Iron-catalyzed, hydrogen-mediated reductive cyclization of 1,6-enynes and diynes: Evidence for bis(imino)pyridine ligand participation

Article abstract of DOI:10.1021/ja902478p

(Chemical Equation Presented) The bis(imino)pyridine iron dinitrogen complex (^iPrPDI)Fe(N₂)₂ catalyzes the hydrogen-mediated reductive cyclization of enynes and diynes with turnover frequencies comparable to those of established precious metal catalysts. Amino, oxygenated, and carbon-based substrates are readily cyclized to the corresponding hetero- and carbocycles with 5 mol % iron and 4 atm H₂ at 23°C. Stoichiometric reactions between selected substrates and the iron compound under a N₂ atmosphere established transfer dehydrogenation from an isopropyl aryl substituent to either the enyne or diyne substrate. In situ monitoring of the catalytic reaction by ¹H NMR spectroscopy coupled with deuterium labeling experiments established rapid cyclization followed by turnoverlimiting hydrogenation. Copyright

Full text of DOI:10.1021/ja902478p

Published on Web 06/05/2009
Iron-Catalyzed, Hydrogen-Mediated Reductive Cyclization of 1,6-Enynes and
Diynes: Evidence for Bis(imino)pyridine Ligand Participation
Kevin T. Sylvester and Paul J. Chirik*
Department of Chemistry and Chemical Biology, Baker Laboratory, Cornell UniVersity, Ithaca, New York 14853
Received March 27, 2009; E-mail: pc92@cornell.edu
Rhodium-catalyzed, hydrogen-mediated reductive cyclization of
1,6-enynes and diynes has emerged as a powerful method for the
construction of five-membered rings,1 including enantiopure sub-
stituted heterocycles.2 These methods augment previously reported
Pd-catalyzed enyne cyclizations using either silanes3,4 or weak acids
as the stoichiometric reductants.4,5 As interest grows in developing
sustainable methods for organic synthesis, there has been a renewed
global effort to replace expensive and toxic precious metals with
more abundant and benign first-row base metals such as iron.6-8
As part of this focus, several iron-catalyzed cycloisomerization
reactions have been described. Echavarren and co-workers have
reported that simple iron salts such as FeCl3 promote catalytic enyne
cycloisomerization, although the substrate scope is limited.9 Using
the well-defined organometallic complex [Li(TMEDA)][(η5-
C5H5)Fe(C2H4)2],10 Fu¨rstner et al. have discovered various iron-
catalyzed enyne and diyne skeletal rearrangements, including Alder-
ene, [4 + 2], [5 + 2], and [2 + 2 + 2] cycloadditions. Our
laboratory has reported that the bis(imino)pyridine iron bis(dini-
trogen)complex(iPrPDI)Fe(N2)2[1-(N2)2;iPrPDI)2,6-(2,6-iPr2C6H3Nd
CMe)2C5H3N] is a functional-group-tolerant precatalyst for the
hydrogenation of olefins with activities that rival those of certain
precious metal catalysts.11,12 In addition, 1-(N2)2 also promotes the
catalytic [2 + 2] cycloisomerization of 1,6-dienes to yield four-
and five-membered bicycles (bicyclo[0.2.3]heptanes),13 likely as a
consequence of the redox-active chelating ligand that promotes
reductive elimination and obviates formation of deleterious Fe(0)
species.12,13 Here we describe a combination of these two processes
and report a base metal-catalyzed, functional group tolerant, hydro-
gen-mediated reductive cyclization of enynes and diynes.
tosyl amine (C), and 2-butynyl allyl ether (D). In each case, clean
and selective reductive cyclization to the (Z)-olefin isomer was
observed over the course of 3 h at 23 °C (eq 1). The conversion of
D is noteworthy, as previous studies from our laboratory have
demonstrated that 1-(N2)2 promotes irreversible C-O bond cleavage
in allyl-substituted ethers and esters.16
Silanes were also examined as terminal reductants to explore
the possibility of iron-catalyzed silylcarbocyclization.17 Addition
of A to the bis(imino)pyridine iron bis(silane) complex 1-(Ph-
11
SiH3)2 produced in >95% yield (1H NMR) the same pyrrolidine
as obtained from transfer dehydrogenation (eq 1). Likewise,
replacing the butynyl group with the terminal alkyne (Table 1, entry
2) also resulted in >95% conversion to the corresponding pyrroli-
dine. The product of dehydrogenative silane coupling, (PhSiH2)2,
was detected in both reactions. Isolated yields ranged between 53
and 77% [see Table S3 in the Supporting Information (SI)].
Observation of a stoichiometric yet iron-promoted carbon-carbon
bond-forming transformation prompted exploration of catalytic
variants of the reaction. On the basis of precedent with rhodium2
and the observation that 2 reacts cleanly with H2 to yield a
catalytically active iron dihydrogen complex,11 H2 was explored
as the stoichiometric terminal reductant. Each hydrogen-mediated
catalytic enyne cyclization was conducted with 5 mol % 1-(N2)2 at
23 °C in benzene solution under 4 atm H2. The results of these
studies are presented in Table 1. Tosyl-, benzyl-, and tert-butyl-
protected aminoenynes all underwent facile hydrogen-mediated
cyclization with turnover frequencies (TOFs) comparable to those
of rhodium catalysts.1 Oxygenated enynes (entries 8 and 9) were
also rapidly cyclized, providing a convenient base-metal-catalyzed
method for the synthesis of 3,4-disubstituted tetrahydrofurans. An
ester-substituted cyclopentane was also assembled using this
method, as the diethyl malonate-substituted enyne was also well
tolerated by 1-(N2)2.
Stirring stoichiometric quantities of 2-butynyl allyl tosylamine
(A) with 1-(N2)2 for 3 h at 23 °C resulted in complete consumption
1
of both starting materials. Analysis of the organic product by H
NMR spectroscopy and GC-MS established clean formation of
the 3,4-disubstituted pyrrolidine with only one (Z)-alkene substitu-
ent, inconsistent with the Alder-ene product, which has two
unsaturated ring substituents. Using established hydrolysis proce-
dures for liberation of the free ligand15 allowed the iron product to
be identified as the intramolecular olefin complex 2 arising from
net transfer hydrogenation to the enyne (eq 1). Thus, dehydroge-
nation of an isopropyl aryl substituent promotes iron-mediated
reductive enyne cyclization.
Analysis of the cyclized products by NMR spectroscopy and
GC-MS established that substitution on the alkyne influenced the
product isolated from iron-catalyzed hydrogen-mediated cyclization.
Monitoring of the hydrogen-mediated cyclization of enynes bearing
1
terminal alkynes (entries 1-4 and 8) by H NMR spectroscopy
established the intermediacy of exo-methylene substituted pyrro-
lidines, tetrahydrofuran, and cyclopentane. Continued hydrogenation
of these intermediates resulted in the formation of the corresponding
dimethyl derivatives, which were the isolated products in each case.
Analysis of the saturated products by NMR spectroscopy established
a preference for the formation of the cis diastereomers over the
trans ones. In three cases (entries 1, 3, and 4), the cis product was
exclusive. Substrates bearing internal alkynes (entries 5-7 and 9)
were also readily cyclized with little erosion in TOF. In these cases,
only the unsaturated products were observed because of the
reluctance of 1-(N2)2 to hydrogenate unactivated trisubstituted
alkenes.11,12
The scope of the stoichiometric transfer hydrogenation reaction
was examined with the benzylated amine (B), the SiMe3-substituted
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C O M M U N I C A T I O N S
Table 1. Hydrogen-Mediated Enyne Cyclizationa
cleanly converted to the (Z,Z)-disubstituted pyrrolidines in high
yield after 3 h at 23 °C. For the malonate, H, the desired
cyclopentane was observed in only 58% yield. The remaining
material was the open chain alkane derived from traditional
homogeneous hydrogenation.
