Iron-catalyzed arene alkylation reactions with unactivated secondary alcohols

Article abstract of DOI:10.1021/ol500606d

A simple, iron-based catalytic system allows for the inter- and intramolecular arylation of unactivated secondary alcohols. This transformation expands the substrate scope beyond the previously required activated alcohols and proceeds under mild reaction conditions, tolerating air and moisture. Furthermore, the use of an enantioenriched secondary alcohol provides an enantioenriched product for the intramolecular reaction, thereby offering a convenient approach to nonracemic products.

Full text of DOI:10.1021/ol500606d

Letter
pubs.acs.org/OrgLett
Iron-Catalyzed Arene Alkylation Reactions with Unactivated
Secondary Alcohols
Latisha R. Jefferies and Silas P. Cook*
Department of Chemistry, Indiana University, 800 East Kirkwood Avenue, Bloomington, Indiana 47405-7102, United States
S
* Supporting Information
ABSTRACT: A simple, iron-based catalytic system allows for the inter- and intramolecular arylation of unactivated secondary
alcohols. This transformation expands the substrate scope beyond the previously required activated alcohols and proceeds under
mild reaction conditions, tolerating air and moisture. Furthermore, the use of an enantioenriched secondary alcohol provides an
enantioenriched product for the intramolecular reaction, thereby offering a convenient approach to nonracemic products.
he Friedel−Crafts acylation and alkylation reactions have
Scheme 1. Advances in Friedel−Crafts Reactions with
Secondary Alcohols
T
occupied a central role in synthesis for nearly a century
and a half.1 The basic Friedel−Crafts alkylation utilizes
nucleophilic arenes, secondary or tertiary halides, and a strong
Lewis or Brønsted acid catalyst to create a new carbon−carbon
bond. Traditionally, Lewis acids (e.g., AlCl3,1 BF3,2 ZnCl2,3
SbCl5,4 Sc(OTf)3,5 and Fe salts6a,b) or strong Brønsted acids
7
(e.g., HF, H3PO4, and H2SO4 ) have been employed to
accelerate these reactions. Since these reactions typically
proceed through a carbocation intermediate, stereochemical
control remains a critical unmet challenge.8
Unfortunately, this venerable carbon−carbon bond-forming
reaction comes with significant drawbacks. The use of potent,
and usually toxic, alkylating agents, such as alkyl halides,
combined with the frequent need for superstoichiometric
amounts of the acid catalyst creates a significant waste stream
with excess salt byproducts. Therefore, strong demand exists for
alternative alkylating agents and catalysts that can be used in
substoichiometric quantities.
The direct catalytic functionalization of alcohols remains a
long-standing challenge in synthesis. More recently, the desire
for “greener” methods in pharmaceutical synthesis has led to
renewed interest in the direct displacement of alcohols over
more wasteful “activation” methods.9 Since hydroxide is such a
poor nucleofuge, however, derivatization of the alcohol remains
the preferred route in modern Friedel−Crafts-type alkylation
methods.5e,f,6b,10 If the direct displacement of an alcohol can be
achieved stereoselectively, it would represent an attractive
approach to nonracemic arylation products.
Recent progress has employed alcohols “activated” by
strain11or adjacent π systems, such as benzylic,6b,12 allyli-
c,5e,6a,13or propargylic alcohols14 (Scheme 1). With this limited
substrate scope, the transition from π-activated alcohols to less
reactive alkyl alcohols remains a major aim.6a,8b,15Despite this
critical goal, there exists only a single report, to the best of our
knowledge, describing two isolated examples of a Friedel−
Crafts-type alkylation using unactivated secondary alcohols
with expensive Yb salts.16 More recently, arene alkylation
reactions based on unactivated alcohols have been reported
with a Ru-catalyzed C−H activation17 and redox chain
reaction.18 Here we report a method for the inter- and
intramolecular arylation of unactivated secondary alcohols
Received: February 26, 2014
© XXXX American Chemical Society
A
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Letter
using a simple iron-based catalytic system that tolerates air and
moisture.
