Controllable one-pot synthesis for scaffold diversity: Via visible-light photoredox-catalyzed Giese reaction and further transformation

Article abstract of DOI:10.1039/c9cc08781h

This study presents a controllable one-pot synthesis for constructing valuable scaffolds (alcohols, 2,3-dihydrofurans, α-cyano-γ-butyrolactones, and γ-butyrolactones) via a visible-light photoredox-catalyzed Giese reaction and further transformation. This

Full text of DOI:10.1039/c9cc08781h

View Article Online
View Journal
ChemComm
Chemical Communications
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: S. B. Nam, N.
Khatun, Y. W. Kang, B. Y. Park and S. K. Woo, Chem. Commun., 2020, DOI: 10.1039/C9CC08781H.
Volume 54
This is an Accepted Manuscript, which has been through the
Number
January 2018
Pages 1-112
1
4
Royal Society of Chemistry peer review process and has been
accepted for publication.
ChemComm
Chemical Communications
rsc.li/chemcomm
Accepted Manuscripts are published online shortly after acceptance,
before technical editing, formatting and proof reading. Using this free
service, authors can make their results available to the community, in
citable form, before we publish the edited article. We will replace this
Accepted Manuscript with the edited and formatted Advance Article as
soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes to the
text and/or graphics, which may alter content. The journal’s standard
Terms & Conditions and the Ethical guidelines still apply. In no event
shall the Royal Society of Chemistry be held responsible for any errors
or omissions in this Accepted Manuscript or any consequences arising
from the use of any information it contains.
ISSN 1359-7345
COMMUNICATION
S. J. Connon, M. O. Senge et al.
Conformational control of nonplanar free base porphyrins:
towards bifunctional catalysts of tunable basicity
rsc.li/chemcomm

Please do not adjust margins
Page 1 of 4
ChemComm
View Article Online
DOI: 10.1039/C9CC08781H
COMMUNICATION
Controllable One-Pot Synthesis for Scaffold Diversity via Visible-
Light Photoredox-Catalyzed Giese Reaction and Further
Transformation
Received 00th January 20xx,
Accepted 00th January 20xx
Su Been Nam a, Nilufa Khatun a, Young Woo Kang a, Boyoung Y. Park* b and Sang Kook Woo* a
DOI: 10.1039/x0xx00000x
This study presents
a
controllable one-pot synthesis for DOS via a controllable one-pot reaction. For the bond-forming
constructing valuable scaffolds (alcohols, 2,3-dihydrofurans, ɑ- reaction, we considered using stabilized radical species as
cyano-γ-butyrolactones, and γ-butyrolactones) via a visible-light useful reaction intermediates in carbon–carbon and carbon–
photoredox-catalyzed Giese reaction and further transformation. heteroatom bond-forming reactions. Recently, visible-light
This one-pot reaction can selectively synthesize the desired scaffold photoredox catalysis has been developed for generating radical
in excellent yields with good functional group tolerance. To further intermediates via photo-induced single-electron transfer (SET).8
highlight the broad applicability of this controllable one-pot In particular, the photoredox-catalyzed C–C bond-forming
reaction, we have established flow reaction conditions with short reaction is a useful green approach because it uses non-toxic
reaction times for the scale-up of each scaffold and demonstrated precursors and visible-light as an abundant, clean, and
the further transformation of 2,3-dihydrofurans and ɑ-cyano-γ- inexpensive energy source under mild reaction conditions.
butyrolactones to achieve scaffold diversity for applications in drug Recently, we developed a neutral silicon-based activation group
discovery.
for
the
visible-light
photoredox-catalyzed
hydroalkoxymethylation of alkenes in 2018.9 Therefore, α-silyl
substituted methanol was chosen for the C-C bond formation
reaction as hydroxymethyl radical equivalent. We applied the
visible-light photoredox-catalyzed Giese reaction of alkenes 2
with α-TMS-substituted alcohols 1 to afford alcohols 3.
Efficient construction of complex and diverse scaffolds is one of
the most important strategies to synthesize natural products
and biologically active pharmaceuticals from readily available
small molecules. Therefore, diversity-oriented synthesis (DOS)
has been studied in organic and medicinal chemistry for drug
discovery because of the effective development of bioactive
molecular libraries comprising multiple scaffolds.1 In particular,
build/couple/pair (B/C/P),2 folding,3 branching pathway,4 and
branching cascade5 strategies have been developed in DOS via
multicomponent reactions (MCRs), cycloisomerization, solid-
phase synthesis, and tandem/cascade/one-pot reactions. For
scaffold diversity, a controllable one-pot synthesis by combining
several useful compatible reactions is proposed to achieve
complexity and diversity (Scheme1, a). First, a bond-forming
reaction is developed to construct structurally complex organic
molecules from simple starting materials. In addition,
a) Controllable one-pot protocol for scaffold diversity
one-pot
simple SMs
complex and diverse scaffolds
multistep
reaction
B
C
T
P1
SM1
P2
P3
+
B
C
one-pot
reaction
SM2
B
C
T
B
bond-forming
C
T
transformation
cyclization
b) This work
NC
HO
CN
R
visible-light
photocatalyst
NC
CN
R
HO
SiMe3
1a
+
intramolecular
cyclization
and
further
functional
2
3
transformation are performed to increase the diversity of
scaffolds, which is often found in biologically active natural
products such as 2,3-dihydro-furans6 and γ-butyrolactones.7
Finally, these three types of reactions (B: bond forming, C:
cyclization, T: transformation) are combined for performing
Diversity-oriented synthesis (DOS)
One-pot protocol
Mild reaction conditions
O
O
H2N
O
NC
HO
CN
CN
R
CN
R
O
O
R
R
a. Department of Chemistry, University of Ulsan, 93 Daehak-Ro, Nam-Gu, Ulsan
44610, Korea. E-mail: woosk@ulsan.ac.kr
-cyano-
-butyro-
6
lactones
2,3-dihydro-
3
alcohols
5
-butyrolactones
4
furans
b. College of Pharmacy, Kyung Hee University, 26 Kyughee-daero, Dongdaemun-gu,
Seoul, 02447, Korea. E-mail: boyoungy.park@khu.ac.kr
Scheme 1. Controllable one-pot protocol using photoredox
catalysis and further transformation
†Electronic
DOI: 10.1039/x0xx00000x
Supplementary
Information
(ESI)
available:
See
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 2 of 4
COMMUNICATION
Journal Name
Table 1. Optimization of the reaction conditionsa
O
Mes
View Article Online
CN
NC
CN
Ph
B
C
T
via
DOI: 10.1039/C9CC08781H
O
H2N
O
Acr+-Mes
HO
SiMe3
+
N+
NC
CN
Ph
NC
HO
CN
Ph
-ClO4
Acr+-Mes
Ph
CN
Ph
Me
6 W blue LEDs
HO
SiMe3
1a
2a
+
+
5a
(78%, 3:1 dr)
additive
solvent (0.1 M)
1a
2a
3a
4a
(100 mol %)
Entry
1
(200 mol %)
Amberlite
IR120
B
C
T
B
via
C
via
(450 nm)
Acr+-Mes
Acr+-Mes
Solvent
(0.1 M)
MeOH/MeCN
(1:1)
Additive
(equiv)
-
Time
(h)
Yield
(%)b
62
O
O
H2N
O
HN
CN
tautom-
erization
NC
CN
Ph
CN
(mol %)
1.0
TEA
HCl
AcOH HO
O
24
Ph
(75%)
Ph
Ph
3a
(90%)
6a
4a
(90%)
4a
'
2
3
1.0
1.0
1.0
1.0
0.5
1.0
1.0
1.0
1.0
1.0
1.0
-
MeCN
-
24
24
24
24
24
1
90
43
30
25
76
58
78
90
74
90
90
nd
Ndd
Scheme 2. Synthesis of diverse scaffolds by controllable one-pot
protocol
MeOH
EtOAc
-
4
-
5
MeCN
-
Compared to other solvents, acetonitrile was deemed optimal,
affording Giese adducts, i.e., 3a and corresponding 4a, in 90%
