Iron-Catalyzed Carbenoid-Transfer Reactions of Vinyl Sulfoxonium Ylides: An Experimental and Computational Study

Article abstract of DOI:10.1002/anie.201810451

A method for the generation of unprecedented vinyl carbenoids from sulfoxonium ylides has been developed and applied in the synthesis of a diverse array of heterocycles such as indolizines, pyrroles, 3-pyrrolin-2-ones, and furans. The reactions proceed by FeBr₂ catalysis under mild reaction conditions with a broad substrate scope. A reaction pathway involving iron carbenoids is proposed based on a series of control experiments and DFT calculations.

Full text of DOI:10.1002/anie.201810451

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Accepted Article
Title: Iron-Catalyzed Carbenoid Transfer Reactions of Vinyl
Sulfoxonium Ylides: An Experimental and Computational Study
Authors: Janakiram Vaitla, Annette Bayer, and Kathrin Helen Hopmann
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201810451
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10.1002/anie.201810451
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Iron-Catalyzed Carbenoid Transfer Reactions of Vinyl
Sulfoxonium Ylides: An Experimental and Computational Study**
Janakiram Vaitla,* Annette Bayer and Kathrin H. Hopmann*
Abstract: A method for the generation of unprecedented vinyl
carbenoids from sulfoxonium ylides has been developed and applied
in the synthesis of a diverse array of heterocycles such as indolizines,
pyrroles, 3-pyrrolin-2-ones, and furans. The reactions proceed under
FeBr2 catalysis at mild reaction conditions with a broad substrate
scope. A reaction pathway involving iron carbenoids is proposed
based on a series of control experiments and DFT calculations.
with various nucleophiles.[8] However, identifying sustainable and
safe alternatives for the generation of vinyl carbenoids has
attracted great attention.[9] In this regard, non-diazo starting
materials such as cyclopropenes,[10] propargylic esters[11] and
alkynes[12] have been explored but they are still rarely used
(Scheme 1). Despite significant achievements in this area, to our
knowledge, there are no reports on iron-catalyzed vinyl carbenoid
transformations.[13]
Sulfoxonium ylide-derived metal carbenoids have been explored for
X-H (X = N, S, O, C) insertions,[1] and have even been optimized at
industrial scale for the production of drug candidates.[2] Despite this
recent progress, several challenges need to be addressed to improve
the versatility of these ylides in metal catalysis: First, metal-catalyzed
sulfoxonium ylide reactions are still restricted to -keto sulfoxonium
ylides only. Second, although these ylides can generate carbenoids
with noble metals (Rh, Ir, Au, Ru, Pt, etc.), base metals (for eg: Cu,
Fe) have been unsuccessful so far.[1a] Third, sulfoxonium ylide
reactions have not been explored beyond X-H insertion reactions.
Moreover metal-accelerated competitive homo-coupling of
sulfoxonium ylides[1b] restricts the further investigation of these ylides
in carbenoid transfer reactions. In fact, the reactivity of sulfoxonium
ylides (R-C=SO) are influenced by the substituents adjacent to the
ylide carbon.[3] Thus, we hypothesized that structural changes of the
sulfoxonium ylides could modulate the generation and reactivity of the
corresponding carbenoids[4] and thereby expand their applicability in
carbenoid transfer reactions in organic synthesis.[5] Further, from the
perspective of sustainable chemistry, it is highly desirable to explore
more economic and environmental friendly metal alternatives to
catalyze these ylide transformations under mild reaction conditions.[6]
With this objective in mind, we embarked on the development of vinyl
sulfoxonium ylides, which can serve as unique four-carbon synthons
for the generation of vinyl carbenoids.
Scheme 1. Generation of vinyl carbenoids.
Scheme 2. Synthesis of heterocycles from vinyl sulfoxonium ylides.
