Revisitation of Organoaluminum Reagents Affords a Versatile Protocol for C-X (X = N, O, F) Bond-Cleavage Cross-Coupling: A Systematic Study

Article abstract of DOI:10.1021/acscatal.7b01058

A revisit of organoaluminum reagents for cross-coupling reactions has opened up several types of C-C bond formation protocols through cleavage of phenolic/alcoholic C-O and C-F and ammonium C-N bonds. Catalyzed by the commercially available NiCl₂(PCy₃)₂ catalyst, these reactions proceed smoothly with a wide range of substrates and broad functional group compatibility, providing a versatile methodology for organoaluminum-mediated cross-coupling processes.

Full text of DOI:10.1021/acscatal.7b01058

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Article
Revisit of Organoaluminum Reagents Affords a Versatile Protocol for
C–X (X = N, O, F) Bond-Cleavage Cross-Coupling: A Systematic Study
Hiroyuki Ogawa, Ze-Kun Yang, Hiroki Minami, Kumiko
Kojima, Tatsuo Saito, Chao WANG, and Masanobu Uchiyama
ACS Catal., Just Accepted Manuscript • Publication Date (Web): 03 May 2017
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Revisit of Organoaluminum Reagents Affords A
Versatile Protocol for C–X (X = N, O, F) Bondꢀ
Cleavage CrossꢀCoupling: A Systematic Study
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†
,#
†,‡,#
†
†
†,‡
Hiroyuki Ogawa, Ze-Kun Yang,
Hiroki Minami, Kumiko Kojima, Tatsuo Saito,
*,†,‡
*,†,‡
Chao Wang,
and Masanobu Uchiyama
†
Graduate School of Pharmaceutical Sciences, University of Tokyo, 7ꢀ3ꢀ1 Hongo, Bunkyoꢀku,
Tokyoꢀto 113ꢀ0033, Japan.
Advanced Elements Chemistry Research Team, RIKEN Center for Sustainable Resource
Science, and Elements Chemistry Laboratory, RIKEN, 2ꢀ1 Hirosawa, Wakoꢀshi, Saitamaꢀken
51ꢀ0198, Japan.
‡
3
KEYWORDS: Organoaluminum, CrossꢀCoupling, Ether, Organic Fluoride Compounds,
Ammonium Salt, Nickel Catalyst, Synthetic Method.
ABSTRACT: A revisit of organoaluminum reagents for crossꢀcoupling reactions has opened up
several types of C–C bond formation protocols through cleavage of phenolic/alcoholic C–O, C–
F, and ammonium C–N bonds. Catalyzed by commercially available NiCl (PCy ) catalyst, these
2
3 2
reactions proceed smoothly with a wide range of substrates and broad functional group
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compatibility, providing versatile methodology for organoaluminumꢀmediated crossꢀcoupling
processes.
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1. INTRODUCTION
Transition metal (TM)ꢀcatalyzed crossꢀcoupling reaction is one of the most important C–C
1
bondꢀforming protocols, and has been widely applied both in academic research and in industry.
2
ꢀ5
6ꢀ9
In recent years, utilization of phenol/alcohol derivatives (C–O) and organic fluorides (C–F)
1
0ꢀ11
as well as ammonium salts (C–N)
as electrophiles in place of traditional halides (Cl, Br, and
I) for TMꢀcatalyzed crossꢀcouplings has attracted much interest. These functional groups are
widely present in nature, or are important structural units for pharmaceuticals and functional
materials. The usage of the C–O/C–F/C–N electrophiles also has the advantage of avoiding
halogenꢀmetal exchange side reactions. Many elegant methodologies have already been
developed, but issues of substrate diversity and selectivity are still challenging. Various types of
C–O bond cleavage crossꢀcoupling reactions have been reported, but in most cases, including
4
aꢀk
4lꢀs,5dꢀi
4tꢀv,5j
5kꢀq
KumadaꢀTamao type,
SuzukiꢀMiyaura type,
Negishi type,
and others,
reactions
are often confined to naphtholꢀrelated substrates; in particular, many phenolic substrates exhibit
low reactivity, even with excess amounts of organometallic nucleophiles and/or under harsh
conditions. As for the pioneering work on C–F bond cleavage crossꢀcoupling, especially with
8
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organoboron and organozinc, reactions are limited to aryl fluorides with extremely electronꢀ
deficient nature or with orthoꢀgroup assistance, and electronꢀrich aryl compounds are invariably
less reactive. Therefore, efficient and versatile methods with broad substrate scope and high
selectivity are still needed.
