Synthesis of heterocyclic allenes via palladium-catalyzed hydride-transfer reaction of propargylic amines

Article abstract of DOI:10.1021/jo0479664

(Chemical Equation Presented) Propargylic diisopropylamines containing heterocycles, which were prepared readily from heterocyclic bromides and propargyldiisopropylamine by the Sonogashira coupling reaction, underwent the allene transformation reaction in

Full text of DOI:10.1021/jo0479664

SCHEME 1. Concept of an Allenyl Anion
Equivalent
Synthesis of Heterocyclic Allenes via
Palladium-Catalyzed Hydride-Transfer
Reaction of Propargylic Amines
Hiroyuki Nakamura,* Shinya Onagi, and
Takaya Kamakura
methods include the homologation of 1-alkynes,7 the
stereoselective reduction of alkynes,8 asymmetric allyla-
tions,9,10 â-eliminations by Horner-Emmons-Wadsworth11
or sulfinyl radical12 reactions, and palladium-catalyzed
hydrogenolysis13 or coupling reactions of allenyl-
stannanes,14 allenylindiums,15 and allenylzincs16 have
been recently reported. However, there are few examples
of the synthesis of allenes containing heterocycles15a due
to unexpected interactions between the substrates and
reagents (or catalysts), which would interrupt the reac-
tion progress. We recently found that propargylic amines
underwent the hydride-transfer reaction in the presence
of a palladium catalyst to afford allenes.17 In this
transformation, propargylic amines can be handled as an
allenyl anion equivalent and introduced into various
electrophiles to be transformed into allenes (Scheme 1).
In this paper, we report the synthesis of heterocyclic
allenes from the corresponding propargylic amines via
the Sonogashira coupling followed by the palladium-
catalyzed hydride-transfer reaction.
The heterocyclic allene precursors were synthesized
using the Sonogashira coupling reaction of N,N-diisoprop-
ylprop-2-ynylamine with various heterocyclic bromides
(R-Br).18 The results are shown in Table 1. The reactions
were carried out in the presence of Pd(PPh3)4 (5 mol %),
CuI (10 mol %) and Et3N (150 mol %) in CH3CN at 60
°C. The propargylic diisopropylamines 1a-f were ob-
tained from the corresponding bromides in 67-99% yields
(entries 1-6). The reaction of 3-bromo-benzo[b]thiophene
with N,N-diisopropylprop-2-ynylamine also proceeded
under the same conditions to give the corresponding
propargylic diisopropylamine 1g in 51% yield (entry 7).
Although 5-bromoindole did not undergo the Sonogashira
coupling reaction, the reaction of N-Boc-5-bromoindole
Department of Chemistry, Faculty of Science, Gakushuin
University, Mejiro, Toshima-ku, Tokyo 171-8588, Japan
hiroyuki.nakamura@gakushuin.ac.jp
Received November 17, 2004
Propargylic diisopropylamines containing heterocycles, which
were prepared readily from heterocyclic bromides and pro-
pargyldiisopropylamine by the Sonogashira coupling reac-
tion, underwent the allene transformation reaction in the
presence of Pd2(dba)3‚CHCl3 catalyst (2.5 mol %) and 1,2-
bis[bis(pentafluorophenyl)phosphino]ethane (10 mol %) at
100 °C in CHCl3, giving the corresponding heterocyclic
allenes in good to high yields via the palladium-catalyzed
hydride-transfer reaction.
Allenes are now very important building blocks for
organic synthesis.1-5 In general, allenes can be prepared
from propargyl alcohol derivatives by SN2′-type displace-
ment with organocopper species.6 Other preparation
(1) (a) The Chemistry of Allenes; Landor, S. R. Ed.; Academic
Press: London, 1982. (b) Hoffmann-Roder, A.; Krause, N. Angew.
Chem., Int. Ed. 2002, 41, 2933. (c) Modern Allene Chemistry; Krause,
N., Hashmi, S., Eds.; Wiley-VCH: Weinheim, 2004.
(2) For transition-metal-catalyzed reactions, see: (a) Yamamoto, Y.;
Al-Masum, M.; Asao, N. J. Am. Chem. Soc. 1994, 116, 6019. (b) Trost,
B. M.; Gerusz, V. J. J. Am. Chem. Soc. 1995, 117, 5156. (c) Franze´n,
J.; Lo¨fstedt, J.; Dorange, I.; Ba¨ckvall, J.-E. J. Am. Chem. Soc. 2002,
124, 11246. (d) Wender, P. A.; Jenkins, T. E.; Suzuki, S. J. Am. Chem.