Herein, we report a new strategy to generate Z-selective vinyl
carbenoids from sulfoxonium ylides using FeBr2 as catalyst. This
strategy is successfully applied in the synthesis of heterocycles
such as indolizines, pyrroles and 3-pyrrolin-2-ones under mild
reaction conditions (Scheme 2). In particular, we were interested
to synthesize indolizines, which are known to display important
biological activities, including antitumor, anti-inflammatory and
antiviral effects.[14] We initiated our investigations for the synthesis
of indolzine 3a using pyridine and vinyl sulfoxonium ylide 1a,[15] by
screening various iron-based catalysts [(TPP)FeCl, Hemin, FeX3
(X= Cl, Br, OTf), FeX2 (X = Cl, Br)] and other catalysts (Cu, In, Ni,
Zn, Ir).[16] The best results were obtained with pyridine (1.5 equiv),
vinyl sulfoxonium ylide 1a (1.0 equiv) and FeBr2 (5 mol%) in
CH2Cl2 as solvent at rt for 16 h, providing the desired indolizine
3a in 82% yield. Although the reaction also was successful under
Cu and Ir catalysis with good yields (77% and 78% respectively),
the side product 2-methoxy furan 5a (Scheme 5) was unavoidable
under these conditions. With suitable reaction conditions in hand,
we investigated the substrate scope of the method (Scheme 3).
A range of vinyl sulfoxonium ylides and pyridine analogues were
efficiently transformed to their corresponding indolizines 3a−n in
moderate to good yields (64−85%).
Over the past two decades, there has been substantial progress
in employing vinyl carbenoids for the construction of heterocycles
and carbocycles.[7] The presence of an active carbenoid carbon
and olefin in their structural framework provides a rich and
versatile chemistry. In this area, vinyl diazo compounds have
occupied the majority of the current landscape of vinyl carbenoid
reactions via cycloadditions [(3+2), (4+2), (3+3)] and annulations
[*]
Dr. J. Vaitla, Dr. K. H. Hopmann
Hylleraas Centre for Quantum Molecular Sciences, Department of
Chemistry, University of Tromsø - The Arctic University of Norway,
N-9037 Tromsø, Norway.
Dr. A. Bayer,
Department of Chemistry,
University of Tromsø- The Arctic University of Norway, N-9037
Tromsø, Norway.
E-mail: janakiray.vaitla@uit.no
kathrin.hopmann@uit.no
[**] Supporting information for this article is given via a link at the end of
the document.
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Scheme 4. Scope of one-pot Iron-catalyzed synthesis of indolizines.
We extended our study to evaluate the reactivity of
sulfoxonium ylide-derived carbenoids in absence of pyridine. One
pot reaction of in situ generated dimethylsulfoxonium methylide
with alkynes (with EDG groups on aryl substituents) in DMSO,
followed by addition of FeBr2 catalyst, gave furans 5a (54%) and
5b (48%) (Scheme 5). Although, the reaction is substrate
selective and failed to afford furan 5c under FeBr2 catalysis,[20] it
was successful in the presence of 2 mol% of [Ir(cod)Cl]2 and
yielded 5c in 78% yield after 2 h, at rt. In 2012, the groups of
Skrydstrup[12b] and Maulide[12c] generated furans via coupling of
cationic Au(I) complex-activated alkynes with nucleophilic stable
sulfoxonium ylides. In our method, the relevant metal carbene
intermediates are probably formed via activation of vinyl
sulfoxonium ylide 1 with FeBr2.
Scheme 3. Scope of Iron-catalyzed synthesis of indolizines.
Sulfoxonium ylides having electron-donating or halo substituents
(F, Cl, Br) on the ortho-, meta- and para- positions of the benzene
ring of 1 underwent smooth cyclization, resulting in the formation
of the corresponding indolizine products. Vinyl sulfoxonium ylides
with esters as acceptor groups (R2 = OMe, Scheme 3) are more
reactive and afforded good yields of corresponding indolizines 3a-
3d compared to ketones as acceptor (R2 = aryl) groups 3h-3k.
With respect to the stability of 1, ketone acceptors on vinyl
sulfoxonium ylides are more stable (bench stable solids) than
ester acceptors (stable at 2–8 C). Preparation of ylides 1 (see SI,
Scheme S1) with electron-poor aryl substituents (R1 = ester,
cyano, keto, nitro substituted aryl groups) was unsuccessful and
therefore, carbenoid transfer reaction of this class of substrates
was not studied further. Indolizines with electron-donating aryl
substituents (3d, 3j, 3k) were obtained in marginally lower yields.
