Reactions of benzocyclic β-keto esters with sulfonyl azides. 2. Further insight into the influence of azide structure and solvent on the reaction course

Article abstract of DOI:10.1021/jo9901541

The reactions of 2-ethoxycarbonyl-1-benzosuberone with 4- methoxybenzenesulfonyl, 2,4,6-triiso-propylbenzenesulfonyl, methanesulfonyl, and trifluoromethanesulfonyl azide, in the presence of triethylamine, have been investigated in N,N-dimethylformamide, a

Full text of DOI:10.1021/jo9901541

5132
J . Org. Chem. 1999, 64, 5132-5138
Rea ction s of Ben zocyclic â-Keto Ester s w ith Su lfon yl Azid es. 2.1
F u r th er In sigh t in to th e In flu en ce of Azid e Str u ctu r e a n d Solven t
on th e Rea ction Cou r se
Luisa Benati,* Daniele Nanni, and Piero Spagnolo
Dipartimento di Chimica Organica “A. Mangini”, Universita` di Bologna,
Viale Risorgimento 4, I-40136 Bologna, Italy
Received J anuary 27, 1999
The reactions of 2-ethoxycarbonyl-1-benzosuberone with 4-methoxybenzenesulfonyl, 2,4,6-triiso-
propylbenzenesulfonyl, methanesulfonyl, and trifluoromethanesulfonyl azide, in the presence of
triethylamine, have been investigated in N,N-dimethylformamide, acetonitrile, or tetrahydrofuran
with the intent of clarifying the influence of both the azide electrophile and solvent on the reaction
course. The present findings, in addition to those previously obtained with tosyl and 4-nitroben-
zenesulfonyl azide, indicate that both the electronic features of the sulfonyl azide and the solvent
polarity greatly affect the possible occurrence of azidation and/or Favorskii-type ring contraction
at the expense of deacylating diazo transfer. Azidation is promoted by the less electrophilic azides,
while it is virtually avoided by the more electrophilic ones. Ring contraction occurs to a limited
extent with the less electrophilic azides, but it becomes the main process with those more
electrophilic. Moreover, azidation is virtually unaffected by the solvent polarity, while ring
contraction can markedly be enhanced by a highly polar solvent. Firm evidence has additionally
been obtained that, in contrast to a previous claim, trifluoromethanesulfonyl azide can normally
perform diazotization of acyclic â-keto esters in preference to azidation.
In tr od u ction
curiously to transfer the azido function to the methine
and even methylene group of acyclic â-diketones and
â-keto esters.8
Sulfonyl azides are important intermediates widely
used to accomplish diazo group transfer to the activated
methylene of â-dicarbonyl compounds as well as to the
poorly activated methylene of monocarbonyl compounds,
in which cases prior activation by suitable acylation is
normally required (deacylating diazo tranfer).2 Toluene-
4-sulfonyl (tosyl) azide (TsN3) is often employed, but in
recent years various studies have clearly revealed that
the efficiency of the diazo transfer process can be mark-
edly improved by a proper choice of sulfonyl diazo donors
other than TsN3.
Among several factors making a single azide not
satisfactory for all uses, there is the fact that sulfonyl
azides, to a varying and rather unpredictable extent, also
have a tendency to transfer the azido group. For instance,
2,4,6-triisopropylbenzenesulfonyl (trisyl) azide, while
proving superior to tosyl azide and 4-nitrobenzenesulfo-
nyl azide (PNBSA) in the diazotization of cyclic ketones,3
is instead inferior to those azides in the diazotization of
acyclic imide and ester enolates owing to preferential
azidation.4 Furthermore, trifluoromethanesulfonyl (tri-
flyl) azide seemingly behaves as a powerful diazo donor
to amines5,6 and enamino ketones,7 but it is reported
In previous work we have studied sulfonyl azide
reactions of monocyclic and benzocyclic â-keto esters.1,9
In the presence of triethylamine (TEA), these dicarbonyl
substrates can successfully be transformed by TsN3 into
synthetically appealing ring-opened N-tosylcarbamoyl-
substituted R-diazo esters through a novel deacylating
diazo transfer process. However, with those benzocyclic
keto esters bearing a conjugated aryl ketone moiety, a
competing R-azidation process occurs to an important or
even exclusive extent.1 Replacement of TsN3 with more
reactive PNBSA interestingly results in suppression of
azidation, but the expected diazo transfer may be pre-
vented by the preferential occurrence of Favorskii-type
ring contraction.1 These observations therefore revealed
that, besides the structural features of the cyclic sub-
strate, those of the azide reagent might greatly influence
the course of our keto ester reactions.
To gain further useful information about the effect of
sulfonyl azide structure, we were then prompted to
consider the use of other arenesulfonyl and alkanesul-
fonyl azides of varying electrophilic power, including
4-methoxybenzenesulfonyl azide (PMBSA), trisyl azide,
methanesulfonyl (mesyl) azide (MsN3), and triflyl azide.
2-Ethoxycarbonyl-1-benzosuberone 1 was chosen as model
substrate for this study in view of our earlier observation
that this readily available benzocyclic keto ester can
actually undergo azidation, diazotization, and ring con-
traction upon reaction with PNBSA and/or TsN3. In the
(1) Part 1: Benati, L.; Calestani, G.; Nanni, D.; Spagnolo, P. J . Org.
Chem. 1998, 63, 4679.
(2) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods
for Organic Synthesis with Diazo Compounds; Wiley-Interscience: New
York, 1998, Chapter 1. Ye, T.; McKervey, M. A. Chem. Rev. 1994, 94,
1091. Regitz, M.; Maas, G. Diazo Compounds: Properties and Syn-
thesis; Academic Press: New York, 1986; Chapter 13.
(3) Lombardo, L.; Mander, L. N. Synthesis 1980, 368. Coates, R. M.;
Kang, H.-Y J . Org. Chem. 1987, 52, 2065. Uyehara, T.; Takehara, N.;
Ueno, M.; Sato, T. Bull. Chem. Soc. J pn. 1995, 68, 2687.
