Facile preparation and chemical transformations of spirocyclopropane-annelated heterocycles

Article abstract of DOI:10.1002/ejoc.200390154

A productive approach has been developed to spirocyclopropane-annelated 1,4-benzoxathiane 17 (85%), 1,4-benzothiazines 20-22 (56-88%) and 1,4-benzoxazines 25, 26 (55-71%), through Michael additions of binucleophilic o-hydroxythiophenol 15, o-aminothiophen

Full text of DOI:10.1002/ejoc.200390154

FULL PAPER
Facile Preparation and Chemical Transformations of Spirocyclopropane-
Annelated Heterocycles[‡]
Armin de Meijere,*[a] Ilya D. Kuchuk,[b] Viktor V. Sokolov,[c] Thomas Labahn,[d]
Karsten Rauch,[a] Mazen Es-Sayed,[e] and Thomas Krämer[f]
Keywords: Heterocycles / Small-ring systems / Spiro compounds / Homogeneous catalysis / Cross-coupling reactions
A productive approach has been developed to spirocyclopro-
pane-annelated 1,4-benzoxathiane 17 (85%), 1,4-benzothia- amount of triphenylphosphane, only the 6-bromobenzoxaz-
zines 20−22 (56−88%) and 1,4-benzoxazines 25, 26 (55−71%), ine underwent Heck coupling accompanied by ring opening
coupling with various alkenes. In the presence of a catalytic
through Michael additions of binucleophilic o-hydroxythio- of the spirocyclopropane moiety. The best yields of cross-
phenol 15, o-aminothiophenols 8 and o-hydroxysulfanilides coupling products 30d−i (60−89%) retaining the spirocyclo-
23 onto methyl and tert-butyl 2-chloro-2-cyclopropylidenea- propane ring were achieved for 6-iodobenzoxazine 26c-Me
cetates (1-Me, 1-tBu), followed by ring closure in the inter-
mediate of type 3 through nucleophilic substitution of the
chlorine atom and, in the case of the intermediates 20, 21
and 25, elimination of benzenesulfinic acid. Reduction of 20a
reacting with methyl acrylate, acrolein, and methyl vinyl ke-
tone, respectively. By treatment with morpholine in DMF, the
heterocyclic esters 26b,c undergo demethoxycarbonylation
to form spirocyclopropane-annelated 1,4-benzoxazines 36b,c
with LiAlH4 led to the hydroxymethyl derivative 28 (88%) in high yields (83−98%). The 1,4-benzoxazine 36b readily
with retention of the N-phenylsulfonyl group, while that of
adds nucleophiles such as p-thiocresol and hydrogen cyanide
the oxazinecarboxylate 26a-Me gave the β-amino alcohol 27
across its C=N double bond to yield compounds 37 (76%) and
(87%). Selective reduction of the C=N double bond in 26a- 38 (95%), respectively.
Me was achieved with NaBH4 in methanol. Halogen-substi-
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
tuted benzoxazines 26b,c were modified further by Heck Germany, 2003)
Introduction
by 1,3-dipolar cycloadditions[3] as well as by two-step pro-
cesses involving a Michael addition and an intramolecular
nucleophilic substitution.[4] These esters 1 are much better
Michael acceptors than any other alkyl 3,3-dialkylacrylates
and even unsubstituted acrylates, which is due mainly to
the release of strain upon changing the hybridization of the
ring carbon atom from sp to sp2 upon attack of a nucleo-
phile, but to a small extent also to the chloro substituent in
the α-position. In the case of a bidentate nucleophile 2, ring
closure of the intermediate 3 through nucleophilic substitu-
tion of the chlorine atom at the newly formed sp3-carbon
center or, alternatively, nucleophilic attack on the methoxy-
carbonyl group (R ϭ Me) can occur to give heterocycles of
either type 4 or 5, respectively (Scheme 1).
1,4-Benzoxazine and 1,4-benzothiazine derivatives thus
obtainable with 1,2-disubstituted benzene derivatives are of
great interest since similar compounds have shown Ca2ϩ
antagonist[5] and aldose reductase inhibitory activities.[6]
The previously reported[4a] reactions of 1-Me with 2-ami-
noethanethiol, catechol, 2-aminophenol, and 2-aminothio-
phenol were all conducted in two-phase systems under
phase-transfer catalysis (PTC), and the yields did not ex-
ceed 45%. We engaged ourselves, therefore, in a project to
develop better conditions for the synthesis of spirocyclopro-
Alkyl 2-chloro-2-cyclopropylideneacetates 1, which are
readily available in three steps from tetrachlorocycloprop-
ene and ethylene,[1] are versatile building blocks for organic
synthesis.[2] As has been demonstrated previously, they can
be used effectively for the construction of various S-, N-,
and O-containing spirocyclopropane-annelated heterocycles
[‡]
Cyclopropyl Building Blocks for Organic Synthesis, 85. Part 84:
A. Leonov, T. Heiner, M. T. Bes, A. de Meijere, Eur. J. Org.
Chem., in press. Part 83: V. N. Belov, A. I. Savchenko, V. V.
Sokolov, A. Straub, A. de Meijere, Eur. J. Org. Chem., in press.
[a]
Institut für Organische Chemie der Georg-August-Universität
Göttingen,
Tammannstrasse 2, 37077 Göttingen, Germany
Fax: (internat.) ϩ 49-551/399475
E-mail: Armin.deMeijere@chemie.uni-goettingen.de
[b]
Department of Chemistry, Indiana University,
Bloomington, Indiana 47405, USA
[c]
Department of Chemistry, St. Petersburg State University,
Universitetski pr. 26, 198504 St. Petersburg, Russia
[d]
Institut für Anorganische Chemie, Georg-August-Universität
Göttingen,
Tammannstraße 4, 37077 Göttingen, Germany
[e]
Bayer CropScience,
Alfred-Nobel-Straße 50, 40789 Monheim am Rhein, Germany
[f]
Bayer HealthCare, Department of Medicinal Chemistry,
Aprather Weg, 42096 Wuppertal, Germany
Eur. J. Org. Chem. 2003, 985Ϫ997  2003 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/03/0306Ϫ0985 $ 20.00ϩ.50/0
985

A. de Meijere et al.
FULL PAPER
Scheme 1. Two possibilities to obtain heterocycles from 2-chloro-
2-cyclopropylideneacetates 1-R and a binucleophile 2
pane-annelated 1,4-benzoxazines, 1,4-benzoxathianes, and
1,4-benzothiazines from 2-chloro-2-cyclopropylideneacet-
ates 1 and 1,2-disubstituted binucleophilic benzene derivat-
ives and to study possible modifications of the resulting het-
erocycles.
Results and Discussion
Preparation of Heterocycles
Most of the previous cocyclizations of 1-Me with binucle-
ophiles were conducted in the presence of excess potassium
hydroxide and dibenzo[18]crown-6 as a phase-transfer cata-
lyst in dichloromethane.[4a] Under these conditions, how-
ever, the methoxycarbonyl group may also be attacked, and
this may be one of the reasons for the low yields obtained
previously for the six-membered ring products. In addition,
products with an unprotected NϪH fragment in the molec-
ule may undergo yet another Michael addition onto a se-
cond molecule of 1-Me. For instance, 2-aminoethanethiol
in the presence of potassium carbonate as a base reacted
with 1-Me to give the tetrahydro[1,4]thiazine derivative 6 in
only 20% yield, and its further adduct 7 (a mixture of two
diastereoisomers) was isolated in 14% yield. A similar prod-
uct distribution was obtained under homogeneous condi-
tions with triethylamine as a base (Scheme 2).
Figure 1. Molecular structures of methyl 3Ј,4Ј,5Ј,6Ј-tetrahydro-
spiro(cyclopropane-1,2Ј-[2H][1,4]thiazine)-3Ј-carboxylate (6) (ob-
tained as 6·0.5HCl·0.25H2O) and methyl 7-bromospiro([2H]-
[1,4]benzothiazine-2,1Ј-cyclopropane)-3-carboxylate (22b) in the
crystals[7]
The treatment of 1-Me with 2-aminothiophenol (8a) in
the presence of KOH under PTC conditions in dichlorome-
thane gave the 1,4-benzothiazine derivative 10a in 46%
yield.[4a] The reaction of 2-aminophenol (11a) with 1-Me
in the presence of K2CO3 under PTC conditions gave the
corresponding 1,4-benzoxazine derivative 14 in 40%
yield.[4a] In the presence of triethylamine at ambient tem-
perature, 1-Me reacted smoothly with 8a and its bromo-
substituted analog 8b to give the open-chain Michael ad-
ducts 9a and 9b in 68 and 92% yields, respectively. When
the reaction of 8a with 1-Me was carried out at 100 °C in
DMF, however, only the benzothiazine 10a (40%) was isol-
ated along with several unidentified minor by-products
(Scheme 3). Under these conditions, the open-chain inter-
mediate 9a could also be cyclized to 10a, but the yield (43%)
Scheme 2. Cocyclization of methyl 2-chloro-2-cyclopropylidenea-
cetate (1-Me) with 2-aminoethanethiol; E ϭ CO2Me
The structure of the amino ester 6 was confirmed by X- was not improved. The cyclization did not occur in re-
ray structural analysis.[7] The compound itself was obtained fluxing THF.
as an oil, but after several months of storage of its solution
In the presence of triethylamine in DMF, 1-Me reacted
in CDCl3, crystals of the unusual hemihydrochloride with 2-aminophenol (11a) at its NH2 group to yield mainly
6·0.5HCl·0.25H2O had precipitated and were analyzed the open-chain adduct 12 (Scheme 4). Usually O-alkylation
(Figure 1).
of phenols requires strong bases, yet in this case treatment
986
Eur. J. Org. Chem. 2003, 985Ϫ997

Spirocyclopropane-Annelated Heterocycles
FULL PAPER
Scheme 5. Reaction of methyl 2-chloro-2-cyclopropylideneacetate
(1-Me) with mercaptohydroquinone (15) under various conditions
Scheme 3. Reaction of methyl 2-chloro-2-cyclopropylideneacetate
(1-Me) with 2-aminothiophenols 8a,b under various conditions
Table 1. Sulfonamides 18a,b, 19a and 1,4-benzothiazines 20a,b, 21a
and 22a,b obtained from 9a,b
of 1-Me with 11a in the presence of 1,8-diazabicy-
clo[5.4.0]undec-7-ene (DBU) in DMF at 70 °C gave only
the unexpected 1,4-benzoxazine derivative 13 in very low
yield and in impure form along with many unidentified by-
products. An attempt to cyclize 12 to 14 by treatment with
K2CO3 and KI in DMF gave also a complex mixture of
products that could not be separated.
9
Y
H
Ar
Ph
18/19
Temp. [°C]/ 20/21
Time [h] (%)
22
(%)
(%)
a
18a (80) 70/2
85/4
18b (97) 70/2
20a (77) 22a (trace)
20a (0) 22a (88)
b
a
Br Ph
H
20a (14) 22b (45)
4-BrC6H4 19a (81) 70/2
21a (56) 22a[a]
[a]
Yield not determined.
Scheme 4. Reaction of methyl 2-chloro-2-cyclopropylideneacetate
(1-Me) with 2-aminophenol (11a) under various conditions
Scheme 6. Synthesis of sulfonamides 18a,b, 19a and their heterocy-
clizations to 1,4-benzothiazine derivatives 20a,b, 21a and 22a,b (for
details see Table 1)
The cocyclization of 2-chloro-2-cyclopropylideneacetates
1-R with o-mercaptophenols is a route to 2,3-dihydro-1,4-
benzoxathiane derivatives. With triethylamine in dichloro-
methane at ambient temperature, 1-Me reacted with mer-
captohydroquinone (15) also to yield the open-chain adduct
16. With K2CO3/KI in DMF, however, the heterocycle 17
was obtained in 85% yield. Under the same conditions, the
initial Michael adduct 16 could be cyclized to 17 in 60%
yield (Scheme 5).
The sulfonamides 23aϪc derived from 2-aminophenol
(11a) and its 4-bromo (11b) and 4-iodo (11c) derivatives,
upon their reactions with chlorocyclopropylideneacetates 1-
To avoid the complications arising from an unprotected
NϪH fragment in the heterocycles of type 10, the open-
chain adducts 9a,b were converted into the sulfonamides
18a,b/19a (Scheme 6). Treatment of 18a with K2CO3/KI in
DMF afforded the cyclic sulfonamide 20a in 77% yield,
while the bromo-substituted analogue 18b gave predomin-
antly the α-imino ester 22b (45%), after elimination of ben-
zenesulfinic acid, along with 20b (14%). When the reaction
of 18a was performed at a higher temperature (85 instead
of 70 °C) and for a longer time (4 instead of 2 h) the yield
of 22a increased to 88%. The structure of compound 22b
was confirmed by an X-ray analysis (Figure 1).[7]
Scheme 7. Cocyclization of 2-chloro-2-cyclopropylideneacetates 1-
R with sulfonamides 23aϪc to form 1,4-benzoxazine derivatives
24-R to 26-R (for details see Table 2)
Eur. J. Org. Chem. 2003, 985Ϫ997
987

A. de Meijere et al.
FULL PAPER
Table 2. Cocyclizations of N-(2-hydroxy-5-Y-phenyl)benzenesulfonamides 23aϪc with methyl (1-Me) and tert-butyl 2-chloro-2-cyclopro-
pylideneacetate (1-tBu) in DMF at 80 °C for 3 h
23
Y
R
24-Me (%)
24-tBu (%)
25-Me (%)
25-tBu (%)
26-Me (%)
26-tBu (%)
a[a]
a
H
H
Br
Br
I
Me
Me
Me
tBu
Me
24a[b]
24a (11)
24b (3)
Ϫ
Ϫ
Ϫ
Ϫ
24b (0)
Ϫ
25a (22)
25a (0)
25b (0)
Ϫ
Ϫ
Ϫ
Ϫ
25b (5)
Ϫ
26a (21)
26a (71)
26b (71)
Ϫ
Ϫ
Ϫ
Ϫ
b
b
c
26b (55)
Ϫ
24c[b]
25c[b]
26c (65)
[a]
[b]
At ambient temperature for 28 h. Yield not determined.
Me or 1-tBu gave up to three products from two regioiso- assigned on the basis of the observed strong nuclear Over-
meric modes of attack (Scheme 7). Products 25-R and 26-R, hauser effect (NOE) between the methoxycarbonyl group
resulting from O-attack of 23 on 1-R, predominated in all at C-3 and the methine proton in the 2D-NOESY NMR
cases, and among these two types of products, compounds spectrum. The uncoupled ring-opened product 29b was ob-
26-R, formed by additional elimination of benzenesulfinic tained as a single diastereoisomer. Like the major coupling
acid, were always the major ones (Table 2), at least when product (Z)-29d, most probably 29b has a (Z) configura-
the reactions were carried out at 80 °C. When 1-Me was tion, but this stereochemistry was not verified by NMR
treated with 23a at ambient temperature for 28 h under spectroscopy.
otherwise identical conditions, the cocyclization product
25a-Me was isolated in 22% yield along with 26a-Me (21%).
Transformations of the New Heterocycles
The CϭN double bonds in the 1,4-benzoxazines 26 and
1,4-benzothiazines 22 could be reduced selectively by treat-
ment with NaBH4 in methanol, whereas treatment with Li-
AlH4 in THF led to reduction of both the CϭN and meth-
oxycarbonyl groups. Upon reduction of 20a under the same
conditions, the N-benzenesulfonyl group remained un-
Scheme 9. Attempted Heck coupling reaction of 6-bromo-1,4-
changed, and the hydroxylmethyl derivative 28 was ob-
tained in 88% yield (Scheme 8).
benzoxazine derivative 26b-Me with methyl acrylate (for details
see Table 3)
Under the same conditions, but without added triphenyl-
phosphane, no reaction was observed after 18 h. Under the
modified conditions according to Jeffery[9] [Pd(OAc)2,
K2CO3, nBu4NBr, no triphenylphosphane] in DMF at 80
°C, complete conversion was observed after 72 h, but only
30% of the coupling product 30d was isolated; apparently
most of the starting material had decomposed. After only
18 h under these conditions, 57% of 26b-Me was recovered
unchanged, while 10% of 30d was obtained (Scheme 10,
Table 3).
Scheme 8. Synthesis of hydroxymethyl derivatives 27 and 28 by
reduction of esters 26a-Me and 20a
All attempts to perform Heck coupling[8] reactions with
the 7-bromo-1,4-benzothiazine derivatives 20b and 22b
failed. The treatment of methyl 6-bromo-1,4-benzoxazine-
3-carboxylate 26b-Me with methyl acrylate in the presence
of a typical palladium catalyst cocktail for Heck reactions[8]
[Pd(OAc)2, PPh3 and nBu3N] in DMF at 80 °C led to open-
ing of the spirocyclopropane ring. After 3.5 h, the un-
coupled product 29b predominated, while after 18 h the
ring-opened coupling products (Z)-29d and (E)-29d were
obtained in 71 and 4% yields, respectively (Scheme 9). The
configuration of the double bond in compound (Z)-29d was oxylates 26b,c-Me with alkenes (for details see Table 3)
Scheme 10. Heck reactions of 6-halo-1,4-benzoxazine-3-carb-
988
Eur. J. Org. Chem. 2003, 985Ϫ997

