crude showed neither diazo nor azido absorption. The
crude was then poured into water, acidified with concentrated
HCl, and extracted with diethyl ether. The solvent was
evaporated and the residue chromatographed to give methyl
2-[(4-nitrophenyl)sulfonyl]-3-oxo-2,3,4,5-tetrahydro-1H-2-ben-
Su p p or tin g In for m a tion Ava ila ble: IR and MS data for
compounds 3a -c, 4a , 5a -c, 6, 7, 9b, 11-13, 14a ,b (R ) Et),
14a (R ) Me), 15, 16, 17a /b (Ar ) 4-Me-C6H4 and 4-NO2-C6H4),
18 (Ar ) 4-Me-C6H4), X-ray crystal structure analysis and
selected bond lengths and angles for the phthalazine 18 (Ar
) 4-Me-C6H4) (15 pages). 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.
1
zazepine-1-carboxylate 16 [mp ) 196-197 °C; H NMR (200
MHz) δ 2.60-2.87 (2H, m), 2.95-3.10 (2H, m), 3.80 (3H, s),
6.40 (1H, s), 7.15-7.53 (4H, m), 8.20 (2H, d, J ) 8.5 Hz), 8.35
(2H, d, J ) 8.5 Hz); 13C NMR (75 MHz) 27.98, 36.34, 54.04,
62.23, 123.69, 127.30, 129.69, 130.41, 130.56, 131.70 (q),
132.19, 136.95 (q), 144.45 (q), 150.57 (q), 170.41 (q), 172.40
(q). Anal. Calcd for C18H16N2O7S: C, 53.46; H, 3.99; N, 6.93;
S, 7.93. Found: C, 53.52; H, 3.98; N, 6.95; S, 7.96.], methyl
1-{[(4-nitrophenyl)sulfonyl]amino}-2-oxo-1,2,3,4-tetrahydro-1-
naphthalenecarboxylate 12 [mp ) 173-174 °C; 1H NMR (200
J O980223W