Facile syntheses of substituted 2,3-dihydrofurans and benzofurans by palladium-catalyzed reactions of propargylic carbonates with nucleophiles

Article abstract of DOI:10.1016/j.tetlet.2004.01.012

Substituted 2,3-dihydrofurans and benzofurans are synthesized by the palladium-catalyzed reaction of 5-methoxycarbonyloxy-3-pentyn-1-ols and 1-(2-hydroxyphenyl)-3-methoxycarbonyloxy-1-propyne with nucleophiles, respectively. Various substituted propargyli

Full text of DOI:10.1016/j.tetlet.2004.01.012

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1861–1864
Facile syntheses of substituted 2,3-dihydrofurans and benzofurans
by palladium-catalyzed reactions of propargylic carbonates
with nucleophiles
Masahiro Yoshida,* Yukio Morishita, Mika Fujita and Masataka Ihara*
Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Aobayama,
Sendai 980-8578, Japan
Received 27 November 2003; revised 5 January 2004; accepted 6 January 2004
Abstract—Substituted 2,3-dihydrofurans and benzofurans are synthesized by the palladium-catalyzed reaction of 5-methoxycar-
bonyloxy-3-pentyn-1-ols and 1-(2-hydroxyphenyl)-3-methoxycarbonyloxy-1-propyne with nucleophiles, respectively. Various
substituted propargylic carbonates and nucleophiles are efficiently transformed to their corresponding products. Additionally, a
reaction using substrates containing a nucleophilic phenoxy group within the same molecule also produces the corresponding
dihydrofuran.
Ó 2004 Elsevier Ltd. All rights reserved.
The chemistry of the reactions of propargylic com-
pounds, via palladium catalysts, has received consider-
able attention due to their versatile and specific
reactivity and extensive studies of these have now been
undertaken.1 Palladium-catalyzed reactions of propar-
gylic carbonates with nucleophiles, first reported by
Tsuji, are one of the most successful chemical processes
that has been developed.2;3 The reaction can be normally
carried out under neutral conditions, and a number of
various complex molecules can be prepared by specific
substrate design. Based upon our current knowledge of
these reactions, we have recently developed several
cascade reactions of propargylic carbonates, containing
a hydroxyl group at the propargylic position, with
phenols. In these reactions, a rearrangement of a cyc-
lobutane ring4 and a CO2-elimination–fixation process5
have been shown to produce cyclopentanones and cyclic
carbonates, respectively. To examine the scope of the
reactivity of hydroxyl-substituted propargylic carbon-
ates with phenols, we specifically investigated a prop-
argylic carbonate, which has a hydroxyl group at the
homopropargylic position. Herein, we describe a palla-
dium-catalyzed reaction of propargylic carbonates,
containing homopropargylic hydroxyl groups, with
nucleophiles. These chemical processes selectively pro-
duce substituted 2,3-dihydrofurans and benzofurans in
good yields (Scheme 1).
The initial reactions utilized 2,2-dimethyl-5-methoxy-
carbonyloxy-3-pentyn-1-ol 1a and p-methoxyphenol
(2a) (Table 1).6 Reaction of 1a with 2a in the presence of
5 mol % Pd2(dba)3 Æ CHCl3 and 20 mol % dppe in diox-
ane at 60 °C, yields a dihydrofuran 3aa at a yield of 45%
(entry 1).7 The structure of the product 3aa was deter-
mined by its transformation into the known compound
4.8 Thus, catalytic hydrogenation of 3aa, followed by
the removal of a p-methoxyphenyl group with CAN
produced compound 4 (Scheme 2). Dihydrofuran 3aa is
obtained in a 40% yield when dppp is used (entry 2) and
it is clear that the reaction successfully proceeds in the
presence of dppb and dppf to produce 3aa in 74% and
84% yields, respectively (entries 3 and 4). In contrast,
these reactions are significantly decreased when the
monodentate ligands P(o-Tol)3 and PPh3 are utilized
(entries 5 and 6).
OH
O
OCO2Me
NuH
Nu
cat. Pd(0)
Keywords: Palladium; Cyclization; Dihydrofurans; Phenols.
* Corresponding authors. Tel.: +81-22-2176887; fax: +81-22-2176877;
e-mail: mihara@mail.pharm.tohoku.ac.jp
Scheme 1.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.01.012