isolated yields (Table 1, entries 2–5). In addition, decreasing the
catalyst loading reduced the isolated yield of the crude products
(Table 1, entry 6). Reaction was completed in 4 h, and the
product was obtained in an excellent yield (Table 1, entries 7–
9). From a mechanistic point of view, a proton source, such as
HOCH2TMS 1a and water, is essential for the completion of the
photoredox-catalyzed Giese reaction. To verify the role of water
as a proton source, the use of anhydrous MeCN under optimal
conditions was explored and the yield decreased by 16% (Table
1, entry 10). Based on this result, a trace amount of water plays
a key role as a proton source to improve the yield. Therefore,
for better reproducibility, two equivalents of water were used
as an additive (Table 1, entries 11–12). Eventually, under these
optimal conditions, the crude mixture was obtained in 90%
yield, as reported in entry 12 of Table 1. Further control
experiments were performed in the absence of a photocatalyst
and a light source to confirm the necessity of using Acr+-Mes
and 6 W blue LEDs; the desired product was not detected in
these cases (Table 1, entries 13–14). After optimization, we
established controllable one-pot synthesis methods to obtain
each desired product, i.e., 4a, α-cyano-γ-butyrolactone 5a, and
γ-butyrolactone 6a (Scheme 2, see details in the ESI).
To assess the generality of the developed controllable one-
pot reaction, various activated alkenes (2a–p) containing either
electron-donating (alkyl, aryl, amino, hydroxy and alkoxy) or
electron-withdrawing (ester and halogen) functional groups
were subjected to the reaction under optimal conditions (Table
2). Corresponding alcohols (3a–p), 2,3-dihydrofurans (4a–p),
and α-cyano-γ-butyrolactones (5a–e, g-o) were obtained in
good to excellent yields, and good functional group tolerance
was observed. Sterically bulky tert-butyl, phenyl-substituted
(2c, d) and o-, m-, and p-MeO-substituted (2e, l, m) alkenes
provided corresponding products in good yields, whereas
hydroxy substituted (2f), 3,4-disubstituted benzylidene
malononitrile (2n) and alkylidene malononitrile (2o-p) delivered
the desired products in slightly lower yields. Unfortunately,
amino-substituted benzylidene malononitrile is not tolerance
under reaction conditions. Notably, the Giese reactions were
completed within 4–8 h.
6
MeCN
-
7
MeCN
-
8
MeCN
-
2
9
MeCN
-
4
10
11
12
13
14
MeCNc
MeCNc
MeCN
-
4
H2O (2.0)
H2O (2.0)
H2O (2.0)
H2O (2.0)
4
4
MeCN
4
1.0
MeCN
4
aReaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), catalyst (quantity
noted), solvent (0.1 M) with 6 W blue LEDs (450 nm) irradiation at room
temperature under argon in a pressure tube. bIsolated yield of the
mixture of 3a and 4a obtained via flash column chromatography.
cAnhydrous MeCN In the absence of a light source. Acr+-Mes (9-mesityl-
10-methylacridinium perchlorate), nd = not detected.
For scaffold diversity, 3 comprising a nucleophilic hydroxyl
group and an electrophilic nitrile group in the same molecule
can be converted to diverse scaffolds, such as 2,3-dihydro-
furans 4, α-cyano-γ-butyrolactones 5, and γ-butyrolactones 6,
via controllable one-pot synthesis (Scheme 1, b). 3 is a useful
building block; and 4 and 6 are valuable scaffolds found in
natural products and pharmaceuticals.
In general, HOCH2TMS 1a can be used as a hydroxymethyl
radical precursor because HOCH2TMS 1a (Eox1/2 = +1.5 V vs SCE
in MeCN) can be more easily oxidized than methanol (Eox
+2.5 V vs SCE) via the β-silicon effect.10 Furthermore, based on
previous studies, Fukuzumi acridium salt (Acr+-Mes) can be used
as a metal-free photoredox catalyst due to its strong oxidation
ability.11 Thus, in the initial experiments, the reaction of
HOCH2TMS 1a with benzalmalonitrile 2a was performed in the
presence of MeCN/MeOH using 1 mol % Acr+-Mes under
irradiation with 6 W blue LEDs for 24 h and a mixture of alcohol
3a and 2,3-dihydrofuran 4a was obtained in 62% yield after
column chromatography (Table 1, entry 1). 1H NMR analysis of
the crude products have revealed that 3a is a single product and
4a is formed via intramolecular cyclization during purification
by column chromatography. Thus, optimization was performed
to improve the yield and to isolate the single desired product 3a
or 4a. First, to optimize reaction conditions in terms of yield,
variations in the solvent, catalyst loading, reaction time, and
additive were explored.
>
1/2
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 4
ChemComm
Please do not adjust margins
Journal Name
Table 2. Substrate scopea
COMMUNICATION
3a
4a
View Article Online
H2N
NC
HO
CN
Ph
CN
1.75 g (94%)
-1
1.71 g (92%)
HO
1a
SiMe3
DOI: 10.1039/C9CC08781H
3.0 mmol h-1
O
3.7 mmol h
pump 1
O
H2N
O
NC
CN
R
Ph
(100 mol %)
+
NC
HO
CN
R
CN
R
conditions
CN
R
BPR
HO
SiMe3
+
O
O
pump 2
CN
NC
CN
1
2
Acr+-Mes (1.0 mol %)
H2O (200 mol %)
MeCN (0.1 M), 80 o
TR=30 min
80 o
O
3
4
5
(100 mol %) (200 mol %)
C
Ph
Ph
1.50 g
C
2a
(200 mol %)
5a,
Amberlite
Entry
3b
4c
5d
3a
TR=15 min for
4a
(80%, 3:1 dr)
2.7 mmol h-1
TEA (150 mol %)
MeCN (0.75 M)
5a
and
TR=18 min for
H2N
O
O
NC
HO
CN
CN
CN
Scheme 3. Controllable synthesis for diverse scaffolds in
continuous flow process
O
R
R
R
1
2
3
4
5
6
7
8
9
3a: R= H, 90%
3b: R= Me, 85%e
3c: R= tBu, 89%
3d: R= Ph, 92%f
3e: R= OMe, 91%
3f: R= OH, 50%
3g: R= F, 80%e
3h: R= Cl, 90%f
3i: R= Br, 75%
3j: R= I, 54%f
4a, 90%
4b, 85%
4c, 89%
4d, 92%
4e, 91%
4f, 30%
4g, 80%
4h, 90%
4i, 75%
4j, 54%
4k, 89%
5a, 78%, 3:1 dr
5b, 63%, 3:1 dr
in 98% yield with the use of 10 mL tuning reactor at 80 °C on a
0.5 mmol scale with extremely shorter residence time of 15 min
(flow rate of 667 μL min−1) compared to the reaction performed
in batch on a 0.2 mmol scale over 4 h. Moreover, representative
reactions were conducted on a 10 mmol scale (see the ESI for
details), delivering diverse scaffolds such as the desired 3a, 4a
and 5a in consistently high 94%, 92% and 80% isolated yields
(3.7 mmol h-1, 3.0 mmol h-1 and 2.7 mmol h-1), respectively
(Scheme 3). To effectively synthesize 5a, a continuous flow to
batch system14 was developed, and the hydrolysis was
completed within 30 min after the collection of the crude
reaction mixture of 4a. This result demonstrates the potential
for predictable scale-up, particularly of the photoredox-
catalyzed reaction because of a high photon concentration with
a microreactor.
5c, 56%, >20:1 dr
5d, 79%, 4:1 dr
5e, 64%, 4.4:1 dr
5f, nd
5g, 50%, 3.4:1 dr
5h, 73%, 3.6:1 dr
5i, 60%, 4.4:1 dr
5j, 40%, 8:1 dr
5k, 70%, 3.6:1 dr
10
11
3k: R= CO2Me, 89%e
H2N
O
CN
Ar
NC
HO
CN
Ar
CN
O
O
Ar
12
13
3l: Ar= o-MeOC6H4, 83%
3m: Ar= m-MeOC6H4, 90%
4l, 83%
4m, 90%
5l, 69%, 3:1 dr
5m, 70%, 3.6:1 dr
Next, we explored
a controllable one-pot reaction of
H2N
O
O
NC
HO
CN
CN
CN
secondary α-silyl alcohol 1b with benzalmalonitriles (2a, 2h)
(Scheme 4, a). The secondary hydroxymethyl radical is less
reactive than the primary hydroxy methyl radical toward
alkenes. Alcohols (3ba, 3bh) and 2,3-dihydrofurans (4ba, 4bh)
were produced at good yields with low levels of
diastereoselectivity by increasing the catalyst loading (2 mol %)
and reaction time (24 h). Unfortunately, ɑ-cyano-γ-
butyrolactone was not obtained by the one-pot reaction due to
steric issues. To further highlight the broad applicability of this
controllable one-pot reaction, we investigated the scaffold
diversity of 2,3-dihydrofuran 4a and ɑ-cyano-γ-butyrolactone
5a (Scheme 4, b-c).
OAc
OAc
OAc
OMe
O
OMe
OMe
14
3n, 75%
4n, 75%
5n, 45%, 5:1 dr
H2N
O
O
O
CN
NC
HO
CN
CN
R
R
R
15
16
3o: R= i-Pr, 75%
3p: R= Cy, 83%
4o, 75%
4p, 83%
5o, 54%, 5:1 dr
5p, nd
aGiese reaction conditions: Table 1, entry 12. bIsolated via column
chromatography using 1% formic acid in the eluent. cGiese reaction
conditions; TEA (1.0 equiv) for 4 h. dGiese reaction conditions; TEA (1.0 equiv)
for 4 h; Amberlite TM IR 120 (1.5 g), H2O (0.2 mL) for 2 h. e8 h. f6 h. See ESI for
details. nd = not detected.
1b
a) controllable one-pot reaction with 2nd -silyl alcohol
H2N
O
NC
HO
CN
Ar
CN
Ar
Furthermore, 4 was converted from 3 with 100% conversion
under mild conditions using TEA as a base via intramolecular
cyclization after the Giese reaction in this controllable one-pot
reaction. However, the one-pot reaction of TMSCH2OH 1a with
alkenes 2 yielded the corresponding 5 in slightly lower yields
with moderate levels of diastereoselectivity. 4f and 4p were not
converted to corresponding 5. Remarkably, tert-butyl-
substituted benzylidenemalononitrile 2c produced anti-lactone
5c with excellent diastereoselectivity.
NC
CN
Ph
conditions
+
HO
SiMe3
Ar
Ph
Ph
2a
2h
(Ar = Ph)
(Ar = 4-ClC6H4)
1b
3ba
3bh
4ba
4bh
(73%, 1.4:1 dr)
(65%, 1.1:1 dr)
(68%, 1.7:1 dr)
(60%, 1.1:1 dr)
4a
b) conversion of 2,3-dihydrofuran
to diverse scaffolds
H2N
H2N
O
H2N
O
CONH2
CONH2
NaI
DMF
CN
Ph
CN
Ph
Pd/C
150 o
(NH4)2MoS4
MeOH
CN
S
140 o
C
C
Ph
Ph
7
4a
(40%)
8
(70%)
9
(43%)
According to the Beer–Lambert law,12 a flow process using a
microreactor can be useful for increasing the surface-area-to-
volume ratio for an increased photon concentration. Thus, we
focused on the applicability of a continuous flow process to
increase the reactivity and to enable simple, predictable scale-
up. After optimization (see the ESI for details), 3a was isolated
5a
c) conversion of -cyano--butyrolactone
to -butyrolactone derivatives
O
O
O
O
CN
Bn
Ph
1) aq. KOH, 68%
N
1) NaH, BnBr, 85%
O
O
H
O
2) EDCI, DMAP
aniline, 74 %
2) conc HCl,AcOH
76%, 14.3:1 dr
Ph
Ph
Ph
10
11
5a
(3:1 dr)
Scheme 4. a) Controllable one-pot reaction with 2nd α -silyl
alcohol 1b, b-c) Futher transformation of 4a and 5a
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 4 of 4
COMMUNICATION
Journal Name
PC*
scaffolds in a controllable one-pot reaction. In addition, we
View Article Online
HO
SiMe3
1a
demonstrated the further transformatioDnOoI:f120,.310-3d9ih/Cy9dCrCo0fu8r7a81nHs
and ɑ-cyano-γ-butyrolactones to achieve scaffold diversity for
applications in drug discovery.
