G. M. Dubowchik et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3147–3149
3149
O
such as 4a, 4d–f, and 4tt were moderately-to-strongly
hygroscopic, and were routinely stored in a dessicator.
These compounds were successfully used for the rapid
optimization of binding affinities for several chemical
classes through parallel, solution-phase synthesis. These
results will be reported in due course.
a
N
Boc
3tt
N
H
2tt
b
N
H
4tt
HCl
Scheme 3. Reagents and conditions: (a) (i) Red-Al (2.5 equiv), toluene,
0 °C to rt, 14 h;(ii) acetone, 0 °C then MeOH, rt, 1 h;(iii) Boc 2O
(1.4 equiv), CH2Cl2, rt, 14 h;(b) 4 M HCl in dioxane (1.2 equiv),
CH2Cl2, rt, 14 h (60% for three steps).
References and notes
1. Adang, A. E. P.;Hermkens, P. H. H. Curr. Med. Chem.
2001, 8, 985.
2. Spaller, M. R.;Burger, M. T.;Fardis, M.;Bartlett, P. A.
Curr. Opin. Chem. Biol. 1997, 1, 47.
3. Lazo, J. S.; Wipf, P. J. Pharmacol. Exp. Ther. 2000, 293, 705.
4. Brown, P. J.;Hurley, K. P.;Stuart, L. W.;Willson, T. M.
Synthesis 1997, 778.
5. Whitten, J. P.;Xie, Y. F.;Erickson, P. E.;Webb, T. R.;De
Souza, E. B.;Grigoriadis, D. E.;McCarthy, J. R. J. Med.
Chem. 1996, 39, 4354.
a
Boc
CN
N
H
9
10
b
NH2
HCl
11
6. Brown, H. C.;Heim, P. J. Org. Chem. 1973, 38, 912.
1
7. All products gave satisfactory H NMR and microanalyt-
Scheme 4. Reagents and conditions: (a) (i) BH3–THF (3 equiv), reflux,
14 h;(ii) MeOH, reflux, 2 h;(iii) Boc 2O (1.4 equiv), CH2Cl2, rt, 14 h;(b)
4 M HCl in dioxane (1.2 equiv), CH2Cl2, rt, 14 h (85% for three steps).
ical results. Representative synthetic procedure for 4c: A
stirred solution of 3,3,3-trifluoroacetic acid N-hydroxysuc-
cinimide ester (12.98 g, 57.65 mmol) in CH2Cl2 (80 mL) at
0 °C was treated with cyclopropylmethylamine (5.0 mL,
1 equiv). The mixture was stirred at rt for 14 h and then
concentrated in vacuo. The residue was partitioned between
ethyl acetate and water. The organic phase was washed with
water, brine, dried over MgSO4, and evaporated to give the
crude amide. This was dried under high vacuum for several
hours and then, under nitrogen at 0 °C, it was carefully
treated with 1 M BH3 in THF (173 mL, 3 equiv). The
mixture was heated at reflux for 14 h and then re-cooled to
0 °C. MeOH (50 mL) was added carefully to avoid excess
foaming, and the mixture was heated at reflux for 5 h. Upon
re-cooling to 0 °C, a solution of Boc2O (17.62 g, 1.4 equiv)
in CH2Cl2 (25 mL) was added. The resulting mixture was
stirred at rt overnight and then concentrated in vacuo. The
residue was partitioned between ethyl acetate and water.
The organic was washed with water, brine, dried over
MgSO4, and evaporated to give the crude Boc-protected
amine. This was dissolved in CH2Cl2 (25 mL) and treated
with 4 M HCl in dioxane (17 mL, 1.2 equiv), carefully to
avoid uncontrolled bubbling. The mixture was stirred at rt
overnight and then evaporated. The resulting white solid
was triturated with ether and the product was collected by
filtration, washed with ether, and dried in vacuo (10.10 g,
F3C
N
H
+
CF3
O
HCl
7
F3C
N
H
CF3
HO
N
H
CF3
6
HCl
8
Scheme 5.
from cyclopropylacetonitrile 9 using a modification of
the general procedure reported herein.
In only one case was a significant impurity formed that
co-precipitated with the desired product (Scheme 5). In
this instance, reduction of amide 6 with borane followed
by further treatment as described above gave the ex-
pected HCl salt 7 as well as the 3-hydroxypropylamine 8
in a roughly 2:1 ratio by an unknown mechanism.9
Conversion of 3,3,3-trifluoropropionyl to 3-hydroxy-
propyl under these conditions is apparently specific to
this substrate since clean reduction to 3,3,3-trifluoro-
propyl occurs in all other cases.
1
86%). H NMR d (D2O) 0.36 (m, 2H), 0.67 (m, 2H), 1.07
(m, 1H), 2.72 (m, 2H), 2.99 (d, 2H), 3.89 (t, 2H). Anal.
Calcd for C7H12NF3–HCl: C 41.29;H 6.43;N 6.88. Found:
C 41.11, H 6.48, N 6.77.
In this way, a diverse set of secondary amine hydro-
chloride salts was generated on a multi-gram-scale in a
relatively short time with a minimum of effort. In gen-
eral, two or three amine preparations could be carried
on at one time by a chemist who was also working on
other tasks. Some of the HCl salts, especially pyridyls
4bb–dd and small, nonhalogen-containing compounds
8. Bazant, V.;Capka, M.;Cerny, M.;Chvalovsky, V.;
Kochloefl, K.;Kraus, M.;Malek, J.
1968, 3303.
Tetrahedron Lett.
9. The structure of 8 was deduced from the 1H NMR and
mass spectrum of its adduct with a halomethyl hetero-
1
aromatic intermediate in comparison with the H NMR of
the mixture of 7 and 8.