Direct Access to 9-Chloro-1 H-benzo[ b]furo[3,4- e]azepin-1-ones via Palladium(II)-Catalyzed Intramolecular syn-Oxypalladation/Olefin Insertion/sp2-C-H Bond Activation Cascade

Article abstract of DOI:10.1021/acs.orglett.9b01482

An efficient Pd(II)-catalyzed cascade approach was established for the synthesis of 9-chloro-1H-benzo[b]furo[3,4-e]azepin-1-ones starting from N-propargyl arylamines having a pendant α,β-unsaturated ester scaffold. The mechanism of this sequential process involved intramolecular syn-oxypalladation followed by olefin insertion and ortho sp²-C-Cl bond formation reactions. This high atom- and step-economical cascade sequence generated two heterocycle rings and three new bonds in a single synthetic operation.

Full text of DOI:10.1021/acs.orglett.9b01482

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Direct Access to 9‑Chloro‑1H‑benzo[b]furo[3,4‑e]azepin-1-ones via
Palladium(II)-Catalyzed Intramolecular syn-Oxypalladation/Olefin
Insertion/sp2‑C−H Bond Activation Cascade
Muthu Karuppasamy,† B. S. Vachan,† Perumal Vinoth,† Isravel Muthukrishnan,† Subbiah Nagarajan,‡
Laura Ielo,§ Vittorio Pace,§ Subrata Banik,∥ C. Uma Maheswari,† and Vellaisamy Sridharan*,†,∥
†Department of Chemistry, School of Chemical and Biotechnology, SASTRA Deemed University, Thanjavur 613401, Tamil Nadu,
India
‡Department of Chemistry, National Institute of Technology, Warangal, Warangal 506004, Telangana, India
§Department of Pharmaceutical Chemistry, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria
∥Department of Chemistry and Chemical Sciences, Central University of Jammu, Rahya-Suchani (Bagla), District-Samba, Jammu
181143, India
S
* Supporting Information
ABSTRACT: An efficient Pd(II)-catalyzed cascade approach was established for the synthesis of 9-chloro-1H-benzo[b]furo-
[3,4-e]azepin-1-ones starting from N-propargyl arylamines having a pendant α,β-unsaturated ester scaffold. The mechanism of
this sequential process involved intramolecular syn-oxypalladation followed by olefin insertion and ortho sp2-C−Cl bond
formation reactions. This high atom- and step-economical cascade sequence generated two heterocycle rings and three new
bonds in a single synthetic operation.
Scheme 1. Inter- and Intramolecular Nucleopalladation of
Alkynes
edium-sized benzannulated aza-heterocycles comprise
Mthe core structure of numerous biologically active
compounds that exhibit a broad range of pharmacological
activities.1,2 Among these compounds, seven-membered nitro-
gen heterocycles including benzazepines represent an
important class of natural products and show antidepressant,
anxiolytic, and neuroleptic activities.3,4 For instance, LY-
411575 has been identified as an effective γ-secretase inhibitor
for the treatment of Alzheimer’s and Parkinson’s diseases,5 and
fenoldopam, a chiral benzo[d]azepine, acts as dopamine D1
receptor agonist and is used as antihypertensive agent.6
Further, mozavaptan, an analogue of 1H-benzo[b]azepine, is
a vasopressin V-2 receptor antagonist, and lotensin is a
commercially available drug used for the treatment of high
blood pressure and congestive heart failure.7 Compounds
containing a benzazepine nucleus as the key subunit serve as
selective 5-HT2C receptor agonists for the treatment of
obesity.8 Although a considerable number of approaches
have been developed for the synthesis of these valuable
compounds, straightforward methods to access densely
functionalized benzazepine analogues are rather limited.9
Inter- and intramolecular nucleopalladation of alkynes and
successive cascade reactions via σ-vinylpalladium intermediates
remain excellent strategies to access various structurally diverse
molecules in a single synthetic operation (Scheme 1).10 The in
situ generated σ-vinylpalladium intermediates could be
captured by carbon monoxide, allylic alcohols, halides, esters,