Spirocyclopropane-Annelated Heterocycles
FULL PAPER
Table 3. Products 30dϪi, 31h and 32i of Heck reactions of 6-halo-
1,4-benzoxazine-3-carboxylates 26b,c-Me with alkenes
Entry
Y
R
30 (%)
(E/Z) ratio[a]
31/32 (%)
d[b]
d
e
Br
I
I
I
I
I
I
CO2Me
CO2Me
CHO
COMe
CN
Ph
OEt
Յ30
86
89
Ͼ96:4
Ͼ96:4
Ͼ96:4
Ͼ96:4
2.7:1
Ͼ96:4
3:1
0
0
0
0
0
f
72
g
h
i
87[c]
75
8
60
35[d]
[a]
[b]
According to NMR spectra.
nBu3N was used instead
[c]
[d]
nBu4NBr. 31% of pure (E)-30g was isolated.
hydrolysis product 32i.
Isolated as the
Under the same Jeffery conditions, however, the more-
reactive 6-iodo-1,4-benzoxazine-3-carboxylate 26c-Me,
could be coupled with methyl acrylate and other typical
Heck coupling partners to give the 6-substituted 2-spirocy-
clopropanated 1,4-benzoxazine derivatives 30dϪi in yields
ranging from 60 to 89% (Scheme 10). In all these cases the
(E) isomers were the only products, except for the coupling
of acrylonitrile, which gave a mixture of (E)-30g (which
could be isolated) and (Z)-30g in a ratio of 2.7:1. In addi-
tion to 75% of (E)-30h, 8% of the α-coupling product 31h
was obtained from 26c-Me and styrene. In the reaction with
ethyl vinyl ether, the isolated products were 60% of a 3:1
mixture of (E)- and (Z)-30i, as well as 35% of the methyl
ketone 32i arising from hydrolysis of the α-coupling prod-
uct. This lack of regioselectivity in Heck couplings with vi-
nyl ethers is well known.[10]
Scheme 11. Attempted palladium-catalyzed aminocarbonylation
and amination reactions of 7-bromo-1,4-benzothiazinecarboxylate
22b and 6-bromo-1,4-benzoxazinecarboxylate 26b-Me
attack of morpholine on the ester’s methyl group, the
amides 34 and 35 must be formed by addition of water onto
the CϭN double bond in the resulting benzoxazines, and
subsequent oxidation.
Several attempts to bring about palladium-catalyzed ami-
nocarbonylation and amination reactions of the 7-bromo-
1,4-benzothiazine 22b and 6-bromo-1,4-benzoxazine 26b-
Me derivatives under established conditions were not met
with success. Treatment of 22b with 4-methoxybenzylamine
(PMBNH2) and CO in the presence of Pd(OAc)2, PPh3, and
nBu3N in DMF at 80 °C for 14 h led mainly to the 4-meth-
oxybenzylamide 33 (55%), along with 4% of the 1,4-benzo-
thiazin-3-one derivative 34 arising from 22b by demeth-
oxycarbonylation and subsequent oxidation. Under the
same conditions, the 1,4-benzoxazine derivative 26b-Me
gave the 1,4-benzoxazin-3-one derivative 35 in 23% yield
(Scheme 11). The same product was formed in 51% yield
upon treatment of 26b-Me with morpholine under condi-
tions as optimized for aminations of haloarenes [Pd(OAc)2,
PPh3, tBuONa, K2CO3 in toluene, 80 °C, 30% H2O2, 20
°C, 10 min].[11]
In a control experiment the 1,4-benzoxazine derivatives
26b,c-Me were heated with morpholine without a catalyst
in anhydrous DMF under nitrogen. Surprisingly, this pro-
cedure led to demethoxycarbonylation to give the spirocy-
clopropane-annelated 1,4-benzoxazine derivatives 36b,c in
excellent yields (83 and 98%, respectively) (Scheme 12).
When this reaction of 26b-Me was carried out in the pres-
ence of air, about 10% of 35 was detected as a byproduct
according to the NMR spectrum. While the demethoxycar-
Scheme 12. Demethoxycarbonylation of 1,4-benzoxazine derivat-
ives 26b,c and nucleophilic additions to the spirocyclopropane-an-
nelated 1,4-benzoxazine moiety in the product 36b
Facile addition of nucleophiles onto the imine moiety in
36b does indeed occur, as was proved in reactions with p-
thiocresol and hydrogen cyanide providing the adducts 37
and 38 in good to excellent yields (76 and 95%, respect-
ively). Hydrolysis of the carbonitrile 38 offers itself as a
better route to 3,4-dihydro-1,4-benzoxazinecarboxylate de-
rivatives of type 13, which are available only in poor yields
by direct cocyclization of alkyl 2-chloro-2-cyclopropylid-
eneacetates with o-aminophenol 11.
Experimental Section
General: 1H NMR spectra were recorded with a Bruker AM 250
spectrometer (250 MHz) at ambient temperature in CDCl3 or
bonylation of 26b,c most probably occurs by nucleophilic [D6]DMSO, using residual CHCl3 (δ ϭ 7.26 ppm) and [D5]DMSO
Eur. J. Org. Chem. 2003, 985Ϫ997 989

A. de Meijere et al.
FULL PAPER
(δ ϭ 2.49 ppm) as internal standards. Chemical shifts (δ) are
quoted in ppm and coupling constants (J) are given in Hz to the
nearest 0.1 Hz. The following abbreviations are used for the signal
Methyl 2-[1-(2-Aminophenylthio)cyclopropyl]-2-chloroacetate (9a):
A solution of 1-Me (1.016 g, 6.93 mmol) in dichloromethane
(5 mL) was added to a solution of 2-aminothiophenol (8a) (882 mg,
multiplicities: s (singlet), d (doublet), t (triplet), q (quadruplet), m 7.05 mmol) and triethylamine (0.5 mL) in dichloromethane
(multiplet), and br (broad). 13C NMR spectra were recorded with (10 mL) under nitrogen, and the mixture was stirred for 24 h at
a Bruker AM 250 spectrometer (62.9 MHz) at ambient temperature
in CDCl3 or [D6]DMSO, with CDCl3 (δ ϭ 77.00 ppm) and the residue was recrystallized from hexane/dichloromethane at Ϫ60
[D6]DMSO (δ ϭ 39.70 ppm) as internal standards. Multiplicities °C to give 9a (1.277 g, 68%) as a light-yellow solid. M.p. 73Ϫ75
were determined by the DEPT 135 pulse sequence and are given °C. Rf ϭ 0.47 (diethyl ether/hexane, 1:1). H NMR (CDCl3): δ ϭ
as follows: ϩ ϭ CH or CH3, Ϫ ϭ CH2, Cquat ϭ quaternary carbon 1.15Ϫ1.35 (m, 4 H, cPr-H), 3.72 (s, 3 H, CH3O), 4.42 (br s, 2 H,
ambient temperature. The reaction mixture was concentrated, and
1
atom. 2D-NOESY NMR spectra were recorded with a Bruker NH2), 4.49 (s, 1 H, CHCl), 6.67Ϫ6.76 (m, 2 H), 7.14 (m, 1 H), 7.39
AMX 300 spectrometer at 300 MHz. Infrared spectra were re-
corded with a Bruker FT-IR spectrometer IFS 66. Mass spectra
(dd, J ϭ 7.6, 1.7 Hz, 1 H). 13C NMR (CDCl3): δ ϭ 13.8 (Ϫ, C-2Ј),
14.0 (Ϫ, C-3Ј), 31.0 (Cquat, C-1Ј), 52.8 (ϩ, CH3O), 61.5 (ϩ, C-2),
were recorded with a Finnigan MAT 95 spectrometer using elec- 115.2 (Cquat), 115.3 (ϩ), 118.3 (ϩ), 130.6 (ϩ), 136.8 (ϩ), 149.0
tron-impact ionization at 70 eV. High-resolution mass spectra
(HRMS) were obtained with a Varian MAT 311 spectrometer using
preselected-ion peak matching at R ഠ 10000 to be within Ϯ2 ppm
of the exact masses. Elemental analyses were performed by the Mi-
kroanalytisches Laboratorium im Institut für Organische Chemie,
Universität Göttingen. M.p.: Büchi 510 capillary melting point ap-
paratus, uncorrected values. Preparative column chromatography:
Merck silica gel 60 (0.063Ϫ0.200 mm). All solvents used for reac-
tions were dried according to procedures commonly used. Unless
specified otherwise, solutions of NaHCO3 and NaCl were saturated
aqueous solutions. Methyl 2-chloro-2-cyclopropylideneacetate (1-
Me)[1] and tert-butyl 2-chloro-2-cyclopropylideneacetate (1-tBu),[4a]
2-amino-5-bromothiophenol (8b),[12] 2-amino-5-bromophenol
(11b),[13] 2-amino-5-iodophenol (11c),[14] mercaptohydroquinone
(15),[15] and 2Ј-hydroxybenzenesulfanilide (23a)[16] were prepared
according to published methods. All other chemicals were used as
commercially available.
(Cquat), 168.5 (Cquat, CO). MS (EI): m/z (%) ϭ 273/271 (37/100)
[Mϩ], 236 (13) [Mϩ Ϫ Cl], 204 (57) [Mϩ Ϫ Cl Ϫ CH4O], 202 (17),
176 (64), 162 (52), 125 (34), 124 (63), 106 (54), 80 (37).
C12H14ClNO2S (271.8): calcd. 271.0433, correct HRMS; calcd. C
53.04, H 5.19, N 5.15; found C 52.96, H 5.16, N 5.16.
Methyl 2-[1-(2-Amino-5-bromophenylthio)cyclopropyl]-2-chloroacet-
ate (9b): A solution of 1-Me (395 mg, 2.69 mmol) in dichlorome-
thane (5 mL) was added to a solution of 2-amino-5-bromothio-
phenol (8b) (418 mg, 2.05 mmol) and triethylamine (0.5 mL) in
dichloromethane (10 mL) under nitrogen. After 1 h, the reaction
mixture was concentrated and the residue was purified by column
chromatography on silica gel (60 g), eluting with diethyl ether/hex-
ane (0:1Ǟ1:1) to give 9b (662 mg, 92%) as a yellowish oil which
crystallized rapidly. M.p. 72Ϫ73 °C. Rf ϭ 0.30 (diethyl ether/hex-
ane, 1:1). 1H NMR (CDCl3): δ ϭ 1.16Ϫ1.38 (m, 4 H, cPr-H), 3.72
(s, 3 H, CH3O), 4.39 (s, 1 H, CHCl), 4.40 (br s, 2 H, NH2), 6.60
(d, J ϭ 8.6 Hz, 1 H, 3Ј-H), 7.22 (dd, J ϭ 8.6, 2.4 Hz, 1 H, 4Ј-H),
Reaction of Methyl 2-Chloro-2-cyclopropylideneacetate (1-Me) with 7.48 (d, J ϭ 2.4 Hz, 1 H, 6Ј-H) ppm. 13C NMR (CDCl3): δ ϭ 14.4
2-Aminoethanethiol Hydrochloride: A mixture of 1-Me (382 mg, (Ϫ, C-2Ј), 14.8 (Ϫ, C-3Ј), 31.4 (Cquat, C-1Ј), 53.0 (ϩ, CH3O), 62.1
2.61 mmol), 2-aminoethanethiol hydrochloride (304 mg, (ϩ, C-2), 109.0 (Cquat), 116.7 (ϩ), 117.2 (Cquat), 133.3 (ϩ), 138.3
2.67 mmol) and triethylamine (0.5 mL) in dichloromethane (ϩ), 148.2 (Cquat), 168.4 (Cquat, CO) ppm. MS (EI): m/z (%) ϭ 353/
(10 mL) was stirred at ambient temperature for 24 h, diluted with 351/349 (29/100/74) [Mϩ], 316/314 (9/6) [Mϩ Ϫ Cl], 284/282 (17/
diethyl ether, washed with NaHCO3 and NaCl solutions, dried with
MgSO4, and concentrated. The residue was subjected to chromato-
graphy on silica gel (60 g), eluting with hexane/diethyl ether and
then methanol/diethyl ether (0 Ǟ 0.15) to yield 6 (132 mg, 27%)
and 7 (70 mg, 16%), respectively.
26) [Mϩ Ϫ Cl Ϫ CH3O], 244/242/240 (14/48/35), 204/202 (57/60),
186/184 (37/37), 123 (77). C12H13BrClNO2S (350.7): calcd.
348.9539, correct HRMS; calcd. C 41.10, H 3.74, N 3.99; found C
41.13, H 3.72, N 3.59.
Methyl 3,4-Dihydrospiro([2H][1,4]benzothiazine-2,1Ј-cyclopropane)-
3-carboxylate (10a): 1-Me (358 mg, 2.44 mmol) was added to a so-
Methyl 3Ј,4Ј,5Ј,6Ј-Tetrahydrospiro(cyclopropane-1,2Ј-[2H][1,4]thi-
azine)-3Ј-carboxylate (6): A colorless oil, Rf ϭ 0.31 (diethyl ether/ lution of 2-aminothiophenol (8a) (335 mg, 2.68 mmol) and triethyl-
methanol, 9:1). For the IR and 1H NMR spectra see ref.[4a] 13C amine (1 mL) in anhydrous DMF (5 mL). The mixture was stirred
NMR (CDCl3): δ ϭ 13.7 (Ϫ, C-2), 15.3 (Ϫ, C-3), 22.8 (Cquat, C-
1), 28.9 (Ϫ, C-6Ј), 43.8 (Ϫ, C-5Ј), 51.6 (ϩ, OCH3), 63.6 (ϩ, C-3Ј),
for 15 h at 100 °C, cooled to room temp., poured into NaHCO3
solution (20 mL), and then extracted with dichloromethane. The
171.4 (Cquat, CO) ppm. For the X-ray crystal structure analysis of combined organic extracts were washed twice with water and once
6 see ref.[7]
with NaCl solution, dried with MgSO4, and concentrated. The res-
idue was purified by column chromatography on silica gel (60 g),
eluting with diethyl ether/hexane (0:1Ǟ3:2) to yield 10a (228 mg,
Methyl 4Ј-{1-[Chloro(methoxycarbonyl)methyl]cyclopropyl}-3Ј,4Ј,
5Ј,6Ј-tetrahydrospiro(cyclopropane-1,2Ј-[2H][1,4]thiazine)-3Ј-carb-
oxylate (7): A light-yellow oil, Rf ϭ 0.54 (diethyl ether/hexane, 2:1).
1H NMR (CDCl3): δ ϭ 0.65Ϫ1.25 (m, 8 H, cPr-H), 2.65Ϫ3.00 (m,
4 H, 5Ј,6Ј-H), 3.75 (s, 3 H, OCH3), 3.83 (s, 3 H, OCH3), 4.24 (s, 1
H), 4.34 (s, 1 H) ppm. 13C NMR (CDCl3): δ ϭ 14.8 (Ϫ, cPr-C),
14.9 (Ϫ, cPr-C), 15.36 (Ϫ, cPr-C), 15.39 (Ϫ, cPr-C), 16.2 (Ϫ, cPr-
C), 16.3 (Ϫ, cPr-C), 28.2 (Cquat, C-1), 33.9 (Ϫ, C-6Ј), 41.6 (Cquat
C-1ЈЈ), 45.47 (Ϫ, C-5Ј), 45.51 (Ϫ, C-5Ј), 52.9 (ϩ, OCH3), 63.1 (ϩ),
63.66 (ϩ), 63.68 (ϩ), 168.4 (Cquat, CO), 168.8 (Cquat, CO) ppm.
1
40%) as a red oil. Rf ϭ 0.35 (diethyl ether/hexane, 2:1). H NMR
(CDCl3, compare with ref.[4]): δ ϭ 0.82Ϫ1.25 (m, 4 H, cPr-H), 3.29
(s, 1 H, CHN), 3.65 (s, 3 H, CH3O), 4.60 (br s, 1 H, NH), 6.52 (m,
2 H), 6.83 (m, 2 H) ppm. 13C NMR (CDCl3): δ ϭ 11.6 (Ϫ, C-2Ј),
16.7 (Ϫ, C-3Ј), 21.0 (Cquat, C-1Ј), 51.4 (ϩ, CH3O), 60.4 (ϩ, C-3),
114.7 (ϩ), 115.1 (Cquat), 117.1 (ϩ), 125.0 (ϩ), 126.6 (ϩ), 139.5
(Cquat), 170.7 (Cquat, CO) ppm. MS (EI) (compare with ref.[4a]):
m/z (%) ϭ 235 (48) [Mϩ], 176 (100) [Mϩ Ϫ COOCH3].
,
Two diastereoisomers, ratio ca. 1:1. MS (EI): m/z (%) ϭ 335/333 Methyl 2-Chloro-2-[1-(2-hydroxyanilino)cyclopropyl]acetate (12): A
(8/20) [Mϩ], 304/302 (4/13) [Mϩ Ϫ CH3O], 209/207 (20/54), 192/ solution of 1-Me (300 mg, 2.05 mmol) in DMF (5 mL) was added
190 (36/100), 171 (47), 140 (38), 108 (58), 59 (48). C14H20ClNO4S
(333.8): calcd. 333.0801, correct HRMS.
to a solution of 2-aminophenol (11a) (225 mg, 2.06 mmol) and trie-
thylamine (0.5 mL) in DMF (10 mL), and then the mixture was
990
Eur. J. Org. Chem. 2003, 985Ϫ997

Spirocyclopropane-Annelated Heterocycles
FULL PAPER
stirred for 24 h at ambient temperature, poured into water (50 mL),
and extracted with dichloromethane. The combined organic phases
were washed with water and NaCl solution, dried with MgSO4,
and concentrated. The residue was chromatographed on silica gel
(60 g), eluting with diethyl ether/hexane (0:1 Ǟ 1:1) to give 12
was subjected to chromatography on silica gel (60 g), eluting with
diethyl ether/hexane (0:1Ǟ2:1) to give 17 (400 mg, 85%) as a color-
less solid. M.p. 140Ϫ141 °C. Rf ϭ 0.32 (diethyl ether/hexane, 2:1).
IR (KBr): ν˜ ϭ 3428, 3403, 3073, 3005, 2956, 2919, 1739, 1718,
1617, 1489, 1437, 1350, 1313, 1278, 1224, 1188, 1089 cmϪ1 1H
.
(335 mg, 64%) as a reddish oil, which rapidly became dark upon NMR (CDCl3): δ ϭ 0.98Ϫ1.20 (m, 3 H, cPr-H), 1.32Ϫ1.41 (m, 1
standing in air. Rf ϭ 0.34 (diethyl ether/hexane, 1:1). IR (film): ν˜ ϭ
H, cPr-H), 3.80 (s, 3 H, CH3O), 4.21 (s, 1 H, 2-H), 5.65 (s, 1 H,
3421 cmϪ1 (br, OH, NH), 2954, 1734 (CO), 1611, 1513, 1438, 1270, OH), 6.39 (d, J ϭ 2.7 Hz, 1 H, 5-H), 6.48 (dd, J ϭ 8.8, 2.7 Hz, 1
1197, 1171, 1103, 1016, 912, 744. 1H NMR (CDCl3): δ ϭ H, 7-H), 6.80 (d, J ϭ 8.8 Hz, 1 H, 8-H) ppm. 13C NMR (CDCl3):
1.00Ϫ1.06 (m, 3 H, cPr-H), 1.28Ϫ1.39 (m, 1 H, cPr-H), 3.75 (s, 3
δ ϭ 11.7 (Ϫ, C-2Ј), 17.1 (Ϫ, C-3Ј), 21.6 (Cquat, C-1Ј), 52.8 (ϩ,
H, CH3O), 4.58 (s, 1 H, CHCl), 5.8 (br s, 2 H, NH ϩ OH), CH3O), 79.5 (ϩ, C-2), 113.6 (ϩ), 114.0 (ϩ), 117.9 (Cquat), 118.7
6.40Ϫ6.97 (m, 4 H, Ar-H) ppm. 13C NMR (CDCl3): δ ϭ 13.6 (Ϫ, (ϩ), 143.8 (Cquat), 149.8 (Cquat), 169.7 (Cquat, CϭO) ppm. MS (EI):
C-2Ј), 14.6 (Ϫ, C-3Ј), 37.2 (Cquat, C-1Ј), 53.1 (ϩ, CH3O), 60.9 (ϩ,
m/z (%) ϭ 252 (100) [Mϩ], 193 (56) [Mϩ Ϫ COOCH3], 166 (63).
C-2), 113.0 (ϩ), 114.8 (ϩ), 118.6 (ϩ), 120.9 (ϩ), 133.6 (Cquat), C12H12O4S (252.2): calcd. 252.0456, correct HRMS; calcd. C 57.13,
143.5 (Cquat), 169.2 (Cquat, CϭO) ppm. MS (EI): m/z (%) ϭ 257/ H 4.79; found C 57.01, H 4.87.
255 (4/13) [Mϩ], 240/238 (3/8) [Mϩ Ϫ OH], 220 (53) [Mϩ Ϫ Cl],
General Procedure for the Preparation of Compounds 18a,b, 19a
(GP1): A solution of benzenesulfonyl chloride in dichloromethane
(5 mL) was added to a solution of 9 and pyridine (1 mL) in di-
chloromethane (10 mL). The reaction mixture was stirred for 20 h
at ambient temperature, diluted with dichloromethane, washed
twice with 5% HCl, once each with both water and NaCl solution,
dried with MgSO4 and then concentrated. The residue was crystal-
lized from hexane/CH2Cl2 at Ϫ20 °C (18a, 19a) or subjected to
chromatography on silica gel (18b).
188 (94) [Mϩ Ϫ Cl Ϫ CH3OH], 160 (29), 148 (44), 146 (100).
C12H14ClNO3 (255.7): calcd. 255.0662, correct HRMS.
Methyl 3,4-Dihydrospiro([2H][1,4]benzoxazine-2,1Ј-cyclopropane)-3-
carboxylate (13): A solution of 1-Me (296 mg, 2.02 mmol) in DMF
(5 mL) was added to a solution of 11a (220 mg, 2.02 mmol) and
DBU (0.31 mL, 2.1 mmol) in DMF (10 mL). The mixture was
stirred at 70Ϫ80 °C for 24 h under nitrogen, cooled, poured into
water (50 mL), and extracted with dichloromethane. The organic
phases were washed three times with water and with NaCl solution,
dried with MgSO4, and concentrated. The residue was subjected to
chromatography on silica gel (60 g), eluting with diethyl ether/hex-
ane (0:1 Ǟ 1:1) to give 13 (20 mg, 4.5%) as a light-yellow oil which
crystallized slowly. M.p. 59Ϫ61 °C. Rf ϭ 0.19 (diethyl ether/hexane,
1:1). 1H NMR (CDCl3): δ ϭ 0.72Ϫ0.82 (m, 1 H, cPr-H), 0.96Ϫ1.17
(m, 2 H, cPr-H), 1.21Ϫ1.32 (m, 1 H, cPr-H), 3.62 (s, 3 H, CH3O),
3.77 (s, 1 H, CHN), 4.43 (br s, 1 H, NH), 6.69Ϫ6.90 (m, 4 H, Ar-
H) ppm. 13C NMR (CDCl3): δ ϭ 11.0 (Ϫ, C-2Ј), 12.6 (Ϫ, C-3Ј),
52.5 (ϩ, CH3O), 58.2 (ϩ, C-3), 59.5 (Cquat, C-1Ј), 115.7 (ϩ), 116.9
Methyl 2-Chloro-2-(1-{2-[(phenylsulfonyl)amino]phenylthio}cyclo-
propyl)acetate (18a): From 9a (645 mg, 2.37 mmol) and benzenesul-
fonyl chloride (402 mg, 2.28 mmol) according to GP1, 18a (753 mg,
80%) was isolated as a colorless solid. M.p. 121Ϫ122 °C. Rf ϭ 0.35
(diethyl ether/hexane, 1:1). IR (KBr): ν˜ ϭ 3239, 3064, 3019, 2971,
2956, 1743, 1700, 1589, 1484, 1449, 1402, 1323, 1275, 1184, 1157,
1
1090, 926 cmϪ1. H NMR (CDCl3): δ ϭ 1.12Ϫ1.38 (m, 4 H, cPr-
H), 3.82 (s, 3 H, CH3O), 4.15 (s, 1 H, CHCl), 7.09 (dt, J ϭ 7.6,
1.3 Hz, 1 H), 7.29Ϫ7.66 (m, 6 H), 7.82 (m, 2 H), 8.03 (br s, 1 H,
NH) ppm. 13C NMR (CDCl3): δ ϭ 13.9 (Ϫ, C-2Ј), 15.5 (Ϫ, C-3Ј),
31.2 (Cquat, C-1Ј), 53.3 (ϩ, CH3O), 62.4 (ϩ, C-2), 121.3 (ϩ), 123.4
(Cquat), 125.0 (ϩ), 127.1 (ϩ, 2 C), 128.8 (ϩ, 2 C), 130.4 (ϩ), 132.9
(ϩ), 135.8 (ϩ), 138.7 (Cquat), 138.9 (Cquat), 168.3 (Cquat, CO) ppm.
MS (EI): m/z (%) ϭ 413/411 (33/75) [Mϩ], 376 (60) [Mϩ Ϫ Cl], 344
(38) [Mϩ Ϫ Cl Ϫ CH3OH], 270 (16), 235 (52), 234 (100), 220 (29),
175 (35), 174 (29), 163 (64), 162 (84), 124 (21), 77 (44).
C18H18ClNO4S2 (411.9): calcd. 411.0365, correct HRMS; calcd. C
52.48, H 4.40, N 3.40; found C 52.56, H 4.59, N 3.24.
(ϩ), 119.0 (ϩ), 122.1 (ϩ), 132.5 (Cquat), 144.0 (Cquat), 171.6 (Cquat
,
CϭO) ppm. MS (EI): m/z (%) ϭ 219 (37) [Mϩ], 160 (100) [Mϩ
Ϫ
COOCH3], 132 (9) [Mϩ Ϫ COOCH3 Ϫ C2H4]. C12H13NO3 (219.2):
calcd. 219.0895, correct HRMS.
Methyl 2-Chloro-2-[1-(2,5-dihydroxyphenylthio)cyclopropyl]acetate
(16): A solution of 1-Me (321 mg, 2.19 mmol) in dichloromethane
(5 mL) was added under nitrogen to a stirred solution of mercap-
tohydroquinone (15) (311 mg, 2.19 mmol) and triethylamine
(0.5 mL) in dichloromethane (10 mL), the mixture was stirred for
an additional 2 h at ambient temperature, and then concentrated.
The residue was subjected to chromatography on silica gel (60 g),
eluting with diethyl ether/hexane to give nearly pure 16 (547 mg,
Methyl
2-(1-{5-Bromo-2-[(phenylsulfonyl)amino]phenylthio}cyclo-
propyl)-2-chloroacetate (18b): From 9b (650 mg, 1.85 mmol) and
benzenesulfonyl chloride (332 mg, 1.88 mmol), according to GP1
with chromatography on silica gel (60 g), eluting with diethyl ether/
hexane (0:1Ǟ1:1), 18b (878 mg, 97%) was isolated as a colorless
glass. Rf ϭ 0.26 (diethyl ether/hexane, 1:1). 1H NMR (CDCl3): δ ϭ
1.06Ϫ1.34 (m, 4 H, cPr-H), 3.73 (s, 3 H, CH3O), 4.06 (s, 1 H,
CHCl), 7.32Ϫ7.54 (m, 6 H), 7.71Ϫ7.79 (m, 2 H), 8.02 (br s, 1 H,
NH). 13C NMR (CDCl3): δ ϭ 14.7 (Ϫ, C-2Ј), 16.4 (Ϫ, C-3Ј), 31.3
(Cquat, C-1Ј), 53.3 (ϩ, CH3O), 63.6 (ϩ, C-2), 117.5 (Cquat), 123.2
(ϩ), 126.4 (Cquat), 126.9 (ϩ, 2 C), 128.8 (ϩ, 2 C), 132.9 (ϩ), 133.0
(ϩ), 137.3 (ϩ), 137.5 (Cquat), 138.5 (Cquat), 168.0 (Cquat, CO) ppm.
MS (EI): m/z (%) ϭ 493/491/489 (34/100/73) [Mϩ], 456/454 (42/37)
[Mϩ Ϫ Cl], 424/422 (15/13) [Mϩ Ϫ Cl Ϫ CH3OH], 315/314/313/
312 (27/60/24/56), 243/242/241/240 (44/58/42/53), 77 (61).
C18H17BrClNO4S2 (490.8): calcd. 488.9471, correct HRMS.
1
86%) as a reddish oil. Rf ϭ 0.54 (ether). H NMR (CDCl3): δ ϭ
1.10Ϫ1.30 (m, 4 H, cPr-H), 3.70 (s, 3 H, CH3O), 4.29 (s, 1 H,
CHCl), 6.70 (br s, 1 H, OH), 6.80 (s, 2 H), 6.97 (s, 1 H), 7.11 (br
s, 1 H, OH) ppm. 13C NMR (CDCl3): δ ϭ 14.0 (Ϫ, C-2Ј), 15.1 (Ϫ,
C-3Ј), 30.7 (Cquat, C-1Ј), 53.2 (ϩ, CH3O), 62.2 (ϩ, C-2), 116.0 (ϩ),
117.1 (ϩ), 118.7 (ϩ), 121.5 (Cquat), 149.0 (Cquat), 150.4 (Cquat),
169.0 (Cquat, CϭO) ppm. MS (EI): m/z (%) ϭ 290/288 (37/100)
[Mϩ], 253 (49) [Mϩ Ϫ Cl], 221 (61) [Mϩ Ϫ Cl Ϫ CH3OH], 193
(52), 181 (44) [Mϩ Ϫ CHClCOOCH3], 141 (50) [C6H5O2Sϩ].
Methyl
cyclopropane)-2-carboxylate (17): K2CO3 (276 mg, 2.00 mmol) was
added under nitrogen to stirred solution of 15 (266 mg,
1.87 mmol), 1-Me (275 mg, 1.88 mmol) and KI (30 mg) in DMF
(15 mL). The mixture was stirred for 4 d at ambient temperature, Methyl 2-[1-(2-{[(4-Bromophenyl)sulfonyl]amino}phenylthio)cyclo-
3,4-Dihydro-6-hydroxyspiro([2H][1,4]benzoxathiine-3,1Ј-
a
diluted with dichloromethane, washed with water and with NaCl
solution, dried with MgSO4, and then concentrated. The residue
propyl]-2-chloroacetate (19a): From 9a (584 mg, 2.15 mmol) with 4-
bromobenzenesulfonyl chloride (660 mg, 2.58 mmol), according to
Eur. J. Org. Chem. 2003, 985Ϫ997
991