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Here we report an efficient protocol for organoaluminumꢀmediated crossꢀcoupling reactions
with a variety of phenol/alcohol derivatives, organic fluorides, and ammonium salts, providing
new methodology for C–C bond formation via C–O/F/N bond cleavage. The initial use of
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organoaluminum in transition metal (TM)ꢀcatalyzed crossꢀcoupling reactions can be traced
1
3
back to Negishi’s reports as early as in 1976, but in subsequent decades, organoaluminum has
1
been largely neglected in favor of other organometallics (Mg, Zn, B, Sn, etc.). A few crossꢀ
coupling reactions with organoaluminums have been reported, though most of them focused on
1
4
reactions with organic halides. Very recently, Niꢀcatalyzed crossꢀcoupling between aryl methyl
4t
ether (ArOMe) and trialkylaluminum (R Al) was reported by Chatani, Tobisu et al., and
3
4
u
Rueping et al. However, organoaluminum reagents offer many synthetic advantages, including
low cost, ready availability, low toxicity, and in particular, their exceptional Lewis acidity. We
14b,15
have also found that organoaluminium reagents exhibit low halogenꢀmetal exchange ability.
This is important, because halogenꢀmetal exchange usually occurs as a side reaction in crossꢀ
coupling, especially in TMꢀcatalystꢀfree singleꢀelectronꢀtransfer (SET)ꢀinduced direct coupling
between organic halides and organometallic reagents, such as Grignard reagents or organozinc
1
6
compounds. In 2015, we serendipitously discovered a direct crossꢀcoupling reaction between
1
4b
organic halides and organoaluminums without any external catalyst. This reaction proceeds
smoothly without formation of detectable amounts of dehalogenated sideꢀproduct, and is
applicable to a wide range of organic halides, including aryl/alkenyl/alkynyl halides, with broad
functional group compatibility (Scheme 1). Further, when aromatic iodides or bromides bearing
tosylate, triflate, and carbamate groups were employed, the reactions took place specifically at
the halogen sites in excellent yield, even for very bulky aluminum reagents with bromide and
17
OTf.
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Ar
AlMe
2
LiCl + X
Ar
isolation yield)
THF, 110 oC, 24 h
(
Aryl Iodide and Bromide
Me
F
3
C
Me
S
OEt
X = I, 90%
X = I, 95%
X = I Me
8%
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Me
Me
Me
O
O
Me
Cl
N
F
i
OEt
N Pr
2
X = I, 87%
X = I, 91%
X = Br, 91%
Me
X = Br
8%
9
Me
EtO
2
Bu
OSiMe t
X = Br, 95%
X = Br, 87% Me
Alkenyl Iodide and Bromide
Aryl, Alkenyl and Alkynyl Chloride
Me
nHex
Ph
Me
Me
Ph
EtO
Me
X = I
2%
S
X = I
63%
X = Br
Me 82%
8
X =Cl, 73%
Ph
EtO
Me
Me
Me
F
Me
nHex
X =Cl, 76%
X =Cl
0%
X =Cl, 82%
7
Me
Me
Me
O
S
O
S
O
tosylate
pTol
Me
O
triflate
CF
3
O
O
Me
Me
X = I, 97%
X = Br, 99%
O
different selectivity with
traditional TM-Catalysis
O
X vs OZ
carbamate NEt
2
Me
X = I, 98%
a
Results from ref. 14b
Scheme 1. Direct crossꢀcoupling between aluminum reagents and various types of organic
a
halides.
Encouraged by the advantages of high reactivity and selectivity, we made a systemic study of
organoaluminum–mediated crossꢀcoupling reactions via inert bond (C–O, C–N, C–F) cleavage.
Notably, all these reaction proceed under mild conditions with the simple and commercially
available NiCl (PCy ) catalyst, and substrates having nonꢀnaphthalene structures, including
2
3 2
electronꢀrich and/or bulky aromatic rings that show little or no reactivity in previously reported
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protocols reacted smoothly to give the desired products in high yields. Therefore this
methodology provides an efficient, selective and versatile synthetic protocol.
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2
. RESULTS AND DISCUSSION
Ni-Catalyzed Cross-Coupling Between Organoaluminum Reagents and Phenol/Alcohol
Derivatives. In recent years, utilization of carboxylates (ester, carbamate, etc.) and ethers as
substrates for crossꢀcouplings via C–O bond cleavage has attracted much attention, owing to
2
ꢀ5
carbamate
their easy accessibility, low cost, and high benchꢀstability. Using 2a
as a model
substrate, initial studies aimed at developing coupling conditions revealed that the combination
i
18ꢀ19
i
14d
of PhAl Bu 1a (prepared from PhMgCl
and ClAl Bu ) as the aluminum reagent, toluene
2
2
2
0
as the solvent, and NiCl (PCy ) as the catalyst was a suitable starting point for examination of
2
3 2
the substrate scope of the present crossꢀcoupling reaction (Table 1). Under optimized conditions,
we evaluated the scope of the coupling reaction using several types of C–O substrates 2a,
including esters, carbonate, tosylate, mesylate, triflate, and phosphate. In most cases, the reaction
proceeded smoothly even with 1.2 eq. of 1a, and the coupling product 3aa was obtained in high
yield (Scheme 2).
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a (0.6 mmol, 1.2 eq.) was treated with 2a (0.5 mmol, 1 eq.) in the presence of NiCl (PCy3)2
2
(
5 mol %) in toluene (3 mL) at r.t. under argon.
Scheme 2. Crossꢀcoupling between aluminum reagent 1a and various naphthol derivatives 2a in
a
the presence of Niꢀcatalyst.
a
Table 1. Modifications of reaction conditions.
O
NiCl
(PCy
3 2
) (5 mol%)
2
i
1a
2a
AlBu
2
+
O
tBu
conditions
1a
2a (1.0 eq.)
3aa (GC yield)
b
Entry Ph–[Al] (1a)
Solvent Temperature GC yield
o
1
2
3
4
5
6
7
8
9
Ph–AlMe Li (PhLi + AlMe3)
2.0 eq. toluene 90 C
trace
18%
57%
90%
64%
81%
>95%
>95%
40%
3
o
Ph–AlMe2
(PhLi + AlMe Cl)
2.0 eq. toluene 90 C
2
o
Ph–AlMe
(PhLi + AlMe Cl)
2.0 eq. THF
2.0 eq. THF
2.0 eq. THF
90 C
2
2
i
i
o
Ph–Al Bu
(PhLi + Al Bu Cl)
70 C
2
2
i
i
o
Ph–Al Bu
(PhLi + Al Bu Cl)
50 C
2
2
i
i
o
Ph–Al Bu
(PhMgCl + Al Bu Cl) 2.0 eq. THF
50 C
2
2
2
2
2
i
i
o
Ph–Al Bu
(PhMgCl + Al Bu Cl) 2.0 eq. toluene 50 C
2
i
i
Ph–Al Bu
(PhMgCl + Al Bu Cl) 1.5 eq. toluene r.t.
2
i
i
Ph–Al Bu
(PhMgBr + Al Bu Cl) 1.5 eq. toluene r.t.
2
a
1
a (0.75 mmol, 1.5 eq., or 1.0 mmol, 2.0 eq.) was treated with 2a (0.5 mmol, 1 eq.) in the
b
presence of NiCl (PCy ) (5 mol %) in toluene (3 mL) at r.t.~90 °C under argon. Internal
standard for GC yield: nꢀdodecane.
2
3 2
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Taking the carbamate as a representative C–O moiety, we next investigated the scope and
limitations of the present crossꢀcoupling of 2 with various aryl aluminum reagents 1 (Scheme 3).
The results can be summarized as follows. 1) Aryl carbamates: the reactivity of many phenol
carbamates appeared to be lower than that of 2ꢀnaphthol derivatives 2a at room temperature, but
heating at higher temperature improved the reactivity, affording the biaryl products in high yields
in most cases. 2) Influence of electronic properties of the aryl carbamates 2: a variety of
functional groups, such as methoxy (2b-c), trifluoromethyl (2d), ester (2e-f), amide (2g), and
heterocycle (2i–k), could be employed, and their electronic properties had little influence on the
reactivity, except for thiopheneꢀcontaining substrates (2l-m, unreacted substrates remained). 3)
Aromatic aluminum reagents: while electronꢀrich aryl aluminums showed higher reactivity than
electronꢀdeficient ones (1b-c, 1e-f vs 1g-h), gentle heating in the reactions of 1g-h bearing
electronꢀwithdrawing groups also led to satisfactory yields. 4) Steric factor: steric bulkiness of
both aromatic aluminum (1b and even 1d) and aryl carbamate (1f) did not greatly affect the
reactivity, though high temperature was needed to achieve a good yield in the reaction with very
bulky aryl carbamate (2h). In general, existing coupling protocols via C–O bond cleavage, such
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4
aꢀk
4lꢀs,5dꢀi
4tꢀv,5j
as KumadaꢀTamao, SuzukiꢀMiyaura,
Negishi types,
are often confined to naphtholꢀ
related substrates; in particular, many phenolic substrates exhibit low reactivity, even under
harsh conditions. In sharp contrast, the present method is broadly applicable to a variety of
phenol derivatives, even those bearing electronꢀdonating or bulky groups, opening up new
potential applications of organoalumium reagents in this area.
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O
NiCl
2 3 2
(PCy ) (5 mol%)
Ar1
AlBu
i
O
Ar
2
1a
2a
1a
2b
OMe
1a
2c
OMe
2
+
o
toluene, T ( C), 24 h
Et
2
N
1
(1.5 eq)
2
(1.0 eq.)
3aa
3ab
3ac
(92%, 50 oC)
(93%, 70 oC)
(95%, r.t.)
Me
Me
O
N
1a
2d
CF3
1a
2e
O
1a
2f
1a
2g
1a
2h
1a
2i
i
N Pr
2
3ad
3ae
i
3af
(83%, 70 C)
3ag
3ah
o
3ai
OPr
O
o
(
91%, 50 oC)
(98%, 50 oC)
(65%, 70 oC)
(91%, 110 C)
(92%, 70 oC)
0
1
2
3
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1
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1
2
3
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0
1
2
3
4
5
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7
8
9
0
OEt
Me
2mS
1a
2j
1a
2k
1a
2l
1a
1b
2k
Me
1c
2d
CF
3
S
N
3
aj
3ak
N
3al
3am
3bk
N
3cd
Me
(
95%, 70 oC)
Me
(91%, 70 oC)
(22%, 90 oC)
(42%, 90 oC)
(94%, 50 oC)
(90%, 70 oC)
Me
Me
MeO
N
N
N
1d
2i
MeO
1e
2a
MeO
1e
2k
1f
2i
F C
1g
2a
F
1h
2i
3
3
di
3ea
3ek
N
3fi
3ga
3hi
Me
MeO
(95%, r.t.)
(98%, 50 oC)
(70%, 90 oC)
(
85%, 70 oC)
(94%, 50 oC)
(90%, 50 oC)
Me
a
1
(0.75 mmol, 1.5 eq.) was treated with 2 (0.5 mmol, 1 eq.) in the presence of NiCl (PCy ) (5
2 3 2
mol %) in toluene (3 mL) at r.t.~90 °C under argon. Isolated yields.
b
Scheme 3. Crossꢀcoupling between aluminum reagent 1 and phenol carbamates 2 in the presence
a,b
of Niꢀcatalyst.
3
2c
Besides aromatic C–O substrates, vinylic (enolic) ones 4 and even benzyl alcohol (Csp –O)
derivatives 5 were also available for this reaction. Representative results of the coupling of these
substrates are summarized in Scheme 4ꢀA. Both acyclic (4a) and cyclic substrates (4b) smoothly
underwent C(alkenyl)–O bond cleavage to give the desired coupling products 6aa-b in good
yields. Alkenyl (1i) or alkynyl (1j) aluminum reagents could also be utilized for this crossꢀ
coupling, affording the corresponding products 6ia or 7jn without difficulty. Therefore, this
reaction provides a simple and direct method for the regioꢀcontrolled synthesis of multiꢀ
pivalate
substituted olefins/alkynes. Furthermore pivalate 5a
reacted with 1a to afford
diarylmethane 8aa in 80% yield. On the other hand, cleavage/functionalization of the ethereal C–
2ꢀ4
O bond is much more difficult due to its inertness. In fact, simple application of the current
OMe
protocol to 2ꢀmethoxynaphthalene 2a
proved to be less effective. For example, heating excess
OMe
o
amounts of 1a (2.0 eq.) and 2a
with NiCl (PCy ) at high temperature (110 C) gave 3aa in
2
3 2
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only 59% yield, but the yield increased to 82% when the reaction mixture was heated in THF in
t
4r
the presence of Ni(cod) , imidazolium ligand (ICy), and NaO Bu as an additive (Scheme 4ꢀB).