(4) Evans, D. A.; Britton, T. C.; Ellman, J . A.; Dorow, R. L. J . Am.
Chem. Soc. 1990, 112, 4011.
(6) Zaloom, J .; Roberts, D. C. J . Org. Chem. 1981, 46, 5173.
(7) Norbeck, D. W.; Kramer, J . B. J . Am. Chem. Soc. 1988, 110, 7217.
(8) Hakimelahi, G. H.; J ust, G. Synth. Commun. 1980, 10, 429.
(9) Benati, L.; Nanni, D.; Spagnolo, P. J . Chem. Soc., Perkin Trans.
1 1997, 457.
(5) Cavender, C. J .; Shiner, V. J ., J r. J . Org. Chem. 1972, 37, 3567.
10.1021/jo9901541 CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/17/1999

Benzocyclic â-Keto Esters and Sulfonyl Azides
J . Org. Chem., Vol. 64, No. 14, 1999 5133
Ta ble 1. Yield s (%)a of Azid o-Tr a n sfer , Rin g-Con tr a ction , a n d Dia zo-Tr a n sfer P r od u cts fr om th e Rea ction s of
Ben zosu ber on e 1 w ith Su lfon yl Azid esb
azido-transfer
product 2 (%)
ring-contraction
product (%)
diazo-transfer
product(s) (%)
entry
sulfonyl azide
solvent
time
1
2
3
4
5
6
7
8
9
PMBSA
MsN3
MsN3
trisyl azide
trisyl azide
triflyl azidec
PNBSAd
TsN3
THF
THF
AN
THF
AN
CH2Cl2
THF
THF
AN
6 d
3 d
15 h
10 d
4 d
1 h
4 h
5 d
1 d
31
24
19
72
80
3a (34)
3b (30)
3b (60)
5a (14)
5b (28)
5b (8)
3c (71)
3e (75)
3d (25)
3d (56)
3d (30)
5c (15)
31
20
32
4d (20), 5d (13)
4d (18)
5d (10)
TsN3
TsN3
10
DMF
10 h
a
b
Yields isolated by column chromatography. Reactions were normally carried out at room temperature in the presence of TEA.
c Reaction carried out at 0 °C. See ref 1.
d
course of this work we happened to discover that triflyl
azide performed no azidation of compound 1. This fact
also led us to explore the reactivity of triflyl azide with
further keto-ester substrates and thence to prove that
this azide can by no means behave as a special azido
transfer agent.
Resu lts a n d Discu ssion
Following our previous procedure, PMBSA was treated
with the benzosuberone 1 in dry tetrahydrofuran (THF),
in the presence of TEA, for ca. 6 days, until TLC showed
essential absence of the initial reactants. After aqueous
acid workup, chromatographic separation gave the azide
2 and the ring-contracted tetralin derivative 3a along
with minor amounts of the pentenoate 5a , which was the
formal â-hydride-elimination carbene product of the
unstable diazo pentanoate 4a (Figure 1 and Table 1,
entry 1).
Under analogous conditions mesyl azide similarly
furnished comparable amounts of 2 and the respective
ring-contraction and carbene products 3b and 5b (Table
1, entry 2). Trisyl azide, instead, reacted even more
slowly and eventually yielded the azide 2 as the exclusive
product (Table 1, entry 4). By contrast, highly hazardous
triflyl azide, which was produced as a dichloromethane
solution from triflic anhydride and sodium azide through
a documented method,5,6 displayed a very fast reaction
with the keto ester 1 and furnished no azidation. This
sulfonyl azide furnished mainly the tetralin 3c and, to a
little extent, the pentenoate 5c (Table 1, entry 6).
The behavior of PNBSA was previously found to
resemble that of triflyl azide. In the presence of the
benzosuberone 1, in fact, PNBSA rapidly yielded the ring-
contracted compound 3e, while it totally failed to afford
any azidation product (Table 1, entry 7). On the other
hand, tosyl azide had been found to exhibit a behavior
closely similar to that of PMBSA and MsN3. Indeed, our
earlier reaction of TsN3 with compound 1 had proved
comparably slow and, additionally, had resulted in
analogous occurrence of both azidation and diazo trans-
fer, although no parallel occurrence of ring contraction
had been revealed at the time. However, a present
reinvestigation led us to establish that the reaction
actually results in ring contraction to an extent compa-
rable to both azidation and diazo transfer (Table 1, entry
8).
F igu r e 1.
distribution of resulting azidation, diazo-transfer, and
ring-contraction products. Poorly electrophilic TsN3, PMB-
SA, MsN3, and, particularly, trisyl azide show a common
propensity to perform significant azidation at the expense
of diazo transfer and ring contraction, whereas highly
electrophilic triflyl azide and PNBSA avoid azidation
essentially in favor of ring contraction.
The observed findings can readily be explained on the
basis of the mechanism previously invoked to explain our
reactions of cyclic keto esters with sulfonyl azides.1,9 This
would primarily involve the triazenyl anion 6 in the
production of azide 2 and the cyclized triazoline 7 in the
formation of both ring-contraction and diazo-transfer
products 3 and 4. PMBSA, TsN3, MsN3, and trisyl azide
normally react with benzosuberone enolate to give ini-
The general evidence provided by the benzosuberone
1 reactions clearly suggests that the electronic features
of the sulfonyl azide reagent can profoundly influence the

5134 J . Org. Chem., Vol. 64, No. 14, 1999
Benati et al.
