Cooperative Metal-Ligand Catalyzed Intramolecular Hydroamination and Hydroalkoxylation of Allenes Using a Stable Iron Catalyst

Article abstract of DOI:10.1021/acs.orglett.7b03828

A new iron-catalyzed chemoselective intramolecular hydroamination and hydroalkoxylation of the readily available α-allenic amines and alcohols to valuable unsaturated 5-membered heterocycles, 2,3-dihydropyrrole and 2,3-dihydrofuran, is reported. Effective

Full text of DOI:10.1021/acs.orglett.7b03828

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Cooperative Metal−Ligand Catalyzed Intramolecular
Hydroamination and Hydroalkoxylation of Allenes Using a Stable
Iron Catalyst
Osama El-Sepelgy,*,‡ Aleksandra Brzozowska,‡,† Jan Sklyaruk,‡,† Yoon Kyung Jang,‡ Viktoriia Zubar,‡
and Magnus Rueping*,‡,§
‡Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
§King Abdullah University of Science and Technology (KAUST), KAUST Catalysis Center (KCC), Thuwal 23955-6900, Saudi
Arabia
S
* Supporting Information
ABSTRACT: A new iron-catalyzed chemoselective intramolecular
hydroamination and hydroalkoxylation of the readily available α-
allenic amines and alcohols to valuable unsaturated 5-membered
heterocycles, 2,3-dihydropyrrole and 2,3-dihydrofuran, is reported.
Effective selectivity control is achieved by a metal−ligand cooperative
activation of the substrates. The mild reaction conditions and the use
of low amounts of an air and moisture stable iron catalyst allow for the
hydrofunctionalization of a wide range of allenes bearing different functional groups in good yields in the absence of base or any
sensitive additives.
been reported, although the products would be valuable
intermediates which could be easily modified. Therefore, we
decided to examine whether the readily available and stable iron
cyclopentadienone catalysts could be applied as general
catalysts for the intramolecular hydro-functionalization of
allenes.
Herein, we report a general and efficient endo-hydro-
functionalization of allenes with nitrogen and oxygen
nucleophiles to afford useful 2,3-dihydropyrroles and 2,3-
dihydrofurans (Scheme 1).
itrogen- and oxygen-containing heterocycles are present
Nin most naturally occurring and biologically relevant
compounds.1 Therefore, the development of efficient atom-
economical methods for the synthesis of heterocyclic
compounds is of importance. One elegant approach for the
synthesis of heterocycles is the transition-metal-catalyzed
intramolecular hydrofunctionalization of allenes with heter-
oatom nucleophiles.2 Recently, we reported that air- and
moisture-stable iron cyclopentadienone complexes can be
applied for carboetherifications and the synthesis of deoxy-
genated 6-membered oxygen-based heterocycles.3 This unusual
transformation was observed during our investigation of iron
cyclopentadienone complexes as hydrogen autotransfer cata-
lysts in dynamic kinetic resolutions.4,5
Scheme 1. Iron-Catalyzed Hydroamination and
Hydroalkoxylation of Allenes
Regarding the intramolecular hydroalkoxylation of α-allenic
alcohols to 2,5-dihydrofuran a procedure using 5−10 mol % of
AuCl was reported by Krause et al.6 More recently, Backvall
̈
3
and co-workers applied 4 mol % of a ruthenium-based catalyst
to achieve the intramolecular addition reaction.7 In addition to
these preliminary studies, the intramolecular hydrofunctional-
ization of allenes with N-nucleophiles has been explored. This
transformation leads to valuable dihydropyrroles, a ring system
which is ubiquitous in natural products and is frequently used
as a precursor in the synthesis of natural products and bioactive
molecules, such as serotonin reuptake inhibitor from Eli Lilly.8
So far, the endo-cyclization of allene amines was achieved using
silver9 and gold(III)10 catalysts. In analogy to the hydro-
alkoxylations, these reactions afford the 2,5-dihydropyrrole
regioisomer.
To the best of our knowledge, a catalytic intramolecular
hydroamination of allenic amines to cyclic enamines has not
Received: December 7, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03828
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Our studies began with the examination of different
cyclopentadienone iron catalysts for the intramolecular hydro-
amination of allenes. From the outset, we focused on readily
removable amine protecting groups, such as the Cbz-protected
amine 1a.
Table 2. Iron-Catalyzed Hydroamination of α-Allenic
Amines
a
The best results were achieved with the tetraphenyl-
substituted cyclopentadienone iron tricarbonyl catalyst [Fe].
