Iron-Catalyzed Arene Prenylation

Article abstract of DOI:10.1002/ejoc.201600531

The syntheses of prenylated arenes and 2,2-dimethylchromans using a Friedel–Crafts-type coupling between activated arenes and isoprene is reported. A combination of catalytic amounts of FeCl₃and AgBF₄promotes a regioselective prenyla

Full text of DOI:10.1002/ejoc.201600531

DOI: 10.1002/ejoc.201600531
Communication
Arene Prenylation
Iron-Catalyzed Arene Prenylation
Alexander J. Villani-Gale[a] and Chad C. Eichman*[a]
Abstract: The syntheses of prenylated arenes and 2,2-dimeth- prenylation event followed by a cyclization to form a 2,2-di-
ylchromans using a Friedel–Crafts-type coupling between acti- methylchroman structure. The method avoids isoprene poly-
vated arenes and isoprene is reported. A combination of cata- merization and allows the facile late-stage derivatization of bio-
lytic amounts of FeCl3 and AgBF4 promotes a regioselective logically active motifs.
Introduction
enes or 2,2-dimethylchromans would be a valuable addition to
the synthetic chemist's toolbox for the synthesis of biorelevant
prenylated arenes.
Prenylated arenes and the related 2,2-dimethylchroman moiety
represent intriguing scaffolds in therapeutic development. Nat-
urally occurring[1] and synthetic prenylated arenes[2] display a
range of biological activity (Figure 1). Additionally, the incorpo-
ration of an isoprene unit into bioactive molecules increases
lipophilicity, which is shown to increase potency in many
cases.[3] The importance of accessing these structures has
driven the development of many methods to incorporate pren-
yl groups into substituted arenes.[4] Catalytic installation of the
isoprene unit represents the most utilized method for arene
prenylation, where the catalysts include precious metals[5] and
Lewis acids.[6] Additionally, the isoprene unit is often derived
from prenyl surrogates such as prenyl halides[6a] and organome-
tallic reagents.[5,6b] The most efficient and atom-economic route
to prenylated arenes and 2,2-dimethylchromans is the direct
implementation of isoprene. This strategy is rare but can be
realized using catalytic amounts of metal triflates[7] or zeolites;[8]
however, inherent complications exist using this approach. First,
the reaction often produces a mixture of mono- and poly-
prenylated products. Second, for non-phenolic substrates, it is
challenging to isolate the linear prenylated arene without sub-
sequent cyclization to an indane product.[7d] The development
of a complimentary catalytic method to access prenylated ar-
Isoprene activation using iron is known in the context of
hydrovinylations[9] and polymerizations;[10] however, these
processes are presumed to operate under a low-valent iron cen-
ter during catalysis. To the best of our knowledge, isoprene
functionalization using a high-valent, or cationic, iron species
has not been reported. Iron-catalyzed processes are becoming
more sophisticated as new methods unveil novel reactivity pat-
terns.[11] These recent advances and our interest in atom-eco-
nomic processes led us to investigate the Lewis -acidic proper-
ties of iron as a catalyst for this Friedel–Crafts (FC) type reac-
tion.[12] An intrinsic issue with FC chemistry is the employment
of organohalides and/or an excess of metal salts, which limits
FC-type reactions on an industrial scale.[13] A recent surge in
methods to circumvent these issues have been reported
through the use of catalytic, nontoxic metals[7c,7d,12d] and
activated alcohols[12a,12d] or π-components[7c,7d,12b] in lieu of or-
ganohalides. The method described herein utilizes an iron/silver
co-catalyst system to promote the efficient and selective prenyl-
ation of activated arenes (Scheme 1).
Scheme 1. Iron-catalyzed arene prenylation.
Results and Discussion
We began our investigations by studying various iron sources
as catalysts for the prenylation of 2,6-dimethylphenol and 4-
chlorophenol (Table 1). A thorough screening of iron sources
and additives (not shown) determined that iron(II) or iron(III)
halides in combination with silver salts were most effective at
producing the desired prenylated arenes or 2,2-dimethylchro-
mans in high yields while minimizing isoprene oligomer by-
product formation. Ferrous bromide (1 mol-%) and AgBF4
Figure 1. Structures of biologically active prenylated arenes.
[a] Department of Chemistry and Biochemistry, Loyola University Chicago
1068 W. Sheridan Road, Chicago, IL 60660, USA
E-mail: ceichman@luc.edu
http://www.luc.edu/chemistry/facultystaff/eichmanchad.shtml
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/ejoc.201600531.
