One-pot borylation/amination reactions: Syntheses of arylamine boronate esters from halogenated arenes

Article abstract of DOI:10.1021/ol060205y

A one-pot protocol for converting 1,3- and 1,4-substituted aryl halides to arylamine boronate esters is described. This is achieved by sequential Ir-catalyzed aromatic borylation at the least hindered C-H bond of the aryl halide and subsequent Pd-catalyze

Full text of DOI:10.1021/ol060205y

ORGANIC
LETTERS
2
006
Vol. 8, No. 7
407-1410
One-Pot Borylation/Amination
Reactions: Syntheses of Arylamine
Boronate Esters from Halogenated
Arenes
1
Daniel Holmes, Ghayoor A. Chotana, Robert E. Maleczka, Jr.,* and
Milton R. Smith, III*
Department of Chemistry, Michigan State UniVersity,
East Lansing, Michigan 48824 USA
smithmil@msu.edu
Received January 24, 2006
ABSTRACT
A one-pot protocol for converting 1,3- and 1,4-substituted aryl halides to arylamine boronate esters is described. This is achieved by sequential
Ir-catalyzed aromatic borylation at the least hindered C−H bond of the aryl halide and subsequent Pd-catalyzed C−N coupling at the halide
position of the crude arylboronic ester.
6
Metal-catalyzed halide substitution reactions have enhanced
the synthetic utility of halogenated aromatic compounds.
Noteworthy examples include C-C, C-N, and C-O bond-
halides to phenols, when the boronic ester is oxidized, or
to biaryls and polyaromatics when the nascent arylboronate
1
2
4,5c,7
esterissubjectedtosubsequentPd-mediatedC-Ccoupling.
forming reactions, which are predominantly Pd-mediated
These results suggest that other metal-catalyzed transfor-
mations of crude arylboronate esters produced from Ir-
catalyzed aromatic borylations might be possible. In this
Letter we describe a one-pot borylation/amination protocol
where aryl halides can be converted to C-borylated anilines.
In addition to requiring that the Pd-catalyzed reaction
operates without interference from Ir species that remain after
borylation, realization of the tandem catalytic process hinges
on the successful differentiation between C-N and C-C
3
processes. Because the scope of these transformations is tied
to commercial availability of halogenated compounds, pro-
cesses that enable functionalization at nonhalogen sites can
augment the substrate pool. In this regard, Ir-catalyzed
borylation reactions are particularly intriguing because C-H
bonds in halogenated aromatic systems can be converted
selectively to C-B bonds.4 We, and others, have shown
that this selectivity enables one-pot elaborations of aryl
,5
(
1) (a) Suzuki, A. J. Organomet. Chem. 1999, 576, 147-168. (b)
Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-2483.
2) (a) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002, 219, 131-
09. (b) Wolfe, J. P.; Wagaw, S.; Marcoux, J. F.; Buchwald, S. L. Acc.
Chem. Res. 1998, 31, 805-818. (c) Hartwig, J. F. Acc. Chem. Res. 1998,
1, 852-860.
3) For recent advances in Cu-catalyzed carbon-heteroatom bond-
forming reactions, see: Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed.
003, 42, 5400-5449.
4) Cho, J. Y.; Tse, M. K.; Holmes, D.; Maleczka, R. E., Jr.; Smith, M.
R., III Science 2002, 295, 305-308.
(5) For related Ir-catalyzed borylations, see: (a) Ishiyama, T.; Takagi,
J.; Ishida, K.; Miyaura, N.; Anastasi, N. R.; Hartwig, J. F. J. Am. Chem.
Soc. 2002, 124, 390-391. (b) Ishiyama, T.; Takagi, J.; Yonekawa, Y.;
Hartwig, J. F.; Miyaura, N. AdV. Synth. Catal. 2003, 345, 1103-1106 (c)
Ishiyama, T.; Nobuta, Y.; Hartwig, J. F.; Miyaura, N. Chem. Commun. 2003,
2924-2925.
(
2
3
(
(6) Maleczka, R. E., Jr.; Shi, F.; Holmes, D.; Smith, M. R., III J. Am.
Chem. Soc. 2003, 125, 7792-7793.
2
(
(7) For a recent review on tandem catalsyis, see: Santos, E. N. D.; Fogg,
D. E. Coord. Chem. ReV. 2004, 248, 2365-2379.
1
0.1021/ol060205y CCC: $33.50
© 2006 American Chemical Society
Published on Web 03/03/2006

