Palladium(II) catalyzed carbonylative dimerization of allenyl ketones: efficient synthesis of difuranylketones

Article abstract of DOI:10.1016/j.tetlet.2009.06.016

Palladium(II) catalyzed carbonylation of 1,2-allenyl ketones 1 in the presence of p-benzoquinone (1 equiv) under a CO atmosphere (balloon) afforded difuranylketones 4 in moderate to good yields. Mechanistically, the electron-withdrawing nature of the acyl

Full text of DOI:10.1016/j.tetlet.2009.06.016

Tetrahedron Letters 50 (2009) 4744–4746
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Palladium(II) catalyzed carbonylative dimerization of allenyl ketones:
efficient synthesis of difuranylketones
b
c
c
d
Keisuke Kato a, , Tomoyuki Mochida , Hiroyuki Takayama , Masayuki Kimura , Hiroshi Moriyama ,
*
Akihito Takeshita d, Yuichro Kanno a, Yoshio Inouye a, Hiroyuki Akita a,
*
a Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan
b Department of Chemistry, Faculty of Science, Kobe University, Rokkodai, Nada, Kobe 657-8501, Japan
c School of Pharmacy, Nihon Pharmaceutical University, 10281, Komuro, Inamachi, Kita-Adachigun, Saitama, Japan
d Department of Chemistry, Faculty of Science, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Palladium(II) catalyzed carbonylation of 1,2-allenyl ketones 1 in the presence of p-benzoquinone
(1 equiv) under a CO atmosphere (balloon) afforded difuranylketones 4 in moderate to good yields. Mech-
anistically, the electron-withdrawing nature of the acyl group should enhance the electrophilicity of the
acylpalladium species B, and thus promote the oxypalladation of an additional molecule of 1, leading to
the difuranyl ketone 4.
Received 5 May 2009
Revised 30 May 2009
Accepted 5 June 2009
Available online 7 June 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Palladium
Carbonylative dimerization
Difuranylketone
Furan rings are a common structure in a range of biologically
active natural products and important pharmaceuticals.1 Diarylke-
tones are also frequently found in natural products and pharma-
ceuticals.2 In addition, they are good precursors for non-steroidal
antiestrogen drugs, such as tamoxifen,3 and for diarylmethyl com-
pounds, such as histamine H1 antagonists,4a antitubercular com-
pounds,4b and inhibitors of tubulin polymerization.4c Transition-
metal-catalyzed reaction of unsaturated systems has recently pro-
ven to be a powerful method for the construction of a variety of
carbo- and heterocycles.5 In particular, transition-metal-catalyzed
cycloisomerization of 1,2-allenyl ketones leading to furan deriva-
tives has been extensively studied.6 Among such reactions, Hashmi
et al. demonstrated the palladium-catalyzed dimeric cyclization of
1,2-allenyl ketones (Scheme 1).6c,d
In that study, the authors suggested that a possible pathway to-
ward formation of 2 and 3 was through a furyl hydridopalladi-
um(IV) species A obtained via the intramolecular oxypalladation
of a palladium-coordinated allene. The intermediate A can form
either product 3 by reductive elimination or product 2 by carbopal-
ladation of an additional molecule of 1 followed by reductive elim-
ination. Recently, we reported on the intramolecular- and
intermolecular-oxycarbonylation of several types of alkynes7 as
well as the tandem carbonylative cyclization of propargyl acetates
with 1,4-diyne8a and 1,5-diyne structures.8b In these reactions, the
insertion of CO into the vinylpalladium species was faster than the
intramolecular insertion of the second triple bond.8 Based on our
previous findings, we have hypothesized that treatment of 1,2-alle-
nyl ketones 1 with PdII under CO atmosphere9 may form the acyl-
palladium species B as a result of CO insertion into the furyl
palladium species A’ (Scheme 1). The electron-withdrawing nature
of the acyl group should enhance the electrophilicity of the acyl-
palladium species B, and thus promote the oxypalladation of an
additional molecule of 1, leading to the difuranyl ketone 4. Conse-
quently, we report on a new PdII-catalyzed carbonylative dimeriza-
tion of allenyl ketones as an efficient synthesis of
difuranylketones10 (Scheme 1).
