CoI-Catalyzed Barbier Reactions of Aromatic Halides with Aromatic Aldehydes and Imines

Article abstract of DOI:10.1002/chem.201806239

The reductive Barbier coupling of aromatic halides and electrophiles has been achieved using a CoBr₂/1,10-phenanthroline catalytic system and over stoichiometric amounts of zinc. The reaction displayed a broad scope of substrates, including (hetero)aryl chlorides as pro-nucleophiles and aldehydes or imines as electrophiles, leading to diarylmethanols and diarylmethylamines in moderate to excellent yields, respectively.

Full text of DOI:10.1002/chem.201806239

DOI: 10.1002/chem.201806239
Full Paper
&
Synthetic Methods
CoI-Catalyzed Barbier Reactions of Aromatic Halides with
Aromatic Aldehydes and Imines
Marc Presset,*[a] Jꢀrꢁme Paul,[a] Ghania Nait Cherif,[a] Nisanthan Ratnam,[a] Nicolas Laloi,[a]
Eric Lꢀonel,[a] Corinne Gosmini,[b] and Erwan Le Gall*[a]
Abstract: The reductive Barbier coupling of aromatic halides
and electrophiles has been achieved using a CoBr2/1,10-phe-
nanthroline catalytic system and over stoichiometric
amounts of zinc. The reaction displayed a broad scope of
substrates, including (hetero)aryl chlorides as pro-nucleo-
philes and aldehydes or imines as electrophiles, leading to
diarylmethanols and diarylmethylamines in moderate to ex-
cellent yields, respectively.
Introduction
The introduction of an additional reductant, provided by elec-
trochemistry[10] or by a reducing metal, allowed to de-
crease[11,12] or avoid[13] the use of greater than stoichiometric
amounts of toxic chromium salts. Recently, Li has described
the RhI-catalyzed Barbier reaction of aryl iodides and aldehydes
in water, through the in situ generation of an arylzinc spe-
cies.[14] Despite the benefits afforded by all these works, they
suffered from some disadvantages: rhodium catalysts are
highly expensive and nickel catalysts could display high toxici-
ty. Thus, a general method allowing the use of diverse sub-
strates, including aryl chloride derivatives, remains necessary.
Cobalt catalysis appeared to be a potential solution as Gosmini
reported the efficient generation of organozinc reagents from
aromatic halides and zinc catalyzed by low valent cobalt spe-
cies,[15,16] and she noticed the beneficial effect of cobalt salts
for the addition of arylzinc species on aldehydes, this transfor-
mation being limited to electron-rich aromatic bromides.[17]
During the course of our studies on the CoI-catalyzed synthesis
of indanamines,[18] we set up a catalytic system able to activate
various halides in the presence of a Michael acceptor. In con-
tinuation of this work, we herein report a general protocol for
the CoI-catalyzed Barbier reaction of various aromatic halides
and aldehydes. This transformation, based on an inexpensive
cobalt catalyst, is easy to set up and tolerates a broad range of
substrates, including aryl chloride derivatives, and has been
further extended to other electrophiles.
The addition of Grignard reagents to carbonyl compounds is
one of the most fundamental CÀC bond-forming reactions,
which is described in all standard textbooks.[1] However, this
approach suffers from two well-known drawbacks: it usually
(a) requires the pre-formation of the requisite organometallic
reagent, and (b) remains limited to substrates without sensitive
functional groups. Among the numerous progresses made in
the field, two main strategies have been elaborated to circum-
vent these issues. Thus, the preparation and use of functional-
ized organometallic species, which has been intensively stud-
ied by Knochel, has allowed to greatly expand the scope of
this reaction.[2–4] On the other hand, the elaboration of reduc-
tive cross-coupling reactions between two electrophiles has re-
cently received a considerable attention.[5,6] Although the zin-
cation of a halide and its addition onto an aldehyde partner
was described by Barbier as early as 1899,[7] the discovery of
the Nozaki–Hiyama–Kishi (NHK) reaction initiated a strong re-
newal of the field.[8,9] Indeed, it allows the arylation of alde-
hydes by an aryl halide (iodide, bromide or pseudo-halide)
using generally a Ni/Cr/Mn trimetallic system. Since then, vari-
ous conditions have been elaborated to improve the Ni-cata-
lyzed arylation of aldehydes using aryl bromides or iodides.
