Unprecedented Transformation of a Directing Group Generated in Situ and Its Application in the One-Pot Synthesis of 2-Alkenyl Benzonitriles

Article abstract of DOI:10.1002/chem.201501449

An unprecedented protocol for the transformation of benzoyl azides into benzonitrile derivatives via iminophosphoranes generated in situ is described. The strategy was successfully applied to the de-novo synthesis of 2-alkenylated benzonitrile derivatives from benzoyl azides through ortho CH activation/alkenylation followed by subsequent rearrangement. The salient features of this protocol involve incorporation of two important functionalities through cyanation and olefination in one pot under mild reaction conditions by using a less expensive Ru catalyst. The mechanism was established by isolating and characterising (using ³¹PNMR) an intermediate with two ortho functionalities, iminophosphorane and olefin, under specific reaction conditions. Directly functional! Cyanation and olefination was accomplished in one pot from benzoyl azides through an unprecedented directing group transformation. The method generates benzonitriles and can be used for the synthesis of 2-alkenylated benzonitrile derivatives (see scheme).

Full text of DOI:10.1002/chem.201501449

DOI: 10.1002/chem.201501449
Full Paper
&
Synthetic Methods
Unprecedented Transformation of a Directing Group Generated In
Situ and Its Application in the One-Pot Synthesis of 2-Alkenyl
Benzonitriles
Ravi Kumar,[a, b] Rajesh K. Arigela,[a] and Bijoy Kundu*[a, b]
Abstract: An unprecedented protocol for the transformation
of benzoyl azides into benzonitrile derivatives via imino-
phosphoranes generated in situ is described. The strategy
was successfully applied to the de-novo synthesis of 2-alke-
nylated benzonitrile derivatives from benzoyl azides through
ortho CÀH activation/alkenylation followed by subsequent
rearrangement. The salient features of this protocol involve
incorporation of two important functionalities through cyan-
ation and olefination in one pot under mild reaction condi-
tions by using a less expensive Ru catalyst. The mechanism
was established by isolating and characterising (using
31P NMR) an intermediate with two ortho functionalities, imi-
nophosphorane and olefin, under specific reaction condi-
tions.
Introduction
such as nitrile may expand the versatility of the DG-mediated
ortho CÀH functionalisation approach. Nitrile functionality re-
mains one of the most prevalent substituent groups and it is
found not only in several natural products from plant/animal
sources, but it is also present in a variety of clinically used
drugs, herbicides, agrochemicals, and dyes.[7] From medicinal
chemistry point of view, the introduction of a nitrile[8] substitu-
ent into a molecule can lead to an enhancement in the bio-
availability, selectivity, metabolic stability and binding affinity
to therapeutic protein targets.[9] Traditionally, the introduction
of benzonitriles has been achieved in numerous ways includ-
ing Rosenmund-von Braun reaction[10] from aryl halides or di-
azotization of anilines and a subsequent Sandmeyer reac-
tion.[11] Direct introduction of benzonitrile[12] has been achieved
through transition-metal-catalysed cyanation either of aryl-X
compounds (X=Cl, Br, I, OTf and H) with readily available cy-
anation agents or of arenes bearing a directing group using
non-cyano[13] or cyano sources[14] (Figure 1). Chang et al. em-
ployed benzaldehyde oximes for the preparation of benzoni-
trile in the presence of ruthenium catalyst,[15a] whereas Prabhu
In recent years, the functionalisation of unreactive ortho arene
CÀH bonds[1] through transition-metal-catalysed directing-
group (DG) assisted strategies[2] has been the subject of
a number of intense investigations. Although numerous DGs
comprising carboxylic,[3a–d] ester,[3e] carbonyl,[3f–g] sulfoximine,[3h–i]
phosphinoxy,[3j] nitroso,[3k] ether,[3l] and heterocycle[3m–o] deriva-
tives have been employed for regioselective arene CÀH olefi-
nation, reports involving the generation of a DG in situ and its
transformation are scarce.[4]
Very recently, we reported[5] the synthesis of isoquinolones
from the corresponding acyl azides by following a domino se-
quence involving iminophosphorane[6] generated in situ as
a DG, ortho CÀH functionalisation, and transformation of the
DG through cyclisation. Inspired by this work involving imino-
phosphorane generated in situ as DG and by the above CÀH
olefination, we wanted to study the CÀH olefination of imino-
phosphoranes generated in situ. Herein, we disclose Ru-cata-
lysed ortho CÀH olefination of iminophosphorane generated in
situ followed by rearrangement to afford 2-alkenyl benzoni-
trile.