Initially, we selected 1a as a standard substrate to optimize po-
tential solvents and catalysts. The carbonylation of 1a was per-
formed under the same conditions as used in our previously
reported PdII/p-benzoquinone catalytic system7,8,11 (Scheme 2, Ta-
ble 1). Briefly, the reaction of 1a with (CH3CN)2PdCl2 (5 mol %) in
the presence of p-benzoquinone (1 equiv) in CH3CN under a carbon
monoxide atmosphere (balloon) generated the expected difura-
nylketone 4a in 27% yield along with the known dimer 2a (26%)
(Table 1, entry 1). Whereas toluene was not suitable as a solvent
for the reaction, the use of CH2Cl2 and MeOH did successfully im-
prove the yield of 4a (Table 1, entries 2–4). When the reaction was
performed in MeOH, 4a was precipitated from the reaction mix-
ture. After collection by filtration, washing with cold MeOH, pure
4a was afforded in 65% yield. A further amount of 4a (4%) along
with the furan carboxylate 5a (13%) could be obtained from the fil-
* Corresponding authors. Fax: +81 474 721 825 (K.K.).
E-mail address: kkk@phar.toho-u.ac.jp (K. Kato).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.016

K. Kato et al. / Tetrahedron Letters 50 (2009) 4744–4746
4745
H
PdIIL2
Me
O
PdIVLn
Carbopalladation
O
O
O
1
+
•
R
R
COR
R
R
R
major
2
3 minor
1
A
A. S. K. Hashmi et al.
PdX2L2
-2HX
CO
O
Oxypalladation
O
O
PdL2
CO
O
1
CO2Me
O
O
O
+
PdL2
•
R
R
R
A'
B
5
R
4
This work
R
O
Scheme 1. Palladium catalyzed reaction of allenyl ketone and this work.
Table 2
O
O
(CH3CN)2PdCl2 catalyzed carbonylative dimerization of allenyl ketones 1a
Catalyst (5 mol %)
O
OMe
+
Entry
R1
R2
Yield of 4 (%)
O
R
O
R
•
O
R
p-Benzoquinone
(1 equiv.)
CO (balloon)
Solvent, rt, 2-9 h
1
2
3
4
5
6
Ph(CH2)2
Nonyl
H
H
H
H
H
H
H
H
4a:69
4b:63
4c:74
4d:73
4e:61
4f:62
4g:59
4h:70
4i:68
4j:64
4k:60
4l:89
4m:90
4n:96
4o:93
4p:85
4q:87
4r:82
4s:85
4t:83
1a
R = Ph(CH2)2
5a
R
4a
Cyclohexyl
BzO(CH2)4
BzO(CH2)3
BzO(CH2)2
BzOCH2
Scheme 2. Carbonylation of allenyl ketone 1a with (CH3CN)2PdCl2.
7
8b
9
TBSO(CH2)3
Ph
Table 1
Carbonylation of allenyl ketone 1a with (CH3CN)2PdCl2 (Scheme 2)
H
H
H
10
11
12
13
14
15
16
17
18
19
20
2-Furanyl
3-Furanyl
Ph(CH2)2
Ph(CH2)2
BzO(CH2)4
BzO(CH2)3
BzO(CH2)2
2-Furanyl
3-Furanyl
Ph
Entry
Solvent
Catalyst
Yield of 4a (%)
Yield of 5a (%)
Me
Et
Me
Me
Me
Et
Et
Et
Me
1a
2
3
4
5
6
7
8
CH3CN
CH2Cl2
Toluene
MeOH
MeOH
MeOH
MeOH
MeOH
(CH3CN)2PdCl2
(CH3CN)2PdCl2
(CH3CN)2PdCl2
(CH3CN)2PdCl2
(C6H5CN)2PdCl2
Pd(TFA)2
27
49
—
—
Complex mixture
69
64
52
58
68
13
19
24
10
3
(CH3CN)4Pd(BF4)2
Pd(TFA)2/(S)-Phbox
2-Furanyl
a
a
2a (R = Ph(CH2)2) was also obtained in 26% yield.
