Copper catalyzed: N-formylation of α-silyl-substituted tertiary N-alkylamines by air

Article abstract of DOI:10.1039/d0gc01242d

A site-selective method to prepare N-formyl amines efficiently that relies on the copper(i)-catalyzed oxidation of α-silyl-substituted tertiary N-alkylamines by air at room temperature is described. The oxidative protocol was shown to exhibit excellent functional group tolerance as it was applicable to a wide variety of amine substrates and a number of bioactive molecules and natural products. Moreover, it delinates a ligand-and additive-free amine oxidation process mediated by a low-cost metal salt with oxygen from air taking on the role of both the terminal oxidant and as part of the formylation reagent, which is unprecedented in copper catalysis. It also offers the first synthetic method that can selectively generate α-amino radical species as reactive intermediates from α-silylamines under non-photochemical reaction conditions.

Full text of DOI:10.1039/d0gc01242d

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DOI: 10.1039/D0GC01242D
ARTICLE
Copper Catalyzed N-Formylation of α-Silyl-Substituted Tertiary N-
Alkylamines by Air
Yichao Zhao,b† Lachlan David Bruce,b† Jianwen Jin,b Bo Xia,*a,b and Philip Wai Hong Chan*a,b,c
Received 00th January 20xx,
Accepted 00th January 20xx
A site-selective method to prepare N-formyl amines efficiently that relies on the copper(I)-catalyzed oxidation of α-silyl-
substituted tertiary N-alkylamines by air at room temperature is described. The oxidative protocol was shown to exhibit
excellent functional group tolerance as it was applicable to a wide variety of amine substrates and a number of bioactive
molecules and natural products. Moreover, it delinates a ligand- and additive-free amine oxidation process mediated by a
low-cost metal salt with oxygen from air taking on the role of both the terminal oxidant and as part of the formylation
reagent, which is unprecedented in copper catalysis. It also offers the first synthetic method that can selectively generate
α-amino radical species as reactive intermediates from α-silylamines under non-photochemical reaction conditions.
DOI: 10.1039/x0xx00000x
nucleophiles such as those of an alkyne, methyl ketone or
Introduction
phosphine. A recent example of this is the N-formylation of
tertiary N-methylamines by
a
sterically demanding
N-Formyl amines are a key structural motif in many bioactive
natural products and pharmaceutical compounds as well as
biological intermediates.1,3 The compound class is also a
versatile solvent, protecting group, reagent or chiral Lewis base
organocatalyst in chemical synthesis.4–7 For this reason, the
development of new efficient synthetic methods for formamide
synthesis continues to be actively pursued.2,8–11 In recent years,
this has been further fuelled by the demand for new synthetic
tools that can streamline routes to synthetically and medicinally
valuable small molecules.8 Along with this is the growing
demand for sustainable synthetic methods that can minimize or
eliminate various reagent and energy resources such as ligands,
additives, high reaction temperatures and pressurized gases
such as CO and CO2, and use low-cost metal catalysts and
renewable oxidants such as oxygen from air.9
Cu(I)/Cu(II)/bipyridyl catalytic system activated by O2 and with
adamantyl N-oxyl as the sacrificial oxidant (Scheme 1a).8a The
iminium species formed in situ during the course of the reaction
was delineated to undergo a hydrolysis/hemiaminal oxidation
cascade. In contrast, a single oxidation process involving tertiary
amines in which oxygen from air acts as both the terminal
oxidant and the formylation reagent to chemoselectively give
N-formyl amines has so far remained unrealized. Presumably,
this could be due to the challenge of supressing preferential
formation of the iminium adduct as the α-amino radical species
Copper-catalyzed α-functionalization of tertiary amines
using oxygen as the oxidant has established itself in recent years
as one of the most powerful synthetic tools to rapidly increase
molecular complexity in a single step (Scheme 1a).8a,11 From a
mechanistic perspective, the reactions rely on the propensity of
the electron-rich amine substrate to undergo single electron
transfer (SET) oxidation to give the corresponding nitrogen-
radical centered cation species.11c–e This is often followed by a
second SET oxidation event to give the iminium species, which
can subsequently engage in addition reactions with weak
aDepartment of Biological Environment, Jiyang College of Zhejiang A&F University,
Zhuji 311800 (China)
bSchool of Chemistry, Monash University, Clayton, Victoria 3800 (Australia)
cDepartment of Chemistry, University of Warwick, Coventry CV4 7AL (United
Kingdom)
Email: phil.chan@monash.edu
† These authors contributed equally to this work.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
Scheme 1 Iminium vs α-amino radical species as reactive intermediates.
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Table 1 Optimization of the reaction conditionsa
has been shown to be more readily oxidized than the starting
amine under reaction conditions involving an excess amount of
oxidant.12 As a consequence, this makes the precise control of
the oxidation process key to exploiting the α-amino radical
species as a reactive intermediate. In this regard and as part of
an ongoing program examining the utility of oxidative copper
catalysis in organic synthesis, we became interested in the
potential reactivity of bench-stable α-silyl-substituted tertiary
N-alkylamines (Scheme 1b).13 We anticipated that the
compound class would readily undergo SET oxidation to give the
nitrogen-centered species I due to the comparable redox
potentials of the substrate and Cu(II)-Cu(I) systems.14 With the
possibility of -silyl hyperconjugative stabilization, this may lead
to facile desilylative fragmentation to afford the corresponding
α-amino and peroxysilyl radical fragments II and III.15,16 Radical
recombination of the two reactive intermediates followed by a
rapid deprotonation/desilylation cascade of the ensuing
peroxide adduct IV might then be envisaged to deliver the
formamide product.17 Herein, we disclose the details of this N-
formylation chemistry which offers an efficient and
chemoselective route a synthetically valuable member of the
amide compound family in good to excellent yields from α-
silylamines. It provides a site-selective N-formylation protocol
with key features that include: (a) the use of inexpensive and
non-toxic CuBr as the catalyst; (b) a catalytic system that did not
require ligands and/or additives; (c) oxygen from air acting as
both the terminal oxidant and as part of the formylation reagent
that is, to our knowledge, an extremely rare mode of reactivity
in copper catalysis;10 (d) extremely mild reaction conditions at
ambient temperature and pressure that enabled exceptional
functional group tolerance as exemplified by the late-stage
modification of 13 bioactive molecules; (e) generation of a
stoichiometric amount of silanol as potentially the only
byproduct. Added to this, it realizes the first example in organic
chemistry that can generate α-amino radical species as reactive
intermediates from α-silylamines under non-photochemical
reaction conditions.15,16
View Article Online
DOI: 10.1039/D0GC01242D
Entry [Cu] (mol %)
Solvent (M)
Additive
Yield
(%)b
55
(equiv)
-
-
-
-
-
-
-
1
2
3
4
5
6
7
8
CuBr (20)
CuBr (20)
CuBr (20)
CuBr (20)
CuBr (20)
CuBr (20)
CuBr (20)
CuBr (20)
CuBr (20)
CuBr (20)
CuBr (10)
CuBr (10)
CuBr (10)
-
toluene (0.2)
Et2O (0.2)
37
6
29
35
18
70
19
EtOAc (0.2)
acetone (0.2)
MeOH (0.2)
MeCN (0.2)
MeCN (0.2)
MeCN (0.2)
MeCN (0.2)
MeCN (0.2)
MeCN (0.4)
MeCN (0.4)
CsF (2)
9
NaHCO3 (2) 58
10
11
12
13
Et3N (2)
45
-
-
70
89d
c
1,10-phen
-
(0.2)
14
15
16
CuCl (10)
Cul (10)
Cu(MeCN)4PF6 MeCN (0.4)
(10)
MeCN (0.4)
MeCN (0.4)
-
-
-
50
50
c
-
17
18
CuBr2 (10)
CuBr2 (10)
MeCN (0.4)
MeCN (0.4)
-
61
c
1,10-phen
-
(0.2)
-
-
19
20
CuCl2 (10)
-
MeCN (0.4)
MeCN (0.4)
57
c
-
a All reactions were performed with 0.1 mmol of 1a with the catalyst
system stated in the Table and exposed to open to air at room
b
temperature for 4 h. All product and recovered substrate yields
were determined by 1H NMR measurements using 2-
c
(bromomethyl)naphthalene as the internal standard. Substrate
recovered in 3 to >99% yield. d Isolated product yield.
