Highly regioselective DABCO-catalyzed nucleophilic aromatic substitution (SNAr) reaction of methyl 2,6-dichloronicotinate with phenols

Article abstract of DOI:10.1002/adsc.200505431

Exclusive formation of 6-aryloxy ethers 9 from an S_NAr reaction of methyl 2,6-dichloronicotinate (2) with phenols 7 catalyzed by 1,4-diazabicyclo[2.2.2]octane (DABCO) in the presence of stoichiometric triethylamine is described. The reaction pr

Full text of DOI:10.1002/adsc.200505431

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DOI: 10.1002/adsc.200505431
Highly Regioselective DABCO-Catalyzed Nucleophilic Aromatic
Substitution (SNAr) Reaction of Methyl 2,6-Dichloronicotinate
with Phenols
Yao-Jun Shi,* Guy Humphrey, Peter E. Maligres, Robert A. Reamer,
J. Michael Williams
Department of Process Research, Merck Research Laboratories, P.O. Box 2000, RY800-B361, Rahway, NJ 07065, USA
Fax: (þ1)-732-594-5170, e-mail: y-j_shi@merck.com
Received: November 1, 2005; Accepted: December 5, 2005
Abstract: Exclusive formation of 6-aryloxy ethers 9
from an SNAr reaction of methyl 2,6-dichloronicoti-
nate (2) with phenols 7 catalyzed by 1,4-diazabicy-
clo[2.2.2]octane (DABCO) in the presence of stoi-
chiometric triethylamine is described. The reaction
proceeds via the regioselective formation of an un-
precedented DABCO-pyridine adduct 10a.
ity (Scheme 1).[5] To our knowledge, the reaction of 2,6-
dichloronicotinate derivatives with phenols has not
been reported.
As part of an ongoing program to develop a practical
synthesis for an investigational drug candidate, synthesis
of the biaryl ether 9a was required. In this paper, we re-
port the discovery of an unprecedented DABCO-pyri-
dine adduct 10a, derived from the SNAr reaction of
methyl 2,6-dichloronicotinate (2) with DABCO and
the successful development of a highly regioselective,
DABCO-catalyzed SNAr reaction of dichloronicotinate
2 with phenols 7 to provide 6-aryloxy ethers 9 in high
yields.
Keywords: aromatic substitution; biaryl ether; DAB-
CO catalysis; nucleophilic substitution; pyridines
Initial examination of the SNAr reaction between di-
Substituted pyridines often appear as important motifs chloronicotinate 2 and 4-chlorophenol (7a) revealed
in both biologically active compounds as well as phar- that slow addition of 7a to a slurry of 2 and an excess
maceuticals.[1] Readily available 2,6-dichloronicotinic of Cs2CO3 in DMF at room temperature, provided the
acid (1) and its derivatives 2–4 are useful starting mate- products 8a/9a (1:4) (Scheme 2).[6] Addition of water di-
rials for the preparation of unique building blocks in the rectly to the reaction mixture led to the crystallization of
synthesis of new drug candidates.[2] Selective substitu- the crude products. Subsequent recrystallization from i-
tion of one or two of the chloride atoms at the 2- and/ PrOH afforded pure 9a in 60% overall yield from di-
or 6-position of these compounds, via a SNAr reaction chloronicotinate 2.[7]
with different nucleophiles, continues to receive intense
interest as a method to access the requisite substituted
pyridines. For example, Kawato and Newkome reported
the treatment of methyl 2,6-dichloronicotinate (2) with
sodium ethoxide in xylene to give a mixture of monosub-
stituted 5b (2-OEt isomer) and 6b (6-OEt isomer) in fa-
vor of 5b, the 2-OEt isomer.[3] Recently, Hirokawa,
et al., reported a new SNAr reaction of dichloronicotinic
acid 1 with potassium methoxide (KOMe) in refluxing
MeOH to produce 6a (6-OMe isomer) as the major
product in 66% overall yield after esterification.[4] This
process was utilized in the preparation of a key inter-
mediate for the synthesis of a potent serotonin 5-HT3
and dopamine D2 receptor antagonist. In addition,
they also reported a highly selective SNAr reaction of
methyl 2,6-dichloronicotinate (2) with sodium 4-meth-
ylbenzenethiolate (p-MePhSNa) in DMF, providing
the 6-isomer 6c in both high yield and excellent selectiv- Scheme 1.
