A one-pot synthesis of substituted salicylnitriles

Article abstract of DOI:10.1016/j.tetlet.2008.05.006

Phenols were converted to salicylaldehydes with paraformaldehyde, MgCl₂-Et₃N in THF, and subsequent treatment with aqueous ammonia gave the corresponding imines which were oxidized with IBX to the desired salicylnitriles. The sequence of reactions was conveniently carried out as a one-pot procedure under mild conditions.

Full text of DOI:10.1016/j.tetlet.2008.05.006

Tetrahedron Letters 49 (2008) 4443–4445
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A one-pot synthesis of substituted salicylnitriles
*
Hany F. Anwar, Trond Vidar Hansen
School of Pharmacy, Department of Pharmaceutical Chemistry, University of Oslo, POB 1068 Blindern, N-0316 Oslo, Norway
a r t i c l e i n f o
a b s t r a c t
Article history:
Phenols were converted to salicylaldehydes with paraformaldehyde, MgCl2–Et3N in THF, and subsequent
treatment with aqueous ammonia gave the corresponding imines which were oxidized with IBX to the
desired salicylnitriles. The sequence of reactions was conveniently carried out as a one-pot procedure
under mild conditions.
Received 7 April 2008
Revised 24 April 2008
Accepted 1 May 2008
Available online 6 May 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Phenols
ortho-Formylation
IBX
Salicylnitriles
Aromatic nitriles can be prepared by metal-mediated displace-
ment of aromatic halides by the cyanide ion, that is, the Rose-
mund–von Braun reaction1,2 and are versatile starting materials
and intermediates for the synthesis of heterocyclic and biologically
active compounds.3 Stoichiometric quantities of toxic cyanide salts
and high temperatures (>150–160 °C) are commonly employed for
this reaction.4 Not many examples of the preparation of substi-
tuted salicylnitriles have been reported using the Rosemund–von
Braun reaction.5 Since few substituted salicylnitriles are commer-
cially available, efforts towards developing mild and reliable meth-
ods are of interest to the synthetic community. Herein we describe
an efficient one-pot method for the conversion of phenols to
substituted salicylnitriles.
The recently reported regioselective ortho-formylation of
substituted phenols using the MgCl2–Et3N base system and para-
formaldehyde affords salicylaldehydes in excellent yields.6 The sal-
icylaldehydes obtained by this method have been converted,
without isolation and in one-pot procedures, to useful products
and intermediates.7 With complete regioselectivity observed in
the aforementioned formylation of phenols, it seemed feasible to
apply this method for the regioselective introduction of a nitrile
group via oxidation of an imine intermediate to give salicylnitriles.
There are several oxidative methods available for the prepara-
tion of nitriles from amines, but few methods exist for the synthe-
sis of salicylnitriles.8
to nitriles using IBX in aqueous ammonia, recently reported by
Akamanchi and co-workers,10 inspired us to develop a one-pot pro-
cedure for the synthesis of substituted salicylnitriles. Preparative
procedures in which two or more transformations can be carried
out as a one-pot process offer a number of advantages, that is,
the time-cost benefits gained by avoiding isolation, handling and
chromatography of intermediates.
The ortho-formylation of 2-chlorophenol afforded 3-chlorosali-
cylaldehyde which was treated, without isolation, with aqueous
ammonia to give the corresponding 3-chlorosalicylimine in the
same pot. The imine was oxidized with a slight excess of IBX to
3-chlorosalicylnitrile in 70% overall yield after purification by chro-
matography. Several 2-substituted phenols were subjected to the
same one-pot procedure, affording the corresponding salicyl-
nitriles in 48–71% isolated yields over three steps.11 As expected,
4-substituted phenols afforded the 5-substituted salicylnitriles in
comparable yields (Table 1). 2,3-(Methylenedioxy)-phenol, a struc-
tural entity found in some highly oxygenated natural products
such as narciclasine and pancratistatin,12 was also converted
cleanly to the desired nitrile in 58% overall yield (entry 12). Com-
plete regioselectivity was observed in all cases and the products
were identified by physical and spectral data. IBX afforded higher
yields compared to the Dess–Martin reagent under these condi-
tions. New compounds were characterized on the basis of physical
and spectral data.11
Recently, hypervalent iodine reagents such as ortho-iodoxybenz-
oic acid (IBX) and Dess–Martin periodinane have attracted interest
as oxidants for synthetic transformations.9 The oxidation of amines
In conclusion, we have reported the transformation of phenols
into salicylnitriles in good overall yields by a simple, regioselective
and one-pot experimental procedure. Since substituted phenols
are readily available, the present method appears to be
a
mild and convenient procedure for preparing salicylnitriles (see
Scheme 1).