PC
CN
CN
CN
CN
HO
SiMe3
H2O
I
HO
HO
This work was supported by the National Research Foundation
of Korea (NRF-2019R1C1C1004015, NRF-2019R1C1C1004453)
grant funded by the Korea government (MSIT).
PC
Ph
Ph
s
IV
s-SiMe3
3a
CN
CN
CN
CN
+
HO
Ph
HO
+
PC
: Acr -Mes, s: solvent
Ph
II
2a
III
Conflicts of interest
Scheme 5. Proposed reaction mechanism
There are no conflicts to declare.
4a can be easily converted to furan
7
by oxidative
aromatization.14a In additional, 4a was converted to
cyclopropane 8 by ring rearrangement.14b The 8 is not only an Notes and references
important motif in natural products and pharmaceuticals, but
1
(a) M. D. Burke, S. L. Schreiber, Angew. Chem. Int. Ed. 2003,
also transforms into dihydrothiophene 9. Furthermore, the 5a
was converted to amide 10, skeletal structure found in
herbicides,14c by hydrolysis and amidation. The 5a can be
alkylated under mild conditions due to the low pKa value of α-
hydrogen in lactone. The alkylation and decyanation of 5a
provided anti-butyrolactone 11 with high dr (Scheme 4, c).
Based on our previous literature9,15 and control experiments, a
43, 46; (b) W. R. J. D. Galloway, A. Isidro-Llobet, D. R. Spring,
Nat. Commun. 2010, 1, 80; (c) C. J. O' Connor, H. S. G.
Beckmann, D. R. Spring, Chem. Soc. Rev. 2012, 41, 4444; (g)
M. Garcia-Castro, S. Zimmermann, M. G. Sankar, K. Kumar,
Angew. Chem. Int. Ed. 2016, 55, 7586.
(a) D. Morton, S. Leach, C. Cordier, S. Warriner, A. Nelson,
Angew. Chem. Int. Ed. 2008, 48, 104; (b) S. L. Schreiber, Nature
2009, 457, 153.
(a) H. Oguri, S. L. Schreiber, Org. Lett. 2005, 7, 47; (b) M. P.
Plesniak, M. H. Garduño-Castro, P. Lenz, X. Just-Baringo, D. J.
Procter, Nat. Commun. 2018, 9, 4802.
(a) O. Kwon, S. B. Park, S. L. Schreiber, J. Am. Chem. Soc. 2002,
124, 13402-13404; (b) E. E. Wyatt, S. Fergus, W. R. J. D.
Galloway, A. Bender, D. J. Fox, A. T. Plowright, A. S. Jessiman,
M. Welch, D. R. Spring, Chem. Commun. 2006, 3296.
W. Liu, V. Khedkar, B. Baskar, M. Schürmann, K. Kumar,
Angew. Chem. Int. Ed. 2011, 50, 6900.
2
3
4
proposed mechanism for
a photoredox-catalyzed Giese
reaction is illustrated in Scheme 5. Single-electron oxidation of
TMSCH2OH 1a by excited Fukuzumi acridium (Acr+-Mes*)
generates a cation radical I, which is desilylated with a solvent
to produce the hydroxymethyl radical II. To confirm the
photoredox-catalyzed SET mechanism, we performed
electrochemical analysis and Stern–Volmer luminescence
quenching studies. The oxidation potential of TMSCH2OH 1a
5
6
7
8
T. G. Kilroy, T. P. O'Sullivan, P. J. Guiry, Eur. J. Org. Chem. 2005,
2005, 4929-4949.
