Boronic acid catalyzed Friedel-Crafts reactions of allylic alcohols with electron-rich arenes and heteroarenes

Article abstract of DOI:10.1021/jo9023073

(Chemical Equation Presented) Pentafluorophenylboronic acid catalyzes the regioselective coupling of structurally diverse allylic alcohols with a variety of electron-rich aromatic and heteroaromatic substrates under ambient conditions. The commercially av

Full text of DOI:10.1021/jo9023073

pubs.acs.org/joc
ability of the OH group, but has been achieved with some
Boronic Acid Catalyzed Friedel-Crafts Reactions of
Allylic Alcohols with Electron-Rich Arenes and
Heteroarenes.
success in recent years with the use of π-activated alcohols
as electrophiles.4 Allylic, propargylic, and benzylic alcohols
(or combinations thereof) lead to resonance-stabilized car-
bocations that can be generated under mild conditions. The
products of these reactions have the added advantage of
functionality that may be further elaborated.
J. Adam McCubbin,* Hamidreza Hosseini, and
Oleg V. Krokhin
Several classes of catalysts have been successfully applied
to the FC reaction of allylic alcohols, including Bronstead
acids,5 conventional Lewis acids,6 and transition metals.7 So
far, reaction scope in terms of allylic alcohols, particularly
with respect to cyclic ones, remains limited. Given the nature
of the proposed allylic carbocation intermediates, regioselec-
tivity in terms of the sight of nucleophilic attack can be
problematic. In several cases, a large excess of the nucleo-
phile is required, and all of the methods reported require
either strongly acidic or toxic and often expensive metal-
based catalysts. Thus, an environmentally benign, mild,
selective, and recoverable catalyst would be a useful alter-
native.
Department of Chemistry, University of Winnipeg,
515 Portage Avenue, Winnipeg, MB R3B 2E9, Canada
a.mccubbin@uwinnipeg.ca
Received October 28, 2009
Diversely substituted arylboronic acids are widely avail-
able due primarily to their common use in Suzuki-Miyaura
cross-coupling reactions.8 In contrast to their use as reac-
tants, there are only sporadic reports of their use as cata-
lysts,9 despite several attractive features, including the Lewis
acidity of the boron atom, their ability to complex with
Pentafluorophenylboronic acid catalyzes the regioselec-
tive coupling of structurally diverse allylic alcohols with a
variety of electron-rich aromatic and heteroaromatic
substrates under ambient conditions. The commercially
available catalyst is recoverable and air and moisture
stable, and the reaction produces water as the only
byproduct.
(4) For an excellent review, see: Bandini, M.; Tragni, M. Org. Biomol.
Chem. 2009, 7, 1501.
(5) (a) Liu, Y.-L.; Liu, L.; Wang, Y.-L.; Han, Y.-C.; Wang, D.; Chen,
Y.- J. Green Chem. 2008, 10, 635. (b) Sanz, R.; Martinez, A.; Miguel, D.;
Alvarez-Gutirrrez, J. M.; Rodriguez, F. Adv. Synth. Catal. 2006, 348, 1841.
(c) Sanz, R.; Martinez, A.; Alvarez-Gutirrrez, J. M.; Rodriguez, F. Eur. J.
Org. Chem. 2006, 1383. (d) Bras, J. L.; Muzart, J. Tetrahedron 2007, 63, 7942.
(6) Intermolecular: (a) Yasuda, M.; Somyo, T.; Baba, A. Angew. Chem.,
Int. Ed. 2006, 45, 793. (b) Yadav, J. S; Subba Reddy, B. V.; Aravind, S.;
Narayana, G. G. K. S.; Reddy, S. Tetrahedron Lett. 2007, 48, 6117. (c) Jana,
U.; Maiti, S.; Biswas, S. Tetrahedron Lett. 2007, 48, 7160. (d) Rao, W.; Chan,
P. W. H. Org. Biomol. Chem. 2008, 6, 2426. (e) Noji, M.; Konno, Y.; Ishii, K.
J. Org. Chem. 2007, 72, 5151. (f) Jana, U.; Biswas, S.; Maiti, S. Tetrahedron
Lett. 2007, 48, 4065. Intramolecular: (g) Namba, K.; Yamamoto, H.; Sasaki,
I.; Mori, K.; Imagawa, H.; Nishizawa, M. Org. Lett. 2008, 10, 1767.
