Multicomponent queuing cascades of bicyclopropylidene, carbon monoxide and aryl iodides or aryl thiols

Article abstract of DOI:10.1002/1099-0690(200210)2002:19<3268::AID-EJOC3268>3.0.CO;2-H

Bicyclopropylidene (1) reacts with N-(2-iodophenyl)-4-methylbenzenesulfonamide (2-NTs) and carbon monoxide (2-3 bar) under mild conditions in a novel palladium-catalysed tetramolecular cascade to give the dispiro compound 3-NTs (61%). The structure of 3-N

Full text of DOI:10.1002/1099-0690(200210)2002:19<3268::AID-EJOC3268>3.0.CO;2-H

FULL PAPER
Multicomponent Queuing Cascades of Bicyclopropylidene, Carbon Monoxide
and Aryl Iodides or Aryl Thiols[‡]
Malte von Seebach,[a] Ronald Grigg,*[a] and Armin de Meijere[b]
Keywords: Spiro compounds / Small ring systems / Palladium / Carbon monoxide / Cascade reactions
Bicyclopropylidene (1) reacts with N-(2-iodophenyl)-4-
methylbenzenesulfonamide (2-NTs) and carbon monoxide
(2−3 bar) under mild conditions in a novel palladium-cata-
lysed tetramolecular cascade to give the dispiro compound
3-NTs (61%). The structure of 3-NTs was determined by X-
ray analysis. With ortho-iodophenol (2-OH) replacing 2-NTs
nucleophile. Various thiophenols reacted with 1 and CO
(2−3 bar) to give the thiocarbonylated products 14a−d,g and
15a−c,g (33−77% yield). With ortho- or para-halo-substituted
thiophenols as substrates the vinyl lactones 16e−h (31−55%
yield) were obtained in a novel palladium-catalysed five-
component cascade. The outcome of this cascade is discus-
a mixture of 3-O (20%) and 3,4-dihydro-2H,5H-pyrano[3,2- sed in terms of the electronic and steric properties of the thi-
c]chromen-2-one (4-O; 11%) was obtained. Mechanistically
this cascade is interpreted in terms of the acylation of 1 fol-
lowed by a cyclopropylcarbinyl-homoallyl rearrangement,
carbon monoxide insertion and intramolecular trapping of a
ophenols.
( Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany,
2002)
Introduction
ent palladium-catalysed cascade reactions combining bi-
cyclopropylidene (1) with carbon monoxide and aryl iod-
ides or aryl thiols.
Organic synthesis is concerned with developing viable
processes to useful materials by methods that minimise
waste, maximise molecular complexity and are highly se- Results and Discussion
lective (regio-, stereo-, chiro- and chemospecific). One of
The palladium-catalysed cross-coupling reaction of bi-
the most elegant ways to achieve this is by cascade reac-
tions,[1] defined as multicomponent ‘‘one-pot’’ sequences, in
which the first reaction creates the functionality to trigger
the second reaction and so on. Cascade reactions are also
termed tandem or domino processes by some authors. Bi-
cyclopropylidene (1) is a unique tetrasubstituted alkene
readily available in preparative quantities.[2] It has been in-
corporated by the de Meijere group in cascade
HeckϪDielsϪAlder reactions[3] and in nucleophilic trap-
ping of π-allylpalladium intermediates generated by car-
bopalladation of 1.[4] Herein we present new multicompon-
cyclopropylidene (1) with N-(2-iodophenyl)-4-methylben-
zenesulfonamide (2-NTs) employing 2Ϫ3 bar of carbon
monoxide gave the unusual 5-azadispiro[2.0.4.3]undecane-
8,11-dione (3-NTs) as the sole product. With ortho-iodo-
phenol (2-OH) as starting material a mixture of 3-O and
3,4-dihydro-2H,5H-pyrano[3,2-c]chromen-2-one (4-O) was
obtained (Scheme 1). The constitution of 3-NTs was deter-
mined by an X-ray crystal structure analysis (Figure 1).[5]
The two spiroannelated cyclopentane moieties of 3-NTs
are perpendicular to each other and make up a central spi-
ro[4.4]nonane unit. The bond lengths in the spirocyclopro-
pane moiety display the expected features arising from the
unique ability of the cyclopropane group to function as an
electron donating moiety:[6] conjugation of the cyclopro-
pane unit with the perfectly syn-periplanar oriented car-
bonyl group in the α-position makes the two proximal
[‡]
Palladium-Catalysed Queuing Processes, Part 3. Part 2:
U. Anwar, A. Casaschi, R. Grigg, J. M. Sansano, Tetrahedron
2001, 57, 1361Ϫ1367. Cyclopropyl Building Blocks for Organic
Synthesis, 80. Part 79: A. de Meijere, C. M. Williams, A.
Kourdioukov, S. V. Sviridov, V. Chaplinski, M. Kordes,
A. Savtchenko, C. Stratmann, M. Noltemeyer, Chem. Eur. J.
2002, 8, 3789Ϫ3801.
˚
bonds longer [1.509(2) and 1.530(2) A, respectively] and
[a]
˚
Molecular Innovation, Diversity and Automated Synthesis
shortens the distal bond [1.482(3) A].
(MIDAS) Centre, School of Chemistry, Leeds University,
Leeds, LS2 9JT, UK
Various catalytic systems were used in attempts to optim-
ise the yields of 3 and 4 (Table 1). The cross-coupling reac-
tion of 1,2-NTs and carbon monoxide under typical Heck
conditions furnished only traces of 3-NTs along with poly-
meric material and a significant amount of starting material
Fax: (internat.) ϩ44-(0)113/233-6501
E-mail: R.Grigg@chem.leeds.ac.uk
[b]
Institut für Organische Chemie der Georg-August-Universität
Göttingen,
Tammannstrasse 2, 37077 Göttingen, Germany
3268
 WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002 1434Ϫ193X/02/1019Ϫ3268 $ 20.00ϩ.50/0 Eur. J. Org. Chem. 2002, 3268Ϫ3275

Multicomponent Queuing Cascades
FULL PAPER
Figure 1. Structure of 3-NTs in the crystal;[5] selected bond lengths [A] and angles [°]: N(1)ϪC(2) 1.414(2), C(2)ϪC(3) 1.396(2), C(3)ϪC(4)
1.457(2), C(4)ϪC(5) 1.536(2), C(4)ϪO(1) 1.218(2), C(5)-N(1) 1.503(2), C(5)ϪC(6) 1.538(2), C(6)ϪC(61) 1.509(2), C(6)ϪC(62) 1.530(2),
C(61)ϪC(62) 1.482(3), C(6)ϪC(7) 1.488(2), C(7)ϪC(8) 1.508(3), C(7)ϪO(2) 1.217(2), C(8)ϪC(9) 1.541(3), C(9)ϪC(5) 1.555(2);
N(1)ϪC(5)ϪC(4) 101.26(13), C(6)ϪC(5)ϪC(9) 105.11(14), C(5)ϪC(6)ϪC(7) 108.67(14), C(61)ϪC(6)ϪC(7) 118.56(14), C(62)ϪC(6)ϪC(7)
116.18(14), C(61)ϪC(6)ϪC(62) 58.33(11), C(6)ϪC(61)ϪC(62) 61.55(11), C(6)ϪC(62)ϪC(61) 60.12(11)
˚
[Pd(PPh3)4], K2CO3 and NBu4Br as additive which afforded
3-NTs in 61% yield (Entry 4).
The four-component cascade with ortho-iodophenol (2-
OH) furnished a mixture of 3-O and 4-O (Entries 5, 8 and
9). Again, K2CO3 was the best base for this transformation
(Entry 5), while the employment of Cs2CO3 or DABCO as
Scheme 1. Four-component reaction involving bicyclopropylidene
bases led to complex mixtures (Entries 6 and 11). The cata-
lytic system involving [Pd2dba3] and TFP (tris-2-furylphos-
phane) was also active (Entry 8), but in this case the addi-
tion of NBu4Br led to decomposition products (Entry 10).
However, NBu4Br together with [Pd(PPh3)4] favoured the
formation of 4-O (24% yield) over 3-O (11% yield)
(Entry 9); normally 3-O is the main product. The reaction
under 1 bar pressure of carbon monoxide gave only a trace
of products along with polymeric material (Entry 7). Using
2-OTMS as starting material with TMS as a temporary
protecting group provided 3-O in 29% yield whilst traces of
4-O were observed by HPLC analysis (Entry 12).
(1), aryl iodide 2 and carbon monoxide; for details see Table 1
Table 1. Four-component reactions of bicyclopropylidene (1), aryl
iodide 2 and carbon monoxide
Entry
X
Conditions[a] Base
t [h] 3 (%)
4 (%)
1
2
3
4
5
6
7
8
9
NTs
NTs
NTs
NTs
O
O
O
O
O
O
O
A
B
B
C
B
B
K2CO3
K2CO3
Ag2CO3 48
K2CO3
K2CO3
Cs2CO3
K2CO3
K2CO3
K2CO3
K2CO3
48
72
trace[b]
40[b]
trace[b]
61
20
1.8
trace
15
11
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
11
Ϫ
trace
13
24
Ϫ
20
15
16
62
40
24
20
B[c]
D
C
E
It is believed that both 3 and 4 arise via a tetramolecular
queuing cascade[7] involving a common intermediate 9,
which is derived from 2 via a sequence of elementary steps
(Scheme 2). Two of these steps are carbonylations involving
an aryl- (5) and an alkyl- (8) palladium intermediate. De-
pending on the nucleophilicity of the deprotonated XϪH
fragment, the intermediate 9 may undergo a 5-endo-trig-
cyclisation (X ϭ NTs) to 10 followed by capture by the de-
protonated internal nucleophile 10 to give 11 and reductive
elimination to 3. The potentially competitive route to 4 in-
volves an intramolecular Michael addition 9Ǟ12 followed
by lactonisation to yield 4 (Scheme 2).
10
11
12
B
B
DABCO 48
K2CO3 18
Ϫ
trace
OTMS
29
[a] A: 10 mol % [Pd(OAc)2], 20 mol % TFP, 100 mol % NBu4Br, CO
(2Ϫ3 bar), DMF. B: 4 mol % [Pd(PPh3)4], MeCN. C: as in B,
150 mol % NBu4Br. D: 3 mol % [Pd2dba3], 12 mol % TFP. E: as in
[b]
D, 150 mol % NBu4Br.
Along with N-(2-iodophenyl)-4-methyl-
[c]
benzenesulfonamide (2-NTs). 1 atm. CO.
2-NTs (Entry 1). However, [Pd(PPh3)4] as catalyst in MeCN
gave 3-NTs as the sole product in 40% yield (Entry 2).
Changing the base from K2CO3 to Ag2CO3 led to recovery
The thiocarbonylation of various unsaturated substrates
of starting material 2-NTs along with traces of 3-NTs at high pressure has been reported previously.[8] We observe
(Entry 3). The best result was obtained employing that bicyclopropylidene (1) reacts with various thiophenols
Eur. J. Org. Chem. 2002, 3268Ϫ3275
3269

M. von Seebach, R. Grigg, A. de Meijere
FULL PAPER
(compare Entries 2 and 3 with Entries 6 and 10). Doubling
the amount of Pd catalyst improved the yield of 16g from
20% to 31% (Entry 8), whereas a reduction of the reaction
time led only to the formation of 14g and 15g (Entry 7).
Different catalytic systems were also investigated. Thus 13h
gives almost the same yield of 16h with both [Pd2dba3]/TFP
and with [Pd(PPh3)4] as catalysts (Entries 9 and 11), while
P(o-tolyl)3 as ligand suppressed the formation of 16h
(Entry 12) and a significant amount of 14h and polymeric
material were formed. Interestingly the type of product
formed from 1 and 13aϪh correlates quite well with the
calculated pKa’s of the thiols (Table 2). Thiols with a calcu-
lated pKa of 6.5Ϫ7.2 give rise to mixtures of 14 and 15 only
(Table 2, Entries 1Ϫ3), whilst thiols with a calculated pKa
of 5.5Ϫ6.4 give rise to only 16 (Table 2, Entries 5, 6, 9Ϫ12),
except for para-chlorothiophenol, which gives mixtures of
all three products (Table 2, Entries 7 and 8). The role of the
ortho-halogen in the thiophenols may be a combination of
an iodide effect together with coordination to Pd via a hal-
ogen lone pair. In the case of ortho-fluorothiophenol the
iodide effect is dominant, whilst progressing from ortho-
chloro to ortho-bromo would be marked by increasing lone
pair coordination. The effect of ortho-bromo substituents
has also been noted in ruthenium metathesis by the Grigg
group.[10]
Scheme 2. Proposed mechanism of the tetramolecular queuing cas-
cade involving bicyclopropylidene (1), aryl iodide 2 and CO
Possible mechanisms for the formation of 14Ϫ16 are
shown in Scheme 4. Pd0 inserts oxidatively into the SϪH
bond to afford 17, which adds to the very reactive electron
rich CϭC double bond of 1 to afford 18. The palladium
atom in intermediate 18 may be coordinated to the ortho-
bromine or chlorine atoms (R1 ϭ Br, Cl). The cyclopro-
pylcarbinyl-homoallyl rearrangement of 18 to 19 appears to
be competitive with carbonylation-reductive elimination to
give 14, while carbonylation-reductive elimination of 19
leads via 20 to 15. However, if R1 ϭ H and R2 ϭ Cl (13g)
the reaction leads exclusively to 14g and 15g after 18 h, al-
and CO under mild pressure (2Ϫ3 bar) to give the thiocar-
bonylated products 14aϪh, 15aϪh or 16aϪh, respectively
(Scheme 3)
Scheme 3. Thiocarbonylation of bicyclopropylidene (1); for details
see Table 2
The reaction between 1 and thiophenols 13a or 13c fur- though after 41 h the product comprised a 3:2 mixture of
nished a mixture of 14a/15a or 14c/15c, respectively, fa- 14g/15g and 16g (Entry 7). One way to account for this re-
vouring 15, in which ring opening of one of the cyclopro- sult is to postulate the interconversion of 20 and 15. Palla-
panes has occurred (Entries 1 and 3). However, with a me- dium insertion into S-acyl bonds has been reported recently
thoxy group ortho to the thiol moiety (13b) the major prod- by several groups.[11] Addition of 20 to 1 furnishes 21 and
uct is 14b (Entry 2). Interestingly, 2-mercaptopyridine (13d) subsequent cyclopropylcarbinyl-homoallyl rearrangement
afforded the bicyclopropyl derivative 14d as the sole prod- affords 22. Finally, Michael addition of thiolate anion to
uct (Entry 4). Only a few other examples are known in 23 furnishes 24, which undergoes ring closure to 16. The
which 1 reacts under palladium catalysis with retention of correlation of product selectivity with the pKa of the thi-
both three-membered rings.[9] With ortho-halothiophenols ophenol would agree with an increasing ease of Pd0 inser-
the unusual vinyl lactones 16e, 16f and 16h, respectively, tion into the S-acyl bond of 15 (and possibly 14) as the pKa
were obtained and products of type 14 and 15 were only of the thiophenol decreases. Such a tendency would pro-
observed in trace amounts (Entries 5, 6, 9 and 10). The best mote the conversion of 15 (and 14) into 16. The selectivity
yield (55%) was obtained with 13h, which afforded 16h. of pyridine-2(1H)-thione for 14d reflects the high pKa of
Therefore, the soft and more nucleophilic bromine atom in the thione tautomer but additionally suggests chelation of
13h apparently stabilises one or more of the reactive inter- Pd. Compound 25 may suppress oxidative addition into the
mediates better than the harder, more electronegative fluor- S-acyl bond.
ine or chlorine substituents. This ortho-effect was investig-
de Meijere et al. reported that thiols add easily to bicyclo-
ated using para-chlorothiophenol (13g), which reacted with propylidene (1) in benzene solution and proposed a radical
1 to afford a mixture of all three products 14g/15g (29%) mechanism.[12] They also reported that the addition is sup-
and 16g (20%) (Entry 7). Therefore, an electronic effect is pressed in the presence of [Pd(OAc)2]. This could explain
operative and a simple buttressing effect can be discounted why only traces of thioethers like 26 were observed in the
3270
Eur. J. Org. Chem. 2002, 3268Ϫ3275

Multicomponent Queuing Cascades
FULL PAPER
Table 2. Thiocarbonylation of bicyclopropylidene (1)[a]
R1
R2
X
pKa
t [h]
14 and 15 (%) (14:15)[c]
16 (%)
[b]
Entry
Thiol
1
2
13a
13b
13c
13d
13e
13f
13g
13g
13h
13h
13h
13h
H
H
H
H
H
H
H
Cl
Cl
H
H
H
H
CH
CH
CH
N
CH
CH
CH
CH
CH
CH
CH
CH
6.6 Ϯ 0.1
6.6 Ϯ 0.4
6.8 Ϯ 0.4
10.1 Ϯ 0.2[e]
6.0 Ϯ 0.4
5.9 Ϯ 0.4
6.1 Ϯ 0.1
42
22
20
24
48
48
41
44
19
48
18
16
71 (1:1.6)
69 (3.6:1)
67 (1:2)
77 (Ͼ96:4)
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
OMe
iPr
H
F
Cl
H
3
4[d]
5
37
6
Ϫ
50 (27)[f]
20[g]
31
7
29 (1.5:1)
33 (1.5:1)
Ϫ
8[h]
9
H
Br
Br
Br
Br
5.9 Ϯ 0.4
45
55
44
27
10
11[i]
12[j]
Ϫ
Ϫ[k]
Ϫ[k]
[a] Conditions: 2.00 equiv. 1, 1.00 equiv. 13aϪh, 2.00 equiv. K2CO3, 4 mol % [Pd(PPh3)4], CO (2Ϫ3 bar), MeCN, 70Ϫ80 °C. [b] pKa values
[c]
1
calculated using the software provided by ACD/I-Lab Web service (ACD/pKa 5.0). Ratio of 14:15 determined by H NMR analysis of
the crude product. Performed without K2CO3 as additional base. [e] pKa of the stable tautomer pyridine-2(1H)-thione. [f] 25 h. After
[d]
[g]
[h]
[i]
[j]
18 h 40% conversion and only 14:15 (1:1.7) were observed.
