Rhodium-Catalyzed Reductive Cleavage of Aryl Carbamates Using Isopropanol as a Reductant

Article abstract of DOI:10.1055/s-0036-1589093

Despite the widespread use of carbamates as a directing group in C-H bond-functionalization reactions, reductive removal of this directing group is not straightforward. Currently available methods are limited to nickel-catalyzed reactions using ⁱ PrMgX or hydrosilane as a reductant, leaving the functional group compatibility issue to be solved. Herein, we report rhodium-catalyzed reductive cleavage of aryl carbamates using ⁱ PrOH as a milder reductant.

Full text of DOI:10.1055/s-0036-1589093

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K. Yasui et al.
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Rhodium-Catalyzed Reductive Cleavage of Aryl Carbamates Using
Isopropanol as a Reductant
Kosuke Yasui
R
R
H
cat. Rh/iPrOH
OCONEt2
Masaya Higashino
Naoto Chatani*
Mamoru Tobisu*
Reductive Removal of
Carbamate
FG
FG
R, FG = ketone, F, NH, double bond, pyridiyl, etc.
Department of Applied Chemistry, Graduate School of
Engineering, Osaka University, Suita, Osaka 565-0871,
Japan
chatani@chem.eng.osaka-u.ac.jp
tobisu@chem.eng.osaka-u.ac.jp
Published as part of the Cluster C–O Activation
Received: 31.05.2017
Accepted after revision: 10.07.2017
Published online: 17.08.2017
nickel-catalyzed reaction of aryl carbmates.4c Although
these reactions allow carbamates to be used as a temporary
directing group in ortho-C–H bond functionalization, func-
tional groups that react with iPrMgX or hydrosilane, such as
ketones and unsaturated bonds, are not applicable.
We have developed a series of reactions by C–O bond
cleavage of inert phenol derivatives catalyzed by nickel5 and
rhodium.6 We recently reported rhodium-catalyzed direct-
ed C–H bond arylation with aryl carbamates by C–O bond
cleavage.6d Based on this finding, we envision that a rhodi-
um catalyst could be applied to reductive cleavage of aryl
carbamates when an appropriate reductant is added. Here-
in, we report rhodium-catalyzed reductive removal of the
carbamate group using iPrOH as a reductant (Scheme 1c).
DOI: 10.1055/s-0036-1589093; Art ID: st-2017-s0413-c
Abstract Despite the widespread use of carbamates as a directing
group in C–H bond-functionalization reactions, reductive removal of
this directing group is not straightforward. Currently available methods
are limited to nickel-catalyzed reactions using iPrMgX or hydrosilane as
a reductant, leaving the functional group compatibility issue to be
solved. Herein, we report rhodium-catalyzed reductive cleavage of aryl
carbamates using iPrOH as a milder reductant.
Key words reductive cleavage, C–O activation, N-heterocyclic car-
bine, rhodium, isopropanol
Transition-metal-catalyzed C–O bond functionalization
of inert phenol derivatives has emerged as an attractive
methodology because this transformation enables the use
of naturally abundant and more environmentally benign
phenol derivatives instead of aryl halides.1 Among the inert
phenol derivatives, carbamates are frequently used not only
as a protected form of phenols but also as a substrate in di-
rected ortho-C–H bond functionalization reactions. In par-
ticular, directed ortho metalation (DoM) reaction is one of
the most powerful methods for regioselective transforma-
tion of arenes.2 Catalytic C–H bond functionalization reac-
tions directed by a carbamate group have also been report-
ed.3,4a,b Although these methods allow access to elaborate
aromatic compounds from simple phenol derivatives, post-
synthetic manipulation of the carbamate directing group is
essential to produce target products. Therefore, the syn-
thetic utility of C–H bond functionalization would be en-
hanced if the carbamate moiety could be reductively re-
moved after ortho-C–H bond functionalization (Scheme
1a). In 1992, Snieckus reported nickel-catalyzed reductive
(a) Reductive Removal of Carbamate Directing Group
R
R
Directed C–H
Transform.