was found to have no influence on the outcome of the reaction, with
the product afforded in 70% yield (entry 11). Our investigations
next found lowering the reaction concentration from 0.2 and
0.4 M at a catalyst loading of 10 mol % gave the best result,
providing an isolated product yield of 89% (entry 12). Under
these latter reaction conditions, slightly lower product yields of
50–61% were furnished in the analogous control reactions
mediated by CuCl, CuI, CuCl2 or CuBr2 (entries 14, 15, 17 and
19). However, no reaction could be observed by either TLC
Results and discussion
We began our studies by examining the N-formylation of α-
silylamine 1a, prepared from chlorotrimethylsilane and
piperidine, mediated by a variety of copper salts and air to
determine the optimum reaction conditions (Table 1). This
initially revealed treating a neat solution of the substrate with
20 mol % of CuBr under ambient reaction conditions at room
1
analysis or H NMR measurements of the crude mixtures of
temperature for
4 h gave a mixture of piperidine-1-
control experiments with Cu(MeCN)4PF6 and the 1,10-
phenanthrolinyl complexes of CuBr and CuBr2 (entries 13, 16
and 18). Similarly, a final control reaction in the absence of the
Group 11 metal salt was found to lead to the detection of only
the starting material by TLC analysis and 1H NMR measurements
of the crude mixture (entry 20). On the basis of the above
results, the N-formylation of 1a with CuBr (10 mol %) as the
catalyst in acetonitrile (0.4 M) and open to air at room
temperature for 4 h was deemed to provide the optimum
reaction conditions.
carbaldehyde 2a and the starting material in 55% yield (entry 1).
In contrast, the use of toluene, diethyl ether, THF, ethyl acetate
or acetone as the solvent was found to lead to lower product
yields of 6–37% (entries 2–6). We were pleased to find a higher
product yield of 70% was subsequently obtained on repeating
the control experiment in acetonitrile in place of methanol as
the solvent (entry 7). With acetonitrile as the solvent, the
introduction of CsF, NaHCO3 or Et3N as an additive was found to
result in lower product yields of 19–58% (entries 8–10). On the
other hand, reducing the catalyst loading from 20 to 10 mol %
2 | J. Name., 2012, 00, 1-3
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Attention was next turned to assessing the scope of the we next sought to define the scope of the pVrieewseAnrtticleCOun(liIn)e-
present procedure with a series of N,N-dialkyl α-silylamines 1b– mediated method to access N-formylDatOeI:d10m.10o3r9p/Dh0oGliCn0e12a4n2Dd
l prepared from the corresponding secondary amine and piperazine derivatives (Scheme 2b). With this in mind, the N-
chlorotrimethylsilane, and the results are summarized in formylation of α-silyl-substituted morphine (1m) under the
Scheme 2a. In general, these experiments showed that the CuBr-catalyzed standard reaction conditions was first examined
oxidative CuBr-mediated reaction conditions were broad, and found to give the corresponding cyclic formamide 2m in
furnishing a variety of substituted formamides 2b–k in 62–94% 86% yield. Likewise, the analogous reactions with the mono-
yield from the corresponding substrates. Experiments of α- and bis-α-silyl-substituted piperazine substrates 1n and 1o
silylamines containing a pyrrolidinyl (1b) or azepanyl (1c) ring afforded the corresponding N-formyl amine products 2n and
system instead of a piperidinyl motif were observed to proceed 2oa in respective yields of 89 and 62%. Notably, we were also
well to produce the corresponding N-formyl amines 2b and 2c pleased to find repeating the experiment of 1o under the CuBr-
in respective yields of 92 and 80%. Starting materials in which mediated standard reaction conditions for 8 h provided the
the nitrogen heterocycle was replaced with an acyclic amine diformylated adduct 2ob in 85% yield. This suggested the
with pendant N-alkyl substituents of varying chain lengths (1d– possibility to selectively N-formylate compounds containing
f) or an ethyl and cyclohexyl moiety (1g) were found to have no more than one nitrogen center by fine-tuning the reaction time.
