Microwave assisted synthesis of triazolobenzoxazepine and triazolobenzoxazocine heterocycles

Article abstract of DOI:10.1016/j.tetlet.2013.08.065

Intramolecular click chemistry was utilized to effect synthesis of the benzofused, triazole ring systems. The trimethylsilyl group was found to impede the reaction progress, and therefore, conditions employing in situ removal of the TMS group coupled with

Full text of DOI:10.1016/j.tetlet.2013.08.065

Accepted Manuscript
Microwave Assisted Synthesis of Triazolobenzoxazepine and Triazolobenzox‐
azocine Heterocycles
Aubrey Ellison, Robert Boyer, Paul Hoogestraat, Michael Bell
PII:
S0040-4039(13)01438-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.08.065
TETL 43428
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
22 July 2013
15 August 2013
19 August 2013
Please cite this article as: Ellison, A., Boyer, R., Hoogestraat, P., Bell, M., Microwave Assisted Synthesis of
Triazolobenzoxazepine and Triazolobenzoxazocine Heterocycles, Tetrahedron Letters (2013), doi: http://
dx.doi.org/10.1016/j.tetlet.2013.08.065
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Microwave Assisted Synthesis of Triazolobenzoxazepine and
Triazolobenzoxazocine Heterocycles
Aubrey Ellisonb, Robert Boyera, Paul Hoogestraata and Michael Bella*
aDiscovery Chemistry Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285.
bAubrey Ellison, Department of Chemistry, University of Wisconsin, Madison, WI 53706
Abstract - Intramolecular click chemistry was utilized to effect synthesis of the benzofused, triazole ring systems.
The trimethylsilyl group was found to impede the reaction progress, and therefore, conditions employing in situ
removal of the TMS group coupled with microwave irradiation gives the penultimate targets with good conversion.
The synthesis of 1,2,3-triazole ring systems represents an interesting
study in structural diversity.[1] The widespread application of a 1,3
dipolar cycloaddition with readily prepared substituted azides and
alkynes offers a broad spectrum of triazole species containing
unique structural elements.[2] The relatively straightforward
chemistries applied to synthesize these analogs cement the triazole
2
1
motif as a key heterocycle in the medicinal chemists’ aresenal.
Although general in nature, the subtleties of this complex annulation
are significant and often require fine tuning synthetic conditions in
order to achieve the desired regiochemical control. To this end, a
number of authors have published papers describing the highly
refined nature of a given set of conditions applied to ensure the most
desirable outcome. The directed synthesis of 1,5-triazoles can be
achieved through the use of silicon as a directing group,[5] or
inclusion of ruthenium complexes.[11] The corresponding 1,4-
isomer can usually be obtained with the addition of copper (I)
iodide.[7] In many cases, nearly absolute regiochemical control can
be obtained. The 1,2,3-triazole ring has established biologically
