Sterically controlled iodination of arenes via iridium-catalyzed C-H borylation

Article abstract of DOI:10.1021/ol303164h

A mild method to prepare aryl and heteroaryl iodides by sequential C-H borylation and iodination is reported. The regioselectivity of this process is controlled by steric effects on the C-H borylation step and is complementary to existing methods to form aryl iodides. The iodination of boronic esters has potential for the synthesis of radiolabeled aryl iodides, as demonstrated by the concise synthesis of a potential tracer for SPECT imaging.

Full text of DOI:10.1021/ol303164h

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Sterically Controlled Iodination of Arenes
via Iridium-Catalyzed CꢀH Borylation
Benjamin M. Partridge and John F. Hartwig*
Department of Chemistry, University of California, Berkeley, California 94720,
United States
jhartwig@berkeley.edu
Received November 16, 2012
ABSTRACT
A mild method to prepare aryl and heteroaryl iodides by sequential CꢀH borylation and iodination is reported. The regioselectivity of this process
is controlled by steric effects on the CꢀH borylation step and is complementary to existing methods to form aryl iodides. The iodination of boronic
esters has potential for the synthesis of radiolabeled aryl iodides, as demonstrated by the concise synthesis of a potential tracer for SPECT
imaging.
Aryl iodides are common intermediates in organic
synthesis. The ease by which they undergo oxidative addi-
tion makes them valuable precursors to aryl organome-
tallic reagents1 and the aryl halide of choice for many
transition metal-catalyzed processes.2 Furthermore, the
decay of the radioisotopes of iodine has allowed aryl
iodides to be used as imaging agents for Positron Emission
Tomography (PET) and Single Photon Emission Com-
puted Tomography (SPECT).3 Compounds containing
131I also have been used to treat tumors.4
recently, the aromatic Finkelstein reaction, developed by
Buchwald and co-workers, has allowed the interconver-
sion of aryl bromides to the corresponding iodide.7
Scheme 1. Traditional Methods to Synthesize Aryl Iodides
Despite their utility, aryl iodides are more expensive, and
fewer aryl iodides are commercially available than aryl
bromides and aryl chlorides. Traditional methods to form
aryl iodides include direct iodination,5 which requires
oxidizing conditions, and the Sandmeyer reaction, which
requires the generation of a diazonium salt (Scheme 1).6
Such methods are either intolerant of functional groups or
involve multistep sequences to reach the aryl iodide. More
In all of these reactions, the position of the iodine in the
product is determined by the electronic properties of the
arene (from nitration in the case of the Sandmeyer reaction
or bromination in the case of the aromatic Finkelstein
reaction). In contrast to these reactions, directed CꢀH iodi-
nation catalyzed by palladium8a,b and rhodium complexes8c
(1) Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F. F.; Kopp,
F.; Korn, T.; Sapountzis, I.; Vu, V. A. Angew. Chem., Int. Ed. 2003,
42, 4302.
(2) Hartwig, J. F. Organotransition Metal Chemistry; University
Science Books: Sausalito, CA, 2010; (b) Sheppard, T. D. Org. Biomol.
Chem. 2009, 7, 1043.
(3) Pimlott, S. L.; Sutherland, A. Chem. Soc. Rev. 2011, 40, 149.
(4) Goldsby, R. E.; Fitzgerald, P. A. Nucl. Med. Biol. 2008, 35, S49.
(5) (a) Stavber, S.; Jereb, M.; Zupan, M. Synthesis 2008, 2008, 1487.
(b) Hanson, J. R. J. Chem. Res. 2006, 2006, 277.
(7) (a) Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124,
14844. (b) Vigalok, A.; Kaspi, A. W. Top. Organomet. Chem. 2010,
31, 19.
(8) (a) Mei, T.-S.; Giri, R.; Maugel, N.; Yu, J.-Q. Angew. Chem., Int.
Ed. 2008, 47, 5215. (b) Kalyani, D.; Dick, A. R.; Anani, W. Q.; Sanford,
M. S. Org. Lett. 2006, 8, 2523. (c) Schroeder, N.; Wencel-Delord, J.;
Glorius, F. J. Am. Chem. Soc. 2012, 134, 8298.
(6) Hodgson, H. H. Chem. Rev. 1947, 40, 251.
r
10.1021/ol303164h
XXXX American Chemical Society

reported recently occur ortho to the directing group. Here-
in, we report a mild copper-catalyzed iodination of aryl
pinacol boronic esters. By combining this process with the
iridium-catalyzed CꢀH borylation of arenes9 the iodina-
tion of arenes occurs with selectivity based on steric effects,
rather than electronic or directing effects.
