Raney-Co Mediated ReductiVe Cyclization
reaction mixture is then quenched by addition of water (11 L). The
mixture was diluted with i-PrAc (23 L), and the organic layer was
separated. The organic layer was washed with saturated aq NaHCO3
(11 L) followed by water (11 L). The organics were then
concentrated to a neat oil which may solidify upon standing, giving
4.52 kg of 6 (88% yield). 1H NMR (CDCl3, 400 MHz) δ 5.45 (br
d, J ) 6.4 Hz, 1H), 4.39 (br t, J ) 8.4 Hz, 1H), 4.16 (q, J ) 7.1
Hz, 2H), 3.66-3.61 (m, 2H), 3.38 (br s, 1H), 2.08-1.99 (m, 1H),
1.65-1.59 (m, 1H), 1.40 (s, 9H), 1.23 (t, J ) 7.1 Hz, 3H). 13C
NMR (CDCl3, 100 MHz) δ 172.9, 162.7, 156.5, 80.4, 61.6, 58.3,
50.8, 36.1, 28.3, 14.1. HRMS (ESI, NaOAc): exact mass calcd
for C11H21NO5 [M + Na], 270.1317. Found 270.1321.
difluorophenylacetonitrile 2 (1.66 kg, 10.8 mol) was added over
10 min. The reaction mixture was stirred at -35 °C for 15
min, then a solution of the aldehyde 3b (2.80 kg, 11.4 mol) in
THF (10 L) was added over 10 min while maintaining the
temperature below -30 °C. After the addition, the reaction
mixture was treated with MsCl (2.48 kg, 21.7 mol) and Et3N (2.74
kg, 27.1 mol). The reaction was allowed to warm to room
temperature and stirred for 2-3 h. This was then quenched
into a mixture of MTBE (40 L) and 10 wt % citric acid solution
(35 L). The aqueous layer was removed, and the organic layer
was washed with 5% NaHCO3 (30 L), brine (5%, 30 L), dried
with MgSO4, filtered, and concentrated in vacuo to a 74 wt %
crude oil of 10b (3.10 kg, 8:1 Z:E, 99% ee, 75% yield). This
material is further purified by column chromatography (gradient
5% to 25% EtOAc in hexanes). 1H NMR (CDCl3, 400 MHz)
δ 7.25-7.09 (m, 3H), 6.92 (t, J ) 7.8 Hz, 1H), 5.32 (br d, J ) 6.5
Hz, 1H), 4.58-4.56 (m, 1H), 4.26 (q, J ) 7.1 Hz, 2H), 3.18-3.12
(m, 1H), 3.05-2.97 (m, 1H), 1.43 (s, 9H), 1.31 (t, J ) 7.1 Hz,
3H). 13C NMR (CDCl3, 100 MHz) δ 170.8, 155.1, 150.9 (dd, JCF
) 249.7, 12.8 Hz), 148.1 (dd, JCF ) 253.9, 14.1 Hz), 147.3 (d, J
) 7.1 Hz), 124.5 (dd, JCF ) 6.9, 5.2 Hz), 124.3 (d, J ) 3.4 Hz),
123.3 (d, J ) 8.3 Hz), 118.0 (d, J ) 17.4 Hz), 115.2, 112.2, 80.3,
62.1, 52.4, 36.2, 14.1. Exact mass calcd for C19H22F2N2O4
[M + Na], 403.1445. Found 403.1450. Assay of enantiomeric
excess: HPLC analysis (Chiralpak AD-H, 5% IPA/heptane, 1 mL/
min, 30 °C, 210 nm; tr (minor isomer) ) 12.9, tr (major isomer) )
14.5), 99.3% ee.
(S)-2-tert-Butoxycarbonylamino-4-oxo-butyric Acid Ethyl Es-
ter (3b). The crude oil (or solid) N-Boc homoserine ethyl ester 6
(2.08 kg, 8.40 mol) was dissolved in CH2Cl2 (9 L) along with
TEMPO (28 g, 179 mmol). This solution was allowed to stir at
room temeprature while a bleach solution was prepared as fol-
lows: KBr (2.10 kg, 17.6 mol) was added to a 5.25 wt % aqueous
bleach solution (47 L) followed by KH2PO4 (1.20 kg, 8.82 mol).
