The synthesis of 2-arylmethyl-6-hydroxybenzenecarbonitriles from the base-mediated aryne reaction of bromophenols with arylacetonitriles

Article abstract of DOI:10.1039/a907980g

A facile one-step synthesis of 2-arylmethyl-6-hydroxybenzenecarbonitriles from readily available arylacetonitriles is described. The substitution pattern was verified by X-ray diffractometric analysis of 2-benzyl-6-hydroxybenzonitrile. An explanation of the addition to and reactivity of the 2,3-didehydrophenoxide intermediate, which is supported by DFT calculations, is presented.

Full text of DOI:10.1039/a907980g

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The synthesis of 2-arylmethyl-6-hydroxybenzenecarbonitriles from
the base-mediated aryne reaction of bromophenols with
arylacetonitriles
1
Sagun Tandel, Hongming Zhang, Nabil Qadri, George P. Ford and Edward R. Biehl*
Department of Chemistry, Southern Methodist University, Dallas, TX 75275, USA.
E-mail: ebiehl@post.smu.edu
Received (in Cambridge, UK) 4th October 1999, Accepted 23rd December 1999
A facile one-step synthesis of 2-arylmethyl-6-hydroxybenzenecarbonitriles from readily available arylacetonitriles is
described. The substitution pattern was verified by X-ray diffractometric analysis of 2-benzyl-6-hydroxybenzonitrile.
An explanation of the addition to and reactivity of the 2,3-didehydrophenoxide intermediate, which is supported
by DFT calculations, is presented.
Introduction
Halophenols form aryne intermediates when treated with
sodium or potassium amide in liquid ammonia only with diffi-
culty.1 We have recently shown that the arynes 4-nitro-2,3-
didehydrophenoxide2 and 3,4-didehydropyridine 5-oxide3 can
be readily generated in the presence of α-lithiated arylaceto-
nitriles from the reaction of 2-bromo-4-nitrophenol and 5-
chloropyridin-3-ol, respectively, with LDA or LiTMP (lithium
2,2,6,6-tetramethylpiperidinide) in THF.
These reactive intermediates display different reactivities
towards the α-lithiated arylacetonitriles. For example, nitrile
anion addition occurs regioselectively at the 3-position of 3,4-
didehydropyridine 5-oxide to give, after proton quench, simple
aryne addition products, i.e. α-aryl-α-(3-hydroxy-5-pyridyl)-
acetonitriles.4 However, nitrile anion addition occurs non-
regioselectively to both positions of 4-nitro-2,3-didehydrophen-
oxide. The adduct from 2-addition undergoes intramolecular
cyclization to supply benzofurans, whereas the adduct from
Fig. 1 ORTEP plot of compound 3a.
3-addition gives benzyl-4-nitro-2-cyanophenols presumably by
the tandem addition rearrangement pathway.5
obtained. Monitoring the reaction by GC-MS showed that
aryne generation commenced very slowly around Ϫ40 ЊC.
Results and discussion
However, by allowing the system to warm to room temperature,
the reactions were essentially over in 6 h. These reaction tem-
peratures and times, which are significantly higher than those
observed for 2-bromo-4-nitrophenol and 5-chloropyridin-3-ol,
reflect the lower acidity of the benzenoid hydrogen atoms
in 1a,b as compared with the those in the nitrogen-containing
aryne analogs.
To see if the replacement of the pyridine ring with a benzene
might lead to an increase in the rate of the rearrangement
pathway, we investigated the reaction of 3-bromo- 1a and 2-
bromophenol 1b with various arylacetonitriles 2a–f under
aryne-forming conditions. In all cases, a 2-arylmethyl-6-
hydroxybenzenecarbonitrile 3a–f was obtained as the major
product. As shown in eqn. 1, the carbonitriles 3a–f were
The use of LDA, which is less expensive but less sterically
demanding than LiTMP, gave lower yields of 3a–f (35–45%)
and greater amounts of phenol (10–18%) as compared with
the LiTMP-mediated reactions. Also, a 2:3 ratio of 2- and 3-
diisopropylaminophenol, respectively, was obtained in 15–25%
yields.
