General copper-catalyzed coupling of alkyl-, aryl-, and alkynylaluminum reagents with organohalides

Article abstract of DOI:10.1021/acs.joc.5b02077

We report the first example of a very general Cu-catalyzed cross-coupling of organoaluminum reagents with organohalides. The reactions proceed for the couplings of alkyl-, aryl-, and alkynylaluminum reagents with aryl and heteroaryl halides and vinyl bromides, affording the cross-coupled products in good to excellent yields. Both primary and secondary alkylaluminum reagents can be utilized as organometallic coupling partners. These reactions are not complicated by β-hydride elimination, and as a result rearranged products are not observed with secondary alkylaluminum reagents even for couplings with heteroaryl halides under "ligand-free" conditions. Radical clock experiment with a radical probe and relative reactivity study of Ph₃Al with two haloarenes, 1-bromonaphthalene and 4-chlorobenzonitrile, having two different redox potentials indicates that the reaction does not involve free aryl radicals and radical anions as intermediates. These results combined with the result of the Hammett plot obtained by reacting Ph₃Al with iodoarenes containing p-H, p-Me, p-F, and p-CF₃ substituents, which shows a linear curve (R² = 0.99) with a ρ value of +1.06, suggest that the current transformation follows an oxidative addition-reductive elimination pathway.

Full text of DOI:10.1021/acs.joc.5b02077

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Article
General Copper-Catalyzed Coupling of Alkyl-, Aryl-
and Alkynylaluminum Reagents with Organohalides
Bijay Shrestha, Surendra Thapa, Santosh K. Gurung, Ryan A. S. Pike, and Ramesh Giri
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02077 • Publication Date (Web): 06 Jan 2016
Downloaded from http://pubs.acs.org on January 11, 2016
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Page 1 of 55
The Journal of Organic Chemistry
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General Copper-Catalyzed Coupling of Alkyl-, Aryl- and Al-
kynylaluminum Reagents with Organohalides
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Bijay Shrestha, Surendra Thapa, Santosh K. Gurung, Ryan A. S. Pike, Ramesh Giri*
Department of Chemistry & Chemical Biology, The University of New Mexico, Albuquerque, NM
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87131
Corresponding author’s email address: rgiri@unm.edu
GRAPHICALABSTRACT
ABSTRACT: We report the first example of a very general Cuꢀcatalyzed crossꢀcoupling of organoaluꢀ
minum reagents with organohalides. The reactions proceeds for the couplings of alkylꢀ, arylꢀ and alꢀ
kynylaluminum reagents with aryl and heteroaryl halides, and vinyl bromides affording the crossꢀ
coupled products in good to excellent yields. Both primary and secondary alkylaluminum reagents can
be utilized as organometallic coupling partners. These reactions are not complicated by βꢀhydride elimiꢀ
nation and as a result rearranged products are not observed with secondary alkylaluminum reagents even
for couplings with heteroaryl halides under ‘ligandꢀfree’ conditions. Radical clock experiment with a
radical probe and relative reactivity study of Ph Al with two haloarenes, 1ꢀbromonaphthalene and 4ꢀ
3
chlorobenzonitrile, having two different redox potentials indicate that the reaction does not involve free
aryl radicals and radical anions as intermediates. These results combined with the result of the Hammett
plot obtained by reacting Ph Al with iodoarenes containing pꢀH, pꢀMe, pꢀF and pꢀCF substituents,
3
3
2
which shows a linear curve (R = 0.99) with a ρ value of +1.06, suggest that the current transformation
follows an oxidative additionꢀreductive elimination pathway.
INTRODUCTION
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Crossꢀcouplings remain one of the most versatile transformations for carbonꢀcarbon (CꢀC) bond forꢀ
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mation in organic synthesis. The versatility of these reactions, generally catalyzed by Pd and Ni, stems
from their excellent ability to exploit a wide range of organometallic reagents, including those of Mg,
Zr, Zn, Sn, Al, B, Si and In as sources of nucleophiles. These organometallic reagents undergo facile
transmetalation with transition metals such as Pd and Ni, the catalysts of choice for crossꢀcoupling reacꢀ
tions. Interestingly, majority of these organometallic reagents are also known to transmetalation with
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Cuꢀsalts with ease under remarkably mild conditions. However, despite their ability to undergo facile
transmetalation with Cuꢀsalts to generate organocopper complexes and extensive application of Cuꢀ
3
catalysts in CꢀC bond forming reactions since the discovery of the dimerization of alkynylcopper(I)
4
complexes by Glaser in 1869, the application of Cuꢀbased catalysts for coupling reactions has proven to
be formidably challenging. As such, the scope of the Cuꢀcatalyzed crossꢀcoupling reactions remained
5
limited to the highly reactive and less functional group tolerant Grignard reagents in most cases and
6
toxic organotin reagents in some instances. A limited application of benign, stable and functional group
tolerant organometallic reagents were also known but were primarily limited to the couplings of zirꢀ
2e, 7
conacyclopentadienyl compounds
using stoichiometric amounts of Cuꢀsalts and reactive arylboronic
8
acids with catalytic quantities of Cuꢀsalts. Recently, our group reported an efficient crossꢀcoupling of
different organoboron reagents using a catalyst derived from the combination of CuI and a PN ligand, 2ꢀ
9
(
diꢀtertꢀbutylphosphino)ꢀN,Nꢀdimethylaniline (PNꢀ2). Our PN/CuI catalyst system remained versatile
10
and enabled the crossꢀcouplings of a variety of other organometallic reagents, such as organosilicon,
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organoindium, organozirconium and organozinc reagents. Brown and coꢀworkers also showed
that similar arylboronate esters could be coupled with aryl iodides using CuCl/Xantphos as a catalyst to
generate biaryl products. Alkylꢀ and arylboron reagents have also been shown to couple with primary
15
16
alkyl halides and pseudohalides, which proceed via a traditional S 2 process. Recently, Riant and
N
2
f, 17
Takeda
also disclosed Cuꢀcatalyzed reactions of aryl and vinylsilicon reagents with alkyl, benzyl
1
0c
and alkynyl halides. Despite these tremendous efforts in recent times in showcasing the effectiveness
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of Cuꢀcatalysts for crossꢀcoupling various organometallic reagents with organohalides, a general reacꢀ
tion that encompases a wide substrate scope is still far from reality. The reported reactions generally
proceed efficiently with aryl iodides. In limited cases, electronꢀdeficient aryl bromides and chlorides
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5e
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have separately been shown to react when Grignard, aryltin, arylindium and arylboron
reagents
are utilized as coupling partners.