Soc. 1995, 117, 1843. (e) Ahmed, M.; Amauld, T.; M. Barrett, A. G.;
Braddock, D. C.; Flack, K.; Procopiou, P. A. Org. Lett. 2000, 2, 551. (f)
Lu, C.; Lu, X. Org. Lett. 2002, 4, 4677.
(3) For [2 + 2] cycloadditions, see: (a) Kimura, M.; Horino, Y.;
Wakamiya, Y.; Okajima, T.; Tamaru, Y. J. Am. Chem. Soc. 1997, 119,
10869. (b) Morimoto, T.; Horiguchi, T.; Yamada, K.; Tsutsumi, K.;
Kurosawa, H.; Kakiuchi, K. Synthesis 2004, 753.
(4) For synthesis of heterocycles, see: (a) Larock, R. C.; Zenner, J.
M. J. Org. Chem. 1999, 64, 7312. (b) Grigg, R.; Sridharan, V.; Xu, L.-
H. Chem. Commun. 1995, 1903. (c) Dieter, R. K.; Yu, H. Org. Lett.
2001, 3, 3855. (d) Hashmi, A. S. K. Angew. Chem., Int. Ed. 1995, 34,
1581. (e) Hashmi, A. S. K.; Schwarz, L.; Choi, J.-H.; Frost, T. M. Angew.
Chem., Int. Ed. 2000, 39, 2285. (f) Brandasma, L.; Nedolya, N.
Synthesis 2004, 735. (g) Rega´s, D.; Palenzuela, J. A. Synthesis 2004,
757. (h) Ishar, M. P.; Kapur, A.; Raj, T.; Girdhar, N. K.; Kaur, A.
Synthesis 2004, 775. (i) Sromek, A. W.; Kel′in, A. V.; Gevorgyan, V.
Angew. Chem., Int. Ed. 2004, 43, 2280.
(7) Searles, S.; Li, Y.; Nassim, B.; Robert Lopes, M.-T.; Tran, P. T.;
Crabbe´, P. J. Chem. Soc., Perkin Trans. 1 1984, 747.
(8) Myers, A. G.; Zheng, B. J. Am. Chem. Soc. 1996, 118, 4492.
(9) (a) Ogasawara, M.; Ikeda, H.; Nagano, T.; Hayashi, T. J. Am.
Chem. Soc. 2001, 123, 2089. (b) Zimmermann, M.; Wibbeling, B.;
Hoppe, D. Synthesis 2004, 765.
(10) Fukuhara, K.; Okamoto, S.; Sato, F. Org. Lett. 2003, 5, 2145.
(11) (a) Tanaka, K.; Otsubo, K.; Fuji, K. Synlett 1995, 993. (b)
Brummond, K. M.; Dingess, E. A.; Kent, J. L. J. Org. Chem. 1996, 61,
6096.
(12) Delouvrie, B.; Lacote, E.; Fensterbank, L.; Malacria, M.
Tetrahedron Lett. 1996, 40, 3565.
(13) (a) Tsuji, J.; Sugiura, T.; Yuhara, M.; Minami, I. Chem.
Commun. 1986, 922. (b) Tsuji, J.; Sugiura, T.; Minami, I. Synthesis
1987, 603.
(14) (a) Badone, D.; Cardamone, R.; Guzzi, U. Tetrahedron Lett.
1994, 35, 5477. (b) Huang, C.-W.; Shanmugasundaram, M.; Chang,
H.-M.; Cheng, C.-H. Tetrahedron 2003, 59, 3635.
(15) (a) Lee, K.; Seomon, D.; Lee, P. H. Angew. Chem., Int. Ed. 2002,
41, 3901. (b) Lin, M.-J.; Loh, T.-P. J. Am. Chem. Soc. 2003, 125, 13042.
(16) (a) Ma, S.; He, Q. Angew. Chem., Int. Ed. 2004, 43, 988. (b)
Ma, S.; Zhang, A. J. Org. Chem. 1998, 63, 9601.
(5) For polymer synthesis, see: Takagi, K.; Tomita, I.; Endo, T.
Macromolecules 1997, 30, 7386.
(6) (a) Allenes in Organic Synthesis; Coppola, G. M., Schuster, H.