The identities of products 3a–f were determined by 1H
NMR, 13C NMR and elemental analyses. The regiochemistry
of nitrile addition was ascertained by X-ray crystallographic
analysis of 2-benzyl-6-hydroxybenzenecarbonitrile 3a, which
is shown in the ORTEP6 drawing in Fig. 1.
An explanation of these findings is shown in Scheme 1 using
the synthesis of 3a from 1a as a typical example. As shown,
treatment of 1a with base can, in principle, generate two arynes:
3,4-didehydrophenoxide 5 via the 4-lithio derivative 4, and 2,3-
didehydrophenoxide 8, via the 2-lithio derivative 7. However,
obtained in highest yields (48–63%) when 1 was allowed to react
with 2a–f in the presence of 2,2,6,6-tetramethylpiperidinide
(LiTMP). A minor amount of phenol (5–10%) was also
DOI: 10.1039/a907980g
J. Chem. Soc., Perkin Trans. 1, 2000, 587–589
This journal is © The Royal Society of Chemistry 2000
587

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Scheme 1
when the Liϩ ions were excluded, i.e. when the calculations were
carried out on the carbanions corresponding to the C2 and C4
deprotonated phenols. The nitrile anion 9a, prepared in situ by
reaction of the base and 1a, then adds to the 3-position of
8 affording the aryne-nitrile adduct 10.
The regioselective 3-addition appears to be due to a similar
stabilization of the carbanionic centre adjacent to the OLi
group observed in 7. DFT calculations on the analogous
acetonitrile adducts suggest this pathway to be 38.8 kJ molϪ1
more stable than addition to the 2-position. The computed
structures of the dilithium salts are shown in Figs. 2c and 2d.
Again, the energy difference was computed to be even greater
in the absence of the Liϩ ions (59.3 kJ molϪ1), i.e. for the
analogous structures resulting from addition of the acetonitrile
anion to the 2- and 3-positions of 2,3-didehydrophenol.
That no simple nitrile products 11 were observed indicates
that adduct 10 preferentially cyclizes to intermediate 12. This
is consistent with previous studies which show that electron-
releasing groups (OLi in this case) enhance the cyclization
step by increasing the nucleophilicity of the lithiated site in 10.
Ring opening of 12 and proton quenching of the rearranged
lithio derivative 13 gives the observed product 3a.
In addition to introducing two biologically important
functional groups concomitantly and regioselectively, the
1,2,3-substitution pattern contained in 3 is difficult to assemble
by traditional methods. Indeed, no method is presently avail-
able that allows one-step synthesis of 3 from readily available
starting materials.
Fig. 2 Computed DFT geometries in Å. Total energies in Hartrees,
(a) Ϫ2895.35147, (b) Ϫ2895.34610, (c) Ϫ453.05672, (d) Ϫ453.0401.
Full structural details can be obtained from the authors on request.
Experimental
General data
Melting points were taken on a Mel-Temp II capillary appar-
atus and are uncorrected with respect to stem correction. IR
spectra were recorded on a Nicolet Magna-IRTM 550 FTIR
the substitution pattern in the nitrile products 3a–f clearly
shows that nitrile addition occurs regioselectively to the 3-
position of 8. DFT calculations suggest that 2-lithiation of
1a, which yields 7, the precursor to 8, is energetically more
favored than 4-lithiation, which yields 4, the precursor to 5.
The optimized structures of 7 and 4 are shown in Figs. 2a and
2b, respectively. The former was computed to be more stable by
14.1 kJ molϪ1. This difference seems to be associated with the
location of the anionic center in the favorable electrostatic
environment between the heteroatoms and is not a consequence
of the interesting lithium bridging evident in the computed
structure. Thus, the energy difference increased to 49.8 kJ molϪ1
1
spectrometer, and the H and 13C NMR spectra were recorded
on a 400 MHz Bruker AVANCE DRX-400 Multi-nuclear
NMR spectrometer; chemical shifts were referenced to TMS
as internal standard. Elemental analyses were obtained from
E ϩ R Microanalytical Laboratories, Inc., Corona, NY. Bromo-
phenols, arylacetonitriles, 2,2,6,6-tetramethylpiperidine, and
n-BuLi were purchased from Aldrich Chemical Company.
Both the diisopropylamine and the 2,2,6,6-tetramethylpiper-
idine were refluxed over and distilled from calcium hydride.
