Step-Economical Photoassisted Diversity-Oriented Synthesis: Sustaining Cascade Photoreactions in Oxalyl Anilides to Access Complex Polyheterocyclic Molecular Architectures

Article abstract of DOI:10.1021/jacs.7b07598

Atom- and step-economy in photoassisted diversity-oriented synthesis (DOS) is achieved with a versatile oxalyl linker offering rapid access to complex alkaloid mimics in very few experimentally simple steps: (i) it allows for fast tethering of the photoac

Full text of DOI:10.1021/jacs.7b07598

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Article
Step-Economical Photoassisted Diversity-Oriented Synthesis:
Sustaining Cascade Photoreactions in Oxalyl Anilides to
Access Complex Polyheterocyclic Molecular Architectures
Dmitry M Kuznetsov, and Andrei G. Kutateladze
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 20 Oct 2017
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Step-Economical Photoassisted Diversity-Oriented Synthesis: Sus-
taining Cascade Photoreactions in Oxalyl Anilides to Access Com-
plex Polyheterocyclic Molecular Architectures
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Dmitry M. Kuznetsov and Andrei G. Kutateladze*
Department of Chemistry and Biochemistry, University of Denver, Denver, CO 80208.
ABSTRACT: Atom- and step-economy in photoassisted DOS is achieved with a versatile oxalyl linker offering rapid access to
complex alkaloid mimics in very few experimentally simple steps: (i) it allows for fast tethering of the photoactive core to the
unsaturated pendants, especially important in the case of (hetero)aromatic amines – essentially a one pot reaction with no isolation of
intermediates; (ii) the α-dicarbonyl tether acts as a chromophore enhancer, extending the conjugation chain and facilitating the ‘har-
vest’ of the lower energy photons for the primary and secondary photoreactions, (iii) it enhances the quantum yield of intersystem
crossing (ISC), i.e. it is capable of sensitizing secondary photochemical processes in the cascade and, (iv) the tether forms an addi-
tional heterocyclic moiety, imidazolidine-4,5-dione, a known pharmacophore. The overall photoassisted cascade is an efficient
complexity-building process as quantified by computed step-normalized complexity indices, leading to extended polyheterocyclic
molecular architectures comparable in complexity to natural products such as paclitaxel while requiring only 2-4 simple synthetic
steps from readily available chemical feedstock.
more advantageous synthetically, given the expected eventual
1. INTRODUCTION
localization of the triplet on the diene moiety as dienes are the
The quest for rapid growth of molecular complexity in syn-
thetic organic chemistry continues, whether the subject at hand
is the target- or diversity-oriented,1 or function-oriented2 syn-
thesis. The general notion of step-economy and various other
economies of synthesis3 is particularly central here and now is
also quantifiable, especially with the modern computer-aided
estimates of step-normalized increase in molecular complexity
indices.4
known “sinks” for triplet energy.11
This rationale of setting up a complex synthetically useful
photochemical cascade required re-thinking the role of the
tether utilized in the “assembly” of linear photoprecursors. In
sum, we sought a multi-functional compact tether which would
(i) allow for straightforward and efficient modular “assembly”
of linear photoprecursors from readily available chemical feed-
stock; (ii) extend the conjugation in the primary chromophores,
i.e. o-aminoketones, and therefore enhance their light-harvest-
ing properties; (iii) enhance UV absorption of the primary pho-
toproducts paving the way for ready re-excitation; (iv) facilitate
fast intersystem crossing, ISC, into the triplet manifold at the
secondary step of the photochemical cascade; and finally, (v) as
the linker becomes an additional heterocyclic moiety, ideally it
would form/enhance the potential pharmacophore.12
In recent reviews by Porco and Stephenson,5 or Remi and
Bochet,6 photochemistry – and especially photoinduced cy-
cloadditions – are shown to offer expedited access to complex
chemotypes where ground state reactions are at best challenging
if not impossible.7 Needless to say we fully share this philoso-
phy. Earlier we developed a general photoassisted synthetic
methodology for rapid generation of molecular complexity and
diversity in nitrogen-containing polyheterocycles based on a
short, three-four steps, synthetic sequence involving (i) experi-
mentally simple modular assembly of photoprecursors, reminis-
cent of multicomponent reactions in simplicity (ii) key photo-
chemical step to construct the core scaffold, accompanied by
significant growth of complexity and (iii) postphotochemical
modification to further diversify the target.8 This expedited ac-
cess to rather complex molecular architectures takes advantage
of excited state intramolecular proton transfer (ESIPT) in aro-
matic amino ketones via the intermediacy of aza-o-xylylenes.
