Iron-catalyzed reductive cyclization of 1,6-enynes

Article abstract of DOI:10.1021/ol403257x

A precatalyst of FeCl₂ and iminopyridine was activated in situ by a combination of diethylzinc and magnesium bromide etherate; it catalyzed the reductive cyclization of 1,6-enynes to give pyrrolidine and tetrahydrofuran derivatives from N-and O

Full text of DOI:10.1021/ol403257x

Letter
pubs.acs.org/OrgLett
Iron-Catalyzed Reductive Cyclization of 1,6-Enynes
Aijun Lin, Zhi-Wei Zhang, and Jiong Yang*
Department of Chemistry, Texas A&M University, College Station, Texas 77843-3255, United States
S
* Supporting Information
ABSTRACT: A precatalyst of FeCl2 and iminopyridine was activated in situ by a
combination of diethylzinc and magnesium bromide etherate; it catalyzed the
reductive cyclization of 1,6-enynes to give pyrrolidine and tetrahydrofuran
derivatives from N- and O-tethered 1,6-enynes. The scope of the transformation
was explored.
ron catalysis for organic synthesis has experienced significant
formation was enabled by the discovery of Et2Zn and MgBr2·
Et2O as a unique combination for activating a precatalyst
consisting of FeCl2 and a bidentate iminopyridine ligand.
At the outset of our research, we envisioned that a
catalytically competent low-valent iron species might be formed
by the reaction of FeCl2 and the Grignard reagents.7 Thus, we
commenced with the reductive enyne cyclization of the N-
tethered 1,6-enyne 1a by treatment with FeCl2 and cyclo-
pentylmagnesium bromide in THF (Table 1, entry 1). The
initial results were promising as the desired cyclization product
2a was obtained in 20% yield as a single (Z)-isomer. Similar
yields were obtained when ethylmagnesium bromide (entry 2)
or isopropylmagnesium bromide (entry 3) were used. In an
effort to improve reaction efficiency, we also tested diethylzinc
as a reducing agent for generating the catalytic iron species.
Whereas diethylzinc alone gave 2a in 26% yield at room
temperature over 12 h or in 43% yield at 60 °C over 6 h
(entries 4 and 5), addition of MgBr2·Et2O and ligand L1 led to
a dramatic improvement of the reaction,8 which was complete
in 6 h at room temperature to give 2a in 78% yield (entry 8).
The same product was obtained with a comparable yield when
FeCl2 of 99.99% purity was employed (entry 9), indicating that
the transformation was indeed under iron catalysis.9 Interest-
ingly, low conversion of the reaction was observed when L1
was used as the sole additive (entry 6), and rapid degradation of
the starting material occurred when MgBr2·Et2O was used by
itself (entry 7). Reduction of the amount of either Et2Zn or
FeCl2 led to decreased yield (entries 10 and 11). Further
screening of the reaction conditions, which included testing
various ligands (L2−L7, entries 10−15), iron precatalysts
(Table S1, Supporting Information), and solvents (Table S1,
Supporting Information), led us to choose the conditions
shown in entry 8 for all subsequent reactions.10
I
growth in recent decades.1 Compared with other late
transition metals, iron stands out because it is one of the most
abundant elements in the Earth’s crust, and most of iron salts
are nontoxic. Thus, development of iron-based catalysis is
desirable because of its relevance to “green” chemical processes
and to a more sustainable chemical industry. Further, iron
catalysis frequently shows reactivities and selectivities comple-
mentary to other transition metal catalysis: facets that can be
exploited synthetically. The reductive cyclization and cyclo-
isomerization of 1,6-enynes are powerful approaches for the
synthesis of five-membered carbo- and heterocycles from
acyclic substrates (Scheme 1).2 Whereas a number of transition
Scheme 1. Reductive Cyclization and Cycloisomerization of
1,6-Enynes
metal catalysts have been developed for these transformations,
very few examples of iron catalysis exist.3 Specifically, Furstner
̈
described the Alder-ene cycloisomerization of 1,6-enynes using
a well-defined low-valent organoiron complex [Li(TMEDA)]-
[(η5-C5H5)Fe(C2H4)2] as the catalyst,4 and the reductive
cyclization of 1,6-enynes with the bis(imino)pyridine iron
bis(dinitrogen) complex [(i‑PrPDI)Fe(N2)2] was reported by
Chirik.5,6 Both of these transformations make use of air-
sensitive organoiron complexes that have to be separately
prepared, and the latter also has to be carried out under an
atmosphere of H2 under pressure. As part of our efforts to
develop practical and sustainable iron-catalyzed transforma-
tions, herein we report an operationally simple approach for
iron-catalyzed reductive cyclization of unactivated 1,6-enynes to
give pyrrolidine and tetrahydrofuran derivatives. This trans-
The scope of the reaction was evaluated using various
substrates, and the results are shown in Figure 1. N-Tethered
1,6-enynes with a methoxy group at either the para- or meta-
position of the aryl group were found to be compatible with the
Received: November 11, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol403257x | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Screening of Reaction Conditions
b
entry
L
RM
additive
time (h) yield 2a (%)
c
1
−
−
−
−
−
L1
C5H5MgBr
EtMgBr
i-PrMgBr
Et2Zn
−
−
−
−
−
−
6
6
20
17
c
2
c
3
6
22
4
12
6
26
d
5
Et2Zn
43
6
7
8
Et2Zn
16
16
6
<10
trace
78
−
Et2Zn
MgBr2·Et2O
MgBr2·Et2O
MgBr2·Et2O
MgBr2·Et2O
MgBr2·Et2O
MgBr2·Et2O
MgBr2·Et2O
MgBr2·Et2O
MgBr2·Et2O
MgBr2·Et2O
MgBr2·Et2O
L1
L1
L1
L1
L2
L3
L4
L5
L6
L7
Et2Zn
e
9
Et2Zn
6
75
f
10
Et2Zn
6
56
g
11
Et2Zn
6
43
12
13
14
15
16
17
Et2Zn
6
41
Et2Zn
6
29
Et2Zn
6
33
Figure 1. Substrate scope. Reactions were carried out with 20 mol %
of FeCl2, 20 mol % of L1, 3.0 equiv of Et2Zn, and 1.0 equiv of MgBr2·
Et2O in THF at room temperature.
Et2Zn
6
18
Et2Zn
6
30
Et2Zn
6
22
a
Reactions typically carried out with 0.2 mmol of 1a, 20 mol % of
FeCl2, 20 mol % of the ligand, 3.0 equiv of Et2Zn, and 1.0 equiv of
the potential competing reductive elimination pathway with
these substrates, methylene tetrahydrofurans 2l−2n were
obtained in good to moderate yields under the reaction
conditions. The Thorpe−Ingold effect likely contributed to the
higher efficiency for formation of 2o.12 Our experiments also
revealed a limitation of the reaction. Despite our efforts, the
enyne substrate with an internal alkene failed to deliver the
desired product 2p under the current reaction conditions. A
diethyl malonate-tether substrate also failed to deliver the
expected product 2q.
Although the exact nature of the iron catalyst is unknown, we
speculate that the reductive cyclization of 1a proceeds as shown
in Scheme 2. It starts with formation of metallacycle A by
oxidative cyclization of 1a with a low-valent iron species, which
was generated from FeCl2 and MgBr2·Et2O with Et2Zn in the
presence of L1. Transmetalation of A with Et2Zn cleaves the
metallacycle and gives intermediates B and C, which can
convert to D and E through rapid β-hydride elimination
followed by reductive elimination of the iron hydride
intermediates. The catalytic iron species is also regenerated.
Protonolysis of D and E gave 2a.13 This proposed mechanistic
pathway is consistent with the following experimental
observation: The monodeuterated products 3 and 4 and the
undeuterated 2a were obtained in 49:31:19 ratio from 1a upon
quenching the reaction with D2O (Scheme 3). Whereas
deuterolysis of D and E led to 3 and 4, formation of a small
b
MgBr2·Et2O in 3.0 mL of THF at room temperature. Isolated yield.
c
d
1.5 equiv of RMgBr was used. The reaction was carried out at 60 °C.
e
f
g
FeCl2 of 99.99% purity was used. 2.0 equiv of Et2Zn was used. 10
mol % of FeCl2 was used.
reaction, and the reductive cyclization products were obtained
in good yields (72% yield for 2b and 81% yield for 2c).
However, the same substituent at the ortho- position of the aryl
led to formation of 2d with significantly reduced efficiency
(29%). This was attributed to unfavorable interactions of the
lone pair of the methoxy group and the catalytic center. Indeed,
the corresponding ortho-methyl substrate gave the product (2e)
in 69% yield.11 Electron-withdrawing chloro- or trifluoromethyl
groups at the para- position of the aryl led to products in 68%
(for 2f) and 64% (for 2g) yield, respectively, and the chloride
substituent remained intact under the reaction conditions.
Disubstitution at the 3′- and 5′-positions of the aryl with two
methyl groups caused a somewhat reduced yield (2h, 55%).
The reaction also proceeded smoothly with a thiophene-
containing 1,6-enyne substrate to give 2i in 52% yield. An alkyl-
substituted enyne substrate was found to give the desired
product 2j in 41% yield. The N-tosyl of the N-tethered enyne
substrate could be replaced with the N-Cbz, and the reductive
cyclization product 2k was obtained in 57% yield. We further
tested this transformation using O-tethered 1,6-enynes. Despite
B
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Letter
Scheme 2. Proposed Reaction Mechanism
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: yang@mail.chem.tamu.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Science Foundation (CHE-1150606)
and the Robert A. Welch Foundation (A-1700) for financial
support.
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In summary, we have developed an operationally simple iron-
catalyzed reductive cyclization of 1,6-enynes. This trans-
formation was enabled by the unique combination of
diethylzinc and MgBr2·Et2O for converting the precatalyst
FeCl2 and the α-iminopyridine ligand into the catalytically
competent species in situ. Functionalized pyrrolidine and
tetrahydrofuran derivatives were obtained from N- and O-
tethered 1,6-enynes in good-to-moderate yields. We elucidated
the scope of the reaction and revealed its limitations. Further
exploration of the utility of this iron-based catalytic system and
elucidation of its exact mechanism of action will be reported in
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details and NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
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(14) The following aldehydes (3 equiv) were used as the
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and hydrocinnamaldehyde.
D
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