Iron-Catalyzed Reductive Cyclization by Hydromagnesiation: A Modular Strategy Towards N-Heterocycles

Article abstract of DOI:10.1002/anie.202106996

A reductive cyclization to prepare a variety of N-heterocycles, through the use of ortho-vinylanilides, is reported. The reaction is catalyzed by an inexpensive and bench-stable iron complex and generally occurs at ambient temperature. The transformation likely proceeds through hydromagnesiation of the vinyl group, and trapping of the in situ generated benzylic anion by an intramolecular electrophile to form the heterocycle. This iron-catalyzed strategy was shown to be broadly applicable and was utilized in the synthesis of substituted indoles, oxindoles and tetrahydrobenzoazepinoindolone derivatives. Mechanistic studies indicated that the reversibility of the hydride transfer step depends on the reactivity of the tethered electrophile. The synthetic utility of our approach was further demonstrated by the formal synthesis of a reported bioactive compound and a family of natural products.

Full text of DOI:10.1002/anie.202106996

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How to cite:
International Edition: doi.org/10.1002/anie.202106996
German Edition: doi.org/10.1002/ange.202106996
Synthetic Methods
Iron-Catalyzed Reductive Cyclization by Hydromagnesiation: A
Modular Strategy Towards N-Heterocycles
Joachim Loup, Egor M. Larin, and Mark Lautens*
Abstract: A reductive cyclization to prepare a variety of N-
heterocycles, through the use of ortho-vinylanilides, is reported.
The reaction is catalyzed by an inexpensive and bench-stable
iron complex and generally occurs at ambient temperature.
The transformation likely proceeds through hydromagnesia-
tion of the vinyl group, and trapping of the in situ generated
benzylic anion by an intramolecular electrophile to form the
heterocycle. This iron-catalyzed strategy was shown to be
broadly applicable and was utilized in the synthesis of
substituted indoles, oxindoles and tetrahydrobenzoazepinoin-
dolone derivatives. Mechanistic studies indicated that the
reversibility of the hydride transfer step depends on the
reactivity of the tethered electrophile. The synthetic utility of
our approach was further demonstrated by the formal synthesis
of a reported bioactive compound and a family of natural
products.
Thomas and co-workers, which typically proceeds with
excellent branch-selectivity.[8] While subsequent work focused
on unravelling the mechanism of the reaction,[9] limited work
has been conducted to expand its synthetic applications
towards known value-added products.[10] Furthermore, those
reactions are conducted in a two-step fashion, with the
electrophile being added after the hydromagnesiation step in
order to prevent its direct reaction with the Grignard reagent.
Hence, it often suffers from poor functional group compat-
ibility, with only simple styrene derivatives being tolerated
(Scheme 1a).
Within our program focusing on the development of novel
transition metal-catalyzed syntheses of pharmaceutically
relevant indoles,[11] we became interested in applying the
recently developed iron-catalyzed hydromagnesiation of
styrenes to access indoles as well as other N-heterocycles
(Scheme 1b). Substituted N-heterocyclic scaffolds are impor-
tant structural motifs found in numerous pharmaceuticals and
natural products, with almost 90% of all heterocycles
synthesized in pursuit of novel drug candidates containing
at least one nitrogen heterocycle.[12] As such, methods for
their de novo preparation without the need for late transition
metals remain in high demand.[13]
We envisioned that the reactive benzylic anion generated
in situ from a styrene derivative could be trapped rapidly with
a tethered electrophile in a true one-operation process to
prepare the desired cyclic compounds. Preliminary studies
identified readily available amides as suitable electrophiles in
the transformation (Scheme 1b, top). It is noteworthy that
a similar strategy for the synthesis of indoles from ortho-
vinylanilides relying on an interrupted Kulinkovich reac-
tion[15] was previously reported by Cha,[16] but was limited to
a single example with poor selectivity and required a stoichio-
metric amount of titanium as well as a large excess of the
organometallic reagent. A notable feature of our strategy is
that only a sub-stoichiometric amount of the organomagne-
sium compound should be present at any given time in the
reaction mixture, potentially resulting in an improved func-
tional group tolerance in comparison to traditional hydro-
magnesiation methods. This claim assumes the Grignard
reagent is consumed rapidly in a fast hydromagnesiation
reaction, after which a rapid intramolecular trapping occurs.
Overall, the process can be described as an iron-catalyzed
hydromagnesiation-initiated Madelung-type indole synthe-
sis[17] and represents an anionic variant of the Fukuyama
indole synthesis which employs similar substrates.[18] Further-
more, this strategy represents expedient access to various N-
heterocyclic cores bearing a 3-methyl group, which are
prevalent in various drug molecules[19] and bioactive natural
Introduction
À
The catalytic hydrometall(oid)ation of C C multiple
bonds is a powerful tool in organic chemistry due to the
possibility to generate useful synthetic intermediates from
simple substrates.[1] More specifically, catalytic transfer hy-
dromagnesiations employing organomagnesium reagents rep-
resent an elegant example of shuttle catalysis,[2] and are
particularly interesting because of the versatility of the
resulting new organometallic compounds and the possibility
to generate Grignard reagents not accessible by traditional
methods.[3] However, the use of transfer hydromagnesiation
remains largely underdeveloped, in part due to poor func-
tional group tolerance and a narrow substrate scope.
In recent years, the development of earth-abundant first
row transition metal catalysts to enable hydrometallation
reactions has attracted significant attention.[4] Iron catalysts
are of particular interest due to the high abundance, unique
reactivity, low cost, and comparatively low toxicity of iron
versus many other transition metals.[5] In this context, the
iron-catalyzed hydromagnesiation of alkenes has experienced
a renaissance over the last decade,[6] long after the early
observations by Kochi.[7] A breakthrough in the field was the
iron-catalyzed hydromagnesiation of styrenes reported by
[*] Dr. J. Loup, Dr. E. M. Larin, Prof. Dr. M. Lautens
Davenport Laboratories, Department of Chemistry
University of Toronto
80 St. George St., Toronto, Ontario, M5S 3H6 (Canada)
E-mail: mark.lautens@utoronto.ca
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202106996.
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Table 1: Optimization of the reaction parameters.[a]
Entry Deviation from standard conditions
Yield of 2a
[%]
1
2
3
4
5
6
7
8
9
none
[
>95
73
19
39
30
MesBIP·FeCl2] instead of [iPrBIP·FeCl2]
FeCl2 instead of [iPrBIP·FeCl2]
FeCl2 +TMEDA (20 mol%) instead of [iPrBIP·FeCl2]
iPrMgCl instead of EtMgBr
Et2Zn instead of EtMgBr
n.r.
57
[iPrBIP·FeCl2] (5.0 mol%)
[iPrBIP·FeCl2] (5.0 mol%), slow addition of EtMgBr
[iPrBIP·FeCl2] (5.0 mol%), slow addition of EtMgBr
(1.3 equiv), 5 min reaction time
[iPrBIP·FeCl2] was omitted
>95
94[b]
10
0
[a] Reaction conditions: 1a (0.20 mmol), [iPrBIP·FeCl2] (10 mol%),
EtMgBr (1.4 equiv, 3.0 M in Et2O), THF (1.5 mL), r.t., 1 h. Yields
determined by 1H NMR spectroscopy using 1,1,2,2-tetrachloroethane as
an internal standard. [b] Isolated yield. n.r.=no reaction. For exper-
imental details, see the Supporting Information.
less effective at stabilizing the iron(0) species, based on steric
effects.[9a] The yield was considerably reduced when running
the reaction at a lower catalyst loading (entry 7), presumably
due to uncatalyzed side reactions between 1a and the
Grignard reagent,[14] but could be restored by the slow
addition of EtMgBr (entry 8). Finally, the amount of EtMgBr
could be reduced to 1.3 equiv and we found out that full
conversion was reached within 5 min (entry 9). Additional
control experiments confirmed the importance of the catalyst
and the superiority of iron over other metals in the desired
reaction (entry 10 and Supporting Information).
