Dearomatizing spirocyclization of thioureas, ureas and guanidines

Article abstract of DOI:10.1016/j.tetlet.2021.153054

An investigation of the dearomatization reactions of benzylic thioureas, ureas and guanidines using hypervalent iodine reagents is described. Initial attempts to perform this reaction with methyl aryl ethers was compromised by electrophilic addition leadi

Full text of DOI:10.1016/j.tetlet.2021.153054

Tetrahedron Letters 72 (2021) 153054
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Dearomatizing spirocyclization of thioureas, ureas and guanidines
Marian N. Aziz a,b, Ravi P. Singh a, Delphine Gout a, Carl J. Lovely a,
⇑
a Department of Chemistry and Biochemistry, 700 Planetarium Place, University of Texas at Arlington, TX 76019, USA
b Department of Pesticide Chemistry, National Research Centre, Dokki, Giza 12622, Egypt
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 dearomatization reactions of benzylic thioureas, ureas and guanidines using
hypervalent iodine reagents is described. Initial attempts to perform this reaction with methyl aryl ethers
was compromised by electrophilic addition leading to the formation of benzo[d]thiazoles. However,
inverting the direction of the process and oxidizing the corresponding phenol delivered the desired spiro
fused heterocycles in moderate to good yields for all three families.
Received 3 March 2021
Revised 19 March 2021
Accepted 30 March 2021
Available online 6 April 2021
Ó 2021 Elsevier Ltd. All rights reserved.
Keywords:
Benzyl guanidine
Benzyl thiourea
Benzyl urea
Oxidative dearomatization
Cyclohexadienones
Dearomatization has emerged as a powerful strategy for the
construction of highly functionalized frameworks which are
primed for further elaboration [1–4]. In particular, oxidative meth-
ods to effect dearomatization have attracted significant attention;
typically this involves the reaction of a phenol with a hypervalent
iodine reagent followed by nucleophilic trapping thus generating a
4,4-disubstituted cyclohexadienone [1–3]. Most frequently amides,
carboxylic acids, and alcohols have served as the trap, although
alkynes [5,6] and alkenes [7] can also be used (Fig. 1a). When this
reaction is conducted intramolecularly it gives rise to spiro fused
derivatives. In connection with an approach to the Leucetta derived
alkaloids [8], spirocalcaridines A (1) and B (2) [9], we have reported
a
tandem oxidative amination dearomatizing spirocyclization
(TOADS) reaction of propargyl guanidines that leads directly to
the complete framework of the natural products [10–12]. The use
of alkynes had been reported previously in dearomatization reac-
tions, but we were unaware of guanidines (or (thio)ureas) [13] par-
ticipating in simple dearomatization reactions when we
commenced this investigation [14]. Further, cyclic guanidines are
prevalent structural motifs in marine derived natural products
[15] and there are numerous examples of spiro fused systems
[16–18]. One particularly attractive target, KB343 (3), contains
two spiro fused guanidines that may be accessible by such a dearo-
matizing spirocyclization [19].
In our prior report, we employed propargyl guanidine and urea
derivatives containing a p-methoxybenzene moiety and proposed
Fig. 1. Dearomatization reactions.
⇑
Corresponding author.
E-mail address: lovely@uta.edu (C.J. Lovely).
https://doi.org/10.1016/j.tetlet.2021.153054
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.

M.N. Aziz, R.P. Singh, D. Gout et al.
Tetrahedron Letters 72 (2021) 153054
Scheme 1. Preliminary dearomatization experiments. Reagents and conditions
(a) = IBDA (1 equiv), Cs2CO3 (1.2 equiv), HFIP; (b) = IBDA (2 equiv), Cs2CO3 (1.2
equiv), HFIP.
that a nitrenium equivalent triggered the cascade process [12]. In
addition, we had found in this earlier investigation that propargyl
thioureas were prone to hydrothiolation [20,21] and did not partic-
ipate in the TOADS chemistry; [12] thus our proposed study would
permit us to establish the utility of thioureas in dearomatization
processes. The investigation was initiated by examining
p-methoxybenzyl derivatives. Accordingly, N-methyl p-methoxy-
benzylamine was treated with phenylisothiocyanate to afford the
corresponding thiourea 4 (see ESI for details). The substrate was
then treated with iodosobenzene diacetate (IBDA) under reaction
conditions (Cs2CO3, hexafluoroisopropanol (HFIP)) previously
utilized in TOADS chemistry. However, the desired dearomatized
product was not obtained but rather benzothiazole 5 was formed
Fig. 2. (a) X-ray crystal structures of compounds 16a and 17a. (b) Additional
products from the dearomatizing spirocyclization of phenolic thioureas.
via electrophilic aromatic substitution in 47% yield (Scheme 1a)
[22,23]. Increasing the oxidant equivalents did not improve the
yield but resulted in the formation of acetoxylation product 6
(see ESI for X-ray crystal structure) in addition to benzothiazole
5 (Scheme 1a). Presumably, this outcome is the result of activation
Table 1
Initial screening experiments.
Entry
Oxidant
Base
Solvent
Yield 16a (%)
1
2
3
4
5
6
7
8
IBDA
IBDA
IBDA
IBDA
IBDA
IBDA
IBDA
IBDA
IBDA
IBDA
PIFA
PhI(OTs)OH
Cs2CO3
Cs2CO3
Cs2CO3
NMM
NMM
NMM
NaHCO3
NaHCO3
NaHCO3
No base
No base
No base
HFIP
43b,c
8b
CH2Cl2
MeCN
HFIP
CH2Cl2
MeCN
HFIP
CH2Cl2
MeCN
HFIP
36b
34b
ND
6b
34b
10b
11b
44c
10c
ND
9
10
11
12
HFIP
HFIP
aReagents and conditions: 15a (0.1 mmol), IBDA for entries 1–10 (0.1 mmol), for entries 11–12 (0.15 mmol), HFIP (7 mL), rt, 2 h.
bThe yield of 16a was determined by NMR spectroscopy using dibromomethane (1 equiv) as an internal reference.
cIsolated yield after chromatography
2

