Continuous Flow α-Arylation of N,N-Dialkylhydrazones under Visible-Light Photoredox Catalysis

Article abstract of DOI:10.1021/acs.orglett.7b00117

The first direct α-arylation of aldehyde-derived N,N-dialkylhydrazones with electron deficient aryl and heteroaryl cyanides under visible-light photoredox catalysis has been developed. Structurally complex α,α′-diaryl-N,N-cycloalkylhydrazones were obtaine

Full text of DOI:10.1021/acs.orglett.7b00117

Letter
pubs.acs.org/OrgLett
Continuous Flow α‑Arylation of N,N‑Dialkylhydrazones under Visible-
Light Photoredox Catalysis
Juan A. Vega,* Jose Manuel Alonso, Gabriela Mendez, Myriam Ciordia, Francisca Delgado,
́
́
and Andres A. Trabanco*
́
Neuroscience Medicinal Chemistry, Janssen Research & Development, Jarama 75A, 45007 Toledo, Spain
S
* Supporting Information
ABSTRACT: The first direct α-arylation of aldehyde-derived
N,N-dialkylhydrazones with electron deficient aryl and heteroaryl
cyanides under visible-light photoredox catalysis has been
developed. Structurally complex α,α′-diaryl-N,N-cycloalkylhy-
drazones were obtained in moderate yields by repetition of the
direct arylation protocol. A continuous-flow procedure for the
preparation of α-aryl-N,N-dialkylhydrazones on a multigram
scale has also been established.
Scheme 1. VLPC in the Synthesis of α-Arylamines and
Reactivity of Hydrazones under VLPC
ecent decades have seen visible-light photoredox catalysis
R(VLPC) emerging not only as a versatile and useful tool
for functionalization of complex organic molecules and
biologically active heterocycles but also for the discovery and
development of novel synthetic methodologies.1 In particular,
late-stage, visible-light, photoredox-catalyzed chemoselective
functionalization of C(sp3)−H bonds adjacent to a nitrogen
atom to C(sp3)−C(sp2) bonds has recently attracted great
interest due to the prominent role α-arylamines play in
pharmaceuticals, with 8 of the 100 top-selling drugs containing
this motif. In 2011, MacMillan et al. reported the direct
arylation of α-amino C(sp3)−H bonds via nucleophilic α-
aminoalkyl radicals generated by photoredox-neutral-catalyzed
aromatic substitution reaction of electron-deficient cyanoarenes
with tertiary amines (Scheme 1a).2 In a subsequent report, this
C(sp3)−C(sp2) bond-forming methodology was extended to α-
amino acids in a direct decarboxylative arylation reaction via
VLPC.3 Doyle and MacMillan jointly reported the photoredox-
nickel catalyzed direct decarboxylative arylation of α-amino
acids with arylhalides, substantially expanding the C(sp2) pool
of aryl coupling partners able to participate in this process.4
Futhermore, an example of regioselective α,α′-diarylation of
pyrrolidines has been recently described by combination of
nickel, hydrogen-atom transfer (HAT), and dual Ni/VLPC.5
Hydrazone derivatives are considered valuable and versatile
building blocks that enable a broad array of synthetic
transformations6 and display a wide range of biological
activities.7 Despite their rich reactivity, hydrazones have been
scarcely explored in photoredox catalysis. Thus, Zhu et al. have
recently reported on the visible-light photoredox-catalyzed
C(sp2)−H difluoroalkylation of aldehyde-derived hydrazones
via an aminyl radical/polar mechanism as a novel way to
synthesize substituted hydrazones (Scheme 1b).8 This method-
ology was extended to the synthesis of fused pyrazoles9 and
dihydropyrazoles10 in a sequential functionalization of C(sp2)−
H/C(sp3)−H bonds of aldehyde hydrazones with 2,2-dibromo-
1,3-dicarbonyls via VLPC (Scheme 1c).
Higly selective difluoro- and perfluoroalkylation of C(sp2)−
H bonds in aldehyde hydrazones has also been achieved in a
gold-catalyzed visible-light photoredox reaction.11 Pyrazoline
Received: January 12, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00117
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
and pyridazine derivatives have been obtained in a cooperative
TEMPO/photoredox catalytic process via a selective oxidative
radical oxyamination of β,γ-unsaturated ketone derived
hydrazones (Scheme 1d).12 This process involved the direct
conversion of a N−H bond into a N-centered radical. More
recently, the C−H amidation of hydrazones via VLPC in a
reductive single-electron transfer (SET) umpolung mechanism
has also been reported.13
Within one of our research programs, we became interested
in the multigram synthesis of structurally complex N,N-
dialkylhydrazones of general structure B bearing an aromatic
ring in α-position to the N−N bond. Inspired by the recent
applications on VLPC with hydrazones and MacMillan’s work
on the direct arylation of α-amino C(sp3)−H bonds, we
hypothesized that hydrazones of general structure A could
undergo direct arylation of α-amino C(sp3)−H (Scheme 1e).
Therefore, herein we describe the first examples of
intermolecular arylation of α-amino C(sp3)−H bonds in N,N-
dialkylhydrazones under flow-VLPC. Iteration of the process
allows for the preparation of α,α′-diarylation products C in
moderate yields.
visible light or photocatalyst (Table 1, entries 5 and 6).
Unfortunately, when the reaction was carried out on a larger
scale (2a, 3 mmol) (Table 1, entry 7), a substantial decrease in
conversion was observed and 3aa could only be isolated in 38%
yield.14 As multigram quantities of α-arylated hydrazones were
required for our purpose, we explored the possibility of
translating the batch model conditions (Table 1, entry 2) to a
continuous-flow process using the commercially available UV-
150 photoreactor.15 Optimization studies showed that subject-
ing a 0.25 M solution of 1a (0.42 mmol), 2a (0.28 mmol),
LiOAc (2 equiv), and Ir(ppy)3 (1 mol %) in DMSO to
irradiation with 455 nm blue LEDs in a 10 mL coil with a
residence time of 10 min resulted in 86% conversion and
allowed for the isolation of 3aa in 64% yield (Table 1, entry 8).
To our delight, the results were comparable when the reaction
was scaled up to 15.3 mmol of 2a (Table 1, entry 9), and 3aa
was isolated in 75% yield.16
These continuous-flow VLPC conditions were extended to
the set of hydrazones 1a−j and cyanoaryls 2a-h shown in
Figure 1. The results obtained can be found in Table 2. N,N-
To verify our hypothesis, we selected hydrazone 1a and 1,4-
dicyano benzene (1,4-DCB, 2a) as model substrates with 1 mol
% of Ir(ppy)3 as photocatalyst under irradiation at 455 nm with
blue light-emitting diodes (LEDs). The reactions were carried
out at 40 °C with LiOAc (2 equiv) as base and DMSO as
solvent (Table 1). Our initial attempts varying 1a/2a
Table 1. Evaluation of Conditions for the Direct Arylation of
a
α-Amino C(sp3)−H Bonds in Hydrazones
b
,c
d
entry
method
1a/2a
3aa, yield (%)
3aa/4a
1
2
3
batch
batch
batch
batch
batch
batch
batch
flow
3.0:1
1.5:1
1.0:1
1.0:3
1.0:1
1.0:1
1.5:1
1.5:1
1.5:1
81
3:1
8:1
5:1
8:1
89 (68)
83
e
4
78
f
h
5
NR
g
h
6
NR
i
7
j
54 (38)
86 (64)
91 (75)
1:1
6:1
8
k
9
flow
10:1
a
Figure 1. Hydrazones and cyanoaryls to study the reaction scope.
