Transition-metal-free oxidative amidation of benzyl alcohols with amines catalyzed by NaI: A new method for the synthesis of benzamides Dedicated to the memory of Professor Ahmad Sodagar

Article abstract of DOI:10.1016/j.tetlet.2014.07.085

A simple, inexpensive, and efficient method for the synthesis of benzamides via the reaction of benzyl alcohols and amine hydrochloride salts in the presence of NaI as a green catalyst is described. Various derivatives of benzamide were synthesized in moderate to good yields using this method.

Full text of DOI:10.1016/j.tetlet.2014.07.085

Tetrahedron Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Transition-metal-free oxidative amidation of benzyl alcohols
with amines catalyzed by NaI: a new method for the synthesis
of benzamides
Meghdad Karimi a, Dariush Saberi b, Kobra Azizi a, Marzban Arefi a, Akbar Heydari a,
⇑
a Chemistry Department, Tarbiat Modares University, PO Box 14155-4838, Tehran, Iran
b Fisheries and Aquaculture Department, College of Agriculture and Natural Resources, Persian Gulf University, 75169 Bushehr, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple, inexpensive, and efficient method for the synthesis of benzamides via the reaction of benzyl
alcohols and amine hydrochloride salts in the presence of NaI as a green catalyst is described. Various
derivatives of benzamide were synthesized in moderate to good yields using this method.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 8 March 2014
Revised 5 July 2014
Accepted 23 July 2014
Available online xxxx
Dedicated to the memory of Professor
Ahmad Sodagar
Keywords:
Benzyl alcohol
Amine
Oxidative amidation
Sodium iodide
The amide bond is an important and prevalent linkage in
organic chemistry. It is the key functional group in peptides and
a number of polymers and is also found in many pharmaceuticals
and natural products.1
amines and azides12 are salient examples of these reactions. Amide
bond formation through the oxidative amidation of tertiary amines
with aldehydes and anhydrides has also been reported.13 More effi-
cient catalytic methods are based on the transition-metal-free oxi-
dative amidation of aldehydes using N-heterocyclic carbenes,
iodine, and KI-TBHP.8c Moreover, heterogeneous catalysts have
also been shown to promote amide formation.14 Following on from
this research, herein we report the NaI-catalyzed direct oxidative
amidation of benzyl alcohols with amine hydrochloride salts. Var-
ious secondary and tertiary amides were synthesized in moderate
to good yields via this method.
Hence, the development of efficient methods for the formation
of amide bonds is important. Traditionally, amide bond synthesis is
achieved by the coupling of the activated derivatives of carboxylic
acids with an amine.2 Some common drawbacks associated with
these methods such as poor atom efficiency and the use of hazard-
ous reagents have led researchers to consider alternative methods.
Subsequently, some excellent synthetic methods such as transami-
dation of primary amides,3 catalytic acylation of amines with car-
boxylic acids,4 hydroamination of alkynes,5 direct amidation of
unactivated carboxylic acids and amines,6 aminocarbonylation,7
and oxidative amidation8 have been developed. In particular, tran-
sition-metal-catalyzed oxidative amidation is a good strategy for
amide bond formation. Various precursors have been used for this
purpose. Oxidative amidation of aldehydes with amines (ammonia,
primary and secondary amines),9 alcohols with amines (ammonia,
primary and secondary amines),10 toluene with amines (primary
and secondary amines),11 and oxidative amidation of alkynes with
The synthesis of N-benzyl benzamide (1a) was chosen as the
model reaction to optimize the oxidative amidation conditions
(Scheme 1).15
The results of the optimization of the reaction conditions are
summarized in Table 1. The first reaction was carried out under
the following conditions: benzyl alcohol (1 mmol), benzyl-
amineÁHCl (1.5 mmol), I2 as the catalyst (10 mol %), tert-butyl
hydroperoxide (TBHP) as oxidant (8 equiv), CaCO3 as the base
(2.2 equiv), CH3CN (4 mL), 100 °C. The corresponding product
was obtained in 51% yield (Table 1, entry 1). To improve the yield
of the product, other iodide source compounds such as KI, NaI, and
PhI were tested. In the presence of NaI the yield increased to 69%
(Table 1, entries 2–4). In the absence of a catalyst, N-benzyl benzam-
ide was obtained in only 10% yield (Table 1, entry 5). Next, the
⇑
Corresponding author. Tel.: +98 21 82883444; fax: +98 21 82883455.
E-mail address: heydar_a@modares.ac.ir (A. Heydari).
URL: http://modares.ac.ir (A. Heydari).
http://dx.doi.org/10.1016/j.tetlet.2014.07.085
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Karimi, M.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.07.085

2
M. Karimi et al. / Tetrahedron Letters xxx (2014) xxx–xxx
O
base (2.2 eq)
Cat. (mol%), oxidant (8 equiv)
N
H
OH
H2N
CH3CN (4 mL), Temp., 4 h
1 mmol
1.5 mmol
1a
Scheme 1. Synthesis of amide 1a catalyzed by NaI.
Table 1
Table 2
Results of screening the reaction conditionsa
Preparation of various benzamides in the presence of NaIa
Yieldb (%)
O
O
O
Entry
Catalyst (mol %)
Oxidant
Base
Temp. (°C)
1
2
3
4
5
6
7
8
I2 (10)
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
mCPBA
H2O2
NaOCl
—
TBHP
TBHP
TBHP
TBHP
TBHP
CaCO3
CaCO3
CaCO3
CaCO3
CaCO3
CaCO3
CaCO3
CaCO3
CaCO3
CaCO3
CaCO3
CaCO3
K2CO3
Na2CO3
Cs2CO3
CaCO3
CaCO3
100
100
100
100
100
120
80
60
80
80
80
80
80
80
80
80
80
51
19
69
33
10
69
87
63
34
61
50
—
21
17
65
33
87
N
H
N
H
N
H
KI (10)
NaI (10)
PhI (10)
-
1a, 68%
Ref. 15f
1b, 53%
Ref. 15e
1c
, 65%
Ref. 10j
NaI (10)
NaI (10)
NaI (10)
NaI (10)
NaI (10)
NaI (10)
NaI (10)
NaI (10)
NaI (10)
NaI (10)
NaI (5)
NaI (20)
O
O
O
OH
N
H
N
H
9
N
H
CO2tBu
10
11
12
13
14
15
16
17
1d
1f
, 87%
Ref. 10j
, 70%
Ref. 15f
1e, 85%
Ref. 10j
O
O
CH3
O
N
N
H
N
O
a
1i
, 67%
Ref. 10j
All reactions were run with benzyl alcohol (1 mmol), benzylamine hydrochlo-
1g, 93%
1h
Ref. 10j
, 72%
ride salt (1.5 mmol), CH3CN (4 mL), oxidant (8 equiv), base (2.2 equiv), under Ar at
Ref. 10j
80 °C for 4 h.
b
Isolated yield.
O
N
O
O
CO2Me
temperature was investigated and we observed that increasing the
temperature to 120 °C had no impact on the yield of the product,
whereas reducing it to 80 °C led to a significant increase in the
amount of product 1a. At 60 °C, the yield decreased to 63%. Thus,
80 °C was regarded as the optimum temperature (Table 1, entries
6–8). The effect of the oxidant on the yield of the reaction was inves-
tigated. The reaction was carried out in the presence of several oxi-
dizing reagents such as mCPBA, H2O2, and NaOCl, as well as under
oxidant-free conditions. TBHP proved to be more effective than
other oxidants. Meanwhile no product was observed in the absence
of an oxidant (Table 1, entries 9–12). This shows that the type of oxi-
dant was important for this reaction. The influence of CaCO3 as the
base was better than other carbonates such as K2CO3, Na2CO3, and
Cs2CO3 (Table 1, entries 13–15). The use of 20 mol % of the catalyst
had no beneficial effect while reduction to 5 mol % reduced the yield
significantly (Table 1, entries 16 and 17).
