Iron-catalyzed C(sp3)-H functionalization of: N, N -dimethylanilines with isocyanides

Article abstract of DOI:10.1039/c7cc09872c

An efficient ligand-free Fe-catalyzed oxidative Ugi-type reaction toward the assembly of α-amino amides and short peptides is described. The reaction proceeds through the α-C(sp³)-H oxidation of N,N-dimethylanilines and further nucleophilic attack of the resulting iminium species by isocyanides. Additive screening showed that judicious choice of the carboxylic acid could lead to the formation of α-amino imides via a 3-component reaction. The process occurs with operational simplicity and is compatible with a variety of sensitive functional groups.

Full text of DOI:10.1039/c7cc09872c

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Iron‐Catalyzed C(sp3)−H Funcꢀonalizaꢀon of N,N‐Dimethylanilines
with Isocyanides
Itziar Guerrero, Marcos San Segundo and Arkaitz Correa*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
the classical Ugi reaction, which occurred through the in situ
oxidation of the corresponding amines6 (Scheme 1, route b), hence
broadening the scope to the formation of structurally related α‐
amino amides. In this respect, Zhu and co‐workers introduced an IBX‐
mediated Ugi‐type reaction of tetrahydroisoquinolines.6k More
recently, Xie and co‐workers elegantly implemented the use of
copper catalysis in combination with tert‐butyl hydroperoxide
(TBHP) as oxidant upon N,N‐dialkylanilines (Scheme 2, route c).6d,h‐i
Rueping6e‐g and Stubbs6b have reported a variety of photoredox‐
catalyzed Ugi‐type reactions using tertiary amines (Scheme 2, route
d). Although significant advantages have been achieved, it is still a
crucial challenge to develop robust and general catalytic approaches
for the synthesis of amino acid and peptide derivatives.
An efficient ligand‐free Fe‐catalyzed oxidative Ugi‐type reaction toward the
assembly of α‐amino amides and short peptides is described. The reaction
proceeds through the α‐C(sp3)−H oxidaꢀon of N,N‐dimethylanilines and
further nucleophilic attack of the resulting iminium species by isocyanides.
Additive screening showed that judicious choice of the carboxylic acid could
lead to the formation of α‐amino imides via a 3‐component reaction. The
process occurs with operational simplicity and is compatible with a variety
of sensitive functional groups.
Multicomponent reactions1 provide efficient and rapid assembly of
small fragments to create molecular diversity in a one‐pot practical
fashion, thus offering wide applications in the area of natural product
synthesis and drug discovery.2 One of the most utilized methods is
the Ugi four‐component reaction (U‐4CR),3 giving straightforward
access to α‐acylamino amides4 which are prevalent compounds in a
plethora of pharmaceuticals and medicinally relevant compounds.
Scheme 2 Oxidative Ugi‐type reactions with tertiary anilines
Scheme 1 Ugi and oxidative Ugi‐type reactions
Given our interest in sustainable C−H funcꢀonalizaꢀon events,7 we
envisioned the advantageous use of environmentally friendly, easy‐
to‐handle, non‐toxic and cheap iron salts8 as alternative catalysts in
oxidative Ugi‐type reactions. Based on the known ability of iron
catalysts to activate the α‐C(sp3)−H bond neighboring to the amino
group,9,10 we hypothesized that the resulting electrophilic N‐aryl
iminium ion would be prone to react with a nucleophilic isocyanide
through an Ugi‐type reaction pathway (Scheme 2). If successful, such
iron‐based protocol would complement existing methodologies6 and
constitute a cost‐efficient and eco‐friendly route toward the
assembly of α‐amino amides and short peptides. In this
communication, we describe an unprecedented Ugi‐type reaction
upon N,N‐dimethylanilines and isocyanides featuring the practical
use of an Fe(II)‐TBHP oxidizing system. Importantly, the employment
of picolinic acid resulted in the formation of α‐amino imides through
a three‐component reaction.
The classical U‐4CR involves the in situ formation of an imine from
combining a primary amine and an aldehyde, and subsequent
reaction with an isocyanide and a carboxylic acid furnishes the
corresponding α‐acylamino amides5 (Scheme 1, route a). Despite its
efficiency, the synthetic scope of the process is often limited and
hence the development of alternative, yet sustainable, protocols
represents a challenging task of paramount significance in organic
chemistry. In this regard, oxidative multicomponent reactions upon
secondary or tertiary amines have emerged as convenient variants of
Department of Organic Chemistry I, University of the Basque Country (UPV/EHU),
Joxe Mari Korta R&D Center, Avda. Tolosa 72, 20018 Donostia‐San Sebastián
(Spain). E‐mail: arkaitz.correa@ehu.es.
† Electronic Supplementary Information (ESI) available.
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Journal Name
3
3
Table
dimethylanilines
2
Fe‐catalyzed C(sp )−H Funcꢀonalizaꢀon of N,N‐
2 Fe‐catalyzed C(sp )−H functionalization of N,N‐
Table
Table 1 Optimization for the Fe‐catalyzed oxidative Ugi‐type
reactiona
Dimethylanilines a,b
a,b
a Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), [M] (10 mol
%), oxidant (2.0 equiv), MeCN (2.0 mL) at 40 ºC for 24 h under
argon. b Yield of isolated product after column chro‐matography.
e
c 1a (1.0 mmol). d 1.0 gram‐scale of 2a
.
under air. f TBHP(dec)
(1.0 equiv). TBHP(dec) = tBuOOH 5.0‐6.0 M in decane; TBHP(aq)
= tBuOOH 70% in H2O.
a
b
b
a
As for Table 1, entry 8. Yield of isolated product after column
As for Table 1, entry 8. Yield of isolated product after column
We initially selected the coupling of N,N‐dimethylaniline (1a) and p‐
toluenesulfonylmethyl isocyanide (2a) as the model system to
evaluate the feasibility of our approach (Table 1). We anticipated
that the nature of the metal source and the oxidant would have a
profound impact on reactivity and accordingly the effect of such
c
c
chromatography, average of at least two independent runs.
chromatography, average of at least two independent runs.
Addition of AcOH (2.0 equiv). Reaction performed at 70 ºC.
Addition of AcOH (2.0 equiv). d Reaction performed at 70 ºC.
d
Cu‐based methods6d,h‐i for the synthesis of α‐amino amides bearing a
variety of synthetically relevant moieties. Interestingly, the addition
variables
was
systematically
examined.
After
some
experimentation,11 we found that the use of bench‐stable Fe(OAc)2
in combination with inexpensive TBHP(dec) as oxidant turned out to of acetic acid was crucial to obtain in certain cases the target α‐amino
be the most effective catalyst system (entry 2). Curiously, the use of
an aqueous solution of TBHP was found less efficient (entry 3).
Likewise, other oxidants such as H2O2, molecular oxygen or DDQ
(entries 4‐6) provided much lower yields of the corresponding amide
amides 3 in high yields. The latter reveals the subtleties of our iron‐
catalyzed process given that the use of carboxylic acids have
commonly resulted in the formation of α‐amino imides through a 3‐
component reaction.6d,i‐k Of particular importance are 3ia and 3ja
3aa. The use of excess of 1a was shown to be beneficial and resulted where high chemoselectivity was achieved toward the preferential
in the formation of 3aa in a remarkable 81% yield (entry 8). Other activation of α‐C(sp3)−H bonds of N,N‐dimethylanilines versus the
iron and cobalt salts11 afforded comparatively lower yields than C(sp3)−H bonds adjacent to a cyclic ether10b or a cyano group,12
Fe(OAc)2 (entries 9‐12). It is worth noting that the performance of the
process under air or with just one equivalent of the oxidant furnished
3aa in useful synthetic yields (entry 13), thus evidencing the
respectively. The use of ortho substituted anilines 1o‐p provided the
target products, albeit in moderate yields. Unfortunately, no reaction
occurred when employing N,N‐diethyl or N,N‐dibenzylanilines as
robustness of our catalyst system. As expected, control experiments substrates. Besides, aliphatic amines such as pyrrolidine and N‐
established the crucial role of both oxidant and iron source as just
traces of 3aa were detected in their absence (entries 1 and 7,
respectively). Importantly, our Fe‐catalyzed Ugi‐type reaction can be
effected in a gram‐scale to provide amide 3aa in 91% yield (entry 8),
hence constituting an additional bonus from a practical and
operational point of view.
methylmorpholine were inactive under our reaction conditons.
Gratifyingly, numerous isocyanides smoothly underwent the Ugi‐
type reaction to afford the corresponding amino amides 3 in
moderate to good yields (Table 3). Not only alkyl isocyanides 2b‐d
but also a SET‐sensitive aromatic derivative 2e were found
competent coupling partners for the Fe‐catalyzed oxidative coupling.
Likewise, biologically relevant compounds such as benzimidazole
(3af), dipeptides (3ag, 3bg), and phosphonate derivative (3bh) are
within reach upon the use of the corresponding functionalized
isocyanides 2f‐h. Notably, once again the addition of acetic acid was
With the optimal conditions in hand, we next evaluated the synthetic
scope of the Fe‐catalyzed Ugi‐type reaction. As depicted on Table 2,
a wide range of N,N‐dimethylanilines underwent the corresponding
coupling reaction in good to excellent yields. Remarkably, numerous
functional groups such as halides (3ba, 3ca, 3da, 3la, 3ma), nitriles crucial for the process to occur in certain cases. In‐trigued by its
(3fa, 3ja), ethers (3ga, 3ia), esters (3ia, 3ja, 3ka), ketones (3ha), and positive effect on the reaction outcome, we conducted a more
even azobenzenes (3na) were perfectly accommodated. As a result,
detailed study on the influence on the process of
our Fe‐catalyzed approach outperforms
2 | J. Name., 2012, 00, 1‐3
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Table 3 Synthetic scope with isocyanides a,b
To gain some insights into the mechanism, we performed the
reaction of N,N‐dimethylaniline 1a with isocyanide 2a in the
presence of a variety of radical scavengers. Whereas the oxidative
coupling was entirely inhibited in the presence of one equivalent of
both TEMPO and 1,1‐diphenylethylene, which may support the
intermediacy of radical intermediates; the addition of BHT [3,5‐
di(tert‐butyl)‐4‐hydroxytoluene] produced 3aa in a much lower 27%
yield. Likewise, the performance of the process under an oxygen
atmosphere provided amino amide 3aa in 41% yield. The latter
experiments indicate that the carbon‐center radical’s oxidation
through a SET process to the iminium ion I may be faster than its
trapping with the radical inhibitor. However, owing to the
controversial discussions on the nature of the active species within
the oxidation of tertiary amines to the corresponding iminium ion by
an Fe(II)/ROOH system,15 we believe in depth mechanistic studies are
required to disclose those elemental SET and HAT events.
Accordingly, a tentative mechanistic scenario is disclosed in Scheme
3. The reaction would start by a first C(sp3)−H oxidaꢀon of N,N‐
dimethylaniline 1 in the presence of [Fe]/TBHP to generate iminium
ion I.15 Next, the subsequent nucleophilic attack of the highly reactive
isocyanide 2 would produce nitrilium ion II, which would be
eventually trapped by water16 to deliver the target amide 3 (Scheme
3, path a). In the presence of picolinic acid, nitrilium II would
alternatively afford intermediate III where an acyl migration17 would
eventually furnish imide 4 (Scheme 3, path b).
a As for Table 1, entry 8. b Yield of isolated product after column
c
chromatography, average of at least two independent runs.
Addition of AcOH (2.0 equiv). d Reaction performed at 70 ºC.
different carboxylic acids (Table S2)11 and we found that the addition
of both acetic acid and 1‐adamantanecarboxylic acid improved the
formation of the corresponding α‐amino amides.13 In striking
contrast, the use of picolinic acid resulted in the preferential
formation of the corresponding picolinamides 4 through an iron‐
catalyzed 3‐component Ugi‐type reaction. As shown on Table 4, a
short family of α‐amino amides of high structural complexity were
easily prepared by simply mixing the corresponding anilines,
isocyanides and picolonic acid in the presence of the cost‐efficient
Fe(II)‐TBHP system. The latter represents an added bonus of our
methodology given the widespread utility of picolinamide derivatives
as versatile substrates in the realm of C−H acꢀvaꢀon14 as well as
medicinal chemistry.
Table 4 Scope for multicomponent reaction a,b
Scheme 3 Proposed mechanism
In summary, we have demonstrated the applicability and practicality
of iron catalysis for the performance of oxidative Ugi‐type reactions
toward the modular synthesis of α‐amino amides. Notably, our
method represents an attractive, yet complementary, strategy which
occurs with high operational simplicity and remarkably increases the
synthetic scope, being found compatible with a variety of biologically
relevant functional groups. On the basis of the inherent cutting‐edge
features of iron salts, this protocol could find potential applications
of utmost importance in peptide chemistry and industrial
environments. Furthermore, we believe that our method can be the
foundation for future discoveries in the challenging area of Fe‐
catalyzed C(sp3)‐H activation processes.
a Reaction conditions:
1 (0.50 mmol), 2 (0.25 mmol), Fe(OAc)2 (10
mol %), picolinic acid (2.0 equiv), TBHP(dec) (2.0 equiv), MeCN
(1.0 mL) at 40 ºC for 24 h under argon. b Yield of iso‐lated product
after column chromatography, average of at least two
independent runs.
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1416; (g) Z. Li, R. Yu and H. Li, Angew. Chem., Int. Ed., 2008,
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We thank for technical and human support provided by Central
Service of Analysis de Alava–SGIker of UPV/EHU. We are grateful to
Gobierno Vasco (IT_1033‐16) and MINECO (CTQ2016‐78395‐P) for
financial support. A. C. thanks MINECO for a Ramón y Cajal research
contract (RYC‐2012‐09873). Cost‐CHAOS action is also acknowl‐
edged.
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4 | J. Name., 2012, 00, 1‐3
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