Transition-metal-free sonogashira-type cross-coupling of alkynes with fluoroarenes

Article abstract of DOI:10.1021/ol401317m

A novel, inexpensive, and efficient palladium-, copper-, ligand-, and amine-free Sonogashira-type cross-coupling reaction of terminal alkynes with unreactive aryl fluorides in the presence of sodium, sodium methoxide, and calcium hydroxide under the assistance of a Grignard reagent was developed. A plausible mechanism was also suggested.

Full text of DOI:10.1021/ol401317m

ORGANIC
LETTERS
2013
Vol. 15, No. 12
3114–3117
Transition-Metal-Free Sonogashira-Type
Cross-Coupling of Alkynes with
Fluoroarenes
Guanyi Jin,† Xuxue Zhang,† and Song Cao*,†,‡
Shanghai Key Laboratory of Chemical Biology, School of Pharmacy,
East China University of Science and Technology, Shanghai 200237, China,
and Key Laboratory of Organofluorine Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
scao@ecust.edu.cn
Received May 11, 2013
ABSTRACT
A novel, inexpensive, and efficient palladium-, copper-, ligand-, and amine-free Sonogashira-type cross-coupling reaction of terminal alkynes with
unreactive aryl fluorides in the presence of sodium, sodium methoxide, and calcium hydroxide under the assistance of a Grignard reagent was
developed. A plausible mechanism was also suggested.
The Sonogashira cross-coupling reaction is one of the
most applied synthetic tools for the construction of inter-
nal acetylenic compounds.1 Typical procedures for the
Sonogashira reaction involve the use of palladium phosphine
complexes with CuI as the cocatalyst and large amounts of
amines as the solvents or cosolvents.2 However, the use of
expensive palladium phosphine complexes, high Pd loadings,
and Pd contamination of the products rendered Pd catalysts
unpopular, in particular, for potential large-scale industrial
applications.3 Furthermore, the presence of the copper salt
can facilitate the homocoupling reaction of the terminal
alkynes and the diyne byproduct is difficult to separate
from the target product due to similar chromatographic
properties.4
Up to now, an impressive variety of modifications of the
traditional Sonogashirareactionhave been developed such
as varying the type of palladium complex, ligand, copper
salts, and transition metals and performing the reaction in
the absence of palladium, or copper.5 However, examples
of Sonogashira cross-coupling reactions without a transition
metal still remain limited.6 In 2003, Leadbeater reported the
first example of a transition-metal-free microwave-assisted
Sonogashira-type coupling reaction using water as a solvent,
poly(ethylene glycol) as a phase-transfer agent, and sodium
hydroxide as a base.7 In 2011, Daugulis et al. described
another practical transition-metal-free alkynylation of aryl
† East China University of Science and Technology.
‡ Shanghai Institute of Organic Chemistry.
(1) (a) Doucet, H.; Hierso, J.-C. Angew. Chem., Int. Ed. 2007, 46, 834.
(b) Schilz, M.; Plenio, H. J. Org. Chem. 2012, 77, 2798. (c) Elangovan,
A.; Wang, Y.-H.; Ho, T.-I. Org. Lett. 2003, 5, 1841. (d) He, C.; Ke, J.;
Xu, H.; Lei, A. Angew. Chem., Int. Ed. 2013, 52, 1527.
(2) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 50, 4467. (b) Dieck, H. A.; Heck, F. R. J. Organomet. Chem. 1975,
93, 259.
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Int. Ed. 2000, 39, 2632. (b) Thome0, I.; Nijs, A.; Bolm, C. Chem. Soc. Rev.
2012, 41, 979. (c) Gonda, Z.; Tolnai, G. L.; Novak, Z. Chem.;Eur. J.
2010, 16, 11822.
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Chinchilla, R.; Najera, C. Chem. Rev. 2007, 107, 874. (c) Plenio, H.
Angew. Chem., Int. Ed. 2008, 47, 6954. (d) Pan, D.; Zhang, C.; Ding, S.;
Jiao, N. Eur. J. Org. Chem. 2011, 4751.
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2005, 44, 5675. (b) Pruger, B.; Hofmeister, G. E.; Jacobsen, C. B.;
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Lahoti, R. J.; Srinivasan, K. V. J. Org. Chem. 2005, 70, 4869. (b) Heuze,
Alberg, D. G.; Nielsen, M.; Jørgensen, K. A. Chem.;Eur. J. 2010, 16,
3783. (c) Maji, M. S.; Murarka, S.; Studer, A. Org. Lett. 2010, 12, 3878.
(7) Leadbeater, N. E.; Marco, M.; Tominack, B. J. Org. Lett. 2003,
5, 3919.
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K.; Mery, D.; Gauss, D.; Astruc, D. Chem. Commun. 2003, 2274. (c)
Yang, L.; Guan, P.; He, P.; Chen, Q.; Cao, C.; Peng, Y.; Shi, Z.; Pang,
G.; Shi, Y. Dalton Trans. 2012, 41, 5020. (d) Prabakaran, K.; Khan,
F. N.; Jin, J. S. Tetrahedron Lett. 2011, 52, 2566.
r
10.1021/ol401317m
Published on Web 06/11/2013
2013 American Chemical Society

chlorides which involved the use of the hindered TMPLi base
in a pentane/THF mixture at rt or a metal alkoxide base in
dioxane at elevated temperatures.8
we tried to realize the Sonogashira reaction involving
various aryl fluorides without a transition metal catalyst.
Hence, the reactions of fluorobenzene 1a with phenylace-
tylene 2a were extensively investigated in the presence of
sodium, base, and a Grignard reagent to obtain the opti-
mum reaction conditions. The detailed results are summar-
ized in Table 1. As indicated in Table 1 (entries 1ꢀ8), the
amount of sodium plays a crucial role in achieving high
conversion of acetylene to cross-coupling product 3aa.
Attempts to decrease the amount of sodium to less than
2.5 equiv resulted in lower yields of the cross-coupling
products (entries 1ꢀ5) along with a considerable amount
of biphenyl 3aa0, a homocoupling product from fluoroben-
zene. Fortunately, the homocoupling reaction of phenyla-
cetylene was sufficiently suppressed and no homocoupling
product diphenylbutadiyne 3aa00 was formed under the
reaction conditions. No reaction was observed if toluene,
benzene, DMSO or DMF were employed instead of THF.
Therefore, THF was found to be the best solvent for the
coupling reaction involving aryl fluorides (entries 8ꢀ12).
The reaction was also influenced significantly by the base
employed (entries 8, 13ꢀ19). In the absence of a base, only a
small amount of the desired product 3aa was formed.
However, when NaOCH3 or Ca(OH)2 was used as the sole
base for this coupling reaction, the expected products were
obtained in low yields. To our delight, the reaction proceeded
smoothly using Ca(OH)2 (3 equiv) combined with NaOCH3
(1 equiv) and a relatively higher yield was obtained (entry 8).
It is well-known that deprotonation of a terminal alkyne
with organomagnesium generates an alkynylmagnesium
halide.16 Acetylide anions are reactive carbon nucleophiles
and useful for the formation of a CꢀC bond.17 To examine
the influence of a Grignard reagent on the reactivity of a
terminal alkyne toward fluorobenzene, a different amount
of n-butylmagnesium chloride was added to this novel
reaction system. The results in Table 1 (entries 8, 20ꢀ22)
clearly indicated that without a Grignard reagent, a cross-
coupling reaction could not proceed. Upon addition of
1.0 equiv of n-BuMgCl, the yield of cross-coupling product
3aa increased dramatically. Furthermore, too little or too
Recently, nonactivated aryl chlorides and unreactive
alkyl halides have been successfully coupled with terminal
alkynes.9 However, less reactive organofluorine compounds
are scarcely used as coupling partners in Sonogashira
reactions due to the strong CꢀF bond.10 Up to now, only
a few reports can be found on the successful coupling of
aryl fluorides.11 For example, Yoakim have demonstrated
that the nucleophilic aromatic substitution reaction be-
tween 2-fluoronitrobenzene derivatives and terminal alkynes
can proceed efficiently using sodium bis(trimethylsilyl)-
amide (NaHMDS) as a base in the absence of transition
metal catalyst.12 More recently, Sandford described efficient
Pd-catalyzed Sonogashira-type cross-coupling reactions of
highly fluorinated nitrobenzene derivatives with terminal
acetylenes.13 However, these two approaches are limited by
the narrow choice of aryl fluorides and the strong electron-
withdrawing nitro group in fluoroarenes is essential for
activation of the CꢀF bond. Therefore, it is highly desirable
to develop an efficient and mild method for the construction
of aryl acetylenes from unreactive aryl fluorides.
Incontinuation ofour researchonthe activationof CꢀF
bonds,14 here, we report a transition-metal-free method for
the Sonogashira coupling reaction of aryl fluorides with
terminal acetylenes in the presence of sodium, calcium
hydroxide, and sodium methoxide underthe assistanceof a
Grignard reagent (Scheme 1).
At the outset of our investigations, we carried out the
Sonogashira cross-coupling reaction of fluorobenzene 1a
with phenylacetylene 2a under standard Sonogashira con-
ditions (PdCl2(PPh3)2/CuI/Et3N/DMF). Unfortunately,
the desired cross-coupling product was not observed, and
a considerable amount of the side product from the
homocoupling reaction of two acetylenes was obtained.
Scheme 1. Cross-Coupling between Various Aryl Fluorides
1aꢀj and Substituted Phenyl Acetylenes 2aꢀe
(10) (a) Ooi, T.; Uraguchi, D.; Kagoshima, N.; Maruoka, K. Tetra-
hedron Lett. 1997, 38, 5679. (b) Tarrant, P.; Savory, J.; Iglehart, E. S.
J. Org. Chem. 1964, 29, 2009. (c) England, D. C.; Melby, L. R.; Dietrich,
M. A.; Lindsey, R. V. J. Am. Chem. Soc. 1960, 82, 5116.
(11) (a) Dutta, T.; Woody, K. B.; Watson, M. D. J. Am. Chem. Soc.
2008, 130, 452. (b) Borah, H. N.; Prajapati, D.; Boruah, R. C. Synlett
2005, 18, 2823.
(12) DeRoy, P. L.; Surprenant, S.; Bertrand-Laperle, M.; Yoakim, C.
Org. Lett. 2007, 9, 2741.
(13) Cargill, M. R.; Sandford, G.; Kilickiran, P.; Nelles, G. Tetra-
hedron 2013, 69, 512.
(14) (a) Zhang, J.; Wu, J.-J.; Xiong, Y.; Cao, S. Chem. Commun.
2012, 48, 8553. (b) Wu, J.-J.; Cao, S. ChemCatChem. 2011, 3, 1582. (c)
Zhao, W.-W.; Wu, J.-J.; Cao, S. Adv. Synth. Catal. 2012, 354, 574. (d)
Xiong, Y.; Wu, J.-J.; Xiao, S.-H.; Xiao, J.; Cao, S. J. Org. Chem. 2013,
78, 4599.
(15) Amii, H.; Uneyama, K. Chem. Rev. 2009, 109, 2119.
(16) (a) Wotiz, J. H.; Hollingsworth, C. A.; Simon, A. W. J. Org.
Chem. 1959, 24, 1202. (b) Bhattacharya, S. N.; Eaborn, C.; Walton,
D. R. M. J. Chem. Soc. C 1968, 1265.
Inspired by recent developments in the transition-metal-
free Sonogashira-type coupling reactions, and also driven
by the striking success of CꢀF activation reactions,15
(8) Truong, T.; Daugulis, O. Org. Lett. 2011, 13, 4172.
ꢁ
ꢀ
(9) (a) Gredicak, M.; Jeric, I. Synlett 2009, 7, 1063. (b) Lee, D.-H.;
Kwon, Y.-J.; Jin, M.-J. Adv. Synth. Catal. 2011, 353, 3090. (c) Jin, M.-J.;
Lee, D.-H. Angew. Chem., Int. Ed. 2010, 49, 1119. (d) Hatakeyama, T.;
Okada, Y.; Yoshimoto, Y.; Nakamura, M. Angew. Chem., Int. Ed. 2011,
50, 10973. (e) Vechorkin, O.; Barmaz, D.; Proust, V.; Hu, X. J. Am.
Chem. Soc. 2009, 131, 12078. (f) Vechorkin, O.; Godinat, A.; Scopelliti,
R.; Hu, X. Angew. Chem., Int. Ed. 2011, 50, 11777. (g) Vechorkin, O.;
Barmaz, D.; Proust, V.; Hu, X. J. Am. Chem. Soc. 2009, 131, 12078. (h)
Anderson, K. W.; Buchwald, S. L. Angew. Chem., Int. Ed. 2005, 44, 6173.
(17) (a) Ishikawa, T.; Mizuta, T.; Hagiwara, K.; Aikawa, T.; Kudo,
T.; Saito, S. J. Org. Chem. 2003, 68, 3702. (b) Scott, L. T.; Cooney, M. J.;
ꢀ
Johnels, D. J. Am. Chem. Soc. 1990, 112, 4054. (c) Krasinski, A.; Fokin,
V. V.; Sharpless, K. B. Org. Lett. 2004, 6, 1237.
Org. Lett., Vol. 15, No. 12, 2013
3115

Table 1. Screening for Optimal Reaction Conditions for
Cross-Coupling of Fluorobenzene 1a with Phenylacetylene 2aa
Scheme 2. Cross-Coupling between Various Aryl Fluorides
1aꢀh and (p-Methoxyphenyl)acetylene 2ba,b
Na
base
n-BuMgCl
yield
(%)b
entry
1
(equiv)
(equiv)
(equiv)
solvent
THF
0.5
1.0
1.5
2.0
2.5
3.0
4.0
5.0
5.0
5.0
5.0
5.0
Ca(OH)2 (3),
NaOCH3 (1)
Ca(OH)2 (3),
NaOCH3 (1)
Ca(OH)2 (3),
NaOCH3 (1)
Ca(OH)2 (3),
NaOCH3 (1)
Ca(OH)2 (3),
NaOCH3 (1)
Ca(OH)2 (3),
NaOCH3 (1)
Ca(OH)2 (3),
NaOCH3 (1)
Ca(OH)2 (3),
NaOCH3 (1)
Ca(OH)2 (3),
NaOCH3 (1)
Ca(OH)2 (3),
NaOCH3 (1)
Ca(OH)2 (3),
NaOCH3 (1)
Ca(OH)2 (3),
NaOCH3 (1)
none
1
1
1
1
1
1
1
1
1
1
1
1
0
2
THF
0
3
THF
10
37
55
69
72
77
0
4
THF
5
THF
6
THF
a Reaction conditions: aryl fluorides (3ꢀ5 mmol), (p-methoxyphenyl)
acetylene 2b (1 mmol), THF (8 mL). b Yields of isolated product after
chromatographic purification and based on 2b. cWithout sodium meth-
oxide and calcium hydroxide.
7
THF
8
THF
1-fluoro-4-methoxybenzene 1g proceeded smoothly and
afforded the desired products in moderate yields (4db, 4gb)
(the substrates 1aꢀj and 2aꢀe; see Supporting Information).
The functional group tolerance was also demonstrated by
the successful reactions of different substituted phenyl
acetylenes with octafluorotoluene 1j (Scheme 3). The results
showed that the electronic nature of the substituents on the
benzene ring (2aꢀe) did not play a significant role in the
reaction. Both electron-rich and -poor substituted phenyl
acetylenes could afford the corresponding products in good
yields (5jb, 5je). It is noteworthy that octafluorotoluene 1j
reacted smoothly with various phenyl acetylenes in the
absence of bases (Ca(OH)2 and NaOCH3) due to the
exceptional reactivity of octafluorotoluene toward an an-
ion. Furthermore, addition of 1 equiv of octafluorotoluene
1j in the reaction system is enough to make the reaction
proceed smoothly.
Finally, this novel synthetic protocol was further applied to
the reactions of unreactive aryl fluorides (1a, 1b, 1d, and 1e)
with nonactivated phenyl acetylenes (2a, 2c, 2d) under the
optimized reaction conditions (Scheme 4). It was found that
these reactions also proceeded smoothly and gave the desired
product in an acceptable yield. Similar to octafluorotoluene
1j, 1-fluoro-2-nitrobenzene 1i is a more reactive substrate.
Only 1 equiv of 1i could make the coupling reaction proceed
smoothly, and no bases were required; however, the yield of
cross-coupling product 3ia was relatively low.
9
toluene
benzene
DMSO
DMF
10
11
12
0
0
0
13
14
15
16
17
18
19
20
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
1
1
1
1
1
1
1
0
THF
THF
THF
THF
THF
THF
THF
THF
38
21
30
41
51
57
62
0
Et3N (3)
NaOCH3 (2)
NaOCH3 (3)
Ca(OH)2 (1)
Ca(OH)2 (2)
Ca(OH)2 (3)
Ca(OH)2 (3),
NaOCH3 (1)
Ca(OH)2 (3),
NaOCH3 (1)
Ca(OH)2 (3),
NaOCH3 (1)
21
22
5.0
5.0
0.5
1.5
THF
THF
30
41
a Reaction conditions: fluorobenzene (5 mmol), phenylacetylene
(1 mmol), solvent (8 mL), 25 °C, 5 h. b Yields referred to the desired
product 3aa. Yields determined by GC analysis and based on 2a.
much n-BuMgCl would lead to incomplete conversion of 2a
to 3aa and a notable amount of byproduct 3aa0was produced.
