Organic Letters
Letter
using inductively coupled plasma (ICP-MS)23 indicated that
<1 ppm of Pd had been incorporated into piridebil (see
Scheme 3. Comparison between Pd/C versus Literature
Processes for RA
Other pharmaceuticals (Scheme 2) such as prozapine24 (5)
(an antispasmodic drug), cinacalcet25 (6) (hyperparathyroid-
ism medication), and fendiline26 (7) (an antiarrhythmic
agent), likewise, were obtained in 87, 88, and 90% yields,
respectively. Similarly, intermediates involved in the synthesis
of fentanyl27 (8) (a pain medication), Amgen’s hyper-
thyroidism drug (9),28 an agent for chronic obstructive
pulmonary disease (10),29 Pfizer’s cancer library (11),30
Ranbaxy’s 5-lipoxygenase inhibitors (12 and 13),31 GSK’s
schizophrenia library (14),32 AbbVie’s cancer library (15),33
an anticancer agent (16),34 and an anti-inflammatory agent
(17)35 could all be prepared using this chemistry in water.
Model compounds 18 and 20, mimicking intermediates
involved in antidiabetic agents,36 were also easily obtained in
high chemical yields. Additionally, reductive aminations that
show further functional group compatibility include amines
bearing a heteroaromatic (20), tertiary nitrogen (21), a
secondary aliphatic nitrogen (22), a primary aliphatic chain
(23), a cyclic array (from methyl estrone; 24), a bicyclic-
containing product (from norcamphor; 25), and an attached
secondary aliphatic carbon chain (26), all of which led
efficiently to the desired products.
While the results illustrated in Scheme 2 demonstrate that
reductive aminations readily proceed in water using minimal
amounts of palladium and afford targets of interest to the
pharmaceutical industry, they are also indicative of the mild
conditions needed and the inherent safety associated with use
of both water as the medium and Et3SiH as the source of
hydrogen on Pd.5 To further emphasize these salient features,
direct comparisons have been made with recently introduced
transition-metal-catalyzed reductive amination processes,
representing both heterogeneous and homogeneous catalysis.
As shown in Scheme 3, products 3 and 27, obtained in 90 and
92% yield, respectively, both proceeding in the presence of
only 0.2 mol % of Pd/C at 45 °C, otherwise require at least 25
times greater loadings of metal, high pressure, and hot organic
solvents.9,10 Similarly, compound 28 was obtained in 83% yield
using ppm Pd/C, but needed higher pressure and temperature
according to literature conditions.11 Interestingly, compound
29 could be obtained in 91% yield using our typical conditions
of 2000 ppm Pd/C, but required 4 mol % (i.e., 40,000 ppm) of
an iridium catalyst at 120 °C to realize a similar outcome.37
The mild reaction conditions associated with use of
nanomicelles in water for reductive aminations offer yet
another major benefit, in addition to the safety aspect:
chemoselectivity. Several potentially reducible or otherwise
sensitive functional groups, such as halide (30−33), nitro (13,
34, and 35), cyano (12, 15), and alkene (28) are tolerated
under these ppm level Pd/C-catalyzed conditions (Scheme 4).
Either replacing Et3SiH with its deuterated analogue or using
D2O in place of H2O led to the desired deuterated product 11′
with ∼70% deuterium incorporation. Incorporation of
deuterium using D2O is evidence that, in addition to the
silane supplying H/D to Pd/C, H-D gas generated during the
reaction in water undergoes heterolytic cleavage on Pd/C as
expected prior to subsequent addition to the C = N bond. Use
of both deuterated silane and D2O, as then expected, led to
100% D incorporation (Scheme 5, eq 1). These results
suggested that hydrogen gas itself might be a sufficient
alternative reductant toward an imine; indeed, aldimine 38
a
Scheme 4. Chemoselective Reductive Aminations in Water
a
Reaction conditions unless otherwise noted: 0.25 mmol aldehyde,
0.28 mmol amine, 1 wt % Pd/C (2000 ppm), 1.2 equiv Et3SiH, stirred
in 2 wt % TPGS-750-M/H2O, 45 °C. Isolated yields.
reacted readily to afford the desired amine 39 in 95% yield
(Scheme 5, eq 2).
Given that today there are many different types of reactions
amenable to chemistry in water, performing sequential
C
Org. Lett. XXXX, XXX, XXX−XXX