Key words
azepane - photochemistry - photo-Fries rearrangement - heterocycles - [5+2] cycloaddition
Seven-membered nitrogen-containing rings present an intriguing challenge compared
to their five- and six-membered analogues. Although they occur with less frequency
than these other ‘common’ rings, their appearance in molecules of biological interest
provides significant motivation to construct these frameworks efficiently and effectively.[1] Additionally, five- and six-membered heterocycles have been heavily explored, while
substantially less work has been done on the construction of seven-membered (and larger)
nitrogen-containing rings (Figure [1]).[2]
Figure 1 a. Prevalence of saturated nitrogen-containing heterocycles in FDA-approved pharmaceuticals
(%)[3] and in patents detailing their construction;[4] b. A conceptualized approach at a formal [5+2] union to form azepanes.
This is particularly evident when considering the incidence of seven- and eight-membered
rings in pharmaceuticals approved by the FDA[3] compared to their coverage in the patent literature (Figure [1]).[4]
Scheme 1 Comparison between this work and prior art
While cyclization strategies dominate azepane and azocane synthesis, we felt that
two component-coupling approaches were fundamentally more powerful and considered
various disconnections. A [5+2] approach proved alluring since the two-atom unit may
be an alkene or surrogate, trivially accessed and abundant, while the five-atom unit
is pyrrolidinone. Such a union could be realized by condensation of pyrrolidinone
with aldehydes followed by a photochemical Fries-like rearrangement to form the azepinone.
This reaction was first described in the patent literature (Scheme [1]);[5] subsequent studies by Booker-Milburn[6], Mazzocchi[7], and others[8] have shown similar photochemical [5+2]-ring-expansion chemistry with the maleimide
and phthalimide frameworks, respectively. Stimulated by the conviction that this photo-Fries-like
chemistry[9] could be a powerful reaction for the synthesis of azepanes, we sought to develop
the method.
The N-vinylpyrrolidinones are readily accessible through the condensation of a desired
aldehyde and pyrrolidinone (Scheme [2]). Unlike the chemistry of the maleimides, this method allows for the facile and
diverse structural modification and functionalization around the azepane motif. Additionally,
the resultant vinylogous amide moiety formed during the reaction is an exemplary functional
group for further manipulation.[10]
Scheme 2 Formation of N-vinylpyrrolidinones
Our investigation into the photochemical[11] [5+2] cycloaddition began with optimization of the reaction conditions on 3a, using the conditions reported in the patent literature[5] as a starting point (Table [1], entry 1). The use of THF as solvent increases the yield of the reaction to 48%
over 24 hours (Table [1], entry 8). Dilution of the reaction to 0.02 M further increases the yield, presumably
due to disfavored competitive polymerization[12] and dimerization[13] pathways.
Table 1 Optimization Conditions
|
|
Entry
|
Solvent
|
Concentration (M)
|
Time (h)
|
Yield (%)
|
|
1
|
MeOH
|
0.2
|
24
|
40
|
|
2
|
MeCN
|
0.2
|
24
|
22
|
|
3
|
THF
|
0.2
|
24
|
48
|
|
4
|
THF
|
0.2
|
48
|
75
|
|
5
|
THF
|
0.5
|
48
|
67
|
|
6
|
THF
|
1.0
|
48
|
55
|
|
7
|
THF
|
0.1
|
48
|
81
|
|
8
|
THF
|
0.02
|
48
|
92
|
The photochemical rearrangement tolerates a broad range of substitution on the enamine
(Scheme [3]) including simple alkyl groups (4c–e) as well as aryl (4f), and electron-rich and electron-poor benzyl substituents (4m–o). Dienamine-substituted pyrrolidinone 3l participates in the reaction, although in diminished yield. A stereocenter present
on the alkene substituent remains intact over the course of the reaction (4j). Unfortunately, efforts to create quaternary centers α to the ketone as well as
substrates which included carbonyl moieties other than the reactive amide showed no
conversion under the irradiative conditions.[14]
Scheme 3 Scope of alkene substituent
Functionalization at any of the positions on the pyrrolidinone ring is also possible
(Scheme [4]). Interestingly, heteroatoms are often tolerated, even in the case of unprotected
alcohols. Pre-existing stereocenters on the pyrrolidinone ring do not racemize in
the rearrangement chemistry with the exception of stereocenters α to the amide. It
is presumed that this is due to the Norrish Type I cleavage of the C–C bond that does
not lead to any productive pathways and recombines, scrambling the stereocenter.
Scheme 4 Scope of pyrrolidinone substituent
The transformation also allows us to access larger rings (6h). A further increase in ring size leads to difficulty in purification due to competitive
polymerization, despite diluting the samples to 0.001 M.
Scheme 5Potential reaction mechanism[15]
A potential mechanism for this reactivity, as argued by Shizuka and coworkers[15], involves the Norrish-type I (α) homolytic cleavage of the amide bond after irradiation
with 254 nm light (Scheme [5]). The resultant biradical III can then either recombine to reform the starting material or combine with the carbon
β to the nitrogen to generate imine V. Tautomerization of V gives the observed product. Investigation of a similar maleimide system by Booker-Milburn
and coworkers[6c] suggests that the reactive biradical intermediate proceeds through an excited singlet
state as opposed to an excited triplet state. When directly irradiated, they solely
observed the [5+2] cycloaddition product whereas when they irradiated the maleimide
in the presence of the triplet sensitizer benzophenone, they solely observed the [2+2]
cycloaddition between the alkene and maleimide backbone.[16] In our system, addition of oxygen or catalytic benzophenone as triplet quenchers
did not interfere with the outcome of the reaction, supporting the likelihood of a
singlet pathway.
Scheme 6 Derivatization reactions
The cyclic vinylogous amide moiety formed in this transformation is easily manipulated
to a variety of useful functional handles (Scheme [6]). Georg[10] and others[17] have extensively studied the modification of the six-membered vinylogous amide analogues;
however, the comparable reactivity with seven-membered azepin-4-ones is relatively
rare.[18] We found that these scaffolds easily convert into other useful seven-membered heterocycles.
Global reduction of the vinylogous amide, as well as semireduction by hydrogenation
to the ketone each proceed uneventfully; a Wolff–Kishner protocol results in deoxygenation
with alkene migration to deliver 11.
In conclusion, we have developed a formal two-step [5+2] cycloaddition to form azepinones
exploiting a relatively understudied photochemical rearrangement.[19]
[20] This facile approach allows for the construction of synthetically useful functionalized
azepin-4-ones in good yields from readily available aldehydes and pyrrolidinones.
Modification of these substrates allows for the access to a diverse set of substituted
azepane derivatives.
Scheme 7
