Conjugate addition from the excited state

Article abstract of DOI:10.1039/c8cc05924a

Conjugate addition occurs efficiently from excited hydrazide based acrylanilides under both UV and metal free visible light irradiations. The reaction proceeds via an excited state encounter complex that bifurcates either via an electron or energy transfer pathway. The generality of excited state conjugate addition is demonstrated using chloromethylation and by thiol addition.

Full text of DOI:10.1039/c8cc05924a

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
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Conjugate addition from the excited state†
b
,*
Akila Iyer,a, Sapna, Ahuja,a Steffen Jockusch,c Angel Ugrinovb and Jayaraman Sivagurua
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Conjugate addition occurs efficiently from excited hydrazide based addition) from the excited-state (Scheme 1-right) clearly
acrylanilides under both UV and metal free visible light demonstrating that the difference in reactivity originating from
irradiations. The reaction proceeds via an excited state encounter the ground state and excited state surfaces.
complex, that bifurcates either via an electron or energy transfer
Scheme 1: Contrasting excited state and ground state reactivities of acrylanilides.
pathway. The generality of excited state conjugate addition is
demonstrated using chloromethylation and by thiol addition.
Conjugate addition is one of the well-known thermal
transformations that has been exploited heavily to build
complex structural skeletons.1-4 In spite of this, the
corresponding excited state analogue has not been explored.
Herein we report the use of hydrazide based acrylanilides that
can undergo excited state conjugate addition with excellent
Scheme 2: Excited state chloromethylation of acrylanilides.
isolated yields. To demonstrate the uniqueness and feasibility
of our strategy and to contrast excited state reactivity with
well-known thermal conjugate addition (including photoredox
mediated
conjugate
addition),5
we
have
as two model
utilized
7
8-11
chloromethylation6, and thiol addition2,
reactions. Recently, we reported the use of hydrazides as a
photoauxiliary for enabling excited state reactivity with visible
light.12-18 To evaluate the reactivity of N-N bond and to expand
the scope of the chromophore, we report the conjugate
addition involving excited hydrazide based acrylanilides
(Schemes 1 and 2). Chloromethylation of acrylanilides through
single electron transfer (SET) process yields oxindole
derivatives (Scheme 1 left).19-21 The SET pathway in both
traditional radical chemistry as well as in photoredox initiated
pathway generates reactive intermediates (radical cations or
radical anions) in the ground state, leading to cyclization
resulting in oxindole derivatives. On the contrary, acrylanilides
1a-f undergo conjugate addition (chloromethylation and thiol
Acrylanilides 1a-f were synthesized from the corresponding
hydrazides16 and were evaluated for conjugate addition. We
first evaluated the feasibility of chloromethylation (Scheme 2)
leading to
2 under visible light illumination with 10-mol% of
thioxanthone (TX) acting as a photocatalyst/sensitizer and
chloroform acting as both a solvent and as a reagent. The
isolated yields of the product
2 ranged from 34-93% (Scheme
1
2).22 The products were characterized using H and 13C NMR
spectroscopy and HRMS and single crystal XRD (for 2a, Scheme
2; inset).22 A closer inspection of the photoproduct reveals that
the chloromethylation occurred at the
b-carbon. To
understand the features necessary for the chloromethylation
reaction, we systematically varied the functionality around the
hydrazide utilizing 1a as our model system. We then
Electronic Supplementary Information (ESI) available: Single-crystal XRD data
(CIF; CCDC # 1850654-1850661), experimental procedures, characterization data,
analytical conditions, and photophysical studies (PDF). See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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synthesized imides 1b-d that underwent chloromethylation to
yield the corresponding chloromethylated products 2b-d
(isolated yields for 2b=75%; 2c=36% and 2d=50%). Cyclic imide
1e underwent chloromethylation efficiently resulting in 93%
isolated yield. The quinazolinone derivate 1f gave the
corresponding chloromethylated product 2f in 80% isolated
yield.