Recently we have shown that aza-o-xylylenes are capable of
dearomatizing appropriately tethered benzenoid aromatic moi-
eties in an unprecedented [2+4] photoreaction topology leading
to privileged scaffolds such as tetrahydroquinolines fused to cy-
clohexadiene moiety.9 As the primary photoprocess occurs in
the triplet state10 we hypothesized that a secondary excitation
and intersystem crossing into the triplet manifold could be even
In this paper, we report one solution under which all these
conditions are met based on the oxalyl amide tether, resulting
from a stepwise “fastening” of two aniline moieties with oxalyl
chloride, which can be carried out in a ‘one-pot’ fashion. As
we show below this experimentally simple modular assembly
of photoprecursors offers a straightforward entry into the cas-
cade photochemical synthetic sequence leading to polyhetero-
cyclic secondary photoproducts suitable for short postphoto-
chemical transformations to yield complex alkaloid mimics.
2. RESULTS AND DISCUSSION
2.1. Two-step photocascade
Non-symmetric oxalyl anilide photoprecursors were readily
accessed via a stepwise reaction with oxalyl chloride as shown
in Scheme 1. This scheme also illustrates a typical primary pho-
toreaction initiated by ESIPT in the photoactive o-amido ketone
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chromophore. The generated triplet aza-o-xylylenes were ca- irradiation conditions included a 100 mg scale (2.5 mM solu-
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pable of dearomatizing the tethered anilide moiety, yielding cy-
clohexadiene-fused tetrahydroquinolines as primary photo-
products.
tion) with seven 2.9W @ 365 nm UV LEDs for 2.5-8 hours for
aminobenzaldehydes or 13-32 hours for aminoacetophenones.
Table 1. Products of the two-step photo-cascade
Photoprecursor
Secondary Photoproduct(s)
Scheme 1. Assembly of non-symmetric oxalyl anilide pre-
cursors and a typical ESIPT-mediated primary photoreac-
tion leading to dearomatization of tethered anilide.
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1a
1b
1c
3a (39%)a
3b (35%)
3c (62%)
Such cycloadditions of aza-o-xylylenes generally reduce UV
absorption of the primary photoproducts, mostly due to decon-
jugation of the aromatic carbonyl group, which becomes ben-
zylic alcohol. However, oxalylamide-based primary photo-
products possess extended conjugation and by design are capa-
ble of secondary photoexcitation. This was indeed observed.
When oxalylamidobenzaldehyde precursor 1a was irradiated
with UV LEDs @ 365nm, the initially formed primary photo-
product 2a was depleted upon extended irradiation to yield pol-
yheterocyclic 3a possessing 2-azabicyclo[2.2.2]octene moiety.
1d
1e
1f
3d (40%)
3d" (trace amounts)
3e (75%)
3f (36%)
Scheme 2. Photochemical cascade with a secondary reac-
tion sensitized by the multifunctional tether.
1g
3g (48%)
3g' (9%)
This newly discovered photochemical cascade is accompa-
nied by a considerable increase of molecular complexity in one
experimentally simple step. The reaction was consistently re-
produced on a broad range of substrates possessing additional
alicyclic and heterocyclic functionalities, Table 1. These pho-
toprecursors are readily diversified based on reductive amina-
tion of anisidine or similar anilines with various aliphatic, aro-
matic, or heteroaromatic aldehydes followed by amide coupling
and other experimentally simple procedures similar to those de-
picted in Scheme 1. For example, starting with 5-aminoindo-
linone and nicotinaldehyde one gains rapid access to photopre-
cursor 1i which upon irradiation yields two regioisomers 3i and
3i' in a stereospecific fashion with the former polyheterocycle
3i possessing five new contiguous stereogenic centers. Typical
1h
1i
3h (50%)
3i (40%)
3h' (33%)
3i' (30%)
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Figure 1. Anti-diastereoselectivity of the primary photo
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3
dearomatization is rationalized in terms of strong intramolecu-
lar H-bonding maintaining the in-OH conformation in the initial
diradical.
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1j
3j+3j' (52%)
3k+3k' (40%)
The secondary photoreaction in the photo cascade, Figure 2,
conceivably involves excitation of the oxalyl anilide chromo-
phore, intersystem crossing into the triplet manifold with triplet
energy transfer from the dicarbonyl moiety to cyclohexadiene,
followed by aliphatic α-hydrogen abstraction and recombina-
tion of two radical centers after ISC to complete the formation
of the azabicyclo[2.2.2]octene core. This rationale is supported
by the DFT calculations, B3LYP/6-311+G(d,p). We were able
to identify the initial T2 state which is localized on the α-dicar-
bonyl chromophore (69.9 kcal/mol relative to the ground state
of the primary photoproduct 2a). The lowest triplet state, T1
(49.7 kcal/mol) is localized on the cyclohexadiene moiety as
expected. Instructively, the critical H-atom transfer is an exer-
gonic step on the triplet hypersurface, with the triplet diradical
DR T1 being approximately 8 kcal/mol ‘downhill.’ This exer-
gonicity is not entirely unexpected, as the triplet cyclohexadi-
ene is transitioned into two conjugated radicals, the methoxyal-
1k
1o
3o (27%)
3o' (10%)
____________
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aisolated yields after two steps
2.2. Mechanistic Rationale.
Unlike our previous dearomatization reaction with phenol-
based photoprecursors which yielded both syn- (major) and
anti-diastereomeric benzylic alcohols (the syn-/anti- nomencla-
ture refers to the relationship between the benzylic OH group
and the cyclohexadiene moiety),9 photo cascade in anilides 1
produced exclusively anti-isomers. After ESIPT, the initial tri-
plet diradical, Figure 1, is born in the in-OH conformation,
which is stabilized by the shown intramolecular hydrogen bond-
ing (blue dashed lines). As the syn-isomer could only be orig-
inated from the out-OH rotamer stabilized by a hydrogen bond
to solvent, we hypothesize that oxalylamides form much
stronger intramolecular hydrogen bonds and, therefore, signifi-
cantly bias the stereochemical outcome toward the observed
anti- products. Figure 1 illustrates that either clockwise or anti-
clockwise rotation around the Ar-N bond in the in-OH con-
former produces two enantiomers of the anti-diastereomer, as
long as the intramolecular H-bonding persists. This intramo-
lecular H-bond could be either between the OH group and the
nitrogen atom or amide’s carbonyl as shown.
lyl radical and the ArNC(O)C(O)N-CH2· radical. Analysis of
Mulliken spin density in the amidomethyl radical supports the
delocalization hypothesis, with the adjacent carbonyl oxygen
carrying 0.15 of alpha spin density (in addition to 0.84 residing
on the methylene carbon).
Figure 2. Plausible mechanism for the secondary step in the
photochemical cascade (relative DFT B3LYP/6-311+G(d,p)
energies are in parentheses).
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H/D = 34 ± 14
Figure 4. Deuterium isotope effect on quantum yields of pro-
duction of 3a from 1a.
Figure 3. Triplet energy profile for the H atom transfer: ZPE-
corrected B3LYP/6-311+G(d,p) DFT energies.
As the transformation of 1a to 3a is a multistep process in-
volving singlet and triplet excited states, we considered that the
cumulative isotope effect on the quantum yield of production of
3a could potentially reflect contributions from isotope effects
on lifetimes of the excited species along the reaction coordinate,
in which case the kinetic isotope effect on the actual H atom
transfer step could be very different. To clarify this point and
rule out isotope effects on the lifetimes, we synthesized mono-
deuterated 1a-d, Figure 4B, and determined the deuterium dis-
tribution in the resulting 3a-d. After statistical correction for
two protons vs one deuterium atom, we arrived at a lower ratio
H/D = 34 ± 14. Based on this result we rationalize that there
is a small isotope effect on lifetimes of excited species in the
previous example, Figure 4A. At the same time this large iso-
tope effect of 34 obtained at ambient temperature, which ex-
ceeds the expected value for a primary isotope effect by a factor
of four, offers proof that hydrogen atom transfer in excited 2a
does occur via quantum tunneling. These large room tempera-
ture values are not unprecedented: KIEs of 5-55 have been ob-
served before for the proton-transfer step in methylamine dehy-
drogenase.15 Hydrogen atom tunneling in the excited states is
also precedented, but mostly studied for hydrogen abstraction
by carbonyls.16
In the case of acetophenone-based photoprecursor 1d we iso-
lated a very small amount of diaza-benzofenestrane 3d", which
,
was characterized by x-ray.13 14 Isolation of 3d" offers addi-
tional support for the biradical mechanism, with DR T1 recom-
bining at the alternative terminus of the allylic radical.