All reactions were performed with (CH3CN)2PdCl2 (5 mol %) in MeOH. In most
cases, furan carboxylate 5 was obtained as a by-product in low yield. See Supple-
mentary data.
b
Partial desilylation was observed during the carbonylation reaction. The prod-
trate (Table 1, entry 4). Next, we investigated other catalysts such
as (C6H5CN)2PdCl2, Pd(TFA)2, and (CH3CN)4Pd(BF4)2; notably, these
gave similar results as the initial catalyst (Table 1, entries 4–7).
However, Pd(OAc)2 and (2,2’-bipyridine)dichloropalladium(II) did
not show catalytic activity, and (Ph3P)2PdCl2 gave 5a in poor yield
(17%).12 These results can be interpreted as a result of the decreas-
ing electrophilicity of the palladium species.7,8,13 Next, in order to
uct was isolated after re-silylation.
O
O
(CH3CN)2PdCl2 (5 mol %)
O
•
O
R1
p
-philicity of PdII complexes,7e,8 we investigated the
R2
p-Benzoquinone (1 equiv.)
enhance the
R2
R1
R2
R1
1
CO, MeOH, rt, 1-4 h
use of the (S)-Phbox ligand (Table 1, entry 8). As expected, the
products ratio (4a/5a) was increased, but the yield of 4a was al-
most the same, and the total yield was decreased. Thus, we se-
lected the (CH3CN)2PdCl2 catalyst in a MeOH solvent as the
optimized conditions.
4
Scheme 3. (CH3CN)2PdCl2 catalyzed carbonylative dimerization of allenyl ketones
1.
We then examined the scope of this reaction, with the results
summarized in Table 2 (Scheme 3). For substrates 1a–c having
hydrocarbon substituents, the reaction proceeded smoothly,
affording the products 4a–c in 63–74% yields along with a small
amount of furan carboxylates 5a–c (4–13%) (Table 2, entries 1–
3). The structure of 4c was determined by X-ray crystallographic
analysis after recrystallization.14
The benzoates 1d–g having different carbon chain lengths gave
almost the same results (Table 2, entries 4–7). Although the reac-
tion of the TBDMS ether 1h proceeded smoothly, partial desilyla-
tion was observed, and thus the product 4h was isolated after re-
silylation of the crude mixture (Table 2, entry 8). The phenyl-
substituted 1i and furanyl-substituted 1j and 1k gave 60–68%
yields (Table 2, entries 9–11). While the product yields of sub-
strates having unsubstituted allenyl ketones (1a–k) were moder-
ate, this improved with the addition of an R2 substituent into the
substrates. For substrates 1l–n, with a methyl or ethyl substituent
at R2, the reactions proceeded well, affording the products 4l–n in
89–96% yields along with a small amount of furan carboxylates 5l–
n (3–9%) (Table 2, entries 12–14). In the case of the substrates 1o–
t, we failed to isolate the furan carboxylates 5o–t in pure form,
although the difuranylketones 4o–t were obtained in good yield
(Table 2, entries 15–20). The precise reason for this substituent ef-
fect is presently unclear, but may be related to stability of the com-
pounds under the reaction condition. In the case of unsubstituted

4746
K. Kato et al. / Tetrahedron Letters 50 (2009) 4744–4746
O
Me2N
O
R
O
1) TiCl4 / Zn
Ph
Et
propiophenone
Ph
Et
O
R
O
R
2) NaOMe
4d
6d
R = HO(CH2)4
R = H :tamoxifen
26 % (2 steps)
R
O
R = BzO(CH2)4
R = OH :4-hydroxytamoxifen
R
Scheme 4. Synthetic approach to the new tamoxifen analogue.
S. Bioorg. Med. Chem. Lett. 2007, 17, 5586; (c) Álvarez, C.; Álvarez, R.; Corchete,
P.; López, J. L.; Pérez-Melero, C.; Peláez, R.; Medarde, M. Bioorg. Med. Chem.
2008, 16, 5952.
allenyl ketones 1a–k, some unidentified small spots were detected
from the reaction mixture by thin-layer chromatography.