2
OMe
2c
Interesting, benzyl ether 6a , which has higher reactivity than aryl ether, reacted smoothly at
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58
59
60
o
5
0 C in the presence of Ni(cod) and dcypb to give 8aa in 75% yield (Scheme 4ꢀB).
2
(A)
Ph
O
NiCl (PCy ) (5 mol%)
2 3 2
R1
i
R2
4a
AlBu
+
O
1a
2
toluene, T (°C)
Et N
Ph
2
1
(1.5 eq.)
2, 4, or 5 (1.0 eq.)
24 h
6
aa (87%, r.t.)
1
j
O
i
Pr Si
2n
Ph
3
EtO
Me
jn (72%, 90 oC)
7
Me 1i
4b
1a
2a
5a
1a
6ab
6ia
72%, 50 oC)
(88%, 50 oC)
8aa
(
80%, 50 oC)
pivalate
(
(B)
ether
condition:
i
Ni(cod)2 (5 mol%)
Ph AlBu
2
+
MeO
R
Ph
3aa (82%)
ICy • HCl (10 mol%)
1
a
(1.5 eq.)
2a or 5a (1.0 eq.)
t
NaO Bu (1.0 equiv.)
toluene, 90 oC, 24 h
condition:
Cl
Cy
Ph
PCy2
Ni(cod)
dcypb (10 mol%)
toluene, 50 C, 24 h
2
(5 mol%)
N
N
Cy
2
Cy P
8aa (75%)
o
ICy • HCl
dcypb
a
1
(0.75 mmol, 1.5 eq.) was treated with 2, 4, or 5 (0.5 mmol, 1 eq.) in the presence of
NiCl (PCy ) (5 mol %) or Ni (cod) (5 mol %)/ligand (10 mol%) in toluene (3 mL) at r.t.~90 °C
under argon. Isolated yields.
2
3 2
2
b
Scheme 4. (A) Crossꢀcoupling between aluminum reagent 1 and carbamate 2, 4, or 5 to afford
Cvinyl–Cphenyl/Calkynyl–Cphenyll/Cphenyl–Calkyl bonds; (B) Crossꢀcoupling between aluminum reagent
a,b
1
a and ether 2a or 5a.
Ni-Catalyzed Cross-Coupling Between Organoaluminum Reagents and Organic
Fluorides. With the success of crossꢀcoupling through C–O bond cleavage, we turned our
6
attention to C–F bond cleavage as the next target for utilization of aluminum reagents. The C–F
bond shows high stability to a wide range of reagents and metals. Several methods for C–C bond
formation via crossꢀcoupling of organic fluorides have been reported to date, mostly involving
7
8
9
Grignard reagent, organoboron, and organozincs. Many pioneering studies on crossꢀcoupling
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with organic fluorides were limited to aryl fluorides with extremely electronꢀdeficient nature or
with orthoꢀgroup assistance, especially for SuzukiꢀMiyaura type and Negishi type reactions. A
more general protocol for SuzukiꢀMiyaura coupling with a wide range of aryl fluorides was
recently developed by Tobisu and Chatani, based on efficient promotion by additional Lewis
0
1
2
3
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5
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9
0
1
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0
8
l
acids. In this section, we demonstrate the remarkable reactivity of aluminum reagents 1 toward
a variety of aryl fluorides 9, ranging from electronꢀrich to electronꢀdeficient aromatic rings, in
the absence of an orthoꢀdirecting group (Scheme 5). It is known that electronꢀrich aryl fluorides
8
9
are normally less reactive electrophiles for the SuzukiꢀMiyaura type, Negishiꢀtype, and even
7
some cases of KumadaꢀTamao type couplings, whereas by using the current protocol, the
reaction with aryl fluoride 9c bearing an electronꢀdonating OMe group took place smoothly,
even with sterically demanding aryl aluminum reagent 1d (albeit at higher temperature).
