Photoredox Decarboxylative C(sp3)-N Coupling of α-Diazoacetates with Alkyl N-Hydroxyphthalimide Esters for Diversified Synthesis of Functionalized N-Alkyl Hydrazones

Article abstract of DOI:10.1021/acs.orglett.9b03020

Herein we report a metal-free photocatalytic coupling reaction for the synthesis of structurally and functionally diverse N-alkyl hydrazones from α-diazoacetates and N-alkyl hydroxyphthalimide esters. By employing Rose Bengal as a photocatalyst with yellow LEDs irradiation, over 60 N-alkyl hydrazones were synthesized. Fluorescence quenching analysis and deuterium incorporation experiments reveal that Hantzsch ester serves as both an electron donor and proton source for the reaction. This strategy offers a simple retrosynthetic disconnection for conventionally inaccessible C(sp³)-rich N-alkyl hydrazones.

Full text of DOI:10.1021/acs.orglett.9b03020

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
3
Photoredox Decarboxylative C(sp )−N Coupling of α‑Diazoacetates
with Alkyl N‑Hydroxyphthalimide Esters for Diversified Synthesis of
Functionalized N‑Alkyl Hydrazones
†
†
Chun-Ming Chan, Qi Xing, Yip-Chi Chow, Sing-Fung Hung, and Wing-Yiu Yu*
State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The
Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong
*
S Supporting Information
ABSTRACT: Herein we report a metal-free photocatalytic
coupling reaction for the synthesis of structurally and function-
ally diverse N-alkyl hydrazones from α-diazoacetates and N-alkyl
hydroxyphthalimide esters. By employing Rose Bengal as a
photocatalyst with yellow LEDs irradiation, over 60 N-alkyl
hydrazones were synthesized. Fluorescence quenching analysis
and deuterium incorporation experiments reveal that Hantzsch
ester serves as both an electron donor and proton source for the reaction. This strategy offers a simple retrosynthetic
3
disconnection for conventionally inaccessible C(sp )-rich N-alkyl hydrazones.
he hydrazone (CN−NH) functional group has found
these earlier achievements, direct N-alkylation of diazo
T
extensive applications in various disciplines including
compounds are largely limited in scope.
1
2
16
organic synthesis, medicinal chemistry, and supramolecular
Pioneered by Baran’s group, alkyl N-hydroxyphthalimide
3
chemistry. The unique azomethine motif containing a
esters (NHPI esters) are superior surrogates of carboradicals
1
7
18−23
nucleophilic imine/amino group and an electrophilic imine
carbon center has endowed distinctive physical and chemical
properties crucial for designing new materials such as covalent
for decarboxylative C−C and C−heteroatom
cross-
coupling reactions. NHPI esters would undergo single-electron
reduction to form radical anions under thermal or photo-
chemical conditions, followed by decarboxylative fragmenta-
4
5
organic frameworks, hole-transporting materials, and molec-
6
24
ular switches. Notably, most studies were limited to libraries
tion to generate alkyl radicals. Here, we describe a
of (hetero)aryl-substituted hydrazones; few studies were
photocatalytic decarboxylative radical cross-coupling of alkyl
N-hydroxyphthalimide ester with diazoacetates for the syn-
thesis of skeletal and functionally diverse N-alkyl hydrazones
(Scheme 1f). This photoredox cross-coupling reaction is highly
modular by independently varying the diazo esters and the
NHPI ester structures under metal-free conditions.
3
designed to examine libraries of C(sp )-rich N-alkyl
7
hydrazones. The current lack of synthetic routes to access
functionally and structurally diverse N-alkyl hydrazones
severely limits the realization of the full potential of this class
of molecules.