[a] Dr. M. Presset, Dr. J. Paul, G. N. Cherif, N. Ratnam, N. Laloi, Prof. E. Lꢀonel,
Prof. E. Le Gall
ꢁlectrochimie et Synthꢂse Organique
Universitꢀ Paris Est, ICMPE (UMR 7182), CNRS, UPEC
2-8 rue Henri Dunant
F-94320 Thiais (France)
E-mail: presset@icmpe.cnrs.fr
Results and Discussion
We began our study with the optimization of the Barbier cou-
pling between bromobenzene 1a-Br and m-anisaldehyde 2a
(Table 1). Starting from our previously reported conditions for
the multicomponent coupling of aryl bromides, Michael ac-
ceptors and aldehydes,[19] we performed a careful analysis of
the reaction parameters, ultimately leading to 82% of 3aa
under the “standard conditions”: CoBr2 (10 mol%), 1,10-phen
(10 mol%), Zn (4.0 equiv) activated by TFA (10 mol%) and allyl
chloride (15 mol%) in CH3CN (C=0.5m) at 808C for 16 h
legall@icmpe.cnrs.fr
[b] Dr. C. Gosmini
LCM, CNRS, Ecole polytechnique
Institut Polytechnique de Paris
91128 Palaiseau Cedex (France)
Supporting information and the ORCID identification number(s) for the au-
thor(s) of this article can be found under:
https://doi.org/10.1002/chem.201806239.
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Table 1. Effect of the reaction parameters.
Table 2. Scope of the CoI-catalyzed Barbier reaction with aldehydes.[a]
Ent Halide 1
Aldehyde 2
Product 3
Yield [%]
82
Entry
Modification from “standard conditions”
Yield [%][a]
1
2
3
4
5
6
7
none
room temperature
no 1,10-phen
82
33[b,c]
50[c]
70
1
1a-Br
2a
2a
3aa
3ba
3ca
2.0 equiv of Zn
dppe instead of 1,10-phen
PhCl instead of PhBr
PhI instead of PhBr
65
62
98
2
82
89
1b-Br
[a] Isolated yields. [b] 50% conversion (GC analysis). [c] 3aa/biphenyl=2:1
(GC analysis).
3
2a
1c-Br
4
2a
2a
70
46
(Entry 1). The main conclusions arising from these experiments
could be summarized as follow. The use of a CoBr2/Zn catalytic
system requires heating of the reaction mixture to 808C as
only limited reactivity was observed at room temperature
(33%, Entry 2), which in turn implies the addition of a ligand
(1,10-phen) to stabilize the CoI active species at such a temper-
ature (Entry 3). In all cases, zinc dust was activated by heating
in the presence of TFA, and allyl chloride was used as an addi-
tive to increase the rate of formation of the organozinc spe-
cies.[20] Moreover, the use of a large excess (4.0 equiv) of Zn
dust is beneficial to the overall efficiency of the protocol
(Entry 4), presumably through a better reduction of the CoII
pre-catalyst. The crucial importance of this catalytic step was
confirmed using a classical diphosphine ligand such as dppe
(Entry 5), known to generate a more stable complex, that led
to a reduced yield for the present transformation. Importantly,
we were pleased to find that the same catalytic system could
also be used with chlorobenzene 1a-Cl (Entry 6) and iodoben-
zene 1a-I (Entry 7) in satisfactory and excellent yields, respec-
tively. To the best of our knowledge, the present catalytic
system allowed us to report the first Barbier coupling of an
aryl chloride with an aldehyde.
