Photo-cross-coupling reaction of electron-rich aryl chlorides and aryl esters with alkynes: A metal-free alkynylation

Article abstract of DOI:10.1002/anie.200501541

(Chemical Equation Presented) Photoheterolysis of aryl halides substituted with electron-donating groups (EDGs) or aryl esters in 2,2,2-trifluoroethanol (TFE) leads to phenyl cations, which can add to alkynes (see scheme, Tf = trifluoromethanesulfonyl). This reaction is an appealing metal-free alternative to the (sila)-Sonogashira reaction.

Full text of DOI:10.1002/anie.200501541

Angewandte
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Addition Reactions
cations. In the last few years we have demonstrated that these
intermediates (in the triplet state) are obtained smoothly by
DOI: 10.1002/anie.200501541
photolysis of aryl halides substitued with electron-donating
groups (for example,chlorophenol
[15]
or fluoroanilines[16]),
Photo-Cross-Coupling Reaction of Electron-Rich
Aryl Chlorides and Aryl Esters with Alkynes:
A Metal-Free Alkynylation**
aryl sulfonates,and aryl phosphates (for example,methoxy-
phenyl mesylate or N,N-dimethylaminophenyl phosphate),[17]
À
and add to alkenes to form an aryl C bond via a phenonium
ion.[15a,18] We surmised that phenyl cations would react with
triple bonds to yield b-phenylvinyl cations,or more probably
cyclic vinylenebenzenium ions (Scheme 1). The last species
have been invoked as intermediates in the thermal solvolysis
of styryliodonium tetrafluoroborate[19] and in the photoheter-
olysis of (E)-bromostyrene[20] (Scheme 1).
Stefano Protti, Maurizio Fagnoni,* and Angelo Albini*
Aryl acetylenes are versatile intermediates in organic syn-
thesis in view of the easy derivatization of their triple bonds[1]
and find application in molecular electronics.[2] The elective
method for the synthesis of these compounds is the Sonoga-
shira reaction,which involves the Pd/Cu-mediated formation
2
À
of a C(sp ) C(sp) bond. Despite many efforts to improve this
method,the most popular protocol in use today still consists
of a mixture of an aryl iodide or bromide,a terminal alkyne,
[PdCl2(PPh3)2],an amine,and CuI: the same protocol as
introduced many years ago by Sonogashira et al.[3,4]
There has been growing interest into extending the
reaction to different aryl precursors; for example,aryl
triflates (or nonaflates) were introduced about 20 years
ago,[5] and more recently aryl tosylates[6] and aryl boronic
acids were also used (in the latter case the presence of air is
tolerated).[7] However,the inexpensive aryl chlorides have
been employed with success in only a few cases,but
necessitated the use of high temperatures.[6,8] The use of a
[9]
single metal compound is possible,and palladium-free and
copper-free[10] protocols have also been investigated for some
aryl bromides and iodides. In some cases,copper salts cause
an adverse effect on the reaction and do not result in the
intended catalysis. Thus,copper can either inhibit the
reaction[6] or promote oxidative homocoupling.[11] An effec-
tive metal-free reaction is clearly desirable and a step in this
direction was recently achieved by using microwave-assisted
reactions,[12] although satisfying results have been obtained
only in one case,namely the reaction between aryl iodides
and phenylacetylenes. The Sonogashira reaction generally
involves non-activated terminal alkynes,although tetraal-
kynyl aluminates[13a] and alkynyl trifluoroborates[13b] make the
coupling reaction with aryl halides (or triflates) cleaner. A
“sila”-Sonogashira reaction starting from alkynylsilanes has
also found limited application.[14]
Scheme 1. Hypothesized photogeneration and reaction of the vinylene-
benzenium ion. Ms=methanesulfonyl, Tf=trifluoromethanesulfonyl,
EDG=electron-donating group.
The usual literature methods for the generation of vinyl-
enebenzenium ions employ a nucleophilic solvent,usually an
alcohol. Under these conditions,addition to form an alkoxy-
styryl derivative occurred (path a,see Scheme 1 for the case
of propyne),[19,21] although proton elimination competed to a
variable extent and led either to an aryl alkyne (path b) or an
aryl allene (path c). Thus,the choice of the conditions is
critical so that the desired elimination occurs to form an aryl
alkyne.
