Organocatalytic Synthesis of Fused Bicyclic 2,3-Dihydro-1,3,4-oxadiazoles through an Intramolecular Cascade Cyclization

Article abstract of DOI:10.1021/acs.orglett.5b02997

Hydrazone-carboxylic acids undergo intramolecular cyclization in the presence of pivaloyl chloride, iPr₂NEt, and catalytic DABCO to form a range of substituted fused tricyclic 2,3-dihydro-1,3,4-oxadiazoles in high yields.

Full text of DOI:10.1021/acs.orglett.5b02997

Letter
pubs.acs.org/OrgLett
Organocatalytic Synthesis of Fused Bicyclic 2,3-Dihydro-1,3,4-
oxadiazoles through an Intramolecular Cascade Cyclization
Alison J. Fugard, Bethany K. Thompson, Alexandra M. Z. Slawin, James E. Taylor,*
and Andrew D. Smith*
EaStCHEM, School of Chemistry, University of St. Andrews, North Haugh, St. Andrews, KY16 9ST, U.K.
S
* Supporting Information
ABSTRACT: Hydrazone-carboxylic acids undergo intramolecu-
lar cyclization in the presence of pivaloyl chloride, iPr2NEt, and
catalytic DABCO to form a range of substituted fused tricyclic
2,3-dihydro-1,3,4-oxadiazoles in high yields.
Scheme 1. Previous and Current Work
eterocyclic motifs are ubiquitous throughout medicinal
Hand synthetic organic chemistry, with novel methods for
the synthesis of heterocyclic cores under constant develop-
ment.1 The organocatalytic synthesis of functionalized hetero-
cycles from readily available carboxylic acid starting materials
has received widespread attention since the seminal contribu-
tion of Romo and co-workers on the nucleophile-catalyzed
aldol-lactonization reaction.2,3 For example, previous work from
this laboratory has demonstrated that ammonium enolates
generated from the reaction of carboxylic acids and isothiourea-
based organocatalysts are versatile intermediates in a variety of
inter- and intramolecular processes for the syntheses of
heterocycles.4−6
We have previously applied this strategy to the stereo-
selective synthesis of β-lactams 2 through HyperBTM 1
catalyzed intermolecular Mannich addition−lactamization of
homoanhydrides and N-sulfonyl aldimines (Scheme 1a).7
Given the biological and synthetic importance of β-lactam
motifs,8 attempts were made to develop an intramolecular
version of this Mannich-lactamization process for the synthesis
of fused bicyclic β-lactams from bench stable hydrazone-
carboxylic acids such as 3. The envisaged reactivity involves
generation of an ammonium enolate through reaction of an
isothiourea catalyst with an activated carboxylic acid, followed
by intramolecular cyclization onto the pendent hydrazone and
subsequent lactamization.9,10 The reaction of 3 with pivaloyl
chloride (2 equiv) and iPr2NEt (1.5 equiv) in CH2Cl2 to form a
mixed anhydride in situ, followed by addition of catalytic DHPB
4 (10 mol %), showed no formation of the expected bicyclic β
(MAO) B inhibition (7),11d immunosuppressive activity,11f and
antiviral properties (Figure 1).11g Current syntheses of 2,3-
dihydro-1,3,4-oxadiazoles typically rely on the intermolecular
cyclization of hydrazones by heating at reflux in acetic
anhydride, with corresponding methods for intramolecular
cyclization reactions to form fused bicyclic systems largely
unknown.12 Various fused oxazepine derivatives also display
biological activities,13 including the antidepressant Sintamil and
tricyclic compounds such as 8 that showed inhibition against
telomerase.13d Considering the unprecedented nature of the
1
-lactam 5. However, crude H NMR analysis showed complete
consumption of 3 into a single major product isolated in 72%
yield, with further characterization revealing its structure to be a
unique 2,3-dihydro-1,3,4-oxadiazole containing a fused seven-
membered oxazepine ring 6 (Scheme 1b).
Various substituted 2,3-dihydro-1,3,4-oxadiazoles have pre-
viously been shown to possess a range of biological activities
including anticancer,11a,b,e antibacterial,11c monoamine oxidase
Received: October 16, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02997
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 2. Reaction Scope
Figure 1. Examples of a biologically active 2,3-dihydro-1,3,4-oxadiazole
and a fused oxazepine.
intramolecular cascade cyclization of hydrazone 3, further
efforts explored the utility of this process.