A. de Meijere et al.
FULL PAPER
GP1, 19a (855 mg, 81%) was isolated as a colorless solid. M.p.
1437, 1323, 1202, 1161, 1086 cmϪ1
.
1H NMR (CDCl3): δ ϭ
113Ϫ115 °C. Rf ϭ 0.32 (diethyl ether/hexane, 1:1). IR (KBr): ν˜ ϭ 0.84Ϫ0.98 (m, 2 H, cPr-H), 1.17Ϫ1.31 (m, 2 H, cPr-H), 3.73 (s, 3
3240, 3066, 3007, 2981, 2955, 1743, 1700, 1653, 1576, 1485, 1407, H, CH3O), 5.03 (s, 1 H, 3-H), 7.12Ϫ7.22 (m, 2 H), 7.40Ϫ7.62 (m,
1327, 1158, 931 cmϪ1. 1H NMR (CDCl3): δ ϭ 1.10Ϫ1.40 (m, 4 H, 4 H), 7.72Ϫ7.78 (m, 2 H) ppm. 13C NMR (CDCl3): δ ϭ 13.9 (Ϫ,
cPr-H), 3.79 (s, 3 H, CH3O), 4.10 (s, 1 H, CHCl), 7.08 (dt, J ϭ 7.8, C-2Ј), 16.1 (Ϫ, C-3Ј), 24.9 (Cquat, C-1Ј), 52.9 (ϩ, CH3O), 64.3 (ϩ,
1.5 Hz, 1 H), 7.32 (dt, J ϭ 7.8, 1.5 Hz, 1 H), 7.44Ϫ7.67 (m, 6 H), C-3), 118.6 (Cquat), 127.1 (ϩ, 2 C), 127.2 (ϩ), 128.7 (ϩ), 129.1 (ϩ,
8.08 (br s, 1 H, NH) ppm. 13C NMR (CDCl3): δ ϭ 14.3 (Ϫ, C-2Ј),
2 C), 129.7 (ϩ), 130.4 (Cquat), 132.9 (Cquat), 133.2 (ϩ), 139.8 (Cquat),
16.0 (Ϫ, C-3Ј), 31.4 (Cquat, C-1Ј), 53.4 (ϩ, CH3O), 62.0 (ϩ, C-2), 168.1 (Cquat, CO) ppm. MS (EI): m/z (%) ϭ 455/453 (72/66) [Mϩ],
121.8 (ϩ), 124.1 (Cquat), 125.4 (ϩ), 128.0 (Cquat), 128.8 (ϩ, 2 C), 396/394 (16/14) [Mϩ Ϫ COOCH3], 314/312 (100/97) [Mϩ
Ϫ
130.5 (ϩ), 132.1 (ϩ, 2 C), 135.9 (ϩ), 138.1 (Cquat), 138.4 (Cquat),
168.4 (Cquat, CO) ppm. MS (EI): m/z (%) ϭ 493/491/489 (17/52/37)
[Mϩ], 456/454 (38/34) [Mϩ Ϫ Cl], 424/422 (22/21) [Mϩ Ϫ Cl Ϫ
CH3OH], 270 (14), 235 (52), 234 (94) [Mϩ Ϫ Cl Ϫ BrC6H4SO2],
C6H5SO2], 255/253 (82/85) [Mϩ Ϫ C6H5SO3 Ϫ COOCH3], 254/252
(55/42) [Mϩ Ϫ C6H5SO2H Ϫ COOCH3]. C18H16BrNO4S2 (454.4):
calcd. 452.9704, correct HRMS; calcd. C 47.58, H 3.55, N 3.08;
found C 47.40, H 3.61, N 2.89. The mother liquor from the crystal-
202 (29), 175 (40), 163 (77), 162 (100). C18H17BrClNO4S2 (490.8): lization of 20b was concentrated and the residue was recrystallized
calcd. 488.9471, correct HRMS; calcd. C 44.05, H 3.49, N 2.85;
found C 44.04, H 3.57, N 2.58.
from hexane/diethyl ether to yield 22b (250 mg, 45%) as yellow
crystals. M.p. 108Ϫ109 °C. Rf ϭ 0.33 (diethyl ether/hexane, 1:1).
1H NMR (CDCl3): δ ϭ 1.08 and 1.62 (AAЈXXЈ, 4 H, cPr-H), 3.86
(s, 3 H, CH3O), 7.32Ϫ7.43 (m, 3 H, Ar-H) ppm. 13C NMR
(CDCl3): δ ϭ 16.8 (Ϫ, 2 C, C-2Ј,3Ј), 17.2 (Cquat, C-1Ј), 53.0 (ϩ,
CH3O), 122.4 (Cquat), 128.6 (Cquat), 129.4 (ϩ), 129.9 (ϩ), 130.1 (ϩ),
140.4 (Cquat), 155.1 (Cquat, CϭN), 163.0 (Cquat, CO) ppm. MS (EI):
m/z (%) ϭ 313/311 (53/52) [Mϩ], 281/279 (9/9) [Mϩ Ϫ CH3OH],
254/252 (18/18), 253/251 (100/95), 172 (18). C12H10BrNO2S (312.2):
calcd. 310.9615, correct HRMS. For the X-ray crystal structure
analysis of 22b see ref.[7]
General Procedure for the Preparation of Compounds 20؊22 (GP2):
A mixture of 18 or 19, K2CO3, KI (50 mg) and DMF (10 mL) was
stirred at 70 °C for 2 h, cooled, diluted with dichloromethane,
washed repeatedly with water and once with NaCl solution, dried
with MgSO4, and then concentrated. The residue was crystallized
from hexane/dichloromethane.
Methyl 4-(Phenylsulfonyl)-3,4-dihydrospiro([2H][1,4]benzothiazine-
2,1Ј-cyclopropane)-3-carboxylate (20a): From 18a (726 mg,
1.76 mmol) and K2CO3 (365 mg, 2.64 mmol) according to GP2,
20a (507 mg, 77%) was obtained as a colorless solid. M.p. 143Ϫ144
°C. Rf ϭ 0.37 (diethyl ether/hexane, 1:1). IR (KBr): ν˜ ϭ 3096, 3000,
Methyl 4-[(4-Bromophenyl)sulfonyl]-3,4-dihydrospiro([2H][1,4]ben-
zothiazine-2,1Ј-cyclopropane)-3-carboxylate (21a): From 19a
(832 mg, 1.70 mmol) and K2CO3 (250 mg, 1.81 mmol), according
to GP2, 21a (435 mg, 56%) was obtained as a colorless solid. M.p.
98Ϫ99 °C. Rf ϭ 0.44 (diethyl ether/hexane, 1:1). IR (KBr): ν˜ ϭ
3083, 3001, 2953, 1756, 1575, 1478, 1439, 1348, 1207, 1159, 1093,
2957, 1751, 1479, 1451, 1436, 1326, 1202, 1161, 1086, 1072 cmϪ1
.
1H NMR (CDCl3): δ ϭ 0.84Ϫ0.98 (m, 2 H, cPr-H), 1.13Ϫ1.33 (m,
2 H, cPr-H), 3.71 (s, 3 H, CH3O), 5.07 (s, 1 H, 3-H), 7.02Ϫ7.16
(m, 3 H), 7.40Ϫ7.62 (m, 4 H), 7.71Ϫ7.76 (m, 2 H) ppm. 13C NMR
(CDCl3): δ ϭ 13.9 (Ϫ, C-2Ј), 15.7 (Ϫ, C-3Ј), 24.9 (Cquat, C-1Ј), 52.6
(ϩ, CH3O), 64.5 (ϩ, C-3), 125.3 (ϩ), 125.6 (ϩ), 126.0 (ϩ), 127.0
(ϩ, 2 C), 127.4 (ϩ), 128.3 (Cquat), 128.8 (ϩ, 2 C), 132.8 (ϩ), 133.6
(Cquat), 139.8 (Cquat), 168.2 (Cquat, CO) ppm. MS (EI): m/z (%) ϭ
1
1068, 873 cmϪ1. H NMR (CDCl3): δ ϭ 0.83Ϫ0.99 (m, 2 H, cPr-
H), 1.09Ϫ1.18 (m, 1 H, cPr-H), 1.23Ϫ1.32 (m, 1 H, cPr-H), 3.73
(s, 3 H, CH3O), 5.06 (s, 1 H, 3-H), 7.05Ϫ7.18 (m, 3 H), 7.57 (s, 4
H, 4-BrC6H4), 7.56Ϫ7.63 (m, 2 H) ppm. 13C NMR (CDCl3): δ ϭ
14.2 (Ϫ, C-2Ј), 15.5 (Ϫ, C-3Ј), 25.4 (Cquat, C-1Ј), 52.8 (ϩ, CH3O),
65.1 (ϩ, C-3), 125.8 (ϩ), 126.0 (ϩ), 126.5 (ϩ), 127.8 (ϩ), 128.0
(Cquat), 128.7 (ϩ, 2 C), 129.1 (Cquat), 132.2 (ϩ, 2 C), 133.6 (Cquat),
138.9 (Cquat), 168.2 (Cquat, CO) ppm. MS (EI): m/z (%) ϭ 455/453
375 (73) [Mϩ], 316 (20) [Mϩ Ϫ COOCH3], 234 (91) [Mϩ
Ϫ
C6H5SO2], 175 (100) [Mϩ Ϫ C6H5SO2 Ϫ COOCH3], 174 (62) [Mϩ
Ϫ C6H5SO2H Ϫ COOCH3]. C18H17NO4S2 (375.5): calcd. 375.0599,
correct HRMS; calcd. C 57.58, H 4.56, N 3.73; found C 57.53, H
4.51, N 3.63.
(40/39) [Mϩ], 396/394 (11/10) [Mϩ Ϫ COOCH3], 234 (90) [Mϩ
Ϫ
BrC6H4SO2], 175 (100) [Mϩ Ϫ BrC6H5SO2 Ϫ COOCH3], 174 (48)
[Mϩ Ϫ BrC6H4SO2H Ϫ COOCH3]. C18H16BrNO4S2 (454.4): calcd.
452.9704, correct HRMS; calcd. C 47.58, H 3.55, N 3.08; found C
47.48, H 3.63, N 2.87. The mother solution contained 22a and
some 21a. The yield of 22a was not determined.
Methyl
Spiro([2H][1,4]benzothiazine-2,1Ј-cyclopropane)-3-carb-
oxylate (22a): A mixture of 18a (733 mg, 1.78 mmol), K2CO3
(622 mg, 4.50 mmol), KI (50 mg) and DMF (15 mL) was stirred at
80Ϫ85 °C for 4 h, cooled, diluted with dichloromethane, washed
repeatedly with water and once with NaCl solution, dried with
MgSO4 and concentrated to give pure 22a (364 mg, 88%) as a yel-
Benzenesulfanilides 23aϪc: These were obtained from the corres-
ponding 2-aminophenols according to the procedure reported[17]
for the synthesis of 2Ј-hydroxy-p-toluenesulfanilide, with yields as
shown in Scheme 7. The new sulfanilides 23b,c were characterized
by their spectroscopic data as follows.
1
low oil. Rf ϭ 0.32 (diethyl ether/hexane, 1:2). H NMR (CDCl3):
δ ϭ 1.06 and 1.58 (AAЈXXЈ, 4 H, cPr-H), 3.87 (s, 3 H, CH3O),
7.18Ϫ7.26 (m, 3 H), 7.48Ϫ7.56 (m, 1 H). 13C NMR (CDCl3): δ ϭ
16.6 (Ϫ, 2 C, C-2Ј,3Ј), 17.1 (Cquat, C-1Ј), 52.7 (ϩ, CH3O), 126.4
(Cquat), 126.6 (ϩ), 126.8 (ϩ), 128.7 (ϩ), 128.8 (ϩ), 141.3 (Cquat),
154.7 (Cquat, CϭN), 163.1 (Cquat, CO). MS (EI): m/z (%) ϭ 233
(62) [Mϩ], 218 (3) [Mϩ Ϫ CH3], 201 (5) [Mϩ Ϫ CH3OH], 174 (25),
173 (100). C12H11NO2S (233.3): calcd. 233.0510, correct HRMS.
5Ј-Bromo-2Ј-hydroxybenzenesulfanilide (23b): Light-brown solid,
m.p. 153Ϫ155 °C. IR (KBr): ν˜ ϭ 3380, 3249, 1506, 1451, 1394,
1
1319, 1159, 1091, 930 cmϪ1. H NMR ([D6]DMSO): δ ϭ 6.68 (d,
J ϭ 8.6 Hz, 1 H, 3Ј-H), 7.09 (dd, J ϭ 8.6, 2.4 Hz, 1 H, 4Ј-H), 7.25
(d, J ϭ 2.4 Hz, 1 H, 6Ј-H), 7.48Ϫ7.60 (m, 3 H), 7.73Ϫ7.77 (m, 2
H), 9.79 (br s, 2 H, NH, OH) ppm. 13C NMR ([D6]DMSO): δ ϭ
Methyl 7-Bromo-4-(phenylsulfonyl)-3,4-dihydrospiro([2H][1,4]benzo-
thiazine-2,1Ј-cyclopropane)-3-carboxylate (20b) and Methyl 7-Bro- 109.5 (Cquat), 117.5 (ϩ), 126.1 (Cquat), 126.9 (ϩ), 127.0 (ϩ), 128.9
mospiro([2H][1,4]benzothiazine-2,1Ј-cyclopropane)-3-carboxylate
(22b): From 18b (870 mg, 1.77 mmol) and K2CO3 (370 mg,
(ϩ), 129.3 (ϩ), 133.0 (ϩ), 140.5 (Cquat), 149.9 (Cquat) ppm. MS
(EI): m/z (%) ϭ 329/327 (9/9) [Mϩ], 188/186 (98/100) [Mϩ
Ϫ
2.68 mmol), according to GP2, 20b (110 mg, 14%) was obtained as C6H5SO2], 160/158 (35/37), 77 (60) [C6H5ϩ], 51 (49).
a colorless solid. M.p. 171Ϫ172 °C. Rf ϭ 0.32 (diethyl ether/hexane,
1:1). IR (KBr): ν˜ ϭ 3097, 3005, 2957, 1775, 1700, 1653, 1473, 1450,
C12H10BrNO3S (328.2): calcd. 326.9565, correct HRMS; calcd. C
43.92, H 3.07, N 4.27; found C 44.02, H 3.12, N 3.89.
992
Eur. J. Org. Chem. 2003, 985Ϫ997