Similarly, the reaction with electronꢀrich 9p also gave a good yield at higher temperature.
2
1
Further, various polar functional groups are well tolerated, such as CF (9d), amide (9g), and
3
ester (9o), as well as heterocycles (9i, 9rꢀs), some of which are sensitive to metal reagents and
base. The reaction also proceeded well at the sterically hindered  ꢀposition of the naphthalene
ring (9q) and the orthoꢀsubstituted phenyl ring (9t).
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NiCl (PCy ) (5 mol%)
2
3 2
1
AlBu
i
F
Ar2
Ar
+
2
THF, 50 °C, 24 h
1
(1.5 eq.)
9
(1.0 eq.)
O
1
a
9c
OMe
1a
9d
CF
Ph
3
1a
1a
1a
9g
i
N Pr
2
3ac (96%)
3ad (93%)
3ag (83%)
N
O
1
a
9i
1a
1a
9n
9o
10
11
12
13
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i
OPr
3ai (75%)
3an (98%)
3ao (75%)
1a
9p
NMe2
9q
9r
N
3ap (90 °C, 80%)
3aq
3ar
(89%)
(93%)
N
1
a
9s
1b
9c
OMe
Me
1c
9c
OMe
3
as (62%)
3bc (91%)
3cc (89%)
Me
Me
same
compound
Me
Me
1
d
9c
OMe MeO
1e
9n
3en (98%)
Ph MeO
1a
9t
Me 3dc (90 °C, 83%)
3at (88%)
a
1
(0.75 mmol, 1.5 eq.) was treated with 9 (0.5 mmol, 1 eq.) in the presence of NiCl (PCy ) (5
2 3 2
mol %) in THF (3 mL) at 50~90 °C under argon. Isolated yields.
b
Scheme 5. Crossꢀcoupling between aryl aluminum reagent 1 and aryl fluoride 9 catalyzed by Niꢀ
a,b
catalyst.
Although alkenyl aluminum reagents could also be utilized in this reaction (Scheme 6ꢀA),
alkyl and alkynyl aluminums gave only small amounts of the coupling product. When 1,4ꢀ
difluorobenzene 9u was employed (Scheme 6ꢀB), both C–F bonds were involved in the reaction
and the double crossꢀcoupling product was obtained in 83% yield. On the other hand, 9v
underwent “single” crossꢀcoupling regioꢀselectively, and only one C–F bond adjacent to the
directing group was arylated (Scheme 6ꢀC). This result suggests the feasibility of a selective
functionalization strategy for multiꢀfluoroarenes.
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5
5
5
5
6
NiCl (PCy ) (5 mol%)
2
3 2
i
R
Al Bu
+
F
Ar
2
THF, 50 °C, 24 h
1
(1.5 eq.)
9
(1.0 eq.)
Me
(A) (B)
Ph Ph
same compound
with 9n
Me
1i
9
n
9u
Ph
+
F
9u
Ph
3audi (83%)
3aumono (trace)
6
in (83%)
(
C)
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
N
N
N
2
9
v
Ph
+
9v
Ph
+
9v
F
4
av2
(61%)
4
3av2,4
3
3av
F
(trace)
(not detected)
Ph
Ph
a
1
(0.75 mmol, 1.5 eq.) was treated with 9 (0.5 mmol, 1 eq.) in the presence of NiCl (PCy ) (5
2 3 2
mol %) in THF (3 mL) at 50 °C under argon. Isolated yields.
b
Scheme 6. Niꢀcatalyzed crossꢀcoupling of (A) alkenyl aluminum 1i with aryl fluoride 9n, (B)
phenyl aluminum 1a with 1,4ꢀdifluorobenzene 9u, and (C) with 2,4ꢀdifluorobenzene 9v bearing
a,b
a directing group.