M.N. Aziz, R.P. Singh, D. Gout et al.
Tetrahedron Letters 72 (2021) 153054
Table 2
Oxidative dearomatization of benzyl thioureas.
Entry
Substrate
Product
Yield (%)
Product
Yield (%)
1
2
3
4
15aa
15ab
15ac
16a
16a
16a
44
55
10
17a
17a
17a
0
15
31
60
15bb
16b
16c
16d
5
6
7
47
15cb
68
15db
80
15eb
16e
aIBDA (1.0 equiv), HFIP, rt. b. IBDA (1.5 equiv), HFIP, rt. c. IBDA (2.0 equiv), HFIP, rt.
of the sulfur of the thiourea via 7 which can then undergo elec-
trophilic aromatic substitution to afford 5 or alternatively addition
of acetate followed by rearomatization to afford 8 (Scheme 1a)
[24]. The acetyloxylated derivative undergoes a second oxidation
at sulfur to trigger the formation of the thiazole. To circumvent this
possibility, a thiourea derivative was prepared in which elec-
trophilic substitution was less likely (Scheme 1b). Specifically, a
deactivated aromatic was employed and, in this case, a spiro fused
product was obtained, but interestingly it was the cyclic urea 13
(confirmed by an X-ray crystal structure, see Scheme 1b) rather
than the expected thiourea or thiazole. Presumably, oxidation of
thiourea 10 to urea 14 precedes oxidative dearomatization. A con-
trol reaction with the corresponding urea derivative 14 confirmed
that it was at least a competent substrate. In addition to the urea,
two further products were obtained from the oxidation of 10
including benzothiazole 11 and isothio urea 12 (see ESI for X-ray
crystal structure) [25].
Given that oxidation to form nitrenium-like intermediates was
compromised by addition to the N-aryl substituent we considered
changing the role of the thiourea to serving as a nucleophilic trap
and oxidizing the phenol, essentially employing an umpolung tac-
tic. Accordingly, the corresponding phenol derivative 15a was con-
structed and subjected to attempted oxidative dearomatization
with IBDA and Cs2CO3 in HFIP [12]. We were gratified to observe
that the dearomatization occurred in moderate yield (Table 1,
entry 1).
3

M.N. Aziz, R.P. Singh, D. Gout et al.
Tetrahedron Letters 72 (2021) 153054
Table 3
Oxidative dearomatization of benzyl ureas.
Entry
1
Substrate
Producta
Yield (%)
36
22a
21a
2
16
21b
22bb
3
56
21c
22c
4
37
21d
23d
5
95
21e
23e
a. IBDA (1.0 equiv), Cs2CO3 (1.2 equiv), HFIP, rt. b. An additional 0.2 equiv of IBDA was added after 5 h.
Optimization of the reaction was conducted by investigating
inorganic bases (Cs2CO3, NaHCO3), an organic base (N-methylmor-
pholine = NMM) and different solvents (Table 1, entries 1–9). The
influence of reaction solvents mirrored that observed in TOADS
chemistry; [12] broadly speaking, reactions conducted in HFIP pro-
vided better yields than dichloromethane or acetonitrile (Table 1,
entries 2–3). Out of the three bases evaluated, Cs2CO3 delivered
the best yields, but ultimately it was determined that base was
not required (Table 1, entry 10). Under these conditions, the
desired spiro thiazoline 16a (for X-ray crystal structure, see
Fig. 2a) was obtained in 44% isolated yield (Table 2, entry 1) along
with small amounts of benzothiazole 18 (for X-ray crystal struc-
ture, see ESI) and thioimidazoline 19 (Fig. 2b). Upon increasing
the oxidant to 1.5 equivalents 16a was obtained in 55% yield
(Table 2, entry 2), along with small amounts of the 4-acetoxy
adduct 17 (for X-ray crystal structure, see Fig. 2a). When the reac-
tion was conducted with 2 equivalents of IBDA, the spiro 4-ace-
toxylated product 17 was now isolated as the major product
4

M.N. Aziz, R.P. Singh, D. Gout et al.
Tetrahedron Letters 72 (2021) 153054
Table 4
Dearomatization of benzyl guanidines.a.
Entry
1
Substrate
Producta
Yield (%)
25
25
24
25
24
2
15
27
26
27
26
3
9
29
28
29
28
aIBDA (1.0 equiv), Cs2CO3 (1.2 equiv), HFIP, rt.
20 (for X-ray crystal structure, see Fig. 2) rather than the desired
spiro derivative.
With this generally positive outcome, the corresponding urea
derivatives 21a-e were prepared (see ESI) and evaluated. In this
case, however, the reactions proceeded better in the presence of
Cs2CO3. All five derivatives produced spiro fused cyclohexa-
dienones 22a-c, 23d-e but interestingly, they did not all cyclize
to form the same heterocycle. Ureas 21a-c with electron-rich aryl
groups provided the corresponding imidazolones 22a-c (Table 3,
entries 1–3) whereas those with electron-poor aryl groups 21d-e
cyclized via the oxygen affording oxazolines 23d-e (Table 3, entries
4–5). Connectivities were established either through X-ray crystal-
lography (22c and 23e) or by comparison of the 13C NMR chemical
shifts of the spiro carbon (dC = 59 ppm (imidazolone) vs dC = 75
ppm (oxazole)).
Fig. 3. Unsuccessful guanidine substrates.
As noted in the introduction, the primary motivation for this
study was to apply the chemistry towards the total synthesis of
spiroguanidines such KB434 (3) and thus we examined the possi-
bility of using guanidines in this reaction. It was found that the
N-methyl bis Boc guanidine 24 underwent dearomatization to
afford spirocyclic derivative 25 (Table 4, entry 1) in modest yield
(confirmed by X-ray crystallography). Interestingly, the corre-
sponding NH derivative 26 also provided the desired spirocyclic
derivative 27 in low yield (Table 4, entry 2). Three other derivatives
were evaluated, the Teoc-protected congener 28 (Table 4, entry 3),
the mono Cbz adduct 30 and the anisole precursor 31 (Fig. 3). Teoc
derivative 28 afforded spirocyclic product 29 but it underwent
mono deprotection whereas the other two substrates did not
afford the spirocyclic derivatives but rather complex reaction
mixtures.
Scheme 2. Putative mechanism for the dearomatization.
(Table 2, entry 3). Extension to other thioureas containing various
aryl-substituents using 1.5 equivalents of IBDA delivered the corre-
sponding spiro derivatives in moderate yields (Table 2, entries 4–
7). An attempt to extend the spirocyclization to a thiourea lacking
the N-methyl substituent resulted in the formation of thiadiazole
We assume mechanistically that these dearomatization reac-
tions proceed via the accepted pathway involving reaction of the
5

