4-Cyanophenols bearing metabolically robust substituents

Article abstract of DOI:10.1016/j.tetlet.2011.04.052

We report a variety of synthetic strategies to access novel 4-cyanophenols bearing substituents expected to be resistant to metabolism.

Full text of DOI:10.1016/j.tetlet.2011.04.052

Tetrahedron Letters 52 (2011) 3226–3227
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Tetrahedron Letters
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4-Cyanophenols bearing metabolically robust substituents
⇑
Patrick S. Johnson, Toby J. Underwood, Simon Wheeler
Sandwich Chemistry, Pfizer Global R and D, Ramsgate Road, Sandwich, Kent CT13 9NJ, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
We report a variety of synthetic strategies to access novel 4-cyanophenols bearing substituents expected
to be resistant to metabolism.
Received 8 March 2011
Revised 29 March 2011
Accepted 12 April 2011
Available online 18 April 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Metabolism
Nitriles
Phenols
The physicochemical properties of the nitrile group have led to
the recognition of this moiety as significant in drug design.1 Like-
wise it is well understood that phenols can be important subunits
of medicinal molecules.2 When these two considerations are borne
in mind, it is unsurprising that various molecules of general struc-
ture 1 have been reported.3
Our second synthetic strategy witnessed the installation of the
nitrile via a functional group transformation. Treatment of alde-
hyde 74 with hydroxylamine-O-sulfonic acid resulted in the one-
pot transformation of this compound into the corresponding nitrile
8.5 (Whilst the dehydration of oximes to nitriles continues to
prompt the development of new methods,6 this more concise tech-
nique has received scant attention.7) The CHF2 group could then be
attached using the well known carbene precursor, sodium chloro-
difluoroacetate, before deprotection of the benzyl group by trans-
CN
R
R = small alkyl,
alkoxy
halo, etc.
OH
Br
1
OCF3
OCF3
OCF3
nBu4Br3
However, many of the published compounds feature substitu-
ents that could be classified as vulnerable to metabolism, or that
would confer unwanted lipophilicity on the final target mole-
cule—both properties likely to be deleterious to a therapeutic
agent. In the context of a drug discovery programme we wished
to prepare analogues of 1 with more metabolically robust substit-
uents. It was found necessary to employ a diverse set of synthetic
strategies to achieve this aim—the first of these saw us install the
nitrile function by C–C bond formation.
Thus commercially available phenol 2 was brominated to give a
mixture of regioisomers with our desired material as the minor
component. Cyanation of bromide 4 could be accomplished only
in poor yield so it was first protected to give 5. The nitrile was then
installed using palladium catalysis in good yield before deprotec-
tion yielded the desired phenol 6. This sequence is shown in
Scheme 1.
Br
DCM/MeOH
rt
OH
OH
OH
2
3
62%
4
32%
TIPS-Cl, imid
DMAP,
DCM, rt
OCF3
CN
OH
Br
i Zn(CN)2, cat Pd(PPh3)4
DMF, 120oC
OCF3
ii TBAF, THF, rt
OTIPS
6
5
64%
71%
⇑
Corresponding author. Tel.: +44 1304 649173.
E-mail address: simon.wheeler@pfizer.com (S. Wheeler).
Scheme 1. Preparation of trifluoromethoxy-substituted cyanophenol.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.04.052

P. S. Johnson et al. / Tetrahedron Letters 52 (2011) 3226–3227
3227
CHO
CN
group ortho to the oxazoline could then be selectively displaced
using excess of an organometallic reagent10 to give 13 or 15. Dehy-
dration of the oxazoline to the nitrile was achieved using POCl3
followed by anisole deprotection using BCl3/Bu4NI (BBr3 was much
less effective) to give the phenols of interest. These syntheses are
shown in Scheme 3.
CN
F
F
Cl
OH
OH
O
F
H2N-OSO3H
CO2Na
11
MeCN/H2O, 80 o
C
F
Cs2CO3,
DMF/H2O
130 o
OBn
OBn
OBn
C
7
8 (64%)
9 (68%)
In summary, we have reported the preparation of a small set of
novel 4-cyanophenols.12 It is noteworthy that it was necessary to
use diverse synthetic strategies to access these compounds. For
example, it proved impossible to prepare 14 using the route de-
scribed in Scheme 1 as attempts at palladium-catalysed cyanation
were uniformly unsuccessful, presumably due to the steric hin-
drance of the tbutyl group.13 Thus our work provides a good exam-
ple of both the flexibility and limitations of contemporary organic
synthesis. Each of the compounds reported herein bears a substitu-
ent designed to confer beneficial physicochemical properties to
drug-like molecules that incorporate the phenols we have de-
scribed. The preparation of such compounds in a drug discovery
programme will be reported in due course.
Pd/C, EtOH
reflux
CN
OH
O
F
F
10 (95%)
Scheme 2. Preparation of difluoromethoxy-substituted cyanophenol.
References and notes
CN
1. Jones, L. H.; Summerhill, N. W.; Swain, N. A.; Mills, J. E. J. Med. Chem. Commun.
2010, 309–318. and references therein..
N
O
i POCl3, py, EtOAc,
reflux
2. See, for example: (a) Tucker, T. J.; Saggar, S.; Sisko, J. T.; Tynebor, R. M.;
Williams, T. M.; Felock, P. J.; Flynn, J. A.; Lai, M.-T.; Liang, Y.; McGaughey, G.;
Liu, M.; Miller, M.; Moyer, G.; Munshi, V.; Perlow-Poehnelt, R.; Prasad, S.;
Sanchez, R.; Torrent, M.; Vacca, J. P.; Wan, B.-L.; Yan, Y. Bioorg. Med. Chem. Lett.
2008, 18, 2959–2966; (b) Middleton, D. S.; Andrews, M.; Glossop, P.; Gymer, G.;
Hepworth, D.; Jessiman, A.; Johnson, P. S.; MacKenny, M.; Stobie, A.; Tang, K.;
Morgan, P.; Jones, B. Bioorg. Med. Chem. Lett. 2008, 18, 5303–5306; (c) Whitlock,
G. A.; Fish, P. V.; Fray, M. J.; Stobie, A.; Wakenhut, F. Bioorg. Med. Chem. Lett.
2008, 18, 2896–2899.
ii BCl3, Bu4NI,
CH2Cl2, 0 oC to rt
OH
OMe
13 (60%)
14 (73% overall)
tBuLi,
THF,
-70 oC
3. Some selected examples: 3-methyl: (a) Smith, C. J.; Ali, A.; Chen, L.; Hammond,
M. L.; Anderson, M. S.; Chen, Y.; Eveland, S. S.; Guo, Q.; Hyland, S. A.; Milot, D.
P.; Sparrow, C. P.; Wright, S. D.; Sinclair, P. J. Bioorg. Med. Chem. Lett. 2010, 20,
346–349; (b) 3-ethyl: Xiang, J.; Lin, X.; Ren, F.; Deng, G. PCT Int. Appl. WO
2010148650; Chem. Abstr. 2010, 154, 88221.; 3-methoxy: (c) Mitchell, L.;
Wang, Z.; Hu, L.-Y.; Kostlan, C.; Carroll, M.; Dettling, D.; Du, D.; Pocalyko, D.;
Wade, K. Bioorg. Med. Chem. Lett. 2009, 19, 1310–1313; 3-chloro: (d) Mowbray,
