Catalytic Tandem and One-Pot Dehydrogenation-Alkylation and -Insertion Reactions of Saturated Hydrocarbons with Alcohols and Alkenes

Article abstract of DOI:10.1021/acscatal.6b02186

The ruthenium-hydride catalyst has been successfully used for the tandem sp³ C-H dehydrogenation-alkylation reaction of saturated hydrocarbon substrates with alcohols to form the alkyl-substituted alkene and arene products. The analogous one-pot dehydrogenation-insertion of saturated ketones with alkenes and dienes directly yielded synthetically useful 2-alkylphenol and benzopyran products in a highly regio- and stereoselective manner without forming any wasteful byproducts. (Chemical Equation Presented).

Full text of DOI:10.1021/acscatal.6b02186

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Letter
Catalytic Tandem and One-pot Dehydrogenation-alkylation and -insertion
Reac-tions of Saturated Hydrocarbons with Alcohols and Alkenes
Junghwa Kim, Nuwan Pannilawithana, and Chae S. Yi
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b02186 • Publication Date (Web): 14 Nov 2016
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Catalytic Tandem and One-pot Dehydrogenation-alkylation and -
insertion Reactions of Saturated Hydrocarbons with Alcohols and
Alkenes
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Junghwa Kim, Nuwan Pannilawithana and Chae S. Yi*
Department of Chemistry, Marquette University, Milwaukee, Wisconsin 53201-1881 United States
ABSTRACT: The ruthenium-hydride catalyst has been successfully used for the tandem sp3 C–H dehydrogenation-
alkylation reaction of saturated hydrocarbon substrates with alcohols to form the alkyl-substituted alkene and arene prod-
ucts. The analogous one-pot dehydrogenation-insertion of saturated ketones with alkenes and dienes directly yielded syn-
thetically useful 2-alkylphenol and benzopyran products in a highly regio- and stereoselective manner without forming any
wasteful byproducts.
Keywords: tandem catalysis, dehydrogenation, alkylation, saturated hydrocarbon, ruthenium catalyst
Transition metal catalyzed sp3 C–H bond activation and
OH
H2O
R'
R
functionalization reactions of saturated hydrocarbon com-
pounds have been regarded as one of the frontier topics in
the field of homogeneous catalysis.1 During the last dec-
ades, concerted research efforts have led to the develop-
ment of many catalytic sp3 C–H coupling methods, and of
these, heteroatom assisted sp3 C–H activation methods
have been shown to be one the most effective strategy in
promoting regioselective C–C coupling reactions for satu-
rated hydrocarbons.2 Soluble transition metal catalysts
have also been successfully employed for the sp3 C–H oxi-
dative cross coupling reactions of saturated hydrocarbons
with heteroatom neighboring group.3 Chiral Rh catalysts
have been extensively used for highly asymmetric sp2 and
sp3 C–H carbene insertion reactions,4 and its synthetic
power has been recently demonstrated for a remarkably
enantioselective carbene insertion of simple linear al-
kanes.5 Bidentate sulfoxide ligands have been found to be
particularly effective for late transition metal catalysts in
promoting sp3 C–H coupling of biologically active complex
organic molecules.6
H
H
[Ru]
[Ru]
H
R'
H2
CO
R
H
CO
Cy3P
H
Ru
Ru PCy3
OH
BF4
PCy3
Ru
O
H
OC Ru
H
Ru
H
OC
O
PCy3
H
CO
2
PCy3
1
Scheme 1. General Tandem Dehydrogenation-
Alkylation Reaction Scheme and the Structure of
Ruthenium Catalysts.
We previously discovered that the tetranuclear rutheni-
um-hydride complex {[(PCy3)(CO)RuH]4(µ-O)(µ-OH)2} (1)
is a uniquely effective catalyst precursor for the dehydro-
genation of saturated hydrocarbon substrates having a
variety of oxygen and nitrogen functional groups.12 We
subsequently disclosed a number of dehydrative sp2 C–H
coupling reactions of alkenes and arenes with alcohols by
Tandem dehydrogenation and functionalization protocol
has emerged as an attractive strategy for the C–H coupling
reactions.7 Over the years, a number of different tandem
sp2 C–H coupling methods have been utilized for the con-
struction of nitrogen and oxygen heterocycles.8 In a pio-
neering report, Brookhart and Goldman devised an elegant
“alkane metathesis” method, where Ir-hydride and Mo-
carbene catalysts were used to promote tandem sp3 C–H
dehydrogenation and olefin metathesis of alkanes.9 More
recently, Jones and Stahl independently reported the de-
hydrogenation of nitrogen heterocycles by using earthly
abundant Fe and Co catalysts.10 Compared to the sp2 C–H
coupling methods, however, a relatively few tandem sp3 C–
H coupling methods have been implemented for the syn-
thesis of complex organic molecules.11
using
the
cationic
ruthenium-hydride
complex
[(C6H6)(PCy3)(CO)RuH]+BF4 (2) as the catalyst precur-
sor.13 Since both dehydrogenation and dehydrative alkyla-
tion reactions are mediated by the similar ruthenium-
hydride catalysts as the complex 2 is synthesized from the
protonation of 1, we reasoned that a direct sp3 C–H cou-
pling of saturated hydrocarbon compounds might be
achievable if we combine these two reactions in tandem as
depicted in Scheme 1 to form elaborate olefins. Herein, we
report an efficient tandem catalytic dehydrogenation-
alkylation and –insertion protocol, which promotes the C–
C coupling reactions on saturated hydrocarbon substrates.
