A general solution for the 2-pyridyl problem

Article abstract of DOI:10.1002/anie.201108608

Problem solved: An air-stable 2-pyridyl borane that can effectively couple to a wide range of aryl and heteroaryl halides and pseudohalides has evaded the synthesis community for decades. The discovery that Cu(DEA)₂ powerfully enables palladium-mediated cross-couplings with air-stable boronates 1 has finally provided a general solution to this problem. DEA=diethanolamine, DMF=N,N′-dimethylformamide, Tf=trifluoromethanesulfonyl. Copyright

Full text of DOI:10.1002/anie.201108608

Angewandte
Chemie
DOI: 10.1002/anie.201108608
Cross-Coupling
A General Solution for the 2-Pyridyl Problem**
Graham R. Dick, Eric M. Woerly, and Martin D. Burke*
Most small molecules are highly modular in their constitution,
which suggests a potential general capacity for simple,
efficient, and flexible construction through iterative coupling
of preassembled building blocks.[1,2] In an idealized form of
this approach, stable subunits representing the most common
substructural elements found in a wide range of small-
molecule targets are readily linked together using only
cross-coupling reactions.[1] In this vein, the 2-pyridyl subunit
is one of the most prevalent and therefore important motifs,
being found in a wide range of pharmaceuticals,[3] natural
products,[4] unnatural nucleotides,[5] fluorescent probes,[6]
materials,[7] and metal-complexing ligands[8] (Figure 1). Tre-
mendous effort over the past three decades has been
dedicated to the development of 2-pyridyl organometallic
reagents that can be efficiently employed in cross-coupling
reactions.[9–16] All of these methods, however, suffer from one
or more important limitations, including lack of air stability of
the 2-pyridyl building blocks,[10,12–16] use of toxic metals,[9]
inability to isolate the building blocks in chemically pure
form,[11] and inefficient couplings with more challenging
halide coupling partners such as deactivated aryl chlor-
ides.[11,12,13b–17] Overcoming all of these limitations, we herein
report the first general solution for the 2-pyridyl problem.
Typically, the 2-pyridyl–boron bond is exquisitely sensitive
to protodeborylation, making most 2-pyridyl boranes unsta-
ble. In contrast, we recently identified 2-pyridyl N-methyl-
iminodiacetic acid (MIDA) boronate (1a; Scheme 1a) as the
first 2-pyridyl borane that is both air stable and can be
Scheme 1. a) 2-pyridyl MIDA boronate 1a is the first air-stable 2-pyridyl
borane that can be isolated in chemically pure form. b) An inexpensive,
environmentally friendly, and scalable method for preparing 2-pyridyl
MIDA boronates. c) A preliminary method for cross-coupling 1a with
activated aryl chlorides. This method is ineffective with more challeng-
ing deactivated aryl halides. dba=dibenzylideneacetone, DMF=N,N’-
dimethylfomamide, DMSO=dimethyl sulfoxide, IPA=isopropyl
alcohol.
Figure 1. The 2-pyridyl motif is found in many important small
molecules.
isolated in a chemically pure form.[17] We also developed an
inexpensive, environmentally friendly, and scalable method
for preparing 1a and many of its derivatives (Scheme 1b).[18]
Importantly, all of these new building blocks are monomeric,
highly crystalline, free-flowing solids that can be stored
indefinitely on the bench top in air without decomposition,
and several are now commercially available.[19]
[*] G. R. Dick, E. M. Woerly, Prof. M. D. Burke
Howard Hughes Medical Institute, Department of Chemistry
University of Illinois at Urbana-Champaign
600 S. Mathews Ave, Urbana, IL 61801 (USA)
E-mail: burke@scs.uiuc.edu
Homepage: http://www.scs.illinois.edu/burke
Having achieved all of these long sought after features in
a collection of 2-pyridyl boranes, finding maximally general
conditions to promote the cross-coupling of these building
blocks became the final key goal. Kinetically competitive in
situ decomposition usually hinders the effective cross-cou-
pling of 2-pyridyl boranes. Because electronically and steri-
[**] We gratefully acknowledge Bristol-Myers Squibb and the NIH
(GM080436) for funding, and E.P. Gillis for helpful discussions.
