o-iodoxybenzoic acid- and tetraethylammonium bromide-mediated oxidative transformation of primary carboxamides to one-carbon dehomologated nitriles

Article abstract of DOI:10.1021/jo0619074

A clean and efficient method for the oxidative transformations of primary carboxamides to one-carbon dehomologated nitriles using the combination of o-iodoxybenzoic acid and tetraethylammonium bromide has been developed. This method exhibits a broad scope and is expected to be of great utility in organic synthesis.

Full text of DOI:10.1021/jo0619074

HCOOH,6 PhI(OTs)OH,7 and PhI(OAc)2-KOH.8 In continu-
ation of our studies on the development of newer applications
of hypervalent iodine (λ5) compounds, herein we wish to report
the application of IBX with tetraethylammonium bromide
(TEAB) for oxidative transformations of primary carboxamides
to one-carbon dehomologated nitriles under neutral conditions.
o-Iodoxybenzoic Acid- and Tetraethylammonium
Bromide-Mediated Oxidative Transformation of
Primary Carboxamides to One-Carbon
Dehomologated Nitriles
Dinesh S. Bhalerao, Ulhas S. Mahajan,
Kiran H. Chaudhari, and Krishnacharya G. Akamanchi*
A variety of ligands have been reported to tune the reactivity
of the iodine nucleus in hypervalent iodine compounds.9 During
the course of our investigations, it was evident that a combina-
tion of IBX and TEAB exerts a strong impact on the reactivity
of IBX.10
Department of Pharmaceutical Sciences & Technology,
UniVersity Institute of Chemical Technology, Matunga,
Mumbai-400 019, India
To begin our study, the effect of the various reaction
parameters on the oxidative transformation of 4-methoxybenzene
acetamide 1 was examined as shown in Table 1. It was evident
from the experiments performed that TEAB plays an important
role in the formation of nitrile and in accelerating the reaction
rate (entries 1-5). When the experiments were carried out in
an equivalent of IBX/TEAB lower than 2.5 equiv, the reactions
remained incomplete and no other byproducts were observed
indicating that first step might be slow followed by rapid
conversion to nitrile 1a (entries 7-9). The reaction also proceeds
at room temperature; however, it required longer reaction time
(entry 10).
kgap@rediffmail.com
ReceiVed September 15, 2006
The reaction was also standardized with respect to solvent
(entries 11-14), and the results are recorded in Table 1. On
the basis of the studies performed, we obtained the best results
with 2.5 equiv of IBX/TEAB in acetonitrile at 60 °C (entry 6),
and all further reactions were carried out using these optimized
parameters.
A clean and efficient method for the oxidative transforma-
tions of primary carboxamides to one-carbon dehomologated
nitriles using the combination of o-iodoxybenzoic acid and
tetraethylammonium bromide has been developed. This
method exhibits a broad scope and is expected to be of great
utility in organic synthesis.
We also examined other hypervalent iodine compounds for
this transformation, as shown in Table 2. The combination of
DMP and TEAB was used and found viable for this transforma-
tion, although the yield of nitrile 1a was comparatively low
The use of hypervalent iodine reagents in synthetic organic
chemistry is a field of much curiosity.1 The surging interest in
iodine compounds is mainly due to the strong oxidizing
properties of polyvalent organic iodine reagents combined with
their benign environmental character and commercial avail-
ability. Hypervalent iodine reagents have found widespread
applications in organic synthesis because of their selectivity and
simplicity in use. Our group has been extensively working on
the development of novel methodologies using hypervalent
iodine reagents,2 mainly, o-iodoxybenzoic acid (IBX) and Dess-
Martin periodinane (DMP). Though IBX finds widespread
application in oxidative transformations, to the best of our
knowledge there are no reports on IBX-mediated oxidative
transformation of primary carboxamide, RCH2C(O)NH2, to
nitrile, RCN, bearing one less carbon atom.
(3) (a) Saito, Y.; Zevaco, T. A.; Agrofoglio, L. A. Tetrahedron 2002,
58, 9593. (b) Sakaguchi, S.; Yamamoto, Y.; Sugimoto, T.; Yamamoto, H.
J. Org. Chem. 1999, 64, 5954. (c) Agrofoglio, L. A.; Jacquinet, J. C.;
Laneelot, G. Tetrahedron Lett. 1997, 38, 1411. (d) Xie, M.; Berges, D. A.;
Robins, M. J. J. Org. Chem. 1996, 61, 5178. (e) Harris, C. E.; Lee, L. Y.;
Dorr, H.; Singaram, B. Tetrahedron Lett. 1995, 36, 2921.
(4) (a) Correia, J. Synthesis 1994, 1127. (b) Wallis, E. S.; Lane, J. F.
Org. React. 1946, 3, 263.
(5) (a) Radhakrishna, A. S.; Parham, M. E.; Riggs, R. M.; Laudon,
G. M. J. Org. Chem. 1979, 44, 1746. (b) Tamura, M.; Jacyno, J.; Stammer,
C. H. Tetrahdron Lett. 1986, 27, 5435. (c) Loudon, G. M.; Radhakrishna,
A. S.; Almond, M. R.; Blodgett, J. K.; Boutin, R. H. J. Org. Chem. 1984,
49, 4272. (d) Loudon, G. M.; Boutin, R. H. J. Org. Chem. 1984, 49, 4277.
(e) Almond, M. R.; Stimmel, J. B.; Thompson, A. E.; Laudon, G. M. Org.
Synth. 1988, 67, 132.
One-carbon dehomologation is a demanding transformation
in organic synthesis and with very little literature precedence.3
Methods allowing the direct transformations of carboxylic acid
derivatives to one-carbon shorter nitriles are rare.4 Hypervalent
iodine reagents normally employed for Hofmann-type one-
carbon shorter transformations are PhI(OCOCF3)2,5 PhIO-
(6) (a) Radhakrishna, A. S.; Rao, C. D.; Varma, R. K.; Singh, B. B.;
Bhatnagar, S. P. Synthesis 1983, 538. (b) Wasielewki, C.; Topolski, M.;
Dembkowski, M. J. Prakt. Chem. 1989, 331, 507.
(7) (a) Lazbin, I. M.; Koser, G. F. J. Org. Chem. 1986, 51, 2669. (b)
Vasudervan, A.; Koser, G. F. J. Org. Chem. 1988, 53, 5158.
(8) Moriarty, R. M.; Chany, C. J., II; Vaid, R. K.; Prakash, O.; Tuladhar,
S. M. J. Org. Chem. 1993, 58, 2478.
(9) (a) Nicolaou, K. C.; Montagnon, T.; Baran, P. S. Angew. Chem., Int.
Ed. 2002, 41, 993. (b) Nicolaou, K. C.; Gray, D. L.; Montagnon, F. T.;
Harrison, S. T. Angew. Chem., Int. Ed. 2002, 41, 996. (c) Nicolaou, K. C.;
Montagnon, T.; Baran, P. S. Angew. Chem., Int. Ed. 2002, 41, 1386. (d)
Katritzky, A. R.; Duell, B. L.; Durst, H. D.; Knier, B. L. J. Org. Chem.
1988, 53, 3972. (e) Zhdankin, V. T.; Arbit, R. M.; Lynch, B. L.; Kiprof, P.
J. Org. Chem. 1998, 63, 6590.
(10) (a) Shukla, V. G.; Salgaonkar, P. D.; Akamanchi, K. G. J. Org.
Chem. 2003, 68, 5422. (b) Shukla, V. G.; Salgaonkar, P. D.; Akamanchi,
K. G. Synlett 2005, 9, 1483.
(1) (a) Varvoglis, A. HyperValent Iodine in Organic Synthesis; Academic
Press: London, 1997. (b) Zhdankin, V. V.; Stang, P. J. Chem. ReV. 2002,
102, 2523. (c) Zhdankin, V. V. Curr. Org. Synth. 2005, 2, 121. (d) Wirth,
T. Angew. Chem., Int. Ed. 2005, 44, 3656.
(2) (a) Ramnarayanan, G. V.; Shukla, V. G.; Akamanchi, K. G. Synlett
2002, 12, 2059. (b) Chaudhari, S. S.; Akamanchi, K. G. Synthesis 1999,
760. (c) Chaudhari, S. S.; Akamanchi, K. G. Tetrahedron Lett. 1998, 39,
3209.
10.1021/jo0619074 CCC: $37.00 © 2007 American Chemical Society
Published on Web 12/23/2006
662
J. Org. Chem. 2007, 72, 662-665

TABLE 1. Optimization of Reagent and Reaction Conditions for
Amide to Dehomologated Nitrilea
TABLE 3. IBX/TEAB-Mediated Oxidative Transformations of
Primary Amides to Dehomologated Nitrilesa
recovered
isolated
yield
starting
materialb
IBX/TEAB
mol equiv
wrt 1
entry
conditions
1a (%) 1b (%)
1 (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
2.5/0
2.5/0.5
2.5/1
2.5/1.5
2.5/2.0
2.5/2.5
2/2
1.5/1.5
1/1
2.5/2.5
2.5/2.5
2.5/2.5
2.5/2.5
2.5/2.5
MeCN, 60 °C, 12 h
MeCN, 60 °C, 5 h
MeCN, 60 °C, 5 h
MeCN, 60 °C, 5 h
MeCN, 60 °C, 5 h
MeCN, 60 °C, 25 min
MeCN, 60 °C, 5 h
MeCN, 60 °C, 5 h
MeCN, 60 °C, 5 h
MeCN, RT, 8 h
-
20
40
60
80
95
80
65
45
70
30
30
70
80
20
10
-
-
-
-
-
-
-
-
-
-
-
70
60
50
30
-
-
-
30
50
toluene, 60 °C, 15 h
THF, 60 °C, 15 h
CHCl3, 60 °C, 3 h
tert-butanol, 60 °C, 2 h
60
60
-
-
-
a Reactions were carried out on 5 mmol. b Starting material quantity is
specified only when it exceeds 30%.
TABLE 2. Evaluation of Other Hypervalent Iodine Reagents for
the Transformation of Amide 1 to Nitrile 1aa
recovered
isolated starting
reagent/TEAB
mol equiv
yield
material
entry reagent
wrt 1
conditions
1a (%)
1 (%)
1
2
3
4
DMP
HIO3
I2O5
2.5/2.5
3/3
3/3
MeCN, 60 °C, 2 h
MeCN, 60 °C, 5 h
MeCN, 60 °C, 5 h
MeCN, 60 °C, 1.5 h
75
20
95
98
-
NRb
NRb
80
a Reactions were carried out on 1-10 mmol scale using 2.5 equiv of
IBX and TEAB in acetonitrile at 60 °C. b Yield of chromatographically
isolated compound. Some starting material was recovered; however, the
quantity is only specified when it exceeds 20%. c Plus 20% recovered
starting material. d Plus 26% recovered starting material.
IBA
5/5
a Reactions were carried out on 5 mmol. b NR ) No reaction.
condition, it led to benzylic oxidation (entry 1),11 whereas
tertiary amides remained unaffected under the reaction condition
(entries 2 and 3).
(entry 1). No reaction was observed when HIO3/TEAB and I2O5/
TEAB combinations were used (entries 2 and 3). The hyper-
valent iodine (λ3) compound IBA was also examined to assert
that the observed conversion of 1 to 1a was occurring as a result
of the action of IBX and also by its byproduct IBA (entry 4).
With these results in hand, we sought to examine the scope
and generality of the method. As can be seen from the results
in Table 3, a wide variety of substrates were studied, including
aromatic, heteroaromatic, and aliphatic carboxamides (entries
1-12), which furnished desired nitriles in excellent to moderate
yields. The reaction is accelerated by incorporation of an
electron-donating group. This is the same trend that is followed
in the other reactions in which migration to an electron-deficient
center occurs. A wide range of functional groups were tolerated
by this protocol, including benzyl ether, alkene, and aromatic
halide, further signifying the chemoselectivity (entries 3, 4, and
9). Interestingly, â-keto amides were also converted to the
corresponding benzoyl cyanides in moderate yields (entries 13
and 14).
If this reaction proceeds through Hofmann rearrangement,
followed by dehydrogenation, the corresponding isocyanate
should be an intermediate, as was the case with trivalent iodine
compounds.6 The isocyanate survives long enough to be isolated
because it hydrolyzes somewhat slower than it is formed.12
While performing the reaction with benzene acetamide in
acetonitrile as well as tert-butanol, the formation of correspond-
ing isocyanate or tert-butylurethane13 was never observed. In
an effort to probe the mechanism, authentic N-bromobenzene
acetamide14 and benzyl isocyanate15 were synthesized and
subjected to established reaction conditions, and benzonitrile
2a was produced in 90 and 93% yields, respectively (Table 5,
entries 1 and 2).
On the basis of these investigations, we propose a plausible
reaction pathway, as shown in Scheme 1. Addition of TEAB
With this result, we then turned our attention to secondary
and tertiary amides, as shown in Table 4. When we performed
the reaction with secondary amide under the established reaction
(11) Nicolaou, K. C.; Baran, P. S.; Zhong, Y. L. J. Am. Chem. Soc. 2001,
123, 3183.
(12) Boutin, R. H.; Loudon, G. M. J. Org. Chem. 1984, 49, 4277.
J. Org. Chem, Vol. 72, No. 2, 2007 663

TABLE 4. IBX/TEAB-Mediated Oxidation of Substituted Amidesa
a Reactions were carried out on 1-5 mmol scale using 2.5 equiv of IBX and TEAB in acetonitrile at 60 °C. b NR ) No reaction.
TABLE 5. IBX/TEAB-Mediated Reactions with Postulated Intermediatesa
a Reactions were carried out on 5 mmol scale using 2.5 equiv of IBX and TEAB in acetonitrile at 60 °C.
SCHEME 1. Postulated Mechanism for the IBX/
TEAB-Mediated Oxidative One-Carbon Dehomologation of
Primary Carboxamide to Nitrile
IBX and TEAB. This method possesses high functional group
tolerance under the reaction conditions. By using this combina-
tion, a series of amides could be dehomologated to nitriles. This
method exhibits a broad scope, affords clean product in moderate
to high yields, and will be of great utility in organic synthesis.
Further investigations are in progress to expand the scope of
reaction and gain the mechanistic understanding of the process.
Experimental Section
General Experimental Procedure for the Preparation of One-
Carbon Dehomologated Nitriles. To a stirred suspension of IBX
(2.5 equiv) in CH3CN was added TEAB (2.5 equiv). A yellow
suspension was observed to which amide (1-10 mmol) was added
in one portion after 5 min. The reaction mixture was stirred at 60
°C until complete consumption of starting material as observed by
TLC. Acetonitrile was removed under reduced pressure, and the
resultant residue was extracted with EtOAc, and the organic layer
was washed with 10% sodium bisulfite solution, saturated sodium
carbonate, and brine. The organic layer was dried over anhydrous
sodium sulfate and concentrated to give crude nitrile. Pure nitrile
was isolated after column chromatography (silica gel mesh size
60-120).
Typical Experimental Procedure for 4-Benzyloxybenzonitrile
(4a). To a stirred suspension of IBX (3.50 g, 12.5 mmol) in CH3-
CN (50 mL) was added TEAB (2.62 g, 12.5 mmol). A yellow
suspension was observed to which 4-benzyloxybenzene acetamide
to IBX causes the oxidation of amide to N-bromoamide, which
on subsequent rearrangement forms isocyanate. Nucleophilic
attack by oxygen of IBA to isocyanate gives the intermediate
(A), which subsequently decomposes to give imine, carbon
dioxide, and o-iodobenzoic acid. Imine on further rapid oxida-
tion gives nitrile.
In summary, we have developed an efficient and novel
method for oxidative transformations of primary carboxamides
to one-carbon dehomologated nitriles using the combination of
(13) Baumgarten, H. E.; Smith, H. L.; Staklis, A. J. Org. Chem. 1975,
40, 3554.
(14) Kajigaeshi, S.; Nakagawa, T.; Fujisaki, S. Chem. Lett. 1984, 12,
2045.
(15) Minisci, F.; Fontana, F.; Coppa, F.; Yan, Y. M. J. Org. Chem. 1995,
60, 5430.
664 J. Org. Chem., Vol. 72, No. 2, 2007

4 (1.20 g, 5 mmol) was added in one portion after 5 min. The
reaction mixture was stirred at 60 °C until complete consumption
of starting material as observed by TLC. Acetonitrile was removed
under reduced pressure, and the resultant residue was extracted with
EtOAc (50 mL) and the organic layer was washed with 10% sodium
bisulfite solution (2 × 50 mL), saturated sodium carbonate (2 ×
50 mL), and brine (50 mL). The organic layer was dried over
anhydrous sodium sulfate and concentrated to give crude nitrile
4a. Silica gel column purification afforded pure nitrile 4a (0.96 g,
92%) as a white solid. mp 87-89 °C. Rf ) 0.78 (silica gel EtOAc/
J ) 8.5 Hz, 2H), 5.09 ppm (s, 2H); 13C NMR (125 MHz, CDCl3):
δ 161.9, 125.6, 133.9, 128.7, 128.3, 127.3, 119.1, 115.5, 105.1,
70.9 ppm; elemental analysis calcd for C14H11NO: C, 80.38; H,
5.26; N, 6.69. Found C, 80.38; H, 5.27; N, 6.70.
Acknowledgment. We thank AICTE and UGC for financial
support.
Supporting Information Available: General methods and
spectral data of all compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
1
hexane, 5:95). IR (KBr) νmax (cm-1): 2221 (CN). H NMR (60
MHz, CDCl3): δ 7.54 (d, J ) 8.5 Hz, 2H), 7.32 (s, 5H), 6.95 (d,
JO0619074
J. Org. Chem, Vol. 72, No. 2, 2007 665