Exhaustive Suzuki-Miyaura reactions of polyhalogenated heteroarenes with alkyl boronic pinacol esters

Article abstract of DOI:10.1039/c7cc00997f

A novel Suzuki-Miyaura protocol is described that enables the exhaustive alkylation of polychlorinated pyridines. This method facilitates a formal synthesis of normuscopyridine and the rapid assembly of a dumbbell shaped portion of a [2]rotaxane.

Full text of DOI:10.1039/c7cc00997f

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
first methanofullerene derivatives of Sc N@D5h-C80
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DOI: 10.1039/C7CC00997F
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Exhaustive Suzuki-Miyaura Reactions of Polyhalogenated
Heteroarenes with Alkyl Boronic Pinacol Esters
Sébastien Laulhé,†a J. Miles Blackburn†b and Jennifer L. Roizenb
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A novel Suzuki-Miyaura protocol is described that enables the
exhaustive alkylation of polychlorinated pyridines. This method
enables a formal synthesis of normuscopyridine and the rapid
assembly of a dumbbell shaped portion of a [2]rotaxane.
O
O
N
N
R
5
5
Ar
Ar
Ar
Ar
Ar
Ar
R = Me, muscopyridine (2a)
R = H, normuscopyridine (2b)
perfumes and fragrances
Ar = 4-tBu-(C6H4)-
rotaxane component (1 )
Figure 1. Utility of the 2-alkylpyridines1b,d
The 2-alkylpyridine scaffold is critical to bioactive small
molecules, to molecular machines, and within ligands for
metal catalyzed transformations (Figure 1).1 Several powerful
approaches have been developed to install alkyl substituents
on pre-formed pyridyl cores.2 In terms of traditional cross-
coupling approaches, 2-pyridyl organometallic reagents have
been advanced, but suffer from air instability3 and reaction-
specific limitations, including requirements for high catalyst
Prior disclosures
selective
(1)
R1
N
N
Cl
Pd2(dba)3, FcPPh2 , K3PO4
R1–B(OR3)2
Cl
N
Cl
serial
(2)
(3)
R1
R2
loadings or a narrow range of cross-coupling partners.4
A
Pd2(dba)3, FcPPh2 , K3PO4
R1–B(OR3)2 then R2–B(OR3)2
R1 = alkyl, R2 = aryl
complementary approach involves the direct functionalization
of affordable, readily accessible, and chemically stable
heteroaryl chlorides by way of a cross-coupling reaction.5 The
Suzuki–Miyaura reaction relies on commercially available
reagents that offer reduced toxicity.6,7 Only a few conditions
can couple alkyl organoboron reagents with 2-halopyridines.8
To complement our disclosed selective and serial Suzuki-
Miyaura reactions of polychlorinated pyridines with alkyl
pinacol boronic esters (Scheme 1, eq 1, 2),9 we now describe
an exhaustive Suzuki-Miyaura reaction of haloarenes, including
2-pyridylchlorides (Scheme 1, eq 3).
The challenges in this transformation derive from (1) the
ability of the Lewis basic pyridine nitrogen to bind the metal
and inhibit further reactivity,10 and (2) the relatively slow
transmetallation of alkyl organoboron species. Slow
transmetallation renders decomposition pathways more
competitive, including protodehalogenation of aryl halides,
protodeborylation11 of the alkyl boronic esters, and β-hydride
elimination processes of palladium-alkyl intermediates.
These investigations
exhaustive
Pd2(OAc)2, AdPnBu , LiOtBu
R1–B(OR3)2
Cl
N
Cl
R1
N
R1
Scheme 1. Prior disclosures and these investigations
Initially, we chose to interrogate the Suzuki-Miyaura
reaction of 2,6-dichloropyridine (3a) with heptyl pinacol
boronic ester to generate 2,6-dialkylpyridine 5a (Table 1). The
targeted bond-forming reactions do not proceed efficiently
using many cutting-edge protocols to couple aryl halides with
alkyl boron compounds.12 We anticipated that this reaction
would be promoted by sterically encumbered alkyl phosphine
ligands. Such ligands favor formation of mono-coordinated
palladium-phosphine complexes, which undergo accelerated
oxidative addition,13 transmetallation, and reductive
elimination processes.14 Moreover, sterically encumbered
ligands can help to mitigate β-hydride elimination following
transmetallation of the organoboron species. We found that
di(1-adamantyl)-n-butylphosphine provided the highest levels
of dialkylpyridine 5a (entries 1–3).