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(2 mol-%) were effective in the production of prenylated prod- ivity of the process, we subjected 3-substituted phenols to our
uct 2a (Entry 1); however, ferric chloride proved to be a more reaction conditions. As expected, increasing the size of the sub-
active catalyst, allowing for higher conversion to 2a (Entry 2). stituent resulted in an increase in regioselectivity (1:1 to 3:1) of
Lowering the catalyst loading or removing the iron source did chroman products 1j–1k. 3-Bromophenol provided a 2:1 mix-
not provide beneficial results (Entries 3 and 4). Reducing the ture of regioisomers (1l), however in increased yield. 2-Naphthol
AgBF4 loading to 1 mol-% did not diminish reactivity (Entry 5), provided the best result where a > 20:1 regioselectivity was
and increasing the amount of isoprene to 2 equiv. afforded observed in 92 % yield (1m). The incorporation of Lewis-basic
higher conversion to 2a (Entry 6). Finally, removing the silver sites on the substrates, such as 4-hydroxybenzamide, resulted
resulted in suppressed activity (Entry 7). Applying the best con- in unproductive reactivity, which is a common problem for
ditions to 4-chlorophenol provided low conversion to 2,2-di- these types of reactions.[12d] Fortunately, products 1a, 1b, and
methylchroman product 1a (Entry 8). Ultimately, increasing the 1l allow further functionalization through cross-coupling chem-
temperature to 60 °C offered the highest conversion to the istry such as Ullmann[15] or Buchwald–Hartwig aminations.[16]
product (Entry 9), which we then employed as our optimized Additionally, increasing catalyst loading for low-yielding sub-
conditions. Performing the reaction in the presence of 2,6-di- strates did not result in higher yields, but rather increased for-
tert-butylpyridine (DTBP) or potassium carbonate resulted in re- mation of diprenylated products and isoprene oligomers. Fi-
duced reactivity (Entries 10 and 11).[14] Because we still observe nally, we were interested in the application of this method to
moderate conversion to the chroman product in the presence the synthesis of known UCP inhibitor CSIC-E379 (1n).[2b] This
of these Brønsted bases, we hypothesize that a combination of method afforded the desired product in 65 % yield, demon-
Brønsted acid activation and Lewis acid activation is opera- strating the utility of the method in the synthesis of bioactive
tive.[14b,14c] The phenolic proton and/or adventitious water are molecules.
likely sources for the acidic media. To corroborate this hypothe-
sis, we performed the reaction with 1 mol-% HBF4·Et2O in place
Table 2. Reaction scope for 2,2-dimethylchroman products.[a]
of the Fe/Ag system and achieved 52 % yield of the chroman
(Entry 12). This result shows that the FeCl3/AgBF4 combination
is a more effective catalyst through slow generation of acidic
media, which is optimal for this reaction.[14c]
Table 1. Optimization of reaction conditions.
Entry[a]
Phenol
Fe source
(amount [mol-%])
AgBF4
[mol-%]
GC conversion
[%][b]
1
2
3
2,6-dimethyl
2,6-dimethyl
2,6-dimethyl
2,6-dimethyl
2,6-dimethyl
2,6-dimethyl
4-chloro
4-chloro
4-chloro
4-chloro
4-chloro
FeBr2 (1)
FeCl3 (1)
FeCl3 (0.5)
–
FeCl3 (1)
FeCl3 (1)
FeCl3 (1)
FeCl3 (1)
FeCl3 (1)
FeCl3 (1)
FeCl3 (1)
–
2
2
1
1
1
1
1
1
1
1
1
–
22
51
25
<5
53
53
71
39
80
72
53
52
4
5
6[c]
7[c]
8[c]
9[c,d]
10[c,d,e]
11[c,d,f]
12[c,d,g]
4-chloro
[a] Reactions performed with isoprene/Ar–OH (1:1) in 1,2-dichloroethane
(1 ) at 23 °C for 12 h. [b] GC conversion based on crude integration of
M
product and starting Ar–OH. [c] Reaction performed with isoprene/Ar–OH
(2:1). [d] Reaction performed at 60 °C. [e] Reaction performed with 2 mol-%
of 2,6-di-tert-butylpyridine. [f] Reaction performed with 1 equiv. of K2CO3. [g]
Reaction performed with 1 mol-% of HBF4·Et2O.
[a] Isolated yields are an average of two reactions on a 1 mmol scale. Products
1j–1m isolated as a mixture of regioisomers where the regioselectivity (r.s.)
was determined by 1H NMR spectroscopy of the crude reaction mixture.
The substrate scope of this method for the synthesis of 2,2-
Employing our method to substrates that are only capable
dimethylchroman products is summarized in Table 2. Phenols of producing the linear prenylated product is depicted in
containing para-substitution afforded the chroman product in Table 3. Using slightly more catalyst (3 mol-%), substituted
high yields with a range of electron-donation ability (1a–1h). phenols were capable of providing prenylated arene 2b in mod-
Interestingly, reaction of 2-methylresorcinol proceeded to give erate yield. Prenylmesitylene (2c) was synthesized in 55 % yield.
bis(chroman) product 1i in high yield. To probe the regioselect- Additionally, dimethoxybenzenes were effective as substrates in
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the production of compounds 2d and 2e. We then examined ation of protected tyrosine 4a and estrone (4b) (Table 4). The
1,3-benzodioxole and benzo-1,4-dioxane for the synthesis of direct prenylation of these molecules has potential applications
prenyl products 2f and 2g. Each substrate produced the desired in the medicinal chemistry and chemical biology arenas. Upon
product in low yield. However, excellent regioselectivity was ob- allowing protected tyrosine 4a to react under our optimized
served. It is important to note that when employing Bi(OTf)3 as conditions, low reactivity was observed presumably due to the
a catalyst for this reaction, complete cyclization to an indane Lewis-basic functional groups. Increasing the loading to 30 mol-
product is observed in 79 % yield.[7d] The ability to truncate the % FeCl3 and 5 mol-% AgBF4, we were pleased to observe the
reaction at the linear prenylated arene under our conditions formation of derivatized tyrosine 5a in a 72 % yield. To the best
demonstrates the unique reactivity of the FeCl3/AgBF4 catalyst of our knowledge, this chroman-functionalized tyrosine has not
system. Additionally, the low to moderate yields for this process been explored as an amino acid derivative in chemical synthe-
is comparable to those of other systems, which underscores the sis. This new product represents an interesting scaffold in pept-
challenge of this reaction.[7c]
ide and peptidomimetic syntheses. This procedure was also ef-
fective in the prenylation of estrone (4b) to obtain 87 % yield
of 5b in a 2:1 regioisomeric ratio. These reactions exhibit the
applicability of the iron-catalyzed prenylation process for natu-
ral product diversification.
Table 3. Reaction scope for prenylated arene production.[a]
Table 4. Prenylation of L
-tyrosine and estrone.[a]
[a] Isolalted yields are an average of two reactions on a 1 mmol scale. Regios-
electivity (r.s.) was determined by 1H NMR spectroscopy of the crude reaction
mixture.
[a] Regioselectivity (r.s.) was determined by 1H NMR spectroscopy of the
crude reaction mixture.
During our examination of veratrole, we observed the forma-
tion of small quantities of indane product 3. We explored the
selective formation of these potentially useful products using a
modified FeCl3/AgBF4 catalyst system (Scheme 2). Subjecting
2e to our original prenylation conditions afforded indane prod-
uct 3 in 99 % yield. Direct conversion to the indane was possi-
ble by increasing the catalyst loading to 20 mol-% FeCl3 and
AgBF4. Using this direct prenylation/cyclization protocol, 35 %
of 3 was obtained. These results demonstrate the unique ability
of the FeCl3/AgBF4 system to stop the reaction at prenylated
arene product 2, and its ability to produce indane products
under modified conditions.
Conclusions
We report a mild and selective iron catalyst system for the pro-
duction of a variety of highly useful 2,2-dimethylchroman and
prenylated arene products. This method avoids the use of stoi-
chiometric Lewis/Brønsted acids and employs isoprene directly,
which makes the process 100 % atom-economic. We applied
the method to the synthesis of a known UCP inhibitor and to
the functionalization of a new tyrosine derivative that has po-
tential utility in peptide synthesis. Efforts to employ this catalyst
system to additional Friedel–Crafts and other atom-economic
processes are ongoing in our laboratory.
Experimental Section
Representative Procedure: In an oven-dried 4 mL vial was added
FeCl3 (1.6 mg, 0.01 equiv.), AgBF4 (2.0 mg, 0.01 equiv.), and 4-chloro-
phenol (135.0 mg, 1.0 mmol). The flask was purged with N2 and
the mixture diluted with freshly distilled 1,2-dichloroethane (DCE)
(1.0 mL). Isoprene (200 μL, 2.0 mmol) was added dropwise to the
stirred reaction mixture over the course of 1 min. Completion of
the reaction was determined by GC–MS, after which the reaction
mixture was placed in a separatory funnel, diluted with ethyl acet-
ate, and washed with a saturated brine solution. The organic layer
Scheme 2. Selective formation of indane products.
To explore the application of the iron-catalyzed process to
the prenylation of privileged scaffolds, we pursued the prenyl- was then washed with 1
M NaOH and again with brine solution.
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Acknowledgments
This work was supported by Loyola University Chicago. Profes-
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insightful discussions. We thank Northwestern University Chem-
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Keywords: Iron · Homogeneous catalysis · Aromatic
substitution · Terpenoids
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Received: April 28, 2016
Published Online: May 30, 2016
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