A radically different approach for the synthesis of aryl
acetylenes is presented here,and is based on the use of phenyl
In view of the above findings,we studied the photolysis of
various precursors of the 4-methoxyphenyl cation,namely,
the corresponding chloride (1a),mesylate ( 1b),triflate ( 1c),
diethylphosphate (1d),and fluoride ( 1e; 0.05m) in the
presence of 1-hexyne (2,a terminal alkyne),ethynyltrimethyl-
silane (3,a partially silylated alkyne),and trimethylsilyl-
propyne (4,a precursor lacking acetylenic hydrogen atoms;
0.5m). The results of the irradiation experiments are shown in
Table 1.
[*] S. Protti, Dr. M. Fagnoni, Prof. A. Albini
Department of Organic Chemistry
University of Pavia
Via Taramelli 10, 27100 Pavia (Italy)
Fax: (+39)0382-987323
E-mail: fagnoni@unipv.it
We were happy to find that cross-coupling with 1-hexyne
took place upon irradiation (lexc = 310 nm,36 h) of 1 in 2,2,2-
trifluoroethanol (TFE) in the presence of an equimolar
amount of base (triethylamine,TEA [22]) to yield 4-(1-hex-
ynyl)anisole (5) in more than 60% yield (90% when using
angelo.albini@unipv.it
[**] Partial support of this work by Murst, Rome, is gratefully
acknowledged.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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5675

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Table 1: Photolysis of 4-methoxyphenyl derivatives 1 (0.05m) in the presence of 0.5m alkyne.
under these conditions the consumption of
1a after 36 h was limited to 37% and the
only significant product was anisole (12%).
The generation of phenyl cat-
ions from aromatic compounds substituted
with other electron-donating groups[25] was
then explored by using the readily accessi-
ble chlorides 8–10 (Table 2). The reaction
was successful also in these cases (44–71%
yield). However,the use of 4-chlorothio-
anisole 8 resulted in clouding of the solution
during the irradiation,which hindered the
complete consumption of the halide and
prolonged the required irradiation time.
This problem was in part overcome by
irradiating at 254 nm. Although 4-chloro-
phenol gave poor results in the reaction,the
tert-butyldimethylsilyl-protected derivative
9 gave aryl alkynes in 51–71% yield. The
chlorinated benzodioxole 10 reacted in a
similar way with 1-hexyne and gave arylated
compound 17 in 52% yield after 30 h of
irradiation.
1 (X=)
1a (Cl)
Alkyne
tIRR [h] ArX consumption [%] Product
Yield [%][a]
62
36
100
1b[b] (OMs)
1c[b] (OTf)
1d (OPO3Et2)
1e (F)
60
60
60
60
75[c]
5
5
5
5
73
83
90
60
80[c]
80[c]
65[c]
1a
36
100
71
1b[b]
1c[b]
1d
60
60
60
75[c]
80[c]
80[c]
6
6
6
54
62
70
1a
36
100
51 (20)
1b[b]
1c[b]
1d
60
60
60
75[c]
80[c]
80
7
7
7
75 (14)
67
50 (10)
[a] Yields of isolated compounds based on consumed aryl halide or ester. The yield of anisole is shown in
parentheses, and is not quoted when less than 5%. [b] Reaction sensitized by 0.9m acetone and
buffered by 0.1m TEA. [c] The consumption of ArX was not increased after prolonged irradiation.
Finally,we explored the reaction of 1a
with the propargylic alcohol 2-methyl-3-
Table 2: Photoinduced synthesis of electron-rich aromatic alkynes.
phosphate 1d). The use of other
solvents,such as MeCN or MeCN/
H2O,gave poor yields.