The optimal conditions vary slightly from those disclosed
recently to affect the Suzuki-Miyaura reaction of halopyridines
with boronic acids (entry 4),15 but the differences have a
dramatic impact on the reaction. Empirical studies with
different palladium sources and solvents revealed a beneficial
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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effect derived from the use of a Pd(OAc)2 pre-catalyst and contrast, 2,6-dibromopyridine generates nearly exclusively
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DOI: 10.1039/C7CC00997F
solvation with 4:1 dioxane:water (entries 4–8). Presumably, exhaustively coupled 5a when 6a is used as the limiting
water mediates pinacol boronic ester speciation.
substrate (entry 17). We hypothesize that during the
transformation, the palladium catalyst remains ligated to the
2-bromo-6-alkylpyridine intermediate, but can dissociate from
2-chloro-6-alkylpyridine species prior to the second
transmetallation event. This differential reactivity could be a
consequence of the higher barrier to oxidative addition to aryl
chlorides relative to bromides.
Table 1. Influence of base, ligand, and palladium source on reaction outcome
Me
Bpin
6
6a
Ad2PnBu:Pd (3:1)
base (6 equiv)
+
X
N
X
X
N
N
6
6
6
Me
Me
Me
solvent
100 °C, 24 h
3a, X = Cl
3b, X = Br
4a
5a
Table 2. A general procedure for Suzuki-Miyaura reactions of aryl chlorides
Pd
source
Pd(OAc)2 Cl
equiv
6a
entry
X
solvent
base
4a (%)a 5a (%)a
Ad2PnBu, Pd(OAc)2, LiOtBu
+
Ar
Ph
ArCl
pinB
(6b, 2.3 equiv)
ArCl
Ph
1
2.3 dioxane/H2O LiOtBu
2.3 dioxane/H2O LiOtBu
2.3 dioxane/H2O LiOtBu
ndb
25%
52%
5
94c
5%
6%
ndb
90
ndb
<5
ndb
<5
ndb
7
dioxane/H2O (4:1)
100 °C, 24 h
2d Pd(OAc)2 Cl
3e Pd(OAc)2 Cl
(1 equiv)
entrya
product
yield (%)b
4
5
6
7
8
9
Pd2(dba)3 Cl
Pd2(dba)3 Cl
Pd(OAc)2 Cl
Pd(OAc)2 Cl
Pd(OAc)2 Cl
Pd(OAc)2 Cl
2.3
PhMe
K3PO4
2.3 dioxane/H2O LiOtBu
5
1c
2
Ph
5b, 81
5c, 95
2.3
2.3
2.3
dioxane
PhMe/H2O
PhMe
LiOtBu
LiOtBu
LiOtBu
CsF
<5
40
<5
29
5
N
Cl
N
Ph
Ph
Ph
N
N
Cl
Cl
N
Cl
Cl
3
3
Ph
2.3 dioxane/H2O
2.3 dioxane
Cl
3
10 Pd(OAc)2 Cl
11 Pd(OAc)2 Cl
12 Pd(OAc)2 Cl
13 Pd(OAc)2 Cl
14 Pd(OAc)2 Cl
15 Pd(OAc)2 Cl
16 Pd(OAc)2 Cl
17 Pd(OAc)2 Br
18 Pd(OAc)2 Br
CsF
3d
5d, 82
5e, 98
2.3 dioxane/H2O Cs2CO3
2.3 dioxane/H2O K3PO4
2.3 dioxane/H2O NaOtBu
2.3 dioxane/H2O KOtBu
2.3 dioxane/H2O LiOMe
1.0 dioxane/H2O LiOtBu
1.0 dioxane/H2O LiOtBu
2.3 dioxane/H2O LiOtBu
72
73
68
39
33
56
ndb
ndb
Ph
N
3
3
13
8
OMe
OMe
4c,e
N
Ph
N
31
66
20
48
94
Cl
Cl
R
Ph
OMe
NO2
5e,f
6e,f
5f, 90
5g, 90
R
R
Cl
Ph
N
7g
N
5h, 84
b
aDetermined by 1H NMR. nd = Not detected. cIsolated yield. dFcPPh2 used in
Cl
Ph
R
place of Ad2PnBu. eTricyclohexylphosphine used in place of Ad2PnBu.
