N,N-diethyl O-carbamate: Directed metalation group and orthogonal Suzuki-Miyaura cross-coupling partner

Article abstract of DOI:10.1021/ja907700e

(Chemical Equation Presented) The first Suzuki-Miyaura cross-coupling of an aryl O-carbamate, a versatile and powerful directed metalation group (DMG) in directed ortho metalation (DoM) chemistry, is described using the inexpensive, bench-stable catalyst NiCl₂(PCy₃)₂. Broad synthetic scope and good efficiency are demonstrated for aryl and heteroaryl O-carbamates. The role of water and hydrolysis equilibrium between free boronic acid and boroxine was established to be a crucial parameter for this transformation. When combined with DoM and traditional Pd-catalyzed Suzuki-Miyaura strategies, the methodology offers concise routes to uniquely substituted molecules, avoiding the need for protection/deprotection of the phenol and the use of strongly nucleophilic cross-coupling partners.

Full text of DOI:10.1021/ja907700e

Published on Web 11/20/2009
N,N-Diethyl O-Carbamate: Directed Metalation Group and Orthogonal
Suzuki-Miyaura Cross-Coupling Partner
Aurora Antoft-Finch, Tom Blackburn, and Victor Snieckus*
Department of Chemistry, Queen’s UniVersity, Kingston, Ontario K7L 3N6, Canada
Received September 17, 2009; E-mail: snieckus@chem.queensu.ca
For C-C bond formation in general, and for the aryl-aryl
conjunction in particular, transition metal-catalyzed cross-coupling
reactions1 have superseded all previous classical methodologies.2
The Pd-catalyzed Suzuki-Miyaura reaction1c,3 has proven par-
ticularly robust, while Ni-catalyzed cross-coupling of organoboranes
has been successfully achieved with a variety of leaving groups
(LG ) halo,4 OTs,5 OMs6). With the background of original results
of Wenkert7 and Dankwardt,8 organoborane couplings with LG )
OMe has been reinforced by the seminal contributions of Chatani9
and Kakiuchi.10 Recently, more manipulable groups (LG ) OAc,11
OPiv12) have been introduced as cross-coupling partners.13
With aims to enhance and extend the scope of directed ortho
metalation (DoM)-cross-coupling strategies,14 we have established
aryl O-carbamate,15,16 S-thiocarbamate,17 sulfonamide,18 and O-
sulfamate19 Ni-catalyzed Grignard (Kumada-Corriu) cross-
coupling reactions (Scheme 1). In addition, we have demonstrated
reductive cleavage of some of these functionalities,15a,18 which
allows their use as latent directed metalation groups (DMGs) for
the synthesis of less common, e.g. meta-substituted, aromatics.
(compare entries 5 and 8). Other potentially critical factors
investigated were the presence of NiO25 (derived from Ni(cod)2
oxidation) (entry 2) and traces of Pd26 (entry 4).
It was only after observing a significant difference in reactivity
using various samples of both commercial and prepared PTBA
under identical experimental conditions that the culprit parameters
of the reaction were revealed.
1
Extensive H NMR studies established that (a) under strictly
anhydrous conditions, the boroxine 1b is a sluggish coupling partner
(entry 7); (b) in organic solvents, PTBA liberates excessive water
which is detrimental to the reaction (entry 6); and (c) a ratio of
