Rhodium catalyzed ortho-cyanation of arylphosphates with N-cyano-N-phenyl-p-toluenesulfonamide

Article abstract of DOI:10.1002/cctc.201301076

A rhodium-catalyzed cyanation of chelation assisted C-H bonds is described. This process provided a useful method for the preparation of diverse 2-cyanated arylphosphonate and related compounds in good yields. The reaction tolerates a variety of synthetic

Full text of DOI:10.1002/cctc.201301076

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DOI: 10.1002/cctc.201301076
Rhodium Catalyzed ortho-Cyanation of Arylphosphates
with N-cyano-N-phenyl-p-toluenesulfonamide
Li-Jun Gu,*[a] Cheng Jin,[b] Rui Wang,[a] and Hong-Yan Ding[a]
A rhodium-catalyzed cyanation of chelation assisted CÀH
bonds is described. This process provided a useful method for
the preparation of diverse 2-cyanated arylphosphonate and
related compounds in good yields. The reaction tolerates a vari-
ety of synthetically important functional groups.
direct silver-catalyzed nitrogenation reaction of alkynes to ni-
triles through CÀC bond cleavage.[14] Despite these advances,
versatile and efficient methods for the direct construction of
arylÀCN bonds that are compatible with various functional
groups and use readily available starting materials remain
highly desirable.
Organophosphorus compounds are important structural
motifs frequently found in pharmaceuticals, natural products,
biologically active molecules, and organic functional materials,
and their functionalization has been attracting great interest
in the synthetic organic chemistry community.[15] Recently, sev-
eral examples on the phosphoryl-related compounds as the
directing group for CÀH activation have been reported
(Scheme 1).[16]
The development of novel methods for the preparation of aryl
nitriles is of long-standing interest to organic chemists because
of the importance of these compounds in chemistry and biol-
ogy.[1] Furthermore, they can serve as synthetic scaffolds to a di-
verse array of building blocks such as aldehydes, ketones,
amides, carboxylic acids, and amines. Consequently, the devel-
opment of synthetic methods for the preparation of aryl ni-
triles has received considerable attention.[2–5] Traditionally,
direct cyanations are achieved through the replacement ap-
proach, in which aryl nitriles are obtained by introducing a ni-
trile group through Sandmeyer reaction of aryldiazonium salts
or by the transition-metal-mediated cyanation of aryl halides
with a cyanide source.[6] However, general problems in these
reactions are the use of expensive aryl halides, highly toxic cy-
anating reagents, high catalyst loading due to the cyanide poi-
soning or need for superstoichiometric amounts of additives
(generally metal salts), and harsh reaction conditions.[7] Alterna-
tively, aryl nitriles can be prepared by the dehydration ap-
proach, for example, dehydration of aryl amides or oximes,[2a,-
Scheme 1. Phosphoryl-related directing groups in RhIII catalysis.
b,3a,b]
or oxidative dehydration of benzylic amines or alcohols
In this context, we were interested in the use of phosphates
as the directing groups for Rh-catalyzed aromatic CÀH bonds
(Scheme 2). Our study was inspired by the recent reports that
with ammonia.[9–10] Selective cyanation of highly abundant
CÀH bonds with a suitable reagent is probably the most eco-
nomic and benign route to the synthesis of aryl nitrile deriva-
tives. For instance, Cu- and Pd-catalyzed CÀH cyanation reac-
tions of 2-arylpyridines with CH3NO2 and DMF/NH3, respective-
ly, as the CN source and a Pd-catalyzed 3-cyanation reaction of
indoles using DMF as the CN source have been reported. In
2013, Fu and Anbarasan independently reported a Rh-cata-
lyzed CÀH cyanation reaction employing N-cyano-N-phenyl-p-
toluenesulfonamide (NCTS) as an efficient cyanating re-
agent.[11–13] Recently, Jiao and co-workers report a new and
Scheme 2. Evolution of the rhodium-catalyzed ortho-selective C-H cyanation
of diverse benzene derivatives.
[a] L.-J. Gu, R. Wang, H.-Y. Ding
Key Laboratory of Chemistry in Ethnic Medicinal Resources
State Ethnic Affairs Commission & Ministry of Education
Yunnan University of Nationalities
Kunming, Yunnan, 650500 (P.R. China)
E-mail: gulijun2005@126.com
phosphates can complement other directing groups for CÀH
functionalization in terms of substrate scope, and functional
group compatibility.[17] In connection with our broader interest
in transition-metal-catalyzed reaction,[15e,f,18] herein we describe
the first example of Rh-catalyzed CÀH cyanation with NCTS
using arylphosphonate as the directing group.[19]
[b] C. Jin
New United Group Company Limited
Changzhou, Jiangsu, 213166 (P.R. China)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cctc.201301076.
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Table 1. Optimization of the reaction conditions.[a]
Table 2. Scope of arylphosphonates 1.[a]
Entry
1
Catalyst
Additive
Ag2CO3
Solvent
Yield [%][b]
31
Entry
1
Arylphosphonates
Product
Yield [%][b]
[RhCp*(CH3CN)3]
·(SbF6)2
1,4-dioxane
78
2
3
4
5
6
7
8
9
10
11
12
13
14
[Cp*Rh(OAc)2]
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
none
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
HOAc
1,4-dioxane
1,4-dioxane
toluene
DCE
MeCN
xylene
DMF
DCE
DCE
DCE
DCE
18
51
43
62
19
49
trace
68
0
77
16
22
0
2
3
4
5
6
7
69
71
62
60
74
44
AgSbF6
Cu(OAc)2
none
DCE
DCE
AgSbF6
[a] Reaction conditions: 1a (0.3 mmol), 2 (0.6 mmol), catalyst (5 mol%),
additive (15 mol%), solvent (2 mL), 24 h, 1108C under argon atmosphere.
[b] Isolated yield.
In the initial phase of this study we investigated the reaction
of diethyl phenylphosphonate 1a with NCTS 2 in the presence
of [RhCp*Cl2]2 (5% mol), Ag2CO3 (15% mol) in 1,4-dioxane at
115 8C with stirring for 18 h. The desired product diethyl 2-cya-
nophenylphosphonate 3a was isolated with 31% yield
(Table 1, entry 1). The catalyst [RhCp*Cl2]2 provided the best re-
sults (Table 1, entries 1–3). The influence of solvent on the re-
action efficiency was also significant; when 1,2-dichloroethane
(DCE) was chosen as the solvent, the yield was enhanced to
62% (Table 1, entries 4–8). Increasing the reaction temperature
to 1258C further improved the efficiency of this transformation
(Table 1, entry 9). Of the additives tested, AgSbF6 proved partic-
ularly suitable (Table 1, entries 9–12). In the absence of AgSbF6
the desired product was obtained in a low yield (Table 1,
entry 13). Without the Rh catalyst, none of the desired product
was obtained (Table 1, entry 14).
8
71
53
56
9
With the optimized reaction conditions, we next investigat-
ed the generality of the Rh-catalyzed cyanation with a variety
of arylphosphonates 1. As summarized in Table 2, a series of ar-
ylphosphonate 1 were found to participate in the reaction, af-
fording the corresponding aryl nitriles in moderate to good
yields. For example, arylphosphonate bearing electron-rich
(methoxy, methyl) and electron-deficient (halogen, phenyl)
substituents on the aryl ring underwent this reaction to furnish
the corresponding products in generally moderate to good
yields (60–78%). Substituent at the para position of the phenyl
ring afforded the desired product smoothly and substituent at
the meta position of the phenyl ring afforded the less sterically
crowded isomer 3g in 74% yield. However, ortho-substituted
derivative 1h gave a much lower yield of 3h (Table 2, entry 7).
These results indicated that the steric effects affected the effi-
ciency of the reactions. Interestingly, the polysubstituted aryl-
10
[a] Reaction conditions: 1 (0.3 mmol), 2 (0.6 mmol), [RhCp*Cl2]2 (5 mol%),
AgSbF6 (15 mol%), DCE (2 mL), 24 h, 1108C under argon atmosphere.