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309

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Table 1. The SNAr reaction between dichloronicotinate 2 and phenol 7a with various bases.
Entry
Base
Solvent
Temp.
Reaction Time [h]
Conversion
8a : 9a
1
2
3
4
5
6
7
8
9
Cs2CO3
Cs2CO3
Cs2CO3
Na2CO3
K2CO3
LiOBu-t
NaOBu-t
KOBu-t
i-PrMgCl
NEt3
DMF
THF
RT
RT
RT
RT
4
16
16
16
16
16
3
100
~80
~50
~90
100
~80
100
100
0
1: 4
1: 2
1: 2
1: 2
1: 3
1: 2
1: 2
1: 2
–
Toluene
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
RT
RT to 608C
RT
ꢀ308C to RT
08C to RT
RT
3
16
16
8
10
11
12
0
100
100
–
DBU
DABCO
RT
RT;
1: 3
0: 100
2
The fact that DABCO (pKa 2.97 and 8.82) is less basic
than triethylamine (pKa 10.75),[8] which alonewas not ef-
fective in producing any products, led us to think that the
unique nucleophility of DABCO might be responsible
for the dramatic improvement in selectivity.[9] When
DABCO (1.2 equivs.) was directly mixed with dichloro-
nicotinate 2 in DMF-d7, NMR analysis clearly showed
the formation of a new product (Scheme 3). The product
was identified as the DABCO-pyridine adduct 10a. In-
terestingly, none of the isomeric DABCO-pyridine ad-
duct 10b was detected. Although DABCO adducts of
purine, pyrimidine, and 2,4-dinitrobenzene have been
reported previously, the formation of the DABCO-pyr-
idine adducts from 2,6-dichloronicotinate derivatives is
to the best of our knowledge unprecedented.[10,11,12]
In contrast to the parent dichloronicotinate 2, the re-
Scheme 2.
In attempting to improve the selectivity of the reac- sulting adduct 10a is much more reactive and readily un-
tion, we screened solvents and bases. Less-polar sol- dergoes the sequential SNAr reaction with chlorophenol
vents, such as THFand toluene (entries 2 and 3) resulted 7a to give the desired product 9a.
in lower selectivity for 9a which was consistent with re-
sults reported in the literature.[5] Exploring the effect
of different cations showed that substitution of Cs2CO3
with K2CO3, or Na2CO3 (entries 4 and 5), led to slower
reactions without improving selectivity. In addition, in
situ generation of the phenolic anion using t-BuOM
(M¼K, Na, or Li, entries 6–8) did not yield any im-
provement in the product ratio. The magnesium pheno-
late generated by pre-treatment of chlorophenol 7a with
isopropylmagnesium chloride, surprisingly, didnot show
any reaction (entry 9).
Substitution of inorganic bases with amine bases pro-
vided some interesting observations (Scheme 2). Use of
triethylamine did not result in any conversion to prod-
ucts (entry 10), and 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) provided a similar ratio of products (1:3 ratio
of 8a/9a) compared with Cs2CO3. A break-through re-
sult was obtained when DABCO was added to a solution
of dichloronicotinate 2 and chlorophenol 7a in DMF.
Under these conditions, we observed both consumption
of the starting materials and exclusive formation of the
desired aryl ether 9a (entry 12).
Scheme 3.
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SNAr Reaction of Methyl 2,6-Dichloronicotinate with Phenols
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Table 2. The SNAr reaction of 2 and 7a using different amine-
bases.
was complete within 5 h at room temperature and pro-
vided the desired biaryl ether 9a in an excellent 92%
yield (Scheme 5). Furthermore, the reaction was ex-
tended successfully to other phenols 7b–d, to provide
the 6-aryloxy ethers 9b–d, exclusively in high yield (en-
tries 2–4).
In conclusion, a highly regioselective, DABCO-cata-
lyzed SNAr reaction of methyl 2,6-dichloronicotinate
(2) with phenols 7a–d in the presence of triethylamine
has been developed to afford, exclusively, the 6-substi-
tuted products 9a–d in high yields. We have also demon-
strated that the reaction proceeds through the regiose-
lective generation of an unprecedented DABCO-pyri-
dine adduct 10a. Additional studies of the DABCO-cat-
alyzed SNAr reaction of 2,6-dichloronicotinic acid (1) or
its derivatives (3 and 4) are in progress and the results
will be reported in due course.