8 mol % [Pd(PPh3)4].
2 mol % [Pd2dba3], 8 mol % TFP.
2 mol %
[k]
1
[Pd2dba3], 8 mol % P(o-tolyl)3. A significant amount of 14h was observed in the H NMR spectrum of the crude product.
Thiophenol (13a) reacted readily with 1 both in C6D6,
as published,[12] and in CD3CN to afford 26 quantitatively
Scheme 5. Radical addition of thiophenol (13a) to 1 in benzene[12]
or acetonitrile
(Scheme 5). However, when the same reaction was per-
formed in CH3CN in the presence of K2CO3, CO and a Pd
catalyst only traces of 26 were detected, whilst in the ab-
sence of K2CO3 26 was isolated in 20% yield indicating that
both the Pd catalyst and K2CO3 are important for the out-
come of the cascade reaction.
The highly reactive lactone 16h undergoes ring opening
with nucleophiles. Benzylamine and phenylhydrazine give
27a and 27b in 82% and 79% yield, respectively, and 16h
was quantitatively converted into the carboxylic acid 27c
upon keeping in a closed flask for 30 days (Scheme 6).
Scheme 6. Ester cleavage in 16h with various nucleophiles (NuH);
A: NuH ϭ benzylamine, THF, 20 °C, 20 h, 27a (82%); NuH ϭ
phenylhydrazine, THF, 20 °C, 45 h, 27b (79%); B: NuH ϭ H2O, 30
days, Ͼ90% conversion.
Scheme 4. Mechanism of the five-component queuing cascade
reactions described above (Scheme 3 and Table 2). However,
in the reactions reported in this paper acetonitrile was the
solvent. Therefore, the possible influence of the solvent
was investigated.
Conclusion
The novel tetramolecular cascade process with bicyclo-
propylidene (1), N-(2-iodophenyl)-4-methylbenzenesulfona-
Eur. J. Org. Chem. 2002, 3268Ϫ3275
3271

M. von Seebach, R. Grigg, A. de Meijere
FULL PAPER
ppm. 13C NMR: δ ϭ 18.1 (CH2, cy-Pr), 21.6 (CH3), 22.4 (CH2, cy-
Pr), 29.9 (CH2), 36.1 (CH2), 37.7 (C, cy-Pr), 79.8 (C), 114.5 (CH),
121.7 (C), 123.6, 124.8 (CH), 126.8, 130.1 (2 CH), 137.6 (C), 137.8
(CH), 144.9, 152.5, 199.2, 214.6 (C) ppm. IR (KBr): ν˜max ϭ 1715,
1593, 1464, 1343, 1300, 1210, 1123, 1071, 1019, 995, 818, 762,
681 cmϪ1. MS (ESI): m/z (%) ϭ 404 (100) [M ϩ Naϩ], 333 (96)
[2 ϫ C7H7SO2 ϩ Naϩ]. MS (EI): m/z (%) ϭ 381 (8) [Mϩ], 227/226
(16/100) [Mϩ Ϫ C7H7SO2], 198 (15), 184 (9), 183 (13), 155 (6)
[C7H7SO2ϩ]. C21H19NO4S (381.4): calcd. C 66.13, H 5.02, N 3.67;
found C 66.35, H 5.10, N 3.80.
mide (2-NTs) or ortho-iodophenol (2-OH) and CO
(2Ϫ3 bar) constitutes a straightforward approach to highly
substituted 5-aza- or 5-oxadispiro[2.0.4.3]undecanes 3-NTs
and 3-O. Under similar reaction conditions 1, CO
(2Ϫ3 bar) and thiophenols 13aϪh afford both thiocarbony-
lated bicyclopropyl derivatives 14aϪd,g and ring-opening
products 15aϪc,g. The reaction with halogen-substituted
thiophenols 13eϪh proceeds via a novel five-component
cascade resulting in highly reactive lactones 16eϪh, which
can be opened with various nucleophiles to give the prod-
ucts 27aϪc.
6,7-Benzo-5-oxadispiro[2.0.4.3]undecane-8,11-dione (3-O) and 3,4-
Dihydro-5,1Ј-spirocyclopropane-2H,5H-pyrano[3,2-c]chromen-2-one
(4-O): Prepared over 15 h from bicyclopropylidene (1) (188 µL,
2.00 mmol, d ϭ 0.854 g/ml) and ortho-iodophenol (2-O) (220 mg,
1.00 mmol) according to the GP. After column chromatography
(hexane/Et2O 1:1) 3-O (46 mg, 20%) and 4-O (26 mg, 11%) were
obtained as pale yellow solids.
Experimental Section
1
General Remarks: H and 13C NMR spectra were recorded at 300
3-O: Rf ϭ 0.23, m.p. 107Ϫ108 °C. 1H NMR: δ ϭ 0.83Ϫ0.90 (m,
1 H, cy-Pr), 1.24Ϫ1.39 (m, 3 H, cy-Pr), 2.32Ϫ2.41 (m, 1 H, CH2),
2.48Ϫ2.59 (m, 1 H, CH2), 2.65Ϫ2.87 (m, 2 H, CH2), 7.07Ϫ7.12 (m,
2 H, Ar-H), 7.62Ϫ7.68 (m, 2 H, Ar-H) ppm. 13C NMR: δ ϭ 14.6
(CH2, cy-Pr), 18.44 (CH2, cy-Pr), 31.9 (CH2), 35.8 (C, cy-Pr), 36.1
(CH2), 94.7 (C), 113.3 (CH), 120.4 (C), 122.2, 124.5, 138.7 (CH),
171.5, 200.6, 214.3 (C) ppm. IR (KBr): ν˜max ϭ 1732, 1703, 1617,
1483, 1092, 893, 754 cmϪ1. MS (ESI): m/z (%) ϭ 251 (100)
[M ϩ Naϩ], 229 (8) [M ϩ Hϩ]. MS (EI): m/z (%) ϭ 228 (48) [Mϩ],
200 (100) [Mϩ Ϫ CO], 185 (26), 172 (38), 121 (39). C14H12O3
(228.2): calcd. C 73.67, H 5.30; found C 73.40, H 5.55.
or 500 MHz (1H) and 75.5 or 125.8 MHz [13C, DEPT (Distor-
tionless Enhancement by Polarization Transfer)] with Bruker
DPX 300 or DRX 500 spectrometers, respectively, in CDCl3 with
TMS (0.03%) as internal standard. Mass spectra (EI and FAB):
VG Autospec. (70 eV); (ESI): LCT Micromass (TOF). The mass
spectra of isomers 14 and 15 were essentially identical in all cases
and hence a single set of data is reported. IR: Midac M-2000 FT-
IR, measured as KBr pellets or as oils between KBr plates. Ele-
mental analysis: Carlo Erba MOD 11016 instrument. Rf values re-
fer to TLC on 0.25 mm precoated silica gel plates (Merck F254
)
with the same eluent as used for the separation of the compound
by flash column chromatography employing silica gel 60
(Merck 9385). Melting points (m.p.): Reichert microscope with a
Reichert heating mantle, values uncorrected. Anhydrous MeCN
and all other chemicals were used as commercially available
(Merck, Lancaster and Aldrich).
4-O: Rf ϭ 0.17, m.p. 88Ϫ90 °C. 1H NMR: δ ϭ 0.86, 1.19 (2 m,
AAЈBBЈ, 4 H, cy-Pr), 2.20, 2.76 (2 t, J ϭ 7.6 Hz, 4 H, CH2), 6.73
(dd, J ϭ 7.7, 1.0 Hz, 1 H, Ar-H), 6.95 (dt, J ϭ 7.7, 1.0 Hz, 1 H,
Ar-H), 7.17 (dt, J ϭ 7.7, 1.6 Hz, 1 H, Ar-H), 7.38 (dd, J ϭ 7.7,
1.6 Hz, 1 H, Ar-H) ppm. 13C NMR: δ ϭ 12.3 (2 C, CH2, cy-Pr),
19.6, 28.9 (CH2), 61.2, 109.2 (C), 116.1 (CH), 118.3 (C), 121.4,
General Procedure (GP) for the Palladium Carbonylation or Thi-
ocarbonylation of Bicyclopropylidene (1) with Aryl Iodides or Thiols:
K2CO3 (276 mg, 2.00 mmol), [Pd(PPh3)4] (46.2 mg, 40.0 µmol), an-
hydrous MeCN (10 mL), bicyclopropylidene (1) (188 µL,
2.00 mmol, d ϭ 0.854 g/ml) and aryl iodide (2-NTs or 2-O,
1.00 mmol) or thiol (13aϪh, 1.00 mmol) were added under a nitro-
gen atmosphere to a 100 mL oven dried Schlenk tube with a stir-
ring bar. The mixture was frozen with liquid nitrogen and left under
vacuum (Ͻ 10Ϫ1 mbar) for around 2 min. The Schlenk tube was
then charged with CO (1 bar), the mixture allowed to reach room
temperature, placed in an oil bath pre-heated to 80 °C and stirred
for an appropriate time. After cooling, the excess CO was vented,
the reaction mixture filtered through silica gel, and the solvent re-
moved by rotary evaporation. The residue was purified by flash
column chromatography on silica gel.
122.1, 130.3 (CH), 142.2, 153.9, 167.8 (C) ppm. IR (KBr): ν˜max
ϭ
1763, 1489, 1387, 1253, 1192, 1169, 1143, 1103, 766 cmϪ1. MS
(FAB): m/z (%) ϭ 245 (7) [M ϩ Naϩ], 229 (50) [M ϩ Hϩ], 228
(100) [Mϩ], 227 (38), 200 (74) [Mϩ Ϫ CO], 199 (28), 185 (33), 147
(21). C14H12O3 (228.2): calcd. C 73.67, H 5.30; found C 73.40,
H 5.50.
S-Phenyl 1,1Ј-Bi(cyclopropyl)-1-carbothioate (14a) and S-Phenyl 4-
Cyclopropylidenebutanethioate (15a): Prepared over 42 h from bi-
cyclopropylidene (1) (188 µL, 2.00 mmol, d ϭ 0.854 g/ml) and thi-
ophenol (13a) (102 µL, d ϭ 1.075 g/ml, 1.00 mmol) according to
the GP. After column chromatography (hexane/Et2O 20:1) a 1:1.6
mixture of 14a/15a (156 mg, 71%) was obtained as a colourless oil;
Rf ϭ 0.20.
14a: 1H NMR: δ ϭ 0.25, 0.66 (2 m, AAЈBBЈ, 4 H, cy-Pr), 0.72, 1.23
6,7-Benzo-5-[(4-methylphenyl)sulfonyl]-5-azadispiro[2.0.4.3]- (2 m, CCЈDDЈ, 4 H, cy-Pr), 1.53Ϫ1.62 (m, 1 H, cy-Pr), 7.37Ϫ7.44
undecane-8,11-dione (3-NTs): Prepared from bicyclopropylidene (1)
(188 µL, 2.00 mmol, d ϭ 0.854 g/ml), NBu4Br (484 mg, 1.50 mmol)
(m, 5 H, Ar-H) ppm. 13C NMR: δ ϭ 4.76 (2 C, CH2), 11.35 (CH),
16.32 (2 C, CH2), 33.87 (C), 129.00 (C), 129.46 (2 C, CH), 129.52
and
N-(2-iodophenyl)-4-methylbenzenesulfonamide
(2-NTs) (CH), 135.31 (2 C, CH), 201.38 (C) ppm.
(373 mg, 1.00 mmol) over 20 h by the GP. Column chromatography 15a: 1H NMR: δ ϭ 1.04Ϫ1.05 (m, 4 H, cy-Pr), 2.58 (virt. q, J ϭ
(hexane/EtOAc 2:1) afforded 3-NTs (233 mg, 61%) as a pale-orange
solid; Rf ϭ 0.20; m.p. 221Ϫ222 °C. Suitable pale yellow prisms for
7.2 Hz, 2 H, CH2), 2.83 (t, J ϭ 7.2 Hz, 2 H, CH2), 5.77Ϫ5.82 (m,
1 H, ϭCH), 7.39Ϫ7.40 (m, 5 H, Ar-H) ppm. 13C NMR: δ ϭ 2.6
(2 C, CH2, cy-Pr), 28.1, 43.5 (CH2), 115.9 (CH), 123.4 (C), 128.3
X-ray analysis were obtained by crystallisation from Et2O/EtOAc
1
(1:1 v/v). H NMR: δ ϭ 0.91Ϫ1.04 (m, 2 H, cy-Pr), 1.26Ϫ1.33 (m, (C), 129.6 (2 C, CH), 129.7 (CH), 134.9 (2 C, CH), 197.6 (C) ppm.
1 H, cy-Pr), 1.43Ϫ1.50 (m, 1 H, cy-Pr), 2.42 (s, 3 H, CH3),
14a/15a: MS (EI): m/z (%) ϭ 218 (2) [Mϩ], 190 (9), 123 (14), 110
2.56Ϫ2.81 (m, 3 H, CH2), 2.96Ϫ3.09 (m, 1 H, CH2), 7.13Ϫ7.26 (m, (26), 109 (100) [Mϩ Ϫ C6H5S], 81 (76) [Mϩ Ϫ C6H5S Ϫ CO], 79
1 H, Ar-H), 7.33 (d, J ϭ 8.4 Hz, 2 H, Ar-H), 7.61Ϫ7.70 (m, 2 H, (41), 65 (34), 53 (39). C13H14OS (218.3): calcd. C 71.52, H 6.46,
Ar-H), 7.76Ϫ7.80 (m, 1 H, Ar-H), 7.82 (d, J ϭ 8.4 Hz, 2 H, Ar-H) S 14.69; found C 71.55, H 6.50, S 14.45.
3272
Eur. J. Org. Chem. 2002, 3268Ϫ3275

Multicomponent Queuing Cascades
FULL PAPER
S-(2-Methoxyphenyl) 1,1Ј-Bi(cyclopropyl)-1-carbothioate (14b) and
100) [M ϩ Hϩ]. C12H13NOS (219.3): calcd. C 65.73, H 5.97,
S-(2-Methoxyphenyl) 4-Cyclopropylidenebutanethioate (15b): Pre- N 6.38, S 14.62; found C 65.55, H 6.05, N 6.35, S 14.35.
pared over 22 h by the GP from bicyclopropylidene (1) (188 µL,
6-(3-Cyclopropylidenepropyl)-5-{1-[(2-fluorophenyl)thio]-
cyclopropyl}-3,4-dihydro-2H-pyran-2-one (16e): Prepared over 48 h
by the GP from bicyclopropylidene (1) (188 µL, 2.00 mmol, d ϭ
0.854 g/ml) and ortho-fluorothiophenol (13e) (107 µL, d ϭ 1.203 g/
ml, 1.00 mmol). After column chromatography (hexane/Et2O 3:1)
16e (126 mg, 37%) was obtained as a pale yellow oil. After storage
for a few days at Ϫ20 °C 16e was obtained as a colourless solid;
Rf ϭ 0.22; m.p. 45 °C. 1H NMR: δ ϭ 0.96 (virt. s, 6 H, cy-Pr),
1.25Ϫ1.31 (m, 2 H, cy-Pr), 1.90Ϫ1.95 (m, 2 H, CH2), 2.00Ϫ2.07
(m, 2 H, CH2), 2.42Ϫ2.46 (m, 2 H, CH2), 2.52Ϫ2.57 (m, 2 H, CH2),
5.52Ϫ5.56 (m, 1 H, ϭCH), 7.08Ϫ7.14 (m, 2 H, Ar-H), 7.34Ϫ7.43
(m, 1 H, Ar-H), 7.45Ϫ7.52 (m, 1 H, Ar-H) ppm. 13C NMR: δ ϭ
2.0 (2 CH2, cy-Pr), 16.6 (2 C, CH2, cy-Pr), 22.9, 28.3, 28.6, 28.8
2.00 mmol, d ϭ 0.854 g/ml) and ortho-methoxythiophenol (13b)
(122 µL, d ϭ 1.152 g/ml, 1.00 mmol). After column chromato-
graphy (hexane/Et2O 2:1) a 3.6:1 mixture of 14b/15b (171 mg, 69%)
was obtained as a pale yellow oil.
1
14b: Rf ϭ 0.35. H NMR: δ ϭ 0.26, 0.66 (2 m, AAЈBBЈ, 4 H, cy-
Pr), 0.69, 1.21 (2 m, CCЈDDЈ, 4 H, cy-Pr), 1.59Ϫ1.66 (m, 1 H, cy-
Pr), 3.83 (s, 3 H, CH3), 6.93Ϫ7.00 (m, 2 H, Ar-H), 7.36Ϫ7.41 (m,
2 H, Ar-H) ppm. 13C NMR: δ ϭ 4.74 (2 C, CH2), 11.50 (CH),
16.06 (2 C, CH2), 33.85 (C), 56.43 (CH3), 111.91 (CH), 117.10 (C),
121.43, 131.76, 137.51 (CH), 159.94, 200.33 (C) ppm.
15b: Rf ϭ 0.41. 1H NMR: δ ϭ 1.04Ϫ1.05 (m, 4 H, cy-Pr), 2.58
(virt. q, J ϭ 7.5 Hz, 2 H, CH2), 2.84 (t, J ϭ 7.5 Hz, 2 H, CH2),
3.84 (s, 3 H, CH3), 5.77Ϫ5.83 (m, 1 H, ϭCH), 6.95Ϫ7.01 (m, 2 H,
Ar-H), 7.36Ϫ7.44 (m, 2 H, Ar-H) ppm. 13C NMR: δ ϭ 2.5 (2 C,
CH2, cy-Pr), 28.1, 43.3 (CH2), 56.4 (CH3), 111.9 (CH), 116.1 (CH),
116.4 (C), 121.5 (CH), 123.2 (C), 132.0, 137.2 (CH), 159.6, 196.9
(C) ppm.
2
(CH2), 29.9 (C, cy-Pr), 113.8 (C), 116.1 (d, JC,F ϭ 24.2 Hz, CH),
2
116.5 (CH), 120.3 (d, JC,F ϭ 19.6 Hz, C), 121.9 (C), 124.6 (d,
3
3JC,F ϭ 3.8 Hz, CH), 131.6 (d, JC,F ϭ 7.5 Hz, CH), 138.3 (CH),
152.1 (C), 163.6 (d, 1JC,F ϭ 246.8 Hz, C), 168.9 (C) ppm. IR (KBr):
ν˜max ϭ 3056, 2982, 2903, 1765, 1688, 1472, 1445, 1256, 1219, 1171,
1136, 1046, 1011, 961, 936, 903, 768 cmϪ1. MS (ESI): m/z (%) ϭ
689 (15) [2 ϫ M ϩHϩ], 345 (100) [M ϩ Hϩ]. C20H21FO2S (344.4):
calcd. C 69.74, H 6.14, S 9.31; found C 69.45, H 6.30, S 9.35.
14b/15b: MS (FAB): m/z (%) ϭ 249 (41) [M ϩ Hϩ], 109 (100)
[Mϩ Ϫ C7H7OS], 81 (50) [Mϩ Ϫ C7H7OS Ϫ CO]. C14H16O2S
(248.3): calcd. C 67.71, H 6.49, S 12.91; found C 67.45, H 6.55,
S 12.85.
5-{1-[(2-Chlorophenyl)thio]cyclopropyl}-6-(3-cyclopropylidene-
propyl)-3,4-dihydro-2H-pyran-2-one (16f): Prepared over 48 h by the
GP from bicyclopropylidene (1) (188 µL, 2.00 mmol, d ϭ 0.854 g/
ml) and ortho-chlorothiophenol (13f) (113 µL, d ϭ 1.277 g/ml,
1.00 mmol). After column chromatography (hexane/Et2O 3:2) 16f
(180 mg, 50%) was obtained as a colourless oil; Rf ϭ 0.28. 1H
NMR: δ ϭ 0.97 (virt. s, 4 H, cy-Pr), 1.00, 1.36 (2 m, AAЈBBЈ, 4 H,
cy-Pr), 1.99Ϫ2.09 (m, 4 H, 2 CH2), 2.43Ϫ2.49 (m, 2 H, CH2),
2.52Ϫ2.58 (m, 2 H, CH2), 5.54Ϫ5.57 (m, 1 H, ϭCH), 7.19Ϫ7.32
(m, 2 H, Ar-H), 7.43Ϫ7.47 (m, 1 H, Ar-H), 7.60Ϫ7.63 (m, 1 H, Ar-
H) ppm. 13C NMR: δ ϭ 2.0, 2.0 (CH2, cy-Pr), 16.6 (2 C, CH2, cy-
Pr), 23.1, 28.3, 28.8, 28.9 (CH2), 29.9 (C, cy-Pr), 113.7 (C), 116.5
(CH), 121.9 (C), 127.1, 130.2, 130.2 (CH), 132.9 (C), 137.5 (CH),
139.1, 152.2, 168.8 (C) ppm. IR (film): ν˜max ϭ 2979, 2913, 1765,
1678, 1449, 1424, 1254, 1188, 1140, 1113, 1036, 901, 756 cmϪ1. MS
(ESI): m/z (%) ϭ 725/723/721 (2/18/28) [2 ϫ M ϩ Hϩ], 363/361 (28/
100) [M ϩ Hϩ]. C20H21ClO2S (360.9): calcd. C 66.56, H 5.86,
Cl 9.82, S 8.88; found C 66.30, H 6.05, Cl 9.90, S 9.00.
S-(2-Isopropylphenyl) 1,1Ј-Bi(cyclopropyl)-1-carbothioate (14c) and
S-(2-Isopropylphenyl) 4-Cyclopropylidenebutanethioate (15c): Pre-
pared over 20 h by the GP from bicyclopropylidene (1) (188 µL,
2.00 mmol, d ϭ 0.854 g/ml) and ortho-isopropylthiophenol (13c)
(152 µL, d ϭ 1.005 g/ml, 1.00 mmol, tech. 90%). After column
chromatography (hexane/Et2O 10:1) a 1:2 mixture of 14c/15c
(157 mg, 67% based on tech. 13c) was obtained as a pale yellow oil.
14c: Rf ϭ 0.39. 1H NMR: δ ϭ 0.25, 0.67 (2 m, AAЈBBЈ, 4 H, cy-
Pr), 0.69 (m, CCЈDDЈ, 2 H, cy-Pr), 1.19 (d, J ϭ 6.8 Hz, 6 H,
2 CH3), 1.23 (m, CCЈDDЈ, 2 H, cy-Pr), 1.58Ϫ1.63 (m, 1 H, cy-Pr),
3.30 (sept, J ϭ 6.8 Hz, 1 H, CH), 7.16Ϫ7.22 (m, 1 H, Ar-H),
7.31Ϫ7.40 (m, 3 H, Ar-H) ppm. 13C NMR: δ ϭ 4.8 (2 C, CH2),
11.6 (CH, cy-Pr), 16.0 (2 C, CH2), 24.0 (2 C, CH3), 31.5 (CH), 33.9
(C), 126.5, 126.7, 130.6, 137.2 (CH), 152.5, 201.2 (C) ppm.
15c: Rf ϭ 0.43. 1H NMR: δ ϭ 1.05 (virt. s, 4 H, cy-Pr), 1.19 (d,
J ϭ 6.9 Hz, 6 H, 2 CH3), 2.59 (virt. q, J ϭ 7.0 Hz, 2 H, CH2), 2.84
(t, J ϭ 7.0 Hz, 2 H, CH2), 3.30 (sept, J ϭ 6.9 Hz, 1 H, CH),
5.77Ϫ5.82 (m, 1 H, ϭCH), 7.17Ϫ7.25 (m, 1 H, Ar-H), 7.35Ϫ7.43
(m, 3 H, Ar-H) ppm. 13C NMR: δ ϭ 2.5, 2.6 (CH2, cy-Pr), 24.0
(2 C, CH3), 28.3 (CH2), 31.5 (CH), 43.6 (CH2), 116.0 (CH), 123.4
(C), 126.6, 126.8, 130.8, 136.9 (CH), 152.2, 197.7 (C) ppm.
S-(4-Chlorophenyl) 1,1Ј-Bi(cyclopropyl)-1-carbothioate (14g), S-(4-
Chlorophenyl) 4-Cyclopropylidenebutanethioate (15g) and 5-{1-[(4-
Chlorophenyl)thio]cyclopropyl}-6-(3-cyclopropylidenepropyl)-3,4-
dihydro-2H-pyran-2-one (16g): Prepared over 44 h by the GP from
bicyclopropylidene (1) (188 µL, 2.00 mmol, d ϭ 0.854 g/ml),
[Pd(PPh3)4] (92.4 mg, 80.0 µmol) and para-chlorothiophenol (13g)
14c/15c: MS (FAB): m/z (%) ϭ 261 (100) [M ϩ Hϩ], 109 (75)
[Mϩ Ϫ C9H11S], 81 (76) [Mϩ Ϫ C9H11S Ϫ CO]. C16H20OS (260.4):
calcd. C 73.80, H 7.74, S 12.31; found C 73.60, H 7.65, S 12.35.
S-(2-Pyridyl) 1,1Ј-Bi(cyclopropyl)-1-carbothioate (14d): Prepared (145 mg, 1.00 mmol). After column chromatography (gradient hex-
over 24 h by the GP (without K2CO3) from bicyclopropylidene (1)
(188 µL, 2.00 mmol, d ϭ 0.854 g/ml) and 2-mercaptopyridine (13d)
(111 mg, 1.00 mmol). After column chromatography (Et2O/hex-
ane 5:1) 14d (169 mg, 77%) was obtained as a pale yellow oil. After
ane/Et2O 10:1 to 2:1) a 1.5:1 mixture of 14g/15g (83 mg, 33%) and
16g (111 mg, 31%) were obtained as colourless oils; Rf (14g/15g) ϭ
0.36 hexane/Et2O 9:1; Rf (16g) ϭ 0.32 hexane/Et2O 2:1.
14g: 1H NMR: δ ϭ 0.25, 0.67 (2 m, AAЈBBЈ, 4 H, cy-Pr), 0.73, 1.22
storage for a few days at Ϫ20 °C 14d was obtained as a colourless (2 m, CCЈDDЈ, 4 H, cy-Pr), 1.50Ϫ1.59 (m, 1 H, cy-Pr), 7.28Ϫ7.40
1
solid; (Rf ϭ 0.43); m.p. 32Ϫ34 °C. H NMR: δ ϭ 0.27, 0.69 (2 m, (m, 4 H, Ar-H) ppm. 13C NMR: δ ϭ 4.8 (2 C, CH2), 11.3 (CH),
AAЈBBЈ, 4 H, cy-Pr), 0.75, 1.25 (2 m, CCЈDDЈ, 4 H, cy-Pr), 16.5 (2 C, CH2), 33.9, 127.56 (C), 129.7 (2 CH), 135.9 (C), 136.5
1.52Ϫ1.61 (m, 1 H, cy-Pr), 7.24Ϫ7.31 (m, 1 H, Py-H), 7.56Ϫ7.62 (2 CH), 200.9 (C) ppm.
(m, 1 H, Py-H), 7.68Ϫ7.76 (m, 1 H, Py-H), 8.62Ϫ8.66 (m, 1 H, Py- 15g: 1H NMR: δ ϭ 1.04Ϫ1.05 (m, 4 H, cy-Pr), 2.57 (virt. q, J ϭ
H) ppm. 13C NMR: δ ϭ 4.9 (2 C, CH2), 11.2 (CH), 16.6 (2 C,
7.6 Hz, 2 H, CH2), 2.83 (t, J ϭ 7.6 Hz, 2 H, CH2), 5.75Ϫ5.81 (m,
CH2), 34.2 (C), 123.8, 131.2, 137.4, 150.8 (CH), 152.7, 200.7 (C) 1 H, ϭCH), 7.28Ϫ7.40 (m, 4 H, Ar-H) ppm. 13C NMR: δ ϭ 2.6,
ppm. IR (film): ν˜max ϭ 3003, 1682, 1574, 1565, 1449, 1424, 1290, 2.6 (CH2, cy-Pr), 28.1 (CH2), 43.6 (CH2), 115.8 (CH), 123.5, 129.6
1248, 1038, 986, 957, 830 cmϪ1. MS (FAB): m/z (%) ϭ 221/220 (13/ (C), 129.8 (2 CH), 136.1 (2 CH, C), 196.9 (C) ppm.
Eur. J. Org. Chem. 2002, 3268Ϫ3275
3273

M. von Seebach, R. Grigg, A. de Meijere
FULL PAPER
14g/15g: MS (ESI): m/z (%) ϭ 255/253 (23/100) [M ϩ Hϩ]. solvent was removed by rotary evaporation and the residue purified
C13H13ClOS (252.8): calcd. C 61.78, H 5.18, Cl 14.03, S 12.68; by flash column chromatography on silica gel (Et2O) to give 27b
found C 62.00, H 5.20, Cl 13.95, S 12.55.
(91.0 mg, 79%) as a pale yellow oil, which comprised a 2:1 rotamer
16g: H NMR: δ ϭ 0.96Ϫ1.01 (m, 6 H, cy-Pr), 1.25 (m, AAЈBBЈ, mixture; Rf ϭ 0.30. 1H NMR: δ ϭ 0.95Ϫ1.12 (m, 6 H, cy-Pr),
2 H, cy-Pr), 1.97Ϫ2.02 (m, 2 H, CH2), 2.08Ϫ2.16 (m, 2 H, CH2), 1.22Ϫ1.30 (m, 2 H, cy-Pr), 1.91Ϫ2.02 (m, 2 H), 2.03Ϫ2.10 (m,
2.35Ϫ2.43 (m, 2 H, CH2), 2.46Ϫ2.54 (m, 2 H, CH2), 5.57Ϫ5.62 (m, 1 H), 2.16Ϫ2.28 (m, 1 H), 2.29Ϫ2.43 (m, 2 H), 2.46Ϫ2.64 (m, 1 H),
1 H, ϭCH), 7.30 (d, J ϭ 8.5 Hz, 2 H, Ar-H), 7.42 (d, J ϭ 8.5 Hz, 2.74Ϫ2.87 (m, 2 H), 5.64Ϫ5.76 (m, 1 H, ϭCH), 5.79 (s, 1 H, NH),
2 H, Ar-H) ppm. 13C NMR: δ ϭ 2.0 (2 CH2, cy-Pr), 16.6 (2 C, 6.69Ϫ6.78 (m, 2 H, Ar-H), 6.84Ϫ6.91 (m, 1 H, Ar-H), 6.96Ϫ7.05
CH2, cy-Pr), 23.2, 28.4, 28.88, 28.93 (CH2), 30.4 (C, cy-Pr), 113.8 (m, 1 H, Ar-H), 7.14Ϫ7.29 (m, 3 H, Ar-H), 7.50Ϫ7.53 (m, 2 H, Ar-
(C), 116.4 (CH), 122.0 (C), 129.1 (2 CH), 132.2, 135.4 (C), 136.4 H), 7.82 (s, 1 H, NH) ppm. 13C NMR (rotamer A): δ ϭ 2.0, 2.2,
(2 CH), 152.3, 168.7 (C) ppm. IR (film): ν˜max ϭ 2979, 1759, 1678, 13.9, 14.5 (CH2, cy-Pr), 25.5, 25.57 (CH2), 26.7 (C, cy-Pr), 31.9,
1476, 1443, 1418, 1256, 1223, 1188, 1130, 1096, 1042, 1015, 901, 43.4 (CH2), 54.5 (CH), 113.2 (2 CH), 116.4, 121.2 (CH), 122.4,
1
824, 747 cmϪ1
. MS (EI): m/z (%) ϭ 747/745/743 (2/19/34) 122.8 (C), 126.9, 127.7, 128.6 (CH), 129.2 (2 CH), 133.3 (CH),
[2 ϫ M ϩNaϩ], 385/383 (21/100) [M ϩ Naϩ]. C20H21ClO2S 137.4, 147.8, 172.2, 210.5 (C) ppm. 13C NMR (rotamer B): δ ϭ 1.9,
(360.9): calcd. C 66.56, H 5.86, Cl 9.82, S 8.88; found C 66.30, 2.1, 13.5, 14.2 (CH2, cy-Pr), 24.6, 25.5 (CH2), 26.5 (C, cy-Pr), 30.3,
H 5.95, Cl 9.90, S 9.00.