Ni-Catalyzed Cross-Coupling Between Organoaluminum Reagents and Aryl Ammonium
Salts. Ammonium salts can easily be prepared directly from the corresponding amines, and show
1
0
much higher C–N reactivity. Hence, TMꢀcatalyzed crossꢀcoupling reactions with ammonium
11
salts as the electrophiles have attracted much attention in recent years. After extensive
experimentation, we found that heating in THF in the presence of Ni catalyst provided
satisfactory reactivity with organoaluminum reagents. Aryl ammonium salts 10 substituted with
electronꢀdonating and electronꢀwithdrawing groups reacted with aryl aluminum reagent 1 to
afford the corresponding coupling products in good yields (Scheme 7). Alkyl ammonium salt
1
1a as well as alkenyl aluminum reagent 1i were also available for this reaction.
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9
NiCl
2
(PCy
3 2
) (5 mol%)
R1 AliBu2
+
TfO • Me
N
R2
3
THF, T (°C), 6 h
10 or 11 (1.0 eq.)
1
(1.5 eq.)
O
1a
10c
OMe
1a
10d
CF3
1a
10o
OiPr
3
ac
3ad
(110 °C, 82%)
3ao
(50 °C, 94%)
(90 °C, 82%)
N
10
11
12
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1a
10s
1b
10c
OMe
Me
1c
10c
OMe
3as
3cc
Me 3bc (70 °C, 90%)
Me
(70 °C, 78%)
(70 °C, 96%)
MeO
1e
10n
Ph
1i
10n
Ph
11a
1a
Me
3
en
6in
8aa
Me
(
90 °C, 83%)
(90 °C, 63%)
(90 °C, 77%)
a
1
(0.75 mmol, 1.5 eq.) was treated with 10 or 11 (0.5 mmol, 1 eq.) in the presence of
NiCl (PCy ) (5 mol %) in THF (3 mL) at 50~110 °C under argon. Isolated yields.
b
2
3 2
Scheme 7. Crossꢀcoupling between aluminum reagent 1 and ammonium salt 10 or 11 catalyzed
a,b
by Niꢀcatalyst.
Comparison of Reactivities of C–O/C–F/C–N substrates in Ni-Catalyzed Cross-Coupling
with Organoaluminum Reagents. Finally, to investigate the chemoselectivity of this coupling,
the reactivities of the cleavage of C–O (carbamate), C–F, and C–N (ammonium) bonds were
examined (Scheme 8). Interestingly, we found that the chemoselectivity of the present coupling
system was dependent upon the reaction solvent. In toluene, both the C–O bond in carbamate
and the C–N bond in ammonium salt showed much higher reactivity than the C–F bond (Scheme
8
, a1ꢀ3). Compared with the case of carbamate C–O bond, the decrease of reactivity of
ammonium salt in toluene is probably due to low solubility (Scheme 8, a2). On the other hand, in
THF, the C–N bond in ammonium salt showed slightly higher reactivity than the carbamate C–O
bond, and is preferentially cleaved over the C–F bond (Scheme 8, b1ꢀ3). Thus, C–F bond
cleavage was the most sluggish process both in toluene and in THF. Although the selectivity is
poor in THF, it is noteworthy that the competitive reactions in toluene for C–O vs. C–F (Scheme
8, a1) and C–F vs. C–N (a3) were highly selective. We also performed a representative
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intramolecular competition reaction of 2y with 1e in toluene (Scheme 9). As in the
intermolecular reaction, although carbamate 2y contains both C–F and the C–O moieties, 3ey
was obtained in good yield as the sole product via C–O cleavage. The characteristic selectivity of
the present coupling reaction in solvents with different coordinating ability and polarity provides
some mechanistic insights. Further studies to elucidate the reaction pathways with the help of
theoretical and spectroscopic studies are in progress in our laboratory.
0
1
2
3
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9
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2
3
4
5
6
7
8
9
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2
3
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0
1
2
3
4
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7
8
9
0
a
1a (0. 5 mmol, 1.0 eq.) was treated with a 1:1 mixture (0.5 mmol, 1 eq. for both components)
of 3n/9w, 3n/10x, 9w/10x in the presence of NiCl (PCy ) (5 mol %) in toluene (3 mL) or THF
2
3 2
b
(
3 mL) at 50 °C under argon. Isolated yields.
