Thio acid-mediated conversion of azides to amides – Investigation of 2-azidotetrahydobenzimidazoles and derivatives

Article abstract of DOI:10.1016/j.tetlet.2020.152484

An investigation of the thio acid-azide coupling reaction to afford amides is reported employing 2-azidotetrahydrobenzimidazoles and the corresponding spiro fused 2-azidoimidazolones. The tetrahydrobenzimidazole derivatives react as expected to produce th

Full text of DOI:10.1016/j.tetlet.2020.152484

Tetrahedron Letters xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Thio acid-mediated conversion of azides to amides – Investigation
of 2-azidotetrahydobenzimidazoles and derivatives
⇑
Lawton A. Seal II, Olatunji S. Ojo, Delphine Gout, Carl J. Lovely
Department of Chemistry and Biochemistry, 700 Planetarium Place, University of Texas at Arlington, TX 76019, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
An investigation of the thio acid-azide coupling reaction to afford amides is reported employing 2-azi-
dotetrahydrobenzimidazoles and the corresponding spiro fused 2-azidoimidazolones. The tetrahy-
drobenzimidazole derivatives react as expected to produce the analogous amides, whereas the
imidazolones result in the formation of the thiohydantoin derivatives. The thiohydantoins appear to
result from an addition elimination pathway.
Received 13 August 2020
Revised 14 September 2020
Accepted 21 September 2020
Available online xxxx
Ó 2020 Elsevier Ltd. All rights reserved.
Keywords:
Ageliferin
Palau’amine
Tetrazole
Thiohydantoin
2-Aminoimidazole
Azides serve as a key functional group in synthetic chemistry, in
particular, they play a central role in the preparation of primary
amines and their derivatives, in addition to serving as 1,3-dipoles
in what has become a textbook example of [3+2] cycloadditions
[1–4]. Several effective methods exist for azidation through classi-
cal substitution pathways. As well, they are relatively robust func-
tional groups which allows them to serve as masked amino groups
[5,6]. In the context of a number of active total synthesis projects of
nitrogen rich alkaloids of the oroidin (e.g., 1 [7–9] and 2, [10–12]
Fig. 1) [13,14] and Leucetta families of sponge metabolites
[15,16], azide intermediates were in hand wherein classical reduc-
tions were either not feasible or in some cases undesirable, because
of chemoselectivity considerations. Furthermore, many of the tar-
get alkaloids contained amides and thus we sought to identify a
process where reduction and acylation could be accomplished
either simultaneously or sequentially, potentially telescoping the
syntheses. One particularly attractive possibility emerged to
accomplish this; specifically the reaction of azides and thio acids
to provide amides [17]. This transformation was observed initially
by Just [18] and Rosen [19] and subsequently investigated system-
atically by Williams and co-workers [20,21]. In prior work, we
investigated predominantly vinyl imidazole derivatives of varying
complexity and discovered this transformation gave amides in
generally good yields with thio acetic acid, and some examples
with thio benzoic acid [17]. Examination of limited examples of
⇑
Figure 1. (a) Oroidin alkaloids ageliferin and palau’amine. (b) systems investigated
in this report.
Corresponding author.
E-mail address: lovely@uta.edu (C.J. Lovely).
https://doi.org/10.1016/j.tetlet.2020.152484
0040-4039/Ó 2020 Elsevier Ltd. All rights reserved.
Please cite this article as: L.A. Seal II, O.S. Ojo, D. Gout et al., Thio acid-mediated conversion of azides to amides – Investigation of 2-azidotetrahydoben-
zimidazoles and derivatives, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.152484

L.A. Seal II, O.S. Ojo, D. Gout et al.
Tetrahedron Letters xxx (xxxx) xxx
C2-substituted azides revealed chemoselectivity for reaction of the
C2-azide in the presence of an allylic azide, and that even unpro-
tected imidazoles participate in this chemistry [17]. However, sev-
eral targets of interest contained tetrahydrobenzimidazole
moieties 3 or could be accessed via their rearrangement 3 ? 4;
specifically ageliferin (1) and palau’amine (2). Accordingly, in the
Table 1
Products from reactions of 2-azidotetrahydrobenzimidazole and imidazolotetrazolones with thio acids.
Entry
1
Substrate
Thio acida
AcSH
Product (%)
Product (%)
3a
3b
9a (59)
9b (60)
2
AcSH
X-ray structure of 9b
3
4
AcSH
AcSH
3c
9c (49)
9d (59)
3d
X-ray structure of 9d
5
6
AcSHb
AcSH
3e
9e (62)
10a (95)
8a
X-ray structure of 10a
7
8
9
AcSH
AcSH
BzSH
10b (80)
8b
10c (70)
11c (7)
8c
3c
12c (68)
X-ray structure of compound 12c
2