(a) M. Seitz, O. Reiser, Curr. Opin. Chem. Biol. 2005, 9, 285; (b)
W. Lau, E. S. Sattely, Science 2015, 349, 1224.
was obtained as Eox = +1.5 V vs. SCE in MeCN by cyclic
1/2
voltammetry measurements. This result indicates that 1a can
be oxidized by Fukuzumi acridinium salt in the excited state
(+2.06 V vs. SCE) based on the Rehm–Weller equation.17
Moreover, the electron transfer between 1a and an excited
catalyst (Acr+-Mes*) was verified by Stern–Volmer
luminescence quenching experiments. The quenching
experiments demonstrated that the luminescence was
quenched in proportion to the concentration of 1a. The addition
of hydroxymethyl radical II to benzalmalonitrile 2a produces α-
cyano radical III. Further single-electron reduction of α-cyano
radical III by reduced Fukuzumi acridium (Acr•-Mes) provides α-
cyano anion IV. Finally, alcohol 3a is produced by the
protonation of α-cyano anion IV with water.
(a) T. P. Yoon, M. A. Ischay, J. N. Du, Nat. Chem. 2010, 2, 527;
(b) J. M. R. Narayanam, C. R. J. Stephenson, Chem. Soc. Rev.
2011, 40, 102; (c) J. Xuan, W.-J. Xiao, Angew. Chem. Int. Ed.
2012, 51, 6828; (d) C. K. Prier, D. A. Rankic, D. W. C. MacMillan,
Chem. Rev. 2013, 113, 5322; (e) N. A. Romero, D. A. Nicewicz,
Chem. Rev. 2016, 116, 10075.
9
N. Khatun, M. J. Kim, S. K. Woo, Org. Lett. 2018, 20, 6239.
10 J. Yoshida, T. Maekawa, T. Murata, S. Matsunaga, S. Isoe, J.
Am. Chem. Soc. 1990, 112, 1962.
11 (a) S. Fukuzumi, H. Kotani, K. Ohkubo, S. Ogo, N. V. Tkachenko,
H. Lemmetyinen, J. Am. Chem. Soc. 2004, 126, 1600; (b) K.
Ohkubo, K. Mizushima, R. Iwata, K. Souma, N. Suzuki, S.
Fukuzumi, Chem. Commun. 2010, 46, 601.
12 J. W. Tucker, Y. Zhang, T. F. Jamison, C. R. J. Stephenson,
Angew. Chem. Int. Ed. 2012, 51, 4144.
We have developed a controllable one-pot synthesis method
for the construction of valuable scaffolds (alcohols, 2,3-
13 A continuous flow to batch system enables collection of 4a at
the end of the flow process, which is simultaneously
converted to the corresponding lactone 5a via hydrolysis in
the presence of solid AmberliteTM IR 120 as an acid.
Furthermore, the initial rate of the hydrolysis reaction is
expected to be extremely high due to the high acid loading
effect, although this effect would weaken over time.
14 (a) N. Nakamichi, Y. Kawashita, M. Hayashi, Org. Lett. 2002, 4,
3955; (b) K. Yamagata, H. Maruoka, Y. Hashimoto, M.
Yamazaki, Heterocycles 1989, 20, 5; (c) T. M. Stevenson, A. D.
Satterfield (2018). U.S. Patent Application No. 15/562,917.
15 Gutenberger, G.; Steckhan, E.; Blechert, S., Angew. Chem. Int.
Ed. 1998, 37, 660.
dihydrofurans,
ɑ-cyano-γ-butyrolactones,
and
γ-
butyrolactones) through a visible-light photoredox-catalyzed
Giese reaction and further transformation. This one-pot
reaction can selectively synthesize the desired scaffold at
excellent yields with good functional group tolerance.
Furthermore, we established optimized flow reaction
conditions and demonstrated gram-scale synthesis of each
scaffold. Mechanistic studies were successfully conducted
regarding the generation of hydroxymethyl radicals from ɑ-TMS
methanol by visible-light photoredox-catalyst-mediated SET.
This simple hydroxymethyl radical can also provide diverse
16 D. Rehm, A. Weller, Israel Journal of Chemistry 1970, 8, 259.
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins