Catalytic and selective conversion of (Z)-2-en-4-ynoic acids to either 2H-pyran-2-ones in the presence of ZnBr2 or (Z)-5-alkylidenefuran-2(5H)-ones in the presence of Ag2CO3

Article abstract of DOI:10.1016/S0040-4039(02)01128-0

Treatment of (Z)-5-alkyl-2-en-4-ynoic acids (1), prepared by the Pd-catalyzed alkynylzinc-β-haloacrylic acid coupling, with 5-10 mol% of ZnBr₂ can produce 6-alkyl-2H-pyran-2-ones (2) along with minor amounts of (Z)-5-alkylidenefuran-2(5H)-ones (3) in >90% combined yields, with often very high (≈95/5) pyranone/furanone ratios. On the other hand, lactonization of 1 catalyzed by Ag₂CO₃ provides a selective synthesis of (Z)-5-alkylidenefuran-2(5H)-ones (3) in >90% yields along with minor amounts (≤5%) of 2.

Full text of DOI:10.1016/S0040-4039(02)01128-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 5673–5676
Catalytic and selective conversion of (Z)-2-en-4-ynoic acids to
either 2H-pyran-2-ones in the presence of ZnBr or
2
(
Z)-5-alkylidenefuran-2(5H)-ones in the presence of Ag CO3
2
Luigi Anastasia, Caiding Xu and Ei-ichi Negishi*
Herbert C. Brown Laboratories, Purdue University, West Lafayette, IN 47907, USA
Received 23 April 2002; accepted 4 June 2002
Abstract—Treatment of (Z)-5-alkyl-2-en-4-ynoic acids (1), prepared by the Pd-catalyzed alkynylzinc–b-haloacrylic acid coupling,
with 5–10 mol% of ZnBr can produce 6-alkyl-2H-pyran-2-ones (2) along with minor amounts of (Z)-5-alkylidenefuran-2(5H)-
2
ones (3) in >90% combined yields, with often very high (:95/5) pyranone/furanone ratios. On the other hand, lactonization of
1
catalyzed by Ag CO provides a selective synthesis of (Z)-5-alkylidenefuran-2(5H)-ones (3) in >90% yields along with minor
2 3
amounts (55%) of 2. © 2002 Published by Elsevier Science Ltd.
We report herein that treatment of 5-alkyl-2-en-4-ynoic
During our study reported herein, conversion of 1 to 2
in low selectivity (2/3 <4) by iodolactonization with 3
acids (1) with 5–10 mol% of ZnBr in THF can produce
2
2a
6
-alkyl-2H-pyran-2-ones (2) in high yields (Scheme 1).
equiv. each of I and NaHCO3 followed by consecutive
2
2b
The pyranone/furanone ratio of approximately 95/5 have
been observed with 1 containing n-hexyl, isobutyl, and
cyclohexyl groups bonded to the C5 atom (entries 1–3 in
Table 1). The use of DMF in place of THF in entry 3
lowered the 2/3 ratio to 67/33, although the combined
yield was 91%. Cyclization of 1 to produce 2 in low yields
treatment with Zn and HCl was reported. As the results
shown in Scheme 2 indicate, the current procedure is
superior to that reported previously in that it is a
ZnBr -catalyzed one-step reaction of higher product
2
yields and higher selectivity.
(
521%) along with the formation of (Z)-5-alkylidene-
We further report that the preparation of (Z)-5-organyl-
2-en-4-ynoic acids by the Pd-catalyzed alkynylzinc–b-
furan-2(5H)-ones (3) in 18–62% yields in the presence of
a catalytic amount of AgI or Ag or 1 equiv. of HgO is
3–5
haloacrylic acid coupling
followed by lactonization
1
known. In the same publication, o-1-pentynylbenzoic
catalyzed by Ag CO provides a superior, albeit two-
2 3
acid was preferentially converted to 3-propylisocoumarin
in good yields in the presence of catalytic amounts of
AgClO , AgNO , AgOTf, or Ag CO . However, (Z)-2-
en-4-ynoic acids (1) have not previously been catalytically
converted to 2 in high yields as the major products.
step, alternative to the recently developed one-pot
6–8
alkyne-alkene coupling–lactonization tandem process
9
run under Sonogashira coupling conditions for selective
4
3
2
3
synthesis of (Z)-5-alkylidenefuran-2(5H)-ones (3) (Table
10
2).
1
2
3
. n-BuLi, -78 o
. ZnBr2, 0 o
. Pd(PPh3)4 (5 mol%)
C
C
ZnBr2 (5-10 mol%)
THF, 23 o
C
R
O
2
O
I
COOZnBr
COOH
Ag2CO3 (5 mol%)
DMF, 23 o
R
THF, 23 o
C
R
1
O
C
O
3
R
Scheme 1.
*
Corresponding author. Tel.: +1-754-494-5301; fax: +1-765-494-0239; e-mail: negishi@purdue.edu
0
040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)01128-0

