Highly substituted furans from 2-propynyl-1,3-dicarbonyls and organic halides or triflates via the oxypalladation-reductive elimination domino reaction

Article abstract of DOI:10.1016/S0040-4020(03)00588-X

The palladium-catalysed reaction of 2-propynyl-1,3-dicarbonyls with organic halides or triflates provides an efficient straightforward entry into highly substituted furans. The best results have been obtained by using an excess of the alkyne. The process can tolerate a wide variety of important functional groups both on the alkyne and the organic halide or triflate. Under an atmosphere of carbon monoxide, the reaction affords furan derivatives incorporating carbon monoxide. Depending on the alkyne to organic halide or triflate ratio, acyl furans (incorporating one molecule of carbon monoxide) or enol esters (incorporating two molecules of carbon monoxide) can be isolated as the main products.

Full text of DOI:10.1016/S0040-4020(03)00588-X

Tetrahedron 59 (2003) 4661–4671
Highly substituted furans from 2-propynyl-1,3-dicarbonyls and
organic halides or triflates via the oxypalladation-reductive
elimination domino reaction
b
b
a
b
Antonio Arcadi,a, Sandro Cacchi, Giancarlo Fabrizi, Fabio Marinelli and Luca M. Parisi
,
*
*
a
` `
Dipartimento di Chimica Ingegneria Chimica e Materiali della Facolta di Scienze, Universita di L’Aquila, Via Vetoio,
Coppito Due, I-67100 L’Aquila, Italy
Dipartimento di Studi di Chimica e Tecnologia delle Sostanze Biologicamente Attive, Universita degli Studi ‘La Sapienza,’
P.le A. Moro 5, 00185 Rome, Italy
b
`
Received 24 January 2003; revised 19 March 2003; accepted 10 April 2003
Abstract—The palladium-catalysed reaction of 2-propynyl-1,3-dicarbonyls with organic halides or triflates provides an efficient
straightforward entry into highly substituted furans. The best results have been obtained by using an excess of the alkyne. The process can
tolerate a wide variety of important functional groups both on the alkyne and the organic halide or triflate. Under an atmosphere of carbon
monoxide, the reaction affords furan derivatives incorporating carbon monoxide. Depending on the alkyne to organic halide or triflate ratio,
acyl furans (incorporating one molecule of carbon monoxide) or enol esters (incorporating two molecules of carbon monoxide) can be
isolated as the main products. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
2. Results and discussion
The palladium-catalysed reaction of organic halides or
triflates with alkynes containing carbon,1 oxygen2 and
nitrogen3 nucleophiles close to the carbon–carbon triple
bond has emerged as one of the most powerful and versatile
tools for the synthesis of a variety of carbo- and
heterocycles. During our studies on the extension of this
chemistry to the construction of the furan ring, a common
unit of numerous biologically active compounds,4 we
observed and previously communicated5 that 2-propynyl-
1,3-dicarbonyl compounds can be used as useful building
blocks for the preparation of 2,3,5-trisubstituted furans
(Scheme 1).
Starting 2-propynyl-1,3-dicarbonyls 1 were readily pre-
pared by alkylation of 1,3-dicarbonyl compounds with
propargyl bromide in the presence of DBU in toluene.6
Initial cyclization attempts were focused on finding a
general set of reaction conditions that could be used with a
wide variety of 2-propynyl-1,3-dicarbonyls and organic
halides or triflates. The influence of the base, the catalyst
system and the 1:2 molar ratio on the reaction outcome was
examined. The nature of the base was found to play a pivotal
role in controlling the cyclization–coupling balance.7 As an
example, the reaction of 1a with methyl p-iodobenzoate
gave the furan derivative 3b as the main product in the
presence of potassium carbonate and the coupling derivative
5a as the main product by using Et3N (Scheme 2).
Now, we wish to report full details on this synthesis of
highly functionalized furans.
Apparently, with K2CO3 the intramolecular nucleophilic
attack of the oxygen across the carbon–carbon triple bond
co-ordinated to palladium is favoured (vide infra), whereas
in the presence of the amine co-ordination of the carbon–
carbon triple bond to palladium results in the activation of
the terminal hydrogen atom towards basic attack. Formation
of the carbon–palladium bond between the incipient
acetylide anion and palladium generates a s-alkynyl-s-
organopalladium complex8 that subsequently affords the
coupling product 5 by a reductive elimination step.
Pd(PPh3)4 was more effective than other commonly used
palladium catalysts (Table 1). As for the 1:2 molar ratio,
we started our study using an excess of the aryl halide
(procedure A). However, better results were possible when
Scheme 1.
Keywords: alkynes; palladium; cyclization; catalysis.
*
Corresponding authors. Tel.: þ39-6-49912795; fax: þ39-6-49912780;
e-mail: sandro.cacchi@uniromal.it; arcadi@univaq.it.
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00588-X

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A. Arcadi et al. / Tetrahedron 59 (2003) 4661–4671
furan derivatives containing branched side chains
(Scheme 3).
Compounds 5a–b could be prepared through the palladium-
catalysed reaction of 1a,c with aryl halides in the presence
of Et3N (Scheme 2). However, better results were obtained
in the presence of added CuI as co-catalyst.9 Particularly,
the highest yields were obtained by using PdCl2, dppf [1,10-
bis(diphenylphosphino)ferrocene], and CuI in the presence
of Et3N10 (Table 3, entries 7 and 8). Depending on the
reaction conditions, competitive cyclization of 1a to 2,5-
dimethyl-3-acetylfuran can be observed (Table 3, entry 2).
As shown by the results shown in Table 3 (entries 3 and 4),
both palladium and copper11 can catalyse this cyclization.
The base-promoted cyclization mechanism appears unlikely
on the basis of the fact that no cyclization product was
observed upon treatment of 1a with K2CO3 or amine bases.
As for the reaction mechanism, most probably 2,3,5-
trisubstituted furans 3 are generated through the oxypalla-
dation–reductive elimination domino mechanism2 which
involves: (a) coordination of the organopalladium complex
formed in situ to the acetylenic system, (b) intramolecular
nucleophilic attack of the oxygen across the activated
carbon–carbon triple bond to give oxypalladation adducts,
(c) reductive elimination of Pd(0) species (Scheme 4).
Scheme 2.
an excess of the alkyne was employed, typically 1.5 equiv.
(Table 1, entry 5).
Subsequently, the following reaction conditions were
employed when we explored the scope and limitations of
this route to highly functionalized furans by examining a
variety of 2-propynyl-1,3-dicarbonyls, aryl halides and
vinyl triflates: (procedure B) 1 (1.5 equiv.), 2 (1 equiv.),
K2CO3 (5 equiv.), Pd(PPh3)4 (0.05 equiv.). Under these
conditions, a wide range of substituted furan derivatives
have been prepared in good yield (Table 2). The reaction
tolerates a variety of functionalized aryl bromides and vinyl
triflates. Several 2-propynyl-1,3-dicarbonyl compounds
have also been employed successfully. As for the latter,
1d,g represent the only exceptions among the 2-propynyl-
1,3-dicarbonyls that we have explored. Compound 1d was
recovered almost unchanged after treatment with 2l under
our standard cyclization conditions. Increase of the reaction
temperature to 1208C resulted in the formation of a mixture
of the isomeric furans 3n,n0 (Table 2, entry 18). Compound
1g, containing aryl and alkyl ketone fragments, gave rise to
a mixture of furan products even at 608C, although with a
prevalence of the furan derived from the cyclization
involving the oxygen of the alkyl ketone fragment
(Table 2, entries 20 and 21).
Isolation of the deuterio derivative 8 (47%) upon treatment
of 6-deuterio-3-acetyl-5-hexyn-2-one 7 with methyl p-iodo-
benzoate under usual conditions (Scheme 5) rules out the
possible formation of the furan ring through a mechanism
involving cleavage of the Csp–H bond.
Further support for the oxypalladation–reductive elimin-
ation mechanism is given by the E stereochemistry of the
alkylidene derivative 4a obtained from the reaction of 1c
with p-nitroiodobenzene (Table 2, entry 15). Interestingly,
the formation of alkylidene intermediates is usually
observed in the related palladium-catalysed reaction of
3-oxo-6-heptynoates with aryl halides,12 but 4a is the only
example of a compound of this type isolated in the
oxypalladation–reductive elimination of 2-propynyl-1,3-
dicarbonyls.
We next investigated the palladium-catalysed reaction of
2-propynyl-1,3-dicarbonyls with organic halides or triflates
in the presence of carbon monoxide with the aim of
preparing substituted furans incorporating a molecule of
carbon monoxide.13 Our task was to develop a simple three
component route to acyl derivatives 9 (Scheme 6).
