One-pot procedure for the synthesis of unsymmetrical diarylalkynes

Article abstract of DOI:10.1021/jo100460v

Unsymmetrical diarylalkynes are accessible by a one-pot procedure from two different aryl halides and (trimethylsilyl)acetylene. The three-component coupling is initialized by a Pd/Cu-catalyzed Sonogashira coupling of an aryl halide with (trimethylsilyl)a

Full text of DOI:10.1021/jo100460v

pubs.acs.org/joc
SCHEME 1. Retrosynthesis of the 1,2,3,4-Tetrahydrobenzyli-
soquinoline Skeleton
One-Pot Procedure for the Synthesis of
Unsymmetrical Diarylalkynes
ꢀ
Rene Severin, Jessica Reimer, and Sven Doye*
€
Institut fu€r Reine und Angewandte Chemie, Universitat
Oldenburg, Carl-von-Ossietzky-Strasse 9-11, 26111
Oldenburg, Germany
doye@uni-oldenburg.de
Received March 12, 2010
is then desilylated under basic conditions to give a terminal
arylalkyne that can finally be used for a second Pd-catalyzed
Sonogashira reaction with an aryl halide. In the past, we used
a corresponding three-step approach toward the synthesis of
(2-alkynylphenyl)acetonitriles of type 3 (Scheme 1) because
these unsymmetrical diarylalkynes can be used as starting
materials for the synthesis of biologically interesting 1,2,3,4-
tetrahydrobenzylisoquinoline derivatives 1.5 For that pur-
pose, the nitriles 3 must initially be reduced to the corre-
sponding aminoalkynes 2. A subsequent one-pot process
that involves an intramolecular Ti-catalyzed hydroamina-
tion of 2 and a final reduction of the resulting cyclic imine
then gives access to the desired 1,2,3,4-tetrahydrobenzyliso-
quinoline derivatives 1. However, the synthetic flexibility of
the overall process strongly depends on a short, flexible,
and efficient method for the synthesis of unsymmetrical
diarylalkynes of type 3. For that reason, we decided to
work toward the development of a reliable one-pot process
for the synthesis of corresponding diarylalkynes. While cor-
responding one-pot Sonogashira processes for the synthesis
of symmetrical1,6-11 and unsymmetrical9-11 diarylalkynes
with one or two aryl halides and an actetylene equiva-
lent [(trimethylsilyl)acetylene,6,11 acetylene gas,1,7,9 calcium
carbide,8 or 2-methyl-3-butyn-2-ol10] as the starting materi-
als have been described before, an application of these
methods for the synthesis of (2-alkynylphenyl)acetonitriles
of type 3 has not been reported yet. Furthermore, most of the
mentioned processes were either applied only to the synthesis
of symmetrical diarylalkynes1,6-8 or they use a large amount
Unsymmetrical diarylalkynes are accessible by a one-pot
procedure from two different aryl halides and (trimethyl-
silyl)acetylene. The three-component coupling is initia-
lized by a Pd/Cu-catalyzed Sonogashira coupling of an
aryl halide with (trimethylsilyl)acetylene. After subse-
quent desilylation of the formed aryl(trimethylsilyl)acety-
lene with aqueous potassium hydroxide, a second Sono-
gashira coupling with an aryl iodide that does not require
any additional Pd/Cu-catalyst gives access to an unsym-
metrical diarylalkyne.
During the past decades, the Sonogashira reaction1,2 has
become one of the most important Pd-catalyzed C-C bond-
forming reactions. This cross-coupling of an aryl halide with
a terminal alkyne has proven to be an experimental simple,
reliable, and high-yielding reaction that can be used effi-
ciently for the synthesis of symmetrical and unsymmetrical
diarylalkynes as well as arylalkylalkynes.2,3 Especially, the
synthesis of unsymmetrically substituted diarylalkynes has
attracted much attention and a typical three-step strategy for
the synthesis of corresponding products starts with an initial
Sonogashira coupling of an aryl halide with (trimethyl-
silyl)acetylene.4 The resulting 2-aryl(trimethylsilyl)acetylene
(5) (a) Mujahidin, D.; Doye, S. Eur. J. Org. Chem. 2005, 2689. (b) Severin,
R.; Mujahidin, D.; Reimer, J.; Doye, S. Heterocycles 2007, 74, 683.
(c) Severin, R.; Reimer, J.; Doye, S. Eur. J. Org. Chem. 2010, 51.
(6) D’Auria, M. Synth. Commun. 1992, 22, 2393.
(1) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 16,
4467.
(2) For recent reviews on Sonogashira reaction, see: (a) Chinchilla, R.;
ꢀ
Najera, C. Chem. Rev. 2007, 107, 874. (b) Doucet, H.; Hierso, J.-C. Angew.
(7) Li, C.-J.; Chen, D.-L.; Costello, C. W. Org. Process Res. Dev. 1997, 1,
325.
(8) Zhang, W.; Wu, H.; Liu, Z.; Zhong, P.; Zhang, L.; Huang, X.; Cheng,
J. Chem. Commun. 2006, 4826.
Chem., Int. Ed. 2007, 46, 834. (c) Plenio, H. Angew. Chem., Int. Ed. 2008, 47,
6954. (d) McGlacken, G. P.; Fairlamb, I. J. S. Eur. J. Org. Chem. 2009, 4011.
(e) Pal, M. Synlett 2009, 2896.
(3) For a recent example of a Sonogashira reaction that is part of a one-
pot procedure for the synthesis of 4-aryl-1,2,3-triazoles, see: Lorincz, K.;
Kele, P.; Novak, Z. Synthesis 2009, 3527.
(9) Pal, M.; Kundu, N. G. J. Chem. Soc., Perkin Trans. 1 1996, 449.
(10) Yi, C.; Hua, R.; Zeng, H.; Huang, Q. Adv. Synth. Catal. 2007, 349,
1738.
(4) Takahashi, S.; Kuroyama, Y.; Sonogashira, N.; Hagihara, N. Synth-
esis 1980, 627.
(11) Mio, M. J.; Kopel, L. C.; Braun, J. B.; Gadzikwa, T. L.; Hull, K. L.;
Brisbois, R. G.; Markworth, C. J.; Grieco, P. A. Org. Lett. 2002, 4, 3199.
3518 J. Org. Chem. 2010, 75, 3518–3521
Published on Web 04/26/2010
DOI: 10.1021/jo100460v
r
2010 American Chemical Society