The reaction also afforded pyrroloisoquinolines (3l, 82%) and
pyrroloquinolines (3m, 76%), scaffolds found in bioactive
compounds like the lamellarins (a family of anticancer marine
alkaloids)[17] and caspase activators[18] respectively.
We further investigated a one-pot approach for the
formation of indolizine 3 from in situ generated ylide 1 (Scheme 4,
Scheme 5. One pot reaction for furan synthesis.
method
1).
Reaction of
pyridine,
alkyne
4
and
dimethylsulfoxonium methylide (in situ generated from
trimethylsulfoxonium iodide with NaH) in DMSO, followed by
addition of FeBr2 catalyst, provided indolizine 3. The yields of the
one-pot approach (method 1) are low compared to the reaction
with isolated ylide 1 (Scheme 4, method 2). However, in situ
generated aliphatic substituted ylide 1 (R1 = n-butyl), which is
difficult to isolate, can be directly converted to 3t. It is particularly
intriguing to note that the one-pot generation of sulfoxonium-
derived vinyl carbenoids (method 1) provides a more facile
strategy than the multistep synthesis involving diazo-derived enal
carbenoid.[19]
Next, to further broaden the scope of vinyl sulfoxonium
ylides 1, we envisioned N-H insertion of ylide 1 with primary
amines (Scheme 6). Although, metal-catalyzed N-H insertions of
-keto sulfoxonium ylides are known,[1a-e] sustainable metal
catalysts have so far not been applicable for this transformation.
Treatment of ylides 1 with ester groups (R2 = OMe) with amines 6
in the presence of FeBr2 (5 mol%) afforded 3-pyrrolin-2-ones (7a
- 7l) in reasonable yields (64-91%). Notably, allyl and propargyl
amines were effectively converted to the corresponding products
3-pyrrolin-2-ones (7g, 7h) without cyclopropanation of the
unsaturated bonds by intermediate metal carbenoids. The
products 7k and 7l are reported intermediates in the syntheses of
the pharmaceuticals Baclofen[21] and Rolipram[22], respectively.
Analogously, treatment of ylides 1 with ketone substituents (R2 =
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Aryl) under the same conditions gave pyrroles (8a – 8i, Scheme
6).
there are no mechanistic investigations on iron carbenoids
generated from non-Iron(III)corrole/phorphyrin catalyst to
compare our hypothesis too. We therefore turned to performing
computational studies, in order to establish plausible
intermediates of the reaction of sulfoxonium ylide 1a with pyridine,
catalyzed by FeBr2 in CH2Cl2 (Scheme 3). Calculations were
performed at the PBE-D3/6-311G(d,p),IEFPCM(DCM) level of
theory (for optimized coordinates, see SI).[25],[26],[27] Gibbs free
energies were calculated at 298 K. In our computations, the FeBr2
complex prefers a quintet (S = 2) spin state, both in absence of
other ligands and with 1a bound (Table S1 and S2, SI). During the
reaction, we anticipate that pyridine may also coordinate to iron,
generating the reactant complex Fe-Sub-Pyr (Fig. 1).
A)
Scheme 6. Scope of iron-catalyzed synthesis of 3-pyrrolin-2-ones and pyrroles.
The present approach transforms simple primary amines and
ylide 1 to pyrroles with a cheap, sustainable catalyst under mild
reaction conditions, whereas previous reports required enamides,
-keto sulfoxonium ylides and a precious metal catalyst at high
temperatures.[1d] The X-H insertion of ylide 1 is also successful
with secondary amines and thiols with excellent yields (Scheme
7). Treatment of vinyl sulfoxonium ylide 1 with 1.1 equiv of FeBr2
afforded allyl brominated compounds 10a – 10c in 87-93% yields.
B)
Scheme 7. X-H insertion insertion and bromination of ylide 1.