L.A. Seal II, O.S. Ojo, D. Gout et al.
Tetrahedron Letters xxx (xxxx) xxx
Table 1 (continued)
Entry
10
Substrate
Thio acida
BzSH
Product (%)
Product (%)
3d
12d (54)
X-ray structure of compound 12d
11
12
BzSH
10a (62)
8a
BzSHb
3e
13e (57)
aReactions were conducted with 2 equiv. of thio acid, 2 equiv. of 2,6-lutidine in MeOH (0.26 M) at room temperature unless indicated otherwise.
bNo 2,6-lutidine was used in this case.
present manuscript, we report the application of this chemistry to
2-azido tetrahydrobenzimidazoles 3 ? 5 and the corresponding 2-
azido spiroimidazolone derivatives 4 ? 6 (Table 1).
The substrates were readily prepared from benzimidazole by
partial hydrogenation and N-substitution [22,23]. Four different
protecting groups were evaluated that provided options for subse-
quent deprotection and in three cases increase the acidity of the
C2-position, facilitating introduction of the azide. Accordingly,
each of the protected tetrahydobenzimidazoles was treated with
n-BuLi and then reacted with tosyl azide [24] providing 2-azidoim-
idazoles in good yields (Scheme 1) [22,23]. Oxidative rearrange-
ment
of
these
N-substituted
intermediates
with
dimethyldioxirane (DMDO), with the exception of the DMAS-pro-
tected derivative, affords the corresponding imidazolones in good
yields [22,23]. One interesting observation that was overlooked
in our initial report of 4a [25], was that it exists as the tetrazole
valence tautomer rather than the azido form [26,27]. This was evi-
dent in the IR data where the stretching frequency corresponding
to the azide was absent and a subsequent X-ray structure of 8a
clearly
shows
the
bicyclic
imidazolotetrazole
system
(Scheme 1b). Closer examination of the spectroscopic data of the
other imidazolones revealed they too were isolated as the tetrazole
tautomer [28–33]. One additional substrate was prepared from the
DMAS-protected derivative on methanolysis with acidic methanol
delivered the parent 2-azido derivative 3e [17,34–35].
With the five azides 3a-e in hand, their reactivity with thioace-
tic acid in methanol with 2,6-lutidine as base was evaluated
[17,20,21]. Each of the substrates delivered the corresponding
amide 9a-e in moderate yield, although no attempt was made to
optimize these yields. Two derivatives were subjected to X-ray
crystallography which clearly revealed the formation of the aceta-
mide. This transformation affords a chemoselective approach to
the preparation of 2-amido imidazole derivatives [36]. Surpris-
ingly, and in contrast to the tetrahydrobenzimidazoles, the spiro
2-azidoimidazolones 4a-c undergo reaction with thio acetic acid
to afford the 2-thiohydantoin derivatives. This was confirmed both
through mass spectrometry and through an X-ray crystal structure
of the Bn-protected congener. In addition to the thiones 10a-c,
small quantities of the expected amide were obtained in the case
of 11c. Several substrates were reacted with thio benzoic acid,
including a tetrazole. In the cases of the tetrahydrobenzimidazoles
the corresponding benzamides 12c-d were obtained. The spiroim-
idazolones again delivered the thiohydantoin derivatives.
Scheme 1. (a) Preparation 2-azide substrates. (b) X-ray crystal structure of
tetrazole 8a.
3

L.A. Seal II, O.S. Ojo, D. Gout et al.
Tetrahedron Letters xxx (xxxx) xxx
acknowledge the Texas Advanced Computing Center (TACC) at The
University of Texas at Austin. for providing resources that have
contributed to the research results reported within this paper.
URL: http://www.tacc.utexas.edu.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2020.152484.
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