
==== Front
Org Lett
Org Lett
ol
orlef7
Organic Letters
1523-7060
1523-7052
American Chemical Society

39190911
10.1021/acs.orglett.4c02270
Letter
Intramolecular Cobalt Porphyrin-Catalyzed Alkylation of 1-Isoindolinones by Site-Selective Insertion into a C(sp3)–H Bond
https://orcid.org/0000-0003-3880-4656
Buchelt Christoph
https://orcid.org/0009-0000-9805-6093
Zuber Julian
https://orcid.org/0000-0002-1342-0202
Bach Thorsten *
Technische Universität München, TUM School of Natural Sciences, Department Chemie and Catalysis Research Center (CRC), 85747 Garching, Germany
* thorsten.bach@ch.tum.de
27 08 2024
06 09 2024
26 35 73027306
20 06 2024
05 08 2024
01 08 2024
© 2024 The Authors. Published by American Chemical Society
2024
The Authors
https://creativecommons.org/licenses/by/4.0/ Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/).

1-Isoindolinones with a reactive hydrazone tether attached to the nitrogen atom underwent an intramolecular alkylation in the presence of cobalt(tetraphenylporphyrin) and a base. Products display saturated heterocyclic rings of various sizes (n = 5–7), and the method was applied to a short synthesis of the azepane alkaloid lennoxamine. The reaction likely involves a diazoalkane intermediate that undergoes dediazotation and a formal insertion into the C3–H bond. If a stereogenic center is present in the tether, a high degree of diastereoselectivity is recorded.

Fonds der Chemischen Industrie 10.13039/100018992 NA Deutsche Forschungsgemeinschaft 10.13039/501100001659 Ba 1372/23 document-id-old-9ol4c02270
document-id-new-14ol4c02270
ccc-price
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pmcConventional synthetic wisdom suggests to close the ring of saturated heterocyclic compounds by formation of a carbon–heteroatom bond.1 Large ring lactams and lactones, for example, are typically synthesized by macrocyclization strategies aiming at the formation of the C–N or C–O bond.2 With the advent of new reactions, which allow for an efficient, catalytic formation of C–C bonds, alternative routes have emerged, and there is an increasing number of macrolactams and macrolactones being prepared by intramolecular C–C bond formation.3 By the same token, cyclic ethers and amines are not necessarily formed any longer by ring closure of a carbon–heteroatom bond. Alternative strategies have received attention, among which the insertion into an existing C–H bond is particularly straightforward and concise.4 There is no need for prefunctionalization as the C–C bond is formed directly by an attack from a low-valent carbon intermediate.

On the basis of the interest of our group in the synthesis of pharmaceutically relevant heterocycles by C–H bond activation reactions,5 we have now explored synthetic access to tricyclic isoindolone derivatives6 of general structure 1 (Scheme 1). There are a large number of compounds with this structural element, many of which have been synthesized in the context of new lead identification campaigns. We envisaged position C3 of 1-isoindolinones to be suited for an intramolecular C–H insertion reaction ideally catalyzed by a transition metal M via a carbene type intermediate. A survey of the literature on the topic showed there is no precedent for this strategy.7 Typical transformations aiming at C–C bond formation at this position employ the weak C–H acidity at C3 to generate a carbanion that undergoes consecutive substitution or conjugate addition reactions.8

Scheme 1 Possible Synthetic Route to Tricyclic Isoindolone Derivatives 1 from 1-Isoindolinones by Intramolecular C–H Insertion into the C3–H Bond

We envisioned diazoalkanes to be suitable precursors for the required carbene intermediates. They are typically formed by base-mediated 1,1-elimination from N-toluenesulfonyl (Ts)-substituted hydrazones.9 Accordingly, the preparation of the starting materials for this study commenced in most cases with condensation of a 2-benzofuran-1(3H)-one (phthalide) and an ω-functionalized amine.10 The terminal ω-carbon atom in the side chain linked to 1-isoindolinone atom N2 was then further manipulated. A protected aldehyde, for example, was deproteced, or an alcohol oxidized. Condensation with Ts hydrazide (TsNHNH2) completed the synthesis (for details, see the Supporting Information).