The pH slowly will decrease from 11.6 to 9.5, then rapidly after
pH 9. When pH has reached 7.8, the 6/TEMPO solution in CH2Cl2
was added in a rapid manner, immediately followed by K2HPO4
(1.50 kg, 8.61 mol). The initially dark red solution became colorless
in 5 min, and the pH will stablize at 6.5-6.8. At this point, if HPLC
indicates remaining alcohol 6 or a pH ) 5, then additional bleach
may be added to complete conversion (an additional 47 L of 5.25
wt % bleach may be added as needed). When conversion was
judged to be >99% by HPLC, the reaction was quenched by
addition of Na2S2O3 (2.80 kg, 17.7 mol). After stirring for 5 min,
the organic phase was separated and the aqueous was extracted
with CH2Cl2 (9 L). The combined organics were washed with sat
aq NaHCO3 (9 L), dried with MgSO4, filtered, and concentrated to
Typical Procedure for Nitrile Hydrogenation. [(S)-6-(2,3-
difluorophenyl)-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-yl]-car-
bamic Acid tert-Butyl Ester (1). A high-pressure reaction vessel
was charged with 1 equiv of either methyl ester 10a or ethyl
ester 10b dissolved in 20 mL/g of methanol followed by 1.5 equiv
of triethylamine. The vessel was then charged with 100-150 wt
% of methanol washed Raney-Co 2724. The mixture was then
heated to 40 °C under 450 psi of hydrogen for 8 h. The mixture
was filtered through a pad of celite with methanol and concen-
trated in vacuo. The crude oil 1 may then be purified directly by
column chromatography (60% EtOAc in hexanes). Alternatively,
the crude oil 1 can be purified by diluting with EtOAc (20 mL/g)
and washing with 1 N HCl (2 × 12.5 mL/g), water (12.5 mL/g),
saturated aq NaHCO3 (12.5 mL/g), and brine (12.5 mL/g). Then
the organic layer is dried with Na2SO4, filtered, and concen-
trated in vacuo. Further purification can be achieved by removal
of the Boc-moiety and crystallization of the HCl salt (addition of
5 equiv of dry HCl in IPA to a solution of 1 in ethanol at 40 °C for
1
a yellow oil of 85 wt % aldehyde 3b (1.44 kg, 70% yield). H
NMR (CDCl3, 400 MHz) δ 9.74 (s, 1H), 5.38 (br d, J ) 6.0 Hz,
1H), 4.60-4.56 (m, 1H), 4.22 (q, J ) 7.1 Hz, 2H), 3.11-2.98 (m,
2H), 1.45 (s, 9H), 1.27 (t, J ) 7.1 Hz, 3H). 13C NMR (CDCl3, 100
MHz) δ 199.3, 170.9, 155.3, 80.1, 61.8, 48.7, 46.0, 28.2, 14.0.
Exact mass calcd for C11H19NO5 [M + Na], 268.1161. Found
268.1156.
(Z)-(S)-2-tert-Butoxycarbonylamino-5-cyano-(2,3-difluorophe-
nyl)-pent-4-enoic Acid Methyl Ester (10a). To a solution of
aldehyde 3b (11.5 g at 88.3 wt %, 41.4 mmol) in 172 mL of THF
was added 2,3-difluorophenylacetonitrile 2 (6.48 g, 42.3 mmol).
After cooling to 0 °C, DBU (8.10 mL, 53.5 mmol) was added
over 5 min. The ice bath was removed, and stirring was continued
at room temperature for 4 h. After this time, iodomethane
(5.55 mL, 89.1 mL) was added and the mixture was stirred for 20
h. The reaction mixture was then poured into a separatory funnel
containing 150 mL of MTBE and 150 mL of 10% aq citric acid.