R
N
R
CF3
Me
8
9
5i, 52
5j, 96
Pinacol boronic ester speciation also depends on reaction
pH. Reaction conversion increases with increasing basicity
(entries 9–12; pKa of corresponding conjugate acids in water:
Ph
Ph
Cl
N
Cl
Cl
3
3
Ph
10c,d
5k, 18
5l, 99
–
2–
12.7; HOtBu, 16.5).16
Me
Me
HF, 3.2; HCO3 , 10.2; HPO4
,
O
O
Interestingly, the identity of the counter cation resulted in
significant differences in conversion to the exhaustively
coupled product, presumably due to differences in
nucleophilicity (entries 13–14).17 Lithium alkoxides were the
only bases screened that favoured exhaustive coupling over
selective coupling (entries 1, 15). Under the optimal
conditions, the reaction of 2,6-dichloropyridine with heptyl
boronic pinacol ester (2.3 equiv) proceeded in a 4:1 mixture of
dioxane:H2O at 100 °C with LiOtBu, 1 mol% Pd(OAc)2 and 3
mol% Ad2PnBu to afford 2,6-diheptylpyridine (5a) in excellent
selectivity and 94% isolated yield (entry 1). In general, LiOtBu is
not included as a base during empirical screens of Suzuki-
Miyaura reaction conditions.12,18 These results suggest that it
could be of broad relevance to base-tolerant substrates.
11e,h
Ph
tBuO
N
Cl
O
N
H
aGeneral reaction conditions: 1.0 equiv aryl chloride, 0.105 M dioxane/H2O (4:1),
2.3 equiv R2Bpin, 1 mol % Pd(OAc)2, 3 mol % Ad2PnBu, 6.0 equiv LiOtBu, 24 h, 100
°C. bIsolated yield. c2 mol % Pd(OAc)2, 6 mol % AdPnBu. d3.5 equiv R2Bpin, 9.0
equiv LiOtBu. e1.5 equiv R2Bpin, 3.0 equiv LiOtBu. 20 h. g16 h. hIsolated after
f
reaction with trifluoroacetic acid.
Under the optimized conditions, 2,6-dibromo- and 2,6-
dichloropyridine react with similar efficiency (entries 1, 18).
Consequently, we have chosen to investigate the reaction
scope with chloroaromatic electrophiles, which are thought to
be more challenging cross-coupling partners, and are often
more readily available and less expensive. An array of aryl
chlorides couple smoothly with pinacol boronic ester 6b (Table
2). Mono-, di-, and trichloropyridines are converted to mono-,
di-, and trialkylpyridines, respectively (entries 1–3). This
With 2,6-dichloropyridine, exhaustively coupled product 5a
is predominately formed only with an excess of boronic ester
6a. Conversely, when 6a is employed as the limiting reagent,
selectively coupled 4a is the major product (entry 16). By
2 | J. Name., 2012, 00, 1-3
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protocol tolerates electron-donating substituents on pyridine,
COMMUNICATION
Pyridyl chlorides react effectively with alkyl pinacol boronic
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which were not effectively transformed under our previously esters that incorporate distal unsaturatiDoOnI,: 1a0c.1e0t3a9ls/C, 7oCrCe00th9e97rFs
reported selective conditions (entry 4–5),9 as well as electron- (Table 3, entries 1–8). The clean formation of unsaturated
deficient aryl chlorides (entry 6). This protocol affects reaction products is notable, as similar selectivity would be difficult to
of other 2-chloroheteroaryl compounds, such as isoquinolines achieve via Heck olefination reactions or Suzuki-Miyaura
(entry 7). In most cases, the starting aryl chloride and the reactions involving transmetallation of in situ-generated
reported product account for the mass balance of the reaction. organoboranes. Additionally, these unsaturated compounds
An exception is 2,6-dichloro-4-trifluoromethyl pyridine, which can be valuable intermediates: the reaction of 2,6-
is known to be unstable at elevated temperatures (entry 8).
dichloropyridine to form 2,6-dihexenylpyridine constitutes a
formal synthesis of the fragrance molecule normuscopyridine,
which can be accessed upon ring-closing metathesis and
reduction (entry 2).20 As might be expected, these conditions
can also be applied to access biaryl compounds (entry 8).
One feature of this exhaustive protocol is that base-
sensitive substrates may undergo multiple base-mediated
transformations in a single operation. Notably, application of
the standard conditions to cross-couple a silyl ether with an
activated 2-pyridyl chloride proceeds with desilylation to
furnish alcohol 5s (entry 9). As an alternative, the base labile
silyl ether coupling partner is amenable to slightly modified
conditions to deliver the intact silylated product (entry 10).
To push the limits of this protocol, we focused on allyl
pinacol boronic ester, which is known to be highly reactive and
easily protodeborylated (entry 11). While our optimized
reaction protocol involving LiOtBu does not generate the
desired product; anhydrous conditions can be applied with a
more organic soluble base to promote productive cross-
coupling. To the best of our knowledge, this represents the
first example of direct Suzuki-Miyaura catalyzed allylation of
an aryl chloride, previous reports being limited to the use of
more reactive aryl iodides and bromides.
Table 3. Functional group tolerance in disclosed Suzuki-Miyaura reactions
Ad2PnBu, Pd(OAc)2
LiOtBu
pinB–R2
+
R1
N
Cl
R2 /R1
N
R2
dioxane/H2O
100 °C, 24 h
(1 equiv)
(2.3 equiv)
R1
organoboron
entrya
product
yield (%)b
n
4
5
1
2
Cl
Cl
pinB
5m, 90
5n, 85
(
)
n
( )
n
N
(
)
n
R3 R4
5o, 44
R3
5p, 45
3c
4d
Cl
Cl
Et
H
H
R3
pinB
R3
(
(
)
(
)
( )
2
2
Et
N
2
R4
R4
R4
R3
R3 R4
5q, 85
5r, 84
5c,e,f tBuO
6d,e,f tBuO
R3
Et
H
H
pinB
pinB
(
)
2
)
O
N
H
2
Et
R4
R4
5s, 90
5t, 99
7f
tBuO
O
O
tBuO
N
O
O
8g tBuO
(HO)2B
Ph
tBuO
N
Ph
R3
H
5u, 84
5v, 89
9f
tBuO
pinB
OTBS
(
)
3
OR3
B2pin2, LiOMe
CuI, PPh3
10g tBuO
TBS
tBuO
N
(
)
3
Cl
Br
Cl
Bpin
11e,i tBuO
5w, 47
3
3
DMF
pinB
7
6x
NaH, NaI
DMF, 80 °C
(85% yield)
O
N
H
(88% yield)
1. Mg, THF
tBu
aGeneral reaction conditions: 1.0 equiv aryl chloride, 0.105 M dioxane/H2O (4:1),
2.3 equiv R2Bpin, 1 mol % Pd(OAc)2, 3 mol % Ad2PnBu, 6.0 equiv LiOtBu, 24 h, 100
°C. bIsolated yield. cPinacol boronic ester and product have isomeric ratios of
>19:1 E:Z. dPinacol boronic ester and product have isomeric ratios of >19:1 Z:E.
eIsolated after reaction with trifluoroacetic acid. f1.5 equiv R2Bpin, 3.0 equiv
LiOtBu. g1.5 equiv RrBpin, 3.0 equiv K3PO4, no LiOtBu. h1.5 equiv PhB(OH)2, no
R2Bpin, 3.0 equiv LiOtBu, 18 h. i4.0 equiv CsF, no LiOtBu.