1b:1a ) 10:1 is most effective.27 Resolution of the reproducibility
problem, as delineated below, and further optimization led to full
conversion within 5 h using only 5 mol % of catalyst (entry 11).
Table 1. Optimization Studies for the Conversion 3 f 4
Scheme 1. Cross-Coupling and Reductive Latency of DMGs
K3PO4
entry solvent T (°C) cat. (5 mol %) L (mol %)b (equiv)
ArB(OR)2
(equiv)c
yield (%)d
1
2
3
4
5
6
7
8
9
dioxane 120 Ni(cod)2
10
10
10
10
10
10
10
-
3
3
3
5
3
5
5
1b:a (2.0)
1b:a (2.0)
2 (2.5)
0
0
0
The positional apex in the DoM hierarchy of the O-carbamate
DMG and its considerable utility in synthetic aromatic chemistry19-22
have motivated our continuing efforts to increase its cross-coupling
potential. Herein we report on the Suzuki-Miyaura cross-coupling
of Ar-OCONEt2 systems as a general methodology for the synthesis
of biaryls and heterobiaryls.23 Furthermore, we demonstrate the
inherent DoM-cross-coupling link that allows the regioselective
preparation of polysubstituted aromatics as well as selective and
sequential orthogonal coupling to establish 1,2-diarylbenzene
substitution. The combined results offer a functional group compat-
ibility advantage over the previous Kumada-Corriu reactions,15,18,19
thereby providing a new general process for the conversion of
phenolic derivatives to biaryls starting from large selections of
commercial materials as well as those derived from DoM tactics.
Based in part on conditions reported by Garg,12 scouting coupling
experiments on 2-naphthyl O-carbamate 3 with p-tolylboronic acid
(PTBA, 1a) were carried out, selected results of which are shown
in Table 1. Initial attempts were not promising, resulting in
irreproducible reaction rates and yields. The more stable
NiCl2(PCy3)2 was used rather than Ni(cod)2 because inconsistent
results were observed with the latter catalyst.24 The hygroscopic
nature of K3PO4 necessitated the use of scrupulously dried material
PhMe
PhMe
PhMe
PhMe
120 NiO
120 Ni(cod)2
e
120
1b:a (2.5) 11
Ni(cod)2
120 NiCl2(PCy3)2
f
f
g
1b:a (2.0) 37
h
o-xylene 150 NiCl2(PCy3)2
o-xylene 150 NiCl2(PCy3)2
26
61
1b:a (2.5)
1b (2.5)
i
i
PhMe
PhMe
120
7.2 1b:a (2.5) 62
1b:a (4.0) 69
7.2 1b:a (2.5) 69
5 1b:a (2.0)
NiCl2(PCy3)2
120 Ni(cod)2
120
10
-
10
5
10 PhMe
11
NiCl2(PCy3)2
o-xylene 150 NiCl2(PCy3)2
f
j
100 (84)
a All reactions run for 20 h. b Ligand ) PCy3HBF4. c Based on
[ArB(OR)2], ratio of 1b:1a ) 10:1. d Yield based on GC/MS analysis.
e With added 1 mol % of PdCl2. f Reaction run for 5 h. g Hydrate was
used. h Ratio of 1b:1a ) 1:1. i 10 mol % used. j Yield of isolated
product.
As shown in related couplings of organoboronates, control of
the hydrolysis equilibrium of free boronic acid with the less reactive
boroxine is important.28 In this context, Shi11 reported the crucial
role of water content for the Suzuki-Miyaura cross-coupling of
aryl acetates, a situation that, however, is inconsequential to
O-carbamates, which are stable to hydrolysis.29 The detailed studies
by Liu30 on the coupling of aryl esters suggest oxidative addition
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10.1021/ja907700e  2009 American Chemical Society