(h) Bandini, M.; Eichholzer, A.; Kotrusz, P.; Tragni, M.; Troisi, S.; Umani-
Ronchi, A. Adv. Synth. Catal. 2009, 351, 319.
Since its discovery over 130 years ago,1 the Friedel-Crafts
(FC) alkylation reaction has been established as a powerful
and versatile method for C-C bond formation.2 This is due
primarily to its broad scope and ability to directly functio-
nalize rings at a C-H bond.3 Significant disadvantages of
classical methods, primarily due to environmental concerns,
have been addressed to some extent, namely their reliance on
harsh reaction conditions, stoichiometric quantities of elec-
trophile activators, and the resulting waste produced. From
an environmental and atom-economical standpoint, the
ideal FC process would be catalytic and employ hydroxide
as a leaving group on the electrophile and, thus, generate
only water as a byproduct of the reaction. This approach has
so far been limited, primarily by the poor leaving group
(7) Pd: (a) Kimura, M.; Futamata, M.; Mukai, R.; Tamaru, Y. J. Am.
Chem. Soc. 2005, 127, 4592. (b) Trost, B. M.; Quancard, J. J. Am. Chem. Soc.
2006, 128, 6314. (c) Usui, I.; Schmidt, S.; Keller, M.; Breit, B. Org. Lett. 2008,
10, 1207. Ru: (d) Zaitsev, A. B.; Gruber, S.; Pregosin, P. S. Chem. Commun.
€
2007, 4692. (e) Zaitsev, A. B.; Gruber, S.; Pluss, P. A.; Pregosin, P. S.; Veiros,
L. F.; Worle, M. J. Am. Chem. Soc. 2008, 130, 11604. (f) Onodera, G.;
€
Imajima, H.; Yamanashi, M.; Nishibayashi, Y.; Hidai, M.; Uemura, S.
Organometallics 2004, 23, 5841. (g) Huang, J.; Zhou, L.; Jiang, H. Angew.
Chem., Int. Ed. 2006, 45, 1945. (h) Yokoyama, Y.; Takagi, N.; Hikawa, H.;
Kaneko, S.; Tsubaki, N.; Okuno, H. Adv. Synth. Catal. 2007, 349, 662.
(8) For reviews, see: (a) Metal Catalyzed Cross Coupling Reactions; de
Meijere, A.; Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004. (b) Dedicated
special issue of 30 years of cross-coupling: Tamao, K., Hiyama, T., Negishi, E.-i.,
Eds. J. Organomet. Chem. 2002, 653. (c) Walker, S. D.; Barder, T. E.; Martinelli,
J. R.; Buchwald, S. L. Angew. Chem., Int. Ed. 2004, 43, 1871.
(9) See, for example: (a) Al-Zoubi, R. M.; Marion, O.; Hall, D. G. Angew.
Chem., Int. Ed. 2008, 47, 2876. (b) Tale, R. H.; Adude, R., N. Tetrahedron
Lett. 2006, 47, 7263. (c) Rao, G.; Philipp, M. J. Org. Chem. 1991, 56, 1505.
(d) Debache, A.; Boumold, B.; Amimour, M.; Belfaitah, A.; Rhouati, S.;
Carboni, B. Tetrahedron Lett. 2006, 47, 5697. (e) Debache, A.; Boulcina, R.;
Belfaitah, A.; Rhouati, S.; Carboni, B. Synlett 2008, 509. (f) Letsinger, R. L.;
MacLean, D. B. J. Am. Chem. Soc. 1963, 85, 2230. (g) Maki, T.; Ishihara, H.;
Yamamoto, H. Synlett 2004, 1355. (h) Wipf, P.; Wang, X. J. Comb. Chem.
2002, 4, 656. (i) Tale, R. H.; Patil, K. M.; Dapurkar, S. E. Tetrahedron Lett.
2003, 3427. (j) Tale, R. H.; Patil, K. M. Tetrahedron Lett. 2002, 43, 9715.
(1) (a) Friedel, C.; Crafts, J. M. C.R. Hebd. Seances Acad. Sci. 1877, 84,
1392. (b) Friedel, C.; Crafts, J. M. C. R. Hebd. Seances Acad. Sci. 1877, 84,
1450.
