Versatile synthesis of 4-aryl chroman and 1-aryl tetralins through metal-free reductive arylations

Article abstract of DOI:10.1002/ejoc.201801375

A metal free approach was developed for accessing 4-aryl chromans and 1-aryl tetralins from their commercially available building blocks. This operationally simple protocol was well tolerated with the presence of labile functional groups, providing biologically relevant chemical libraries, which can be used for late stage modification. Dearylated analogues of the drugs Ormeloxifene and Lasofoxifene were synthesized using this approach.

Full text of DOI:10.1002/ejoc.201801375

A Journal of
Accepted Article
Title: Versatile Synthesis of 4-aryl Chroman and 1-aryl Tetralins
through Metal free Reductive Arylations
Authors: Gautam Panda and Srinivas Lavanya Kumar M
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801375
Link to VoR: http://dx.doi.org/10.1002/ejoc.201801375
Supported by

10.1002/ejoc.201801375
European Journal of Organic Chemistry
FULL PAPER
Versatile Synthesis of 4-aryl Chroman and 1-aryl Tetralins
through Metal free Reductive Arylations
Gautam Panda,*[a], [b] Srinivas Lavanya Kumar M[b]
serotonin reuptake inhibitor also endorses 1-aryl tetralin skeleton.
Abstract: A metal free approach was developed for accessing
4-aryl chromans and 1-aryl tetralins from their commercially
available building blocks. This operationally simple protocol was well
tolerated with existence of labile functional groups providing
biologically relevant chemical libraries which are poised for their late
stage modification. Dearylated analogues of drugs Ormeloxifene and
Lasofoxifene were synthesized using this approach.
The antimitotic agent podophyllotoxin Fig:1, (V) has a very
distinguished biological profile8 and known as potent inhibitor of
microtubule assemblage. Its semisynthetic derivatives9
etoposide and teniposide were relatively less cytotoxic and are
presently used as frontline cancer chemotherapeutics. The
pauciflorol-F, caraphenol-B, ampelosine-D which are much
familiar as the oligomers10 of resveratrol shares this common
congeners. The ethanolic extract from the bark of M. robusta
constitutes several bioactive neolignans of this class.11 The
chiroptical studies12 on these systems revealed that these
molecules exhibited essential switching properties like dynamic
helicity and thermal stability.
Accessing a divergent functional library of 4-aryl chromans
and 1-aryl tetralins is however complemented with the synthetic
limits. A careful literature study specifies that retrosynthetic
deficiencies exist in accessing these widely acknowledged
architectures through a unified approach. Their conventional
synthesis13 involves a 2 steps protocol; the addition of aryl
Grignard or lithium on the chromanone/ tetralone skeletons and
dehydrating them to their alkenes followed by Pd catalysed
hydrogenation of these alkenes. The convergent approach
Introduction
4-Aryl chromans and 1-aryl tetralins are essential structural
components which are generally found integrated into the cores
of several secondary metabolites and pharmaceutically
important molecules. Their clinical efficiencies were well
documented1 exhibhiting a diverse array of therapeutic contours
thereby compelling reposition2 in the drug discovery pipeline.
Notable drug candidates in this realm includes centchroman
(ormeloxifene)3 and lasofoxifene4 Fig:1, (I) and (III) which are
potent non-steroidal selective estrogen receptor modulators
(SERMs) and are currently being marketed. The prospective
drug candidate NNC 45-0781 Fig: 1, (II)5 developed for post-
menopausal osteoporosis holds 4-aryl chroman in its
pharmacophore. The flavonoid Myristinin A,6 Fig:1, (IV) isolated
from Myristica cinnamomea and Knema elegans, displays
antifungal and DNA -polymerase inhibitory activities. The anti-
depressant sertraline7 which belongs to the class of selective
N
N
N
O
O
O
MeO
O
HO
O
HO
Centchroman I
NNC 45-0781 II
Lasofoxifene III
OMe
OMe
OH
O
MeO
10
O
O
HO
OH
O
O
HO
O
OH
OH
Podophyllotoxin V
Myristinin A IV
[a]
[b]
Prof. Dr. Gautam Panda; Mr. Srinivas Lavanya Kumar M; Academy
of Scientific and Innovative Research, New Delhi 110001, India.
Fax: (+91)-522-2771941; Phone: (+91)-522-2772450, ext 4659;
E-mail: gautam_panda@cdri.res.in; gautam.panda@gmail.com
CSIR-Central Drug Research Institute, BS 10/1, Sector 10,
Jankipuram extension, Sitapur Road, Lucknow 226031, India
Fig:1 Some structurally important 4-aryl chromans and 1-aryl tetralins
(a, scheme-1) developed by Zanda14 et al was an aryl sulfoxide
based alkylation/cyclization sequence on electron rich aryl
systems. Hajra et al demonstrated that rationally tethered
alkenes15 can be used to develop these architectures through
lewis acid promoted halo-arylations (b, scheme-1). Urbano et al
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801375
European Journal of Organic Chemistry
FULL PAPER
in an effort to synthesize 8-aryl-2-tetralones,16 demonstrated the
synthesis of 1-aryl tetralins by selective Birch reduction of 1-aryl-
Results and Discussion
a
pioneering report,17a K. A.
All the sulfonyl hydrazones of chromanones and tetralones
were prepared as per standard procedures.23, 24c At the outset,
we engaged chroman derived tosyl hydrazone 1aA with phenyl
boronic acid 2a for the title transformation under Barleunga
conditions,23 (Table-1, entry-1) resulting 42% of 4-aryl chroman
3a. CaCO3 couldn’t initiate any tosyl hydrazone decomposition
whereas Ag2CO3 resulted in complete decomposition of starting
materials. K3PO4 promoted this thermolytic cross-coupling about
39%, but Cs2CO3 seemed optimal (Table-1, entry-4, 5). Organic
bases remained ineffective and N-alkylated products became
dominant when any nucleophilic base was used (Table-1, entry-
6, 7).29,30,31,32 Molecular sieves and additives such as (n-Bu)4NI,
KI were already proved detrimental for this coupling.24c,29
Temperatures below 110ºC resulted in either prolonged reaction
times or poor conversions. (Table-1, entry- 8, 9). pKa of the
conjugate acid that corresponds to the sulfonyl group on the
hydrazone had a remarkable effect on the product outcome.
With electron-poor aryl sulfonyl hydrazones, rate of
decomposition becomes faster but either alkene or dimerized
products were observed at larger extent. (Table-1, entry- 10,
11).31 Electron-rich sulfonyl hydrazones needed longer reaction
times but yields appeared optimal and p-methoxyphenyl sulfonyl
hydrazone (pmp) 1ad analogue underwent this metal free
coupling reaction resulting 68% of chroman. This prompted us in
using 4- methoxybenzene substituted sulfonyl hydrazones in
subsequent reactions. A short screen was set using the
solvents having boiling range higher than 90 oC. Reaction
became sluggish with DMSO and DMF (Table-1, entry- 14, 15).
Yields were moderate while using solvents such as
nitromethane and fluorobenzene (Table-1, entry- 17, 18).
Although dioxane resulted in comparable yield, optimal
conditions were chosen considering toluene as solvent, and
Cs2CO3 as base.
7-methoxynaphthalenes. In
Jorgenson developed diphenyl prolinol ether catalysed Friedel-
Crafts cyclization cascade between unsaturated aldehydes
and phenols to access the 4-aryl chromans. Later, this strategy
17b
was extended to the naphthols by Wang
et al and to the
unsaturated ketoesters.17c Pericas et al utilized a lewis
acid18 catalyzed cyclization of aryl glycidyl ethers for
synthesizing 4-aryl 3-chromanols. Wang et al also synthesized
these structures through one pot tandem process19 employing a
lewis acidic ionic liquid BPyCl–SnCl2·2H2O. However, the
synthesis
of
these
4-aryl
chromans
through
orthoquinomethides20 necessitates the choice of specially
functionalized, relatively unstable substrates and requires
stringent reaction conditions.
