Reactivity insight into reductive coupling and aldol cyclization of chalcones by visible light photocatalysis

Article abstract of DOI:10.1021/jo300796j

The reductive coupling and cyclization of chalcones to generate cyclopentanol derivatives in up to 84% yield by visible light photoredox catalysis is described. This reaction involves radical anion homocoupling, monoprotonation, and intramolecular cycliza

Full text of DOI:10.1021/jo300796j

Note
pubs.acs.org/joc
Reactivity Insight into Reductive Coupling and Aldol Cyclization of
Chalcones by Visible Light Photocatalysis
Guolei Zhao,† Chao Yang,† Lin Guo,† Hongnan Sun,† Run Lin,† and Wujiong Xia*,†,‡
†State Key Lab of Urban Water Resource and Environment, Academy of Fundamental and Interdisciplinary Sciences, Harbin Institute
of Technology, Harbin 150080, China
‡State Key Lab of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China
S
* Supporting Information
ABSTRACT: The reductive coupling and cyclization of chalcones to
generate cyclopentanol derivatives in up to 84% yield by visible light
photoredox catalysis is described. This reaction involves radical anion
homocoupling, monoprotonation, and intramolecular cyclization cascade.
halcones are widely distributed in plants and have been
associated with various of pharmacological activi-
substituent at the β-position of enone is limited to the alkyl
groups, and the extension of this strategy to chalcones still
remains unexploited.
C
ties.1Moreover, they have attracted widespread research
interests from organic chemists to investigate their chemical
reactivities in a variety of reactions, e.g., classical Claisen−
Schmidt condensation,2 Suzuki coupling,3 and Heck reaction.4
Due to the unique structure feature, chalcones have also
emerged as a reliable class of reactants and important
precursors in synthetic chemisry.5 Among them, reductive
dimerization of chalcones is an available approach for
establishing C−C bonds by means of a single-electron-transfer
process. In general, the initial step is the single-electron
reduction of enone to the corresponding radical anion, which is
achieved by electrochemical reduction6 or a single-electron-
transfer reagent such as nBu3SnH,7 SmI2,8 Yb,9 Sm,10 Zn,11 etc.
In such cases, however, specialized equipment or strong
stoichiometric reductant is generally required.
Scheme 1. Reaction Mechanism of [2 + 2] Cycloaddition
Because of our continuous interest in photochemical
reactions,18 we endeavored to investigate the chemical behavior
of chalcones through the application of visible light photo-
catalysis and found that it preferentially undergoes a reductive
dimerization reaction rather than the typical [2 + 2]
cycloaddition. Based upon a series of control experiments,
the reaction process was suggested to involve both electron and
proton transfers, and the intermolecular C−C bond formation
was generated from a biradical coupling reaction instead of
radical Michael addition, which was comparatively different
from an overall redox-neutral [2 + 2] cycloaddition. In this
paper, we present a unique and efficient approach to prepare
polysubstituted cyclopentanol derivatives by visible-light photo-
redox catalysis.
Recently, an intriguing and promising strategy for the
application of photoredox catalyst to initiate a single-electron-
transfer process has been developed in the realm of organic
chemistry12 and well demonstrated by some valuble work that
explored the reactions of aryl enone and its derivatives, such as
intra- and intermolecular [2 + 2] cycloaddition,13 intra-
molecular reductive cyclization,14 hetero-Diels−Alder reac-
tion,15 [3 + 2] cycloaddition of aryl cyclopropyl ketone,16
reduction, as well as reductive allylation of epoxide and
aziridine.17
In particular, Yoon and co-workers disclosed an elegant
strategy access to cyclobutane skeleton under visible light
photoredox catalysis.13a The mechanism of reaction involved
the generation of radical anion from the corresponding enone,
subsequent addition to Michael acceptor, and then cyclization
to afford [2 + 2] adduct (Scheme 1). However, variation of the
Received: April 20, 2012
Published: June 25, 2012
© 2012 American Chemical Society
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The Journal of Organic Chemistry
Note
Our initial investigation focused on the reaction of chalcone
1a with 5 mol % of Ru(bpy)3(PF6)2, LiBF4 (1 equiv), and
iPr2NEt (5 equiv) in MeCN without deoxygenization (Scheme
2).19 After irradiation for 2 h with a blue LED (1 W, λmax = 470
24 h. As expected, no formation of 2a was observed. Such a
result is in good agreement with the designed experiment in
which 1a was subjected to the photocatalytic conditions except
LiBF4 was replaced by CH3CO2H leading to 3a as the major
product (Table 1, entry 2). These experiments indicate the
critical role of the proton transfer.