(2) (a) Larock, R. C., Comprehensive Organic Transformations: VCH:
New York, 1999; (b) Olah, G. A.; Krishnamurti, R.; Prakash, G. K. S. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon:
Oxford, 1991; Vol. 3, pp 293-339. (c) Roberts, R. M.; Khalaf, A. A. Friedel-
Crafts Alkylation Chemistry. A Century of Discovery; Dekker: New York,
1984. (d) Olah, G. A. Friedel-Crafts and Related Reactions; Wiley- Inter-
science: New York, 1964; Vol. II, Part 1.
(3) For a concise review of FC reactions in the context of direct trans-
formations of C-H bonds, see: Dyker, G. In Handbook of C-H Transfor-
mations: Applications in Organic Synthesis; Dyker, G., Ed.; Wiley-VCH:
Weinheim, 2005; Vol. 1, pp 137-142.
DOI: 10.1021/jo9023073
r
Published on Web 01/07/2010
J. Org. Chem. 2010, 75, 959–962 959
2010 American Chemical Society

McCubbin et al.
JOCNote
SCHEME 1. Attempted Allylic Alcohol Rearrangement
TABLE 1. Allylation of 2-Methylfuran
sterically hindered alcohols, solubility in organic solvents,
and stability in the presence of air and moisture.10 Further-
more, arylboronic acids are easily recovered from complex
mixtures via basic extraction.11
During the course of a study on boronic acid catalyzed
rearrangement reactions of allylic alcohols (e.g., 1f to 2),12 we
noted the formation of dehydration byproducts (e.g., 3a
and 3b), which suggested the possible intermediacy of a
carbocation (4, Scheme 1). We reasoned that these inter-
mediates could be trapped with nucleophiles to afford useful
substitution products (5).
Indeed, treatment of a mixture of alcohol 1a, 2-methylfur-
˚
an (6), and 4 A molecular sieves in CH2Cl2 with pentafluor-
ophenylboronic acid at room temperature for 16 h afforded
allylated methylfuran 5a in good yield and excellent regios-
electivity with respect to both the position of alkylation on
the furan ring and the site of nucleophilic attack (Table 1,
entry 1). Similarly, alcohol 1b underwent addition regio- and
stereoselectively to afford 5b in near-quantitative yield, with
only the E product observed (entry 2). Compound 1c, with an
unsubstituted phenyl substituent, failed to react under the
specified conditions (entry 3), but upon modification with an
electron-donating substituent in 1d, the reaction proceeds in
good yield, with excellent regio- and stereoselectivity. Similarly
to 1c, electron-poor derivative 1e failed to react (entry 5).
Endocyclic allylic alcohols are also effective substrates in the
reaction. Phenyl-substituted, medium-sized ring substrates
1f-h undergo reaction in good to near-quantitative yields,
affording single regioisomers 5f-h, respectively, as products
(entries 6-8). Alkyl (1i) as well as alkynyl (1j,) substrates are
well tolerated, albeit with the latter producing products in
somewhat decreased yields (entries 9-11). Bis-allylic alcohol
substrate 1l undergoes substitution exclusively at the exo-
cyclic site and exhibits low E/Z selectivity in the product (5l,
entry 12). The related, semisaturated exocyclic-only deriva-
tive 1m failed to undergo reaction under the specified con-
ditions (entry 13).
Other aryl-substituted cyclic allylic alcohols (1n-p) are
highly effective substrates for the reaction, regardless of
electronic (entries 14 and 15) or steric (entry 16) factors,
(10) Boronic Acids;Preparation and Applications in Organic Synthesis
and Medicine; Hall, D. G., Ed.; Wiley-VCH: Weinheim, 2005.
(11) Bhat, S.; Punachithaya, S.; Ganesh, S. Int. Patent 019229, 2005. See
also the Supporting Information
(12) McCubbin, J. A. Unpublished results. For related reactions, see:
ꢀ
(a) Leleti, R. R.; Hu, B.; Prashad, M.; Repic, O. Tetrahedron Lett. 2007, 48,
8505. (b) Yoshihito, A.; Akio, O.; Hiroshi, I. Chem. Pharm. Bull. 1982, 30,
881. (c) Mukhopadhyay, M.; Reddy, M. M.; Maikap, G. C.; Iqbal, J. J. Org.
Chem. 1995, 60, 2670. (d) Morrill, C.; Grubbs, R. H. J. Am. Chem. Soc. 2005,
127, 2842. (e) Morrill, C.; Beutner, G.; Grubbs, R. H. J. Org. Chem. 2006, 71,
7813. (f) Ge, W.; Ampa, J.; Rudy, L. L. Inorg. Chem. Acta 2005, 358, 933.