Optimization studies toward the desired cyclization were performed with hydrazone 2a, which was obtained from parent phthalide in three steps (28% yield). With regard to the choice of metal catalyst, we were inspired by seminal contributions of the Zhang and de Bruin groups, who had successfully used cobalt(II) porphyrin complexes as catalysts to facilitate C–H insertion reactions.11,12 We consequently started to screen possible conditions with 5,10,15,20-tetraphenyl-21H,23H-porphincobalt(II) [Co(TPP)] as the catalyst (Table 1).

Table 1 Optimization of the Reaction Parameters for the Alkylation of 1-Isoindolinone 1aa

 	mol %b	base	equiv	T (°C)	solvent	yield (%)c	
1	5.0	Cs2CO3	1.5	40	PhMe	–	
2	5.0	Cs2CO3	1.5	60	PhMe	41	
3	5.0	Cs2CO3	1.5	60	PhCl	59	
4	5.0	Cs2CO3	1.5	60	oDCB	65	
5	5.0	Cs2CO3	2.0	60	oDCB	71	
6	5.0	Cs2CO3	2.5	60	oDCB	73	
7	5.0	Cs2CO3	5.0	60	oDCB	71	
8	2.5	Cs2CO3	2.5	60	oDCB	58	
9	1.0	Cs2CO3	2.5	60	oDCB	78	
10	–	Cs2CO3	2.5	60	oDCB	–	
11	1.0	DBU	2.5	60	oDCB	83	
a The reactions were performed on a 0.10 mmol scale employing 5,10,15,20-tetraphenyl-21H,23H-porphincobalt(II) as the catalyst. oDCB = o-dichlorobenzene. DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene.

b Amount of catalyst.

c Yield of the isolated product.

Cesium carbonate was used as the ancillary base,13 and toluene as the solvent. Because the projected reaction was intramolecular, the influence of the concentration was considered marginal. The chosen concentration (c) of 20 mM allowed the substrate to be soluble in most solvents (see the Supporting Information for a complete set of optimization data). The reaction was consistently run for 24 h, enabling a meaningful comparison of the reaction profiles. While no reaction was observed at 40 °C in toluene (entry 1), a notable conversion was achieved at 60 °C with 5 mol % catalyst (entry 2). Chlorinated benzenes as solvents resulted in a better yield, and o-dichlorobenzene was found to be the solvent of choice (entries 3 and 4). In all cases, the reaction remained incomplete and starting materials were detected. An increase in the amount of base had a beneficial influence on the yield, and the conversion was complete when 2.5 equiv of base was used. A further increase in the amount of base did not improve the performance (entries 5–7). The catalyst loading could be decreased to 1.0 mol % without compromising the yield (entries 8 and 9), and it was shown that the catalyst was required to achieve the desired transformation (entry 10). With the conditions of entry 6, other cobalt(II) tetraarylporphyrin complexes were tested but the influence of the aryl group was found to be insignificant [67–75% yield (see the Supporting Information)]. A screening of bases revealed DBU to perform slightly better than Cs2CO3 (entry 11).

The conditions of entry 11 were considered to be best suited for studying the scope of the intramolecular alkylation with various hydrazones 2 (Scheme 2). Five-membered ring formation was facile for almost any of the tested substrates, and high yields were recorded (77–95%). The tolerated functional groups include bromo (products 1c, 1f, 1h, and 1m), chloro (1e), fluoro (1g), cyano (1j), methoxycarbonyl (1k), methoxy (1l), and trifluoromethyl (1n) substituents. Only nitro-substituted substrate 2i reacted sluggishly and gave a lower product yield (43%). The reaction to 9-bromo-1,2,3,9b-tetrahydro-5H-pyrrolo[2,1-a]isoindol-5-one (1m) was also performed on a millimole scale and required an elongated reaction time of 48 h. C–C bond formation at a C3-substituted isoindolinone was possible, as was the alkylation of an aza-1-isoindolinone (products 1o and 1p).