Tetrahydrofuran (THF) was distilled from Na–benzophenone
588
J. Chem. Soc., Perkin Trans. 1, 2000, 587–589

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Table 1 Analytical data for the benzenecarbonitriles 3a–f
Found (%) (Required %)
C15H13NO: C, 80.69; H, 5.87; N, 6.27. Found: C, 80.87; H, 6.18;
N, 6.25%.
Compound
(Formula)
Yield
(%)
2-Hydroxy-6-[(naphthalen-1-yl)methyl]benzenecarbonitrile
3e. δH(400 MHz; CDCl3) 4.69 (s, 2 H), 6.62 (d, J = 7.6 Hz, 1 H),
6.91 (d, J = 8.2 Hz, 1 H), 7.38 (m, 2 H), 7.58 (m, 3 H), 7.90
(d, J = 8.2 Hz, 1 H), 7.97 (m, 2 H); δC(400 MHz; CDCl3) 39.5,
100.4, 114.5, 116.1, 122.1, 123.0, 123.5, 126.4, 126.7, 126.8,
127.0, 126.8, 127.2, 128.1, 133.0, 134.0, 147.2, 158.5.
Mp/ЊCa
C
H
N
3a
48
54
46
61
60
63
155–157
122–123
220–221
125–127
208–209
144–145
80.2
(80.4)
75.1
(75.3)
74.0
(74.3)
80.1
(80.7)
83.4
5.2
(5.3)
5.4
(5.5)
4.7
(4.8)
6.2
(5.9)
5.1
6.6
(6.7)
5.8
(5.85)
13.3
(13.3)
6.3
(6.3)
5.4
(C14H11NO)
3b
(C15H13NO2)
3c
(C13H10N2O)
3d
(C18H13NO)
3e
(C18H13NO)
3f
(C16H13NO3)
2-Hydroxy-3-[(3Ј,4Ј-dimethoxyphenyl)methyl]benzenecarbo-
nitrile 3f. δH(400 MHz; CDCl3) 3.86 (s, 3 H), 3.87 (s, 3 H), 4.10
(s, 2 H), 6.80–6.86 (m, 5 H), 7.35 (t, J = 8.0 Hz, 1 H).
(83.4)
71.4
(71.6)
(5.05)
5.6
(5.7)
(5.4)
5.2
(5.4)
X-Ray analysis of 3a
X-Ray analysis of crystals of 3a† (C14H11NO, M 209.02) was
carried out on a Bruker AXS P4 diffractometer at 228 K.
The crystal was monoclinic space group P21/n with unit cell
a = 10.496(1), b = 11.407(1), c = 19.715(1) Å, β = 91.53(1)Њ,
V = 2239.9(3) Å3, Z = 8, Dx = 1.241 g cmϪ3, µ = 0.079 mmϪ1.
Mo-Kα radiation (λ = 0.71073 Å). 4414 reflections measured,
3944 unique, 2409 with F ≥ 2σ(F) gave R1 = 0.047 in a full-
matrix, least-squares refinement7 with 289 parameters.
a All products were recrystallized from hexane–ethyl acetate (4:1).
immediately prior to use. The glassware was heated at 125 ЊC in
an oven overnight prior to use. All benzyne reactions were done
under an atmosphere of dry oxygen-free N2 via balloon.
General procedure for aryne reactions
In a flame-dried flask flushed with nitrogen, fresh LiTMP or
LDA (40 mmol) was prepared by adding n-BuLi (40 mmol,
2.5 M in hexane) to a solution of 2,2,6,6-tetramethylpiperidine
(6.6 g, 40 mmol) or diisopropylamine (4.0 g, 40 mmol) in THF
(50 mL) at Ϫ70 ЊC. After stirring for 10 min, the appropriate
arylacetonitrile (20 mmol) was added, and the stirring con-
tinued for 20 min to ensure complete anion formation. The
bromophenol (0.174 g, 10 mmol) was added and the resulting
solution was allowed to warm to room temperature over 6 h.