Received: April 28, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01482
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Nucleopalladation-Initiated Cascade Reactions of N-Propargyl Arylamines with Pendant α,β-Unsaturated Carbonyl
Compounds
a
allenes, α,β-unsaturated carbonyl compounds, norbornene,
styrene, unactivated alkenes, nitriles, and isonitriles to obtain
complex compounds.11 Among the various nucleopalladation
reactions, oxypalladation-initiated cascade reactions are partic-
ularly important as these reactions lead to a variety of
biologically significant compounds including oxygen hetero-
cycles.12,13
Table 1. Optimization of the Reaction Conditions
Recently, we established a syn-chloropalladation/olefin
insertion/oxidative chlorination cascade for the synthesis of
dichlorinated tetrahydroquinolines 2 starting from N-propargyl
arylamines 1 tethered with α,β-unsaturated ketones in the
presence of a palladium catalyst and CuCl2·2H2O as the
chloride source (Scheme 2, eq 1).14 When we swapped the
α,β-unsaturated ketone moiety of 1 with α,β-unsaturated ester
(compound 3), the reactivity was entirely altered and the
unpredicted 1H-benzo[b]furo[3,4-e]azepin-1-ones 4 bearing
an Ar−Cl substituent was obtained as the major product
(Scheme 2, eq 2). This interesting cascade transformation
intrigued us to further explore the reactivity of compounds 3 to
obtain the biologically significant tricyclic 1H-benzo[b]furo-
[3,4-e]azepin-1-ones 4 and to investigate the mechanism of the
annulation/sp2-C−Cl bond formation cascade.
Initially, we tested the reaction conditions established for the
syn-chloropalladation-initiated cascade14 using N-propargyl
arylamine 3a bearing an α,β-unsaturated ester functionality
as the model substrate, and only traces of product 4a were
observed in the presence of 10 mol % of Pd(OAc)2 and 2 equiv
of CuCl2·2H2O in THF and DME at ambient temperature
(Table 1, entries 1 and 2). Remarkably, an increase of the
reaction temperature to 50 °C in THF triggered the cascade
transformation to allow access to the desired product 4a in
58% yield, and the results in DME were inferior (entries 3 and
4). Our investigation moved forward when switching the
catalyst to PdCl2, and a maximum yield of 66% of 4a was
observed after 7 h in THF at 50 °C (entries 5−8).
Subsequently, with an aim to further improve the yield, we
tested the reaction in various common organic solvents
including MeCN (entry 9), toluene, DCM, DCE, ethanol,
methanol, DMSO, and DMF. Nonetheless, these solvents were
completely ineffective to furnish the desired product
irrespective of the polarity effects (not shown in the table).
It is interesting to note that, in addition to THF (entries 3 and
catalyst
additive
(equiv)
time yield of 4a
b
entry
(10 mol %)
solvent
THF
DME
THF
DME
THF
DME
THF
DME
MeCN
dioxane
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
THF
THF
THF
THF
THF
(h)
(%)
c
c
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
48
48
7
traces
traces
58
48
48
48
7
48
48
7
8
4
16
5
5
5
5
5
48
5
20
28
48
48
48
48
14
13
10
66
23
d
38
68
69
63
72
77
71
84
76
d
c
c
9
10
11
e
12
f
13
14
15
16
H2O (4)
H2O (1)
H2O (4)
H2O (1)
H2O (1)
H2O (1)
H2O (1)
H2O (1)
H2O (1)
H2O (1)
H2O (1)
H2O (1)
H2O (1)
g
17
18
19
20
21
Pd(OAc)2
PdCl2(PPh3)2
PdCl2(MeCN)2
Pd(OTf)2
PdCl2
83
31
42
d
THF
THF
THF
THF
THF
THF
h
22
23
e
24
d
i
25
j
PdCl2
PdCl2
traces
d
26
a
Unless otherwise noted, all reactions were carried out with 3a (0.5
mmol), CuCl2·2H2O (2.0 equiv), palladium catalyst (10 mol %) in 6
b
c
mL of solvent at 50 °C. Isolated yield. Reactions were carried out at
d
e
room temperature. No reaction. 4.0 equiv of CuCl2·2H2O was used.
f
g
1.0 equiv of CuCl2·2H2O was used. Optimized reaction condition.
h
i
5 mol % of catalyst was used. Reaction was carried out without
j
CuCl2·2H2O. 2.0 equiv of CuBr2 was used.
