Journal of the American Chemical Society
Article
enecarbamates were tolerated. Coupling of a sterically
demanding β,β′-disubstituted enecarbamate had a modest
yield (48%) but a high er (94:6) (4i). Vinylamine, a
synthetically useful substrate that poses a challenge in
regioselectivity,16 was coupled to give a single regioisomer
(4j) with a high yield and high enantioselectivity with modified
reaction conditions. The reaction with a trisubstituted
enecarbamate was unsuccessful, however (end of section 6 in
the Supporting Information), probably due to steric hindrance
that blocked Ni−H insertion.
2.3. Functionalization of Natural Products and Drugs.
The enantioselective hydroalkylation method worked for alkyl
halide substrates derived from natural products and drugs,
generating chiral alkyl amines bearing the corresponding
complex or bioactive alkyl fragments (Table 3).17 Alkyl
iodides derived from cholestanol, a biomarker (5a),17a
nootkatone, a sesquiterpenoid (5b),17b and naproxen, a
nonsteroidal anti-inflammatory drug (5c),17c which contained
one or more stereocenters, reacted to give the corresponding
chiral alkyl amines in good yields, high enantioselectivity, and
modest to good diastereoselectivity. Alkyl iodides derived from
drugs such as gemfibrozil (5e), indomethacin (5f,g), and
adapalene (5h) as well as from the herbicide 2,4-D (5d) were
viable reaction partners. These results underscore the high
group tolerance of the hydroalkylation method and its
potential application in the synthesis of bioactive chiral amines.
2.4. Synthetic Applications. The chiral alkyl amines
produced from the above hydroalkylation method proved to be
useful synthetic intermediates.18 For example, simple silyl ether
deprotection of 3m afforded the amino alcohol 6 in high yield
(Figure 2). Compound 6 is a common synthon in asymmetric
organic synthesis because its OH moiety can be easily
converted to other functional groups without erosion in
enantiomeric excess: for instance, in the synthesis of a chiral
piperidine (7a)18a and a β-amino acid (7b).18b In another
example, a Finkelstein reaction of 3l followed by base
treatment provided a (R)-coniine analogue (8) in 53% yield
and 94:6 er. The chiral amine (−)-3s was a reported
intermediate to (R)-1,2,3,4-tetrahydroisoquinoline (11), an
inhibitor of phenylethanolamine N-methyltransferase. Previ-
ously (−)-3s was prepared in three steps from 10, which was in
turn prepared by organocatalytic conjugate addition of a
nitroalkane to vinylsulfone.18c With the current method,
(−)-3s was prepared in one step from enecarbamate 1a and
benzyl bromide. Deprotection of the Cbz moiety in (−)-3s by
Pd/C-catalyzed hydrogenation gave the primary amine, which
was converted without isolation into intermediate 9 with
perfect stereocontrol.
2.5. Mechanistic Investigation. Several experiments were
conducted to probe the origin of the enantioselectivity in the
present hydroalkylation reactions. When the E isomer of 1a
was subjected to the standard conditions (entry 8, Table 1), 3a
was produced just using (Z)-1a. The reaction of (E)-1a was
slightly slower and had a lower yield and enantioselectivity in
comparison to the reaction of (Z)-1a (Figure 3a). This result is
consistent with Ni−H insertion into the alkene as the
enantiodetermining step. If reductive elimination were the
enantiodetermining step, a similar er would be expected for
reactions using either (Z)-1a or (E)-1a.12,14,19 The reactions of
(Z)-1a and (E)-1a with DBpin gave diastereomerically pure D-
3h and D-3h′ (Figure 3b,c). Likewise, reactions of (Z)-1c and
its deuterated analogue, enecarbamate D-(Z)-1c, gave
diastereomerically pure D-4k and D-4k′, respectively (Figure
3d,e). These results again suggest that syn-hydrometalation of
NiH or NiD to N-Cbz enamine is the enantiodetermining step.
Otherwise, a diastereomeric mixture of deuterated products
would be formed. In the reactions involving deuterated
substrates, the enantioselectivity was not influenced by the
1
deuteration. The H NMR spectrum of D-4k′ indicated that
no H/D exchange occurred at the N α-position, suggesting
that the hydride insertion step was irreversible. Overall, the
above results indicate that a reaction pathway involving
reversible Ni−alkyl homolysis followed by stereoselective
reductive elimination12,14,19 can be excluded for the current
system.
When the allylic amine derivative 1a′ was used as the pro-
nucleophile, 3a was also produced, albeit in a lower yield and
er, together with other regioisomers (Figure 3f). This result
indicates chain walking of the distal alkenyl group mediated by
Ni−H to form an α-CbzHN-stabilized Ni−alkyl species.10
When the N-methyl enecarbamate (Z)-1a′′ was used as the
substrate, less than 5% hydroalkylation occurred (Figure 3g).
The low activity toward this tertiary carbamate might be due to
the conformational rigidity of a tertiary carbamate, which
precluded the Cbz group to act as a directing group for Ni−H
insertion (see below). To probe the possibility of Ni-catalyzed
hydroboration of enecarbamate followed by alkyl−alkyl Suzuki
cross-coupling, we treated the hydroboration product relevant
to the hydroalkylation reaction. However, no cross-coupling
occurred, ruling out the Suzuki coupling pathway (Figure 3h).
When 1.0 equiv of (2,2,6,6-tetramethylpiperidin-1-yl)oxyl
(TEMPO), a radical scavenger, was added to the reaction
mixture, the conversion decreased to 54% and the yield
decreased to 12% while the er remained the same (Figure 3i).
This result is consistent with the intermediate of an alkyl
Figure 2. Synthetic applications. See section 7 in the Supporting
Information for full details. TBAF = tetrabutylammonium fluoride.
Legend: (a) with ent-L*1.
1963
J. Am. Chem. Soc. 2021, 143, 1959−1967