* Corresponding author. Tel.: +47 22857450; fax: +47 22855947.
E-mail address: t.v.hansen@farmasi.uio.no (T. V. Hansen).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.006

4444
H. F. Anwar, T. V. Hansen / Tetrahedron Letters 49 (2008) 4443–4445
Table 1
One-pot synthesis of substituted salicylnitriles
Phenol
Product
Yield %
70
Phenol
Product
Yield %
67
OH
OH
OH
OH
CN
CN
CI
CI
CN
CN
F
7
F
1
OH
OH
OH
OH
Br
Br
55
48
71
70
67
54
Br
2
Br
8
OH
OH
OH
CN
OH
F
CN
F
t-Bu
3
t-Bu
9
OH
OH
OH
CN
OH
OH
t-Bu
CN
t-Bu
Me
O
Ph
O
4
Ph
10
OH
OH
t-Bu
CN
OH
t-Bu
Me
CN
62
56
t-Bu
11
5
t-Bu
OH
OH
OH
OH
O
O
CN
CN
O
O
53
58
6
12
Scheme 1.
2. (a) von Braun, J.; Manz, G. Liebigs Ann. Chem. 1931, 488, 111–126; (b)
Rosemund, K. W.; Struck, E. Chem. Ber. 1919, 52B, 1749–1756.
3. (a) Herr, R. J. Bioorg. Med. Chem. 2002, 10, 3379–3393; (b) Schmidt, A. In Science
of Synthesis; Murahashi, S.-I., Ed.; Georg Thieme, 2004; Vol. 19, pp 133–161; (c)
Larock, R. Comprehensive Organic Transformations. A Guide to Functional Group
Preparations; VCH: New York, 1989.
Acknowledgement
Financial support to H.F.A. from the University of Oslo (The
Quota Scheme) is gratefully acknowledged.
4. (a) Lindley, J. Tetrahedron 1984, 40, 1433–1456; (b) Ellis, G. P.; Romney-
Alexander, T. M. Chem. Rev. 1987, 87, 779–794; (c) Sundermeier, M.; Zapf, A.;
Beller, M. Eur. J. Inorg. Chem. 2003, 3513–3526; (d) Cristau, H.-J.; Ouali, A.;
Spindler, J.-F.; Tailefer, M. Chem. Eur. J. 2005, 11, 2483–2492 and references
cited therein.
References and notes
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H. F. Anwar, T. V. Hansen / Tetrahedron Letters 49 (2008) 4443–4445
4445
5. (a) Ellis, G. P.; Hudson, H. V. J. Chem. Res. (S) 1985, 372–373; (b) Jones, T. H.;
Blum, M. S.; Fales, H. M. Synth. Commun. 1981, 11, 889–894; (c) Shah, M. V.;
Sethna, S. J. Chem. Soc. 1961, 2663–2666; (d) Bigi, F.; Maggi, R.; Sartori, G.;
Casnati, G.; Bocelli, G. Gazz. Chim. Ital. 1992, 122, 283–289; (e) Adachi, M.;
Sugasawa, T. Synth. Commun. 1990, 20, 71–84.
1H), 1.41 (s, 9H); 13C NMR (75 MHz, CDCl3, ppm): d = 157.08, 137.82, 132.25,
129.78, 120.88, 116.77, 100.17, 34.98, 29.29; LC/MS: m/z 176.0 (M+H+, 100%);
HRMS calcd for
C11H13NO: 175.0997, found: 175.1002. 2-Hydroxy-3-
methylbenzonitrile (5): yellow solid; mp 87–88 °C (lit.5d mp 89–91 °C); IR
(KBr, cmÀ1) m: 3306, 2233, 1590; 1H NMR (300 MHz, CDCl3, ppm): d = 7.33–
7.35 (m, 2H), 6.90 (t, J = 7.7 Hz, 1H), 5.75 (br s, 1H), 2.28 (s, 3H); 13C NMR
(75 MHz, CDCl3, ppm): d = 156.43, 135.87, 129.95, 125.72, 120.93, 116.45,
99.00, 15.75; LC/MS: m/z 134.0 (M+H+, 100%). 3-Allyl-2-hydroxybenzonitrile
(6): pale yellow solid; mp 34–37 °C (lit.14 mp 38–39 °C); IR (KBr, cmÀ1) m: 3328,
2231, 1590; 1H NMR (300 MHz, CDCl3, ppm): d = 7.40 (dd, J = 7.8, 1.8 Hz, 1H);
7.33–7.36 (m, 1H), 6.94 (t, J = 7.5 Hz, 1H), 6.06 (br s, 1H), 5.91–6.04 (m, 1H),
5.13–5.21 (m, 2H), 3.43 (d, J = 6.6 Hz, 2H); 13C NMR (75 MHz, CDCl3, ppm):
d = 156.59, 135.20, 134.99, 130.83, 127.16, 121.06, 117.45, 116.36, 99.81,