B
DOI: 10.1021/acs.orglett.9b01482
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
7) and DME (entry 8), other ethereal solvents including
dioxane and 2-MeTHF were efficient and made the cascade
process attainable (entries 10 and 11). Although DME and
dioxane could not deliver the product in appreciable yields, the
highest yield of 68% was achieved in 2-MeTHF (entry 11).
Increasing the amount of CuCl2·2H2O to 4 equiv did not
improve the yield significantly; however, the reaction time was
reduced to 4 h (entry 12). Further, the reaction delivered the
desired product in a comparable yield of 63% in the presence
of 1 equiv of CuCl2·2H2O in 16 h (entry 13).
Scheme 3. Scope and Limitations of the syn-Oxypalladation-
Initiated Cascade
Owing to the crucial role of water in the proposed cascade
process, the reaction was further investigated in the presence of
water as the additive. As anticipated, addition of 1 equiv of
water increased the yield to 77%, and the reaction was
completed within 4 h in 2-MeTHF (entries 14 and 15).
Substantial improvement was observed in THF under similar
conditions with a maximum yield of 84% (entries 16 and 17).
Next, 10 mol % of palladium catalyst, 2 equiv of CuCl2·2H2O,
1 equiv of H2O, and THF solvent were employed to further
screen palladium catalysts including Pd(OAc)2, PdCl2(PPh3)2,
PdCl2(MeCN)2, and Pd(OTf)2 (entries 18−21). In the list of
tested catalysts, PdCl2(MeCN)2 furnished the product in a
manner comparable to that of PdCl2, and other catalysts
displayed inferior results. As shown in entry 22, 5 mol % of
PdCl2 was inefficient and delivered only 42% of the product
after 28 h. To prove the role of both palladium catalyst and
CuCl2·2H2O in the cascade process, the reaction was tested
only with 2−4 equiv of CuCl2·2H2O (entries 23 and 24) and
with 10 mol % of PdCl2 without CuCl2·2H2O (entry 25). In
the former case, no product formation was observed and traces
of the product were noted in the absence of copper salt.
Finally, CuBr2 was tested instead of CuCl2·2H2O to access the
corresponding brominated benzazepine; however, the reaction
failed to deliver the desired product (entry 26). After an
extensive optimization study, the condition given in entry 17
was elected to investigate the scope and limitations of the
cascade process (10 mol % of PdCl2, 2 equiv of CuCl2·2H2O, 1
equiv of H2O, THF, 50 °C).
With the optimal reaction conditions established, the scope
and limitations of the cascade process were investigated
(Scheme 3). A variety of N(O)-propargyl arylamines 3a−s
bearing an α,β-unsaturated ester moiety were treated with 10
mol % of PdCl2, 2 equiv of CuCl2·2H2O, and 1 equiv of water
in THF at 50 °C to access the corresponding 9-chloro-1H-
benzo[b]furo[3,4-e]azepin-1-ones 4. At the outset, a series of
electron-donating and -withdrawing substituents were intro-
duced at R1, R2, and R3 positions (Me: 4b, 4c, 4e, and 4f;
OMe: 4d; F: 4h; Cl: 4i), and in all cases, the desired products
were obtained in high yields of 84−88%. The N-propargyl
arylamine 3g with a strong electron-withdrawing m-nitro
substituent delivered the corresponding product 4g in
moderate yield (61%).
The alkyne bearing a terminal ethyl group delivered the
nonchlorinated 1H-benzo[b]furo[3,4-e]azepin-1-one 5j in 54%
yield under reflux conditions in 36 h, and attempts to insert the
9-chloro substituent by adding excess CuCl2·2H2O were
unsuccessful. Further, a set of N-propargyl arylamines 3k−n
bearing a bromo substituent on the N-aryl ring was synthesized
to derive densely substituted benzazepines. Unexpectedly,
alkynes 3k and 3l afforded the nonchlorinated products 5k and
5l in 85% yields under the optimized conditions. In the cases
of alkynes 3m and 3n, inseparable mixtures of chlorinated
benzazepines 4 together with nonchlorinated products 5 in
64−66% overall yields were isolated. The reaction also
tolerated an additional N-protecting mesyl functionality. Two
examples of N-mesyl 9-chloro-1H-benzo[b]furo[3,4-e]azepin-
1-ones 4o and 4p were synthesized in 81−84% yields under
similar conditions. Next, benzo[b]furo[3,4-e]oxepin-1-ones 4q
and 4r were derived in 60−64% yields starting from the
corresponding O-propargyl arylamines. Finally, the tert-
butyloxycarbonyl (Boc)-protected N-propargyl arylamine 3s
was also tested; however, the reaction failed to furnish the
desired product 4s due to the poor stability of compound 3s
under the experimental conditions. The structures of the
synthesized compounds were established by NMR and
confirmed by single-crystal X-ray analysis of the representative
compound 4a.
Our mechanistic rationale for the cascade process involves
the activation of alkyne 3 by a palladium(II) catalyst followed
by intramolecular syn-oxypalladation to generate σ-vinyl-
C
DOI: 10.1021/acs.orglett.9b01482
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
palladium intermediate B via species A (Scheme 4).12a,c
Subsequent olefin insertion comprising a 5-exo-trig cyclization
CuCl2·2H2O-mediated oxidation of intermediate C, where
σ−π−σ rearrangement would be difficult due to the presence
of the bulky bromine atom.
To further attain additional information concerning the
mechanism of the cascade process, the reaction was performed
using α,β-unsaturated acid 6a under optimized conditions, and
the expected product 4a was obtained in 71% yield (Scheme
5). On the basis of this experiment, an alternative mechanism
Scheme 4. Plausible Mechanism for the syn-Oxypalladation-
Initiated Cascade
Scheme 5. Annulation of α,β-Unsaturated Acid 6a
involving a carboxylic acid intermediate is depicted in Scheme
6. Initial hydrolysis of ester 3 to carboxylic acid 6 could be
Scheme 6. Proposed Mechanism via a Carboxylic Acid
Intermediate
achieved under the experimental conditions, which would
generate the key σ-vinylpalladium intermediate G via syn-
oxypalladation of palladium species F generated in situ from
the carboxylic acid 6 and the palladium catalyst.
generates intermediate C bearing the furanone ring system,
where β-hydride elimination would be difficult to occur due to
geometrical constrains. The ortho-chlorination process involv-
ing sp2-C−H bond activation could be visualized through
σ−π−σ rearrangement of intermediate C to deliver species E
via π-benzylpalladium(II) species involving the dearomatiza-
tion reaction as summarized by Trost.15,16 Final rearomatiza-
tion followed by the CuCl2·2H2O-mediated ortho-chlorina-
tion/oxidation sequence would afford the desired product 4 via
the intermediacy of E by regenerating the Pd(II) species.
Further, we carried out DFT calculations using the M062x
functional to understand the formation of intermediate E from
species C. Our study reveals the formation of intermediate E
by migration of the hydrogen atom from sp2-C to sp3-C via
transition state D. Such a migration process is triggered by sp2-
C−H bond activation by an adjacent Pd(II) species. The
activation energy of this transformation is estimated to be
about 53.7 kcal mol−1 in our calculations. Additional
computational calculations to understand the reaction pathway
in detail are in progress.
In summary, we have established a Pd(II)-catalyzed
nucleopalladation-initiated cascade process for the direct
synthesis 9-chloro-1H-benzo[b]furo[3,4-e]azepin-1-ones in
good yields. The reaction involved a sequential intramolecular
syn-oxypalladation/olefin insertion/sp2-C−H bond activation
of N-propargyl arylamines bearing an α,β-unsaturated ester
moiety. Insertion of an ortho-chloro substituent was visualized
via σ−π−σ rearrangement involving a dearomatization process
followed by a rearomatization/chlorination sequence. This
simple high atom-economical cascade approach allowed the
construction of two heterocycle rings including seven- and five-
membered rings and three new bonds (1 C−C, 1 C−O, and 1
C−Cl bonds) under mild conditions in a single operation.
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.9b01482.
Formation of nonchlorinated 1H-benzo[b]furo[3,4-e]-
azepin-1-ones 5 observed in sterically hindered substrates
(R1 = Br) could be explained by protonation followed by
Experimental details, characterization data of com-
pounds, NMR, and X-ray crystallographic data (PDF)
D
DOI: 10.1021/acs.orglett.9b01482
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Accession Codes
Letter
Menzaghi, F.; Webb, R. R.; Beeley, N. R. A. Bioorg. Med. Chem. Lett.
2005, 15, 1467−1470. (b) Smith, B. M.; Smith, J. M.; Tsai, J. H.;
Schultz, J. A.; Gilson, C. A.; Estrada, S. A.; Chen, R. R.; Park, D. M.;
Prieto, E. B.; Gallardo, C. S.; Sengupta, D.; Dosa, P. I.; Covel, J. A.;
Ren, A.; Webb, R. R.; Beeley, N. R. A.; Martin, M.; Morgan, M.;
Espitia, S.; Saldana, H. R.; Bjenning, C.; Whelan, K. T.; Grottick, A. J.;
Menzaghi, F.; Thomsen, W. J. J. Med. Chem. 2008, 51, 305−313.
(9) For recent examples of the synthesis of benzazepines, see:
(a) Shen, H.-Q.; Gao, X.; Liu, C.; Hu, S.-B.; Zhou, Y.-G. Org. Lett.
2016, 18, 5920−5923. (b) Sharif, S. A. I.; Calder, E. D. D.; Delolo, F.
G.; Sutherland, A. J. Org. Chem. 2016, 81, 6697−6706. (c) Wu, L.;
Meng, Y.; Ferguson, J.; Wang, L.; Zeng, F. J. Org. Chem. 2017, 82,
4121−4128. (d) Rahman, A.; Xie, E.; Lin, X. Org. Biomol. Chem.
2018, 16, 1367−1374. (e) Zhao, Y.; Chen, J.-R.; Xiao, W.-J. Org. Lett.
2018, 20, 224−227.
CCDC 1911784 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: vesridharan@gmail.com or sridharan.che@cujammu.
ac.in.
ORCID
(10) For an account, see: Lu, X.; Han, X. Synlett 2018, 29, 2461−
2480.
Subbiah Nagarajan: 0000-0003-2233-4872
Vittorio Pace: 0000-0003-3037-5930
Subrata Banik: 0000-0001-5155-3957
Vellaisamy Sridharan: 0000-0002-3099-4734
Notes
(11) For recent selected example of nucleopalladation-initiated
cascade reactions, see: (a) Nimmagadda, S. K.; Liu, M.; Karunananda,
M. K.; Gao, D.-W.; Apolinar, O.; Chen, J. S.; Liu, P.; Engle, K. M.
Angew. Chem., Int. Ed. 2019, 58, 3923−3927. (b) Wu, W.; Li, M.;
Zheng, J.; Hu, W.; Li, C.; Jiang, H. Chem. Commun. 2018, 54, 6855−
6858. (c) Li, J.; Yang, S.; Wu, W.; Jiang, H. Eur. J. Org. Chem. 2018,
2018, 1284−1306. (d) Liu, Z.; Ni, H.-Q.; Zeng, T.; Engle, K. M. J.
Am. Chem. Soc. 2018, 140, 3223−3227. (e) Wu, W.; Chen, T.; Chen,
J.; Han, X. J. Org. Chem. 2018, 83, 1033−1040. (f) Yang, Y.; Fei, C.
C.; Wang, K.; Liu, B.; Jiang, D.; Yin, B. Org. Lett. 2018, 20, 2273−
2277.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the Department of Science and
Technology−Science and Engineering Research Board, DST-
SERB (No. EMR/2016/001619), is gratefully acknowledged.
We thank Dr. Kazuhiro Takenaka, ISIR, Osaka University, for
fruitful discussion on the mechanism. We also thank Dr.
Alexander Roller, University of Vienna, for single-crystal X-ray
analysis.
(12) For recent intramolecular oxypalladation-initiated cascade
reactions, see: (a) Zheng, M.; Huang, L.; Tong, Q.; Wu, W.; Jiang,
H. Eur. J. Org. Chem. 2016, 2016, 663−667. (b) Zhang, J.; Han, X.;
Lu, X. J. Org. Chem. 2016, 81, 3423−3429. (c) Tian, P.-P.; Cai, S.-H.;
Liang, Q.-J.; Zhou, X.-Y.; Xu, Y.-H.; Loh, T.-P. Org. Lett. 2015, 17,
1636−1639. (d) Li, J.; Zhu, Z.; Yang, S.; Zhang, Z.; Wu, W.; Jiang, H.
J. Org. Chem. 2015, 80, 3870−3879. (e) Vinoth, P.; Vivekanand, T.;
REFERENCES
■
́
Suryavanshi, P. A.; Menendez, J. C.; Sasai, H.; Sridharan, V. Org.
Biomol. Chem. 2015, 13, 5175−5181. (f) Fujino, D.; Yorimitsu, H.;
(1) For reviews on medium-ring benzo-fused nitrogen heterocycles,
see: (a) Evans, P. A.; Holmes, A. B. Tetrahedron 1991, 47, 9131−
9166. (b) Ramig, K. Tetrahedron 2013, 69, 10783−10795.
(2) (a) Ladd, D. L.; Weinstock, J.; Wise, M.; Gessner, G. W.;
Sawyer, J. L.; Flaim, K. E. J. Med. Chem. 1986, 29, 1904−1912.
(b) Ryan, J. H.; Hyland, C.; Meyer, A. G.; Smith, J. A.; Yin, J.-X. Prog.
Heterocycl. Chem. 2012, 24, 493−536.
Osuka, A. J. Am. Chem. Soc. 2014, 136, 6255−6258.
(13) For recent intermolecular oxypalladation-initiated cascade
reactions, see: (a) Santhini, P. V.; Smrithy, A. S.; Irfana Jesin, C. P.;
Varughese, S.; John, J.; Radhakrishnan, K. V. Chem. Commun. 2018,
54, 2982−2985. (b) Yamaguchi, M.; Ozawa, H.; Katsumata, H.;
Akiyama, T.; Manabe, K. Tetrahedron Lett. 2018, 59, 3175−3178.
(c) Shukla, R. K.; Pal, K.; Volla, C. M. R. Chem. - Asian J. 2018, 13,
2435−2439. (d) Zheng, J.; Li, Z.; Wu, W.; Jiang, H. Org. Lett. 2016,
18, 6232−6235. (e) Li, J.; Yang, W.; Yan, F.; Liu, Q.; Wang, P.; Li, Y.;
Zhao, Y.; Dong, Y.; Liu, H. Chem. Commun. 2016, 52, 10644−10647.
(f) Vinoth, P.; Nagarajan, S.; Maheswari, C. U.; Sudalai, A.; Pace, V.;
Sridharan, V. Org. Lett. 2016, 18, 3442−3445.
(3) For a review on benzazepine alkaloids and related compounds,
see: (a) Kametani, T.; Fukumoto, K. Heterocycles 1975, 3, 931−1004.
(4) (a) Corbel, J. C.; Uriac, P.; Huet, J.; Martin, C. A. E.; Advenier,
C. Eur. J. Med. Chem. 1995, 30, 3−13. (b) Seto, M.; Aramaki, Y.;
Okawa, T.; Miyamoto, N.; Aikawa, K.; Kanzaki, N.; Niwa, S.-I.;
Iizawa, Y.; Baba, M.; Shiraishi, M. Chem. Pharm. Bull. 2004, 52, 577−
590. (c) Hoyt, S. B.; London, C.; Gorin, D.; Wyvratt, M. J.; Fisher, M.
H.; Abbadie, C.; Felix, J. P.; Garcia, M. L.; Li, X.; Lyons, K. A.;
McGowan, E.; MacIntyre, D. E.; Martin, W. J.; Priest, B. T.; Ritter, A.;
Smith, M. M.; Warren, V. A.; Williams, B. S.; Kaczorowski, G. J.;
Parsons, W. H. Bioorg. Med. Chem. Lett. 2007, 17, 4630−4634.
(5) Wong, G. T.; Manfra, D.; Poulet, F. M.; Josien, H.; Zhang, Q.;
Bara, T.; Engstrom, L.; Pinzon-Ortiz, M.; Fine, J. S.; Lee, H.-J. J.;
Zhang, L.; Higgins, G. A.; Parker, E. M. J. Biol. Chem. 2004, 279,
12876−12882.
(14) Vinoth, P.; Karuppasamy, M.; Vachan, B. S.; Muthukrishnan, I.;
Maheswari, C. U.; Nagarajan, S.; Pace, V.; Roller, A.; Bhuvanesh, N.;
Sridharan, V. Org. Lett. 2019, 21, 3465−3469.
(15) For a review on structure and reactivity of late transition metal
η3-benzyl complexes, see: Trost, B. M.; Czabaniuk, L. C. Angew.
Chem., Int. Ed. 2014, 53, 2826−2851.
(16) For selected recent reports involving η3-benzylpalladium
́
́
intermediates, see: (a) Martín-Ruiz, B.; Perez-Ortega, I.; Albeniz, A.
́
C. Organometallics 2018, 37, 1665−1670. (b) Martín-Ruiz, B.; Perez-
(6) (a) Pettersson, I.; Liljefors, T.; Boegesoe, K. J. Med. Chem. 1990,
33, 2197−2204. (b) Post IV, J. B.; Frishman, W. H. J. Clin. Pharmacol.
1998, 38, 2−13.
́
Ortega, I.; Albeniz, A. C. Organometallics 2018, 37, 1074−1085.
(c) Huang, J.; Yan, W.; Tan, C.; Wu, W.; Jiang, H. Chem. Commun.
2018, 54, 1770−1773. (d) Schwarz, K. J.; Yang, C.; Fyfe, J. W. B.;
Snaddon, T. N. Angew. Chem., Int. Ed. 2018, 57, 12102−12105.
(e) Hikawa, H.; Izumi, K.; Ino, Y.; Kikkawa, S.; Yokoyama, Y.;
Azumaya, S. Adv. Synth. Catal. 2015, 357, 1037−1048. (f) Hikawa,
H.; Toyomoto, M.; Kikkawa, S.; Azumaya, I. Org. Biomol. Chem. 2015,
13, 11459−11465. (g) Gutman, E. S.; Arredondo, V.; Van Vranken,
D. L. Org. Lett. 2014, 16, 5498−5501.
(7) (a) Hou, F.; Zhang, X.; Zhang, G.; Xie, D.; Chen, P.; Zhang, W.;
Jiang, J.; Liang, M.; Wang, G.; Liu, Z.; Geng, R. N. N. Engl. J. Med.
2006, 354, 131−140. (b) Decaux, G.; Soupart, A.; Vassart, G. Lancet
2008, 371, 1624−1632. (c) Robertson, G. L. Nat. Rev. Endocrinol.
2011, 7, 151−161. (d) Robles, N. R.; Hernandez-Gallego, R.
Cardiovasc. Ther. 2012, 30, 193−198.
(8) (a) Smith, B. M.; Smith, J. M.; Tsai, J. H.; Schultz, J. A.; Gilson,
C. A.; Estrada, S. A.; Chen, R. R.; Park, D. M.; Prieto, E. B.; Gallardo,
C. S.; Sengupta, D.; Thomsen, W. J.; Saldana, H. R.; Whelan, K. T.;
E
DOI: 10.1021/acs.orglett.9b01482
Org. Lett. XXXX, XXX, XXX−XXX