-
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Ar
tion conditions (eq 2). Thus, the treatment of 1-tetralone
1) TBE (5 mmol), 1 (0.1 mol %)
1
2
3
4
5
6
7
8
(5 mmol) with 1 (0.1 mol %) at 180 °C under acceptorless
conditions for 12 h led to the clean formation of 1-
naphthol (TON = 640). For the second step, styrene (4
mmol) and the cationic Ru–H catalyst 2 (3 mol %) in tolu-
ene (2 mL) were added, and the reaction tube was stirred
at 120 °C for 12 h. The insertion product 4a was formed
with an overall TON = 364 as analyzed by both GC and
NMR spectroscopic methods. It should be noted that add-
ing the Ru–H catalyst 2 for the insertion reaction was
found to be essential in this case because the in-situ gener-
ation method of the cationic Ru–H catalyst by the addition
of HBF4·OEt2 was found to give a mixture of the styrene
dimer PhCH(CH3)CH=CHPh and the coupling products.
neat, 180 oC, 12 h
(1)
2) ArCH2OH (4 mmol)
HBF4OEt2 (1 mol %)
C6H5Cl (2 mL), 120 oC, 12 h
Ar = C6H4-4-OMe
(5 mmol)
3a
TON = 284 (28% conv)
We initially tested the feasibility of tandem dehydro-
genation-alkylation reaction of cyclooctane by using the
tetranuclear ruthenium catalyst 1 (eq 1). The dehydro-
genation of cyclooctane (5 mmol) was performed in the
presence of 1 (0.1 mol %) under neat conditions at 180 °C
for 12 h by following the previously reported procedure
using t-butylethylene (TBE) (5 mmol) as the hydrogen
scavenger.12 For the second alkylation step, HBF4·OEt2 (1
mol %) in chlorobenzene (2 mL) was added to the reaction
mixture to generate a cationic Ru-H complex in-situ. After
stirring at room temperature for 15 min, 4-methoxybenzyl
alcohol (4 mmol) was added, and the reaction mixture was
stirred at 120 °C for 12 h. The overall turnover number
(TON) of product 3a was determined to be 284 based on
the consumption of cyclooctane substrate (28% conver-
sion, >95% selectivity), as analyzed by both GC and NMR
spectroscopic methods.
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Table 1. Tandem Dehydrogenation-Alkylation of
Saturated Hydrocarbons with Alcoholsa
entry
hydrocarbon
alcohol
product(s)
R
TON
1
2
3a R = Ar
3b R = CH2CH2Ar
284
182
Ar-CH2OH
ArCH2CH2CH2OH
To demonstrate synthetic utility of the tandem catalytic
dehydrogenation-alkylation reaction, we explored the
scope of hydrocarbon substrates by using the catalyst 1
(Table 1). Aryl-substituted hydrocarbons such as indan
and tetrahydronaphthalene readily reacted with both ali-
phatic and benzyl alcohols to form the alkylation products
3c-3g (entries 3-7). The tandem dehydrogenation-
alkylation of saturated cyclic ketones occurred predictively
to give the ortho-alkylated phenol products 3i-3m (en-
tries 9-13). The tandem coupling of 2,3-dihydrobenzofuran
led to the C2-alkylation product 3h (entry 8), while the
formation of exclusive C3-alkylation products 3n-3q was
obtained from the coupling with N-methylindole (entries
14-17). The tandem dehydrogenation-alkylation of N-
methylpyrrolidine with benzyl alcohol afforded the 2-
benzylpyrrole product 3r (entry 18), and methoxy-
substituted cyclohexane with benzyl alcohol gave 4-
benzylanisole products 3s and 3t (entries 19, 20). The
salient features for the tandem catalytic method from a
synthetic point of view are: the C–C coupling products are
directly formed from the dehydrogenation-alkylation of
oxygen and nitrogen-containing saturated hydrocarbon
substrates, a single Ru precatalyst is used to carry out both
reaction steps, and the catalytic method does not generate
any toxic byproducts as it employs inexpensive and widely
available alcohols as the alkylating reagent.
R
3
4
5
64
98
84
1-hexanol
PhCH2OH
ArCH2OH
3c R = n-pentyl
3d
3e
R = Ph
R = Ar
R
3f
3g
154
86
R = Ph
R = Ar
6
7
PhCH2OH
ArCH2OH
O
O
Ar
8
ArCH2OH
Ar-CH2OH
280
3h
OH
O
153b
Ar
9
3i
OH R'
O
R
418b,c
439c
1-hexanol
PhCH(OH)CH2CH3
R = n-pentyl, R' = H
R = Ph, R' = Et
R
10
11
3j
3k
O
OH
142b,c
130c
1-pentanol
PhCH2OH
R = n-butyl
3m R = Ph
3l
12
13
Me
N
Me
N
R
R'
14
15
16
17
3n
3o
1410b,d
R = Ar, R' = H
R = n-pentyl, R' = H 1080b,d
3p R = Ph, R' = Et
ArCH2OH
1-hexanol
PhCH(OH)CH2CH3
380d
O
OH
(-)-PhCHMeCH2OH
(-)-3q
560b,d
R = CHMePh, R' = H
1) 1 (0.1 mol %) neat, 180 oC, 12 h
Ph
Me
N
Me
(2)
2) CH2=CHPh (4 mmol), 2 (3 mol %)
toluene (2 mL), 120 oC, 12 h
N
Ar
4a
TON = 364 (36% conv)
18
ArCH2OH
PhCH2OH
82
(5 mmol)
3r
R
R
To further extend its synthetic versatility, we next sur-
veyed the tandem dehydrogenation-alkene insertion reac-
tion of saturated hydrocarbon compounds. In this case, the
choice of hydrocarbon substrates is limited to the ones
that can undergo the dehydrogenation under the acceptor-
less conditions because TBE was found to react with the
resulting naphthol during the insertion step. Initially, we
have chosen 1-tetralone and styrene to optimize the reac-
Ph
MeO
MeO
19
20
84
78
R = OMe
R = H
3s
3t
a Reaction conditions. Dehydrogenation: hydrocarbon compound (5
mmol), TBE (5 mmol), 1 (0.1 mol %), 180 °C, 12 h. Alkylation: alcohol
(4 mmol), HBF4·OEt2 (1 mol %), C6H5Cl (2 mL), 120 °C, 12 h. TON was
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b
c
determined by GC. 2 (3 mol %) was used for the alkylation step.
200 °C. d 1 (0.05 mol %), 160 °C. Ar = C6H4-4-OMe
mol %), toluene (2 mL), 120 °C, 12 h. TON was determined by GC. b At
180 °C.
1
2
3
4
5
6
7
8
9
The one-pot dehydrogenation-insertion reaction scope
was explored by using different alkenes and dienes under
these optimized conditions (Table 2).14 In general, both 1-
and 2-tetralone substrates readily reacted with aryl-
substituted alkenes to form the corresponding alkylation
products 4a, 4b, 4f and 4g (entries 1, 2, 6, 7). In case of
indoline, a preferential formation of C3-alkylation prod-
ucts 4k and 4l was observed over the C2-alkylation prod-
ucts 5k and 5l (entries 11, 12). The dehydrogenation-
insertion of 1- and 2-tetralone with 1,3-dienes also pro-
ceeded smoothly to give the corresponding benzopyran
products 4c, 4e and 4h (entries 3, 5, 8).
The one-pot treatment of 1-teralone with vinylcyclohex-
ene led to the stereoselective formation of a trans-fused
benzofuran product 4d (entry 4). The relative stereochem-
istry of 4d has been tentatively assigned from the NMR
spectroscopic analysis. The methine proton peak at δ 3.16
(pseudo quintet, J = 3.2 Hz), which exhibited vicinal cou-
plings with both neighboring CH2 groups, is a diagnostic
feature for the assigned anti-stereochemistry. We com-
1
pared the H NMR of the methine peak of the previously
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reported cis-fused stereoisomer of benzofuran analog,
which showed a simple triplet δ 3.09 (t, J = 5.1 Hz), devoid
of the coupling with the neighboring CH3 group (p. S3,
Supporting Information).15 Since we have not been able to
obtain the cis-stereoisomer of 4d independently, we could
not unambiguously determine the stereochemistry of 4d.
