Cross-coupling of mesylated phenol derivatives with potassium alkoxymethyltrifluoroborates

Article abstract of DOI:10.1021/ol201469r

Cross-coupling of mesylated phenol derivatives with various potassium alkoxymethyltrifluoroborates has been achieved. The corresponding aryl and heteroaryl alkoxymethyl compounds have been obtained with equal facility with both electron-rich and electron-poor substituents on the activated alcohol.

Full text of DOI:10.1021/ol201469r

ORGANIC
LETTERS
2011
Vol. 13, No. 15
3948–3951
Cross-Coupling of Mesylated Phenol
Derivatives with Potassium
Alkoxymethyltrifluoroborates
Gary A. Molander* and Floriane Beaumard
Roy and Diana A. Vagelos Laboratories, Department of Chemistry, University of
Pennsylvania, Philadelphia, Pennsylvania 19104-6323, United States
gmolandr@sas.upenn.edu
Received May 31, 2011
ABSTRACT
Cross-coupling of mesylated phenol derivatives with various potassium alkoxymethyltrifluoroborates has been achieved. The corresponding aryl
and heteroaryl alkoxymethyl compounds have been obtained with equal facility with both electron-rich and electron-poor substituents on the
activated alcohol.
Ethers are encountered in a large variety of natural
products including lipids, oxiranes, terpenoıds, and carbo-
hydrate derivatives.1 They are known to be of interest in
the pharmaceutical, agrochemical, and other industrial
sectors. As an example, the quinolylmethoxyphenyl group
is recognized as a pharmacophore in leukotriene inhibitors
(Figure 1).2 Ethers are also important in organic synthesis
as protecting groups for alcohols.3
Figure 1. Leukotriene biosynthesis inhibitors.
Cross-coupling reactions of alkoxymethylmetallic spe-
cies, embodying a dissonant reactivity pattern, would rep-
resent one of the more straightforward approaches for the
associated with their purification.5 Recently, more envi-
ronmentally sound alkoxymethylboron species have been
employed in the SuzukiÀMiyaura reaction to afford the
same scaffolds. For example, methoxymethylboronic acid
has been used in large excess (2.3 equiv) in the presence of
chloro-1,8-naphthyridine to obtain the corresponding
cross-coupled compound with a moderate yield of 45%.6
Prior to that report, our laboratory had efficiently synthe-
sized and cross-coupled air- and moisture-stable potas-
sium alkoxymethyltrifluoroborates with aryl halides in
synthesis of these alkyl ether compounds. Unfortunately,
thisapproach is somewhat restrictedowing tothe dearth of
readily available reagents and because Csp2ÀCsp3 cross-
couplings are known to be quite challenging.4
Alkoxymethylstannanes were first reported as nucleo-
philic partners in the Stille reaction, but their use was
limited because of their inherent toxicity and difficulties
(1) Dominguez de Maria, P.; Van Gemert, R. W.; Straathof, A. J. J.;
Hanefeld, U. Nat. Prod. Rep. 2010, 27, 370–392.
(2) Kolasa, T.; Gunn, D. E.; Bhatia, P.; Woods, K. W.; Gane, T.;
Stewart, A. O.; Bouska, J. B.; Harris, R. R.; Hulkower, K. I.; Malo,
P. E.; Bell, R. L.; Carter, G. W.; Brooks, C. D. W. J. Med. Chem. 2000,
43, 690–705.
(3) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis; John Wiley: New York, 1999.
(4) (a) Jana, R.; Pathak, T. P.; Sigman, M. S. Chem. Rev. 2011, 111,
1417–1492. (b) Doucet, H. Eur. J. Org. Chem. 2008, 12, 2013–2030. (c)
Mitchell, T. A.; Bode, J. W. J. Am. Chem. Soc. 2009, 131, 18057–18059.
(5) (a) Kosugi, M.; Sumiya, T.; Ohhashi, K.; Sano, H.; Migita, T.
Chem. Lett. 1985, 997–998. (b) Majeed, A. J.; Antonsen, O.; Benneche,
T.; Undheim, K. Tetrahedron 1989, 45, 993–1006. (c) Ferezou, J. P.;
Julia, M.; Yun, L.; Liu, L. W.; Pancrazi, A. Synlett 1991, 53–56.
(6) Salmon, R.; Mitchell, G.; Morris, J. A. 2009, WO091115788.
(7) (a) Molander, G. A.; Canturk, B. Org. Lett. 2008, 10, 2135–2138.
(b) Molander, G. A.; Sandrock, D. L. J. Am. Chem. Soc. 2008, 130,
15792–15793.
r
10.1021/ol201469r
Published on Web 07/06/2011
2011 American Chemical Society

Table 1. Optimization of the Conditions
entry
[Pd]
ligand
conversionb yield (%)b
1a
2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2(dppe)
Cy3PHBF4
t-Bu3PHBF4
XPhos I
23%
76%
43%
47%
37%
39%
17%
23%
21%
18%
100%
5%
À
À
3
À
4a
5a
6a
7
RuPhos II
SPhos III
DPEPhos IV
Q-Phos V
(S)-TolBinap VI
dppm
À
À
À
À
8
À
9
<5
10
11
12
13
dppb
<5
dippf VII
À
61
À
PdCl2(COD) dippf
100%
75 (71)c
Figure 2. Ligands (IÀVII) and palladium dimer precatalyst VIII.
a Time = 1 h. b Relative GC yield using dodecane as the internal
standard. c Isolated yield.
has been reported in cross-coupling reactions with any
alkoxymethylmetallic species. Among all the sulfonated
activating groups available, we focused our work on the
methanesulfonyl (mesyl) counterpart, which has the ad-
vantages of being stable, inexpensive, atom-economical,
and easy to handle, even though it is known to be among
the least reactive of these nucleofugal species.9i,k,m,n,p We
disclose herein the first system for the Csp2ÀCsp3 Suzu-
kiÀMiyaura cross-coupling of aryl and heteroaryl mesy-
lates with various potassium alkoxymethyltrifluoroborates.
Previous reports from our laboratory underscore the
fact that the use of potassium trifluoroborates in the cross-
coupling of CÀO bonded species is facilitated by employ-
ing potassium phosphate as a base in a mixture of t-BuOH/
H2O (1/1).9i,p Keeping these observations in mind, we
screened different palladium and ligand sources with mes-
ylated naphthalene 1 and potassium methoxymethyltri-
fluoroborate2a, apartnerknowntobe difficult,10 asmodel
substrates (Table 1). Various alkyl or biaryl (Figure 2)
monodentate phosphines (including Buchwald ligands)
have been tested without success. RuPhos (II), which was
the best ligand when halides were used as electrophilic
partners,7a does not afford the desired compound 3a
(Table 1, entry 4). After extensive screening, only one
(bidentate) ferrocenic ligand, dippf (VII), led to the
formation of 3a with a 61% GC yield (Table 1, entry
11). Different palladium sources were also tested, and
PdCl2(COD) appeared to be the best catalyst precur-
sor, with 3a obtained with complete conversion and
71% isolated yield after 4 h (Table 1, entry 13).
highyields.7 That study was restrictedtothe use of aryl and
heteroaryl chlorides and bromides but afforded the desired
target structures in moderate to good yields without em-
ploying a large excess of the organoboron reagent.7a
Tanaka extended the scope of the reaction to an intramo-
lecular SuzukiÀMiyaura cross-coupling with sodium al-
koxymethylaryltrifluoroborates bearing an attendant chlo-
ride.8 However, this method, carried out on a very small
scale (0.10 mmol), suffered from a lack of generality, with
yields ranging from 4 to 71%.
All of these previous reports employed halides as elec-
trophilic partners, but to develop more environmentally
sound processes, more attention is currently given to
electrophilic alcohol derivatives.9 To our knowledge, no
example employing these activating electrophilic partners
(8) Tanaka, K.; Murai, N.; Shirotori, S.; Nagao, S.; Watanabe, Y.
2008, WO08032702.
(9) For recent examples using activated alcohols as electrophilic
partners: (a) Quasdorf, K. W.; Tian, X.; Garg, N. K. J. Am. Chem.
Soc. 2008, 130, 14422–14423. (b) Li, Z.; Zhang, S. L.; Fu, Y.; Guo, Q. X.;
Liu, L. J. Am. Chem. Soc. 2009, 131, 8815–8823. (c) Guan, B. T.; Wang,
Y.; Li, B. J.; Yu, D. G.; Shi, Z. J. J. Am. Chem. Soc. 2008, 130, 14468–
14470. (d) Quasdorf, K. W.; Riener, M.; Petrova, K. V.; Garg, N. K.
J. Am. Chem. Soc. 2009, 131, 17748–17749. (e) Antoft-Finch, A.;
Blackburn, T.; Snieckus, V. J. Am. Chem. Soc. 2009, 131, 17750–
17752. (f) Xu, L.; Li, B. J.; Wu, Z. H.; Lu, X. Y.; Guan, B. T.; Wang,
B. Q.; Zhao, K. Q.; Shi, Z. J. Org. Lett. 2010, 12, 884–887. (g) Tobisu,
M.; Shimasaki, T.; Chatani, N. Angew. Chem., Int. Ed. 2008, 47, 4866–
4869. (h) Lipshutz, B. H.; Butler, T.; Swift, E. Org. Lett. 2008, 10, 697–
700. (i) Molander, G. A.; Beaumard, F. Org. Lett. 2010, 12, 4022–4025.
(j) Rosen, B. M.; Quasdorf, K. W.; Wilson, D. A.; Zhang, N.; Resmerita,
A.-M.; Garg, N. K.; Percec, V. Chem. Rev. 2011, 3, 1346–1416. (k) So,
C. M.; Lau, C. P.; Kwong, F. Y. Angew. Chem., Int. Ed. 2008, 47, 8059–
8063. (l) So, C. M.; Lau, C. P.; Chan, A. S. C.; Kwong, F. Y. J. Org.
Chem. 2008, 73, 7731–7734. (m) Bhayana, B.; Fors, B. P.; Buchwald,
S. L. Org. Lett. 2009, 11, 3954–3957. (n) Chow, W. K.; So, C. M.; Lau,
C. P.; Kwong, F. Y. J. Org. Chem. 2010, 75, 5109–5112. (o) Kuroda, J. I.;
Inamoto, K.; Hiroya, K.; Doi, T. Eur. J. Org. Chem. 2009, 2251–2261.
(p) Molander, G. A.; Beaumard, F. Org. Lett. 2011, 13, 1242–1245.
We then investigated the scope of this reaction by varying
the nature of the potassium alkoxymethyltrifluoroborates
(10) The SuzukiÀMiyaura cross-couplings between 4-chorobenzoni-
trile or 4-chloroanisole and 2a resulted in low yields of 34% and 41%,
respectively.
Org. Lett., Vol. 13, No. 15, 2011
3949