couplings with an aryl halide when amines and boronic esters
are present in the reaction milieu.
After an initial attempt of the one-pot reaction sequence
failed, we explored aminations of the purified borylation
product of 3-chlorotoluene. To our delight, selective C-N
coupling was found by using anhydrous K PO as the base
3 4
according to eq 1. Returning to the one-pot sequence, we
Cross-couplings of aryl boron reagents or amines with aryl
halides constitute two of the most important reactions for
aryl halides. These reactions are typically facilitated by Pd
catalysts in the presence of stoichiometric quantities of base.
Given the similar reaction conditions for C-C and C-N
couplings, attempted catalytic amination of the halogenated
arylboronate ester in Scheme 1 could produce an arylamine
Scheme 1. Possible Outcomes for a One-Pot Borylation/
Amination Sequence
examined the effects of the Ir and Pd precatalysts, base, and
solvent on yields for the “one-pot” sequence in Scheme 2.
The results are tabulated in Table 1.
Entries 1-4 examine the effects of the Ir source and the
Ir ligand. While room temperature borylations are prohibi-
tively slow for 3-chlorotoluene, the borylations could be
carried out at 80 °C when the Ir ligand was 4,4′-di-tert-butyl-
2
,2′-bipyridyl (dtbpy). The best yields of the borylated
arylamine were obtained when borylations were carried out
with the (Ind)Ir(COD)/1,2-bis(dimethylphosphino)ethane
(dmpe) Ir precatalyst/ligand formulation. In all cases, conver-
sion of 3-chlorotoluene to the intermediate boronate ester
was complete. Hence, the variations in yields for entries 1-4
likely arise from the efficiencies of the amination step.
Entries 1 and 5-8 illustrate the effects of the base on the
if C-N coupling is favored, polyaromatic products if C-C
coupling dominates, or a mixture of these products if C-N
and C-C formation is competitive.
3 4 2 3
amination step. K PO and Cs CO are both effective,
t
t
whereas NaO Bu and KO Bu gave very low yields of the
amino boronate ester. Entry 5 shows the deleterious effects
of water as the amino boronate ester is not detected when
In terms of literature precedent, the prospects for selective
amination according to Scheme 1 were bleak. As well as
we are aware, there are no examples where C-B bonds
survive during Pd-catalyzed amination conditions. Moreover,
there are numerous examples where cross couplings of
arylboronic acids8 and esters9 are accomplished in the
presence of primary and secondary amines. However, our
examinations of one-pot aromatic borylation/C-C coupling
of arenes offered a ray of hope for the amination pathway
in Scheme 1. Specifically, we found that Suzuki-Miyaura
cross-couplings of pinacolate esters of arylboronic acids were
typically slower than reactions of the arylboronic acids
themselves.10 Moreover, the rates of C-C couplings for
pinacol boronate esters further diminish when the reactions
are carried out under anhydrous conditions. Since virtually
all examples of B-C/C-X cross-couplings of substrates with
amine functionality involve boronic acids or boronate esters
in the presence of either water or hydroxide, we reasoned
that the combination of an aprotic base and an anhydrous,
aprotic solvent offered the best chance for realizing C-N
in lieu of C-C coupling.
t
t
K
3
PO
4
2
‚nH O is the base. In contrast to NaO Bu and KO Bu,
where predominance of the intermediate boronate ester
indicates that conversion to the amino boronate is simply
slow, with K
3
PO
4
2
‚nH O the intermediate boronate ester is
completely consumed. Entries 1, 9, and 10 show that the
amination step is moderately sensitive to variations in the
solvent, with DME giving superior results. Last, entries 1
and 11 illustrate the effect of the Pd precatalyst with Pd
2
-
dba being superior to Pd(OAc) , the principle difference
3
2
being significant generation of the deborylated arylamine for
the latter Pd precatalyst.
Armed with the results from Table 1, we examined the
scope of the borylation/amination sequence for various
3-substituted halobenzenes for which borylation at the
5-position predominates. The general conditions in Scheme
3 were used and the results are listed in Table 2.
The isolated yields for the reactions in Table 2, based on
the starting aryl halide, range from 47% to 83% with an
average yield of 64%. This average corresponds to an 80%
yield for the individual steps, assuming that the borylation
and amination yields are identical. When the pure aryl
boronate ester derived from borylation of 3-chlorotolene was
isolated and subsequently aminated with aniline, the product
in entry 1 was isolated in 60% overall yield based on
3-chlorotoluene, compared to the 75% yield obtained for the
one-pot reaction. Thus, higher isolated yields are realized in
the one-pot tandem reactions where isolation and purification
(8) For selected examples, see: (a) Miura, Y.; Oka, H.; Momoki, M.
Synthesis 1995, 11, 1419-1422. (b) Miura, Y.; Mamoki, M.; Nakatsuji,
M. J. Org. Chem. 1998, 63, 1555-1565. (c) Miura, Y.; Nishi, T.; Teki, Y.
J. Org. Chem. 2003, 68, 10158-10161. (d) Barder, T. E.; Walker, S. D.;
Martinelli, J. R.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 4685-
4
696.
9) Read, M. W.; Escobedo, J. O.; Willis, D. M.; Beck, P. A.; Strongin,
R. M. Org. Lett. 2000, 2, 3201-3204.
10) Chotana, A. G.; Holmes, D.; Maleczka, R. E., Jr.; Smith, M. R.,
III. Manuscript in preparation.
(
(
1408
Org. Lett., Vol. 8, No. 7, 2006