Sch em e 1
tially the respective triazenyl anions 6a ,b,d ,f. The in-
termediates 6a ,b,d , owing to the limited reactivity of the
aromatic ketone moiety,1 are discouraged from cyclizing
to the corresponding triazolines 7a ,b,d and thence some-
what entitled to furnish the azide 2. The intermediate
6f, whose cyclization to triazoline 7f is further discour-
aged by the steric hindrance afforded by the o-isopropyl
groups, yields only 2. By contrast, triflyl azide and
PNBSA fail to give the corresponding triazenyl anions
6c,e, which in principle might have led to the azide 2
more readily than their congeners 6a ,b,d . Presumably,
those highly reactive azides react with the benzosuberone
enolate to give directly triazoline adducts 7c,e via a
concerted 1,3-dipolar cycloaddition process.
Sch em e 2
The ensuing triazolines 7a ,b,d show a comparable
propensity for causing ring contraction and diazo trans-
fer, whereas the analogues 7c,e, bearing a more strongly
electron-attracting sulfonyl substituent, largely favor ring
contraction. This observation interestingly suggests that
those intermediates 7 can decompose through two dis-
tinctly different modes. Single-step [3 + 2] cycloreversion
would result in deacylating diazo transfer, whereas
heterolytic ring opening would lead to a diazonium
zwitterion 8 and thence to ring contraction with nitrogen
loss. This possibility is actually substantiated by the
findings that we obtained by reacting the keto ester 1
with TsN3 and MsN3 in acetonitrile (AN) or N,N-di-
methylformamide (DMF). In fact, in such highly polar
solvents, both reactions, besides proceeding much more
quickly, could result in a marked enhancement of the
proportion of ring contraction relative to diazo transfer
(Table 1, entries 2, 3, and 8-10). Under these circum-
stances, the extent of the azidation process remained
instead roughly constant. This fact indicates that the
possible fragmentation of triazenyl anion 6 to azide 2,
with respect to its cyclization to triazoline 7, is hardly
affected by the solvent polarity. Accordingly, exclusive
formation of azide 2 still occurred, although in a shorter
time, when trisyl azide was reacted with the benzo-
suberone 1 using AN in place of THF (Table 1, entries 4
and 5).
Sch em e 3
Sch em e 4
The total failure of triflyl azide to perform azidation
of the compound 1, although being consistent with the
reactivity trend displayed by all of our azides, seemed
rather surprising in view of the mentioned report that
triflyl azide transfers the azido group to â-dicarbonyl
compounds, at least the acyclic ones.8 We were then led
to study further reactions of that azide with the five- and
six-membered 1- and 2-benzocycloalkanones 9-12 (Fig-
ure 1), which we had already investigated with both TsN3
and PNBSA.1
In the usual solvent dichloromethane, triflyl azide
rapidly reacted with the indanones 9 and 10 to afford
exclusively the diazo amido esters 13 and 14, respec-
tively. The diazo ester 13 was obtained in virtually
quantitative yield as its triethylammonium salt (Scheme
1). The diazo ester 14 was decomposed under the reaction
conditions to give an isomeric mixture of the ring-
expanded compounds 15 and 16, which were formally
produced through intramolecular attack of a transient
carbene at the nitrogen and oxygen atom of the carbam-
oyl moiety (Scheme 2).1,9 With the tetralone homologue
11, under analogous conditions, triflyl azide furnished
the indan derivative 17, but in moderate yield, and
provided no evidence for any production of azide (Scheme
3). Moreover, with the isomeric tetralone 12, triflyl azide
yielded only the aminated derivative 18, which actually
was the expected product of an intermediate triazoline
suffering a peculiar decomposition mode (Scheme 4).1
The above findings clearly support our initial observa-
tion with the benzosuberone 1, that the highly reactive
triflyl azide can display a chemical behavior closely
resembling that of PNBSA. Indeed, consistent with our
earlier results encountered with PNBSA,1 triflyl azide
proved generally reluctant to perform azidation, but it
was fairly prone to effect diazotization of the indanones
9,10, ring contraction of the 1-tetralone 11, and, ad-
ditionally, amination of the 2-tetralone 12. Incidentally,
it is worth noting that TsN3, while similarly performing
diazo transfer to both indanones 9 and 10, exhibits only
azido transfer with the tetralone 11.1
In the light of the conclusive evidence obtained with
the cyclic keto esters 1 and 9-12, we subsequently turned
to examine the acylated propionates 19a ,b (Scheme 5).
We aimed to ascertain the possible reasons why triflyl
azide might act as a peculiar azido group donor toward
the acyclic counterparts. Dicarbonyl analogues of 19a ,b
have recently been shown by Taber and co-workers to
undergo deacylating diazo transfer smoothly with PN-
BSA or MsN3 and DBU.10 Nevertheless, compound 19a
itself and other acyclic congeners were originally reported

Benzocyclic â-Keto Esters and Sulfonyl Azides
J . Org. Chem., Vol. 64, No. 14, 1999 5135
Sch em e 5a
to cyclize to triazolines. Conversely, azidation is almost
avoided by the highly electrophilic azides able to give
directly the triazoline cycloadducts. However, with such
highly reactive azides, ring contraction may become the
most preferred process as a likely result of a special
preference of ensuing triazolines to suffer heterolytic
fragmentation to diazonium zwitterions over concerted
cycloreversion to deacylated diazo componds. Azidation
is hardly affected by the solvent polarity, but ring
contraction can be markedly enhanced by the use of a
highly polar solvent. Furthermore, our present findings
have also revealed that, in contrast with a previous claim,
highly reactive triflyl azide can normally be envisaged
as a diazo-transfer agent rather than an azido-transfer
one.
a
Reagents: i, triflyl azide, TEA, CH2Cl2; ii, TsN3 or PNBSA,
DBU, CH2Cl2.