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As our longꢀterm interests in developing Cuꢀbased catalytic systems for crossꢀcoupling, we are constentꢀ
ly exploring the feasibility of using various organometallic reagents as nucleophile sources that can unꢀ
dergo transmetalation to Cuꢀsalts. Among different metals whose organometallic complexes are known
to participate in transmetalation with Cuꢀsalts, Al tenders a distinctive feature owing to its high
2
0
chemoselectivity and Lewis acidity. In addition, Al also has low toxicity and remains one of the most
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1
inexpensive and earthꢀabundant metals. A recent seminal work by Knochel and coworkers that reꢀ
vealed a convenient reaction protocol for the synthesis of various functionalized organoalanes directly
from metallic aluminum further highlights the potential scope of organoaluminum reagents in organic
synthesis. However, despite widespread applications of organometallic reagents derived from Si, B, Mg,
Zn and Sn in crossꢀcoupling with Pd and Ni, utility of similar organometallic complexes of Al are limꢀ
2
1a, b, 22
23
ited. Successful reactions are largely restricted to the couplings of arylalanes
and alkenylalanes
24
while those of alkylalanes are still limited. In many cases, direct transmetalation of organoalanes to Pd
has been found to be slow and shown to require the addition of ZnCl or CdCl as intermediaries to faꢀ
2
2
2
3c
cilitate reactions through sequential transmetalations. In some circumstances, intramolecular coordiꢀ
2
4a, 25
nation to Al has been shown to enable crossꢀcoupling of alkylalanes with organohalides.
Surprisꢀ
2
1c, 26
27
2i
ingly, Knochel,
Hoveyda and others have shown that organoaluminum reagents undergo a facile
transmetalation with Cuꢀsalts as demonstrated by their participation in the allylic and conjugate addition
reactions. Encouraged by these literature reports and our recent studies, we anticipated that organoaluꢀ
minum reagents could potentially be excellent coupling partners for Cuꢀcatalyzed crossꢀcoupling reacꢀ
tions. In this article, we disclose for the first time that organoaluminum reagents are versatile coupling
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partners for Cuꢀcatalysts that enable crossꢀcouplings to proceed with a variety of organohalides such as
aryl iodides, and electronꢀdeficient aryl and heteroaryl bromides, heteroaryl chlorides and vinyl broꢀ
mides in good to excellent product yields. In these reactions, organoaluminum reagents such as arylꢀ,
alkylꢀ and alkynylalanes can be utilized as coupling partners.
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RESULTS AND DISCUSSION
Our initial investigation began with an attempt to crossꢀcouple commercially available triphenylalumiꢀ
num reagent with pꢀiodotoluene under our previsously reported conditions using 2 mol % of 2ꢀ
(diphenylphosphino)ꢀN,Nꢀdimethylaniline (PNꢀ1)/CuI in DMF at 120 °C. However, the reaction proꢀ
duced the coupled product, 4ꢀphenyltoluene (3), only in 45% yield (Table 1, entry 1). Further screening
of the reaction conditions using various bases and additives revealed that LiCl had a dramatic effect
which enabled the coupling to proceed with the formation of the product 3 in 88% GC yield in 6 h (enꢀ
try 2). While addition of 3 equivalents of LiCl also afforded the product 3 in a comparable yield (entry
3), 2 equivalents of LiCl remained optimal for the standard reaction with the commercially available
Ph Al. Increasing or decreasing the amounts of LiCl to 1 or 4 equvalents resulted in lower product
3
yields (entries 4 and 5). The reaction did not proceed at all in the absence of CuI and formed the product
3
only in 26% yield in the absence of PNꢀ1 (entries 6 and 7). The reaction furnished the product 3 in onꢀ
ly 17% yield in the absence of both PNꢀ1 and LiCl (entry 8). Decreasing the reaction time to 3 h also
diminished the product yield to 73% (entry 9). The reaction can also be performed with [CuOtBu) puriꢀ
fied by sublimation affording the coupled product 3 in 73% yield (entry 10). Replacing CuI with Pdꢀ or
Niꢀcatalysts, well established catalysts for crossꢀcoupling, produced the product 3 only in low yields
(entries 11ꢀ14), suggesting that the current reaction is unlikely to be catalyzed by low levels of Pd and
Ni contaminants. Use of Coꢀ and Feꢀcatalysts instead of CuI furnished the product 3 in 11% and 0%
yields, respectively (entries 15 and 16).
a
Table 1. Optimization of Reaction Conditions
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Reactions were run 0.1 mmol scale in 0.5 mL DMF. One equiv of 1 was used with respect to 2. Calibrated GC yields (averꢀ
age of at least two parallel runs). Value in parenthesis is the isolated yield (1.0 mmol).
Next, we examined the effects of various types of ligands that are either analogous to PNꢀ1 or are well
known for Cuꢀbased catalytic reactions. Various types of ligands used in the reaction are shown in
Scheme 1 and the corresponding yields of the product 3 are presented in the bar diagram in Figure 1.
Replacing Ph Pꢀ group in PNꢀ1 with (tBu) Pꢀ group (PNꢀ2) decreased the product yield significantly
2
2
(
56%). Use of PNꢀ3 and PNꢀ4 in which the dimethylamino goup of PNꢀ1 was replaced by piperidinyl
PNꢀ3) and morpholinyl (PNꢀ4) groups afforded significantly low product yields (54% and 72%, respecꢀ
(
tively). Changing the dimethylamino group of PNꢀ1 to pyridinyl (PNꢀ5 and PNꢀ6) and carbazolyl (PNꢀ
) groups also furnished the product 3 only in 30%, 36% and 21% yields, respectively. Use of rotationꢀ
7
ally flexible ligand PNꢀ8 also afforded the product 3 in 35% yield. Diphenylphosphorus amide ligand
PNꢀ9 provided the product 3 in a reasonable yield (65%). Bidentate phosphineꢀbased ligands such as
bis(diphenylphosphino)benzene (PPꢀ1) afforded the product 3 in lower yield (29%) than the reaction
without a ligand (45%). Phenanthroline (NNꢀ1) and bidentate amineꢀbased ligands (NNꢀ2, NNꢀ3 and
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2
8
NNꢀ4) that are known to generate excellent Cuꢀcatalysts for arylation of amines and phenols also afꢀ
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fected reaction adversely and decreased the product yields to 32%, 23%, 35% and 28%, respectively.
Similarly, anionic ligands such as 8ꢀhydroxyquinoline (NOꢀ1) and 2,2,6,6ꢀtetramethylꢀ3,5ꢀheptanedione
28
(
OOꢀ1), which are also excellent ligands for CꢀN and CꢀO bond formation, afforded lower product
yields (27% and 26%, respectively) than without a ligand. Nꢀheterocyclic carbene (NHC) ligands, such
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as 1,3ꢀBis(2,4,6ꢀtrimethylphenyl)imidazolium chloride (SIMes•HCl), also decreased the product yield
(25%).
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Ligands
PN-5
NN-4
PN-1
PP-1
PN-2
NN-1
PN-3
NN-2
PN-4
NN-3
PN-6
NO-1
PN-7
OO-1
PN-8
PN-9
SIMes•HCl
no ligand
Figure 1. Bar diagram showing the percentage yields of 4ꢀphenyltoluene (3) from the reaction of triꢀ
phenylaluminum reagent with 4ꢀiodotoluene in the presence of various types of ligands instead of PNꢀ1
under the standard reaction conditions from Table 1, entry 2. Yields are GC yields (average of at least
two parallel runs) of the product 3 calibrated against 2ꢀnitrobiphenyl as an external standard.