Scheme 2. One-Pot Borylation/Amination of 3-Chlorotoluene
Table 1. Effects of Ir and Pd Precatalyst, Base, and Solvent on One-Pot Borylation/Amination of 3-chlorotoluene
entry
Ir precatalyst
Ir ligand
borylation conditions
Pd precatalyst
base
K3PO4
K3PO4
K3PO4
solvent
GC yielda
1
2
3
4
5
6
7
8
9
(Ind)Ir(COD)
(Ind)Ir(COD)
(Ind)Ir(COD)
[Ir(µ-OMe)(COD)]2
(Ind)Ir(COD)
(Ind)Ir(COD)
(Ind)Ir(COD)
(Ind)Ir(COD)
(Ind)Ir(COD)
(Ind)Ir(COD)
(Ind)Ir(COD)
dmpe
dppe
150 °C, 18 h
150 °C, 18 h
150 °C, 18 h
80 °C, 24 h
150 °C, 18 h
150 °C, 18 h
150 °C, 18 h
150 °C, 18 h
150 °C, 18 h
150 °C, 18 h
150 °C, 18 h
Pd2dba3
Pd2dba3
Pd2dba3
Pd2dba3
Pd2dba3
Pd2dba3
Pd2dba3
Pd2dba3
Pd2dba3
Pd2dba3
Pd(OAc)2
DME
DME
DME
DME
DME
DME
DME
DME
dioxane
toluene
DME
93
89
87
87
0
88
18
10
85
84
56
dtbpy
dtbpy
dmpe
dmpe
dmpe
dmpe
dmpe
dmpe
dmpe
K3PO4
K3PO4‚nH2O
Cs2CO3
t
NaO Bu
t
KO Bu
K3PO4
K3PO4
K3PO4
1
1
0
1
a
GC yields based upon starting arene as an average of three runs.
amination reactions using these substrates suggest that
extensions beyond the regiochemistries in Table 2 are
possible. Because unsymmetrical ortho-disubstituted ben-
zenes typically exhibit poor borylation regioselectivities, the
only 2-substituted halogenated benzene examined is o-
dichlorobenzene. Regioselective borylation at the 4-position
affords an intermediate boronate ester where the chloride
positions are chemically distinct. Thus, synthetic utility
depends on high regioselectivity in the amination step.
Fortunately, the BPin group exerts a directing effect that,
regardless of its origins (i.e., steric or electronic), responds
to variations in the Pd phosphine ligand. While good
Scheme 3
3
regioselectivity is found for PtBu (2:1) and 2-dicyclohexyl-
of the intermediate aryl halide boronate esters are avoided.11
Entries 1-4 examine the effect of varying the amine on
aminations of the borylation product of 3-chlorotoluene. The
yields for aniline, morpholine, and N-methylaniline are
excellent, while amination with dibutylamine gave a signifi-
cantly lower yield of the 3-amino boronate ester. Entries 1,
phosphino-2′-(dimethylamino)-1,1′-biphenyl (6:1), 2-(dicy-
clohexylphosphino)biphenyl gave superior results affording
a 19:1 ratio of isomers in the isolated product favoring
amination at the chloride position para to the BPin group.
With the exception of regioselective amination at the
12
2
-position of 2,3-dichloropyridine, regioselectivities of this
6, 7, 10, and 11 show the effect of varying the Z substituent
type have not been previously reported.
in Scheme 3. Electron-withdrawing substituents give lower
yields of the 3-amino boronate esters. Since electron-
withdrawing substituents on aryl boronic acids accelerate
Suzuki-Miyaura cross-couplings, competition from this side
reaction may contribute to the lower yields for electron-
deficient aryl chlorides. Consistent with this notion, small
quantities of aminated biaryls that arise from Suzuki-
Miyaura coupling can be detected in the crude reaction
mixture for entry 8.
p-Dichlorobenzene similarly affords a single monoboryl-
ated product where the chloride positions are also chemically
distinct. For this substrate, a 2-fold excess of arene is required
to minimize diborylation. Consequently, the intermediate
boronate ester was isolated. In contrast to the one-pot reaction
for o-dichlorobenzene, subsequent amination of this boronate
ester with aniline was less efficient and less regioselective,
and deborylation was also observed. Attempts to isolate the
pure amino boronate esters were unsuccessful.
Examples of 2- and 4-substituted halogenated benzenes
that react with a high degree of regioselectivity are more
limited. Nevertheless, the results from one-pot borylation/
When the 4-subtituent in 4-substituted chlorobenzenes is
sufficiently large, borylation at the 2-position predominates.
For example, 4-(trifluoromethyl)chlorobenzene affords a 95:5
(
11) For a discussion of costs involved in product isolation, see:
(12) Jonckers, T. H. M.; Maes, B. U. W.; Lemiere, G. L. F.; Dommisse,
R. Tetrahedron 2001, 57, 7027-7034.
Anderson, N. G. Org. Process Res. DeV. 2004, 8, 260-265.
Org. Lett., Vol. 8, No. 7, 2006
1409

