Acetonitrile Derivatives as Carbonyl Synthons. One-Pot Preparation of Diheteroaryl Ketones via a Strategy of Sequential SNAr Substitution and Oxidation

Article abstract of DOI:10.1021/jo030234b

The anion of 2-aryl acetonitrile derivatives reacted with a variety of heteroaryl chlorides or bromides in an S_NAr manifold to afford intermediate anions which were susceptible to oxidation. The addition of sodium peroxide and aqueous NH₄OAc solution effected oxidation to afford aryl heteroaryl ketones in good yields. Aryl acetonitrile derivatives are thus umpolung-type synthons of the corresponding aryl carbonyl functionality.

Full text of DOI:10.1021/jo030234b

Aceton itr ile Der iva tives a s Ca r bon yl
Syn th on s. On e-P ot P r ep a r a tion of
Dih eter oa r yl Keton es via a Str a tegy of
Sequ en tia l SNAr Su bstitu tion a n d
Oxid a tion
F IGURE 1. Alternative carbonyl synthons.
Zhiwei Yin, Zhongxing Zhang, J ohn F. Kadow,
Nicholas A. Meanwell, and Tao Wang*
Department of Chemistry, The Bristol-Myers Squibb
Pharmaceutical Research Institute, 5 Research Parkway,
Wallingford, Connecticut 06492
wangta@bms.com
Received J uly 18, 2003
Abstr a ct: The anion of 2-aryl acetonitrile derivatives
reacted with a variety of heteroaryl chlorides or bromides
in an SNAr manifold to afford intermediate anions which
were susceptible to oxidation. The addition of sodium
peroxide and aqueous NH4OAc solution effected oxidation
to afford aryl heteroaryl ketones in good yields. Aryl aceto-
nitrile derivatives are thus umpolung-type synthons of the
corresponding aryl carbonyl functionality.
F IGURE 2. Drugs with diaryl ketone subunits.
SCHEME 1
In a previous study, we demonstrated that N,N-
disubstituted aminoacetonitrile derivatives 1 functioned
as effective synthons for the corresponding amides 2, as
depicted in Figure 1A.1,2 This reaction sequence relies
upon the interception of the intermediate anion with
readily available oxidants followed by release of HCN to
form the carbonyl moiety, a process detailed in Scheme
1. The success of this protocol suggested that the reaction
may be broadened to encompass a wider range of car-
bonyl derivatives if more prevalent acetonitrile reagents
3 were to participate, affording a synthon for 4, Figure
1B.3 Aryl heteroaryl ketones are of interest both as syn-
thetic intermediates and as structural elements present
in several drugs, including the anti-inflammatory agent
ketorolac, the estrogen receptor modulator raloxifene, and
the anti-arrhythmic agent amiodarone (Figure 2).4,5
In an attempt to identify mild conditions distinct from
the traditional oxidative decyanation process mediated
by base and oxygen,3 a series of acetonitrile derivatives
were exposed to a panel of solid peroxides suspended in
THF at room temperature and the reactions were care-
fully monitored by LC-MS. Perhaps not surprisingly, the
combination of structurally diverse acetonitriles and solid
peroxides provided a range of outcomes. The most
impressive result was obtained with 2,2-diaryl acetoni-
triles, which were oxidized by sodium peroxide6 to afford
the corresponding diaryl ketones predominantly. Thus,
treatment of the disubstituted acetonitrile 7a with an
excess of Na2O2 in dry THF provided the corresponding
ketone 8a (77% yield by LC-MS analysis and 58% yield
after physical isolation of the product) along with a small
amount of the dimerized species 9a .7 In contrast, when
a solution of 7a in THF was exposed to excess of NiO2-
H2O,8,9 the primary product was the dimerized species
9a , isolated in 60% yield after chromatography, as
(1) Yang, Z.; Zhang, Z.; Meanwell, N. A.; Kadow, J . F.; Wang, T.
Org. Lett. 2002, 4, 1103.
(2) Zhang, Z.; Yin, Z.; Meanwell, N. A.; Kadow, J . F.; Wang, T. J .
Org. Chem. 2004, 69, 1360.
(3) (a) Heinisch, G.; Langer, T. J . Heterocycl. Chem. 1993, 30, 1685.
(b) Hermann, C. K. F.; Sachdeva, Y. P.; Wolfe, J . F. J . Heterocycl. Chem.
1987, 24, 1061. (c) Deutsch, H. M.; Shi, Q.; Gruszecka-Kowalik, E.;
Schweri, M. M. J . Med. Chem. 1996, 39, 1201. (d) Haider, N.; Heinisch,
G.; Moshuber, J . Heterocycles 1994, 38, 125. (e) Ohba, S.; Sakamoto,
T.; Yamanaka, H. Heterocycles 1990, 31, 1301. (f) Kulp, S. S.; McGee,
M. J . J . Org. Chem. 1983, 48, 4097. (g) Adam, S. Tetrahedron 1991,
47, 7609.
(4) (a) Huang, Y.-C.; Majumdar, K. K.; Cheng, C.-H. J . Org. Chem.
2002, 67, 1682. (b) Miyashita, A.; Matsuda, H.; Suzuki, Y.; Iwamoto,
K.; Higashino, T. Chem. Pharm. Bull. 1994, 42, 2017. (c) Walsh, D.
A.; Moran, H. W.; Shamblee, D. A.; Welstead, W. J ., J r.; Nolan, J . C.;
Sancilio, L. F.; Graff, G. J . Med. Chem. 1990, 33, 2296. (d) Krug, C.;
Hartwig, J . F. J . Am. Chem. Soc. 2002, 124, 1674. (e) Archer, G. A.;
Kalish, R. I.; Ning, R. Y.; Sluboski, B. C.; Stempel, A.; Steppe, T. V.;
Sternbach, L. H. J . Med. Chem. 1977, 20, 1312.
(6) (a) Holland, H. L.; Daum, U.; Riemland, E. Tetrahedron Lett.
1981, 22, 5127. (b) Ho, T.-L.; Olah, G. A. Synthesis 1976, 611. (c)
Vaughn, H. L.; Robbins, M. D. J . Org. Chem. 1975, 40, 1187.
(7) When R,R-diphenyl acetonitrile was used, Li2O2, ZnO2, SrO2,
BaO2, CaO2, and MgO2 afforded acetophenone 8h with lower yields
than Na2O2, while MnO2 and NiO2-H2O provided a dimerized product
9h . Oxone did not promote any reaction.
(8) (a) Sugita, J . Nippon kagaku Zasshi 1967, 88, 1235. (b) Sugita,
J . Nippon kagaku Zasshi 1967, 88, 668. (c) Golding, B. T.; Hall, D. R.
J . Chem. Soc. D 1970, 1574. (d) Hawkins, E. G. E.; Large, R. J . Chem.
Soc., Perkin Trans. 1 1974, 280.
(5) (a) Gillis, J . C.; Brogden, R. N. Drugs 1997, 53, 139. (b) Kellen,
J . A. Curr. Drug Targets 2001, 2, 423. (c) Tomaselli, G. HeartDrug
2001, 1, 183-185.
10.1021/jo030234b CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/22/2004
1364
J . Org. Chem. 2004, 69, 1364-1367