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Scheme 1. Ligands Used for Reaction Optimization
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After establishing the combination of PNꢀ1 and CuI as the best catalyst, we began to explore the subꢀ
strate scope of the reaction. The reaction proceeds with electronꢀneutral and electronꢀrich triarylalumiꢀ
num reagents (Table 2). The reactions of these triarylaluminum reagents proceed with both electronꢀ
poor and electronꢀrich aryl iodides and afford corresponding biaryl products in good yields. The reaction
tolerates sensitive functional groups such as nitrile, thiomethoxy and TBSꢀprotected alcohol (entries 4ꢀ
6
) and sterically hindered substituents like isoꢀpropyl group at the orthoꢀposition of iodoarenes (entry
7).
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a
Table 2. Coupling of triarylaluminum reagents with aryl iodides
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a
Reactions were run in 1.0 mmol scale in 5 mL DMF. One equiv of Ar Al was used with respect to ArI. Reactions for entries
3
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, 4, 6 and 8 were run for 12 h. Reactions for entries 2, 3, 5 and 7 were run for 6 h. Each reaction contains 3 equivalents of
LiCl, written in parenthesis below the reaction arrow, which is generated during the preparation of triarylaluminum reagents.
b
c
Yields are for analytically pure products isolated by column chromatography from a 1.0 mmol scale reaction. 5 mol%
d
CuI/PNꢀ1 was used. 2 mol% CuI/PNꢀ1 was used.
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Biaryl molecules containing heteroarenes widely occur in natural products, pharmaceuticals, drug canꢀ
29
didates and bioꢀactive molecules. These heteroarenes are previliged structures, which play vital roles
3
0
in biological functions. We are pleased to report that our current reaction conditions can be applied for
the arylation of heteroaryl iodides for the synthesis of a variety of heterobiaryl compounds (Table 3).
These reactions afford heterobiaryl molecules in best yields without the addition of the PNꢀ1 ligand. Reꢀ
actions with heteroaryl iodides under the standard conditions that contain PNꢀ1 ligand afford the crossꢀ
coupled products in lower yields. Reactions can be performed with nitrogenꢀcontaining heteroaryl ioꢀ
dides such as 2ꢀiodopyridine, 2ꢀchloroꢀ4ꢀiodopyridine, 6ꢀiodoquinoline, 7ꢀchloroꢀ4ꢀiodiquinoline, 1ꢀ
iodoisoquinoline and 2ꢀiodopyrazine and the corresponding heterobiaryl compounds are obtained in
I
good to excellent yields. This reactivity pattern of Cu ꢀcatalysts is in constrast to the reactivity of estabꢀ
lished metals Pd and Ni for crossꢀcoupling with heteroaryl halides. Generally, the known Pdꢀ and Niꢀ
catalyzed crossꢀcoupling reactions are less tolerant of heteroarenes because the heteroaryl substrates
compete with ligands to bind with these transition metals. Consequently, the Pdꢀ and Niꢀcatalysts are
3
1
deactivated eventually leading to the termination of the crossꢀcoupling reactions. Therefore, Pdꢀ and
Niꢀbased catalytic systems for coupling with heteroaryl halides generally require sterically hindered,
3
2
bulky phosphineꢀ or carbeneꢀbased ligands in order to suppress multiple ligations of heteroaryl subꢀ
I
10
strates to prevent the untoward deactivation pathway. In this respect, Cu ꢀbased catalysts, which are d
0
0
congeners of Pd and Ni , display a unique property in the current crossꢀcoupling reactions with hetꢀ
eroaryl substrates. This unique reactivity pattern is very general, and was observed previously by our
9
10a, b
11
12
group in the crossꢀcouplings of arylboron, arylsilicon,
organoindium, arylzirconium, and orꢀ
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1
3a
5e
ganozinc reagents with heteroaryl halides. In addition, Hintermann and coworkers have previously
demonstrated that Grignard reagents could be coupled with heteroaryl chlorides under ‘ligandꢀfree’
conditions using CuI as a catalyst. Nitrogenꢀbased molecules are known to be excellent ligands in many
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
28
I
Cuꢀcatalyzed arylation of amines, amides and phenols. Catalytically competent discrete Cu ꢀ
complexes that contain nitrogenꢀbased ligands have also been synthesized and fully characterized strucꢀ
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
3
turally. Therefore, we believe that the Nꢀbased heteroaryl substrates and products function as ligands
in our current reaction.
a
Table 3. Coupling of triarylaluminum reagents with heteroaryl iodides
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The Journal of Organic Chemistry
a
Reactions were run in 1.0 mmol scale in 5 mL DMF. One equiv of Ar Al was used with respect to ArI. Reactions for entries
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
, 3, 6, 9 and 10 were run for 6 h. Reactions for entries 2, 4, 5, 7, 8 and 11 were run for 12 h. Each reaction contains 3 equivꢀ
alents of LiCl, written in parenthesis below the reaction arrow, which is generated during the preparation of triarylaluminum
b
c
reagents. Yields are for analytically pure products isolated by column chromatography from a 1.0 mmol scale reaction. 2
d
mol% CuI was used. 5 mol% CuI was used.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
We also found that our current reaction conditions enable the crossꢀcoupling of electronꢀdeficient aryl
and heteroaryl bromides and afford products in good to excellent yields when 10 mol% CuI or CuI/PNꢀ1
was used as a catalyst (Table 4). However, in situ generated triarylaluminum reagents usually gave lowꢀ
er product yields than purified triarylalumimun reagents. As such, pure triarylaluminum reagents were
used for all the reactions with aryl bromides, which gave the best product yields. The triarylaluminum
3
4
reagents were prepared and purified according to the literature procedure. Consistent with the reactiviꢀ
ty with aryl iodides, the reaction of aryl bromides requires PNꢀ1 ligand. The reaction proceeds well with
electronꢀdeficient aryl bromides such as 4ꢀbromobenzonitrile and 4ꢀbromobenzotrifluoride affording the
crossꢀcoupled products in 62ꢀ90% yields (entries 1ꢀ5). The reaction also proceeds with a variety of niꢀ
trogenꢀbased heteroaryl bromides and afford the heterobiaryl products in good yields in the absence of
the PNꢀ1 ligand (entries 6ꢀ10). Heteroaryl bromides such as 2ꢀbromopyridine, 3ꢀbromoquinoline, 5ꢀ
bromoquinoline, 6ꢀbromoquinoline and 8ꢀbromoquinoline are good substrates for the current reaction.
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a
Table 4. Coupling of triarylaluminum reagents with electronꢀdeficient aryl and heteroaryl bromides
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
Reactions were run 1.0 mmol scale in 5 mL DMF. One equiv of Ar Al was used with respect to ArBr. Reactions for entries
3
1ꢀ5 require 10 mol% PNꢀ1 ligand. No ligand was added to the reactions for entries 6ꢀ10. Since pure triarylaluminum reagents
b
were used, 2 equivalents of LiCl were added to the reactions. Yields are for analytically pure products isolated by column
chromatography from a 1.0 mmol scale reaction.