Experiments were also performed with D2 gas to gain insight
into the mechanism of the iron-catalyzed, hydrogen-mediated
reductive enyne and diyne cyclizations. Tosylated amino enynes
and diynes were used as representative substrates, and the isotopic
compositions of all products were determined by a combination of
1H and 2H NMR spectroscopy and GC-MS. Catalytic cyclization
of A with 5 mol % 1-(N2)2 and 4 atm D2 furnished the pyrrolidine-
d2 isotopologue with the isotopic labels exclusively in the methyl
group and the vinyl position of the exo alkenyl substituent (Figure
2). Repeating the experiment with the related terminal alkyne
substrate furnished the d4 isotopologue of the expected pyrrolidine
with the additional deuterium incorporation arising from deuteration
of the exo methylene pyrrolidine intermediate that was observed
by 1H and 2H NMR spectroscopy during turnover. Analogous results
were obtained with diynes, as catalytic deuteration of E furnished
the pyrrolidine-d2 with the two labels in the vinyl positions of the
product (Figure 2).
cis/trans
(saturated)
c
)
entry
E
R
time (min) yield (%)b TOF (h-1
1
2
3
4
5
6
7
8
9
NtBu
NTs
NBn
H
H
H
H
180
60
68
79
71
57d
79
71
82
95
62
74e
6.7
20.0
6.7
4.9
6.7
6.7
2.2
3.3
6.7
6.7
>99:1
75:25
>99:1
>99:1
-
180
180
180
180
540
360
180
180
NCH2C6Me5
NTs
NBn
NTs
O
Me
Me
SiMe3
H
Me
H
-
-
61:39f
-
O
10 (EtCO2)2C
79:21
a Conditions: 4 atm H2 at 23 °C. b Isolated yield. c Determined at
>95% conversion by 1H NMR spectroscopy and 99% GC-MS.
d Reduced alkyne compound (16%) was observed. e Reduced alkyne
complex (26%) was observed. f After 24 h, 53% conversion to the
3,4-dimethyltetrahydrofuran was found.
Attempts to cyclize substrates bearing allylic substitution were
also made. Catalytic hydrogenation of tosyl-protected butynyl
butenyl amine under standard conditions furnished mostly open
chain products resulting from conventional hydrogenation, with little
evidence for cyclization. Interestingly, repeating the reaction with
2 equiv of PhSiH3 as the stoichiometric reductant furnished the
desired pyrollidine in >95% conversion (eq 2).
Figure 2. Catalytic reactions with D2 gas.
Because transfer hydrogenation chemistry was observed in the
stoichiometric cyclization reactions, experiments were also per-
formed with the labeled iron dinitrogen complex 1*-(N2)2, in which
the isopropyl methyl substituents were deuterated.11 Addition of 1
equiv of enyne A resulted in complete and exclusive conversion
into two pyrrolidine-d1 isotopomers (Figure 3), confirming transfer
hydrogenation from the isopropyl aryl substituents. Monitoring of
Following the discovery of a versatile iron-catalyzed hydroge-
native carbon-carbon bond-forming reaction with enynes, the
cyclization method was extended to diynes. The stoichiometric
reaction between 1-(N2)2 and tosyl-substituted bis(2-butynyl)amine
(E) cleanly furnished the (Z,Z)-3,4-diethylene-substituted pyrrolidine
in high yield along with the expected dehydrogenated iron complex
2 (Figure 1).
1
the stoichiometric reaction between 1-(N2)2 and A by H NMR
spectroscopy revealed immediate formation of a red, paramagnetic
(S ) 2) intermediate identified as the iron metallocycle 3. Repeating
the experiment with the isotopically labeled iron compound 1*-
(N2)2 furnished the corresponding deuterated isotopologue 3*
(Figure 3), with no spectroscopic evidence for isotopic scrambling
from the isopropyl methyl groups. Degradation studies with 3* were
also performed with NaOH/H2O and NaOD/D2O followed by
analysis of the organic products by 1H and 2H NMR spectroscopy.
This procedure established formation of natural abundance (exclu-
sively) and pyrrolidine-d2, respectively (Figure 3). Accordingly,
treatment of natural abundance 3 with NaOD/D2O yielded tosylated
pyrrolidine-d2.
Observation of 3 and its deuterated isotopologue 3* allowed the
measurement of the kinetic isotope effect (KIE) for transfer
dehydrogenation and liberation of pyrrolidine. Monitoring of the
formation of the isotopologues of the pyrrolidines from two separate
solutions of 3 and 3* by 1H NMR spectroscopy at 23 °C yielded a
normal primary KIE of 5.8(2) based on the time to reach >95%
conversion. First-order rate constants (kH/kD) were also determined
by monitoring the isotopologues of the pyrrolidine products as a
function of time (see the SI). These experiments yielded a
Figure 1. Stoichiometric and catalytic diyne cyclizations with 1-(N2)2.
This outcome inspired the exploration of catalytic hydrogen-
mediated diyne cyclization with substrates E-H in the presence
of 5 mol % 1-(N2)2 and 4 atm H2. Substrates E, F, and G were
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C O M M U N I C A T I O N S
principle) 1-(N2)2. The dinitrogen complex is drawn for simplicity,
but it is likely that under catalytic conditions the iron dihydrogen
or alkyne complex forms following product release.11
The lack of deuterium incorporation from the D2-mediated
catalytic cyclization of A eliminates a pathway involving
ꢀ-hydrogen elimination from the iron alkyl hydride to form a
bis(alkenyl)-substituted pyrrolidine that is subsequently hydro-
genated. A cycle similar to the one presented in Figure 4 is likely
operative for catalytic diyne cyclization. The mechanism of the
stoichiometric transfer hydrogenation cyclization is also worthy
of comment. Following formation of 3, it is likely that an
oxidative addition/reductive elimination or a σ-bond metathesis
sequence of a C-H bond from an isopropyl methyl group forms
the iron dialkyl or alkenyl alkyl intermediate. Subsequent
ꢀ-hydrogen elimination from the cyclometalated isopropyl group
yields an iron alkenyl (or alkyl) hydride, which undergoes C-H
reductive elimination to yield the observed product. It is
important to note that because the labeled iron dinitrogen
complex 1*-(N2)2 was deuterated only in the methyl position,
only pyrrolidine-d1 isotopologues were formed (Figure 3).
In summary, an iron-catalyzed, hydrogen-mediated method for
the reductive cyclization of enynes and diynes has been discovered.
The substrate scope and turnover frequencies are comparable to
those for established precious metal catalysts, demonstrating that
when coaxed into the appropriate coordination environment, iron
can indeed perform noble tasks.
Figure 3. Detection of catalytic intermediates and isotopic-labeling studies.
statistically indistinguishable KIE of 6.0(2) at 23 °C. KIEs of this
direction and magnitude are consistent with a C-H bond-breaking
event in the turnover-limiting step.
On the basis of these observations, a mechanism for the iron-
catalyzed, hydrogen-mediated enyne cyclization is proposed (Figure
4). Cyclization of the substrate upon addition to 1-(N2)2 is rapid.
On the basis of previous studies from our laboratory with model
complexes14 and the [2 + 2] cycloaddition,13 we believe that
reductive cyclization to form the carbon-carbon bond involves
electron transfer and formal oxidation of the bis(imino)pyridine
chelate rather than the iron center. Thus, the ferrous oxidation state
is preserved throughout the catalytic cycle (Figure 4).
Acknowledgment. We thank the Packard Foundation (Fellow-
ship in Science and Engineering to P.J.C.) and Cornell University
for financial support.
Supporting Information Available: Complete experimental pro-
cedures and representative NMR spectra. This material is available free
of charge via the Internet at http://pubs.acs.org.
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Observation of 3 under a variety of conditions in conjunction
with the KIEs establishes the hydrogenation step as turnover-
limiting (Figure 4). Unfortunately, the lack of observables following
metallocycle formation limits the amount of available experimental
data. Hydrogenation of 3 can occur either at the alkyl or alkenyl
position of the metallocycle to form the corresponding iron alkenyl
or alkyl hydride intermediate. Deuterium-labeling studies with 3*
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occur either by oxidative addition/reductive elimination or by
σ-bond metathesis. Unlike the rhodium-catalyzed variant of this
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