To investigate the utility of the present reaction, a preliminary
study for the synthesis of a new tamoxifen analogue is shown in
Scheme 4. Tamoxifen (NolvadexÒ) is one of the most important che-
motherapeutic agents for the treatment of breast cancer. Its primary
metabolite, 4-hydroxytamoxifen has a greater affinity for the estro-
gen receptor than tamoxifen, and may contribute to the in vivo anti-
tumour activity.3 However, after a period of response, tamoxifen-
resistant tumours eventually develop, creating the need for new po-
tent non-toxic antiestrogens. Towards this aim, coupling of the dif-
uranylketone 4d with propiophenone using TiCl4/Zn in THF3e
followed by methanolysis afforded the tamoxifen analogue 6d in
26% yield.
5. (a) Handbook of Organopalladium Chemistry for Organic Synthesis; Negishi, E.,
Ed.; Wiley: New York, 2002; Vol. II, p 2309; For recent reviews, see: (b)
Zimmer, R.; Dinesh, C. U.; Nandanan, E.; Khan, F. A. Chem. Rev. 2000, 100, 3067;
(c) Bates, R. W.; Satcharoen, V. Chem. Soc. Rev. 2002, 31, 12; (d) Ma, S. Acc. Chem.
Res. 2003, 36, 701; (e) Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104, 2127;
(f) Zeni, G.; Larock, R. C. Chem. Rev. 2004, 104, 2285; (g) Soderberg, B. C. G.
Coord. Chem. Rev. 2004, 248, 1085; (h) Vizer, S. A.; Yerzhanov, K. B.; Quntar, A. A.
A. A.; Dembitsky, V. M. Tetrahedron 2004, 60, 5499; (i) Muzart, J. Tetrahedron
2005, 61, 9423; (j) Asao, N. Synlett 2006, 1645; (k) Zeni, G.; Rarock, R. C. Chem.
Rev. 2006, 106, 4644.
6. (a) Marshall, J. A.; Robinson, E. D. J. Org. Chem. 1990, 55, 3450; (b) Marshall, J. A.;
Sehon, C. A. J. Org. Chem. 1995, 60, 5966; (c) Hashmi, A. S. K. Angew. Chem. 1995,
107, 1749; . Angew. Chem., Int. Ed. Engl. 1995, 34, 1581; (d) Hashmi, A. S. K.;
Ruppert, T. L.; Knöfel, T.; Bats, J. W. J. Org. Chem. 1997, 62, 7295; (e) Hashmi, A.
S. K.; Schwarz, L.; Choi, J.-H.; Frost, T. M. Angew. Chem. 2000, 112, 2382; . Angew.
Chem., Int. Ed. 2000, 39, 2285; (f) Ma, S.; Li, L. Org. Lett. 2000, 2, 941; (g) Ma, S.;
Zhang, J.; Lu, L. Chem. Eur. J. 2003, 9, 2447; (h) Ma, S.; Yu, Z. Chem. Eur. J. 2004,
10, 2078; (i) Ma, S.; Yu, Z.; Gu, Z. Chem. Eur. J. 2005, 11, 2351; (j) Deng, Y.; Li, J.;
Ma, S. Chem. Eur. J. 2008, 14, 4263; (k) Alcaide, B.; Almendros, P.; Martínez del
Campo, T. Eur. J. Org. Chem. 2007, 2844.
7. Propargyl acetates: (a) Kato, K.; Nouchi, H.; Ishikura, K.; Takaishi, S.; Motodate,
S.; Tanaka, H.; Okudaira, K.; Mochida, T.; Nishigaki, R.; Shigenobu, K.; Akita, H.
Tetrahedron 2006, 62, 2545; 4-Alkynols: (b) Kato, K.; Matsuba, C.; Kusakabe, T.;
Takayama, H.; Yamamura, S.; Mochida, T.; Akita, H.; Peganova, T. A.; Vologdin,
N. V.; Gusev, O. V. Tetrahedron 2006, 62, 9988; 4-Alkynones: (c) Kusakabe, T.;
Kato, K.; Takaishi, S.; Yamamura, S.; Mochida, T.; Akita, H.; Peganova, T. A.;
Vologdin, N. V.; Gusev, O. V. Tetrahedron 2008, 64, 319; Propargyl ketols: (d)
Kato, K.; Motodate, S.; Takaishi, S.; Kusakabe, T.; Akita, H. Tetrahedron 2008, 64,
4627; Intermolecular methoxycarbonylation: (e) Kato, K.; Motodate, S.;
Mochida, T.; Kobayashi, T.; Akita, H. Angew. Chem., Int. Ed. 2009, 48, 3326.
