Organic Letters
Letter
Scheme 1. Typical Branched Amine Derivatives and
Transition-Metal-Catalyzed Synthesis of γ-Amine
Derivatives
Table 1. Optimization of Reaction Conditions for the Ir-
Catalyzed γ-Selective Hydroboration of 1a
a
yield of 2a
b
c
entry
variations
2a:3a
(%)
1
2
none
90:10
81:19
78
trace
[Cp*RhCl2]2 was used instead of
[Cp*IrCl2]2
3
4
I or II was used instead of [Cp*IrCl2]2
Crabtree’s catalyst was used instead of
[Cp*IrCl2]2
NR
NR
−
−
5
6
styrene in lieu of A
without A
89:11
92:8
65
29
7
8
9
10
11
Davephos (2.5 mol %) was added
PPh3 (2.5 mol %) was added
Xantphos (2.5 mol %) was added
THF was used instead of CyH
1,4-dioxane was used instead of CyH
89:11
ND
88:12
84:16
84:16
75
NR
70
65
71
a
Unless otherwise noted, all of the reactions were carried out with 1a
(0.20 mmol) and HBpin (0.32 mmol) in solvent (1.0 mL) at room
b
temperature for 5 h. The 2a:3a ratio was determined by GC analysis.
c
Isolated yield.
substituents are investigated when R′ is an ethyl group (1a−h).
All of the reactions could reach completion within 5 h in
moderate to good yields (2a−h, 64−80%). The regioselectivity
strongly depended on the substituent. For example, o-methyl-
substituted 2b gave higher γ-selectivity (92%) while a para
substituent usually gave inferior results (2c−h, 82−90% γ-
selectivity). The reaction was also tolerated with a thiophenyl
group, although only 80% regioselectivity was observed (2i).
We next focused on the variation of the R′ group. When R′ is a
methyl group, the reaction afforded the products in 63−80%
isolated yields with γ-selectivity ranging from 86% to 90% (2j−
l). The regioselectivity remained at the same level when the
chain length of R′ was extended to n-propyl (1m) and n-butyl
(1n). In addition to alkyl substrates, benzyl and homobenzyl
groups (1o and 1p, respectively) were also compatible with
reaction conditions. In particular, an excellent γ-selectivity
(97%) was observed when R′ was a benzyl group. The
moderate isolated yield (45%) is due to the partial
decomposition of 2o upon column chromatography. The
lower stability of 2o is probably due to its C−B bond being
closer to the inductively electron-withdrawing sp2 carbon of
the phenyl ring compared to that of 2p. Apart from arylamides,
alkylamide (1q) could also undergo the hydroboration
smoothly to afford the product (2q) in 68% yield with inferior
γ-selectivity (86%) compared to the reaction of 1j. We then
surveyed the compatibility of other relatively sensitive
functionalities. Fortunately, ester (1r), ether (1s), aldehyde
(1t), and free hydroxy (1u) groups were well tolerated,
affording 2r−2u, respectively, in 57−69% isolated yields with
γ-selectivity ranging from 85% to 91%. Although isolated olefin
was not compatible, the bishydroborated product (2v) was
obtained in 66% yield with 90% γ-selectivity. To further extend
the generality of the current protocol, we examined the
catalytic amount of [Cp*IrCl2]2 (1.25 mol %) and a
stoichiometric amount of 1,1-diphenylethene (A) (1.0 equiv)
in cyclohexane for 5 h afforded γ-borylated product 2a in 78%
yield with 90% γ-selectivity (Table 1, entry 1). Replacement of
the Ir catalyst with its Rh analogue afforded only a trace
amount of the product with 81% γ-selectivity (Table 1, entry
2). Neither CpIr(cod) (I) (cod = 1,5-cyclooctadiene) nor
chiral CpIr(cod) (II) showed reactivity for this reaction (Table
1, entry 3).17 The use of Crabtree’s catalyst also showed no
reactivity (Table 1, entry 4). When styrene was used in lieu of
A, almost the same level of regioselectivity was observed.
However, 2a was obtained in inferior yield (Table 1, entry 5).
A low yield was observed (29%) when the reaction was carried
out without A (Table 1, entry 6). The role of A was to act as
the hydrogen acceptor to inhibit the hydrogenation byproduct
of 1a, which was evidenced by the 1,1-diphenylethane (44%
1
yield) observed by H NMR of the crude reaction mixture
under standard reaction conditions (Table 1, entry 1). We next
investigated the effect of phosphine ligands on the current
reaction. However, none of them could further enhance the
performance of the reaction in terms of the outcome of
product 2a (Table 1, entries 7−9). Further examination of
solvent effects revealed that cyclohexane was optimal in terms
of both yield and regioselectivity (Table 1, entry 1 vs entries 10
and 11).
With optimized reaction conditions in hand (Table 1, entry
1), we then determined the additional substrate scope of the
current Ir-catalyzed γ-selective hydroboration of γ-substituted
allylic amides as shown in Scheme 2. First, a variety of N
B
Org. Lett. XXXX, XXX, XXX−XXX