Scheme 8. Reactivity and Chemoꢀselectivity in Niꢀcatalyzed crossꢀcoupling with arylaluminum
a,b
reagents 1 via C–O/C–N/C–F bond cleavages.
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a
1
e (0. 75 mmol, 1.5 eq.) was treated with 2y (0.5 mmol, 1 eq.) in the presence of NiCl (PCy )
2 3 2
b
(5 mol %) in toluene (3 mL) at 50 °C under argon. Isolated yields.
a,b
Scheme 9. Chemoꢀselective coupling between 1e and 2y.
3
. Conclusion
In summary, we have established new protocols for crossꢀcoupling reactions utilizing
organoaluminum reagents and transition metal catalysts. The present reꢀexamination has greatly
expanded the range of applicability of organoaluminums in crossꢀcoupling reactions. The use of
commercially available Ni catalyst and easily accessable organoaluminum resources as a
coupling partner is highly attractive: 1) Taking advantage of the Rieke method, various
organoaluminum reagents could be readily prepared from RMgCl and directly used for coupling
reaction without the need for isolation/purification, in contrast to the case of organoboron
reagents; 2) aluminum reagents show broad compatibility with various active functional groups,
especially in C–O substrates, that might be poorly compatible with sole use of Grignard reagent;
3
) the present methods demonstrate the superior reactivity of aluminum reagents, especially
towards nonꢀnaphtholꢀrelated C–O substrates that bear electronꢀdonating or bulky groups, as
well as electronꢀrich aryl fluorides (C–F), which show little or no reactivity in existing coupling
protocols with Zn, B, or Mg reagents. In general, the current protocols of aluminum reagents
show favorable reaction characteristics, mild conditions, wide substrate scope, and broad
functional group compatibility, suggesting that the new reactions should be widely useful in
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organic synthesis. Detailed mechanistic studies and work to extend the present methodology to
other important carbonꢀcarbon/carbonꢀheteroatom bondꢀforming reactions are in progress.
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AUTHOR INFORMATION
Corresponding Author
*Email: chaowang@mol.f.uꢀtokyo.ac.jp (C.W.); uchiyama@mol.f.uꢀtokyo.ac.jp (M.U.).
Author Contributions
#H.O. and Z.ꢀK.Y. contributed equally to this work.
Notes
The authors declare no competing fi nancial interest.
ASSOCIATED CONTENT
Supporting Information. This material is available free of charge via the Internet at
http://pubs.acs.org.
1
13
Experimental procedures, characterization data, and H and C NMR spectra for all compounds
PDF)
(
ACKNOWLEDGMENT
This work was supported by JSPS KAKENHI (S) (No. 24229011) (to M. U.) and TeiꢀSoku
Program (PU14008) (to C. W.). This research was also partly supported by grants (to M. U.)
from Asahi Glass Foundation, Nagase Science Technology Development Foundation, Sumitomo
Foundation and Kobayashi International Scholarship Foundation.
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2
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(19) For the reaction with C–O substrates 2, it is noteworthy that, 1) a decrease of reactivity of
i
1
(prepared from ClAl Bu and ArMgBr or ArLi in 1 : 1 ratio) was observed in some cases, 2)
2
use of Ar Al (0.75 eq., prepared from AlCl and ArMgCl in 1 : 3 ratio) showed similar high
3
3
reactivity as 1, and 3) Ar Al prepared from AlCl and ArMgBr or ArLi also showed higher
3
3
reactivity than corresponding 1 from ArMgBr or ArLi. Details are shown in supporting
information. The differences in reactivity of aryl aluminum reagents depending on the use of
ArLi or ArMgX (X = Cl, Br) as organometallic precursor may be attributed to the different
complexation states. Related effects have been noted in organozinc chemistry, see (a) Jin, L.;
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Chem. Soc. 2009, 131, 16656–16657. (b) Hevia, E.; Chua, J. Z.; GarciaꢀAlvarez, P.; Kennedy, A.
R.; McCall, M. D. Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 5294–5299.
(20) No coupling products but remain of C–O electrophiles were observed when Ni catalyst
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was not added to the reaction of 1a with 2a, 2d, 2j or 5a, respectively.
(21) Without adding Ni catalyst, no coupling product but remain of fluoride 9d was observed.
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