F., Eds.; Wiley: New York, 1984. (b) Alexakis, A.; Marek, I.; Mangeney,
P.; Normant, J. F. J. Am. Chem. Soc. 1990, 112, 8042.
(17) Nakamura, H.; Kamakura, T.; Ishikura, M.; Biellmann, J.-F.
J. Am. Chem. Soc. 2004, 126, 5958.
(18) (a) Bleicher, L.; Cosford, N. D. P. Synlett 1995, 1115. (b) Russo,
O.; Alami, M.; Brion, J.-D.; Sicsic, S.; Berque-Bestel, I. Tetrahedron
Lett. 2004, 45, 7069.
10.1021/jo0479664 CCC: $30.25 © 2005 American Chemical Society
Published on Web 02/04/2005
J. Org. Chem. 2005, 70, 2357-2360
2357

TABLE 1. Preparation of the Heterocyclic Allene Precursors 1a-h from R-Br by the Sonogashira Coupling Reactiona
a All reactions were carried out in the presence of Pd(PPh3)4 (5 mol %), CuI (10 mol %), and Et3N (150 mol %) in CH3CN at 60 °C.
b Isolated yields based on the bromides.
TABLE 2. Allene Transformation Reaction of 1a in the
with N,N-diisopropylprop-2-ynylamine gave the corre-
Presence Pd2Dba3‚CHCl3 Catalyst at 100 °C under
Various Conditions
sponding propargylic diisopropylamine 1h in 26% yield
(entry 8).
The allene transformation reaction of diisopropyl-(3-
pyridin-3-yl-prop-2-ynyl)-amine 1a under various condi-
tions was initially examined (Scheme 3 and Table 2). The
reaction progress was monitored by GC analysis. The
reaction of 1a proceeded in the presence of Pd2(dba)3‚
CHCl3 catalyst (2.5 mol %) and (C6F5)3P (20 mol %) at
100 °C in dioxane for 48 h, giving 3-pyridylallene 2a in
96% yield (entry 1). Although the use of THF and ethyl
acetate as a solvent gave 2a in moderate yields (entries
2 and 3), acceleration of the reaction was observed in
DMF (entry 4). CH3CN and CHCl3 were also effective
solvents for the reaction (entries 5 and 6). Next, the effect
of ligands on the allene transformation was examined.
The reactions of 1a using Ph3P or (PhO)3P (20 mol %),
as a ligand, at 100 °C in dioxane for 12 h gave 2a in very
poor yields (entries 7 and 8). The use of dppe as a
bidentate ligand was effective for the reaction and the
yield increased to 57% (entry 9). Interestingly, 2a was
obtained in 94% yield when 1,2-bis[bis(pentafluoro-
phenyl)phosphino]ethane was employed as a ligand
(entry 10). Finally, the best result was obtained in the
case of entry 11: the reaction of 1a proceeded in the
presence of Pd2(dba)3‚CHCl3 catalyst (2.5 mol %) and 1,2-
bis[bis(pentafluorophenyl)phosphino]ethane (10 mol %)
at 100 °C in CHCl3 for 24 h, giving 2a, quantitatively.
entry solvent
ligand (mol %)b
time, h yielda, %
1
dioxane (C6F5)3P (20)
48
24
24
8
24
24
12
12
24
24
24
96
80
79
84
93
91
7
2
THF
(C6F5)3P (20)
(C6F5)3P (20)
(C6F5)3P (20)
3
AcOEt
DMF
4
5
CH3CN (C6F5)3P (20)
6
CHCl3
(C6F5)3P (20)
7
dioxane Ph3P (20)
8
dioxane (PhO)3P (20)
dioxane dppe (10)
20
57
94
>99
9
10
11
dioxane (C6F5)2PC2H4P(C6F5)2 (10)
CHCl3
(C6F5)2PC2H4P(C6F5)2 (10)
a Yields were determined by GC analysis using hexadecane as
an internal standard. b Four atom equivalents of phosphines
toward the Pd2dba3‚CHCl3 catalyst (2.5 mol %) was used for the
reactions.