Scheme 2 Intramolecular, Cobalt(II) Porphyrin-Catalyzed Alkylation of 1-Isoindolinones Starting from Hydrazones 2 as Precursors

The reactions were performed on a 0.10 mmol scale employing 5,10,15,20-tetraphenyl-21H,23H-porphincobalt(II) as the catalyst.

The reaction was also performed on a 1.00 mmol scale in 81% yield (t = 48 h; see the Supporting Information for details).

Encouraged by the results in the pyrrolo series, we attempted to apply the reaction conditions to the formation of six-membered rings, and 1,3,4,10b-tetrahydropyrido[2,1-a]isoindol-6(2H)-one (1q) was obtained in 66% yield. In contrast to products 1a–1p, a small amount of a side product could be detected, which was identified as 2-(but-3-en-1-yl)isoindolin-1-one [4q, 10% (see Scheme 3)]. The observation is in agreement with previous studies of the formation of piperidines from hydrazones11e and indicates a second competitive 1,5-hydrogen abstraction of the radical intermediate (vide supra). It was suggested that the pathway could be suppressed if no abstractable hydrogen atom was available at the α-position of the hydrazone. This hypothesis was verified with hydrazone 2r, which was derived from a substituted benzaldehyde substrate and provided tetracyclic product 1r in almost perfect yield (99%). The benzene ring within the tether likely rigidifies the chain and facilitates a smooth reaction. Along the same lines, the formation of a seven-membered ring, starting from a precursor with an aliphatic linker, was not productive. Once the rotational freedom was restricted by an o-benzene ring in the tether, the alkylation became feasible. The reactivity pattern was initially probed with an otherwise unsubstituted starting material 2s, which led to a remarkable yield of 92% of the desired product 1s. The success encountered with this reaction inspired an application of the method to the synthesis of the alkaloid lennoxamine (1t), an azepane alkaloid isolated from the Chilean barberry.14,15 Here, the respective substrate 2t required both the benzene ring of the indolinone and the benzene ring within the tether to be substituted with oxygen. The Co-catalyzed alkylation proceeded smoothly and provided the natural product in 94% yield.

Scheme 3 Experiments with Deuterated 1-Isoindolinones 2a-d2 and 3-d2 Indicating That Position C3 Is Susceptible to H/D Exchange and the Putative Formation of Side Product 4q

Limitations of the method include the formation of smaller and larger rings. Four-membered ring formation was not successful, nor could aliphatic seven-membered ring formation be observed (vide infra). Hydrazones derived from ketones did not react. A practical advantage is the use of an in situ procedure for the generation of the hydrazones.11e Starting directly from the aldehyde, treatment with p-toluenesulfonyl hydrazide generates hydrazone 2ain situ and enables a one-pot reaction to afford compound 1a. Following this procedure, the desired alkylation product was isolated in 81% yield.

To shed some light on the course of the reaction, we studied a selection of deuterated 1-isoindolones (Scheme 3). Subjecting deuterated substrate 2a-d2 to the optimized conditions afforded expected product 1a-d2 in 71% yield. While the degree of deuteration at C9b remained unaffected (97%), the extent of incorporation of deuterium at C1 of the product was slightly diminished (88%). On the basis of literature precedent,8,16 we suspected that position C3 of 2a would display a weak C–H acidity and, thus, be responsible for the loss of deuterium. In fact, when we subjected N-methylated substrate 3-d2 to the standard reaction conditions, we observed a slight decrease in the deuterium content. Although the latter observation made the accurate determination of a primary kinetic isotope effect impossible, we could clearly show for monodeuterated substrate 2a-d1 that the C–H bond is significantly more reactive in the alkylation reaction than the C–D bond (see the Supporting Information).

Deuterium incorporation combined with the previous observation of hydrogen abstraction product 4q agrees with the reaction course established for cobalt porphyrin-catalyzed alkylation reactions11 (Scheme 4). Accordingly, we assume that the base is responsible for the generation of diazoalkane 5 by 1,1-elimination. The latter expels a nitrogen molecule (N2) upon coordination to cobalt, and ensuing radical 6 initiates intramolecular hydrogen abstraction at the C3–H bond of the 1-isoindolinone. Radical 7 releases the cobalt fragment by homolytic ring closure but can also abstract a hydrogen atom in the α-position to the Co-substituted carbon atom. The side reaction manifests itself by leading to olefinic byproducts such as 4q (vide infra).