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M. Yoshida et al. / Tetrahedron Letters 45 (2004) 1861–1864
Table 1. Optimization of the palladium-catalyzed reaction of 1a with
2a
Table 2. Reactions of propargylic carbonate 1a with various phenols
2b–2i
R
OH
HO
OMe
O
OH
HO
O
2a
OPMP
OCO2Me
OAr
2b-2i
OCO2Me
5 mol % Pd2(dba)3·CHCl3
20 mol % ligand
dioxane, 60°C
5 mol % Pd2(dba)3·CHCl3
20 mol % dppf, dioxane
60 °C
3aaa
1a
3ab-3ai
1a
Entry
Ligand
Yield (%)b
Entry
ArOH
Product
3ab
Yield (%)a
1
2
3
4
5
6c
dppe
45 (61)
40 (45)
74
1
2
3
4
5
6
7
8
2b: R ¼ 2-OMe
2c: R ¼ 4-Me
2d: R ¼ 2,4,6-trimethyl
2e: R ¼ H
83
76
dppp
dppb
dppf
3ac
3ad
3ae
3af
3ag
3ah
3ai
76
82
84
N.R.
15 (28)
P(o-Tol)3
PPh3
2f: 1-Naphthol
2g: R ¼ 4-Cl
64
70
a PMP ¼ p-methoxyphenyl.
2h: R ¼ 4-F
43 (55)
61
b The yields shown in parentheses are based on the recovered starting
material.
2i: R ¼ 4-acetyl
a The yields shown in parentheses are based on the recovered starting
material.
c Pd(PPh3)410 mol % was used as a palladium catalyst.
internal hydroxide to produce a p-allylpalladium inter-
mediate 7. Finally, regioselective addition of phenoxide
to 7 at the less hindered site produces dihydrofuran 3. In
another possible pathway, the initial reactivity of a
phenoxide group with the p-propargyl complex 8 fol-
lowed by cyclization of the resulting p-allylcomplex 9
could yield dihydropyran 10.10 No formation of 10 was
observed, however, which indicates that the hydroxide
anion acts as a good nucleophile for the formation of
five-membered rings, even in the presence of nucleo-
philic phenols.
1) Pd/C, H2, MeOH
O
O
92%
OPMP
OH
2) CAN, Py, MeCN/H2O
32%
3aa
4
Scheme 2.
A plausible mechanism for the formation of the
dihydrofuran 3 is depicted in Scheme 3. In this process,
a palladium catalyst initially promotes decarboxylation
of a propargylic carbonate 1 to generate an allenylpal-
ladium complex 5. Species 5 is regarded as a p-propar-
To more fully examine the scope of these reactions,
various substituted phenols were introduced and tested
as substrates (Table 2). The corresponding dihydro-
furans 3ab–3ad are formed in high yields when phenols
bearing an electron donating group 2b–2d are used
(entries 1–3). Reactions of phenol (2e) and 1-naphthol
(2f) also produce the corresponding products 3ae and
3af in good yields (entries 4 and 5). Dihydrofurans 3ag–
3ai are also obtained in acceptable yields by reactions
employing the electron withdrawing group substituted
phenols 2g–2i (entries 6–8).
gylpalladium
complex
6,9
which
undergoes
intramolecular nucleophilic attack by the resulting
OH
O
OAr
OCO2Me
3
1
Pd(0)
CO2
MeOH
The results of the reactions of propargylic carbonates
1b–1d, containing a substituent at the propargylic
position, with p-methoxyphenol (2a) are summarized in
Table 3. A methyl substituted compound 1b undergoes a
reaction that forms dihydrofuran 3ba at a 64% yield
(entry 1). Reactions of pentyl and phenyl substituted
substrates 1c and 1d also synthesize the corresponding
products 3ca and 3da at 70% and 66% yields, respec-
tively (entries 2 and 3). These results show that the
regioselective addition of phenol can proceed even in the
presence of a bulky substituent at the propargylic posi-
tion.
OAr
O
O
·
Pd+
Pd+
5
7
O
Pd+
ArOH
OAr
6
O
Pd+
HO
O
A reaction of propargylic carbonate 1e, which has no
substituent at the 2-position was then examined (Scheme
4). This reaction, in the presence of palladium, with dppf
at 60 °C forms the corresponding product 3ea at a 33%
yield, as an unstable compound. After several attempts,
OAr
OAr
Pd+
8
10
9
Scheme 3.