Internal alkynes can also be used in this chemistry to give
Table 1. Catalyst system and 1a:2a ratio in the synthesis of 3b
Since our related study on the carbonylative amino-
palladation–reductive elimination of o-alkynyltrifluoro-
acetanilides with organic halides showed that reactions
with electron-poor aryl halides are likely to prove the most
difficult,14 we turned our attention to optimising the reaction
of 1a with p-chlorophenyl iodide 2a.
Entry
Catalyst system
1a:2a
Yield % of 3ba
1
2
3
4
5
Pd2(dba)3
Pd(dppe)2
Pd(OAc)2/P(o-tol)3
Pd(PPh3)4
Pd(PPh3)4
1:2
1:2
1:2
1:2
30
40
40
52
93
b
c
1.5:1.0
The reaction was carried out under a balloon of carbon
monoxide. The nature of the catalyst system, the reaction
temperature and the 1a:2a molar ratio were found to
influence the course of the reaction. The best results were
obtained at 608C by use of a 1a:2a 1.5:1 molar ratio in the
Reactions were carried out in DMF, at 608C, in the presence of 5 equiv. of
K2CO3 and 0.05 equiv. of [Pd] under a nitrogen atmosphere.
a
Yields are given for isolated products.
dppe¼[1,2-bis(diphenylphosphino)ethane].
b
c
0.1 equiv. of P(o-tol)3.

A. Arcadi et al. / Tetrahedron 59 (2003) 4661–4671
4663
Table 2. Palladium-catalysed synthesis of 2,3,5-trisubstituted furans 3 from 2-propynyl-1,3-dicarbonyl compounds 1 and organic halides or triflates 2
Entry
Alkyne 1
Organic halide or
triflate 2
Procedure
t (h)
Product 3
Yield
a
%
1a
1a
2a
2a
1
2
A
B
1.5
4
52
93
3a
3a
3
4
1a
1a
A
B
1.5
5
56
70
2b
2b
3b
3b
5
6
1a
1a
2c
2c
Ab
Bb
3
3
3c
3c
62
98
3d
7
1a
2d
B
6
67
8
9
1a
1a
2e
2f
B
B
1.5
2.5
66
67
3e
3f
3g
3h
10
11
1a
1a
2g
2h
B
B
2.5
2.5
71
56
2i
3i
3j
12
13
1a
1b
B
B
7
66
55
2g
3.5
1c
1c
14
15
2a
2j
B
B
3
5
3k
4a
93
74
16
1c
2g
B
24
3l
31
(continued on next page)

4664
A. Arcadi et al. / Tetrahedron 59 (2003) 4661–4671
Table 2 (continued)
Entry
Alkyne 1
Organic halide or
triflate 2
Procedure
t (h)
Product 3
Yield
a
%
2k
2l
17
1c
B
6
35
83
3m
18
Bc
1d
3n
3n0 (3n:3n0¼1.4:1)
2m
19
20
B
B
1.5
60
78
1f
3o
2g
2
1g
3p
3q
3p0 (3p:3p0¼2.25:1)
2n
2o
21
22
B
B
4
5
79
66
1g
1h
3q0 (3q:3q0¼3.12:1)
3r
Unless otherwise stated, reactions were carried out at 608C in DMF, under a nitrogen atmosphere, using (procedure A) 1 equiv. of 1, 2 equiv. of 2, 5 equiv. of
K2CO3, and 0.05 equiv. of Pd(PPh3)4 or (procedure B) 1.5 equiv. of 1, 1 equiv. of 2, 5 equiv. of K2CO3, and 0.05 equiv. of Pd(PPh3)4.
Yields are given for isolated products.
a
b
908C.
1208C.
c
presence of Pd(OAc)2 and P(o-tol)3 (Table 4, entry 10). The
catalyst system was prepared in situ from 1 equiv. of
Pd(OAc)2 and 4 equiv. of P(o-tol)3. We have not
investigated the effect of the Pd/P ratio on the course of
the reaction. Both Pd(OAc)2 (Table 4, entry 2) and
PdCl2(PhCN)2 (Table 4, entry 3) were found to be effective
catalysts. However, precipitation of palladium was
occasionally observed, precluding reproducibility. Use of
phosphine ligands such as PPh3, P(p-tol)3, dppf, and dppe
resulted in the formation of significant amounts of 3a,
derived from the noncarbonylative cyclization of 1a.
An excess of 2a was found to favour the formation of the
enol ester 10a and with the Pd(OAc)2/P(o-tol)3 catalyst
system at 608C, 10a was isolated in 51% yield (Table 4,
entry 7).
Using the best conditions found for the formation of 9a
[(procedure C) 1 (1.5 equiv.), 2 (1 equiv.), Pd(OAc)2
(0.05 equiv.), P(o-to)3 (0.20 equiv.), K2CO3 (5 equiv.) in
MeCN at 608C under a balloon of carbon monoxide], a
variety of furan derivatives 9 have been prepared in good
yield. Our preparative results are summarized in Table 5
(entries 1, 3, 5–8, 10, 12).
Application of these conditions to vinyl triflates, however,
met with failure. For example, no evidence of the
corresponding furan derivative was attained when 1b was
treated with naphthyl triflate 2g (Table 6, entry 1). After
some experimentation (Table 6, entries 2–11), we were
pleased to find that acyl furans containing a vinyl fragment
could be formed in satisfactory yield by using the following
conditions: (procedure D) 1 (1.5 equiv.), 2 (1 equiv.),
Pd(PPh3)4 (0.05 equiv.), K2CO3 (5 equiv.) in MeCN at
608C under 2 atm of carbon monoxide. Our preparative
results are listed in Table 5 (entries 14, 15, 17, 18).
Scheme 3.

A. Arcadi et al. / Tetrahedron 59 (2003) 4661–4671
4665
Table 3. Palladium–copper catalysed synthesis of 5 from 2-propynyl-1,3-dicarbonyls and aryl halides
Entry
Alkyne 1
Aryl halide 2
T (8C)/t (h)
1:2
Catalytic system
Base
Yield %a
2,5-dimethyl-3-acetylfuran
5
3
1b
2c,d
3e
1a
1a
1a
1a
1a
1a
1a
1c
2b
2b
2b
2b
2b
2b
2b
2o
60/3.5
rt/12
rt/12
rt/12
60/4
60/5
30/24
30/24
1:2
1:1
1:1
1:1
1.2:1
1.2:1
1.2:1
1.2:1
Pd(PPh3)4
Et3N
55 (5a)
41 (5a)
–
–
–
–
–
–
Pd(PPh3)4, CuI
Pd(PPh3)4
CuI
PdCl2, dppf, CuI
PdCl2, tcpp,h CuI
PdCl2, dppf, CuI
PdCl2, dppf, CuI
Et2NH
Et2NH
Et2NH
Et3N
Et3N
Et3N
Et3N
30
80
50
–
–
–
4f
–
5g
6g
7g
8g
34 (5a)
40 (5a)
85 (5a)
94 (5b)
35 (3b)
18 (3b)
–
–
All the reactions were carried out in DMF.
a
Yields are given for isolated products.
1a:2b:Pd(PPh3)4:Et3N¼1:2:0.02:5.
b
c
1a:2b:Pd(PPh3)4:CuI:Et2NH¼1:0.02:20.
d
Methyl 4-iodobenzoate was recovered in 36% yield.
1a:Pd(PPh3)4:Et3N¼1:2:0.02:5.
e
f
1a:CuI:Et2NH¼1:0.01:20.
g
h
1:2:PdCl2:ligand:CuI:Et3N¼1.2:1:0.04: 0.04:0.02:5.
tcpp¼tris(p-chlorophenyl)phosphine.
Scheme 4.
Enol esters 10 have been prepared in satisfactory yield by
use of the following conditions: (procedure E) 1 (1 equiv.),
2 (3 equiv.), Pd(OAc)2 (0.05 equiv.), P(o-tol)3 (0.2 equiv.),
K2CO3 (5 equiv.) in DMF at 608C under a balloon of carbon
monoxide (Table 5, entries 2, 4, 9, 11, 13). Compound 10
were obtained exclusively or predominantly as E isomers.
Their stereochemistry was assigned by NMR analysis.15
Vinyl protons in the E isomers are downfield from vinyl
protons in the Z isomers.
Scheme 6.