Exp er im en ta l Section
to undergo azidation with triflyl azide, which was be-
lieved to form cleanly in situ in DMF upon treatment of
triflyl chloride with sodium azide.8 However, both keto
esters 19a ,b, when usually reacted in dichloromethane
with triflyl azide, furnished the deacylated diazo com-
pound 20 in moderate yields (40-50%). In either case
there was no occurrence at all of any possible azido-
transfer product, 21a or 21b, as clearly proven by
spectral comparison of the crude mixtures with authentic
azides 21a ,b, produced through bromination of 19a ,b and
subsequent displacement of halide with azide ion. In full
agreement with Taber’s findings, the diazo compound 20
was also exclusively formed, but in higher yields
(75-85%), from further reactions of 19a ,b with PNBSA
and TsN3 using DBU as the base (Scheme 5).10,11
Our overall observations therefore lead to the conclu-
sion that triflyl azide can normally act with â-keto esters
and, presumably, â-diketones as a reactive diazo group
donor. Consequently, the reported azidations were not
due to claimed azido-transfer reactions of triflyl azide,
but they must have been caused by other unclear
reactions which could occur under those circumstances
as a presumable result of improper choice of triflyl
chloride8,12 for the in situ production of the azide target
in DMF. It is hoped that future studies will succeed in
explaining such intriguing results.
Gen er a l P r oced u r es. The starting keto esters 1 and
9-12, as well as tosyl and 4-nitrobenzenesulfonyl azide
(PNBSA), were prepared by the known methods cited in
part 1.1 Ethyl 2-methyl-3-oxobutanoate (19a ) was com-
mercially available; ethyl 2-methyl-3-oxo-3-phenylpro-
panoate (19b) was prepared from commercially available
ethyl benzoyl acetate according to the procedure used by
Taber10c for 1,3-diketones and was authenticated by
spectral comparison with the literature.13 4-Methoxyben-
zenesulfonyl azide (PMBSA),14 mesyl azide,15 and trisyl
azide16 were obtained by literature methods. Triflyl azide
was prepared by the protocol of Cavender and Shiner5
by treating triflic anhydride in dichloromethane with
aqueous sodium azide. The resulting dichloromethane
solution of triflyl azide was washed with aqueous NaOH,6
dried with magnesium sulfate, and then directly used.
[Ca u tion : All the employed sulfonyl azides are poten-
tially explosive; these compounds have recently been
subjected to risk evaluation.17 Explosions may be ex-
pected to result in situations involving neat triflyl azide,5
and although we experienced no problems in handling
dichloromethane solutions of the azide (even stored at
-14 °C for several weeks), we feel that for safety’s sake
the solutions should under no circumstances be allowed
to evaporate.] Common reaction products such as the
azide 21 and the diazopropanoate 2018 were normally
identified by spectral comparison with authentic samples.
All solvents were distilled before use. THF was distilled
from sodium benzophenone and dichloromethane from
calcium hydride. Anhydrous acetonitrile (AN) and dim-
ethylformamide (DMF) were available from Aldrich. All
melting points (Kofler melting point apparatus) are
uncorrected. 1H and 13C NMR spectra were normally
carried out in CDCl3 solutions, using tetramethylsilane
as the internal standard. Mass spectra were determined
by the electron impact method (70 eV). IR spectra were
recorded in chloroform solutions, unless otherwise stated.
Column chromatography 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 acetone.
Con clu sion s
Present and previous findings from our cyclic keto ester
reactions with sulfonyl azides have clearly shown that,
at least in the case of the 1-benzocycloalkanone deriva-
tives, both the azide electrophile structure and the
solvent polarity can greatly affect the outcome of azida-
tion and/or ring contraction at the expense of deacylating
diazo transfer. Azidation is especially promoted by slightly
electrophilic (and sterically hindered) sulfonyl azides,
owing to a limited proneness of derived triazenyl anions
(10) Taber, D. F.; You, K.; Song, Y. J . Org. Chem. 1995, 60, 1093.
(b) Taber, D. F.; Herr, R. J .; Pack, S. K.; Geremia, J . M. J . Org. Chem.
1996, 61, 2908. (c) For related deacylating diazo transfer reactions of
â-diketones with PNBSA, see: Taber, D. F.; Gleave, D. M.; Herr, R.
J .; Moody, K.; Hennessy, M. J . J . Org. Chem. 1995, 60, 2283.
(11) It is noteworthy that acyclic â-keto esters, contrary to our cyclic
counterparts, normally undergo deacylating diazo transfer in prefer-
ence to azidation and/or Favorskii-type rearrangement, irrespective
of the aromatic or aliphatic ketone moiety and the sulfonyl azide
reagent. This fact probably arises from comparatively easier production
of monocyclic triazolines as well as from higher propensity of such
monocyclic intermediates to suffer ring-cleavage fragmentations to
diazo compounds.
(13) Newman, M. S.; Stalick, W. M. J . Org. Chem. 1973, 38, 3386.
(14) Reagan, M. T.; Nickon, A. J . Am. Chem. Soc. 1968, 90, 4096.
(15) Danheiser, R. L.; Miller, R. F.; Brisbois, R. G.; Park, S. Z. J .
Org. Chem. 1990, 55, 1959.
(16) Harmon, R. E.; Wellman, G.; Gupta, S. K. J . Org. Chem. 1973,
38, 11.
(17) Bollinger, F. W.; Tuma, L. D. Synlett 1996, 407.
(18) Regitz, M.; Menz, F. Chem. Ber. 1968, 101, 2622.
(12) Hakimelahi, G. H.; J ust, G. Tetrahedron Lett. 1979, 38, 3643.

5136 J . Org. Chem., Vol. 64, No. 14, 1999
Benati et al.