Severin et al.
JOCNote
SCHEME 2. Sequential Desilylation and Sonogashira Coupling
of TMS-Protected Alkyne 4
must be noted that under these conditions, complete conver-
sion to the (trimethylsilyl)alkyne 7 was observed by GC after a
reaction time of 16 h while a corresponding reaction performed
with NEt3 proceeded with significantly decreased rate. The
resulting crude reaction mixtures were then directly treated
with a solution of 2 equiv of KOH in MeOH/H2O (4:1) to
remove the TMS group from the initially formed alkyne 7.
After the resulting mixtures had been stirred for 3 h at room
temperature (>98% conversion), either 4-iodotoluene or
4-iodotrifluoromethylbenzene were added and the mixtures
were stirred for an additional 16 h at room temperature to
achieve a second Sonogashira coupling. Fortunately, after that
time, it was indeed possible to isolate the desired, unsymme-
trical diarylalkynes 3b and 3c in 85% and 83% yield, respec-
tively. Most impressively, it turned out that the second
Sonogashira coupling did not require the addition of any
additional amounts of the Pd/Cu catalyst.
SCHEME 3. One-Pot Synthesis of (2-Alkynylphenyl)-
acetonitriles
With these results in hand, we turned our attention to-
ward the one-pot synthesis of a variety of more simple but
still unsymmetrical diarylalkynes (Table 1). Corresponding
three-component coupling experiments were initially per-
formed with two different aryl iodides and (trimethylsilyl)-
acetylene as the starting materials (Table 1, entries 1-7). Due
to the fact that aryl iodides usually show a higher reactivity
than aryl bromides in Pd-catalyzed reactions, the initial
Sonogashira couplings could easily be achieved at room
temperature in the presence of 2 mol % Pd(PPh3)2Cl2, 4
mol % PPh3, 2 mol % CuI, and i-Pr2NH in toluene. Sub-
sequent addition of a solution of 2 equiv of KOH in MeOH/
H2O (4:1) and stirring at room temperature (3 h) followed by
the addition of a second aryl iodide and additional stirring at
room temperature (16 h) led to the clean formation of the
expected diarylalkynes 9-15 in very good yields (74-87%).
As can be seen from Table 1 (entries 1-7), the one-pot
reaction sequence tolerates electron-donating (Me, i-Pr,
MeO) and -withdrawing (CF3) substituents on the benzene
ring of the substrates as well as ortho-substitution. Particu-
larly impressive are the very good results obtained for the
products 14 and 15 (81% and 83%) which possess a sterically
demanding i-Pr group in the ortho-position. Additional
three-component couplings could also be performed success-
fully with one aryl bromide, (trimethylsilyl)acetylene, and
one aryl iodide (Table 1, entries 8-12). However, in these
cases the initial Sonogashira coupling of the aryl bromide
needs to be performed at 80 °C. Using a corresponding
experimental procedure we were able to obtain the desired
diarylalkynes 16-20 in modest to very good yields
(45-78%). Again, the one-pot process makes it possible to
synthesize products which bear electron-donating (MeO)
and -withdrawing (F, CF3) as well as ortho-substituents on
the benzene rings. However, it must also be noted that
reaction sequences which use an aryl bromide and an aryl
iodide give slightly decreased yields when the Sonogashira
couplings are performed in reverse order. An explanation for
this observation is the more harsh reaction conditions (80 °C)
which are then necessary for the second Sonogashira reac-
tion of the aryl bromide. Under these conditions, the pre-
sence of the strong base KOH caused decomposition
reactions which led to the formation of side products and
consequently to decreased overall yields. On the other hand,
comparable decomposition reactions were not observed
when the second Sonogashira reaction was performed with
(6.0 equiv) of the expensive amidine base 1,8-diazabicyclo-
[5.4.0]undec-7-ene (DBU) together with a substoichiometric
amount of water for the in situ desilylation of initially formed
2-aryl(trimethylsilyl)acetylenes.11
On the basis of the idea that the desilylation of 2-aryl-
(trimethylsilyl)acetylenes can easily be achieved with less
expensive potassium hydroxide in a mixture of methanol
and water, we used these conditions for an initial one-pot
reaction between 2-(4-chlorophenyl)(trimethylsilyl)acety-
lene (4) and the commercially available aryl bromide 6
(Scheme 2). For that purpose, 4 was first stirred at room
temperature for 2 h with 2 equiv of KOH in a 20:1 mixture
of MeOH and water. The resulting reaction mixture that
contained the in situ generated terminal alkyne 5 was then
added to a mixture of aryl bromide 6, 2 mol % Pd(PPh3)2Cl2,
4 mol % PPh3, 2 mol % CuI, i-Pr2NH, and toluene. After this
mixture had been stirred for 12 h at 80 °C, the desired
diarylalkyne 3a could be isolated in 78% yield after column
chromatography. This result clearly indicates that the desi-
lylation conditions which rely on the inexpensive base KOH
are compatible with the catalyst system used for the subse-
quent Sonogashira coupling.
In a further set of experiments (Scheme 3), we performed
initial Sonogashira reactions of aryl bromide 6 with (trimeth-
ylsilyl)acetylene at 80 °C in the presence of 2 mol % Pd(PPh3)2-
Cl2, 4 mol % PPh3, 2 mol % CuI, i-Pr2NH, and toluene. It
J. Org. Chem. Vol. 75, No. 10, 2010 3519

