Synthesis, structures and reactions of isolable terminal aryl/biarylbutadiynes (Ar-C≡C-C≡CH)

Article abstract of DOI:10.1002/ejoc.200800618

The synthesis and isolation is reported of five terminal aryl/biaryl-butadiynes, Ar-C≡C-C≡CH, (5a-c, 10a and 10b) from 2-methyl-6-aryl/biaryl-hexa-3,5-diyn-2-ol precursors [Ar-C≡C-C≡C- C(Me)₂OH; Ar = 2-MeOC₆H₄, 3-MeOC

Full text of DOI:10.1002/ejoc.200800618

FULL PAPER
DOI: 10.1002/ejoc.200800618
Synthesis, Structures and Reactions of Isolable Terminal Aryl/Biaryl-
butadiynes (Ar–CϵC–CϵCH)
Kara West,[a] Laura N. Hayward,[a] Andrei S. Batsanov,[a] and Martin R. Bryce*[a]
Keywords: Butadiynes / Cross-couplings / Sonogashira reactions / Suzuki reactions / Triazoles
The synthesis and isolation is reported of five terminal aryl/
biaryl-butadiynes, Ar–CϵC–CϵCH, (5a–c, 10a and 10b) from
2-methyl-6-aryl/biaryl-hexa-3,5-diyn-2-ol precursors [Ar–
CϵC–CϵC–C(Me)2OH; Ar = 2-MeOC6H4, 3-MeOC6H4, 4-
gen bonds are not always reliable tools for crystal engineer-
ing. Palladium-catalysed cross-coupling of 5c with 2-iodopyr-
imidine gave the unsymmetrical 1,4-diarylbutadiyne deriva-
tive 12; copper-catalysed reactions of 5c and 10a with benzyl
azide proceeded regioselectively to give alkynyltriazoles 13
and 14.
MeOC6H4,
2-phenylpyridin-5-yl,
3-phenylpyridin-2-yl,
respectively]. The X-ray crystal structures have been ob-
tained for compounds 5c and 10a. Surprisingly, no ϵC–H···X
(X = N or O) hydrogen bonds exist in the crystals of 5c and
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
10a. These structures illustrate the fact that ϵC–H···X hydro- Germany, 2008)
Recently, we have developed the fragmentation of precur-
Introduction
sors Ar–CϵC–CϵC–C(Me)2OH as an efficient route to
Ar–CϵC–CϵCH species, and we have described the first
X-ray crystal structures of compounds possessing the ter-
minal arylbutadiyne structure, namely derivatives 1a–f
(Scheme 1).[8] In the crystal structures of 1a,b,d–f the he-
teroatoms engage in weak intermolecular hydrogen bonding
with a terminal alkyne proton (i.e. ϵC–H···X, where X =
N or O) thereby stabilising the structures.[8]
The synthesis, isolation and properties of conjugated di-
yne molecules is a topic of great interest within contempo-
rary acetylene chemistry.[1] In this context, simple terminal
arylbutadiynes, Ar–CϵC–CϵCH, have generally been con-
sidered unsuitable for isolation and purification, due to
their reported instability to decomposition or polymerisa-
tion.[2] They have usually been generated by desilylation of
trialkylsilylated precursors (Ar–CϵC–CϵC–SiR3)[3] or by
dehydrohalogenation of haloene-yne (R–CϵC–CH=
CHCl)[4] or ene-haloyne (R–CH=CH–CϵCCl) deriva-
tives[5] and trapped in situ by reaction with aryl iodides to
yield diarylbutadiyne derivatives, or homocoupled in situ to
yield the symmetrical diaryloctatetrayne system. Lithiated
phenylbutadiyne (Ph–CϵC–CϵC–Li) has been generated
from a dibromoolefinic precursor [Ph–C(=CBr2)–CϵCH]
and efficiently trapped in situ with electrophiles.[6] However,
some terminal arylbutadiyne derivatives have been isolated
and spectroscopically characterised, for example, ferrocen-
ylbutadiyne[2e] and 4-tBuC6H4–CϵC–CϵCH.[2f] Comple- Scheme 1. Arylbutadiyne derivatives previously characterised by X-
ray crystallography.[8]
mentary studies have concerned oligoyne systems end-
capped with organometallic groups where stability is en-
hanced by bulky ligands on the metal centre.[7]
To probe further the stabilising effect of intermolecular
hydrogen bonding in Ar–CϵC–CϵCH species, we reasoned
that (methoxyphenyl)butadiyne derivatives might display
ϵC–H···OMe hydrogen bonding, and phenylpyridinyl de-
[a] Department of Chemistry, Durham University,
rivatives could engage in ϵC–H···N bonding. This paper
extends our methodology for preparing Ar–CϵC–CϵCH
derivatives and describes the characterisation of new species
(Ar = methoxyphenyl and biaryl), including two X-ray crys-
Durham DH1 3LE, UK
Fax: +44-191-384-4737
E-mail: m.r.bryce@durham.ac.uk
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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K. West, L. N. Hayward, A. S. Batsanov, M. R. Bryce
FULL PAPER
tal structures (compounds 5c and 10a). We also describe with both a protected butadiyne group and a reactive
their reactions with benzyl azide to yield alkynyltriazoles in bromo substituent for a subsequent Suzuki–Miyaura cross-
good yields.