With the optimized reaction conditions in hand, we
explored the versatility of the iron-catalyzed reductive
cyclization in the synthesis of 1,2,3-trisubstituted indoles
(Scheme 2). A broad range of benzamides 1 bearing electron-
donating and withdrawing groups participated in the reaction,
providing the corresponding 2-arylindoles 2 in good to
excellent yields. Fortunately, even the very hindered 2-(3-
methoxy-2-naphthyl)-indole 2h was obtained in satisfactory
yield. While 2-heteroarylindoles 2i,j were only obtained in
moderate yields, bulky ferrocenyl substituents are compatible
with the transformation. Various alkyl, aryl and benzyl groups
were tolerated as N-substituents of the 2-vinylanilides 1. The
reaction was found to be highly selective for styrene
derivatives as additional non-conjugated double bonds were
left entirely untouched. Additional functionalities on the
Scheme 1. a) General reaction scheme of the iron-catalyzed hydro-
magnesiation of styrenes and subsequent trapping with external
electrophiles. b) Iron-catalyzed hydromagnesiation of styrenes and
trapping with intermolecular electrophiles for the synthesis of N-
heterocycles. c) Selected 3-methyl(ox)indole derivatives which display
bioactivity.
products.[20] Improved synthetic pathways towards these
important structures are warranted (Scheme 1c).
Results and Discussion
We initiated our study by investigating the reaction of
benzamide 1a with EtMgBr in the presence of the iron
catalyst
[
iPrBIP·FeCl2][21] (BIP = bis(imino)pyridine) em-
ployed by Thomas for the hydromagnesiation of styrenes[8]
(Tables 1 and S-1[14]). The desired indole 2a was obtained in
high yield (entry 1). Control experiments confirmed iPrBIP
and EtMgBr to be the optimal ligand and hydride source
(entries 2–4 and Supporting Information). In contrast to
previous reports, surprisingly poor results were obtained with
TMEDA, possibly because the ortho-vinylanilide substrate is
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the sterically crowded product with an adamantyl group
between two other substituents, 2s.
Finally, the utility of the methodology was further
illustrated by the facile synthesis and modification of drug
motifs. Amide 1v, derived from the analgesic drug cincho-
phen,[23] was submitted to the reaction conditions to afford
indole 2v. Moreover, an expedient formal synthesis of the
antiosteoporotic drug bazedoxifene was realized. Its dimethyl
ether 2w, which has been reported as the final intermediate in
several synthetic routes towards the drug,[24] was obtained in
80% yield through this iron-catalyzed reductive cyclization
strategy.
Furthermore, our approach could be expanded beyond
the synthesis of diversely decorated indoles. In keeping with
our interest in the development of metal-catalyzed ap-
proaches toward the oxindole core,[25] we attempted to apply
the methodology to the synthesis of 3-methyloxindoles 4. The
latter could be prepared by submitting carbamates 3 to the
reaction conditions (Scheme 3a). In comparison to indoles,
higher temperatures and increased reaction times were
needed to obtain the oxindole products 4 in fair yields. It
should be noted that a related strategy was previously
described by Taguchi, but was a non-catalyzed process
requiring excess pre-formed Negishi reagent.[26]
Additionally, the putative intermediate I could be trapped
with external electrophiles in a one-pot process to access
oxindoles
bearing
all-carbon
quaternary
centers
(Scheme 3b). It is noteworthy that this process represents
a formal 1,1-dicarbofunctionalization of the styrene moiety.
Scheme 2. Iron-catalyzed synthesis of indoles 2. [a] 1.5 mmol scale.
For experimental details, see the Supporting Information.
indoleꢀs benzene ring were well accommodated, including
sensitive chloro substituents. It should be mentioned that the
dechlorination of chloroarenes had previously been reported
under similar conditions employing Grignard reagents and an
iron catalyst,[10a,22] but this pathway could be prevented in our
case presumably thanks to a very short reaction time and fast
intramolecular trapping of reactive intermediates. Unfortu-
nately, more reactive electrophiles were not tolerated.[14]
The transformation was not limited to the preparation of
2-arylindoles. Indeed, 1,2,3-trisubstituted indoles bearing
primary, secondary as well as tertiary alkyl groups at the C2
position were obtained in good to excellent yields, including
Scheme 3. Iron-catalyzed synthesis of oxindoles 4 and 5. For exper-
imental details, see the Supporting Information.