TABLE 1
TABLE 2. Op tim iza tion of Na 2O2 Oxid a tion
oxidant
yield of 8a (%)
yield of 9a (%)
NiO2-H2O
Na2O2
7
66, 60a
11
LC-MS
yield (%)
LC-MS
yield (%)
LC-MS
yield (%)
69, 58a
a
solution in
step 1
of 7b after of 8b after of 9b after
Isolated yield; all other yields were determined by LC-MS.
entry
12 h
12 h
12 h
1
2
3
4
5
6
none
water
NH4Cl (satd)
NaHCO3 (satd)
NH4OAc
36
14
9
<2
0
36
76
77
88
92
78
4
2
3
0
0
0
depicted in the scheme associated with Table 1. Only a
very minor amount of the oxidized ketone 8a was
observed under these conditions.9 The rather clean
transformation of 7a to 8a by simply stirring with Na2O2
provided mild conditions for mediating the oxidation and
subsequent in situ loss of HCN10 and established these
acetonitrile derivatives as effective and convenient car-
bonyl synthons.11
MeOH
3.5
TABLE 3. Oxid a tion of Dia r yla ceton itr ile to Dia r yl
Keton e by Na 2O2
To extend the utility of this synthetic protocol, a
process designed to provide aryl heteroaryl ketones by
way of the reaction of heterocyclic halides with aryl
acetonitrile derivatives was developed. This process relies
upon the sequential SNAr substitution of a heterocyclic
halide and in situ oxidation of the product. On the basis
of the electron-withdrawing properties of heterocyclic ring
nitrogen atoms, it was anticipated that halogen-substi-
tuted pyridine, pyrazine, pyrimidine, pyridazine, triazine,
imidazole, pyrazole, oxazole, and thiazole derivatives
would react via an SNAr process at the position R to the
nitrogen atom.3b,12 Subsequent addition of Na2O2 to the
products in situ would then provide the desired aryl
heteroaryl ketones in a protocol summarized in the
scheme associated with Table 2. To establish the viability
of this process, the anion of phenyl acetonitrile (1a ),
generated by treatment with a 2.5-fold excess of NaH-
MDS, was reacted with quinoxaline chloride 5b in THF
at room temperature to provide the intermediate anion
of 7b. In an attempt to accelerate the reaction with
Na2O2, a saturated aqueous solution of NH4OAc was
added to the reaction mixture, conditions that provided
the phenyl quinoxaline ketone 8b in 92% yield by LC-
MS and an isolated yield of 60%). Several other additives
were also examined in this context, as summarized in
Table 2. The majority of these conditions provided
mixtures of diaryl acetonitrile 7b and diaryl ketone 8b,
along with minor amounts of the dimerized product 9b.
a
Isolated yield; all other yields were determined by LC-MS.
b
Without NH4OAc, 8f 64% and 9f 27%.
Following these encouraging initial results, several
commercially available disubstituted acetonitrile deriva-
tives were exposed to Na2O2 and saturated NH4OAc in
THF to test the efficiency of this oxidation procedure.
From the results compiled in Table 3 it is apparent that
this oxidation process is both general and efficient,
providing products in yields ranging from 41 to 83%, as
determined by LC-MS. To further confirm the efficiency,
two products were physically isolated and the yields were
found to mirror those determined by LC-MS (Table 3,
entries 1 and 2). Notably, this process is compatible with
a range of heterocycles, including the π-excessive het-
erocycles thiophene and N-alkyl pyrrole that might be
(9) Similarly, compound 7d was treated by NiO2-H2O in dry THF
to afford less than 5% (LC-MS) of 8d and 76% (LC-MS)/83% (isolated)
of 9d , the dimer.
(10) Reaction and the following workup process should be under-
taken cautiously in a well-ventilated hood due to the possibility of HCN
liberation.
(11) (a) Larock, R. C. In Comprehensive Organic Transformation;
Wiiley-VCH: New York, 1989; p 733. (b) Hase, T. A. In Umpoled
Synthons: A Survey of Sources and Uses in Synthesis; Wiley-Inter-
science: New York, 1987.
(12) Yamanaka, H.; Ohba, S. Heterocycles 1990, 31, 895.
J . Org. Chem, Vol. 69, No. 4, 2004 1365