The organic layer was then separated and washed with 100 mL
of water followed by 100 mL of saturated aq NaHCO3. The organics
were then dried with Na2SO4, filtered, and concd in vacuo to a
crude oil which was purified by column chromatography (gra-
dient 17% to 25% EtOAc in hexanes). This gave 11.5 g of a
1
4 h gives crystalline solid). H NMR (CDCl3, 400 MHz) δ 7.13-
7.01 (om, 3H), 6.93 (m, 1 H), 6.42 (br t, J ) 6.0 Hz, 1 H), 5.88-
5.87 (m, 1H), 5.80 (br d, J ) 6.0 Hz, 1H), 5.07-5.01 (m, 1H),
4.59 (br d, J ) 17.7 Hz, 1H), 3.66 (dd, J ) 17.5, 7.6 Hz, 1H),
2.95-2.89 (m, 1H), 2.46-2.38 (m, 1H), 1.47 (s, 9H). 13C NMR
(CDCl3, 100 MHz) δ 174.0, 155.2, 151.4 (dd, JCF ) 249.0, 12.8
Hz), 147.6 (dd, JCF ) 124.0, 13.0 Hz), 132.8, 132.3 (d, J ) 11.7
Hz), 130.9, 124.3 (m, 2C), 116.5 (d, J ) 8.6 Hz), 79.9, 49.3, 43.1
(d, J ) 5.1 Hz), 33.5, 28.4. Exact mass calcd for C17H20F2N2O3
[M + Na], 361.1340. Found 361.1342. Melting point of 8% ee
solids 202.8-206.2 °C. Assay of enantiomeric excess: SFC analysis
(Chiralpak AD-H, 20% (25 mM i-BuNH2 in MeOH)/CO2, 1.5 mL/
min, 200 bar, 35 C; tr (isomer 1) ) 6.1, tr (isomer 2) ) 7.4), 80-
90% ee.
1
92 wt % oil (70% yield) of 10a. H NMR (CDCl3, 400 MHz) δ
7.22-7.07 (m, 3H), 6.89 (dd, J ) 8.1, 7.4 Hz, 1H), 5.38 (br
d, J ) 7.8 Hz, 1H), 4.58-4.56 (br m, 1H), 3.77 (s, 3H),
3.16-3.08 (m, 1H), 3.01-2.92 (m, 1H), 1.39 (s, 9H). 13C NMR
(CDCl3, 100 MHz) δ 171.4, 155.2, 150.9 (dd, JCF ) 249.4, 13.1
Hz), 148.2 (dd, JCF ) 253.9, 13.6 Hz), 147.3 (d, J ) 7.0 Hz),
124.6 (dd, JCF ) 7.0, 5.0 Hz), 124.3 (d, J ) 3.0 Hz), 123.4
(d, J ) 8.0 Hz), 118.0 (d, J ) 17.1 Hz), 115.2, 112.3, 80.4, 52.8,
52.5, 36.1, 28.2. Exact mass calcd for C18H20F2N2O4 [M +
Na], 389.1289. Found 389.1294. Assay of enantiomeric excess:
HPLC analysis (Chiralpak AD-H, 5% IPA/heptane, 1 mL/min,
30 °C, 210 nm; tr (minor isomer) ) 13.4, tr (major isomer) ) 15.8),
99.0% ee.
Acknowledgment. We thank Lisa DiMichele and Robert
Reamer for assistance with the NMR spectra, Mirlinda Biba
and Mr. Peter Sajonz for chiral HPLC analysis, and Thomas
Novak for LC-MS analysis. Kan Eng is also gratefully
acknowledged.
Supporting Information Available: Copies of the 1H and 13
C
(Z)-(S)-2-tert-Butoxycarbonylamino-5-cyano-(2,3-difluorophe-
nyl)-pent-4-enoic Acid Ethyl Ester (10b). A 75 L round-bottomed
flask was charged with THF (27 L) and LiHMDS (1 M in THF,
13.1 L, 13.1 mol). The solution was cooled to -45 °C, and 2,3-
spectra for compounds 1, 10a, 10b, 11, 12, and 13. This material
JO8000996
J. Org. Chem, Vol. 73, No. 8, 2008 3217