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Chemie
Accepted Article
Title:
Catalytic Reduction of Alkyl and Aryl Bromides Using Isopropanol
Authors:
Michael C. Haibach, Brian M. Stoltz, and Robert H. Grubbs
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content of this Accepted Article.
To be cited as:
Angew. Chem. Int. Ed.
10.1002/anie.201708800
Angew. Chem.
10.1002/ange.201708800
Link to VoR:
http://dx.doi.org/10.1002/anie.201708800
http://dx.doi.org/10.1002/ange.201708800
COMMUNICATION
Catalytic
Reduction of Alkyl
and Aryl
Bromides U
sing Isopropanol
Michael C. Haibach
[a]
,
Brian M. Stoltz,
[a
]
and
Robert H. Grubbs
*
[a]
Abstract:
Milstein’s complex
(PNN)Ru
HCl(CO)
catal
yzes the
efficient reduction of
aryl and alkyl halides
under relatively mild
conditions, using isopropanol and a base. Sterically hindered tertiary
and neopentyl substrates are reduced efficiently, as
well as more
functionalized ary
l and alkyl bromides
. The reduction process is
proposed to occur via
radical a
bstraction/
hydrodehalogenation
steps
at ruthenium. Our research represents a safer and more sustainable
al
ternative to typical silane, lithium aluminium hydride
, and tin
-
based
conditions for these reductions.
The reduction of carbonyl and carboxyl groups
to the
corresponding alkyl groups is an important process in the
construction of saturated hydrocarbon frameworks, particularly
those bearing all
-
carbon quaternary centers.
[
1
]
The final step in
this sequence often requires the reduction of an alkyl halide
or
alkyl sulfonate ester. Alkyl halides are traditionally reduced with
reactive metal hydrides such as LiAlH
4
or under ionic and radical
conditions using silanes, hydroiodic acid/phosphorus (HI
-
P), or
Bu
3
SnH/AIBN.
[
2a
-
b
]
Each of these reagents presents a si
gnificant
challenge: LiAlH
4
is pyrophoric and challenging to handle on a
large scale, some silanes can generate explosive SiH
4
via
disproportionation, HI
-
P is strictly controlled due to its use in
illicit methamphetamine synthesis, and Bu
3
SnH is both toxic
and
difficult to remove from lipophilic products.
[
2c
-
d
]
Recent
developments in transfer hydrogenation catalysis have led to
safer conditions for the reduction of esters
[
3
]
and ketones
[
4
]
, and
we wondered whether the same advance could be achieved for
alkyl halides.
Scheme 1.
Recent approaches to transfer dehalogenation
.
Table 1.
Optimization of the reduction of 1
-
bromodecane
Entry
[a]
Catalyst
% conv. to
n
-
decane
[b]
Temp.
1
none
0%
[c]
100
°
C
2
3
4
5
6
7
8
9
{d,e]
10
[d,f]
11
[g]
12
1a
1b
1c
1d
1e
2a
2b
2c
2c
2c
2c
49
61
18
51
27
44
33
97 (93)
87
91
91
100
°
C
100
°
C
100
°
C
100
°
C
100
°
C
100
°
C
100
°
C
100
°
C
100
°
C
50
°
C
50
°
C
[a]
Reactions carried out in
a sealed vial under N
2
on a 0.1 mmol scale
.
[b]
Conversions into
n
-
decane measured using GC/authentic samples/internal
standards
after 18 h reaction time
.
Isolated yield in parentheses
.
[c] 9%
conversion to a mixture of decenes. [d] 1.0 mmol scale [e] 1 mo
l % 2c, 1.2
equiv NaO
t
-
Bu [f] 0.4 mol % 2c, 1.2 equiv NaO
t
-
Bu [g] 1.2 equiv Cs
2
CO
3
Grubbs, Nolan, and Fort have independently reported
transition
-
metal catalyzed reduction of aryl halides using metal
alkoxides/alcohols as bases and hydrogen donors.
[
5
]
(Scheme 1)
Alternatively, Stephenson and coworkers have reported an
efficient photoredox approach to alkyl halide reduction, using
i
-
Pr
2
NEt/HCOOH or
i
-
Pr
2
NEt/Hantzsch ester as the co
-
reductant.