We next turned our attention to the scope of the CoI-cata-
lyzed Barbier reaction of aryl halides 1 and aromatic aldehydes
2 (Table 2). As illustrated by these results, the reaction tolerates
a broad range of substitution on each substrate. Indeed, the
expected products were obtained in fair to excellent yields
using methyl- (Entries 2–6), methoxy- (Entries 7–10) and tri-
fluoromethyl- (Entries 11–13) substituted halobenzenes in reac-
tion with m-anisaldehyde 2a. From a general point of view,
aryl chlorides and bromides could be used, these latter being a
little more efficient (Entries 3 and 4), as anticipated. In all cases,
a complete conversion of the aromatic halide has been ob-
served and the lower yields observed with chlorides could be
attributed to the formation of reduced and dimeric products.
The introduction of a methyl group at the ortho- and meta-po-
sition of bromobenzene has almost no influence on the yield
(82 and 89%, respectively) whereas the use of para-bromoto-
luene 1d-Br surprisingly delivered a lower 46% of 3da (En-
1c-Cl
5
1d-Br
6
2a
3da
46
49
1d-Cl
7
1e-Cl
2b
2a
3eb
3 fa
8
89
99
1 f-Cl
9
1g-Br
2c
2a
3gc
10
51
42
1g-Cl
3ga
3ha
11
2a
1h-Br
12
2a
2a
30
20
1i-Br
3ia
13
1i-Cl
14
2a
2a
75
86
99
1k-Br
3ka
3la
15
1l-Cl
16
1m-I
2d
3md
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methyl group in ortho (92%), meta (84%) and para (69%) posi-
tions revealed the importance of electronic factors over steric
hindrance (Entries 19–21). This observation was supported
using p-anisaldehyde 2g and 4-fluorobenzaldehyde 2d, which
delivered the expected products in 69 and 99% yields, respec-
tively (Entries 22 and 23). A heteroaromatic aldehyde such as
thiophene 2-carboxaldehyde 2h was also found to be a suita-
ble partner as it gave 3eh in a good 72% yield (Entry 24). Ali-
phatic aldehydes were not tolerated in the reaction, probably
due to undesired reactions with a-protons under such basic
conditions.
Table 2. (Continued)
Ent Halide 1
Aldehyde 2
Product 3
Yield [%]
87
17
2d
1n-Br
3nd
3na
3ab
3ae
The present conditions could be extended to the prepara-
tion of phthalides (Scheme 1).[21] Indeed, in the case of a halide
bearing an ester function in the 2-position such as 1o-Cl, a
Barbier/lactonization domino reaction occurred and delivered
the expected 4, albeit in a moderate 31% yield. This limited re-
activity could be attributed to the presence of the EWG at the
ortho position, which strongly decreased the nucleophilicity of
the transient organometallic species.
18
2a
2b
47
92
84
1n-Cl
19
20
1a-Br
1a-Br
2e
2 f
21
22
23
24
1a-Br
1a-Br
1g-Br
69
69
99
72
3af
3ag=3gc
Scheme 1. Barbier/lactonization domino reaction.
2g
2d
The feasibility of an intramolecular version of the present re-
action was also examined. To do so, substrate 5 bearing both a
bromide and an aldehyde, prepared by a SNAr of 2-bromophe-
nol on 2-fluorobenzaldehyde,[22] was subjected to the standard
conditions. 9-Xanthenol 6a, arising from the aimed intramolec-
ular Barbier coupling, was isolated in 30% yield, together with
the 18% of the corresponding xanthone 6b (Scheme 2). The
formation of this latter could be explained by a Oppenauer ox-
idation of 6a by the starting aldehyde 5, as previously ob-
served in electrochemical NHK couplings.[23]
3gd
3eh
1e-Br
2h
[a] Yields of isolated products. Reaction conditions:
1 (1.5 equiv), 2
(1.0 mmol), CoBr2 (10 mol%), 1,10-phen (10 mol%), Zn (4.0 equiv) activat-
ed with TFA (10 mol%) and allyl chloride (15 mol%), CH3CN (C=0.5m),
808C, 16 h.