TABLE 4. On e-P ot P r ep a r a tion of P h en yl Heter oa r yl a n d Dih eter oa r yl Keton es via a SNAr -Oxid a tion Str a tegy
a
b
Isolated yield; all other yields were determined by LC-MS. 3.5 equiv of NaHMDS was used since the dianion of indole was assumed
to be involved.
considered as substrates sensitive toward oxidation
(Table 3, entries 1 and 4). Interestingly, the inclusion of
NH4OAc solution appeared to suppress the formation of
dimerized product 9 (Table 1, entry 1 and Table 3, entry
6; Table 3, entry 4).
A one-pot procedure starting from heterocyclic halides
(5) and aryl acetonitriles (1) was examined with a series
of heterocyclic halides, a process that afforded the cor-
responding aryl heteroaryl ketones in yields ranging from
25 to 92%, as compiled in Table 4. Noteworthy is the
compatibility of this process with heterocycles such as
thiophenes that are potentially subject to oxidation and
the limited formation of dimerized products.
In summary, we have established mild, neutral condi-
tions for the oxidation of aryl heteroaryl acetonitrile
derivatives to the corresponding ketones. Combining this
protocol with a strategy of sequential SNAr substitution
of heterocyclic halides and Na2O2 oxidation, a convenient
one-pot process was developed that takes advantage of
the umpolung nature of aryl acetonitrile derivatives as
aryl carbonyl synthons. Extension of this process to
encompass unactivated aromatic halides via transition
metal catalysis14 and provide diaryl ketones from aryl
acetonitriles is currently under examination.
Exp er im en ta l Section
A detailed understanding of the mechanism underlying
these oxidation procedures has not been developed. The
role of saturated NH4OAc may be to facilitate dissolution
of the Na2O2 in THF, effect protonation to produce sodium
hydroperoxide and hydrogen peroxide, or a combination
of both effects. However, the stability of diarylacetoni-
triles toward 30% H2O2 suggests that the latter is not
the effective oxidant in this procedure.13
Gen er a l Meth od s. Heterocyclic halides 5 (Tables 2 and 4),
acetonitriles 1 and 7 (Tables 1 and 3), and oxidative agents are
commercially available and were used as received. 1H and 13C
NMR spectra were obtained at 500 MHz with samples dissolved
in CDCl3.
Gen er a l P r oced u r es for th e P r ep a r a tion of Heter ocy-
clic Dia r yl Keton es As Exem p lified by th e P r ep a r a tion of
Com p ou n d 8b. NaHMDS (2.5 mL, 1.0 M in THF, 2.5 mmol)
(13) H2O2 (30% in water) did not oxidize diaryl acetonitriles in THF
at room temperature.
(14) (a) Culkin, D. A.; Hartwig, J . F. J . Am. Chem. Soc. 2002, 124,
9330. (b) You, J .; Verkade, J . G. Angew. Chem., Int. Ed. 2003, 42, 5051.
1366 J . Org. Chem., Vol. 69, No. 4, 2004

was added to a solution of 2-chloroquinoxaline (164 mg, 1.0
mmol) and benzyl nitrile (140 mg, 1.2 mmol) in dry THF
(20 mL). After the mixture was stirred for 10 h at room
temperature, saturated NH4OAc solution (5 mL) and Na2O2 (340
mg, 4 mmol) was added and the mixture stirred a further 10 h
at room temperature. Insoluble solids were filtered off and
washed with MeOH. Concentration of the filtrate in vacuo
afforded a residue which was purified by silica gel chromatog-
raphy, using mixed hexane and EtOAc as eluting solvents, to
provide phenylquinoxalin-2-ylmethanone 8b (140 mg, 60%).
Ack n ow led gm en t. We thank Mr. Alan Xiang-dong
Wang for valuable discussions. We are also very grateful
to Dr. Li Pan for assistance in obtaining exact mass
spectral data.
Su p p or tin g In for m a tion Ava ila ble: 1H and 13C spectra
and HRMS data of compounds 8a -d ,i-o and 9a ,d . This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O030234B
J . Org. Chem, Vol. 69, No. 4, 2004 1367