2 in the presence of the mesylated naphthalene 1 (Table 2).
All these nucleophiles 2 have first been prepared starting
from the potassium chloromethyltrifluoroborate, instead
of its corresponding bromo counterpart as earlier
reported,7a to avoid any KBr salt contamination.9p,11 It
is important to note that, among them, some of the
potassium alkoxymethyltrifluoroborates (2b, 2c, 2f, and
2i) bear alcohol protecting groups (Table 2, entries 2, 3, 6
and 9) known to be stable under SuzukiÀMiyaurareaction
conditions but which can be easily removed to generate the
corresponding hydroxymethyl group.
under the reaction conditions. Of particular note, potassium
phenyloxymethyltrifluoroborate does not react well in the
cross-coupling, as a complex mixture of compounds was
formed in the reaction with naphthyl mesylate (1).
The introduction of the menthyl group (Table 2, entry 8)
required the use of 5 mol % of catalyst for the reaction to
go to completion and afforded 3h with 65% yield. By
switching the palladium source from PdCl2(COD) to a
palladium dimer precatalyst VIII developed by Buchwald
(Figure 2) and reducing the amount of base to 4 equiv, we
were able to increase the yield of 3h to 72%.12 This air-stable
precatalyst is known to form the catalytically active species
by cleavage of the dimer in favor of the ligand insertion
under conditions where protodeboronation is slowed.13
We next pursued an examination of electron-rich and -
poor aryl mesylates as electrophilic partners (Table 3).
Encouraged by the previous result withthe menthyl species
We applied the previously optimized conditions (Table 1,
entry 13) to a broad spectrum of potassium alkoxymethyl-
trifluoroborates 2 (Table 2).
Table 2. Scope of Potassium Alkoxymethyltrifluoroborates
Table 3. Scope of Functionalized Aryl Mesylates
a 5 mol % PdCl2(COD), 10 mol % dippf, 110 °C, 4 h. b Reaction run
on a 4 mmol scale using 2 mol % of PdCl2(COD) and 4 mol % of dippf.
c 5 mol % palladium precatalyst VIII, 10 mol % dippf, 4 equiv of K3PO4,
110 °C, 4 h.
The cross-coupling reaction is very tolerant of both
acyclic and cyclic substituents on the alkoxymethyl coun-
terpart: the desired compounds 3aÀi were obtained with
yields ranging from 71% to 91%. The catalyst loading
could be reduced significantly by scaling the reaction
(Table 2, entry 2). Moreover, even on a small scale the
catalyst and ligand loadings can be reduced to 3 and 6 mol %,
respectively, for almost all the substrates by increasing the
reaction time to 20 h. The potassium methoxymethyltrifluor-
oborate 2a does not follow this trend, affording a lower yield
of desired compound 3a, perhaps because of decomposition
(11) (a) Raushel, J.; Sandrock, D. L.; Josyula, K. V.; Pakyz, V.;
Molander, G. A. J. Org. Chem. 2011, 8, 2762–2769. (b) Molander, G. A.;
Colombel, V.; Braz, V. A. Org. Lett. 2011, 7, 1852–1855.
3950
Org. Lett., Vol. 13, No. 15, 2011