(g) Frank, R. F.; Rudy, L. L.; Ge, W. Inorg. Chem. Commun. 2002, 5, 384.
(h) Schoop, T.; Roesky, H. W.; Noltermeyer, M.; Schmidt, H.-G. Organo-
metallics 1993, 12, 571. (i) Jacob, J.; Espenson, J. H.; Jensen, J. H.; Gordon,
M. S. Organometallics 1998, 17, 1835.
aThe product is an inseparable 10:3 mixture of diastereomers.
affording products 5n-p in near-quantitative yields. Similarly,
enantiomerically and diastereomerically pure carvone-derived
960 J. Org. Chem. Vol. 75, No. 3, 2010

McCubbin et al.
JOCNote
TABLE 2. Comparison with Other Catalysts
TABLE 3. Allylation of Other Nucleophiles
entry
catalyst
conditions
yield (%)
˚
1
2
3
4
5
C6F5B(OH)2
TsOH
BF3 OEt2
FeCl3
AuCl3
4 A M.S. CH2Cl2, 16 h, rt
CH3CN, 16 h, rt
CH2Cl2, 16 h, rt
95
38
81
52
92
3
MeNO2, 16 h, rt
˚
4 A M.S. CH2Cl2, 16 h, rt
alcohol 1q affords product 5q in excellent yield, but as a 10:3
mixture of diastereomers.
In order to compare our method with established proto-
cols for FC reactions of this type, we tested the reaction of
cyclic substrate 1o with 6 with a selection of known catalysts
(Table 2). In each case, the literature method was adhered to
with the exception of catalyst loading (10 mol % was used in
each case), and the molar ratio of alcohol to aromatic
substrate (a 1:1 ratio was used) so that results in terms of
yield and purity could be compared directly.13 As a protic
acid, TsOH afforded the product in low yield (entry 2), with
significant byproduct formation as illustrated by the NMR
spectra of the crude reaction product 5o. By comparison,
BF3 was effective, affording the product in moderate purity
and good yield (entry 3).14 FeCl3, which has been shown to be
very effective in FC reactions of benzylic alcohols,15 afforded
the product in modest yield and with significant impurities
(entry 4). Of the four alternative catalysts tested, AuCl3
performed the best (entry 5).6d These conditions afforded
5o in comparable yield to ours (entry 1), with only very minor
impurities evident by NMR. However, pentafluorophenyl-
boronic acid is significantly less expensive than AuCl3 on a
per mole basis.
Having established the scope of the reaction with 2-
methylfuran as the nucleophile, we began testing the efficacy
of a variety of other electron-rich heterocycles in the reaction
with a selection of our allylic alcohol substrates (Table 3).
1,3-Dimethoxybenzene (7), indole (9), 2-methoxynaphtha-
lene (10), and pyrrole (11) all react with alcohol 1a to afford
the corresponding products (7a, 9a-11a) in good to excellent
yields, with excellent regioselectivity with respect to the site
of allylic substitution (entries 1, 3-5). In the case of pyrrole,
a ca. 5:1 mixture of C2 and C3 allylation products was
observed (entry 5). In contrast, anisole (8) failed to react
with 1a (entry 2). Indole reacts with alcohol 1r to afford the
product 9r in good yield, but with moderate E/Z selectivity as
an inseparable mixture of stereoisomers (entry 6). 1,3,5-
Trimethoxybenzene 12 is also an effective nucleophile, af-
fording monoallylated product 12s in moderate yield, along
with a small amount of diallylated product 12t (entry 7). Free
2-naphthol 13 alkylates selectively at C1 upon treatment with
(13) Purity of the products was compared qualitatively by comparison of
the 1H and 13C NMR spectra of the reaction mixtures prior to chromato-
graphic purification. See the Supporting Information.
aInseparable 4:1 mixture of E/Z isomers. b23% of disubstitued
product (12t) was isolated.
€
(14) Liu, J.; Muth, E.; Florke, U.; Henkel, G.; Merz, K.; Sauvageau, J.;
Schwake, E.; Dyker, E. Adv. Synth. Catal. 2006, 348, 456.
(15) Mertins, K.; Iovel, I.; Kischel, J.; Zapf, A.; Beller, M. Angew. Chem.,
Int. Ed. 2005, 44, 238.
cyclic alcohol 1i to afford 13i in high yield (entry 8).