ZPE-corrected energy of the transition state for the critical
hydrogen atom transfer, Figure 3, revealed a small activation
barrier of only 15.9 kcal/mol, which explains the relatively fast
reaction rate at ambient temperature. Fully optimized structure
of cyclohexadiene-localized triplet T1 also revealed very short
distance for hydrogen transfer, Figure 3.
To further support this triplet diradical mechanism the rela-
tive quantum yields of the protic and deuterated substrates
2a/2a-d3 at 23 oC were compared with the expectation of a pri-
mary isotope effect. The actual experimental value that we ob-
tained, H/D = 72 ± 12, implied quantum tunneling, Figure
4A.
(A)
The cyclopropyl radical clock (in 1g) indicates that DR T1 is
probably too short-lived and collapses fast following ISC to
form products 3g and 3g' with the cyclopropane probe intact.
Also, with the exception of the N-methyl substituted 1a, all
other substrates (i.e. N-CHn-R substituted amides) expectedly
exhibited very fast H atom transfer due to additional radical sta-
bilization by R, especially by aromatic or olefinic substituents.
In all these cases, the primary photoproducts 2 are barely de-
tectable in the reaction mixture as the H-transfer step is much
faster than the first photochemical step, so only azabicy-
clo[2.2.2]octenes 3 dominate the products.
Formation of tertiary alcohol 3c from free phenol 1c in good
yield (62% over two steps) is another instructive example of the
efficiency of the secondary photochemical step, Scheme 3. The
primary photoproduct in this case, dienol 2c, is re-excited and
efficiently engaged in the second step of the photo cascade to
yield azabicyclo[2.2.2]octene 3c. An alternative reaction, tau-
tomerization of dienol 2c into the corresponding enone was not
observed.
H/D = 72 ± 12
(B)
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Scheme 3. Free aminophenol precursor 1c yields dienol 2c
photoconverted into azabicyclo[2.2.2]octene 3c instead of
tautomerization into enone.
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2.3. Postphotochemical transformations.
(B)
From the synthetic standpoint, this photoinduced cascade in-
cluding the dearomatization followed by the azabicycle for-
mation, produces new complex polyheterocyclic cores which
are readily decorated with additional functionalities or het-
ero/alicyclic pendants via experimentally simple tweaking of
the starting photoprecursors.
Topologically, there is another critical point to highlight: this
two-step process brings the para- extremities of the initial aro-
matic system into the close proximity of each other, Figure 5,
which we exploited for simple and straightforward postphoto-
chemical modifications.
(C)
Figure 5. Topology of the two-step photocascade: bringing the
para-substituents into the vicinal relationship.
Scheme 4A illustrates this point with the acid-catalyzed for-
mation of 7-azaindole 4 from photoprecursor 1l ‘assembled’
from o-aminoacetophenone, mono Boc-protected p-phenylene-
diamine, and 2-fluoro-nicotinaldehyde. Scheme 4B shows that
the photoinduced topological change, which brings an amine
into the proximity of methyl carboxylate in 3m, offers an op-
portunity to access lactam 5. Another example is the Pictet-
Spengler reaction, which is readily set to fuse an additional tet-
rahydroquinoline moiety to the already complex polyheterocy-
clic core of the primary photoproduct 3n, Scheme 4C.
These short and experimentally simple procedures are ac-
companied by a considerable increase of complexity after each
photochemical and postphotochemical step, attesting to the pre-
parative value of the method: while the yields are moderate,
they are achieved in 3-4 steps from readily available chemical
feedstock. It is also easy to see that examples in Scheme 4
produce two double bonds suitable for an additional one-step
functionalizations. Due to significantly different reactivity of
styrenic vs azabicyclo[2.2.2]octene moieties, these double
bonds are “addressable,” i.e. can be selectively engaged with
electrophiles or 1,3-dipoles.
Scheme 4. Postphotochemical modifications of the primary
photoproducts via one additional step.
Scheme 5 shows that two double bonds of diene 8, prepared
by postphotochemical dehydration of photoproduct 3b in re-
fluxing TFA, differ in reactivity to the extent that they are “ad-
dressable” with different reagents. For example, epoxidation of
(A)
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8 is directed at its styrenic alkene yielding epoxide 9 in 27%
yield over three steps. In contrast, the 1,3-dipolar cycloaddition
of benzonitrile-oxide affects the azabicyclo[2.2.2]octene moi-
ety furnishing isoxazoline 10 and a product of double addition
11. Similar bis dipolar cycloadditions yielding isoxazolo-isox-
azolidines, such as 11, are precedented in the literature. 17
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This difference in reactivity of the two double bonds could be
rationalized in terms of hyperconjugative deactivation of the
azabicyclo[2.2.2]octene moiety via the π→σ*CN interaction, de-
pleting it of the π density. On the other hand, the styrenic dou-
ble bond is more nucleophilic due to the electron-donating or-
tho-nitrogen, given that in this rigid molecular framework its
lone pair does not overlap well with the carbonyl. This could
be another example of a stereoelectronic chameleon described
recently.18
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Scheme 5. Chemoselectivity of alkenic moieties in dehy-
drated photoproducts.
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Figure 6. Molecular complexity graph for selected starting ma-
terials and photoproducts (numerical labels show calculated
molecular complexity indices as defined in DataWarrior 4.6.0,
Osiris).
The increase of molecular complexity per step is one im-
portant metric, particularly in the context of developing new
photoassisted DOS methodologies. We also note that other
DataWarrior’s metrics such as druglikeness or drugscore are
also favorable for the new alkaloid mimics. For example, drug-
score for 7-azaindole 4, 0.46, exceeds the calculated value for
paclitaxel, 0.24, almost by a factor of two.
ESIPT-based generation of aza-o-xylylenes and subsequent
dearomatization of tethered benzenoid aromatics require polar
solvents, such as DMSO, for the efficient photochemical cas-
cade. However, DMSO is not a suitable solvent for the post-
photochemical 1,3-dipolar cycloadditions, for example, the
ones shown in Scheme 5. Replacing DMSO with DMF offered
an opportunity to implement a one-pot synthesis of heterocycles
such as 12 directly from photoprecursors, Scheme 6. Again,
this experimentally simple one-pot procedure diastereoselec-
tively sets seven contiguous stereogenic centers in a complex
nitrogen polyheterocycle.
3. CONCLUSIONS
We have developed a robust photoassisted methodology for
rapid access to complex alkaloid-like polyheterocyclic molecu-
lar architectures, which involves photochemical two-step cas-
cade as a key step. With photoprecursors assembled from read-
ily available chemical feedstock via experimentally simple pro-
cedures this overall synthetic DOS strategy is centered around
the multifunctional oxalylamide tether, which improves photo-
physical properties of the precursor and the primary photoprod-
uct alike, and effectively sensitizes synthetically useful second-
ary photoreactions. Subsequent, one-two step experimentally
simple postphotochemical modifications take advantage of the
reactive functionalities installed in the photochemical step and
allow for further growth of complexity and diversity of the
products. The key step, dearomatization of the tethered anilide
moiety by the triplet aza-o-xylylene generated via ESIPT, pro-
duces a tetrahydroquinoline fused to cyclohexadiene fragment.
The secondary photochemical step utilizes the low triplet en-
ergy of the diene, rendering this a general strategy for genera-
tion of tetrahydroquinoline cores with fused aza-bicy-
clo[2.2.2]octene. The formation of the bicyclo[2.2.2]octene
moiety occurs via hydrogen atom transfer from the α-position
in N-CHn-R to the triplet diene. The isotope effect on the rela-
tive quantum yields of formation of the secondary photoproduct
reveal that this hydrogen atom transfer occurs via quantum tun-
neling.
Scheme 6. One-pot implementation of the ESIPT-based
photoassisted cascade with postphotochemical modifica-
tions.
2.4. Molecular Complexity
Molecular complexity was quantified using the DataWarrior
(Actelion Pharmaceuticals Ltd.) software.4c As Figure 6 illus-
trates, photoprecursors 1 have complexity indices similar to the
initial feedstock chemicals, such as carboxaldehydes used for
reductive amination with anisidines or p-phenylenediamine,
and also o-aminoacetophenone which makes up the photoactive
ESIPT core. In contrast, the photoassisted cascade accounts
for a dramatic increase of complexity, which puts photoprod-
ucts – obtained in a total of two-four experimentally easy steps
– in the same league as paclitaxel, while possessing much
smaller molecular weight.
ASSOCIATED CONTENT
Supporting Information. Experimental details. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: akutatel@du.edu
ORCID: 0000-0003-3066-517X
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Notes
1
The author declare no competing financial interest.
This research is supported by the NSF, CHE-1362959. We thank
Bruce Noll, Bruker AXS Inc, for help with solving a difficult xray
structure of compound 6.
2
3
ACKNOWLEDGMENT
4
5
This paper is dedicated to Al Padwa, a mentor and friend, on the
occasion of his 80th birthday.
REFERENCES
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