Severin et al.
JOCNote
TABLE 1. One-Pot Synthesis of Unsymmetrical Diarylalkynes
SCHEME 4. One-Pot Synthesis of Heteroaromatic Unsymme-
trical Diarylalkynes
reaction with the less reactive aryl halide especially when the
corresponding reaction needs more forcing conditions.
With these results in hand, we finally investigated the use of
the two heteroaryl halides 2-iodothiophene and 2-bromopyri-
dine as substrates for the new one-pot process (Scheme 4).
Interestingly, it was initially found that the two heteroaro-
matic substrates could successfully be reacted under standard
conditions with (trimethylsilyl)acetylene and 4-iodotoluene
to give the unsymmetrical diarylalkynes 21 and 22 in 89%
and 58% yield, respectively. However, when 2-bromopyri-
dine was used together with (trimethylsilyl)acetylene and
2-iodothiophene the second Sonogashira coupling had to
be performed at 80 °C to give the desired product 23 in
acceptable yield (81%). Otherwise, the diarylalkyne 23 was
not formed at all.
In summary, we have presented a one-pot synthesis of
unsymmetrically substituted diarylalkynes. The process re-
lies on an initial Pd/Cu-catalyzed Sonogashira coupling of
(trimethylsilyl)acetylene with an aryl halide, a subsequent
desilylation of the generated aryl(trimethylsilyl)acetylene
performed with aqueous potassium hydroxide, and a second
Sonogashira coupling with an aryl iodide that does not
require the addition of any additional amounts of a Pd/Cu
catalyst.
Experimental Section
aReaction conditions: (1) aryl halide (3 mmol), (trimethylsilyl)-
acetylene (3.6 mmol), Pd(PPh3)2Cl2 (2 mol %), PPh3 (4 mol %), CuI
(2 mol %), i-Pr2NH (1 mL), toluene (5 mL), 25 or 80 °C, 16 h; (2) KOH
(6 mmol), MeOH (2 mL), H2O (0.5 mL), 25 °C, 3 h; (3) aryl iodide
(3 mmol), 25 °C, 16 h. bInitial reaction at 25 °C. cInitial reaction at 80 °C.
Typical Reaction Procedure for the One-Pot Synthesis of
Diarylalkynes Exemplified by the Synthesis of 1-Methyl-4-
((4-(trifluoromethyl)phenyl)ethynyl)benzene (9, Table 1, entry 1).
1-Iodo-4-methylbenzene (654 mg, 3.00 mmol), Pd(PPh3)2Cl2
(42 mg, 0.06 mmol, 2 mol %), CuI (11 mg, 0.06 mmol,
2 mol %), and PPh3 (31 mg, 0.12 mmol, 4 mol %) were placed
in an oven-dried and argon-filled Schlenk tube. After addition of
an aryl iodide at room temperature. For that reason, it is
strongly recommended to perform the initial Sonogashira
3520 J. Org. Chem. Vol. 75, No. 10, 2010

