Selective radical amination of aldehydic C(sp2)-H bonds with fluoroaryl azides via Co(ii)-based metalloradical catalysis: Synthesis of N-fluoroaryl amides from aldehydes under neutral and nonoxidative conditions

Article abstract of DOI:10.1039/c4sc00697f

The Co(ii) complex of the D_2h-symmetric amidoporphyrin 3,5-Di^tBu-IbuPhyrin, [Co(P1)], has proven to be an effective metalloradical catalyst for intermolecular amination of C(sp²)-H bonds of aldehydes with fluoroaryl azides. The [Co(P1)]-catalyzed process can employ aldehydes as the limiting reagents and operate under neutral and nonoxidative conditions, generating nitrogen gas as the only byproduct. The metalloradical aldehydic C-H amination is suitable for different combinations of aldehydes and fluoroaryl azides, producing the corresponding N-fluoroaryl amides in good to excellent yields. A series of mechanistic studies support a stepwise radical mechanism for the Co(ii)-catalyzed intermolecular C-H amination. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4sc00697f

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Selective radical amination of aldehydic C(sp2)–H
bonds with fluoroaryl azides via Co(II)-based
metalloradical catalysis: synthesis of N-fluoroaryl
amides from aldehydes under neutral and
nonoxidative conditions†
Cite this: DOI: 10.1039/c4sc00697f
Li-Mei Jin, Hongjian Lu, Yuan Cui, Christopher L. Lizardi, Thiago N. Arzua,
*
Lukasz Wojtas, Xin Cui and X. Peter Zhang
The Co(II) complex of the D2h-symmetric amidoporphyrin 3,5-DitBu-IbuPhyrin, [Co(P1)], has proven to be
an effective metalloradical catalyst for intermolecular amination of C(sp2)–H bonds of aldehydes with
fluoroaryl azides. The [Co(P1)]-catalyzed process can employ aldehydes as the limiting reagents and
operate under neutral and nonoxidative conditions, generating nitrogen gas as the only byproduct. The
metalloradical aldehydic C–H amination is suitable for different combinations of aldehydes and
fluoroaryl azides, producing the corresponding N-fluoroaryl amides in good to excellent yields. A series
of mechanistic studies support a stepwise radical mechanism for the Co(II)-catalyzed intermolecular
C–H amination.
Received 6th March 2014
Accepted 27th March 2014
DOI: 10.1039/c4sc00697f
www.rsc.org/chemicalscience
pursued as alternative nitrene sources for metal-catalyzed C–H
amination.7 To date, only phosphoryl azides8 have been recently
Introduction
demonstrated as effective nitrene sources for Ru-catalyzed
amination of aldehydic C–H bonds, forming N-acylphosphor-
amidates.9,10 Other more common organic azides such as aryl
azides7c,11 have not been demonstrated in a catalytic process. It
would be synthetically attractive if N-aryl amides could be
prepared directly from aldehydes by catalytic aldehydic C–H
amination with aryl azides.
N-Fluoroaryl amide functionalities have been incorporated
into many synthetic molecules with demonstrated biological
activity and pharmaceutical importance.12 Representative
examples include insulin-like growth factor-I (IGF-1) receptor
GSK1904529A (I),13 sirtuin-activating compound (STAC) (II),14
androgen receptor (AR) agonist (III)15 and others (Fig. 1). In
Amides represent a class of common functional groups in
organic chemistry and exist ubiquitously as key functional and
structural motifs in a broad range of important compounds
such as natural products, synthetic drugs and polymeric mate-
rials.1 Many methods have been established for constructing
amide functionalities, including the traditional condensation
of carboxylic acids and derivatives with amines,1d transition
metal-catalyzed cross-coupling of aryl and alkyl halides with
amides,2 direct amidation of alcohols and esters with amines,3
and other approaches.4 As a new development in the eld,
amide synthesis based on amination of aldehydic C–H bonds
via metal-catalyzed nitrene insertion has attracted recent
interest due to the wide availability of aldehydes and the advent
of new nitrene sources.5 Several transition metal-based cata-
lysts, such as Rh,5e Ru,5f Fe5g,h and Cu5i complexes, have been
shown to be effective in catalyzing C(sp2)–H amination of
aldehydes with iminoiodinanes and their in situ variants as
nitrene sources, generating N-sulfonylcarboxamides.6 In view of
their many attributes such as structural diversity, wide avail-
ability and ease of synthesis, organic azides have been actively
Department of Chemistry, University of South Florida, Tampa, FL 33620-5250, USA.
E-mail: xpzhang@usf.edu; Fax: +1-813-974-3203; Tel: +1-813-974-7249
† Electronic supplementary information (ESI) available: Experimental procedures
and analysis data for new compounds. CCDC 990222 and 990223. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c4sc00697f
Fig. 1 Selected examples of biologically active N-fluoroaryl amides.
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addition, N-uoroaryl amides have been recently demonstrated protocol that operates under neutral and nonoxidative condi-
as effective directing groups for palladium-catalyzed C–H tions, permitting high tolerance of other functionalities.
functionalization.16 The existing synthetic methods for N-uo-
roaryl amides typically rely on traditional condensation reac-
tions of carboxylic acids or their derivatives with uoroanilines.
Results and discussion
Due to the poor nucleophilicity of polyuoroanilines, these
reactions oen suffered from low yields and poor substrate
scope, limiting their wide application for preparation of N-u-
oroaryl amide derivatives.17 Undoubtedly, a catalytic process
based on the C–H amination of aldehydes with uoroaryl azides
would be particularly attractive for the synthesis of N-uoroaryl
amides. However, uoroaryl azides, which can be conveniently
prepared from readily available uoroanilines, are a class of
common aryl azides that have not been previously applied for
catalytic C–H amination, including aldehydic C–H amination.18
As stable metalloradicals with well-dened open-shell
doublet d7 electronic structure, cobalt(II) complexes of
porphyrins, [Co(Por)], have shown to be effective metal-
loradical catalysts for amination of different types of C–H
bonds with various azides.19,20 Recently, Co(II)-based metal-
loradical catalysis (MRC) was successfully applied for
asymmetric olen aziridination with uoroaryl azides as
effective nitrene sources.21 The Co(II)-catalyzed aziridination
was believed to proceed through Co(III)-nitrene radical A as the
key intermediate (Fig. 2), which undergoes radical addition to
olen, followed by 3-exo-tet radical cyclization.21 As a further
application of the concept of MRC, we anticipated
the possibility of a Co(II)-based catalytic process for aldehydic
C–H amination with uoroaryl azides if the Co(III)-supported
uoroaryl nitrene radical A is capable of H-atom abstraction
from aldehydes to generate Co(III)-amido complex B, followed
by acyl radical substitution (Fig. 2). As a result of our studies in
this direction, herein we wish to report an effective catalytic
system based on Co(II)-MRC that enables selective amination
of aldehydic C–H bonds with uoroaryl azides for amide
formation. The Co(II)-based metalloradical amination is suit-
able for a wide range of aldehydes and can also utilize different
uoroaryl azides, producing the corresponding N-uoroaryl
amides in good to excellent yields. In addition to using alde-
hydes as the limiting reagent and generating N2 as the only
byproduct, the new MRC system is highlighted with a practical
Initially, we examined the reaction of benzaldehyde (1a) with
pentauorophenyl azide (2a) using Co(II) complexes of different
D2h-symmetric amidoporphyrins as the catalysts. We were
delighted to nd that the catalyst [Co(P1)] (P1 ¼ 3,5-DitBu-Ibu-
Phyrin)22 gave the desired amide 3aa in 56% yield in the solvent
of benzene (Table 1, entry 1). Subsequent experiments with
various solvents revealed that chlorobenzene was the optimal
medium for the catalytic reaction, producing the desired
product in 77% yield (Table 1, entries 2–6). Low conversion was
observed at lower reaction temperature, possibly due to the
coordination of the aldehyde to the cobalt center (Table 1,
entry 7).23 When [Co(TPP)] (H2TPP ¼ 5,10,15,20-tetraphe-
nylporphyrin) was used as the catalyst, it gave no obvious
reaction (Table 1, entry 8), indicating the important role of the
possible N–H/F hydrogen bonding as depicted for the Co(III)-
supported uoroaryl nitrene radical A (Fig. 2).21 As expected, no
reaction occurred without a catalyst (Table 1, entry 9).