Scheme 2. Preliminary Reaction Result
a
Table 1. Investigation of Lewis Acid Additives
nm) as a light source,20 complete consumption of 1a was
observed by TLC analysis, and a complex mixture of reductive
dimer was afforded, including linear dimer, cyclic dimer, and
pinacol coupling products instead of the [2 + 2] cycloadduct.
After recrystallization, cyclic dimer 2a was obtained in 24%
isolated yield as the preliminary result.
b
c
entry
additive (equiv)
time (h)
yield (%)
1
2
3
4
5
6
7
LiBF4 (1)
2.0
0.5
1.0
3.5
2.0
3.0
4.0
24
d
CH3CO2H (3)
None
0
7
53
19
62
45
La(OTf)3 (1)
Mg(ClO4)2 (1)
Sm(OTf)3 (1)
Yb(OTf)3 (1)
To our knowledge, chalcones can produce radical anion A in
a single-electron-transfer process (Scheme 3), however, a
a
Scheme 3. Reaction Pathways of Reductive Dimerization
Reaction conditions: 1a (1 mmol), Ru(bpy)3(PF6)2 (0.05 mmol),
iPr2NEt (5 mmol) in CH3CN (10 mL), irradiation with a blue LED (1
b
c
d
W). Complete consumption for substrate 1a. Isolated yield. The
mixture of linear dimer 3a and pinacol products were obtained in 94%
yield.
It should be pointed out that Lewis acid or Brønsted acid was
not necessary for activating the chalcones toward one-electron
reduction in this process (Table 1, entry 3), but the presence of
LiBF4 undoubtedly resulted in a higher yield of 2a. Therefore,
several Lewis acid additives were subjected to the reaction,
including La(OTf)3, Mg(ClO4)2, Sm(OTf)3, and Yb(OTf)3,
and the results are listed in Table 1 (entries 4−7). As can be
seen, the best yield was obtained by using Sm(OTf)3 as an
additive (Table 1, entry 6). Therefore, we reasoned that the
presence of Sm(OTf)3 was in coordination with the carbonyl
and enol groups in a stable transition state responsible for the
high yield and chemical selectivity (eq 1).
detailed reaction pathway for the formation of 2a still remains
ambiguous and impedes our efforts to optimize the reaction
conditions. Therefore, a series of control experiments needed
to be performed before we started to optimize the reaction
conditions. Initially, we envisioned that the generated reactive
radical anion A from chalcone could be intercepted by the
better Michael acceptor, methyl vinyl ketone (MVK), leading
to the cross coupling product. Nevertheless, treatment of 1a
with 10 equiv of MVK under the same photocatalytic
conditions preferentially formed the homocoupling products
from 1a. Such a result shows the likelihood of generation of
linear dianion species B from two radical anions coupling rather
than a radical anion addition to Michael acceptor.
Having developed conditions for this unique reaction, our
next work focused on the investigation of structure−reactivity
relationships. Thus, a variety of chalcones were synthesized and
subjected to the reaction conditions. As shown in Table 2, the
reactions led to the desired products in moderate to high yields.