5
674
L. Anastasia et al. / Tetrahedron Letters 43 (2002) 5673–5676
Table 1. Selective conversion of (Z)-2-en-4-ynoic acids to
H-pyran-2-ones catalyzed by ZnBr in THF
version of 1 into 3. In cases where R is alkyl, however,
2
2
we find that AgNO and a few of other Ag salts, such
3
as AgOTf and AgBF , are unsatisfactory for selectively
4
converting 1 into 3. On the other hand, the use of
Ag CO or AgOAc, namely carbonate or carboxylate
2
3
salts of Ag, leads to selective synthesis of 3 (Table 3).
On the basis of all of the findings presented above, it
now appears reasonable to state that (i) the preparation
of (Z)-2-en-4-ynoic acids (1) by the Pd-catalyzed cou-
Table 2. Comparison of Ag-catalyzed lactonization of (Z)-
2
-en-4-ynoic acids with Pd-catalyzed alkyne–alkene cross-
coupling–lactonization tandem process
Aa
AgX
O
I
O
HO
1
H
R
HO
+
R
+
O
O
O
R
O
2
R
Ba
3
yield of 2 + 3 (%)
based based on
entry
alkyne
procedurea 2 : 3
on 1
alkyne
Thus, in those cases where the R groups of the starting
alkynes are n-Hex, i-Pr, cyclohexyl, t-Bu, and Ph, the
overall yield of 3 are 82–88% over the two steps. These
results favorably compare with the yield range of 46–
1A n-Hex
A
B
4 : 96
96
90
b
1B
"
"
34 : 66
77
2A
A
B
5 : 95
99
93
75
7
4% for 3 observed in the one-pot tandem process.
b
2B
20 : 80
Furthermore, whereas the 3/2 ratio observed in the
one-pot tandem process for those cases where the R
groups are n-Hex, i-Pr, and cyclohexyl are only 2–4,
those observed in the Ag-catalyzed lactonization are
3A
A
B
3 : 97
95
88
65
b
3B
"
"
"
20 : 80
1
9–22. These comparative results are summarized in
Table 2. Some of the reported difficulties associated
with the one-pot Pd-catalyzed cross-coupling-lactoniza-
tion tandem process, such as alkyne dimerization and
Michael-type addition reactions have not been observed
in the two-step process.
4A
A
B
2 : 98
3 : 97
95
86
76
6
,7
b
4B
5A
Ph
A
B
2 : 98
94
88
c
b
46 d
5B
Although o-alkynylbenzoic acids have been converted
to dihydrobenzofuranone derivatives in high yields in
a
1
Procedure A: (1) Compound 1 was prepared under the cross-cou-
the presence of Ag CO , AgI, or Ag, AgI-catalyzed
2
3
pling conditions described in Ref. 11; (2) Ag CO (5–10 mol%),
2
3
conversion of 5-phenyl-2-penten-4-ynoic acid into the
DMF, 23°C, 1 h; Procedure B: CuI (5–10 mol%), Et N (4 equiv.),
3
1
corresponding 3 and AgNO -catalyzed synthesis of
b
3
Pd(PPh3)4 (5 mol%), MeCN, 23°C, 12 h. The formation of com-
pound 1 was never observed under conditions B. Ratio not deter-
10
c
TBS-protected lissoclinolide are the only previously
reported examples of the Ag-catalyzed high-yield con-
d
mined. Ref. 6.
cat. ZnBr2
This study
2
(89%, 2/3 = 16)
COOH
n-Bu
O
2
O
n-Bu
1
I
IZn
2 (57%, 2/3 = 2)
Ref. 2
a
b
c
n-Bu
O
O
n-Bu
O
O
a: I2 (3 eq), NaHCO3 (3 eq), 65%; b: Zn; c: HCl, 88%.
Scheme 2.

L. Anastasia et al. / Tetrahedron Letters 43 (2002) 5673–5676
5675
Table 3. The effects of Ag catalysts and solvents in the
Ag-catalyzed lactonization of (Z)-2-en-4-ynoic acids
general and selective protocol for the synthesis of 2
and 3 from terminal alkynes and (Z)-b-haloacrylic
13,14
acids (Scheme 1).
combined
a
entry
alkyne
n-Hex
catalyst solvent
2: 3 yield (%)
In our hands, Pd catalysts, such as Pd(PPh ) , have
3 4
not been effective in converting preformed and
purified (Z)-2-en-4-ynoic acids into 2 and/or 3. Only
a very slow cyclization to give 2 and 3, which can
take place at comparable rates even in the absence of
a Pd complex, has been observed. This point, how-
ever, is under further investigation. Interestingly, the
zinc salts of (Z)-2-en-4-ynoic acids cannot be lac-
1
2
Ag CO
DMF
DMF
DMF
4 : 96
9 : 91
96
97
2
3
"
AgOAc
3
4
"
"
AgNO3
AgNO3
64 : 36
95
96
MeOH 89 : 11
5
6
"
"
AgOTf
AgBF4
DMF
DMF
80 : 20
88 : 12
93
93
tonized under the influence of ZnBr either. However,
2
addition of 3 M DCl in D O (1 mol equiv.) to the
2
zinc salt of (Z)-2-nonen-4-ynoic acid induced a slow
but smooth and quantitative lactonization with incor-
poration of D at the C4 position to the extent of
7
8
Ag2CO3
AgOAc
DMF
3 : 97
4 : 96
95
95
>
98%, indicating the intermediacy of the correspond-
ing zinco derivative of 2H-pyran-2-one (Scheme 3).
"
MeCN
9
"
"
AgOAc
AgOAc
DMF
8 : 92
9 : 91
97
92
At this point, factors affecting the pyranone/furanone
ratio are not yet very clear. It is nevertheless tempt-
ing to speculate that polarization of the unsaturated
bonds in (Z)-2-en-4-ynoic acids would favor the for-
mation of 2H-pyran-2-ones via a Lewis acid-catalyzed
polar process, whereas transition metal-catalyzed pro-
cesses, in which bond polarization is less important,
may stereoelectronically favor a 5-exo-mode cycliza-
tion (Scheme 4). Irrespective of the precise mecha-
nisms of these cyclization reactions, however, the
selective conversion of 1 into 2 and 3 catalyzed by
ZnBr and Ag CO , respectively, significantly comple-
1
0
MeOH
11
"
"
AgNO3
AgOTf
MeOH 57 : 43
DMF
88 : 48
93
93
1
2
a
Combined yield of 2 and 3 based on 1.
pling of alkynylzincs with (Z)-b-haloacrylic acids, (ii)
the ZnBr -catalyzed cyclization of 1 to produce 2H-
2
11
pyran-2-ones (2),
and (iii) the Ag CO -catalyzed
2 3
2
2
3
cyclization of 1 to give (Z)-5-alkylidenefuran-2(5H)-
ment a few related lactonization protocols developed
over the past decade.
1
2
ones (3), all combine to provide an unprecedentedly
I
COOZnBr
DCl (3 M in
D2O), 48h
Pd(PPh3)4 (5 mol%)
COOZnBr
n-Bu
ZnBr2
94%, >97% D
THF, 3 h
n-Bu
D
n-Bu
O
O
1
2
. n-BuLi, 0 oC, THF
ZnBr2 (5 mol%)
48h
. DCl (3 M in D2O)
COOH
COOD
98%, >98% D
1
n-Bu
n-Bu
Scheme 3.
-
δ+ δ-
X2Zn
H
X2Zn
ZnX2
AgX
δ-
δ+ δ-
O
- ZnX2
δ+
O
H
R
O
H
O
R
O
ZnX2
O
O
+
R
ZnX2
2
O
O
Ag
H
R
H
-AgX
AgX
R
1
O
O
O+
Z
O
3
O
Z
R
R
X-
Z = H or Ag
Scheme 4.

5
676
L. Anastasia et al. / Tetrahedron Letters 43 (2002) 5673–5676
Sonogashira, K.; Hagihara, N. J. Chem. Soc., Chem.
Acknowledgements
Commun. 1976, 839; (c) Tohda, Y.; Sonogashira, K.;
Hagihara, N. Synthesis 1977, 777; (d) Takahashi, S.;
Kuroyama, Y.; Sonogashira, K.; Hagihara, N. Synthesis
1980, 627.
We thank the National Institutes of Health (GM
3
0
6792), the National Science Foundation (CHE-
080795), and Purdue University for support of this
10. Xu, C.; Negishi, E. Tetrahedron Lett. 1999, 40, 431.
11. A representative procedure for the synthesis of 1 from the
corresponding terminal alkyne is as follows: A solution of
EtMgBr (1 M solution in THF, 2.1 mL) in 5 mL of THF
was successively treated with ZnBr2 (1 M solution in
THF, 2.1 mL, freshly prepared from flame-dried ZnBr2)
and (Z)-3-iodo-2-propenoic acid (3.96 g, 2 mmol) in 2
mL of THF at 0°C under an Ar atmosphere. In a second
flask a solution of a terminal alkyne (2 mmol) in 5 mL of
THF was treated with n-BuLi (2.5 M solution in hexanes,
research.
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4
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2
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4
3
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2
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4
5
1
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1
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4
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6
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9
1
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