Once a suitable condition for the palladium-catalyzed
allene transformation reaction was established, we next
investigated the synthesis of various heterocyclic allenes
(2a-h) from the corresponding propargylic amines con-
taining heterocycles (1a-h) as shown in Table 3. The
reaction of 1b, which was prepared from 5-bromopyri-
2358 J. Org. Chem., Vol. 70, No. 6, 2005

TABLE 3. Synthesis of Heterocyclic Allenes from
Various Propargylic Diisopropylamines 1a-h via the
Palladium-Catalyzed Hydride-Transfer Reactiona
SCHEME 3. Proposed Mechanism
entry propargylic amines 1 time, h allene 2 yieldb of 2, %
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
24
48
28
30
30
24
24
29
2a
2b
2c
2d
2e
2f
>99c
89
91
95
86
51
1g
1h
2g
2h
87
88
a The reaction was carried out in the presence of Pd2(dba)3‚CHCl3
catalyst (2.5 mol %) and 1,2-bis[bis(pentafluorophenyl)phos-
phino]ethane (10 mol %) at 100°C in CHCl3. b Isolated yield. c GC
yield.
carbon triple bond would form the complex 8 and the
hydride transfer from the isopropyl carbon assisted by a
lone pair electron of the nitrogen would generate the
palladium anion species 9. The migration of the hydride
on palladium to the alkyne moiety of 9 followed by the
rearrangement of the π-bond would give the allene 2 and
the imine 10, and palladium(0) is regenerated. Since 1,2-
bis[bis(pentafluorophenyl)phosphino]ethane, as well as
(C6F5)3P, were effective for the allene transformation
reaction of heterocyclic compounds, it is considered that
these electron-deficient phosphine ligands would stabilize
the anionic palladium intermediate 9 in the equilibrium
between 8 and 9 to accelerate the generation of allenes
2 in the catalytic cycle. Furthermore, the bidentate
phosphine ligand such as 1,2-bis[bis(pentafluorophenyl)-
phosphino]ethane would prevent the other heterocyclic
molecules from coordinating to the palladium catalyst in
the reaction. Therefore, 1,2-bis[bis(pentafluorophenyl)-
phosphino]ethane is more suitable than (C6F5)3P in the
current transformation of heterocyclic allenes. It has been
reported that the iminium ion can be generated by the
insertion of palladium coordinated to the nitrogen lone
pair into the carbon-hydrogen bond adjacent to nitro-
gen.19
In conclusion, we developed a novel synthesis of
heterocyclic allenes from the corresponding bromides
with N,N-diisopropylprop-2-ynylamine, as an allenyl
anion equivalent, through the Sonogashira coupling
reaction followed by the palladium-catalyzed hydride-
transfer reaction. The bidentate phosphine ligand, 1,2-
bis[bis(pentafluorophenyl)phosphino]ethane, as well as
(C6F5)3P, were effective for the allene transformation
reaction of heterocyclic compounds. It is now possible to
conduct heterocyclic allenes not only as a building block
for organic synthesis but also as a biofuctional group for
medicinal chemistry.20
SCHEME 2. Deuterium Labeling Study
midine, was complete after 48 h to give 5-allenylpyrimi-
dine 2b in 89% yield (entry 2). The dimethoxy pyrimidine
1c, which can be easily introduced into the uracil
derivative by deprotection of methyl ethers, also under-
went the allene transformation reaction to afford 2c in
91% yield (entry 3). An ethyl ester substituted pyridine
1d was readily transformed into 2d in 95% yield (entry
4). Although the reaction of 1e afforded 3-allenylquinoline
2e in 86% yield (entry 5), the reaction of the isoquinoline
1f resulted in a lower yield of 2f (entry 6). The benzo[b]-
thiophene 1g and N-Boc-protected indole 1h were also
examined, and the corresponding allenes 2g and 2h were
obtained in 87% and 88% yields, respectively (entries 7
and 8). The transformation reactions of 1b-e under the
combination of Pd2(dba)3‚CHCl3/(C6F5)3P catalyst at 100
°C gave the corresponding allenes 2b-e in lower yields
(40-68%) compared to previous reports.17
To clarify the mechanism of the current allene trans-
formation reaction, a deuterium labeling study was
performed as shown in Scheme 2. The reduction of the
imine 3 generated in situ from acetone and isoprop-
ylamine was carried out using NaBD4 to afford the
corresponding to the monodeuterium-labeled diisoprop-
ylamine 4, which was treated with 3-bromo-1-phenyl-1-
propyne in the presence of K2CO3 in MeCN, giving N,N-
diisopropyl-3-phenylprop-2-ylamine 5 (d-94%). The allene
transformation of 5 proceeded in the presence of Pd2-
(dba)3‚CHCl3/(C6F5)3P catalyst at 100 °C in dioxane to
afford a 4:1 mixture of phenylallene 6 and 1-deurerio-1-
phenylallene 7. This ratio was due to the isotope effect
and the hydride-transfer step from the isopropyl carbon
would be considered as a rate-determining step in the
allene transformation. Based on the result of the deute-
rium labeling study, the proposed mechanism is shown
in Scheme 3. π-Coordination of Pd(0) with 1 at a carbon-
Experimental Section
Representative Procedure for the Synthesis of 1b by
the Sonogashira Coupling Reaction. A mixture of 5-bro-
mopyrimidine (318 mg, 2.0 mmol), Pd(PPh3)4 (116 mg, 0.10
mmol), CuI (38.1 mg, 0.20 mmol), and N,N-diisopropylprop-2-
ynylamine (334 mg, 2.4 mmol) was dissolved in acetonitrile (10
mL) under Ar, and triethylamine (0.42 mL, 3.0 mmol) was
added. The mixture was stirred at 60 °C for 6 h. The reaction
progress was monitored by TLC. The solvent was removed under
(19) (a) Murahashi, S.-I.; Hirano, T.; Yano, T. J. Am. Chem. Soc.