Spirocyclopropane-Annelated Heterocycles
FULL PAPER
2Ј-Hydroxy-5Ј-iodobenzenesulfanilide (23c): Yellow solid, m.p.
ethyl ether/hexane, 1:4). 1H NMR (CDCl3): δ ϭ 1.22 and 1.54
172Ϫ174 °C. IR (KBr): ν˜ ϭ 3362, 3235, 3063, 1590, 1498, 1432, (AAЈXXЈ, 4 H, cPr-H), 3.84 (s, 3 H, CH3O), 6.71 (dd, J ϭ 7.9,
1385, 1326, 1287, 1162, 1118, 1089, 1072, 921 cmϪ1
([D6]DMSO): δ ϭ 6.55 (d, J ϭ 8.6 Hz, 1 H, 3Ј-H), 7.23 (dd, J ϭ
.
1H NMR
1.4 Hz, 1 H), 6.96 (dt, J ϭ 7.9, 1.4 Hz, 1 H), 7.14 (dt, J ϭ 7.9,
1.7 Hz, 1 H), 7.43 (dd, J ϭ 7.9, 1.7 Hz, 1 H) ppm. 13C NMR
8.6, 2.4 Hz, 1 H, 4Ј-H), 7.37 (d, J ϭ 2.4 Hz, 1 H, 6Ј-H), 7.48Ϫ7.60 (CDCl3): δ ϭ 14.9 (Ϫ, 2 C, C-2Ј,3Ј), 52.7 (ϩ, CH3O), 58.0 (Cquat
,
(m, 3 H), 7.71Ϫ7.75 (m, 2 H), 9.52 (br s, 1 H), 9.93 (br s, 1 H) C-1Ј), 115.8 (ϩ), 122.6 (ϩ), 128.3 (ϩ), 131.0 (ϩ), 132.9 (Cquat),
ppm. 13C NMR ([D6]DMSO): δ ϭ 80.2 (Cquat, C-5Ј), 118.2 (ϩ), 147.6 (Cquat), 155.9 (Cquat, CϭN), 162.0 (Cquat, CϭO) ppm. MS
126.3 (Cquat), 126.9 (ϩ), 129.2 (ϩ), 133.0 (ϩ), 133.0 (ϩ), 134.9 (ϩ), (EI): m/z (%) ϭ 217 (54) [Mϩ], 202 (2) [Mϩ Ϫ CH3], 185 (10)
140.6 (Cquat), 150.7 (Cquat) ppm. MS (EI): m/z (%) ϭ 375 (20) [Mϩ], [Mϩ Ϫ CH3OH], 158 (20), 157 (100). C12H11NO3 (217.2): calcd.
234 (100) [Mϩ Ϫ C6H5SO2], 206 (17), 77 (21) [C6H5ϩ], 51 (18). 217.0738, correct HRMS; calcd. C 66.35, H 5.10, N 6.45; found
C12H10INO3S (375.2): calcd. 374.9426, correct HRMS; calcd. C 66.67, H 5.20, N 6.20.
38.42, H 2.69, N 3.73; found C 38.59, H 2.82, N 3.40.
Methyl 6-Bromo-4-(phenylsulfonyl)-3,4-dihydrospiro([2H][1,4]benz-
Methyl 4-(Phenylsulfonyl)-3,4-dihydrospiro([2H][1,4]benzoxazine-
2,1Ј-cyclopropane)-3-carboxylate (25a-Me): mixture of 23a Bromospiro([2H][1,4]benzoxazine-2,1Ј-cyclopropane)-3-carboxylate
(486 mg, 1.95 mmol), 1-Me (288 mg, 1.96 mmol), K2CO3 (418 mg, (26b-Me): From 23b (3.54 g, 10.8 mmol), K2CO3 (2.07 g,
oxazine-3,1Ј-cyclopropane)-2-carboxylate (24b-Me) and Methyl 6-
A
3.03 mmol), KI (50 mg), and DMF (15 mL) was stirred for 28 h at
ambient temperature, then diluted with dichloromethane, washed
repeatedly with water and once with NaCl solution, dried with
MgSO4, and concentrated. The residue was subjected to chromato-
graphy on silica gel (60 g), eluting with diethyl ether/hexane
(0:1Ǟ1:2) to give 26a-Me (87 mg, 21%) and a mixture of 24a-Me
(see below) and 25a-Me. This mixture was recrystallized from di-
ethyl ether to yield of 25a-Me (153 mg, 22%) as a colorless solid.
15.0 mmol), and 1-Me (1.60 g, 10.9 mmol), according to GP3, 24b-
Me (140 mg, 3%) and 26b-Me (2.27 g, 71%) were obtained. 24b-
Me: Colorless solid. M.p. 165Ϫ166 °C. Rf ϭ 0.23 (diethyl ether/
hexane, 1:1). 1H NMR (CDCl3): δ ϭ 0.70Ϫ0.95 (br s, 2 H, cPr-H),
1.10Ϫ1.22 (m, 1 H, cPr-H), 1.74Ϫ2.05 (br s, 1 H, cPr-H), 3.72 (s,
3 H, CH3O), 4.12 (s, 1 H, 2-H), 6.86 (d, J ϭ 8.6 Hz, 1 H, 8-H),
7.28 (dd, J ϭ 8.6, 2.1 Hz, 1 H, 7-H), 7.48Ϫ7.58 (m, 2 H), 7.59Ϫ7.73
(m, 4 H) ppm. 13C NMR (CDCl3): δ ϭ 11.0 (Ϫ, C-2Ј), 13.3 (br,
Ϫ, C-3Ј), 38.1 (Cquat, C-1Ј), 52.6 (ϩ, CH3O), 74.8 (br, ϩ, C-2),
1
M.p. 125Ϫ126 °C. Rf ϭ 0.21 (diethyl ether/hexane, 1:2). H NMR
(CDCl3): δ ϭ 0.50Ϫ0.62 (m, 1 H, cPr-H), 0.72Ϫ0.84 (m, 1 H, cPr- 112.5 (Cquat), 118.8 (ϩ), 126.5 (Cquat), 127.6 (ϩ), 129.2 (br, Cquat),
H), 1.27Ϫ1.40 (m, 2 H, cPr-H), 3.76 (s, 3 H, CH3O), 4.72 (s, 1 H, 129.6 (ϩ, 4 C), 130.3 (ϩ), 133.8 (ϩ), 146.4 (Cquat), 167.1 (Cquat
,
3-H), 6.77Ϫ7.03 (m, 3 H), 7.48Ϫ7.67 (m, 4 H), 7.90Ϫ7.98 (m, 2 H)
CϭO) ppm. MS (EI): m/z (%) ϭ 439/437 (15/14) [Mϩ], 298/296
ppm. 13C NMR (CDCl3): δ ϭ 11.7 (Ϫ, C-2Ј), 12.7 (Ϫ, C-3Ј), 52.8 (96/100) [Mϩ
Ϫ
C6H5SO2], 238/236 (18/14), 77 (10).
(ϩ, CH3O), 60.1 (Cquat, C-1Ј), 60.8 (ϩ, C-3), 117.6 (ϩ), 120.7 (ϩ), C18H16BrNO5S (438.3): calcd. C 49.33, H 3.68, N 3.20; found C
121.8 (ϩ), 124.3 (Cquat), 124.6 (ϩ), 127.2 (ϩ, 2 C), 129.2 (ϩ, 2 C), 49.30, H 3.70, N 3.02. 26b-Me: Yellow oil. Rf ϭ 0.48 (hexane/di-
1
133.3 (ϩ), 140.2 (Cquat), 145.4 (Cquat), 168.2 (Cquat, CϭO) ppm. ethyl ether, 1:1). H NMR (CDCl3): δ ϭ 1.20 and 1.54 (AAЈXXЈ,
MS (EI): m/z (%) ϭ 359 (79) [Mϩ], 300 (29) [Mϩ Ϫ COOCH3], 4 H, cPr-H), 3.82 (s, 3 H, CH3O), 6.58 (d, J ϭ 8.5 Hz, 1 H, 8-H),
218 (92) [Mϩ Ϫ C6H5SO2], 190 (13), 174 (18), 159 (100) [Mϩ
C6H5SO2 Ϫ COOCH3]. C18H17NO5S (359.4): calcd. 359.0827, cor-
rect HRMS; calcd. C 60.16, H 4.77, N 3.90; found C 60.46, H 4.85,
N 3.62.
Ϫ
7.23 (dd, J ϭ 8.5, 2.0 Hz, 1 H, 7-H), 7.53 (d, J ϭ 2.0 Hz, 1 H, 5-
H) ppm. 13C NMR (CDCl3): δ ϭ 15.2 (Ϫ, 2 C, C-2Ј,3Ј), 52.8 (ϩ,
CH3O), 58.3 (Cquat, C-1Ј), 114.2 (Cquat), 117.3 (ϩ), 130.8 (ϩ), 133.4
(ϩ), 133.9 (Cquat), 146.8 (Cquat), 157.2 (Cquat, CϭN), 161.8 (Cquat
,
CϭO) ppm. MS (EI): m/z (%) ϭ 297/295 (52/55) [Mϩ], 265/263
(31/30) [Mϩ Ϫ CH3OH], 237/235 (100/97), 156 (10), 128 (14).
C12H10BrNO3 (296.1): calcd. C 48.67, H 3.40, N 4.73; found C
48.85, H 3.30, N 4.60.
General Procedure for the Preparation of Benzoxazines 24؊26
(GP3): K2CO3 was added to a stirred mixture of N-(2-hydroxy-
5-Y-phenyl)benzenesulfonamide 23, 1-R and KI (30 mg) in DMF
(40 mL). The mixture was stirred at 80 °C for 3 h, cooled, diluted
with dichloromethane, washed repeatedly with water and once with
NaCl solution, dried with MgSO4, and then concentrated. The res-
idue was subjected to chromatography on silica gel (60 g), eluting
with diethyl ether/hexane (0:1Ǟ1:4).
Methyl 6-Iodospiro([2H][1,4]benzoxazine-2,1Ј-cyclopropane)-3-carb-
oxylate (26c-Me): From 23c (2.25 g, 6.00 mmol), K2CO3 (1.66 g,
12.0 mmol), and 1-Me (0.89 g, 6.07 mmol), according to GP3, 26c-
Me (1.34 g, 65%) was obtained as a yellow solid. M.p. 72 °C. Rf ϭ
0.48 (hexane/diethyl ether, 1:1). 1H NMR (CDCl3): δ ϭ 1.23Ϫ1.29
(m, 2 H, cPr-H), 1.56Ϫ1.62 (m, 2 H, cPr-H), 3.88 (s, 3 H, CH3O),
6.52 (d, J ϭ 8.4 Hz, 1 H, 8-H), 7.47 (dd, J ϭ 8.4, 2.0 Hz, 1 H, 7-
H), 7.77 (d, J ϭ 2.0 Hz, 1 H, 5-H) ppm. 13C NMR (CDCl3): δ ϭ
15.4 (Ϫ, 2 C, C-2Ј,3Ј), 53.0 (ϩ, CH3O), 58.5 (Cquat, C-1Ј), 84.1
(Cquat, C-6), 118.0 (ϩ), 134.5 (Cquat), 136.9 (ϩ), 139.6 (ϩ), 147.8
(Cquat), 157.2 (Cquat, CϭN), 162.0 (Cquat, CϭO) ppm. MS (EI):
m/z (%) ϭ 343 (100) [Mϩ], 310 (25), 282 (95), 156 (18). C12H10INO3
(343.1): calcd. C 42.01, H 2.94, N 4.07; found C 42.16, H 3.02,
N 3.81.
Methyl 4-(Phenylsulfonyl)-3,4-dihydrospiro([2H][1,4]benzoxazine-
3,1Ј-cyclopropane)-2-carboxylate (24a-Me) and Methyl Spi-
ro([2H][1,4]benzoxazine-2,1Ј-cyclopropane)-3-carboxylate
(26a):
From 23a (497 mg, 1.99 mmol), K2CO3 (689 mg, 4.99 mmol), and
1-Me (294 mg, 2.01 mmol), according to GP3, 24a-Me (80 mg,
11%) and 26a-Me (306 mg, 71%) were obtained. 24a-Me: Colorless
1
solid. M.p. 124Ϫ125 °C. Rf ϭ 0.12 (diethyl ether/hexane, 1:4). H
NMR (CDCl3): δ ϭ 0.75Ϫ0.90 (br m, 2 H, cPr-H), 1.16 (br m, 1
H, cPr-H), 1.92 (br m, 1 H, cPr-H), 3.71 (s, 3 H, CH3O), 4.18 (s,
1 H, 2-H), 6.92Ϫ7.00 (m, 2 H), 7.17 (m, 1 H), 7.45Ϫ7.70 (m, 6 H)
ppm. 13C NMR (CDCl3): δ ϭ 11.0 (Ϫ, C-2Ј), 13.3 (br, Ϫ, C-3Ј), tert-Butyl
6-Bromo-4-(phenylsulfonyl)-3,4-dihydrospiro([2H][1,4]-
38.2 (Cquat, C-1Ј), 52.5 (ϩ, CH3O), 74.7 (br, ϩ, C-2), 117.3 (ϩ), benzoxazine-2,1Ј-cyclopropane)-3-carboxylate (25b-tBu) and tert-
120.7 (ϩ), 125.3 (Cquat), 126.7 (br, ϩ), 127.4 (br, ϩ, 2 C), 127.6 Butyl 6-Bromospiro([2H][1,4]benzoxazine-2,1Ј-cyclopropane)-3-
(ϩ), 129.4 (ϩ, 2 C), 133.5 (ϩ), 138.9 (br, Cquat), 147.2 (Cquat), 167.4 carboxylate (26b-tBu): From 23b (660 mg, 2.01 mmol), K2CO3
(Cquat, CϭO) ppm. MS (EI): m/z (%) ϭ 359 (16) [Mϩ], 300 (2) [Mϩ
Ϫ COOCH3], 218 (100) [Mϩ Ϫ C6H5SO2], 159 (27) [Mϩ
(690 mg 5.0 mmol), and 1-tBu (374 mg, 1.98 mmol), according to
GP3, crude 25b-tBu (50 mg, 5%) and 26b-tBu (369 mg, 55%) were
obtained. 25b-tBu: Light-brown oil. Rf ϭ 0.24 (hexane/diethyl
ether, 4:1). 1H NMR (CDCl3): δ ϭ 0.46Ϫ0.57 (m, 1 H, cPr-H),
Ϫ
C6H5SO2 Ϫ COOCH3]. C18H17NO5S (359.4): calcd. 359.0827, cor-
rect HRMS. 26a-Me: Yellow solid. M.p. 52Ϫ53 °C. Rf ϭ 0.21 (di-
Eur. J. Org. Chem. 2003, 985Ϫ997
993

