Journal of the American Chemical Society
Article
AII state of the metal catalyst. The resultant thiolate could then
receive a proton from the solvent, regenerating the radical-
trapping HAT catalyst through the unused electron from the
hydride source. Together, these observations presented the
tantalizing possibility of a unified, earth abundant element
catalytic system wherein a metal and thiol might achieve
radical alkene reduction driven by a hydride reductant and
proton source.
of TBHP.9−11 These results highlight the unique ability of
Fe(acac)3 to function cooperatively with thiophenol in the
absence of oxidant. Finally, efforts to reduce phenylsilane
loading from 2 equiv to 1.2 resulted in diminished yield and
heating was not effective for improving efficiency (Table 1,
entries 11 and 12).
With these optimized conditions in hand, we sought to gain
some insight into the substrate tolerance of this new catalyst
system. Terminal, 1,1 and 1,2-di, and trisubstituted aliphatic
alkenes are generally well-behaved substrates for the system,
both in aliphatic and cyclic contexts (Table 2). The system
also tolerates a range of functional groups, including esters,
amides, nitriles, ethers, and even free alcohols. Vinyl halides are
also able to be reduced without protodehalogenation (Table 2,
products 11−13), a distinct advantage of radical hydro-
genation methods when compared to organometallic meth-
ods.9−12
RESULTS AND DISCUSSION
■
Having found candidates for all components of the cHAT
scheme, we sought to test its viability in the reduction of a
representative unactivated alkene, 4-phenylbut-1-ene 1 (Table
1). To our delight, we found that simply combining 1, 10 mol
Table 1. Development of a Cooperative Hydrogen Atom
a
Transfer Catalyst System
Another recognized advantage of radical HAT hydro-
genation methods is the ability to achieve exquisite levels of
thermodynamic stereocontrol.2,9−12,45 To probe this possibil-
ity, we assayed the diastereoselectivity of a variety of alkenes
known to exhibit a high preference for thermodynamic
products under the Shenvi hydrogenation conditions.9 Gratify-
ingly, we found our method similarly shows high preference for
the thermodynamic product, achieving comparable diaster-
eoselectivity and yield for each of these molecules (Table 2,
products 17−20).9
Finally, we wondered whether this method would be
amenable to preparative scale chemistry. To our delight, we
found that hydrogenation of alkene 21 on a 1 g scale proceeds
exceptionally smoothly under our optimized conditions,
forming our desired product 8 in 98% yield and excellent
purity (Figure 3).
b
entry
deviation from conditions
yield (%)
c
1
2
3
4
5
6
7
8
none
93
no Fe(acac)3
no PhSH
under air
dodecanethiol instead of PhSH, 72 h
Mn(dpm)3 instead of Fe(acac)3
Co(acac)3 instead of Fe(acac)3
Co(Salen) + 10 mol % NFPY instead of Fe(acac)3
Co(acac)2 instead of Fe(acac)3
Co(Salen) instead of Fe(acac)3
50 °C
n.d.
27
d
48
43
30
14
trace
n.d.
20
49
57
9
10
11
12
MECHANISTIC INVESTIGATION
■
1.2 equiv PhSiH3
Substrate Tolerance and Selectivity. While broad, the
substrate scope of the method is not without limitations. In
particular, styrenyl substrates are a challenge for our system,
with examples ranging from reduced efficiency (Table 2,
product 15) to minimal reactivity (Table 3, substrates 22 and
23). We considered that this might arise from the two-step
mechanistic scheme of cHAT, whereby both HAT steps must
be kinetically efficient with a high driving force. Styrenyl
substrates exhibit high driving force for the first mHAT step
due to the stability of the benzylic radical. However, this
enthalpic driving force comes at the cost of the second radical
trapping HAT step, where this same stability severely curtails
the driving force of radical reduction.
a
b
1H NMR yield using 1,3,5-trimethoxybenzene as an internal
c
d
standard. Isolated yield. Significant Wacker side product observed.
% of Fe(acac)3, 10 mol % of PhSH, and 2 equiv of phenylsilane
in ethanol provided our desired product 2 in 93% yield (Table
1, entry 1). Control experiments found both catalyst
components to be critical for efficient reduction, with no
product detected in the absence of Fe(acac)3 and modest yield
in the absence of thiol (Table 1, entries 2 and 3). We observed
that inert atmosphere was also necessary for selective and
efficient reduction, with competitive formation of the Wacker
product 4-phenylbutanone occurring under ambient atmos-
phere conditions, consistent with the work of Han (Table 1,
entry 4).44 Further, we found this catalyst combination to be
uniquely effective in reducing unactivated olefins, with efforts
to replace thiophenol with dodecanethiol significantly
diminishing the reaction efficiency (Table 1, entry 5).
Similarly, efforts to replace Fe(acac)3 with other mHAT
catalysts were not successful, forming the product in a much
reduced yield for MIII complexes Mn(dpm)3, Co(acac)3, or in
situ generated CoIIISalen (Table 1, entries 6−8). CoII
complexes were similarly ineffective, with Co(acac)2 forming
no product and Co(Salen) producing a modest 20% yield
(Table 1, entries 9 and 10), both notable results as Co(Salen)
Cl is effective in the presence of stoichiometric thiophenol41
and Co(acac)2 has high hydrogenation activity in the presence
This effect is implied most clearly when comparing the
reduction of radical intermediates 25 and 26, leading to
products 15 and 27, respectively (Figure 4). Comparing the
bond dissociation enthalpies of the hypothetical radical
terminating HATs between thiophenol (BDES−H = 84 kcal
mol−1)46 and the radical intermediates reveals divergent
outcomes: a mildly exothermic process for the formation of
15 (BDEC−H = 88 kcal mol−1)47 and an endothermic process
for 27 (BDEC−H = 82 kcal mol−1).48 These thermochemical
data translate in the reaction flask, with the reaction leading to
15 proceeding with moderate efficiency and that hoping to
afford 27 leading only to trace product. The moderate
efficiency of the former reaction can also be understood
kinetically, as proton-coupled electron transfer (PCET)
processes can be well-described by Marcus Theory, wherein
C
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX