Benzamide synthesis by direct electrophilic aromatic substitution with cyanoguanidine

Article abstract of DOI:10.1016/j.tetlet.2012.06.135

Cyanoguanidine is an inexpensive commodity chemical and it is found to be a useful reagent for the direct Friedel-Crafts carboxamidation of arenes. The reaction works best in an excess of Bronsted superacid, an observation suggesting the involvement of a superelectrophilic intermediate. Theoretical calculations indicate that the most stable diprotonated species involves protonation at the guanidine and cyano nitrogen atoms.

Full text of DOI:10.1016/j.tetlet.2012.06.135

Tetrahedron Letters 53 (2012) 4779–4781
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Benzamide synthesis by direct electrophilic aromatic substitution with
cyanoguanidine
⇑
Rajasekhar Reddy Naredla, Douglas A. Klumpp
Department of Chemistry and Biochemistry, Northern Illinois University, DeKalb, IL 60115, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Cyanoguanidine is an inexpensive commodity chemical and it is found to be a useful reagent for the
direct Friedel–Crafts carboxamidation of arenes. The reaction works best in an excess of Brønsted super-
acid, an observation suggesting the involvement of a superelectrophilic intermediate. Theoretical calcu-
lations indicate that the most stable diprotonated species involves protonation at the guanidine and
cyano nitrogen atoms.
Received 11 June 2012
Revised 26 June 2012
Accepted 28 June 2012
Available online 6 July 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Benzamide
Superacid
Superelectrophile
Friedel–Crafts
Carboxamidation
Benzamide compounds are useful building blocks in organic
synthesis and they are sub-structures in a variety of pharmaceuti-
cal agents.1 Benzamides have been synthesized by hydrolysis of
aromatic nitriles, interconversions of carboxylic acid derivatives,
rearrangement of oximes, aminocarbonylation, and other routes.2
Aromatic amides have also been prepared by the Friedel–Crafts-
type reactions of isocyanates, especially 2° amides.3 Primary
benzamides have been previously synthesized using trimethylsily-
lisocyanate and chlorosulfonylisocyanate—two reagents that are
not readily accessible and likely exhibit high levels of toxicity.4
We recently reported a low yield (12%) synthesis of benzamide
by the superacid-catalyzed reaction of cyanamide with benzene
tries. We sought to use this material as a substrate in electrophilic
aromatic substitution chemistry, primarily because of its similari-
ties to cyanamide. We also reasoned that the guanidinium groups
would be easily protonated and consequently it should activate the
adjacent cyano group or nitrilium ion for use in Friedel–Crafts
chemistry. Our initial experiment involved reacting cyanoguani-
dine (2) with benzene in superacidic CF3SO3H (Eq. 2). In a reaction
at 25 °C, a mixture of benzamide
ð2Þ
5
(Eq. 1). Despite being a direct route to
(1) and benzonitrile was obtained. By increasing the reaction tem-
perature to 60 °C and using 10 equiv of CF3SO3H, no benzonitrile
is observed and the benzamide product 1 can be isolated in 56%
yield. Although the conversion has not been fully optimized, it
was observed that similar yields could be obtained with as little
as 5 equiv of CF3SO3H. With less acid, the product yield drops con-
siderably. Both H2SO4 and CF3CO2H (in excess quantities) were also
reacted with compound 2 in the presence of benzene, but no benz-
amide product was formed. Presumably, any byproducts or the
starting material 2 were lost in the aqueous phase during workup.
Using compound 2, a series of aromatic primary amides were
synthesized from electrophilic aromatic substitution (Table 1).6
Alkyl-substituted benzenes were generally converted into the
amides in good overall yields. In the case of toluene and ortho-
xylene, mixtures of regioisomers were formed (6 and 7). For the
ð1Þ
benzamide, this chemistry was not particularly useful as most of
the cyanamide is consumed in side-reactions. Nevertheless, the re-
sults prompted us to search for alternative reagents that might pro-
vide a route to benzamides by electrophilic aromatic substitution.
In this Letter, we report the direct conversion of arenes to the benz-
amide derivatives by electrophilic aromatic substitution.
Cyanoguanidine (or dicyanodiamide, 2) is an inexpensive, crys-
talline solid that is used as a feedstock chemical in various indus-
⇑
Corresponding author. Tel.: +1 815 753 1959; fax: +1 815 753 4802.
E-mail address: dklumpp@niu.edu (D.A. Klumpp).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.135

4780
R. R. Naredla, D. A. Klumpp / Tetrahedron Letters 53 (2012) 4779–4781
Table 1
Amide products (3–13) from the direct electrophilic aromatic substitution of arenes with cyanoguanidine (2) and CF3SO3H
Product
Yielda (ratio of isomers) (%)
Product
Yielda (ratio of isomers) (%)
47 (o:p, 2.2:7.8)b
67
80
10
90
47 (o:p, 2.5:7.5)b
89 (o:p, 3:7)b
11
88 (
a
:b, 3:7)b
86 (a
:b, 8:2)b
89 (o:p, 1:3)c
a
b
c
Isolated yield.
Product ratio determined by GC–FID.
Product ratio determined by isolation of regioisomers by flash chromatography.
2 were prepared by dissolving 2 in methanol-d4, CF3CO2H, and
CF3SO3H. 13C NMR spectra were obtained, however the results were
inconclusive. The acidic solutions gave very complex 13C NMR spec-
tra. This may be the result of multiple reactions and equilibria, or
given the tendency for nitrilium ions to form 1,3,5-triazines,9 the
complex spectra may be the result of slow trimerization reactions.
In our synthetic reactions, triazine products were never observed.
However, this may be a consequence of the water solubility of the
triazine products from 2 (likely lost upon aqueous workup).
Theoretical calculations were done to explore the protonated
structures that could arise from cyanoguanidine 2 in acidic med-
ia.10 Calculations were done at the B3LYP 6-311G⁄⁄ level,11 ener-
gies are corrected for ZPE, and all structures were characterized
as true minima (zero imaginary frequencies) by frequency calcula-
tions. Initial protonation is thought to occur at the guanidine group
(Fig. 1). Thus, cation 17 is about 28 kcal/mol more stable than the
cyano protonated species 18. This observation is certainly a
consequence of the stability of the guanidinium cation. Neverthe-
less, electrophilic aromatic substitution with nitriles—the
mono-substituted benzenes, the para regioisomer is the major
product (6–9, 11). With para-dichlorobenzene, product 10 may
be isolated in 10% yield. Although the yield for this conversion is
low, para-dichlorobenzene is a moderately deactivated arene, so
product formation indicates that compound 2 generates a reactive
electrophile in superacid. Despite the high degree of activation of
2,6-dimethylphenol, product 12 could only be isolated in 11% yield.
This may be due to protonation of the phenol by the superacid,7
greatly decreasing its reactivity toward electrophilic attack. Naph-
thalene gave product 13 in good yield, although the reaction leads
to the mixture of regioisomers.
In order to probe the mechanism of this conversion, we
conducted experimental, spectroscopic, and theoretical studies.
For example, substituted cyanoguanidines are readily prepared
8
from dimethyl N-cyanodithioiminocarbonate (14, Eq. 3). We
ð3Þ
reasoned that the Friedel–Crafts chemistry is likely occurring at the
cyano group, and therefore, reaction with the alkyl-substituted
derivative 15 should provide benzamide 1. If the electrophilic reac-
tion occurs at the guanidium carbon however, the product should
be the secondary amide 16. When compound 15 is reacted with
benzene in CF3SO3H, only benzamide 1 is observed in the product
mixture, suggesting that the Friedel–Crafts chemistry occurs at
the cyano group. In spectroscopic studies, solutions of compound
Figure 1. Calculated relative energies from optimized structures 17/18 and 19/20
(B3LYP 6–311G⁄⁄ level).

R. R. Naredla, D. A. Klumpp / Tetrahedron Letters 53 (2012) 4779–4781
4781
diprotonated species involves protonation at the guanidine and cy-
ano nitrogen atoms.
Acknowledgments
We gratefully acknowledge the support of the NIH-National
Institute of General Medical Sciences (GM085736-01A1).
References and notes
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Figure 2. Proposed mechanism for the conversion of 2 to benzamide products.
3. (a) Gauvreau, D.; Dolman, S. J.; Hughes, G.; O’Shea, P. D.; Davies, I. W. J. Org.
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5. Raja, E.; Klumpp, D. A. Tetrahedron 2011, 67, 4494–4497.
6. General synthetic procedure: Cyanoguanidine 2 (0.084 g, 1 mmol) is suspended
in 2 mL of neat aromatic substrate (alternatively, the arene may be suspended
in CH2Cl2) and freshly distilled triflic acid (0.5 mL, 6 mmol) is slowly added. The
mixture is stirred at 60 °C for 2 h, after which 1 mL of cold water is added to the
solution. The mixture is then stirred overnight. Product isolation is
accomplished with basification of the mixture using 10 M NaOH and
extraction of the mixture twice with chloroform. The organic extracts are
washed with water, and then brine, and dried with anhydrous MgSO4. Crude
products may be further purified by silica gel column chromatography
(hexanes:ethyl acetate).
Houben–Hoesch reaction—generally occurs through a nitrilium ion
(via protonation of the nitrile). This suggests the involvement of a
diprotonated species in the reactions of 2 with arene nucleophiles.
Earlier studies by Olah and co-workers showed that guanidine it-
self could be diprotonated in superacid.12 Although double proton-
ation at the guanidine group (19) is found to be a stable minimum
on the potential energy surface, a significantly more stable dication
(20) is formed by protonation at the guanidine and cyano nitrogen
atoms. Presumably, ion 19 is destabilized by the proximity of the
two positive charges and the loss of resonance interactions with
the –NH2 group. We propose that superelectrophile 20 is the key
intermediate in the conversions to the benzamide products.13 In
accord with this suggestion, the LUMO level of 20 is such that
the reaction with benzene appears to be favorable. Calculations
show cyanoguanidine (2) with a LUMO at 0.00509 eV, monocation
17 with a LUMO at ꢀ0.021873 eV, and dication 20 with a LUMO at
ꢀ0.4320 eV. For comparison, the HOMO of benzene is calculated to
be at ꢀ0.25636 eV.
7. Olah, G. A.; Prakash, G. K. S.; Molnar, A.; Sommer, J. M. Superacids, 2nd ed.; John
Wiley & Sons: New York, 2009.
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Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A.
F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.;
Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai,
H.; Vreven, T.; Montgomery, Jr., J. A.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.;
Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand,
J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.;
Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas,
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1993, 98, 5648–5652; (c) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37,
785–789; (d) Krishnan, R.; Binkley, J. S.; Seegar, R.; Pople, J. A. J. Chem. Phys.
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13. Olah, G. A.; Klumpp, D. A. Superelectrophiles and their Chemistry; John Wiley &
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The proposed mechanism involves further steps that include
formation of the new C–C bond to give intermediate 21 (Fig. 2).
Based on the observed products, we suggest cleavage of the C–N
bond to give protonated benzonitrile (22) and the guanidinium
cation. Previous studies by Shudo and co-workers suggested that
the nitrilium ion 22 may itself react with triflic acid to give the ad-
duct with triflate anion (23).14 Hydrolytic work up of the reaction
mixture then provides the benzamide (1).
In conclusion, we have found that cyanoguanidine 2 is a useful
reagent for the direct Friedel–Crafts carboxamidation of arenes.
The reaction works best in an excess of Brønsted superacid, an
observation suggesting the involvement of a superelectrophilic
intermediate. Theoretical calculations indicate that the most stable
14. Yato, M.; Ohwada, T.; Shudo, K. J. Am. Chem. Soc. 1991, 113, 691–692.