Three-component metal-free arylation of isocyanides

Article abstract of DOI:10.1002/anie.201302659

Mumm's the word: The title reaction can be performed by the addition of isocyanides to benzenediazonium salts in the presence of sodium or potassium carboxylates. The reaction involves nitrilium intermediates which may be trapped by water or carboxylic ac

Full text of DOI:10.1002/anie.201302659

Angewandte
Chemie
Communications
Synthetic Methods
U. M. V. Basavanag, A. Dos Santos,
L. El Kaim,* R. Gꢀmez-MontaÇo,*
L. Grimaud*
&&&& — &&&&
Mumm’s the word: The title reaction can
be performed by the addition of isocya-
nides to benzenediazonium salts in the
presence of sodium or potassium car-
boxylates. The reaction involves nitrilium
intermediates which may be trapped by
Three-Component Metal-Free Arylation of
Isocyanides
water or carboxylic acids to form amides
and imides, respectively, after Mumm
rearrangement.
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DOI: 10.1002/anie.201302659
Synthetic Methods
Three-Component Metal-Free Arylation of Isocyanides**
Unnamatla M. V. Basavanag, Aurꢀlie Dos Santos, Laurent El Kaim,* Rocio Gꢁmez-MontaÇo,*
and Laurence Grimaud*
Though the efficiency of isocyanides as strong ligands for
transition metals was recognized very early,[1] the disclosure of
metal-catalyzed arylation of isocyanides has only been
explored quite recently.[2] In most of these studies, the
formation of a metal/aryl complex starting from aryl iodide
or bromide is followed by isocyanide insertion and trapping of
the metal/imidoyl complex with various nucleophiles
(Scheme 1). These three-component couplings are mostly
isocyanides is a fast process with rate constants estimated at
over 107 LmolÀ1 at 08C.[3d–e] To form structures close to the
ones obtained under transition-metal catalysis (Scheme 1),
one has to address the fate of the resulting imidoyl radicals,
which, if not reduced by hydride donors, are usually engaged
in further intramolecular cyclizations[3b,c,g] or fragmentations
towards nitriles.[3d,f,g] As these radicals are rather electron
rich,[4] more general three-component couplings could be
achieved through oxidative pathways leading to nitrilium
intermediates and subsequent addition of various nucleo-
philes (Scheme 1). Because of their ease of reduction and
wide availibility from anilines, diazonium salts are often
selected as starting materials whenever aryl radicals are
expected as reactive intermediates. The conversion of diazo-
nium salts into aryl radicals is a well-studied proccess[5] and
triggered by various electron-rich organic species or metal
salts, and involved in several classical transformations such as
the Sandmeyer reaction[6] or the Meerwein arylation.[7]
Scheme 1. Three-component arylation of isocyanides.
To prove the concept, water was selected as a nucleophile
towards the isocyanide/diazonium couple. When para-nitro-
phenyldiazonium tetrafluoroborate was added to a solution of
cyclohexyl isocyanide in a water/acetonitrile mixture, we
observed a slow reaction leading to the expected amide in
10% yield after one hour (Scheme 2). Diazonium salts are
described with palladium and suffer from the highly coordi-
nating nature of isocyanides, which often limits the efficiency
of bulky isocyanides. To circumvent these difficulties the
choice of a metal with moderate affinity for isocyanides or the
development of metal-free arylation would be highly desir-
able. It is in this context that we herein present new three-
component couplings involving isocyanides and aryl diazo-
nium salts.
Considering the known reactivity of radicals with isocya-
nides,[3] we envisioned that the choice of aryl radical additions
might bring an answer to the limitations of the transition-
metal triggered couplings. The addition of aryl radicals to
[*] A. Dos Santos, Dr. L. El Kaim
UMR 7652 (Ecole Polytechnique/ENSTA/CNRS)
Laboratoire Chimie et Procꢀdꢀs, ENSTA-Paristech
828 Bd des marꢀchaux, 91120 Palaiseau (France)
E-mail: laurent.elkaim@ensta.fr
Scheme 2. Amide formation from diazonium salts.
Dr. L. Grimaud
Laboratoire d’ꢀlectrochimie, CNRS-UMR 8640-Division 1328
Ecole Normale Supꢀrieure—Dꢀpartement de chimie
24 rue Lhomond, 75231 Paris cedex 05 (France)
E-mail: laurence.grimaud@ens.fr
known to generate aryl radicals more efficiently in the
presence of nucleophilic weak bases such as tertiary amines,[8]
pyridine,[9] or sodium acetate.[10] In addition, the reaction
should progress with evolution of tetrafluoroboric acid,
a sufficiently strong acid to trigger the hydrolysis of the acid
sensitive isocyanide. This analysis was confirmed by the much
higher yields obtained when the following trials were
performed with added bases.