A. de Meijere et al.
FULL PAPER
0.67Ϫ0.78 (m, 1 H, cPr-H), 1.23Ϫ1.32 (m, 2 H, cPr-H), 1.40 (s, 9 C-2Ј), 18.4 (Ϫ, C-3Ј), 22.4 (Cquat, C-1Ј), 61.7 (Ϫ, CH2O), 62.0 (ϩ,
H, tBu), 4.52 (s, 1 H, 3-H), 6.63 (d, J ϭ 8.3 Hz, 1 H, 8-H), 7.04 C-3), 124.8 (ϩ), 125.9 (ϩ), 126.3 (ϩ), 127.2 (ϩ), 127.5 (ϩ, 2 C),
(dd, J ϭ 8.3, 2.1 Hz, 1 H, 7-H), 7.47Ϫ7.73 (m, 3 H), 7.81 (d, J ϭ 128.3 (Cquat), 128.7 (ϩ, 2 C), 130.6 (Cquat), 132.7 (ϩ), 140.3 (Cquat
)
2.1 Hz, 1 H, 5-H), 7.88 (m, 2 H) ppm. 13C NMR (CDCl3): δ ϭ ppm. MS (EI): m/z (%) ϭ 347 (44) [Mϩ], 316 (60) [Mϩ Ϫ CH2OH],
11.5 (Ϫ, C-2Ј), 12.7 (Ϫ, C-3Ј), 27.7 (ϩ, 3 C, CH3), 60.6 (ϩ, C-3), 206 (16) [Mϩ Ϫ C6H5SO2], 176 (100) [Mϩ Ϫ C6H5SO2 Ϫ CH2O],
60.9 (Cquat, C-1Ј), 83.0 (Cquat, tBu), 113.5 (Cquat), 118.8 (ϩ), 123.1 175 (79) [Mϩ Ϫ C6H5SO2 Ϫ CH2OH], 174 (48) [Mϩ Ϫ C6H5SO2 Ϫ
(ϩ), 125.8 (Cquat), 127.2 (ϩ, 2 C), 129.3 (ϩ, 2 C), 130.4 (ϩ), 133.5
CH3OH], 77 (17) [C6H5ϩ]. C17H17NO3S2 (347.5): calcd. 347.0649;
(ϩ), 139.7 (Cquat), 144.7 (Cquat), 166.1 (Cquat, CϭO) ppm. 26b-tBu: found 347.0649, correct HRMS.
1
Yellow solid. M.p. 70 °C. Rf ϭ 0.60 (hexane/diethyl ether, 4:1). H
Palladium-Catalyzed Coupling of 6-Bromobenzoxazine 26b-Me with
NMR (CDCl3): δ ϭ 1.20Ϫ1.27 (m, 2 H, cPr-H), 1.39Ϫ1.46 (m, 2
H, cPr-H), 1.53 (s, 9 H, tBu), 6.60 (d, J ϭ 8.5 Hz, 1 H, 8-H), 7.23
(dd, J ϭ 8.5, 2.1 Hz, 1 H, 7-H), 7.54 (d, J ϭ 2.1 Hz, 1 H, 5-H)
ppm. 13C NMR (CDCl3): δ ϭ 15.0 (Ϫ, 2 C, C-2Ј,3Ј), 27.8 (ϩ, 3 C,
CH3), 58.0 (Cquat, C-1Ј), 83.9 (Cquat, tBu), 114.2 (Cquat), 117.2 (ϩ),
130.7 (ϩ), 132.8 (ϩ), 134.3 (Cquat), 146.8 (Cquat), 159.3 (Cquat, Cϭ
N), 161.0 (Cquat, CϭO) ppm. MS (EI): m/z (%) ϭ 339/337 (3/3)
[Mϩ], 283/281 (63/62), 265/263 (12/11), 237/235 (44/39), 229 (17),
224/222 (10/10), 57 (100), 41 (20).
Methyl Acrylate: A mixture of 26b-Me (100 mg, 0.34 mmol),
methyl acrylate (0.05 mL, 0.60 mmol), nBu3N (0.1 mL, 0.42 mmol),
PPh3 (14 mg, 0.053 mmol) and Pd(OAc)2 (4 mg) in DMF (6 mL)
was stirred under nitrogen at 80 °C for 3.5 h. After cooling to ambi-
ent temperature, the mixture was diluted with dichloromethane
(30 mL) and washed repeatedly with water and once with NaCl
solution. The organic phase was dried with MgSO4 and concen-
trated. The residue was subjected to chromatography on silica gel
(30 g) eluting with diethyl ether/hexane (0:1Ǟ1:2) to give methyl 6-
Reduction of Methyl Spiro([2H][1,4]benzoxazine-2,1Ј-cyclopropane)-
3-carboxylate (26a-Me). Method A (with LiAlH4). [3,4-Dihydrospi-
ro([2H][1,4]benzoxazine-2,1Ј-cyclopropan)-3-yl]methanol (27): A so- bonylethenyl][2H][1,4]benzoxazine-3-carboxylate
bromo-2-ethylidene[2H][1,4]benzoxazine-3-carboxylate
(50 mg, 50%) and methyl (Z)-2-ethylidene-6-[(E)-2-methoxycar-
[(Z)-29d]
(29b)
lution of 26a-Me (510 mg, 2.35 mmol) in THF (5 mL) was added
dropwise to a suspension of LiAlH4 (150 mg, 3.95 mmol) in THF
(20 mL) under nitrogen, then the mixture was stirred overnight and
(38 mg, 37%). 29b: Yellow crystals. M.p. 59Ϫ60 °C. Rf ϭ 0.22 (di-
ethyl ether/hexane, 1:2). 1H NMR (CDCl3): δ ϭ 1.79 (d, J ϭ
7.3 Hz, 3 H, CH3), 3.92 (s, 3 H, CH3O), 5.73 (q, J ϭ 7.3 Hz, 1 H,
the reaction carefully quenched with water (0.15 mL), 15% NaOH CHϭ), 6.73 (d, J ϭ 8.5 Hz, 1 H, 8-H), 7.28 (dd, J ϭ 8.5, 2.4 Hz,
(0.15 mL) and water (0.45 mL). The precipitate was filtered off and
washed thoroughly with diethyl ether. The filtrate was washed with
NaCl solution, dried with MgSO4, and concentrated. The residue
was subjected to chromatography on silica gel (60 g), eluting with
diethyl ether/hexane to give 27 (391 mg, 87%) as a colorless oil.
Rf ϭ 0.24 (ether). 1H NMR (CDCl3): δ ϭ 0.53Ϫ0.64 (m, 1 H, cPr-
1 H, 7-H), 7.50 (d, J ϭ 2.4 Hz, 1 H, 5-H) ppm. 13C NMR (CDCl3):
δ ϭ 10.3 (ϩ, CH3), 53.2 (ϩ, CH3O), 112.2 (ϩ, CHϭ), 114.8 (Cquat),
116.3 (ϩ), 131.5 (ϩ), 132.4 (Cquat), 133.4 (ϩ), 140.9 (Cquat), 146.0
(Cquat), 152.0 (Cquat, CϭN), 163.4 (Cquat, CϭO) ppm. MS (EI): m/
z (%) ϭ 297/295 (42/43) [Mϩ], 265/263 (15/15), 239 (30), 237/235
(98/68), 199/197 (10/10), 162 (54), 131 (100), 103 (54), 77 (42), 63
H), 0.74Ϫ0.95 (m, 2 H, cPr-H), 1.10Ϫ1.21 (m, 1 H, cPr-H), 3.69, (24), 51 (28). C12H10BrNO3 (296.2): calcd. 294.9844, correct
3.73 and 2.98 (ABX, JAB ϭ 11.0, JAX ϭ 8.6, JBX ϭ 5.1 Hz, 3 H, HRMS. (Z)-29d: Yellow solid. M.p. 99Ϫ101 °C. Rf ϭ 0.30 (diethyl
1
α-H and 3-H), 3.96 (br s, 2 H, NH and OH), 6.68Ϫ6.88 (m, 4 H,
ether/hexane, 1:1). H NMR (CDCl3): δ ϭ 1.80 (d, J ϭ 7.4 Hz, 3
Ar-H) ppm. 13C NMR (CDCl3): δ ϭ 9.7 (Ϫ, C-2Ј), 11.7 (Ϫ, C-3Ј), H, CH3), 3.77 (s, 3 H, CH3O), 3.93 (s, 3 H, CH3O), 5.78 (q, J ϭ
52.6 (ϩ, C-3), 58.4 (Cquat, C-1Ј), 62.3 (Ϫ, CH2O), 116.0 (ϩ), 116.8 7.4 Hz, 1 H, CHϭC), 6.30 (d, J ϭ 15.8 Hz, 1 H, MeOCOCHϭ),
(ϩ), 118.4 (ϩ), 121.9 (ϩ), 132.3 (Cquat), 143.8 (Cquat) ppm. MS 6.84 (d, J ϭ 8.4 Hz, 1 H, 8-H), 7.34 (dd, J ϭ 8.4, 2.0 Hz, 1 H, 7-
(EI): m/z (%) ϭ 191 (31) [Mϩ], 160 (100) [Mϩ Ϫ CH2OH]. H), 7.55 (d, J ϭ 2.0 Hz, 1 H, 5-H), 7.56 (d, J ϭ 15.8 Hz, 1 H,
C11H13NO2 (191.2): calcd. 191.0946, correct HRMS. Method B ArCHϭ) ppm. 13C NMR (CDCl3): δ ϭ 10.3 (ϩ, CH3), 51.7 (ϩ,
(with NaBH4): NaBH4 (40 mg, 1.1 mmol) was added over 5 min at
0 °C to a stirred solution of 26a-Me (161 mg, 0.741 mmol) in meth-
anol (10 mL). After another 5 min of stirring, the solution was
acidified with two drops of glacial acetic acid, poured into diluted
NaHCO3 solution and the mixture extracted with dichloromethane.
The combined organic phases were washed with NaCl solution,
dried with MgSO4 and concentrated. The residue was subjected to
chromatography on silica gel (60 g), eluting with diethyl ether/hex-
ane (0:1Ǟ2:1) to give 13 (52 mg, 32%), which was identified on the
basis of its spectroscopic data (see above).
CH3O), 53.3 (ϩ, CH3O), 112.4 (ϩ, 2-CHϭ), 115.3 (ϩ), 117.0 (ϩ),
128.1 (ϩ), 129.8 (Cquat), 131.1 (ϩ), 131.4 (Cquat), 140.9 (Cquat),
143.2 (ϩ, ArCHϭ), 148.2 (Cquat), 151.5 (Cquat, CϭN), 163.4 (Cquat
,
CϭO), 167.3 (Cquat, CϭO) ppm. MS (EI): m/z (%) ϭ 301 (100)
[Mϩ], 270 (11) [Mϩ Ϫ OCH3], 242 (22) [Mϩ Ϫ COOCH3], 241
(97), 210 (19), 172 (12). C16H15NO5 (301.3): calcd. 301.0950, cor-
rect HRMS. When the reaction mixture was heated at the same
temperature for 18 h, (Z)-29d (73 mg, 71%) and methyl (E)-2-
ethylidene-6-[(E)-2-methoxycarbonylethenyl][2H][1,4]benzox-
azine-3-carboxylate [(E)-29d] (4 mg, 4%) were isolated. (E)-29d:
Yellow oil. Rf ϭ 0.24 (diethyl ether/hexane, 1:1). 1H NMR (CDCl3):
δ ϭ 1.77 (d, J ϭ 7.2 Hz, 3 H, CH3), 3.77 (s, 3 H, CH3O), 3.93 (s,
3 H, CH3O), 5.07 (q, J ϭ 7.0 Hz, 1 H, CHϭ), 6.31 (d, J ϭ 15.8 Hz,
1 H, MeOCOCHϭ), 6.81 (d, J ϭ 8.0 Hz, 1 H, 8-H), 7.27 (dd, J ϭ
8.0, 2.0 Hz, 1 H, 7-H), 7.42 (d, J ϭ 2.0 Hz, 1 H, 5-H), 7.59 (d, J ϭ
15.8 Hz, 1 H, ArCHϭ) ppm. 13C NMR (CDCl3): δ ϭ 10.0 (ϩ,
CH3), 51.7 (ϩ, CH3O), 53.3 (ϩ, CH3O), 110.8 (ϩ, 2-CHϭ), 115.3
(ϩ), 116.6 (ϩ), 127.2 (ϩ), 129.3 (ϩ), 129.6 (Cquat), 132.5 (Cquat),
143.6 (ϩ, ArCHϭ), 144.3 (Cquat), 148.0 (Cquat), 151.5 (Cquat, Cϭ
N), 163.4 (Cquat,CϭO), 167.3 (Cquat, CϭO) ppm.
[4-(Phenylsulfonyl)-3,4-dihydrospiro([2H][1,4]benzothiazine-2,1Ј-
cyclopropan)-3-yl]methanol (28):
A solution of 20a (462 mg,
1.23 mmol) in THF (5 mL) was added dropwise to a stirred suspen-
sion of LiAlH4 (50 mg, 1.3 mmol) in THF (30 mL) that was cooled
with ice. After the mixture had been stirred for an additional 4 h,
it was worked up and purified by chromatography as described for
compound 27 to give 28 (375 mg, 88%) as a colorless oil, which
crystallized slowly. M.p. 96Ϫ98 °C. Rf ϭ 0.52 (ether). 1H NMR
(CDCl3): δ ϭ 0.62 (m, 2 H, cPr-H), 1.07 (m, 2 H, cPr-H), 2.53 (br
s, 1 H, OH), 3.52 (dd, J ϭ 11.7, 8.9 Hz, 1 H, α-H), 3.70 (dd, J ϭ
11.7, 4.6 Hz, 1 H, α-H), 4.21 (dd, J ϭ 8.9, 4.6 Hz, 1 H, 3-H),
General Procedure for Palladium-Catalyzed Coupling Reactions of
6.95Ϫ7.10 (m, 3 H), 7.39 (t, J ϭ 8.8 Hz, 1 H), 7.50 (t, J ϭ 8.8 Hz, 6-Iodobenzoxazine 26c-Me with Alkenes (GP4): The alkene
1 H), 7.60Ϫ7.74 (m, 4 H) ppm. 13C NMR (CDCl3): δ ϭ 11.3 (Ϫ, (0.70 mmol) and Pd(OAc)2 (4 mg) were added to a stirred mixture
994
Eur. J. Org. Chem. 2003, 985Ϫ997

