T. R. Johnson, R. B. Silverman / Bioorg. Med. Chem. 7 (1999) 1625±1636
1633
3
3
be puri®ed to homogeneity; it was used without fur-
1
(Z)- and (E)-tert-Butyl 4-[(tert-butoxycarbonyl)amino]-2-
(tri¯uoromethyl)-2-butenoate (13 and 14). The method
of Allmendinger and Lang was modi®ed as follows. A
suspension of activated zinc dust (4.90 g, 75 mmol),
Ê
copper(I) chloride (0.74 g, 7.5 mmol), and powdered 4 A
19
ther puri®cation; H NMR (CDCl ): d 10.88 (s, 1H);
F
3
1
3
16
NMR (CDCl ): d � 76.4 (s); C NMR (CDCl ): d 120.7
3
3
(
HRMS (EI) (m/z): [M+H] calcd for C H Cl F O ,
q, J=283 Hz), 164.47 (CCl hidden beneath CDCl ).
2
+
3
3
2
2
3
2
196.9384; found, 196.9391.
molecular sieves (2.5 g) in THF (50 mL) was re¯uxed for
5 min. After cooling to room temperature, acetic
1
tert-Butyl 2,2-dichloro-3,3,3-tri¯uoropropionate (9). The
esteri®cation reaction was divided equally in two Ace
pressure tubes (38 mL). A solution of 8 (9.85 g,
anhydride (2.6 mL, 27.5 mmol) was added in one por-
tion followed by the dropwise addition of a solution of
12 (6.48 g, 25 mmol) and 9 (6.96 g, 27.5 mmol) in THF
(25 mL). Following a brief induction period (ca. 5 min),
an exothermic reaction ensued which was controlled
5
0 mmol) in CH Cl (5 mL) containing concd H SO
2 2 2 4
ꢀ
(
0.14 mL, 5 mmol) was cooled to � 78 C, and iso-
ꢀ
butylene (17±18 g, ca. 300 mmol) was condensed into the
tube. The vessel was sealed, and the reaction mixture
was stirred at room temperature for 70 h. The solution
with a 0±5 C bath. Once the initial exothermic reaction
subsided, the mixture was re¯uxed for 1 h. Upon cool-
ing, the reddish brown mixture was diluted with ether
(150 mL) and was ®ltered through Celite. The ®ltrate
ꢀ
was cooled again to � 78 C, and the vessel opened.
After allowing the contents to slowly warm to room
temperature, the contents of both reaction vessels were
diluted with ether (250 mL), washed with 1 M NaHCO3
was washed with saturated NH Cl (50 mL), 5%
4
NaHCO3 (50 mL), and brine (50 mL), dried over
Na SO , and evaporated to a dark red oil. The crude
2
4
(
evaporated. The crude product was chromatographed
75 mL) and brine (50 mL), dried over MgSO , and
product was chromatographed (85:15 hexanes:EtOAc)
to yield the mono-Boc product as a yellow wax (3.60 g,
44%) as a 1:1 mixture of the (Z)- and (E)-isomers (13
and 14, respectively). The minor di-Boc product was
isolated as a viscous yellow oil (1.49 g, 14%) containing
a 1:1 mixture of the (Z)- and (E)-isomers. Isomers 13
and 14 were separated on an Alltech Econosil C18 pre-
parative scale HPLC column (250Â22 mm, 10 mm) using
4
(
7
(
8
pentanes) to give 9 as a clear colorless oil (17.94 g,
1
19
1%); H NMR (CDCl ): d 1.56 (s, 9H); F NMR
3
13
CDCl ): d � 76.0 (s); C NMR (CDCl ): d 27.3, 30.3,
3
3
7.3, 121.0 (q, J=283 Hz), 159.2. HRMS (EI) (m/z):
+
[
M-CH3] calcd for C H Cl F O , 236.9697; found,
6 6 2 3 2
236.9699.
a mobile phase of 35:35:30 MeCN:MeOH:H O at a ¯ow
2
N,N-Bis(tert-butoxycarbonyl)allylamine (11). A solution
of allyl bromide (11.0 mL, 127.5 mmol) in anhydrous
DMF (500 mL) was cooled to 0±5 C, and potassium
rate of 10 mL/min, monitoring at 254 nm. Multiple
injections (1.5 mL) were made of a solution of the iso-
meric mixture in mobile phase (ca. 70 mg/mL). Under
these chromatographic conditions 13 and 14 eluted at
25 and 27 min, respectively. Fractions were collected
manually. The organic portions of the fractions were
evaporated, and the remaining aqueous layer was
extracted with ether several times. The pooled ether
extracts were washed with brine, dried over Na SO ,
ꢀ
bis(tert-butoxycarbonyl)aminide (21.7 g, 85.0 mmol),
prepared from bis-(tert-butoxycarbonyl)aminide (10)
2
1
according to the procedure of Allan et al. was added
portionwise over 5 min. The mixture was heated to
ꢀ
water (1000 mL). The mixture was extracted with ether
100 C for 2 h, allowed to cool, and poured into cold
2
4
(
4Â250 mL), and the pooled ether layers were washed
and evaporated, yielding pure 13 as a colorless crystal-
ꢀ
with water (150 mL) and brine (150 mL), dried over
Na SO , and evaporated. The crude product was chro-
matographed (hexanes, then 1:1 hexanes:ether) to give
line solid, mp 67±68 C (0.976 g) and 14 as a clear, col-
1
orless, viscous oil (0.723 g). 13: H NMR (CDCl ): d 1.46
2
4
3
(s, 9H), 1.51 (s, 9H), 4.15 (br s, 2H), 4.87 (br s, 1H), 7.03
19
ꢀ
13
1
4
1
1
1 as a colorless, crystalline solid, mp 42±43 C (lit. 47±
(t, J=5.8 Hz, 1H); F NMR (CDCl ): d-59.5 (s);
C
3
ꢀ
8H), 4.17 (d, J=5.5 Hz, 2H), 5.12 (dd, J=10.4, 1.4 Hz,
34
1
8 C) (21.79 g, 100%); H NMR (CDCl ): d 1.50 (s,
NMR (CDCl ): d 27.9, 28.3, 38.7, 80.11, 82.9, 122.3 (q,
3
3
J=274 Hz), 124.8 (q, J=31 Hz), 150.2, 155.7, 161.1.
+
H), 5.17 (dd, J=17.3, 1.5 Hz, 1H), 5.78-5.91 (m, 1H);
C NMR (CDCl ): d 27.9, 48.4, 82.2, 116.1, 133.6,
HRMS (EI) (m/z): M
325.1501; found, 325.1501. 14: H NMR (CDCl ): d
calcd for C H F NO ,
14 22 3 4
1
3
1
3
3
+
152.2, HRMS (EI) (m/z): [M-C H ]
C H NO , 201.1001; found, 201.0996.
calcd for
1.46 (s, 9H), 1.52 (s, 9H), 4.23 (br s, 2H), 4.94 (br s, 1H),
6.77 (t, J=5.2 Hz, 1H); F NMR (CDCl ): d � 65.0 (s);
4
8
19
9
15
4
3
13
C NMR (CDCl ): d 27.9, 28.2, 39.3, 79.8, 83.2, 121.6,
3
N,N-Bis(tert-butoxycarbonyl)glycinal (12). A solution of
1 (20.59 g, 80 mmol) in CH Cl (500 mL) was cooled
(q, J=273 Hz), 125.2 (q, J=30 Hz), 147.9, 155.8, 160.9.
+
1
HRMS (EI) (m/z): M
325.1501; found, 325.1502.
calcd for C H F NO ,
14 22 3 4
2
2
ꢀ
sion tube until a blue color persisted. Methyl sul®de
to � 78 C, and O was introduced through a gas disper-
3
(
29.5 mL, 400 mmol) was added, and the clear colorless
(Z)-4-Amino-2-(tri¯uoromethyl)-2-butenoic acid (4). To
a solution of ester 13 (0.651 g, 2 mmol) in CH Cl
solution was slowly allowed to warm to room tempera-
ture over 17 h. The solvent was evaporated, and the
crude product was chromatographed (4:1 hexanes:
2
2
(12 mL) was added TFA (3.1 mL, 40 mmol) dropwise.
The solution was stirred at room temperature for
30 min, and then diluted with ether (25 mL). The mix-
ture was extracted with water (2Â15 mL), and the
pooled aqueous extracts were washed with ether
(20 mL) and applied to a plug (6 mL) of Dowex 50 resin.
The plug was washed with water (100 mL), and the
product was eluted with 0.1 M pyridine (250 mL). The
EtOAc) to give 12 as a clear, colorless oil which solidi-
1
®
ed to a colorless wax upon standing (11.51 g, 55%); H
NMR (CDCl ): d 1.51 (s, 18H), 4.39 (d, 2H), 9.55 (s,
1
HRMS (EI) (m/z): [M+H] calcd for C H NO ,
260.1498; found, 260.1481.
3
1
3
H); C NMR (CDCl ): d 27.8, 55.1, 83.3, 151.6, 196.6
3
+
1
2
21
5