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The synthetic utility of the transformation was demonstrated
transfer, with the in situ generated benzylic anion serving as
by the expedient preparation of 5b, an advanced intermediate
of the synthesis of both enantiomers of esermethole and other
related bioactive alkaloids.[27]
Finally, the iron-catalyzed reductive cyclization strategy
was applied to the synthesis of the novel polycyclic tetrahy-
drobenzoazepinoindolone scaffold 7 in good yield and
moderate diastereoselectivity (Scheme 4). The connectivity
a hydride source in the hydromagnesiation of another
molecule of the substrate rather than EtMgBr. These
observations are in agreement with a recent mechanistic
study by Neidig and Thomas who proposed the iron-catalyzed
hydromagnesiation of styrenes to be reversible.[9b] On the
other hand, the absence of H/D scrambling or deuterium
crossover in the case of the synthesis of indoles 2 can be
rationalized by a fast trapping of the in situ generated benzylic
anion with the more reactive amide, resulting in an irrever-
sible hydromagnesiation step.
On the basis of our results and literature precedent,[9]
a plausible mechanism of the indole synthesis is depicted in
Scheme 5c. An initial branch-selective iron-catalyzed hydro-
magnesiation delivers intermediate E. The in situ generated
benzylic anion can then attack the amide moiety, yielding
species F or G. According to control experiments,[14] this step
seems to be a direct Grignard reaction not requiring the iron
catalyst. Finally, aqueous workup generates intermediate H,
which can readily undergo imine condensation and aromati-
zation to provide the indole product 2. It is noteworthy that in
the case of the sterically crowded indole 2s, intermediate H
1
(S-2) was sufficiently stable to be observed by H NMR and
HRMS analysis of the crude product.[14] However, a mecha-
nism involving the protonation of intermediate F cannot be
fully excluded. Intermediates related to both F and H have
previously been proposed or observed as intermediates in
a related, multi-step, indole synthesis.[31]
Finally, the synthetic versatility of the indole products 2
was explored (Scheme 6). While the reaction remains so far
limited to the preparation of 3-methylindoles, the methyl
substituent can readily be converted to other functionalities.
Indeed, aldehyde 8 was easily prepared from 2a by oxidation
with MnO2, and the resulting formyl group can be removed[32]
or employed as a versatile handle for further downstream
derivatization.
Scheme 4. Iron-catalyzed synthesis of tetrahydrobenzoazepinoindo-
lones 7.
and relative stereochemistry of product 7a were unambigu-
ously confirmed by X-ray diffraction analysis.[28] The reaction
seemingly proceeds through an intramolecular dearoma-
tive[29] 1,4-addition of the in situ generated benzylic anion
into the indole-3-carboxamide to yield cis-indoline 7. It is
notable that this iron-catalyzed strategy enables the selective
hydromagnesiation across the styrene, utilizing the a,b-
unsaturated amide as a terminating electrophile. This result
is in contrast with a previous report which describes the 1,4- Conclusion
conjugate addition of Grignard reagents across related indole
scaffolds.[30]
In conclusion, we report a reductive cyclization for the
Given the unique features and versatility of this iron-
expedient synthesis of sterically congested 1,2,3-trisubstituted
indoles, and related N-heterocycles. The transformation,
which is catalyzed by an inexpensive bench-stable iron
complex, proceeds at ambient temperature with ample
substrate scope. The fast intramolecular trapping of the in
situ generated benzylic anion resulted in a short reaction time
and an improved functional group tolerance in comparison to
other hydromagnesiation reactions. Sensitive chlorides and
amides are tolerated. This strategy also provides a concep-
tually innovative approach towards the one-pot synthesis of
oxindoles with all-carbon quaternary centers and a novel
polycyclic tetrahydrobenzoazepinoindolone scaffold. Prelimi-
nary mechanistic studies indicated that the reversibility of the
hydride transfer step depends on the tethered electrophile.
Finally, the applicability of the transformation was demon-
strated by various derivatizations of the obtained indole
products and the formal syntheses of an FDA-approved drug
and several bioactive natural products. Further applications
catalyzed reductive cyclization, studies to probe the mecha-
nism were undertaken. To this end, reactions with isotopically
labeled ortho-vinylanilides were performed (Scheme 5). A
complete and selective deuterium transfer to the 3-methyl
group of indole [D]2-2a was observed when benzamide [D]2-
1a was submitted to the reaction conditions (Scheme 5a, left).