Table 4. Palladium-catalysed reaction of 1a with p-chloroiodobenzene in
MeCN under a balloon of carbon monoxide
Entry
Catalyst system
(Pd–ligand ratio)
T
(8C)
1a:2a
Yield %a
3a
9a
10a
1
2
3
Pd(PPh3)4
Pd(OAc)2
PdCl2(PhCN)2
45
45
60
45
45
25
60
45
60
60
60
60
60
60
0.8
0.8
1.5
0.8
0.8
0.8
0.5
0.5
0.8
1.5
1.5
1.5
1.5
1.5
23 19
2
–
–
–
–
–
–
51
34
19
–
54
69
We believe that the formation of acylfurans 9 proceeds
through a mechanism similar to that proposed by us for
the related synthesis of 3-acylindoles from o-alkynyltrifluoro-
acetanilides14 and that ultimately involves: (a) coordination of
the alkyne to an acylpalladium complex, (b) intramolecular
–
4
5
6
7
8
9
10
11
12
13
14
Pd(dba)2/P(o-tol)3 (1:4)
Pd(OAc)2/P(o-tol)3 (1:4)
Pd(OAc)2/P(o-tol)3 (1:4)
Pd(OAc)2/P(o-tol)3 (1:4)
Pd(OAc)2/P(o-tol)3 (1:4)
Pd(OAc)2/P(o-tol)3 (1:4)
Pd(OAc)2/P(o-tol)3 (1:4)
Pd(OAc)2/P(p-tol)3 (1:4)
Pd(OAc)2/dppf (1:2)
Pd(OAc)2/dpppb (1:2)
Pd(dppe)2
–
–
–
–
–
–
–
22
33
Traces
–
12
30
64
20 17
21 18
– 33
23 47
–
–
–
–
Reactions were carried out at 608C overnight in anhydrous MeCN under a
balloon of carbon monoxide using 1 equiv. of 1a, 5 equiv. of K2CO3, and
0.05 equiv. of [Pd].
a
Yields are given for isolated products.
dppp¼1,3-bis(diphenylphosphino)propane.
b
Scheme 5.

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A. Arcadi et al. / Tetrahedron 59 (2003) 4661–4671
Table 5. Palladium-catalysed synthesis of furans 9 and 10
Entry
Alkyne 1
Organic halide or triflate 2
Procedure
Yield %a
9
10
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1a
1a
1a
2a
2a
C
E
C
E
C
C
C
C
E
C
E
C
E
D
D
C
D
D
64 (9a)
–
55 (9b)
–
–
51 (10a)
m-F–C6H4–I 2p
2p
54 (10b)b
–
–
–
–
54 (10c)
2b
33 (9c)c
53 (9c)e
41 (9c)f
45 (9c)
–
2bd
2b
2bf,g
9
2b
PhI 2q
2q
m-Me–C6H4–I 2r
2r
2g
2m
2d
2d
2h
10
11
12
13
14
15
16
17
18
60 (9d)
–
60 (9e)
–
62 (9f)
62 (9g)
–
50 (9h)
57 (9i)
–
58 (10d)h
–
57 (10e)i
–
–
–
–
Unless otherwise stated, reactions were carried out at 608C overnight, in anhydrous acetonitrile, under an atmosphere of carbon monoxide, using: (procedure C,
balloon of carbon monoxide) 1.5 equiv. of 1, 1 equiv. of 2, 5 equiv. of K2CO3, 0.05 equiv. of Pd (OAc)2 and 0.20 equiv. of P(o-tol)3; (procedure D,
pCO¼2 atm) 1.5 equiv. of 1, 1 equiv. of 2, 5 equiv. of K2CO3, 0.05 equiv. of Pd(PPh3)4; (procedure E, balloon of carbon monoxide) 1 equiv. of 1, 2 equiv. of 2,
5 equiv. of K2CO3, and 0.05 equiv. of Pd (OAc)2 and 0.20 equiv. of P(o-tol)3.
a
Yields are given for isolated products.
E:Z¼90:10 (NMR analysis). Further purification gave the pure E isomer in 45% yield.
b
c
Compound 3b was isolated in 21% yield.
1.5 atm of carbon monoxide.
d
e
Compound 3b was isolated in 15% yield.
2 atm of carbon monoxide.
f
g
1a:2b¼2:1.
h
E:Z¼77:23 (NMR analysis). Further purification gave the pure E isomer in 40% yield.
i
E:Z¼68:32 (NMR analysis). Further purification gave the pure E isomer in 37% yield.
nucleophilic attack of the oxygen across the activated
carbon–carbon triple bond to give oxypalladation adducts,
(c) reductive elimination of Pd(0) species, (d) isomerization of
the resultant alkylidene derivative.
As for the enol esters, presumably they are generated
through acylation of enolates 12 (formed from the
acylfurans 9) as shown in Scheme 7.
In summary, easily available 2-propynyl-1,3-dicarbonyl and
Scheme 7.
Table 6. Palladium-catalysed reaction of 1b with naphthyl triflate 2g in the
presence of carbon monoxide
2-propynyl-1-cyano-3-carbonyl derivatives may represent
useful building blocks for the preparation of highly
substituted furans through oxypalladation–reductive
elimination domino reactions. Employing K2CO3 instead
of amine bases tends to favour the oxypalladation–
reductive elimination mechanism over the coupling process.
With internal alkynes, furan derivatives containing
branched side chains can be prepared. In the presence of
carbon monoxide, and depending on reaction conditions, the
reaction can produce 1,2,5-trisubstituted furans incorporat-
ing one or two molecules of carbon monoxide.
Entry
Catalyst system
(Pd:ligand ratio)
nBu4NCl
(1 equiv.)
Time
(h)
Yield %a
3j
9f
1
2
3
4
5
6
7
Pd(OAc)2/P(o-tol)3 (1:4)
Pd(OAc)2/P(o-tol)3 (1:4)
PdCl2(PhCN)2
Pd2(dba)3
Pd(dppe)2
Pd(dppe)2
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
2
þ
2
2
2
2
2
þ
2
–
21
–
–
–
–
–
57
73
15
53
–
11
11
42
20
62
10b
11c,d
Unless otherwise stated, reactions were carried out in MeCN overnight, at
608C, under a balloon of carbon monoxide using 1.5 equiv. of 1b, 1 equiv.
of 2g, 5 equiv. of K2CO3, and 0.05 equiv. of [Pd].
3. Experimental
3.1. General
a
Yields are given for isolated products.
2,5-Dimethyl-3-acetylfuran was isolated in 10% yield.
2 atm of carbon monoxide.
2,5-Dimethyl-3-acetylfuran was isolated in 5% yield.
b
c
d
Melting points were uncorrected and were measured with a

A. Arcadi et al. / Tetrahedron 59 (2003) 4661–4671
4667
Bu¨chi apparatus. 1H NMR (200 MHz) and 13C NMR
(50.3 MHz) spectra (CDCl3, unless otherwise stated; TMS
as internal standard) were recorded with a Bruker AC 200 E
spectrometer. EI (70 eV) mass spectra were recorded with a
Saturn 2100T GC/MS Varian instrument and a TSQ 700
Finnigan/Mat instrument. IR spectra (KBr, unless otherwise
stated) were recorded with a Perkin–Elmer 683 spec-
trometer. Only the most significant IR absorptions are given.
Unless otherwise stated, all starting materials, catalysts,
ligands, bases, and solvents are commercially available and
were used as purchased, without further purification. Vinyl
triflates were prepared according to Ref. 16. 2-Propynyl-
1,3-dicarbonyl derivatives 1a–h were prepared according to
Ref. 6. Reaction products were purified by flash chroma-
tography on silica gel eluting with n-hexane/EtOAc
mixtures.
6.7. C19H20O3 requires C, 77.00; H, 6.80]; nmax 1660, 1590,
655, 615 cm21; dH 2.23–2.29 (m, 2H, –CH2–CH2–CHv),
2.32 (s, 3H, furanyl-CH3), 2.51 (s, 3H, COCH3), 2.76 (t,
J¼7.8 Hz, 2H, CH2CH2), 3.67 (s, 2H, vC–CH2), 3.77 (s,
3H, –OCH3), 5.76 (t, J¼4.5 Hz, 1H, vC–H), 6.21 (s, 1H,
furanyl-H), 6.65–6.65 (m, 2H, Ar-H), 7.10–7.14 (m, 1H,
Ar-H); dC 11.0, 14.5, 23.1, 28.6, 29.1, 31.7, 55.1, 108.8,
110.8, 122.2, 123.8, 125.2, 127.3, 131.9, 138.3, 152.0,
157.1, 158.5, 194.2; MS; m/z (relative intensity): 297
[(Mþ1)þ, 100], 296 (Mþ, 67), 160 (84).
Compound 3f. 67% yield; oil. [Found: C, 79.9; H, 5.8.
C23H20O3 requires C, 80.21; H, 5.85]; nmax (neat) 1680,
1600, 710, 660 cm21; dH 2.35 (s, 3H, furanyl-CH3), 2.54 (s,
3H, COCH3), 3.57 (s, 2H, vC–CH2), 5.62 (d, J¼2.4 Hz,
1H, –OCH), 5.86 (d, J¼2.4 Hz, 1H, vC–H), 6.30 (s, 1H,
furanyl-H), 7.10–7.44 (m, 9H, Ar-H); dC 14.3, 29.1, 30.3,
76.6, 107.5, 110.1, 116.3, 118.0, 121.3, 123.4, 126.2, 126.5,
126.9, 128.2, 128.6, 129.6, 140.6, 150.3, 153.3, 157.3,
194.0; MS; m/z (relative intensity): 345 [(Mþ1)þ, 100], 344
(Mþ, 24).
