P-directed borylation of phenols

Article abstract of DOI:10.1021/ol303203m

Internal borylation occurs upon activation of aryl di-isopropylphosphinite boranes with HNTf₂ to give heterocyclic intermediates that can be reductively quenched to afford 6 or treated with KHF₂ to give the phenolic potassium aryl trifluoroborate salts 10. The latter salts are useful for Pd-catalyzed coupling with aryl iodides under Molander conditions, provided that precautions are taken to remove the KNTf₂ byproduct from the preceding KHF₂ step.

Full text of DOI:10.1021/ol303203m

ORGANIC
LETTERS
2013
Vol. 15, No. 5
984–987
P‑Directed Borylation of Phenols
ꢀ
Clement Cazorla, Timothy S. De Vries, and Edwin Vedejs*
Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109,
United States
edved@umich.edu
Received November 20, 2012
ABSTRACT
Internal borylation occurs upon activation of aryl di-isopropylphosphinite boranes with HNTf2 to give heterocyclic intermediates that can be
reductively quenched to afford 6 or treated with KHF2 to give the phenolic potassium aryl trifluoroborate salts 10. The latter salts are useful for
Pd-catalyzed coupling with aryl iodides under Molander conditions, provided that precautions are taken to remove the KNTf2 byproduct from the
preceding KHF2 step.
Arylboron derivatives are valuable intermediates in
organic synthesis due to their important potential for
CꢀC bond formation.1 Simple arylboronic acid deriva-
tives are usually prepared by treating an arylmagnesium
or -lithium reagent with (RO)3B (R = Me, iPr)2 or by the
reaction ofelectrophilicboraneswithelectron-richarenes.3
In the case of the highly electrophilic BCl3, modified
FriedelꢀCrafts procedures are effective using aluminum
metal (Muetterties borylation)3b,c or a carefully selected
amine additive3d to scavenge the HCl byproduct and to
help generate reactive electrophilic intermediates in situ.
Recently, transition metal catalyzed borylation procedures
have also become important.4 These methods are sensitive
to steric effects or internal complexation effects and often
allow efficient borylation with complementary regioselec-
tivity compared to the electrophilic borylations.
been known, including interesting cases of nitrogen- or
oxygen-directed borylation.5,6 Surprisingly, examples of
this chemistry have been reported over a very broad range
of temperatures (ranging from 05f to 200 °C5a). We became
intrigued by this variation in borylation conditions and
suspected that the difference between facile and difficult
borylations may reflect differences in reagents and activation
procedures that influence the relative ease of borenium cation
formation.7 Accordingly, a program was initiated in our
laboratory to investigate heteroatom-directed borylation un-
der conditions expected to promote the generation of tethered
borenium cations as potential borylation intermediates.
We have already reported relevant N-directed borylations8