R2
R2 Ar
R1
Bronsted acid
Ar
R1
promoted cyclization
a
R3
S
X
R3
X
O
NH
O
X= O, CH2
Ar
Ar
Ar
Br
Br
NBS, MLn (Cat)
b
X
X
X
X= O, CH2
Scheme-1 Previously reported convergent strategies for developing
4-aryl chromans and 1-aryl tetralins
Given our ongoing efforts towards synthesizing chroman
based scaffolds of medicinal and synthetic importance,21 we
undertook the objective of developing a unified approach to
access diversely substituted 1-aryl tetralins and 4-aryl chromans
and the related libraries from their carbonyl feedstock. The
easily accessible hydrazones were demonstrated as versatile
building blocks by several research groups.22 In a seminal report,
Barleunga23 et al developed base induced reductive arylation of
tosyl hydrazones with aryl boronic acids circumventing the
necessity of transition metal catalysts. This approach was
validated on a wide range of substrates in terms of both coupling
partners where conventional organometallic reagents were
proven incompatible. This coupling strategy was later highly
generalized with α-heterocyclic aldehyde and ketone derived
tosyl hydrazones and also with allyl, alkenyl and even alkyl
boronic acids by several groups.24 This strategy was extended to
several C(sp3)-heteroatom couplings such as C-O,25 C-S,26 C-F,
C-N,27 C-P28 systems. Accordingly, we anticipated that tosyl
hydrazones would be a very good precursors to develop a
relatively mild and operationally simple protocol for establishing
this highly demanding C(sp3)−C(sp2) bonds and to develop a
library with an access to late stage functional group
modifications.
R
O
O
S
HN
N
O
B(OH)2
+
O
1a a-e
3a
2a
1aA R: 4-Me
1aB R: 4-Br
1aC R: 4-NO2
1aD R: 4-OMe
1aE R: H
Table 1. Optimization studies
Time
(h)
Yield
(%)b
Entrya
Hydrazone
Solvent
Base
1
2
1aA
1aA
Toluene
Toluene
K2CO3
CaCO3
12
24
42
NR
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801375
European Journal of Organic Chemistry
FULL PAPER
demanding chromans (3eh, 3ee) could also be accessed
utilising this coupling approach. Chroman systems such as 3b
and 3d typically constitute the cores of drugs Ormeloxifene and
NNC 45-0781 providing direct access to their libraries.
3
4
1aA
1aA
1aA
1aA
1aA
1aA
1aA
1aB
1aC
1aD
1aE
1aD
1aD
1aD
1aD
1aD
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DMF
Ag2CO3
Cs2CO3
K3PO4
14
10
14
15
24
20
36
7
NDc
58
5
39
O
O
O
6
KOtBu
-
S
Br
7
NaOH
<10 d
51e
26 f
34
O
O
O
O
O
3ae, 71%
3aa, 76%
3ab, 68%
F
3ac, 77%
3ad, 80%
8
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
S
O
9
S
10
11
12
13
14
15
16
17
18
O
O
O
O
O
O
O
3ah, 72%
3ag, 67%
3bi, 65%
3be, 54%
3af, 74%
3
<10 c
76
O
F
14
10
18
10
10
14
12
S
Br
Br
F
Br
48
O
O
O
O
O
O
O
3ce, 66%
3bb, 56%
3bg, 42%
3cj, 69%
3df, 72%
19
S
O
O
O
S
c
S
DMSO
-
F
TsO
O
Dioxane
Nitro methane
Floro benzene
68
40
64
O
O
O
TsO
O
3fe, 67%
3eh, 61%
3fc, 69%
3di, 74%
3ee, 56%
Table:-2 Synthesis of 4-aryl chromans from reductive arylation of hydrazones
After successfully testing this methodology in synthesizing
4-aryl chromans, we intended to expose the hydrazones derived
a Reaction conditions: 0.5 mmol of 1a(A-E); 0.75 mmol of boronic acid; 1 mmol
b
base, sealed tube, 110 ºC Isolated yields cdecomposed starting materials or from 4-methoxy benzene sulfonyl hydrazide and
complex reaction mixture d N-alkylated products observed e Reaction performed at
90 ºC f Reaction performed at 70 ºC, NR: No Reaction, ND: Not Determined.
OMe
O
O
S
R2
HN
With the optimal conditions, the generality of this metal
free coupling reaction was evaluated. Hydrazones synthesized
from both commercially available and tailor-made chromanones
were subjected to this reductive arylations. A range of boronic
acids including electron rich, heteroaryl and even halogen
substituted boronic acids participated in this coupling providing
moderate to excellent yields. However, electron rich boronic
acids resulted in slightly better yields (Table 2; 3ac, 3ad, 3af,
3di, 3fc). Electron rich chroman system suffered from
comparatively less yields (Table 2; 3be, 3bb, 3bg) probably due
to the reluctance of stabilized carbenes to participate in the
coupling. Accordingly, chromans bearing electron deficient
substitutions such as F, Br, OTs (1d, 1c, 1f) underwent this
reaction in good yields (Table 2; 3df, 3di, 3ce, 3cj, 3fc, 3fe).
Functional groups such as OTs, Br survived this coupling
conditions which are usually found to be incompatible with
typical metal promoted couplings, providing a handle for late
stage functional group modification and thus generating diverse
chemical libraries having sensitive groups. The sterically
N
B(OH)2
Cs2CO3
+
Toluene,
110 °C
R
R
R2
2
R1
4
R1
5
OMe
S
O
5bj, 74%
5ae, 77%
5af, 85%
O
O
NHBoc
5cc, 78%
NHBoc
5ca, 81%
Table:-3 Synthesis of 1-aryl tetralins from hydrazones
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801375
European Journal of Organic Chemistry
FULL PAPER
tetralones to this coupling conditions. Delightfully, several
hydrazones underwent this coupling reaction to give products
having relatively labile functionalities (Table:3) in excellent yields.
Tetralin hydrazones served as better coupling partners than
chromanones resulting in slightly higher yields as the later
suffers from assistance of ethereal oxygen.
Experimental Section
General procedure B for the preparation of 4-aryl chromans and 1-
aryl tetralins:
To the 0.5 mmol of hydrazone, was added 0.75 mmol of boronic
acid and 1 mmol Cs2CO3 followed by 2 ml toluene in a screw-capped vial.
The reaction mixture was sealed under N2 atmosphere and was allowed
to heat at 110ºC and TLC was monitored. After the completion of reaction,
toluene was evaporated and brine solution was added to the reaction
mixture. It was extracted with DCM and dried over Na2SO4. Purification
over column chromatography resulted final compounds.
This approach can be conveniently explored for
constructing the dearylated analogues of drug molecules
ormeloxifene and lasofoxifene. Hydrazone systems 1b, 4b here
serve as viable precursors for assembling this essential
C(sp3)−C(sp2) bond targeting these valuable architectures.
Under optimal conditions, hydrazones 2bd, 4bd were made to
react with synthetically prepared boronic acid 2k (scheme: 2) for
installing aryl pendant on the cores of these hydrazones
resulting 3bk and 5bk respectively. The 3bk and 5bk upon
debenzylation were alkylated with chloroethyl pyrrolidine
hydrochloride 6 leading to dearylated ormeloxifene 7 and
lasofoxifene 8 respectively with high yields.
General procedure C for the debenzylation:
To an oven dried RB fitted with the septum, 1 mmol of benzopyran
or tetralin was dissolved in methanol under nitrogen atmosphere and
then added 0.1 mmol of Pd/C which was further degassed and backfilled
with nitrogen. Then hydrogen was introduced slowly turning off the
nitrogen supply and reaction was ran for 3 hrs. Within 4 hrs starting
material was consumed as evidenced from TLC and reaction mixture
was filtered through celite bed. The filtrate was concentrated resulting in
debenzylated analogue quantitatively. The products were utilized for
subsequent reaction without any purification.
General procedure D for the alkylation with 1-(2-Chloroethyl)pyrrolidine:
To the 1 mmol of debenzylated analogue dissolved in acetone,
was added 2.2 equiv of K2CO3 and 1.05 equiv of 1-(2-
chloroethyl)pyrrolidine hydrochloride and refluxed overnight. TLC was
monitored and after the consumption of starting material, acetone was
distilled off. Reaction mixture was partitioned between brine and EtOAc.
Organic layer was collected, dried over Na2SO4, concentrated and
column chromatography was performed.
General procedure E for the preparation of (4-(benzyloxy)phenyl)boronic
acid 2k:
Scheme:2 Synthesis of dearylated analogues of Ormeloxifene and
To the oven-dried RB equipped with magnetic stir-bar sealed with
septum, was added 1.0 mmol of 1-(benzyloxy)-4-bromobenzene in dry
THF. At -78ºC, about 1.5 equiv of 2M n-BuLi was added and stirred at
that same temperature for 1 hr. Later, about 1.2 mmol of trimethyl borate
was added and reaction was allowed to stir for 8 hrs at ambient
temperature. Upon the completion of reaction as confirmed by TLC, it
was quenched with sat. NH4Cl solution and extracted with EtOAc 3 times.
Organic layer was dried under sodium sulphate and concentrated.
Column chromatography was performed.
Lasofoxifene
Conclusions
We developed a metal free approach for the synthesis of
4-aryl chromans and 1-aryl tetralins from their carbonyl
feedstock. With easily accessible hydrazones, this strategy
displayed a very good propensity to engage a range of aryl
boronic acids to give highly valuable 4-aryl chromans and 1-aryl
tetralins. This approach tolerated a relatively labile functionality
allowing access to their modification at later stages. Chromans
3b, 3c and 3d constitute the core of the Ormeloxifene and NNC
45-0781 respectively while tetralin systems 5b represent the
libraries of Lasofoxifene. This versatile methodology can also be
utilized for assembling the tetralin and chroman core of other
related drugs.
1-(2-(4-(7-methoxy-2,2-dimethylchroman-4-yl)phenoxy)ethyl)pyrrolidine
7:
Following the experimental procedure C, benzopyran 3bk was
debenzylated resulting the hydroxyl counterpart of 3bk which was
subsequently utilized for the alkylation reaction. The chroman analogue 7
was obtained after an overnight reflux following the experimental
procedure D as colorless oil in 85% yield. R¬f = 0.5 (6% methanol/DCM).
1H NMR (400 MHz, CDCl3, 25oC): δH 7.09 (d, J= 8.00 Hz, 2H), 6.87 (d,
J= 7.80 Hz, 2H), 6.63 (d, J= 8.26 Hz, 1H), 6.38-6.34 (m, 2H), 4.12-4.06
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801375
European Journal of Organic Chemistry
FULL PAPER
Maloney, J.-Z. Deng, S. R. Starck, Z. Gao, S. M. Hecht, J. Am. Chem.
Soc. 2005, 127, 41404141.
(m, 2H), 3.98-3.95 (m, 1H), 3.75 (s, 3H), 2.92 (t, J= 5.64 Hz, 2H), 2.64
(bs, 4H), 2.00-1.89 (m, 2H), 1.82 (bs, 4H), 1.43 (s, 3H), 1.35 (s, 3H) ppm.
13C NMR (100 MHz, CDCl3, 25 oC): δC 159.31, 157.55, 154.85, 137.33,
130.37, 129.53, 117.21, 114.63, 107.09, 101.48, 74.94, 66.99, 55.20,
55.10, 54.68, 43.77, 38.53, 29.95, 24.25, 23.49 ppm.
[7]
(a) K. B. Koe, A. Weisman, W. M. Welch, R. G. Broune, J.Pharmacol.
Exp. Ther. 1983, 226, 686700. (b) W. M. Welch, A. R. Kraska, R.
Sarges, K. B. Koe, J. Med. Chem. 1984, 27, 1508–1515.(c) K. Maggon,
Drug Discovery Today. 2005, 10, 739742.
[8]
[9]
(a) M. G. Kelly, J. L. Hartwell, J. Cancer Inst. 1954, 967–1010. (b) T.
Imbert, Biochimie, 1998, 80, 207222.
1-(2-(4-(6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)phenoxy)ethyl)
pyrrolidine 8:
(a) H. Stähelin, Eur. J. Cancer, 1973, 9, 215221. (b) K. R. Hande, Eur.
J. Cancer. 1998, 34, 15141521.
Following the experimental procedure C, tetralin 5bk11 was
debenzylated resulting the hydroxyl counterpart of 3bk which was
subsequently utilized for the alkylation reaction. The tetralin analogue 8
was obtained after an overnight reflux following the experimental
procedure D as colorless oil in 80% yield. R¬f = 0.5 (4% methanol/DCM).
1H NMR (400 MHz, CDCl3, 25oC): δH 6.98 (d, J= 8.25 Hz, 2H), 6.82 (d,
J= 8.25 Hz, 2H), 6.74 (d, J= 8.25 Hz, 1H), 6.65-6.59 (m, 2H), 4.08 (t, J=
5.70 Hz, 2H), 4.00-3.99 (m, 1H), 3.76 (s, 3H), 2.90-2.78 (m, 4H), 2.62 (bs,
4H), 2.11-2.09 (m, 1H), 1.87-1.71 (m, 7H) ppm. 13C NMR (100 MHz,
CDCl3, 25 oC): δC 157.57, 157.09, 139.94, 138.68, 132.01, 131.11,
129.57, 114.27, 113.22, 112.03, 66.96, 55.17, 55.14, 54.67, 44.09, 33.53,
30.14, 23.50, 20.96 ppm.
[10] T. Ito, T. Tanaka, M. Iinuma, K.-I. Nakaya, Y. Takahashi, R. Sawa, J.
Murata, D. Darnaedi, J. Nat. Prod. 2004, 67, 932937.
[11] (a) Y. Li, W. Cheng, C. Zhu, C. Yao, L. Xiaong, Y. Tian, S. Wang, S.
Lin, J. Hu, Y. Yang, Y. Guo, Y. Yang, Y. Li, Y. Yuan, Y. Chen, J. Shi, J.
Nat. Prod. 2011, 74, 14441452.
[12] J. C. M. Kistemaker, S. F. Pizzolato, T. V-Leeuwen, T. C. Pijper, B. L.
Feringa, Chem.-Eur. J. 2016, 22, 1347813487.
[13] (a) A. E. Garcia, S. Ouizem, X. Cheng, P. Romanens, E. P. Kundig,
Adv. Synth. Catal. 2010, 352, 23062314. (b) S. Chandrasekhar, M. V.
Reddy, Tetrahedron. 2000, 56, 11111114.
[14] A. Volonterio, M. Zanda, Tetrahedron Lett. 2005, 46, 87238726.
[15] (a) S. Hajra, B. Maji, A. Karmakar, Tetrahedron Lett. 2005, 46,
85998603. (b) J. Barluenga, M. Trincado, E. Rubio, M. Jose, Gonza
lez. J. Am. Chem. Soc. 2004, 126, 34163417.
Acknowledgements
[16]
M. C. Carreno, M. Gonzalez-Lopez, A. Latorre, A. Urbano, J. Org.
Chem. 2006, 71, 49564964.
This research project (3511410812018-BRNS/35032) was
supported by Department of Atomic Energy (DAE), Board of
Research in Nuclear Sciences (BRNS), New Delhi, India. SLKM,
thank Council of Scientific and Industrial Research (CSIR), India
for research fellowship. Instrumental facilities from SAIF, CDRI
are highly acknowledged (CDRI Communication No. 9770 )
[17] (a) P. H. Poulsen, K. S. Feu, B. M. Paz, F. Jensen, K. A. Jørgensen,
Angew. Chem. Int. Ed. 2015, 54, 82038207. Angew. Chem. 2004, 116,
560–566. (b) L. Hong, L. Wang, W. Sun, K. Wong, R. Wang, J. Org.
Chem. 2009, 74, 68816884. (c) H. Hao, L. Lin, F. Tan, S. Ge X. Liu, X.
Feng, Org. Chem. Front. 2017, 4, 16471650.
Keywords: Chromans • Tetralins • Metal free coupling •
[18] R. Macros, C. Rodriguez, C. I. Herrerias, M. A. Pericas, J. Am. Chem.
Soc. 2008, 130, 16838–16839.01.06.207
Hydrazones • Reductive arylation
[19] X-L. Zhao, L. Liu, Y-J. Chen, D. Wang, Synlett. 2007, 9,
13571364.01.06.207
[1]
[2]
[3]
[4]
[5]
(a) T. T. Ashburn, K. B.Thor, Nat. Rev. Drug Discov. 2004, 3, 673–683.
(b) L. King, M. Sullivan, Science, 1946, 104, 244245. (c) P. Kumar, Z.
H. Song, Biochem. Biophys. Res. Commun. 2014, 443, 144–149.
[20] (a) C. Gharuo, S. Singh, S. C. Pan, Org. Biomol. Chem., 2017, 15,
72727276. (b) S. K. Allamsetti, M. Spanka, C. Schneider, Angew.
Chem. Int. Ed. 2016, 55, 2392–2396. Angew. Chem. 2015, 127,
83218325. (c) Z. Wang, J. Sun, Org. Lett. 2017, 19, 2334−2337 (d) E.
E. Allen, C. Zhu, J. S. Panek, S. E. Schaus, Org. Lett. 2017, 19,
1878−1881. (e) P. Batsomboon, W. Phakhodee, S. Ruchirawat, P.
Ploypradith, J. Org. Chem. 2009, 74, 4009–4012. (f) C-C. Hsiao, S.
Raja, H-H. Liao, I. Atodiresei, M. Rueping, Angew. Chem. Int. Ed. 2015,
54, 5762–5765. Angew. Chem. 2015, 127, 58545857. (g) K. Zhao, Y.
Zhi, T. Shu, A. Valkonen, K. Rissanen, D. Enders, Angew. Chem. Int.
Ed. 2016, 55, 12104–12108. Angew. Chem. 2016, 128, 12283-12287.
(a) N. C. Baker, S. Ekins, A. J. Williams, Drug Discovery Today, 2018,
23, 661−672. (b) S. Khan, S. Shukla, S. Sinha, A. D. Lakra, H. K. Bora,
S. M. Meeran, Int. J. Biochem. Cell Biol. 2015, 58, 116.
(a) S. Ray, P. K. Grover, V. P. Kamboj, B. S. Setty, A. B. Kar, N. Anand,
J. Med. Chem. 1976, 19, 276279. (b) P. Jacobsen, S. Treppendahl, B.
Stanley, A. Kanstrup, C. L. Brown, WO Patent WO 9818776. 1998.
(a) K. O. Cameron, P. A. Jardine, R. L. Rosati, Patents EP 802910, JP
98503215, US 5552412, WO 9621656. (b) I. Shiina, Y. Sano, K.
Nakata, U.S. Patent US20090012314, 2009.
[21] (a) M. S. L. Kumar, J. Singh, S. K. Manna, S. Maji, R. Konwar, G.
Panda, Bioorg. & Med. Chem. Lett. 2011, 21, 6203–6205. (b) R. Singh,
M. K. Parai, G. Panda, Syn. Commun., 2002, 32, 3549–3560 (c) S. K.
Manna, M. K. Parai, G. Panda, Tetrahedron lett. 2011, 52, 59515955.
(d) Shagufta, M. K. Parai, G. Panda, Tetrahedron Lett. 2005, 46, 8849–
8852. (e) R. Singh, G. Panda, RSC Adv. 2013, 3, 1953319544. (f) R.
Singh, G. Panda, Org. Biomol. Chem., 2011, 9, 47824790. (g) K.
P. S. Bury, L. B. Christiansen, P. Jacobsen, A. S. Jørgensen, A.
Kanstrup, L. Nærum, S. Bain, C. Fledelius, B. Gissel, B. S. Hansen, N.
Korsgaard, S. M. Thorpe, K. Wassermann, Bioorganic & Medicinal
Chemistry. 2002, 10, 125145.
[6]
(a) S. Sawadjoon, P. Kittakoop, K. Kirtikara, V. Vichai, M. Tanticharoen,
Y. Thebtaranonth, J. Org. Chem. 2002, 67, 54705475. (b) D. J.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801375
European Journal of Organic Chemistry
FULL PAPER
Samanta, N. Srivastava, S. Saha, G. Panda, Org. Biomol. Chem. 2012,
10, 15531564.
[22] (a) J. Barluenga, C. Valdés. Angew. Chem., Int. Ed. 2011, 50,
74867500. Angew. Chem. 2011, 123, 7626-7640. (b) J. Barluenga, C.
Valdés, Z. Shao, H. Zhang, Chem. Soc. Rev. 2012, 41, 560572.
[23] J. Barluenga, M. Tomás-Gamasa, F. Aznar, C. Valdés, Nat. Chem.
2009, 1, 494499.
[24] (a) C. Peng, W. Zhang, G. Yan, J. Wang, Org. Lett. 2009, 11,
16671670. (b) S. Nakagawa, K. A. Bainbridge, K. Butcher, D. Ellis, W.
Klute, T. Ryckmans, Chem. Med. Chem. 2012, 7, 233236. (c) D. M.
Allwood, D. C. Blakemore, A. D. Brown, S. V. Ley, J. Org. Chem. 2014,
79, 328338. (d) C. Li, Y. Zhang, Q. Sun, T. Gu, H. Peng, W. Tang, J.
Am. Chem. Soc. 2016, 138, 10774−10777.
[25] J. Barluenga, M. T-Gamasa, F. Aznar, C. Valde´s, Angew. Chem., Int.
Ed. 2010, 49, 49934996; Angew. Chem. 2010, 122, 5113.
[26] (a) M. Alfredo, G-Carrillo; A. Guzmán, E. Díaz, Tetrahedron Lett. 2017,
58, 19521956. (b) Q. Ding, B. Cao, J. Yuan, X. Liu, Y. Peng, Org.
Biomol. Chem. 2011, 9, 748751.
[27] (a) J. Barluenga, J.; Tomas-Gamasa, M.; Valdes, C. Angew. Chem.,
Int. Ed. 2012, 51, 59505952. Angew. Chem. 2012, 124, 6052-6054.
(b) A. Hamze, B. Treguier, J.-D. Brion, M. Alami, Org. Biomol. Chem.
2011, 9, 62006204.
[28] (a) W. J. Miao, Y. Z. Gao, X. Q. Li, Y. X. Gao, G. Tang Y. F. Zhao,
Adv. Synth. Catal. 2012, 354, 26592664. (b) Z-S Chen, Z-Z. Zhou, H-
L. Hua X-H. Hua, J-Y. Luo, J. Wang, P-X. Zhou, Y-M. Liang,
Tetrahedron. 2013, 69, 10651068. (c) P. Wu, L. Zhang X. Zhang X.
Guo, B. Chen, Chin. J. Chem. 2016, 34, 363367.
[29] Q. Sha, Y. Wei, Tetrahedron. 2013, 69, 38293835.
[30] J.-B. Liu, H. Yan, G. Lu, Tetrahedron Lett. 2013, 54, 891895.
[31] P. Xu, F.-S. Han, Y.-H. Wang, Adv. Synth. Catal. 2015, 357,
34413446.
[32] A. S. Tsai, J. M. Curto, B. N. Rocke. A. R. D-Schmitt, G. K. Ingle, V.
Mascitti, Org. Lett., 2016, 18, 508−511.
This article is protected by copyright. All rights reserved.