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DOI: 10.1039/C8CC05924A
Table 1. Solvent isotope effect on chloromethylation of 1a. a
Entry
Solvent
CCl4
CHCl3
CDCl3
CH2Cl2
CD2Cl2
% Yield b
45 (3a)
79 (2a)
59 (3a)
78
2a:3a c
1:99d
1
2
3
4
5
80:20e
20:80
25:75f
02:98
70
a [1a]=3.26 mM. l»420 nm, 10 mol% TX under N2 atmosphere for 40 h. b NMR yield of
c
2a (entry 4 2a+3a) calculated using HCPh3 as internal standard (±5% error). From
d
e
f
crude 1H-NMR.
trace amount of 2a.
dichloromethylated product.
ratio at 12 h.
Corresponding
Figure 1. Left: Determination of the bimolecular quenching rate constants kq for
quenching of TX triplet states by acrylanilides using laser flash photolysis (λex = 355 nm,
7 ns pulse width). Inverse TX triplet lifetime from triplet absorption decay traces
monitored at 620 nm vs. varying hydrazide concentrations in argon saturated CHCl3 (A)
and MeCN (C) solutions. Right: Transient absorption decay traces of TX triplets different
concentrations of 1a and 6 in argon saturated CHCl3 (B) and MeCN (D) solutions.
Scheme 3: Control substrates for chloromethylation.
2a was observed exclusively in CHCl3 (Table 1; entry 2).
Changing the solvent to CH2Cl2 resulted in both 2a and 3a in
the ratio 1:3 (Table 1; entry 4). This indicated that the C-H
hydrogen in the solvent played
a crucial role in the
chloromethylation reaction. To understand the mechanism,
we evaluated the chloromethylation reaction in deuterated
solvents viz., CDCl3 and CD2Cl2. Chemoselective formation of
chloromethylated product 2a was observed in chloroform
(Table 1; entry 2) whereas in chloroform-d 3a was observed
exclusively (Table 1; entry 3). Similarly, changing the solvent
from CH2Cl2 to CD2Cl2 resulted in 3a exclusively (Table 1;
compare entries 4 and 5). Our observation with the solvent
Table 2. Physical parameters of hydrazides.
b
c
d
Ered
(V)
DGeT
(kcal/mol)
ET
kq e (M-1 s-1)
Entry
Cmpd a
study indicated that the chloromethylation leading to
2 and
(kcal/mol)
1
2
1a
-1.15
-1.2
62.4
3.1(±0.1)×108
8.9(±0.1)×107 f
9.7(±0.2)×108
2.1(±0.1)×107
2.2(±0.1)×107
7.2(±0.2)×107
1.8(±0.1)×107 f
6
p
-photocyclization leading to are competing excited state
3
processes. To evaluate the nature of the excited state
involved, we performed direct irradiation of 1a in CHCl3 at 300
nm (without TX) under both N2 and O2 atmospheres. Direct
irradiation of 1a under the optimized reaction conditions in
oxygen-saturated atmosphere proceeded to yield the
photoproduct 3a with 17% conversion.22 On the other hand,
under N2 atmosphere chloromethylation of 1a leading to 2a
was observed exclusively (89% conversion). This implicates the
3
1b
-1.30
3.5
62.3
4
5
6
7
1c
1e
6
-1.14
-1.26
-0.99
-1.4
1.4
-4.8
62.8
62.7
70.7
a [1a]=0.49 mM, [1b]=0.89 mM, [1c]=0.58 mM, [1e]=1.0 mM and [6]=0.76 mM;
b
vs. SCE, glassy carbon working electrode in MeCN. Eox=1.7 eV for TX. Eox=-1.11
3
d
eV for TX*; ET of TX from ref. 23 c From Rehm-Weller equation (ref. 24). From
likely involvement of triplet-excited states in acrylanilides
further understand the reactivity of hydrazides 1a-f towards
chloromethylation, we investigated control substrates and
(Scheme 3). Irradiation of the oxoamide , that features both
phthalimide and hydrazide functionalities, resulted in the
Paternò-Büchi reaction via BR- . We envisioned trapping of
1. To
phosphorescence in Me-THF at 77 K. e By laser flash photolysis in MeCN f or CHCl3.