tries 5 and 6). The situation is somewhat different using a
strongly donor methoxy substituent as it increased the reactivi-
ty of the intermediate organometallic species and thus the
overall efficiency of the protocol (Entries 8–10), except in the
case of 1,2-disubstituted substrate 1e-Cl in which steric factors
appeared to become significant (Entry 7). The situation is re-
versed in the case of the trifluoromethyl group which de-
creased the electronic density of the nucleophilic species and
therefore led to much lower yields: 42% with 1h-Br, 30% with
1i-Br and only 20% with 1i-Cl (Entries 11–13). Bicyclic halides
such as 1-bromonaphthalene 1k-Br or 1l-Cl could also be
used in the reaction to give 3ka and 3la in good yields (En-
tries 14 and 15). Even though the use of heteroaryl halides re-
mained limited to the case of thiophene derivatives 1m and
1n (Entries 16–18), 3-chlorothiophene 1n-Cl was found to be a
possible substrate in a decent 47% yield (Entry 18). The scope
of aromatic aldehydes was also explored. The introduction of a
Scheme 2. Intramolecular version of the CoI-catalyzed Barbier reaction.
To expand the usefulness of the present CoII/Zn catalytic
system, we wondered if it might be suitable for other electro-
philes, such as imines. Indeed, the reductive Barbier coupling
of an aromatic halide and a sulfonyl imine would provide an
alternative to organometallic Mannich reactions,[24–26] which
usually require the use of a stoichiometric strong reductant
such as Mn.[27] We thus applied the standard conditions to a
variety of aryl halides and imines, and the results have been re-
ported in Table 3. Initial attempts performed with chloro-,
bromo- or iodobenzene with imine 7a-TPs, bearing an easily
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Table 3. Scope of CoI-catalyzed Barbier reactions with imines.[a]
cleavable 2-thiophenesulfonyl (TPs) group on the nitrogen
atom,[28,29] revealed that only bromide (35%) and iodide (61%)
derivatives were suitable substrates for the preparation of di-
arylmethylamine 8aa (Entries 1–3). These results constitute the
first examples of the Barbier coupling of an aryl halide on a
sulfonated imine. The scope of iodoarenes was then explored
in reaction with 7a-TPs. As previously observed in the case of
reductive couplings with aldehydes, the substitution of the
aryl halide by a methyl (Entries 4–6) or a methoxy (Entries 7–9)
group was possible in all positions (ortho, meta, para), yields
being usually lower but remaining useful (34–53%). Diversely
substituted imines 7b-TPs and 7c-TPs constituted valuable
partners with similar efficiencies (Entries 11 and 12) and the in-
troduction of a 2-thienyl group was possible on both sub-
strates (Entries 10 and 13). The use of a more electron-with-
drawing tosyl group allowed to reach similar yields as those
observed with iodides using bromides derivatives (58%,
Entry 14). The use of an aliphatic imine 7e-Ts was also possible
but delivered a low 21% yield, presumably due to decomposi-
tion of the poorly stable imine under the reaction conditions
(Entry 15).
Entry
1
Halide 1
Imine 7
Product 8
Yield [%]
1a-Cl
<5
2
3
1a-Br
1a-I
7a-TPs
7a-TPs
8aa
35
61
4
5
1b-I
1c-I
52
53
8ba
8ca
7a-TPs
6
7
8
1d-I
1e-I
1 f-I
7a-TPs
7a-TPs
7a-TPs
42
49
48
8da
8ea
8 fa
We also briefly explored the possibility of a reductive cou-
pling between an aryl halide and an isocyanate using our con-
ditions. Indeed, this transformation has only been reported
under Ni catalysis.[30,31] As an illustrative example, we submitted
a mixture of bromide 1g-Br and phenyl isocyanate 9 to the
CoII/Zn catalytic system and were delighted to isolate the ex-
pected amide 10 in a promising 66% yield (Scheme 3).
9
1g-I
7a-TPs
7a-TPs
34
44
8ga
10
1m-I
Scheme 3. CoI-catalyzed Barbier reaction with an isocyanate.
