of 10
SUPPORTING INFORMATION
1
Supporting Information
©
Wiley
-
VCH 2016
69451 Weinheim, Germany
Catalytic Reduction of Alkyl and Aryl Bromides using Isopropanol
Michael C. Haibach, Brian M. Stoltz, and Rober H.
Grubbs*
Abstract:
Milstein’s complex (PNN)RuHCl(CO) catalyzes 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, a
s well as more functionalized aryl
and alkyl bromides. The reduction process is proposed to occur via
radical abstraction/hydrodehalogenation steps
at ruthenium. Our research
represents a safer and more sustainable alternative to typical silane, lithium al
uminium hydride, and tin
-
based conditions for these reductions.
DOI: 10.1002/ani
e.2016
XXXXX
SUPPORTING INFORMATION
2
Table of Contents
Additional Optimization
Information
Experimental Procedures
Characterization of Products
Preparation of 1
-
bromo
-
1
-
methylcyclohexane
3h
References
Author Contributions
NMR Spectra
SFC Trace
2
3
3
-
4
4
4
-
5
5
6
-
9
10
1.
Additional Optimization Information
Fi
gure S1
.
Comparison of the reaction kinetics for
1b
and
2c
Given that
2c
resulted in ca. 30% higher conversion than the next best catalyst during optimization,
1b
, we compared the
kinetic
profiles of these two species. Under the optimized reaction conditions (1.00 mmol scale, 1.2 equiv NaO
t
-
Bu, 1 mol % cat., 0.2 M
i
-
PrOH), we monitored the reaction of
3a
with both
2c
and
1b
over time as shown in Figure 2. The reaction using
2c
is in
itially faster,
and reaches a maximum conversion of 96% in
40 minutes at 100
°
C. The reaction using
1b
requires ~90 min to reach a maximum
conversion of 70%. Hence the iridium complex
1b
is both initially slower and more readily deactivated than the ruthenium complex
2c
.
Figure S2
.
Results using Cs
2
CO
3
as a base.
SUPPORTING INFORMATION
3
2.
Experimental Procedures
General Information
:
All manipulati
ons of metal complexes were carried out under atmospheres of N
2
or argon using standard
airfree techniques.
1
H,
13
C and
31
P NMR were recorded on Varian and Bruker 300 and 400 MHz spectrometers.
1
H and
13
C NMR are
reported in ppm (
δ
) and referenced
[
1
]
to residual solvents.
31
P NMR are referenced to 85% H
3
PO
4
(0.00 ppm). GC analyses were
conducted on an Agilent 6800 instrument with an Agilent HP
-
5 column. Column chromatography was carried out using silica gel F60,
230
-
400 mesh from Silicycle. CAM (cerium ammonium molbydate) and PMA (phosphomolybdic acid) stai
ns were prepared according
to Not Voodoo.
[
2
]
Isopropanol (anhydrous) was purchased from Sigma
-
Aldrich and sparged with argon before use. Iridium complexes
1a
-
e
were prepared according to the literature.
[
3
]
Ruthenium complexes
2a
-
c
were purchased from Sigma
-
Aldrich. Co
mmercially
available halide substrates were purchased in the highest available purity and used as received. Older substrates from existi
ng
chemical stock were purified by filtration through a plug of neutral alumina before use.
General procedure for reduct
ion with 2c
:
Inside a N
2
glovebox, a 20 mL septum
-
capped vial was charged with 1.00 mmol
organohalide (if solid), 115 mg NaOt
-
Bu (1.20 mmol) and 4.4 mg
2c
(0.01 mmol, 1 mol%). The vial was capped and removed from
the glovebox. 5.0 mL anhydrous degassed
i
-
P
rOH was then added via syringe, followed by 1.00 mmol organohalide (if liquid). The
vial was then stirred
at 10
0
°C on a hotplate using an aluminum block, with the solvent level remaining above the top of the well. The
reaction was monitored by GC
or TLC
.
Workup procedure A
:
After completion, the vial was cooled to room temperature and the reacti
on mixture diluted with
pentane.
The mixture was washed with
H
2
O and brine
. The combined aqueous layers were extracted
with
pentane. The organic layers were
dried
over Na
2
SO
4
and purified by column chromatography (SiO
2
, pentane).
Workup procedure B
: After completion, the vial was cooled to room temperature and the reaction mixture was concentrated in
vacuo. The resulting crude
product was dissolved in
EtOAc and wash
ed with
H
2
O and brine. The organic layer was dried over MgSO
4
,
concentrated in vacuo and purified by column chromatography (SiO
2
).
3.
Characterization of Products
n
-
Decane
: Isolated as
a colorless oil (134 mg, 0.93 mmol, 9
3% yield) from 1
-
bromodecane followin
g
the general procedure
and
workup procedure A
.
Spectral data matched the literature:
1
H NMR (400 MHz, Chloroform
-
d
) δ 1.47
1.16 (m, 16H), 0.92 (t,
J
= 6.8
Hz, 6H).
13
C NMR (101 MHz, Chloroform
-
d
) δ 31.97, 29.71, 29.41, 22.72, 14.10.
[
4
]
1
-
Ethyl
-
4
-
methoxybenzene
: Isolated as a colorless oil (129 mg, 0.95 mmol, 95% yield) from 1
-
(2
-
chloroethyl)
-
4
-
methoxybenzene following the general procedure
and workup procedure A
. Spectral data matched the literature:
1
H NMR (400 MHz,
Chloroform
-
d
) δ 7.
17 (d,
J
= 8.7 Hz, 2H), 6.89 (d,
J
= 8.6 Hz, 2H), 3.83 (s, 3H), 2.86
2.49 (m, 2H), 1.28 (t,
J
= 7.6 Hz, 3H).
13
C NMR
(101 MHz, Chloroform
-
d
) δ 157.67,
136.38, 128.71, 113.75, 55.20, 28.02, 15.93.
[
5
]
Adamantane:
Isolated as a colorless sol
id (128 mg, 0.94 mmol, 94% yield) from 1
-
bromoadamantane following the general
procedure
and workup procedure A
. Spectral data matched the literature:
1
H NMR (400 MHz, Chloroform
-
d
) δ 1.87 (s, 3H), 1.75 (t,
J
= 3.2 Hz, 9H).
13
C NMR (101 MHz, Chloroform
-
d
)
δ 37.90, 28.48. mp 192
-
195°C (sublimed)
[
6
]
Adamantane:
Isolated as a colorless solid (131 mg, 0.95 mmol, 95% yield) from 2
-
bromoadamantane following the general
procedure
and
workup procedure A
. Spectral data matched the literature:
1
H NMR (400 MHz, Chloroform
-
d
) δ 1.87 (s, 3H), 1.75 (t,
J
= 3.2 Hz, 9H).
13
C NMR (101 MHz, Chloroform
-
d
) δ 37.90, 28.48.
n
-
Propoxybenzene:
Isolated as a colorless oil (120 mg, 0.88 mmol, 88% yield)
from (3
-
bromopropoxy)benzene
following the
general procedure and workup procedure A
. Spectral data matched the literature:
1
H NMR (400 MHz, Chloroform
-
d
) δ 7.45
7.18 (m,
2H), 7.05
6.82 (m, 3H), 3.97 (t,
J
= 6.6 Hz, 2H), 1.87 (dtd,
J
= 13.9, 7.4, 6.5 Hz, 2H), 1.10 (t,
J
= 7.4 Hz, 3H).
13
C NMR (101 MHz,
Chloroform
-
d
) δ 159.14, 129.44, 120.48, 114.51, 69.38, 22.66, 10.59.
[
7
]
Naphthalene:
Isolated as a colorless solid (122 mg, 0.95 mmol, 95% yield) from 1
-
bromonaphthalene
following the general
p
rocedure and workup procedure A
. Spectral data matched the literature:
1
H NMR (400 MHz, Chloroform
-
d
) δ 7.88 (dq,
J
= 6.2, 2.8
Hz, 4H), 7.52 (dt,
J
= 6.3, 3.1 Hz, 4H).
13
C NMR (101 MHz, Chloroform
-
d
) δ 133.46, 127.90, 125.83.
mp 72
-
76
°C
[
8
]
Isopropyl benzoate
: Isolated as a colorless oil (148 mg, 0.90 mmol, 90% yield) from methyl 4
-
bromobenzoate
and workup
procedure B
. Spectral data matched the literature:
1
H NMR (400 MHz, Chloro
form
-
d
) δ 8.09
7.99 (m, 2H), 7.63
7.51 (m, 1H), 7.51
7.35 (m, 2H), 5.26 (hept,
J
= 6.3 Hz, 1H), 1.37 (d,
J
= 6.3 Hz, 6H).
13
C NMR (101 MHz, Chloroform
-
d
) δ 166.13, 132.69, 130.90,
129.50, 128.26, 68.35, 21.97.
[
9
]
1,3
-
Bis(trifluoromethyl)benzene
: Isolated as a colorless oil (158 mg, 0.74 mmo
l, 74% yield) from 1,3
-
bis(trifluoromethyl)
-
5
-
bromobenzene
following the general procedure and workup procedure A
. Volatile product. Spectral data matched the literature:
1
H
NMR (400 MHz, Chloroform
-
d
) δ 7.89 (s, 1H), 7.82 (d,
J
= 8.1 Hz, 2H), 7.64 (t,
J
= 7.9 Hz, 1H).
19
F NMR (376 MHz, Chloroform
-
d
) δ
-
63.17.
[
10
]
SUPPORTING INFORMATION
4
Mesitylene
: Isolated as a colorless oil (107 mg, 0.89 mmol,
89% yield) from 2
-
bromomesitylene following the general procedure
with 2 mol%
2c
, and 48 h reaction time.
Workup procedure A was used.
Spectral data matched the literature:
1
H NMR (500 MHz,
Chloroform
-
d
) δ 6.86 (s, 1H), 2.34 (s, 3H).
[
1
]
1,1
-
dimethylcyclohexane
: Isolated as a colorless oil (78 mg, 0.70 mmol, 70% yield)
from
3h
following the general procedure
and
workup procedure A
. Volatile product. Spectral data match
ed the literature:
1
H NMR (500 MHz, Chloroform
-
d
) δ 1.47
1.40 (m, 5H),
1.24 (dt,
J
= 11.2, 6.1 Hz, 5H), 1.14 (s, 2H), 0.83 (s, 3H).
13
C NMR (126 MHz, Chloroform
-
d
) δ 37.94, 32.22, 26.64, 22.13.
[
11
]
Benzyl
(S)
-
2
-
methylpyrrolidine
-
1
-
carboxylate:
Inside an N
2
glovebox, a 20 mL septum
-
capped vial was charged with 115 mg
NaOt
-
Bu (1.20 mmol) and 4.4 mg
2c
(0.01 mmol, 1 mol%). The vial was capped and removed from the glovebox. 5.0 mL anhydrous
degassed i
-
PrOH was then added via syringe, followed by 298 mg
3n
(1.00 mmol). The reaction was stirred at room temperature.
After 24 h, the reaction appeared complet
e by TLC (DCM, CAM stain). The reaction mixture was extracted with ether, washed with
water, brine and dried over MgSO
4
. The crude product was purified by column chromatography (SiO
2
, DCM) to afford the title
compound as a colorless oil (187 mg, 0.85 mmol,
85% yield). Spectral data matched the literature:
1
H NMR (500 MHz, Chloroform
-
d
)
δ 7.42
7.20 (m, 5H), 5.14 (p,
J
= 12.0 Hz, 2H), 3.99 (s, 1H), 3.44 (s, 2H), 2.04
1.74 (m, 3H), 1.58 (s, 1H), 1.16 (s, 3H).
13
C NMR
(126 MHz, Chloroform
-
d
), observed as t
wo rotamers, δ 128.40, 127.78, 66.58, 66.34, 53.43, 52.84, 46.63, 46.25, 33.25, 23.65, 22.91,
20.86, 20.00.
[
12
]
Enantiomeric excess was determined to be >99% by SFC (AD
-
H, 2% i
-
PrOH, 3.0 mL/min), using a racemic sample
prepared by the reaction of
rac
-
2
-
methylpyrrolidine with Cbz
-
Cl and i
-
Pr
2
NEt in DCM.
H
exahydro
-
2H
-
3,5
-
methanocyclopenta[b]furan
-
2
-
one
: Isolated as a colorless solid
(99 mg, 0.72 mmol, 72% yield)
from
bromolactone
3
r
following the general
procedure, using 1.0 equiv NaO
t
-
Bu at room temperature. Workup procedure B was used.
Column condition: 50% hexanes/DCM. Spectral data matched the literature
:
1
H NMR (400 MHz, Chloroform
-
d
) δ
4.76 (dd
,
J
= 5.0
,
7.9 Hz,
1H), 3.17 (tq,
J
= 4.9, 1.5 Hz, 1H), 2.51 (ddt,
J
= 11.3, 4.9, 1.5 Hz, 1H), 2.43 (ddp,
J
= 3.8, 2.9, 0.9 Hz, 1H), 1.94 (ddt,
J
= 13.0,
11.3, 3.4 Hz, 1H), 1.80
1.66 (m, 3H), 1.62
1.54 (m, 2H), 1.50 (ddd,
J
= 14.1, 2.3, 0.9 Hz, 1H).
13
C NMR (101 MHz, Ch
loroform
-
d
)
δ 181.58, 80.93, 46.50, 39.14, 38.16, 37.94, 36.52, 34.52.
4.
Preparation of unreported compound
1
-
bromomethyl
-
1
-
methylcyclohexane
1
-
hydroxymethyl
-
1
-
methylcyclohexane
: A solution of 2.84 g (20.0 mmol) 1
-
methylcyclohexane carboxylic acid in THF (40
mL,
0.2 M) was cooled with an ice
-
water bath and 3.8 mL (40 mmol) BH
3
-
DMS complex was added dropwise (gas evolves). The ice
-
water
bath was removed and the reaction was stirred for 48 h at room temperature, then cooled again with an ice
-
water bath. H
2
O was
added carefully until no more gas evolved, then the mixture was extracted with 3 x 25 mL DCM. The DCM layers were washed with
aq. NaHCO
3
and dried over MgSO
4
. Concentration in vacuo afforded the title compound as a clear colorless oil: 2.40 g (18.8 mmol,
94% yield). Spectral data matched the literature:
1
H NMR (400 MHz, Chloroform
-
d
) δ 3.73 (s, 1H), 3.32 (s, 2H), 1.84 (s, 1H), 1.74
1.10 (m, 11H), 0.89 (s, 3H).
13
1
-
bromomethyl
-
1
-
methylcyclohexane
: A stirred solution of 614 mg (5.00 mmol) 1
-
hydroxymethyl
-
methylcy
clohexane and 1.44
g (5.50 mmol) PPh
3
in 5.0 mL (1.0 M) DMF was cooled in a water bath under argon. Br
2
was added dropwise until an orange color
persisted (ca. 0.13 mL). The reaction mixture was then heated to 150°C for 30 min, and cooled to room temperatu
re. The resulting
dark solution was diluted with 25 mL water and 25 mL pentane, stirred and filtered. The mixture was separated and extracted w
ith 2 x
10 mL pentane. The pentane extracts were washed with 2 x 25 mL brine, then dried (Na
2
SO
4
) and filtered th
rough a plug of SiO
2
.
Concentration afforded the title product as a clear colorless oil: 279 mg (1.46 mmol, 29% yield). This compound was previousl
y
reported in the literature but not fully characterized.
14
1
H NMR (500 MHz, Chloroform
-
d
) δ 3.34 (s, 2H), 1.52
1.42 (m, 5H), 1.42
1.35 (m, 4H), 1.35
1.28 (m, 1H), 1.00 (s, 3H).
