A practical and efficient preparation of the releasable naphthosultam side chain of a novel anti-MRSA carbapenem

Article abstract of DOI:10.1021/jo991490k

A practical large-scale synthesis of the naphthosultam-based side chain of the anti-MRSA antibiotic 1 has been achieved in 29% overall yield over seven steps from 1-methylnaphthalene. The synthesis was completed without the use of protecting groups, featu

Full text of DOI:10.1021/jo991490k

J . Org. Chem. 2000, 65, 1399-1406
1399
A P r a ctica l a n d Efficien t P r ep a r a tion of th e Relea sa ble
Na p h th osu lta m Sid e Ch a in of a Novel An ti-MRSA Ca r ba p en em
Ross A. Miller,* Guy R. Humphrey,* David R. Lieberman,* Scott S. Ceglia, Derek J . Kennedy,
Edward J . J . Grabowski, and Paul J . Reider
Department of Process Research, Merck Research Laboratories, P.O. Box 2000,
Rahway, New J ersey 07065
Received September 22, 1999
A practical large-scale synthesis of the naphthosultam-based side chain of the anti-MRSA antibiotic
1 has been achieved in 29% overall yield over seven steps from 1-methylnaphthalene. The synthesis
was completed without the use of protecting groups, featuring a novel naphthosultam annelation,
a chemoselective acid-catalyzed triflation, and the use of a novel naphthosultam dianion to effect
functionalization through benzylic metalation.
Sch em e 1
In tr od u ction
The Merck Research Laboratories have recently dis-
closed the novel â-lactam (1) as an anti-MRSA (Methi-
cillin-resistant Staphylococcus aureus) antibiotic from a
series of 1â-methyl-2-(naphthosultamyl)methyl cationic
carbapenems.1 The 1,8-naphthosultamyl side chain (2)
was identified as a novel PBP2a-binding, anti-MRSA
pharmacophore, designed to be released upon opening of
the â-lactam ring (Scheme 1), in analogy to the cepha-
losporin and penem antibiotics.2
Our strategy for the synthesis of 1 relied on the highly
convergent coupling of this naphthosultam side chain 2
with an appropriately substituted â-methyl carbapenem
nucleus (Scheme 2).3 The clinical needs of 1 as a
potentially life-saving drug prompted us to develop a
highly efficient and practical synthesis of 2.
The initial synthesis of 1 was developed with the goal
of defining structure-activity relationships which re-
quired divergence of intermediates and did not incorpo-
rate the entire naphthosultam fragment 2.1 Instead, the
naphthosultam ethanol piece 3 (Scheme 3) was coupled
and the diazabicyclooctane unit incorporated in an
activation-displacement, two-step manner. Convergent
retrosynthetic analyses that focus solely on the synthesis
of 1 ideally incorporate the zwitterionic bis cation-(1,8-
naphthosultam) DABCO-acetamide 2 as a complete unit
and, herein, we report the attainment of the first
convergent synthesis of this essential fragment.
Our retrosynthetic analysis (Scheme 3) highlights
three important issues in the synthesis of compound 2:
(1) the availability and cost of the naphthalene starting
material, (2) the method of installation of the sultam ring
system, and (3) the method of incorporation of the
cationic DABCO acetamide. Naphthylethanol 5 had been
used previously as starting material in the initial syn-
thesis (route A), but was extremely expensive compared
to other naphthalene derivatives and not commercially
available on large scale. Additionally, protection of the
primary hydroxyl was needed in order to carry out the
nitration and sulfonation. We envisioned 1-methylnaph-
thalene 4 as the starting material of choice as it would
not require the use of a protecting group and was
available from a wide variety of suppliers at low cost.4
(1) Ratcliffe, R. W.; Wilkening, R. R.; Wildonger, K. J .; Waddell, S.
T.; Santorelli, G. M.; Parker, D. L., J r.; Morgan, J . D.; Blizzard, T. A.;
Hammond, M. L.; Heck, J . V.; Huber, J .; Kohler, J .; Dorso, K. L.; St.
Rose, E.; Sundelof, J . G.; May, W. J .; Hammond, G. G. Biochem. Med.
Chem. Lett. 1999, 9, 679.
(2) (a) Wilkening, R. R.; Ratcliffe, R. W.; Wildonger, K. J .; Cama, L.
D.; Dykstra, K. D.; DiNinno, F. P.; Blizzard, T. A.; Hammond, M. L.;
Heck, J . V.; Dorso, K. L.; St. Rose, E.; Kohler, J .; Hammond, G. G.
Biochem. Med. Chem. Lett. 1999, 9, 673. (b) Faraci, W. S.; Pratt, R. F.
Biochemistry 1985, 24, 903. (c) Grabowski, E. J . J .; Douglas, A. W.;
Smith, G. B. J . Am. Chem. Soc. 1985, 107, 7, 268. (d) Perrone, E.; J abes,
D.; Alpegiani, M.; Andreini, B. P.; Bruna, C. D.; Nero, S. D.; Rossi, R.;
Visentin, G.; Zarini, F.; Franceschi, G. J . Antibiot. 1992, 45, 589.
(3) Humphrey, G. R.; Miller, R. A.; Pye, P.; Rossen, K.; Ceglia, S.
S.; Maliakal, A.; Volante, R. P.; Grabowski, E. J . J .; Reider, P. J . J .
Am. Chem. Soc. 1999, 121, 11261.
(4) At the time of writing, the cost of 1-methylnaphthalene was $4/
kg and available in 55-gallon drum quantities.
10.1021/jo991490k CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/16/2000

1400 J . Org. Chem., Vol. 65, No. 5, 2000
Miller et al.
Sch em e 2
Sch em e 4a
Sch em e 3
a
(a) 3 equiv of ClSO3H; (b) HNO3, H2SO4; (c) BnNH2, K2CO3,
90 °C; (d) 10% Pd/C (50% wet), TEA, HCOOH, EtOH, 78 °C; (e)
HNEt2, IPA; (f) KO2CH, 10% Pd/C; (g) 5% Pd/C, H2; (h) HCl.
naphthosultam 6, and last achieve functionalization
through benzylic metalation to the naphthosultam etha-
nol 3. Incorporation of the DABCO-acetamide fragment
would then furnish our complete bis cation (1,8-naph-
thosultam) DABCO-acetamide 2 (route B).
Resu lts a n d Discu ssion
Syn th esis of th e Meth yln a p h th osu lta m Cor e. Un-
til now, synthetic strategies for the naphthosultam ring
system have been limited to dehydration of the corre-
sponding 1-amino-8-sulfonic acid using various phospho-
rus chloride reagents.7 This ring-closure has been noto-
riously capricious, though recently patented processes
claim to improve the methodology.8 Alternatively, Merck
Research Laboratories has uncovered a base-catalyzed
intramolecular nucleophilic displacement reaction with
a nitro leaving group to form the naphthosultam ring.