This air- and moisture-stable complex can be easily synthesized
by reaction of two commercially available inexpensive
substrates, tetraphenylcyclopentadienone and iron pentacar-
bonyl.11 [Fe] can be activated in situ by oxidative decarbon-
ylation using trimethylamine N-oxide. The hydroamination of
the Cbz-allenic amine 1a was subsequently examined using 5
mol % of [Fe] at 70 °C in different solvents (Table 1). When
a
Table 1. Optimization of the Reaction Conditions
entry
solvent
yield (%)
1
2
3
4
5
6
7
toluene
hexane
DCE
72
40
39
90
89
76
32
87
THF
dioxane
CPME
acetonitrile
THF
b
8
a
Reaction conditions: 1 (0.1 mmol), [Fe] (5 mol %), and Me3NO (6
mol %) in solvent (0.5 mL) were stirred at 70 °C for 24 h in a Schlenk
tube under an inert atmosphere. Yields determined by 1H NMR using
b
mesitylene as internal standard. 1 (0.5 mmol) in 1 mL of THF. Yield
of product after chromatography. CPME = cyclopropyl methyl ether
a
Reaction conditions: 1 (0.5 mmol), [Fe] (5 mol %) and Me3NO (6
the reaction was performed in toluene, the desired enamine 2a
was obtained in 72% yield (Table 1, entry 1). The application
of hexane as a solvent led to only 40% yield (Table 1, entry 2).
Furthermore, the halogenated solvent dichloroethane gave
the same product in low yield (Table 1, entry 3). Further
screening of solvents showed that ethers are superior to
nonpolar solvents (Table 1, entries 4−6). The best results were
obtained when the reaction was performed in tetrahydrofuran,
and the desired product was isolated in 87% yield (Table 1,
entries 4 and 8). Use of acetonitrile gave only 32% yield, which
can be explained by the strong coordination of the acetonitrile
with the active iron species (Table 1, entry 7).
In order to demonstrate the broad practicability of our newly
developed method, we applied the optimized cyclization
protocol to various allenic amines (Table 2) bearing different
functionalities. Thus, various 2,3-dihydropyrroles can be
effectively obtained in good yields. Next to 2,3-dihydropyrrole
2a, which was isolated in 87% yield (Table 2, entry 1),
dihydropyrroles 2b−e bearing electron-withdrawing substitu-
ents in the para position of the arene were also obtained in very
good yields (Table 2, entries 2−5). Allenic amine 1f with an
mol %) in THF (1 mL) were stirred at 70 °C for 24 h in a Schlenk
b
tube under inert atmosphere. Isolated yields are given. [Fe] (10 mol
%) and Me3NO (12 mol %).
electron-withdrawing substituent in the ortho position gave the
corresponding pyrrole in 74% yield (Table 2, entry 6), while 1g
with an electron-donating methyl group was cyclized in a good
yield of 69% (Table 2, entry 7). Furthermore, the 2-naphthyl-
substituted 2,3-dihydropyrrol 2h was isolated in 81% yield
(Table 2, entry 8). Our method could also be applied to the
aliphatic allenic amines 1i−l, leading to the corresponding
heterocycles 2i−l in moderate to good yields (Table 2, entries
9−12). This cyclic enamine 2l is of relevance as it can be used
for the synthesis of the pyrrole analogues of several
antibiotics.12
Following the successful development of the intramolecular
hydroamination of allenes to provide 2,3-dihydropyrroles, we
became interested in the generalization of this new protocol by
applying α-allenic alcohols.
B
DOI: 10.1021/acs.orglett.7b03828
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Organic Letters
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This hydroalkoxylation would result in valuable 2,3-
dihydrofurans. To our delight, α-allenic alcohols could also
successfully be applied. Indeed, if compared to α-allenic amines
the reaction proceeded faster, and thus, a reduction to 2.5 mol
% of the [Fe] catalyst was feasible to provide the product in 2
h. It is noteworthy that the required catalyst loading for the
previously reported Ru protocol was 4 mol %, which further
highlights the advantage of the current base-metal alternative.
We then investigated the scope of iron-catalyzed intramolecular
hydroalkoxylation of allenic alcohols (Table 3). Various aryl-
substituted allenic alcohols could be applied, showing the
generality of our method. All investigated substrates bearing
electron-withdrawing groups and electron-donating groups 3a−
g reacted smoothly, providing the corresponding 2,3-
dihydrofurans in high yields (Table 3, entries 1−7).
Furthermore, the carboetherification of the naphthyl-substi-
tuted allenic alcohol 3h proceeds well to afford the
corresponding furan in 95% yield (Table 3, entry 8). Moreover,
several cyclic and acyclic aliphatic derivatives 3i−l were cyclized
to the unsaturated furans 4i−l in good yields (Table 3, entries
9−12). Importantly, deoxysugar 4l is of high relevance as it is
industrially used in the synthesis of clinically relevant antibiotics
such as AZT, d4T, and puromycin.12 Interestingly, the
unsaturated furan bearing conjugated double bond 4m was
also obtained in good yield (Table 3, entry 13). The new
protocol was also found to be applicable to heteroarenes as
demonstrated for the derivatives 4n and 4o (Table 3, entries 14
and 15). Importantly, our catalytic system has been useful for
the construction of the spirocyclic ethers such as 4p (Table 3,
entry 16). Moreover, the hydroalkoxylation of the tertiary
alcohol 3q gave the furan 4q bearing a quaternary carbon atom
(Table 3, entry 17). Following the successful demonstration of
the applicability of the newly developed iron catalyzed
hydroalkoxylation of 1-substituted allenols, we turned our
attention to the use of 1,2-disubstituted α-allenols, which
should provide two different diastereomers. Applying the same
protocol, we could convert the disubstituted allenic alcohol 3r
to the corresponding disubstituted dihydrofuran in 68% yield
and 4:1 diastereomeric ratio, demonstrating a new and efficient
method for the construction of cyclic ethers with two chiral
centers (Table 3, entry 18).
Table 3. Iron-Catalyzed Hydroalkoxylation of Allenic
Alcohols
a
Based on the results and our previous work,3 we propose that
the reaction is catalyzed by the in situ generated 16e iron
species A, which is obtained by decarbonylation of the iron
tricarbonyl precatalyst [Fe]. The bifunctional catalytic species A
bearing a noninnocent ligand13 exhibits a dual catalytic task.
While the CO group of the ligand activates the nucleophile
through hydrogen bonding the iron metal center activates the
terminal double bond of allene by coordination. The activated
O- or N-nucleophile of B can undergo intramolecular attack
with transfer of a hydrogen atom to the cyclopentadienone
ligand, producing the iron vinylidene intermediate C. The next
steps involve two consecutive hydrogen transfers, leading to the
isomerization of the iron vinylidene intermediate C into the
more stable iron vinylidene intermediate E via the iron carbene
intermediate D. Finally, the desired product is selectively
formed via protodemetalation of the intermediate E (Scheme
2).
a
Reaction conditions: 3 (1 mmol), [Fe] (2.5 mol %), and Me3NO (4
mol %) in toluene (1 mL) were stirred at 70 °C for 2 h in a Schlenk
tube under an inert atmosphere. Isolated yields are shown.
In conclusion, we report the first example of an intra-
molecular hydroamination of allenic amines to enamines as well
as an efficient base metal catalyzed hydroalkoxylation of α-
allenic alcohols to valuable cyclic enol ethers.7b The general
applicability of this protocol is highlighted by the synthesis of
30 unsaturated heterocycles with good yields and excellent
chemoselectivity. The key to achieve this unusual selectivity is
the use of an iron-based metal−ligand catalyst which can
activate the substrate in a dual catalytic fashion. The absence of
any sensitive chemicals as well as base additives is an additional
C
DOI: 10.1021/acs.orglett.7b03828
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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Scheme 2. Proposed Reaction Mechanism
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ASSOCIATED CONTENT
* Supporting Information
K. P. J.; Mai, B. K.; Yang, B.; Himo, F.; Backvall, J.-E. ACS Catal. 2018,
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03828.
Experimental procedures and NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*Email: osama.elsepelgy@rwth-aachen.de.
*Email: magnus.rueping@rwth-aachen.de.
ORCID
(10) (a) Morita, N.; Krause, N. Org. Lett. 2004, 6, 4121−4123. For
further applications, see: (b) Lee, P. H.; Kim, H.; Lee, K.; Kim, M.;
Noh, K.; Kim, H.; Seomoon, D. Angew. Chem., Int. Ed. 2005, 44,
1840−1843. (c) Alcaide, B.; Almendros, P.; Martinez del Campo, T.;
Redondo, M. C.; Fernandez, I. Chem. - Eur. J. 2011, 17, 15005−15013.
Osama El-Sepelgy: 0000-0003-3131-4988
Magnus Rueping: 0000-0003-4580-5227
Author Contributions
†A.B. and J.S. contributed equally to this work
Notes
(11) (a) Weiss, E.; Hubel, W. J. Inorg. Nucl. Chem. 1959, 11, 42.
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(12) McDonald, F. E.; Gleason, M. M. J. Am. Chem. Soc. 1996, 118,
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The authors declare no competing financial interest.
(13) (a) Khusnutdinova, R.; Milstein, D. Angew. Chem., Int. Ed. 2015,
54, 12236−12273. (b) Luca, O. R.; Crabtree, R. H. Chem. Soc. Rev.
2013, 42, 1440−1459. (c) Lyaskovskyy, V.; de Bruin, B. ACS Catal.
2012, 2, 270−279.
ACKNOWLEDGMENTS
J.S. thanks FCI for the predoctoral fellowship.
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Org. Lett. XXXX, XXX, XXX−XXX