toluene provided clean reactions with somewhat lower
isolated yields. In contrast, diethyl ether and DME exhibited
substantially slower reaction rates (yields reported for 1 h
reactions) and the slow development of unidentified aromatic
byproducts. Dimethyl formamide proved to be unsuitable for
the cross-condensation as the rate of reaction was exception-
ally slow and unrecognizable aromatic products were rapidly
formed. In regards to base, KOt-Amyl provided the highest
yields and fastest reactions in most solvents.
Upon completion of our solvent and base screen, we
examined the scope of the acylation reaction with a variety
of nitriles 4a-d and esters 5w-z using the optimal base
and solvent combination: KOt-Amyl and THF (Table 3).
In contrast, the â-branched nitrile 4d with various esters,
and acetonitrile (4a) with the enolizable and branched esters,
required elevated temperatures for high yields. The best
conditions for these more difficult cases involved heating
the reaction mixture at 60 °C for varying amounts time
dependent on nitrile and ester. Higher temperatures often lead
to undesired byproducts while lower temperatures resulted
in incomplete reaction. The elevated temperature provided
excellent yields of the desired â-ketonitriles 6ay, 6az, 6by,
6bz, 6dx, 6dy, and 6dz (84%,15 88-99%, respectively).
Preliminary results have shown that â-ketonitriles are
competent templates for unnatural cytosine analogues via the
corresponding enaminonitrile (Scheme 3). This sequence
Scheme 3. â-Ketonitriles as a Template for an Unnatural
Table 3. Acylation of Nitrile Anions with Ethyl Esters
Cytosinea
a Reagents and conditions: (a) BzNCO, pyridine, CH2Cl2, rt; (b)
NaOEt, EtOH/PhH, reflux.
entry nitrile ester temp (°C) time (h) product yielda (%)
1
2
3
4
5
6
7
8
4a
4a
4a
4a
4b
4b
4b
4b
4c
4c
4c
4c
4d
4d
4d
4d
5w
5x
5y
5z
5w
5x
5y
5z
5w
5x
5y
5z
5w
5x
5y
5z
rt
rt
60
60
rt
11
1
3
3
0.33
0.33
1
0.17
48
0.17
23
0.75
3
6aw
6ax
6ay
6az
6bw
6bx
6by
6bz
6cw
6cx
6cy
6cz
99
99
84b
96
99
99
98
99
89
95
89
88
83
89
92
90
validates the utility of â-ketonitriles as templates for 5,6-
disubstituted pyrimidines and showcases our previously
reported method for pyrimidine annulation.6 The scope of
this method for pyrimidine construction will be expanded
upon in future publications.
In conclusion, we have developed the reaction of nitrile
anions with esters to provide â-ketonitriles in unprecedented
yields. Our procedure employs operationally facile reaction
conditions and provides excellent yields even with tradition-
ally difficult substrates. Further studies are underway to
examine the scope of these transformations. These studies
will be reported in due course.
rt
60
60
rt
rt
rt
9
10
11
12
13
14
15
16
rt
140c
60
60
60
6dw
6dx
6dy
6dz
0.17
15
15
Acknowledgment. We are grateful to acknowledge
Brown University for research support, Dr. Russell Hopson
for assistance with NMR analyses, and Dr. Tun-Li Shen for
assistance with mass spectral analyses. W.C.T. and J.V.V.
acknowledge financial support from the Karen T. Romer
Undergraduate Teaching and Research Assistantships pro-
gram at Brown University.
a Isolated yield after silica gel chromatography. b Isolation of â-ketonitrile
6ay was hindered by its volatility. c This reaction was performed in a sealed
vessel in a PersonalChemistry microwave reactor.
In our study of the acylation, good to excellent yields were
obtained after reaction at room temperature for most cases.14
Supporting Information Available: Experimental pro-
cedures for the preparation of 7 and 8 as well as character-
ization data and spectra of 6aw-6dz, 7, and 8. This material
(14) Representative procedure: A solution of KOt-Amyl (1.33 mL, 2.61
mmol, 3.0 equiv, 1.7 M in PhMe, Fluka) was added dropwise to a stirred
room temperature solution of nitrile 4b (101.5 mg, 0.87 mmol, 1.0 equiv)
in THF (3.0 mL) followed by dropwise addition of ester 5w (0.32 mL,
3.48 mmol, 4.0 equiv). After 20 min at room temperature, the reaction
mixture was diluted with 0.25 M HCl (100 mL) and EtOAc (100 mL). The
layers were separated and the organic layer is washed sequentially with
H2O (2 × 50 mL) and brine (2 × 50 mL), dried (Na2SO4), concentrated,
and chromatographed (silica gel, EtOAc/Hex) to provide 149.5 mg (99%)
of 6bw as a colorless oil.
OL053164Z
(15) â-Ketonitrile 6ay is exceptionally volatile, which made isolation
difficult.
Org. Lett., Vol. 8, No. 6, 2006
1163