OH
then (EtO)2CO
2. HCl, PhOH
(59% yield)
Ar
Ar
Br
Ar
Ar
8
9
O
Bpin
Ad2PnBu, Pd(OAc)2, LiOtBu
dioxane:H2O, 100 °C, 24 h
(75% yield)
5
+
Ar
Ar
Cl
N
Cl
Ar
6y
3a
These conditions do not productively transform more
acidic substrates, such as 6-chloroindole and 6-chloropyridin-
2-one, both of which would be expected to be deprotonated
under the reaction conditions. Even p-chloroacetophenone
does not undergo efficient cross-coupling, possibly due to
competitive deprotonation (Table 2, entry 10). Relative to
HOtBu, p-chloroacetophenone is more acidic in DMSO (pKa
O
O
N
Ar
Ar
Ar
1
Ar
Ar
Ar
Scheme 2. Application to the synthesis of a dumbbell shaped molecule for a
rotaxane
23.78 vs 32.2), and slightly more basic in water (pKa 18.1 vs.
19
16.5.16b,
Many base-originated limitations can be
The utility of the disclosed reaction has been demonstrated
in the synthesis of a dumbbell shaped molecule for a rotaxane
(i.e., 1). Pyridine 1 has been previously accessed in a longest
linear sequence of five steps, or in three steps and 54% yield
surmounted through use of a weaker base or by substrate
design. For example, substrate redesign permits access to 6-
alkylpyridin-2-ones from 2-alkoxy-6-chloropyridines (entry 11).
Therefore, this protocol may be used as a launching point for
optimization of Suzuki-Miyaura reactions of 2-halopyridines
with alkyl boronic esters displaying increased base sensitivity.
from common intermediate
9
via palladium-catalyzed
Sonagashira cross-coupling and hydrogenation reactions.1d
This new protocol furnishes 1 in in two steps and 64% yield
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Angew. Chem. Int. Ed., 2012, 51, 2667; (e) S. Sakashita, M.
from common intermediate 9. This protocol could assist in the
development of new molecular machines, as, in principle, the
alkyl boronic ester substrate can be easily modified to access
threads of varying length or to generate differentially
substituted dumbbell shaped molecules if deployed in
sequence with the previously disclosed selective method.9
In conclusion, these optimized Suzuki-Miyaura reaction
conditions enable the controlled alkylation of series of 2,6-
dichloropyridines in presence of unsaturation, etherial
linkages, or acetals. The use of bulky Ad2PnBu in combination
with LiOtBu facilitates oxidative addition onto 2-chloro-6-
alkylpyridines, thereby forming exhaustively alkylated
products. Importantly, these reaction conditions minimize β-
hydride elimination processes as well as protodehalogenation
of the starting materials. These conditions have been applied
to gain efficient access to a known [2]rotaxane component.
This project was funded by the American Chemical Society
Petroleum Research Fund Doctoral New Investigator Program
(PRF# 54824-DNI1) and by Duke University. J.M.B. was
supported by the National Institute of General Medical
Sciences (T32GM007105-41). Characterization data were
obtained on instrumentation secured by funding from the NSF
(CHE-0923097, ESI-MS, George Dubay, the Duke Dept. of
Chemistry Instrument Center), or the NSF, the NIH, HHMI, the
North Carolina Biotechnology Center and Duke (Duke
Magnetic Resonance Spectroscopy Center). Jacob Timmerman
and Prof. R. Widenhoefer of Duke University are thanked for
their insights. Ekaterina Khlystova and Brendan Sweeney are
thanked for their contributions to initial investigations.
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2
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3
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