coupling. The significant feature here is that the reactions
of 7a and 7b with phenylboronic acid (8) proceeded cleanly
to yield 9a and 9b (57 and 75% yields, respectively) under
the basic conditions of the reaction [PdCl2(PPh3)2, Na2CO3
(aq.), refluxing THF] without fragmentation of the 2-meth-
ylhexa-3,5-diyn-2-ol substituent. A directly analogous reac-
tion of 7a in refluxing dioxane (i.e. at higher temperature)
gave only dark base-line material on TLC analysis, probably
due to the formation and subsequent decomposition of 10a
under these conditions. Attempted reactions of 7a with
both 3- and 4-pyridylboronic acid were unsuccessful.[15] De-
protection of 9a and 9b gave compounds 10a and 10b which
were isolated in high yields as white solids. Crystals of 10a
suitable for X-ray analysis were grown; however, crystals of
10b could not be obtained.
Results and Discussion
The reaction of 2-, 3- and 4-iodoanisole 2a–c, with 2-
methyl-3,5-hexadiyn-2-ol (3)[9] under standard Sonogashira
conditions[10] [triethylamine, CuI, PdCl2(PPh3)2, 20 °C] gave
precursors 4a–c (50–75% yields) (Scheme 2).[11] The depro-
tection of 4a–c with loss of acetone was achieved by using
a catalytic amount of NaOH in refluxing toluene.[12] The
isomeric (methoxyphenyl)butadiyne derivatives 5a–c were
thereby obtained in 89, 65 and 84% yields, respectively, af-
1
ter column chromatography and were characterised by H
and 13C NMR spectroscopy and mass spectrometry. Com-
pounds 5a and 5b were isolated as oils which gradually
The single-crystal X-ray structures of both 5c and 10a
darkened on storage within a few hours, whereas 5c is a (Figures 1, 2, and 3) contain slanted arrays of diyne rods;
crystalline solid which is stable to storage for several days in 5c the adjacent rods are related by the a translation and
without any observable decomposition.[13] The X-ray crys- hence are rigorously parallel, whereas in 10a they are re-
tal structure of 5c is discussed below.
lated by the b glide plane and are parallel within 5.6°. Such
We next turned to new terminal biarylbutadiyne deriva- stacking, described by the length d of the vector connecting
tives. The relative stability of 1c is notable, as in contrast to the diyne centres and the angle φ between this vector and
1a,b,d–f, there is no heteroatom in structure 1c to act as a the rod, is a well-known prerequisite for solid-state topoch-
hydrogen-bond acceptor. Instead, the herringbone layers of emical polymerisation of 1,3-diynes. Efficient reaction re-
molecules in the crystal prevent close interactions of the quires either φ ≈ 45° and d ≈ 4.7–5.2 Å (optimum 4.9 Å) or
butadiyne rods, thereby disfavouring polymerisation.[8b] φ ≈ 90° and d Յ 4.0 Å, to achieve close contact (R) between
Analogous phenylpyridinyl systems 10a and 10b were, reactive carbon atoms.[16] As shown in Figure 3, 10a adopts
therefore, interesting targets.