[b] Isolated yield.
phosphonate derivative gave the desired oxidative product 2i
with a good yield. In addition, arylphosphonates with a naph-
thyl group (1j) also participated in this Rh-catalyzed cyanation,
affording C3-cyanated product in 53% yield. Notably, the intro-
duction of heterocycles into this system made this methodolo-
gy more useful for the preparation of pharmaceuticals and ma-
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terials (Table 2, entry 10). In this case, cyanation occurred only
at the 2-position and not at the 4-position.
The subsequent screening of various arylphosphonate-based
chelating groups was also examined under the optimized rho-
dium catalyzed cyanation conditions. Dimethyl phenylphosph-
onate 1e could be smoothly converted into the expected
product 3e in 54% yield. Diisopropyl phenylphosphonate 1 f
could also efficiently furnish the desired product in a good
yield (Table 3, entry 2). To highlight the utility of this transfor-
Table 3. Scope of other directing groups.[a]
Entry
1
Arylphosphonates
Product
Yield [%][b]
Scheme 4. Plausible mechanism.
76
ylphosphonate and related compounds, a plausible mechanis-
tic pathway is proposed (Scheme 4). Initially, treatment of a rho-
dium precursor with AgSbF6 generates the reactive cationic
rhodium(III) species A, which on reaction with 1a affords the
cyclic rhodium species B through CÀH functionalization. Coor-
dination of NCTS 2 with rhodium species B affords intermedi-
ate C, after which insertion of the CN moiety into the CÀRhIII
bond generates D. Rearrangement of D affords the desired
cyanated product along with the reactive rhodium species E.
lastly, ligand exchange will furnish the active rhodium species
A to complete the catalytic cycle.
2
3
62
54
[a] Reaction conditions: 1 (0.3 mmol), 2 (0.6 mmol), catalyst (5 mol%), ad-
ditive (15 mol%), DCE (2 mL), 24 h, 1108C under argon atmosphere.
[b] Isolated yield.
In summary, we have addressed a new strategy based on
the dialkyl phosphoryl directing group to achieve the ortho
CÀH functionalization of arylphosphonate and related com-
pounds. This tactic was used for the highly selective ortho CÀH
cyanation of easily available arylphosphonates to prepare
2-cyanated arylphosphonate and related compounds. This pro-
tocol offers several advantages including avoidance of biscya-
nated arylphosphonates, complete ortho selectivity, and rela-
tively broad functional group tolerance. We believe that this
protocol represents a practical route to 2-cyanated arylphosph-
onate and related compounds.
mation, a bulky phosphonic diethylamino group was subjected
to the standard reaction conditions. The desired product was
isolated in a moderate yield (Table 3, entry 3).
To shed more light on the reaction mechanism, a deuteri-
um-labeling experiment was were performed (Scheme 3).[12,16a]
When a 1:1 mixture of 1a and 1a-[D5] was subjected to the
Experimental Section
Scheme 3. Deuteration experiment.
Rh-catalyzed ortho-cyanation of arylphosphates with NCTS: General
procedure: A 10 mL oven-dried Schlenk tube was charged with
1
(0.3 mmol), NCTS (0.6 mmol), [RhCp*Cl2]2 (5 mol%), AgSbF6
(15 mol%), DCE (2 mL), Then the tube was charged with argon,
and was stirred at 1108C for about 24 h. After the reaction was fin-
ished, the reaction mixture was diluted in 3 mL dichloromethane.
The solution was filtered through a celite pad and washed with
10–20 mL of dichloromethane. The filtrate was concentrated and
the residue was purified by silica gel column chromatography
(hexane/ethyl acetate) to provide the desired products 3.
Rh-catalyzed reaction conditions, we obtained the cyanation
products 3a and 3a-[D4] in a ratio of 4.9:1. This kinetic isotope
effect (KIE) value of 4.9 is typical of Rh-catalyzed CÀH activa-
tion processes.
On the basis of the above KIE experiment and previous re-
ports on the rhodium(III)-catalyzed CÀH functionalization of ar-
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We are grateful for the financial support from The Educational
Bureau of Yunnan Province (2010Y431), the State Ethnic Affairs
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Keywords: arylphosphonate
groups · rhodium · synthetic methods
· C-H activation · directing
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