Crossover experiments were conducted, and no deuterium
exchange was detected in the products of a reaction with
substrates [D]2-1a and 1n or 1d (Scheme 5b, top and
Supporting Information). In contrast, a reaction with carba-
mate [D]2-3a delivered oxindole [D]n-4a as a mixture of
isotopologues with an overall reduced content of deuterium
(Scheme 5a, right). The loss of deuterium content can be
attributed to H/D exchange with the Grignard reagent.[14]
Furthermore, a deuterium crossover was observed in a reac-
tion with carbamates [D]2-3a and 3d (Scheme 5b, bottom).
These findings can be explained by a reversible hydride
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Scheme 5. Reactions with isotopically labeled substrates and proposed mechanism. For experimental details, see the Supporting Information.
of hydromagnesiation-initiated cascade reactions are under
way in our laboratory.
fellowship (Grant P2SKP2_187649). E.M.L. thanks NSERC
for a postgraduate scholarship (CGS-D). We thank Dr. Alan
Lough (U of T) for single-crystal X-ray structural analysis of
7a and Dr. Darcy Burns (U of T) for assistance with NMR
experiments.
Acknowledgements
We thank the Natural Science and Engineering Research
Council (NSERC), the University of Toronto (U of T) and
Kennarshore Inc. for financial support. J.L. thanks the Swiss
National Science Foundation (SNSF) for a postdoctoral
Conflict of Interest
The authors declare no conflict of interest.
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3938; e) M. D. Greenhalgh, A. Kolodziej, F. Sinclair, S. P.
Thomas, Organometallics 2014, 33, 5811 – 5819.
[10] a) C. B. Huehls, A. Lin, J. Yang, Org. Lett. 2014, 16, 3620 – 3623;
b) A. S. Jones, J. F. Paliga, M. D. Greenhalgh, J. M. Quibell, A.
Steven, S. P. Thomas, Org. Lett. 2014, 16, 5964 – 5967.
[11] Selected examples: a) N. Zeidan, S. Bognar, S. Lee, M. Lautens,
Org. Lett. 2017, 19, 5058 – 5061; b) J. Ye, Z. Shi, T. Sperger, Y.
Yasukawa, C. Kingston, F. Schoenebeck, M. Lautens, Nat. Chem.
2017, 9, 361 – 368; c) S. G. Newman, M. Lautens, J. Am. Chem.
Soc. 2010, 132, 11416 – 11417; d) D. A. Candito, M. Lautens, Org.
Lett. 2010, 12, 3312 – 3315; e) N. Isono, M. Lautens, Org. Lett.
2009, 11, 1329 – 1331; f) Y.-Q. Fang, M. Lautens, J. Org. Chem.
2008, 73, 538 – 549; g) M. Nagamochi, Y.-Q. Fang, M. Lautens,
Org. Lett. 2007, 9, 2955 – 2958; h) A. Fayol, Y.-Q. Fang, M.
Lautens, Org. Lett. 2006, 8, 4203 – 4206; i) Y.-Q. Fang, M.
Lautens, Org. Lett. 2005, 7, 3549 – 3552; j) C. Bressy, D. Alberico,
M. Lautens, J. Am. Chem. Soc. 2005, 127, 13148 – 13149.
[12] a) M. Kaur, M. Singh, N. Chadha, O. Silakari, Eur. J. Med. Chem.
2016, 123, 858 – 894; b) N. K. Kaushik, N. Kaushik, P. Attri, N.
Kumar, C. H. Kim, A. K. Verma, E. H. Choi, Molecules 2013, 18,
6620 – 6662; c) S. D. Roughley, A. M. Jordan, J. Med. Chem.
2011, 54, 3451 – 3479; d) A. J. Kochanowska-Karamyan, M. T.
Hamann, Chem. Rev. 2010, 110, 4489 – 4497; e) F. R. de Sa Alves,
E. J. Barreiro, C. A. M. Fraga, Mini-Rev. Med. Chem. 2009, 9,
782 – 793.
Scheme 6. Product diversification. a) Ph3PCHCO2Me, PhMe, reflux.
b) Pd(OAc)2 (16 mol%), K2CO3, 4 ꢁ MS, EtOAc, 1508C. c) p-Anisidine,
NaBH(OAc)3, AcOH, DCE, r.t. PMP=para-methoxyphenyl.
Keywords: hydromagnesiation · indole · iron catalysis ·
oxindole · reductive cyclization
[13] a) M. Inman, C. J. Moody, Chem. Sci. 2013, 4, 29 – 41; b) G. R.
Humphrey, J. T. Kuethe, Chem. Rev. 2006, 106, 2875 – 2911.
[14] See the Supporting Information.
[15] J. K. Cha, O. G. Kulinkovich, Org. React. 2012, 77, 1 – 160.
[16] J. Lee, J. D. Ha, J. K. Cha, J. Am. Chem. Soc. 1997, 119, 8127 –
8128.
[17] a) W. Madelung, Ber. Dtsch. Chem. Ges. 1912, 45, 1128 – 1134.
For a recent review, see: b) G. W. Gribble in Indole Ring
Synthesis (Ed.: G. W. Gribble), Wiley, Chichester, 2016, pp. 147 –
155.
[18] H. Tokuyama, T. Yamashita, M. T. Reding, Y. Kaburagi, T.
Fukuyama, J. Am. Chem. Soc. 1999, 121, 3791 – 3792.
[19] a) Y.-J. Wu in Heterocyclic Scaffolds II: Reactions and Applica-
tions of Indoles (Ed.: G. W. Gribble), Springer-Verlag Berlin
Heidelberg, Berlin, 2010, pp. 1 – 29; b) C. P. Miller, M. D. Collini,
B. D. Tran, H. A. Harris, Y. P. Kharode, J. T. Marzolf, R. A.
Moran, R. A. Henderson, R. H. W. Bender, R. J. Unwalla, L. M.
Greenberger, J. P. Yardley, M. A. Abou-Gharbia, C. R. Lyttle,
B. S. Komm, J. Med. Chem. 2001, 44, 1654 – 1657; c) E. von An-
gerer, Cancer Treat. Rev. 1984, 11, 147 – 153.
[20] a) J. D. Mason, S. M. Weinreb in The Alkaloids: Chemistry and
Biology, Vol. 81 (Ed.: H.-J. Knçlker), Academic Press, Cam-
bridge, 2019, pp. 115 – 150; b) S. Takano, K. Ogasawara in The
Alkaloids: Chemistry and Pharmacology, Vol. 36 (Ed.: A.
Brossi), Academic Press, San Diego, 1990, pp. 225 – 251.
[21] a) P. J. Chirik, Acc. Chem. Res. 2015, 48, 1687 – 1695; b) V. C.
Gibson, C. Redshaw, G. A. Solan, Chem. Rev. 2007, 107, 1745 –
1776; c) B. L. Small, M. Brookhart, A. M. A. Bennett, J. Am.
Chem. Soc. 1998, 120, 4049 – 4050; d) G. J. P. Britovsek, V. C.
Gibson, S. J. McTavish, G. A. Solan, A. J. P. White, D. J. Wil-
liams, G. J. P. Britovsek, B. S. Kimberley, P. J. Maddox, Chem.
Commun. 1998, 849 – 850.
[1] a) P. G. Andersson, I. J. Munslow, Modern reduction methods,
Wiley-VCH, Weinheim, 2008; b) B. M. Trost, Z. T. Ball, Syn-
thesis 2005, 853 – 887; c) N. D. Smith, J. Mancuso, M. Lautens,
Chem. Rev. 2000, 100, 3257 – 3282.
[2] a) B. N. Bhawal, B. Morandi, Angew. Chem. Int. Ed. 2019, 58,
10074 – 10103; Angew. Chem. 2019, 131, 10178 – 10209; b) B. N.
Bhawal, B. Morandi, Chem. Eur. J. 2017, 23, 12004 – 12013;
c) B. N. Bhawal, B. Morandi, ACS Catal. 2016, 6, 7528 – 7535.
[3] F. Sato, J. Organomet. Chem. 1985, 285, 53 – 64.
[4] a) J. Chen, J. Guo, Z. Lu, Chin. J. Chem. 2018, 36, 1075 – 1109;
b) J. V. Obligacion, P. J. Chirik, Nat. Rev. Chem. 2018, 2, 15 – 34;
c) M. D. Greenhalgh, A. S. Jones, S. P. Thomas, ChemCatChem
2015, 7, 190 – 222.
[5] General reviews on iron catalysis: a) S. Rana, J. P. Biswas, S.
Paul, A. Paik, D. Maiti, Chem. Soc. Rev. 2021, 50, 243 – 472; b) P.
DaBell, S. P. Thomas, Synthesis 2020, 52, 949 – 963; c) A. Casnati,
M. Lanzi, G. Cera, Molecules 2020, 25, 3889; d) P. Gandeepan, T.
Mꢁller, D. Zell, G. Cera, S. Warratz, L. Ackermann, Chem. Rev.
2019, 119, 2192 – 2452; e) A. Piontek, E. Bisz, M. Szostak,
Angew. Chem. Int. Ed. 2018, 57, 11116 – 11128; Angew. Chem.
2018, 130, 11284 – 11297; f) A. Fꢁrstner, ACS Cent. Sci. 2016, 2,
778 – 789; g) I. Bauer, H.-J. Knçlker, Chem. Rev. 2015, 115,
3170 – 3387; h) B. Plietker, Iron Catalysis in Organic Chemistry,
Wiley-VCH, Weinheim, 2008; i) C. Bolm, J. Legros, J. Le Paih, L.
Zani, Chem. Rev. 2004, 104, 6217 – 6254.
[6] a) M. D. Greenhalgh, S. P. Thomas, Synlett 2013, 24, 531 – 534;
b) E. Shirakawa, D. Ikeda, S. Masui, M. Yoshida, T. Hayashi, J.
Am. Chem. Soc. 2012, 134, 272 – 279; c) E. Shirakawa, D. Ikeda,
S. Yamaguchi, T. Hayashi, Chem. Commun. 2008, 1214 – 1216.
[7] M. Tamura, J. K. Kochi, Bull. Chem. Soc. Jpn. 1971, 44, 3063 –
3073.
[22] W. M. Czaplik, S. Grupe, M. Mayer, A. J. von Wangelin, Chem.
Commun. 2010, 46, 6350 – 6352.
[23] W. C. Hueper, Medicine 1948, 27, 43 – 104.
[8] M. D. Greenhalgh, S. P. Thomas, J. Am. Chem. Soc. 2012, 134,
11900 – 11903.
[24] a) S.-H. Choi, S.-K. Hwang, D.-H. Kim, K.-D. Kim, C.-H. Park,
R.-S. Seo, KR20180095239A, 2018; b) L. Han, CN107935906A,
2018; c) X. Ren, L. Shu, A. Su, L. Xie, X. Xu, Q. Zhang,
CN103772261A, 2014.
[25] Selected examples: a) A. Whyte, K. I. Burton, J. Zhang, M.
Lautens, Angew. Chem. Int. Ed. 2018, 57, 13927 – 13930; Angew.
Chem. 2018, 130, 14123 – 14126; b) H. Yoon, A. D. Marchese, M.
[9] a) P. G. N. Neate, M. D. Greenhalgh, W. W. Brennessel, S. P.
Thomas, M. L. Neidig, Angew. Chem. Int. Ed. 2020, 59, 17070 –
17076; Angew. Chem. 2020, 132, 17218 – 17224; b) P. G. N. Neate,
M. D. Greenhalgh, W. W. Brennessel, S. P. Thomas, M. L.
Neidig, J. Am. Chem. Soc. 2019, 141, 10099 – 10108; c) J. A.
Rogers, B. V. Popp, Organometallics 2019, 38, 4533 – 4538; d) Q.
Ren, N. Wu, Y. Cai, J. Fang, Organometallics 2016, 35, 3932 –
Angew. Chem. Int. Ed. 2021, 60, 2 – 9
ꢀ 2021 Wiley-VCH GmbH
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Angewandte
Research Articles
Chemie
Lautens, J. Am. Chem. Soc. 2018, 140, 10950 – 10954; c) H. Yoon,
M. Rçlz, F. Landau, M. Lautens, Angew. Chem. Int. Ed. 2017, 56,
10920 – 10923; Angew. Chem. 2017, 129, 11060 – 11063; d) Y. J.
Jang, E. M. Larin, M. Lautens, Angew. Chem. Int. Ed. 2017, 56,
11927 – 11930; Angew. Chem. 2017, 129, 12089 – 12092; e) C. M.
Le, T. Sperger, R. Fu, X. Hou, Y. H. Lim, F. Schoenebeck, M.
Lautens, J. Am. Chem. Soc. 2016, 138, 14441 – 14448; f) K.
Yamamoto, Z. Qureshi, J. Tsoung, G. Pisella, M. Lautens, Org.
Lett. 2016, 18, 4954 – 4957; g) C. M. Le, X. Hou, T. Sperger, F.
Schoenebeck, M. Lautens, Angew. Chem. Int. Ed. 2015, 54,
15897 – 15900; Angew. Chem. 2015, 127, 16127 – 16131; h) Y. J.
Jang, H. Yoon, M. Lautens, Org. Lett. 2015, 17, 3895 – 3897. For
a review, see: i) A. D. Marchese, E. M. Larin, B. Mirabi, M.
Lautens, Acc. Chem. Res. 2020, 53, 1605 – 1619.
free of charge by the joint Cambridge Crystallographic Data
Centre and Fachinformationszentrum Karlsruhe Access Struc-
tures service www.ccdc.cam.ac.uk/structures.
[29] Selected reviews on dearomatization reactions of indoles: a) H.
Abou-Hamdan, C. Kouklovsky, G. Vincent, Synlett 2020, 31,
1775 – 1788; b) N. Zeidan, M. Lautens, Synthesis 2019, 51, 4137 –
4146; c) S. P. Roche, J.-J. Youte Tendoung, B. Trꢂguier, Tetrahe-
dron 2015, 71, 3549 – 3591; d) C. Beemelmanns, H.-U. Reissig,
Chem. Soc. Rev. 2011, 40, 2199 – 2210.
[30] a) L. Wang, Y. Shao, Y. Liu, Org. Lett. 2012, 14, 3978 – 3981. For
a multistep synthesis of dihydrobenzazepinoindolones involving
the use of organolithium reagents in an intermolecular reaction,
see: b) K. Kobayashi, D. Nakai, S. Fukamachi, H. Konishi,
Heterocycles 2009, 78, 2769 – 2776.
[26] Y. Takigawa, H. Ito, K. Omodera, M. Ito, T. Taguchi, Tetrahe-
dron 2004, 60, 1385 – 1392.
[31] A. Kessler, C. M. Coleman, P. Charoenying, D. F. OꢀShea, J. Org.
Chem. 2004, 69, 7836 – 7846.
[27] a) A. D. Marchese, M. Wollenburg, B. Mirabi, X. Abel-Snape, A.
Whyte, F. Glorius, M. Lautens, ACS Catal. 2020, 10, 4780 – 4785;
b) A. Pinto, Y. Jia, L. Neuville, J. Zhu, Chem. Eur. J. 2007, 13,
961 – 967; c) M. Pallavicini, E. Valoti, L. Villa, P. Lianza,
Tetrahedron: Asymmetry 1994, 5, 111 – 116.
[32] Akanksha, D. Maiti, Green Chem. 2012, 14, 2314 – 2320.
Manuscript received: May 25, 2021
[28] Deposition Number 2085934 (for 7a) contains the supplemen-
tary crystallographic data for this paper. These data are provided
Revised manuscript received: July 29, 2021
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,
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Research Articles
Synthetic Methods
J. Loup, E. M. Larin,
M. Lautens*
&&&& — &&&&
Iron-Catalyzed Reductive Cyclization by
Hydromagnesiation: A Modular Strategy
Towards N-Heterocycles
An iron-catalyzed reductive cyclization of
2-vinylanilides to prepare a variety of N-
heterocycles is reported. The reaction,
which usually occurs at room temper-
ature over a short reaction time, employs
an inexpensive and bench-stable iron
catalyst and EtMgBr as a hydride source.
The breadth of this strategy was demon-
strated by the synthesis of densely sub-
stituted indoles, oxindoles and novel tet-
rahydrobenzoazepinoindolones, as well
as the application towards the formal
syntheses of bioactive compounds.
Angew. Chem. Int. Ed. 2021, 60, 2 – 9
ꢀ 2021 Wiley-VCH GmbH
www.angewandte.org
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These are not the final page numbers!