Syn t h esis of E t h yl 2-Azid o-2-m et h yl-3-oxob u -
ta n oa te (21a ) a n d Eth yl 2-Azid o-2-m eth yl-3-oxo-3-
p h en ylp r op a n oa te (21b). Ketoester 19a (9 mmol) was
treated with N-bromosuccinimide (9 mmol) in tetrachlo-
romethane (50 mL) in the presence of catalytic amounts
of dibenzoyl peroxide, and the resulting solution was
refluxed for 10 h. After cooling, succinimide was filtered
off and the filtrate was concentrated under vacuum to
give ethyl 2-bromo-2-methyl-3-oxobutanoate in almost
quantitative yield. Without any further purification, the
bromide was dissolved in dimethyl sulfoxide (7 mL) and
treated with sodium azide (9 mmol). The mixture was
stirred at room temperature for 2 h, and then it was
poured into water and extracted with diethyl ether. The
organic phase was dried, the solvent was evaporated, and
the residue was chromatographed on a silica gel column
eluting with light petroleum/diethyl ether 95:5 v/v. Azide
The reactions of TsN3 and PNBSA with the acyclic
compounds 19a ,b were performed by treating with DBU
(2 equiv)10 a dichloromethane solution of the starting
reagents. The resulting mixture was kept at 0 °C for 1 h
and then at room temperature overnight. The triflyl azide
reactions with the keto esters 19a ,b were performed at
0 °C by adding dropwise triethylamine (3 mmol) to a
solution of the appropriate keto ester (3 mmol) in 20 mL
of a 0.15 M solution of triflyl azide in dichloromethane.
The resulting mixture was kept at 0 °C for 1 h and then
at room temperature for 5 h. In all cases, the reaction
mixtures were carefully concentrated under atmospheric
pressure at ca. 40 °C to give a yellow oily residue. This
1
was preliminarily shown by IR and H NMR analysis to
contain the diazopropanoate 20 with no accompanying
azide 21a or 21b. The mixture was then quickly chro-
matographed, under a slight nitrogen pressure, on a very
short silica gel (230-400, 60 Å) column eluting with
pentane. The yellow-colored fractions were evaporated
under atmospheric pressure at ca. 40 °C to give the
diazopropanoate 20.
21a was obtained in 50% yield as an oil:19 IR νmax (cm-1
,
1
CH2Cl2) 2100 (N3), 1740 (CO), 1720 (CO); H NMR (200
MHz) δ 1.32 (3H, t, J ) 7 Hz), 1.58 (3H, s), 2.24 (3H, s),
4.28 (2H, q, J ) 7 Hz); 13C NMR (50 MHz) δ 14.44, 19.65,
25.78, 63.30, 73.46 (q), 168.91 (q), 200.85 (q). Following
the same procedure, azide 21b was obtained in 45% yield
as an oil: IR νmax (cm-1) 2120 (N3), 1740 (CO), and 1690
(CO); 1H NMR (200 MHz) δ 1.11 (3H, t, J ) 6.4 Hz), 1.82
(3H, s), 4.13-4.29 (2H, 2 overlapped quartets, J ) 6.4
Hz), 7.37-7.64 (3H, m), 7.91-8.04 (2H, m); 13C NMR (50
MHz) δ 14.26, 20.65, 63.24, 71.51 (q), 129.09, 129.84,
134.04 (q), 134.14, 170.22 (q), 191.48 (q).
Rea ction of P MBSA w ith th e Ben zosu ber on e 1 in
THF . Column chromatography of crude A gave 2. Chro-
matography of crude B afforded ethyl 1-({[(4-methoxyphen-
yl)sulfonyl]amino}carbonyl)-1,2,3,4-tetrahydro-1-naphthalene-
carboxylate (3a ) as a white solid, mp ) 145-146 °C (from
2-propanol) [IR νmax (cm-1) 3380 (NH), 1730 (CO), 1710
1
(CO); MS m/z 417 (M+, 3), 204 (100), 129 (82); H NMR
(200 MHz) δ 1.14 (3H, t, J ) 6.9 Hz), 1.58-1.92 (2H, m),
2.20-2.49 (2H, m), 2.78 (2H, t, J ) 6.7 Hz), 3.84 (3H, s),
4.11 (2H, q, J ) 6.9 Hz), 6.93 (2H, d, J ) 9.4 Hz), 7.02-
Rea ction s of Su lfon yl Azid es w ith Keto Ester s 1,
9-12, a n d 19a ,b. Gen er a l P r oced u r e. The reactions
of PMBSA, MsN3, TsN3, and trisyl azide (3 mmol) with
the benzosuberone 1 (3 mmol) in the presence of triethy-
lamine (TEA) (3 mmol) were properly carried out in 5
mL of THF, AN, or DMF by following the same general
procedure as described in part 11 for corresponding
reactions of TsN3 and PNBSA with benzocyclic keto
esters. With all of the above azides, every reaction
mixture was normally quenched by addition of water (20
mL) and extracted with diethyl ether (3 × 10 mL). The
combined organic extract was dried and concentrated,
and the residue (crude A) was chromatographed. The
aqueous layer was acidified with concentrated HCl and
extracted with diethyl ether (3 × 10 mL). Evaporation
of the solvent eventually gave a residue (crude B) that
was chromatographed.
The triflyl azide reactions with the keto esters 1 and
9-12 were performed at 0 °C by adding dropwise TEA
(3 mmol) to a solution of the appropriate keto ester (3
mmol) in 20 mL of a 0.15 M solution of triflyl azide in
dichloromethane. The resulting mixture was kept at 0
°C for 15-60 min and then at room temperature for 4-5
h. After IR analysis of the crude, to verify the absence of
any azidation product, the mixture was generally poured
into water, acidified, and extracted with dichloromethane.
The organic phase was dried and the solvent evaporated
to give a residue that was usually chromatographed.
Approximate times and isolated yields of the azido-
transfer, diazo-transfer, and ring-contraction products for
the reactions of the benzosuberone 1 with the sulfonyl
azides are given in Table 1. The yields of the compounds
obtained from the reactions of the keto esters 9-12 with
triflyl azide are shown in Schemes 1-4.