Scheme 2. Intermolecular Friedel-Crafts-Type Alkylation of
Secondary Alcohols
a
Cognizant of reports on the difficulty of alcohol-based
electrophiles in the Friedel−Crafts-type alkylation,6a we were
surprised to find that FeCl3 catalyzes the intermolecular
Friedel−Crafts-type alkylation of p-xylene (1) with cyclo-
hexanol in low, but isolable, 4% yield (Table 1, entry 1). During
Table 1. Select Catalytic Conditions Evaluated for the
Intermolecular Friedel-Crafts-Type Reaction of Unactivated
Secondary Alcohols
entry
catalyst
% yield
1
FeCl3
FeCl2
<5
0
2
3
FeCl3·6H2O
Fe(BF4)2·3H2O
FeF3·3H2O
0
a
Yields are isolated yields. Regioselectivity provided in parentheses.
4
0
5
0
2-acetylfuran, ethyl-2-furoate, ethyl-3-furoate, 2-acetylthio-
phene, and 2-naphthaldehyde failed to react under these
conditions, in contrast to the numerous side reactions observed
with strong Brønsted acid promoted Friedel−Crafts alkyla-
tions.15 While thiophene proved to be a competent nucleophile
for this reaction (11, Scheme 2), furan produced an intractable
mixture. Nitrogen-containing arenes such as pyrrole, N,N-
dimethylaniline, and pyridine all returned the starting arene,
consistent with previous reports devoid of nitrogen-containing
substrates.6b Attemps to attenuate the lone-pair basicity of
aniline substrates through the use of N-phenyl methanesulfona-
mide or N-phenyl acetamide also resulted in the recovered
arene, suggesting the electron-withdrawing group on nitrogen is
sufficient to deactivate the aromatic ring.
Interestingly, modest regioselectivity (o/p ratios) was
observed in many cases with substituted benzene derivatives
6−11, which is consistent with other Friedel−Crafts-type
reactions.5f,11 Even increasing the steric hindrance of the
alcohol from cyclohexanol to cyclododecanol did not affect the
regioselectivity of 6 and 7. This low regioselectivity denotes
insensitivity to steric encumbrance and suggests a particularly
facile alkylation event from the iron-activated intermediate.
While the reaction proceeded well with a range of cyclic,
secondary alcohols (2−11), low weight linear alcohols, such as
isopropanol and 2-butanol, provided low yields, likely due to
competitive olefin formation while higher weight linear
alcohols, such as 2-hexanol and 2-octanol, led to a mixture of
product isomers.
6
CuOTf
0
7
CuCl2
0
8
ZnCl2
0
9
FeCl3 w/ 3AgSbF6
FeCl3 w/ 3AgAsF6
FeCl3 w/ 3AgPF6
FeCl3 w/ 3AgOTf
FeCl3 w/ 3AgNO3
FeCl3 w/ 3AgOAc
H2SO4
83
83
<5
<5
<5
<5
<5
10
11
12
13
14
15
an extensive evaluation of Lewis acidic metal salts (Cu and Zn
shown in Table 1, entries 6−8), iron(III) chloride was found to
be uniquely effective in catalyzing the desired reaction. We
reasoned that the addition of silver salts to the iron catalyst
might provide a more active, cationic iron complex for the
dehydration. We were pleased to find both AgSbF6 and AgAsF6
led to substantially higher yields of desired product 2 (Table 1,
entries 9−10). Furthermore, AgSbF6 proved critical in the
successful, albeit low yielding, alkylation with other Lewis acids
(see Supporting Information (SI)). Because of the greater cost
of AgAsF6, we decided to proceed with the FeCl3/AgSbF6
combination for subsequent studies. Interestingly, both a lower
catalyst loading (<15 mol %) and temperature (<50 °C)
resulted in a significantly lower yield (see SI). The alkylation of
p-xylene proved difficult under the influence of a variety of
Brønsted acids (Table 1, entry 15 and SI), thereby
demonstrating that strong acids traditionally used in Friedel−
Crafts alkylations are ineffective in substoichiometric quantities.
With the identification of suitable reaction conditions for the
intermolecular alkylation of p-xylene (1) with cyclohexanol, the
substrate scope was evaluated (Scheme 2). It was determined
that the reaction followed traditional electrophilic aromatic
substitution trends where electron-rich arenes reacted faster,
and in higher yield, than electron-neutral or -deficient arenes.