43.5 (CH2), 54.1 (CH), 112.4 (2 CH), 116.5, 121.3 (CH), 122.1,
122.5 (C), 126.7, 127.6, 128.3 (CH), 129.5 (2 CH), 133.3 (CH),
137.7, 146.9, 178.0, 210.6 (C) ppm. MS (FAB): m/z (%) ϭ 515/513
(39/39) [M ϩ Hϩ], 325 (17), 217 (33), 109 (72), 97 (61), 85 (46), 83
(78), 81 (99), 71 (61), 69 (100). MS (HR-ESI): 535.1017
(C26H29BrN2O2SNa, calcd. 535.1031).
5-{1-[(2-Bromophenyl)thio]cyclopropyl}-6-(3-cyclopropylidene-
propyl)-3,4-dihydro-2H-pyran-2-one (16h): Prepared over 48 h by
the GP from bicyclopropylidene (1) (188 µL, 2.00 mmol, d ϭ
0.854 g/ml) and ortho-bromothiophenol (13g) (118 µL, d ϭ
1.604 g/ml, 1.00 mmol). After column chromatography (hexane/
Et2O 2:1) 16h (223 mg, 55%) was obtained as a colourless oil; Rf ϭ
0.29. 1H NMR: δ ϭ 0.94Ϫ0.99 (m, 4 H, cy-Pr), 1.01, 1.38 (2 m,
AAЈBBЈ, 4 H, cy-Pr), 2.05Ϫ2.12 (m, 4 H, 2 CH2), 2.45Ϫ2.49 (m,
2 H, CH2), 2.53Ϫ2.57 (m, 2 H, CH2), 5.56Ϫ5.60 (m, 1 H, ϭCH),
7.16Ϫ7.20 (m, 1 H, Ar-H), 7.25Ϫ7.29 (m, 1 H, Ar-H), 7.62Ϫ7.65
(m, 2 H, Ar-H) ppm. 13C NMR: δ ϭ 2.0, 2.1 (CH2, cy-Pr), 16.7
(2 C, CH2, cy-Pr), 23.3, 28.4, 28.9, 29.1 (CH2), 30.2 (C, cy-Pr),
113.7 (C), 116.6 (CH), 122.1 (C), 127.8 (CH), 129.8 (C), 130.1,
133.6 (CH), 135.4 (C), 136.9 (CH), 152.4, 168.7 (C) ppm. IR (film):
ν˜max ϭ 1765, 1445, 1134, 1042, 1021, 754 cmϪ1. MS (EI): m/z (%) ϭ
406/404 (1/1) [Mϩ], 378/376 (21/21) [Mϩ Ϫ CO], 326/325/324/323
(16/99/16/100) [Mϩ Ϫ C6H9], 297/295 (9/9), 283/281 (6/6).
C20H21BrO2S (405.3): calcd. C 59.26, H 5.21, Br 19.71, S 7.91;
found C 59.35, H 4.95, Br 19.65, S 7.60.
4-{1-[(2-Bromophenyl)thio]cyclopropyl}-8-cyclopropylidene-5-
oxooctanoic Acid (27c): Vinyl lactone 16h was hydrolysed with
Ͼ 90% conversion into 27c after storage in a closed but not sealed
flask at room temperature for 1 month, and purified by column
chromatography (Et2O/hexane 3:1) to afford 27c as a colourless oil;
Rf ϭ 0.32. 1H NMR: δ ϭ 1.01Ϫ1.10 (m, 6 H, cy-Pr), 1.26Ϫ1.29
(m, 2 H, cy-Pr), 1.91Ϫ2.03 (m, 2 H), 2.14Ϫ2.21 (m, 1 H),
2.26Ϫ2.33 (m, 1 H), 2.35Ϫ2.41 (m, 2 H), 2.53Ϫ2.60 (m, 1 H),
2.79Ϫ2.87 (m, 2 H), 5.71Ϫ5.75 (m, 1 H, ϭCH), 7.03Ϫ7.07 (m, 1 H,
Ar-H), 7.28Ϫ7.31 (m, 1 H, Ar-H), 7.52Ϫ7.55 (m, 2 H, Ar-H),
8.00Ϫ11.50 (br. s, 1 H, CO2 H) ppm. 13C NMR: δ ϭ 2.0, 2.1, 13.4,
14.3 (CH2, cy-Pr), 24.6, 25.5 (CH2), 26.5 (C, cy-Pr), 31.8, 43.9
(CH2), 53.6 (CH), 116.3 (CH), 122.4, 122.8 (C), 126.9, 127.6, 128.4,
133.3 (CH), 137.5, 179.0, 210.2 (C) ppm. MS (ESI): m/z (%) ϭ
447/445 (99/100) [M ϩ Naϩ]. C20H23BrO3S (423.4): calcd. C 56.74,
H 5.48, Br 18.87, S 7.57; found C 56.60, H 5.70, Br 18.60, S 7.30.
N-Benzyl-4-{1-[(2-bromophenyl)thio]cyclopropyl}-8-cyclopropyl-
idene-5-oxooctanamide (27a):
A solution of 16h (52.0 mg,
128 µmol) and benzylamine (28.0 µL, d ϭ 0.981 g/ml, 256 µmol) in
anhydrous THF (2 mL) was stirred at room temperature for 20 h.
The solvent was removed by rotary evaporation and the residue
purified by flash column chromatography on silica gel (Et2O) to
give 27a (54.0 mg, 82%) as a colourless oil; Rf ϭ 0.34. 1H NMR:
δ ϭ 0.99Ϫ1.02 (m, 4 H, cy-Pr), 1.02Ϫ1.10 (m, 2 H, cy-Pr),
1.23Ϫ1.33 (m, 2 H, cy-Pr), 1.90Ϫ2.00 (m, 2 H), 2.01Ϫ2.06 (m,
1 H), 2.11Ϫ2.18 (m, 1 H), 2.33Ϫ2.41 (m, 2 H), 2.54Ϫ2.61 (m, 1 H),
2.79Ϫ2.86 (m, 2 H), 4.32 (dd, J ϭ 8.8, 3.4 Hz, 1 H, NCH2), 4.38
(dd, J ϭ 8.8, 3.4 Hz, 1 H, NCH2), 5.69Ϫ5.74 (m, 1 H, ϭCH), 5.81
(s, 1 H, NH), 7.01Ϫ7.05 (m, 1 H, Ar-H), 7.19Ϫ7.31 (m, 6 H, Ar-
H), 7.50Ϫ7.54 (m, 2 H, Ar-H) ppm. 13C NMR: δ ϭ 1.9, 2.1, 13.8,
14.2 (CH2, cy-Pr), 25.5, 25.7 (CH2), 26.5 (C, cy-Pr), 34.2, 43.5, 43.6
(CH2), 54.2 (CH), 116.5 (CH), 122.3, 122.6 (C), 126.8, 127.5, 127.6
(CH), 127.8 (2 CH), 128.3 (CH), 128.7 (2 CH), 133.3 (CH), 137.5,
138.1, 171.7, 210.5 (C) ppm. MS (FAB): m/z (%) ϭ 514/512 (14/14)
[M ϩ Hϩ], 406/404 (6/6), 324 (19), 216 (8), 109 (21), 91 (100). MS
(ESI): m/z (%) ϭ 536/534 (12/39) [M ϩ Naϩ], 514/512 (99/100)
[M ϩ Hϩ]. MS (HR-ESI): 512.1278 (C27H31BrNO2S, calcd.
512.1259). MS (HR-ESI): 534.1075 (C27H30BrNO2SNa, calcd.
534.1078).
Acknowledgments
The authors are grateful to Mr. Colin A. Kilner and Dr.
M. Thornton-Pett for the X-ray structure analysis. We thank Leeds
University and the EU (Cascade Combinatorial Chemistry,
ERB FMRX CT980235) for financial support.
[1] [1a]
[1b]
G. H. Posner, Chem. Rev. 1986, 86, 831Ϫ844.
L. F. Ti-
F. E. Ziegler,
[1c]
etze, J. Heterocycl. Chem. 1990, 27, 47Ϫ69.
in Comprehensive Organic Synthesis, Vol. 5 (Eds.: B. M. Trost,
[1d]
I. Fleming), Pergamon Press, Oxford, 1991, pp. 875Ϫ898.
T.-L. Ho, Tandem Organic Reactions, Wiley-Interscience, New
[1e]
York, 1992.
E. Negishi, Pure Appl. Chem. 1992, 64,
[1f]
323Ϫ334.
L. F. Tietze, U. Beifuß, Angew. Chem. 1993, 105,
[1g]
137Ϫ170; Angew. Chem. Int. Ed. Engl. 1993, 32, 131Ϫ163.
[1h]
L. F. Tietze, Chem. Rev. 1996, 96, 115Ϫ136.
P. J. Parsons,
[1i]
C. S. Penkett, A. J. Shell, Chem. Rev. 1996, 96, 195Ϫ206.
A.