relevant activity in a number of areas. Of recent interest include
cardiovascular diseases,[1f] anti-HIV,[1e] and anti-bacterial
agents,[1a,d] to name only a few. Given the ease of intermediate
synthesis, the high degree of structural flexibility, and the biological
importance of these molecules, investigative studies into the
mechanistic understanding of different synthetic approaches offers a
field worthy of exploration.
Over the course of the last decade, a number of benzofused
heterocyclic systems have been targeted.[3,6] Interestingly, very few
have broached the issue of a 1,3 dipolar cycloaddition to afford
seven and eight membered fused triazole systems. Of note is the
work by Alajarin et al in the synthesis of triazolobenzodiazepines,[6]
where utilization of a novel triphenylphosphorane affords a number
of N-phenyl triazole systems. Of particular interest to our group
was the work of Chowdhury et al, in which a one pot synthesis of
isoindolotriazoles is described,[3] and sufficient utility is
Figure 1. Triazolobenzoxazepine 1 and triazolobenzoxazocine 2.
Initial scanning of the literature revealed the previously
mentioned Chowdhury paper, and their convenient one pot synthesis
of isoindolotriazoles. A number of structural analogs were prepared
highlighting the utility of the reaction, noting minimal impact of
substituting the alkyne on the overall yield. Further analysis of the
proposed mechanism suggested that application to larger ring
synthesis, while favourable according to Baldwin’s rules, may not
be quite as straightforward. In our hands, application of this route
according to Scheme 1 provided 1 and 2, in very low yield (12% and
10% yields, respectively). In this particular set of conditions,
several aspects were hypothesized to conspire against a successful
reaction. First, inherent entropic cost in preparing seven and eight
membered rings cannot be discounted. Second, silicon containing
alkynes, although directing to the 1,5 regioisomer, may decrease
reaction rates not observed in the isoindolotriazole system. It is
quite plausible that the activation energies required for the 1,3-
dipolarcycloaddition with the silyl group intact, were sufficiently
high as to impede the reaction. And third, the presence of even
residual amounts of copper (I) iodide should actually retard the
overall rate, as the reaction strives to deliver the preferred 1,4
regioisomer under those conditions.
Pd(PPh3)2Cl2
CuI, Et3N
( )n
( )n
demonstrated.
However, the specific targeting of the
triazolobenzoxazepine and triazolobenzoxazocine systems have yet
to be described. Herein, we report the successful synthesis and
characterization of both fused, tricyclic ring systems 1 and 2, shown
in Figure 1.
DMF
115°C
n = 0, 12% yield
n = 1, 10% yield
Keywords: click chemistry, 1,3-dipolar cycloaddition, microwave,
triazole.
Scheme 1. Penultimate step of the literature inspired synthesis of 1
and 2.
*Corresponding author. Tel.: (317) 276-4726;
E-mail address: bell_michael_g@lilly.com
1