Table 2. Preparation of 1,3,5-Arylamino Boronate Esters by
One-Pot Aromatic Borylation/Amination of aryl halidesa
Table 3. One-Pot Borylation/Amination of Ortho- and
Para-Substituted Chlorobenzenesa
a
b
See Supporting Information for specific reaction conditions. Isolated
c
yield based upon an average of two runs. The intermediate boronate ester
was isolated. d Upon consumption of the boron pinacolate ester, substantial
aniline remained. Approximately 87% of the arene starting material is
unaccounted for in the GC analysis of volatile products.
In summary, one-pot borylation/amination provides an
efficient protocol for preparing the 1,3,5-arylamino boronate
esters from 3-substituted aryl halides. The one-pot sequence
can be extended to ortho- and para-substituted chloroben-
zenes. In the case of dichlorobenzenes, a highly regioselective
substitution has been observed para to the BPin group in
the boronate ester derived from the borylation of o-
dichlorobenzene. The key feature that enables the one-pot
sequence is preference of C-N over C-C coupling when a
primary or secondary amine, a pinacolate boron ester, and
an aryl halide are subjected to Pd coupling conditions where
1
3,14
anhydrous K
3
PO
4
is the requisite base.
We are presently
evaluating the generality and pursuing applications of this
1
5
selectivity.
Acknowledgment. We thank the Michigan Life Sciences
Corridor, the Michigan Technology Tri-Corridor Fund, NIH
(GM63188 to M.R.S.), and the Astellas USA Foundation
for generous support. We thank BASF, Inc. for a generous
gift of pinacolborane.
a
General synthetic procedure: In a drybox, aryl halide (2.0 mmol),
HBPin (4.0 mmol), (Ind)Ir (COD) (0.04 mmol), and dmpe (0.04 mmol)
were transferred to a thick-walled, air-free flask equipped with a magnetic
stirbar. The flask was sealed and the mixture stirred at 150 °C until the
arene was consumed (GC-FID). The cooled reaction mixture was placed
under vacuum for 1-2 h, after which anhydrous K3PO4 (2.8 mmol), Pd2dba3
0.02 mmol), P(t-Bu)3 (0.06 mmol), amine (2.4-2.6 mmol), and DME (3
mL) were added. The mixture was stirred at 100 °C until the boronate ester
was consumed (GC-FID). See the Supporting Information for specific
reaction conditions. Isolated yields based upon an average of two runs.
Supporting Information Available: Spectral data for all
new compounds pictured, as well as general experimental
procedures. This material is available free of charge via the
Internet at http://pubs.acs.org.
(
b
OL060205Y
c
d
Dppe was used in the borylation step. Small amounts of aminated
biphenyls were detected.
(
13) Although K3PO4 has been previously used in Suzuki-Miyaura cross-
1b,13a 13b
couplings
and Buchwald-Hartwig aminations, preservation of an
arylboronate ester under amination conditions has not been reported to our
knowledge: (a) Miyaura, N.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.; Satoh,
M.; Suzuki, A. J. Am. Chem. Soc. 1989, 111, 314-321. (b) Old, D. W.;
Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120, 9722-9733.
ratio of 2- and 3-monoborylated products. Subsequent
amination of the crude reaction mixture with aniline and
isolation gives isomerically pure 2-borylated amine. As was
the case for p-dichlorobenzene, approximately 20% of the
intermediate boronate ester suffers deborylation, suggesting
that this may be a general problem for aminations of
chlorides ortho to BPin groups.
(
14) Compatability of pinacolate ester with uncatalyzed aminations of
14a
14b
aryl fluorides and chloropyrimidines has been noted: (a) Holland, R.;
Spencer, J.; Deadman, J. J. Synthesis 2002, 2379-2382 (b) Gong, B. Q.;
Hong, F.; Kohm, C.; Jenkins, S.; Tulinsky, J.; Bhatt, R.; de Vries, P.; Singer,
J. W.; Klein, P. Bioorg. Med. Chem. Lett. 2004, 14, 2303-2308.
(15) Shi, F.; Smith, M. R., III; Maleczka, R. E., Jr. Org. Lett. 2006, 8,
1411-1414.
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