We envisaged that such a transformation of functional
groups (FGs) through in situ generated DG into another FG
[a] R. Kumar, R. K. Arigela, Dr. B. Kundu
Medicinal & Process Chemistry Division
Institution CSIR-Central Drug Research Institute
Lucknow, 226031 (India)
Tel.: (+91)522-2612411-18
Fax: (+91)522-2623405
E-mail: bijoy_kundu@yahoo.com
[b] R. Kumar, Dr. B. Kundu
Academy of Scientific and Innovative Research
New Delhi, 110001 (India)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201501449.
Figure 1. Previously reported methods and the current approach to the syn-
thesis of benzonitrile derivatives.
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et al. converted benzaldehyde into benzonitrile by using triflic
acid and sodium azide.[15b] Thus, none of the methods involve
transformation via DG intermediacy generated in situ and may
not find application in ortho CÀH functionalisation.
failed to initiate the transformation (Table 1, entries 2–4). Re-
placing either Cu-salt with another oxidant such as Cs(OAc)
and phenyl iododiacetate (PIDA) or DCE with other solvents
such as trifluoroacetic acid (TFA), toluene, N,N-dimethylform-
amide (DMF) or acetonitrile furnished 4a in diminished yields
(entries 5–10). Thus, these findings led us to believe that DCE
was the best solvent for the transformation and that it occurs
via iminophosphorane 2a generated in situ as an intermediate.
This was further confirmed by treating pre-synthesised imino-
phosphorane 2a with Ru and Cu-salt to afford the correspond-
ing benzonitrile 4a in 72% yield (Scheme 1).
Results and Discussion
We commenced our studies by using benzoyl azide and the
unactivated alkene styrene as model substrates to optimize
the coupling conditions. Initially, 1a was treated with triphe-
nylphosphine (TPP) in 1,2-dichloroethane (DCE) at 608C for
30 min to generate iminophosphorane 2a. Styrene 3a was
then added to the reaction mixture, which was then stirred at
808C with the addition of catalyst [Ru(p-cymene)Cl2]2 and an
oxidant Cu(OAc)2·H2O in 5.0 and 100.0 mol%, respectively.
After 12 h, a new product, 4a, was isolated in 93% yield
(Table 1, entry 1). The structure of the resulting compound was
identified as a cyano-containing compound benzonitrile in-
stead the desired ortho CÀH alkenylated derivative 5 (Table 1).
Scheme 1. Transformation of pre-synthesised iminophosphorane 2a into
benzonitrile 4a.
However, ruling out any possible involvement of
benzamide generated in situ, the latter failed to un-
dergo transformation to yield 4a. The scope and limi-
tations of the method were demonstrated by synthe-
sising ten nitrile derivatives from their corresponding
acyl azides (Table 2) with minimal variation in isolated
yields. However, the presence of an electron-with-
drawing group in the aryl ring failed to facilitate con-
version into the corresponding benzonitrile deriva-
Table 1. Transformation of benzoyl azide 1a into benzonitrile 4a.[a]
tives. Similarly, aliphatic acyl azides such as 2-phenyl
acetyl azide also failed to furnish the desired benzo-
nitrile derivative. This may be attributed to the de-
crease in the electron density on the nitrogen of the
iminophosphorane moiety, which, in turn, prevents
its chelation with the metal and subsequent transfor-
mation into benzonitrile derivative.
Entry
Cat.
[5 mol%]
Oxidant
[100 mol%]
Solvent
Yield of 4a
[%][c]
1
2[b]
3[d]
4[e]
5[f]
6
7
8
9
10
[Ru(p-cymene)Cl2]2
–
[Ru(p-cymene)Cl2]2
–
Cu(OAc)2·H2O
–
–
Cu(OAc)2·H2O
–
Cs(OAc)
PhI(OAc)2
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
DCE
DCE
DCE
DCE
TFA
DCE
DCE
toluene
DMF
CH3CN
93
n.d.
n.d.
n.d.
n.d.
46
63
42
28
36
–
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
After successfully optimising the transformation,
we then studied the DG-assisted CÀH alkenylation
with activated alkenes. We embarked with the appli-
cation of iminophosphoranes generated in situ from
acyl azides as a DG for ortho CÀH alkenylation with
activated alkenes and subsequent transformation of
the DG into a nitrile group to furnish compounds
based on 6 (Figure 2a). Although there are several re-
ports dealing with oxidative aromatic CÀH alkenyla-
[a] Reaction conditions: 1a (1.02 mmol), 3a (1.02 mmol), catalyst (5.0 mol%), oxidant
(100 mol%), solvent (5 mL), 808C, 12 h. [b] Conducted without PPh3. [c] Yield of isolat-
ed product. n.d.=not detected. [d] Conducted without Cu(OAc)2·H2O. [e] Conducted
without [Ru(p-cymene)Cl2]2. [f] Reaction carried out in TFA for 12 h.