3.1.1. Synthesis of 2,3,5-trisubstituted furans 3a–r
(procedure B). A typical procedure is as follows: to a
solution of 1a (0.189 g, 1.37 mmol) in DMF (4 mL),
1-chloro-4-iodobenzene 2a (0.217 g, 0.91 mmol), potas-
sium carbonate (0.630 g, 4.56 mmol), and Pd(PPh3)4
(0.045 g, 0.052 mmol) were added. The reaction mixture
was gently purged with nitrogen and stirred at 608C under a
nitrogen atmosphere. After 4 h, ethyl acetate and 0.1N HCl
were added; the organic layer was separated, washed with
water, dried (Na2SO4) and the solvent evaporated in vacuo.
The residue was purified by flash chromatography (95/5
n-hexane/EtOAc) to give 3a.
Compound 3g. 71% yield; mp 51–528C. [Found: C, 81.7; H,
6.0. C18H16O2 requires C, 81.79; H, 6.10]; nmax 1660,
620 cm21; dH 2.29 (s, 3H, furanyl-CH3), 2.51 (s, 3H,
COCH3), 4.01 (s, 2H, Ar-CH2), 6.18 (s, 1H, furanyl-H),
7.30–7.44 (m, 3H, Ar-H), 7.63–7.80 (m, 4H, Ar-H); dC
14.3, 29.0, 34.3, 106.9, 122.1, 125.5, 126.1, 127.0, 127.1,
127.5, 127.6, 128.2, 132.3, 133.5, 134.7, 152.3, 157.5,
194.1; MS; m/z (relative intensity): 264 (Mþ, 100), 222 (11).
Compound 3a. 0.21 g, 93% yield; mp 94–968C. [Found: C,
67.4; H, 5.3. C14H13ClO2 requires C, 67.61; H, 5.27]; nmax
1660, 655, 610 cm21; dH 2.32 (s, 3H, furanyl-CH3), 2.51 (s,
3H, COCH3), 3.85 (s, 2H, Ar-CH2), 6.21 (s, 1H, furanyl-H),
7.15 (dd, J¼8.5, 4.3 Hz, 2H, Ar-H), 7.25 (dd, J¼8.5, 4.3 Hz,
2H, Ar-H); dC 14.3, 29.0, 33.4, 107.0, 122.1, 128.7, 130.0,
132.5, 135.8, 151.8, 157.6, 194.0; MS; m/z (relative
intensity): 249 [(Mþ1)þ, 100], 234 (57).
Compound 3h. 56% yield; mp 132–1358C. [Found: C, 76.5;
H, 8.4. C27H34O3 requires C, 79.76; H, 8.43]; nmax 1740,
1680 cm21; dH 0.91 (s, 3H, steroidal-CH3), 0.95 (s, 3H,
steroidal-CH3), 1.00–2.30 (m, 15H, steroidals-H), 2.37 (s,
3H, furanyl-CH3), 2.54 (s, 3H, COCH3), 3.28 (s, 2H, vC–
CH2), 4.92 (bs, 1H, vC–H), 5.23 (s, 1H, vC–H), 6.25 (s,
1H, furanyl-H); dC 13.7, 14.4, 18.9, 20.4, 21.8, 25.9, 29.7,
30.6, 31.4, 34.9, 35.7, 35.8, 47.4, 48.4, 51.9, 106.6, 121.9,
122.1, 126.1, 132.5, 141.5, 151.7, 157.3, 194.3, 221.1; MS;
m/z (relative intensity): 407 [(Mþ1)þ, 100].
Compound 3b. 70% yield; mp 69–708C; lit. mp 69–708C
and data consistent with that reported in the literature.5
Compound 3c. 98% yield; mp 116–1188C. [Found: C, 66.8;
H, 5.6; N, 12.8. C12H12N2O2 requires C, 66.65; H, 5.59; N,
12.96]; nmax 1720, 710, 620 cm21; dH 2.37 (s, 3H, furanyl-
CH3), 2.54 (s, 3H, COCH3), 3.98 (s, 2H, Ar-CH2), 6.35 (s,
1H, furanyl-H), 8.88 (s, 2H, Ar-H), 9.14 (s, 1H, Ar-H); dC
14.3, 28.8, 29.1, 107.7, 122.2, 128.3, 131.9, 148.5, 156.9,
157.4, 158.1, 193.7; MS; m/z (relative intensity): 217
[(Mþ1)þ, 100], 201 (30).
Compound 3i. 66% yield; mp 178–1808C. [Found: C, 79.4;
H, 8.3. C34H42O4 requires C, 79.34; H, 8.22]; nmax 1690,
1660, 1260, 700, 610 cm21; dH 0.83 (s, 3H, steroidal-CH3),
0.90 (s, 3H, steroidal-CH3), 1.00–1.90 (m, 15H, steroidals-
H), 2.39 (s, 3H, furanyl-CH3), 2.55 (s, 3H, COCH3), 2.57 (s,
2H, vC–CH2), 4.95 (m, 1H, OCH), 5.89 (bs, 1H, vC–H),
6.30 (s, 1H, furanyl-H), 6.01–6.06 (m, 2H, Ar-H), 7.41–
7.53 (m, 3H, Ar-H); dC 12.3, 14.4, 18.9, 21.1, 24.7, 27.5,
29.1, 29.8, 31.8, 34.0, 35.2, 35.6, 35.7, 36.7, 44.7, 45.3,
54.1, 54.4, 74.1, 105.7, 106.3, 122.8, 128.2, 129.4, 130.8,
132.6, 152.0, 155.9, 156.3, 166.0, 194.2; MS; m/z (relative
intensity): 515 [(Mþ1)þ, 100].
Compound 3d. 67% yield; mp 103–1048C. [Found: C, 83.1;
H, 10.4. C35H52O2 requires C, 83.28; H, 10.38]; nmax 1700,
1620, 620 cm21; dH 0.70–1.42 (m, 41H, steroidals-H), 2.38
(s, 3H, furanyl-CH3), 2.53 (s, 3H, COCH3), 3.26 (s, 2H,
vC–CH2), 5.40 (bs, 1H, vC–H), 5.77 (s, 1H, vC–H),
6.23 (s, 1H, furanyl-H); dC 11.0, 12.4, 18.7, 18.9, 21.1, 22.5,
23.7, 23.8, 28.0, 28.2, 30.3, 31.8, 34.0, 35.8, 36.1, 38.7,
39.5, 39.7, 42.4, 46.2, 56.1, 56.9, 68.1, 106.6, 123.0, 126.4,
128.7, 132.0, 141.4, 151.8, 157.2, 194.4; MS; m/z (relative
intensity): 504 (Mþ, 100).
Compound 3j. 55% yield; mp 59–608C. [Found: C, 77.6; H,
6.2. C19H18O3 requires C, 77.53; H, 6.16]; nmax 1720, 1600,
680 cm21; dH 1.27 (t, J¼7.1 Hz, 3H, CH2CH3), 2.47 (s, 3H,
furanyl-CH3), 4.07 (s, 2H, Ar-CH2), 4.23 (q, J¼7.1 Hz, 2H,
OCH2), 6.27 (s, 1H, furanyl-H), 7.31–7.47 (m, 3H, Ar-H),
7.64 (s, 1H, Ar-H), 7.74–7.81 (m, 3H, Ar-H); dC 13.7, 14.3,
34.3, 59.9, 107.2, 114.0, 125.6, 126.0, 127.1, 127.5, 127.6,
128.2, 132.3, 133.5, 134.9, 152.3, 158.3, 164.2; MS; m/z
Compound 3e. 66% yield; mp 102–104. [Found: C, 76.8; H,

4668
A. Arcadi et al. / Tetrahedron 59 (2003) 4661–4671
(relative intensity): 294 (Mþ, 100), 266 (48), 249 (11), 205
(25).
133.1, 138.1, 147.1, 147.3, 165.2, 166.5, 191.9; MS; m/z
(relative intensity): 561 (5), 261 (100), 105 (100).