To begin, we treated α-(4-bromophenyl)diazoacetate 1a
While diazo compounds are versatile reagents for metal-
8
(
0.1 mmol) with N-cyclopentyl NHPI ester 2a (0.15 mmol),
Hantzsch ester (1.2 equiv), and 1,8-diazabicyclo(5.4.0)undec-
-ene (DBU, 2.3 equiv) with Rose Bengal in CH Cl (1.0 mL)
carbene mediated C−C bond formations, we are attracted to
some studies using diazo compounds for selective C−N bonds
9
7
coupling reactions to afford hydrazones. A classic example is
2
2
at room temperature under illumination by 22 W blue LEDs
450 nm) for 12 h, and N-cyclopentyl hydrazone 3a was
the Japp−Klingemann reaction, in which aryldiazonium salts
10
(
react with β-ketoesters or acids to form hydrazones. The
11a,b
11c
obtained in 99% yield (Table 1, entry 1). No desired product
was obtained without Rose Bengal (entry 2). Performing the
reaction using Fluorescein and Eosin Y was found to promote
the hydrazone formation in 82−88% yields (entries 3−4). The
research groups of Takamura
and Zhao independently
reported nucleophilic N-alkylation of diazoesters by organo-
lithium and Grignard reagents to afford N-alkyl hydrazones
(Scheme 1a). Notably, Feng and co-workers developed the
analogous reactions employing [Ru(bpy) ]Cl and [Ir(ppy)-
catalytic asymmetric α-hydrazonation of ketones with diazo-
3
2
12
(
bpy) ]PF as photocatalysts also gave the desired N-
esters (Scheme 1b). In 2016, Cui and co-workers reported
an Fe-catalyzed alkene hydroamination with diazo esters to
2 6
cyclopentyl hydrazone 3a in 95−99% yield (entries 5−6).
For the solvent effect, common organic solvents such as
13
furnish N-alkyl hydrazones (Scheme 1c). Likewise, Wang
and co-workers developed a Cu(I)-catalyzed aminoborylation
of alkenes with diazo esters to produce borylated hydrazones
CH OH, DMF, and toluene gave poor results (entries 7−9).
3
Evidently, organic bases are critical for effective hydrazone
1
4
(
Scheme 1d). Recently, Nikolaev and co-workers reported
photoactivated coupling of 2-diazocyclopentane-1,3-diones
with THF to form N-alkyl hydrazones (Scheme 1e). Despite
Received: August 23, 2019
15
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03020
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. N-Alkyl Hydrazones Synthesis by N-Alkylation of
Diazo Compounds
K CO as bases (entries 10−11). No 3a formation was formed
2
3
in the absence of bases (entry 12). Regarding the use of DBU,
less effective coupling reactions (<5−22% product yield) were
observed when DBU (0.1 and 1.0 equiv) was used (entries
1
3−14). It was found that a stoichiometric amount of
Hantzsch ester is necessary for complete reaction (entries
1
1
5−16). To our delight, employing 22 W yellow LEDs (entry
7) produced the best results with 99% of 3a formation being
achieved in 6 h (see Supporting Information for details).
With the optimized conditions in hand, we next examined
the scope of the diazo esters. Diazo esters with electron-
donating (FG = 4-Me, −OMe, −NH ) and -withdrawing (FG
2
=
4-F, −CF , −Cl) substituents on the para-position of the aryl
3
groups are equally effective coupling partners, and the
corresponding hydrazones 3a−3f were obtained in 62−99%
yields (Scheme 2A). Diazo esters bearing functional groups on
ad
Scheme 2. Substrate Scope Study on Diazo Compounds
Table 1. Optimization of Reaction: Catalysts, Solvents and
−
a b
Additives
b
entry
variation from standard conditions
none
without RB
yield (%)
1
2
3
4
5
6
7
8
9
99
<5
82
88
99
95
22
36
<5
88
<5
<5
<5
22
13
99
99
Eosin Y instead of RB
Fluorescein instead of RB
[Ru(bpy) ]Cl instead of RB
3
2
[Ir(bpy)(ppy) ]PF instead of RB
2
6
CH OH instead of CH Cl
2
a
3
2
Reaction conditions: 1 (0.1 mmol), 2 (0.15 mmol), Rose Bengal
DMF instead of CH Cl
2
2
(
5.0 mol %), Hantzsch ester (1.2 equiv) and DBU (2.3 equiv), in
toluene instead of CH Cl
2
2
CH Cl (1.0 mL) under 22 W yellow LEDs (585 nm) at room
temperature for 6 h. Isolated yield. NMR yields. 4-MeOC H
2
2
b
c
d
10
11
12
13
14
15
16
17
iPrNEt instead of DBU
2
6
4
K CO instead of DBU
instead of Ph on diazo.