Table 1. Effect of Reaction Conditions on the Yield of the
Iodination of a Model Aryl Pinacol Boronate Ester
Previously, we reported the combination of borylation
and bromination, and the combination of borylation and
chlorination, by the conversion of arylboronic esters to
aryl halides with stoichiometric amounts of CuBr2 and
CuCl2 respectively.10 However, thecorresponding reaction
with CuI did not lead to iodination. Although the iodode-
boronation of arylboronic acids,11aꢀd trifluoroborate
salts11e,f and borates11g has been reported, the conversion
of aryl pinacol boronic esters to aryl iodides has not;12 the
iodination of pinacolboronate esters is needed for the
conversion of arenes to aryl iodides via CꢀH borylation.
Thus, we sought conditions for the conversion of pinacol-
substituted arylboronates to aryl iodides. The effects of
ligand, solvent, reaction time, and temperature on the con-
version of the arylboronate ester and the yield of iodoarene
are summarized in Table 1. The reaction of p-methoxyphenyl
pinacol boronate ester (1) with CuI and a substoichiometric
amount of phenanthroline in air led to 4-iodoanisole (2)
in good yield (Table 1). By adding KI as the iodide source,
the reaction occurred with a substoichiometric amount of
CuI. In contrast, iodide 2 was not formed when elemental
iodine was used in place of KI. CuBr and CuCl also
catalyzed the reaction, but the product was contaminated
in these cases with the corresponding aryl bromide and aryl
chloride. The reactions conducted with other bidentate
nitrogen ligands occurred to lower conversions, and increas-
ing the reaction temperature above 100 °C led to catalyst
decomposition and competing protodeboronation.
time
(h)
conversion
(%)
yielda
(%)
ligand
phen
solvent
DMF
1b
2c
3
39
47
23
23
23
23
39
1
100
84
58
36
51
0
phen
phen
bpy
DMF
DMF
88
4
DMF
<5
5
dtbpy
Me4phen
phen
phen
DMF
25
<5
8
6
DMF
30
7d
8
DMF
100
100
50
63
(62)
27
MeOH/H2O
(4:1)
9
phen
phen
MeOH/H2O
(1:1)
1
9
100
100
10e
MeOH/H2O
(4:1)
57
a Corrected GC yield using 1,3,5-trimethoxybenzene as an internal
standard (0.10 mmol scale); isolated yield in parentheses (1.25 mmol
scale). b 1.5 equiv of CuI (without KI). c 0.1 equiv of phen. d 100 °C.
e 50 °C. pin = pinacol; phen = 1,10-phenanthroline; bpy = 2,20-
bipyridine; dtbpy = 4,40-di-tert-butyl-2,20-dipyridyl; Me4phen =
3,4,7,8-tetramethyl-1,10-phenanthroline.
concentrations of water. Thus, a compromise was struck
between rate of reaction and extent of protodeboronation.
Reaction of the arylboronate ester in a 4:1 mixture of methanol
and water at 80 °C gave iodide 2 in a promising 63% yield
within 1 h. The reaction of the arylboronate ester at 50 °C
formed iodide 2 in comparable yield after 9 h.
We hypothesized that transmetalation of the boronic
esterwas the rate-determining stepinthe catalytic cycle. To
increase the rate of transmetalation, we investigated reac-
tions in protic solvents.13 Although the reactions in methanol
occurred faster than those in DMF, the reactions in mixtures
of methanol and water occurred much faster than those in
one solvent, and complete conversion of the boronic ester
occurred within 1 h.
The conditions in entry 8 of Table 1 were successfully
combined with the iridium-catalyzed CꢀH borylation to form
aryl iodides from arenes with steric control. After the boryla-
tion step, the volatile materials were evaporated in vacuo
before addition of the reagents and solvent for the iodination
reaction. No further purification of the intermediate boronate
ester was required prior to iodination. The presence of the
iridium catalyst and HBpin byproduct from the borylation
reaction did not affect the yield of the iodination reaction.
A variety of aryl iodides were synthesized by the two-
step, one-pot process in good to excellent yields (Scheme 2).
The iodination reaction was found to tolerate a range of
functional groups, including tertiary amines, esters, amides
and nitriles. Substrates containing ketones underwent iodi-
nation; however, some oxidation of the ketone to the cor-
responding ester was also observed when 3-bromoproprio-
phenone was used as the substrate.14 Most striking, the
reactions of arylboronates containing an aryl bromide, chlo-
ride and fluoride were all tolerated without any halide ex-
change. Electron-deficient substrates underwent iodination
in higher yield than electron rich arenes, although this
Anisole, formed by protodeboronation of 1, was the
only side product observed. This side product was formed
in greater amounts at higher temperatures and higher
(9) Mkhalid, I. A. I.; Barnard, J. H.; Marder, T. B.; Murphy, J. M.;
Hartwig, J. F. Chem. Rev. 2010, 110, 890.
(10) Murphy, J. M.; Liao, X.; Hartwig, J. F. J. Am. Chem. Soc. 2007,
129, 15434.
(11) (a) Kabalka, G. W.; Sastry, K. A. R.; Sastry, U.; Somayaji, V.
Org. Prep. Proced. Int. 1982, 14, 359. (b) Zhang, G.; Lv, G.; Li, L.; Chen,
F.; Cheng, J. Tetrahedron Lett. 2011, 52, 1993. (c) Yang, H.; Li, Y.;
Jiang, M.; Wang, J.; Fu, H. Chem.;Eur. J. 2011, 17, 5652. (d) Thiebes,
C.; Prakash, G. K. S.; Petasis, N. A.; Olah, G. A. Synlett 1998, 1998, 141.
(e) Kabalka, G. W.; Mereddy, A. R. Nucl. Med. Biol. 2004, 31, 935.
(f) Yong, L.; Yao, M.-L.; Kelly, H.; Green, J. F.; Kabalka, G. W.
J. Labelled Compd. Radiopharm. 2011, 54, 173. (g) Akula, M. R.; Yao,
M.-L.; Kabalka, G. W. Tetrahedron Lett. 2010, 51, 1170.
(12) The iodination of neopentyl glycol boronic esters has been
reported: Kabalka, G. W.; Akula, M. R.; Zhang, J. Nucl. Med. Biol.
2002, 29, 841 However, these cannot be prepared by C-H borylation.
(13) Use of KOtBu to enhance transmetalation led to competing
formation of the homodimer of the boronic ester.
(14) Also, during the iodination of 6-fluorotetralone, competing
aromatization to the corresponding naphthol was observed.
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 2. Scope of the Combination of CꢀH Borylation and Iodination of the Arylboronate Estera
b
c
a Isolated yield (1.25 mmol scale). Iodination for 3 h at 80 °C. B2pin2 as limiting reagent (2 equiv of arene); yield based on 2 atoms of boron
incorporated. d Contains ∼3% diiodide by 1H NMR. e 1 mol % [Ir(cod)(OMe)]2, 2 mol % dtbpy. cod = 1,5-cyclooctadiene.
higher yield resulted, in part, from the higher yield of the
CꢀH borylation step. The only observed side product was
Scheme 3. Scope of CꢀH BorylationꢀIodination of
the starting arene, resulting from protodeboronation of the
intermediate boronic ester.
Heteroarenesa
In all examples, the product was obtained as a single
constitutional isomer with selectivity arising from the
sterically controlled CꢀH borylation reaction. The iodide
was formed at the least sterically hindered position, re-
gardless of the electronic properties of the arene. Most
important, this selectivity is complementary to that of
existing methods for generating aryl iodides. Reactions
with 1,4-substituted arenes preferentially formed the pro-
duct containing an iodide ortho to the less bulky group. A
single isomer was obtained when the smaller group of the
1,4-arene was either fluoride or chloride.
The combined reaction was also suitable for the iodina-
a Isolated yield (1.25 mmol scale). b [Ir(cod)OMe]2 (0.1 mol %), dtbpy
tion of a range of heteroarenes (Scheme 3), although in
slightlyloweryield thantheiodination ofarenes. Thelower
yields, as compared to the yields for the iodination of arenes,
can be attributed to a more facile protodeboronation of the
intermediate boronic esters. Indoles underwent the proto-
deborylation particularly rapidly. Bicyclic heteroarenes were
iodinated exclusively on the ring containing the heteroatom,
with the borylation step occurring at the 2-position of
benzofuran and indole and the 3-position of the quinoline.15
However, substitution at the 2-position of indole allowed
selective iodination at the 7-position with the nitrogen
directing the borylation.16 In addition, pyrroles were selec-
tively iodinated at the 2-position in the absence of a group on
nitrogen or at the 3-position when the pyrrole contained a
sterically demanding TIPS group at nitrogen.15
(0.2 mol %), B2pin2 (0.75 equiv), THF, 80 °C, 24 h. c CuI (10 mol %),
d
phen (20 mol %), KI (1 equiv), MeOH/H2O, 80 °C, 1 h. B2pin2 as
limiting reagent using 4 equiv of heteroarene. e Yield based on 2 atoms of
boron incorporated from B2pin2. f 2 mol % [Ir(cod)(OMe)]2, 4 mol %
dtbpy. TIPS = triisopropylsilyl.