34.59; LC/MS: m/z 160.0 (M+H+, 100%). 5-Fluoro-2-hydroxybenzonitrile (7):
white solid; mp 120–121 °C; IR (KBr, cmÀ1) m: 3269, 2236, 1508; 1H NMR
(300 MHz, CDCl3, ppm): d = 7.21–7.28 (m, 2H), 6.96–7.02 (m, 1H), 6.11 (br s,
1H); 13C NMR (75 MHz, CDCl3, ppm): d = 156.01 (d, J = 240.0 Hz), 154.87 (d,
J = 2.2 Hz), 122.42 (d, J = 23.3 Hz), 118.42 (d, J = 25.7 Hz), 118.10 (d, J = 7.9 Hz),
115.13, 99.90 (d, J = 9.4 Hz); LC/MS: m/z 138.1 (M+H+, 100%); HRMS calcd for
C7H4FNO: 137.0277, found: 137.0272. 5-Bromo-2-hydroxybenzonitrile (8):
pale yellow solid; mp 155–156 °C (lit.15 mp 157–158 °C); IR (KBr, cmÀ1) m:
3427, 2227, 1644; 1H NMR (300 MHz, DMSO-d6, ppm): d = 10.45 (br s, 1H), 7.44
(d, J = 2.4 Hz, 1H), 7.35 (dd, J = 8.9, 2.4 Hz, 1H), 6.83 (d, J = 8.9 Hz, 1H); 13C NMR
(75 MHz, DMSO-d6, ppm): d = 159.14, 136.41, 134.31, 117.79, 115.23, 109.76,
101.03; LC/MS: m/z 198.1 (M+H+, 77%), 199.8 (M+2+H+, 100%). 5-tert-Butyl-2-
hydroxybenzonitrile (9): white solid; mp 130–131 °C; IR (KBr, cmÀ1) m: 3432,
2230, 1641; 1H NMR (300 MHz, CDCl3, ppm): d = 7.52–7.47 (m, 2H), 6.92 (dd,
J = 8.5, 0.6 Hz, 1H), 5.90 (br s, 1H), 1.29 (s, 9H); 13C NMR (75 MHz, CDCl3, ppm):
d = 155.90, 144.16, 132.11, 129.07, 116.57, 116.12, 98.75, 34.13, 31.05; LC/MS:
m/z 175.9 (M+H+, 100%); HRMS calcd for C11H13NO: 175.0997, found:
175.0990. 2-Hydroxy-5-phenoxybenzonitrile (10): white solid; mp 114–
115 °C; IR (KBr, cmÀ1) m: 3291, 2238, 1594, 1H NMR (300 MHz, CDCl3, ppm):
6. (a) Hofsløkken, N. U.; Skattebøl, L. Acta Chem. Scand. 1999, 53, 258–262; (b)
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11. Typical experimental procedure for the synthesis of salicylnitriles: To a dry THF
solution (30 ml) of the phenol (2 mmol), anhydrous magnesium chloride
(0.38 g, 4 mmol) and triethylamine (0.40 g, 4 mmol) paraformaldehyde (0.18 g,
6 mmol) were added. The reaction mixture was heated to reflux under an
argon atmosphere for 2–4 h, and monitored by TLC (hexane–ethyl
acetate = 9:1). After complete consumption of the phenol, the reaction
mixture was cooled, and aqueous ammonia (10 ml of a 25% solution) and
methanol (3 ml) were added. After stirring for 30 min IBX (45 wt. %, 1.20 g) was
added, and the yellow coloured solution was stirred for an additional 2–10 h.
The reaction mixture was diluted with water and extracted with ethyl acetate
(2 Â 15 ml), the combined organic layers were washed successively with water
(2 Â 15 ml) and a solution of Na2S2O5 (2 Â 15 ml), and then dried (MgSO4). The
product was purified by column chromatography using a gradient of hexane–
ethyl acetate (95:5–70:30). Spectral and physical data of products: 3-Chloro-2-
hydroxybenzonitrile (1): Orange solid; mp 113–114 °C (lit.13 mp 114–115 °C);
IR (KBr, cmÀ1 ) m: 3414, 2245, 1641; 1H NMR (300 MHz, CDCl3, ppm): d = 7.56
(dd, J = 8.0, 1.5 Hz, 1H), 7.48 (dd, J = 7.8, 1.5 Hz, 1H), 6.96 (t, J = 7.9 Hz, 1H), 6.29
(br s, 1H); 13C NMR (75 MHz, CDCl3, ppm): d = 154.22, 134.17, 132.47, 121.94,
121.56, 115.47, 101.62; LC/MS: m/z 154.0 (M+H+, 100%), 156.0 (M+2+H+, 36%).