Experiments carried out with 0.28 mmol of the limiting reagent at
b
0.25 M concentration. LCMS yields with 1,3,5-trimethoxybenzene as
internal standard. Isolated yields are shown in parentheses. In general,
c
Cycloalkyl- (1a-h), N,N-arylalkyl- (1i), and N,N-dialkylhydra-
zones (1j) derived from benzaldehydes underwent α-arylation
with a set of representative electron-deficient benzonitriles 2a−
f and 4-cyanopyridines 2g,h, and the corresponding products 3
were obtained in good to moderate yields together with variable
quantities of the corresponding α-cyano-substituted byproducts
4 (Table 2, entries 1−22). Interestingly, electron-withdrawing
substituents in the hydrazone aromatic ring (Table 2, entry 4)
are detrimental for the arylation reaction, while electron-
donating groups (Table 2, entries 3 and 19) do not have strong
influence on the reaction outcome when compared with the
plain phenyl (Table 2, entries 1 and 16). Hydrazone 1e
containing a 4-methylpiperidine ring was α-arylated to yield 3ea
as a 1:1 mixture of cis/trans diastereoisomers (Table 2, entry 5).
isolated yields of hydrazones 3 were 15−20% lower than LCMS yields
d
due to decomposition on silica gel. LCMS ratio with 1,3,5-
e
trimethoxybenzene as internal standard. Reaction time 45 min.
f
g
h
Reaction run in the absence of light. No Ir(ppy)3. NR: no reaction.
i
Experiment carried out with 3 mmol of 2a at 0.25 M concentration;
j
k
irradiation time 1 h. Residence time 10 min. Experiment carried out
with 15.3 mmol of 2a at 0.25 M concentration; residence time 10 min.
stoichiometry (Table 1, entries 1−4) were successful and the
α-arylation product 3aa was observed together with variable
amounts of byproduct 4a. The best result was obtained with 1.5
equiv of 1a (Table 1, entry 2) resulting in 89% conversion and
a 3aa/4a ratio of 8:1. The direct arylation product 3aa was
isolated in 68% yield. The reaction did not occur in absence of
B
DOI: 10.1021/acs.orglett.7b00117
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 2. Scope of the Continuous Flow Direct α-Arylation of
N,N-Dialkylhydrazones under VLPC
Scheme 2. Direct α′-Arylation of α-Arylhydrazones 3ad, 3ag,
a
and 3hd VLPC
b
b
entry
1
2
3, yield (%)
4, yield (%)
c
1
1a
1b
1c
1d
1e
1f
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2f
3aa, 75
3ba, 70
3ca, 72
3da, 22
4a, 7
c
2
4b, 4
3
4c, 11
4d, 10
traces
4f, 22
4g, 17
traces
4j, 6
4
d
5
3ea, 70
6
3fa, 75
3ga, 60
3ha, 80
3ja, 70
3ab, 70
3ac, 73
3ad, 63
3af, 68
3ag, 70
3ah, 51
3bd, 56
3be, 50
3bg, 51
3 cd, 60
3hd, 57
3id, 55
3ig, 60
7
1g
1h
1j
8
9
10
11
1a
1a
1a
1a
1a
1a
1b
1b
1b
1c
1h
1i
4a, 12
traces
4a, 11
4a, 11
4a, 9
e
12
Scheme 3. Proposed Mechanism
13
f
14
2g
2h
2d
2e
2g
2d
2d
2d
2g
g
15
traces
4b, 15
4b, 15
4b, 28
4c, 15
4h, 4
16
17
f
18
19
h
20
i
21
traces
traces
i
22
1i
a
Experiments carried out with 0.40 mmol of the cyanoaryl 2 at 0.25 M
b
c
concentration. Isolated yields. Experiment carried out with 10.6
mmol of 2a at 0.25 M concentration. Yield of a 1:1 mixture of cis/
trans diastereoisomers. Experiment carried out with 15.3 mmol of 2d
at 0.25 M concentration. Residence time 30 min. Residence time 40
min. Experiment carried out with 6.22 mmol of 2d at 0.25 M
concentration. Residence time 60 min.
d
e
new SET process with hydrazone 1a forming the radical cation
5, and the Ir(III) species that initiates the photocatalytic cycle.
Deprotonation of 5 with LiOAc followed by radical−radical
coupling of the formed α-amine radical 6 with 7 results in the
coupled product 8. Aromatization of 8 with loss of CN−
renders the α-arylation product 3aa.18 The α-amino alkyl
radical 6 can also undergo a SET event and get oxidized by an
Ir(IV) species to form the iminium intermediate 9. Reaction of
9 with the CN− group coming from 8 would explain the
formation of byproduct 4a.
In summary, the first intermolecular α-arylation of aldehyde-
derived N,N-diakylhydrazones with electron-deficient arylcya-
nides has been described. The reaction occurs under VLPC,
and an efficient flow-chemistry protocol leading to the
corresponding α-aryltated products has been developed. The
introduction of a second aryl group in α′-position was achieved
with complete regioselectivity by simple repetition of the
protocol, leading to structurally complex hydrazone derivatives.
f
g
h
i
Interestingly, α-arylation of the bicyclic hydrazone 1h was
diastereoselective and only compounds 3ha and 3hd, where the
aryl group is in trans disposition with the fused cyclopentyl ring,
were obtained (Table 2, entries 8, 20).
A second aryl group could be incorporated in α′-position of
the hydrazone cyclic amine moiety by simple repetition of the
photoredox catalytic process. Thus, hydrazones 3ad, 3ag, and
3hd were selectively arylated in the α′-position with different
cyano aromatics 2 under the VLPC continuous-flow reaction
conditions shown in entry 8 of Table 1. For this second
arylation, 2 mol % of photocatalyst, higher temperature, and
longer residence times were needed (Scheme 2). In the case of
3ad and 3ag, the corresponding products 3ada, 3adb, 3adg,
and 3agh were obtained with moderate yields and cis
diastereoselectivity ratios up to 9:1. A fourth stereocenter was
introduced in hydrazone 3hd by reaction with 1,2-dicyano-
benzene 2b where the resulting product 3hdb was obtained in
61% yield as a single diastereoisomer.17
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00117.
A plausible mechanism is outlined in Scheme 3, where an
initial SET from the excited-state form *Ir(III) of the iridium
photocatalyst to the cyanoarene 2a to form the radical anion 7
takes place. The oxidized Ir catalyst Ir(IV) then undergoes a
Experimental procedures, a comparison between batch
and continuous flow protocols, and spectral data for the
new compounds (PDF)
C
DOI: 10.1021/acs.orglett.7b00117
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(13) Zhang, M.; Duan, Y.; Li, W.; Xu, P.; Cheng, J.; Yu, S.; Zhu, C.
Org. Lett. 2016, 18, 5356.
(14) (a) Braun, A. M.; Maurette, M.; Oliveros, E. Photochemical
Technology; Wiley: New York, 1991. (b) Garlets, Z. J.; Nguyen, J. D.;
Stephenson, C. R. J. Isr. J. Chem. 2014, 54, 351.
(15) Reactor coil: 10 mL volume with an internal bore of 1.3 mm and
a wall thickness of 0.15 mm. Further information about the Vapourtec
photoreactor can be found at www.vapourtec.com.
(16) The hydrazone 3aa was hydrolyzed to the corresponding
hydrazine derivative 10 under standard conditions. Hydrazine 10 was
subsequently reduced to the amine derivative 11, applying standard
methodology. For additional details, see the Supporting Information.
(17) Only traces of the corresponding α′-cyano derivative side
product could be observed by LCMS analysis.
(18) Additionally, it cannot be ignored that the radical 6 could be
formed via sequential SET reaction from the excited-state form
*Ir(III) to the sp2 carbon of hydrazone 1a to form an intermediate α-
amino radical anion that then undergoes a 1,4-hydrogen-atom transfer
(HAT) event. For SET events on imine sp2 carbons, see: (a) Hager,
D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2014, 136, 16986. For 1,4-
HAT reaction paths see: (b) Nechab, M.; Mondal, S.; Bertrand, M. P.
Chem.−Eur. J. 2014, 20, 16034.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: javega@its.jnj.com.
*E-mail: atrabanc@its.jnj.com.
ORCID
Andres A. Trabanco: 0000-0002-4225-758X
́
Notes
The authors declare no competing financial interest.
DEDICATION
Dedicated to the memory of Prof. Jose
■
́
Barluenga.
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DOI: 10.1021/acs.orglett.7b00117
Org. Lett. XXXX, XXX, XXX−XXX