8. (a) Kato, K.; Teraguchi, R.; Yamamura, S.; Mochida, T.; Akita, H.; Peganova, T. A.;
Vologdin, N. V.; Gusev, O. V. Synlett 2007, 638; (b) Kato, K.; Teraguchi, R.;
Motodate, S.; Uchida, A.; Mochida, T.; Peganova, T. A.; Vologdin, N. V.; Akita, H.
Chem. Commun. 2008, 3687; (c) Kato, K.; Akita, H. J. Synth. Org. Chem. Jpn. 2009,
67, 16.
In conclusion, we have developed a new type of PdII-catalyzed
carbonylative dimerization of allenyl ketones 1. The difuranylke-
tones 4 were obtained in moderate to good yields. The electrophi-
licity of the acylpalladium species B is considered to contribute to
the oxypalladation of an additional molecule of 1. We are currently
investigating a new tandem reaction for the synthesis of other
kinds of diheteroaromatic ketones based on the cyclization–car-
bonylation–cyclization strategy presented here while also trying
to improve the synthetic efficiency of some tamoxifen analogues.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.06.016.
9. Fe(CO)5 catalyzed cyclization of 1,2-allenyl ketones with CO afforded lactones:
Sigman, M. S.; Kerr, C. E.; Eaton, B. E. J. Am. Chem. Soc. 1993, 115,
7545.
10. Synthesis of difuranylketones amd arylfuranylketones: (a) Benassi, R.; Folli, U.;
Larossi, D.; Schenetti, L.; Taddei, F.; Musatti, A.; Nardelli, M. J. Chem. Soc., Perkin
Trans. 2 1989, 1741; (b) Yang, Y.; Wong, H. N. C. Tetrahedron 1994, 50, 9583; (c)
Okuro, K.; Furuune, M.; Miura, M.; Nomura, M. J. Org. Chem. 1992, 57, 4754.
11. Marshall, J. A.; Yanik, M. M. Tetrahedron Lett. 2000, 41, 4717.
12. In addition, the use of (À)-sparteine/Pd(TFA)2 and (2,2’-bipyridine)
dichloropalladium(II) resulted in no reaction and complex mixture, respectively.
13. Xu, Y.-H.; Lu, J.; Loh, T.-P. J. Am. Chem. Soc 2009, 131, 1372.
14. Crystallographic data (excluding structure factors) for the structure have been
deposited with the Cambridge Crystallographic Data Center as supplementary
publication No. 723226. See the Supplementary data of this article.
References and notes
1. Yang, Y.; Wong, H. N. C. Tetrahedron 1994, 50, 9583. and references cited therein.
2. Neumann, H.; Brennführer, A.; Beller, M. Chem. Eur. J. 2008, 14, 3645. and
references cited therein.
3. (a) Nguyen, A.; Top, S.; Pigeon, P.; Vessières, A.; Hillard, E. A.; Plamont, M.-A.;
Huché, M.; Rigamonti, C.; Jaouen, G. Chem. Eur. J. 2009, 15, 684; (b) Chao, E. Y. H.;
Collins, J. L.; Gaillard, S.; Miller, A. B.; Wang, L.; Orband-Miller, L. A.; Nolte, R. T.;
McDonnell, D. P.; Willson, T. M.; Zuercher, W. J. Bioorg. Med. Chem. Lett. 2006, 16,
821;(c) Pandey, R. K.; Wakharkar, R. D.; Kumar, P. Synth. Commun. 2005, 35, 2795;
(d) Olier-Reuchet, C.; Aitken, D. J.; Bucourt, R.; Husson, H.-P. Tetrahedron Lett.
1995, 36, 8221; (e) Coe, P. L.; Scriven, C. E. J. Chem. Soc., Perkin Trans. 1 1986, 475.
4. (a) Schmidt, F.; Stemmler, R. T.; Rudolph, J.; Bolm, C. Chem. Soc. Rev. 2006, 35,
454; (b) Das, S. K.; Panda, G.; Chaturvedi, V.; Manju, Y. S.; Gaikwad, A. K.; Sinha,