Compound 3k. 93% yield; mp 49–508C. [Found: C, 70.3; H,
5.1. C20H17ClO3 requires C, 70.49; H, 5.03]; nmax 1710,
1265, 735, 640 cm21; dH 1.32 (t, J¼7.1 Hz, 3H, CH2CH3),
3.88 (s, 2H, Ar-CH2), 4.26 (q, J¼7.1 Hz, 2H, OCH2), 6.43
(s, 1H, furanyl-H), 7.20–7.39 (m, 5H, Ar-H), 7.40–7.43 (m,
2H, Ar-H), 7.92–7.95 (m, 2H, Ar-H); dC 14.2, 33.6, 60.4,
109.6, 114.4, 128.0, 128.2, 128.7, 129.1, 130.1, 132.6,
135.6, 152.8, 156.6, 163.5; MS; m/z (relative intensity): 342
[(Mþ2)þ, 34] 340 (Mþ, 100), 311 (26), 295 (21), 105 (27),
77 (14).
Compound 3p. 54% yield; mp 85–878C. [Found: C, 84.5; H,
5.5. C23H18O2 requires C, 84.64; H, 5.56]; nmax 1650, 680,
660 cm21; dH 2.46 (s, 3H, furanyl-CH3), 4.07 (s, 2H, Ar-
CH2), 6.24 (s, 1H, furanyl-H), 7.37–7.89 (m, 12H, Ar-H);
dC 13.6, 34.3, 108.3, 127.0, 127.6, 127.8, 128.0, 128.2,
128.8, 130.6, 131.4, 132.3, 135.5, 134.8, 139.2, 152.2,
158.7, 191.3; MS; m/z (relative intensity): 326 (Mþ, 100).
Compound 3p0. 24% yield; mp 80–828C. [Found: C, 84.4;
H, 5.4. C23H18O2 requires C, 84.64; H, 5.56]; nmax 1680,
680 cm21; dH 2.31 (s, 3H, COCH3), 4.14 (s, 2H, Ar-CH2),
6.35 (s, 1H, furanyl-H), 7.37–7.88 (m, 1 2H, Ar-H); dC
29.7, 34.4, 109.0, 127.5, 127.8, 127.9, 128.1, 128.4, 128.8,
129.1, 129.4, 130.0, 132.3, 133.3, 133.5, 134.4, 138.2,
153.8, 155.7, 194.1; MS; m/z (relative intensity): 326 (Mþ,
100), 311 (35).
Compound 3l. 31% yield; mp 60–618C. [Found: C, 80.7; H
5.7. C20H24O3 requires C, 80.88; H, 5.66]; nmax 1710, 1280,
670 cm21; dH 1.28 (t, J¼7.1 Hz, 3H, CH2CH3), 4.16 (s, 2H,
Ar-CH2), 4.27 (q, J¼7.1 Hz, 2H, OCH2), 6.45 (s, 1H,
furanyl-H), 7.35–7.48 (m, 6H, Ar-H), 7.71–7.79 (m, 4H,
Ar-H), 7.83–7.98 (m, 2H, Ar-H); dC 14.2, 34.4, 60.4, 109.6,
114.4, 125.6, 126.1, 127.1, 127.2, 127.8, 128.0, 128.2,
128.3, 129.0, 129.5, 129.8, 132.3, 133.5, 153.4, 156.5,
163.6; MS; m/z (relative intensity): 356 (Mþ, 100), 327 (22),
311 (13), 105 (40), 77 (15).
Compound 3q. 60% yield; mp 69–728C. [Found: C, 81.9; H,
8.0. C30H40O3 requires C, 82.22; H, 8.12]; nmax 1710, 1670,
700 cm21; dH 0.58 (s, 3H, steroidal-CH3), 0.85 (s, 3H,
steroidal-CH3), 0.97–2.01 (m, 19H, steroidals-H), 2.06 (s,
3H, furanyl-CH3), 2.39 (s, 3H, COCH3), 2.41 (s, 2H, vC–
CH2), 5.32 (bs, 1H, vC–H), 5.73 (s, 1H, vC–H), 6.15 (s,
1H, furanyl-H), 7.32–7.47 (m, 3H, Ar-H), 7.69–7.66 (m,
2H, Ar-H); dC 12.3, 13.2, 17.8, 20.0, 21.7, 23.3, 24.8, 28.6,
30.5, 30.6, 34.7, 37.8, 43.0, 47.1, 56.0, 62.6, 108.4, 121.5,
125.2, 127.2, 127.9, 128.3, 130.9, 131.3, 138.2, 140.3,
150.5, 191.0, 208.5; MS; m/z (relative intensity): 497
[(Mþ1)þ, 100].
Compound 3q0. 19% yield; mp 135–1408C. [Found: C,
82.4; H, 8.2. C30H40O3 requires C, 82.22; H, 8.12]; nmax
1720, 1690, 690 cm21; dH 0.72 (s, 3H, steroidal-CH3), 0.94
(s, 3H, steroidal-CH3), 1.13–1.72 (m, 19H, steroidals-H),
2.13 (s, 3H, COCH3), 2.38 (s, 3H, COCH3), 3.39 (s, 2H,
vC–CH2), 5.42 (bs, 1H, vC–H), 5.84 (s, 1H, vC–H),
6.43 (s, 1H, furanyl-H), 7.39–7.43 (m, 3H, Ar-H), 7.83–
7.88 (m, 2H, Ar-H); dC 12.3, 17.9, 20.8, 21.7, 23.3, 25.0,
28.6, 28.7, 30.5, 30.6, 30.7, 33.0, 34.8, 37.8, 43.1, 47.1,
56.0, 62.6, 107.6, 124.4, 121.7, 125.5, 127.3, 127.9, 128.3,
130.9, 140.3, 152.4, 193.2, 208.6; MS; m/z (relative
intensity): 497 [(Mþ1)þ, 100].
Compound 3m. 35% yield; oil. [Found: C, 80.6; H 5.6.
C20H24O3 requires C, 80.88; H, 5.66]; nmax (neat) 1705,
1250, 670 cm21; dH 1.24 (t, J¼7.1 Hz, 3H, CH2CH3), 4.20
(q, J¼7.1 Hz, 2H, OCH2), 4.43 (s, 2H, Ar-CH2), 6.32 (s, 1H,
furanyl-H), 7.35–7.52 (m, 8H, Ar-H), 7.77–8.06 (m, 4H,
Ar-H); dC 14.1, 31.7, 60.3, 109.7, 114.5, 123.7, 125.5,
126.2, 127.1, 127.7, 127.9, 128.1, 128.7, 129.0, 129.3,
131.7, 133.8, 153.1, 156.2, 163.6; MS; m/z (relative
intensity): 356 (Mþ, 100).
Compound 3n. 48% yield; mp 95–968C. [Found: C, 77.5; H,
4.8; N, 3.76. C24H18FNO2 requires C, 77.61; H, 4.88; N,
3.77]; nmax 3300, 1710, 1600, 750, 680 cm21; dH 3.90 (s,
2H, Ar-CH2), 6.35 (s, 1H, furanyl-H), 7.06–7.74 (m, 14H,
Ar-H); dC 30.8, 108.5, 115.4, 119.8, 127.1, 127.6, 128.3,
128.6, 128.9, 129.1, 129.5, 130.0, 130.3, 131.6, 154.0,
159.3, 164.1, 166.0; MS; m/z (relative intensity): 372
[(Mþ1)þ, 36], 280 (100).
Compound 3n0. 35% yield; mp 92–948C. [Found: C, 77.8;
H, 4.8; N, 3.79. C24H18FNO2 requires C, 77.61; H, 4.88; N,
3.77]; nmax 3350, 1685, 1600, 730, 680 cm21; dH 3.89
(s, 2H, Ar-CH2), 6.27 (s, 1H, furanyl-H), 7.04–7.77 (m,
14H, Ar-H), 10.68 (s, 1H, NH); dC 33.3, 99.8, 115.6, 118.5,
126.7, 127.9, 128.3, 129.4, 131.6, 132.8, 131.6, 144.7,
160.1, 164.2, 188.0; MS; m/z (relative intensity): 371 (Mþ,
100).
Compound 3r. 66% yield; mp 73–758C. [Found: C, 79.5; H,
5.1; N, 4.64. C20H15NO2 requires C, 79.72; H, 5.02; N,
4.65]; nmax 2200, 1680, 670, 650 cm21; dH 2.60 (s, 3H,
COCH3), 4.06 (s, 2H, Ar-CH2), 6.30 (s, 1H, furanyl-H),
7.34–8.14 (m, 9H, Ar-H); dC 28.6, 34.1, 109.9, 125.1,
128.6, 128.9, 129.0, 129.3, 132.5, 136.0, 141.7, 153.7,
159.2, 171.7, 197.7; MS; m/z (relative intensity): 301 (Mþ,
21), 300 (100).