Contrary to synthesis of the isoindolotriazoles, in which CuI was
required for appreciable yields, our lab sought to investigate dipolar
click chemistry in order to obtain the targets in the absence of any
additives. To this end, both benzofused triazole structures 1 and 2
above were prepared in good overall yield as shown in Scheme 2.
alone. It is important to note, that in every case, there was a mixture
of starting material, product, and then predominantly baseline
material, possibly polymerization due to intermolecular reactions.
Even after exhaustive analysis of crude mixtures, no other side
products or minor components could be identified. Finally,
additions of cesium fluoride and DMF (to aid solubility) showed
rapid removal of the TMS group within four hours. Because
conversion from the desilylated alkyne 6 to each product was
already demonstrated, we set out to combine all of these learnings
into one optimized set of conditions. Therefore, from the advanced
intermediate 8, cesium fluoride was used to effect an in situ
desilylation. DMF was choosen to enhance solubility of cesium
fluoride, but also is a suitable solvent for the extreme temperatures
of microwave chemistry. Microwave irradiation was desirable to
achieve high temperatures in a very short timeframe. Gratifyingly,
all of these when taken together in a two-step, one pot reaction,
provided excellent conversion to the respective products in thirty
minutes.
From
the
commercially
available
2-iodophenol,
the
trimethylsilylacetylene phenol 3 can be prepared according to
literature methods.[9] The subsequent alkylation with either the
chloroethanol or chloropropanol is accompanied with desilylation to
give 4. With the alcohol 4 in hand, the mesylate 5 is formed,
followed by azide displacement in very good yield over both steps,
to afford the key intermediate 6.[8] Finally, subjecting the respective
azido-alkynes to thermal click conditions provides the penultimate
targets, 1 and 2 in good overall yields.
( )n
( )n
Cs2CO3
DMF
70°C
28-36% yield
TMS-acetylene
Pd(PPh3)2Cl2
CuI, Et3N
4
3
( )n
( )n
MsCl DCM
TEA
82-95% yield
DMF, r.t.
45-65%
7
8
( )n
( )n
NaN3
DMF
Table 1.
50°C
6
5
76-90% yield
( )n
Toluene
115°C
( )n
1 and 2
59-63% yield
Scheme 3. Optimized synthesis of the triazolobenzoxazepine and
triazolobenzoxazocine systems.
Scheme 2. Complete synthesis of the triazolobenzoxazepine and
triazolobenzoxazocine systems.
Recognizing that the increased flexibility of the seven and eight
membered rings gives rise to the potential for 1,5- and 1,4-
regioisomers, we sought to confirm the desired isomer through
The question remains as to why application of the one pot
synthesis described by the Chowdhury group was not successful
NMR experiments (Figure 2).
First, looking at the
triazolobenzoxazocine systems, 13C, 1H NMR, and heteronuclear
single quantum coherence (HSQC) experiments allowed for a
reasonable identification of the key signals at C2 and H10. Next,
heteronuclear multiple bond correlation (gHMBC) studies showed a
long range correlation between C2 and H10 which further supported
the 1,5-isomer 9. This data was consistent for both ring systems,
providing the necessary support for the given assignment.
when
applied
to
the
triazolobenzoxazepine
and
triazolobenzoxazocine systems. Based on the yield of the dipolar
cycloadditions to deliver 1 and 2, simple entropic cost arguments
can be discounted. Both reactions occurred in greater than 60%
yields. This places the emphasis on either the silicon group or one
or more reagents needed for the Sonagoshira coupling. In order to
more fully assess this, the silicon containing azido alkynes 8 were
prepared and a number of test reactions ensued as shown in Scheme
3. The advanced intermediate 7 was prepared in an analogous
manner to 6, simply starting with the 2-iodophenol in place of
compound 3, in excellent overall yield. Therefore according to
Table 1, the data firmly points to the silicon group as the culprit.
Whereas the cycloaddition works well in the absence of the TMS
protecting group, inclusion of this motif retards the reaction to less
than 20% conversion, demonstrating a significant reduction from
59-63% yield as shown in Scheme 2. Neither addition of CuI, nor
the ruthenium catalyst improved the conversion compared to solvent
10
Figure 2. NMR experiments to confirm the 1,5-regioisomer.
9
2