Electron-rich precursor Alkyne
tIRR [h] ArX consumption [%] Product
Yield [%][a]
55
2
72[b]
90
80
Esters 1b and 1c absorbed
poorly at 310 nm and underwent a
sluggish reaction under these con-
ditions. Acetone (0.9m) sensitiza-
tion was adopted and enabled a
high conversion to be obtained
(> 75% in 60 h),provided that
the amount of base was doubled
(0.1m). To our knowledge,these
are the first examples reported of
an alkynylation reaction using an
aryl phosphate,[23] a mesylate,or,
noteworthy,an aryl fluoride,which
is usually an unreactive derivative.
The photoinduced arylation of
alkyne 3 by compounds 1 led to the
8
8
3
4
2
3
4
72[b]
72[b]SUP>
45
58
44
51
64
71
100
100
100
100
9
9
45
45
2
30
100
52
[a] Yields of isolated compounds based on consumed aryl chloride; the corresponding dehalogenated
aromatic compounds (<10%) were identified in the irradiated solutions by GC analysis. [b] Irradiation
carried out at 254 nm. Cloudy solutions were obtained after irradiation.
silicon-containing
alkyne
(p-
methoxyphenylethynyl)trimethyl-
silane, 6).[24] However,arylation of
alkyne 4 occurred with elimination
of
the
trimethylsilyl
(TMS)
group
and
gave
butyn-2-ol (18). In this case,an unexpected route was
followed and the Z-enone 19 was obtained as the only
product (35% yield,Scheme 2).
The above results show that aryl alkynes are obtained by
reaction of aryl cations with terminal acetylenes or their
silylated derivatives. The cations are readily obtained by
photolysis of electron-rich aryl esters or aryl halides,with the
readily available chlorides being a particularly convenient
choice. Furthermore,aromatic compounds bearing an SMe,
4-(1-propynyl)anisole (7) in a medium to good yield. When
this alkyne was used,the aryl derivatives 1 were in part
reduced to anisole,except for the case of triflate 1d.
Aromatic alkynes could not be used conveniently in this
procedure because they absorbed a significant fraction of the
incident light and underwent photoreactions to give strongly
absorbing products. Thus,irradiation of phenylacetylene in
TFE led to darkening and clouding of the reaction mixture;
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philic medium such as MeCN/H2O. Rearrangement to yield
allenes also does not compete,and the straightforward
formation of the alkynes is by far the preferred pathway
and involves elimination of the acetylenic hydrogen atom. Of
particular note is that deprotonation is the only process
observed in the arylation of ethynyltrimethylsilane—to the
exclusion of the elimination of the other potential electro-
fugal group TMS+.[32] Nevertheless,when the TMS + ion is the
only leaving group present (as in the case of 4),this is
eliminated and an aryl alkyne is again formed in a good
yield,[33] although in this case reduction of the phenyl cation to
anisole plays a greater role.[28]
A new cationic path was found in the reaction with
propargylic alcohol 18,where a methyl group migrated onto
the vinyl cation intermediate (Scheme 2). In this case the
driving force is the stability of the a-hydroxy cation formed,
and no deprotonation occurred to give an alkyne. Precedents
for the migration of a methyl (or a methylene) group adjacent
to a vinyl cation have been reported,[34] but examples that lead
to an a-hydroxy cation are rare.[35] Moreover,formation of the
enone 19 as the Z isomer demonstrates a new route to the
synthesis of related compounds which are currently accessible
by the Rupe or Meyer–Schuster rearrangement.[36]
To summarize,a metal-free protocol for the mild alkynyl-
ation of aromatic compounds substituted with electron-
donating groups has been developed. The reaction proceeds
via a phenyl cation formed by photoheterolysis and allows for
the use of a variety of precursors,such as readily available aryl
chlorides as well as aryl esters (mesylates or phosphates).
Interestingly,aryl fluorides,which are virtually unreactive
under metal catalysis in the Sonogashira reaction,could also
be used,although the consumption of the reagent was
incomplete. Phenylalkynes are obtained in good,although
not excellent,yields in TFE. Despite some limitation,this
method has distinct advantages over the thermal alternatives,
since the reaction is carried out at room temperature,with no
need of a sensitive and/or expensive metallic catalyst or of
water-free or oxygen-free conditions,and the experimental
procedure is quite simple.[37]
Scheme 2. Addition of the 4-methoxyphenyl cation onto propargylic
alcohol 18.
an O-trialkylsilyl (as a protected OH group),or a dioxolanyl
group were used for the first time in the generation of aryl
cations,[25] thus broadening the scope of the arylation reaction.
Alkynes are known to be less reactive with electrophiles
than the corresponding alkenes. However,Mayr et al.
reported that 1-hexyne is less reactive by one order of
magnitude than 1-hexene in the reaction with (p-
MeC6H4)2CH+ at À708C,[26a] but that the difference is reduced
at higher temperatures. In some cases the reactivity towards
the carbenium ion is similar or even higher than that of
alkenes.[26b] In the present case,the reactions involving
alkynes 1–3 required a longer irradiation time (> 30 h) than
alkenes (14 h),[15a] but this can probably be attributed to a
stronger filter effect of the product formed (conjugated
phenylalkynes versus alkyl benzenes) rather than to a less-
efficient reaction. The photolysis requires a polar (preferably
a protic) medium for reaction to occur.[27] TFE was found to
be the best solvent for the arylation of alkynes,but the same
products were formed in lower yields in MeCN,MeOH,
MeCN/TFE,and MeCN/H 2O. Among these,MeCN/H 2O
(5:1) gave the best results,although reduction of the aryl
cations was competitive with the reaction with the alkynes[28]
(for example,the reaction between 1a and 4 gave 34% of 7
and 30% of anisole).
The complete H+ versus TMS+ selectivity coupled with
the successful application to silylated alkynes when no
acetylene proton is present is an appealing characteristic of
the reaction. The thermal-catalyzed sila-Sonogashira reaction
has been exploited to a limited degree up to now,but the use
of a silyl derivative may be advantageous for application to
complex derivatives where protection is required,as well as
making it easier to handle low-boiling alkynes (for example,
4).[38] Finally,the synthesis of a b-aryl-substituted enone by
addition onto a propargylic alcohol opens up yet a new
synthetic pathway.
The mechanism of the reaction is outlined in Scheme 3.
The vinylenebenzenium ion resulting from the trapping of
3Ar+ [29,30] by the alkyne does not undergo solvent addition in
TFE (a poor nucleophile),[31] nor indeed in a more nucleo-
Experimental Section
Typical procedure for the photochemical synthesis of arylalkynes: A
solution of an aryl ester or halide (1, 8–-10,1.5 mmol,0.05 m),
triethylamine (TEA,0.05 m),and an alkyne ( 2–4,0.5 m) in TFE
(30 mL) was poured into two quartz tubes and purged for 10 min with
argon,serum capped,and irradiated with six 15-W phosphor-coated
lamps (emission centered at 310 or 254 nm). The photolyzed solution
Scheme 3. Mechanism of the photoinduced metal-free formation of
aryl alkynes.
Angew. Chem. Int. Ed. 2005, 44, 5675 –5678
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Communications
was concentrated under reduced pressure and purified by column
Guarna,C. Faggi, J. Org. Chem. 2003, 68,6360 – 6368; F. Lepifre,
C. Buon,P. Bouyssou,G. Coudert, Heterocycl. Commun. 2000, 6,
397 – 402.
chromatography (cyclohexane/ethyl acetate as eluant). Acetone
(3 mL,0.9 m) was added to the reaction mixtures involving esters
1b,c and the amount of TEA was increased to 0.1m.
[24] This observation parallels the result from the classical Sonoga-
shira reaction with a Pd catalyst,where 6 was obtained from the
reaction of 4-bromoanisole and 3; see: T. Hundertmark,A. F.
Littke,S. L. Buchwald,G. C. Fu, Org. Lett. 2000, 2,1729 – 1732.
[25] The 2,6-dimethyl analogue of 9 has been used succesfully in the
arylation of allyltrimethysilane; see ref. [15b].
[26] a) H. Mayr,J. L. Gozalez,K. Lꢀdtke, Chem. Ber. 1994, 127,525 –
531; b) G. Melloni,G. Modena,U. Tonellato, Acc. Chem. Res.