U. M. V. Basavanag, Dr. R. Gꢁmez-MontaÇo
Noria Alta S/N, Departamento de Quꢂmica, Universidad de
Guanajuato, Noria Alta S/N, Guanajuato,Gto. (Mꢀxico)
E-mail: rociogm@ugto.mx
[**] We gratefully thank CONACYT for the grant 166747-Q as well as for
a fellowship awarded to M.V.B. (378051/252139).
Sodium acetate was selected because of the lower
reproducibility when using pyridine. Finally, lower concen-
trations (0.25m and 0.5m) gave much lower yields in
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201302659.
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Chemie
Table 1: Scope of the amide formation.
issues because of the potential attack of nucleophiles to
either side of the benzyne moiety. In all our trials, the isolation
of a single regiomer possessing the same substitution pattern
as the starting diazonium salt rejects benzyne as a possible
intermediate. For instance, no trace of a 3-substituted amide
has been isolated in the case of 2-trifluoromethyl benzene-
diazonium tetrafluoroborate, in opposition to what would be
expected for a benzyne-type reaction path (Table 1, entry 11).
Alternative known fragmentations of diazonium salts
through SNAr or SN1 paths[5] (Scheme 3c,d) may also be
discarded because of the close behavior of both electron-rich
(Table 1, entries 2,4, and 10) and electron-poor (Table 1,
entries 3, 5–7, and 9) benzenediazonium salts. In addition, the
triggering effect of added acetate is more in favor of a radical
pathway. Single-electron transfer (SET) between radical
intermediates and diazonium salts has been classically
observed in Meerwein arylation of electron-rich alkenes[13]
or in the reduction of diazonium salts by THF when used as
solvent.[14] In our case the electron-rich nature of the imidoyl
radical probably favors the electron transfer with the starting
diazonium salt over competing fragmentation to nitriles.
In terms of synthetic efficiency, the required preparation
of diazonium tetrafluoroborate may be considered as a limi-
tation of the synthetic interest of this new arylation process.
Very few diazonium salts are commercially available and
when a large amount of dry salts are required, even though
tetrafluoroborates are considered rather safe, explosion
hazards must always be considered. To lower such risks,
their in situ preparation from anilines with addition of
nucleophiles in an additional step offers a good alternative.[15]
In our case, as a result of their moderate nucleophilicity, the
presence of isocyanides in the medium may not disturb the
nitrosation process of anilines. This was indeed the case as
shown by the successful preparation of the amides 3a–f and
3m under addition of a solution of sodium nitrite in water to
a solution of aniline, acetic acid, and isocyanide in acetonitrile
at 08C (Table 2). Most impressive is the resulting increase in
yields, thus converting this new reaction into an efficient
formal homologation of anilines into amides.
Entry
Ar
R1
3
Yield [%]
1
2
3
4
5
6
7
8
4-ClC6H4
Cy
Cy
tBu
tBu
3b
3c
3d
3e
3 f
3g
3h
3i
50
55
35
43
55
42
60
52
4-MeOC6H4
4-NO2C6H4
4-MeOC6H4
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
4-ClC6H4
CH2C6H4-4-OMe
CH2C6H4-4-Cl
9
10
11
4-NO2C6H4
4-MeOC6H4
2-CF3C6H4
CH2CO2Et
CH2CO2Et
tBu
3j
3k
3l
76
67
33
acetonitrile as classically observed in many isocyanide-based
multicomponent reactions. Different diazonium salts and
isocyanides were then treated under these reaction conditions
to give amides in overall moderate yields (Table 1).
The formation of amides with isocyanides prone to easy
fragmentation towards nitriles under radical conditions was
rather unexpected (Table 1, entries 3–6 and 11) and raised
questions about the radical nature of the reaction. Indeed
several different mechanisms may be proposed for the
process. Beside the Meerwein-type radical chain reaction
initiated by the decomposition of the acetoxyazo intermedi-
ate A (Scheme 3), a nonradical pathway involving the
Even if this amide formation is formally a new three-
component coupling of isocyanides,[16] water as the third
component does not allow much diversity. The integration of
Table 2: Direct arylation of isocyanides with anilines.
Entry
Ar
R1
3
Yield [%]
Scheme 3. Possible mechanisms for the arylation of isocyanides.
1
2
3
4
5
6
7
4-NO2C6H4
4-ClC6H4
Cy
Cy
Cy
tBu
3a
3b
3c
3d
3e
3 f
92
60
61
85
59
63
71
4-MeOC6H4
4-NO2C6H4
4-MeOC6H4
4-NO2C6H4
4-ClC6H4
benzyne intermediate C could also lead to the final amides
3 (Scheme 3). The latter mechanism is supported by the
known formation of benzamides under addition of isocya-
nides to benzyne[11] (obtained through nitrosation of anthra-
nilic acid) together with few reports on the generation of
benzyne under treatment of simple diazonium salts with
sodium acetate.[12] However, the formation of benzyne
intermediates is usually associated with regioselectivity
tBu
CH2C6H4-4-OMe
tBu
3m
Reaction conditions: acetic acid (1.5 mmol) and isocyanide (1 mmol)
were added successively to aniline (1 mmol) in 7.5 mL of CH3CN. The
mixture was cooled to 08C before the addition of of sodium nitrite
(1.5 mmol) in water (2.5 mL).
