The different, but interesting behaviors of benzyl systems in the Willgerodt-Kindler reaction under solvent-free conditions

Article abstract of DOI:10.1080/10426500211708

On the benzyl system, bearing various functional groups, have been carried out the Willgerodt-Kindler reaction to obtain thiobenzmorpholide (1). The reactions, under solvent-free conditions, were performed in both classical (reflux, room temperature) and

Full text of DOI:10.1080/10426500211708

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Phosphorus, Sulfur, and Silicon and the Related
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The Different, but Interesting Behaviors of Benzyl
Systems in the Willgerodt-Kindler Reaction under
Solvent-Free Conditions
Kioumars Aghapoor a , Hossein Reza Darabi a & Kourosh Tabar-Heydar a
a Chemistry and Chemical Engineering Research Center of Iran , Tehran, Iran
Published online: 27 Oct 2010.
To cite this article: Kioumars Aghapoor , Hossein Reza Darabi & Kourosh Tabar-Heydar (2002) The Different, but Interesting
Behaviors of Benzyl Systems in the Willgerodt-Kindler Reaction under Solvent-Free Conditions, Phosphorus, Sulfur, and Silicon
and the Related Elements, 177:5, 1183-1187, DOI: 10.1080/10426500211708
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Phosphorus, Sulfur and Silicon, 2002, Vol. 177:1183–1187
C
Copyright 2002 Taylor & Francis
1042-6507/02 $12.00 + .00
DOI: 10.1080/10426500290092460
THE DIFFERENT, BUT INTERESTING BEHAVIORS
OF BENZYL SYSTEMS IN THE
WILLGERODT-KINDLER REACTION UNDER
SOLVENT-FREE CONDITIONS
Kioumars Aghapoor, Hossein Reza Darabi,
and Kourosh Tabar-Heydar
Chemistry and Chemical Engineering Research Center of Iran,
Tehran, Iran
(Received January 31, 2001; accepted April 24, 2001)
On the benzyl system, bearing various functional groups, have been car-
ried out the Willgerodt-Kindler reaction to obtain thiobenzmorpholide
(1). The reactions, under solvent-free conditions, were performed in both
classical (reflux, room temperature) and nonclassical (microwave) con-
ditions to attempt our elucidation of the reactions pathways. Unlike
benzylamine and benzyl mercaptan, benzyl halides give poor result due
to the type of amine. The experimental results suggest that the proposed
reaction pathway involves the oxidation coupling of benzylic substrates,
followed by a thiolation step and an attack of the amine on the thiolated
product to give (1).
Keywords: Benzyl system; solvent-free conditions; the Willgerodt-
Kindler reaction
Since thioamides have found widespread applications as intermediates
in medicine and organic synthesis1–4 their syntheses have attracted
attention in the various field of chemistry.5–8 The Willgerodt-Kindler
reaction is one of the oldest and well-known methods for the synthesis
of thioamides.9–11 In the reaction, the starting materials are reacted
with sulfur and primary or secondary amines to give thioamides with
the same number of carbon atoms.
The present study is focused on the Willgerodt-Kindler reactions
of compounds bearing benzyl skeletons. We believe that the use of
novel nonclassical procedures and modern laboratory facilities allows
us to extend our knowledge of the Willgerodt-Kindler reaction with new
Address correspondence to H. R. Darabi, Chemistry and Chemical Engineering
Research Center of Iran, Faculty of Science, PO Box 14335-186, Tehran, Iran.
E-mail: darabi@ccerci.ac.ir
1183

1184
K. Aghapoor et al.
TABLE I The Formation of Thiobenzmorpholide (1) from Various
Starting Materials Under Different Proceduresa
Microwave
(3 min) 1 (%)
Classical heating
(4 h) 1 (%)
Room temperature
(4 h) 1 (%)
Entry
Substrate
1
2
3
4
5
6
PhCH2SH
PhCH2NH2
PhCH2Clb
PhCH2Brb
PhCH2OH
PhCH3
99
95
17
10
5
98
95
11
5
5
4
19
55
6
4
4
5
2
aThe reactions were monitored by TLC and the product characterized by
its spectral data. (Thiobenzmorpholide (1): Yellow crystals, IR (cm 1) 820 (m),
1010 (m), 1100 (s), 1230 (m), 1430 (m), 1505 (s), 2810 (m), 2900 (m); 1H-NMR
(90 MHz, CDCl3) 7.25 (s, 5H), 4.30 (t, 2H), 3.75 (t, 2H), 3.45 (s, 4H); 13C-NMR
(25 MHz, CDCl3) 201.45, 142.23, 128.55, 128.24, 125.64, 66.42, 66.19, 52.23,
49.29, MS, m/e (rel. intensity %) 207 (M+, 40), 121 (100), 86 (20), 77 (40).)
bThe main products is N-benzyl morpholine (83–95%).
viewpoints. It is also of interest to know whether these compounds show
similar behavior in the Willgerodt-Kindler reaction.
The reactions were carried out based on our established optimum re-
action conditions.12 All starting materials were treated with two equiv-
alents of sulfur and three of morpholine. Under solvent-free conditions,
benzylic compounds were treated with sulfur and morpholine and gave
thiomorpholide 1 in low to high yields.
The results from different types of benzylic compounds are arranged
in Table I. All the results clearly show that thermal effect is the only
factor for promotion of the reaction. Microwave activation is due to
its super-heating effects. Conducting the reaction at room temperature
may offer the possibility of obtaining reactive intermediates whose iso-
lation at higher temperature would be impossible.
In all three series, benzyl mercaptan and benzylamine exhibit the
highest tendency to form thiomorpholide 1 (entries 1 and 2). How-
ever, benzyl halides mainly transformed into the N-benzyl morpholine
(entries 3 and 4). In the case of toluene and benzyl alcohol considerable

Willgerodt-Kindler Reaction
1185
quantities of unreacted starting materials were recovered to show their
low activity in the reaction (entries 5 and 6).
Although McMillan et al. reported the synthesis of 1 (41%) by the
Willgerodt-Kindler reaction of benzyl amine under classical heating,
they did not mention the formation of other products.13 We, however, ob-
tained 1 (95%) under microwave heating. The experimental data show
that the reaction pathway, presented in Scheme 1, involves three basic
steps.
1. In the presence of sulfur, the oxidative coupling of benzylamine gives
amine 4.
2. Thiolation, followed by desulfurization of 4, leads to Schiff base 2.
Of course, when either benzylamine or 4 were treated with sulfur at
room temperature (1 h) in CH2Cl2, Schiff base 2 was the sole/isolated
product (82–95%).
3. The Willgerodt-Kindler reaction of 2 under microwave heating
affords the thioamides 1 or 3 in high yield.
SCHEME 1
The Willgerodt-Kindler reaction of benzyl mercaptan under mi-
crowave heating gave 1 in quantitative yield. Conducting the same
reaction at room temperature gave dibenzyl disulfide15 in 64% yield.
Conducting the Willgerodt-Kindler reaction on dibenzyldisulfide under
microwave heating resulted in further thiolation followed by an amina-
tion process to give 1.
The other main objective in this study was to determine why other
benzylic compounds gave low yields of 1. This fact may pose the question

1186
K. Aghapoor et al.
us to what happened during the reaction. The Willgerodt reaction
of benzyl chloride with sulfur and ammonium sulfide at 190 C gave
benzamide in 60% yield.14 The reaction of benzyl halides with a mix-
ture of sulfur and amine may be performed in two ways. In the first,
a nucleophilic substitution of amine or sulfur at the chlorine atom [or
bromine atom] is expected to give benzylamine or benzyl mercaptan,
respectively (path a and b is Scheme 2). In the second, addition of sul-
fur on a carbon atom is possible (path c in Scheme 2). When we applied
the reaction of benzyl chloride with sulfur and morpholine, benzyl mor-
pholide was obtained as a main product (entries 3 and 4 in Table I). This
fact confirms that path a is the more feassible way. We also found that,
under microwave heating, N-benzyl morpholine is inert to Willgerodt-
Kindler reaction conditions, which is due to lack of formation of imine
2. Therefore, the fact that benzyl halides do not give 1 is not due to their
nature but to type of applied amine in the reaction.
SCHEME 2
The OH and H groups on benzyl skeleton are poor leaving groups,
which under the reaction conditions are inert. Of course, the existence
of trace amounts of by-products, such as methyl thiomorpholide, sug-
gests that some of benzyl alcohol, like benzyl mercaptan, may convert
to dibenzyl peroxide, which is an active radical source.
In general, it can be concluded that imine and dibenzyldisulfide are
possible intermediates of this study. The experimental results suggest
that the proposed reaction pathway involve the oxidative coupling of
benzylic substrates, followed by a thiolation step and attack of an amine
on the thiolated product to give 1.
Further work on the Willgerodt-Kindler reaction is in progress to
extend the scope of the reaction by using different substrates.

Willgerodt-Kindler Reaction
1187
REFERENCES
[1] A. Padwa, L. Scott Beall, T. M. Heidelbaugh, B. Liu, and S. M. Sheehan, J. Org.
Chem., 65, 2684 (2000).
[2] P. J. May, M. Bradley, D. C. Harrowven, and D. Pallin, Tetrahedron Lett., 41, 1627
(2000).
[3] D. C. Harrowven, M. C. Lucas, and P. D. Howes, Tetrahedron Lett., 40, 4443 (1999).
[4] P. Metzner, Synthesis, 1185 (1992).
[5] A. F. Spatola, Chemistry and Biochemistry of Aminoacids, Peptides and Proteins,
B. Weinstein Ed. (Marcel Dekker, New York, 1983), vol. 7, 267–357.
[6] T. Hoeg-Jensen, C. Olsen, and A. Holm, J. Org. Chem., 59, 1257 (1994).
[7] A. L. Katritzky, J. L. Moutou, and Z. Yang, Synlett, 99 (1995).
[8] M. C. Murguia and R. A. Rossi, Tetrahedron Lett., 38, 1335–1338 (1997).
[9] F. Asinger and H. Offermanns, Angew. Chem. Int. Ed. Engl., 6, 907–919 (1967).
[10] F. Asinger, W. Schafer, K. Halcour, A. Saus, and H. Triem, Angew Chem., Int. Ed.
Engl., 3, 19–28 (1964).
[11] E. V. Brown, Synthesis, 358–373 (1975).
[12] M. Nooshabadi, K. Aghapoor, H. R. Darabi, and M. M. Mojtahedi, Tetrahedron Lett.,
40, 7549–7552 (1999).
[13] F. H. McMillan and J. A. King, J. Am. Chem. Soc., 70, 4143 (1948).
[14] M. A. Naylor and A. W. Anderson, J. Am. Chem. Soc., 75, 5395 (1963).
[15] F. H. McMillan, J. Am. Chem. Soc., 70, 868 (1948).