Compounds 9, 12, and 11 are also effective substrates for
J. Org. Chem. Vol. 75, No. 3, 2010 961

McCubbin et al.
JOCNote
coupling with cyclic derivative 1i, affording the correspond-
ing products 9i, 12i, and 11i in good yields. Similarly to
coupling with 1a (entry 5), pyrrole (11), upon treatment
with 1i, affords a mixture of regioisomers with moderate
selectivity (entry 11).
In contrast to the mixtures obtained upon reaction of 12
with acyclic alcohols (entry 7), reaction with aryl- or alkynyl-
substituted cyclic derivates 1p and 1k affords monoallylated
products exclusively (12p and k, entries 12 and 13). A second
allylation in these cases may be precluded for steric reasons.
Indole is an effective nucleophile for reaction with electron-
rich aryl-substituted alcohol 1o and affords the product 9o in
excellent yield (entry 14).
In summary, we have developed a mild, catalytic method
for the allylation of electron-rich aromatic and heteroaro-
matic rings. This method is amenable to a large array of
cyclic and acyclic allylic substrates without the need for
preactivation of the alcohol moiety. This protocol compares
favorably to other methods in terms of yield and selectivity
for the desired product. Initial studies suggest that a reso-
nance-stabilized carbocation is involved and the observed
high regioselectivity is due mainly to steric control. Further
mechanistic studies and expansion of the scope of this
reaction are ongoing in our laboratory.
Experimental Section
5a. To a vial containing 1a (0.5 mmol) in CH2Cl2 (2.5 mL)
˚
were added freshly dried powdered 4 A molecular sieves
SCHEME 2. Mechanistic Study
(500 mg), 6 (1.0 equiv), and pentafluorophenyl boronic acid
(11 mg, 0.1 equiv). The vial was capped and the mixture allowed
to stir for 16 h at room temperature. The suspension was filtered
through a 1 in. plug of silica, eluting with CH2Cl2, and the eluent
concentrated in vacuo. Purification of the residue by flash
chromatography (0-2% EtOAc/Hex) afforded the desired
product (5a) as a colorless oil (96 mg, 70%): 1H NMR (400 MHz,
CDCl3) δ 7.37-7.33 (m, 2H), 7.31-7.28 (m, 1H), 7.25-7.22
(m, 7H), 6.25-6.21 (t, J = 7.5 Hz, 1H), 5.90-5.89 (d, J = 3.0 Hz,
1H), 5.85-5.83 (d, J = 3.0 Hz, 1H), 3.41-3.39 (d, J = 7.5 Hz, 1H),
2.24 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 152.4, 150.6, 143.1,
142.3, 139.5, 129.8, 128.2, 128.1, 127.4, 127.14, 127.10, 124.4, 105.9,
105.8, 29.0, 13.5; FTIR (neat) υ 3057, 3027, 2921, 1953, 1889, 1661,
1494, 1445, 1020, 756 cm-1; HRMS (m/z) calcd for C20H17O
273.1280, found 273.1282.
In all examples of the coupling reaction studied thus far,
only products attributable to a formal conjugate nucleophi-
lic addition to the allylic alcohol have been observed, which
suggests the possibility that an SN20 mechanism is involved.
On the other hand, the site of attack also consistently
corresponds to the least hindered terminus of an allylic
carbocation, which would be formed during the course an
SN1-type process. In order to determine which mechanism is
operative, we prepared alcohol 2 and subjected it to the
reaction conditions in the presence of 6. We obtained in 96%
isolated yield product 5f (Scheme 2), a nearly identical result
for the analogous reaction of 1e (cf. Table 1, entry 6). This
suggests formation of a delocalized carbocation followed by
nucleophilic attack, where steric effects control the regios-
electivity. Indeed, such a mechanism is consistent with the
partial loss of stereochemical information in Table 1, entry
17, and the failure of substrates that would lead to poorly
stabilized carbocations (e.g., 1e,m) to undergo reaction.
Acknowledgment. Financial support of this work was
provided by the University of Winnipeg in the form
of a Major Research Grant (J.A.M) and the Natural
Sciences and Engineering Research Council of Canada
(O.V.K).
Supporting Information Available: Experimental proce-
dures and spectroscopic data. This material is available free of
charge via the Internet at http://pubs.acs.org.
962 J. Org. Chem. Vol. 75, No. 3, 2010