1978, 100, 348. (b) Murahashi, S.-I.; Watanabe, T. J. Am. Chem. Soc.
1979, 101, 7430. (c) Saa´, J. M.; Dopico, M.; Martorell, G.; Garc´ıa-Raso,
A. J. Org. Chem. 1990, 55, 991.
(20) (a) Krause, N.; Hoffmann-Ro¨der, A. In Modern Allene Chem-
istry; Krause, N., Hashmi, S., Eds.; Wiley-VCH: Weinheim, 2004; p
997. (b) Brummond, K. M.; Chen, H. In Modern Allene Chemistry;
Krause, N., Hashmi, S., Eds.; Wiley-VCH: Weinheim, 2004; p 1041.
J. Org. Chem, Vol. 70, No. 6, 2005 2359

reduced pressure, and the residue was purified by silica gel
column chromatography with hexane/ethyl acetate (1/1) to give
was purified by silica gel column chromatography with hexane/
ethyl acetate (5/1) to give 2c (50.6 mg, 0.284 mmol, 91% yield)
as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.20 (s, 1H), 6.17
(t, J ) 6.8 Hz, 1H), 5.11 (d, J ) 6.8 Hz, 2H), 3.98 (s, 3H), 3.96
(s, 3H). 13C NMR (75 MHz, CDCl3) δ 209.4, 167.2, 164.2, 156.1,
108.7, 84.0, 78.7, 54.8, 54.0. IR (KBr) 2953, 1944, 1564, 1468,
1383, 1350, 1283, 1190, 1086, 1009 cm-1. HRMS (EI) calcd for
C9H10N2O2 (M+) 178.0742, found 178.0740.
1
1b (429 mg, >99% yield) as a colorless oil. H NMR (400 MHz,
CDCl3) δ 9.05 (s, 1H), 8.68 (s, 2H), 3.62 (s, 2H), 3.19 (sept, J )
6.4 Hz, 2H), 1.10 (d, J ) 6.4 Hz, 12H). 13C NMR (75 MHz, CDCl3)
δ 158.6, 156.4, 120.2, 97.1, 76.7, 48.7, 34.9, 20.6. IR (KBr) 2968,
2233, 1539, 1412, 1383, 1325, 1269, 1184, 1119, 1030 cm-1
.
HRMS (EI) calcd for C13H19N3 (M+) 217.1579, found 217.1578.
Representative Procedure for the Synthesis of 2c. A
mixture of 3-(2,4-dimethoxy-pyrimidine-5-yl)-prop-2-ynyl-N,N-
diisopropylamine 1c (86.6 mg, 0.312 mmol), Pd2(dba)3‚CHCl3 (8.1
mg, 0.0078 mmol), and 1,2-bia[bis(pentafluorophenyl)phosphino]-
ethane (23.7 mg, 0.031 mmol) was dissolved in dry chloroform
(2 mL) under Ar. The mixture was stirred at 100 °C for 28 h in
a vial tube. The reaction progress was monitored by TLC. The
solvent was removed under reduced pressure, and the residue
Supporting Information Available: Experimental de-
tails and characterization data for compounds 1a-h and 2a-
h. This material is available free of charge via the Internet at
http://pubs.acs.org.
JO0479664
2360 J. Org. Chem., Vol. 70, No. 6, 2005