The substituent group had significant effect on the reaction
efficiency and reactivity of aldol cyclization. For example, the
carbonyl substituent R1 bearing electron-withdrawing groups
on aromatic rings led to the products in good yields (entries 2
and 4). In contrast, substituent R1 bearing electron-donating
groups resulted in the relatively lower yields (entries 3, 5, 6, and
9). When the alkene substituent R2 bearing a electron-donating
group, it took longer reaction time and gave rise to the
cyclization product in moderate yields (entry 7). The
stereochemistry of 2a−i was assigned based upon the previous
work23 as well as NMR spectra. However, the reaction is
i
It is well-known that Pr2NEt is a competent electron and
hydrogen atom donor, which has been demonstrated in
previous work.21 Given the observed reactivity, we speculated
that the reaction pathway for the conversion of 1a to 2a was
dominated by the proton transfer from tertiary amine,22 and
consequently, cyclic dimer 2a resulted from the monoproto-
nation of dianion B followed by the intramolecular Aldol
cyclization of C. To add credence to our hypothesis, a control
experiment was conducted by preparation and sequential
treatment of 3a under the same photocatalytic conditions for
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Note
Table 2. Investigation of Structure−Reactivity
Scheme 4. Proposed Mechanism
a
Relationships
b
entry
substrate
time (h) yield (%)
1
2
3
4
5
6
7
8
9
1a, R1 = C6H4, R2 = C6H5
3
3
4
3
3
7
6
3
7
2a, 62
2b, 84
2c, 47
2d, 78
2e, 51
2f, 40
2g, 54
2h, 59
2i, 65
1b, R1 = 4-ClC6H5, R2 = C6H5
1c, R1 = 4-MeOC6H4, R2 = C6H5
1d, R1 = 4-ClC6H4, R2 = 4-FC6H4
1e, R1 = 4-MeOC6H4, R2 = 4-FC6H4
1f, R1 = 4-MeOC6H4, R2 = 4-MeOC6H4
1g, R1 = C6H5, R2 = 4-MeOC6H4
1h, R1 = C6H5, R2 = 4-FC6H4
provides a dianion species. Sequential monoprotonation and
intramolecular aldol cyclization gave access to polysubstituted
cyclopentanol derivatives. An appropriate Lewis acid additive,
Sm(OTf)3, is beneficial for the aldol cyclization.
In summary, we have developed a photocatalytic system for
the reductive cyclization of chalcones under visible light
irradiation. This work indicates an available reactivity of radical
anion, which should be helpful to extend the scope of reaction
by visible light photocatalysis. Further work to realize this goal
is underway in our laboratory.
1i, R1 = 3,5-(MeO)2C6H3, R2 = C6H5
a
Reaction conditions: substrate (1 mmol), Ru(bpy)3(PF6)2 (0.05
mmol), iPr2NEt (5 mmol), Sm(OTf)3 (1 mmol) in CH3CN (10 mL),
irradiation with a blue LED (1 W). Isolated yield.
b
sensitive to steric bulk. No reaction was observed when the
chalcones bear methyl substituent at α or β position. In
addition, the substituent on ortho position of R1 led to γ-
hydroxyl phenyl ketone 3j instead of the desired cyclopentanol
compound (eq 2). The structure and stereochemistry of 3j
EXPERIMENTAL SECTION
General Methods. All reagents were purchased from commercial
sources unless otherwise noted. Solvents were dried according to
standard procedures prior to use. Chemical shifts in H NMR (400
■
1
MHz) and 13C NMR (100 MHz) spectra are reported in parts per
million from tetramethylsilane (TMS) or solvent resonance (e.g.,
CDCl3) as the internal standard. HR-MS spectra were recorded on an
LC mass spectrometer using electrospray ionization (ESI, TOF).
General Procedure for the Synthesis of Cyclopentanols 2.
To a solution of chalcone 1 (1 mmol) in dried CH3CN (10 mL) were
added i-Pr2NEt (5 mmol), Sm(OTf)3 (1 mmol), and Ru(bpy)3(PF6)2
(0.05 mmol), respectively. The mixtrure was stirred at room
temperature under irradiation with a blue LED (1 W) as the light
source. Upon consumption of starting material, the solvent was
concentrated in vacuo. The residue was purified by flash
chromatography and recrystallization to afford the desired product 2.
Spectroscopic data were in accord with those previously published for
the known compounds.
Compound 2a: 129 mg; yield 62%; white solid; mp 194−195 °C;
1H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 7.2 Hz, 2H), 7.43 (d, J =
7.2 Hz, 4H), 7.37−7.06 (m, 14H), 5.25 (s, 1H), 4.56 (d, J = 12.0 Hz,
1H), 4.13 (dd, J = 11.6, 10.4 Hz, 1H), 3.81 (m,1H), 3.03 (dd, J = 14.4,
12.0 Hz, 1H), 2.61 (dd, J = 14.4, 6.0 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 205.0, 145.3, 144.0, 139.9, 137.6, 133.3, 128.5, 128.4, 128.3,
128.2, 128.1, 128.0, 127.6, 127.0, 126.9, 126.4, 124.9, 84.3, 63.6, 59.6,
51.4; HRMS-ESI (TOF, m/z) [M + Na]+ calcd for C30H26O2Na
441.1830, found 441.1819.
were determined by NMR spectra and X-ray crystal analysis.24
However, such a result adds more credence to the intermediate
A and the radical coupling process (Scheme 3).
The benzylacetones 1k and 1l were also investigated under
the same photocatalytic conditions (eq 3). The reactions
Compound 2b: 204 mg; yield 84%; white solid; mp 175−176 °C;
1H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 8.8 Hz, 2H), 7.39−7.07
(m, 16H), 5.27 (s, 1H), 4.39 (d, J = 12.0 Hz), 4.06 (dd, J = 11.6, 10.4
Hz, 1H), 3.78 (m, 1H), 2.91 (dd, J = 14.0, 12.8 Hz, 1H), 2.56 (dd, J =
14.4, 6.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 203.6, 143.8, 143.7,
140.2, 140.0, 135.7, 133.0, 129.5, 128.7, 128.6, 128.5, 128.5, 127.8,
127.6, 127.2, 126.5, 126.3, 84.0, 63.5, 60.0, 51.3, 51.1; HRMS-ESI
(TOF, m/z) [M + Na]+ calcd for C30H24Cl2O2Na 509.1051, found
509.1057.
proceeded smoothly, but the linear dimer products, not the
desired cyclopentanol derivatives, were obtained. These results
indicated the critical role of the aromatic groups in formation of
cyclization products which might stabilize the reactive radical
anion formed in the reaction.
Based upon the above investigations and previous work,25 we
propose the reaction mechanism that is outlined in Scheme 4.
The reactive radical anion is generated from the corresponding
chalcone in the photocatalytic conditions. An initial C−C bond
formation process based on two-radical-anion coupling
Compound 2c: 112 mg; yield 47%; white solid; mp 146−147 °C;
1H NMR (400 MHz, CDCl3) δ 7.51−7.48 (m, 4H), 7.43 (d, J = 7.6
Hz, 2H), 7.27−7.07 (m, 8H), 6.84 (d, J = 8.8 Hz, 2H), 6.66 (d, J = 8.8
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The Journal of Organic Chemistry
Note
Hz, 2H), 5.50 (s, 1H), 4.47 (d, J = 12.0 Hz, 1H), 4.10 (dd, J = 12.0,
10.0 Hz, 1H), 3.78 (s, 6H), 2.97 (dd, J = 14.0, 12.0 Hz, 1H), 2.57 (dd,
J = 14.4, 5.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 203.1, 163.8,
158.4, 144.3, 140.2, 137.6, 130.7, 130.6, 128.4, 128.4, 127.9, 127.6,
126.8, 126.3, 126.1, 113.6, 113.4, 84.1, 62.7, 59.6, 55.4, 55.2, 51.3, 51.3;
HRMS-ESI (TOF, m/z) [M + Na]+ calcd for C32H30O4Na, 501.2042,
found 501.2037.
59.3, 55.4, 55.3, 51.3, 51.2; HRMS-ESI (TOF, m/z) [M + Na]+ calcd
for C34H34O6Na 561.2248, found 561.2248.
Compound 3j: 138 mg; yield 57%; white solid; mp 163−164 °C;
1H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 7.6 Hz, 2H), 7.69 (d, J =
7.6 Hz, 2H), 7.54−7.09 (m, 14H), 6.66 (d, J = 16.0 Hz, 1H), 6.49 (d, J
= 16.0 Hz, 1H), 4.79 (dd, J = 10.4, 3.2 Hz, 1H), 3.74 (m, 1H), 3.09
(dd, J = 17.6, 3.2 Hz, 1H), 2.36 (s, 1H); 13C NMR (100 MHz, CDCl3)
198.5, 144.5, 138.0, 137.9, 137.0, 136.0, 135.1, 133.2, 133.0, 129.7,
129.5, 128.9, 128.8, 128.6, 128.5, 128.2, 128.1, 127.4, 127.2, 127.0,
126.7, 125.5, 124.7, 79.7, 46.2, 39.2; HRMS-ESI (TOF, m/z) [M +
Na]+ calcd for C30H24Cl2O2Na 509.1046, found 509.1044.
Compound 2d: 204 mg; yield 78%; white solid; mp 192−193 °C;
1H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 8.4 Hz, 2H), 7.36 (d, J =
8.8 Hz, 2H), 7.34−7.26 (m, 4H), 7.18 (d, J = 8.8 Hz, 2H), 7.12−7.08
(m, 2H), 6.94 (t, J = 8.4 Hz, 2H), 6.84 (t, J = 8.4 Hz, 2H), 5.19 (s,
1H), 4.35 (d, J = 12.0 Hz, 1H), 3.98 (dd, J = 11.6, 10.4 Hz, 1H), 3.66
(m, 1H), 2.90 (dd, J = 14.0, 12.8 Hz, 1H), 2.49 (dd, J = 14.8, 6.0 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 203.3, 143.4, 140.5, 135.5,
133.1, 129.4, 129.3, 129.2, 129.0, 128.9, 128.8, 128.6, 126.3, 115.7,
115.5, 115.4, 115.2, 83.9, 63.2, 59.2, 51.2, 50.9; HRMS-ESI (TOF, m/
z) [M + Na]+ calcd for C30H22Cl2F2O2Na 545.0863, found 545.0871.
Compound 2e: 131 mg; yield 51%; white solid; mp 174−175 °C;
1H NMR (400 MHz, CDCl3) δ 7.46 (t, J = 8.4 Hz, 4H), 7.34 (dd, J =
8.8, 5.6 Hz, 2H), 7.09 (dd, J = 8.8, 5.6 Hz, 2H), 6.93 (t, J = 8.8 Hz,
2H), 6.84−6.79 (m, 4H), 6.66 (d, J = 8.8 Hz, 2H), 5.43 (s, 1H), 4.39
(d, J = 12.0 Hz, 1H), 3.98 (dd, J = 11.6, 10.4 Hz, 1H), 3.77 (s, 3H),
3.75 (s, 3H), 3.64 (m, 1H), 2.91 (dd, J = 14.0, 12.0 Hz, 1H), 2.47 (dd,
J = 14.4, 6.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 202.8, 164.0,
158.5, 139.8, 137.2, 135.7, 135.7, 130.7, 130.4, 129.4, 129.3, 129.0,
129.0, 126.0, 115.5, 115.3, 115.1, 113.7, 113.6, 84.0, 62.4, 59.2, 55.4,
55.3, 51.1, 51.0; HRMS-ESI (TOF, m/z) [M + Na]+ calcd for
C32H28F2O4Na 537.1853, found 537.1880.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: xiawj@hit.edu.cn.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful for financial support from China NSFC (Nos.
21002018 and 21072038) and ZJNSF (No. LY12B02009).
■
Compound 2f: 108 mg; yield 40%; white solid; mp 139−140 °C;
1H NMR (400 MHz, CDCl3) δ 7.47 (dd, J = 8.8, 6.4 Hz, 4H), 7.30 (d,
J = 8.4 Hz, 2H), 7.06 (d, J = 8.8 Hz, 2H), 6.80 (d, J = 8.4, 2H), 6.78
(d, J = 8.0 Hz, 2H), 6.65 (d, J = 8.8 Hz, 4H), 5.42 (s, 1H), 4.38 (d, J =
12.0 Hz, 1H), 3.97 (dd, J = 11.6, 10.4 Hz, 1H), 3.76 (s, 6H), 3.74 (s,
3H), 3.67 (s, 3H), 3.65 (m, 1H), 2.89 (dd, J = 14.0, 12.0 Hz, 1H), 2.48
(dd, J = 14.8, 6.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 203.3,
163.8, 158.4,158.3, 158.0, 157.8, 136.4, 132.3, 130.7, 128.9, 128.6,
126.1, 113.8, 113.7, 113.6, 113.5, 83.9, 62.8, 59.1, 55.4, 55.2, 55.1, 51.4,
50.7; HRMS-ESI (TOF, m/z) [M + Na]+ calcd for C34H34O6Na
561.2253, found 561.2262.
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■
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Compound 2g: 129 mg; yield 54%; white solid; mp 191−192 °C;
1H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 8.4 Hz, 2H), 7.41 (d, J =
8.0 Hz, 2H), 7.34−7.15 (m, 8H), 7.06 (d, J = 8.0 Hz, 2H), 6.79 (d, J =
8.8 Hz, 2H), 6.64 (d, J = 8.4 Hz, 2H), 5.17 (s, 1H), 4.48 (d, J = 12.0
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Compound 2h: 134 mg; yield 59%; white solid; mp 175−176 °C;
1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 8.0 Hz, 2H), 7.42 (d, J =
7.2 Hz, 2H), 7.37−7.09 (m, 10H), 6.94 (t, J = 8.4 Hz, 2H), 6.81 (t, J =
8.4 Hz, 2H), 5.19 (s, 1H), 4.49 (dd, J = 12.4, 3.2 Hz, 1H), 4.02 (td, J =
12.0, 3.2 Hz, 1H), 3.68 (m, 1H), 2.98 (dd, J = 14.0, 12.0 Hz, 1H), 2.52
(m, 1H); 13C NMR (100 MHz, CDCl3): δ 204.7, 163.0, 162.9, 160.5,
160.4, 144.9, 139.5, 139.5, 137.5, 135.4, 135.4, 129.4, 129.3, 129.1,
129.0, 128.4, 128.3, 128.1, 127.2, 124.8, 115.5, 115.3, 115.3, 115.1,
84.2, 63.3, 59.2, 51.2, 51.1; HRMS-ESI (TOF, m/z) [M + Na]+ calcd
for C30H24F2O2Na 477.1642, found 477.1646.
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1H NMR (400 MHz, CDCl3) δ 7.54 (d, J = 7.6 Hz, 2H), 7.45 (d, J =
7.6 Hz, 2H), 7.36 (t, J = 8.0 Hz, 1H), 7.28 (t, J = 7.6 Hz, 2H), 7.19−
7.15 (m, 3H), 6.63 (d, J = 2.4 Hz, 2H), 6.30−6.28 (m, 3H), 6.13 (t, J =
2.0 Hz, 1H), 5.10 (s, 1H), 4.46 (d, J = 12.0 Hz, 1H), 4.06 (t, J = 10.0
Hz, 1H), 3.76 (s, 6H), 3.69−3.64 (m, 1H), 3.60 (s, 6H), 2.95 (dd, J =
14.0, 11.6 Hz, 1H), 2.54 (dd, J = 14.0, 6.0 Hz, 1H); 13C NMR (100
MHz, CDCl3): 205.0, 160.9, 160.8, 146.7, 145.3, 142.6, 137.8, 133.4,
128.5, 128.3, 128.2, 127.2, 125.0, 106.2, 106.0, 99.0, 98.5, 84.2, 63.4,
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