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Table 3: Scope of the three-component imide formation.
more complex nucleophiles would be highly desirable.
Sodium acetate is used to trigger aryl radical formation and
to buffer the reactive medium, therefore we surmised that
sodium acetate could also act as a nucleophile for nitrilium
intermediates in the absence of water. To our delight, when
para-nitrobenzenediazonium tetrafluoroborate was added
portionwise to a mixture of sodium acetate and cyclohexyl
isocyanide in acetonitrile, the new imide 4a was isolated
instead of the former amide 3a (Scheme 4). The outcome of
Entry Ar
R1
R2
4
Yield [%][a]
1
2
3
4
5
6
7
8
4-MeOC6H4 Cy
Me
Me
Me
4b 31 (35)
4c 39 (45)
4d 45 (54)
4e 53 (62)
4 f 60 (57)
4g 40 (48)
4h 76 (78)
4-ClC6H4
CH2C6H4-4-Cl
Cy
CH(iPr)CO2Me Me
2-CF3C6H4
2-CF3C6H4
2-CF3C6H4
CH(Me)CO2Me Ph
4-NO2C6H4 Cy
Ph
Ph
2-CF3C6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
tBu
tBu
tBu
tBu
CH2C6H4-4-F 4i 51
Ph
iPr
tBu
9
10
11
4j 47 (57)[b]
4k 54
4-NO2C6H4 CH2C6H4-4-Cl
3g 54[c]
[a] Yield determined for the reaction using procedure A. The value within
parentheses is that determined for the reaction using procedure B.
[b] Yield is 12% with PhCO2Na and no imide formation with PhCO2Li
and PhCO2Ag. [c] Amide was obtained instead of the expected imide.
Scheme 4. Three-component imide formation. Ar = 4-NO2C6H4.
DIPEA=diisopropylethylamine.
ylate ion pair which may further evolve by different pathways
(fragmentation, hydrolysis, etc.). The high yielding formation
of the 2-substituted imide (Table 3, entries 3–5 and 7) addi-
tionally rejects the mechanistic path involving benzyne
intermediates. In the case of pivalic acid (Table 3, entry 11),
the expected imide was not formed. The steric hinderance of
the tert-butyl group probably prevents the intermediate
pivaloyl imidate from undergoing the Mumm rearrangement.
The conversion of the latter into the amide 3g may be
explained by an intermolecular attack of a pivalate on the
imidate with evolution of pivalic anhydride.
In conclusion, we have developed a new arylation of
isocyanides with diazonium salts. The reaction features a new
mode of coupling for isocyanides with aryl nitrilium species as
key intermediates. The initially disclosed amide formation
could be easily extended to highly diverse three-component
imide formation from carboxylic acids, isocyanides, and
diazonium salts. Though the formation of imides in isocya-
nide-based multicomponent reactions was disclosed very
early by Ugi, they still remain rather uncommon scaffolds.[19]
Additional work is in progress to extend these first successful
trappings to the use of other nucleophiles with or without
added metal catalyst as described in the Sandmeyer reactions.
this modified process may be easily explained by a final
Mumm rearrangement[17] of an intermediate imidoyl acetate.
Various acetate or acetic acid/base combinations were tested
in acetonitrile showing the higher efficiency of the potassium
salt added as such, or obtained in situ with addition of K2CO3.
As observed for amides, acetonitrile remains the best solvent
for this reaction (Scheme 4).
The combination of acetic acid and potassium carbonate
appears slightly less satisfying than the direct use of potassium
acetate. However, it represents an interesting procedure for
the extension of this reaction to more complex carboxylic
acids, thus avoiding the tedious preparation of dry potassium
carboxylates. To test the scope of this new three-component
coupling, a set of isocyanides, diazonium salts, and carboxylic
acids were added together in acetonitrile with potassium
carbonate (Table 3). For acetic and benzoic acid, this proce-
dure could be compared with the direct addition of the
potassium carboxylate, which proved to be more efficient in
most cases. The better behavior of the potassium salts over
sodium salts was confirmed in the coupling of benzoic acid
with tert-butyl-isocyanide and 4-chlorophenyldiazonium tet-
rafluoroborate (Table 2, entry 9). In the latter case, the
lithium or silver salt did not give any imide.
Received: March 30, 2013
Published online: && &&, &&&&
Compared to the previous amide formation, the behavior
of the 4-methoxybenzenediazonium salt turned out to be
much less efficient, thus giving imide in low yields (Table 3,
entry 1) whereas the 2-trifluoromethylphenyl diazonium salt
behaved surprisingly well in the coupling (Table 3, entries 3–5
and 7). These differences could be analyzed considering the
Mumm rearrangement in the last step of the process. Indeed,
these rearrangements normally proceed through four-mem-
Keywords: arylation · isocyanides · reaction mechanisms ·
.
rearrangement · synthetic methods
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4
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