Catalyst-Controlled [3 + 2] and [4 + 2] Annulations of Oximes with Propargyl Alcohols: Divergent Access to Indenamines and Isoquinolines

Article abstract of DOI:10.1021/acs.orglett.7b03546

Rhodium(III)- and iridium(III)-catalyzed C-H activation of oximes and coupling with propargyl alcohols is discussed. Depending on the catalyst, the reaction pathway switched between [3 + 2] and [4 + 2] annulations, thus giving divergent access to indenami

Full text of DOI:10.1021/acs.orglett.7b03546

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Catalyst-Controlled [3 + 2] and [4 + 2] Annulations of Oximes with
Propargyl Alcohols: Divergent Access to Indenamines and
Isoquinolines
Wanchun Gong,†,§,⊥ Zhi Zhou,†,§ Jingjing Shi,‡,§ Bo Wu,† Biyun Huang,† and Wei Yi*,†
†Key Laboratory of Molecular Clinical Pharmacology & Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou,
Guangdong 511436, China
‡VARI/SIMM Center, Center for Structure and Function of Drug Targets, CAS-Key Laboratory of Receptor Research, Shanghai
Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
S
* Supporting Information
ABSTRACT: Rhodium(III)- and iridium(III)-catalyzed C−H
activation of oximes and coupling with propargyl alcohols is
discussed. Depending on the catalyst, the reaction pathway
switched between [3 + 2] and [4 + 2] annulations, thus giving
divergent access to indenamines and isoquinolines in a one-pot
and atom-economical manner. The hydroxyl group in the
tertiary propargyl alcohol substrate was found to be crucial in
controlling chemoselectivity. Five-membered rhodacycle and
iridacycle intermediates have also been identified for
mechanism hypotheses.
Scheme 1. Diversified Reaction Modes of Oximes via TM-
Catalyzed C−H Annulation
he construction of heterocyclic scaffolds via transition-
Tmetal (TM)-catalyzed C−H annulation represents a step-
and atom-economical synthetic method owing to obviating the
need for prefunctionalized substrates.1 Over the past decades, a
variety of heterocycles can be accessed through this protocol
from less-functionalized substrates bearing nitrogen-, oxygen-,
sulfur-, and phosphorus-containing directing groups (DGs).2
Despite these notable advances, the development of classical
DGs with novel diverse synthetic features is still in demand.
Among a broad range of DGs, oximes3 are easily accessible and
viewed as a class of efficient and installable DGs for the synthesis
of nitrogen-containing heterocycles via rhodium(III)-,
ruthenium(II)-, iridium(III)-, and cobalt(III)-catalyzed cou-
plings of C−H bonds with alkynes,4 alkenes,5 diazo compounds,6
and other coupling partners.7 Typically, the TM-catalyzed
coupling of oxime derivatives with alkynes follows a redox-
neutral [4 + 2] annulation mode, leading to the synthesis of
pyridines or isoquinolines (Scheme 1a, left). In 2015, by
designing the proper alkynes to increase the polarity of the Rhδ+−
Cδ− bond, Li and co-workers disclosed an alternative and
attractive rhodium(III)-catalyzed [3 + 2] annulation mode of
oximes with electron-deficient alkynes, such as trifluoromethane-
sulfonyl phenylacetylenes, for one-pot synthesis of indenamines
(Scheme 1a, right).8
same substrates. To the best of our knowledge, such a catalyst-
controlled annulation mode remains an unexploited area.
To validate our working hypothesis and in search for
innovative transformation modes with oxime derivatives, we
turned our attention to versatile and relatively electron-neutral
propargyl alcohols as the model coupling partners, which have
Inspired by these findings and taking into account the
differences of various [Cp*TM(III)] in terms of Lewis acidity
and steric effects, we envisaged that the reaction pathway
between [3 + 2] and [4 + 2] annulation can be switched by
tuning the TM catalyst species under similar reaction conditions,
thus giving rise to completely different types of products from the
Received: November 15, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03546
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
been used as one-, two-, or three-carbon synthons in TM-
catalyzed C−H functionalization to deliver valuable structures.9
Herein, we reveal the catalyst-controlled regioselective room-
temperature C−H activation followed by [3 + 2] and [4 + 2]
annulations of oximes with propargyl alcohols in rhodium(III)
and iridium(III) catalysis, respectively (Scheme 1b). The
hydroxyl group in the tertiary propargyl alcohol substrate is
crucial for the chemoselectivity, probably due to its different
binding affinities and modes with TM catalysts to induce the
polarity of TM−C bonds at different levels, thus leading to
efficient and chemoselective synthesis of indenamines and
isoquinolines. Since both of the resulting products are privileged
structural frameworks and present in many bioactive natural
products and drug candidates,10 the two atom-economical
transformations should have broad synthetic utility.