C. E.; Corbau, R.; Hawes, M.; Jones, L. H.; Mills, J. E.; Perros, M.; Selby, M. D.;
Stupple, P. A.; Webster, R.; Wood, A. Bioorg. Med. Chem. Lett. 2009, 19, 5603–
5606; 3-trifluoromethyl: (e) Mitchell, L. H.; Johnson, T. R.; Lu, G. W.; Du, D.;
Datta, K.; Grzemski, F.; Shanmugasundaram, V.; Spence, J.; Wade, K.; Wang, Z.;
Sun, K.; Lin, K.; Hu, L.-Y.; Sexton, K.; Raheja, N.; Kostlan, C.; Pocalyko, D. J. Med.
Chem. 2010, 53, 4422–4427; (f) 3-cyano: Berke, H.; Duplantier, A. J.; Efremov, I.;
Mchardy, S. F.; Rogers, B. N.; Qian, W.; Zhang, L.; Zhang, Qi. PCT Int. Appl. WO
2007135527; Chem. Abstr. 2007, 148, 33731.
CO2H
OMe
i (COCl)2, cat DMF
CH2Cl2, rt
N
O
OMe
ii
OH
H2N
OMe
Et3N, CH2Cl2, rt
OMe
iii SOCl2, CH2Cl2, rt
11
12 (76%)
Mg,
Br
4. This material is commercially available from Alfa Aesar.
THF,
0
oC to rt
5. Streith, J.; Fizet, C.; Fritz, H. Helv. Chim. Acta 1976, 59, 2786–2792.
6. See, for example: Jian, N.; Ragauskas, A. J. Tetrahedron. Lett. 2010, 51, 4479–
4481.
7. For a recent exception, see: Madhusudana Reddy, M. B.; Pasha, M. A. Chin.
Chem. Lett. 2010, 21, 1025–1028.
8. For a review of the chemistry of this substituent, see: Reumann, M.; Myers, A. I.
Tetrahedron 1985, 41, 837–860.
i POCl3, py, EtOAc,
reflux
CN
N
O
9. Since this work was carried out an improved protocol for this transformation
has been reported, see: Kangani, C. O.; Kelley, D. E. Tetrahedron. Lett. 2005, 46,
8917–8920.
ii BCl3, Bu4NI,
CH2Cl2, 0 oC to rt
OH
10. Grant, T. G.; Myers, A. I. J. Am. Chem. Soc. 1992, 114, 1010–1015.
11. Dordor, I. M.; Mellor, J. M.; Kennewel, P. D. Tetrahedron. Lett. 1983, 24, 1437.
OMe
15 (71%)
12. Brief characterisation data for each compound are as follows. For compound 6: 1
H
16 (67% overall)
NMR (400 MHz, CDCl3) 6.72–6.76 (2H, m) 7.46 (1H, d, J = 8.6 Hz); MS (ESI): m/z
202 [MÀ1]À.
Scheme 3. Preparation of tbutyl- and cpropyl-substituted phenols.
For compound 10: 1H NMR (400 MHz, CDCl3) 6.72–6.77 (2H, m), 7.36 (1H, t,
J = 72.6 Hz), 7.68 (1H, d, J = 8.8 Hz), 11.05 (1H, br s); MS (ESI): m/z 184 [MÀ1]À.
For compound 14: 1H NMR (400 MHz, CDCl3) 1.48 (9H, s), 5.92 (1H, br s), 6.72
(1H, dd, J = 8.6, 2.3 Hz), 6.93 (1H, d, J = 2.3 Hz), 7.55 (1H, d, J = 8.6 Hz); MS (ESI):
m/z 174 [MÀ1]À.
fer hydrogenation yielded the cyanophenol of interest. This series
of reactions is shown in Scheme 2.
For compound 16: 1H NMR (400 MHz, CDCl3) 0.78 (2H, m), 1.14 (2H, m), 2.24
(1H, m), 6.39 (1H, m), 6.69 (1H, m), 7.48 (1H, d, J = 8.6 Hz), MS (ESI): m/z 158
[MÀ1]À.
Our third strategy involved revealing the nitrile function from
an oxazoline8 which was in turn used to direct the attachment of
alkyl substituents using an SNAr reaction. Readily available 2,4-
dimethoxybenzoic acid (11) was transformed into the oxazoline
12 via a well-known three-step, two-pot process.9 The methoxy
13. Since the completion of this work conditions have been reported that allow
such a transformation: Schareina, T.; Zapf, A.; Cotté, A.; Müller, N.; Beller, M.
Synthesis 2008, 3351–3355.