3-Bromo-2-hydroxybenzonitrile (2): yellow solid; mp 116–117 °C (lit.13 mp
116 °C); IR (KBr, cmÀ1) m: 3278, 2242, 1591; 1H NMR (300 MHz, CDCl3, ppm):
d = 7.70 (dd, J = 8.1, 1.5 Hz, 1H), 7.52 (dd, J = 7.7, 1.5 Hz, 1H), 6.91 (t, J = 7.9 Hz,
1H), 6.22 (br s, 1H); 13C NMR (75 MHz, CDCl3, ppm): d = 154.54, 136.78, 132.84,
121.93, 115.07, 110.98, 100.95; LC/MS: m/z 197.9 (M+H+, 75%), 199.8 (M+2+H+,
100%). 3-Fluoro-2-hydroxybenzonitrile (3): yellow solid; mp 115–117 °C; IR
(KBr, cmÀ1) m: 3417, 2240, 1643; 1H NMR (300 MHz, CDCl3, ppm): d = 7.29–
7.35 (m, 2H), 6.94–6.98 (m, 1H), 6.10 (br s, 1H); 13C NMR (75 MHz, CDCl3,
ppm):d = 151.24 (d, J = 237.0 Hz), 147.16 (d, J = 16.0 Hz), 128.95 (d, J = 3.9 Hz),
121.49 (d, J = 7.0 Hz), 120.76 (d, J = 17.0 Hz), 115.20, 102.30 (d, J = 3.3 Hz); LC/
MS: m/z 138.2 (M+H+, 100%); HRMS calcd for C7H4FNO: 137.0277, found:
137.0273. 3-tert-Butyl-2-hydroxybenzonitrile (4): white solid; mp 131–
132 °C; IR (KBr, cmÀ1) m: 3298, 2234, 1580; 1H NMR (300 MHz, CDCl3, ppm):
d = 7.50 (dd, J = 7.9, 1.3 Hz, 1H), 7.34 (dd, J = 7.7, 1.6 Hz, 1H), 6.93 (t, J = 7.8 Hz,
d = 7.31–7.38 (m, 2H), 7.10–7.20 (m, 3H), 6.93–6.98 (m, 3H), 6.80 (br s, 1H); 13
C
NMR (75 MHz, CDCl3, ppm): d = 157.42, 155.34, 150.76, 130.41, 126.91, 124.15,
122.66, 118.81, 118.51, 116.29, 100.14; LC/MS: m/z 211.9 (M+H+, 100%); HRMS
calcd for
C13H9NO2: 211.0633, found: 211.0633. 3,5-Di-tert-butyl-2-
hydroxybenzonitrile (11): white solid; mp 135–136 °C (lit.16 mp 135–
136 °C); IR (KBr, cmÀ1) m: 3401, 2230, 1638; 1H NMR (300 MHz, CDCl3, ppm):
d = 7.52 (d, J = 2.4 Hz, 1H), 7.30 (d, J = 2.4 Hz, 1H), 5.70 (br s, 1H), 1.41 (s, 9H),
1.29 (s, 9H); 13C NMR (75 MHz, CDCl3, ppm): d = 154.68, 143.65, 136.96,
129.76, 125.96, 117.15, 99.53, 35.13, 34.42, 31.22, 29.34; LC/MS: m/z 232.2
(M+H+, 100%). 2-Hydroxy-3,4-(methylenedioxy)benzonitrile (12): white solid;
mp 180–181 °C; IR (KBr, cmÀ1) m: 3185, 2233, 1635; 1H NMR (300 MHz, CDCl3,
ppm): d = 7.10 (d, J = 8.3 Hz, 1H), 6.54 (d, J = 8.3 Hz, 1H), 6.08 (s, 2H), 5.70 (br s,
1H); 13C NMR (75 MHz, CDCl3, ppm): d = 153.15, 142.36, 135.01, 128.38,
116.37, 103.35, 103.07, 95.61; LC/MS: m/z 163.9 (M+H+, 100%); HRMS calcd for
C8H5NO3: 163.0269, found: 163.0264.
12. (a) Jin, Z. Nat. Prod. Rep. 2007, 24, 886–905; (b) Chapleur, Y.; Chretien, F.;
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