Initially, we hoped to modify this strategy for the large-
scale production of naphthosultam 6 (Scheme 4, route
A).9
Another option would be the preparation of naphthyl-
ethanol 5 from 1-methylnaphthalene 4,5 or from naph-
thylacetic acid.6 However, a protecting group sequence
would still be required. Thus, our approach was to use
1- methylnaphthalene as the key raw material, develop
a practical methodology for the conversion to methyl-
(6) Yoon, N. M.; Pak, C. S.; Brown, H. C.; Krishnamurthy, S.; Stocky,
T. P. J . Org. Chem. 1973, 38, 38.
(7) Vesely, V.; Bubenik, H. Collect. Czech. Chem. Commun. 1939,
11, 412.
(5) Guggisberg, Y.; Faigl, F.; Schlosser, M. J . Organomet. Chem.
1991, 415, 1-6.
(8) (a) Korhummel, C. PCT Int. WO9821192A1. (b) Grondard, L.;
Henriet, D. PCT Int. WO9736884A1.

Novel Anti-MRSA Carbapenem
J . Org. Chem., Vol. 65, No. 5, 2000 1401
Sch em e 5
The chlorosulfonation of 1-methylnaphthalene pro-
ceeded in 83% isolated yield and >99:1 regioselectivity
using chlorosulfonic acid. The chlorosulfonation was
carried out by addition of a total of 3 equiv of chlorosul-
fonic acid to a suspension of 1-methylnaphthalene in
trifluoroacetic acid (TFA). Addition of the first equivalent
was carried out at 0-5 °C and gave rise to a rapid and
exothermic formation of the sulfonic acid intermediate
that was not isolated. After addition of the remaining
chlorosulfonic acid and aging at 20 °C for 1 h, the reaction
mixture was simply poured into cold water to crystallize
the sulfonyl chloride 15 in 83% yield. Nitration of 15
proceeded smoothly with 1 equiv of fuming nitric acid in
a mixture of 20% sulfuric acid in TFA.10 The nitration
gave rise to a 3:1 mixture of the required 8-nitro-isomer
to the undesired 5-isomer. Carrying out the nitration
under a number of other standard nitration conditions
did not improve the regioselectivity. However, the minor
regioisomer was easily removed by swishing the crude
isolated solid with methyl tert-butyl ether or ethyl
acetate/hexane, resulting in a 59% overall isolated yield
of >99% isomerically pure 1,8-nitrosulfonyl chloride. The
low cost of 1-methylnaphthalene starting material offset
the inherent modest regioselectivity in this nitration.
Formation of the sultam ring was achieved by direct
addition of ammonia or benzylamine to the reaction
mixture to form the nitrosulfonamides, respectively. The
sulfonamides were cyclized by the addition of potassium
carbonate and heating. In the case of the benzyl deriva-
tive, the yield (85%) and purity of the product 7 were
superior to that of the ammonia derivative, and direct
crystallization of the benzylsultam 7 was easily achieved
from the reaction mixture by addition of water. Removal
of the benzyl group under standard or transfer hydroge-
nation conditions furnished the key methyl NH naph-
thosultam 6. The product was conveniently crystallized
in >99% purity and 85% yield directly from the reaction
mixture by the simple addition of water. This synthetic
sequence was achieved without recourse to chromatog-
raphy and consistently provided high-purity material.
carried out using a novel one-pot hydrogenation-cycliza-
tion reaction. Reduction to the amine was accomplished
cleanly under either standard hydrogen/catalyst or trans-
fer hydrogenation conditions in quantitative yield. The
intermediate aminosulfonamide (20) could be isolated or,
more conveniently, was cyclized to the key methylnaph-
thosultam 6 upon acidification with hydrochloric acid and
heating at reflux for 3 h. Crystallization directly from
the reaction mixture was possible by simple addition of
water and methylnaphthosultam 6 could be isolated in
85% yield (calculated from 19) and in >99% purity. Thus,
three different ways of forming the novel naphthosultam
ring system have been explored with the newest meth-
odology fulfilling all the requirements for a scalable
synthesis (Scheme 5).
During our scale-up demonstration, however, opera-
tional hazards analysis of the nitration reaction revealed
that the n itr osu lfon yl ch lor id e in ter m ed ia te 16 w a s
sh ock sen sitive and exhibited an extraordinarily high
rate of temperature and pressure release (dT/dt ) 17,-
380 °C/min; dP/dt ) 5234 psi/min) initiating at 42 °C.11
In light of these findings, a revised synthesis of the key
methyl naphthosultam 6 was evaluated (Scheme 4, route
B). The methylnaphthalene sulfonyl chloride 15 was
converted to the diethylsulfonamide 18 in quantitative
yield by addition of diethylamine to a solution of the
sulfonyl chloride 15 in 2-propanol. This substrate was
then nitrated to give the nitrosulfonamide 19 under
conditions similar to those used for the nitration of
sulfonyl chloride 15. Similar regiochemistry, rejection of
the regioisomer, and isolated yield (55%) were observed.
This intermediate did not possess the high-energy release
of the nitrosulfonyl chloride, was not shock sensitive, and
therefore was safely isolable. Cyclization of the nitrosul-
fonamide 19 to the required methylnaphthosultam was
Ch a in Exten sion of Meth yln a p h th osu lta m 6. Key
to the use of methylnaphthalene as starting material was
the chain extension of the sultam 6 to naphthosultam
ethanol 3. Lithiation of aromatic substrates have been
extensively studied and have revealed that substituents
on the ring have dramatic consequences for the regio-
chemical outcome of alkylation.12 Attempted deprotona-
tion of the N-protected sultam 7 with LDA or other bases
gave no C-methyl benzylic lithiation; rather, the major
product was an unusual rearrangement to an R-amino
sulfone 8, presumably from undesired directed metala-
tion of the sultam.
(9) Unpublished results. See ref 1, footnote 16.
(10) (a) Vesely, V. Collect. Czech. Chem. Commun. 1929, 1, 493, 504.
(b) Steiger, R. E. Helv. Chim. Acta 1934, 17, 1142. (c) Steiger, R. E.
Helv. Chim. Acta 1930, 13, 173.
(11) We thank Linda Tuma of the Operational Hazards Lab at
Merck for obtaining these data.
An example of this type of ring-expansion with a
saccharin derivative has been previously reported.13

1402 J . Org. Chem., Vol. 65, No. 5, 2000
Miller et al.
Because of this complication and a desire to avoid any
protecting group sequences, we envisioned generating a
N,C-dianion and selectively alkylating on the carbon.
Although there has been a large amount of literature
dedicated to dianions in general, only a few examples of
N,C-dianions could be found, and no examples involving
p-methylsulfonamides could be located.14 As a prelimi-
nary study, naphthosultam 6 was treated with LDA in
THF at 0 °C, followed by addition of D2O. Gratifyingly,
clean incorporation of deuterium at the benzylic position
occurred, as evidenced by NMR.15 Although the dianion
rapidly reacted with air, it proved to be quite thermally
stable.16 Table 1 shows a range of electrophiles that
ketones and unsaturated carbonyl compounds, no useful
yield of products could be obtained. No further optimiza-
tion was done for these substrates, because they were
without practical utility.
Critical to the synthesis of 2 was the hydroxymethy-
lation of the dianion. The use of paraformaldehyde or
monomeric formaldehyde17 gave good yet variable yields
of desired compound 3. Variability in conversion and bis-
alkylation, which were dependent on quality of starting
material and reagent, were significant. Reacting with
DMF or other formyl synthons, followed by an in situ
reduction, was similarly capricious. Alternatively, carbon
dioxide consistently gave high conversions and isolated
yields of acid 14. After isolation, the intermediate was
reduced in excellent yield to the desired hydroxyethyl-
naphthosultam 3 by a sodium borohydride/boron trifluo-
ride reduction.18 This carboxylation-reduction sequence
provided significantly higher overall yield and purity
than did the one-step hydroxymethylation process.
Ta ble 1. Con ver sion s a n d Yield s of Electr op h iles w ith 6a
electrophile
product
% conversion
% yield
MeI
9
3
3
99
50
70
90
90
95
98
98
92
45
65
50-80
90
93
83
paraformaldehyde
monomeric formaldehyde
DMFb
ClCH2I
(CH3)3CCHO
TMSCl
3
10
11
12
13
14
Com p letion of th e Syn th esis of 2. Completion of the
synthesis of 2 required two more synthetic operations:
(1) the preparation of DABCO-acetamide salt (DAT), and
(2) its coupling with hydroxyethylnaphthosultam 3.
Because preliminary work had shown competitive dis-
placement of the counteranion of DABCO-acetamide with
the leaving group of hydroxyethylnaphthosultam, a
weakly nucleophilic counteranion such as triflate was
needed. Although two-step preparations of the DAT have
been previously reported, an optimized one-pot process
has now been achieved (Scheme 6).19 In this revised
procedure, DABCO, sodium triflate, and chloroacetamide
are mixed together in acetonitrile, and simple filtration
of the insoluble salts resulted in an essentially chloride-
free DAT solution. The low solubility of sodium chloride
and the chloride salt of DABCO acetamide in acetonitrile
drove concurrent anion exchange/nucleophilic displace-
PhCHO
CO2
87
95
97-99
a
b
See the Experimental Section for a general procedure. After
adding DMF, the reaction mixture was treated with sodium
borohydride.
successfully reacted with dilithiated 6. In all cases, an
inverse addition of the dianion into the electrophile
produced higher yields and more reproducible results
than did a normal addition, presumably due to proton
abstraction from the more acidic product by the highly
basic dianion. Alkylation on nitrogen was not observed
in any example under these conditions. Bis- and tris-
silylation (12B and 12C, respectively) on carbon was
observed during the quench with trimethylsilyl chloride
and excess base, suggesting that further substitution of
the naphthosultam skeleton through lithiation would be
possible.
(12) (a) Schlosser, M.; Katsoulos, G.; Takagishi, S. Synlett. 1990,
747. (b) Schlosser, M. Tetrahedron 1998, 54, 2763.
(13) Zinnes, H.; Comes, R. A.; Shavel, J ., J r. J . Org. Chem. 1964,
24, 2068.
(14) (a) For general reviews on dianions in general, see Kaiser, E.
M.; Petty, J . D.; Knutson, P. L. A. Synthesis 1977, 509. (b)Thompson,
C. M.; Green, D. L. C. Tetrahedron 1991, 47, 4223. (c) For an example
of a â-sultam dianion, see Szymonifka, M. J .; Heck, J . V. Tetrahedron
Lett. 1989, 30, 2873. (d) Watanabe, H.; Gay, R. L.; Hauser, C. R. J .
Org. Chem. 1968, 33, 900. (e) Watanabe, H.; Hauser, C. R. J . Org.
Chem. 1968, 33, 4278.
(15) This type of benzylic dianion formation was precedented by the
work on methyl-substituted benzoic acids: Creger, C. J . Am. Chem.
Soc. 1970, 92, 1396.
(16) For example, a naphthosultam dianion was prepared and
allowed to stir under nitrogen at 20 °C, for 18 h, after which it was
quenched into trimethylacetaldehyde. An identical result was obtained
when a freshly prepared dianion solution was quenched into trim-
ethylacetaldehyde.
(17) Schlosser, M.; J enny, T.; Guggisberg, Y. Synlett 1991, 704.
(18) Attempted in situ reduction of the carboxylate with borohydride
led to a reductive amination of diisopropylamine with the carboxylate;
see Gribble, G. W.; J asinski, J . M.; Pellicone, J . T.; Panetta, J . A.
Synthesis 1978, 766 for similar reductive aminations.
(19) Yasuda, N. et. al. J . Org. Chem. 1998, 64, 5438.
Aldehydes lacking acidic protons reacted cleanly with
this dilithio-anion. However, in attempts to react with

Novel Anti-MRSA Carbapenem
J . Org. Chem., Vol. 65, No. 5, 2000 1403
Sch em e 6
ment. The solution could be used directly in the next step,
or the triflate salt isolated in 85% yield by addition of
MTBE.
Initial experiments on the coupling of DAT with the
naphthosultam fragment focused on the chloroethyl
derivative 10, available from the alkylation of the dianion
of methylnaphthosultam 6 with chloroiodomethane. After
exchange to the iodide, alkylation was achieved giving 2
as the iodo, triflate salt in 65% overall yield. Attempted
coupling of this compound with the carbonate failed, and
alternate counteranions were desired.
The addition of 1 equiv of triflic anhydride into a
solution of 3 in acetonitrile gave a 95% conversion to the
monotriflate, as evidenced by reaction with tetrabuty-
lammonium bromide. When reacted with 2 equiv of DAT,
identical conversion was observed and, after crystalliza-
tion, an 83% isolated yield of 2 was obtained. Under these
low pH conditions, no evidence of N-triflation was
observed, and <1% of the DABCO acetonitrile from
dehydration of the acetamide was obtained. This opera-
tionally simple procedure has been successfully demon-
strated on the multikilo scale, yielding high-purity
(>99%) releasable side chain.
In summary, we have described a seven-step synthesis
of 2 (Scheme 7), which proceeds in 29% overall yield. The
synthesis was achieved without the use of any protecting
groups, and features a new and operationally safe naph-
thosultam ring synthesis, a chemoselective chain exten-
sion of a novel methyl naphthosultam dianion and a
chemoselective acid-catalyzed monotriflation. The syn-
thesis has been reproducibly demonstrated on the mul-
tikilogram scale in high purity and has allowed for the
production of side chain essential for the large-scale
synthesis of the novel â-lactam antibiotic 1.3
Exp er im en ta l Section
Gen er a l Con sid er a tion s. All reactions were carried out
under an atmosphere of dry N2. All solvents were commercial
grade and used without purification or drying. Melting points
were measured with a Buchi 510 apparatus and are uncor-
rected. Low resolution mass spectroscopy was obtained from
M Scan Inc. NMR spectra were recorded on a Bruker DPX-
250 instrument (1H NMR at 250 MHz, 13C NMR at 63 MHz)
or a Bruker DPX-400 (1H NMR at 400 MHz, 13C NMR at 100
MHz). The IR spectra were recorded on a Perkin-Elmer 781
instrument. New compounds were characterized by C, H, N
analysis from Quantitative Technologies Inc.