4, 6
Keeping 1a as the model system, we then varied the source
of chloroalkane by changing the solvent from CHCl3 to CCl4 and
CH2Cl2. Inspection of Table 1 shows that the type of solvent
had a profound impact on the observed photoproduct. Use of
CCl4 as the solvent for the photoreaction (10 mol% TX under N2
atmosphere) afforded the dihydroquinolinone 3a exclusively
(Table 1, entry 1). On the other hand, chloromethylated
product
8
4
4
similar intermediates if the intramolecular reactions can be
side-stepped using chloromethylation. To achieve this, we
employed acrylimide
trapped intermolecularly leading to
6
where the intermediate (vide infra) was
. Irradiation of , that
7
8
features a restricted bond rotation around N-CAryl bond, under
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Scheme 4: Mechanistic pathway for chloromethylation of 1a-f
.
DOI: 10.1039/C8CC05924A
optimized conditions resulted in the expected cross [2+2]- transfer pathway in addition to the energy transfer pathway
photocycloadduct was bolstered by our observation that the bimolecular
through biradical BR-8 25
9
.
As the triplet excited state was likely implicated in the quenching constant was higher in the more polar MeCN
chloromethylation of 1a, bimolecular quenching rate constants compared to CHCl3 (Figure 1, Table 2).
(kq) were determined by quenching of TX triplet states by using
To rationalize the above observations, we propose a
laser flash photolysis (Figure 1; λex = 355 nm, 7 ns pulse width). mechanistic model for chloromethylation from the excited
The triplet state of the TX sensitizer was quenched by model state as detailed in Scheme 4-left. Based on the triplet energy
hydrazide 1a and the control substrate
6 in CHCl3 with a as well as the redox potential of thioxanthone and
quenching rate constant of 8.9×107 M-1s-1 and 1.8×107 M-1s-1 acrylanilides, an encounter complex26 is postulated that leads
respectively (Figure 1A). Similarly, in MeCN, the quenching rate to either an electron transfer or energy transfer pathways.27
constant of 1a and
respectively (Figure 1C). The rate constants in chloroform case of
(where chloromethylation leading to was observed) and in abstracts an acidic hydrogen from an appropriate solvent (e.g.
acetonitrile (where cyclization leading to -centered radical RAD- (can also be in
was observed)16 CHCl3) leading to a
indicate that the initial quenching of TX triplet excited state resonance with RAD- The proton abstraction from
6
was 3.1×108 M-1s-1 and 7.2×107 M-1s-1 The encounter complex leads to a radical anion (e.g. in the
6
) of acrylanilides 1•− and TX•+. This radical anion
2
3
b
1
b
1
)
depends on the nature of the quencher leading to energy chloroalkane is accompanied by the generation of
and/or electron transfer. To further understand the system, corresponding haloalkyl anion that eventually gets reduced to
the lowest excited triplet state energies of the substrates were the corresponding haloalkyl radical intermediate by SET to TX•+
ascertained from their phosphorescence spectra at 77 K in Me- thereby regenerating TX. This explains the requirement of
THF glass (Table 2). Inspection of Table 2 shows that the triplet catalytic amounts of TX for chloromethylation of acrylanilides.
energies (ET) of the N-N based substrates 1a-c and 1e were The
-centered radical RAD-1 (Scheme 4-left) generated by
b b
between 62-63 kcal/mol while for the control substrate ET an electron transfer pathway is responsible for the formation
6
was ~71 kcal/mol. Based on the lowest triplet excited state of anilide-based product 2a-f in contrast to oxindole product.
energy of TX (ET = ~63 kcal/mol) we believe that an energy The reaction could also be envisioned to occur via a triplet
transfer pathway is likely for substrates with favorable triplet energy transfer (if the triplet energies are favorable as in the
energies. We also calculated the feasibility of electron transfer case of 1a) from the encounter complex or by direct irradiation
from thioxanthone triplet excited state to imides
Inspection of Table 2 shows that the free energy for electron acrylanilide [
transfer is exergonic for 1a while it was endergonic for 1b. As biradical (TBR-
they feature the same chromophore with similar triplet biradical subsequently cyclizes to 3,4-dihydroquinolinone
energies, we postulate that the reaction can occur both via an product . On the other hand, when the reaction is carried out
electron transfer (if GeT is exergonic) and/or via energy in chlorinated solvents featuring abstractable hydrogen(s) (e.g.
transfer pathway (if the triplet energy is favorable as in the CHCl3), the triplet biradical TBR- abstracts the hydrogen from
case of 1a and 1c). In the case of 1b and 1e, the energetics the solvent leading to -centered radical RAD- and the
dictate that the reaction will likely proceed via triplet energy corresponding haloalkyl radical. The radicals subsequently
transfer due to the endergonic nature of electron transfer. In recombine to form . Based on the above mechanism, the
the case of substrate that features a ET of ~71 kcal/mol and photoreactivity of can be rationalized (Scheme 4-right). In
an exergonic electron transfer, we believe an electron transfer the case of , exergonic electron transfer from excited TX leads
pathway is likely leading to
1
and
6
.
followed by intersystem crossing leading to triplet excited
3
1
]* that subsequently leads to a reactive triplet
). In deuterated solvents (e.g. CDCl3), the triplet
1
3
D
1
b
1
b
2
6
6
6
7
. The involvement of the electron to a radical anion of
6
, that subsequently undergoes conjugate
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addition. The resulting enolate radical abstracts a proton from
CHCl3 to form the primary radical RAD-6a and Cl3Cy. The
primary radical RAD-6a rearranges to a more stable tertiary
Conflicts of interest
There are no conflicts to declare.
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DOI: 10.1039/C8CC05924A

radial RAD-6b that recombines with Cl3C (formed from Cl3Cy
through electron transfer to TX•+ regenerating TX) to form
7.
Notes and references
One aspect that we are not able to rationalize is the solvent
isotope effect dependent chemoselectivity. Isotope dependent
chemoselectivity is known in literature due to delicate balance
of competing reaction rates,28 a similar phenomenon can be
envisioned in our system (cyclization vs H-abstraction). Efforts
are underway in our lab to further understand this
observation.
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To showcase the generality of our strategy, we employed
conjugate addition involving thiols to N-N substituted
acrylanilides. As shown in the Scheme 5, direct irradiation
(
l»300 nm) of 1 in 1:1 v/v of thiophenol/chloroform gave the
expected 1,4 addition product 10 in 50-93% isolated yields.
The thiol addition photoproduct was unambiguously identified
by single crystal XRD (for 10f). Control studies in the absence
of light did not result in the conjugate addition product. While
light initiated conjugate addition of thiols to hydrazide can be
rationalized based on our proposed mechanism (Scheme 4-
left), we cannot rule out the formation of ground state/excited
state complex with thiols under our direct irradiation
conditions. Further investigations are underway in our lab to
showcase the utility of our findings and to understand the
mechanism.
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Conclusions
Our study has shown that the photochemistry of hydrazides
offers new avenues to uncover photoreactivity due to their
unique excited state properties. In the present case,
acrylanilides that typically undergo
6p-photocyclization
underwent conjugate addition (chloromethylation and thiol
addition) from the excited state. The prospect of altering and
uncovering new excited state reactivity will create new
opportunities to develop novel and catalytic light initiated
reactions.29-32 Efforts along these lines are currently underway
in our laboratory.
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