C-O cross-coupling of activated aryl and heteroaryl halides with aliphatic alcohols

Article abstract of DOI:10.1002/anie.201203460

A robust and general catalyst system facilitates the alkoxylation of activated heteroaryl halides with primary, secondary, and select tertiary alcohols without the need for an excess of either coupling partner (see scheme). This catalyst system displays broad functional-group tolerance and excellent regioselectivity, and is insensitive to the order of reagent addition. Copyright

Full text of DOI:10.1002/anie.201203460

Angewandte
Chemie
DOI: 10.1002/anie.201203460
Cross-Coupling
À
C O Cross-Coupling of Activated Aryl and Heteroaryl Halides with
Aliphatic Alcohols**
Peter E. Maligres,* Jing Li,* Shane W. Krska, John D. Schreier, and Izzat T. Raheem*
Aromatic ethers are ubiquitous structural motifs present in
both natural and synthetic compounds including dozens of the
200 top-selling drugs on the market today (Figure 1).[1]
Traditional methods for accessing this functionality, such as
direct nucleophilic aromatic substitution (SNAr) and Ullmann
coupling, typically require reactive aryl halides or harsh
reaction conditions and thus display limited substrate scope
and functional-group compatability. As a result, over the past
15 years there has been a dramatic increase in the develop-
À
ment of transition-metal-catalyzed C O bond-forming reac-
tions. In particular, advances in ligand design have resulted in
improved methods for Pd-[2] and Cu-catalyzed[3] C O cou-
À
pling reactions of aliphatic alcohols with aryl halides. For
example, Buchwald and co-workers recently reported bulky
biarylphosphine ligands that show high activity with Pd for
the coupling of a broad range of primary and secondary
aliphatic alcohols and (hetero)aryl halides.[4]
Despite these advances, significant limitations remain
with respect to generality, functional-group tolerance, alcohol
stoichiometry, coupling partner scope, and catalyst availabil-
ity. Herein, we describe a Pd/Josiphos catalyst system for the
alkoxylation of activated aryl and heteroaryl halides with
primary, secondary, and select tertiary alcohols. The catalyst
system displays broad functional-group tolerance at both
coupling partners, and provides a robust, complementary
approach to existing methods.
Our interest in heteroaryl alkyl ethers for drug discovery
led us to explore conditions for Pd-catalyzed CO coupling
reactions that would allow general access to these systems. To
survey the catalyst system that would display the broadest
generality, a screen was performed for the coupling of three
heteroaryl halides with alcohol 2a (Figure 2).[5] While several
ligands provided active catalysts for the coupling of 1b,[6] only
the Josiphos analogue CyPF-tBu (Figure 3), utilized exten-
À
À
sively by Hartwig and co-workers for C N and C S
couplings,[7] displayed superior performance for the more
challenging aryl halides 1a and 1c. A follow-up ligand screen
with a total of 72 ferrocenyl-type phosphine ligands for the
coupling of 1a with 2a confirmed CyPF-tBu to provide the
most active catalyst/ligand system.[5]
Figure 1. Selected pharmaceuticals containing aryl–alkyl ether units;
the corresponding ether oxygen atoms are in bold.
In a broader solvent screen using CyPF-tBu, optimal
results were obtained consistently with THF and toluene,
although a number of solvents examined also gave moderate
to high yields.[5] The Pd source [(allylPdCl)2][5] provided the
most active catalyst, followed by [Pd2(dba)3]. Under opti-
mized conditions the coupling of heterocyclic halides 1a–c
with 2-phenylethyl alcohol (2a) on a 1 mmol scale using
1 mol% of CyPF-tBu and 0.5 mol% of [(allylPdCl)2] (3 equiv
Cs2CO3, THF, 808C, 20 h) proceeded with more than 99%
conversion and provided the isolated product in yields of at
least 90%.[8]
[*] P. E. Maligres,[+] S. W. Krska
Department of Process Chemistry, Merck Research Laboratories,
Rahway, NJ 07065 (USA)
E-mail: peter_maligres@merck.com
J. Li[+]
Department of Discovery Process Chemistry, Merck Research
Laboratories, West Point, PA 19486 (USA)
E-mail: jing_li9@merck.com
J. D. Schreier, I. T. Raheem[+]
Department of Discovery Chemistry, Merck Research Laboratories,
West Point, PA 19486 (USA)
E-mail: izzat_raheem@merck.com
[+] These authors contributed equally to this work.
The surprisingly low reactivities observed with the Rock-
Phos ligand (Figure 3)[4] in the initial screen prompted us to
examine this catalyst in more detail (Table 1). The original
publication noted that preformation of the catalyst was
required for couplings of heteroaryl halide substrates, pre-
sumably because of competitive displacement of the phos-
[**] We thank Prof. Stephen L. Buchwald and Michael Palucki for helpful
discussions and Janine Noelle Brouillette for her contribution to the
NMR structure elucidaton.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201203460.
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chloride, and 4 ꢀ molecular
sieves in toluene at 908C for
10 min prior to the introduc-
tion of the alcohol was
required to achieve high con-
version and yield (Table 1,
entry 7). In contrast, the
CyPF-tBu/Pd catalyst system
did not require catalyst pre-
formation and was not sensi-
tive to the order of addition
of reagents (Table 1). This
increased robustness of the
CyPF-tBu/Pd system in the
presence of heterocyclic sub-
strates is attributed to the
bidentate nature of the
ligand[7a] and was further
illustrated by comparing the
performance of RockPhos
and CyPF-tBu in the cou-
pling of the heterocyclic alco-
hol 2b with the heterocyclic
aryl halides 1c and 1d: under
the optimized conditions the
RockPhos-derived catalyst
Figure 2. Initial ligand screen for the coupling of aryl halides 1a–1c with alcohol 2a. Reactions were
performed using 0.02 mmol of each coupling partner in 0.1 mL of solvent. Assay yields are based on the aryl
halide calculated from quantitative HPLC data. dba=dibenzylideneacetone. For ligand abbreviations see the
Supporting Information.
gave yields of 30% and 70%, respectively, with significant
by-product formation, while CyPF-tBu gave full conversion
and more than 99% yield.[5]
The scope of the (hetero)aryl halide component of the
reaction using 2b as a representative alcohol was explored.
We were pleased to find that the optimized reaction
conditions were tolerant of a wide variety of electron-
deficient aromatic and heteroaromatic systems.[9] In all
cases, only one equivalent of alcohol was used, and minimal
background reactions were observed. This is highlighted by
the selective functionalization of 2-fluoro-4-chloropyridine
(Table 2, entry 7) which provided only the product of reaction
at chlorine under the optimized reaction conditions. Addi-
Figure 3. CyPF-tBu and RockPhos ligands. cyHx=cyclohexyl.
Table 1: Exploring the order of addition for different ligands.[a]
À
tionally, no C N coupling reactions were observed for amine-
bearing substrates 1a and 1 f.
In contrast to electron-deficient aromatic and heteroar-
omatic halides, electron-neutral aryl halides typically reacted
with low conversion (Table 2, entries 12–14). Since CyPF-tBu/
Yield [%]
Premixed reagents
Cat.
Cat., 1b, Cs2CO3
Cat., 2a, Cs2CO3
Cat., 1b, 2a
Cat., 1b, 2a, Cs2CO3
Cat., 1b, Cs2CO3
Cat., 1b, Cs2CO3, 4 ꢀ M.S.
RockPhos
CyPF-tBu
99
>99
>99
>99
99
À
À
Pd is known to be reactive for C N and C -S couplings of
unactivated aryl chlorides,[7] it is unlikely that sluggish
oxidative addition explains our observation. Rather, it is
possible that either alcohol displacement of the halide in the
Pd–(aryl halide) complex, or the subsequent reductive
1
2
3
4
5
6
7
22
58
26
4
0
56[b]
98[b]
–
–
À
elimination of the C O bond to form the product ether are
disfavored at this highly hindered, electron-rich metal
center.[10]
[a] Assay yields based on aryl halide calculated from quantitative HPLC
data. Reaction conditions: [1b]0 =[2a]0 =0.2m, 0.5 mol% [(allylPdCl)2],
2 equiv Cs2CO3, 908C, 24 h. RockPhos or tBu-BrettPhos/Pd=1.5:1.0;
CyPF-tBu/Pd=1:1. [b] [1b]0 =0.5m, 2 equiv 2a.
The reaction exhibited excellent functional-group toler-
ance for structurally diverse alcohols in couplings with 1c
(Table 3). Unexpectedly, an alkyne was concurrently trans-
formed to the 1,3-diene 3ci, presumably by means of 1,2-
aryloxy migration (Table 3, entry 8).[11] Complete regioselec-
tivity was observed for primary over secondary over tertiary
alcohols (Table 3, entries 6 and 14).[12]
phine ligand by the heterocycle.[4] After examining a number
of variations on catalyst preformation and orders of addition,
we found that heating the palladium source, ligand, heteroaryl
2
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Table 2: Aryl halide scope.[a]
Table 3: C O cross-coupling of 5-bromoquinoline with structurally
À
diverse alcohols.[a]
À
Ar X
À
Ar X
Yield
temp.
time
Yield
temp.
time
R-OAr
Yield
temp.
time
R-OAr
Yield
temp.
time
86%
808C
16 h
66%
1408C
1 h
84%
808C
20 h
72%[b]
1408C
6 h
1
2
8
9
1
2
3
4
5
6
7
8
82%
808C
16 h
55%
1408C
1 h
75%
1008C
20 h
87%
808C
20 h
9
82%
808C
2 h
58%
808C
16 h
74%
1008C
20 h
90%
1408C
6 h
3
10
10
11
12
13
14
75%
1008C
20 h
88%
1408C
6 h
49%
808C
16 h
70%
1408C
1 h
4
5
11
12
72%
1008C
20 h
86%
1008C
20 h
67%
808C
2 h
<5%
1208C
16 h
56%
1408C
1 h
60%
1408C
1 h
<5%
1208C
16 h
<5%
1208C
16 h
77%
1008C
20 h
83%
1408C
6 h
6
7
13
14
86%
1008C
20 h
81%
1408C
6 h
[a] Reaction conditions: CyPF-tBu (10 mol%), [Pd2(dba)3] (5 mol%),
Cs2CO3 (2 equiv), toluene (0.2m).
[a] Reaction conditions: CyPF-tBu (10 mol%), [Pd2(dba)3] (5 mol%),
Cs2CO3 (2 equiv), toluene (0.2m). [b] Alcohol starting material was but-2-
yn-1-ol.
À
Table 4: C O coupling of 2-chloro-4-methylquinoline with tertiary alco-
hols.[a]
Furthermore, tertiary alcohols were found to couple
successfully (Table 4), although the more sterically demand-
ing alcohol 2r failed to give significant conversion to product.
The use of [(allylPdCl)2] rather than [Pd2(dba)3] as well as
higher reaction temperatures was found neccessary for
efficient couplings with these more challenging substrates.
To the best of our knowledge, this is the first example of
R-OAr
Yield
72%
R-OAr
Yield
77%
1
4
À
a general intermolecular Pd-catalyzed C O cross-coupling
reaction tolerant of primary, secondary, and tertiary alcohols
employing a relatively mild base.
2
3
58%[b]
5
6
83%
85%
In conclusion, a robust and general Pd/Josiphos catalyst
system has been identified for the alkoxylation of activated
heretoaryl halides with primary, secondary, and select tertiary
alcohols without the need for an excess of either coupling
partner. The commercial availability of the Josiphos CyPF-
tBu ligand, excellent regioselectivity, absence of a required
catalyst preformation step, insensitivity to the order of
reagent addition, and broad functional-group tolerance
make this protocol a robust, complementary approach to
<5%[c]
[a] Yield of isolated product after chromatographic purification.
[b] Product is hydrolytically unstable. [c] No isolation attempted.
Received: May 4, 2012
Revised: June 1, 2012
À
existing methods for C O bond formation.
Published online: && &&, &&&&
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À
catalysis (SnAr conditions), and only very sluggish conversion
with the formation of byproducts in DMF, DMAc, and DMSO at
80–1408C.
Keywords: C O cross-coupling · heterocycles ·
homogeneous catalysis · palladium · synthetic methods
.
[9] Because of its widespread availability, shelf stability, and ease of
handling, [Pd2(dba)3] was chosen as the Pd source for studies
aimed at demonstrating the synthetic scope of this catalyst
system.
[10] a) G. Mann, C. Incarvito, A. L. Rheingold, J. F. Hartwig, J. Am.
Chem. Soc. 1999, 121, 3224 – 3225; b) G. Mann, J. F. Hartwig, J.
Am. Chem. Soc. 1996, 118, 13109 – 13110; c) R. A. Widenhoefer,
S. L. Buchwald, G. Mann, J. F. Hartwig, J. Am. Chem. Soc. 1998,
120, 6504 – 6511.
[11] G. Li, G. Zhang, L. Zhang, J. Am. Chem. Soc. 2008, 130, 3740.
The structure of the product was determined by 2D NMR
correlation techniques.
[12] Regioselectivity was confirmed by 2D NMR correlation tech-
niques.
[1] D. J. Mack, M. L. Weinrich, E. Vitaku, J. T. Njaroarson, http://
cbc.arizona.edu/njardarson/group/top-pharmaceuticals-poster.
[2] S. Enthaler, A. Company, Chem. Soc. Rev. 2011, 40, 4912 – 4924.
[3] a) J. Niu, P. Guo, J. Kang, Z. Li, J. Zu, K. Hu, J. Org. Chem. 2009,
74, 5075 – 5078; b) R. A. Altman, A. Shafir, A. Choi, P. A.
Lichtor, S. L. Buchwald, J. Org. Chem. 2008, 73, 284 – 286.
[4] X. Wu, B. Forrs, S. L. Buchwald, Angew. Chem. 2011, 123,
10117 – 10121; Angew. Chem. Int. Ed. 2011, 50, 9943 – 9947.
[5] See the Supporting Information for further details.
[6] Similar results were obtained using K3PO4 as the base in toluene.
[7] a) J. F. Hartwig, Acc. Chem. Res. 2008, 41, 1534 – 1544; b) M. A.
Fernꢁdez-Rodrꢂguez, J. F. Hartwig, Chem. Eur. J. 2010, 16, 2355 –
2359.
[8] Substrates 1a–c showed no appreciable product formation with
phenylethyl alcohol (2a) in toluene or THF in the absence of Pd
4
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Cross-Coupling
P. E. Maligres,* J. Li,* S. W. Krska,
J. D. Schreier,
I. T. Raheem*
&&&& — &&&&
À
C O Cross-Coupling of Activated Aryl and
Heteroaryl Halides with Aliphatic
Alcohols
A robust and general catalyst system
facilitates the alkoxylation of activated
heteroaryl halides with primary, secon-
dary, and select tertiary alcohols without
the need for an excess of either coupling
partner (see scheme). This catalyst
system displays broad functional-group
tolerance and excellent regioselectivity,
and is insensitive to the order of reagent
addition.
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!