(Table 2, entry 8), we tested the two optimized conditions
[PdCl2(COD) versus palladium precatalyst VIII with 7.2
or4 equiv of K3PO4, respectively], and it has been observed
thatalmostall the yieldsincreased by 10À15% byusing the
latter set of conditions. The reaction seems to proceed well
without being influenced by the electronic density on the
aryl ring, and the desired compounds 4aÀj can be obtained
with yields up to 92%. Moreover, the reaction is compa-
tible with a large variety of substituents such as ethers
(4bÀd), ketones (4fÀh), and trifluoromethyl (4i) and nitrile
(4j) groups (Table 3, entries 2À4, 6À10). It has also been
noticed that purifying the compounds under basic alumina
instead of silica gel increases almost all the yields by 10%
(Table 3, entries 1, 3, 5À8, 10).
been demonstrated that cross-couplings of heteroaryl halides
with potassium alkoxymethyltrifluoroborates remains very
challenging because of their lack of reactivity.7a Using the
least reactive electrophilic species, we were pleased to be able
to couple several heteroaryl mesylates with moderate to
good yields. Mesylated quinoline, dibenzothiophene, and
isoquinoline provided the alkoxymethyl compounds 5a, d,
e with yields ranging from 57% to 81% (Table 4, entries 1,
4, and 5). To favor the completion of the reaction for the
dibenzofuran and the benzothiazole, 5 mol % of precata-
lyst were used to afford 5b and 5c with 69% and 46%
yields, respectively (Table 4, entries 2 and 3).
In summary, we have developed an efficient method that
enables the cross-coupling of various potassium alkoxy-
methyltrifluoroborates with mesylated partners through
CÀO activation in very high yields. When desired, hydro-
xymethyl compounds should be easily accessed by following
this procedure utilizing alkoxymethyl derviatives that are
easily cleaved to the corresponding alcohol. A large array of
functionalized aryl electrophilic partners has been success-
fully engaged in the cross-coupling to obtain the desired
compounds with good yields. Moreover, several heteroaryl
mesylates have also proven to be suitable electrophilic
partners in this reaction even though the scope of the reac-
tion is more limited. This method represents a complementary
way to generate an alkoxymethyl linkage, which is known to
be encountered in compounds of biological interest.
We further extended the scope of the reaction to more
difficult heteroaryl mesylate partners (Table 4). It has already
Table 4. Scope of Heteroaryl Mesylates
Acknowledgment. This research was supported by a
National Priorities Research Program (NPRP) grant from
the Qatar National Research Fund (Grant No. 08-035-1-
008) and the NIGMS (R01 GM-081376). We acknowledge
Dr. Matthew Tudge (Merck Research Laboratories) for a
donation of biphenyl palladium dimer VIII and Johnson
Matthey for its donation of PdCl2(COD). Dr. Rakesh
Kohli (University of Pennsylvania) is acknowledged for
obtaining HRMS data. Dr. Virginie Colombel and Dr. Valerie
Braz (University of Pennsylvania) are acknowledged for
making some potassium alkoxymethyltrifluoroborates.
Supporting Information Available. Experimental pro-
cedures and spectral data. This material is available free
of charge via the Internet at http://pubs.acs.org.
(12) Pd(0) species such as Pd2dba3 were inefficent in this reaction.
(13) Kinzel, T.; Zhang, Y.; Buchwald, S. L. J. Am. Chem. Soc. 2010,
132, 14073–14075.
a 5 mol % palladium precatalyst VIII, 10 mol % dippf.
Org. Lett., Vol. 13, No. 15, 2011
3951