Scheme 2. Scope of Oxime Substrates
We commenced our investigation by examining the reaction of
O-methyl oxime (1a) with 2-methyl-4-phenylbut-3-yn-2-ol (2a)
under rhodium(III)-catalyzed conditions (see Supporting
Information). In the presence of CsOAc (1 equiv), a trace of
indenamine product 3aa with specific regioselectivity could be
obtained via a [3 + 2] annulation. As the rhodium(III)-catalyzed
coupling between ketoximes and alkynes typically affords
isoquinoline derivatives via a [4 + 2] annulation, the novel [3
+ 2] selectivity prompted us to do further studies. A screening of
additives indicated that AgOAc was an optimal base, affording
the desired indenamine 3aa in 90% yield, while other additives
gave inferior results. Interestingly, an alternative [4 + 2]
annulation could be achieved by simply switching [Cp*RhCl2]2
to [Cp*IrCl2]2 with the same substrates, leading to the efficient
synthesis of isoquinoline product 4aa with specific regioselec-
tivity. The molecular structures of 3aa and 4aa were confirmed
by single-crystal X-ray analysis (CCDC 1476867 and CCDC
1476868, respectively).
With the optimal conditions in hand, we next examined the
reaction scope of oximes under rhodium(III)-catalyzed con-
ditions for the synthesis of indenamine derivatives (Scheme 2a).
Fortunately, various commonly encountered functional groups,
including methyl (3ba), methoxyl (3ca), halogens (3da and
3ea), phenyl (3fa), ester (3ga), and cyano (3ha), were well
tolerated to furnish the corresponding products in moderate to
good yields. With ortho-methoxyl-substituted O-methoxy oxime,
the reaction proceeded smoothly to give the desired product in
moderate yield (3ja), whereas ortho-methyl-substituted O-
methoxyl oxime resulted in no reaction (3ia). When meta-
methoxyl-substituted O-methoxyl oxime was used, the arene
rhodation occurred at both sites, giving a mixture of regioisomers
(3ka and 3ka′). The reaction was also compatible with substrates
bearing different substituents on the oxygen atom (3la) or α
position of oxime (3ma), leading to the corresponding
indenamine skeletons in good yields.
Encouraged by the above results, we were next intrigued to
explore the feasibility of complex bioactive substrates for the late-
stage C−H bond modifications. To our delight, the oxime
derivatives of marketed drugs Dyclonine (1o) and Haloperidol
(1p) underwent the coupling with 2a smoothly to afford the
desired indenamines, which not only provided an efficient and
attractive strategy to generate new analogues of Haloperidol and
Dyclonine for immediate drug screening but also further
illustrated profound potential for late-stage C−H bond
modifications in synthetic chemistry.
a
All reactions were carried out in 0.2 mmol scale; isolated yield was
b
reported. Contained an inseparable mixture of isomers; the ratio was
determined by H NMR. Yield of the product obtained with O-ethyl
oxime 1l is shown in the parentheses.
c
1
ortho-methyl-, methoxyl-, halogen-, phenyl-, and ester-substi-
tuted oximes was observed, furnishing the desired isoquinoline
derivatives in moderate to good yields (4aa−ga, 4ia, and 4ja). In
the case of meta-methoxy-substituted O-methoxy oxime, an
inseparable mixture of regioisomers was obtained (4ka and
4ka′). Moreover, α-propyl- and phenyl-substituted O-methoxy
oximes also reacted smoothly, affording moderate yields of
expected products (4ma and 4na). It is necessary to note that
other oximes bearing heterocyclic skeletons, such as furan and
benzothiophene, as well as O-phenyl and O-tert-butyl oximes,
were not tolerated for such rhodium(III)- or iridium(III)-
catalyzed transformations (see the Supporting Information).