the former motif with φ = 43°, d = 5.20 Å (half the crystal-
The syntheses of 10a and 10b are shown in Scheme 3. lographic parameter b) and uniform intermolecular Cα···Cδ
Selective displacement of the iodide substituent[14] of 6a and contacts R = 3.57 Å. The packing of 5c is a slanted (φ =
6b gave the isomeric products 7a and 7b, functionalised 75°) version of the latter motif, where both d and R are
Scheme 2. Reagents and conditions: (i) PdCl2(PPh3)2, CuI, triethylamine, 20 °C; (ii) NaOH, toluene, reflux.
Scheme 3. Reagents and conditions: (i) 3, PdCl2(PPh3)2, CuI, triethylamine, THF, 20 °C; (ii) 8, PdCl2(PPh3)2, Na2CO3 (aq.), THF, reflux;
(iii) NaOH, toluene, reflux.
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Isolable Terminal Aryl/Biaryl-butadiynes (Ar–CϵC–CϵCH)
Figure 1. Molecular structures of 5c (left) and 10a (right) showing thermal ellipsoids at 50% probability level. Bond lengths [Å]: C(Ar)–
C(7) 1.435(3) and 1.436(2), C(7)–C(8) 1.203(3) and 1.200(2), C(8)–C(9) 1.380(3) and 1.371(2), C(9)–C(10) 1.187(3) and 1.187(2), respec-
tively. The angle between the aromatic ring planes in 10a is 32°.
equal to the lattice parameter a (Figure 2). Thus, both contain acetylene hydrogen atoms and electronegative
structures are close to the upper limit of d suitable for poly- atoms in a 1:1 ratio. Instead, CϵC–CϵCH groups in 5c
merisation, which nevertheless does not occur readily. In form a herringbone pattern with an inter-rod angle of 75°
fact, it does not occur even for 1b,d–f,[8b] and HC4PyC4H and shortest contacts ϵC(10)–H···C(8) and···C(9) of 2.71
(Py = pyridin-2,5-diyl),[17] all of which are arrayed in crys- and 2.73 Å, respectively,[19] which is rather awkward for a
tals similarly to 5c, with even a shorter value of d (ca. C–H···π(CϵC) interaction, the C(8)–C(9) bond being a sin-
3.8 Å).[8b]
gle one. Even for an optimum geometry, the ϵC–
H···π(CϵC) hydrogen bond is weaker than ϵC–H···O (1.2–
1.4 kcalmol–1 vs. 2.2 kcalmol–1 from MO calculations),[18]
yet the oxygen atom in 5c contacts only with a methyl hy-
drogen atom, the energy estimates for such interactions vary
from 0.3 to 0.8 kcalmol–1. Similarly, in the structure of 10a
the ϵC–H bond points toward the pπ orbital of the phenyl
C(14) atom (see Figure 3, rH···C = 2.73 Å[19]), whereas the
N atom contacts with two aryl hydrogen atoms.
To illustrate the synthetic potential of these terminal ar-
ylbutadiynes to yield diverse products we have performed:
(i) a cross-coupling reaction (Scheme 4) and (ii) reactions
with benzyl azide (Scheme 5).
Unsymmetrical 1,4-biaryl/heteroaryl-butadiynes are fun-
damentally important targets for optoelectronic studies.[20]
Terminal butadiynes are particularly attractive reagents in
this regard as their cross-coupling reactions will not yield
the symmetrical (self-coupled) 1,4-biaryl byproducts which
are obtained as byproducts during the oxidative coupling
of two different acetylene precursors.[21] Accordingly, as a
prototype reaction, purified compound 5c was treated with
2-iodopyrimidine (11) to cleanly yield the unsymmetrical
push-pull system 12 in 62% yield.
Figure 2. Crystal structure of 5c (H atoms, except acetylene ones,
are omitted).