Under the optimized conditions, we then investigated the
scope of aldehyde substrate for the catalytic amination by
[Co(P1)] with pentauorophenyl azide (2a). As shown in Table 2,
this [Co(P1)]-based MRC system was found to be suitable for a
broad range of aldehydes with different steric and electronic
properties, including aromatic, heteroaromatic, and aliphatic
aldehydes as well as a,b-unsaturated aldehydes. For example,
Table 1 Amination of benzaldehyde (1a) with pentafluorophenyl azide
(2a) catalyzed by [Co(Por)]a
Entry
Catalyst
Temp. (ꢀC)
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
9
[Co(P1)]
[Co(P1)]
[Co(P1)]
[Co(P1)]
[Co(P1)]
[Co(P1)]
[Co(P1)]
[Co(TPP)]
—
80
80
80
80
80
80
40
80
80
PhH
PhCl
56
77
71
56
69
65
Trace
Trace
NRc
4-CF3C6H4Cl
PhF
Hexane
ClCH2CH2Cl
PhCl
PhCl
PhCl
a
All reactions were carried out with 1.0 equiv. of aldehyde (0.2 M) and
1.2 equiv. of azide using 3 mol% [Co(Por)] as catalyst. b 19F-NMR yields.
Fig. 2 Proposed pathway for C–H amination of aldehydes with fluo-
roaryl azides via [Co(Por)]-based metalloradical catalysis.
c
NR ¼ no reaction.
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Table 2 [Co(P1)]-catalyzed C–H amination of various aldehydes with
pentafluorophenyl azide (2a)a,b
aldehydic C–H bonds could also be aminated. For example,
furanyl, pyrrolyl, and indolyl substituted amides could be
readily produced in good yields (Table 2, entries 16–20).
Importantly, aldehydes with free N–H group could also be used
in the transformation, albeit in lower yields compared to that of
N-Boc-protected aldehydes (Table 2, entries 17 vs. 18 and entries
19 vs. 20). Aliphatic aldehydes, such as valeraldehyde and
cyclopropanecarbaldehyde, also gave the desired products in
satisfying yields (Table 2, entries 21 and 22).24 It is worthy to
mention that no obvious decarbonylation or ring-opening
products were observed for the reaction of cyclo-
propanecarbaldehyde, indicating fast rate of the last step of
radical substitution. Vinyl aldehydes, such as cinnamaldehyde
and perillaldehyde, could produce the corresponding amides
without affecting the C]C double bonds (Table 2, entries 23
and 24). Even for substrates containing terminal aromatic C]C
and C^C bonds, the aldehydic C–H amination was still domi-
nated (Table 2, entries 25 and 26). The priority of aldehydic C–H
amination over C]C aziridination was further demonstrated by
the competition reaction of benzaldehyde (1a) and styrene (1a0)
with azide 2a (eqn (1)). Under the same reaction conditions, the
yield of the amide 3aa was found to be double that of aziridine
3a0a (eqn (1)).21 It is worth mentioning that the metalloradical
amination could be readily scaled up, as demonstrated with the
gram-scale synthesis of amide 3ba in 79% yield.
a
All reactions were carried out in PhCl using 3 mol% of [Co(P1)] as
catalyst with 1.0 equiv. of aldehyde (0.2 M) and 1.2 equiv. of azide for
In addition to pentauorophenyl azide, the [Co(P1)]-based
metalloradical catalytic system could effectively enable alde-
hydic C–H amination with other haloaryl azides (Table 3). As
exemplied with p-anisaldehyde (1b), various uoroaryl azides,
including monouoro-, diuoro-, triuoro-, and tetrauoroaryl
azides (2b–f), were found to be effective nitrene sources for the
metalloradical amination process, giving the corresponding
b
c
d
24 h at 80 ꢀC. Isolated yields. At 100 ꢀC. Small amounts of
aziridine and unidentied compounds were observed by NMR.
aromatic aldehydes with various electron-donating substitu-
ents, including alkyl, alkoxy, and alkylthio groups, could be
effectively used as substrates, yielding the desired N-uoroaryl
amides in high yields (Table 2, entries 1–7). It is notable that the
easily oxidizable alkylthio functionality was well tolerated
because of the neutral and nonoxidative conditions of this
metalloradical process (Table 2, entry 5). Interestingly, the
Co(II)-based radical amination was shown to be highly chemo-
selective toward aldehydic C–H bonds in the presence of other
C–H bonds, including benzylic, allylic and aliphatic C–H bonds
(Table 2, entries 6–7 and 21–22 and 24). As well, electron-poor
aromatic aldehydes, such as cyano-, nitro-, and ester-
substituted benzaldehydes, could be smoothly aminated in
good yields under the MRC system (Table 2, entries 8–10).
Moreover, various halogenated benzaldehydes, including the
highly sterically demanding 2,6-dibromobenzaldehyde, could
be aminated by the Co(II)-MRC system to generate the corre-
sponding N-uoroaryl halobenzamides (Table 2, entries 11–13),
the aryl halide units of which may be further functionalized via
palladium-catalyzed amidation.2 In addition to benzaldehyde
derivatives, both naphthyl and anthracenyl aldehydes could be
employed as the substrates for the amination process (Table 2,
entries 14 and 15). Like aromatic aldehydes, heteroaromatic
Table 3 [Co(P1)]-catalyzed amination of p-anisaldehyde (1b) with
various aryl azidesa,b
a
All reactions were carried out in PhCl using 3 mol% of [Co(P1)] as
catalyst with 1.0 equiv. of aldehyde (0.2 M) and 1.2 equiv. of azide for
b
c
d
24 h at 80 ꢀC. Isolated yields. At 100 ꢀC. The yield was based on
1H NMR.
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amides in good yields (Table 3, entries 1–5). Fluoroaryl azide involving the hydrogen-atom abstraction by the key Co(III)-
with other substituents such as bromotetrauorophenyl azide nitrene radical intermediate A (Fig. 2).
(2g) was also a suitable nitrene source for the transformation
To gain insights on the resulting acyl radical intermediate and
(Table 3, entry 6). Similar to that of azide 2g, 4-tetra- its subsequent substitution reaction in the Co(II)-catalyzed
uoropyridinyl azide (2h) produced the corresponding amide in process (Fig. 2), phenylacetaldehyde (1z0) was employed as the
a high yield as well (Table 3, entry 7). Interestingly, 2,6- amination substrate since the corresponding phenylacetyl
dichlorophenyl azide (2i) and 2-pyrimidine azide (2j) could also radical is a known acyl radical clock.5a,26 Under the standard
function as nitrene sources for this type of catalytic trans- conditions, the catalytic reaction of 1z0 afforded N-benzylpenta-
formation, but in much lower efficiency (Table 3, entries 8 and uoroaniline (4) in 14% yield in addition to the expected alde-
9). However, 3,4,5-triuorophenyl azide,21 without ortho-uo- hydic C–H amination product 3z0a in 36% yield (eqn (2)).27 The
rine substituents, gave only trace amount of the desired product formation of compound 4 is attributed to the decarbonylation of
under the same condition, again indicating the importance of the initially generated acyl radical to give benzyl radical, followed
the possible hydrogen bonding in the catalytic process (Fig. 2).25 by its substitution reaction with the Co(III)-amido complex. The
Increasing evidence supports that Co(II)-based metal- fact that the amide 3z0a was found to be the major product also
loradical C–H amination and related olen aziridination reac- suggests that the rate of the last step of radical substitution is
tions with azides undergo a stepwise radical mechanism greater than that of decarbonylation of the phenylacetyl radical,
involving unusual Co(III)-nitrene radical intermediates, which which is 5.2 ꢁ 107 sꢂ1
.
This result is consistent with the
26
are fundamentally different from metallonitrene intermediates extremely low barrier for the radical substitution suggested from
associated with the widely studied Rh2- and Cu-based closed- the previous computational studies.19 To provide further proof
shell systems.19,20 Accordingly, the current catalytic process of for the existence of the acyl radical intermediate, catalytic ami-
intermolecular aldehydic C–H amination with uoroaryl azides nation of aldehyde 1b with azide 2a was carried out in the pres-
is supposed to undergo a similar stepwise radical mechanism ence of an excess amount of radical trapping agent TEMPO
(Fig. 2). To obtain direct evidence for the proposed mechanism, (eqn (3)). While the amination product 3ba was still formed as
we rst sought to measure the deuterium kinetic isotope effect the major product in 67% yield, the corresponding acyl radical
(KIE) for the reaction of benzaldehyde (1a) with penta- was successfully trapped to give compound 5 in 24% yield. In the
uorophenyl azide (2a) by [Co(P1)] (Scheme 1). Since differen- absence of either catalyst [Co(P1)] (eqn (4)) or azide 2a (eqn (5)),
tiation between protonated (3aa) and deuterated (3aa-d) no reaction was observed, indicating that TEMPO alone could not
1
products by H-NMR was problematic for a direct competition trigger the formation of 5.
experiment between aldehydes 1a and 1a-d due to the acidity of
While the mechanistic studies evidently support the
the resulting amide group, indirect competition experiments proposed radical mechanism and validate the genuine radical
between them with the use of 4-methylbenzaldehyde (1h) as a character of the Co(III)-nitrene radical intermediate A (Fig. 2),
reference were conducted to address the issue (Scheme 1). the less than unity value of kH/kR in the competition experiment
Through separate measurements of kH/kR and kD/kR, the KIE between benzaldehyde and 4-methylbenzaldehyde (Scheme 1)
(kH/kD) was derived to be 10.2. This high degree of primary suggests that the radical intermediate A has some degree of
intermolecular KIE is consistent with the proposed mechanism electrophilicity. To verify the electrophilic radical nature of the
intermediate A, we carried out systematic competition experi-
ments using a selected set of para-substituted benzaldehydes
with wide-ranging electronic properties for their amination
reactions with pentauorophenyl azide. The results revealed a
Scheme 1 Double competition experiments for measurement of the Fig. 3 Correlation of log(kx/kH) versus sp plot for amination of para-
Kinetic Isotope Effect (KIE).
substituted benzaldehydes with pentafluorophenyl azide by [Co(P1)].
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strong linear correlation between the log(kx/kH) and the Ham-
mett constants (sp)28 of the para-substituents with a negative
slope of ꢂ0.867 (Fig. 3).29 This trend signies the electronic
inuence of the radical C–H amination with uoroaryl azides by
[Co(P1)], which is also well reected in the results summarized
in Table 2. The strong electron-withdrawing effect of the uo-
roaryl group is likely responsible for the electrophilic radical
reactivity prole of the catalytic system.
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Conclusions
In summary, we have demonstrated that [Co(P1)] is an effective
catalyst for C–H amination of aldehydes with uoroaryl azides
via metalloradical catalysis. The Co(II)-based metalloradical
amination system represents the rst example of aldehydic C–H
amination with aryl azides as the nitrene source. The [Co(P1)]-
catalyzed process, which can be operated under neutral and
nonoxidative conditions without the need of any additives,
proceeds effectively with the use of aldehydes as the limiting
reagent and tolerates various functionalities. The resultant
N-uoroaryl amides may nd a myriad of potential applications.
Efforts are underway to expand the Co(II)/azide-based radical
amination system for other types of C–H bonds, including
asymmetric intermolecular C–H amination.
Acknowledgements
We are grateful for nancial support by NSF (CHE-1152767) and
NIH (R01-GM098777). We thank Dr Edwin Rivera for his valu-
able assistance with NMR measurements.
Notes and references
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Fig. S1–5 in the ESI.†
Chem. Sci.
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