Entry Base
Product(s) Comments
1
2
3
4
5
Me3N·HCl
quinuclidine
3-quinuclidinol 9a
TMEDA
DMAP
9a
9a
1.5 equivs. NEt3 added
9a
8a/9a
Low conversion
~1: 1 ratio
Experimental Section
Formation of DABCO-Pyridine Adduct (10a)
To a solution of methyl dichloronicotinate 2 (5.2 g, 25.2 mmol)
in THF (50 mL) at 58C was added solid DABCO (3.3 g,
29.4 mmol) to provide a clear solution. The reaction mixture
was stirred at 58C for 0.5 h to produce a white slurry. The slurry
was warmed to room temperature and stirred for 16 h. After
HPLC showed no remaining 2, the slurry was diluted with
THF (25 mL) to aid the filtration. The resulting slurry was fil-
tered to give DABCO-pyridine adduct 10a as a white solid;
yield: 8.0 g (quantitative); mp 1658C (dec.); 1H NMR
(400 MHz, DMF-d7): d¼3.43 (br t, J¼7.4 Hz, 6H), 4.01 (s,
Scheme 4.
Additional experiments carried out using amine bases
similar to DABCO, such as trimethylamine,[13] quinucli-
dine,[11] 3-quinuclidinol and N,N,N’N’-tetramethylethy-
lenediamine (TMEDA), all provided the desired biaryl
ether 9a exclusively, although a slower reaction with
TMEDAwas observed (Scheme 4, entries 1–4). It is in-
teresting to note that when 4-dimethylaminopyridine
(DMAP) was used, no selectivity was observed (entry
5).[14]
After gaining an understanding of the function of
DABCO during this two-stage SNAr reaction sequence,
a catalytic DABCO reaction was investigated.[15] In or-
der to regeneratethe catalyst (DABCO) from the result-
ing unreactive HCl salt (DABCO·HCl), a stoichiomet-
ric amount of stronger base was required. Triethylamine
was an ideal choice since it is more basic than DABCO
and not effective alone in promoting the reaction of di-
chloronicotinate 2 and chlorophenol 7a. Indeed when
catalytic DABCO (0.15 equivs.) and stoichiometric tri-
ethylamine (1.3 equivs.) were used, the reaction of di-
chloronicotinate 2 with chlorophenol 7a (1.0 equiv.) Scheme 5.
Table 3. DABCO-catalyzed SNAr reaction of dichloronicotinate 2 with phenols 7a–d.
Entry
Phenol (R)
6-Aryloxy Ethers
Reaction Time [h]
Yield [%]
1
2
3
4
7a (Cl)
7b (H)
7c (OMe)
7d (NO2)
9a
9b
9c
9d
5
10
8
92
86
91
88
4
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Yao-Jun Shi et al.
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3H), 4.29 (br t, J¼7.4 Hz, 6H), 8.73 (d, J¼8.4 Hz, 1H), 8.86 (d,
J¼8.4 Hz, 1H); 13C NMR (100 MHz, DMF-d7): d¼45.7, 53.3,
sources and is readily prepared from 2,6-dichloropyri-
dine (see: Laeckmann et al., Bioorg. Med. Chem. 2002,
10, 1793–1804).
54.8, 117.7, 129.4, 145.2, 147.0, 157.1, 163.9; HR-MS: calcd.
þ
ꢀ
for C13H17ClN3O2 (M Cl): 282.1004; found: 282.1004.
[3] T. Kawato, G. R. Newkome, Heterocycles 1990, 31, 1097–
1104.
[4] Y. Hirokawa, I. Fujiwara, K. Suzuki, H. Harada, T. Yosh-
ikawa, N. Yoshida, S. Kato, J. Med. Chem., 2003, 46, 702–
715.
[5] Y. Hirokawa, T. Horikawa, S. Kato, Chem. Pharm. Bull.
2000, 48, 1847–1853.
[6] Personnel communication with Dr. Guo Q. Shi in our
Laboratories.
[7] Unpublished results.