(5) N-Directed borylation:(a) Dewar, M. J. S.;Kubba, V. P.; Pettit, R.
€
J. Chem. Soc. 1958, 3073. (b) Koster, R.; Iwasaki, K.; Hattori, S.; Morita,
€
Y. Liebigs Ann. Chem. 1968, 720, 23. (c) Muller, B. W. Helv. Chim. Acta
Intramolecular adaptations of Muetterties borylation
directed by tethered heteroatom substituents have long
1978, 61, 325. Grassberger, M. A.; Turnowsky, F.; Hildebrandt, J.
J. Med. Chem. 1984, 27, 947. (d) Grassberger, M. A. Liebigs Ann. Chem.
1985, 683. (e) Boldyreva, O. G.; Dorokhov, V. A.; Mikhailov, B. M. Izv.
Akad. Nauk, Ser. Khim. 1985, 2, 428. (f) Allaoud, S.; Frange, B. Inorg.
Chem. 1985, 24, 2520. (g) Ganaev, A. M.; Nagy, S. M.; Salnikov, G. E.;
Shubin, V. G. Chem. Commun. 2000, 1587. (h) Ashton, P. R.; Harris,
K. D. M.; Kariuki, B. M.; Philp, D.; Robinson, J. M. A.; Spencer, N.
J. Chem. Soc., Perkin Trans. 2 2001, 2166. (i) Lee, G. T.; Prasad, K.;
(1) (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(b) Ishiyama, T.; Miyaura, N. Chem. Rec. 2004, 3, 271.
(2) (a) Khotinsky, E.; Melamed, M. Chem. Ber 1909, 42, 3090.
(b) Sharp, M. J.; Snieckus, V. Tetrahedron Lett. 1985, 49, 5997. (c) Snieckus,
V. Chem. Rev. 1990, 90, 879.
ꢁ
Repic, O. Tetrahedron Lett. 2002, 43, 3255. (j) Niu, L.; Yang, H.; Wang,
(3) (a) Hurd, D. T. J. Am. Chem. Soc. 1948, 70, 2053. (b) Muetterties,
E. L. J. Am. Chem. Soc. 1960, 82, 4163. (c) Muetterties, E. L.; Tebbe,
F. N. Inorg. Chem. 1968, 7, 2663. (d) Del Grosso, A.; Helm, M. D.;
Solomon, S. A.; Caras-Quintero, D.; Ingleson, M. J. Chem Commun.
2011, 47, 12459.
(4) (a) Review: Hartwig, J. F. Acc. Chem. Res. 2012, 45, 864. (b)
Chotana, G. A.; Rak, M. A.; Smith, M. R., III. J. Am. Chem. Soc. 2005,
127, 10539 and references therein. (c) Boebel, T. A.; Hartwig, J. F. J. Am.
Chem. Soc. 2008, 130, 7534. (d) For other leading references for transition-
metal-catalyzed borylation ortho to heteroatoms, see: Yamazaki, K.;
Kawamorita, S.; Ohmiya, H.; Sawamura, M. Org. Lett. 2010, 12, 3978.
Kawamorita, S.; Miyazaki, T.; Ohmiya, H.; Tomohiro, I.; Sawamura,
M. J. Am. Chem. Soc. 2011, 133, 19310. Xiao, B.; Li, Y.-M.; Liu, Z.-J.;
Yang, H.-Y.; Fu, Y. Chem. Commun. 2012, 48, 4854.
R.; Fu, H. Org. Lett. 2012, 14, 2618.
(6) Miscellaneous directed borylations: (a) Dewar, M. J. S.; Dietz, R.
J. Chem. Soc. 1960, 1344. (b) Dewar, M. J. S.; Kaneko, C.; Bhattacharjee,
M. K. J. Am. Chem. Soc. 1962, 84, 4884. (c) Davis, F. A.; Dewar, M. J. S.
J. Am. Chem. Soc. 1968, 90, 3511. (d) Maringgele, W.; Meller, A.;
Noltemeyer, M.; Sheldrick, G. M. Z. Anorg. Allg. Chem. 1986, 536, 24.
(e) Arcus, V. L.; Main, L.; Nicholson, B. K. J. Organomet. Chem. 1993,
460, 139. (f) Zhou, Q. J.; Worm, K.; Dolle, R. E. J. Org. Chem. 2004, 69,
5147.
(7) De Vries, T. S.; Prokofjevs, A.; Vedejs, E. Chem. Rev. 2012,
112, 4246.
(8) De Vries, T. S.; Prokofjevs, A.; Vedejs, E. J. Am. Chem. Soc. 2009,
131, 14679.
r
10.1021/ol303203m
Published on Web 03/01/2013
2013 American Chemical Society