4-Meth yl-1-n a p h th a len esu lfon yl Ch lor id e (15). A 22 L
three-neck flask fitted with mechanical stirrer, temperature
probe, and nitrogen inlet was charged with 1-methylnaphtha-
lene 4 (2.63 kg) and trifluoroacetic acid (13.2 L). The two-phase
mixture was stirred and cooled to 5 °C using an ice-water
bath. Chlorosulfonic acid (1.0 L) was added via an addition
funnel over 30 min, maintaining the reaction temperature
The preferred synthesis of 2 as the bis-triflate salt was
achieved using an activation/displacement sequence from
3. Selective triflation of the difunctional hydroxyethyl-
naphthosultam, without recourse to any protecting group,
was desired. However, selective O-triflation could not be
achieved under a variety of basic conditions.20 In most
cases, statistical mixtures of N-triflation, O-triflation, bis-
triflation, and starting material 3 were obtained. Alter-
natively, triflation in the absence of base was expected
to selectively react with the more basic alcohol function.
(20) For
a review on triflates, see Stang, P. J .; Hanack, M.;
Subramanian, L. R. Synthesis 1982, 85.

1404 J . Org. Chem., Vol. 65, No. 5, 2000
Miller et al.
16: 1H NMR (400.25 MHz, d6-acetone) δ 8.72 (d, J ) 7.9
Hz, 1H), 8.66 (dd, J ) 8.6, 1.1 Hz, 1H), 8.44 (dd, J ) 7.6, 1.1
Hz, 1H), 7.9 (m, 2H), 2.96 (s, 3H); 13C NMR (100.64 MHz, d6-
acetone) δ 147.7 (br), 146.9, 139.0, 136.1, 135.0, 132.2, 128.7,
128.4, 127.6, 120.0, 20.0; MS (EI) m/e (relative intensity) 250
(10) loss of Cl, 186 (90), 156 (60), 128 (100); IR (KBr) 3094,
1539, 1369, 1349, 1166, 668, 611, 560, 540 cm-1. Anal. Calcd
for C11H8NO4SCl; C, 46.24; H, 2.82; N, 4.90; S, 11.22; Cl, 12.41;
Found C, 46.34; H, 3.05; N, 4.75; S, 11.02; Cl, 12.25; mp 157-
160 °C (dec).
Sch em e 7
N,N-Dieth yl-4-m eth yl-1-n a p h th a len esu lfon a m id e (18).
A 72 L flask fitted with mechanical stirrer, temperature probe,
condenser, addition funnel, and nitrogen inlet was charged
with methylnaphthalenesulfonyl chloride 15 (4.0 kg) and
2-propanol (6.2 L). Diethylamine (3.73 L) was added to the
slurry over 10 min. An exotherm around 65 °C was noted. The
starting material dissolved as the reaction progressed and was
fully dissolved at complete reaction. No external cooling or
heating was used during the reaction. The solution was cooled
to 30 °C, and water (2 L) was then added. The mixture was
seeded with sulfonamide product (2 g) and aged at 20 °C for
20 min. The remaining water (16.6 L) was added over 1 h and
the resultant slurry mixed for 20 min. at 20 °C. The slurry
was filtered and washed with water (12 L). The cake was dried
under vacuum with a nitrogen sweep overnight. A total of 3.8
kg was obtained, which adjusted for purity at 95 wt % equaled
99% yield.
18: 1H NMR (400.25 MHz, d6-acetone) δ 8.72 (dd, J ) 9.9,
1.9 Hz, 1H), 8.1(dd, J ) 8.5, 1.4 Hz, 1H), 8.07 (d, J ) 7.5 Hz,
1H), 7.7 (m, 2H), 7.49 (dd, J ) 7.4, 0.8 Hz, 1H), 3.37 (q, J )
7.0 Hz, 4H), 2.76 (s, 3H), 1.07 (t, J ) 7.0 Hz, 6H); 13C NMR
(100.64 MHz, d6-acetone) δ 141.0, 134.4, 133.5, 128.9, 128.7,
127.3, 126.7, 125.7, 125.1, 125.0, 41.0, 19.1, 13.4; MS (EI) m/e
(relative intensity) 277 (35), 262 (55), 205 (70), 157 (20), 141
(100), 115 (40); IR (KBr) 2977, 1308, 1136, 942, 764, 707, 580
cm-1. Anal. Calcd for C15H19NO2S: C, 64.95; H, 6.90; N, 5.05;
S, 11.56; Found C, 65.19; H, 6.87; N, 4.98; S, 11.43.; mp 67-
68 °C.
a
(a) 2 equiv of ClSO3H; (b) HNEt2, IPA; (c) HNO3, H2SO4; (d)
KO2CH, 5% Pd/C, HCl; (e) LDA, CO2; (f) NaBH4, BF3OEt; (g) TF2O,
DAT.
N,N-Diet h yl-4-m et h yl-8-n it r o-1-n a p h t h a len esu l-
fon a m id e (19). A 2 L flask fitted with nitrogen inlet, me-
chanical stirrer, addition funnel, and temperature probe was
charged with N,N-diethyl-1-methyl-4-naphthalenesulfonamide
(18, 30 g) and TFA (150 mL). The resultant solution was cooled
to 15 °C, and concentrated sulfuric acid (30 mL) was added.
The solution was cooled to -3 °C and fuming nitric acid (6.2
mL) added with rapid stirring over 30 min. The reaction
temperature was maintained between -3 and +5 °C. Rapid
stirring is essential for complete conversion. Water (375 mL)
was added to the solution over 60 min while keeping the
internal temperature less than 25 °C with an ice-water bath.