Synthesis of Biaryl Ether 9a by the DABCO-Catalyzed
SNAr Reaction
To a solution of 19.6 g of dichloronicotinate 2 (95.0 mmol) in
DMF (80 mL) was added a solution of 4-chlorophenol (7a;
12.2 g, 95.0 mmol, 36.6 mL of DMF) at 228C, followed by addi-
tion of triethylamine (17.3 mL, 124.0 mmol) at 22–248C over
15 min. To the resulting solution was added solid DABCO
(1.6 g, 14.2 mmol) in one portion (a temperature increase by
~38C was observed, a water bath was used to maintain the re-
action temperature). The reaction mixture was stirred at 228C
for 4–5 h and monitored by HPLC (the solution turned into a
light slurry and the completion of the reaction was determined
by the disappearance of chlorophenol 7a). To the resulting light
slurry was added acetic acid (2.72 mL, 47.5 mmol) and 2-prop-
anol (57.5 mL). Water (30 mL) was added over 0.5 h maintain-
ing the internal temperature at 22–258C (during the addition
of water, the slurry turned into a clear solution, and eventually
a slurry of 9a was formed providing a good seed-bed). After
stirring at 228C for 0.5 h, the remaining water (86 mL) was add-
ed over 0.5 h. After the slurry had been stirred at228C for 2 h, it
was filtered. The product was washed with mixed solvents
(60 mL of IPA/H2O¼1/1). The isolated solid was dried in the
vacuum-oven at 508C for 8 h to provide a white cotton-like sol-
id 9a; yield: 24.6 g (89%);[16] mp 103–1058C; 1H NMR
(400 MHz, CDCl3): d¼3.92 (s, 3H), 6.85 (d, J¼8.5 Hz, 1H),
7.11 (d, J¼8.9 Hz, 2H), 7.38 (d, J¼8.9 Hz, 2H), 8.22 (d, J¼
8.5 Hz, 1H); 13C NMR (100 MHz, CDCl3): d¼52.6, 109.2,
120.7, 122.6, 129,8, 130.8, 143.9, 149.3, 151.3, 163.5, 164.4.
[8] Internet website: http://daecr1.harvard.edu., see Evans
pKa Table.
[9] DABCO used as a dual nucleophilic catalyst, see: W.-C.
ˇ
Shieh, S. Dell, A. Bach, O. Repic, T. J. Blacklock, J. Org.
Chem., 2003, 68, 1954–1957, and references cited there-
in.
[10] a) J. A. Lim, E. W. McLean, J. L. Kelley, J. Chem. Soc.
Chem. Commun. 1994, 913–914; b) N. K. Lembicz, S.
Grant, W. Clegg, R. J. Griffin, S. L. Heath, B. T. Golding,
J. Chem. Soc. Perkin Trans. 1 1997, 185–186.
[11] W. Gçhring, J. Schildknecht, M. Federspiel, Chimia 1996,
50, 538–543.
[12] a) W. Clegg, B. T. Golding, R. W. Harrington, R. Scott,
Acta Cryst. 2004, E60, o291-o293; b) S. D. Ross, J. J.
Bruno, R. C. Petersen, J. Am. Chem. Soc. 1963, 85,
3999–4003.
[13] M. Ashwell, C. Bleasadale, B. T. Golding, I. K. OꢁNeill, J.
Chem. Soc. Chem. Commun. 1990, 955–956.
[14] For the formation of DMAP-purine adduct, see: R.
Schirrmacher, B. Wꢂngler, E. Schirrmacher, T. August,
F. Rçsch, Synthesis 2002, 4, 538–542.
[15] For previous DABCO-catalyzed SNAr reaction of: a) 2-
chloropyrimidine, see ref.[10] b) 1-fluoro-2,4-dinitroben-
zene, see: H. J. Koeners, A. J. de Kok, J. H. van Boom,
Rec. Trav. Chim. 1980, 99, 355–362.
[16] The product loss to the mother liquor was at ~3%; the
retention time (Rt) obtained by HPLC was identical to
the authentic 9a provided by Dr. Guo Q. Shi from our
Laboratories.
References and Notes
[1] For recent reviews, see a) X. Ma, D. R. Gang, Nat. Prod.
Rep. 2004, 21, 752–772; b) A. Nayyar, R. Jain, Curr. Med.
Chem. 2005, 12, 1873–1886.
[2] a) W. Yang, Y. Wang, J. R. Corte, Org. Lett. 2003, 5,
3131–3134, and references cited therein; b) 2,6-dichloro-
nicotinic acid (1) is available from various commercial
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