Severin et al.
JOCNote
i-Pr2NH (1.0 mL) and toluene (5.0 mL), the mixture was
stirred at 25 °C for 5 min and (trimethylsilyl)acetylene (354 mg,
3.60 mmol) was added. After this mixture had been stirred at
25 °C for 16 h, a solution of KOH (337 mg, 6.00 mmol) in water
(0.5 mL) and methanol (2.0 mL) was added in one portion and
the mixture was stirred for an additional 3 h at 25 °C. Then
1-iodo-4-(trifluoromethyl)benzene (816 mg, 3.00 mmol) was
added and stirring was continued for 16 h at 25 °C. The reaction
mixture was quenched with saturated NH4Cl solution (60 mL)
and extracted with CH2Cl2 (3 ꢀ 50 mL). The combined organic
layers were washed with HCl (2 N, 50 mL), water (50 mL), and
saturated NaCl solution (50 mL) and dried with MgSO4. After
concentration under vacuum, the residue was purified by flash
chromatography (SiO2, 115 g, light petroleum ether, Rf 0.30)
to give 9 (662 mg, 2.54 mmol, 85%) as a light yellow solid (mp
133.4 °C). 1H NMR (500 MHz, CDCl3) δ 2.37 (s, 3 H), 7.17 (d,
J = 8.0 Hz, 2 H), 7.43 (d, J = 8.0 Hz, 2 H), 7.58 (d, J = 8.7 Hz,
2 H), 7.60 (d, J = 8.6Hz, 2 H) ppm; 13C NMR(126MHz, DEPT,
CDCl3) δ 21.5 (CH3), 87.4 (C), 92.0 (C), 119.5 (C), 124.0 (q, J =
272 Hz, CF3), 125.2 (q, J = 4 Hz, CH), 127.3 (C), 129.2 (CH),
129.7 (q, J = 33 Hz, C), 131.6 (CH), 131.7 (CH), 139.1 (C) ppm;
IR (neat) 1/λ 2923, 2218, 1315, 1164, 1122, 1104, 1063, 1013, 842,
819 cm-1; MS (EI) m/z (%) 260 (100) [M]þ, 259 (32), 191 (12),
189 (16), 115 (4); HRMS calcd (C16H11F3) 260.0813, found
260.0811.
Acknowledgment. We thank the Deutsche Forschungsge-
meinschaft (DFG) for financial support of our research.
Supporting Information Available: Experimental details,
analytical data, and NMR spectra for compounds 3a-c and
9-23. This material is available free of charge via the Internet at
http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 10, 2010 3521