A mild, expedient, one-pot trifluoromethanesulfonic anhydride mediated synthesis of N-arylimidates

Article abstract of DOI:10.1016/j.tetlet.2010.11.019

The direct transformation of various secondary amides into N-arylimidates via mild electrophilic amide activation with trifluoromethanesulfonic anhydride (Tf₂O) in the presence of 2-chloropyridine (2-ClPyr) is described. Low-temperature amide a

Full text of DOI:10.1016/j.tetlet.2010.11.019

Tetrahedron Letters 52 (2011) 270–273
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Tetrahedron Letters
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A mild, expedient, one-pot trifluoromethanesulfonic anhydride mediated
synthesis of N-arylimidates
⇑
Mehdi Ghandi , Saleh Salahi, Mohammad Hasani
School of Chemistry, College of Science, University of Tehran, Tehran, PO Box 14155 6455, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 June 2010
Revised 24 October 2010
Accepted 5 November 2010
Available online 11 November 2010
The direct transformation of various secondary amides into N-arylimidates via mild electrophilic amide
activation with trifluoromethanesulfonic anhydride (Tf2O) in the presence of 2-chloropyridine (2-ClPyr)
is described. Low-temperature amide activation followed by C–O bond formation with 2-naphthol
provides the desired N-arylimidates in short overall reaction times. In contrast, reaction with oxindole
proceeds via formation of a C–C bond to give 1-(1H-indol-2-yl)naphthalene-2-ol.
Ó 2010 Elsevier Ltd. All rights reserved.
N-Arylimidates, serve as starting materials in the Chapman
rearrangement for the production of N,N-diarylamides and polya-
mides.1 Therefore, general methods reported for the synthesis of
N-arylimidates imply the Beckman rearrangement of ketoximes2
or the addition of phenols to imidoyl chlorides.3 Another way to
synthesize N-arylimidates is to react N-aryl imidoyl chlorides with
an alkoxide anion in THF at reflux with exclusion of moisture under
nitrogen.4 The dehydration of secondary amides to give imidoyl
chlorides has traditionally been carried out by heating with re-
agents such as SOCl2, PCl5, or POCl3 in excess, or by treatment with
Ph3P/CCl4 at room temperature.5 The major drawbacks of these
methods are that the excess dehydrating agent and reagent-de-
rived by-products need to be removed. Moreover, the pure imidoyl
chlorides are separated either by fractional distillation or precipita-
tion methods under anhydrous conditions. Due to the low reactiv-
ity of imidoyl chlorides, stoichiometric amounts of Lewis acids6 or
more nucleophilic phenoxide anions7 are required. An alternative
method for the formation of N-arylimidates includes the use of
oxalyl chloride as a chlorinating agent in the presence of 2,6-luti-
dine at 0 °C, which generates the imidoyl chlorides in situ without
the formation of by-products.8
A nitrilium ion generated as an intermediate under Beckmann
rearrangement conditions or via activation of imidoyl chlorides
with stoichiometric amounts of Lewis acids plays the key role in
the production of N-arylimidates. A combination of trifluorometh-
anesulfonic anhydride (Tf2O) and pyridine in the pioneering work
of Charette and Grenon, in their synthesis of amidines, thiazolines,
thioamides, and cyclic orthoesters, has proven to be a useful meth-
od for the activation of amides and their subsequent conversion
into other functional groups.9 In 2006, Movassaghi developed an
efficient method for the conversion of amides into highly electro-
philic 2-chloropyridinium adducts by using a combination of
Tf2O and 2-ClPyr, which enabled the synthesis of a variety of
azaheterocycles.10
Compared to the reported methods for the synthesis of N-ary-
limidates, we considered that the development of new methodol-
ogies would allow the highly effective activation of a variety of
amide substrates, including N-arylamides, without requiring isola-
tion of sensitive intermediates or the use of Lewis acid additives.
Herein, we describe an expedient transformation of various sec-
ondary amides into N-arylimidates via mild electrophilic amide
activation with Tf2O in the presence of 2-ClPyr.
First we optimized the conditions for the synthesis of
naphthalen-2-yl N-4-methoxyphenylpivalimidate (2a) from N-(4-
methoxyphenyl)pivalamide (1a) and 2-naphthol (Table 1).11 All
analytical data including IR, 1H and 13C NMR, and the mass frag-
mentation pattern of 2a12 were in agreement with the proposed
structure.13
2-ClPyr proved to be the best base and gave a 96% yield of the
desired product (Table 1, entry 7). While base additives such as tri-
ethylamine and pyridine had no effect on the reaction progress
(Table 1, entries 3 and 4), other bases activated amide 1a with
moderate efficiencies (Table 1, entries 2 and 5). An excess of 2-
ClPyr was found to have a minor inhibitory effect (Table 1, entry
8), perhaps by shifting the equilibrium away from 5, the more ac-
tive nitrilium intermediate, toward 4, the less active amidinium
intermediate, in order to counteract the increasing concentration
of 2-ClPyr (see Scheme 1).14 The reaction proceeds with less effi-
ciency when using the Hendrickson reagent15 (Table 1, entry 6).
Therefore, the superiority of the Tf2O–2-ClPyr combination as an
amide activating agent is evident.
We next explored the substrate scope using the optimal condi-
tions with a variety of secondary amides. The results are presented
in Table 2 and revealed that substrates with electron-donating as
well as electron-withdrawing groups were tolerated in the
reactions. While relatively electron-rich pivalamides gave the
corresponding products in 94% to 96% yields (Table 2, entries 1, 3
⇑
Corresponding author. Tel.: +98 21 61112250; fax: +98 21 66495291.
E-mail address: ghandi@khayam.ut.ac.ir (M. Ghandi).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.019

M. Ghandi et al. / Tetrahedron Letters 52 (2011) 270–273
271
Table 1
Results obtained for the direct conversion of amide 1a into N-arylimidate 2a
H
N
N
OMe
N
C(Me)3
(Me)3C
C(Me)3
O
OH
O
MeO
MeO
conditionsa
1a
2a
2a'
(not formed)
Entry
Base additive
Equiv
Isolated yield (%)
1
2
3
4
5
6
7
8
None
K2CO3
Et3N
—
35
37
0
2.0
1.2
1.2
1.2
1.2
1.2
2.0
Pyridineb
2,6-Lutidine
Hendrickson reagentc
2-ClPyr
0
73
61
96
91
2-ClPyr
a
b
c
Conditions: amide (1.0 equiv), Tf2O (1.1 equiv), base, CH2Cl2, À78 °C, 5 min, then warmed to 0 °C, 2-naphthol (1.0 equiv), then 25 °C, 3 h.
Naphthalen-2-yl trifluoromethanesulfonate and recovered starting amide were obtained.
Triphenylphosphonium anhydride trifluoromethanesulfonate was used without 2-ClPyr at 0 °C.
OTf
N
R1
Cl
N
H
OTf
R2
R2
4
N
- 2-ClPyr
TfOH
H
N
R2
Tf2O
R1
TfO
R2
2-ClPyr
O
N
R1
2-naphthol
OTf
H
O
R1
1
3
2
R2
N
+ 2-ClPyr
TfOH
R1
OTf
5
Scheme 1. Reaction mechanism for the formation of 2.
Table 2
Results obtained for the direct conversion of amides 1 into N-arylimidates 2a–m via mild electrophilic activation by Tf2O–2-ClPyr
R2
H
N
N
R2
OH
conditionsa
+
O
O
R1
R1
1
2
Entry
R1
R2
Product
Isolated yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
4-MeO-
H-
4-Me-
3-Me-
3,4-(Me)2-
4-Cl-
4-NO2-
H-
4-Me-
4-MeO-
H-
4-Me-
4-Cl-
tert-Bu-
2a
2b
2c
2d
2e
2f
2g
2h
2i
96
93
94
87
94
83
66
78
80
81
63
66
58
tert-Bu-
tert-Bu-
tert-Bu-
tert-Bu-
tert-Bu-
tert-Bu-
Cyclohexyl-
Cyclohexyl-
Cyclohexyl-
Ph-
2j
2k
2l
Ph-
Ph-
2m
a
Conditions: amide (1.0 equiv), Tf2O (1.1 equiv), 2-ClPyr (1.2 equiv), CH2Cl2, À78 °C, 5 min, then warmed to 0 °C, 2-naphthol (1.0 equiv), then 25 °C, 3 h.

272
M. Ghandi et al. / Tetrahedron Letters 52 (2011) 270–273
Table 3
Rections of amides 1c and 1g with 1-naphthol and 4-tert-butylphenola
Entry
Amide
Ar-OH
Product
Isolated yield (%)
OH
Me
Me
N
Me
O
1
1c
88
Me
2n
OH
Me
Me
Me
N
O
2
1c
98
Me
Me
Me
Me
Me
Me
Me
Me
2o
OH
Me
Me
Me
N
O
3
1g
80
Me
Me
Me
Me
O2N
2p
Me
a
Conditions: amide (1.0 equiv), Tf2O (1.1 equiv), 2-ClPyr (1.2 equiv), CH2Cl2, À78 °C, 5 min, then warmed to 0 °C, Ar-OH (1.0 equiv), then 25 °C, 3 h.
and 5), reactions of relatively electron-deficient benzamides pro-
ceed to the products less efficiently (Table 2, entries 11, 12, and
13). Cyclohexanecarboxamides with moderate electronic character
afforded N-arylimidates 2 in 78–81% yields (Table 2, entries 8–10).
We also examined the effect of 1-naphthol, and 4-tert-butyl-
phenol and the results are shown in Table 3. Reactions with 1-
naphthol16 and 4-tert-butylphenol17 proceeded similar to those
with 2-naphthol affording the corresponding N-arylimidates. It is
notable that while relatively electron-rich N-p-tolylpivalamide
gave 2o in 98% yield, electron-deficient N-(4-nitrophenyl)pivala-
mide afforded 2p in 80% yield (Table 3, entries 2 and 3).
To rationalize the results, the pathway depicted in Scheme 1
seems to be operative in our method. Activation of amides 1 af-
fords the O-triflyliminium triflate 3. Addition of 2-ClPyr to 3 then
gives the 2-chloropyridinium adduct 4. Subsequent reaction of 2-
naphthol with either 4 or the nitrilium ion 5 affords the N-arylim-
idates 2.14 Electron-rich amides with higher propensity to form a
nitrilium ion upon activation with the Tf2O–2-ClPy combination
are expected to give the highest yields. On the other hand, elec-
tron-deficient amides, which are reluctant to form the correspond-
ing nitrilium ions afford the lowest yields, probably due to the
inductive effect of the nitrogen substituent.13
Particularly significant is oxindole, reaction of which proceeds
by formation of a C–C bond to give 1-(1H-indol-2-yl)naphthalen-
2-ol (2q) in 52% yield under the reported reaction conditions
(Scheme 2).18 We believe that the different behavior of oxindole
in comparison to other amides relies on the different intermediates
reacting with 2-naphthol (Scheme 3). Activation of oxindole
affords the O-triflyliminium triflate 6. It is conceivable that
aromatization rapidly converts 6 into the intermediate 7. It has
been reported that aryl triflates appear to be extremely stable
HO
Tf2O-2-ClPyr
O
2-naphthol
N
H
N
H
2q
Scheme 2. Formation of 2q from oxindole.
O
H
Tf2O
O
2-naphthol
OTf
+ TfOH
+ TfOH
N
N
H
N
H
H
H
TfO
TfO
6
2-ClPyr
HO
OTf
(TfOH, 2-ClPyr)
+
N
H
N
H
7
2q
Scheme 3. Suggested mechanism for the formation of 2q.

M. Ghandi et al. / Tetrahedron Letters 52 (2011) 270–273
273
another 3 h. The progress of the reaction was monitored by TLC. After
completion, aq. NaOH (10 mL, 0.1 M) was added in order to neutralize the
acidic salts. The organic phase was separated, washed with brine (10 mL), and
dried over anhydrous Na2SO4. The solvent was evaporated under reduced
pressure and the residue purified by column chromatography (silica gel, 10%
EtOAc in hexane) to afford 2a as a white solid (480 mg, 96%).
and unreactive compounds in comparison to triflates 3 derived
from amides 1 (see Scheme 1).19 In contrast to compounds 3 which
are easily converted into intermediates 4 (see Scheme 1), triflate 6
persists in the reaction medium until it attacks the 2-naphthol.
Compared to 4 which is a hard electrophile, triflate 6 is a soft spe-
cies which reacts with 2-naphthol via formation of a C–C bond to
give 2q.20
In conclusion, we have developed a new one-pot synthesis of N-
arylimidates via reaction of 2-naphthol with activated secondary
amides using Tf2O and 2-ClPyr. With the exception of oxindole,
reaction of which proceeds via C–C bond formation to give 1-
(1H-indol-2-yl)naphthalene-2-ol (2q), the other amides investi-
gated in this study afforded N-arylimidates via formation of a C–
O bond.
12. Naphthalen-2-yl N-4-methoxyphenylpivalimidate (2a): White crystals, mp: 64–
65 °C; 1H NMR (500 MHz, CDCl3) d 1.47 (s, 9H), 3.57 (s, 3H), 6.55 (d, J = 8.3 Hz,
2H), 6.82 (d, J = 8.3 Hz, 2H), 7.02 (br d, J = 8.6 Hz, 1H), 7.10 (br s, 1H), 7.30–7.71
(m, 5H); 13C NMR (125 MHz, CDCl3) d 28.5, 39.7, 55.7, 114.0, 118.9, 121.4,
123.1, 124.7, 126.7, 127.3, 127.4, 128.0, 129.5, 130.1, 134.3, 139.6, 152.7 (C–O),
156.1 (C@N); IR (KBr) m: 3252 (w), 3054 (w), 2969 (m), 1672 (s), 1503 (s), 1242
(s), 1080 (s) cmÀ1; MS (EI) m/z: 333 (M+, 8), 190 (100), 134 (87), 115 (12), 77
(7), 57 (22). Anal. Calcd for C22H23NO2: C, 79.25; H, 6.95; N, 4.20. Found: C,
79.34; H, 6.89; N, 3.96.
13. No signal due to the OH group was evident in the IR and 1H NMR spectra of 2a.
Compared to 2-[(phenylimino)methyl)]naphthalene-1-ol which displays the
imine carbon at d 172.3 in the 13C NMR spectra,21 the analogous carbon signal
of 2a appears at d 156.1.12 The internal hydrogen bonding between the OH and
imine nitrogen in the former seems to be responsible for deshielding the C@N.
Based on X-ray crystallography results obtained for 1-[(3,5-dichlorophenyl-
imino)methyl)]naphthalen-2-ol, the presence of internal hydrogen bonding
between the C@N nitrogen and OH was substantiated.22 More importantly, the
appearance of the most abundant ion (or base peak) at m/z 190 in the mass
spectrum12 of 2a reveals that the parent ion had mainly undergone C–O fission,
leading to nitrilium ion 5 (Scheme 1, R1 = MeO–C6H4–, R2 = (CH3)3C–). On the
other hand, observation of a low abundant nitrilum ion similar to 5 in the mass
spectrum of 1-[(2-aminophenylimino)methyl]naphthalen-2-ol indicated that
C–C fission is not a dominant fragmentation pathway in this imine.23
14. Medley, J. W.; Movassaghi, M. J. Org. Chem. 2009, 74, 1341–1344.
15. Hendrickson, J. B.; Hussoin, M. D. J. Org. Chem. 1987, 52, 4137–4139.
16. Naphthalen-1-yl N-p-tolylpivalimidate (2n): White crystals, mp: 59–60 °C; 1H
NMR (500 MHz, CDCl3) d 1.51 (s, 9H), 2.05 (s, 3H), 6.68 (br s, 4H), 6.78 (s, 1H),
7.17 (t, J = 7.8, 1H), 7.39 (d, J = 7.8, 1H), 7.47–8.17 (m, 4H); 13C NMR (125 MHz,
CDCl3) d 21.0, 28.7, 40.0, 112.5, 121.1, 122.2, 122.9, 123.2, 125.5, 125.8, 126.5,
Acknowledgment
The authors acknowledge the University of Tehran for financial
support of this research.
References and notes
1. (a) Chapman, A. W. J. Chem. Soc. 1925, 127, 1992; (b) Dauben, W. G.; Hodgson,
R. L. J. Am. Chem. Soc. 1950, 72, 3479; (c) Relles, H. M. J. Org. Chem. 1968, 33,
2245; (d) Burdukovskii, V. F.; Mognonov, D. M.; Allayarov, S. R.; Botoeva, S. O.;
Mazurevskaya, Z. P. Russ. Chem. Bull. 2004, 53, 1773; (e) Barclay, R. J. Can. J.
Chem. 1965, 43, 2125–2131.
2. (a) Oxley, S. J. Chem. Soc. 1948, 1514–1522; (b) Titus, P. E. Can. J. Chem. 1976, 54,
647–650.
128.0, 129.0, 132.6, 134.9, 144.5, 150.4 (C–O), 162.6 (C@N); IR (KBr) m: 3056
(w), 2972 (m), 2868 (w), 1666 (s), 1463 (m), 1207 (s), 1077 (s) cmÀ1; MS (EI) m/
z: 317 (M+, 12), 174 (100), 118 (93), 91 (19), 57 (16%). Anal. Calcd for
3. (a) Burdukovskii, V. F.; Mognonov, D. M. Russ. Chem. Bull. 2008, 57, 1247–1251;
(b) Chapman, A. W. J. Chem. Soc. 1927, 1748; (c) Sechaud, J. Helv. Chim. Acta
1956, 39, 1257–1260; (d) Rowe, J. E. Synthesis 1980, 114–115; (e) Ruane, P. H.;
Ahmed, A. R.; McClelland, R. A. J. Chem. Soc., Perkin Trans. 2 2002, 312–317.
4. Schenck, T. G.; Bosnich, B. J. Am. Chem. Soc. 1985, 107, 2058–2066.
5. Kantlehner, W. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I.,
Eds.; Pergamon: New York, 1991; Vol. 6, p 485.
6. (a) Meerwein, H.; Laasch, P.; Mersch, R.; Spille, J. Ber. 1956, 89, 224; (b) Gordon,
J.; Turrell, G. J. Org. Chem. 1959, 24, 269–271; (c) Mistryukov, E. A.; Sorokina, O.
N. Mendeleev Commun. 1998, 8, 153–154; (d) Chen, S.; Zhang, X.; Ma, H.; Lu, Y.;
Zhang, Z.; Li, H.; Lu, Z.; Cui, N.; Hu, Y. J. Organomet. Chem. 2005, 690, 4184–
4191.
7. (a) Shishkin, E. V.; Safonov, S. A.; Shishkin, V. E. Russ. J. Gen. Chem. 1999, 69,
843–844; (b) Shishkin, E. V.; Isleim, K. I.; Tkhankom, P.; Shishkin, V. E. Russ. J.
Org. Chem. 1998, 34, 1792–1793; (c) Burdukovskii, V. F.; Mognonov, D. M.;
Botoeva, S. O.; Mazurevskaya, Z. P. Russ. J. Appl. Chem. 2006, 79, 430–432.
8. Manley, P. J.; Bilodeau, M. T. Org. Lett. 2002, 4, 3127–3129.
9. (a) Charette, A. B.; Grenon, M. Tetrahedron Lett. 2000, 41, 1677; (b) Charette, A.
B.; Chua, P. J. Org. Chem. 1998, 63, 908; (c) Charette, A. B.; Chua, P. Tetrahedron
Lett. 1998, 39, 245; (d) Charette, A. B.; Chua, P. Tetrahedron Lett. 1997, 38, 8499.
10. (a) Movassaghi, M.; Hill, M. D. J. Am. Chem. Soc. 2006, 128, 4592; (b)
Movassaghi, M.; Hill, M. D. J. Am. Chem. Soc. 2006, 128, 14254; (c)
Movassaghi, M.; Hill, M.; Ahmad, O. K. J. Am. Chem. Soc. 2007, 129, 10096.
11. Modified procedure for the preparation of naphthalen-2-yl N-4-
methoxyphenylpivalimidate (2a): A solution of amide 1a (310 mg, 1.5 mmol,
C
22H23NO: C, 83.24; H, 7.30; N, 4.41. Found: C, 83.27; H, 7.21; N, 4.28.
17. 4-tert-Butylphenyl N-p-tolylpivalimidate (2o): White crystals, mp: 71–72 °C; 1
H
NMR (500 MHz, CDCl3) d 1.25 (s, 9H), 1.42 (s, 9H), 2.17 (s, 3H), 6.56 (d, J = 8.2,
2H), 6.67 (br s, 2H), 6.80 (d, J = 7.4, 2H), 7.06 (br s, 2H); 13C NMR (125 MHz,
CDCl3) d 21.1, 28.6, 31.8, 34.5, 39.5, 118.8, 121.4, 125.9, 128.9, 132.0, 144.3,
146.5, 152.8, 163.6; IR (KBr) m: 2963 (m), 1668 (s), 1503 (s), 1214 (s), 1082 (s),
819 (s) cmÀ1; MS (EI) m/z: 323 (M+, 6), 174 (100), 118 (94), 91 (24), 57 (13%);
Anal. Calcd for C22H29NO: C, 81.69; H, 9.04; N, 4.33. Found: C, 81.76; H, 9.37; N,
4.88.
18. 1-(1H-Indol-2-yl)naphthalen-2-ol (2q): White crystals, mp: 171–172 °C; 1H
NMR (500 MHz, CDCl3) d 6.15 (br s, 1H, OH), 6.82 (s, 1H), 7.27 (t, J = 7.9, 1H),
7.31 (m, 2H), 7.42 (m, 2H), 7.49 (d, J = 8.2, 1H), 7.72 (d, J = 8.2, 1H), 7.78 (d,
J = 7.9, 1H), 7.88 (t, J = 8.9, 2H), 8.23 (br s, 1H, NH); 13C NMR (125 MHz, CDCl3) d
105.0, 111.6, 112.3, 117.7, 121.0, 121.2, 123.3, 124.1, 124.7, 127.7, 128.7, 129.1,
129.3, 130.7, 131.4, 133.8, 137.5, 152.6; IR (KBr) m: 3451 (s, OH), 3344 (s, NH),
3049 (w), 1589 (m), 1340 (s), 1199 (s) cmÀ1; MS (EI) m/z: 259 (M+, 100), 230
(28), 202 (12), 120 (8%); Anal. Calcd for C18H13NO: C, 83.37; H, 5.05; N, 5.40.
Found: C, 83.41; H, 5.12; N, 5.44.
19. Nenajdenko, V. G.; Balenkova, E. S.; Baraznenok, I. L. Tetrahedron 2000, 56,
3077–3119.
20. Black, D. S.; Ivory, A. J.; Kumar, N. Tetrahedron 1996, 52, 4697–4708.
21. Nedeltcheva, D.; Kamounah, F. S.; Mirolo, L.; Fromm, K. M.; Antonov, L. Dyes
Pigments 2009, 83, 121–126.
22. Elmali, A.; Elerman, Y.; Svoboda, I.; Fuess, H. Acta Crystallogr., Sect. C 1998, 54,
974–976.
23. Sondhi, S. M.; Singh, N.; Kumar, A.; Lozachc, O.; Meijer, L. Bioorg. Med. Chem.
2006, 14, 3758–3765.
1 equiv) and 2-ClPyr (169
lL, 1.8 mmol, 1.2 equiv) in CH2Cl2 (10 mL) was
cooled to À78 °C with dry ice in acetone, and Tf2O (277
l
L, 1.65 mmol,
1.1 equiv) was added via syringe under an argon atmosphere. After 5 min, the
reaction mixture was warmed to 0 °C and 2-naphthol (216 mg, 1.5 mmol,
1 equiv) was added. The mixture was allowed to warm to 25 °C and stirred for