M.D.B. is an Early Career Scientist of the Howard Hughes Medical
Institute.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201108608.
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cally deactivated aryl halides tend to react more slowly than
their activated counterparts, they are especially challenging
coupling partners.[20] To overcome similar challenges with
other sensitive 2-heterocyclic boronic acids, we introduced
the slow-release cross-coupling strategy.[17] Specifically, in the
presence of mild bases and water as a cosolvent, air-stable
MIDA boronates undergo in situ hydrolysis to liberate the
corresponding boronic acids at a rate that is slower than
catalyst turnover.[17] Analogous to utilizing a syringe pump,
such conditions strongly favor cross-coupling over boronic
acid decomposition.[17,21]
Presumably as a result of the extreme lability of the 2-
pyridyl–boron bond, even under these slow-release condi-
tions, the cross-coupling of 2-pyridyl MIDA boronate
remained challenging. As shown in Scheme 1c, modified
reaction conditions employing isopropyl alcohol instead of
water as a cosolvent and Cu(OAc)2 as a substoichiometric
additive were somewhat effective with activated, electron-
deficient aryl chlorides such as 3a. However, when we
attempted to cross-couple 1a with more challenging deacti-
vated aryl chlorides, such as 3b, very little of the desired cross-
coupling product 4b was observed.
provided no notable advantage (entries 5–7). In contrast,
addition of the trivalent ligand diethanolamine (DEA)
resulted in the intriguing formation of a royal-blue reaction
mixture and the formation of 4b in a substantially increased
yield of 70% (entry 8).
To enable further optimization of these reaction condi-
tions, we sought to understand the mechanistic underpinnings
of this DEA-promoted increase in efficiency. Deng and co-
workers have shown that the cross-coupling of 2-pyridyl
boronic esters promoted by copper(I) salts likely involves an
À
À
initial C B to C Cu transmetalation to produce an inter-
mediate 2-pyridyl copper species which, in turn, undergoes
transmetalation with palladium(II).[14a] Starting with this
general mechanistic framework, we considered two possible
pathways for DEA to promote the transformation of 1a into
a the putative 2-pyridyl copper intermediate 6 (Scheme 2). In
pathway 1, DEA reacts with the conformationally rigid 1a in
An extensive survey of palladium/ligand combinations,[22]
copper salts,[14,16,17,23] bases, solvents, temperatures, and reac-
tion times resulted in reaction conditions that were somewhat
more effective, but the yield of 4b remained modest (Table 1,
entry 1). Driven by our then working hypothesis that the role
of IPA in these reactions was to promote initial transligation
of 1a to the corresponding 2-pyridyl isopropyl boronic ester,
we investigated a range of different alcohols as additives.
However, less (entries 2 and 3) or more (entry 4) sterically
bulky alcohols were all inferior to IPA, and common diols also
Scheme 2. Two possible pathways for the DEA-promoted coupling of
1a.
a novel transligation reaction to form a conformationally
flexible and thereby more reactive DEA adduct 5,[1d] which in
turn transmetalates with Cu(OAc)2 to form 6. In pathway 2,
DEA alternatively reacts with Cu(OAc)2 to yield a Cu(DEA)n
complex[24,25] and KOAc. The released KOAc then reacts with
1a to generate a reactive 2-pyridyl boronate intermediate 7
(X = acetate[26] or other ion), which in turn transmetalates
with Cu(DEA)n to form 6.
Table 1: Cross-coupling of 2-pyridyl MIDA boronate 1a with deactivated
aryl chloride 3b.[a]
To determine whether pathway 1 was operative, we first
mixed DEA with 1a in the presence of K3PO4 in deuterated
DMF at 1008C and monitored the reaction by 1H NMR
spectroscopy. Seeming to support this mechanism, we
observed the slow transligation of 1a to 5 over the course of
four hours (see the Supporting Information) and succeeded in
isolating 5 as a crystalline solid (Scheme 3). However, when
we attempted to couple to 5 to 3b with or without syringe-
pump-mediated slow addition of 5 over the course of four
hours to mimic the rate of its in situ formation,[17] we observed
only very low yields of 4b (Scheme 3). Thus, pathway 1
Entry
ROH
Equiv
Yield [%][b]
1
2
3
4
IPA
3
3
3
3
49
36
39
43
MeOH
EtOH
tBuOH
5
6
7
1.5
1.5
1.5
51
35
31
8
1.5
70
DEA
[a] Reaction conditions: 1.0 equiv 3b (1.0 mmol), 1.5 equiv 1a, 5 mol%
XphosPdcycle, 50 mol% Cu(OAc)2, 5 equiv K3PO4, 0.125m in DMF.
[b] Determined by GC analysis. XPhosPdcycle=chloro(2-dicyclohexyl-
phosphino-2’,4’,6’-triisopropyl-1,1’-biphenyl)[2-(2-aminoethyl)phenyl]-
palladium(II) methyl tert-butyl ether adduct.
Scheme 3.
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Table 2: General cross-coupling of air-stable 2-pyridyl MIDA boronate 1a
with aryl and heteroaryl chlorides 3.[a]
cannot account for the beneficial effects of DEA on the
coupling of 1a and 3b.
To interrogate the possibility of pathway 2, we alterna-
tively combined DEA with Cu(OAc)2 in the presence of
K3PO4 in DMF at 1008C (Scheme 4). In less than 15 minutes
the reaction turned royal blue, and both Cu(DEA)2 and
Entry
1
3
4
Yield [%][b]
76
3c
3d
4c
4d
Scheme 4.
2
96
KOAc were formed. After extensive experimentation, we
developed a new procedure for preparing and purifying
Cu(DEA)2 from CuCl2, DEA, and K3PO4 (see the Supporting
Information).[27] Strikingly, when we attempted to couple 1a
and 3b in the presence of purified Cu(DEA)2 and KOAc
under our otherwise standard conditions we observed an 84%
yield of 4b (Scheme 5; see entry 1). Consistent with important
3
3e
3 f
3g
3h
3i
4e
4 f
4g
4h
4i
75
79
72
49
86
82
83
77
80
4
5
6[c]
7
Scheme 5.
roles for both of these additives, in the absence of Cu(DEA)2,
without or with added KOAc, none of this cross-coupling
product was observed (Scheme 5; see entries 2 and 3). The
Cu(DEA)2 was superior to Cu(OAc)2 (Scheme 5; see
entry 4), and the addition of Cu(DEA)2 but not KOAc
provided only a modest yield of 4b (entry 5).[28]
To further probe the role of KOAc in this reaction, we
treated 1a with K3PO4 in DMF at 1008C with or without
adding KOAc and monitored the consumption of 1a by
1H NMR spectroscopy. In both the absence and presence of
Cu(DEA)2, the addition of KOAc to otherwise identical
reaction conditions resulted in substantially accelerated
conversion of 1a into pyridine, presumably through proto-
8
3j
4j
9[c]
10
11
3a
3k
3l
4a
4k
4l
12
3m
4m 62
demetalation of the short-lived intermediates
7 or 6.
Although additional studies will be needed to characterize
this mechanism in further detail, all of this data is consistent
with pathway 2 (Scheme 2).
Importantly, this mechanism also proved to be predictive
for further optimizing this cross-coupling system. Specifically,
the intermediacy of Cu(DEA)2 predicts that the optimum
13
14
3n
3o
4n
4o
64
82
[a] General reaction conditions: 1.0 equiv aryl halide (1 mmol), 1.5 equiv
MIDA boronate 1a, 5 mol% XphosPdcycle, 50 mol% Cu(OAc)2,
1.0 equiv DEA, 5.0 equiv K3PO4, 0.125m DMF, 1008C, 24 h. [b] Yield of
isolated product. [c] 808C.
ratio of DEA/Cu(OAc)2 would be 2:1. We tested this
hypothesis systematically and found that in fact a 2:1 ratio
provided the highest yield (GC) of 4b (Scheme 6). By
Scheme 6.
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Table 3: General cross-coupling of air-stable 2-pyridyl MIDA boronate derivatives 1 with deactivated aryl
chlorides 3.
pharmaceuticals, materials, and
ligands, were successfully coupled
to a representative series of steri-
cally and electronically deactivated
aryl chlorides (entries 1–7).
Finally, it is often the case that
reaction conditions optimized for
one class of halides or pseudoha-
lides are less effective with others.
However, the exact same conditions
also promote the efficient coupling
of 1a with a diverse range of
electrophilic coupling partners
(Table 4), including bromides (8a–
e), iodides (8 f–i), and triflates (8j–
n), with all three classes of electro-
philes represented as deactivated,
activated, and heteroaryl variants.
The ubiquity of the 2-pyridyl
subunit in a wide range of important
small molecules has for decades
stimulated the search for an isolable
2-pyridyl borane that is both air-
stable and a generally effective
cross-coupling partner. The Cu-
Entry
1
3
4
Yield
[%][b]
1
2
1b
1c
3b
4p
4q
72
81
3b
3b
3
1d
4r
81
4
5
1e
1 f
3h
4s
4t
77
87
3b
(DEA)2/KOAc-promoted
cross-
6
7
1g
1h
3c
4u
4v
78
85
coupling with the air-stable 2-pyr-
idyl MIDA boronates described
herein represents the first general
solution to this problem. As the 2-
pyridyl motif is in many ways the
archetype for unstable boronic
acids, this discovery has widespread
implications for many other types of
challenging cross-coupling process-
es. Moreover, this platform stands
3b
[a] General reaction conditions: 1 equiv aryl halide (1 mmol), 1.5 equiv MIDA boronate, 5 mol%
XphosPdcycle, 50 mol% Cu(OAc)2, 5 equiv K3PO4, 0.125m DMF, 1008C, 24 h. [b] Yield of isolated
product.
employing this rationally optimized ratio of additives on
Table 4: General coupling of air-stable 2-pyridyl MIDA boronate 1a with
aryl and heteroaryl bromides, iodides, and triflates 8.
a 1 mmol scale, we obtained a 94% yield upon product
isolation for this very challenging cross-coupling reaction.
With this optimized methodology in hand, we explored its
scope with respect to both the 2-pyridyl MIDA boronate and
halide coupling partners. Remarkably, the same set of
reaction conditions proved to be highly general. For example,
as shown in Table 2, a series of electron-rich and sterically
bulky aryl chlorides were coupled with 1a in typically good to
excellent yields (entries 1–5). Even the highly deactivated 2,6-
dimethoxy chlorobenzene (3h) was coupled in synthetically
useful yield (entry 6). Importantly, the same reaction con-
ditions optimized for deactivated substrates were also effec-
tive for coupling 1a with electronically activated aryl
chlorides (entries 7–9), and a diverse series of heteroaryl
chlorides (entries 10–14).
Entry
8
4
Yield
[%][b]
1
2
3
4
8a
8b
8c
8d
4w
4c
4j
83
79
84
47
As shown in Table 3, these same reaction conditions were
also successfully applied to very challenging couplings with
a range of other 2-pyridyl MIDA boronate derivatives.
Specifically, a series of both electron-rich (1b–e) and elec-
tron-deficient (1 f–h) 2-pyridyl MIDA boronates, represent-
ing substructural motifs that appear in a wide variety of
4x
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Chem. 2010, 122, 9044 – 9047; Angew. Chem. Int. Ed. 2010, 49,
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Entry
8
4
Yield
[%][b]
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[a] General reaction conditions: 1.0 equiv aryl halide (1 mmol), 1.5 equiv
MIDA boronate 1a, 5 mol% XphosPdcycle, 50 mol% Cu(OAc)2,
1.0 equiv DEA, 5.0 equiv K3PO4, 0.125m DMF, 1008C, 24 h. [b] Yield of
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Received: December 6, 2011
Published online: January 27, 2012
Keywords: boronates · copper · cross-coupling · heterocycles ·
.
synthetic methods
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2672 www.angewandte.org
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