First, a catalyst screen was performed on the cyclization of
hydrazone 3 into 2,3-dihydro-1,3,4-oxadiazole 6 (Table 1). The
a
Table 1. Catalyst Screen
b
entry
Lewis base
mol %
yield (%)
c
1
2
3
4
5
6
7
−
−
46
DMAP, 9
10
10
10
10
5
39
24
53
DHPB, 4
a
Reaction performed at 40 °C using 20 mol % 11.
TBD, 10
c
DABCO, 11
DABCO, 11
DABCO, 11
DABCO, 11
97
89
60
well, forming 2,3-dihydro-1,3,4-oxadiazole 16 in 84% yield. The
presence of a 10-Br substituent required an elevated temper-
ature of 40 °C and a higher catalyst loading to form product 17
in 54% yield. A slight reduction in reactivity was also observed
with the introduction of an 8-Br substituent, but product 18
could still be isolated in 58% yield after 1 h at room
temperature.
1
d
c
8
10
70
a
b
Reactions performed on a 0.25 mmol scale. Determined by 1H
c
NMR using 1,4-dinitrophenol as an internal standard. Isolated yield.
d
Reaction performed on a 3.75 mmol (1.12 g of 3) scale.
reaction occurs in the presence of only pivaloyl chloride (2
equiv) and iPr2NEt (1.5 equiv) with the addition of Lewis bases
such as DMAP 9, DHPB 4, and TBD 10 having little effect on
the yield (Table 1, entries 1−4).14,15
However, adding DABCO 11 (10 mol %) significantly
increased the rate of reaction, allowing 6 to be isolated in 97%
yield after only 30 min at room temperature (Table 1, entry 5).
The yield of 6 reduced in line with decreased catalyst loadings
(Table 1, entries 6 and 7). The reaction could be performed on
a preparative scale (3.75 mmol of 3), forming 737 mg of 6
(70%) under the optimized reaction conditions (Table 1, entry
8).
The scope of this process was then explored through
incorporation of substituents within the benzenoid ring. A
range of substituted hydrazones was synthesized in three steps
from the corresponding salicylaldehyde derivatives and treated
under the previously optimized reaction conditions (Table 2).16
Electron-donating Me− and MeO− groups were tolerated in
various positions around the ring, forming products 12−15 in
excellent yield. Incorporation of a 9-Cl substituent also worked
Next, the scope and limitations with regard to the hydrazone
substituent were examined (Table 3). Both electron-donating
and electron-withdrawing substituents were well tolerated,
forming 2,3-dihydro-1,3,4-oxadiazoles 19−21 in high yields.
Introduction of halogen substituents generally led to reduced
reactivity, for example 2′-F-22 was formed in 52% yield while
elevated temperatures were required to form 4′-Cl-23 and 4′-
Br-24 in 64% and 23% yield, respectively. Notably, the
cyclization of hydrazones bearing halogen substituents did
not proceed at all in the absence of DABCO 11, even after
extended reaction times. Heteroaromatic 2-furyl and 3-pyridyl
substitution was also possible, forming functionalized products
25 and 26 in good yields, respectively. The cyclization did not
proceed as smoothly in the presence of an NH-indole
substituent, forming 27 in only low 33% yield. Alkyl-substituted
hydrazones could be utilized, forming cyclized products 28 and
29 albeit in slightly reduced yields. Alkenyl substitution was not
possible under the previously optimized reaction conditions,
with only a trace amount of a cinnamyl substituted product
formed even at higher temperatures.16 The extent to which the
B
DOI: 10.1021/acs.orglett.5b02997
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
through synthesis of a carbon analogue (X = CH2). However,
reaction under the previously optimized conditions led to only
a trace amount of product 30, indicating that the oxygen atom
is essential for this process.
Table 3. Reaction Scope
Single-crystal X-ray analysis of 2,3-dihydro-1,3,4-oxadiazole
20 confirmed the structural assignment and revealed the
conformation of the fused-tricyclic products in the solid state
(Figure 2).17 A particularly striking feature is the angle of
113.84° (C11−O12−C13) between the plane of the benzenoid
ring and the fused seven-membered oxazepanone ring.
Figure 2. Representation of the single-crystal X-ray structure of 2,3-
dihydro-1,3,4-oxadiazole 20.
The proposed mechanism begins with acylation of carboxylic
acid 3 using pivaloyl chloride and iPr2NEt to form mixed
anhydride 31 (Scheme 2). Intramolecular cyclization of the
Scheme 2. Proposed Mechanism
hydrazone onto the mixed anhydride forms oxazepinium
intermediate 32, which undergoes a second intramolecular
cyclization to form 2,3-dihydro-1,3,4-oxadiazole 6. As the
phenolic oxygen atom is essential for the reaction to proceed, it
is possible that conjugation of the oxygen atom in 32 is
necessary to allow the second cyclization to occur. The
mechanism by which catalytic DABCO 11 significantly
accelerates the rate of this process is unclear. One possibility
is that the DABCO 11 undergoes N-acylation through reaction
with mixed anhydride 31 to form an activated N-acyl
ammonium that is more susceptible to cyclization. However,
more traditional N-acylating agents such as DMAP 9 and
DHPB 4 did not accelerate this process (see Table 1).
Therefore, an alternative possibility is that DABCO 11 acts as a
proton-transfer agent and helps to promote the cyclization of
32 into 6.
a
b
Reaction performed at 40 °C. 20 mol % 11.
In conclusion, hydrazone-acid starting materials underwent
efficient intramolecular cyclization in the presence of catalytic
DABCO 11 to form oxazepine fused 2,3-dihydro-1,3,4-
phenolic linker within the hydrazone aids the cyclization to
form the 2,3-dihydro-1,3,4-oxadiazole ring was investigated
C
DOI: 10.1021/acs.orglett.5b02997
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(9) For a review on β-lactam synthesis through ester enolate−imine
cyclization reactions, see: Hart, D. J.; Ha, D. C. Chem. Rev. 1989, 89,
1447−1465.
(10) For an example of an intramolecular ester enolate−imine
cyclization reaction, see: Evans, C. D.; Mahon, M. F.; Andrews, P. C.;
Muir, J.; Bull, S. D. Org. Lett. 2011, 13, 6276−6279.
oxadiazoles. A wide range of substituents was tolerated on both
the benzenoid ring and the hydrazone moiety, forming the
functionalized fused tricyclic products in high yields under mild
reaction conditions.
ASSOCIATED CONTENT
(11) For selected examples, see: (a) Jin, L.; Chen, J.; Song, B.; Chen,
Z.; Yang, S.; Li, Q.; Hu, D.; Xu, R. Bioorg. Med. Chem. Lett. 2006, 16,
5036−5040. (b) Lee, L.; Robb, L. M.; Lee, M.; Davis, R.; Mackay, H.;
Chavda, S.; Babu, B.; O’Brien, E. L.; Risinger, A. L.; Mooberry, S. L.;
Lee, M. J. Med. Chem. 2010, 53, 325−334. (c) Ishii, M.; Jorge, S. D.; de
Oliveira, A. A.; Palace-Berl, F.; Sonehara, I. Y.; Pasqualoto, K. F. M.;
Tavares, L. C. Bioorg. Med. Chem. 2011, 19, 6292−6301. (d) Maccioni,
E.; Alcaro, S.; Cirilli, R.; Vigo, S.; Cardia, M. C.; Sanna, M. L.;
Meleddu, R.; Yanez, M.; Costa, G.; Casu, L.; Matyus, P.; Distinto, S. J.
Med. Chem. 2011, 54, 6394−6398. (e) Hu, Y.; Lu, X.; Chen, K.; Yan,
R.; Li, Q.-S.; Zhu, H.-L. Bioorg. Med. Chem. 2012, 20, 903−909.
(f) Yan, R.; Zhang, Z.-M.; Fang, X.-Y.; Hu, Y.; Zhu, H.-L. Bioorg. Med.
Chem. 2012, 20, 1373−1379. (g) Grishko, V. V.; Tolmacheva, I. A.;
Galaiko, N. V.; Pereslavceva, A. V.; Anikina, L. V.; Volkova, L. V.;
Bachmetyev, B. A.; Slepukhin, P. A. Eur. J. Med. Chem. 2013, 68, 203−
211.
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02997.
1
Experimental procedures, H and 13C{1H} NMR spectra
for all novel compounds (PDF)
Crystallographic data for 20 (CIF)
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: jet20@st-andrews.ac.uk.
*E-mail: ads10@st-andrews.ac.uk.
Notes
(12) For a single example of a fused bicyclic 2,3-dihydro-1,3,4-
oxadiazole investigated as an antioxidant, see: El Sadek, M.; Abd El-
Dayem, N.; Hassan, S.; Mostafa, M.; Yacout, G. Molecules 2014, 19,
5163−5190.
The authors declare no competing financial interest.
(13) (a) Ott, I.; Kircher, B.; Heinisch, G.; Matuszczak, B. J. Med.
Chem. 2004, 47, 4627−4630. (b) Samet, A. V.; Marshalkin, V. N.;
Kislyi, K. A.; Chernysheva, N. B.; Strelenko, Y. A.; Semenov, V. V. J.
Org. Chem. 2005, 70, 9371−9376. (c) Liu, Y.; Chu, C.; Huang, A.;
Zhan, C.; Ma, Y.; Ma, C. ACS Comb. Sci. 2011, 13, 547−553. (d) Liu,
X.-H.; Jia, Y.-M.; Song, B.-A.; Pang, Z.-x.; Yang, S. Bioorg. Med. Chem.
Lett. 2013, 23, 720−723. (e) Hajishaabanha, F.; Shaabani, A. RSC Adv.
2014, 4, 46844−46850.
ACKNOWLEDGMENTS
■
We thank the European Research Council under the European
Union’s Seventh Framework Programme (FP7/2007−2013)
ERC Grant Agreement No. 279850 (A.D.S. and J.E.T.) and
The Leverhulme Trust for an Early Career Fellowship (J.E.T.).
We also thank the EPSRC UK National Mass Spectrometry
Facility at Swansea University.
(14) Leaving the uncatalyzed reaction for 3 h allows 6 to be isolated
in 79% yield.
(15) Reaction with the enantiomerically pure isothiourea HyperBTM
1 led to formation of racemic 6.
(16) See the Supporting Information for details.
(17) CCDC 1430692 contains the supplementary crystallographic
data for 2,3-dihydro-1,3,4-oxadiazole 20.
REFERENCES
■
(1) Joule, J. A.; Mills, K. Heterocyclic Chemistry, 5th ed.; Wiley: 2010.
(2) Cortez, G. S.; Tennyson, R. L.; Romo, D. J. Am. Chem. Soc. 2001,
123, 7945−7946.
(3) For a review on the Lewis base functionalization of carboxylic
acids, see: Morrill, L. C.; Smith, A. D. Chem. Soc. Rev. 2014, 43, 6214−
6226.
(18) The data underpinning this research can be found at DOI:
http://dx.doi.org/10.17630/9c704848-8ca9-4e41-8811-2f2fea2e5f6c.
(4) For a review on isothioureas in organocatalysis, see: Taylor, J. E.;
Bull, S. D.; Williams, J. M. J. Chem. Soc. Rev. 2012, 41, 2109−2121.
(5) For seminal examples, see: (a) Belmessieri, D.; Morrill, L. C.;
Simal, C.; Slawin, A. M. Z.; Smith, A. D. J. Am. Chem. Soc. 2011, 133,
2714−2720. (b) Simal, C.; Lebl, T.; Slawin, A. M. Z.; Smith, A. D.
Angew. Chem., Int. Ed. 2012, 51, 3653−3657. (c) Morrill, L. C.; Lebl,
T.; Slawin, A. M. Z.; Smith, A. D. Chem. Sci. 2012, 3, 2088−2093.
(d) Morrill, L. C.; Douglas, J.; Lebl, T.; Slawin, A. M. Z.; Fox, D. J.;
Smith, A. D. Chem. Sci. 2013, 4, 4146−4155.
(6) For selected examples of heterocycle synthesis using isothiourea
catalysis, see: (a) Belmessieri, D.; Cordes, D. B.; Slawin, A. M. Z.;
Smith, A. D. Org. Lett. 2013, 15, 3472−3475. (b) Stark, D. G.; Morrill,
L. C.; Yeh, P.-P.; Slawin, A. M. Z.; O'Riordan, T. J. C.; Smith, A. D.
Angew. Chem., Int. Ed. 2013, 52, 11642−11646. (c) Belmessieri, D.; de
la Houpliere, A.; Calder, E. D. D.; Taylor, J. E.; Smith, A. D. Chem. -
Eur. J. 2014, 20, 9762−9769. (d) Stark, D. G.; O’Riordan, T. J. C.;
Smith, A. D. Org. Lett. 2014, 16, 6496−6499. (e) Yeh, P.-P.; Daniels,
D. S. B.; Cordes, D. B.; Slawin, A. M. Z.; Smith, A. D. Org. Lett. 2014,
16, 964−967.
(7) (a) Smith, S. R.; Douglas, J.; Prevet, H.; Shapland, P.; Slawin, A.
M. Z.; Smith, A. D. J. Org. Chem. 2014, 79, 1626−1639. (b) Morrill, L.
C.; Smith, S. M.; Slawin, A. M. Z.; Smith, A. D. J. Org. Chem. 2014, 79,
1640−1655.
(8) (a) Durckheimer, W.; Blumbach, J.; Lattrell, R.; Scheunemann, K.
̈
H. Angew. Chem., Int. Ed. Engl. 1985, 24, 180−202. (b) Alcaide, B.;
Almendros, P.; Aragoncillo, C. Chem. Rev. 2007, 107, 4437−4492.
D
DOI: 10.1021/acs.orglett.5b02997
Org. Lett. XXXX, XXX, XXX−XXX