The scope of propargyl alcohols for the synthesis of
indenamines and isoquinolines was then explored (Scheme 3).
It is noteworthy that the tertiary alcohols are essential in
controlling the chemo- and regioselectivity of these reactions.
When 1c was used as the model substrate, several propynol
derivatives bearing different substituents on the phenyl ring were
Subsequently, a variety of oximes were assessed for the
synthesis of isoquinolines under optimized iridium(III)-
catalyzed conditions (Scheme 2b). Good tolerance of para- or
B
DOI: 10.1021/acs.orglett.7b03546
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 3. Scope of Propargyl Alcohols
Scheme 4. Experimental Investigation
a
All reactions were carried out in 0.2 mmol scale; isolated yield was
reported.
well tolerated to afford corresponding indenamine (3cb−cd)
and isoquinoline (4cb−cd) derivatives in good yields.
To gain more insights into the effect of the tertiary alcohol
group for these transformations, a series of experimental
investigations were then carried out (Scheme 4). Diphenyl
acetylene (2e) resulted in no reaction for both rhodium(III)- and
iridium(III)-catalyzed conditions (Scheme 4a), whereas prop-1-
yn-1-ylbenzene (2f) converted into a mixture of regioisomers of
isoquinoline product under the standard conditions (Scheme
4b). When (3,3-dimethylbut-1-yn-1-yl)benzene (2g) was
subjected to the reaction under rhodium(III)-catalyzed con-
ditions, an exclusive regioselctive isoquinoline product (4ag) was
obtained instead of an indenamine derivative (Scheme 4c).
Moreover, both primary and secondary alcohols (2h and 2i)
resulted in contrary regioselectivity compared with tertiary
alcohols, thus yielding only isoquinoline derivatives regardless of
what catalyst was used (Scheme 4d,e). Summarizing these
results, we can draw the following conclusions for these
transformations: (1) the specific regioselectivity is probably
due to the steric hindrance between gem-dimethyl and the C3−H
of the oxime substrate;11 (2) the hydroxyl group in the tertiary
propargyl alcohol substrate is essential for the [3 + 2] selectivity
under rhodium(III)-catalyzed conditions.
Finally, stoichiometric amounts of [Cp*RhCl2]2 as well as
[Cp*IrCl2]2 were treated with 1a to capture the potential
reactive intermediates (Scheme 4f). To our delight, both
rhodacycle intermediate (CCDC 1502584) and iridacycle
intermediate (CCDC 1502583) could be isolated successfully
and characterized by X-ray crystallography. The following
annulation of metallocycles with 2a easily converted into the
final indenamine and isoquinoline products, revealing that the
reactions were initiated with the same arene metalation to afford
the five-membered metallocycles as active intermediates, even
though different KIE values were given in further isotope-
labeling experiments (see the Supporting Information).
and isoquinoline skeletons. Switchable [3 + 2] and [4 + 2]
annulations can be achieved, respectively, under rhodium(III)-
and iridium(III)-catalyzed conditions. The hydroxyl group in the
tertiary propargyl alcohol substrate is crucial in controlling the
chemoselectivity probably due to its distinctive coordination
interaction with different TM catalysts depending on their Lewis
acidities and steric effects. Considering the mild reaction
conditions, good functional group tolerance, the valuable
structure of the products, and the application potential for late-
stage C−H functionalization, the present protocols should have
further synthetic utility in constructing complex compounds and
can also evoke more catalyst-controlled C−H activation
reactions for divergent synthesis of other important structural
motifs. More detailed investigations to understand the reaction
mechanism and exploration for new transformation properties of
propargyl alcohols in other TM catalysts, such as the recently
popular cobalt(III) and manganese(I) species,12 are in progress.
ASSOCIATED CONTENT
* Supporting Information
■
In summary, by employing tertiary propargyl alcohol
derivatives as versatile coupling partners, we have developed
efficient catalyst-controlled room-temperature C−H trans-
formations of oximes for divergent synthesis of indenamine
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b03546.
C
DOI: 10.1021/acs.orglett.7b03546
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(5) For some recent examples of transition-metal-catalyzed C−H
annulation of oximes with alkenes, see: (a) Chu, H.; Sun, S.; Yu, J.-T.;
Cheng, J. Chem. Commun. 2015, 51, 13327. (b) Wen, J.; Wu, A.; Miao,
Y.; Zhu, J. Tetrahedron Lett. 2015, 56, 5512. (c) Chen, R.; Qi, J.; Mao, Z.;
Cui, S. Org. Biomol. Chem. 2016, 14, 6201. (d) Boerth, J. A.; Ellman, J. A.
Chem. Sci. 2016, 7, 1474. (e) Zhang, Z.; Tang, M.; Han, S.; Ackermann,
L.; Li, J. J. Org. Chem. 2017, 82, 664.
Experimental procedures, characterization of products,
and 1H and 13C NMR spectra (PDF)
Accession Codes
CCDC 1476867−1476868 and 1502583−1502584 contain 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 Cambridge Crystallographic Data Centre,
12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223
336033.
(6) (a) Shi, Z.; Koester, D. C.; Boultadakis-Arapinis, M.; Glorius, F. J.
Am. Chem. Soc. 2013, 135, 12204. (b) Iagafarova, I. E.; Vorobyeva, D. V.;
Peregudov, A. S.; Osipov, S. N. Eur. J. Org. Chem. 2015, 2015, 4950.
(c) Phatake, R. S.; Patel, P.; Ramana, C. V. Org. Lett. 2016, 18, 292.
(7) For selected examples, see: (a) Yu, S.; Li, X. Org. Lett. 2014, 16,
1220. (b) Zhou, X.; Yu, S.; Kong, L.; Li, X. ACS Catal. 2016, 6, 647.
(c) Kim, H.; Chang, S. Angew. Chem., Int. Ed. 2017, 56, 3344.
(8) Zhou, X.; Yu, S.; Qi, Z.; Li, X. Sci. China: Chem. 2015, 58, 1297.
(9) For the lastest examples of transition-metal-catalyzed C−H
annulation with propargyl alcohols, see: (a) Wu, X.; Wang, B.; Zhou, S.;
Zhou, Y.; Liu, H. ACS Catal. 2017, 7, 2494. (b) Wu, X.; Wang, B.; Zhou,
Y.; Liu, H. Org. Lett. 2017, 19, 1294. (c) Sen, M.; Dahiya, P.; Premkumar,
J. R.; Sundararaju, B. Org. Lett. 2017, 19, 3699. (d) Lu, Q.; Greßies, S.;
Klauck, F. J. R.; Glorius, F. Angew. Chem., Int. Ed. 2017, 56, 6660. (e) Lu,
Q.; Greßies, S.; Klauck, F. J. R.; Glorius, F. Angew. Chem., Int. Ed. 2017,
56, 6660. (f) Hu, X.; Chen, X.; Zhu, Y.; Deng, Y.; Zeng, H.; Jiang, H.;
Zeng, W. Org. Lett. 2017, 19, 3474. (g) Xu, Y.; Wang, F.; Yu, S.; Li, X.
Chin. J. Catal. 2017, 38, 1390. (h) Lu, Q.; Greßies, S.; Cembellín, S.;
Klauck, F. J. R.; Daniliuc, C. G.; Glorius, F. Angew. Chem., Int. Ed. 2017,
56, 12778.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: yiwei@gzhmu.edu.cn.
ORCID
Wei Yi: 0000-0001-7936-9326
Present Address
⊥Central Research Institute of Shanghai Pharmaceuticals
Holding Co., Ltd., Shanghai 201203, China.
Author Contributions
§W.G., Z.Z., and J.S. contributed equally.
(10) (a) Vieth, M.; Cummins, D. J. J. Med. Chem. 2000, 43, 3020.
(b) Alajarín, R.; Burgos, C. In Modern Heterocyclic Chemistry; Alvarez-
Builla, J., Vaquero, J. J., Barluenga, J., Eds.; Wiley-VCH: Weinheim,
2011; Vol. 3, p 1527.
Notes
The authors declare no competing financial interest.
(11) Liao, G.; Song, H.; Yin, X.-S.; Shi, B.-F. Chem. Commun. 2017, 53,
7824.
(12) For selected recent reviews, see: Wang, S.; Chen, S.-Y.; Yu, X.-Q.
Chem. Commun. 2017, 53, 3165. (b) Yoshino, T.; Matsunaga, S. Adv.
Synth. Catal. 2017, 359, 1245.
ACKNOWLEDGMENTS
■
The authors thank NSFC (81502909), Guangdong Natural
Science Funds for Distinguished Young Scholar
(2017A030306031) for financial support on this study.
REFERENCES
■
(1) (a) Eicher, T.; Hauptmann, S. The Chemistry of Heterocycles; Wiley-
VCH: Weinheim, 2003. For selected reviews, see: (b) Zhang, M. Adv.
Synth. Catal. 2009, 351, 2243. (c) Colby, D. A.; Bergman, R. G.; Ellman,
J. A. Chem. Rev. 2010, 110, 624. (d) Gulías, M.; Mascarenas, J. L. Angew.
̃
Chem., Int. Ed. 2016, 55, 11000.
(2) For selected reviews, see: (a) Song, G.; Wang, F.; Li, X. Chem. Soc.
Rev. 2012, 41, 3651. (b) Colby, D. A.; Tsai, A. S.; Bergman, R. G.;
Ellman, J. A. Acc. Chem. Res. 2012, 45, 814. (c) Song, G.; Li, X. Acc. Chem.
Res. 2015, 48, 1007. (d) Ackermann, L. Acc. Chem. Res. 2014, 47, 281.
(e) Zhang, Y.; Zhang, Y.; Jie, X.; Zhao, H.; Li, G.; Su, W. Org. Chem.
Front. 2014, 1, 843. (f) Wencel-Delord, J.; Glorius, F. Nat. Chem. 2013,
5, 369. (g) Sun, H.; Guimond, N.; Huang, Y. Org. Biomol. Chem. 2016,
14, 8389. (h) Gensch, T.; Hopkinson, M. N.; Glorius, F.; Wencel-
Delord, J. Chem. Soc. Rev. 2016, 45, 2900. (i) Agasti, S.; Dey, A.; Maiti, D.
Chem. Commun. 2017, 53, 6544. (j) Wei, Y.; Hu, P.; Zhang, M.; Su, W.
Chem. Rev. 2017, 117, 8864. (k) Park, Y.; Kim, Y.; Chang, S. Chem. Rev.
2017, 117, 9247. (l) Rao, W.-H.; Shi, B.-F. Org. Chem. Front. 2016, 3,
1028.
(3) For selected recent reviews of C−H functionalization of oximes,
see: (a) Huang, H.; Ji, X.; Wu, W.; Jiang, H. Chem. Soc. Rev. 2015, 44,
1155. (b) Huang, H.; Cai, J.; Deng, G.-J. Org. Biomol. Chem. 2016, 14,
1519. (c) Li, J.; Hu, Y.; Zhang, D.; Liu, Q.; Dong, Y.; Liu, H. Adv. Synth.
Catal. 2017, 359, 710.
(4) For selected examples of transition-metal-catalyzed C−H
annulation of oximes with alkynes, see: (a) Kornhaaβ, C.; Li, J.;
Ackermann, L. J. Org. Chem. 2012, 77, 9190. (b) Xie, F.; Qi, Z.; Yu, S.; Li,
X. J. Am. Chem. Soc. 2014, 136, 4780. (c) Wang, H.; Koeller, J.; Liu, W.;
Ackermann, L. Chem. - Eur. J. 2015, 21, 15525. (d) Sun, B.; Yoshino, T.;
Kanai, M.; Matsunaga, S. Angew. Chem., Int. Ed. 2015, 54, 12968.
(e) Muralirajan, K.; Kuppusamy, R.; Prakash, S.; Cheng, C.-H. Adv.
Synth. Catal. 2016, 358, 774.
D
DOI: 10.1021/acs.orglett.7b03546
Org. Lett. XXXX, XXX, XXX−XXX