[
6
]
Their system is highly functional
-
group tolerant and
applies to “activated” alkyl halides (benzylic or α
-
carbonyl). To
the best of our knowledge, there is no general catalytic transfer
[a]
Dr. M. C. Haibach, Prof B. M. Stoltz, Prof. R. H. Grubbs
Division of Chemistry and Chemical Engineering
California Institute of Technology
Pasadena, CA 91125, USA
E
-
mail:
rhg@caltech.edu
Supporting information for this article is
given via a link at the end of
the document.
10.1002/anie.201708800
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article
is protected
by
copyright.
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rights
reserved.
COMMUNICATION
reduction of alkyl halides, especially for unactivated or hindered
sub
strates.
[
7
]
In this paper we report an efficient catalyst system
for the reduction of both aryl and unactivated alkyl halides using
i
-
PrOH as the hydrogen source.
[
8
-
9
]
Pincer
complexes of Ir and Ru
are among the most
effective catalysts for alcohol dehydr
ogenation.
[
10
]
Iridium pincers,
such as those of the type (PCP)Ir and (PNP)Ir, undergo net
oxidative addition of various aryl and alkyl halides.
[
11
]
We thus
envisioned combining these steps into a catalytic cycle for
transfer halide reduction
using
i
-
PrOH
and a base
.
We began by
examining the reaction of 1
-
bromodecane
(
3a
)
with 3.0
equivalents of NaO
t
-
Bu in
i
-
PrOH in the presence of a catalytic
amount of
various readily available pincer
-
Ir and Ru complexes
shown in Table 1.
Milstein’s catalyst precursor
2c
[
12
a]
generated
n
-
de
cane in near quantitative yield.
Iridium pincers
1a
-
e
and
ruthenium pincers
2a
-
b
afforded low to moderate conversion
after 18 hours at 100
°
C
. No
obvious
relationship between
conversion and reported catalyst activity for dehy
drogenation or
steric hindrance existed
.
[1
3]
Using
2c
, we were also able to decrease the amount of
NaO
t
-
Bu to 1.2 equiv
alents
and the catalyst loading to 1 mol %
without affecting the yield.
[
14
]
Notably, we detected no decene or
n
-
decyl isopropyl ether in the reactions using
1
or
2
. As a control
experiment, only li
mited conversion into decenes was
observed
in the absence of a pincer catalyst, suggesting that these
alternative reaction pathways are slow under our conditions
(Entry 1
).
In all catalytic reactions, the formation of
acetone and
t
-
BuOH
was
observed.
[15
]
The standard conditions were applied to a
several
unactivated
alkyl bromides and chlorides, using 1 mol % of
2c
as shown in Figure 1
.
High
conversions a
nd good to
excellent
yields were obtained after 18 hours
.
Chlorodecane
3b
exhibited
decreased reactivity, and conversion stalled at <50%. Addition of
excess LiBr allowed the reaction to proceed to full conversion.
The phenethyl chloride
3c
reacted efficiently to aff
ord the
reduced product in excellent yield without modification. The
tertiary bromide
3d
and neopentyl bromide
3
h
, challenging
substrates for C
–
X bond reduction, both afforded the
corresponding reduction products in
high yield.
Significantly, no
rearrangem
ent of the neopentyl bromide was detected.
Hindered
neophyl bromide
3
f
also reacted readily, and we observed the
formation of both
tert
-
and
iso
-
butylbenzene by GC. The phenyl
group of
3
f
is well
-
known to migrate under both radical
conditions
.
[16]
D
ecyl to
sylate
3
k
afforded no
n
-
decane when
subjected to the reaction conditions.
The high reactivity of
hindered alkyl bromides, the rearrangement of
3f
, and the
divergent reactivity of tosylate
3k
are all consistent with a C
–
X
bond activation via a radical mecha
nism.
[17]
We also
evaluated
more functionalized substrates
to probe
the chemoselectivity of our process. The reaction tolerated the
presence of
ether,
CF
3
, pyridyl and ester groups
in the aryl
substrates
3l
-
p
.
The methyl ester in
3p
was not reduced
[18]
,
though it did undergo full
transesterification.
These examples
demonstrate improved chemoselectivity compared to LiAlH
4
and
other re
active metal hydride reagents. The sterically h
indered
mesityl bromide
3j
could also be reduced in high yield using 2
mol
%
2c
after 48 h.