The coupling reaction of 2-tetralone with vinylcyclohexene
and 1-methyl-4-(1-methylethenyl)cyclohexene also result-
ed in the coupling products 4i and 4j with the same rela-
tive stereochemistry (entries 9, 10). In contrast, the analo-
gous reaction of indoline with vinylcyclohexene selectively
gave the C3-alkylation product 4m (entry 13). Traditional
synthetic methods to hydrobenzofuran structures typically
involve multiple manipulation steps,16 but our catalytic
method expediently assembles the structure in a stereose-
lective manner without using any reactive reagents.
Table 2. Tandem Dehydrogenation-Alkylation and
Annulation of Saturated Hydrocarbons with Al-
kenes and Dienesa
entry hydrocarbon
alkene/diene
product(s)
OH
TON
O
Ph
1
2
Ph
364
4a
OH
328
4b
O
3
310
284
OH
H2
OH
H2O
4c
R
O
H
H
R
[Ru]
[Ru]4
4
H
3j (R = n-pentyl)
OH
Ph
4d
4e
H2
O
O
H
H
Ph
5
6
266
308
[Ru]4
[Ru]
Ph
4a
OH
OH
OH
O
H2
Ph
O
Ph
(10 : 1)
H
H
4f
5f
R
[Ru]4
[Ru]
OH
4c
288
7
Scheme 2. Synthesis of Naphthol Derivatives from
the One-Pot Dehydrogenation-Alkylation of 1-
Tetralone with an Alcohol, Styrene and a 1,3-
Diene.
R
4g
(1 : 8)
O
5g
R = 1-indanyl
8
9
260
282
H
O
4h
In summary, we successfully developed a highly regio-
and stereoselective catalytic tandem and one-pot dehydro-
genation-alkylation and -insertion protocol to achieve sp3
C–H couplings of oxygen and nitrogen containing saturated
hydrocarbons.16 As illustrated in Scheme 2, the one-pot
dehydrogenation-alkylation reaction of tetralones with
alcohols and styrene furnishes a number of synthetically
useful naphthol derivatives with a high degree of efficien-
cy. The dehydrogenation-insertion of tetralones with 1,3-
dienes directly led to the formation of benzopyran and
benzofuran products. The tandem catalytic method also
validates a number of environmentally attractive features
in that it does not employ any reactive reagents or forms
any toxic byproducts. Efforts to extend the scope and syn-
thetic utility of the catalytic method are continuing in our
laboratory.
4i
CH3
H
H
10
242b
O
O
(2 : 1)
5j
4j
R
N
R
N
R
N
Ar
Ar
244b
210b
11
12
4k
4l
5k
5l
R = H
R = Me
Ar = Ph
Ar = p-Tol
(5 : 1)
(8 : 1)
Ar
R
N
430
13
R = H
4m
a Reaction conditions. Dehydrogenation: hydrocarbon compound (5
mmol), 1 (0.1 mol %), 200 °C, 12 h. Insertion: alkene (4 mmol), 2 (3
ASSOCIATED CONTENT
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(5) Liao, K.; Negretti, S.; Musaev, D. G.; Bacsa, J.; Davies, H. M. L.
Nature 2016, 533, 230-234.
(6) Recent review: Pulis, A. P.; Procter, D. J. Angew. Chem., Int.
Ed. 2016, 55, ASAP.
Supporting Information
1
2
The Supporting Information is available free of charge on the
ACS Publications website.
3
4
5
6
7
8
9
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Chem. Rev. 2004, 248, 2365-2379. (b) Wasilke, J.-C.; Obrey, S. J.;
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Grossmann, A.; Enders, D. Angew. Chem., Int. Ed. 2012, 51, 314-
325.
(8) (a) Aïssa, C.; Fürstner, A. J. Am. Chem. Soc. 2007, 129,
14836-14837. (b) Wang, C.; Piel, I.; Glorius, F. J. Am. Chem. Soc.
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W.-C.; Ong, T.-G. Org. Lett. 2013, 15, 5358-5361. (d) Shi, Z.;
Koester, D. C.; Boultadakis-Arapinis, M.; Glorius, F. J. Am. Chem.
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Experimental procedure and NMR spectral data (PDF)
AUTHOR INFORMATION
Corresponding Author
* E-mail: chae.yi@marquette.edu
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Financial support from the National Science of Foundation
(CHE-1358439) is gratefully acknowledged.
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(14) A reviewer pointed out a more accurate definition for the
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(15) (a) Chiba, K.; Fukuda, M.; Kim, S.; Kitano, Y.; Tada, M. J.
Org. Chem. 1999, 64, 7654-7656. (b) Kim, S.; Noda, S.; Hayashi, K,
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(3) (a) Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2005, 127, 6968-6969.
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ACS Catalysis
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t-Bu
t-Bu
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Dehydrogenation Alkylation
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-H2
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* Exhibit high efficiency and selectivity for direct sp3 C-H coupling
* Tolerate oxygen and nitrogen functional groups
* Do not form any toxic byproducts
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