M. Yoshida et al. / Tetrahedron Letters 45 (2004) 1861–1864
1863
Table 3. Reactions of various propargylic carbonates 1b–1d with
p-methoxyphenol 2a
O
O
Entry
Substrate
Product
Yield (%)
O
( )n
2j n = 1
2k n = 2
OH
O
OCO2Me
OH
5 mol %
( )n
O
OCO2Me
O
Pd2(dba)3·CHCl3
20 mol % dppf
OPMP
1b
64
3gj n = 1 87% yield
3gk n = 2 77% yield
1g
1g
dioxane, 60 °C, 12 h
1b
3ba
O
O
OH
OH
Pen
O
O
OH
MeO
OMe
OCO2Me
Pen
O
O
OCO2Me
2l
2b
70
66
OPMP
OPMP
O
5 mol %
Pd2(dba)3·CHCl3
20 mol % dppf
1c
O
OMe
3ca
dioxane, 60 °C, 12 h
3gl 83% yield
Ph
OMe
O
O
H3O+
OCO2Me
Ph
O
O
O
3c
3gl
Pd+
MeO
OMe
1d
O
OMe
3da
11
Scheme 6.
12
a Reactions were carried out in the presence of 5 mol %
Pd2(dba)3 Æ CHCl3, 20 mol % ligand, and 1.1 equiv of p-methoxyphe-
nol 2a in dioxane at 60 °C for 12–24 h.
resulting in the formation of polymerized products.
However, we were delighted that a reaction that pro-
duced benzofuran 3gj at an 87% yield proceeded suc-
cessfully when 2-methyl-1,3-cyclopentanedione 2j was
used as a nucleophile. The corresponding product 3gk
was obtained by reaction with 2-methyl-1,3-cyclohex-
anedione 2k at a 77% yield. Interestingly, when dimethyl
malonate 2l is subjected to these reactions with 1g, O-
alkylated benzofuran 3gl is produced at an 83% yield.12
It was expected that in this case the reaction would
proceed via a regioselective addition from the oxygen
site to the p-allyl complex 11 followed by hydrolysis of
the resulting enol ether 12 during the workup. It is not
clear why the unusual O-alkylation occurs prior to the
C-alkylation, and few examples have been previously
reported concerning the regioselective O-alkylation of
malonates to p-allylpalladium complexes.13
b dppf was used as a ligand.
c dppb was used as a ligand.
HO
OMe
OH
O
2a
OCO2Me
OPMP
10 mol % Pd(PPh3)4
dioxane, 50 °C, 13 h
1e
Scheme 4.
3ea 47% yield
the yield was slightly increased to 47% by carrying out
the reaction using Pd(PPh3)4 at 50 °C.11
The reaction of 1f, containing a latent nucleophilic
p-methoxyphenolic moiety as a part of the carbonate
leaving group, was then examined (Scheme 5). When 1f
is subjected to a palladium–catalyzed reaction, the cor-
responding dihydrofuran 3aa is formed at a 74% yield.
In this reaction, the substrate initially releases the
phenoxide, which then acts as a nucleophile for the
resulting p-allyl complex 7 to efficiently produce the end
product.
In conclusion, we have developed a methodology for the
synthesis of substituted 2,3-dihydrofurans and benzo-
furans using a palladium catalyst. This process can
produce a variety of dihydrofurans and benzofurans by
reaction of propargylic carbonates, having a hydroxyl
group at the homopropargylic position, with nucleo-
philes. Much attention has been paid to the synthesis of
natural products containing these furan rings, which
exhibit potentially very interesting biological activities.14
Our process could therefore provide an efficient protocol
for production of these molecules. Efforts to extend the
scope of these reactions and their consequent applica-
tion to the syntheses of natural products are currently in
progress.
We further evaluated the reaction of 1g, which has an
introduced benzene ring within the molecule (Scheme 6).
Our attempts to test the reaction of 1g with various
different phenols failed, because the reactive phenolic
alcohol would also act as an additional nucleophile,
5 mol %
Pd2(dba)3·CHCl3
20 mol % dppf
OH
O
OPMP
OCO2PMP
Acknowledgements
dioxane, 60 °C, 11 h
This study was supported in part by a Grant-in-Aid for
the Encouragement for Young Scientists (B) from the
Japan Society for the Promotion of Science (JSPS) (for
1f
Scheme 5.
3aa 74% yield

1864
M. Yoshida et al. / Tetrahedron Letters 45 (2004) 1861–1864
1
v/v); mp 28–29 °C; H NMR (300 MHz, CDCl3) d 1.15 (s,
6H), 3.76 (s, 3H), 4.07 (s, 2H), 4.46 (s, 2H), 4.91 (s, 1H),
6.82 (dt, J ¼ 9:3 and 2.8 Hz, 2H), 6.89 (dt, J ¼ 9:3 and
2.8 Hz, 2H); 13C NMR (75 MHz, CDCl3) d 27.6, 43.0,
55.6, 64.2, 83.1, 110.5, 114.6, 116.1, 152.3, 152.9, 154.3; IR
(neat) 2866, 1506, 1229 cmꢀ1; MS (EI) m=z (relative
intensity) 234 [Mþ, 75], 219 (4), 111 (46), 96 (4), 81 (9),
65 (3), 51 (2); HRMS (EI) calcd for C14H18O3 [Mþ]
234.1256, was found to be 234.1275.
M.Y.) and Scientific Research on Priority Areas (A)
from the Ministry of Education, Culture, Sports, Sci-
ence and Technology, Japan. We are grateful to Prof.
Masahiko Yamaguchi for his generosity and helpful
discussions.
References and notes
7. Recently, Mori reported a similar type of palladium-
catalyzed reaction of propargylic carbonates with benzo-
ate leading to formation of substituted carbapenams. In
these reactions, nucleophilic benzoate reacts strongly with
the p-allylpalladium complex from a more hindered site
and produces a corresponding product having an exo-
olefin, and hence exhibiting different regioselectivity from
our result; see Ref. 3g.
1. Tsuji, J. Palladium Reagents and Catalysts: Innovations in
Organic Synthesis; Wiley: New York, 1995. p 453.
2. (a) Tsuji, J.; Minami, I. Acc. Chem. Res. 1987, 20, 140; (b)
Minami, I.; Yuhara, M.; Watanabe, H.; Tsuji, J. J.
Organomet. Chem. 1987, 334, 225; (c) Tsuji, J.; Mandai, T.
Angew. Chem. Int. Ed. Engl. 1995, 34, 2589.
3. (a) For recent examples of palladium-catalyzed reactions
of propargylic carbonates with nucleophiles, see: Four-
nier-Nguefack, C.; Lhoste, P.; Sinou, D. Synlett. 1996,
553; (b) Labrosse, J.-R.; Lhoste, P.; Sinou, D. Tetrahedron
Lett. 1999, 40, 9025; (c) Labrosse, J.- R.; Lhoste, P.;
Sinou, D. Org. Lett. 2000, 2, 527; (d) Kozawa, Y.; Mori,
M. Tetrahedron Lett. 2001, 42, 4869; (e) Kozawa, Y.;
Mori, M. Tetrahedron Lett. 2002, 43, 1499; (f) Damez, C.;
Labrosse, J.-R.; Lhoste, P.; Sinou, D. Tetrahedron Lett.
2003, 44, 557; (g) Kozawa, Y.; Mori, M. J. Org. Chem.
2003, 68, 8068.
4. Yoshida, M.; Nemoto, H.; Ihara, M. Tetrahedron Lett.
1999, 40, 583.
5. (a) Yoshida, M.; Ihara, M. Angew. Chem. Int. Ed. 2001,
40, 616; (b) Yoshida, M.; Fujita, M.; Ishii, T.; Ihara, M. J.
Am. Chem. Soc. 2003, 125, 4874; (c) Yoshida, M.; Fujita,
M.; Ihara, M. Org. Lett. 2003, 5, 3325.
6. General procedure for palladium-catalyzed reactions of
propargylic carbonates with phenols. Reaction of 1a with
2a (entry 5 in Table 1): To a stirred solution of propargylic
carbonate 1a (38.7 mg, 0.208 mmol) in dioxane (2 mL) we
added p-methoxyphenol (2a) (28.4 mg, 0.229 mmol),
Pd2(dba)3 Æ CHCl3 (10.8 mg, 10.4 lmol) and dppf (23 mg,
41.6 lmol) in a sealed tube at room temperature. The
reaction mixture was allowed to warm to 60 °C, and
stirring was continued for 17 h. After evaporation of the
solvent, the residue was chromatographed on silica gel
with AcOEt–hexane (2:98 v/v) as an eluent to produce 5-
phenoxymethyl-2,3-dihydrofuran 3aa (41 mg, 0.175 mmol,
84%) as colorless needles; Rf ¼ 0:70 (AcOEt–hexane ¼ 3:7
8. Tan, H.; Espenson, J. H. J. Mol. Cat. A 2000, 152, 83.
9. (a) Ogoshi, S.; Tsutsumi, K.; Kurosawa, H. J. Organomet.
Chem. 1995, 493, C19; (b) Tsutsumi, K.; Ogoshi, S.;
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Jpn. 1999, 72, 2687; (d) Ogoshi, S.; Kurosawa, H. J. Synth.
Org. Chem. Jpn. 2003, 61, 14.
10. We previously observed the formation of phenoxy substi-
tuted dihydrofuran as a byproduct by the reaction of 4-
methoxycarbonyloxy-2-butyn-1-ol with phenol, see Refs.
5a and 5b.
11. It is generally believed that a monodentate ligand is not
suitable for the reaction of propargylic compounds with
soft nucleophiles (see Refs. 2c,3g and 9c). The obtained
result using monodentate PPh3 is therefore interesting in
view of this hypothesis, although the precise details of this
reaction mechanism are still unclear.
12. The structure of 3gl has been confirmed by the hydrolysis of
this product to form a known benzofuran-2-yl methanol.
ꢀ
13. Akermark, B.; Zetterberg, K.; Hansson, S.; Krakenberger,
B.; Vitagliano, A. J. Organomet. Chem. 1987, 335, 133.
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D.; Hamblett, J.; Hilditch, A.; Hirst, G. C.; Jack, T.;
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