N
CH3
N
1k
, 75%
Ref. 10j
1j, 55%
Ref. 15f
1l, 73%
Ref. 15f
O
O
N
O
N
Ph
Ph
N
N
1m
, 60%
Ref. 15f
1n,
57%
Ref. 15f
1o, 0%
O
CH3
O
CH3
N
H
N
H
O
Cl
Having established optimum conditions as follows: benzyl alco-
hol (1 mmol), amine hydrochloride salt (1.5 mmol), NaI (10 mol %),
CaCO3 (2.2 equiv), TBHP (8 equiv), CH3CN (4 mL), a series of sec-
ondary and tertiary amides were synthesized by the reaction
between various amine hydrochloride salts (aliphatic and aro-
matic) and benzyl alcohols (Table 2). As can be seen in Table 2, ali-
phatic ethyl, allyl, and butyl amines and 2-aminobutan-1-ol were
converted into the corresponding amides in good yields (68%,
53%, 65%, and 70%, respectively). Notably, no oxidation occurred
on the alcohol functional group in 1d. By using phenylalanine
tert-butyl ester as amine, the corresponding amide (1e) was iso-
1q, 65%
Ref. 10j
1p, 65%
Ref. 10j
O
CH3
O
CH3
N
H
N
H
O2N
1r, 65%
Ref. 10j
1s, 85%
Ref. 10j
a
Reaction conditions: alcohol (1 mmol), amine hydrochloride salt (1.5 mmol),
CH3CN (4 mL), TBHP (8 equiv), CaCO3 (2.2 equiv), NaI (10 mol %), under Ar, 80 °C, 4 h.
lated in 85% yield. Benzylamine and (s)-a-methylbenzylamine
were also coupled with benzyl alcohol in 87% (1f) and 93% (1g)
yields, respectively. Moreover, various secondary amines (cyclic,
aliphatic, and aromatic) were converted into the corresponding
tertiary amides (1h–n) in moderate to good yields under the opti-
mized reaction conditions. Decreasing isolated yields in some
cases, because of steric effects, was a foreseeable outcome. In the
case of imidazole, amide 1o was not observed. Various benzyl
alcohols were next probed in this reaction (1p–s) and a-methylben-
zylamine hydrochloride was chosen as the amine source. Generally
speaking, in the case of benzyl alcohols with electron-withdrawing
groups, the yield was higher than those with electron-donating
groups. With electron-donating groups, oxidation to the acid was
faster than for amide formation. In the case of enantiomerically
Please cite this article in press as: Karimi, M.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.07.085

M. Karimi et al. / Tetrahedron Letters xxx (2014) xxx–xxx
3
tBuOH
1/2 I2
4. Choudary, B. M.; Bhaskar, V.; Kantam, M. L.; Rao, K. K.; Raghavan, K. V. Catal.
Lett. 2001, 74, 207–211.
5. (a) Severin, R.; Doye, S. Chem. Soc. Rev. 2007, 36, 1407–1420; (b) Wong, V. H. L.;
Hor, T. S. A.; Hii, K. K. Chem. Commun. 2013, 9272–9274.
6. (a) Marcelli, T. Angew. Chem., Int. Ed. 2010, 49, 6840–6843; (b) Allen, C. L.;
Chhatwal, A. R.; Williams, J. M. J. Chem. Commun. 2012, 666–668; (c) Ishihara,
K.; Ohara, S.; Yamamoto, H. J. Org. Chem. 1996, 61, 4196–4197; (d) Lanigan, R.
M.; Starkov, P.; Sheppard, T. D. J. Org. Chem. 2013, 78, 4512–4523; (e) Sasaki, K.;
Crich, D. Org. Lett. 2011, 13, 2256–2259.
tBuOOH
I
O
7. (a) Martinelli, J. R.; Clark, T. P.; Watson, D. A.; Munday, R. H.; Buchwald, S. L.
Angew. Chem., Int. Ed. 2007, 46, 8460–8463; (b) Brennführer, A.; Neumann, H.;
Beller, M. Angew. Chem. Int. Ed. 2009, 48, 4114–4133; (c) Dang, T. T.; Zhu, Y.;
Ghosh, S. C.; Chen, A.; Chai, C. L. L.; Seayad, A. M. Chem. Commun. 2012, 1805–
1807.
R1
R2
R1
CaCO3
H
OH
NH
NH.HCl
R2
8. (a) Yao, H.; Yamamoto, K. Chem. Asian J. 2012, 7, 1542–1545; (b) Xu, K.; Hu, Y.;
Zhang, S.; Zha, Zh.; Wang, Zh. Chem. Eur. J. 2012, 18, 9793–9797; (c) Reddy, K.
R.; Maheswari, C. U.; Venkateshwar, M.; Kantam, M. L. Eur. J. Org. Chem. 2008,
3619–3622; (d) Vora, H. U.; Rovis, T. J. Am. Chem. Soc. 2007, 129, 13796–13797;
(e) Bode, J. W.; Sohn, S. S. J. Am. Chem. Soc. 2007, 129, 13798–13799; (f) Ekoue-
Kovi, K.; Wolf, C. Org. Lett. 2007, 9, 3429–3432; (g) De Sarkar, S.; Studer, A. Org.
Lett. 2010, 12, 1992–1995; (h) Ohmura, R.; Takahata, M.; Togo, H. Tetrahedron
Lett. 2010, 51, 4378–4381.
O
R1
OH
R1
N
N
R2
R2
hemiaminal
9. (a) Philip, J. W. W. C.; Chan, W. H. Angew. Chem., Int. Ed. 2008, 47, 1138–1140;
(b) Nakagawa, K.; Inoue, H.; Minami, K. Chem. Commun. 1966, 17–18; (c)
Ekoue-Kovi, K.; Wolf, C. Chem. Eur. J. 2008, 14, 6302–6315; (d) Wang, L.; Fu, H.;
Jiang, Y.; Zhao, Y. Chem. Eur. J. 2008, 14, 10722–10726; (e) Tillack, A.; Rudloff, I.;
Beller, M. Eur. J. Org. Chem. 2001, 523–528; (f) Liu, X.; Jensen, K. F. Green Chem.
2012, 14, 1471–1474; (g) Yoo, W. L.; Lee, C.-J. J. Am. Chem. Soc. 2006, 128,
13064–13065; (h) Ghosh, S. C.; Ngiam, J. A. Y.; Seayad, A. M.; Tuan, D. T.; Chai,
C. L. L.; Chen, A. J. Org. Chem. 2012, 77, 8007–8015; (i) Ghosh, S. C.; Ngiam, J. S.
Y.; Chai, C. L. L.; Seayad, A. M.; Dang, T. T.; Chen, A. Adv. Synth. Catal. 2012, 354,
1407–1412; (j) Gao, J.; Wang, G.-W. J. Org. Chem. 2008, 73, 2955–2958; (k) Li, J.;
Xu, F.; Zhang, Y.; Shen, Q. J. Org. Chem. 2009, 74, 2575–2577; (l) Zhu, M.; Fujita,
K.; Yamaguchi, R. J. Org. Chem. 2012, 77, 9102–9109; (m) Seo, S. Y.; Marks, T. J.
Org. Lett. 2008, 10, 317–319; (n) Qian, C.; Zhang, X.; Li, J.; Xu, F.; Zhang, Y.; Shen,
Q. Organometallics 2009, 28, 3856–3862; (o) Goh, K. S.; Tan, Ch. RSC Adv. 2012,
2, 5536–5538; (p) Tamaru, Y.; Yamada, Y.; Yoshida, Z. Synthesis 1983, 474; (q)
Liang, J.; Lv, J.; Shang, Z. Tetrahedron 2011, 67, 8532–8535; (r) Suto, Y.;
Yamagiwa, N.; Torisawa, Y. Tetrahedron Lett. 2008, 49, 5732–5735; (s) Zhang,
M.; Wua, X. Tetrahedron Lett. 2013, 54, 1059–1062.
1/2 I2
I
tBuOOH
tBuOH
Scheme 2. Proposed mechanism for the oxidative amidation of alcohols with
amine hydrochloride salts in the presence of NaI–TBHP
pure amines, according to chiral HPLC data (on products 1e, g, k),
no racemization was observed.16 Products were characterized from
their melting points (in some cases), and from their IR, mass, 1H
NMR, and 13C NMR spectra.
10. (a) Ghosh, S. C.; Muthaiah, S.; Zhang, Y.; Xu, X.; Hong, S. H. Adv. Synth. Catal.
2009, 351, 2643–2649; (b) Wang, Y.; Zhu, D.; Tang, L.; Wang, S.; Wang, Zh.
Angew. Chem., Int. Ed. 2011, 50, 8917–8921; (c) Kegneas, S.; Mielby, J.; Mentzel,
U. V.; Jensen, T.; Fristrup, P.; Riisager, A. Chem. Commun. 2012, 2427–2429; (d)
Wu, X.; Sharif, M.; Pews-Davtyan, A.; Langer, P.; Ayub, K.; Beller, M. Eur. J. Org.
Chem. 2013, 2783–2787; (e) Soule, J. F.; Miyamura, H.; Kobayashi, S. J. Am.
Chem. Soc. 2011, 133, 18550–18553; (f) Muthaiah, S.; Ghosh, S. C.; Jee, J.; Chen,
C.; Zhang, J.; Hong, S. H. J. Org. Chem. 2010, 75, 3002–3006; (g) Gaspa, S.;
Porcheddu, A.; De Luca, L. Org. Biomol. Chem. 2013, 11, 3803–3807; (h)
Gunanathan, C.; Ben-David, Y.; Milstein, D. Science 2007, 317, 790–792; (i)
Ghosh, S. C.; Ngiam, J. S. Y.; Seayad, A. M.; Tuan, D. T.; Johannes, C. W.; Chen, A.
Tetrahedron Lett. 2013, 54, 4922–4925; (j) Bantreil, X.; Fleith, C.; Martinez, J.;
Lamaty, F. Chem. Catal. Chem. 2012, 4, 1922–1925.
11. (a) Liu, H.; Laurenczy, G.; Yan, N.; Dyson, P. J. Chem. Commun. 2014, 341–343;
(b) Wang, Y.; Yamaguchi, K.; Mizuno, N. Angew. Chem., Int. Ed. 2012, 51, 1–5.
12. (a) Cho, S. H.; Yoo, E. J.; Bae, I.; Chang, S. J. Am. Chem. Soc. 2005, 127, 16046–
16047; (b) Chan, W.; Ho, C.; Wong, M.; Che, C. J. Am. Chem. Soc. 2006, 128,
14796–14797; (c) Chen, Z.; Jiang, H.; Pan, X.; He, Z. Tetrahedron 2011, 67, 5920–
5927.
A proposed mechanism for this reaction is shown in Scheme 2.
Initially, the oxidation of benzyl alcohol into benzaldehyde is per-
formed by TBHP in the presence of NaI. The oxidative amidation of
benzaldehyde may be achieved by initial deprotonation of the ami-
neÁHCl salt to give the free amine. Nucleophilic addition of the free
amine to benzaldehyde would generate a hemiaminal intermedi-
ate, which can then be oxidized by IÀ/TBHP to generate the desired
amide product.
In summary, we have developed an efficient and direct synthe-
sis of secondary and tertiary amides from alcohols catalyzed by
NaI. This transition-metal-free strategy provides a practical syn-
thesis of various amides. More studies on other catalytic methods
in this reaction class are ongoing.
Acknowledgments
13. (a) Li, Y.; Jia, F.; Li, Zh. Chem. Eur. J. 2013, 19, 82–86; (b) Li, Y.; Ma, L.; Jia, F.; Li,
Zh. J. Org. Chem. 2013, 78, 5638–5646; (c) Mai, W.; Song, G.; Yuan, J.; Yang, L.;
Sun, G.; Xiao, Y.; Mao, P.; Qu, L. RSC Adv. 2013, 3, 3869–3872; (d) Wang, S.;
Wang, J.; Guo, R.; Wang, G.; Chen, S.; Yu, X. Tetrahedron Lett. 2013, 54, 6233–
6236.
The authors would like to acknowledge the financial support
provided by the Tarbiat Modares University for carrying out this
research.
14. (a) Wang, Y.; Zhu, D.; Tang, L.; Wang, S.; Wang, Z. Angew. Chem., Int. Ed. 2011,
50, 8917–8921; (b) Yamaguchi, K.; Kobayashi, H.; Oishi, T.; Mizuno, N. Angew.
Chem., Int. Ed. 2012, 51, 544–547; (c) Shimizu, K.; Ohshima, K.; Satsuma, A.
Chem. Eur. J. 2009, 15, 9977–9980; (d) Ghosh, S.; Bhaumik, A.; Mondal, J.;
Mallik, A.; Sengupta, S.; Mukhopadhyay, C. Green. Chem. 2012, 14, 3220–3230;
(e) Soulé, J.; Miyamura, H.; Kobayashi, S. J. Am. Chem. Soc. 2011, 133, 18550–
18553; (f) Saberi, D.; Heydari, A. Appl. Organomet. Chem. 2014, 28, 101–108.
15. General procedure: To a mixture of NaI (10 mol %), amine hydrochloride salt
(1.5 mmol), and CaCO3 (2.2 mmol) in CH3CN (4 mL) were added benzyl alcohol
(1 mmol) and TBHP (70 wt % in H2O, 8 equiv) under an argon atmosphere at
room temperature. The reaction vessel was capped and the mixture allowed to
stir at 80 °C for 4 h. The progress of the reaction was monitored by TLC. After
completion, the mixture was allowed to cool to room temperature. The product
was extracted with EtOAc (3 Â 10 mL). The combined organic layers were dried
over anhydrous Na2SO4 and concentrated in vacuum. The crude product was
purified by column chromatography. All compounds were identified from their
melting points (in some cases), and IR, mass, 1H NMR, and 13C NMR spectra.
The spectral data of known compounds were compared with those reported in
the literature.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.07.
085.
References and notes
1. Pattabiraman, V. R.; Bode, J. W. Nature 2011, 480, 471–479.
2. (a) Zeng, H.; Guan, Z. J. Am. Chem. Soc. 2011, 133, 1159–1161; (b)
Gnanaprakasam, B.; Balaraman, E.; Ben-David, Y.; Milstein, D. Angew. Chem.,
Int. Ed. 2011, 50, 12240–12244.
3. (a) Allen, C. L.; Atkinson, B. N.; Williams, J. M. J. Angew. Chem., Int. Ed. 2012, 51,
1383–1386; (b) Zhang, M.; Imm, S.; Bähn, S.; Neubert, L.; Neumann, H.; Beller,
M. Angew. Chem., Int. Ed. 2012, 51, 3905–3909; (c) Tamura, M.; Tonomura, T.;
Shimizu, K.; Satsuma, A. Green Chem. 2012, 14, 717–724; (d) Eldred, S. E.; Stone,
D. A.; Gellman, S. H.; Stahl, S. S. J. Am. Chem. Soc. 2003, 125, 3422–3423.
16. It was assumed, by analogy, that no racemization occurred during the
synthesis of 1p–s.
Please cite this article in press as: Karimi, M.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.07.085