Scheme 4 Mechanistic Proposal for the Intramolecular Alkylation, Possible Conformations of Intermediates, and Diastereoselective Reactions

The hydrogen abstraction/ring closure event is responsible for any diastereoselectivity observed in the alkylation reactions. We probed the outcome of the reaction with a selection of substrates displaying a stereogenic center in the tether. Configuration assignments were based on nuclear Overhauser exchange spectroscopy (NOESY) experiments. In the pyrrolo series, a stereogenic center adjacent to the nitrogen atom induced a high diastereoselectivity, and five-membered product 1u was obtained in a diastereomeric ratio (dr) of 95/5. The diastereoselectivity can be explained by the conformation of the chain as enforced by 1,3-allylic strain17 (n = 5). For the closure of a piperidine ring (n = 6), we observed divergent diastereoselectivity depending on the substituent within the chain. With an oxygen-substituted stereogenic center in the β-position to the radical, formation of products 1v and 1w was observed. Product 1v adopts a chair conformation, as one can also see in the crystal structures of related 1,3,4,10b-tetrahydropyrido[2,1-a]isoindol-6(2H)-ones.18 In the major diastereoisomer, the tert-butyldimethylsilyloxy (OTBS) group resides in an equatorial position, which supports the idea that hydrogen abstraction and cyclization had also occurred in a chairlike transition state. In contrast, major product 1v of a related substrate with a p-methoxybenzyl (PMB)-protected oxygen atom adopts a boat-like conformation, possibly also in the transition state. The major diastereoisomer of product 1x displayed a strong NOE contact between the C10b hydrogen atom and the methyl group residing in an axial position at C2. The relative configuration of this compound and its conformation in the solid state were corroborated by single-crystal X-ray crystallography (see the Supporting Information for details). Here, a 1,2-repulsion with the bulky [Co] fragment might enforce the axial position in a chair type transition state. In any case, the preliminary results indicate that a high degree of diastereoselectivity can be expected in the alkylation reaction and that the outcome might even be tunable by a judicious choice of protecting groups.

In summary, the cobalt porphyrin-catalyzed alkylation has been shown to be a useful and reliable method for the intramolecular alkylation of 1-isoindolinones at position C3. The starting materials are readily available, and the method is compatible with a wide array of functional groups. The differentiation of diastereotopic hydrogen atoms is possible if a stereogenic center is implemented in the reactive tether.

Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.orglett.4c02270.Materials and methods, optimization of reaction conditions, synthetic procedures and full characterization for all starting materials and products (2a–2x and 1a–1x), spectroscopic data, NMR spectra, and X-ray crystallographic details (PDF)

FAIR data, including the primary NMR FID files, for compounds 2a–2x, 2a-d, 2a-d2, SI-1a-d, Si-1b, Si-1e, Si-1f, Si-1l, Si-1u, Si-1x, SI-2c, SI-2d, SI-2g, SI-2h, SI-2j, SI-2m, SI-2s, SI-3a, SI-3i, SI-3k, SI-3n–SI-3p, SI-4r, SI-4s, SI-6, SI-7a, SI-7b, SI-9, SI-11, SI-13, SI-15, 1a–1x, 1a-d1, 1a-d2, and 3-d2 (ZIP)

Supplementary Material

ol4c02270_si_001.pdf

ol4c02270_si_002.zip

The authors declare no competing financial interest.