C O M M U N I C A T I O N S
via a monophosphine-Ni0 intermediate and transmetalation with
K[PhB(OH)3]. Qualitative rate experiments varying the boraxine:
water ratio clearly showed the requirement of an optimal balance.31
Strictly anhydrous conditions resulted in sluggish reaction rates,
eventually reaching near completion, while the presence of large
amounts of water resulted in poor conversions and almost complete
catalyst deactivation after 5 h. On the basis of these observations,
we speculate that very little water is necessary to generate the
required boronate for entry into the catalytic cycle. However, a
large excess of water, generated from trimerization of the free
boronic acid, significantly reduces catalytic activity by forming
inactive nickel hydroxides/oxides.32
Table 2. Ni-Catalyzed Cross-Coupling of Aryl O-Carbamates
After considerable time and effort in the optimization studies,33
we turned our attention to defining the scope and functional group
tolerance of this transformation (Table 2). Prototype naphthyl and
phenyl substrates underwent smooth cross-coupling (entries 1, 2).
For simple aryl substrates, electron-withdrawing group (EWG)-
substituted systems (entry 4) showed higher reactivity, while those
with electron-donating groups (EDGs) (entry 3) gave poor yields,
including ortho-substituted cases (entries 6, 9). The cyano derivative
(entry 5) appeared aberrant, leading to low yields of product as a
result of cross-coupling at the cyano group, thus resulting in a
mixture of products.34 The attribution of poor reactivity to steric
hindrance is not warranted at present since coupling of o-benzyl,
-styryl, and -phenyl O-carbamates proceeded in good to excellent
yields (entries 7, 8, 10).
Scheme 2. Synthetic DoM-Cross-Coupling Interconnections of
Aryl O-Carbamates
The high reactivity of 3-pyridyl O-carbamate and ease of purification
of derived products led to a more extensive exploration of this substrate
with a variety of boroxines (entries 11-15). Aside from phenylborox-
ine (entry 11), arylboroxines bearing both EDGs (entries 12, 13) and
EWGs (entries 14, 15) afforded products in good yields. Extension of
coupling to quinolyl and carbazole heterocycles was also achieved,
albeit in modest yields (entries 16, 17).
The availability of the new O-carbamate cross-coupling manifold
in context of the DoM-cross-coupling strategy14 adds new synthetic
dimensions, as demonstrated by the construction of three types of
heterocycles (Scheme 2). Thus, the 2H-chromene O-carbamate 5,
prepared previously by a one-pot DoM-cyclization sequence35 and
employed in total synthesis,36 was converted into the uniquely
substituted 5-phenyl-2H-chromene 6, representing a heterocyclic
a ArB(OR)2 (2.5 equiv), ratio of Ar3B3O3:ArB(OH)2 ) 10:1. b Yield by GC/
MS analysis (yield of isolated product).
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C O M M U N I C A T I O N S
framework of bioactivity37 and natural product38 interest. Similarly,
compounds 7 and 9, whose origins are rooted in the combined DoM/
Suzuki-Miyaura methodology, were transformed into heterobiaryls
839 and 10,40 respectively.41 The inertness of the O-carbamate to
Pd-catalyzed coupling allows it to assume an orthogonal cross-
coupling partner role when linked with the Ni coupling strategy.
The 1,2,3-substitution pattern of heterobiaryl 8 is unique, while
compound 10 represents a class of pyridines with nonidentical diaryl
substitution for which only two synthetic methods are available.42
In summary, an efficient and general Suzuki-Miyaura cross-
coupling reaction of aryl O-carbamates has been demonstrated. The
transformation was optimized for use with only 5 mol % of the
cost-effective, bench-stable catalyst NiCl2(PCy3)2. The critical
dependence of water, a point of potential general significance for
boronic acid coupling reactions, was delineated. The results, together
those of Garg and co-workers,23 especially on the aryl O-sulfamates,
are agreeably complementary for synthetic application. A new
DoM-Ni-catalyzed cross-coupling nexus for the prominent OCO-
NEt2 DMG was established whose orthogonal use with the Pd-
catalyzed Suzuki-Miyaura reaction anticipates further utility in
aromatic and heteroaromatic synthesis.
bearing an attached DMG, see Ihara, H.; Suginome, M. J. Am. Chem. Soc.
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(23) During the course of our work, we learned of the studies of Garg and co-
workers (accompanying Communication) which, in addition to O-carbamate
systems, significantly expand the Suzuki-Miyaura reaction to carbonates
and O-sulfamates. We are grateful to Prof. Garg for liberal exchange of
results and for agreement to consecutive publication.
(24) Although precautions were taken, Ni(cod)2 was observed to undergo rapid
oxidation when maintained outside of the glove box, thus giving irrepro-
ducible results. This was also noted by Garg and co-workers; see ref 12.
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Acknowledgment. We are grateful to NSERC Canada for
sustained support of our research programs. We very much
appreciate the assistance of Dr. Franc¸oise Sauriol (NMR) and Lina
Yuan (HRMS). We offer a special gratitude to Professor Garg
(UCLA) for agreement to consecutive publication.
Supporting Information Available: Detailed experimental proce-
dures and compound characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
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