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Cuꢀcatalyzed crossꢀcoupling that involves aryl chlorides as coupling partners are formidably challengꢀ
ing and therefore are rare. Hintermann and coꢀworkers have previously utilized CuI as a catalyst to couꢀ
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
5
e
ple Grignard reagents with various nitrogenꢀbased heterocyclic chlorides. It has also been reported that
8b
Cuꢀnanoparticles can catalyze the coupling of arylboronic acids with aryl chlorides. However, the reꢀ
action requires the addition of molecular iodine, which is proposed to convert aryl chlorides to aryl ioꢀ
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
5
dides in situ as reactive species via an iodideꢀchloride (I/Cl) exchange (aromatic Finkelstein reaction).
Therefore, this reaction only represents a ‘formal’ reaction with aryl chorides. Pleasingly, our current
reaction condition can also be applied for crossꢀcouplings with heteroaryl chlorides (Table 5). The reacꢀ
tion provides products in good to excellent yields for the crossꢀcouplings of arylaluminum reagents with
nitrogenꢀbased heteroaryl chlorides such as 2ꢀchlorobenzothiazole, 2ꢀchloroquinoxaline and 4ꢀchloroꢀ2ꢀ
phenylquinazoline.
a
Table 5. Coupling of triarylaluminum reagents with heteroaryl chlorides
a
Reactions were run in 1.0 mmol scale in 5 mL DMF. One equiv of Ar Al was used with respect to ArCl. Each reaction conꢀ
3
tains 3 equivalents of LiCl, written in parenthesis below the reaction arrow, which is generated during the preparation of triꢀ
b
arylaluminum reagents. Yields are for analytically pure products isolated by column chromatography from a 1.0 mmol scale
c
d
reaction. 5 mol% CuI was used. 10 mol% CuI was used.
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1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Cuꢀcatalyzed crossꢀcouplings of alkylorganometallic reagents with organohalides are also rare. Alkylꢀ
5
6c,
d
magnesium halides,
αꢀheteroatomꢀsubstituted alkyltributylstannanes
and Bꢀalkylꢀ9ꢀ
15
borabicyclo[3.3.1]nonane (Bꢀalkylꢀ9ꢀBBN) have previously been shown to react with alkyl halides
and aryl halides in limited cases. We have recently shown that Cuꢀcatalysts can also crossꢀcouple alꢀ
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
1
13a
kylindium and alkylzinc reagents with aryl halides. We are now pleased to find that our current reꢀ
action conditions are also amenable for the coupling of trialkylaluminum reagents with aryl and hetꢀ
eroaryl halides when 10 mol% CuI or CuI/PNꢀ1 was used a catalyst (Table 6). Under the reaction condiꢀ
tions optimized for the coupling of triarylaluminum reagents, commercially available trioctylaluminum
reacted with 1ꢀiodonaphthalene to afford the alkylated product 39 in 39% GC yield (entry 1). Further
optimization of the reaction conditions in the presence of various bases (see the Supporting Information
for details) indicated that the alkylated product was formed in the best yield (55% GC yield; 46% isolatꢀ
ed) when NaOMe was used as a base in combination with 6 equivalents of LiCl. Under this newly optiꢀ
mized conditions, reactions of trialkylaluminum reagents proceeds with electronꢀneutral and electronꢀ
deficient aryl iodides such as 1ꢀiodonaphthalene and 4ꢀiodobenzonitrile affording the products in good
yields (entries 1 and 2). The reactions also proceed in good yields with heteroaryl iodides such as 6ꢀ
iodoquinoline, 7ꢀchloroꢀ4ꢀiodoquinoline and 1ꢀiodoisoquinoline (entries 3ꢀ11). Both primary and secꢀ
ondary alkylaluminum reagents are good substrates for the current reactions. The new conditions can
also be used for the couplings of primary alkylaluminum reagents with heteroaryl chlorides such as 2ꢀ
chlorobenzothiazole, 1ꢀchloroisoquinoline and 4ꢀchloroꢀ2ꢀphenylquinazoline, which afford the coupled
products in good yields (Table 7). Consistent with the reactivity pattern observed with triarylaluminum
reagents, reactions of trialkylaluminum reagents also require PNꢀ1 ligands for coupling with nonꢀ
heteroaryl iodides and no ligands for coupling with heteroaryl iodides. Despite the absence of exogeꢀ
nous ligands, it is surprising to observe that the coupling reactions of both primary and secondary alkylꢀ
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The Journal of Organic Chemistry
aluminum reagents are not complicated by βꢀhydride elimination and no rearranged product is formed
with secondary alkylaluminum reagents. It is noteworthy that coupling of alkylorganometallic reagents
with established metals such as Pd and Ni are generally complicated by βꢀhydride elimination and rearꢀ
ranged products are usually observed when coupling is performed with secondary alkylorganometallic
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
reagents. Coupling of alkylorganometallic reagents with heteroaryl halides are further challenging due
to complications from both βꢀhydride elimination of alkyl substrates and catalyst deactivation by hetꢀ
3
1
eroarenes. As a result, these reactions usually require customꢀdesigned, sterically hindered phosphineꢀ
32
or carbeneꢀbased ligands to prevent both βꢀhydride elimination and catalyst deactivation. Therefore,
the current Cuꢀcatalyzed reaction protocols offer a convenient and practical method for the coupling of
alkylorganometallic reagents with aryl halides.
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a
Table 6. Coupling of trialkylaluminum reagents with electronꢀdeficient aryl and heteroaryl iodides
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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a
Reactions were run 1.0 mmol scale in 5 mL DMF. One equiv of R Al was used with respect to ArI. Reactions for entries 1
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
and 2 require 10 mol% PNꢀ1 ligand. No ligand was added to the reactions for entries 3ꢀ11. 6 equivalents of LiCl was added
to the reactions of commercially available triꢀnꢀoctylbutylꢀ and triꢀisoꢀbutylaluminum reagents. Reactions of triꢀnꢀbutylꢀ and
triꢀsecꢀbutylaluminum reagents also contain 6 equivalents of LiCl, 3 equivalents generated during the preparation of trialkylꢀ
b
aluminum reagents plus extra 3 equivalents added separately. Yields are for analytically pure products isolated by column
chromatography from a 1.0 mmol scale reaction. Value in parenthesis is the calibrated GC yield.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
Table 7. Coupling of trialkylaluminum reagents with heteroaryl chlorides
1
0 mol % CuI
R Al
3
+
Ar' Cl
Ar' R
[
LiCl (6 equiv)], NaOMe (1 equiv)
DMF, 120 °C, 12 h
yield (%)b
entry R in R Al
Ar' Cl
Ar Ar'
3
Cl
N
Me
Me
1
71
N
N
N
Ph
Cl
N
50
Ph
Me
Me
Me
2
55
53
Me
N
N
N
Ph
Ph
51
Cl
S
3
Me
N
N
Me
S
52
Me
Me
Cl
N
Me
4
N
S
51
52
S
Me
53
Me
Cl
Me
5
N
N
54
a
Reactions were run in 1.0 mmol scale in 5 mL DMF. One equiv of R Al was used with respect to ArCl. 6 equivalents of
3
LiCl was added to the reactions of commercially available triꢀisoꢀbutylaluminum reagent. Reaction of triꢀnꢀbutylaluminum
reagent also contain 6 equivalents of LiCl, 3 equivalents generated during the preparation of triꢀnꢀbutylaluminum reagent
b
plus extra 3 equivalents added separately. Yields are for analytically pure products isolated by column chromatography from
a 1.0 mmol scale reaction.