2
3
without base
0.1 equiv of DBU
1.0 equiv of DBU
0.1 equiv of HE
1.5 equiv of HE
other positions such as 2-Me (3i), 2-MeO (3j), and 2,6-
disubstituted (FG = 2-Cl, 6-F) (3k) diazo ester reacted
successfully to give hydrazones in comparable yields (62−
75%). A series of α-phenyldiazoacetates derived from simple
22 W yellow LED (585 nm) for 6 h
aliphatic alcohols reacted with 2a to afford 3l−3p in 69−86%
yields. Notably, diazoesters bearing reactive CC bonds are
also compatible with this reaction furnishing 3q (78%), 3r
(79%), and 3s (62%) in good yields.
a
Reaction conditions: 1a (0.1 mmol), 2a (0.15 mmol), catalyst (5.0
mol %), solvent (1.0 mL), additives (2.3 equiv), and Hantzsch ester,
N under 22 W blue LED irradiation (450 nm) at room temperature
for 12 h unless otherwise specified. NMR yield.
2
b
Heteroaromatic functions such as thiophenyl (4c: 76%; 4d:
7
2%) and indolyl groups (4e: 69%) are compatible with the
25
formation, and DBU (2.3 equiv) seems to furnish the best
coupling reaction (Scheme 2B). The diazo substrates with a
results (3a in 99% yield) compared to those using iPrNEt and
CF group was also found to be effective coupling partners,
2
3
B
DOI: 10.1021/acs.orglett.9b03020
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
and the corresponding hydrazone 4f was formed in 42% yield.
For alkyl-substituted diazo derivatives, the corresponding
hydrazones 4g−4j were formed in ca. 45% yields based on
NMR analysis of the crude reaction mixture. An attempt to
isolate 4g−4j by column chromatography was futile, as the
isolated compound readily decomposed.
The synthetic versatility of this reaction is further explored
with the scope of the NHPI esters. With 1a as substrate, we
first examined the reactivity of tertiary alkyl radicals (Scheme
are also achieved to afford the corresponding hydrazones in
73% and 76% yield, respectively.
The coupling reactions employing secondary alkyl radicals
involving 2-propyl, 2-butyl, 2-pentyl, 2-hexyl, 2-heptyl, 3-
pentyl, 3-heptyl, and 4-heptyl radicals gave excellent product
yields (6a−6h, 76−97%) (Scheme 3B). The desired cyclo-
butyl- (6i) and cyclohexyl- (6j) hydrazones were also formed
in 63−76% yields. 4-Methyl- (6k) and 4-difluoro- (6l)
substituents on the cyclohexyl- ring are excellent coupling
partners for the transformation, and up to 70% yields of the
desired hydrazones were obtained. 1-Adamantyl- (6m),
pyranyl- (6n), and piperidinyl- (6o) type radicals are effective
for the hydrazones formation (63−70% yields). It is well
accepted that primary radicals are less accessible than those
secondary and tertiary radicals. To our pleasure, successful
coupling reactions were achieved for the primary alkyl radicals
3
A). Trisubstituted carbon radicals such as tert-butyl and 2-
methylalkyl radicals are effectively coupled to the diazo, and
the corresponding hydrazones 5a−5d were furnished in 92−
9
9% yields. A gram-scale reaction has been performed with 1.4
g of 5a being obtained in 83% yield. The coupling reactions
with 1-methylcyclohexyl (5e) and 3-noradamantyl (5f) radicals
(
7a−7e) to give the corresponding hydrazones in 52−72%
Scheme 3. Substrate Scope Study on NHPI Esters ,
a e
yields (Scheme 3C).
Coupling reactions of 1a with NHPI esters derived from
some natural products such as abietic acid (8a) and
gemfibrozil (8b) gave the corresponding hydrazones in 65−
6
9% yields (Scheme 3D). Interestingly, the coupling reaction
employing NHPI ester derived from citronellic acid produced
8
c in 77% yield. Presumably, the primary radical (CA′)
undergoes spontaneous radical addition to the CC bond to
generate a tertiary radical (CA′) prior to the N-alkylation of
the 1a. For the reactions with N-acetyl amino acids derived
NHPI esters, the expected hydrazone products were found to
undergo further transformation to afford 1,2,4-triazoles 10a−
1
0d in 62−73% (Scheme 3E). 1,2,4-Triazoles are key skeletons
26
of many applicational compounds, which are conventionally
prepared by intramolecular cyclization of N-acyl amidrazones
and carboxylic acid derivatives. Several copper-catalyzed 1,2,4-
triazoles synthesis are known in the literature. Our protocol
offers an alternative approach for direct access to this class of
molecules under mild conditions.
27
Regarding the mechanism, addition of TEMPO suppressed
the 3a formation in a concentration-dependent manner
consistent with a radical-mediated transformation. For
instance, when 1.5 equiv of TEMPO was used, no 3a
formation was detected and the TEMPO-trapped radical 2a′
can be detected by GC-MS (Scheme 4a). The role of Hantzsch
ester has been examined by deuterium incorporation experi-
ments using a series of deuterated Hantzsch esters (Scheme
28
4
b). Under the standard reaction conditions with the 1-d-
Scheme 4. Radical Trap Experiments and Deuterium
a
Isotope Studies
a
Reaction conditions: 1a (0.1 mmol), 2 (0.15 mmol), Rose Bengal
(
5.0 mol %), Hantzsch ester (1.2 equiv) and DBU (2.3 equiv), in
a
CH Cl (1.0 mL) under 22 W yellow LEDs (585 nm) at room
temperature for 6 h. Isolated yield. Gram scale: 83%, 1.4 g. NMR
yield. Ar = Ph, E = CO Me.
Reaction conditions: 1a (0.1 mmol), 2a (0.15 mmol), Rose Bengal
2
2
b
c
d
(5.0 mol %) and DBU (2.3 equiv), in CH Cl (1.0 mL) under 22 W
yellow LEDs (585 nm) at room temperature for 6 h. NMR yield.
2
2
e
b
2
C
DOI: 10.1021/acs.orglett.9b03020
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Figure 1. (a) Excitation of the Rose Bengal at wavelength 565 nm resulted in an emission band at λmax = 575 nm. (b) The emission intensity of the
5
plot.
75 nm band is dependent only on the [Hantzsch Ester]. (c) The fluorescence quenching of RB by Hantzsch Ester display a linear Stern−Volmer
3
Hantzsch ester (i.e., N−D labeled) as reagent, 24% (3a′)
radical R ·. The alkyl radical would then couple to the terminal
3
deuterium incorporation was observed on the corresponding
nitrogen of the diazo compound to give a C(sp )−N bond. To
hydrazone product. When the 4,4-d Hantzsch ester and 1-d,
furnish the hydrazone product, the nitrogen-centered radical
should undergo hydrogen-atom abstraction from the cationic
radical Hantzsch ester.
2
4
,4-d Hantzsch ester derivatives were employed, higher levels
2
of deuteration of the hydrazones were observed [56% (for 4,4-
d -HE) and 61% (for 1-d, 4,4-d -HE)]. This result implies that
the Hantzsch ester is involved in the N−H bond formation for
product turnovers.