At the outset of this work, we were aware of only two
reports of cycloaddition reactions of terminal butadiynes;
both described the Huisgen 1,3-dipolar cycloaddition reac-
tion of benzyl azide at the terminal alkyne bond to yield an
alkynyltriazole product.[22] While our work was in progress,
Tykwinski et al. reported the in situ trapping of arylbuta-
diynes (Ar = Ph, 4-OMeC6H4, 4-FC6H4 and 4-tBuC6H4)
generated by desilylation of Ar–CϵC–CϵC–SiR3 precur-
sors[23] with benzyl azide by using copper catalysis.[24] Our
results with the isolated and purified aryl/biaryl-butadiynes
5c and 10a reported herein, complement these studies. In
particular the regioselectivity of the reaction is the same in
Figure 3. Crystal structure of 10a (H atoms, except acetylene ones,
are omitted).
Molecules 1 (except 1c) in crystals are linked by con- all cases.
tinuous networks of hydrogen bonds ϵC–H···X, where X =
Scheme 5 shows the formation of alkynyltriazole deriva-
N or O. Due to the relatively high acidity of the acetylene tives from 5c and 10a. The regiochemistry of 13 and 14 was
hydrogen atom, they are stronger than most hydrogen established by NMR spectroscopic data, in agreement with
bonds with a CH donor.[18] Thus, it came as a surprise that the literature precedent that only one regioisomer is formed
no such bonds exist in the crystals of 5c and 10a, which at 25 °C in the presence of a copper catalyst.
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Scheme 4. Reagents and conditions: (i) 11, PdCl2(PPh3)2, CuI, triethylamine, 20 °C.
1
forded 7a as a white solid (552 mg, 85%); m.p. 128.3–128.8 °C. H
NMR (CDCl3, 400 MHz): δ = 8.62 (s, 1 H), 7.77 (dd, J = 8.4,
2.4 Hz, 1 H), 7.33 (d, J = 8.0 Hz, 1 H), 2.65 (s, 1 H), 1.52 (s, 6 H)
ppm. 13C NMR (CDCl3, 100 MHz): δ = 151.5, 140.4, 138.9, 128.9,
121.0, 88.6, 76.9, 74.5, 66.5, 65.6, 40.0 ppm. MS (EI): m/z = 265.1
[M+]. C12H10BrNO (264.1): calcd. C 54.57, H 3.82, N 5.30; found
C 54.57, H 3.93, N 4.98.
2-(5-Hydroxy-5-methyl-1,3-hexadiynyl)-5-phenylpyridine (9a): Com-
pound 7a (382 mg, 1.45 mmol), phenylboronic acid (8) (264 mg,
2.17 mmol) and PdCl2(PPh3)2 (76 mg) were dissolved in degassed
THF (40 mL), to which degassed Na2CO3 (aq.) (1 , 4.24 mL) was
added and the reaction refluxed under argon whilst being carefully
monitored by TLC analysis. THF was removed and the remaining
residue dissolved in diethyl ether. The organic layer was washed
with brine (3ϫ50 mL), dried with MgSO4, filtered and the solvent
removed. A white solid of 9a (215 mg, 57% yield) was obtained
after column chromatography (silica, eluent DCM changing to
DCM/Et2O, 90:10 v/v) and recrystallisation from cyclohexane; m.p.
122.1–122.6 °C. 1H NMR (CDCl3, 400 MHz): δ = 8.82 (s, 1 H),
7.86–7.83 (dd, J = 8.4, 2.4 Hz, 1 H), 7.59–7.41 (m, 6 H), 2.48 (s, 1
H), 1.60 (s, 6 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 148.9,
140.8, 137.1, 136.6, 134.5, 129.4, 128.8, 128.2, 127.2, 88.2, 73.9,
67.7, 65.8, 65.2, 31.2 ppm. MS (ES+): m/z = 262.3 [M+]. C18H15NO
(261.3): calcd. C 82.73, H 5.79, N 5.36; found C 82.44, H 5.72, N
5.41.
Scheme 5. (i) benzyl azide, DMF, water, CuSO4·5H2O, sodium as-
corbate, 25 °C.
Conclusions
We have extended our methodology for the synthesis of
terminal aryl/biaryl-butadiynes to yield a series of new iso-
lable derivatives. It is now apparent that a wide range of
simple terminal arylbutadiyne derivatives can be purified
and thoroughly characterised by standard spectroscopic
and X-ray crystallographic techniques. These structures il-
lustrate the fact that ϵC–H···X hydrogen bonds are not al-
ways effective tools for crystal engineering, and can be eas-
ily overruled, e.g. by packing requirements. Arylbutadiynes
should no longer be considered as unstable intermediates
which require generation and trapping in situ, or need bulky
substituents or heteroatoms on the aryl ring to provide ste-
ric hindrance to prevent polymerisation. The terminal al-
kyne bond of arylbutadiynes can be functionalised by ef-
ficient Sonogashira cross-coupling and cycloaddition reac-
tions with benzyl azide. The clean Suzuki–Miyaura reac-
tions of 7a and 7b [Scheme 3, step (ii)] clearly provide scope
for the synthesis of new aryl/biaryl-butadiynes and their de-
rived products – these reactions also illustrate the versatility
of the 2-hydroxy-2-propyl protecting group in oligoyne
chemistry.
General Procedure for the Preparation of 5a–c, 10a,b: Compound
4a–c, 9a,b was dissolved in dry toluene. NaOH powder was added,
and the mixture was stirred and heated with an oil-bath at 135 °C
under Ar for ca. 10 min. TLC was used to monitor the end-point
of the reaction. The reaction mixture was concentrated and the
residue purified by column chromatography on silica. CAUTION:
Care should be taken when handling solid samples of the terminal
butadiynes. No problems were encountered in the present work,
but there is a history of explosions with analogous compounds in
other laboratories, e.g. terminal hexatriynes.[25]
2-(Buta-1,3-diynyl)-5-phenylpyridine (10a): Compound 9a (136 mg,
0.524 mmol), NaOH (65 mg) and toluene (20 mL) afforded 10a as
a white solid (82 mg, 85%) after purification by column chromatog-
raphy (silica, eluent DCM). 1H NMR (CDCl3, 400 MHz): δ = 8.83
(s, 1 H), 7.87–7.84 (dd, J = 7.6, 2.0 Hz, 1 H), 7.59–7.42 (m, 6 H),
2.53 (s, 1 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 148.9, 140.1,
136.8, 136.7, 134.3, 129.2, 128.8, 128.7, 128.3, 127.1, 74.1, 73.7,
72.4, 67.8 ppm. MS: m/z = 204.1 [M+]. Crystals for X-ray analysis
were grown by slow concentration of a cyclohexane solution.
Experimental Section
General Procedure for the Preparation of 4a–c and 7a,b: A mixture
of the iodoarene 2a–c, 6a,b, and 2-methyl-3,5-hexadiyn-2-ol (3),
PdCl2(PPh3)2, CuI and triethylamine was stirred at 20 °C (18 h for
4a–c; 3 h for 7a, b) as detailed below. The volatile liquids were
removed by vacuum evaporation, and the residue was chromato-
graphed on a silica column and/or recrystallised to afford products
4a–c and 7a,b.
2-[4-(4-Methoxyphenyl)buta-1,3-diynyl]pyrimidine (12): 2-Iodopyri-
midine (11) (229 mg, 1.12 mmol), compound 5c (116 mg,
0.74 mmol), PdCl2(PPh3)2 (20 mg) and CuI (3 mg) were stirred in
anhydrous triethylamine (30 mL) at 20 °C for 18 h. Vacuum evapo-
5-Bromo-2-(5-hydroxy-5-methyl-1,3-hexadiynyl)pyridine (7a): 5- ration of volatiles followed by column chromatography (silica, elu-
Bromo-2-iodopyridine (6a) (700 mg, 2.46 mmol), 2-methyl-3,5-
hexadiyn-2-ol (3) (534 mg, 4.94 mmol), PdCl2(PPh3)2 (87 mg), CuI
(24 mg) and triethylamine (100 mL) were stirred at 20 °C for 3 h.
Column chromatography (silica, eluent DCM/Et2O, 90:10 v/v) af-
ent DCM/Et2O, 90:10 v/v) afforded 12 as a pale yellow solid
(107 mg, 62%); m.p. 164.6–165.9 °C. 1H NMR (CDCl3, 400 MHz):
δ = 8.72 (d, J = 4.8 Hz, 2 H), 7.50 (d, J = 8.0 Hz, 2 H), 7.25–7.24
(m, 1 H), 6.88–6.85 (m, 2 H), 3.84 (s, 3 H) ppm. 13C NMR (CDCl3,
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Isolable Terminal Aryl/Biaryl-butadiynes (Ar–CϵC–CϵCH)
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100 MHz): δ = 168.2, 158.5, 152.7, 134.6, 120.1, 114.3, 112.8, 83.5,
78.9, 73.0, 72.3, 55.4 ppm. MS (EI): m/z = 234.0 [M+]. C15H10N2O
(234.3): calcd. C 76.91, H 4.30, N 11.96; found C 76.49, H 4.25, N
11.71.
[5]
[6]
[7]
2-[(1-Benzyl-1H-1,2,3-triazol-4-yl)ethynyl]-5-phenylpyridine
(14):
CuSO4·5H2O (50 mg) and sodium ascorbate (50 mg) were added
to a stirred mixture of benzyl azide (0.07 mL, 0.52 mmol), 10a
(105 mg, 0.52 mmol), DMF (7 mL) and water (2 mL). The mixture
was then stirred at 25 °C for 18 h to afford a green solution. Ethyl
acetate (30 mL) was added, and the organic layer was separated
and washed with a saturated EDTA solution (3ϫ30 mL), and the
organic phase was dried with MgSO4, filtered and the solvent re-
moved. Purification by column chromatography (silica, DCM, fol-
lowed by gradual addition of Et2O) afforded 14 as a white solid
(152 mg, 87%); m.p. 168.0–168.4 °C. 1H NMR (CDCl3, 400 MHz):
δ = 8.84 (d, J = 0.8 Hz, 1 H), 7.90–7.87 (m, 1 H), 7.42 (s, 1 H),
7.63–7.59 (m, 3 H), 7.51–7.47 (m, 2 H), 7.44–7.39 (m, 4 H), 7.31–
7.28 (m, 2 H), 5.79 (s, 2 H), 3.87 (s, 3 H) ppm. 13C NMR (CDCl3,
100 MHz): δ = 188.6, 148.7, 141.4, 137.1, 136.1, 134.5, 134.1, 130.8,
129.32, 129.3, 129.1, 128.6, 128.2, 127.2, 127.1, 126.9, 91.9, 79.0,
77.3, 54.5 ppm. MS (ES+): m/z = 337.2 [M+]. C22H14N4 (336.4):
calcd. C 78.55, H 4.79, N 16.65; found C 78.37, H 4.71, N 16.91.
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Compound 4c has been synthesised previously by Cadiot–
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[8]
[9]
[10]
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures and characterisation data for com-
pounds 4a–c, 5a–c, 7b, 9b, 10b and 13; X-ray crystallographic data
for structures 5c and 10a.
[11]
[12]
a) Aromatic hydrocarbons are the usual solvents for the re-
moval of a 2-hydroxy-2-propyl group to liberate an alkyne:
D. E. Ames, D. Bull, C. Takunda, Synthesis 1981, 364–365; b)
the use of polar solvents with higher boiling points (DMF,
nBuOH, DMSO and DMA) has been reported: Z. Novák, P.
Nemes, A. Kotschy, Org. Lett. 2004, 6, 4917–4920; c) the 2-
hydroxy-2-propyl protecting group has been used previously
for the synthesis of alkylbutadiynes: A. Carpita, D. Neri, R.
Rossi, Gazz. Chim. Ital. 1987, 117, 481–489; M. J. Dabdoub,
V. B. Dabdoub, E. J. Lenardão, Tetrahedron Lett. 2001, 42,
1807–1809.
Acknowledgment
We thank the UK Engineering and Physical Sciences Research
Council (EPSRC) for funding this work.
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Eur. J. Org. Chem. 2008, 5093–5098
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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K. West, L. N. Hayward, A. S. Batsanov, M. R. Bryce
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Received: June 23, 2008
Published Online: September 12, 2008
5098
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 5093–5098