Acknowledgments

Financial support by the Deutsche Forschungsgemeinschaft (Ba 1372/23) and by the Fonds der Chemischen Industrie (Kekulé fellowship to C.B.) is gratefully acknowledged. The authors thank the following students for experimental assistance: R. Bergmann and V. König (both TU München). O. Ackermann and J. Kudermann (both TU München) are acknowledged for their help with HPLC and GLC analyses.
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References

Warren S. ; Wyatt P. Organic Synthesis: The Disconnection Approach, 2nd ed.; Wiley: Chichester, U.K., 2008; pp 217–227.
a Parenty A. ; Moreau X. ; Niel G. ; Campagne J. M. Update 1 of: Macrolactonizations in the Total Synthesis of Natural Products. Chem. Rev. 2013, 113 , PR1–PR40. 10.1021/cr300129n.23005342
b Valeur E. ; Bradley M. Amide bond formation: beyond the myth of coupling reagents. Chem. Soc. Rev. 2009, 38 , 606–631. 10.1039/B701677H.19169468
a Saridakis I. ; Kaiser D. ; Maulide N. Unconventional Macrocyclizations in Natural Product Synthesis. ACS Cent. Sci. 2020, 6 , 1869–1889. 10.1021/acscentsci.0c00599.33274267
b Rivera D. G. ; Ojeda-Carralero G. M. ; Reguera L. ; Van der Eycken E. V. Peptide macrocyclization by transition metal catalysis. Chem. Soc. Rev. 2020, 49 , 2039–2059. 10.1039/C9CS00366E.32142086
a Docherty J. H. ; Lister T. M. ; McArthur G. ; Findlay M. T. ; Domingo-Legarda P. ; Kenyon J. ; Choudhary S. ; Larrosa I. Transition-Metal-Catalyzed C–H Bond Activation for the Formation of C–C Bonds in Complex Molecules. Chem. Rev. 2023, 123 , 7692–7760. 10.1021/acs.chemrev.2c00888.37163671
b He Y. ; Huang Z. ; Wu K. ; Ma J. ; Zhou Y.-G. ; Yu Z. Recent advances in transition-metal-catalyzed carbene insertion to C–H bonds. Chem. Soc. Rev. 2022, 51 , 2759–2852. 10.1039/D1CS00895A.35297455
Examples:

a Ahmed H. ; Ghosh B. ; Breitenlechner S. ; Feßner M. ; Merten C. ; Bach T. Intermolecular Enantioselective Amination Reactions Mediated by Visible Light and a Chiral Iron Porphyrin Complex. Angew. Chem., Int. Ed. 2024, 63 , e202407003 10.1002/anie.202407003.
b Xiong Y. ; Großkopf J. ; Jandl C. ; Bach T. Visible Light-Mediated Dearomative Hydrogen Atom Abstraction/ Cyclization Cascade of Indoles. Angew. Chem., Int. Ed. 2022, 61 , e202200555 10.1002/anie.202200555.
c Wahl J. M. ; Pöthig A. ; Bach T. Pyrrole as a Directing Group: Regioselective Pd(II)-Catalyzed Alkylation and Benzylation at the Benzene Core of 2-Phenylpyrroles. Org. Lett. 2016, 18 , 852–855. 10.1021/acs.orglett.6b00141.26845081
d Wamser M. ; Bach T. Regioselectivity of Intramolecular Rhodium-Catalyzed C–H Insertion Reactions of α-Aryl-α-diazocarboxylates: Influence of the Aryl Substituent. Synlett 2014, 25 , 1081–1084. 10.1055/s-0033-1341062.
a Upadhyay S. P. ; Thapa P. ; Sharma R. ; Sharma M. 1-Isoindolinone scaffold-based natural products with a promising diverse bioactivity. Filoterapia 2020, 146 , 104722 10.1016/j.fitote.2020.104722.
b Speck K. ; Magauer T. The chemistry of isoindole natural products. Beilstein J. Org. Chem. 2013, 9 , 2048–2078. 10.3762/bjoc.9.243.24204418
For the electrochemical oxidation of 1-isoindolinones and subsequent C–C bond formation, see:

Sim J. ; Ryou B. ; Choi M. ; Lee C. ; Park C.-M. Electrochemical C(sp3)–H Functionalization of γ-Lactams Based on Hydrogen Atom Transfer. Org. Lett. 2022, 24 , 4264–4269. 10.1021/acs.orglett.2c01528.35675591
Examples:

a Moreau A. ; Couture A. ; Deniau E. ; Grandclaudon P. ; Lebrun S. A new approach to isoindoloisoquinolinones. A simple synthesis of nuevamine. Tetrahedron 2004, 60 , 6169–6167. 10.1016/j.tet.2004.05.033.
b Luci D. K. ; Lawson E. C. ; Ghosh S. ; Kinney W. A. ; Smith C. E. ; Qi J. ; Wang Y. ; Minor L. K. ; Maryanoff B. E. Tetrahedron Lett. 2009, 50 , 4958–4961. 10.1016/j.tetlet.2009.06.025.
c Gómez-Prado R. A. ; Silva A. L. ; Miranda L. D. Synthesis of nuevamine and a cyano-chilenine analog via divergent C(sp3)–H bond functionalization of isoindolinone derivatives. Org. Biomol. Chem. 2022, 20 , 7325–7331. 10.1039/D2OB01304E.36069857
a Bamford W. R. ; Stevens T. S. The decomposition of toluene-p-sulphonylhydrazones by alkali. J. Chem. Soc. 1952, 4735–4740. 10.1039/jr9520004735.
b te Grotenhuis C. ; Das B. D. ; Kuijpers P. F. ; Hageman W. ; Trouwborst M. ; de Bruin B. Catalytic 1,2-dihydronaphthalene and E-aryl-diene synthesis via CoIII–Carbene radical and o-quinodimethane intermediates. Chem. Sci. 2017, 8 , 8221–8230. 10.1039/C7SC03909C.29568470
Norman M. H. ; Minick D. J. ; Rigdon G. C. Effect of Linking Bridge Modifications on the Antipsychotic Profile of Some Phthalimide and Isoindolinone Derivatives. J. Med. Chem. 1996, 39 , 149–157. 10.1021/jm9502201.8568802
a Cui X. ; Xu X. ; Jin L. M. ; Wojtas L. ; Zhang X. P. Stereoselective Radical C−H Alkylation with Acceptor/Acceptor-Substituted Diazo Reagents via Co(II)-Based Metalloradical Catalysis. Chem. Sci. 2015, 6 , 1219–1224. 10.1039/C4SC02610A.25685314
b Karns A. S. ; Goswami M. ; de Bruin B. Catalytic Synthesis of Indolines by Hydrogen Atom Transfer to Cobalt(III)–Carbene Radicals. Chem. - Eur. J. 2018, 24 , 5253–5258. 10.1002/chem.201704626.29143995
c Wen X. ; Wang Y. ; Zhang X. P. Enantioselective Radical Process for Synthesis of Chiral Indolines by Metalloradical Alkylation of Diverse C(sp3)-H Bonds. Chem. Sci. 2018, 9 , 5082–5086. 10.1039/C8SC01476K.29938039
d Wang Y. ; Wen X. ; Cui X. ; Zhang X. P. Enantioselective Radical Cyclization for Construction of 5-Membered Ring Structures by Metalloradical C-H Alkylation. J. Am. Chem. Soc. 2018, 140 , 4792–4796. 10.1021/jacs.8b01662.29584958
e Lankelma M. ; Olivares A. M. ; de Bruin B. [Co(TPP)]-Catalyzed Formation of Substituted Piperidines. Chem. - Eur. J. 2019, 25 , 5658–5663. 10.1002/chem.201900587.30844097
f Xie J. ; Xu P. ; Zhu Y. ; Wang J. ; Lee W. C. C. ; Zhang X. P. New Catalytic Radical Process Involving 1,4-Hydrogen Atom Abstraction: Asymmetric Construction of Cyclobutanones. J. Am. Chem. Soc. 2021, 143 , 11670–11678. 10.1021/jacs.1c04968.34292709
g Epping R. F. J. ; Vesseur D. ; Zhou M. ; de Bruin B. Carbene Radicals in Transition-Metal-Catalyzed Reactions. ACS Catal. 2023, 13 , 5428–5448. 10.1021/acscatal.3c00591.37123600
General reviews and books:

a Desai B. ; Uppuluru A. ; Dey A. ; Deshpande N. ; Dholakiya B. Z. ; Sivaramakrishna A. ; Naveen T. ; Padala K. The recent advances in cobalt-catalyzed C(sp3)–H functionalization reactions. Org. Biomol. Chem. 2023, 21 , 673–699. 10.1039/D2OB01936A.36602117
b Hapke M. , Hilt G. , Eds. Cobalt Catalysis in Organic Synthesis; Wiley-VCH: Weinheim, Germany, 2020.
Rabie R. ; Hammouda M. M. ; Elattar K. M. Cesium carbonate as a mediated inorganic base in some organic transformations. Res. Chem. Intermed. 2017, 43 , 1979–2015. 10.1007/s11164-016-2744-z.
Valencia E. ; Freyer A. J. ; Shamma M. ; Fajardo V. (±)-Nuevamine, an isoindoloisoquinoline alkaloid, and (±)-lennoxamine, an isoindolobenzazepine. Tetrahedron Lett. 1984, 25 , 599–602. 10.1016/S0040-4039(00)99948-9.
For previous syntheses, see:

a Teitel S. ; Klötzer W. ; Borgese J. ; Brossi A. A New Synthesis of ″Schöpf’s Base VI″ and Related 10H-Isoindolo[2,3-c] benzazepines. Can. J. Chem. 1972, 50 , 2022–2024. 10.1139/v72-325.
b Napolitano E. ; Spinelli G. ; Fiaschi R. ; Marsili A. A simple total synthesis of the isoindolobenzazepine alkaloids lennoxamine and chilenamine. J. Chem. Soc., Perk. Trans. 1 1986, 785–787. 10.1039/p19860000785.
c Moody C. J. ; Warrellow G. J. Synthesis of the isoindolobenzazepine alkaloid lennoxamine. Tetrahedron Lett. 1987, 28 , 6089–6092. 10.1016/S0040-4039(00)96871-0.
d Rodríguez G. ; Cid M. M. ; Saá C. ; Castedo L. ; Domínguez D. A Radical Cyclization Approach to Isoindolobenzazepines. Synthesis of Lennoxamine. J. Org. Chem. 1996, 61 , 2780–2782. 10.1021/jo952113k.11667113
e Sahakitpichan P. ; Ruchirawat S. A practical and highly efficient synthesis of lennoxamine and related isoindolobenzazepines. Tetrahedron 2004, 60 , 4169–4172. 10.1016/j.tet.2004.03.049.
a Pérard-Viret J. ; Prangé T. ; Tomas A. ; Royer J. A simple and efficient asymmetric synthesis of 3-alkyl-isoindolin-1-ones. Tetrahedron 2002, 58 , 5103–5108. 10.1016/S0040-4020(02)00462-3.
b Couture A. ; Deniau E. ; Grandclaudon P. ; Hoarau C. ; Rys V. Diastereoselective addition of metalated isoindolin-1-ones to aldehydes. Stereoselective preparation of (E)-3-arylideneisoindolin-1-ones. Tetrahedron Lett. 2002, 43 , 2207–2210. 10.1016/S0040-4039(02)00236-8.
a Hoffmann R. W. Allylic 1,3-Strain as a Controlling Factor in Stereoselective Transformations. Chem. Rev. 1989, 89 , 1841–1860. 10.1021/cr00098a009.
b Ledovskaya M. S. ; Molchanov A. P. ; Boitsov V. M. ; Kostikov R. R. ; Stepakov A. V. An efficient synthesis of substituted isoxazolopyrroloisoquinolines via diastereoselective N-acyliminium ion cyclization. Tetrahedron 2015, 71 , 1952–1958. 10.1016/j.tet.2015.02.031.
Indukuri K. ; Unnava R. ; Deka M. J. ; Saikia A. K. Stereoselective Synthesis of Amido and Phenyl Azabicyclic Derivatives via a Tandem Aza Prins-Ritter/Friedel–Crafts Type Reaction of Endocyclic N-Acyliminium Ions. J. Org. Chem. 2013, 78 , 10629–10641. 10.1021/jo401450j.24083489
