A concise access to (polyfluoroaryl)allenes by Cu-catalyzed direct coupling with propargyl phosphates

Article abstract of DOI:10.1021/ol300886k

A copper-based catalyst system for the direct coupling of polyfluoroarenes with propargyl phosphates has been developed. The catalysis can provide a rapid and concise access to (polyfluoroaryl)allenes, which can be important building blocks for the synthesis of fluorinated functional materials.

Full text of DOI:10.1021/ol300886k

ORGANIC
LETTERS
2012
Vol. 14, No. 10
2586–2589
A Concise Access to (Polyfluoroaryl)allenes
by Cu-Catalyzed Direct Coupling with
Propargyl Phosphates
Akihiro Nakatani, Koji Hirano,* Tetsuya Satoh, and Masahiro Miura*
Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita,
Osaka 565-0871, Japan
k_hirano@chem.eng.osaka-u.ac.jp; miura@chem.eng.osaka-u.ac.jp
Received April 6, 2012
ABSTRACT
A copper-based catalyst system for the direct coupling of polyfluoroarenes with propargyl phosphates has been developed. The catalysis can
provide a rapid and concise access to (polyfluoroaryl)allenes, which can be important building blocks for the synthesis of fluorinated functional
materials.
Allenes are important building blocks in organic synthe-
sis due to their high reactivity associated with two ortho-
gonal π-bonds1 and frequently occur in natural products
and pharmaceuticals.2 In particular, arene-conjugated al-
lenes constitute anattractivestructuralclass ofcompounds
in the synthetic point of view. A metal-catalyzed SN20-type
substitution of propargylic electrophiles with arylmetal
reagents is one of the most common and reliable ap-
proaches to allene functionalities.3 A variety of catalyst
systems based on Pd,4 Rh,5 and Cu6 have been developed
to enable arylꢀallenyl coupling with organoboron, -mag-
nesium, and -lithium. However, these precedentsstill suffer
from the indispensable preactivation step, stoichiometric
metalation, of arenes or halogenated arenes to prepare the
starting organometallic compounds. Although the Lewis
(1) (a) Modern Allene Chemistry; Krause, N., Hashmi, A. S. K., Eds.;
Wiley-VCH: Weinheim, Germany, 2004; Vols. 1 and 2. (b) Sydnes, L. K.
Chem. Rev. 2003, 103, 1133. (c) Ma, S. Chem. Rev. 2005, 105, 2829.
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Roder, A. Tetrahedron 2004, 60, 11671. (b) Yu, S.; Ma, S. Chem.
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Garcıa, P.; Fernandez-Rodrıguez, M. A.; Alvarez, E.; Rodrıguez, F.
Commun. 2011, 47, 5384.
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(4) Selected recent work: (a) Yoshida, M.; Gotou, T.; Ihara, M.
Tetrahedron Lett. 2004, 45, 5573. (b) Yoshida, M.; Ueda, H.; Ihara, M.
Tetrahedron Lett. 2005, 46, 6705. (c) Molander, G. A.; Sommers, E. M.;
Baker, S. R. J. Org. Chem. 2006, 71, 1563. (d) Yoshida, M.; Okada, T.;
Ihara, M. Tetrahedron Lett. 2007, 63, 6996.
Eur. J. Org. Chem. 2010, 7027. (b) Xu, C.-F.; Xu, M.; Yang, L.-Q.; Li,
C.-Y. J. Org. Chem. 2012, 77, 7027 and references cited therein.
(8) Selected recent reviews: (a) Alberico, D.; Scott, M. E.; Lautens,
M. Chem. Rev. 2007, 107, 174. (b) Satoh, T.; Miura, M. Chem. Lett.
2007, 36, 200. (c) Campeau, L. C.; Stuart, D. R.; Fagnou, K. Aldrich-
chim. Acta 2007, 40, 35. (d) Seregin, I. V.; Gevorgyan, V. Chem. Soc. Rev.
2007, 36, 1173. (e) Park, Y. J.; Park, J.-W.; Jun, C.-H. Acc. Chem. Res.
2008, 41, 222. (f) Lewis, L. C.; Bergman, R. G.; Ellman, J. A. Acc. Chem.
Res. 2008, 41, 1013. (g) Kakiuchi, F.; Kochi, T. Synthesis 2008, 3013.