Compound 3o. 60% yield; mp 162–1648C. [Found: C, 82.8;
H, 6.9. C44H44O4 requires C, 82.99; H, 6.96]; nmax 1730,
1670, 1620, 1280, 720 cm21; dH 0.92 (s, 3H, steroidal-
CH3), 0.95 (s, 3H, steroidal-CH3), 1.25–2.00 (m, 20H,
steroidals-H), 2.38 (s, 2H, vC–CH2), 4.75 (t, J¼7.6 Hz,
1H, OCH), 5.40 (d, J¼3.4 Hz, 1H, vC–H), 6.30 (s, 1H,
furanyl-H), 8.09–7.25 (m, 15H, Ar-H); dC 11.9, 12.3, 13.4,
20.7, 22.6, 23.6, 27.7, 28.0, 28.8, 30.9, 31.4, 32.0, 34.7,
35.3, 38.3, 42.0, 45.0, 50.8, 53.5, 83.3, 109.7, 111.3, 124.4,
126.7, 127.2, 128.2, 128.5, 128.6, 128.8, 130.7, 132.7,
Compound 4a. 74% yield; mp 103–1058C. [Found: C, 68.2;
H, 4.8; N, 4.1. C20H17NO5 requires C, 68.37; H, 4.88; N,
3.99]; nmax 1720, 1600, 1590, 1520, 750, 680 cm21; dH 1.25
(t, J¼8.0 Hz, 3H, CH2CH3), 2.10 (s, 2H, vCCH2), 4.22 (q,
J¼8.0 Hz, 2H, OCH2), 5.01 (s, 1H, vCH), 7.38–7.42 (m,
3H, Ar-H), 7.78 (d, J¼8.1 Hz, 2H, Ar-H), 7.81–7.85 (m,
2H, Ar-H), 8.06 (d, J¼8.1 Hz, 2H, Ar-H); dC 14.1, 30.9,
49.2, 60.8, 110.8, 111.4, 124.0, 128.1, 128.4, 128.9, 129.5,

A. Arcadi et al. / Tetrahedron 59 (2003) 4661–4671
4669
145.6, 146.3, 150.8, 151.6, 157.2, 163.0; MS; m/z (relative
intensity): 351 (Mþ, 21), 350 (100), 322 (15), 105 (30), 77
(20).
added dropwise, under nitrogen atmosphere, a solution of
n-BuLi (1.6 M) in hexanes (6.25 mL). The reaction mixture
was stirred under a nitrogen atmosphere at rt. After 0.5 h,
trifluoroacetic acid-d (1 mL) was added. Then, ethyl acetate
and HCl 0.1 M were added, the organic layer was washed
with water, dried (Na2SO4) and the solvent evaporated in
vacuo. The residue was purified by chromatography (85/15
n-hexane/EtOAc) to afford the deuterated and the
undeuterated product in 40% yield (0.28 g). 3-Acetyl-7-
3.1.2. Synthesis of 2-arylalkynyl-1,3-dicarbonyls 5a–b. A
typical procedure is as follows: to a solution of 1a. (0.176 g,
1.27 mmol) in DMF (5 mL), methyl 4-iodobenzoate 2b
(0.278 g, 1.06 mmol), Et3N (0.536 g, 5.30 mmol), CuI
(0.004 g, 0.02 mmol), dppf (0.023 g, 0.042 mmol) and
PdCl2 (0.005 g, 0.042 mmol) were added. The reaction
mixture was gently purged with nitrogen and stirred at 308C
under a nitrogen atmosphere. After 24 h, ethyl acetate and
0.1N HCl were added; the organic layer was separated,
washed with water, dried (Na2SO4) and the solvent
evaporated in vacuo. The residue was purified by flash
chromatography (90/10 n-hexane/EtOAc) to give 5a.
1
deuterio-hex-5-yn-2-one was determined by H NMR and
MS. From these analyses an abundance of D of approxi-
mately 70% was calculated.
Compound 8. 47% yield; dH 2.31 (s, 3H, furanyl-CH3), 2.34
(s, 3H, COCH3), 3.90 (s, 1.3H, CDH), 3.94 (s, 3H, OCH3),
6.23 (s, 1H, furanyl-H), 7.27–7.31 (m, 2H, Ar-H), 7.96–
8.00 (m, 2H, Ar-H); dC 14.1, 29.2, 33.8 (t, 1J¼
(C,D)
Compound 5a. 0.24 g, 85% yield; mp 78–808C. [Found: C,
70.4; H, 6.0. C16H16O4 requires C, 70.57; H, 5.92]; nmax
2200, 1710, 1600, 1260, 750, 680 cm21; dH 2.29 (s, 6H,
COCH3), 2.95 (d, J¼7.5 Hz, 2H, CHCH2), 3.91 (s, 3H,
OCH3), 3.96 (t, J¼7.5 Hz, 1H, CH2CH), 7.40 (d, J¼6.6 Hz,
2H, Ar-H), 7.96 (d, J¼6.6 Hz, 2H, Ar-H); dC 14.1, 29.3,
52.0, 66.3, 82.0, 88.2, 127.5, 129.1, 129.7, 131.3, 166.2,
202.1; MS; m/z (relative intensity): 272 (Mþ, 8), 230 (100).
21.1 Hz), 107.3, 128.8, 128.9, 142.7, 151.4, 157.7, 166.9,
194.1; MS; m/z (relative intensity): 274 [(Mþ1)þ, 100], 273
(Mþ, 70), 258 (95).
3.1.4. Synthesis of furans 9a–e (procedure C). A typical
procedure is as follows: to a solution of 1a (0.2 g,
1.45 mmol) in anhydrous acetonitrile were added 4-chloro-
phenyl iodide 2a (0.23 g, 0.96 mmol), K2CO3 (0.67 g,
4.82 mmol), P(o-tol)3 (0.059 g, 0.19 mmol) and Pd(OAc)2
(0.011 g, 0.05 mmol). The flask was purged with carbon
monoxide for a few seconds and connected to a balloon of
carbon monoxide. The reaction mixture was stirred at 608C
overnight and poured in a separatory funnel containing 0.1N
HCl and ethyl acetate. The organic layer was separated and
the aqueous layer was extracted twice with ethyl acetate.
The combined organic layers were dried (Na2SO4) and the
solvent was evaporated in vacuo. The residue was purified
by flash chromatography (85/15 n-hexane/EtOAc) to give
0.169 g (64% yield) of 9a.
Compound 5b. 94% yield; oil. [Found: C, 75.6; H, 5.7.
C22H20O4 requires C, 75.84; H, 5.79]; nmax (neat) 2200,
1730, 1680, 1260, 720, 660 cm21; dH 1.66 (t, J¼7.1 Hz, 3H,
CH2CH3), 2.56 (s, 3H, COCH3), 3.15 (dd, J¼6.1, 1.3 Hz,
2H, CHCH2), 4.19 (q, J¼7.1 Hz, 2H, OCH2), 4.68 (t,
J¼6.1 Hz, 1H, CH2CH), 7.34 (d, J¼6.6 Hz, 2H, Ar-H),
7.50–7.62 (m, 3H, Ar-H), 7.83 (d, J¼8.6 Hz, 2H, Ar-H),
8.04–8.09 (m, 2H, Ar-H); dC 14.0, 19.5, 26.5, 53.0, 61.6,
81.9, 89.8, 126.1, 126.7, 128.8, 131.9, 133.8, 135.9, 168.3,
193.5, 197.3; MS; m/z (relative intensity): 249 [(Mþ1)þ.
Compound 6a. 63% yield; mp 103–105. [Found: C, 75.6; H,
5.7. C22H20O4 requires C, 75.84; H, 5.79]; nmax 1725,
1680 cm21; dH 2.33 (s, 3H, furanyl-CH3), 2.51 (s, 3H,
COCH3), 3.87 (s, 3H, OCH3), 5.43 (s, 1H, Ar3CH), 6.13 (s,
1H, furanyl-H), 7.14–7.31 (m, 7H, Ar-H), 7.98–8.02 (m,
2H, Ar-H); dC 14.3, 29.0, 50.5, 52.0, 109.2, 122.0, 127.4,
128.7, 128.9, 129.8, 129.9, 140.3, 142.6, 146.2, 151.4,
158.8, 166.7, 193.9; MS; m/z (relative intensity): 348 (Mþ,
100), 333 (24), 317 (15), 305 (17).
Compound 9a. Mp 108–1098C; lit. mp 109–1108C and data
consistent with that reported in the literature.13
Compound 9b. 55% yield; mp 83–858C. [Found: C, 69.1; H,
5.1. C15H13FO3 requires C, 69.22; H, 5.03]; nmax 1720,
1690, 650, 620 cm21; dH 2.37 (s, 3H, furanyl-CH3), 2.55 (s,
3H, COCH3), 4.27 (s, 2H, COCH2), 6.51 (s, 1H, furanyl-H),
7.30–7.61 (m, 4H, Ar-H); dC 14.2, 28.8, 37.8, 109.1, 115.0
(d, J¼22.4 Hz), 120.5 (d, J¼22.4 Hz), 124.1, 130.3, 137.9,
145.6, 157.9, 162.6 (d, J¼250.4 Hz), 193.3, 193.8; MS; m/z
(relative intensity): 260 (Mþ, 81), 137 (65), 123 (100), 95
(39).