The combination of high functional-group tolerance
and short reaction time makes this method suitable for
late-stage incorporation of radiolabeled iodide for the
synthesis of imaging agents and anticancer agents.17 In
addition, the ability to carry pinacol boronate esters intact
though many synthetic sequences makes it an excellent
handle for late stage functionalization.18
With iodide as the limiting reagent, and only a small
excess of boronic ester, a range of boronic esters were suc-
cessfully iodinated in good to excellent yield (Scheme 4).
(15) (a) Takagi, J.; Sato, K.; Hartwig, J. F.; Ishiyama, T.; Miyaura,
N. Tetrahedron Lett. 2002, 43, 5649. (b) Tajuddin, H.; Harrisson, P.;
Bitterlich, B.; Collings, J. C.; Sim, N.; Batsanov, A. S.; Cheung, M. S.;
Kawamorita, S.; Maxwell, A. C.; Shukla, L.; Morris, J.; Lin, Z.; Marder,
T. B.; Steel, P. G. Chem. Sci. 2012, 3, 3505.
(16) Paul, S.; Chotana, G. A.; Holmes, D.; Reichle, R. C.; Maleczka,
R. E.; Smith, M. R. J. Am. Chem. Soc. 2006, 128, 15552.
(17) (a) Kabalka, G. W.; Varma, R. S. Tetrahedron 1989, 45, 6601. (b)
Gildersleeve, D. L.; Van Dort, M. E.; Johnson, J. W.; Sherman, P. S.;
Wieland, D. M. Nucl. Med. Biol. 1996, 23, 23. (c) Ceusters, M.; Tourwe,
D.; Callaerts, J.; Mertens, J.; Peter, A. J. Org. Chem. 1995, 60, 8324.
(18) Matteson, D. S. J. Organomet. Chem. 1999, 581, 51.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 4. Iodination of Arenes with Limiting Iodidea
Scheme 5. Synthesis of Potential SPECT Imaging Agent 11a
a Isolatedyield (1.25 mmol scale). b NMR yield using 1,3,5-trimethoxy-
benzene as an internal standard. c 0.1 mmol scale. d 48 h at 80 °C, 18%
boronic ester remaining.
Additional functional groups that were found to be tolerated
by the iodination reaction (with limiting iodide) included
alcohol, alkene and nitro groups, as well as an aldehyde in
the ortho position. A benzoic acid substrate was tolerated,
but the rate of the reaction was much slower; only 80%
conversion of the boronic ester occurred after 48 h. This
slow rate is presumably due to displacement of phenanthro-
line by the carboxylic acid on copper, forming a less active
catalyst. Alkenylboronic esters were also successfully iodi-
nated, but in lower yield. The reaction also occurred with
Cu2O, instead of CuI, as the source of the copper catalyst, in
comparable yield. This change in catalyst would allow >99%
radiochemical purity to be obtained with Na*I used in place of
KI. Although we did not explore reactions with NaI exten-
sively, initial studies on the reactions of Table 1 with NaI
in place of KI gave the iodoarene in comparable yield.
The iodination method was applied to the concise
synthesis of SPECT Imaging Agent 11 (Scheme 5). This
compound, when enriched with 125I, has been reported to
have potential to act as a SPECT tracer for the identifica-
tion of amyloid beta plaques.19 The boronic ester moiety
was introduced through amide coupling of amine 8 and
carboxylic acid 9. The key iodination step proceeded to
give iodide 11 in 66% yield, with iodide as the limiting
reagent. By using limiting Na125I in the final step of this
reaction, we anticipate that enriched 11 could be prepared
in high radiochemical purity without the need to carry a
a dba = dibenzylideneacetone, TFA = trifluoroacetic acid, HBTU =
O-(benzotriazol-1-yl)-N,N,N0,N0-tetramethyluronium hexafluorophosphate,
9 = 3-carboxyphenylboronic acid pinacol ester.
radioactive isotope through more than one step of a
synthesis.
In conclusion, we report a mild method to prepare aryl
and heteroaryl iodides through a telescoped combination
of CꢀH borylation and iodination of the arylboronate
ester. The sterically controlled regioselectivity, due to the
CꢀH borylation step, is complementary to the regioselec-
tivity of existing methods for arene iodination. The iodina-
tion of boronic esters has potential for the synthesis of
radiolabeled aryl iodides, as demonstrated by the concise
synthesis of compound 11.
Acknowledgment. We thank the NSF (CHE-1156496)
for support of this work, Johnson Matthey for
[Ir(COD)OMe]2, and BASF for B2pin2.
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data for all new com-
pounds. The Material is available free of charge via the
Internet at http://pubs.acs.org.
(19) Schmitt-Willich, H.; Heinrich, T.; Brockschnieder, D. SPECT
Imaging of Amyloid Plaques. 2011, WO2011110511.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX