Regioselective functionalization of alkanes by sequential dehydrogenation-hydrozirconation

Article abstract of DOI:10.1039/c0cc00243g

We have succeeded in formal regioselective functionalization of alkanes by iridium-catalyzed dehydrogenation, hydrozirconation of the resulting alkenes, and electrophilic reaction of the generated alkylzirconium intermediate.

Full text of DOI:10.1039/c0cc00243g

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Regioselective functionalization of alkanes by sequential
dehydrogenation–hydrozirconationw
Yoichiro Kuninobu,* Tomonari Ureshino, Shun-ichi Yamamoto and Kazuhiko Takai*
Received 5th March 2010, Accepted 1st June 2010
First published as an Advance Article on the web 14th June 2010
DOI: 10.1039/c0cc00243g
We have succeeded in formal regioselective functionalization of
alkanes by iridium-catalyzed dehydrogenation, hydrozirconation
of the resulting alkenes, and electrophilic reaction of the generated
alkylzirconium intermediate.
Alkanes are highly abundant in petroleum and natural gas,
and are the foundation of modern chemistry. Direct func-
tionalization of alkanes, such as C–H bond activation,1 is an
Fig. 1 Concept of regioselective functionalization of alkanes.
ideal method to synthesize organic molecules because such
transformations can reduce the number of reaction steps and
improve the total yields of the desired products. However,
this transformation presents a fundamental problem, i.e.,
the difficulty of introducing functional groups into alkanes
directly. Additionally, the regioselectivity of the reaction and
the number of functional groups introduced are difficult to
control. For example, the halogenation of alkanes produces a
complex mixture of mono- and multisubstituted halogenated
alkanes without regioselectivity.2 Such problems are due to
the many numbers and kinds of carbon–hydrogen bonds
with nearly identical reactivities, which exist in every alkane.
Recently, there have been several reports on C(sp3)–H bond
functionalization.3 However, the substrates have been limited
to special cases, such as reactions that occur at allylic and
benzylic positions, and a-positions of heteroatoms. Regio-
selective carbonylation4 and borylation5 of alkanes are also
well known. It remains difficult to introduce other functional
groups and substituents into alkanes regioselectively. To over-
come this difficulty, we predicted that functionalization of
alkanes could be achieved by sequential reactions, such as
transition metal-catalyzed dehydrogenation of alkanes6 and
functionalization of the resulting alkenes.7 However, to realize
such transformations, it is necessary to resolve the issue that
the alkenes generated are a complex mixture of terminal and
internal olefins. To this end, we employed the following
strategy: isomerization of the olefinic moieties to the terminal
position and successive functionalization of the resulting
terminal alkenes (Fig. 1).
Thus, using hydrozirconation, the formation of a complex
mixture of terminal and internal olefins by transition metal-
catalyzed dehydrogenation can be overcome. We chose the
iridium complex, IrH5(PiPr3)2,9 although the catalytic activity
of this complex for dehydrogenation was less than that of the
iridium–pincer complex10 (see ESIw).11 Reaction of dodecane
(1) with 3,3-dimethyl-1-butene (hydrogen acceptor) and a
catalytic amount of the iridium complex, IrH5(PiPr3)2, at 150 1C
for 6 h, followed by treatment with Schwartz’s reagent,
Cp2ZrHCl (2), at 40 1C for 12 h and successive reaction with
N-bromosuccinimide (NBS, 3a), afforded 1-bromododecane
6a,12,13
(4a) in 57% yield (eqn (1)).z
The yield of 4a was
determined based on 3a. In this reaction, neither monobromo-
alkanes with a bromine at the internal positions nor multi-
bromoalkanes were formed and 4a was obtained as a single
product. This result shows that hydrozirconation of the
formed dodecenes occurred only at the terminal position.
For the second step, we focused on hydrozirconation because
these two steps, i.e., isomerization to terminal alkanes and
hydrometalation, can be combined into one operation due to
fast reversible hydrozirconation–retro-hydrozirconation.8
ð1Þ
Next, we investigated the regioselective functionalization of 1
(Table 1). When iodine (I2, 3b) was used as an electrophile,
1-iodododecane (4b) was obtained in 74% isolated yield
(entry 1).6a,12 The introduced functional groups are not limited
to halogen atoms. By quenching the alkyl zirconium intermediate
with 2-hydroperoxy-2-methylpropane (3c), 1-dodecanol (4c)
was produced in 58% yield as a single product (entry 2).14 This
reactivity is in sharp contrast to industrial processes which
generate a complex mixture of alcohols.15 The selectivity is
Division of Chemistry and Biochemistry, Graduate School of Natural
Science and Technology, Okayama University, Tsushima, Kita-ku,
Okayama 700-8530, Japan. E-mail: kuninobu@cc.okayama-u.ac.jp,
ktakai@cc.okayama-u.ac.jp; Fax: +81 (0)86-251-8094;
Tel: +81 (0)86-251-8095
w Electronic supplementary information (ESI) available: General
experimental procedure. See DOI: 10.1039/c0cc00243g
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Table 1 Functionalization of dodecane (1) using several electrophiles
Entry
Electrophile
Product
Yielda (%)
1b
2c
I2
3b
3c
nC12H25–I
4b
4c
74(80)
58(70)
tBuOOH
nC12H25–OH
3d
3d
4d
—(57)
4e
CO (1.0 atm)
3e
4e
44(55)
a
Isolated yields are reported except in entry 3. The yields determined
b
by 1H NMR are reported in parentheses. 1.1 equivalent of 2 was
c
used. 1.1 equivalent of 2 was used. In step 3, the reaction was carried
out in a co-solvent (THF : dichloroethane = 2 : 1) at 0 1C for
4 h. 1.0 equivalent of 2 was used. In step 3, CuCl (20 mol%) was
d
e
added and the reaction was performed at 40 1C. 1.6 equivalent of 2
was used. In step 3, the reaction was carried out for 3 h. After the
reaction, the reaction mixture was quenched with aq. HCl.
Scheme 1 Proposed mechanism of the regioselective functionaliza-
tion of alkanes.
alkane I in the presence of hydrogen acceptor II; (2) hydro-
zirconation of the formed alkenes IV by the reaction with V
giving a 1-alkylzirconocene chloride VI; and (3) nucleophilic
substitution of the resulting alkyl zirconocene intermediate VI
with an electrophile VII to give the functionalized alkane IX.
In conclusion, we have succeeded in terminal-selective func-
tionalization of alkanes by iridium-catalyzed dehydrogena-
tion of alkanes, successive hydrozirconation of the resulting
alkenes leading to isomerized 1-alkylzirconocene species,
followed by trapping with electrophiles. Using hydrozircona-
tion, the regioselectivity problem can be solved, i.e., hydro-
zirconation occurs only at the terminal position, whereas the
iridium-catalyzed dehydrogenation initially gives a mixture of
alkenes. When the hydrozirconation product was treated with
also interesting because the addition of water to terminal
alkenes occurs in anti-Markovnikov fashion to give 2-hydroxyl
alkanes.
Cross-coupling reactions are powerful methods to construct
new carbon–carbon bonds and produce complex organic
molecules efficiently.16 In the cross-coupling of the alkyl
zirconium intermediate with allyl bromide (3d) in the presence
of a copper(I) catalyst, CuCl, a new carbon–carbon single
bond was constructed between a C(sp3)–C(sp3) bond, and
1-pentadecene (4d) was produced in 57% yield (entry 3).17
A
carbon–carbon bond was also constructed by treatment of
the alkyl zirconium intermediate with carbon monoxide (3e)
(entry 4). After quenching with aq. HCl, tridecanal (4e) was
afforded in 44% yield.18
t
suitable electrophiles, e.g., NBS, I2, BuOOH, allyl bromide,
Finally, we examined the reactions using a branched alkane
(2-methylheptane), phenylalkane (butylbenzene (5)), or ether
(dibutyl ether). In the reactions, the yields of a mixture of
alkenes by dehydrogenation of the substrates were lower than
that of dodecane; however, by using ten times the amounts of
5, 3,3-dimethyl-1-butene, and iridium catalyst, the sequential
functionalization process of 5 occurred regioselectively at
the terminal position, and 1-iodo-4-phenylbutane (6) was
produced in 30% yield (eqn (2)).
and CO, without isolation of the hydrozirconation product,
alkanes with a functional group at the terminal position were
obtained regioselectively. Although the iridium-catalyzed
dehydrogenation has low activity and a stoichiometric amount
of Schwartz’s reagent is required, this reaction provides a new
concept for functionalizing alkanes.
This work was partially supported by the Ministry of Educa-
tion, Culture, Sports, Science, and Technology of Japan.
Notes and references
z Synthesis of 4a: a mixture of IrH5(PiPr3)2 (2.8 mg, 5.5 mmol),
3,3-dimethyl-1-butene (12.8 mL, 99 mmol), and dodecane (1, 0.5 mL,
2.2 mmol) was stirred at 150 1C for 6 h under an argon atmosphere.
After the reaction mixture was cooled to 25 1C, 3,3-dimethyl-1-butene
and 2,2-dimethylbutane, which was derived by hydrogenation of
3,3-dimethyl-1-butene, were removed in vacuo. The 1H NMR spectrum
indicated the formation of a mixture of internal alkenes. Under the
reaction conditions, 1-dodecene was not formed. After dehydrogena-
tion of alkane, THF (2.5 mL) and Cp2ZrHCl (2, 12.8 mg, 50.0 mmol)
were added to the reaction mixture under argon atmosphere. After
stirring at 40 1C for 12 h, the mixture was cooled to 25 1C. After
hydrozirconation, N-bromosuccinimide (3a, 8.9 mg, 50 mmol) was
ð2Þ
A proposed mechanism is as follows (Scheme 1): (1) formation of
a mixture of alkenes IV by iridium-catalyzed dehydrogenation of
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added and the mixture was stirred at 25 1C for 1 h. The resulting
solution was concentrated and filtered through a silica gel pad
(hexane). After distillation, 4a was obtained as a colourless oil
(7.1 mg, 57%).
10 The structure of the iridium–pincer complex is as follows:
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