M.N. Aziz, R.P. Singh, D. Gout et al.
Tetrahedron Letters 72 (2021) 153054
phenolic oxygen via substitution of one of the acetates 32 ? 33 on
the iodine(III) center (Scheme 2). There is some debate whether
ionization to the phenoxonium ion followed by nucleophilic attack
(shown 33 ? 34) or a concerted process ensues [26–29] whichever
sequence is followed, the spirocyclic derivative is formed by
intramolecular nucleophilic attack and proton transfer [30]. One
observation that requires further comment is the divergent activity
of ureas which deliver different heterocycles depending on the
electronic character of the urea nitrogen substituent. Presumably,
the nitrogen atom of the urea is rendered more electron rich with
electron donating substituents on the aromatic moiety thus facili-
tating attack by nitrogen and formation of the imidazolone.
Whereas with the electron withdrawing groups deprotonation of
the aniline nitrogen may occur prior to cyclization thus resulting
in negative charge character on oxygen resulting in the formation
of the oxazoline. It is also conceivable in latter case there is a mech-
anistic changeover such that with electron withdrawing sub-
stituents activation of the urea occurs rather than the phenol.
Oxazolines are formed in TOADS chemistry where it is likely that
activation of the urea occurs which may also be operative in the
present case for some substrates [12].
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2021.153054.
References
[1] S.P. Roche, J.A. Porco Jr, Angew. Chem. Int. Ed. 50 (2011) 4068–4093.
[2] S. Quideau, L. Pouysegu, D. Deffieux, Synlett (2008) 467–495.
[3] Q. Ding, Y. Ye, R. Fan, Synthesis (2013) 1–16.
[4] W.C. Wertjes, E.H. Southgate, D. Sarlah, Chem. Soc. Rev. 47 (2018) 7996–8018.
[5] J.-C. Andrez, M.-A. Giroux, J. Lucien, S. Canesi, Org. Lett. 12 (2010) 4368–4371.
[6] A.K. Clarke, J.T.R. Liddon, J.D. Cuthbertson, R.J.K. Taylor, W.P. Unsworth, Org.
Biomol. Chem. 15 (2017) 233–245.
[7] S. Desjardins, J.-C. Andrez, S. Canesi, Org. Lett. 13 (2011) 3406–3409.
[8] P.B. Koswatta, C.J. Lovely, Nat. Prod. Rep. 28 (2011) 511–528.
[9] R.A. Edrada, C.C. Stessman, P. Crews, J. Nat. Prod. 66 (2003) 939–942.
[10] P.B. Koswatta, J. Das, M. Yousufuddin, C.J. Lovely, Eur. J. Org. Chem. (2015),
2603-2013.
[11] R.P. Singh, J.A. Spears, A. Dalipe, M. Yousufuddin, C.J. Lovely, Tetrahedron Lett.
57 (2016) 3096–3099.
[12] R.P. Singh, J. Das, M. Yousufuddin, D. Gout, C.J. Lovely, Org. Lett. 19 (2017)
4110–4113.
[13] W.-S. Guo, H. Gong, Y.A. Zhang, L.-R. Wen, M. Li, Org. Lett. 20 (2018) 6394–
6397.
[14] M. Odagi, K. Okuda, H. Ishizuka, K. Adachi, K. Nagasawa, Asian J. Org. Chem. 9
(2020) 218–221.
[15] A.R. Carroll, B.R. Copp, R.A. Davis, R.A. Keyzers, M.R. Prinsep, Nat. Prod. Rep. 37
(2020) 175–223.
[16] Lindel T Alkaloids 2017; 77: 117-219..
Declaration of Competing Interest
[17] W.SM. Nat, Prod. Rep. 24 (2007) 931–948.
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
[18] Y. Ma, S. De, C. Chen, Tetrahedron 71 (2015) 1145–1173.
[19] K. Matsumura, T. Taniguchi, J.D. Reimer, S. Noguchi, M.J. Fujita, R. Sakai, Org.
Lett. 20 (2018) 3039–3043.
[20] R. Singh, D. Gout, C.J. Lovely, Eur. J. Org. Chem. (2019) 1726–1740.
[21] R.P. Singh, M.N. Aziz, D. Gout, W. Fayad, M.A. El-Manawaty, C.J. Lovely, Bioorg.
Med. Chem. 27 (2019) 115047.
[22] A. Mariappan, K. Rajaguru, S.S. Roja, S. Muthusubramanian, N. Bhuvanesh, Eur.
J. Org. Chem. (2016) 302–307.
Acknowledgements
[23] R.K. Kumar, S. Manna, D. Mahesh, D. Sar, T. Punniyamurthy, Asian J. Org. Chem.
2 (2013) 843–847.
This work has been supported by the Robert A. Welch Founda-
tion (Y-1362), the NSF (CHE-1956328) and by instrumentation
grants from the NSF (CHE-0234811 and CHE-0840509) for the pur-
chase of the NMR spectrometers used in this research. The authors
acknowledge the Texas Advanced Computing Center (TACC) at The
University of Texas at Austin for providing resources that have con-
tributed to the research results reported within this paper. URL:
http://www.tacc.utexas.edu.
[24] H. Ghosh, R. Yella, J. Nath, B.K. Patel, Eur. J. Org. Chem. (2008) 6189–6196.
[25] See SI for a putative mechanism for the formation of compound 12..
[26] T. Tang, A.M. Harned, Org. Biomol. Chem. 16 (2018) 6871–6874.
[27] H.AM. Org, Biomol. Chem. 16 (2018) 2324–2329.
[28] B. Ganji, A. Ariafard, Org. Biomol. Chem. 17 (2019) 3521–3528.
[29] A. Kaur, A. Ariafard, Org. Biomol. Chem. 18 (2020) 1117–1129.
[30] K. Kraszewski, I. Tomczyk, A. Drabinska, K. Bienkowski, R. Solarska, M. Kalek,
Chem. Eur. J. 26 (2020) 11584–11592.
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