Although, iron-catalyzed diazo-derived carbenoid transfer
reactions are known,[23] the unexpected formation of an allyl
bromide 10 led us to postulate the involvement of an iron carbene
in the mechanism (Scheme 2), which may form a bromide
intermediate via metal halo exchange.[24] We carried out several
control experiments,[16] however, these did not provide conclusive
evidence about the underlying mechanism. To our knowledge,
Figure 1. A) Computed free energies for the FeBr2-catalyzed reaction of 1a with
pyridine (PBE-D3/6-311G(d,p),IEFPCM, kcal/mol, 298 K), B) Computed
mechanism for the FeBr2-catalyzed reaction of 1a with pyridine (Sub = 1a).
The iron-coordinated 1a easily looses DMSO (TS_DMSO_off,
barrier 8.4 kcal/mol, Fig. 1A) to form an Fe-carbene (0.9 kcal/mol
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above Fe-Sub-Pyr, Fig. 1A). Direct attack of Br onto 1a was not
successful in our calculations. This result, including the low barrier
for DMSO dissociation, indicates that Fe-carbene formation is the
initial step of the reaction. The carbene can then undergo
intermolecular attack by the nucleophiles Br or pyridine. Attack by
Br has a low barrier (TS_Br_on_carb, 6.1 kcal/mol relative to the
Fe-carbene) and leads to an unstable Fe-alkylBr intermediate (5.8
kcal/mol above Fe-carbene, Fig. 1A). We conclude that the
brominated alkyl species 10a observed in experiments (Scheme
7) is formed from the off-cycle Fe-alkylBr intermediate, which is in
rapid equilibrium with the on-cycle iron-carbene. Attack of pyridine
on the carbene has a higher barrier than Br attack, 11.8 kcal/mol
relative to the Fe-carbene (TS_Pyr_on_carb, Fig. 1A). However,
the resulting intermediate is low in energy (-12.2 kcal/mol below
the carbene), making this step irreversible. Subsequently, very
fast C-C bond formation occurs (barrier of only 2.5 kcal/mol, Fig.
1A). The cyclized intermediate may undergo loss of a hydride and
a proton to form the final aromatized product[8b] observed in our
experiments (Scheme 3). The overall mechanism, as deduced
from our computations and in agreement with our experimental
observations, is shown in Fig. 1B.
It can be noted that iridium-carbenes in similar reactions readily
form a furan-type product (Scheme 5), which originates from
intramolecular oxygen attack on the carbene. With iron-carbenes,
we observed furans (5a, 5b) from substrates with electron-rich
aryl groups, however, 1a only provided trace amounts of the
corresponding furan 5c in experiments (Scheme 5). In our
calculations, the barrier for O-C bond formation is 1 kcal/mol
above the barrier for pyridine attack (Fig. 1A). We believe that the
two processes (intramolecular oxygen vs. intermolecular pyridine
attack on the carbene) are in competition and that small changes
in the substrate may result in kinetic preference for one pathway
over the other. For substrate 1a, pyridine attack on the carbene is
kinetically preferred, as supported by both experiment and
computation.
Keywords: Carbenoids • Sulfur ylides • Heterocycles • Iron
catalysis • Indolizines
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In summary, we have reported a novel strategy for the
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This work has been performed with support from the Research
Council of Norway (FRINATEK Grant No. 231706 and Centre of
Excellence Grant No. 262695), the Tromsø Research Foundation
(Grant No. TFS2016KHH) and Notur - The Norwegian Metacenter
for Computational Science (CPU Grant No. nn9330k). We also
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Janakiram Vaitla,* Annette Bayer and
Kathrin H. Hopmann*
Page No. – Page No.
Iron-Catalyzed Carbenoid Transfer
Reactions of Vinyl Sulfoxonium
Ylides: An Experimental and
Computational Study
Metal-carbenoids: A new method for vinyl carbenoid transfer using sulfoxonium
ylides is reported. In situ generation of S-ylide/Iron-carbenoid/N-ylide followed by
annulation to give a one-pot indolizine synthesis further demonstrates the efficiency
of this method in vinyl carbenoid-mediated transformations.
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