In summary, we have developed a metal-free photocatalytic
synthesis of structurally and functionally diverse N-alkyl
hydrazones from α-diazoacetates and alkyl N-hydroxy-
phthalimide esters. This photoredox strategy offers a simple
retrosynthetic disconnection for conventionally inaccessible
C(sp )-rich N-alkyl hydrazones that may be of interest for
designing advanced materials and drug discovery.
2
2
Moreover, we performed luminescence quenching experi-
ments of Rose Bengal with NHPI ester 2a, DBU, and Hantzsch
ester. Upon excitation at λmax = 565 nm, the fluorescence
intensity at λmax = 575 nm was observed and monitored at
various quencher concentrations (Figure 1a and 1b).
Apparently, only Hantzsch ester showed effective luminescence
quenching of the Rose Bengal in a concentration-dependent
manner (Figure 1c). This result clearly suggests that the
excited state of the Rose Bengal is quenched selectively by the
Hantzsch ester.
3
ASSOCIATED CONTENT
■
*
S
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03020.
Based on the above findings, a plausible mechanism is
proposed (Scheme 5). Photoexcitation of the Rose Bengal
Experimental procedures, physical characterization data
1
13
19
(
H, C, and F NMR spectra) of the substrates and
Scheme 5. Proposed Mechanism
products, photochemical experiments, UV−vis titration
studies, Stern−Volmer luminescence studies, and cyclic
voltammetry studies (PDF)
AUTHOR INFORMATION
■
*
Corresponding Author
E-mail: wing-yiu.yu@polyu.edu.hk.
ORCID
Wing-Yiu Yu: 0000-0003-3181-8908
Author Contributions
†C.-M.C. and Q.X. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
•
−
(
+
RB) should generate an excited state RB* [E(RB*/RB ) =
0.81 V vs SCE]; and the RB* would react with Hantzsch
Financial support of The Hong Kong Research Grants Council
(PolyU 153037-14P, PolyU 153023-17P) and The State Key
Laboratory for Chemical Biology and Drug Discovery
(Postdoctoral Fellowship, Dr. Qi Xing) and assistance in
electrochemical experiments by Dr. Kwong-Chak Cheung and
Mr. Hiu-Lok Ngan (The Hong Kong Polytechnic University)
are gratefully acknowledged.
•+
ester [E(HE /HE) = +0.89 V vs SCE] by single-electron
•
−
transfer (SET) to afford the Rose Bengal radical anion (RB ).
The RB• [E(RB/RB ) = −0.99 V vs SCE] should reduce
−
•−
29
•−
the NHPI esters [E(NHPI/NHPI ) = −1.32 V vs SCE] by
3
0
SET, followed by C−C bond fragmentation to give alkyl
D
DOI: 10.1021/acs.orglett.9b03020
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
State Dye-Sensitized Solar Cells. J. Phys. Chem. C 2014, 118, 7832.
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(
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E
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2
1
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photoabsorption characteristic coincides with the use of yellow LED
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2
(
(
019, 141, 3854.
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the signle-electron reduction of the NHPI ester by the RB• should
be thermodynamically unfavorable. We hypothesized the hydrogen
−
(
19) For selected examples for C−N coupling of NHPI esters, see:
3
(
a) Mao, R.; Frey, A.; Balon, J.; Hu, X.; Decarboxylative, C. sp )−N
F
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bonding interaction of the NHPI ester with the protonated DBU
should shift the NHPI reduction anodically, and the single electron
•
−
reduction of the NHPI by RB would become spontaneous. For a
related reference, see: Sherwood, T. C.; Xiao, H.-Y.; Bhaskar, R. G.;
Simmons, E. M.; Zaretsky, S.; Rauch, M. P.; Knowles, R. R.; Dhar, T.
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G
DOI: 10.1021/acs.orglett.9b03020
Org. Lett. XXXX, XXX, XXX−XXX