OCONEt2
H
DG Removal
H
FG
(b) Prior Arts
R
R
OCONEt2
H
cat. Ni/Reductant
FG
FG
Reductant = iPrMgBr
Snieckus
(Me2SiH)2O (TMDSO) Garg
(c) This Work
R
R
OCONEt2
H
cat. Rh/iPrOH
FG
FG
• Rhodium for inert C–O activation
• No strong base required
• iPrOH as a reductant
Scheme 1 Reductive removal of the carbamate directing group
First, we investigated reductive cleavage of ortho-substi-
tuted phenyl carbamate 1a in the presence of a rhodium
bis(NHC) catalyst6d using iPrOH as a reducing agent.7
Among the NHC ligands tested, L2 was optimal and provid-
i
cleavage of aryl carbamates using PrMgX as a reducing
agent (Scheme 1b).4a,b Garg reported that tetramethyldi-
siloxane (TMDSO) can be used as a milder reductant for the
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

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K. Yasui et al.
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ed 2a in 40% yield (Table 1, entries 1–3). The yield of 2a in-
creased by changing the base, with K3PO4 being the most ef-
fective base, giving 2a in 75% yield (entry 7).8 For the reduc-
tant, both primary (entries 8 and 9) and tertiary (entry 10)
alcohols were totally ineffective.9 The reaction was com-
plete within 4 h by using 1 equiv of iPrOH (entry 11).
mates with basic nitrogen (i.e., 1h) and an acidic proton
(i.e., 1i) were also tolerated. It should be noted that these
four substrates (i.e., 1e, 1f, 1g, and 1i) did not form any of
the corresponding reductive cleavage product when the
Ni/TMDSO system4c was used.
"RhCl(L2)2" (10 mol%)
iPrOH (1 equiv)
K3PO4 (2 equiv)
Table 1 Optimization Studiesa
H
OCONEt2
R
R
toluene
O
NEt2
"RhCl(NHC)2" (10 mol%)
H
180 °C, 4 h
2a–i
1a–i
OCONEt2
alcohol (4 equiv)
base (2 equiv)
toluene
O
Ph
Ph
1a
2a
OCONEt2
TMS
180 °C, 16 h
R = H
= F
78%
64%a (2b)
(2a)
Entry
NHC
Alcohol
Base
GC yield of 2a (%)
= OMe 72%b (2c)
R
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
MeOH
EtOH
tBuOH
iPrOH
Na2CO3
Na2CO3
Na2CO3
K2CO3
KOAc
12
76%b (2d)
1
2
L1
L2
L3
L2
L2
L2
L2
L2
L2
L2
L2
OMe
40
OCONEt2
OCONEt2
OCONEt2
3
20
O
4
67
Ph
O
5
27
72%b (2f)
(Ni/TMDSO: 2%)c
96%b,d (2g)
(Ni/TMDSO: 0%)c
74% (2e)
(Ni/TMDSO: 0%)c
6
KOPiv
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
16
7
75
8
0
N
OCONEt2
OCONEt2
9
trace
trace
75 (12)c
N
H
10
11b
75%a (2i)
(Ni/TMDSO: 0%)c
80% (2h)
R
R
Scheme 2 RhCl(L2)2-catalyzed reductive cleavage of aryl carbamates.
Reagents and conditions: RhCl(L2)2 (0.030 mol), K3PO4 (0.60 mmol), 1
(0.30 mmol), 2-propanol (0.30 mmol), toluene (1.0 mL), 180 °C, 4 h.
a “RhCl(L2)2” (20 mol%) was used. b Reacted for 16 h. c Yield when the
previously reported method4c was used. d Isolated as a mixture of stil-
bene and 1,2-diphenylethane (82:18).
N+
Cl–
N
N+
Cl–
L1•HCl
N
L2•HCl (R = H)
L3•HCl (R = Me)
a Reaction conditions: [RhCl(C2H4)2]2 (5.8 mg, 0.015 mmol), NHC·HCl
(0.060 mmol), KOtBu (7.4 mg, 0.066 mmol), base (0.60 mmol), and tolu-
ene (0.40 mL) at 60 °C for 1 h; 1a (53 mg, 0.30 mmol), iPrOH (72 mg, 1.2
mmol) and toluene (0.60 mL) at 180 °C for 16 h.
Next, we investigated carbamates bearing an alcohol
moiety (i.e., 1j), with the expectation that intramolecular
hydride transfer would occur (Scheme 3). The desired reac-
b iPrOH (1.0 equiv) was used and reacted for 4 h.
c Yield of recovered 1a.
i
tion proceeded without adding PrOH to form reduced
With the optimal reaction conditions in hand, we next
investigated the scope of the reaction with respect to aryl
carbamates (Scheme 2).10 Substrates bearing electron-with-
drawing (1b) and electron-donating (1c) groups both un-
derwent the reaction to give the corresponding reduced
products in 64% and 72% yields, respectively. In the case of
1b, defluorinated starting material was also formed in ca.
4%. Carbamates with a variety of ortho functional groups,
such as trimethylsilyl (1d), benzoyl (1e), and methoxy (1f)
are applicable, demonstrating the utility of this method in
carbamate-directed ortho-C–H functionalization reactions.
Importantly, the ketone group in substrates 1e and 1f re-
mained intact under these conditions without accompany-
ing reduction of the carbonyl group. Reductive cleavage oc-
curred when a carbamate with an alkene moiety (i.e., 1g)
was used as substrate.11 Moreover, heteroaromatic carba-
product 2j, with the pendant alcohol moiety oxidized to the
corresponding ketone, as expected.
"RhCl(L2)2"
(10 mol%)
OCONEt2
H
w/o alcohol
K3PO4
toluene
180 °C, 16 h
OH
O
1j
82% (2j)
Scheme 3 Rh-catalyzed reductive cleavage of aryl carbamates using
an internal alcohol group as the reductant
This reductive cleavage method broadens the utility of
the carbamate group in the synthesis of multiply function-
alized arenes (Scheme 4). For example, palladium-catalyzed
cross-coupling of 1k proceeded without affecting the car-
bamate moiety. Subsequent ortho acylation by the DoM
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

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N
B(OH)2
[Pd2(dba)3] (1 mol%)
PCy3 (2.4 mol%)
1) LiTMP
2) ArCO-Cl
Br
OCONEt2
N
OCONEt2
H
K3PO4 (1.7 equiv)
dioxane/H2O
180 °C, 12 h
OMe
OMe
OMe
1k
82% (1h)
Ar :
"RhCl(L2)2" (10 mol%)
iPrOH (1 equiv)
K3PO4 (2 equiv)
N
OCONEt2
N
H
toluene
O
O
180 °C, 16 h
MeO
OMe
MeO
OMe
OMe
OMe
90% (1l)
75% (2l)
(Ni/TMDSO: 0%)
Scheme 4 Synthetic application
OH
strategy followed by rhodium-catalyzed C–O bond cleavage
delivered 2l in 75% yield.12 Again, the final reductive cleav-
age reaction did not proceed when the Ni/TMDSO system4c
was used, further demonstrating the robustness of the rho-
dium system.
Finally, we performed a deuterium labeling experiment
to obtain insight into the hydrogen source (Scheme 5). The
reductive cleavage reaction with alcohol 3, bearing a deute-
rium atom at the 3-position instead of iPrOH, revealed that
the deuterium atom was incorporated into the reduced
product and the corresponding ketone was produced. This
experiment indicates that the hydrogen in the product is
derived from the hydrogen adjacent to the hydroxyl group
of the added alcohol.
[Rh]
X
A
H
HX
Ar
H
[Rh] = Rh(L2)2
2
Ar
[Rh]
O
X = Cl or PO4
OCONEt2
Et2NOCO [Rh]
H
H
D
B
O
Ar OCONEt2
[Rh]
H
C
Scheme 6 Proposed mechanism
In summary, we have developed rhodium-catalyzed re-
ductive cleavage of aryl carbamates using iPrOH as a reduc-
tant. Unlike previously reported methods using iPrMgX and
TMDSO,4 this reaction tolerates carbonyl groups, alkenes
and heteroaromatic rings, such as carbazole and pyridine.
Further studies aimed at the catalytic transformation of in-
ert bonds using rhodium bis(NHC) complexes are under
way.
OCONEt2
OH
"RhCl(L2)2" (10 mol%)
+
iPr
iPr
K3PO4 (2 equiv)
1,4-dioxane
180 °C, 4 h
Ar
D
1c
3 (1 equiv)
(96%D)
D
O
+
Ar:
OMe
iPr
iPr
Ar
73% (GC)
63% (2c-d)
(93%D)
Funding Information
Scheme 5 Mechanistic studies
This work was supported by ACT-C (JPMJCR12ZF) from JST, Japan and
Scientific Research on Innovative Area ‘Precisely Designed Catalysts
with Customized Scaffolding’ (16H01022) from MEXT, Japan. K.Y.
The proposed mechanism is shown in Scheme 6. Rhodi-
um(I) bis(NHC) complex A, generated in situ, initially reacts
i
thanks JSPS Research Fellowship for Young Scientists.
a
Jp
an
Secince
a
n
d
Tech
n
o
lg
y
A
g
e
n
c
y
P
J(M
C
J
R
1
2
Z
F
M)nisitry
of
E
d
u
coaitn
,
Cutler,
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p
or,ts
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n
o
lg
y
1(
6
H
0
1
0
2
2)
with PrOH to produce alkoxorhodium(I) complex B, and
subsequent β-hydrogen elimination gives rhodium(I) hy-
dride C.7 Complex C mediates oxidative addition of the C–O
bond in the aryl carbamate to form arylrhodium(III) inter-
mediate D. Subsequent reductive elimination gives the re-
ductive cleavage product, and complex A is regenerated.
Acknowledgment
We thank the Instrumental Analysis Center, Faculty of Engineering,
Osaka University, for their assistance with HRMS.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

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K. Yasui et al.
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Supporting Information
(i) Morioka, T.; Nishizawa, A.; Nakamura, K.; Tobisu, M.;
Chatani, N. Chem. Lett. 2015, 44, 1729. (j) Nakamura, K.; Tobisu,
M.; Chatani, N. Org. Lett. 2015, 17, 6142.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1589093.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
(6) (a) Kinuta, H.; Hasegawa, J.; Tobisu, M.; Chatani, N. Chem. Lett.
2015, 44, 366. (b) Nakamura, K.; Yasui, K.; Tobisu, M.; Chatani,
N. Tetrahedron 2015, 71, 4484. (c) Kinuta, H.; Tobisu, M.;
Chatani, N. J. Am. Chem. Soc. 2015, 137, 1593. (d) Tobisu, M.;
Yasui, K.; Aihara, Y.; Chatani, N. Angew. Chem. Int. Ed. 2017, 56,
1877.
(7) Spogliarich, R.; Zassinovich, G.; Mestroni, G.; Graziani, M.
J. Organomet. Chem. 1980, 198, 81.
(8) Addition of stoichiometric base is essential for this reaction to
proceed. See the Supporting Information for details.
References and Notes
(1) For reviews on cross-coupling using inert phenol derivatives,
see: (a) Rosen, B. M.; Quasdorf, K. W.; Wilson, D. A.; Zhang, N.;
Resmerita, A.-M.; Garg, N. K.; Percec, V. Chem. Rev. 2011, 111,
1346. (b) Li, B.-J.; Yu, D.-G.; Sun, C.-L.; Shi, Z.-J. Chem. Eur. J.
2011, 17, 1728. (c) Yamaguchi, J.; Muto, K.; Itami, K. Eur. J. Org.
Chem. 2013, 19. (d) Cornella, J.; Zarate, C.; Martin, R. Chem. Soc.
Rev. 2014, 43, 8081. (e) Tobisu, M.; Chatani, N. Acc. Chem. Res.
2015, 48, 1717.
(9) Non-alcoholic reducing agents, such as 1,4-cyclohexadiene and
hydrosilane were ineffective. See the Supporting Information
for details.
(2) For reviews on DoM strategy, see: (a) Snieckus, V. Chem. Rev.
1990, 90, 879. (b) Snieckus, V. Beilstein J. Org. Chem. 2011, 1215.
(3) (a) Bedford, R. B.; Webster, R. L.; Mitchell, C. J. Org. Biomol.
Chem. 2009, 7, 4853. (b) Xiao, B.; Fu, Y.; Xu, J.; Gong, T.-J.; Dai, J.-
J.; Yi, J.; Liu, L. J. Am. Chem. Soc. 2010, 132, 468. (c) Bedford, R. B.;
Mitchell, C. J.; Webster, R. L. Chem. Commun. 2010, 3095.
(d) Gong, T.-J.; Xiao, B.; Liu, Z.-J.; Wan, J.; Xu, J.; Luo, D.-F.; Fu, Y.;
Liu, L. Org. Lett. 2011, 13, 3235. (e) John, A.; Nicholas, K. M. J.
Org. Chem. 2012, 77, 5600. (f) Li, J.; Kornhaass, C.; Ackermann, L.
Chem. Commun. 2012, 11343. (g) Li, B.; Ma, J.; Liang, Y.; Wang,
N.; Xu, S.; Song, H.; Wang, B. Eur. J. Org. Chem. 2013, 1950.
(h) Bedford, R. B.; Brenner, P. B.; Durrant, S. J.; Gallagher, T.;
Mendez-Gálvez, C.; Montgomery, M. J. Org. Chem. 2016, 81,
3473.
(4) (a) Sengupta, S.; Leite, M.; Raslan, D. S.; Quesnelle, C.; Snieckus,
V. J. Org. Chem. 1992, 57, 4066. (b) Jørgensen, K. B.; Rantanen, T.;
Dörfler, T.; Snieckus, V. J. Org. Chem. 2015, 80, 9410.
(c) Mesganaw, T.; Fine Nathel, N. F.; Garg, N. K. Org. Lett. 2012,
14, 2918.
(5) (a) Tobisu, M.; Shimasaki, T.; Chatani, N. Angew. Chem. Int. Ed.
2008, 47, 4866. (b) Tobisu, M.; Shimasaki, T.; Chatani, N. Chem.
Lett. 2009, 38, 710. (c) Shimasaki, T.; Tobisu, M.; Chatani, N.
Angew. Chem. Int. Ed. 2010, 49, 2929. (d) Tobisu, M.; Yasutome,
A.; Yamakawa, K.; Shimasaki, T.; Chatani, N. Tetrahedron 2012,
68, 5157. (e) Tobisu, M.; Yasutome, A.; Kinuta, H.; Nakamura, K.;
Chatani, N. Org. Lett. 2014, 16, 5572. (f) Tobisu, M.; Takahira, T.;
Ohtsuki, A.; Chatani, N. Org. Lett. 2015, 17, 680. (g) Tobisu, M.;
Takahira, T.; Chatani, N. Org. Lett. 2015, 17, 4352. (h) Tobisu, M.;
Morioka, T.; Ohtsuki, A.; Chatani, N. Chem. Sci. 2015, 6, 3410.
(10) The catalyst generated in situ by the reaction of [RhCl(C2H4)2]2,
L2·HCl and KOtBu at 60 °C for 1 h in toluene is described as
“RhCl(L2)2” throughout this paper.
(11) The reaction afforded an inseparable mixture of desired stil-
bene and 1,2-diphenylethane in a ratio of 82:18 (96% combined
isolated yield).
(12) [6-(Pyridin-3-yl)naphthalen-2-yl](3,4,5-trimethoxyphe-
nyl)methanone (2l); Typical Procedure
[RhCl(C2H4)2]2 (5.8 mg, 0.015 mmol), L2·HCl (21 mg, 0.060
mmol), KOtBu (7.4 mg, 0.066 mmol), K3PO4 (64 mg, 0.60 mmol),
and toluene (0.40 mL) were added to a 5 mL screw-capped vial
in a glovebox filled with nitrogen, and the resulting mixture
was stirred at 60 °C for 1 h. After 1 h, 1l (154 mg, 0.30 mmol),
iPrOH (18 mg, 0.30 mmol) and toluene (0.60 mL) were added to
the vial in the glove box. The vessel was stirred at 180 °C for 16
h followed by cooling to room temperature. The mixture was
purified by flash column chromatography over silica gel (eluting
with hexane/EtOAc, 100:1) to give 2l as a white solid (90 mg,
75%); Rf 0.33 (EtOAc); pale-orange oil. 1H NMR (CDCl3, 400
MHz): δ = 9.02 (br. s, 1 H), 8.68 (br. s, 1 H), 8.33 (s, 1 H), 8.13 (s,
1 H), 7.96–8.07 (m, 4 H), 7.81 (d, J = 8.2 Hz, 1 H), 7.46 (br. s, 1 H),
7.14 (s, 2 H), 3.97 (s, 3 H), 3.89 (s, 6 H). 13C NMR (CDCl3, 100
MHz): δ = 195.5, 152.9, 149.0, 148.6, 142.2, 137.6, 136.0, 135.5,
135.3, 134.6, 132.7, 131.7, 131.1, 130.3, 128.5, 126.6, 126.1,
126.0, 123.7, 107.8, 61.0, 56. 3. IR (ATR): 2939 (w), 1715 (w),
1652 (w), 1626 (w), 1581 (m), 1503 (m), 1464 (m), 1413 (m),
1378 (w), 1328 (s), 1275 (w), 1234 (m), 1215 (m), 1171 (m),
1124 (s), 1001 (m), 912 (m), 823 (w), 801 (w), 750 (m), 726 (s),
645 (w) cm–1; HRMS (EI): m/z calcd for C25H21NO4: 399.1471;
found: 399.1470.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D