13
C NMR (126 MHz, Chloroform
-
d
) δ 47.62, 35.89, 34.27, 26.10, 22.02. HRMS (EI+)
for C
8
H
15
Br: cal
culated 190.0357, measured 190.0358.
References
[1]
G. R. Fulmer, A. J. M. Miller, N. H. Sherden, H. E. Gottlieb, A. Nudelman, B. M. Stoltz, J. E. Bercaw, K. I. Goldberg,
Organometallics
2010
,
29
, 2176
-
2179.
[2]
http://chem.chem.rochester.edu/~nvd/pages/magic_formulas.php?page=tlc_stains
[3]
a
)
M. Gupta, C. Hagen, W. C. Kaska, R. E. Cramer, C. M. Jensen,
J. Am. Chem. Soc.
1997
,
119
, 840
-
841; b
)
I. Göttker
-
Schnetmann, P. White, M.
Brookhart,
J. Am. Chem. Soc.
2004
,
126
, 1804
-
1811; c
)
M. Yamashita, Y. Moroe, T. Yano, K. Nozaki,
Inorganica Chimica Acta
2011
,
369
, 15
-
18; d
)
R.
Ahuja, B. Punji, M. Findlater, C. Supplee, W. Schinski, M. Brookhart, A. S
. Goldman,
Nature chemistry
2011
,
3
, 167
-
171; e
)
W. Yao, Y. Zhang, X. Jia, Z.
Huang,
Angewandte Chemie International Edition
2014
,
53
, 1390
-
1394.
[4]
T. Ogoshi, Y. Shimada, Y. Sakata, S. Akine, T.
-
a. Yamagishi,
Journal of the American Chemical Society
2017
,
139
, 5664
-
5667.
[5]
D. Leow, Y.
-
H. Chen, T.
-
H. Hung, Y. Su, Y.
-
Z. Lin,
European Journal of Organic Chemistry
2014
,
2014
, 7347
-
7352.
[6]
A. Dewanji, C. Mück
-
Lichtenfeld, A. Studer,
Angewandte Chemie International Edition
2016
,
55
, 6749
-
6752.
[7]
Y.
-
W. Zhe
ng, P. Ye, B. Chen, Q.
-
Y. Meng, K. Feng, W. Wang, L.
-
Z. Wu, C.
-
H. Tung,
Organic Letters
2017
,
19
, 2206
-
2209.
[8]
L. Liu, P. E. Floreancig,
Organic Letters
2010
,
12
, 4686
-
4689.
[9]
Q. Jiang, A. Zhao, B. Xu, J. Jia, X. Liu, C. Guo,
The Journal of Organic Chemistry
2014
,
79
, 2709
-
2715.
SUPPORTING INFORMATION
5
[10]
K. A. Giffin, I. Korobkov, R. T. Baker,
Dalton Transactions
2015
,
44
, 19587
-
19596.
[11]
R. J. Abraham, M. A. Warne, L. Griffiths,
Journal of the Chemical Society, Perkin Transactions 2
1997
, 31
-
40.
[12]
W. H. Nijhuis, W. Verboom, A. Abu El
-
Fadl, G. J. Van Hummel, D. N. Reinhoudt,
The Journal of Organic Chemistry
1989
,
54
, 209
-
216.
[13]
V. Shiner Jr, J. J. Tai,
Journal of the American Chemical Society
1981
,
103
, 436
-
442.
[14]
W. Parker, R. A. Raphael
,
Journal of the Chemical Society (Resumed)
1955
, 1723
-
1727.
Author Contributions
M.C.H.: designed the project, carried out experiments, analysed the data, wrote the manuscript
B.M.S.: designed the project, analysed the data, contributed to writing the
manuscript
R.H.G. designed the project, analysed the data, contributed to writing the manuscript
SUPPORTING INFORMATION
6
SUPPORTING INFORMATION
7
SUPPORTING INFORMATION
8
SUPPORTING INFORMATION
9
SUPPORTING INFORMATION
10