37
38
Pdꢀ or Cuꢀcatalyzed Sonogashira coupling of alkynes with aryl halides is one of the straightforward
methods to synthesize arylalkynes. Alternatively, Cahiez and coworkers have shown that alkynyl halꢀ
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ides can also be used as a coupling partner in Cuꢀcatalyzed crossꢀcoupling with aryl halides to afford
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
5
c
arylalkynes. Riant and coworkers recently disclosed a similar reaction for coupling vinyltriethoxꢀ
1
6a
ysilanes with alkynyl bromides. CuI, ligated by 8ꢀhydroxyquinoline, has also been used as an active
8e
catalyst to facilitate the coupling of arylboronic acids with alkynyl bromides. Pdꢀcatalyzed crossꢀ
3
9
40
41
42
couplings of alkynylsilane, alkynylboron, alkynylzinc and alkynyltin reagents with aryl halides
are also powerful methods to synthesize arylalkynes. Similarly, in situ generated alkynylcopper(I) inꢀ
termediates are also used as coupling partners in Pdꢀcatalyzed Sonogashira couplings coꢀcatalyzed by
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
37
Cuꢀsalts. A few examples of Niꢀcatalyzed crossꢀcouplings of alkynylalanes with benzylic and aryl halꢀ
4
3
44
45
ides have also been reported. Nishihara demonstrated that alkynylboron and alkynylsilane reagents
could be coupled with aryl iodides using a CuI/Ph P catalyst. We have recently shown that alkynylꢀ
3
copper(I) species could also be generated in situ from the transmetalation of alkynylzinc halides with
13a
CuI that directly react with aryl iodides to form crossꢀcoupled products. We now demonstrate in this
article that trialkynylaluminum reagents are also viable nucleophiles that undergo transmetalation with
CuI and subsequently react with aryl iodides to offer arylalkynes as crossꢀcoupled products (Table 8). In
these reactions, neutral and electronꢀrich triarylaluminum reagents, such as triphenylaluminum, triꢀpꢀ
tolylaluminum and triꢀpꢀanisolylaluminum, can be utilized as coupling partners to react with aryl ioꢀ
dides such as iodonaphthalene and 1ꢀiodoisoquinoline, which afford crossꢀcoupled products in good
yields.
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The Journal of Organic Chemistry
a
Table 8. Coupling of trialkynylaluminum reagents with aryl and heteroaryl iodides
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
[
0 mol % CuI
LiCl (3 equiv)]
DMF, 120 °C, 12 h
I
Ar Ar'
R Al
+
Ar'
I
Ar'
R
3
yield (%)b
entry R in R Al
Ar'
3
Ph
I
1
67
Ph
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
55
Ph
I
2
46
N
Ph
N
56
Me
I
3
48
N
Me
N
57
OMe
I
4
71
N
MeO
N
58
a
Reactions were run in 1.0 mmol scale in 5 mL DMF. One equiv of R Al was used with respect to ArI. Reaction for entry 1
3
requires 10 mol% PNꢀ1 ligand. No ligand was added to the reactions for entries 2ꢀ4. Each reaction contains 3 equivalents of
LiCl, written in parenthesis below the reaction arrow, which is generated during the preparation of trialkynylaluminum reaꢀ
b
gents. Yields are for analytically pure products isolated by column chromatography from a 1.0 mmol scale reaction.
While a number of reports on Cuꢀcatalyzed crossꢀcouplings have focused on the couplings of aryl halꢀ
ides, application of vinyl halides as electrophiles is limited. A few examples of couplings of organotin
reagents with vinyl halides are known in the literature that are performed with stoichiometric or catalytꢀ
6
aꢀc
ic amounts of Cuꢀsalts. Li and coꢀworkers utilized a combination of CuI and 1,4ꢀdiazabicyclo[2.2.2]ꢀ
8c
octane (DABCO) as a catalyst for coupling arylboronic acids with vinyl iodides and bromides. Despite
these devopments, Cuꢀcatalyzed crossꢀcoupling of simple alkylorganometallic reagents with vinyl halꢀ
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ides are not known. We are pleased to report that our current reaction conditions also allow the coupling
of both arylꢀ and alkylaluminum reagents with vinyl halides and afford the products in good yields (Taꢀ
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
4
6
ble 9). The reactions proceed well for the couplings of triphenylaluminum, triꢀoꢀtolylaluminum, triꢀmꢀ
tolylaluminum and triꢀpꢀtolylaluminum reagents with transꢀβꢀbromostyrene and transꢀ4ꢀmethylꢀβꢀ
bromostyrene (entries 1ꢀ5). Similarly, the reactions also work well for the couplings of triꢀnꢀ
butylaluminum and triꢀisoꢀbutylaluminum reagents with transꢀβꢀbromostyrene and transꢀ4ꢀmethylꢀβꢀ
bromostyrene (entries 6ꢀ8).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
Table 9. Coupling of triarylꢀ and trialkylaluminum reagents with vinyl bromides
5-10 mol % CuI
Br
5-10 mol % PN-1
[LiCl (3 equiv)]
R Al
3
+
Ar
R
R
DMF, 120 °C, 12 h
yield (%)b
54
entry R in R Al
vinyl Br
Ar Ar'
3
R
1
59, R = H
(E/Z: 10:1)
60, R = o-Me
(
Br
R
2
3
4
51
Ph
(E/Z: 10:1) Ph
E/Z: 10:1)
61, R = m-Me 45
E/Z: 9:1)
62, R = p-Me
E/Z: 10:1)
(
61
41
(
Br
5
Me
(
E)
Me
62 (E)
nBu
Br
Me
50c,d
6
6
3 (E/Z: 10:0.6)
Me
Me
Me
(
E)
Me
Br
Me
Me
49c,d
7
Me
Me
64 (E)
(
E)
Br
Me
Me
Me
45c
8
Me
(
E/Z: 10:1)
65 (E/Z: 10:1)
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The Journal of Organic Chemistry
a
Reactions were run in 1.0 mmol scale in 5 mL DMF. One equiv of R Al was used with respect to vinyl bromides. 5 mol%
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
CuI/PNꢀ1 was used for the reactions of arylaluminum reagents (entries 1ꢀ5). 10 mol% CuI/PNꢀ1 was used for the reactions of
alkylaluminum reagents (entries 6ꢀ8). 3 equivalents of LiCl was added to the reactions of commercially available triꢀisoꢀ
butylaluminum reagent. Reaction of triꢀnꢀbutylꢀ and triarylaluminum reagents contain 3 equivalents of LiCl, which is generꢀ
1
ated during the preparation of triꢀnꢀbutylꢀ and triarylaluminum reagents. E/Z ratios of the products were determined by H
b
c
NMR. Yields are for analytically pure products isolated by column chromatography from a 1.0 mmol scale reaction. Reacꢀ
d
tions require 1 equiv of NaOMe. Reactions were run for 24 h.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
We also propose a catalytic cycle for the current reaction (Scheme 2) based on literature reports and our
9ꢀ10, 11
recent work on Cuꢀcatalyzed crossꢀcouplings.