CAUTION! Th e in itia l 10% w a ter ch a r ge sh ou ld be
a d d ed ver y slow ly d u e to exoth er m . The resultant slurry
was filtered and washed with water (100 mL). The cake was
dried in a nitrogen stream until the residual water content
was <35% w/w. A total of 28.6 g at 67 wt % was obtained;
19.2 g pure basis, 55% yield. Water content by Karl-Fisher
titration was 7 wt %, (19): 1H NMR (400.25 MHz, d6-DMSO)
δ 8.47 (d, J ) 11.8 Hz, 1H), 8.23 (d, J ) 7.0 Hz, 1H), 8.03 (d,
J ) 7.6 Hz, 1H), 7.8 (m, 1H), 7.69 (d, J ) 7.7 Hz, 1H), 3.10 (q,
J ) 7.0 Hz, 4H), 2.78 (s, 3H), 0.95 (t, J ) 7.0 Hz, 6H); 13C
NMR (100.64 MHz, d6-DMSO) δ 148.1, 141.2, 135.2, 134.3,
131.2, 130.7, 128.0, 126.3, 126.2, 121.1, 43.0, 20.4, 14.9; MS
(EI) m/e (rel intensity) 250 (100) loss of NEt2, 186 (85), 170
(55), 156 (80), 128 (100); IR (KBr) 2973, 1531, 1353, 1327, 1202,
1131, 1023, 955, 703, 560 cm-1. Anal. Calcd for C15H18N2O4S:
C, 55.89; H, 5.63; N, 8.69; S, 9.94; Found C, 55.89; H, 5.61; N,
8.58; S, 9.88; mp 164-165 °C.
between 5 and 10 °C. After complete addition, the slurry mixed
for 10 min and warmed to 15 °C, and the remaining chloro-
sulfonic acid (1.93 L) was added over 15 min. The reaction
temperature was allowed to increase to 20 °C during the
addition and then maintained at 20 °C. The hydrogen chloride
generated during sulfonation was trapped using a nitrogen
sweep to a dilute sodium hydroxide solution. The slurry was
stirred at 20 °C for 1 h and was then added to cold (5 °C)
deionized water (19.7 L) at 10-25 °C over 15 min. The
resultant slurry mixed at 15-20 °C for 30 min, was filtered,
washed with water (9.5 L), and dried under a nitrogen stream
overnight. Yield of 15: 3.52 kg, 83%. mp 80-81 °C (lit. mp 81
°C).21
4-Meth yl-8-n itr o-1-n a p h th a len esu lfon yl Ch lor id e (16).
(CAUTION: SHOCK SENSITIVE). A 72L flask fitted with
nitrogen inlet, mechanical stirrer, addition funnel, and tem-
perature probe was charged with 1-methylnaphthalene-4-
sulfonyl chloride (15, 5.0 kg) and trifluoroacetic acid (50 L).
The resultant slurry was cooled to 5 °C. Concentrated sulfuric
acid (1.11 L) was added over 2 min. The reaction mixture was
stirred at 5 °C for 10 min. Fuming nitric acid (1.0 L) was added
to the slurry, maintaining the reaction temperature between
10 and 15 °C. The slurry was aged at 10-15 °C for 15 min.
Water (40 L) was added to the slurry over 30 min, maintaining
the internal temperature between 15 and 20 °C using an ice-
water bath. The resultant slurry was aged at 20 °C for 30 min
and filtered, and the cake was washed with 1:1 TFA/water (10
L) and water (5 L). The wet cake was slurried in ethyl acetate
(20 L) at 20 °C for 1 h. Hexane (20 L) was added over 30 min
and the slurry aged at 20 °C for 1 h and filtered. The cake
was washed with 1:1 ethyl acetate/hexane (5 L) and dried
under a nitrogen stream at rt overnight. The yield was 3.60
kg at 97 wt %; 3.49 kg pure basis, 59%.
6-Meth yl-2H-n a p h th [1,8-cd ]isoth ia zole 1,1-Dioxid e (6).
A 72 L flask was equipped with a N2 inlet, thermocouple, and
an overhead stirrer. To the flask were charged 2.20 kg of
nitrodiethylsulfonamide naphthalene (19) and ethanol (20 L).
Pd/C (10 wt %, 50 wt % water wet, 0.17 kg) was charged as a
slurry in water (800 mL) and rinsed down with water (80 mL)
and ethanol (6 L). To the resultant slurry was added potassium
formate (1.74 kg) in one portion. The slurry was warmed to
(21) Baliga, B. Can. J . Chem. 1966, 44, 363.

Novel Anti-MRSA Carbapenem
J . Org. Chem., Vol. 65, No. 5, 2000 1405
60 °C for 1 h and then refluxed for 1 h. The reaction was
considered complete when no starting material remained
relative to the intermediate aminonaphthalene 20 (character-
ization included below), typically 2 h. Upon complete reaction,
the mixture was cooled to 20 °C and concentrated hydrochloric
acid (2.73 L) added over about 20 min. The resultant slurry
was filtered through a pad of Solka-floc, and the cake was
washed with 10% concentrated hydrochloric acid in ethanol
(total of 13 L). The combined filtrates were recharged to the
cleaned 72 L flask and heated to reflux (81 °C) for 3-4 h to
achieve complete cyclization. The solution was cooled to 40 °C
and concentrated to about 15 L (100 mmHg.). The slurry was
cooled to 20 °C, and water (7.5 L) was added over 30 min. The
slurry was cooled to 5 °C, mixed for 15 min, filtered, and finally
washed with water (5 L). The crystalline solid was dried under
a stream of nitrogen overnight. Obtained: 1.0 kg (85%)
6: 1H NMR (250.1 MHz, d6-DMSO) δ 11.35 (br s, 1H), 8.03
(d, J ) 7.33 Hz, 1H), 7.64 (m, 3H), 6.94 (dd, J ) 2.7 Hz, 5.17
Hz, 1H), 2.72 (s, 3H); 13C NMR (62.5 MHz, CD3OD) δ 141.9,
137.1, 131.7, 131.6, 130.3, 129.6, 121.9, 120.4, 117.0, 106.8,
18.7; MS (EI) m/e (rel intensity) 219 (100), 154 (30), 140 (24),
127 (17), 115 (10); IR (Nujol) 3260, 1590, 1625, 1290, 1155,
755 cm-1. Anal. Calcd for C11H9NSO2: C, 60.26; H, 4.14; N,
6.39; S, 14.62. Found: C, 60.07; H, 4.16; N, 6.35; S, 14.27; mp
221-225 °C.
8-Am in o-N,N-d iet h yl-4-m et h yl-1-n a p h t h a len esu l-
fon a m id e (20): 1H NMR (400.25 MHz, d6-DMSO) δ 7.66 (d,
J ) 7.5 Hz, 1H), 7.33 (m, 3H), 6.91 (d, J ) 7.6 Hz, 1H), 6.28
(s, 2H), 3.3 (m, 4H), 2.6 (s, 3H), 1.11 (m, 6H); 13C NMR (100.64
MHz, d6-DMSO) δ 145.6, 141.2, 136.2, 134.0, 128.2, 126.4,
124.8, 117.6, 113.4, 112.9, 43.3, 21.2, 15.2; MS (EI) m/e (relative
intensity) 292 (50), 219 (100), 157 (80), 129 (70), 128 (65); IR
(KBr) 3476, 3386, 2971, 1647, 1572, 1461, 1294, 1126, 712
cm-1. Anal. Calcd for C15H20N2SO2: C, 61.62; H, 6.89; N, 9.58;
S, 10.96. Found C, 61.67; H, 6.97; N, 9.33; S, 10.74; mp 126-
128 °C.
under vacuum at 40 °C until <0.3 wt % water remained as
analyzed by Karl-Fisher titration. Obtained: 1.04 kg of product
(85% yield).