7.29 (4H, m), 7.91 (2H, d, J ) 9.4 Hz), 8.44 (1H, bs); 13
C
NMR (50 MHz) δ 14.31, 19.80, 29.44, 31.93, 56.20, 60.85
(q), 62.79, 114.50, 127.31, 129.06, 129.31, 129.82 (q),
130.99, 131.40, 138.50 (q), 164.47 (q), 170.10 (q), 171.79
(q). Anal. Calcd for C21H23NO6S: C, 60.42; H, 5.55; N,
3.36; S, 7.68. Found: C, 60.68; H, 5.54; N, 3.37; S, 7.65.],
and a 1:1 E/Z mixture of ethyl 5-[2-({[(4-methoxyphenyl)-
sulfonyl]amino}carbonyl)phenyl]-2-pentenoate (5a ) [E-
isomer: 1H NMR (200 MHz) δ 1.23 (3H, t, J ) 6.9 Hz),
2.22-2.40 (2H, m), 2.82 (2H, bt, J ) 8 Hz), 3.93 (3H, s),
4.22 (2H, q, J ) 6.9 Hz), 5.73 (1H, d, J ) 15.5 Hz), 6.86
(1H, dt, J d ) 15.5 Hz, J t ) 6.6 Hz), 7.08 (2H, d, J ) 9.7
Hz), 7.26-7.32 (2H, m), 7.42-7.55 (2H, m), 8.13 (2H, d,
J ) 9.7 Hz). Z-isomer: 1H NMR (200 MHz) δ 1.20 (3H, t,
J ) 6.9 Hz), 2.89-3.02 (2H, m), 3.38-3.49 (2H, m), 3.89
(3H, s), 4.04 (2H, q, J ) 6.9 Hz), 5.69 (1H, d, J ) 11.1
Hz), 6.07 (1H, dt, J d ) 11.1 Hz, J t ) 6.9 Hz), 6.97-7.98
(8H, m). Anal. Calcd for C21H23NO6S: C, 60.42; H, 5.55;
N, 3.36; S, 7.68. Found: C, 60.65; H, 5.53; N, 3.35; S,
7.64.]. This reaction also yielded 4-methoxybenzene-
sulfonamide (0.3 mmol).20
Rea ction s of MsN3 w ith th e Ben zosu ber on e 1 in
THF or AN. Column chromatography of crude A gave
2. Chromatography of crude B afforded ethyl 1-{[(meth-
ylsulfonyl)amino]carbonyl}-1,2,3,4-tetrahydro-1-naphtha-
lenecarboxylate (3b) as a solid, mp ) 168-170 °C [IR
ν
max (cm-1) 3340 (NH), 1740 (CO), 1720 (CO); MS m/z 325
(M+, 21), 204 (65), 129 (100); 1H NMR (200 MHz) δ 1.23
(3H, t, J ) 6.9 Hz), 1.64-1.98 (2H, m), 2.31-2.55 (2H,
m), 2.82 (2H, t, J ) 6.2 Hz), 3.25 (3H, s), 4.20 (2H, q, J
) 6.9 Hz), 7.11-7.31 (4H, m), 8.31 (1H, bs); 13C NMR
(50 MHz) δ 14.40, 19.88, 29.44, 31.84, 41.57, 61.04 (q),
63.00, 127.42, 128.84, 129.42, 131.11, 131.27 (q), 138.59
(19) Azide 21a had been previously reported, but no spectral data
were available: Forster, M. O.; Mu¨ller, R. J . Chem. Soc. 1910, 97, 126.
(20) Commercially available (Lancaster).

Benzocyclic â-Keto Esters and Sulfonyl Azides
J . Org. Chem., Vol. 64, No. 14, 1999 5137
(q), 171.48 (q), 172.02 (q). Anal. Calcd for C15H19NO5S:
C, 55.37; H, 5.89; N, 4.30; S, 9.85. Found: C, 55.52; H,
5.86; N, 4.32; S, 9.90.], and a 1.5:1 E/Z mixture of ethyl
5-(2-{[(methylsulfonyl)amino]carbonyl}phenyl)-2-pen-
tenoate (5b) [E-isomer: 1H NMR (200 MHz) δ 1.19 (3H,
t, J ) 6.9 Hz), 2.36-2.52 (2H, m), 2.90 (2H, bt, J ) 8
Hz), 3.31 (3H, s), 4.05 (2H, q, J ) 6.9 Hz), 5.69 (1H, d, J
) 16.0 Hz), 6.83 (1H, dt, J d ) 16.0 Hz, J t ) 6.8 Hz), 7.09-
7.48 (4H, m), 9.00 (1H, bs). Z-isomer: 1H NMR (200 MHz)
δ 1.15 (3H, t, J ) 6.9 Hz), 2.72-3.02 (2H, m), 3.23-3.50
(2H, m), 3.29 (3H, s), 4.04 (2H, q, J ) 6.9 Hz), 5.78 (1H,
d, J ) 12.0 Hz), 6.17 (1H, dt, J d ) 12.0 Hz, J t ) 7.6 Hz),
MS m/z 401 (M+, 4), 204 (100), 129 (82), 91 (44); 1H NMR
(200 MHz) δ 1.14 (3H, t, J ) 7.1 Hz), 1.52-1.93 (2H, m),
2.22-2.43 (2H, m), 2.48 (3H, s), 2.83 (2H, t, J ) 6.5 Hz),
4.19 (2H, q, J ) 7.1 Hz), 7.17-8.38 (4H, m), 7.43 (2H, d,
J ) 8.3 Hz), 7.99 (2H, d, J ) 8.3 Hz), 8.57 (1H, bs); 13C
NMR (50 MHz) δ 14.27, 19.79, 20.20, 29.43, 31.91, 60.85
(q), 62.79, 127.31, 129.03, 129.32, 129.97, 130.99, 131.43
(q), 131.51 (q), 138.52 (q), 145.62 (q), 170.08 (q), 171.78
(q). Anal. Calcd for C21H23NO5S: C, 62.83; H, 5.77; N,
3.49; S, 7.99. Found: C, 63.02; H, 5.80; N, 3.48; S, 8.04.