Figure 1
.
Scope of the reduction using isopropanol
a) All reactions were carried out on a 1.00 mmol scale in a sealed vial under
N
2
, and reached >95% conversion according to GC.
Percentages are isolated
yields of reduction product unless otherwise noted. b
)
Yield determined using
GC c
)
with 10 equiv LiBr d) 1.8:1 ratio of
t
-
BuPh:
i
-
BuPh observed by GC e
)
Reduced isolated yield due to volatile product f) 2 mol %
2c
, 48 h reaction time
g) Formation of
i
-
PrO
-
n
-
Dec observed by GC h) 1 h reaction time i) Reaction
carried out at
23
°
C
for 24 h j)
Reduction of
3
p
(R = Me) afforded PhO
i
-
Pr
k)
1.0 equiv NaO
t
-
Bu,
23
°
C
, 24 h
l) 2.4 equiv NaO
t
-
Bu, pyridine observed as the
exclusive product.
One common application of
the Bu
3
SnH/AIBN system has
been the reduction of nonracemic
aminoalkyl halides, affording
valuable protected chiral amines from the corresponding amino
acids.
[19
]
The reduction of
3
q
proceeds in high yield
after 24 h at
room temperature, with no loss of optical purity. The yield and
stereoretention compare well to the literature preparation using
Bu
3
SnH/AIBN, and a shorter reaction time is required (24 h at
23 °C vs 72 h at 80 °C).
[20
]
The sensitive bicycli
c bromolactone
3r
was also
reduced
selectively
at ambient temperature
without
any ring
-
opening observed
.
The phosphorus atom in
2c
provides a convenient
spectroscopic handle for det
ermining catalyst
speciation during
the
reaction
.
The reduction of
3q
was monitored under the
10.1002/anie.201708800
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article
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reserved.
COMMUNICATION
conditions shown in Equation 1, using unlocked
31
P NMR.
After
2 h reaction time,
we observed
2c
and a new species
with
δ
=
88.4
ppm
in approximately a 1:1 ratio.
[21
]
This
new species
resonates signific
antly upfield of the known
hydride complexes
derived from
2c
.
[22
]
It falls much closer to the reported value
s
of
(PNN)RuCl
2
(CO),
δ
=
91
.4
and [(PNN)RuCl
2
]
2
(
μ
-
N
2
),
δ
= 87.8
.
[23
]
Thus it seems likely that both complexes of the type
(PNN)RuHX(CO) and (PNN)RuX
2
(CO
)
are
the catalyst resting
state
.
As noted earlier, several reactivity trends point to a radical
mechanism for the C
–
X bond reduction step. To probe
this
hypothesis, we subjected 5
-
bromohex
-
1
-
ene to our optimized
conditions (Equation 2). The reaction proceeded efficiently to
generate methylcyclopentane with >99:1 selectivity, im
plying the
intermediacy of the 5
-
hexenyl radical.
[24]
Alternatively, the
reaction could proceed via insert
ion of the olefin into a Ru
–
C
bond, however this insertion would be expected to be slow.
[25]
Our proposed
radical
mechanism
[26
-
27]
is shown in Scheme 2
.
Initiation likely occurs via
ho
molysis of the benzylic C
–
H
bonds
in (PNN)RuH
2
(CO), ultimately
generating H
2
and a
putative 15e
-
species
,
(PNN)RuH(CO). This reactive species could abstract a
bromine atom from the organic substrate, generating the
corresponding
alkyl
radical
and
(PNN)RuHBr(CO).
(PNN)RuHBr(CO) can undergo facile hydrodehalogenation by
i
-
PrO
-
to form (PNN)RuH
2
(CO), which in turn serves as an H
atom donor towards the organic radical.
Thus the observed
reduced organic product and the active intermediate
(PNN)RuH(CO) are regenerated. Entering the same reaction
pathway starting from (PNN)R
uHBr(CO) would generate
(PNN)RuBr
2
(CO), the observed catalyst resting state.
Due to
metal
-
ligand cooperation
[23]
, this intermediate can also re
-
enter
the main cycle via the reaction with
i
-
PrO
-
.
Scheme 2.
Proposed mechanism
.