(2R,S)-2,3-Dih yd r o-7-m eth yl-2-p h en yln a p h th o[1,8-d e]-
1,3-th ia zin e 1,1-Dioxid e (8). N-Benzyl-8-methylnaphthalene
sultam (7, 1.0 g, 3.23 mmol) and 10 mL of dry THF were placed
in a 50 mL flask and cooled to -30 °C. In a separate flask,
diisopropylamine (0.72 g, 2.2 equiv) and 10 mL of THF were
prepared and cooled to -30 °C. To this solution was slowly
added 4.0 mL (2.0 equiv) of 1.6 M nBuLi. The resulting LDA
solution was added slowly to the sultam solution over 20 min,
maintaining the temperature <-20 °C. After complete LDA
addition, a total of 28 mL of 2 N HCl was added to crystallize
product. The resultant slurry was cooled to 0 °C, filtered, and
washed with water to afford 0.80 g (80% yield) of product.
8: 1H NMR (400.08 MHz, d6-DMSO) δ 7.90 (d, J ) 7.32 Hz,
1H), 7.80 (s, 1H), 7.71 (m, 2H), 7.56 (m, 6H), 7.22 (d, J ) 6.73
Hz, 1H), 5.86 (s, 1H), 2.71 (s, 3H); 13C NMR (100.6 MHz, d6-
DMSO) δ 141.3, 140.4, 133.0, 132.5, 130.1, 130.0, 128.7, 128.3,
127.9, 125.7, 119.4, 117.2, 114.9, 112.1, 75.1, 19.9. MS (EI)
m/e (rel intensity) 309 (10), 275 (30), 245 (100), 230 (80), 160
(75). IR (Nujol) 3350, 1610, 1590, 1290, 1140, 1120, 830, 780,
750 cm-1; HRMS calculated for C18H15NO2S ) 309.0824, found
309.0796; mp 231-235 °C.
Gen er a l Dia n ion F or m a tion a n d Electr op h ile Ad d i-
tion . A 100 mL flask equipped with a nitrogen inlet, a stirrer,
and a temperature probe was charged with anhydrous THF
(50 mL), 1-Me-NH-naphthosultam 6 (2.5 g, 11.4 mmol) and
diisopropylamine (3.0 g, 29.6 mmol). Three vacuum/purge
cycles were then done to remove dissolved oxygen. The solution
was cooled to -20 °C, and 10.7 g of n-butyllithium (1.6 M in
hexane) was added dropwise, maintaining the internal tem-
perature between -20 °C and 0 °C. The dark dianion solution
was aged for 30 min at -15 °C.
Wor k u p P r oced u r e for CO2 Ad d ition (14). Bone-dry
grade CO2 was bubbled into -20 °C THF (400 mL) until
approximately 45.6 mmol of CO2 (2.0 g) was added. The
dianion solution was added quickly to this carbonated solution
while ensuring efficient mixing of the resulting slurry. After
warming to 10 °C, 28 mL of 2 N HCl was slowly added to the
solution. The solution was then concentrated atmospherically
to about 28 mL to remove THF and initiate crystallization.
The resultant slurry was aged at 5 °C for 30 min, filtered,
washed with water (55 mL), and dried in a nitrogen stream.
Obtained 2.94 gm at about 97 wt % ) 2.85 g, 95% yield as a
white solid.
6-Meth yl-2-(p h en ylm eth yl)-2H-n a p h th [1,8-cd ]isoth ia -
zole 1,1-Dioxid e (7). A 100 L flask was equipped with a N2
inlet, thermocouple, addition funnel, and an overhead stirrer.
The flask was charged with 2.00 kg of nitronaphthalene 16,
along with 18 L of DMF. Potassium carbonate (2.42 kg) was
then charged followed by slow addition of benzylamine (0.79
kg). The solution changed from a yellow to a brownish color
as the intermediate sulfonamide formed. The reaction mixture
was heated to 90 °C until the starting material was consumed,
typically 2 h. The solution was cooled to 25 °C, and 39 L of
water was added over 1-2 h. The resultant slurry was filtered
and washed with approximately 40 L water. The light brown
powder was dried under vacuum at 40 °C overnight. A total
of 2.17 kg (80% yield) was obtained.
7: 1H NMR (250.1 MHz, CD2Cl2) δ 7.71 (d, J ) 7.39 Hz,
1H), 7.27 (m, 8H), 6.34 (dd, J ) 7.15 Hz, 0.62 Hz, 1H), 4.79 (s,
2H), 2.56 (d, J ) 0.76 Hz, 3H); 13C NMR (62.5 MHz, CD2Cl2)
δ 141.4, 136.9, 135.9, 130.4, 129.2, 129.1, 128.8, 128.3, 128.2,
127.9, 120.1, 119.5, 115.9, 104.0, 45.6, 18.9; MS (EI) m/e (rel
intensity) 309 (20), 91 (100); IR (Nujol) 1630, 1590, 1500, 1290,
1170, 820, 795, 760 cm-1. Anal. Calcd. for C18H15NSO2: C,
69.88; H, 4.89; N, 4.53; S, 10.36. Found: C, 69.56; H, 4.85; N,
4.40; S, 10.37; mp 123-125 °C.
6-Meth yl-2H-n a p h th [1,8-cd ]isoth ia zole 1,1-Dioxid e (6).
To a 50 L flask equipped with a N2 inlet, thermocouple,
addition funnel, and an overhead stirrer was added 1.73 kg of
N-benzylnaphthylsultam 7 and 17 L of ethanol. Triethylamine
(850 g) was charged followed by 10% Pd/C (1.73 kg). Finally,
formic acid (360 g) was charged via an addition funnel slowly,
over 20-30 min. The reaction was heated to 80 °C until the
starting material had been consumed. The reaction mixture
was cooled to 25 °C and filtered through Celite to remove the
Pd/C, washing the cake with 11 L of warm (30-40 °C) ethanol.
The filtrate was then acidified with 6.6 L of 2 N HCl (pH 2-3),
followed by slow addition of 31 L of water to crystallize out
the product. The resultant slurry was cooled to 5 °C, filtered,
and washed with 32 L of cold water. The product was dried
Wor k u p P r oced u r e for Oth er Electr op h iles. A separate
250 mL flask equipped with a stirrer, a nitrogen inlet, and a
temperature probe was charged with THF (25 mL) and the
electrophile and then degassed with a vacuum/nitrogen purge.
The dianion was added to this solution and then mixed with
100 mL of ethyl acetate and 100 mL of water. The layers were
cut, and the organic solution was dried over sodium sulfate.
The organic layer was concentrated, and hexanes were added
to crystallize out the naphthosultam products.
6-Eth yl-2H-n a p h th [1,8-cd ]isoth ia zole 1,1-d ioxid e (9):
1H NMR (250.1 MHz, d6-DMSO) δ11.33 (br s, 1H), 8.06 (d, J
) 7.45 Hz, 1H), 7.63 (m, 3H), 6.93 (dd, J ) 6.95, 0.8 Hz, 1H),
3.12 (q, J ) 7.6 Hz, 2H), 1.29 (t, J ) 7.5 Hz, 3H); 13C NMR
(62.5 MHz, d6-DMSO) δ 146.6, 135.9, 130.2, 129.8, 129.4, 127.6,
120.4, 120.2, 115.7. 105.9, 25.2, 15.6; MS (EI) m/e (rel intensity)
233 (100), 218 (25), 154 (20); IR (Nujol) 3300, 1625, 1590, 1495,
1380, 1305, 1150, 1110, 840, 750 cm-1. Anal. Calcd for C12H11
-
NSO2: C, 61.78; H, 4.75; N, 6.00; S, 13.74. Found: C, 61.66;
H, 4.71; N, 5.97; S, 13.50; mp 175-179 °C.
2H -Na p h t h [1,8-cd ]isot h ia zole-6-et h a n ol 1,1-d ioxid e
(3): 1H NMR (250.1 MHz, CD3CN) δ 8.43 (br s, 1H), 7.85 (d,
J ) 7.42 Hz, 1H), 7.56 (m, 3H), 6.89 (d, J ) 7.22 Hz, 1H), 3.76
(t, J ) 6.54 Hz, 2H), 3.23 (t, J ) 6.52 Hz, 2H), 2.67 (br s, 1H):
13C NMR (62.5 MHz, d6-DMSO) δ 142.5, 135.8, 130.3, 130.1,
129.7, 129.5, 120.4, 119.9, 116.1, 105.8, 61.9, 35.8; MS (EI)
m/e (rel intensity) 249 (100), 218 (85), 155 (50), 127 (30); IR
(Nujol) 3530, 3200, 1640, 1580, 1490, 1300, 1285, 1170, 825,
750 cm-1. Anal. Calcd for C12H11NSO3: C, 57.82; H, 4.45; N,

1406 J . Org. Chem., Vol. 65, No. 5, 2000
Miller et al.
5.62; S, 12.86. Found: C, 57.65; H, 4.65; N, 5.57; S, 12.47; mp
175-177 °C.
130.5, 130.3, 130.1, 120.3, 120.0, 116.2, 106.0, 38.0; MS (EI)
m/e (rel intensity) 263 (100), 218 (50), 154(20); IR (Nujol) 3320,
6-(2-Ch lor oet h yl)-2H -n a p h t h [1,8-cd ]isot h ia zole 1,1-
d ioxid e (10): 1H NMR (400.3 MHz, d6-DMSO) δ 8.01 (d, J )
7.5 Hz, 1 H), 7.8 (d, J ) 7.3 Hz, 1H), 7.77 (d, J ) 8.6 Hz, 1H),
7.65 (m, 1H), 7.01 (d, J ) 7.3 Hz, 1H), 3.99 (t, J ) 7.0 Hz,
2H); 3.65 (t, J ) 7.0 Hz, 2H);13C NMR (62.5 MHz, d6-acetone)-
140.25, 135.90, 131.57, 130.03, 129.67, 129.35, 120.75, 119.18,
115.59, 105.97, 44.17, 34.89; MS (EI) m/e (rel intensity) 269
(35) chlorine isotope, 267 (100), 218 (80), 154 (30); IR (KBr)
3187, 1498, 1359, 1296, 1148, 1111, 831, 752 cm-1. Anal. Calcd
for C12H10ClNO2S: C, 53.83; H, 3.76; N, 5.23; S, 11.98, Cl,
13.24. Found C, 53.93; H, 3.83; N, 5.04; S, 11.99; Cl, 12.94;
mp 148-151 °C.
1695, 1630, 1590, 1310, 1280, 1255, 1220, 1145, 805, 740 cm-1
.
Anal. Calcd for C12H9NSO4: C, 54.75; H, 3.45; N, 5.32; S, 12.18.
Found: C, 54.74; H, 3.55; N, 5.35; S, 12.13; mp: 247-250 °C.
2H-Naph th [1,8-cd]isoth iazole-6-eth an ol 1,1-Dioxide (3).
The dried sultam carboxylic acid 14 (1.14 kg) was slurried in
THF (18 L) and cooled to 15 °C. To this solution was added
NaBH4 (327 g), followed by slow addition of BF3 etherate. The
addition of BF3 etherate caused vigorous evolution of gas. The
slurry was aged for about 1 h. MeOH (1.2 L) was slowly added
to quench excess borane, followed by slow addition of 11 L of
2 N HCl. After aging for 30 min to ensure homogeneity, the
reaction mixture was distilled at atmospheric pressure to
concentrate and then cooled to 55 °C, seeded, and cooled to 15
°C. The slurry was filtered, washed with 10 L water, and dried
under a stream of nitrogen. Obtained: 1007 g of 3 (4.04 mol,
93% yield) as a white solid.
1-(2-Am in o-2-oxoet h yl)-4-a za -1-a zon ia b icyclo[2.2.2]-
oct a n e sa lt w it h t r iflu or om et h a n esu lfon ic Acid (1:1)
(21). To a 250 mL RB flask under a nitrogen blanket contain-
ing DABCO (1.93 g, 17.2 mmol) and acetonitrile (100 mL) at
25 °C were added NaOTf (2.69 g, 15.6 mmol) and 2-chloroac-
etamide (1.46 g, 15.6 mmol). The reaction mixture was heated
to reflux (82 °C) for 2-3 h. The crude reaction mixture was
cooled to 25 °C, filtered through Solka Floc to remove the
insoluble chloride salts, and washed with an additional 15 mL
of acetonitrile. The filtrate and wash were combined and
concentrated under reduced pressure to 15 mL, and then tert-
butyl methyl ether (30 mL) was slowly added at 25 °C with
stirring; the slurry was then aged for 20 min. The product was
filtered and washed with an additional 10 mL of tert-butyl
methyl ether. The product was dried in vacuo (25 °C) with a
nitrogen sweep to give 4.45 g, 89% yield of DAT; <0.3 wt %
Cl- by analysis with capillary zone electrophoresis.
1-(2-Am in o-2-oxoet h yl)-4-[2-(1,1-d ioxid o-2H -n a p h t h -
[1,8-cd ]isot h ia zol-6-yl)et h yl]-1,4-d ia zon ia b icyclo[2.2.2]-
octa n e Sa lt w ith Tr iflu or om eth a n esu lfon ic Acid (1:2) (2).
A solution (1100 µg/mL water as determined by Karl-Fischer
titration) of naphthosultam ethanol (2370 g) in acetonitrile
(27.9 kg) was cooled to 0 °C, and then triflic anhydride (2548
g) added slowly while keeping the temperature <5 °C. The
reaction was aged 0.5 h at <5 °C. DAT was added (5765 g),
and the reaction was allowed to warm to ambient temperature.
Crystallization of the product occurred after stirring at room
temperature for approximately 2-3 h. The crude reaction
mixture was then solvent switched to methanol and concen-
trated to approximately 24 L, cooled to 5 °C, filtered, and
washed with cold methanol (3 × 4 L, approximately 6% loss
in mother liquors). 2: Yield 83%, 5.08 kg; 1H NMR (400.25
MHz, d6-DMSO) δ 8.16 (d, J ) 7.4 Hz, 1H), 8.04 (br s, 1H),
7.71 (m, 4H), 6.98 (d, J ) 6.9 Hz, 1H), 4.3 (s, 2H), 4.15 (m,
12H), 3.85 (m, 2H), 3.65 (m, 2H); 13C NMR (100.64 MHz, d6-
DMSO) δ 165.1, 138.1, 136.2, 131.8, 130.7, 129.9, 129.8, 120.4,
120.3, 121.2 (q, J ) 322.3 Hz), 115.6, 106.4, 63.4, 61.8, 51.8,
50.9, 24.7; MS (EI) m/e (relative intensity) 401.1(100); IR(KBr)
3438, 3348, 3220, 3040, 1702, 1262, 1151, 1031, 1031, 640
cm-1. Anal. Calcd for C22H26N4O9S3F6: C, 37.71; H, 3.74; N,
8.00; F, 16.27; S 13.73. Found C, 37.77; H, 3.84; N, 7.91; F,
17.00; S, 14.24; mp>250 °C (dec).
(r-(1,1-Dim eth yleth yl)-2H-n aph th [1,8-cd]isoth iazole 1,1-
d ioxid e (11): 1H NMR (250.1 MHz, CD2Cl2) δ 7.94 (d, J )
7.45 Hz, 1H), 7.67 (m, 3H), 7.12 (br s, 1H), 7.00 (dd, J ) 7.20,
0.6 Hz, 1H), 3.57 (m, 2H), 3.01 (dd, J ) 13.6, 10.7 Hz, 1H)
1.55 (br s, 1H), 1.13 (s, 9H); 13C NMR (62.5 MHz, CD2Cl2) δ
143.6, 135.2, 130.8, 130.2, 129.9, 129.2, 121.8, 119.9, 117.4,
107.2, 80.3, 35.8, 35.2, 25.9; MS (EI) m/e (rel intensity) 305
(20), 219 (50), 155 (100); IR (Nujol) 3450, 3295, 1625, 1590,
1495, 1360, 1320, 1150, 830, 795, 760 cm-1. Anal. Calcd for
C
16H19NSO3: C, 62.93; H, 6.27; N, 4.59; S, 10.5. Found: C,
62.69; H, 6.28; N, 4.49; S, 10.29; mp: 196-199 °C.
(6-[(Tr im eth ylsilyl)m eth yl]-2H-n a p h th [1,8-cd ]isoth ia -
zole 1,1-d ioxid e (12): 1H NMR (250.1 MHz, d6-DMSO) δ
11.28 (br s, 1H), 8.02 (d, J ) 7.5 Hz, 1H), 7.59 (m, 3H), 6.91
(d, J ) 7.06 Hz, 1H), 2.77 (s, 2H), 0.00 (s, 9H); 13C NMR (62.5
MHz, d6-DMSO) δ 144.8, 135.7, 129.2, 128.9, 128.0, 127.5,
120.6, 120.0, 116.9, 105.7, 23.8, -1.1; MS (EI) m/e (rel
intensity) 291 (80), 212 (30), 201 (95), 73 (100); IR (Nujol) 3240,
1630, 1585, 1495, 1145, 1120, 860, 840, 795, 750 cm-1. Anal.
Calcd for C14H17NSO2Si: C, 57.70; H, 5.88; N, 4.81; S, 11.00.
Found: C, 57.30; H, 5.83; N, 4.67; S, 10.84; mp 205-208 °C.
8-Tr im eth ylsilyl-6-[(tr im eth ylsilyl)m eth yl]-2H-n a ph th -
[1,8-cd ]isoth ia zole 1,1-d ioxid e (12B): 1H NMR (250.1 MHz,
CD2Cl2) δ 7.48 (m, 3H), 6.87 (dd, J ) 6.8, 1.1 Hz, 1H), 6.87 (br
s, 1H), 2.62 (s, 2H), 0.45 (s, 9H), -0.04 (s, 9H); 13C NMR (62.5
MHz, CD2Cl2) δ 144.5, 137.4, 136.6, 134.8, 131.5, 129.8, 123.4,
119.3, 108.4, 108.1, 25.8, 1.3, 0.0; MS (EI) m/e (rel intensity)
363 (70), 273 (90), 227 (20), 73 (100); IR (Nujol) 3200, 1625,
1560, 1160, 1140, 850, 825, 750 cm-1. Anal. Calcd. for C17H25
-
NSO2Si2: C, 56.15; H, 6.93; N, 3.85; S, 8.82. Found: C, 56.25;
H, 6.96; N, 3.77; S, 8.77; mp: 154-157 °C.
12C was not isolated; however, an NMR was obtained using
an LC NMR. The data have been included in the Supporting
Information.
(r-P h en yl-2H-n a p h th [1,8-cd ]isoth ia zole-6-eth a n ol 1,1-
d ioxid e) (13): 1H NMR (250.1 MHz, d6-DMSO) δ 11.32 (br s,
1H), 8.03 (d, J ) 7.45 Hz, 1H), 7.43(m, 8H), 6.92 (d, J ) 7.05
Hz, 1H), 5.46 (d, J ) 3.26 Hz, 1H), 4.93 (s, 1H), 3.41 (m, 2H);
13C NMR (62.5 MHz, d6-DMSO) δ 145.7, 141.8, 135.7, 130.3,
130.2, 129.5, 128.4, 127.3, 126.3, 125.8, 120.3, 119.6, 116.3,
105.7, 73.5, 42.4; 13C NMR (62.5 MHz in CD3OD) δ 145.9,
142.6, 137.5, 132.4, 132.1, 131.4, 130.7, 129.7, 128.9, 127.5,
122.5, 120.4, 117.4, 107.0, 76.0, 43.8; MS (EI) m/e (rel intensity)
325 (5), 307 (30), 219 (60), 155 (100), 107 (55), 77 (35); IR
(Nujol) 3500, 3020, 1625, 1595, 1495, 1380, 1150, 1110 cm-1
.
Anal. Calcd for C18H15NSO3: C, 66.44; H, 4.65; N, 4.30; S, 9.85.
Found: C, 66.40; H, 4.71; N, 4.25; S, 9.75; mp: 191-194 °C.
2H-Na p h th [1,8-cd ]isoth ia zole-6-a cetic a cid 1,1-d ioxid e
(14): 1H NMR (250.1 MHz, d6-DMSO) δ 12.66 (br s, 1H), 11.42
(br s, 1H), 8.10 (d, J ) 7.38 Hz, 1H), 7.77 (d, J ) 7.43 Hz, 1H),
7.63 (m, 2H), 6.96 (dd, J ) 5.13, 2.70 Hz, 1H), 4.12 (s, 2H);
13C NMR (62.5 MHz, d6-DMSO) δ 172.4, 137.8, 135.8, 131.2,
Su p p or tin g In for m a tion Ava ila ble: Spectral data of 8
and 12C. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O991490K