In AN or DMF, crude A gave 2 and 5d and crude B
afforded 3d . In THF and DMF 0.23 mmol of tosyl amide
was also recovered.
7.09-7.48 (4H, m), 9.00 (1H, bs). Anal. Calcd for C15H19
-
NO5S: C, 55.37; H, 5.89; N, 4.30; S, 9.85. Found: C,
55.54; H, 5.85; N, 4.32; S, 9.91.].
Rea ction of Tr iflyl Azid e w ith th e In d a n on e 9 in
CH2Cl2. Evaporation of the solvent gave the triethylam-
monium salt ofmethyl2-diazo-2-[2-(2-oxo-2-{[(trifluorometh-
yl)sulfonyl]amino}ethyl)phenyl]acetate (13) as a yellow
solid: IR νmax (cm-1) 2080 (CdN2); 1H NMR (200 MHz) δ
1.21 (9H, t, J ) 6.9 Hz), 3.06 (6H, q, J ) 6.9 Hz), 3.78
(2H, s), 3.83 (3H, s), 7.28-7.46 (4H, m).
Rea ction s of Tr isyl Azid e w ith th e Ben zosu b-
er on e 1 in THF or AN. In THF, without aqueous
workup, column chromatography of the crude product
obtained by evaporation of the solvent gave the azide 2;
the two starting materials were recovered in ca. 25%
yield. By replacing THF with AN, we observed complete
conversion of the starting azide and 67% conversion of
the starting keto ester; azide 2 was obtained in 80% yield
together with an hitherto unidentified white solid, which
was also obtained in a control experiment performed with
trisyl azide and triethylamine in AN in the absence of
keto ester 1.
Rea ction of Tr iflyl Azid e w ith th e In d a n on e 10
in CH2Cl2. After usual workup, column chromatography
afforded ethyl 1-oxo-2-[(trifluoromethyl)sulfonyl]-1,2,3,4-
tetrahydro-3-isoquinolinecarboxylate (15), mp ) 86-87
°C [IR νmax (cm-1) 1740 (CO), 1720 (CO); MS m/z 351 (M+
1
- 73, 1), 278 (100), 128 (39); H NMR (200 MHz) δ 1.14
(3H, t, J ) 7.1 Hz), 3.58 (1H, dd, J 1 ) 2.8 Hz, J 2 ) 16.6
Hz), 3.69 (1H, dd, J 1 ) 5.3 Hz, J 2 ) 16.6 Hz), 4.22 (2H,
q, J ) 7.1 Hz), 5.44 (1H, dd, J 1 ) 2.8 Hz, J 2 ) 5.3 Hz),
Rea ction of Tr iflyl Azid e w ith th e Ben zosu ber on e
1 in CH2Cl2. Without column chromatography, the oily
residue was treated with diethyl ether to give a precipi-
tate of ethyl 1-({[(trifluoromethyl)sulfonyl]amino}carbonyl)-
1,2,3,4-tetrahydro-1-naphthalene-carboxylate (3c), white
solid: mp ) 128-130 °C; IR νmax (cm-1) 3320 (NH), 1750
(b, CO); MS m/z 379 (M+, 11), 204 (59), 158 (32), 129
7.44 (1H, bd, J ) 6.6 Hz), 7.59 (1H, dd, J 1 ) 6.6 Hz, J 2
)
7.3 Hz), 7.75 (1H, dd, J 1 ) 6.6 Hz, J 2 ) 7.3 Hz), 8.31
(1H, bd, J ) 6.6 Hz); 13C NMR (50 MHz) δ 14.26, 32.32,
59.19, 63.32, 119.20 (q, CF3), 127.39 (q), 128.51, 128.92,
130.19, 135.32, 136.13 (q), 162.29 (q), 168.77 (q). Anal.
Calcd for C13H12F3NO5S: C, 44.45; H, 3.44; N, 3.99; S,
9.13. Found: C, 44.55; H, 3.45; N, 3.97; S, 9.16.], and
ethyl 1-{[(trifluoromethyl)sulfonyl]imino}-3,4-dihydro-
1H-isochromene-3-carboxylate (16), mp ) 118-120 °C [IR
1
(100); H NMR (200 MHz) δ 1.25 (3H, t, J ) 7.1 Hz),
1.75-2.02 (2H, m), 2.39-2.54 (2H, m), 2.86 (2H, t, J )
6.5 Hz), 4.25 (2H, q, J ) 7.1 Hz), 7.12-7.36 (4H, m); 13
C
NMR (50 MHz) δ 14.29, 19.76, 29.31, 32.43, 61.02 (q),
63.54, 119.67 (q, CF3), 127.52, 128.84, 129.59, 131.12,
138.62 (q), 142.17 (q), 169.42 (q), 172.48 (q). Anal. Calcd
for C15H16F3NO5S: C, 47.49; H, 4.25; N, 3.69; S, 8.45.
Found: C, 47.61; H, 4.23; N, 3.68; S, 8.50.
ν
max (cm-1) 1740 (CO), 1620 (CdN); MS m/z 351 (M+, 10),
282 (74), 278 (100); HRMS calcd for C13H12F3NO5S
351.0388, found 351.0375; 1H NMR (300 MHz) δ 1.20 (3H,
t, J ) 7.2 Hz), 3.40 (1H, dd, J 1 ) 3.5 Hz, J 2 ) 17.0 Hz),
3.64 (1H, dd, J 1 ) 6.2 Hz, J 2 ) 17.0 Hz), 4.22 (2H, q, J )
7.2 Hz), 5.42 (1H, dd, J 1 ) 3.5 Hz, J 2 ) 6.2 Hz), 7.35
(1H, bd, J ) 6.6 Hz), 7.51 (1H, dd, J 1 ) 6.6 Hz, J 2 ) 7.3
Hz), 7.69 (1H, dd, J 1 ) 6.6 Hz, J 2 ) 7.3 Hz), 8.17 (1H,
bd, J ) 6.6 Hz); 13C NMR (75 MHz) δ 13.69, 29.33, 62.68,
76.35, 118.80 (q, CF3), 123.42 (q), 128.12, 128.58, 129.98,
134.81 (q), 135.82, 165.64 (q), 167.23 (q)].