Encouraged by these preliminary interesting results, we
studied the scope and limitation of this sodium and
Grignard reagent-promoted Sonogashira-type cross-coupling
reaction. First, the reactions of various aryl fluorides 1aꢀh
with (p-methoxyphenyl)acetylene 2b under the optimized
reaction conditions (Table 1, entry 8) were examined, and
the results are summarized in Scheme 2. In most cases, the
cross-coupling products were obtained in high yields. The
cross-coupling reaction of unactivated fluorobenzene 1a
with 2b worked well. We were also delighted to find that
the less reactive 1,3-difluoro-5-methoxybenzene 1d, and
Based on the above observations, it can be concluded that
the presence of electron-withdrawing groups such as CF3,
NO2 on the aryl fluorides or phenyl acetylenes bearing
electron-donating groups such as CH3O significantly pro-
motes the cross-coupling reactions and affords internal
alkynes in good to high yields, whereas electron-rich
fluoroarenes or electron-poor aryl acetylenes appear to be
unfavorable for the reaction; only moderate yields were
obtained. Aliphatic terminal alkynes such as 1-pentyne were
3116
Org. Lett., Vol. 15, No. 12, 2013

Scheme 3. Cross-Coupling between Various Substituted Phenyl
Acetylenes 2aꢀe and Octafluorotoluene 1ja,b
Scheme 5. Proposed Mechanism
a Reaction conditions: octafluorotoluene 1j (1 mmol), substituted
b
phenyl acetylenes 2aꢀe (1 mmol), THF (8 mL). Yields of isolated
According to the mechanism of the WurtzꢀFittig reac-
tion and SRN1 reaction, we proposed a simplified reaction
mechanism of this novel Sonogashira-type cross-coupling
protocol (Scheme 5). In the first step, electron transfer
from an electron-donor species, sodium, to aryl fluoride I
results in the formation of free aryl radical II and the
fluoride anion. The fluoride anion reacts with the calcium
ion to form insoluble calcium fluoride which is favorable
for the cleavage of the CꢀF bond. Another key intermedi-
ate, alkynylmagnesium chloride IV, could be generated by
the reaction of aryl acetylene III with n-butylmagnesium
chloride with the assistance of NaOCH3. In the next step,
the phenyl acetylide anion attacks aryl radical II in an
product after chromatographic purification and based on 2aꢀe.
Scheme 4. Cross-Coupling Reaction of Various Aryl Fluorides
with Phenyl Acetylenesa,b
SRN1 manner, forming the desired product V. Since the
aryl radicals are formed, a side reaction such as the Fittig
reaction leading to biphenyl derivatives VI is also possible;
however, only a trace or small amount of VI was detected.
When1 equiv of a radical scavenger, galvinoxyl, was added
to the reaction system, the reaction could not proceed
smoothly. It is indicated that a radical intermediate is
involved in this Sonogashira-type coupling reaction.
In conclusion, we have successfully achieved the
Sonogashira-type reaction of aryl fluorides and terminal
acetylenes in the presence of sodium, calcium hydroxide,
and sodium methoxide with the assistance of Grignard reagent
under Pd-, Cu-, and ligand-free conditions. The commercially
available reagents, exceptional functional group tolerance,
and good to high isolated yields make this an interesting
alternative for the synthesis of substituted CꢀC triple bonds.
a Reaction conditions: Aryl fluorides (3ꢀ5 mmol), substituted phenyl
acetylenes 2a, 2c, 2d (1 mmol), THF (8 mL). b Isolated yields and based
on 2a, 2c, 2d. c 1-Fluoro-2-nitrobenzene 1i (1 mmol), without addition of
Ca(OH)2 and NaOCH3.
also investigated, however, no obvious product was detected.
In addition, if the model reaction was performed under dark
conditions, the reaction also proceeded efficiently.
In order to gain insight into this novel reaction, three
additional experiments were carried out using the model
reaction (reaction of 1a with 2a). First, when 1 or 5 equiv of
KF were added to the reaction system under the optimized
reaction conditions, the yields of coupling product 3aa
decreased to 52% or 35% (GC), respectively. It indicated that
the addition of Fꢀ would inhibit the CꢀF bond cleavage.
Second, if the reaction was performed under an air atmo-
sphere, the yield of 3aa was decreased and the yield of 3aa0 was
increased; however, only a trace amount of 3aa00 was detected.
Finally, the replacement of fluorobenzene with benzaldehyde
underwent the reaction under identical reaction conditions,
and acetylenic alcohol (1,3-diphenylprop-2-yn-1-ol) was
obtained in moderate yield. The latter two experiments
suggested that it might be the acetylide anion, not the alkyne
radical, that reacted with the phenyl radical to form the cross-
coupling product 3aa.
Acknowledgment. We are grateful for financial support
from the National Natural Science Foundation of China
(Nos. 21072057, 21272070), the Twelfth Five-year Plan
of China (2011BAE06B01-15), and the 973 Program
(2010CB126101).
Supporting Information Available. Experimental pro-
cedures and characterization data. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 12, 2013
3117