The structure was established base on NMR spectroscopic anal-
ysis and also by comparison with reported data.[16] Although
a survey of the literature revealed a single report involving
transformation of iminophosphoranes through aza-Wittig reac-
tion, in our hands, we failed to observe such a transforma-
tion.[17]
tion by employing numerous DGs[18] (Figure 2b), to our knowl-
edge, there are no reports dealing with the synthesis of com-
pounds based on 6 except for the traditional Mirozoki–Heck
reaction[19] (Figure 2c).
We commenced our studies with the condensation of ben-
zoyl azide (1a) and the activated alkene tert-butyl acrylate (3b)
as model substrates for optimising reaction conditions for the
synthesis of 2-alkenyl benzonitriles 6 (Table 3). We treated 1a
with TPP (100 mol%) in DCE at 608C for 30 min to generate
iminophosphorane 2a in situ. Alkene 3b (1.02 mmol) was then
added and the reaction mixture was stirred at 808C with
the addition of catalyst [Ru(p-cymene)Cl2]2 and oxidant
Our strategy of transformation of azides into nitriles has an
advantage over traditional cross-coupling methods because it
expands the scope of the reaction to include ortho CÀH func-
tionalisation. This prompted us to initially study the transfor-
mation of acyl azides into nitriles. Carrying out the reaction
either in the absence of PPh3 or Ru-catalyst/Cu(OAc)2·H2O
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underwent a smooth CÀH activation/coupling sequence with
acrylate 3b and 3c affording the corresponding alkenylation
product 6bb and 6bc in 73 and 62% isolated yield, respective-
ly. Similarly, the presence of other electron-donating groups in
1 such as 3,4 di-methyl 1c and 3,4 methylene dioxy 1d of the
aromatic ring had no effect on the outcome of yields and fur-
nished products in 66–75% isolated yields (Table 4, 6cb–de).
Similarly replacing R1 of 1 with an electron-withdrawing group
(e.g., 4-fluro-, 4-chloro-, 4-bromo-, 4-iodo-, or 4-CF3) led to the
corresponding product 6 in good yields (65–72%) irrespective
of the nature of the olefin (Table 4, 6 fb–pc). In addition, the
yields increased significantly when R2 was replaced with
a benzyl group (Table 4, 6de and 6oe). Nevertheless, we also
observed the formation of only one regioisomer (Table 4, 6qb)
from the corresponding 3-halogenated reactant 1q. Replacing
benzoyl azides with naphthalene substrate 1g and treatment
with 3b and 3c furnished 6gb and 6gc regioselectively in sat-
isfactory yields (Scheme 2). This result is noteworthy because
1g has two potential CÀH bond activation sites (at C1 and C3)
Table 2. Substrate scope for the formation of nitrile derivatives 4.[a]
[a] Reaction conditions: 1 (1.02 mmol), PPh3 (100 mol%), [Ru(p-cyme-
ne)Cl2]2 (5.0 mol%), Cu(OAc)2·H2O (100 mol%) in DCE (5 mL) at 808C.
Scheme 2. Synthesis of 6 through regioselective olefination.
and only C3 was alkenylated. Replacing acrylates with acryloni-
trile, (vinylsulfonyl)benzene or 1-phenylprop-2-en-1-one failed
to give the desired product; instead, the corresponding imino-
phosphoranes were isolated as the only product. Similarly, re-
placing benzoyl azides with heteroaroyl azides failed to afford
the desired ortho-alkenylated nitrile products; this reaction led
to the formation of the corresponding nitrile derivatives 4j
and 4k.
Figure 2. Previously reported methods and the current approach to the syn-
thesis of 2-alkenyl benzonitrile derivatives 6.
As part of a mechanistic investigation, an attempt was made
to search for intermediates during the iminophosphorane (DG)
directed ortho CÀH olefination. Thus, the reaction was per-
formed under the optimised conditions but at lower tempera-
ture (508C). Gratifyingly, after quenching the reaction, we de-
tected two products with a high Rf difference by TLC analysis,
coupled with the complete disappearance of 2a (Scheme 3).
Following their isolation, the non-polar product was character-
ised as 6ab (8%) and the polar product was characterised as
intermediate 7 (62%) bearing both iminophosphorane and
ortho-alkenylated groups. This suggested that the iminophos-
Cu(OAc)2·H2O in 5.0 and 100.0 mol% respectively. The progress
of the reaction was monitored by thin-layer chromatography
and, after 20 h, 6ab was obtained in 68% isolated yield
(Table 3, entry 1). The investigation into the role of the oxidant
and screening of solvents in this transformation led either to
the recovery of intermediate 2a or to the production of 6ab
in reduced yield (entries 2–13). The results showed that both
catalyst and oxidant are essential for this transformation and
that DCE remains the best choice as solvent.
With these optimised results in hand, we then investigated
the scope and limitations of our new protocol for the synthesis
of 6 under the optimised reaction conditions. Accordingly,
a series of benzoyl azides 1a–q, bearing electron-donating (R1)
and electron-withdrawing groups (R1) were subjected to oxida-
tive CÀH olefination with a range of acyrlates 3b–e; the results
are summarised in Table 4. A set of 20 compounds based on 6
were synthesised with yields ranging from 62 to 75%. Sub-
strate 1b, with an electron-donating p-methoxy substituent,
Scheme 3. Isolation of intermediate 7 during DG-assisted synthesis of 6.
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phorane 2a generated in situ first undergoes DG-as-
sisted oxidative ortho CÀH olefination to afford 7,
which is then followed by the unprecedented trans-
formation of iminophosphorane into the CN group,
furnishing the desired 2-alkenylated benzonitrile 6ab.
Based on previous reports[20] and on our own
mechanistic studies, we propose the mechanism
shown in Figure 3. Initially, the ruthenium dimer pre-
catalyst undergoes dissociation to the coordinatively
unsaturated monomer in solution, which exchanges
ligand with Cu(OAc)2·H2O to form an acetate-ligated
species. The latter then coordinates with the N-atom
of the iminophosphane 2 (derived from 1) followed
by ortho cyclometallation to afford a five-membered
ruthenacycle intermediate I with the loss of acetic
acid through an acetate-assisted mechanism. This is
then accompanied by the insertion of an olefin into
the RuÀC bond to afford a seven-membered ruthena-
cycle intermediate II. Subsequent b-hydride elimina-
tion of II followed by reductive elimination affords 7.
Intermediate 7, upon further coordination with Ru
metal, forms III, which is then transformed into
a cyclic phosphooxetane structure V via intermediate
IV. Subsequent elimination of triphenylphosphine
oxide from V affords VI, which finally undergoes elim-
ination of the Ru metal to give 4 and 6. The rutheni-
um Ru0 from II undergoes oxidation to regenerate
the catalytically active RuII complex with the aid of
copper oxidant.
Table 3. Optimisation studies for the synthesis of 6ab.[a]
Entry
Oxidant
[100 mol%]
Solvent
Yield of 2a
[%][b]
Yield of 6ab
[%][b]
1
2[c]
3[d]
4[e]
5
6
7
8
9
10
11
12
13
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
–
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
CuBr2
DCE
DCE
DCE
DCE
toluene
CH3CN
THF
DMF
DCE
DCE
DCE
DCE
DCE
–
–
68
56
n.r.
n.r.
42
80
67
28
42
41
56
63
60
63
62
72
28
30
n.r.
n.r.
n.r.
n.r.
n.r.
n.r.
CuCl2·H2O
CsOAc
AgCO3
PhI(OAc)2
[a] Reaction conditions: 1a (1.02 mmol), 3b (1.02 mmol), [Ru(p-cymene)Cl2]2
(5.0 mol%), oxidant (100 mol%), DCE (5 mL), 808C, 20 h. [b] Yield of isolated product.
n.r.=no reaction. [c] Reaction carried out at 1008C for 15 h, more undesired products.
[d] Conducted without [Ru(p-cymene)Cl2]2. [e] Conducted without Cu(OAc)2·H2O.
Table 4. Substrate scope for the formation of 6.[a]
Conclusion
We have described a one-pot protocol for the con-
version of DG into FG. We have also described the
DG-assisted synthesis of 2-alkenyl benzonitriles from
aromatic acyl azides. The salient features involve
i) generation of iminophosphorane in situ as a DG, ii)
transformation of the DG into the corresponding ni-
trile group, and iii) oxidative ortho CÀH olefination.
The mechanism was clarified by isolating and charac-
terising an intermediate with two ortho functionali-
ties, iminophosphorane and olefin, during the forma-
tion of 2-alkenyl benzonitrile.