1981, 14,227 – 233.
[27] M. Freccero,M. Fagnoni,A. Albini, J. Am. Chem. Soc. 2003, 125,
13182 – 13190.
[28] Reduction of phenyl cations is often a main pathway in the
absence of an effective nucleophilic trap; see: B. Guizzardi,M.
Mella,M. Fagnoni,M. Freccero,A. Albini, J. Org. Chem. 2001,
66,6353 – 6363.
Received: May 5,2005
Published online: August 5,2005
Keywords: alkynes · aryl cations · arylation · cross-coupling ·
.
photochemistry
[1] L. Brandsma,S. F. Vasilevsky,H. D. Vekruijsse, Application of
Transition Metal Catalysts in Organic Synthesis,Springer,Berlin,
1998,pp. 179 – 225; K. C. Nicolaou,E. J. Sorensen,
Classics in
Total Synthesis,Wiley-VCH, Weinheim, 1996,pp. 582 – 586.
[2] J. M. Tour, Acc. Chem. Res. 2000, 33,791 – 804.
[3] R. R. Tykwinski, Angew. Chem. 2003, 115,1604 – 1606; Angew.
Chem. Int. Ed. 2003, 42,1566 – 1568.
[4] K. Sonogashira,Y. Tohda,N. Hagihara, Tetrahedron Lett. 1975,
4467 – 4470.
[29] The attack is favored by the 2-propenyl cation formed being
about 21–25 kcalmolÀ1 (in the gas phase) more stable than the
initial phenyl cation; see: Y. Apeloig,D. Arad, J. Am. Chem. Soc.
1985, 107,5285 – 5286.
[5] Q.-Y. Chen,Z.-Y. Yang, Tetrahedron Lett. 1986, 27,1171 – 1174.
[6] D. Gelman,S. L. Buchwald, Angew. Chem. 2003, 115,6175 –
6178; Angew. Chem. Int. Ed. 2003, 42,5993 – 5996.
[7] G. Zou,J. Zhu,J. Tang, Tetrahedron Lett. 2003, 44,8709 – 8711.
[8] A. Köllhofer,T. Pullmann,H. Plenio, Angew. Chem. 2003, 115,
1086 – 1088; Angew. Chem. Int. Ed. 2003, 42,1056 – 1058; M. R.
Eberhard,Z. Wang,C. M. Jensen, Chem. Commun. 2002,818 –
819; D. Mery,K. HeuzØ,D. Astruc, Chem. Commun. 2003,1934 –
1935.
[30] The formation of aryl alkynes by attack of an aryl radical onto a
non-activated triple bond can be excluded on two grounds: first,
À
homolytic clevage of the Ar X bond is an endothermic process
for all of the precursors considered (e.g. 1e)[27] and second,the
generation of the 4-methoxyphenyl radical (by irradiation of 4-
bromoanisole in TFE) in the presence of hexyne did not lead to
the formation of 5; for further comments see also note 28 in
ref. [17].
[31] S. Minegishi,S. Kobayashi,H. Mayr, J. Am. Chem. Soc. 2004,
126,5174 – 5181.
[9] M. B. Thathagar,J. Beckers,G. Rothenberg, Green Chem. 2004,
6,215 – 218.
[32] Vinyl cations are known to be stabilized by both an a- and by a b-
trimethylsilyl substituent; see: G. A. McGibbon,M. A. Brook,
J. K. Terlouw, J. Chem. Soc. Chem. Commun. 1992,360 – 362.
[33] Alkynes such as 4 are reported to yield disubstituted alkynes in
the reaction with tert-butyl or adamantyl cations; see: G.
[10] J. Cheng,Y. Sun,F. Wang,M. Guo,J.-H. Xu,Y. Pan,Z. Zhang,
J.
Org. Chem. 2004, 69,5428 – 5432; A. Soheili,J. Albaneze-
Walker,J. A. Murry,P. G. Dormer,D. L. Hughes, Org. Lett. 2003,
5,4191 – 4194.
[11] P. Siemsen,R. C. Livingston,F. Diederich, Angew. Chem. 2000,
112,2740 – 2767; Angew. Chem. Int. Ed. 2000, 39,2632 – 2657.
[12] N. E. Leadbetter,M. Marco,B. J. Tominack, Org. Lett. 2003, 5,
3919 – 3922; P. Appukkuttan,W. Dahaen,E. Van der Eycken,
Eur. J. Org. Chem. 2003,4713 – 4716.
Capozzi,G. Romeo,F. Marcuzzi,
Commun. 1982,959 – 960.
J. Chem. Soc. Chem.
[34] A. G. Martinez,M. Hanack,R. H. Summerville,P. von R.
Schleyer,P. J. Stang, Angew. Chem. 1970, 82,323 – 324; Angew.
Chem. Int. Ed. Engl. 1970, 9,302 – 303; P. J. Stang,T. E. Deuber,
Tetrahedron Lett. 1977,563 – 566.
[35] A shift of a dialkylaminophenyl group after addition of the
arene–ruthenium(ii) derivatives onto propargylic alcohols has
been reported; see: D. Pilette,S. Moreau,H. Le Bozec,P. H.
[13] a) D. Gelman,D. Tsvelikhovsky,G. A. Molander,J. Blum,
Org. Chem. 2002, 67,6287 – 6290; b) G. A. Molander,B. W.
Katona,F. Machrouhi, J. Org. Chem. 2002, 67,8416 – 8423.
J.
[14] Y. Nishihara,K. Ikegashira,A. Mori,T. Hiyama,
Chem. Lett.
1997,1233 – 1234.
Dixneuf,J. F. Corrigan,A. J. Carty,
Commun. 1994,409 – 410.
J. Chem. Soc. Chem.
[15] a) S. Protti,M. Fagnoni,M. Mella,A. Albini, J. Org. Chem. 2004,
69,3465 – 3473; b) I. Manet,S. Monti,M. Fagnoni,S. Protti,A.
Albini, Chem. Eur. J. 2005, 11,140 – 151.
[36] G. Sartori,A. Sartorio,R. Maggi,F. Bigi, Tetrahedron 1996, 52,
8287 – 8296.
[37] For example,the reaction between 1a and 3 was slower (by
about 20%) in an air-equilibrated rather than in an argon-
equilibrated solution,but the product distribution did not
change significantly.
[38] Only a few reports (all of them using aryl iodides) are available
concerning the sila-Sonogashira reaction using trimethylsilyl-
propine; see: M. Krause,X. Ligneau,H. Stark,M. Garbarg,J.-C.
Schwartz,W. Schunack, J. Med. Chem. 1998, 41,4171 – 4176;
A. K. Dutta,M. C. Davis,X.-S. Fei,P. M. Beardsley,C. D. Cook,
M. E. A. Reith, J. Med. Chem. 2002, 45,654 – 662.
[16] B. Guizzardi,M. Mella,M. Fagnoni,A. Albini,
J. Org. Chem.
2003, 68,1067 – 1074.
[17] M. De Carolis,S. Protti,M. Fagnoni,A. Albini, Angew. Chem.
2005, 117,1258 – 1262; Angew. Chem. Int. Ed. 2005, 44,1232 –
1236.
[18] S. Milanesi,M. Fagnoni,A. Albini, J. Org. Chem. 2005, 70,603 –
610.
[19] T. Okuyama, Acc. Chem. Res. 2002, 35,12 – 18.
[20] R. Gronheid,H. Zuilhof,M. G. Hellings,J. Cornelisse,G.
Lodder, J. Org. Chem. 2003, 68,3205 – 3215.
[21] In some cases a hydride shift within the b-phenylvinyl cation led
to the more stable a-phenylvinyl cation,as revealed by the
formation of 1-alkoxystyrenes.
[22] The presence of a base is required to buffer the acidity generated
in the reaction; omitting TEA led to a rapid darkening of the
solution.
[23] Vinyl but not aryl phosphates have been used to some extent in
thermal-catalyzed reactions,see: F. Lo Galbo,E. G. Occhiato,A.
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