Spirocyclopropane-Annelated Heterocycles
FULL PAPER
of 26c-Me (103 mg, 0.30 mmol), nBu4NBr (120 mg, 0.37 mmol) 31%) was isolated. The isomer (Z)-30g was not isolated as a pure
and K2CO3 (125 mg, 0.90 mmol) in DMF (6 mL) under nitrogen, substance. (E)-30g: Yellow solid. M.p. 103Ϫ104 °C. Rf ϭ 0.38 (di-
1
and the mixture heated at 80 °C for 10 h. After cooling to ambient
temperature, the mixture was filtered, diluted with dichloromethane
(30 mL), and then washed repeatedly with water and once with
NaCl solution. The organic phase was dried with MgSO4 and con-
centrated. The residue was subjected to chromatography on silica
gel (30 g), eluting with diethyl ether/hexane (0:1Ǟ1:2).
ethyl ether/hexane, 1:2). H NMR (CDCl3): δ ϭ 1.25Ϫ1.32 (m, 2
H, cPr-H), 1.61Ϫ1.68 (m, 2 H, cPr-H), 3.89 (s, 3 H, CH3O), 5.75
(d, J ϭ 16.8 Hz, 1 H, NCCHϭ), 6.76 (d, J ϭ 8.4 Hz, 1 H, 8-H),
7.28 (dd, J ϭ 8.4, 2.2 Hz, 1 H, 7-H), 7.30 (d, J ϭ 16.8 Hz, 1 H,
ArCHϭ), 7.56 (d, J ϭ 2.2 Hz, 1 H, 5-H) ppm. 13C NMR (CDCl3):
δ ϭ 15.8 (Ϫ, 2 C, C-2Ј,3Ј), 53.1 (ϩ, CH3O), 59.1 (Cquat, C-1Ј), 95.1
(ϩ, NCCHϭ), 116.6 (ϩ), 118.2 (Cquat, CϵN), 126.9 (ϩ), 128.4
(Cquat), 130.6 (ϩ), 132.9 (Cquat), 149.1 (ϩ, ArCH), 150.2 (Cquat),
157.4 (Cquat, CϭN), 161.8 (Cquat, CϭO) ppm. MS (EI): m/z (%) ϭ
268 (56) [Mϩ], 236 (8), 208 (100). C15H12N2O3 (268.3): calcd. C
67.16, H 4.51, N 10.44; found C 67.32, H 4.72, N 10.54. (Z)-30g:
Rf ϭ 0.30 (diethyl ether/hexane, 1:2). 1H NMR (CDCl3): δ ϭ
1.23Ϫ1.30 (m, 2 H, cPr-H), 1.57Ϫ1.65 (m, 2 H, cPr-H), 3.88 (s, 3
H, CH3O), 5.37 (d, J ϭ 16.8 Hz, 1 H, NCCHϭ), 6.78 (d, J ϭ
8.4 Hz, 1 H, 8-H), 7.01 (d, J ϭ 16.8 Hz, 1 H, ArCHϭ), 7.71 (d,
J ϭ 2.2 Hz, 1 H, 5-H), 7.82 (dd, J ϭ 8.4, 2.2 Hz, 1 H, 7-H) ppm.
13C NMR (CDCl3): δ ϭ 15.6 (Ϫ, 2 C, C-2Ј,3Ј), 52.9 (ϩ, CH3O),
Methyl (E)-6-(2-Methoxycarbonylethenyl)spiro([2H][1,4]benzoxaz-
ine-2,1Ј-cyclopropane)-3-carboxylate [(E)-30d]: From 26c-Me and
methyl acrylate, according to GP4, (E)-30d (78 mg, 86%) was ob-
tained as a yellow solid. M.p. 102Ϫ103 °C. Rf ϭ 0.36 (diethyl ether/
1
hexane, 1:2). H NMR (CDCl3): δ ϭ 1.21Ϫ1.26 (m, 2 H, cPr-H),
1.56Ϫ1.61 (m, 2 H, cPr-H), 3.75 (s, 3 H, CH3O), 3.84 (s, 3 H,
CH3O), 6.22 (d, J ϭ 16.0 Hz, 1 H, MeOCOCHϭ), 6.71 (d, J ϭ
8.5 Hz, 1 H, 8-H), 7.32 (dd, J ϭ 8.5, 1.9 Hz, 1 H, 7-H), 7.57 (d,
J ϭ 16.0 Hz, 1 H, ArCHϭ), 7.60 (d, J ϭ 1.9 Hz, 1 H, 5-H) ppm.
13C NMR (CDCl3): δ ϭ 15.6 (Ϫ, 2 C, C-2Ј,3Ј), 51.7 (ϩ, CH3O),
53.1 (ϩ, CH3O), 58.9 (Cquat, C-1Ј), 116.4 (ϩ), 116.8 (ϩ), 127.8 (ϩ),
129.4 (Cquat), 131.2 (ϩ), 132.9 (Cquat), 143.5 (ϩ, ArCHϭ), 149.6
(Cquat), 157.0 (Cquat, CϭN), 162.0 (Cquat, CϭO), 167.4 (Cquat, Cϭ
O) ppm. MS (EI): m/z (%) ϭ 301 (97) [Mϩ], 270 (14), 242 (21)
[Mϩ Ϫ COOCH3], 241 (100), 210 (22). C16H15NO5 (301.3): calcd.
301.0950, correct HRMS. When the bromo derivative 26b-Me and
nBu3N were used instead of 26c-Me and nBu4NBr, the compound
(E)-30d was isolated with a yield of only 30%.
58.9 (Cquat, C-1Ј), 93.8 (ϩ, NCCHϭ), 116.5 (ϩ), 117.3 (Cquat
,
CϵN), 128.5 (Cquat), 129.9 (ϩ), 131.1 (ϩ), 132.7 (Cquat), 147.1 (ϩ,
ArCHϭ), 149.9 (Cquat), 157.0 (Cquat, CϭN), 161.9 (Cquat, CϭO)
ppm.
Methyl (E)-6-(2-Phenylethenyl)spiro([2H][1,4]benzoxazine-2,1Ј-cy-
clopropane)-3-carboxylate [(E)-30h] and Methyl 6-(1-Phenylethe-
nyl)spiro([2H][1,4]benzoxazine-2,1Ј-cyclopropane)-3-carboxylate
(31h): From 26c-Me and styrene, according to GP4, (E)-30h
(72 mg, 75%) and 31h (8 mg, 8%) were obtained. (E)-30h: Yellow
solid. M.p. 75Ϫ76 °C. Rf ϭ 0.38 (diethyl ether/hexane, 1:1). 1H
NMR (CDCl3): δ ϭ 1.24Ϫ1.31 (m, 2 H, cPr-H), 1.58Ϫ1.66 (m, 2
H, cPr-H), 3.88 (s, 3 H, CH3O), 6.73 (d, J ϭ 8.2 Hz, 1 H, 8-H),
7.02 (s, 2 H, PhCHϭCH), 7.21Ϫ7.29 (m, 1 H), 7.30Ϫ7.39 (m, 3
H), 7.48 (m, 2 H), 7.66 (d, J ϭ 2.0 Hz, 1 H, 5-H) ppm. 13C NMR
Methyl (E)-6-(2-Formylethenyl)spiro([2H][1,4]benzoxazine-2,1Ј-cy-
clopropane)-3-carboxylate [(E)-30e]: From 26c-Me and acrolein, ac-
cording to GP4, (E)-30e (72 mg, 89%) was obtained as a yellow
solid. M.p. 140 °C. Rf ϭ 0.26 (diethyl ether/hexane, 1:2). 1H NMR
(CDCl3): δ ϭ 1.25Ϫ1.32 (m, 2 H, cPr-H), 1.62Ϫ1.69 (m, 2 H, cPr-
H), 3.89 (s, 3 H, CH3O), 6.60 (dd, J ϭ 15.9, 7.6 Hz, 1 H, CHCHO),
6.78 (d, J ϭ 8.1 Hz, 1 H, 8-H), 7.41 (dd, J ϭ 8.1, 2.1 Hz, 1 H, 7-
H), 7.38 (d, J ϭ 15.9 Hz, 1 H, ArCHϭ), 7.66 (d, J ϭ 2.1 Hz, 1 H,
5-H), 9.78 (d, J ϭ 7.6 Hz, 1 H, CHO) ppm. 13C NMR (CDCl3):
δ ϭ 15.8 (Ϫ, 2 C, C-2Ј,3Ј), 53.0 (ϩ, CH3O), 59.1 (Cquat, C-1Ј),
116.7 (ϩ), 127.7 (ϩ), 128.4 (ϩ), 129.0 (Cquat), 131.5 (ϩ), 133.0
(Cquat), 150.4 (Cquat), 151.4 (ϩ, ArCHϭ), 157.3 (Cquat, CϭN),
161.9 (Cquat, CϭO), 193.4 (ϩ, CHO) ppm. MS (EI): m/z (%) ϭ 271
(100) [Mϩ], 211 (42), 183 (13). C15H13NO4 (271.3): calcd. 271.0844,
correct HRMS.
(CDCl3): δ ϭ 15.2 (Ϫ, 2 C, C-2Ј,3Ј), 52.8 (ϩ, CH3O), 58.5 (Cquat
,
C-1Ј), 116.0 (ϩ), 126.0 (ϩ), 126.3 (ϩ, 2 C), 127.1 (ϩ), 127.5 (ϩ),
128.0 (ϩ), 128.6 (ϩ), 129.3 (ϩ), 132.4 (Cquat), 133.0 (Cquat), 137.0
(Cquat), 147.2 (Cquat), 156.3 (Cquat, CϭN), 162.1 (Cquat, CϭO) ppm.
MS (EI): m/z (%) ϭ 319 (100) [Mϩ], 259 (37), 165 (16). C20H17NO3
(319.4): calcd. 319.1208, correct HRMS. 31h: Yellow oil. Rf ϭ 0.31
1
(diethyl ether/hexane, 1:1). H NMR (CDCl3): δ ϭ 1.24Ϫ1.32 (m,
2 H, cPr-H), 1.57Ϫ1.65 (m, 2 H, cPr-H), 3.87 (s, 3 H, CH3O), 5.35
(d, J ϭ 1.2 Hz, 1 H, CϭCH2), 5.44 (d, J ϭ 1.2 Hz, 1 H, CϭCH2),
6.72 (d, J ϭ 8.4 Hz, 1 H, 8-H), 7.23 (dd, J ϭ 8.4, 2.2 Hz, 1 H, 7-
H), 7.33 (br. s, 5 H), 7.47 (d, J ϭ 2.2 Hz, 1 H, 5-H) ppm. 13C NMR
Methyl (E)-6-(3-Oxobut-1-enyl)spiro([2H][1,4]benzoxazine-2,1Ј-cy-
clopropane)-3-carboxylate [(E)-30f]: From 26c-Me and methyl vinyl
ketone, according to GP4, (E)-30f (62 mg, 72%) was obtained as a
yellow oil. Rf ϭ 0.23 (diethyl ether/hexane, 1:2). 1H NMR (CDCl3):
δ ϭ 1.20Ϫ1.27 (m, 2 H, cPr-H), 1.55Ϫ1.62 (m, 2 H, cPr-H), 2.32 (s,
3 H, Ac), 3.85 (s, 3 H, CH3O), 6.57 (d, J ϭ 16.1 Hz, 1 H, AcCHϭ),
6.72 (d, J ϭ 8.3 Hz, 1 H, 8-H), 7.34 (dd, J ϭ 8.3, 2.0 Hz, 1 H, 7-
H), 7.38 (d, J ϭ 16.1 Hz, 1 H, ArCHϭ), 7.61 (d, J ϭ 2.0 Hz, 1 H,
5-H) ppm. 13C NMR (CDCl3): δ ϭ 15.6 (Ϫ, 2 C, C-2Ј,3Ј), 27.6 (ϩ,
Ac), 53.0 (ϩ, CH3O), 58.8 (Cquat, C-1Ј), 116.4 (ϩ), 126.0 (ϩ), 127.9
(ϩ), 129.3 (Cquat), 131.3 (ϩ), 132.8 (Cquat), 142.0 (ϩ, ArCHϭ),
149.6 (Cquat), 156.9 (Cquat, CϭN), 161.9 (Cquat, COOMe), 198.0
(Cquat, MeCϭO) ppm. MS (EI): m/z (%) ϭ 285 (100) [Mϩ], 270
(13) [Mϩ Ϫ CH3], 238 (11), 225 (40), 210 (33), 143 (10). C16H15NO4
(285.3): calcd. 285.1001, correct HRMS.
(CDCl3): δ ϭ 15.3 (Ϫ, 2 C, C-2Ј,3Ј), 52.9 (ϩ, CH3O), 58.4 (Cquat
,
C-1Ј), 113.8 (Ϫ, ϭCH2), 115.6 (ϩ), 127.8 (ϩ), 128.2 (ϩ), 128.3 (ϩ,
3 C), 130.8 (ϩ), 132.6 (Cquat), 136.4 (Cquat), 141.2 (Cquat), 147.5
(Cquat), 148.8 (Cquat), 159.8 (Cquat, CϭN), 162.3 (Cquat, CϭO) ppm.
MS (EI): m/z (%) ϭ 319 (100) [Mϩ], 259 (82), 165 (18). C20H17NO3
(319.4): calcd. 319.1208, correct HRMS.
Methyl (E/Z)-6-(2-Ethoxyethenyl)spiro([2H][1,4]benzoxazine-2,1Ј-
cyclopropane)-3-carboxylate [(E/Z)-30i] and Methyl 6-Acetyl-
spiro([2H][1,4]benzoxazine-2,1Ј-cyclopropane)-3-carboxylate (32i):
26c-Me and ethyl vinyl ether gave, according to GP4, a mixture of
(E)- and (Z)-30i (52 mg, 60%) in a ratio of 3:1 (according to the
NMR spectra), and 32i (27 mg, 35%). (E/Z)-30i: Yellow oil. Rf ϭ
0.38 (diethyl ether/hexane, 1:1). MS (EI): m/z (%) ϭ 287 (100) [Mϩ],
227 (24), 199 (17), 185 (12), 170 (14), 158 (10). C16H17NO4 (287.3):
Methyl (E)- and (Z)-6-(2-Cyanoethenyl)spiro([2H][1,4]benzoxazine-
2,1Ј-cyclopropane)-3-carboxylates [(E)- and (Z)-30g]: From 26c-Me calcd. 287.1157, correct HRMS. (E)-30i: 1H NMR (CDCl3): δ ϭ
and acrylonitrile, according to GP4, a mixture of (E)- and (Z)-30g
(70 mg, 87%) in a ratio of 2.7:1 (according to the NMR spectra)
was obtained. After chromatography on silica gel (E)-30g (25 mg,
1.20Ϫ1.27 (m, 2 H, cPr-H), 1.32 (t, J ϭ 7.1 Hz, 3 H, CH3),
1.53Ϫ1.60 (m, 2 H, cPr-H), 3.87 (q, J ϭ 7.1 Hz, 2 H, OCH2), 3.88
(s, 3 H, CH3O), 5.76 (d, J ϭ 13.0 Hz, 1 H, ArCHϭ), 6.65 (d, J ϭ
Eur. J. Org. Chem. 2003, 985Ϫ997
995

A. de Meijere et al.
7.8 Hz, 1 H, 8-H), 6.90 (d, J ϭ 13.0 Hz, 1 H, OCHϭ), 7.03 (dd, 1.01 mmol), tBuONa (192 mg, 2.00 mmol), K2CO3 (276 mg,
FULL PAPER
J ϭ 7.8, 2.1 Hz, 1 H, 7-H), 7.36 (d, J ϭ 2.1 Hz, 1 H, 5-H) ppm.
2.00 mmol) and PPh3 (14 mg, 0.053 mmol) in toluene (5 mL). The
13C NMR (CDCl3): δ ϭ 14.8 (ϩ, CH3), 15.1 (Ϫ, 2 C, C-2Ј,3Ј), 52.9 reaction mixture was stirred at 80 °C for 13 h, cooled to ambient
(ϩ, CH3O), 58.2 (Cquat, C-1Ј), 65.5 (Ϫ, OCH2), 104.7 (ϩ, ArCHϭ temperature, diluted with diethyl ether (20 mL), filtered, and then
), 115.9 (ϩ), 124.3 (ϩ), 128.0 (ϩ), 131.6 (Cquat), 133.1 (Cquat), 145.7
(Cquat), 147.5 (ϩ, OCHϭ), 156.2 (Cquat, CϭN), 162.3 (Cquat, Cϭ
O) ppm. (Z)-30i: H NMR (CDCl3): δ ϭ 1.19Ϫ1.27 (m, 2 H, cPr-
stirred for 10 min with 30% H2O2 (10 mL). The diethyl ether phase
was washed with water, saturated FeSO4 solution, then again with
water, and NaCl solution, dried with MgSO4 and concentrated.
1
H), 1.35 (t, J ϭ 7.1 Hz, 3 H, CH3), 1.52Ϫ1.60 (m, 2 H, cPr-H), The residue was purified by chromatography on silica gel (40 g),
3.88 (s, 3 H, CH3O), 3.96 (q, J ϭ 7.1 Hz, 2 H, OCH2), 5.14 (d, J ϭ eluting with diethyl ether/hexane (0:1Ǟ1:2) to yield 35 (130 mg,
6.8 Hz, 1 H, ArCHϭ), 6.16 (d, J ϭ 6.8 Hz, 1 H, OCHϭ), 6.67 (d, 51%) as colorless needles, which were recrystallized from diethyl
J ϭ 8.2 Hz, 1 H, 8-H), 7.43 (dd, J ϭ 8.2, 2.1 Hz, 1 H, 7-H), 7.74
ether/hexane. M.p. 174Ϫ175 °C. Rf ϭ 0.20 (diethyl ether/hexane,
(d, J ϭ 2.1 Hz, 1 H, 5-H) ppm. 13C NMR (CDCl3): δ ϭ 14.9 (Ϫ, 1:1). 1H NMR (CDCl3): δ ϭ 1.22Ϫ1.30 (m, 2 H, cPr-H), 1.42Ϫ1.50
2 C, C-2Ј,3Ј), 15.5 (ϩ, CH3), 52.9 (ϩ, CH3O), 58.1 (Cquat, C-1Ј), (m, 2 H, cPr-H), 6.72 (d, J ϭ 8.4 Hz, 1 H, 8-H), 6.97 (d, J ϭ
69.1 (Ϫ, OCH2) 104.1 (ϩ, ArCHϭ), 115.5 (ϩ), 124.3 (ϩ), 130.9 2.0 Hz, 1 H, 5-H), 7.05 (dd, J ϭ 8.0, 2.0 Hz, 1 H, 7-H), 9.42 (br s,
(ϩ), 131.3 (Cquat), 132.8 (Cquat), 145.6 (Cquat), 146.0 (ϩ, OCHϭ), 1 H, NH) ppm. 13C NMR (CDCl3): δ ϭ 14.4 (Ϫ, 2 C, C-2Ј,3Ј),
155.9 (Cquat, CϭN), 161.1 (Cquat, CϭO) ppm. 32i: Yellow oil. Rf ϭ
61.2 (Cquat, C-1Ј), 114.7 (Cquat), 118.1 (ϩ), 118.3 (ϩ), 126.5 (ϩ),
0.27 (diethyl ether/hexane, 1:1). 1H NMR (CDCl3): δ ϭ 1.23Ϫ1.30 128.2 (Cquat), 142.9 (Cquat), 169.6 (Cquat, CϭO) ppm. MS (EI): m/
(m, 2 H, cPr-H), 1.60Ϫ1.67 (m, 2 H, cPr-H), 2.53 (s, 3 H, CH3), z (%) ϭ 255/253 (98/100) [Mϩ], 228/226 (25/40), 224 (15).
3.87 (s, 3 H, CH3O), 6.78 (d, J ϭ 8.7 Hz, 1 H, 8-H), 7.85 (dd, J ϭ C10H8BrNO2 (254.1): calcd. C 47.27, H 3.17, N 5.51; found C
8.7, 2.0 Hz, 1 H, 7-H), 8.02 (d, J ϭ 2.0 Hz, 1 H, 5-H) ppm. 13C
NMR (CDCl3): δ ϭ 15.8 (Ϫ, 2 C, C-2Ј,3Ј), 26.4 (ϩ, CH3), 53.0 (ϩ,
47.05, H 3.22, N 5.73. When the compound 26b-Me was treated
with 4-methoxybenzylamine under conditions used for the prepara-
CH3O), 59.1 (Cquat, C-1Ј), 116.1 (ϩ), 129.4 (ϩ), 131.4 (ϩ), 132.0 tion of the 1,4-benzothiazine derivatives 33 and 34, the product
(Cquat), 132.2 (Cquat), 151.9 (Cquat), 156.8 (Cquat, CϭN), 161.8 35 was isolated with a yield of 23% along with 63% of recovered
(Cquat, COOMe), 196.0 (Cquat, MeCO) ppm. MS (EI): m/z (%) ϭ
259 (100) [Mϩ], 244 (17) [Mϩ Ϫ CH3], 227 (11), 199 (56), 184 (58).
C14H13NO4 (259.3): calcd. C 64.86, H 5.05, N 5.40; found C 64.65,
H 5.15, N 5.44.
26b-Me.
General Procedure for the Demethoxycarbonylation of 26b,c (GP5):
A solution of 26 and morpholine in DMF (5 mL) was heated at 80
°C for 2Ϫ3 d under nitrogen. After cooling to ambient temperature,
the solution was diluted with dichloromethane (20 mL) and washed
repeatedly with water and once with NaCl solution. The dichloro-
methane phase was dried with MgSO4, concentrated and the res-
idue purified by chromatography on silica gel (20 g), eluting with
diethyl ether/hexane (0:1Ǟ1:0).
7-Bromo-N-(4-methoxybenzyl)spiro([2H][1,4]benzothiazine-2,1Ј-
cyclopropane)-3-carboxamide (33) and 7-Bromospiro([2H][1,4]ben-
zothiazine-2,1Ј-cyclopropan)-3(4H)-one (34): Pd(OAc)2 (4 mg) was
added under nitrogen to a stirred solution of 22b (200 mg,
0.64 mmol), 4-methoxybenzylamine (96 mg, 0.70 mmol), PPh3
(14 mg, 0.053 mmol) and nBu3N (130 mg, 0.71 mmol) in DMF
(3 mL). The nitrogen was replaced with carbon monoxide by three
freeze-pump-thaw cycles, and then the mixture was heated at 80 °C
and 1 atm of CO pressure for 14 h with stirring. After cooling to
ambient temperature, the mixture was diluted with diethyl ether,
filtered, and washed with 10% HCl, water and NaCl solution. The
diethyl ether phase was dried with MgSO4, concentrated and the
residue separated by column chromatography on silica gel (50 g),
eluting with diethyl ether/hexane (0:1Ǟ1:4) to give recovered 22b
(53 mg, 26%), 33 (147 mg, 55%) and 34 (6 mg, 4%). 33: Yellow
6-Bromospiro([2H][1,4]benzoxazine-2,1Ј-cyclopropane) (36b): From
26b-Me (200 mg, 0.68 mmol) and morpholine (60 mg, 0.69 mmol),
after heating for 3 d according to GP5, 36b (134 mg, 83%) was
isolated as a colorless solid. M.p. 75 °C. Rf ϭ 0.23 (diethyl ether/
1
hexane, 1:1). H NMR (CDCl3): δ ϭ 0.97Ϫ1.05 (m, 2 H, cPr-H),
1.25Ϫ1.32 (m, 2 H, cPr-H), 6.56 (d, J ϭ 8.6 Hz, 1 H, 8-H), 7.17
(s, 1 H, CHϭN), 7.19 (dd, J ϭ 8.6, 2.5 Hz, 1 H, 7-H), 7.40 (d, J ϭ
2.5 Hz, 1 H, 5-H) ppm. 13C NMR (CDCl3): δ ϭ 15.0 (Ϫ, 2 C, C-
2Ј,3Ј), 59.0 (Cquat, C-1Ј), 113.8 (Cquat), 117.2 (ϩ), 130.0 (ϩ), 131.7
(ϩ), 133.8 (Cquat), 146.4 (Cquat), 162.7 (ϩ, CHϭN) ppm. MS (EI):
m/z (%) ϭ 239/237 (94/100) [Mϩ], 236 (35), 130 (19), 75 (10).
C10H8BrNO (238.2): calcd. C 50.45, H 3.39, N 5.88; found C 50.21,
H 3.49, N 6.09.
1
solid. M.p. 112Ϫ114 °C. Rf ϭ 0.28 (diethyl ether/hexane, 1:2). H
NMR (CDCl3): δ ϭ 1.03Ϫ1.10 (m, 2 H, cPr-H), 2.00Ϫ2.07 (m, 2
H, cPr-H), 3.80 (s, 3 H, CH3O), 4.43 (d, J ϭ 7.0 Hz, 2 H, CH2N),
6.89 (m, 2 H, 3ЈЈ,5ЈЈ-H), 7.20Ϫ7.37 (m, 5 H), 7.71 (br s, 1 H, NH)
ppm. 13C NMR (CDCl3): δ ϭ 16.8 (Ϫ, 2 C, C-2Ј,3Ј), 17.1 (Cquat
,
6-Iodospiro([2H][1,4]benzoxazine-2,1Ј-cyclopropane) (36c): From
26c-Me (100 mg, 0.29 mmol) and morpholine (50 mg, 0.57 mmol),
after heating for 2 d according to GP5, 36c (81 mg, 98%) was isol-
ated as a colorless oil. Rf ϭ 0.26 (diethyl ether/hexane, 1:1). 1H
NMR (CDCl3): δ ϭ 0.97Ϫ1.04 (m, 2 H, cPr-H), 1.25Ϫ1.32 (m, 2
H, cPr-H), 6.43 (d, J ϭ 8.4 Hz, 1 H, 8-H), 7.15 (s, 1 H, CHϭN),
7.37 (dd, J ϭ 8.4, 2.2 Hz, 1 H, 7-H), 7.57 (d, J ϭ 2.2 Hz, 1 H, 5-
C-1Ј), 42.9 (Ϫ, NCH2), 55.3 (ϩ, CH3O), 114.1 (ϩ, 2 C), 122.2
(Cquat), 129.18 (ϩ, 2 C), 129.22 (ϩ), 129.3 (Cquat), 129.6 (ϩ), 129.71
(ϩ), 129.73 (Cquat), 140.1 (Cquat), 155.8 (Cquat) 158.4 (Cquat, CϭN),
162.5 (Cquat, CϭO) ppm. MS (EI): m/z (%) ϭ 418/416 (13/13) [Mϩ],
121 (100) [C7H6OCH3ϩ]. C19H17BrN2O2S (417.4): calcd. 416.0194,
correct HRMS. 34: Light-yellow oil. Rf ϭ 0.15 (diethyl ether/
1
H) ppm. 13C NMR (CDCl3): δ ϭ 15.0 (Ϫ, 2 C, C-2Ј,3Ј), 59.0 (Cquat
,
hexane, 1:2). H NMR (CDCl3): δ ϭ 1.00Ϫ1.08 (m, 2 H, cPr-H),
1.58Ϫ1.66 (m, 2 H, cPr-H), 6.72 (d, J ϭ 8.0 Hz, 1 H, 5-H), 7.28
(dd, J ϭ 8.0, 1.7 Hz, 1 H, 6-H), 7.37 (d, J ϭ 1.7 Hz, 1 H, 8-H),
8.77 (br. s, 1 H, NH) ppm. 13C NMR (CDCl3): δ ϭ 16.3 (Ϫ, 2 C,
C-2Ј,3Ј), 21.3 (Cquat, C-1Ј), 116.0 (Cquat), 118.0 (ϩ), 122.5 (Cquat),
129.9 (ϩ), 130.1 (ϩ), 135.3 (Cquat), 170.1 (Cquat, CϭO) ppm.
C-1Ј), 83.5 (Cquat, C-6), 117.8 (ϩ), 134.1 (Cquat), 135.8 (ϩ), 137.7
(ϩ), 147.3 (Cquat), 162.5 (ϩ, CHϭN) ppm. MS (EI): m/z (%) ϭ
285 (37) [Mϩ], 142 (100). C10H8INO (285.1): calcd. C 42.13, H
2.83, N 4.91; found C 42.17, H 2.91, N 4.69.
6-Bromo-3-[(4-methylphenyl)thio]-3,4-dihydrospiro([2H][1,4]-
benzoxazine-2,1Ј-cyclopropane) (37): A solution of 36b (100 mg,
0.42 mmol) and 4-methylthiophenol (55 mg, 0.44 mmol) in anhyd-
rous benzene (6 mL) was heated for 10 h under reflux. After cool-
6-Bromospiro([2H][1,4]benzoxazine-2,1Ј-cyclopropan)-3(4H)-one
(35): Morpholine (110 mg, 1.26 mmol) and Pd(OAc)2 (4 mg) were
added under nitrogen to a stirred suspension of 26b-Me (300 mg,
996
Eur. J. Org. Chem. 2003, 985Ϫ997

Spirocyclopropane-Annelated Heterocycles
FULL PAPER
[5]
[6]
[7]
A. Ota, H. Suhara, Y. Kawashima, Chem. Pharm. Bull. 1992,
40, 833Ϫ836.
ing to ambient temperature and evaporation of the solvent, the
residue was purified by chromatography on silica gel (20 g) eluting
with diethyl ether/hexane (0:1 Ǟ 1:0) to give 37 (115 mg, 76%) as
a light-yellow solid. M.p. 99Ϫ100 °C. Rf ϭ 0.52 (diethyl ether/hex-
ane, 1:1). 1H NMR (CDCl3): δ ϭ 0.65Ϫ0.75 (m, 1 H, cPr-H),
0.90Ϫ1.15 (m, 2 H, cPr-H), 1.22Ϫ1.32 (m, 1 H, cPr-H), 2.35 (s, 3
H, CH3), 4.25 (br s, 1 H, 3-H), 4.45 (br s, 1 H, NH), 6.63 (d, J ϭ
8.0 Hz, 1 H, 8-H), 6.67 (br s, 1 H, 5-H), 6.84 (m, 1 H, 7-H),
7.16Ϫ7.22 (m, 2 H), 7.35Ϫ7.41 (m, 2 H) ppm. 13C NMR (CDCl3):
δ ϭ 11.5 (br, Ϫ, C-2Ј), 14.7 (br, Ϫ, C-3Ј), 21.2 (ϩ, CH3), 60.9
(Cquat, C-1Ј), 65.6 (br, ϩ, C-3), 113.7 (Cquat), 118.3 (ϩ), 122.4 (ϩ),
128.8 (Cquat), 129.8 (ϩ), 130.1 (ϩ, 2 C), 131.8 (br, Cquat), 135.3 (ϩ,
2 C), 138.8 (Cquat), 143.1 (br, Cquat) ppm. MS (EI): m/z (%) ϭ 363/
361 [Mϩ], 246 (16), 239/237 (100/96) [Mϩ Ϫ CH3C6H4SH], 222
(29), 130 (15), 124 (70), 91 (93), 77 (12), 63 (10). C17H16BrNOS
(362.3): calcd. 361.0136, correct HRMS.
T. Aotsuka, H. Hosono, T. Kurihara, Y. Nakamura, T. Matsui,
F. Kobayashi, Chem. Pharm. Bull. 1994, 42, 1264Ϫ1271.
Colorless crystals (m.p. 75Ϫ77 °C) with the composition of
6·0.5HCl·0.25H2O had formed from the amino acid ester 6
after 4 months of storage of its CDCl3 solution at ambient
temperature. The yellow crystals of 22b (m.p. 108Ϫ109 °C)
were obtained by crystallization from a hexane/diethyl ether
solution. Both crystals were measured with a StoeϪSiemens
AED four-circle diffractometer using graphite-monochromated
Mo-Kα radiation, λ ϭ 71.073 pm. The structure solutions and
refinements on F2 were performed by direct methods with the
SHELXS-97 and SHELXL-97 programs. The hydrogen atoms
were located in a difference-Fourier map and refined as riding
groups with the 1.2-fold isotropic displacement parameter of
the
corresponding
C
atom.
6·0.5HCl·0.25H2O:
C32H56Cl2N4O9S4 (839.95), crystal size 0.40 ϫ 0.30 ϫ 0.30 mm,
triclinic, a ϭ 1165.2(2), b ϭ 1352.6(3), c ϭ 1421.8(3) pm; α ϭ
6-Bromo-3,4-dihydrospiro([2H][1,4]benzoxazine-2,1Ј-cyclopropane)-
3-carbonitrile (38): Acetic acid (0.03 mL) was added to a stirred
solution of 36b (50 mg, 0.21 mmol) and NaCN (11 mg, 0.22 mmol)
in anhydrous ethanol (10 mL). The mixture was stirred for 3 h at
ambient temperature, diluted with dichloromethane (20 mL), then
washed with water and NaCl solution. The organic phase was con-
centrated, and the residue purified by chromatography on silica gel
(20 g), eluting with diethyl ether/hexane (0:1Ǟ1:0) to give 38
(53 mg, 95%) as a light-yellow solid. M.p. 151Ϫ152 °C. Rf ϭ 0.10
90.08(3), β ϭ 112.33(3), γ ϭ 98.88(3)°, V ϭ 2.0435(7) nm3,
3
¯
Z ϭ 2, space group P1, T ϭ 133(2) K, ρ ϭ 1.365 Mg/m ,
intensities measured: 21962 (2.24° Յ θ Յ 24.71°), independent:
6833 (Rint ϭ 0.0189), 496 parameters refined, R1 ϭ 0.0304,
wR2 (all data) ϭ 0.0706, Gof ϭ 1.041, maximum and minimum
residual electron density 411 and Ϫ297 e nmϪ3
. 22b:
C12H10BrNO2S (312.18), crystal size 0.30 ϫ 0.20 ϫ 0.15 mm,
triclinic, a ϭ 723.78(14), b ϭ 818.55(16), c ϭ 1083.0(2) pm;
α ϭ 85.23(3), β ϭ 87.18(3), γ ϭ 68.40(3)°, V ϭ 0.5944(2) nm3,
3
¯
Z ϭ 2, space group P1, T ϭ 133(2) K, ρ ϭ 1.744 Mg/m ,
1
(diethyl ether/hexane, 1:1). H NMR (CDCl3): δ ϭ 0.72Ϫ0.81 (m,
intensities measured: 7288 (1.89° Յ θ Յ 26.50°), independent:
2447 (Rint ϭ 0.0373), 155 parameters refined, R1 ϭ 0.0331,
wR2 (all data) ϭ 0.0817, Gof ϭ 1.044, maximum and minimum
residual electron density 931 and Ϫ1088 e nmϪ3. CCDC-
176186 (6) and -176187 (22b) contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html [or
from the Cambridge Crystallographic Data Centre, 12 Union
Road, Cambridge CB2 1EZ, UK; Fax: (internat.) ϩ 44-1223/
336-033; E-mail: deposit@ccdc.cam.ac.uk].
1 H, cPr-H), 0.99Ϫ1.17 (m, 2 H, cPr-H), 1.29Ϫ1.39 (m, 1 H, cPr-
H), 3.83 (d, J ϭ 3.1 Hz, 1 H, 3-H), 4.51 (br s, 1 H, NH), 6.67 (d,
J ϭ 8.2 Hz, 1 H, 8-H), 6.83Ϫ6.69 (m, 2 H) ppm. 13C NMR
(CDCl3): δ ϭ 10.5 (Ϫ, C-2Ј), 13.3 (Ϫ, C-3Ј), 47.5 (ϩ, C-3), 59.8
(Cquat, C-1Ј), 114.4 (Cquat), 117.4 (Cquat, CN), 118.4 (ϩ), 118.8 (ϩ),
123.1 (ϩ), 131.3 (Cquat), 142.4 (Cquat) ppm. MS (EI): m/z (%) ϭ
266/264 (100/100) [Mϩ], 251/249 (34/38), 240/238 (18/32) [Mϩ
Ϫ
CN], 226/224 (78/78), 200/198 (15/16), 185 (10), 157 (12), 145 (10),
130 (10), 102 (10), 78 (23). C11H9BrN2O (265.1): calcd. 263.9898,
correct HRMS.
[8] [8a]
A. de Meijere, F. E. Meyer, Angew. Chem. 1994, 106,
2473Ϫ2506; Angew. Chem. Int. Ed. Engl. 1994, 33, 2379Ϫ2411.
[8b]
S. Bräse, A. de Meijere in Metal-catalyzed Cross-coupling
Reactions (Eds.: F. Diederich, P. J. Stang), Wiley-VCH,
Weinheim, 1998, pp. 99Ϫ166.
Acknowledgments
[9] [9a]
[9b]
T. Jeffery, Tetrahedron Lett. 1985, 26, 2667Ϫ2670.
T.
[9c]
This work was supported by the Bayer AG and the Fonds der
Chemischen Industrie. The authors are indebted to Dr. Burkhard
Knieriem, Göttingen, for his careful proofreading of the final ma-
nuscript.
Jeffery, J. Chem. Soc., Chem. Commun. 1984, 1287Ϫ1289.
T. Jeffery, Tetrahedron 1996, 52, 10113Ϫ10130.
[10]
C.-M. Andersson, A. Hallberg, G. D. Daves, Jr., J. Org. Chem.
1987, 52, 3529Ϫ3536.
[11] [11a]
M. Beller, Angew. Chem. 1995, 107, 1436Ϫ1437; Angew.
[11b]
Chem. Int. Ed. Engl. 1995, 34, 1316Ϫ1317.
A. S. Guram,
[1]
[1a] T. Liese, F. Seyed-Mahdavi, A. de Meijere, Org. Synth. 1990,
R. A. Rennels, S. L. Buchwald, Angew. Chem. 1995, 107,
1456Ϫ1459; Angew. Chem. Int. Ed. Engl. 1995, 34, 1348Ϫ1350.
[1b]
69, 148Ϫ153.
1-Chloro-1-(trichloroethenyl)cyclopropane,
[12] [12a]
the direct precursor to methyl 2-chloro-2-cyclopropylideneacet-
ate, is commercially available from Merck-Schuchardt, Ger-
many.
A. J. Lin, S. Kasina, J. Heterocycl. Chem. 1981, 18,
[12b]
759Ϫ761.
2148Ϫ2150.
R. L. Mital, S. K. Jain, J. Chem. Soc. C 1969,
[2]
[3]
[13]
[14]
For a review see: A. de Meijere, S. I. Kozhushkov, L. P. Hadji-
arapoglou, Top. Curr. Chem. 2000, 207, 149Ϫ227.
H. Irving, A. R. Pinnington, J. Chem. Soc. 1957, 285Ϫ290.
K. C. Roberts, C. G. M. de Worms, H. B. Clark, J. Chem. Soc.
1935, 196Ϫ200.
R. P. Hanzlik, P. E. Weller, J. Desai, J. Zheng, L. R. Hall, D.
E. Slaughter, J. Org. Chem. 1990, 55, 2736Ϫ2742.
C. B. Pollard, L. H. Amundsen, J. Am. Chem. Soc. 1935, 57,
357Ϫ358.
[3a] C. Zorn, A. Goti, A. Brandi, K. Johnsen, S. I. Kozhushkov,
[3b]
[15]
[16]
[17]
A. de Meijere, Chem. Commun. 1998, 903Ϫ904.
A. Goti, A. Brandi, K. Johnsen, M. Noltemeyer, S. I. Kozhush-
C. Zorn,
kov, A. de Meijere, J. Org. Chem. 1999, 64, 755Ϫ763.
[4] [4a]
A. de Meijere, S. Teichmann, D. Yu, J. Kopf, M. Oly, N.
[4b]
von Thienen, Tetrahedron 1989, 45, 2957Ϫ2968.
Nötzel, M. Tamm, T. Labahn, M. Noltemeyer, M. Es-Sayed,
A. de Meijere, J. Org. Chem. 2000, 65, 3850Ϫ3852.
M. W.
K. Kurita, Chem. Ind. 1974, 345.
Received September 6, 2002
[O02502]
Eur. J. Org. Chem. 2003, 985Ϫ997
997