Experimental Section
General information and methods
All reagents and solvents were purchased from commer-
cial sources and were used without purification. NMR
spectra were recorded with a Bruker/Ascend 400 at 400,
1
100, and 161.9 MHz for H, 13C, and 31P nuclei, respective-
ly. Chemical shifts d are given in ppm relative to the re-
sidual signals of tetramethylsilane in CDCl3 or deuterated
solvent CDCl3/[D6]DMSO and [D6]benzene. Multiplicities
are reported as: singlet (s), doublet (d), doublet of dou-
blets (dd), doublet of triplets (dt), triplet (t), quartet (q),
multiplet (m), broad singlet (br. s). HRMS were obtained
[a] Reaction conditions: 1 (1.02 mmol), 3 (1.02 mmol), PPh3 (100 mol%), [Ru(p-cyme-
ne)Cl2]2 (5.0 mol%), Cu(OAc)2·H2O (100 mol%) in DCE (5 mL), 808C.
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column chromatography on silica
gel (n-hexanes/EtOAc, 9:1) to give
the product.
General procedure for the syn-
thesis of 2-alkenyl benzonitrile
derivatives (6)
To an oven-dried round-bottomed
flask equipped with a stir bar, acyl
azide
(5.0 mL)
1
(1.02 mmol) in solvent
followed by TPP
(1.0 equiv) were added and the
mixture was stirred and heated to
608C (the progress of the reaction
was monitored for formation of
iminophosphorane 2 by TLC; ca.
30 min was required). Acrylate 3
(1.02 equiv) was then added, fol-
lowed by the addition of [RuCl2(p-
cymene)]2 (5.0 mol%) and Cu(OA-
c)2·H2O (1.02 mmol) and the tem-
Figure 3. Tentative mechanism for the formation of 4 and 6.
perature was raised to 808C. Upon
completion of the reaction (as indi-
cated by TLC analysis), the resulting mixture was diluted with
water and extracted with EtOAc (3”20 mL). The combined organic
layers were washed with brine (20 mL) and dried over Na2SO4. The
solvent was evaporated in vacuo and the residue was purified by
column chromatography on silica gel (n-hexanes/EtOAc, 9:1) to
give the product.
with a Agilent 6520/QTOF-MS/MS by using the electrospray ioniza-
tion (ESI) technique and a time-of-flight (TOF) analyzer. Column
chromatography was performed with silica gel (100–200 mesh) as
the stationary phase. All reactions were monitored by thin-layer
chromatography (TLC). The purity and characterization of these
compounds were further established by using HRMS (ESI) with
a Agilent 6520/QTOF-MS/MS. Melting points were measured with
a BESTO capillary melting point apparatus and are uncorrected.
Acknowledgements
General procedure for the preparation of aryl acyl azides
1a–q
R. K and R. K. A. are thankful to UGC, and CSIR New Delhi,
India for fellowships. The authors would like to thank SAIF,
CDRI, India for providing NMR data. Authors are also thankful
to one of the reviewers for suggesting fruitful modifications in
the mechanism. CDRI communication No. 8993
Starting materials 1a–q were prepared according to the a reported
procedure (the yields were not optimised).[1] A solution of sodium
azide (1.99 g, 30 mmol) in water (10 mL) was added dropwise over
1 h to a solution of acyl chloride (20 mmol) in acetone (20 mL) at
08C. The mixture was warmed to RT and stirred for 8–12 h. Ace-
tone was removed under reduced pressure and the reaction mix-
ture was extracted with EtOAc (3”30 mL). The combined organic
layers were dried over Na2SO4 and solvent was evaporated in
vacuo. The residue was purified on a silica gel column (n-hexanes/
EtOAc, 9:1). Compounds 1a–h,[21] 1j,[21] 1k,[21] 1m–q,[5] and 1o[21]
are known and their corresponding data match well with reported
data.
Keywords: azides
olefination · rearrangement
·
CÀC coupling
·
CÀH activation
·
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General procedure for the synthesis of benzonitrile deriva-
tives 4
In an oven-dried round-bottomed flask equipped with a stir bar,
acyl azide 1 (1.02 mmol) in solvent (5.0 mL) followed by TPP
(1.0 equiv) were added and the mixture was stirred and heated to
808C (the progress of the reaction was monitored for the forma-
tion of iminophosphorane 2a by TLC; ca. 30 min was required).
[RuCl2(p-cymene)]2 (5.0 mol%) and Cu(OAc)2·H2O (1.02 mmol) were
then added and, upon completion of reaction as indicated by TLC,
the resulting mixture was diluted with water and the mixture was
extracted with EtOAc (3”20 mL). The combined organic layers
were washed with brine (20 mL) and dried over Na2SO4. The sol-
vent was evaporated in vacuo and the residue was purified by
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Received: April 14, 2015
Published online on July 2, 2015
Chem. Eur. J. 2015, 21, 11807 – 11812
www.chemeurj.org
11812
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