The typical red-colored reaction solution (indicative of a
successful base-mediated benzyne reaction) was not achieved
until the solution was warmed to room temperature. The
reaction was quenched with saturated NH4Cl solution (30 mL)
and then extracted with methylene dichloride. The combined
extracts were washed with dilute HCl, then dried (Na2SO4) and
concentrated (rotary evaporator) to give a crude oily material.
Chromatography of this material on silica gel (hexane–ethyl
acetate, 4:1) gave the pure product 3a–f. The yields, mp
and elemental analyses for 3a–f are shown in Table 1 and the
spectral data of 3a–f are given below.
DFT calculations
DFT calculations were carried out using Density Functional
Theory (DFT) as implemented in the Spartan package.8
Geometries were fully optimized within the constraints of
CS symmetry. Exchange and correlation functions of Becke9 and
Perdew10 were used with the DN* numerical basis developed
by Wavefunction, Inc.11 The latter is a polarized split-valence
basis set designed to mimic the analytical Gaussian basis set
6-31G(d).12 For computational efficiency non-local corrections
to the exchange and correlation functions are added “per-
turbatively” following convergence of the local density model.13
Acknowledgements
This work was supported, in part, by grants from the Welch
Foundation, Houston, TX, and the Petroleum Research
Corporation, administered by the American Chemical Society.
† CCDC reference number 207/389. See http://www.rsc.org/suppdata/
p1/a9/a907980g for crystallographic files in .cif format.
2-Hydroxy-6-(phenylmethyl)benzenecarbonitrile 3a. δH(400
MHz; CDCl3) 4.12 (s, 2 H), 6.77 (d, 1 H), 6.82 (d, 1 H), 7.21–
7.32 (m, 5 H); δC(400 MHz; CDCl3) 39.8 , 100.5, 114.5, 116.2,
122.5, 126.3, 127.9, 130.2, 134.3, 138.5, 138.8, 146.6, 159.6.
References
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2-Hydroxy-6-[(4-methoxyphenyl)methy]benzenecarbonitrile
3b. δH(400 MHz; CDCl3) 3.86 (s, 3 H), 4.14 (s, 2 H), 6.87
(t, J = 8.7 Hz, 2 H), 6.92 (d, J = 8.6 Hz, 2 H), 7.21 (d, J = 8.6 Hz,
2 H), 7.40 (t, J = 8.0 Hz, 1 H); δC(400 MHz, CDCl3) 39.9, 55.7,
100.4, 114.4, 114.5, 116.2, 122, 130.4, 131.3, 134.6, 147.1, 158.7,
159.8.
2-Hydroxy-6-[(pyridin-3-yl)methyl]benzenecarbonitrile
3c.
δH(400 MHz; CDCl3) 4.01 (s, 2 H), 6.59 (d, J = 7.6 Hz, 1 H),
6.77 (d, J = 8.2 Hz, 1 H), 7.13–7.21 (m, 2 H), 7.48 (d, J = 7.6 Hz,
1 H), 8.36 (d, J = 4.8 Hz, 1 H), 8.41 (s, 1 H); δC(400 MHz;
CDCl3) 42.5, 105, 119.6, 120.5, 125.5, 128.7, 139.1, 139.9, 141.5,
149.5, 152.9, 155.1, 166.4.
11 W. J. Hehre and L. Lou, A Guide to Density Functional Calculations
in Spartan, Wavefunction, Inc., Irvine, CA, 1997.
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Molecular Orbital Theory, John Wiley & Sons, New York, 1986,
pp. 64–68.
2-Hydroxy-6-[(2Ј-methylphenyl)methyl]benzenecarbonitrile
3d. δH(400 MHz; CDCl3) 2.41 (s, 3 H), 4.19 (s, 2 H), 6.87 (d,
J = 7.6 Hz, 1 H), 6.94 (d, J = 8.3 Hz, 1 H), 7.14 (s, 3 H), 7.28 (t,
J = 7.8 Hz, 1 H), 7.44 (t, J = 8.1 Hz, 1 H); δC(400 MHz; CDCl3)
21.8, 40.7, 100.5, 114.5, 116.1, 122.3, 126.3, 126.4, 127.9, 128.9,
130.1, 134.6, 138.7, 138.9, 146.6, 159.6. Anal. calcd for
13 A. St-Amant, Rev. Comput. Chem., 1996, 7, 217.
Paper a907980g
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