Optimization of reaction conditions showed that
both PNꢀ1 and LiCl are critical for the Cuꢀcatalyzed crossꢀcoupling of organoaluminum reagents with
organohalides (Table 1, entries 2 and 8). As such, we reason that organoaluminate complexes such as 66,
generated from the complexation of LiCl with threeꢀcoordinate organoaluminum reagents, could be the
active species in solution that transmetalate with the PNꢀbound CuX (X = I, Br or Cl) to generate
(PN)CuR complexes as the orgnaocopper(I) intermediates. Triorganoaluminum complexes have previꢀ
ously been shown to form triorganoaluminate species in the presence of anions in solution due to their
3
4,
Lewis acidity, and a few of such complexes have been previously synthesized and fully characterized.
47
In addition, organoaluminum reagents have been shown to participate in allylic and conjugate addiꢀ
2
i, 21c, 26ꢀ27
tion reactions
suggesting that they are capable of tranmetalating to Cuꢀsalts. The (PN)CuR inꢀ
termediates then react with organohalides to afford the crossꢀcoupled products. We have recently synꢀ
thesized and fully characterized (PN)CuPh as a threeꢀcoordinate complex, which readily reacts with ArI
9
48
at 120 °C in DMF to afford biaryl products. A number of other ‘ligandless’ and ligated [CuAr] speꢀ
3
3e
I
cies have also been shown to react with aryl halides to afford biaryl products. Reactions of Cu speꢀ
cies, either generated in situ during reactions or as discrete isolated complexes, with aryl halides have
been a subject of debate for years. These reactions are generally considered to proceed via either radical
4
9
or nonꢀradical processes. We have recently demonstrated in our previous work that Cuꢀcatalyzed
crossꢀcouplings do not involve aryl free radicals based on reactions of aryl halides with organometallic
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reagents in the presence of radical scavengers under catalytic reaction conditions as well as with disꢀ
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
10, 12
crete, fully characterized organocopper(I) complexes, and radical clock experiments.
We believe
that a similar mechanism could be operating in the current Cuꢀcatalyzed crossꢀcoupling of organoalumiꢀ
num reagents with organohalides.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 2. Proposed catalytic cycle
We have conducted futher experiments to understand the mechanism of the current reaction. In order to
probe the possibility of the presence of free aryl radicals in the reaction generated via a single electron
transfer (SET) to aryl halides, we have utilized a radical clock experiment. The radical probe 71 is
8
ꢀ1
known to undergo cyclization in DMF at 50 °C with a rate constant of 5.0 × 10 s when the correꢀ
sponding aryl radical 73 is generated to form the cyclic product 75 after proton abstraction by the primaꢀ
5
0
ry alkyl radical 74. Similar radical probes have also been shown previously to undergo tandem radical
cyclizationꢀcoupling in Cuꢀcatalyzed coupling reactions under condiditons that are amenable to the forꢀ
51
mation of aryl radicals via SET. Cuꢀcatalyzed coupling reactions that do not involve aryl radicals have
been shown to afford direct coupling products without cyclization when similar radical probes are utiꢀ
33b, c
lized as substrates for radical clock experiments.
Under our current reaction conditions, crossꢀ
coupling of Ph Al with the radical probe 71 afforded the direct crossꢀcoupling product 72 in 50% GC
3
yield (Scheme 3). The cyclized product 75 and the tandem cylizationꢀcoupling product 76 were not
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The Journal of Organic Chemistry
formed, suggesting that the current reaction is unlikely to proceed via the generation of free aryl radiꢀ
cals.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 3. Radical clock experiment
In order to provide further evidence for or against SET in the current Cuꢀcatalyzed crossꢀcoupling reacꢀ
tion, we studied the relative rates of reactions of 1ꢀbromonaphthalene and 4ꢀchlorobenzonitrile with
Ph Al in a competition experiment. 4ꢀChlorobenzonitrile has a lower reduction potential (−2.03 V vs.
3
52
SCE in DMF) than 1ꢀbromonaphthalene (−2.17 V vs. SCE in DMF) and, therefore, should be easier to
reduce by SET to generate a radical anion that eventually leads to the formation of an aryl radical after
the dissociation of the halide anion. Despite having a more favorable environment for the reduction of
4
ꢀchlorobenzonitrile by SET, 1ꢀbromonapthalene reacted much faster with Ph Al affording the respecꢀ
3
tive crossꢀcoupling products 77 and 78 in 48% and 16% GC yields (3:1 ratio) (Scheme 4). This experiꢀ
mental result is consistent with a previous Cuꢀcatalyzed coupling in which the reaction was shown to
3
3b, c
proceed via an oxidative additionꢀreductive elimination pathway,
and in sharp constrast to another
5
1
similar coupling reaction which was demonstrated to proceed by a SET mechanism. Therefore, we beꢀ
lieve that the current Cuꢀcatalyzed crossꢀcoupling of organoaluminum reagents with organohalides does
not involve aryl radicals and radical anions as intermediates and likely proceed via a nonꢀradical mechꢀ
5
3
anism such as oxidative additionꢀreductive elimination pathway.
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Scheme 4. Competition for the Reaction of Ph Al with 1ꢀbromonaphthalene and 4ꢀchlorobenzonitrile
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Finally, we obtained a Hammett relationship for the quantitative assessment of the effect of the elecꢀ
tronic properties of substituted iodoarenes on the rate of the reaction with triarylaluminum reagents to
form biaryl products. The initial rates of reaction of Ph Al with iodobenzene, paraꢀiodotoluene, paraꢀ
3
iodofluorobenzene and paraꢀiodobenzotrifluoride were determined by GC for less than 30% product
formation that showed a linear curve at different time points by quantifying the products using 2ꢀ
nitrobiphenyl as a calibration standard (Table 10). A plot of log values of the ratio of initial rates of subꢀ
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
stituted iodoarenes to unsubstituted iodoarene (iodobenzene) versus σ was linear (R = 0.99) with a ρ
54
value of +1.06 (Figure 2). This result is consistent with oxidative addition of aryl halides to electronꢀ
rich metal centers in which electronꢀdeficient aryl halides oxidize low valent metals to high valent faster
5
5
than electronꢀrich aryl halides. Therefore, we believe, based on the result of the linear freeꢀenergy relaꢀ
tionship and the evidence for the lack of aryl radicals and aryl radical anions, that the Cuꢀcatalyzed
crossꢀcoupling reaction of organoaluminum reagents with organohalides proceeds via oxidative addiꢀ
tionꢀreductive elimination pathway as proposed in the catalytic cycle in Scheme 2.