In summary, we have developed a catalyst system for the
efficient transfer reduction of a range of unactivated and
functionalized alkyl and aryl halides, which requires only the
relatively inexpensive and safe stoichiometric reagents N
aO
t
-
Bu
and
i
-
PrOH. Reaction setup and workup is simple. While many
iridium and ruthenium pincer complexes show catalytic activity,
Milstein’s complex
2c
was key to obtaining high yields.
The
reaction appears to proceed via a radical mechanism.
Our
conditio
ns offer a greener alternative for several types of
stoichiometric
LiAlH
4
or Bu
3
SnH
-
mediated reductions.
Future
studies will be directed
the reaction mechanism and catalyst
design
.
Acknowledgements
We acknowledge funding from King Fahd University of
Petroleum and Minerals
.
M.C.H. acknowle
d
ges funding from the
Resnick Sustainablility Instute in the form of a postdoctral
fellowship.
Keywords:
halogens
•
hydrogen transfer
•
green chemistry
•
hydrides
•
hydrocarbons
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Organometallics
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2002,
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i. Fujita,
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R.
Yamaguchi,
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[
7]
For interesting alternative approaches to the reduction of
aryl
halides,
see:
a
)
X. Jurvilliers,
R. Schneider, Y. Fort, J. Ghanbaja,
Appl.
Organomet. Chem.
2001,
15
, 744
-
748;
b)
W.
He,
J.
-
M. Fontmorin, I.
Soutrel
, D. Floner,
F. Fourcade, A. Amrane, F. Geneste,
J. Mol. Catal.
A: Chem.
2017,
432
, 8
-
14.
[
8]
Studer and coworkers recently reported an oxygen
-
mediated radical
transfer reduction of sp and sp
2
C
–
I bonds:
a)
A. Dewanji, C. Mück
-
Lichtenfeld, A.
Stud
er,
Angew. Chem., Int
. Ed.
2016,
55
, 6749
-
6752;
Beller and coworkers recently reported a heterogeneous Co
-
catalyzed
hydrogenation of aryl halides. Their system had reduced reactivity
when a
pplied to a neopentyl bromide.
b)
B. Sahoo,
A.
-
E. Surkus, M.
-
M.
Pohl, J. Radnik, M. Schn
eider,
S. Bachmann, M. Scalone, K. Junge, M.
Beller,
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c) Dai and Li recently reported
10.1002/anie.201708800
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COMMUNICATION
a tandem reduction of sp
3
alcohols using Ru/Ir dehydrogenation
catalysts and Wolff
-
Kishner conditions:
X.
-
J. Dai, C.
-
J. Li
,
J. Am. Chem.
Soc.
2016
,
138
, 5433
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5440.
[
9
]
The catalyst systems in r
efs. 5
–
6 have not been reported to be effective
for alkyl halides.
In particular, Stephenson noted that higher
photocatalyst reduction potentials would be required for unactivated
substrates.
[
10
]
a)
J. Choi, A. H. R. MacArthur, M. Brookhart, A. S. Goldman,
Chem.
Rev. 2011, 111
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1779;
b)
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Chem. Rev.
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[
11
]
a)
L. Fan, S. Parkin,
O. V. Ozerov,
J. Am. Chem. Soc. 2005, 127
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16773;
b)
J. Cho
i, D. Y. Wang,
S. Kundu,
Y. Choliy,
T. J. Emge,
K. Krogh
-
Jespersen
, A. S. Goldman,
Science
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c)
D. A. Laviska,
Ph.D. Thesis, Rutgers, The State University of New
Jersey, New Brunswick, 2013.
[12]
a)
J. Zhang, G. Leitus,
Y. Ben
-
David,
D. Milstein,
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2005,
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-
10841.
;
b)
Iridium complexes
1a
-
e
were prepared
according to the literature, while Ru complexes
2a
-
c
were purchased
from commercial sources. See the supporting information for details.
Milstein has proposed
that
the NEt
2
group in
2c
is hemilabile,
which
may be importa
nt for our reaction. See ref. 10b
for details.
[
13]
See the supporting information for a comparison of the kinetic profiles
of
1b
and
2c
.
No induction period was observed.
[
14
]
Other bases were
briefly investigated: Na
2
HPO
4
, NaHCO
3
, K
2
CO
3
and
NaOAc all afforded poor conversion or byproducts. Cs
2
CO
3
, KO
t
-
Bu
and NaO
t
-
Bu were found to be equally effective
for the reduction of
3a
.
NaO
t
-
Bu was chosen due to
its lower cost per mole and lower toxicity
t
han
Cs
2
CO
3
.
See the supporting information for example reductions
using Cs
2
CO
3
.
[
15
]
Self
-
condensation of the acetone byproduct does not seem to be an
issue. In the reduction of
3a
, <1% mesityl oxide was detected by GC.
Isophorone and diacetone
alcohol were not detected.
[
16
]
J. A. Franz, R. D.
Barrows, D. M.
Camaioni,
J. Am. Chem. Soc
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106
, 3964
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3967.
[
17
]
While single electron chemistry has not been previously observed with
complex
2c
, many stoichiometric reductions of alkyl halides with
transition metals are known to proceed via radicals. See ref. 2a for
details.
[
18
]
2c
is catalytically active for ester hydrogenation under basic conditions
(Ref. 3a),
however
i
-
PrOH is
apparently
less
effective
as a hydrogen
source for this transformation. S
ee
:
A. Dubey, E. Khaskin,
ACS Catal.
2016
,
6
, 3998
-
4002.
[
19
]
For a recent approach
using
Pd catalysis, see:
P. K. Mandal, J.
Sanderson Birtwistle, J. S, McMurray,
J. Org. Chem.
2014
,
79
, 8422
-
842
7. High
-
pressure H
2
or Et
3
SiH are employed as reductants.
[
20
]
W. H. Nijhuis,
W. Verboom, A. Abu El
-
Fadl, G. J. Van Hummel,
D. N.
Reinhoudt,
J. Org. Chem.
1989,
54
, 209
-
216.
[
21
]
The remaining amount of
2c
is likely due to incomplete initiation of the
catalyst under the limitations imposed by running the reaction in an
NMR tube with a higher ratio of
2c
:NaO
t
-
Bu.
[
22
]
For example,
δ
(PNN)RuH
2
(
CO
)
= 124.9 ppm (C
6
D
6
)
, (PNN*)RuH(CO)
= 94.7 ppm (C
6
D
6
), see ref.
12.
δ
(PNN)
RuH
Cl(
CO
)
= 107.1
ppm
(
i
-
PrOH
)
, our measurement.
[
23
]
J. Zhang, M. Gandelman, L. J. W. Shimon, D. Milstein.
Dalton Trans.
2007
, 107
-
113.
[24]
C. Walling, A. Cioffari
J. Am. Chem. Soc.
1972
,
94
, 6059
-
6064.
[
25
]
Complex
2c
is a poor olefin hydrogenation catalyst due to slow olefin
insertion into the Ru
–
H bond. For a similar discussion in a Ni/silane
system see: J. Breitenfeld, R. Scopelliti, X. Hu.
Organometallics
2012
,
31
, 2128
-
2136.
[
26
]
Our reaction may also be
represented via electron injection, where e
-
takes the place of (PNN)RuH(CO). See
A. Studer, D. Curran.
Nature
Chemistry
,
2014
,
6
, 765
-
773.
[
27
]
For a recently proposed radical mechanism for the reduction of aryl
halides, see
T. Hokamp, A. Dewanji, M. L
übbesmeyer, C. Mück
-
Lichtenfeld, E.
-
U. Würthwein, A. Studer.
Angew. Chem. Int. Ed.
2017
,
56
, 1
-
5.
10.1002/anie.201708800
Angewandte Chemie International Edition
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article
is protected
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copyright.
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COMMUNICATION
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COMMUNICATION
Milstein’s complex (PNN)RuHCl(CO) catalyzes the efficient reduction of alkyl
bromides and chlorides under relatively mild conditions, using isopropanol and a
base. Sterically hindered tertiary and neopentyl subst
rates are reduced efficiently,
as well as more functionalized aryl and alkyl bromides.
The reaction appears to
occur via a radical pathway, and provides an
alternati
ve to
silane, lithium aluminium
hydride, and tin
-
based
reductions
.
Michael C. Haibach, Brian M. Stoltz,
Robert H. Grubbs*
Page No.
–
Page No.
Catalytic Reduct
ion of Alkyl and Aryl
Bromides U
sing Isopropanol
10.1002/anie.201708800
Angewandte Chemie International Edition
This
article
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copyright.
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