(h) Daugulis, O.; Do, H.-Q.; Shabashov, D. Acc. Chem. Res. 2009, 42,
1074. (i) Kulkarni, A. A.; Daugulis, O. Synthesis 2009, 4087. (j) Chen, X.;
Engle, K. M; Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48,
5094. (k) Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew. Chem., Int.
Ed. 2009, 48, 9792. (l) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Commun.
2010, 46, 677. (m) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110,
1147. (n) Dudnik, A. S.; Gevorgyan, V. Angew. Chem., Int. Ed. 2010, 49,
2096. (o) Satoh, T.; Miura, M. Chem.ꢀEur. J. 2010, 16, 11212.
(p) Ackermann, L. Chem. Commun. 2010, 46, 4866. (q) Hirano, K.;
Miura, M. Synlett 2011, 294.
(5) (a) Murakami, M.; Igawa, H. Helv. Chim. Acta 2002, 85, 4182.
(b) Miura, T.; Shimada, M.; Ku, S.-Y.; Tamai, T.; Murakami, M.
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Angew. Chem., Int. Ed. 2007, 46, 7101. (c) Uc-uncu, M.; Karakus, E.;
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Elmaci, N.; Artok, L. J. Org. Chem. 2011, 76, 5959.
(6) Selected reviews: (a) Ogasawara, M.; Hayashi, T. In Modern
Allene Chemistry; Krause, N., Hashmi, A. S. K., Eds.; Wiley-VCH:
Weinheim, 2004; pp 93ꢀ140. (b) Ohno, H.; Nagaoka, Y.; Tomioka, K.
In Modern Allene Chemistry; Krause, N., Hashmi, A. S. K., Eds.; Wiley-
VCH: Weinheim, 2004; pp 141ꢀ181. Recent advances: (c) Ohmiya, H.;
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r
10.1021/ol300886k
Published on Web 05/02/2012
2012 American Chemical Society

acid promoted FriedelꢀCrafts type reactions of arenes
themselves with propargylic alcohol derivatives appear to
bea good alternative, theyaregenerallylimitedtoelectron-
rich aromatics.7 Thus, further developments of more effi-
cient and rapid access to the arylallenes are quite appealing.
Meanwhile, recent advances in the metal-mediated
CꢀH functionalization can provide a powerful protocol
for the decoration of aromatics to make arylꢀaryl, arylꢀ
alkenyl, and arylꢀalkyl CꢀC bonds directly.8 Very
recently, our group9 and others10 have succeeded in the
copper- and palladium-catalyzed direct allylation of
electron-deficient aromatics, polyfluoroarenes,11 with allyllic
electrophiles. In the course of the above study, we envis-
aged that the allylation methodology could be extended to
the direct propargylation. Herein, we report a copper-
catalyzed direct allenylation of polyfluoroarenes with pro-
pargyl phosphates. The copper catalysis allows for a
straightforward access to the (polyfluoroaryl)allenes of
potentially useful building blocks for the synthesis of
fluorinated functional molecules.12
The formation of 3aa0 would follow from a base-mediated
isomerization of the initially formed R-substituted alkyne
(vide infra). The choice of leaving group was critical: the
corresponding propargyl acetate or carbonate gave neither
3aa nor 3aa0.13 Tetrafluorobenzenes that bear electron-
donating methyl and methoxy groups showed somewhat
lower reactivity and γ/R selectivity (entries 2 and 3). On the
other hand, the introduction of trifluoromethyl substitu-
tion of electron-withdrawing nature furnished the corre-
sponding allene with higher γ-selectivity (entry 4). A
pyridine analogue 1e could be employed without any
difficulties (entry 5). In the case of 1,2,4,5-tetrafluoroben-
zene (1f) that possesses two equivalent reactive CꢀH
bonds, the monoallenylation selectively occurred, albeit
with moderate efficiency and regioselectivity (entry 6). The
coupling with other fluoroarenes having less than four
fluorine atoms completely failed (data not shown), indi-
cating that the step of CꢀH bond cleavage highly depends
on the acidity of CꢀH.14
On the basis of our previous work,9 we initially selected
pentafluorobenzene (1a) and propargyl phosphate 2a as
model substrates and investigated various reaction param-
eters such as copper salt, ligand, base, and solvent.
Pleasingly, a combination of CuCl/phen catalyst (phen =
1,10-phenanthroline) and LiO-t-Bu, a similar catalyst
system to which has been developed by Daugulis for the
direct arylation of polyfluoroarenes,11b was observed to be
effective for the coupling of 1a with 2a in 1,4-dioxane even
atroom temperaturetoafforda mixtureofthecorrespond-
ing γ- and R-substituted allenes (3aa and 3aa0) in a ratio
of 92:8 with a good combined yield (Table 1, entry 1).
Table 1. Copper-Catalyzed Direct Coupling of Polyfluoroar-
enes 1 with Propargyl Phosphate 2a for the Synthesis of
(Polyfluoroaryl)allenesa
(9) Yao, T.; Hirano, K.; Satoh, T.; Miura, M. Angew. Chem., Int. Ed.
2011, 50, 2990.
(10) (a) Fan, S.; Chen, F.; Zhang, X. Angew. Chem., Int. Ed. 2011, 50,
5918. (b) Makida, Y.; Ohmiya, H.; Sawamura, M. Angew. Chem., Int.
Ed. 2012, 51, 4122.
entry
X 1
3 þ 30, yield (%)b
3/30 (γ/R)c
1
X = CF 1a
3aa þ 3aa0, 78
3ba þ 3ba0, 43
3ca þ 3ca0, 51
3da þ 3da0, 59
3ea þ 3ea0, 62
3fa þ 3fa0, 45
92:8
(11) Metal-catalyzed CꢀH functionalization of polyfluoroarenes:
Arylation: (a) Lafrance, M.; Rowley, C. N.; Woo, T. K.; Fagnou, K.
J. Am. Chem. Soc. 2006, 128, 8754. (b) Do, H.-Q.; Daugulis, O. J. Am.
Chem. Soc. 2008, 130, 1128. (c) He, C.-Y.; Fan, S.; Zhang, X. J. Am.
Chem. Soc. 2010, 132, 12850. (d) Wei, Y.; Su, W. J. Am. Chem. Soc. 2010,
132, 16377. Alkenylation and alkylation: (e) Nakao, Y.; Kashihara, N.;
Kanyiva, K. S.; Hiyama, T. J. Am. Chem. Soc. 2008, 130, 16170.
(f) Zhang, X.; Fan, S.; He, C.-Y.; Wan, X.; Min, Q.-Q.; Yang, J.; Jiang,
Z.-X. J. Am. Chem. Soc. 2010, 132, 4506. (g) Sun, Z.-M.; Zhang, J.;
Manan, R. S.; Zhao, P. J. Am. Chem. Soc. 2010, 132, 6935. Benzylation:
(h) Fan, S.; He, C.-Y.; Zhang, X. Chem. Commun. 2010, 46, 4926.
Alkynylation: (i) Wei, Y.; Zhao, H.; Kan, J.; Su, W.; Hong, M. J. Am.
Chem. Soc. 2010, 132, 2522. (j) Matsuyama, N.; Kitahara, M.; Hirano,
K.; Satoh, T.; Miura, M. Org. Lett. 2010, 12, 2358. Carboxylation:
(k) Boogaerts, I. I. F.; Nolan, S. P. J. Am. Chem. Soc. 2010, 132, 8858.
Stannylation: (l) Doster, M. E.; Hatnean, J. A.; Jeftic, T.; Modi, S.;
Johnson, S. A. J. Am. Chem. Soc. 2010, 132, 11923. Amination:
(m) Wang, Q.; Schreiber, S. L. Org. Lett. 2009, 11, 5178. (n) Zhao, H.;
Wang, M.; Su, W.; Hong, M. Adv. Synth. Catal. 2010, 352, 1301.
(o) Miyasaka, M.; Hirano, K.; Satoh, T.; Kowalczyk, R.; Bolm, C.;
Miura, M. Org. Lett. 2011, 13, 359. (p) Matsuda, N.; Hirano, K.; Satoh,
T.; Miura, M. Org. Lett. 2011, 13, 2860. Hydroxylation: (q) Liu, Q.; Wu,
P.; Yang, Y.; Zeng, Z.; Liu, J.; Yi, H.; Lei, A. Angew. Chem., Int. Ed.
201210.1002/anie.201200750.
2d
3d
4
X = CMe 1b
X = COMe 1c
X = CCF3 1d
X = N 1e
70:30
75:25
98:2
5
6d
99:1
X = CH 1f
80:20
a Reaction conditions: CuCl (0.050 mmol), phen (0.050 mmol), LiO-
t-Bu (1.50 mmol), 1 (0.50 mmol), 2a (1.0 mmol), 1,4-dioxane (3.0 mL), rt,
4 h, N2. b Yield of isolated product as a mixture of 3 and 30. c Determined
by 1H NMR or GC. d With 30 mol % of CuCl/phen and 1.5 mmol of 2a
at 80 °C.
We next evaluated the scope of propargyl phosphates
with pentafluorobenzene (1a) (Table 2). The copper catal-
ysis accommodated various aromatic substituents at the R-
position in the propargylic phosphate: chloro-, methyl-,
and methoxyphenyl groups were equally tolerated (entries
1ꢀ3). A polyfluoroarene/thiophene-conjugated allene was
also readily available (entry 4). At the alkyne terminus,
smaller methyl and functional primary alkyl groups
(12) (a) Meyer, E. A.; Castellano, R. K.; Diederich, F. Angew. Chem.,
€
Int. Ed. 2003, 42, 1210. (b) Muller, K.; Faeh, C.; Diederich, F. Science
2007, 317, 1881. (c) Hird, M. Chem. Soc. Rev. 2007, 36, 2070. (d) Purser,
S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37,
320. (e) Amii, H.; Uneyama, K. Chem. Rev. 2009, 109, 2119.
(f) Kenwright, A. M.; Sandford, G.; Tadeusiak, A. J.; Yufit, D. S.;
Howard, J. A. K.; Kilickiran, P.; Nelles, G. Tetrahedron 2010, 66, 9819.
(13) See the Supporting Information for details.
(14) For pKa values of representative fluoroarenes, see: Shen, K.; Fu,
Y.; Li, J.-N.; Liu, L.; Guo, Q.-X. Tetrahedron 2007, 63, 1568.
Org. Lett., Vol. 14, No. 10, 2012
2587

containing chloride and silyl ether moieties were com-
patible (entries 5ꢀ7). In the above cases, a satisfying
γ-selectivity was observed. However, the sterically demand-
ing secondary and tertiary alkyl substituents decreased the
γ/R selectivity, although the reaction proceeded smoothly
(entries 8 and 9). Particularly, the tert-butyl-substituted
propargyl phosphate 2j gave the R-substituted allene 3aj0 as
a major regioisomer.15
Scheme 1. Stoichiometric and Catalytic Reactions of
(phen)CuC6F5 (4) with Propargylic Phosphates 2a and 2j
Table 2. Copper-Catalyzed Direct Coupling of Pentafluoro-
benzene (1a) with Various Propargyl Phosphates 2a
entry
R, Ar 2
3 þ 30, yield (%)b 3/30 (γ/R)c
1
2
3
4
5
6
7
8
9
R = Bu, Ar = 4-ClC6H4 (2b)
R = Bu, Ar = 4-MeC6H4 (2c)
3ab þ 3ab0, 67
91:9
93:7
95:5
98:2
95:5
93:7
93:7
76:24
12:88
3ac þ 3ac0, 79
R = Bu, Ar = 3-MeOC6H4 (2d) 3ad þ 3ad0, 69
R = Bu, Ar = 3-thienyl (2e)
R = Me, Ar = Ph (2f)
3ae þ 3ae0, 57
3af þ 3af0, 52
3ag þ 3ag0, 68
R = (CH2)4Cl, Ar = Ph (2g)
R = (CH2)3OTBS, Ar = Ph (2h) 3ah þ 3ah0, 71
the formation of γ-substituted allene 3aa to be as follows
(Scheme 2). Initial ligand exchange of CuCl with LiO-t-Bu
and phenformsthe (phen)CuO-t-Bu (5). Subsequentdirect
cupration of pentafluorobenzene (1a) occurs with the aid
of an O-t-Bu ligand of strongly basic nature to furnish the
key intermediate (phen)CuC6F5 (4).16 An addition/
elimination sequence17 in the reaction of 4 with 2a delivers
the corresponding γ-substituted allene 3aa along with the
copper phosphate 6. Finally, the starting alkoxide complex
5 is regenerated by the action of LiO-t-Bu to complete the
catalytic cycle. Although the detailed pathway directed
toward the R-substituted allene 3aa0 remains elusive at the
present stage, an ate-type organocopper species generated
from 4 undergoes oxidative addition of 2a to form an
allenylcopper intermediate. The allenylcopper is in equili-
brium to the corresponding propargylcopper, en route to a
mixture of γ-substituted allene and R-substituted alkyne.18
The formed R-substituted alkyne is isomerized by LiO-
t-Bu to the observed R-substituted allene. The proposed
mechanisms can account for the results in Scheme 1: under
catalytic conditions, two distinct addition/elimination and
oxidative addition pathways are competitive, and thus the
γ-selectivity is generally lower than that under stoichio-
metric conditions. Exemplified by 2j, the increasing steric
bulkiness at the γ-position in the propargyl phosphate
would hamper the addition/elimination process to allow
the ate-type-copper-mediated oxidative addition pathway
to be predominant under catalytic conditions.
R = cyclohexyl, Ar = Ph (2i)
R = t-Bu, Ar = Ph (2j)
3ai þ 3ai0, 66
3aj þ 3aj0, 55
a Reaction conditions: CuCl (0.050 mmol), phen (0.050 mmol), LiO-
t-Bu (1.50 mmol), 1a (0.50 mmol), 2 (1.0 mmol), 1,4-dioxane (3.0 mL), rt,
4 h, N2. b Yield of isolated product as a mixture of 3 and 30. c Determined
by 1H NMR or GC.
To attain some mechanistic insight, we synthesized a
putative organocopper intermediate, (phen)CuC6F5 (4),16
and performed the following stoichiometric and catalytic
reactions (Scheme 1). Upon exposure of 2a to a stoichio-
metric amount of 4, the corresponding allenes were ob-
tainedin78% combinedyield with98:2γ/R selectivity. The
copper complex 4 also could act as an effective catalyst for
the reaction of 1a with 2a to afford the same products but
with slightly lower regioselectivity (γ/R = 91:9). On the
otherhand, the stoichiometricreactionof 4 with2jgavethe
corresponding γ-substituted allene 3aj as a major product
(γ/R = 98:2), albeit in 36% yield, the regioselectivity of
which runs counter to that under optimal conditions (γ/R =
12:88, Table 2, entry 9). In sharp contrast, the catalytic
reaction with 4 gave 11:89 γ/R selectivity similar to the
result of entry 9 in Table 2. These phenomena suggest that
the monoarylcopper 4 would give the γ-substituted allene
selectively, while an intermediate responsible for the
R-substitution could be another organocopper species
derived from 4 under catalytic conditions.
Based on the above outcomes and literature informa-
tion, we are tempted to assume the reaction mechanism for
(17) (a) Normant, J. F.; Alexakis, A. Synthesis 1981, 841. (b) Alexakis,
A.; Marek, I.; Mangeney, P.; Normant, J. F. J. Am. Chem. Soc. 1990, 112,
8042 and ref 6cꢀ6e. At this stage, the stereochemistry in the addition/
elimination (syn or anti) is not clear, which will be reported in due course.
(15) See the Supporting Information for the result of the reaction
with R,γ-dialkylphosphate.
(16) Do, H.-Q.; Khan, R. M. K.; Daugulis, O. J. Am. Chem. Soc.
2008, 130, 15185.
ꢀ
(18) Dollat, J.-M.; Luche, J.-L.; Crabbe, P. J. Chem. Soc., Chem.
Commun. 1977, 761. For relevant discussion, see ref 6cꢀ6e.
2588
Org. Lett., Vol. 14, No. 10, 2012

phosphates, providing the (polyfluoroaryl)allenes di-
rectly. To the best of our knowledge, this is the first
example of the direct introduction of allenyl moieties to
electron-deficient arenes, although the regioselectivity
is still dependent on the substitution pattern of the
phosphates. Further efforts seek to improve the γ/R
selectivity by catalyst control and to expand the arene
substrate scope.
Scheme 2. Plausible Mechanism for the Formation of
γ-Substituted Allene 3aa
Acknowledgment. This work was partly supported by
Grants-in-Aid from MEXT and JSPS, Japan.
Supporting Information Available. Detailed experimen-
tal procedures and characterization data of compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
In conclusion, we have developed an efficient copper
catalyst for the reaction of polyfluoroarenes with propargyl
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 10, 2012
2589