Table 10. Iodoarenes used for the Hammett plot and the values for the initial rates of reactions
ꢀ1
iodoarenes kX(initial) (M s ) log[kX(initial)/ kH(initial)
]
σ
ꢀ
5
X = H
X = Me
X = F
1.9 × 10
1.3 × 10
2.2 × 10
7.5 × 10
0.0000
ꢀ0.1576
0.05541
0.5894
0.00
ꢀ0.17
0.06
0.54
ꢀ
5
ꢀ5
ꢀ5
X = CF3
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0
0
0
0
.8
.6
.4
.2
0
1
2
3
4
5
6
7
8
9
CF3
F
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Me
-
0.2
-0.4
-
0.4
-0.2
0
0.2
0.4
0.6
0.8
σ
Figure 2. The Hammett plot for the reaction of Ph Al with 5.0 equivalents of iodobenzene, paraꢀ
3
iodotoluene, paraꢀiodofluorobenzene and paraꢀiodobenzotrifluoride. The curve depicts the result of an
ꢀ3
2
unweighted leastꢀsquare fit to y = a*x + b (a = +1.06, b = 7.27 × 10 , R = 0.99).
CONCLUSION
In summary, we have developed the first Cuꢀcatalyzed crossꢀcoupling of organoaluminum reagents with
organohalides. Unlike previously reported Cuꢀcatalyzed crossꢀcoupling with other organometallic reaꢀ
gents, couplings with organoaluminum reagents are more general and show a wide substrate scope for
both the organoaluminum reagents and organohalides. The reactions can be performed using various
organoaluminum reagents, such as alkylꢀ, arylꢀ and alkynylaluminum, and a variety of organohalides
like aryl and heteroaryl iodides, aryl and heteroaryl bromides, heteroaryl chlorides and vinyl bromides.
Reactions proceed with both the primary and secondary alkylaluminum reagents in good yields. The
reactions for alkylꢀaryl, arylꢀaryl and arylꢀvinyl coupling require the addition of PNꢀ1 ligand to obtain
the best yields of the products. However, the couplings with heteroaryl halides do not require PNꢀ1 ligꢀ
and even for reactions that crossꢀcouple primary and secondary alkylaluminum reagents with heteroaryl
halides. These ‘ligandꢀfree’ crossꢀcouplings are not complicated by the formation of rearranged products
that are known to arise usually by rapid βꢀhydride elimination and olefin reꢀinsertion process with estabꢀ
lished transition metals such as Pd and Ni. Preliminary mechanistic studies with a radical probe and relꢀ
ative reactivity studies for the reaction of of Ph Al with 1ꢀbromonaphthalene and 4ꢀchlorobenzonitrile
3
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indicate that the transformation does not involve aryl radicals or aryl radical anions as intermediates.
These results combined with the result of the linear freeꢀenergy relationship (the Hammett plot) study
suggest that the reaction is likely to proceed via an oxidative additionꢀreductive elimination pathway.
EXPERIMENTAL SECTION
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
General Information. Unless stated otherwise, all the reactions and chemicals were handled inside a
nitrogenꢀfilled glovebox. Glassware were dried in an oven immediate before their use. All commercial
reagents were used as received without further purification. Triphenylaluminum, triꢀisoꢀbutylaluminum
and triꢀnꢀoctylaluminum were purchased from SigmaꢀAldrich. Triorganoaluminum reagents were preꢀ
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
pared from the reaction of 3 equivalents of RLi reagents with AlCl (99.99% purity) in THF at room
3
temperature and were used without further purification. Pure triarylaluminum reagents other than Ph Al
3
3
4
were synthesized following the reported procedure. Ligands PNꢀ2, PNꢀ6, PNꢀ7, PNꢀ8, PPꢀ1, NNꢀ1,
NNꢀ4, NOꢀ1, OOꢀ1 and SIMes•HCl were purchased from commercial sources. Ligands PNꢀ1, PNꢀ3,
5
6
57
58
59 1
13
PNꢀ4, PNꢀ5, PNꢀ9, NNꢀ2, and NNꢀ3 were synthesized following the reported procedures. H, C
1
9
and F NMR spectra were recorded on a 300, 75 and 282 MHz, respectively, and internally referenced
1
13
to the residual solvent signals of CDCl for H and C NMR at 7.26 and at 77.16 ppm, respectively, and
3
19
C F for F NMR at −164.9 ppm.
6
6
General Procedure for Cross-Coupling with Triarylaluminum Reagents. To a suspension of AlCl3
(133.3 mg, 1.0 mmol) in THF (2 mL) was added dropwise a solution of aryllithium (3.0 mmol) (generꢀ
ated from the lithiation of aryl iodides with nꢀBuLi in THF) at room temperature. After 45 minutes, the
solvent was removed to obtain a triarylaluminum reagent containing 3 equivalents of LiCl, which was
then dissolved in DMF (5 mL). Aryl halide (1.0 mmol) and CuI (3.8 – 19.0 mg, 0.020 – 0.10 mmol)
were then added to the solution of the triarylaluminum reagent. For reactions containing nonꢀheteroaryl
halides, PN-1 (6.1 – 30.5 mg, 0.020 – 0.10 mmol) was added to the reaction mixture. For reactions conꢀ
taining heteroaryl halides, no ligand was added. The reaction mixture was then tightly capped, taken out
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of the glovebox, placed in an oil bath preꢀheated to 120°C and vigorously stirred. After 6ꢀ24 h, the reacꢀ
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
tion mixture was cooled to room temperature, diluted with ethyl acetate (15 mL) and washed with H O
2
(5 mL × 3). The aqueous fraction was extracted back with ethyl acetate (5 mL × 3) and combined with
the first ethyl acetate fraction. The combined ethyl acetate fraction was dried over Na SO and the solꢀ
2
4
vent was removed in a rotary evaporator. The product was purified by silica gel column chromatography
using hexanes as an eluting solvent for nonꢀheterocyclic products and 10–20% ethylacetate/hexanes for
heterocyclic products.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
General Procedure for Cross-Coupling with Trialkylaluminum Reagents. To a suspension of AlCl3
(133.3 mg, 1.0 mmol) in THF (2 mL) was added dropwise a solution of alkyllithium (3.0 mmol) at room
temperature. After 45 minutes, the solvent was removed to obtain a trialkylaluminum reagent containing
3 equivalents of LiCl, which was then dissolved in DMF (5 mL). Aryl halide (1.0 mmol), NaOMe (54.0
mg, 1.0 mmol), CuI (19.0 mg, 0.10 mmol) and LiCl (127.2 mg, 3.0 mmol, except for reactions with viꢀ
nyl bromides, which do not need additional LiCl) were then added to the solution of the trialkylalumiꢀ
num reagent. For reactions containing nonꢀheteroaryl halides, PN-1 (30.5 mg, 0.10 mmol) was added to
the reaction mixture. For reactions containing heteroaryl halides, no ligand was added. The reaction
mixture was then tightly capped, taken out of the glovebox, placed in an oil bath preꢀheated to 120°C
and vigorously stirred. After 12ꢀ24 h, the reaction mixture was cooled to room temperature, diluted with
ethyl acetate (15 mL) and washed with H O (5 mL × 3). The aqueous fraction was extracted back with
2
ethyl acetate (5 mL × 3) and combined with the first ethyl acetate fraction. The combined ethyl acetate
fraction was dried over Na SO and the solvent was removed in a rotary evaporator. The product was
2
4
purified by silica gel column chromatography using hexanes as an eluting solvent for nonꢀheterocyclic
products and 10–20% ethylacetate/hexanes for heterocyclic products.