Compound 6b. 70% yield; mp 106–1108C. [Found: C, 79.6;
H, 7.0. C41H44O5 requires C, 79.84; H, 7.19]; nmax 1740,
1720, 1690, 1610, 710, 690 cm21; dH 0.90 (s, 3H, steroidal-
CH3), 0.93 (t, J¼7.1 Hz, 3H, CH2CH3), 1.21–2.00 (m, 17H,
steroidals-H), 2.59 (s, 3H, COCH3), 4.27 (q, J¼7.1 Hz, 2H,
OCH2), 4.80 (s, 1H, vC(Ar2)CH), 5.38 (bs, 1H, vCH),
5.71 (s, 1H, vCH), 6.42 (s, 1H, furanyl-H), 7.34–7.40 (m,
5H, Ar-H), 7.89–8.01 (m, 4H, Ar-H); dC 13.6, 14.2, 19.0,
20.3, 21.7, 25.7, 26.6, 30.7, 31.4, 34.0, 34.9, 35.8, 47.6,
48.3, 51.7, 51.9, 60.5, 111.0, 114.4, 123.5, 127.7, 128.0,
129.2, 134.9, 136.0, 141.2, 145.3, 153.8, 163.5, 197.7,
220.9; MS; m/z (relative intensity): 616 (Mþ, 100), 587 (40).
Compound 9c. 53% yield; mp 87–898C. [Found: C, 68.1; H,
5.3. C17H16O5 requires C, 67.99; H, 5.37]; nmax 1720, 1690,
1260, 740, 670 cm21; dH 2.37 (s, 3H, furanyl-CH3), 2.55 (s,
3H, COCH3), 3.95 (s, 3H, OCH3), 4.32 (s, 2H, COCH2),
6.52 (s, 1H, furanyl-H), 8.03–8.16 (m, 4H, Ar-H); dC 14.3,
29.1, 38.1, 109.3, 122.3, 128.3, 129.9, 134.2, 139.1, 145.7,
155.0, 165.8, 193.9, 194.8; MS; m/z (relative intensity): 300
(Mþ, 7), 163 (100), 137 (21).
Compound 9d. 60% yield; mp 83–858C. [Found: C, 74.2; H,
5.9. C15H14O3 requires C, 74.36; H, 5.82]; nmax 1700, 1680,
750 cm21; dH 2.37 (s, 3H, furanyl-CH3), 2.55 (s, 3H,
COCH3), 4.28 (s, 2H, COCH2), 6.50 (s, 1H, furanyl-H),
3.1.3. 3-Acetyl-7-deuterio-hex-5-yn-2-one 7. To a stirred
mixture of NaH (0.24 g, 6.07 mmol) and 3-acetyl-hex-5-yn-
2-one 1a (0.70 g, 5.06 mmol) in anhydrous THF (5 mL) was

4670
A. Arcadi et al. / Tetrahedron 59 (2003) 4661–4671
7.49–7.60 (m, 3H, Ar-H), 7.98–8.03 (m, 2H, Ar-H); dC
14.3, 29.1, 37.8, 109.1, 122.3, 128.4, 128.7, 133.6, 135.9,
146.2, 158.0, 194.1, 194.5; MS; m/z (relative intensity):
243[(Mþ1)þ, 30], 105 (100).
35.7, 36.4, 39.5, 42.5, 48.1, 56.1, 56.7, 108.5, 122.3, 133.8,
134.3, 140.3, 141.8, 194.2, 195.3; MS; m/z (relative
intensity): 533 [(Mþ1)þ, 34], 395 (100), 137 (28).
Compound 9i. 57% yield; mp 144–1468C. [Found: C, 77.2;
H, 7.8. C28H34O4 requires C, 77.39; H, 7.89]; nmax 1740,
1710, 1680 cm21; dH 0.93–2.19 (m, 23H, steroidals-H),
2.37 (s, 3H, furanyl-CH3), 2.55 (s, 3H, COCH3), 4.00 (s, 2H,
COCH2), 5.95 (bs, 1H, vCH), 6.42 (s, 1H, vCH), 7.04 (s,
1H, furanyl-H); dC 13.4, 14.1, 18.9, 20.1, 21.5, 28.9, 29.6,
30.1, 31.0, 31.1, 31.2, 34.8, 41.5, 51.5, 62.0, 108.4, 122.30
132.8, 133.7, 139.8, 141.5, 148.9, 157.5, 193.0, 195.1,
220.4; MS; m/z (relative intensity): 435 [(Mþ1)þ, 5], 297
(100).
Compound 9e. 60% yield; mp 65–678C. [Found: C, 74.8; H,
6.2. C16H16O3 requires C, 74.98; H, 6.29]; nmax 1680, 1660,
720, 670 cm21; dH 2.35 (s, 3H, Ar-CH3), 2.42 (s, 3H,
furanyl-CH3), 2.55 (s, 3H, COCH3), 4.26 (s, 2H, COCH2),
6.49 (s, 1H, furanyl-H), 7.20–7.40 (m, 2H, Ar-H), 7.78–
7.82 (m, 2H, Ar-H); dC 14.3, 21.3, 29.1, 37.8, 109.0, 122.3,
125.7, 128.6, 128.9, 134.4, 136.0, 138.6, 146.3, 157.9,
194.1, 194.7; MS; m/z (relative intensity): 257 [(Mþ1)þ, 8],
119 (100).
3.1.5. Synthesis of furans 9f–1 (procedure D). A typical
procedure is as follows: to a 50 mL stainless steel autoclave
charged with a solution of 1b (0.186 g, 1.10 mmol) in
anhydrous acetonitrile were added b-napthyl triflate 2g
(0.203 g, 0.70 mmol), K2CO3 (0.51 g, 3.70 mmol) and
Pd(PPh3)4 (0.040 g, 0.035 mmol). The autoclave was
charged with carbon monoxide (2 atm) and the reaction
mixture was stirred at 608C overnight. Then, the mixture
was poured in a separatory funnel containing 0.1N HCl and
ethyl acetate. The organic layer was separated and the
aqueous layer was extracted twice with ethyl acetate.
The combined organic layers were dried (Na2SO4) and the
solvent was evaporated in vacuo. The residue was purified
by flash chromatography (80/20 n-hexane/EtOAc) to give
0.140 g (62% yield) of 9f.
3.1.6. Synthesis of vinyl esters 10a–e (procedure E). A
typical procedure is as follows: to a solution of 1a (0.21 g,
1.52 mmol) in anhydrous acetonitrile were added 4-chloro-
phenyl iodide 2a (0.724 g, 3.04 mmol), K2CO3 (1.05 g,
7.60 mmol), P(o-tol)3 (0.092 g, 0.30 mmol) and Pd(OAc)2
(0.017 g, 0.08 mmol). The flask was purged with carbon
monoxide for a few seconds and connected to a balloon of
carbon monoxide. The reaction mixture was stirred at 608C
overnight and poured in a separatory funnel containing 0.1N
HCl and ethyl acetate. The organic layer was separated and
the aqueous layer was extracted twice with ethyl acetate.
The combined organic layers were dried (Na2SO4) and the
solvent was evaporated in vacuo. The residue was purified
by flash chromatography (85/15 n-hexane/EtOAc) to give
0.320 g (51% yield) of 10a.
Compound 9f. Mp 155–1578C. [Found: C, 74.4; H, 5.6.
C20H18O4 requires C, 74.52; H, 5.63]; nmax 1710, 1680,
1265, 660, 620 cm21; dH 1.18 (t, J¼6.7 Hz, 3H, CH2CH3),
2.40 (s, 3H, furanyl-CH3), 4.12 (q, J¼6.7 Hz, 2H,
OCH2CH3), 4.22 (s, 2H, COCH2), 6.42 (s, 1H, furanyl-H),
7.42–7.87 (m, 6H, Ar-H), 8.51 (s, 1H, Ar-H); dC 13.7, 14.3,
38.0, 60.0, 109.3, 114.5, 127.8, 129.1, 130.0, 135.7, 146.2,
158.8, 164.0, 168.3, 194.5; MS; m/z (relative intensity): 322
(Mþ, 10), 155 (100), 127 (34).
Compound 10a. E isomer: mp 134–1358C; lit. mp 133–
1358C and data consistent with that reported in the
literature.13
Compound 10b. E isomer: (45% yield); mp 89–918C.
[Found: C, 69.3; H, 4.1. C22H16F2O4 requires C, 69.11; H,
4.22]; nmax 1735, 1665, 760, 720 cm21; dH 2.27 (s, 3H,
furanyl-CH3), 2.30 (s, 3H, COCH3), 6.64 (s, 1H, furanyl-H),
6.71 (s, 1H, vCH), 7.28–810 (m, 8H, Ar-H); dC 14.1, 28.8,
105.8, 111.3 (d, J¼23.5 Hz) 111.8, 115.5, 115.7 (d,
J¼27.2 Hz), 117.1 (d, J¼23.2 Hz), 120.1, 120.5 (d,
J¼36.8 Hz), 121.3, 122.9, 130.3, 130.5, 131.3, 136.6,
143.8, 147.1, 158.6, 162.7 (d, J¼248.0 Hz), 163.1 (d,
J¼235.9 Hz), 193.5; MS; m/z (relative intensity): 382 (Mþ,
29), 123 (100).
Compound 9g. 62% yield; mp 60–628C. [Found: C, 75.4; H,
7.8. C36H44O6 requires C, 75.50; H, 7.74]; nmax 1710, 1660,
1270, 750, 690 cm21; dH 0.73 (s, 3H, steroidal-CH3), 0.94
(s, 3H, steroidal-CH3), 1.32 (t, J¼7.1 Hz, 3H, CH2CH3),
1.36–2.40 (m, 20H, steroidals-H), 2.53 (s, 3H, furanyl-
CH3), 3.93 (s, 2H, COCH2), 4.25 (q, J¼7.1 Hz, 2H,
OCH2CH3), 4.95 (t, J¼7.8 Hz, 1H, OCHCH2), 6.41 (s,
1H, furanyl-H), 6.94 (bs, 1H, vCH), 7.43–7.55 (m, 3H, Ar-
H), 8.02–8.06 (m, 2H, Ar-H); dC 12.0, 12.3, 12.4, 13.7,
14.3, 20.6, 23.6, 27.6, 28.2, 31.4, 34.4, 34.9, 35.2, 36.5,
36.9, 40.8, 42.9, 43.1, 46.9, 50.6, 53.5, 59.9, 108.7, 114.3,
128.3, 129.4, 130.6, 132.7, 137.5, 140.5, 147.0, 158.4,
164.0, 166.4, 195.2; MS; m/z (relative intensity): 573
[(Mþ1)þ, 20], 527 (9), 451 (50), 405 (60), 105 (100).
Compound 10c. E isomer: (54% yield); mp 147–1508C.
[Found: C, 67.3; H, 4.9. C26H22O8 requires C, 67.53; H,
4.80]; nmax 1720, 1675, 750, 700 cm21; dH 2.41 (s, 6H,
furanyl-CH3 and COCH3), 3.91 (s, 3H, OCH3), 3.99 (s, 3H,
OCH3), 6.68 (s, 1H, furanyl-H), 6.83 (s, 1H, vCH), 7.60
(BB00 part of an AA00BB00 system, J¼8.5 Hz, 2H, Ar-H), 8.02
(AA part of an AA BB system, J¼8.5 Hz, 2H, Ar-H), 8.24
(BB00 part of an AA0BB0 system, J¼8.7 Hz, 2H, Ar-H), 8.36
(AA part of an AA0BB0 system, J¼8.7 Hz, 2H, Ar-H); dC
14.1, 28.8, 52.1, 52.5, 108.5, 112.2, 122.9, 129.9, 128.8,
128.9, 130.1, 132.7, 134.7, 138.1, 143.8, 147.0, 158.8,
163.8, 165.9, 168.2, 193.3; MS; m/z (relative intensity): 462
(Mþ, 4), 163 (100).
Compound 9h. 50% yield; mp 108–1118C. [Found: C, 81.3;
H, 9.8. C36H52O3 requires C, 81.15; H, 9.84]; nmax 1680,
1670 cm21; dH 0.71–2.16 (m, 41H, steroidals-H), 2.26 (s,
3H, furanyl-CH3), 2.54 (s, 3H, COCH3), 3.99 (s, 20H,
COCH2), 5.93 (bs, 1H, vCH), 6.41 (s, 1H, vCH), 7.01 (s,
1H, furanyl-H); dC 11.9, 14.3, 17.3, 18.7, 19.1, 20.7, 22.65
23.8, 24.1, 28.0, 28.2, 29.1, 29.3, 31.7, 32.6, 33.1, 34.9,
Compound 10d. E isomer: (40% yield); mp 85–868C.
[Found: C, 76.1; H, 5.2. C22H18O4 requires C, 76.29; H,

A. Arcadi et al. / Tetrahedron 59 (2003) 4661–4671
4671
5.24]; nmax 1710, 1670 cm21; dH 2.24 (s, 3H, furanyl-CH3),
2.33 (s, 3H, COCH3), 6.64 (s, 1H, furanyl-H), 6.72 (s, 1H,
vCH), 7.32–8.32 (m, 10H, Ar-H); dC 14.1, 28.8, 108.5,
110.7, 124.4, 127.1, 128.7, 128.9, 130.2, 133.8, 134.3,
145.4, 147.6, 158.2, 164.4, 193.7; MS; m/z (relative
intensity): 346 (Mþ, 18), 105 (100).
Cacchi, S.; Fabrizi, G. Eur. J. Org. Chem. 2002, 2671–2681.
(g) Battistuzzi, G.; Cacchi, S.; Fabrizi, G.; Marinelli, F.; Parisi,
L. M. Org. Lett. 2002, 4, 1355–1358. (h) Dai, G.; Larock, R. C.
Org. Lett. 2002, 4, 193–196. (i) Dai, G.; Larock, R. C. J. Org.
Chem. 2002, 67, 7042–7047. (j) Dai, G.; Larock, R. C. J. Org.
Chem. 2003, 68, 920–928.
4. See, for example: (a) Boykin, D. W.; Kumar, A.; Xiao, G.;
Wilson, W. D.; Bender, B. C.; McCurdy, D. R.; Hall, J. E.;
Tidwell, R. R. J. Med. Chem. 1998, 41, 124–129.
(b) Francesconi, I.; Wilson, W. D.; Tanious, F. A.; Hall,
J. E.; Bender, B. C.; Tidwell, R. R.; McCurdy, D.; Boykin,
D. W. J. Med. Chem. 1999, 42, 2260–2265. (c) Rahmathullah,
S. M.; Hall, J. M.; Bender, B. C.; McCurdy, D. R.; Tidwell,
T. R.; Boykin, D. W. J. Med. Chem. 1999, 42, 3994–4000.
(d) Mortensen, D. S.; Rodriguez, A. L.; Carlson, K. E.; Sun, J.;
Katzenellenbogen, B. S.; Katzenellenbogen, J. A. J. Med.
Chem. 2001, 44, 3838–3848. (e) Mortensen, D. S.; Rodriguez,
A. L.; Sun, J.; Katzenellenbogen, B. S.; Katzenellenbogen,
J. A. Bioorg. Med. Chem. Lett. 2001, 11, 2521–2524.
(f) Dupre, D. J.; Le Gouill, C.; Rola-Pleszczynski, M.;
Stankova, J. J. Pharmacol. Exp. Ther. 2001, 299, 358–365.
(g) Fayol, A.; Zhu, J. Angew. Chem., Int. Ed. 2002, 41,
3633–3635.
Compound 10e. E isomer: (37% yield); mp 60–628C.
[Found: C, 76.8; H, 6.0. C24H22O4 requires C, 76.99; H,
5.92]; nmax 1730, 1660, 760, 720 cm21; dH 2.22 (s, 3H,
furanyl-CH3), 2.32 (s, 6H, ArCH3), 2.44 (s, 3H, COCH3),
6.62 (s, 1H, furanyl-H), 6.69 (s, 1H, vCH), 7.31–8.10 (m,
8H, Ar-H); dC 14.1, 21.2, 21.4, 28.7, 104.6, 110.6, 121.6,
122.8, 124.1, 125.0, 127.2, 127.3, 128.3, 128.6, 129.7,
130.6, 134.3, 134.6, 145.7, 158.1, 164.6, 193.4; MS; m/z
(relative intensity): 374 (Mþ, 18), 119 (100).
Acknowledgements
`
We thank the Universita degli Studi di L’Aquila and the
Ministero dell’Universita e della Ricerca Scientifica
`
(MURST; National Project ‘Stereoselezione in Sintesi
Organica. Metodologie ed Applicazioni’) for their
continuing financial support of the work done in our
laboratories.
5. Arcadi, A.; Cacchi, S.; Larock, R. C.; Marinelli, F.
Tetrahedron Lett. 1993, 34, 2813–2816.
6. Ono, N.; Yoshimura, T.; Tanigaka, R.; Kaji, A. Chem. Lett.
1977, 871–872.
7. Arcadi, A.; Cacchi, S.; Marinelli, F. Tetrahedron 1993, 49,
4955–4964.
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