and now describe key features of an analogous P-directed
borylation from phosphinite boranes. This approach al-
lows the net conversion of suitable phenols into ortho-
borylated products using the inexpensive THFꢀborane as
the boron source. The same net conversion has recently
been reported by Hartwig et al. using iridium catalysis and
bis-pinacolatodiboron as the boron source.4c
Scheme 1. Directed Borylation of Aryl Diisopropylphosphinites
Our initial experiments followed the N-directed boryla-
tion analogy8 but replaced the benzylic amine borane
substrates with the isosteric phosphinite boranes 2, readily
available from the corresponding phenols and commercial
ClP(iPr)2/Et3N via the precedented di-isopropyl arylpho-
sphinites 1.9 Without isolation, crude 1 were treated with
excess THFꢀBH3 to afford 2 in a one-pot procedure
(typically 78ꢀ95% overall after chromatography). For
the subsequent activation and intramolecular borylation,
the benzylamine analogy suggested that typical hydride
acceptors Eþ might generate transient borenium cations 3
or equivalent electrophilic species.7 Electrophilic cycliza-
tion might then give a transient intermediate 4, and loss of
hydrogen should afford the stabilized borenium cation 5.
Indeed, activation of the simplest example 2a using 90 mol
% of the trityl salt Ph3Cþ(C6F5)4Bꢀ in bromobenzene, the
conditions previously developed for generation of bore-
nium cation equivalents in our N-directed borylations,8
resulted in partial conversion of the substrate at rt accord-
ing to the 1H NMR assay of the aromatic region. However,
attempts to detect the presumed intermediate borenium
cation 3a or the hypothetical cationic product of electro-
philic borylation 5a were inconclusive. Attempted deriva-
limited to 90 mol %, and this procedure also gave a cleaner
product. Similar results were obtained in o-dichloroben-
zene, but the reaction was somewhat slower in toluene
(30ꢀ35% conversion after 24 h). After further optimiza-
tion, consistently good yields of the boryation product 6a
were obtained with 90 mol % of Tf2NH in fluorobenzene
using a thick-walled Schlenk tube at 140 °C (16 h),
followed by quenching with borohydride. When phosphi-
nite-borane 2a was reacted with 90 mol % of triflimide for
1 h at room temperature, the activated intermediate 8a was
observed according to the 11B signal at δ = ꢀ18.9 ppm in
C6D5Br (Scheme 1). Stirring this mixture for 16 h at 140 °C
led to the conversion of 8a into an intermediate assigned as
€
tization of the borylation products with pinacol/Hunig’s
base gave variable mixtures of the isolable neutral complex
6a as well as a second product that could not be purified.
The latter product was tentatively assigned as the expected
1
pinacol ester 7a based on H NMR data of the product
mixture, the recovery of small amounts of catechol after
exposure of crude 7a to air, and the formation of a deeply
colored insoluble byproduct from attempts to separate 7a
via extraction with aqueous base.10 These initial studies
encountered significant material losses apparently due to
partial decomposition of 6a as well as 7a, but subsequent
experiments demonstrated that 6a is quite stable when
prepared using an optimized borylation procedure.
Activation of 3 with other electrophiles gave no boryla-
tion products at rt. However, treatment with 60 mol % of
molecular iodine at 100 °C in bromobenzene for 24 h
followed by quenching with Bu4NBH4 returned sufficient
6a for NMR detection at ca. 5% conversion of 3. A similar
experiment with 1.1 equiv of TfOH as the activating
electrophile gave only traces of the borylation product 6a
after 24 h in bromobenzene at 100 °C, but Tf2NH under
the same conditions gave better conversion (50ꢀ60% by
NMR assay). A small improvement (to 60ꢀ70% con-
version) was observed when the amount of Tf2NH was
1
9a, 11B δ = ꢀ9.5 ppm. The H NMR spectrum showed
two new multiplets corresponding to the two diastereoto-
pic isopropyl methines at δ = 2.04 and 2.84 ppm (1:1
integral ratio) as expected for a structure containing a
stereogenic boron. In addition, the downfield shift of the
broad BꢀH proton signal at δ = 3.9 ppm relative to δ =
2.8 ppm for 8a supports the proposed structure of 9a. This
evidence is consistent with 8a acting as an equivalent (or a
source) of the transient borenium cation 3a which under-
goes electrophilic cyclization, but neither 3a nor related
borocations were detected.
Structure 6a is an example of a previously unknown hetero-
cycle family, but we were more interested in access to the related
trifluoroborate salt 10a due to its utility in palladium catalyzed
Suzuki coupling chemistry.11 Initial attempts to convert
6a to 10a using standard conditions (KHF2/MeOH)12 did
not give significant conversion after 16 h at 65 °C. On the
(9) Bedford, R. B.; Hazelwood, S. L.; Horton, P. N.; Hursthouse,
M. B. Dalton Trans. 2003, 4164.
(10) “Darkpolymericmaterial”formsuponexposureofo-hydroxyphenyl
trifluoroborate to basic aqueous conditions: Yuen, A. K. L.; Hutton, C. A.
Tetrahedron Lett. 2005, 46, 7899.
(11) Review: Molander, G. A.; Canturk, B. Angew. Chem., Int. Ed.
2009, 48, 9240.
(12) Vedejs, E.; Chapman, R. W.; Fields, S. C.; Lin, S.; Schrimpf,
M. R. J. Org. Chem. 1995, 60, 3020–3027.
Org. Lett., Vol. 15, No. 5, 2013
985

Table 1. Activation of Aryl Di-isopropylphosphinites
a Conditions: Aryl di-isopropylphosphinites (0.2 mmol), Tf2NH (0.18 mmol), PhF (1 mL), 140 °C, 16 h, sealed tube, quenched with n-Bu4NBH4.
b Isolated yields. c Conditions: Aryl di-isopropylphosphinites (0.5 mmol), Tf2NH (0.45 mmol), toluene (2 mL), 140 °C, 16 h, sealed tube, quenched with
KHF2. d Mixture of two regioisomers.
other hand, similar KHF2 treatment of the crude boryla-
tion product 9a without any reductive quenching resulted
in smooth conversion to 10a, identified by NMR
comparison with known material.10 The crude 10a ob-
tained after solvent removal contained KNTf2 according
to the 19F signal at δ = ꢀ79.8 ppm, but the contaminant
986
Org. Lett., Vol. 15, No. 5, 2013

could be removed by extracting 10a with hot acetone,
followed by crystallization from minimal methanol (Table
1, entry 1, 71% of 10a isolated).
Table 2. Suzuki Couplinga
The HNTf2 procedure was then applied to several other
derivatives 3(Table 1, entries 2ꢀ9). The borylation products
6 and 10 were usually obtained in yields of 50ꢀ75% for the
more electron-rich aryl substrates (entries 2ꢀ6). However,
no borylation was detected with electron-withdrawing
substituents (CO2Me, CN) attached to the aromatic ring.
Furthermore, regioselectivity was near 1:1 starting with
m-substituted substrates (entries 3, 8). Unexpectedly, the
KArBF3 salt 10c (entry 3) was isolated as a single regio-
isomer even though the corresponding 6c was obtained as a
mixture of isomers. This discrepancy results from the lower
solubility of 10c compared to the regioisomer (not shown)
and isolation by crystallization. We note that the most
valuable reagent in these experiments is the 90 mol % of
HNTf2 used for the activation step. Accordingly, the yields
in Table 1 are reported based on HNTf2 as limiting reagent.
Having established an O-directed borylation route to
phenolic trifluoroborate salts, we were interested in eval-
uating their suitability for palladium-catalyzed coupling
with iodobenzene as the test substrate. Using classical
conditions13 for this coupling, we encountered difficulties
and poor reactivity in early experiments. This problem
resulted from rate inhibition by KNTf2, a contaminant
that was present because 10 had been isolated without
crystallization. Supporting evidence was obtained by con-
ducting the reaction of 10b with iodobenzene using Pd-
(PPh3)4 as catalyst (K2CO3/toluene/EtOHꢀH2O, 80 °C)
in the presence of varying amounts of KNTf2. Thus, the
yield of coupled product 11 increased from <2% to 91%
when the amount of KNTf2 contaminant decreased from
100 mol % to <1 mol % (19F NMR assay). In view of
these results, all yields for coupling products 11 in Table 2
are reported using 10 that contains <1% of KNTf2.
The findings presented above demonstrate access to
ortho-borylated phenols from substrates containing donor
substituents. Although cationic intermediates 3 could not
be detected, the phosphorus-directed borylation probably
involves borenium equivalents as the active borylating
agents.7,8 In terms of cost for laboratory scale synthesis,
we believe that the method reported here for the prepara-
tion of potassium aryltrifluoroborates 10 derived from
simple, monofunctional phenols is competitive with re-
ported alternatives due to the low cost of the boron source
(THFꢀBH3). However, the conditions are relatively harsh
compared to the method of Hartwig et al.4c The latter
procedure is likely to perform better with polyfunctional
a Condition: Iodobenzene (1.5 equiv), Pd(PPh3)4 (5 mol %), toluene/
EtOH/H2O (3/1/1, 1.25 M), 80 °C, 16 h. b Isolated yields.
substrates and may also have advantages with meta-substi-
tuted phenols, judging from the two examples reported to date.
In terms of practicality from a broader perspective, we note
that several plausible alternatives to the corrosive and expen-
sive HNTf2 as the activating electrophile and “hydridophile”
remain to be explored. A catalytic variation of the current
method would also be a desirable goal for future work.14
Acknowledgment. This work was supported by the
National Institute of General Medicine (GM067146).
Supporting Information Available. Experimental pro-
cedures and characterization data. This material is
available free of charge via the Internet at at http://pubs.
acs.org.
(13) (a) Molander, G. A.; Biolatto, B. J. Org. Chem. 2003, 68, 4302.
(b) Molander, G. A.; Biolatto, B. Org. Lett. 2002, 11, 1867. (c) Ishikawa,
S.; Manabe, K. Chem. Commun. 2006, 2589. (d) Liu, J.; Fitzgerald, A. E.;
Mani, N. S. J. Org. Chem. 2008, 73, 2951. (e) Makino, T.; Yamasaki, R.;
Saito, S. Synthesis 2008, 6, 859.
(14) An attempt to perform a catalytic reaction with 10 mol % of
Tf2NH gave <10% conversion to 6a after 16 h at 140 °C.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 5, 2013
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