General Procedure for Cross-Coupling with Trialkynylaluminum Reagents. To a suspension of
AlCl (133.3 mg, 1.0 mmol) in THF (2 mL) was added dropwise a solution of alkynyllithium (3.0
3
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mmol) (generated from the lithiation of arylacetylene with nꢀBuLi in THF) at room temperature. After
5 minutes, the solvent was removed to obtain a trialkynylaluminum reagent containing 3 equivalents of
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
4
LiCl, which was then dissolved in DMF (5 mL). Aryl halide (1.0 mmol) and CuI (19.0 mg, 0.10 mmol)
were then added to the solution of the trialkynylaluminum reagent. For reactions containing nonꢀ
heteroaryl halides, PN-1 (30.5 mg, 0.10 mmol) was added to the reaction mixture. For reactions containꢀ
ing heteroaryl halides, no ligand was added. The reaction mixture was then tightly capped, taken out of
the glovebox, placed in an oil bath preꢀheated to 120°C and vigorously stirred. After 12 h, the reaction
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
mixture was cooled to room temperature, diluted with ethyl acetate (15 mL) and washed with H O (5
2
mL × 3). The aqueous fraction was extracted back with ethyl acetate (5 mL × 3) and combined with the
first ethyl acetate fraction. The combined ethyl acetate fraction was dried over Na SO and the solvent
2
4
was removed in a rotary evaporator. The product was purified by silica gel column chromatography usꢀ
ing 5–20% ethylacetate/hexanes for heterocyclic products.
6
0
4
-Phenylanisole (4) : The title compound 4 was obtained as a white solid (160 mg, 87% yield) after
1
purification by silica gel column chromatography. mp 83 °C; H NMR (300 MHz, CDCl ) δ 3.91 (s,
3
13
3
H), 7.04ꢀ7.09 (m, 2H), 7.36ꢀ7.42 (m, 1H), 7.47ꢀ7.54 (m, 2H), 7.60ꢀ7.67 (m, 4H); C NMR (75 MHz,
+
CDCl ) δ 55.4, 114.3, 126.8, 126.8, 128.2, 128.8, 133.8, 140.9, 159.3; HRMS (APPI /TOF) Calcd for
3
+
C H O (M) 184.0888, found 184.0892.
13
12
61
4
-Trifluromethyl-1,1’-biphenyl (5) : The title compound 5 was obtained as a white solid (184 mg, 83%
yield from the reaction of 1ꢀIodoꢀ4ꢀ(trifluoromethyl)benzene with triphenylaluminium reagent and 167
mg, 75% yield from the reaction of 1ꢀBromoꢀ4ꢀ(trifluoromethyl)benzene with triphenylaluminium reaꢀ
1
gent) after purification by silica gel column chromatography. mp 64 °C; H NMR (300 MHz, CDCl )
3
1
3
δ 7.38ꢀ3.52 (m, 3H), 7.58ꢀ7.63 (m, 2H), 7.70 (s, 4H); C NMR (75 MHz, CDCl ) δ 125.6 (q, J = 3.8
3
CF
28
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Page 29 of 55
The Journal of Organic Chemistry
19
Hz), 125.9, 127.4, 127.6, 127.8, 128.3, 129.1, 139.9, 144.9; F NMR (282 MHz, CDCl ) δ ꢀ65.0;
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
+
HRMS (APPI /TOF) Calcd for C H F (M) 222.0656, found 222.0660.
1
3
19
3
6
2
3,5-Bis(trifluromethyl)-1,1’-biphenyl (6) : The title compound 6 was obtained as colorless oil (157 mg,
1
5
7
1
4% yield) after purification by silica gel column chromatography. H NMR (300 MHz, CDCl ) 7.46ꢀ
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
.55 (m, 2H), 7.60ꢀ7.64 (m, 2H), 7.87 (s, 1H), 8.01ꢀ8.04 (m, 3H); C NMR (75 MHz, CDCl ) 121.1,
3
1
9
21.8, 125.4, 127.4, 129.0, 129.4, 132.3 (q, J = 33.0 Hz), 138.4, 143.5; F NMR (282 MHz, CDCl ) δ
CF
3
ꢀ
62.9; GCꢀMS (m/z) 290.1.
6
3
4-Tolylbenzonitrile (7) : The title compound 7 was obtained as a white solid (135 mg, 70% yield) after
1
purification by silica gel column chromatography. H NMR (300 MHz, CDCl ) δ 2.42 (s, 3H), 7.29 (d, J
3
1
3
= 8.1 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H), 7.65ꢀ7.72 (m, 4H); C NMR (75 MHz, CDCl ) δ 21.3, 110.7,
3
+
+
1
1
19.2, 127.2, 127.6, 130.0, 132.7, 136.4, 138.9, 145.7; HRMS (APPI /TOF) Calcd for C H N (M)
14 11
93.0891, found 193.0895.
6
4
4-(2-Methylphenyl)thioanisole (8) : The title compound 8 was obtained as colorless oil (133 mg, 62%
1
yield) after purification by silica gel column chromatography. H NMR (300 MHz, CDCl ) δ 2.28 (s,
3
13
3H), 2.53 (s, 3H), 7.21ꢀ7.33 (m, 8H); C NMR (75 MHz, CDCl ) δ 16.0, 20.6, 125.9, 126.4, 127.4,
3
+
+
1
29.8, 129.9, 130.5, 135.5, 137.0, 138.9, 141.4; HRMS (APPI /TOF) Calcd for C H S (M) 214.0816,
14 14
found 214.0818.
6
5
4’-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-3-methoxy-1,1’-Biphenyl (9) : The title compound 9 was
1
obtained as yellow oil (126 mg, 40% yield) after purification by silica gel column chromatography. H
NMR (300 MHz, CDCl ) δ 0.24 (s, 6H), 1.02 (s, 9H), 3.87 (s, 3H), 6.84ꢀ6.93 (m, 3H), 7.09ꢀ7.10 (m,
3
1
3
1
H), 7.13ꢀ7.16 (m, 1H), 7.31ꢀ7.36 (m, 1H), 7.44ꢀ7.49 (m, 2H); C NMR (75 MHz, CDCl ) δ −4.2, 18.4,
3
29
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