In conclusion, we have successfully applied standard Huisgen
1,3-dipolar cycloaddition conditions to the synthesis of the
triazolobenzoxazepine and triazolobenzoxazocine ring systems.
Attempts to utilize the chemistry developed for the synthesis of the
isoindolotriazole rings gave low yields and therefore a re-evaluation
of the standard was employed to good success. Investigation into
the reaction conditions revealed the trimethylsilyl group to be a rate
limiting culprit. Interestingly, although the use of silicon as a
directing group normally favors the desired 1,5 regioisomer, in the
case of these two analogs, the reaction simply failed to progress in a
reasonable timeframe. Further investigation into the reaction
conditions demonstrated that in situ deprotection and subsequent
cyclization could be achieved with cesium fluoride in DMF, and
microwave heating, all within thirty minutes. NMR characterization
confirmed formation of the assigned 1,5-isomers completing the
first published synthesis of the triazolobenzoxazepine and
triazolobenzoxazocine systems.
[5] S. Coats, J. Link, D. Gauthier, and D. Hlasta, Organic Letters,
2005, 7, 1469-1472.
[6] M. Alajarin, J. Cabrera, A. Pastor, J. M. Villalgordo,
Tetrahedron. Lett., 2007, 3495-3499.
[7] V. Rostovtsev, L. Green, V. Fokin, K. B. Sharpless, Angew.
Chem. Int. Ed. 2002, 41, p. 2596-2599.
[8] H. Yamakoshi, N. Kanoh, C. Kudo, A. Sato, K. Ueda, M.
Muroi, S. Kon, M. Satake, H. Ohori, C. Ishioka, Y. Oshima,
H. Osada, N. Chiba, H. Shibata, and Y. Iwabuchi, ACS Med.
Chem. Lett., 2010, 1, 273-276.
[9] M. Khan, M. Alam, M. Rashid, R. Chowdhury, Bioorg. Med.
Chem. 2005, 13, 4796-4805.
[10] B. C. Boren, S. Narayan, L. K. Rasmussen, L. Zhang, H.
Zhao, Z. Lin, G. Jia, V. V. Fokin, J. Am. Chem. Soc., 2008,
130, 8923-8930.
[11] B. C. Boren, S. Narayan, L. K. Rasmussen, L. Zhang, H.
Zhao, Z. Lin, G. Jia, V. V. Fokin, J. Am. Chem. Soc., 2008,
130, 8923-893.
Table 1. Various reaction conditions optimizing 8 to 1 and 2.
Ring
System
(n)
Solvent
Additive
Temp
(oC)
LCMS[d]
%
Conversion
0
1
0
0
1
1
0
0
0
1
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene/DMF
DMF
---
---
115
115
100
100
115
115
100
100
180
180 [c]
23%
19%
20%
30%
21%
17%
0%
CuI
Ru[a]
CuI
Ru[a]
CsF
CsF
CsF
CsF
100%[b]
61%
87%
DMF
[a] Chloro(cyclopentadienyl)bis(triphenylphosphine)ruthenium (II)
[b] Complete conversion to desilylated intermediate with less 10%
product after 4 hours. [c] microwave irradiation, 30 minutes. [d]
Liquid chromatography – mass spectroscopy.
[1] a) M. J. Genin, D. A. Allwine, D. J. Anderson, M. R.
Barbachyn, D. E. Emmert, S. A. Garmon, D. R. Graber, K. C.
Grega, J. B. Hester, D. K. Hutchinson, J. Morris, R. J.
Reischer, C. W. Ford, G. E. Zurenko, J. C. Hamel, R. D.
Schaadt, D. Stapert, and B. H. Yagi J. Med. Chem. ,2000 , 43,
953; b) A. K. Mandadapu, S. K. Sharma, S. Gupta, D. G. V.
Krishna, and B. Kundu. Org. Lett. 2011, 13 (12), 3162–3165;
c) F. Suzuki, T. Kuroda, T. Kawakita, H. Manabe, S.
Kitamura, K. Ohmori, M. Ichimura, H. Kase, S. Ichikawa J.
Med. Chem. 1992, 35 (26), 4866–4874; d) M. Yamada, S.
Hamamoto, K. Hayashi, K. Takaoka, H. Matsukura, M.
Yotsuji, K. Yonezawa, K. Ojima, T. Takamatsu, K. Taya, H.
Yamamoto, T. Kiyoto, H. Kotsubo, PCT Int. Appl., WO
9921849, 1999; e) R. Alvarez, S. Velazquez, F. San, S.
Aquaro, C. De-Clercq, C. Perno, A. Karlsson, J. Balzarini, M.
J. Camarasa, J. Med. Chem. 1994, 37, 4185–4194; f) M. G.
Bell, R. A. Doti, M. S. Dowling, M. J. Genin, P. A. Lander, T.
Ma, N. B. Mantlo, J. M. Ochoada, L. S. Stelzer, R. E. Stites,
A. M. Warshawsky, US 8106077, 2012.
[2] a) R. Huisgen, Pure Appl. Chem., 1989, 61, 613; b) R.
Huisgen, In 1,3-Dipolar Cycloaddition chemistry, A. Padwa,
Ed., Wiley, New York, NY, 1984, pp. 1-176.
[3] C. Chowdhury, S. Mandal, B. Achari, Tetrahedron Lett., 2005,
46, 8531-8534.
[4] Yamakoshi et al, ACS Med. Chem. Lett., 2010 , 1, 273-276.
3

MW, 180oC
( )n
( )n
30 minutes
CsF/DMF
61-87%
1: Triazolobenzoxazepine, n = 0
2: Triazolobenzoxazocine, n = 1