A photochemical ring expansion of 6-to 8-membered nitrogen heterocycles by [1,3]-sigmatropic rearrangement

Article abstract of DOI:10.1039/d1cc00393c

A new route to azocines and benzoazocines from furopyridinones is described through a photochemically induced [1,3]-sigmatropic rearrangement. The method gives access to these 8-membered nitrogen heterocycles from dimethyl squarate in four stages and with excellent atom economy by sequencing thermal and photochemical ring expansion steps under continuous flow.

Full text of DOI:10.1039/d1cc00393c

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A photochemical ring expansion of 6- to
-membered nitrogen heterocycles by
[1,3]-sigmatropic rearrangement†‡
8
Cite this: Chem. Commun., 2021,
7, 4556
5
Received 22nd January 2021,
Accepted 30th March 2021
Morgan A. Manning, Wei Sun, Mark E. Light and David C. Harrowven
*
DOI: 10.1039/d1cc00393c
rsc.li/chemcomm
A new route to azocines and benzoazocines from furopyridinones is furopyridinones 2b and 2c gave furoazocines 3b and 3c in 47%
described through a photochemically induced [1,3]-sigmatropic and 54% yield respectively on irradiation.
rearrangement. The method gives access to these 8-membered
Attention next turned to aryl-substituted furopyridinones
nitrogen heterocycles from dimethyl squarate in four stages and 5a–h, which were readily prepared by thermal rearrangement
with excellent atom economy by sequencing thermal and photo- of the corresponding alkynylcyclobutenones 4 (Scheme 4 and
1
0
chemical ring expansion steps under continuous flow.
ESI‡). Each underwent ring expansion on irradiation with
UVA to give the corresponding benzoazocines 6a–h (Tables 1
Azocanes and their unsaturated analogues form a class of 8- and 2) with a skipped diene unit. Yields were typically in the
membered nitrogen heterocycles that includes the manzamine range of 51–74%, except for substrate 5h with the electron
1
–5
alkaloids and other natural products. Though they have the deficient arene which was significantly lower (28%). Cases
6
attributes of a privileged structure in medicinal chemistry,
where the migrating bond was between two benzylic centres,
they remain underexploited in that context due to challenges e.g. 5i–n (Table 2), were also high yielding and notably gave
7
associated with their synthesis. In particular, syntheses based benzoazocines 6i–n as single diastereoisomers. Their relative
on ‘end-to-end’ cyclisation strategies have to overcome trans- stereochemistry was confirmed by x-ray crystallographic analy-
3
,7,8
annular strain and the loss of entropy on ring closure,
making it necessary to employ high dilution or pseudo-high
sis of 6i and 6l (Fig. 1).
The mechanistic course of the reaction was next examined
1
8
dilution conditions to reduce competing intermolecular by TD-DFT, using 5a - 6a as the exemplar. Calculations
9
1
reactions. Herein we describe a new route to azocines 3 and showed that the singlet excited state [5a]* could relax directly
1
9
benzoazocines 6 by photo-induced ring expansion of vinyl- and to azocine 7a via a 1,3-sigmatropic rearrangement (Fig. 2),
1
0,11
aryl-furopyridinones 2 and 5 respectively (Scheme 1).
In before giving benzoazocine 6a via a thermal [1,5]-sigmatropic
À1 20
a
addition we show how the same products can be formed H-shift (estimated E = 16.0 kcal mol ).
directly from alkynylcyclobutenones 1 and 4 by sequencing
thermal and photochemical rearrangements under flow.
The discovered was made during a follow-up study on the
Interestingly, for the related thiophene derivative 5n the
conjugated tetraene 7n was evidenced as an intermediate by
H NMR, albeit as a mixture with 6n. On standing that sample
1
1,12
1
thermal rearrangement of aminocyclobutenones 1/4 to furopyr- underwent isomerization to give tris-heterocycle 6n as the sole
1
0,12
idinones 2/5.
The presence of an extended chromophore in
13
the products prompted us to examine their photochemistry.
Pleasingly, when an acetonitrile solution of 2a was irradiated with
UVA light (l = 370 nm, 36 W) under continuous flow, using a set-
13–15
up akin to that described by Booker-Milburn and Berry et al.,
it gave furoazocine 3a in 48% yield (Scheme 2). Similarly,
Chemistry, University of Southampton, Highfield, Southampton, SO17 1BJ, UK.
E-mail: dch2@soton.ac.uk
†
‡
Dedicated to Prof. Kevin Booker-Milburn on the occasion of his retirement.
Electronic supplementary information (ESI) available: Experimental accounts,
1
13
spectral and analytical details together with copies of H and C NMR spectra.
CCDC 1969077 and 2025763. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/d1cc00393c
Scheme 1 Sequential thermal and photochemical ring expansion reactions
for the synthesis of azocines and benzoazocines from cyclobutenones.
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Table 2 Photochemical rearrangements of diarylfuropyridinones
1
2
16,17
Scheme 2 Photochemical ring expansions of furopyridinones to azocines.
Table 1 Benzoazocines from furopyridinones following UVA irradiation
3
4
5
product (Scheme 3). TD-DFT analysis indicated that the barrier
À1
for the [1,5]-H-shift, 7n - 6n (26.7 kcal mol , see ESI‡), was
significantly higher than for 7a - 6a, suggesting that isomeriza-
tion may be by protonation and deprotonation in this case. The
method was then extended to the 2-thiophenyl and 3-pyridyl
analogues, 5o and 5p with both giving a tris-heterocyclic product,
6o and 6p, albeit in low yield with the electron deficient hetero-
aromatic (Scheme 4).
Finally, we have been able to produce benzoazocines 6 from
alkynylcyclobutenones 4, directly and in high yield, by sequen-
cing the respective thermal and photochemical rearrangements
under flow (Scheme 5). Thus, dioxane solutions of cyclobute-
nones 4a, e, g, i, l were first subjected to thermolysis at 210 1C
for a residence time of 100 min, then irradiated with UVA light
Fig. 1 X-Ray crystal structures of benzoazocines 6i [CCDC 1969077‡] and
6
l [CCDC 2025763‡].
Sequential thermal and photochemical rearrangements
from 6 Â 1.7 W LEDs for 10 min to give the corresponding were also effective with alkynylcyclobutenone 1c (Scheme 6).
benzoazocines 6a, e, g, i, l in 74–84% yield. Notably, the In this case it was found advantageous to conduct the ther-
efficiency with which each starting material was prepared molysis in two stages due to its poor conversion to the inter-
ensured that these four-stage sequences from dimethyl squa- mediate furopyridinone 2c following a single pass at 160 1C. As
2
1
rate 8 each proceeded in B50% overall yield.
with the aforementioned examples, the overall yield of azocine
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Fig. 2 Calculated free energy barriers for the rearrangement of 5a.
Scheme 5 Preparation of cyclobutenones 4 and conversion to benzoa-
zocines 6 by sequenced thermal and photochemical rearrangement under
continuous flow.
Scheme 3 Evidence for the intermediacy of polyene 7 was provided by
17
extension to the heteroaromatic analogue 5n.
Scheme 6 Sequenced thermal and photochemical rearrangement of
cyclobutenone 1c to azocine 3c under continuous flow.
We gratefully acknowledge financial support from the European
Regional Development Fund [ERDF Interreg Va programme (Pro-
ject 121)] and EPSRC [EP/P013341/1, EP/L003325/1 and EP/
K039466/1].
Conflicts of interest
There are no conflicts of interest to declare.
Notes and references
17
Scheme 4 Further examples involving heteroaromatic ring systems.
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and benzoazocines involving the photochemical ring expansion
of furopyridinones. The ease with which these products can be
prepared from dimethyl squarate 8 in high yield and diaster-
eoselectivity, and with excellent atom economy, makes this an
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Dr Wei Sun and Morgan Manning contributed equally in
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21 A significant loss of mass balance to mixed fractions occurs on
purification of furopyridinones 2 and 5 by column chromatography.
We believe this to be the primary reason for the yield
elevation observed when the thermal and photochemical steps are
sequenced.
1
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