A general Br?nsted acid-catalyzed allylation of benzhydryl alcohols

Article abstract of DOI:10.1016/j.tetlet.2016.11.044

Efficient Br?nsted acid-catalyzed allylation of benzhydryl alcohols has been developed. The reaction occurs within 5?min in the presence of sub-stoichiometric amounts of HBF₄·OEt₂to afford the desired products in good to excellent yields. A variety of functional groups were tolerated under the developed conditions including amides, aldehydes, hydroxyl and carboxylic acid.

Full text of DOI:10.1016/j.tetlet.2016.11.044

Accepted Manuscript
A General Brønsted acid-catalyzed allylation of benzhydryl alcohols
Ifedi Orizu, Yuri Bolshan
PII:
S0040-4039(16)31512-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.11.044
TETL 48330
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
18 October 2016
7 November 2016
8 November 2016
Please cite this article as: Orizu, I., Bolshan, Y., A General Brønsted acid-catalyzed allylation of benzhydryl alcohols,
Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.11.044
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A General Brønsted acid-catalyzed allylation
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Ifedi Orizu and Yuri Bolshan

1
Tetrahedron Letters
A General Brønsted acid-catalyzed allylation of benzhydryl alcohols
Ifedi Orizua and Yuri Bolshanb, 
a University of Arkansas, 345 N. Campus Drive, Fayetteville, Arkansas 72701, USA
b University of Ontario Institute of Technology (UOIT), 2000 Simcoe Street North, Oshawa, Ontario L1H 7K4, Canada
ARTICLE INFO
ABSTRACT
Article history:
Received
Efficient Brønsted acid-catalyzed allylation of benzhydryl alcohols has been developed. The
reaction occurs within 5 minutes in the presence of sub-stoichiometric amounts of HBF4 OEt2 to
.
Received in revised form
Accepted
Available online
afford the desired products in good to excellent yields. A variety of functional groups were
tolerated under the developed conditions including amides, aldehydes, hydroxyl and carboxylic
acid.
2009 Elsevier Ltd. All rights reserved.
Keywords:
Brønsted acid
allylation
benzhydryl alcohol
catalysis
metal-free
1. Introduction
most powerful and practical approaches.2 Traditionally, the
allylation of alcohols was achieved via a two-step process, where
the alcohol is first converted to a good leaving group such as
halide, carbonate, phosphonate, acetate, or ether.3 However, the
formation of large amounts of waste salts limited the application
of these protocols.
The benzhydryl moiety is an important structural motif
present in various drugs including Prozapine, Detrol and
Pimozide (Figure 1).
Lewis acid catalysis emerged as an alternative to the
conventional approaches for the direct allylation of alcohols
using allyltrimethylsilane. Lewis acids such as BF3,4 [B(C6F5)3],5
BiCl3,6 InBr3,7 InCl3-Me3SiBr,8 Bi(OTf)3,9 TiCl4,10 and
FeCl3.6H2O11 have been found to effectively catalyze the
reaction. A Lewis acid-based organocatalyzed approach, which
proceeds via a halogen exchange was developed.12 Moreover,
13
transition metal complexes such as (dppm)ReOCl3 and
NaAuCl4.2H2O14 have also been employed to promote a direct
allylation. Furthermore, Nickel-catalyzed reaction between Boc-
protected allylic alcohol and diarylmethane has been reported.15
In addition to Lewis acid and metals, Brønsted acids were
shown to catalyze the direct allylation of alcohols. Several
catalysts including [HN(SO2F)2],16
p-toluenesulfonic acid
(PTSA),17 and phosphomolybdic acid (PMA)18 are known to
afford the allylation products. Moreover, heterogeneous catalysts
such as (HClO4-SiO2),19 proton- and metal-exchanged
montmorillonites (H- and Mn+-mont),20 and Amberlite IR-
120H21 resin were shown to promote the allylation reaction.
Figure 1. Active pharmaceutical ingredients, which contain
benzhydryl motif.
While numerous procedures for alcohol allylation were
reported, the major drawbacks included low functional group
tolerance and poor atom economy. In many instances, excess
amounts of Lewis acids, sensitive and expensive metal
Therefore, the allylation of benzhydryl alcohols can serve an
important tool for the synthesis of biologically active molecules.1
The allylation of alcohols using allyltrimethylsilane is one of the
———
 Corresponding author. Tel.: +1-905-721-8668 ext. 5353; e-mail: yuri.bolshan@uoit.ca

2
Tetrahedron
complexes or strong Brønsted acids are required, which limits
dichloromethane the temperature could not be elevated any
the scope and practicality of the reported protocols.
further. Therefore, we attempted the reaction in dichloroethane at
600C, which resulted in excellent 96% yield of the desired
product (Table 1, entry 10).
2. Results and Discussion
Our research is focused on efficient Brønsted acid-catalyzed
reactions. Previously, we have developed alkynylation and
alkenylation of benzhydryl alcohols.22 The derivatization of
benzhydryl alcohols with trifluoroborate salts occurred smoothly
We then investigated the scope of the methodology (Figure 1).
It was found that electron-donating substituents promoted the
formation of the product in high yields. For instance, 4-methoxy
and 4,4’-dimethoxybenzhydrols afforded products 2a and 2b in
excellent 97% and 94% yield respectively. The effect of steric
hindrance was probed using 4-methyl and 2-methylbenzhydrol.
Product 2c was isolated in 96% yield, while its more sterically
hindered isomer 2d was obtained in 81% yield.
.
in the presence of tetrafluoroboric acid (HBF4 OEt2), an
environmentally benign and affordable reagent. While the
developed protocol exhibited excellent functional group
tolerance, the main limitation was the necessity to use 1.6
.
equivalents of HBF4 OEt2. Furthermore, our attempts to expand
this methodology to the allylation of benzhydryl alcohols using
allyltrifluoroborate salt were fruitless. Here, we report a Brønsted
acid-catalyzed methodology for the allylation of benzhydryl
alcohols using allyltrimethylsilane in the presence of
.
substoichiometric amount of HBF4 OEt2.
Table 1. Optimization of Brønsted acid-catalyzed allylation
reaction
Entrya
C3H5SiMe3 Acid
Solvent
Temp. Yield %
(0C)
(equiv)
1.1
(equiv)
1
2
3
4
5
6
7
8
9
10
1.1
1.1
1.1
1.1
1.0
0.8
0.4
0.4
0.4
0.4
CH3CN
Toluene
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCE
rt
60
64
83
91
83
88
87
63
75
96
1.1
rt
1.1
rt
1.3
rt
1.3
rt
1.3
rt
1.3
rt
1.3
rt
1.3
40
1.3
60
aReactions 1-7 were conducted using substrate 1a; reactions 8-10 were
conducted using substrate 1b.
Our initial solvent screen revealed that DCM was the most
suitable solvent for this reaction (Table 1, entries 1-3). The yield
of the desired product increased to 91% when 1.3 equivalents of
allyltrimethylsilane instead of 1.1 equivalents were used (Table
1, entry 4). Subsequently, we investigated the optimal acid
loading (Table 1, entries 4-7). Gratifyingly, we observed high
yield of the allylation product even at sub-stoichiometric loadings
of the acid-catalyst (Table 1, entry 7). While excellent 87% yield
was observed for 4-methoxybenzhydrol (Table 1, entry 7), 4-
methylbenzhydrol only afforded 63% of the desired product
under the optimized conditions (Table 1, entry 8). In addition to
lower yield, we observed the formation of the dibenzyhydryl
ether, which is a common byproduct in Brønsted acid-catalyzed
reactions of benzhydrols.22,23 Heating the reaction to 400C lead to
the elimination of dibenzhydryl ether, and increased the yield to
75% (Table 1, entry 9). Due to the low boiling point of
Figure 2. Reactions of allyltrimethylsilane with benzhydryl
alcohols.
.
aReaction was performed at 80°C. bUsing 1.4 equivalents of HBF4 OEt2.
Product 2e was isolated in 78% yield, which showed that the
unprotected phenol functionality was tolerated under the reaction
conditions. Unsubstituted benzhydrol afforded the product 2f in