For example, benzene, chlorobenzene, and bromobenzene only
produced modest 50+% yields (5, 8, and 9, Scheme 2) while p-
xylene, toluene, cumene, and phenol provided the desired
products in significantly higher yields (2−4, 6, 7, and 10,
Scheme 2). Electron-deficient arenes such as perfluorobenzene,
This methodology is useful for the synthesis of the recently
reported antiproliferative compound 12 (Scheme 3).19 Previous
syntheses of 2 utilize mesylated cyclohexanol in combination
5f
with expensive Sc(OTf)3 or cyclohexene and air sensitive
11
CpMoCl(CO)3 to produce a low yield (34%) of cyclo-
hexylated p-xylene 2. In contrast, our mild, iron-catalyzed
reaction provides gram quantities of 2 in 74% yield. Treating 2
under traditional Friedel−Crafts alkylation conditions (super-
stoichiometric AlCl3) provides 12 in 90% yield.
To further explore the synthetic versatility of this iron-
catalyzed alkylation, different intramolecular variants were
explored to access interesting polycyclic ring systems (Scheme
B
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Organic Letters
Letter
of the more electron-rich substrates are finished within just a
few hours. Interestingly, attempts to close a five-membered ring
led to low conversion and substantial olefin formation (data not
shown), while the larger, and traditionally more difficult to
close, seven-membered ring 23 proceeded in 77% yield. The
closure of eight-membered ring 24 also led to significant
elimination products, but was isolated in 34% yield.
Scheme 3. Synthesis of Antiproliferative Compound 12
In the field of drug discovery, the evaluation of enantiopure
compounds is of critical importance.20 With this in mind,
nonracemic secondary alcohol 25 was evaluated for a
stereospecific alkylation reaction. Using the CBS reduction of
the parent ketone,21 we prepared and isolated optically active
25 in 65% ee. When 25 was subjected to the optimized reaction
conditions, only slight erosion of the enantiomeric excess was
observed (Scheme 5a). This is in stark contrast to the
4). The intramolecular variant proceeded best with the same
FeCl3/AgSbF6 system, but at a lower temperature (see SI).
Scheme 5. (a) Transfer of Stereochemistry in the Reaction of
Enantioenriched 25; (b) Racemization of Enantioenriched
25 under Standard Friedel−Crafts Conditions
Scheme 4. Intramolecular Friedel-Crafts-Type Alkylation of
a
Secondary Alcohols
formation of racemic 26 under standard Friedel−Crafts
conditions (Scheme 5b).22This result represents the first
example of a stereoselective arylation of unactivated alcohols.23
In summary, we have developed a general method for the
arylation of unactivated secondary alcohols using a simple-to-
prepare catalytic system that tolerates air and stoichiometric
water generation. The synthesis of a variety of alkylated arenes
is possible under mild reaction conditions (50−80 °C) without
strong acids or bases. A variety of substituted ring systems can
be accessed with six-, seven-, and eight-membered carbocycles.
The use of iron and secondary alcohols renders this approach a
particularly advantageous variant of Friedel−Crafts chemistry,
as the only stoichiometric byproduct of the reaction is water.
Furthermore, the conversion of chiral alcohols to enantioen-
riched arylation products provides a synthetically appealing
approach to nonracemic compounds.
a
b
Yields are isolated yields. Regioselectivity provided in parentheses.
This isolated yield is after an osmylation reaction to remove the
contaminating olefin.
Similar to the intermolecular case, the reaction followed
traditional electrophilic aromatic substitution trends where
arenes possessing pendant electron-donating substituents
reacted faster, and in higher yield, than electron-neutral or
-deficient arenes. For example, while the slightly activated
phenyl product 14 was produced in moderate, 50% yield, a
>90% yield was achieved for p-methyl 15, p-isopropyl 16, and
p-methoxy 19. When the aromatic ring carried the ortho/para
directing, deactivating halogens, p-bromo and p-chloro, good
yields were obtained, 91% for 17 and 72% for 18. When
unsymmetrical arene substrates 21−22 were employed, good
yields were obtained, but only modest regioselectivity was
observed, again mirroring the results of the intermolecular
reactions. Although the substrates were subjected to reaction
conditions for 24 h for convenience, it is noteworthy that some
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and spectral data for all new
compounds are provided. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: sicook@indiana.edu.
Notes
The authors declare no competing financial interest.
C
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Organic Letters
Letter
(23) For the only example of a nonracemic arylation of activated
enantioenriched alcohols, see: Vicennati, P.; Cozzi, P. G. Eur. J. Org.
Chem. 2007, 2248−2253.
ACKNOWLEDGMENTS
■
We acknowledge generous funding from Indiana University in
support of this work. We also gratefully acknowledge the
American Chemical Society Petroleum Research Fund (PRF
52233-DNI1) and NSF-CAREER Award (CHE-1254783) for
partial support of this work.
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