Rea ction of Tr iflyl Azid e w ith th e Tetr a lon e 11
in CH2Cl2. After usual workup, column chromatography
afforded ethyl 1-({[(trifluoromethyl)sulfonyl]amino}-
carbonyl)-1-indanecarboxylate (17): mp ) 98-100 °C; IR
The filtrate contained small amounts of 3c and ethyl
(E)-5-[2-({[(trifluoromethyl)sulfonyl]amino}carbonyl)-
phenyl]-2-pentenoate (5c), contaminated with trace
amounts of the Z-isomer: 1H NMR (200 MHz) δ 1.19 (3H,
t, J ) 7.1 Hz), 2.36-2.52 (2H, m), 2.90-3.05 (2H, m),
4.18 (2H, q, J ) 7.1 Hz), 5.79 (1H, d, J ) 16 Hz), 6.89
(1H, dt, J d ) 16 Hz, J t ) 6.8 Hz), 7.20-7.62 (4H, m).
Rea ction s of TsN3 w ith th e Ben zosu ber on e 1 in
THF , AN, a n d DMF . In THF, without aqueous workup,
column chromatography of the crude product obtained
by evaporation of the solvent gave, eluting with light
petroleum/diethyl ether 95:5 v/v, azide 2. Further elution
with diethyl ether afforded ethyl 2-diazo-5-[2-({[(4-
methylphenyl)sulfonyl]amino}carbonyl)phenyl]penta-
noate (4d ) [1H NMR (200 MHz) δ 1.24 (3H, t, J ) 7.2
Hz), 1.49-1.71 (2H, m), 2.10-2.22 (2H, m), 2.44 (3H, s),
2.69 (2H, bt), 4.13 (2H, q, J ) 7.2 Hz), 7.09-7.47 (6H,
m), 8.02 (2H, d, J ) 8.3 Hz), 8.93 (1H, bs)] and 5d .1 Final
elution with acetone yielded an oily residue that was
suspended in water, acidified, and extracted with diethyl
ether to give small amounts of 4d together with ethyl
1-({[(4-methylphenyl)sulfonyl]amino}carbonyl)-1,2,3,4-
tetrahydro-1-naphthalenecarboxylate (3d ): mp ) 121-
122 °C; IR νmax (cm-1) 3360 (NH), 1740 (CO), 1720 (CO);
ν
max (cm-1) 3340 (NH), 1750 (CO), 1700 (CO); MS m/z 365
(M+, 6), 190 (92), 115 (100); H NMR (200 MHz) δ 1.26
(3H, t, J ) 6.7 Hz), 2.79-2.97 (2H, m), 3.15-3.26 (2H,
m), 4.32 (2H, 2 overlapped quartets, J ) 6.7 Hz), 7.35-
7.56 (4H, m), 10.44 (1H, bs); 13C NMR (50 MHz) δ 13.81,
31.42, 32.97, 63.54, 66.73 (q), 119.00 (q, CF3), 123.68,
125.92, 127.65, 129.97, 138.27 (q), 144.74 (q), 166.92 (q),
171.93 (q). Anal. Calcd for C14H14F3NO5S: C, 46.03; H,
3.86; N, 3.83; S, 8.78. Found: C, 46.12; H, 3.85; N, 3.85;
S, 8.82.
1
Rea ction of Tr iflyl Azid e w ith th e Tetr a lon e 12
in CH2Cl2. After usual workup, column chromatography
gave methyl 2-oxo-1-{[(trifluoromethyl)sulfonyl]amino}-

5138 J . Org. Chem., Vol. 64, No. 14, 1999
Benati et al.
1,2,3,4-tetrahydro-1-naphthalenecarboxylate (18): mp )
143-144 °C; IR νmax (cm-1) 3310 (NH), 1750 (CO), 1730
(CO); MS m/z 351 (M+, 2), 218 (85), 175 (54), 130 (100);
1H NMR (200 MHz) δ 2.90-3.44 (4H, m), 3.76 (3H, s),
6.82 (1H, bs), 7.26-7.44 (4H, m); 13C NMR (50 MHz) δ
27.91, 38.68, 54.88, 69.97 (q), 118.40 (q, CF3), 127.49,
127.63, 128.84, 129.52, 133.04 (q), 137.24 (q), 167.55 (q),
201.95 (q). Anal. Calcd for C13H12F3NO5S: C, 44.45; H,
3.44; N, 3.99; S, 9.13. Found: C, 44.52; H, 3.43; N, 4.01;
S, 9.16.
Rea ction s of P NBSA w ith th e Keto Ester s 19a a n d
19b in CH2Cl2. Following the general procedure de-
scribed above, the keto esters 19a ,b afforded 20 in 80%
and 85% yield, respectively.
Rea ction s of TsN3 w ith th e Keto Ester s 19a a n d
19b in CH2Cl2. Following the general procedure de-
scribed above, the keto esters 19a ,b afforded 20 in 78%
and 76% yield, respectively.
Rea ction s of Tr iflyl Azid e w ith th e Keto Ester s
19a a n d 19b in CH2Cl2. Following the general procedure
described above, the keto esters 19a ,b afforded ethyl
2-diazopropanoate (20), as a yellow oil, in 51% and 36%
yield, respectively: IR νmax (cm-1) 2080 (CN2), 1670 (CO);
1H NMR (200 MHz) δ 1.26 (3H, t, J ) 7.0 Hz), 1.97 (3H,
s), 4.23 (2H, q, J ) 7.0 Hz).
Ack n ow led gm en t. We gratefully acknowledge fi-
nancial support from MURST, CNR, and the University
of Bologna (1997-1999 Funds for selected research
topics).
J O9901541