3
3.
(a) Hosomi, A.; Imai, T.; Endo, M.; Sakurai, H. J. Organomet.
Chem. 1985, 285, 95-107; (b) Morizawa, Y.; Kanemoto, S.;
Oshima, K.; Nozaki, K. Tetrahedron Lett. 1982, 23, 2953-2954;
(c) Yokozawa, T.; Furuhashi, K.; Natsume, H. Tetrahedron Lett.
1995, 36, 5243-5246.
modest 67% yield. Only 34% yield of 2g was observed when 4-
chlorobenzhydrol was submitted to the developed conditions.
The yield of 2g improved to 59% when the temperature of the
reaction was raised to 800C. In contrast, 4,4’-
chloromethoxybenzhydrol yielded 2h in 97% yield. Both
unprotected aldehyde and carboxylic acid functionalities were
well-tolerated under the developed conditions affording products
2i and 2j in 77% and 99% yield respectively.
Dimethylaminobenzhydrol afforded product 2k in 48% yield the
4.
5.
6.
Cella, J. A. J. Org. Chem. 1982, 47, 2125-2130.
Rubin, M.; Gevorgyan, V. Org. Lett. 2001, 3, 2015-2707.
(a) Zhan, Z.; Yang, W.; Yang, R.; Yu, J.; Li, J.; Liu, H. Chem.
Commun. 2006, 3352-3354; (b) De, S. K.; Gibbs, R. A.
Tetrahedron Lett. 2005, 46, 8345-8350.
Kim, S. H.; Shin, C.; Pae, A. N.; Koh, H. Y.; Chang, M. H.;
Chung, B. Y.; Cho, Y. S. Synthesis 2004, 10, 1581-1584.
Saito, T.; Yasuda, M.; Baba, A. Synlett. 2005, 11, 1737-1739.
Narayana Kumar, G. G. K. S.; Laali, K. K. Org. Biomol. Chem.
2012, 10, 7347-7355.
7.
.
presence of 1.4 equivalents of HBF4 OEt2. Finally, product 2l
indicated that amido-substituted starting material reacted well
under the developed conditions.
8.
9.
10. Hassner, A.; Bandi, C. R. Synlett 2013, 10, 1275-1279.
11. Han, J.; Cui, Z.; Wang, J.; Liu, Z. Synth. Commun. 2010, 40,
2042-2046.
12. Saito, M.; Tsuji, N.; Kobayashi, Y.; Takemoto, Y. Org. Lett. 2015,
17, 3000-3003.
The proposed mechanism is outlined in Scheme 1. The
reaction between tetrafluoroboric acid and benzhydrol yields a
benzhydrylium ion 3. It is trapped by allyltrimethylsilane to
afford intermediate 4. We believe that tetrafluoroborate, which is
known to facilitate desilylative elimination,24 acts as a source of
fluoride to generate the final product and fluorotrimethylsilane.
In addition, significantly lower yield and conversion were
13. Luzung, M. R.; Toste, F. D. J. Am. Chem. Soc. 2003, 125, 15760-
15761.
14. (a) Georgy, M.; Boucard, V.; Campagne, J.-M. J. Am. Soc. 2005,
127, 14180-14181; (b) Georgy, M.; Boucard, V.; Debleds, O.;
Zotto, C. D.; Campagne, J.-M. Tetrahedron 2009, 65, 1758-1766.
15. Sha, S.-C.; Jiang, H.; Mao, J.; Bellomo, A.; Jeong, S. A; Walsh, P.
J. Angew. Chem., Int. Ed. 2016, 55, 1070-1074.
16. Kaur, G.; Kaushik, M.; Trehan, S. Tetrahedron Lett. 1997, 38,
2521-2524.
.
observed when less than 0.4 equivalents of HBF4 OEt2 were used.
While we propose that tetrafluoroborate acts as a primary
desylilating agent, the involvement of water in this process
cannot be ruled out.
17. Sanz, R.; Martinez, A.; Álvarez-Gutiérrez, J. M.; Rodríguez, F.
Eur. J. Org. Chem. 2006, 1383-1386.
18. Kadam, S. T.; Lee, H.; Kim, S. S. Appl. Organomet. Chem. 2010,
24, 67-70.
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20. Motokura, K.; Nakagiri, N.; Mizugaki, T.; Ebitani, K.; Kaneda, K.
J. Org. Chem. 2007, 72, 6006-6015.
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2013, 125, 3550-3553.
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3750-5752.
24. For selected references, see: (a) Olah, G. A.; Rochin, C. J. Org.
Chem. 1987, 52, 701-702; (b) Mayr, H.; Grimm, K. J. Org. Chem.
1992, 57, 1057-1059.
Supplementary Material
Experimental procedures and characterization data for
synthesized compounds.
Scheme 1. Proposed mechanism for the allylation of benzhydrols.
3. Conclusion
In conclusion, a general Brønsted acid-catalyzed allylation of
benzhydrols has been developed using sub-stoichiometric amount
of tetrafluoroboric acid. This protocol features excellent
functional group tolerance. In addition, the reaction is completed
within 5 minutes. We believe that this methodology will be of a
general interest due to the biological importance of benzhydrol
derivatives.
Acknowledgments
This work was supported by the Natural Sciences and
Engineering Research Council of Canada (NSERC).
References and notes
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(a) Das, B.; Reddy, C. R.; Kashanna, J.; Mamidyala, S. K.;
Kumar, C. G. Med. Chem. Res. 2012, 21, 3321-3325; (b) Deml,
K.-F.; Beermann, S.; Neumann, D.; Strasser, A.; Seifert, R. Mol.
Pharmacol. 2009, 76, 1019-1030.
2.
Chaskar, A.; Murugan, K. Catal. Sci. Technol. 2014, 4, 1852-
1868.

4
Tetrahedron
Highlights
A General Brønsted acid-catalyzed allylation of
benzhydryl alcohols.
Ifedi Orizu and Yuri Bolshan
 The developed methodology exhibits
excellent functional group tolerance.
 The reaction is done within 5 minutes.
 The developed protocol only requires 0.4
equivalents of HBF4.