´
Heumann, M. Reglier, Tetrahedron 1996, 52, 9289Ϫ9346;
R. Grigg, V. Sridharan, J. Organomet. Chem. 1999, 576, 65Ϫ87.
[2] [2a]
A. de Meijere, S. I. Kozhushkov, T. Späth, N. S. Zefirov, J.
[2b]
Org. Chem. 1993, 58, 502Ϫ505.
A. de Meijere, S. I. -
Kozhushkov, T. Späth, Org. Synth. 2000, 78, 142Ϫ151.
[3] [3a]
S. Bräse, A. de Meijere, Angew. Chem. 1995, 107,
2741Ϫ2743; Angew. Chem. Int. Ed. Engl. 1995, 34, 2545Ϫ2547.
4-{1-[(2-Bromophenyl)thio]cyclopropyl}-8-cyclopropylidene-5-oxo-N-
phenyloctanohydrazide (27b): A solution of 16h (91.0 mg, 225 µmol)
and phenylhydrazine (66.0 µL, d ϭ 1.099 g/ml, 675 µmol) in anhyd-
rous THF (2 mL) was stirred at room temperature for 45 h. The
[3b]
A. de Meijere, H. Nüske, M. Es-Sayed, T. Labahn,
M. Schroen, S. Bräse, Angew. Chem. 1999, 111, 3881Ϫ3884;
Angew. Chem. Int. Ed. 1999, 38, 3669Ϫ3672.
3274
Eur. J. Org. Chem. 2002, 3268Ϫ3275

Multicomponent Queuing Cascades
FULL PAPER
[4]
H. Nüske, M. Noltemeyer, A. de Meijere, Angew. Chem. 2001,
rahedron Lett. 1992, 33, 1207Ϫ1210. [7c] R. Grigg, V. Sridharan,
[7d]
113, 3509Ϫ3511; Angew. Chem. Int. Ed. 2001, 40, 3411Ϫ3413.
Tetrahedron Lett. 1993, 34, 7471Ϫ7474.
R. Grigg, J.
[5]
Crystal Structure of 3-NTs: Crystals (prisms) of 3-NTs were
Redpath, V. Sridharan, D. Wilson, Tetrahedron Lett. 1994, 35,
[7e]
grown from a solution of Et2O/EtOAc (1:1) and measured on
a Nonius Kappa CCD area-detector diffractometer using
graphite-monochromated Mo-Kα radiation. A correction was
applied for the prismatic shape of the crystals
(0.56 ϫ 0.42 ϫ 0.31 mm size). The structure was solved by dir-
ect methods (SHELXS-97) and refined by full-matrix least-
squares on F2 (SHELXL-97). All non-hydrogen atoms were re-
fined anisotropically and all hydrogen atoms were located on
the difference Fourier maps and refined isotropically.
4429Ϫ4432.
R. Grigg, J. Redpath, V. Sridharan, D. Wilson,
[7f]
Tetrahedron Lett. 1994, 35, 7661Ϫ7664.
R. Grigg, B. Putni-
kovic, C. Urch, Tetrahedron Lett. 1996, 37, 695Ϫ698.
Doi, A. Yanagisawa, S. Nakanishi, K. Yamamoto, T. Takah-
[7g]
T.
ashi, J. Org. Chem. 1996, 61, 2602Ϫ2603. For a review of term-
olecular carbonylation reactions with the emphasis on CO
[7h]
pressures Ͼ 1 bar, see:
E. I. Negishi, C. Coperet, S. Ma,
S. Y. Liou, F. Liu, Chem. Rev. 1996, 96, 365Ϫ394.
For the thiocarbonylation of conjugated dienes,[8e,8g] enynes,[8d]
[8]
C21H19NO4S (381.43), monoclinic, a ϭ 7.27750(10), b ϭ
terminal acetylenes,[8f] allenes,[8b] allylic[8c] and propargylic al-
[8a]
cohols[8a] under high pressure, see:
W.-J. Xiao, H. Alper, J.
˚
8.17050(10),
c
ϭ
15.6703(3) A, β ϭ 102.5370(6)°, V ϭ
3
909.55(2) A , Z ϭ 2, space group P21, T ϭ 100(2) K, ρ ϭ
Org. Chem. 1997, 62, 3422Ϫ3423. [8b] W.-J. Xiao, G. Vasapollo,
˚
1.393 g cmϪ3 F(000) ϭ 400, µ ϭ 0.206 mmϪ1
,
,
intensities
H. Alper, J. Org. Chem. 1998, 63, 2609Ϫ2612.
H. Alper, J. Org. Chem. 1998, 63, 7939Ϫ7944.
W.-J. Xiao,
W.-J. Xiao,
[8c]
[8d]
measured: 15935 (2.87° Յ θ Յ 25.99°), independent reflections:
3486 (Rint ϭ 0.0455), observed reflections: 3451 [I Ͼ 2σ(I)],
R1 ϭ 0.0306, wR2 {final [I Ͼ 2σ(I)]} ϭ 0.0805, Goodness of
fit ϭ 1.064, maximum residual electron density 0.327 and
G. Vasapollo, H. Alper, J. Org. Chem. 1999, 64, 2080Ϫ2084.
[8e]
W.-J. Xiao, G. Vasapollo, H. Alper, J. Org. Chem. 2000, 65,
[8f]
4138Ϫ4144.
B. El Ali, J. Tijani, A. El-Ghanam, M. Fet-
Ϫ0.284 e AϪ3. CCDC-180833 contains the supplementary
touhi, Tetrahedron. Lett. 2001, 42, 1567Ϫ1570.
W.-J. Xiao,
[8g]
˚
crystallographic 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.) ϩ44-1223/
336-033; E-mail: deposit@ccdc.cam.ac.uk].
H. Alper, J. Org. Chem. 2001, 66, 6229Ϫ6233.
[9a] T. Pohlmann, A. de Meijere, Org. Lett. 2000, 2, 3877Ϫ3879.
[9]
[9b]
For reviews see:
A. de Meijere, S. I. Kozhushkov, T. Späth,
M. von Seebach, S. Löhr, H. Nüske, T. Pohlmann, M. Es-
[9c]
Sayed, S. Bräse, Pure Appl. Chem. 2000, 72, 1745Ϫ1756.
[6]
[6a] W. R. Dolbier, S. F. Sellers, B. E. Smart, H. Oberhammer, J.
A. de Meijere, S. I. Kozhushkov, Eur. J. Org. Chem. 2000,
[6b]
Mol. Struct. 1983, 101, 193Ϫ197.
H. Irngartinger, S. Gries,
3809Ϫ3822.
[6c]
[10] [10a]
P. Klaus, R. Gleiter, Chem. Ber. 1992, 125, 2503Ϫ2512.
P. Evans, R. Grigg, M. Monteith, Tetrahedron Lett. 1999,
[10b]
A. P. Marchand, K. A. Kumar, D. Rajagopal, R. Eckrich,
40, 5247Ϫ5250.
P. Evans, R. Grigg, M. York, Tetrahedron
S. G. Bott, Tetrahedron Lett. 1996, 37, 467Ϫ470. For reviews
Lett. 2000, 41, 3967Ϫ3970.
[6d]
[11] [11a]
see:
A. de Meijere, Angew. Chem. 1979, 91, 867Ϫ884; A. d-
L. S. Liebeskind, J. Srogl, J. Am. Chem. Soc. 2000, 122,
[6e]
e Meijere, Angew. Chem. Int. Ed. Engl. 1979, 18, 809Ϫ826.
A. de Meijere, S. I. Kozhushkov, Chem. Rev. 2000, 100,
93Ϫ142.
11260Ϫ11261. [11b] B. Zeysing, C. Gosch, A. Terfort, Org. Lett.
[11c]
2000, 2, 1843Ϫ1845.
C. Savarin, J. Srogl, L. S. Liebeskind,
Org. Lett. 2000, 2, 3229Ϫ3231.
S. I. Kozhushkov, M. Brandl, A. de Meijere, Eur. J. Org. Chem.
1998, 1535Ϫ1542.
[7]
[12]
For further examples of termolecular and tetramolecular cas-
cade reactions with carbon monoxide at atmospheric pressure,
see: [7a] W. Oppolzer, J.-Z. Xu, C. Stone, Helv. Chim. Acta 1991,
Received March 12, 2002
[7b]
74, 465Ϫ468.
R. Keese, R. Guidetti-Grept, B. Herzog, Tet-
[O02134]
Eur. J. Org. Chem. 2002, 3268Ϫ3275
3275