8ma
From a mechanistic point of view (Scheme 4), this transfor-
mation relies on the in situ generation of a low valent CoI cata-
lytic species by reduction of the CoII pre-catalyst with zinc.[32]
This catalyst should play an important role in the process as
the reaction using preformed organozinc species requires its
presence.[17] As previously described,[15] it leads to the genera-
tion of an arylcobalt species and zinc halide from the aryl
11
12
13
1a-I
1a-I
1a-I
8ab=8ca
38
48
22
7b-TPs
8ac=8 fa
7c-TPs
7d-TPs
8ad=8ma
14
15
1g-Br
1g-Br
58
7a-Ts
8ga-Ts
8ge-Ts
21
7e-Ts
[a] Yields of isolated products. Reaction conditions:
1
(1.5 equiv), 7
(1.0 mmol), CoBr2 (10 mol%), 1,10-phen (10 mol%), Zn (4.0 equiv) activat-
ed with TFA (10 mol%) and allyl chloride (15 mol%), CH3CN (C=0.5m),
808C, 16 h. TPs=2-thiophenesulfonyl; Ts=tosyl.
Scheme 4. Plausible reaction mechanism. Ligands are omitted for clarity.
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halide and zinc. By taking advantage of the stabilization of CoI
species by ZnII salts,[32,33] a tentative six-membered transition
state for the nucleophilic addition should occur, leading to the
zinc alkoxide with concomitant regeneration of the active
cobalt species. Such an enhancement of electrophilicity of the
aldehyde could be explained by the high oxophilicity of ZnII
salts and was previously observed using magnesium[34] or alu-
minium[35] Lewis acids.
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Conclusions
We have developed a broadly applicable CoII/Zn catalytic
system for Barbier couplings. This reductive coupling has been
applied to a large variety of halides and electrophiles, such as
aldehydes and imines. Among the different enhancements pro-
vided by this system, the first activation of chloride derivatives
in the context of Barbier couplings and the use of iodoarenes
for the direct preparation of sulfonated diarylmethylamines
constitute important results.
Experimental Section
General procedure: In air, an oven-dried 10 mL reaction tube
equipped with a stir bar was charged with Zn (262 mg, 4.0 mmol,
4.0 equiv), closed with a septum and flushed with Ar. CH3CN (2 mL,
C=0.5m), TFA (8 mL, 0.1 mmol, 10 mol%) and allyl chloride (12 mL,
0.15 mmol, 15 mol%) were added and the mixture was heated to
reflux using a heat gun and then cooled down to room tempera-
ture. CoBr2 (22 mg, 0.1 mmol, 10 mol%) and 1,10-phenanthroline
(18 mg, 0.1 mmol, 10 mol%) were added and the mixture was
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stirred at room temperature for 5 min. Halide
1 (1.5 mmol,
1.5 equiv) and electrophile 2, 7 or 9 (1.0 mmol) were successively
added and the tube was sealed. The reaction was stirred at 808C
(external temperature) for 16 h. Then, the reaction mixture was
poured into sat aq NH4Cl (50 mL) and the solution was extracted
with EtOAc (2ꢃ25 mL). The combined organic layers were washed
with brine (50 mL), dried (Na2SO4) and evaporated. The crude ma-
terial was purified by FC to afford the desired product.
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Acknowledgements
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The financial support of this work by the CNRS and the Univer-
sity Paris-Est (Ph.D. grant to J. P.) is gratefully acknowledged.
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Conflict of interest
The authors declare no conflict of interest.
Manuscript received: December 17, 2018
Revised manuscript received: January 24, 2019
Version of record online: && &&, 0000
Keywords: Barbier · cobalt · Mannich · reductive coupling ·
zinc
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FULL PAPER
&
Synthetic Methods
M. Presset,* J. Paul, G. N. Cherif,
N. Ratnam, N. Laloi, E. Lꢀonel, C. Gosmini,
E. Le Gall*
&& – &&
The reductive Barbier coupling of aro-
matic halides and electrophiles has
been achieved using a CoBr2/1,10-phe-
nanthroline catalytic system and over
stoichiometric amounts of zinc. The re-
action displayed a broad scope of sub-
strates, including (hetero)aryl chlorides
as pro-nucleophiles and aldehydes or
imines as electrophiles, leading to di-
arylmethanols and diarylmethylamines
in moderate to excellent yields, respec-
tively.
CoI-Catalyzed Barbier Reactions of
Aromatic Halides with Aromatic
Aldehydes and Imines
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