influence on the course of the reaction. In these experiments,
To further illustrate the synthetic utility of the present Cu(I)-
catalyzed N-formylation protocol, the late stage modification of
a variety of α-silyl-substituted natural products and bioactive
molecules were evaluated (Scheme 3). Under the CuBr-
mediated standard reaction conditions, the reaction of the α-
silyl-functionalized synthetic stimulants MeOPP (1p), pCPP (1q),
pFPP (1r), mCPP (1s), DCPP (1t) and BZP (1u) gave the
corresponding formamides 2p–u in 68–90% yield. The
analogous transformation with the L-proline ethyl ester (1v)
and antidepressants paroxetine (1w), nortriptyline (1x) and
fluoxetine (1y) were likewise found to provide the
corresponding aldehyde-containing products 2v–y in 72–78%
the corresponding acyclic N-formylation adducts 2d–g were
furnished in 88–94% yield. N-Phenylethyl-substituted α-
silylamines containing a pendant methyl ester (1h), 1,3-dioxanyl
(1i), allyl (1j) or cyclohexenyl (1k) side-chain were also observed
to provide the corresponding formamides 2h–k in 69–78% yield.
The oxidation of the N-methyl-N-phenyl substrate 1l was found
to be the only exception, which gave a mixture of unidentifiable
decomposition products under the standard reaction
1
conditions at room temperature or –10 °C based on H NMR
measurements.
Scheme 2 CuBr-mediated N-formylation of 1b–o by air. All reactions were
performed with 0.2 mmol of 1 and 10 mol % of CuBr in 0.5 mL of acetonitrile
exposed to air at room temperature for 4 h. Values in parentheses denote
a
isolated product yield. Unknown decomposition products observed based
on 1H NMR measurements of the crude reaction mixture.
Scheme 3 Late-stage CuBr-mediated N-formylation of modified natural
products and bioactive molecules 1p–α by air. All reactions were performed
with 0.2 mmol of 1 and 10 mol % of CuBr in 0.5 mL of acetonitrile exposed to
In view of their role as privileged scaffolds in many bioactive
compounds such the fungicide fenpropimorph, antidepressant air at room temperature for 4 h. Values in parentheses denote isolated
amoxapine and anti-ischemic metabolic agent trimetazidine,
product yield.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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Table 2 Control experiments with 1aa
yield. Finally, the analogous Cu(I)-catalyzed N-formylations of
(S)-duloxetine (1z), serotonin-norepinephrine reuptake
inhibitor, and sertraline (1 ), a selective-serotonin reuptake
inhibitor, were found to afford the corresponding N-formyl
amine adducts 2z and 2 in yields of 88 and 76%, respectively.
View Article Online
DOI: 10.1039/D0GC01242D
a
α
α
Entry Catalyst loading Reaction conditions
(mol %)
Yield (%)b
To gain a better understanding of whether the N-formylation
protocol was more likely to proceed via pathways a or b illustrated
in Scheme 4, the following control reactions were performed (Table
2). In a first set of control experiments, the surmised involvement of
a radical pathway was supported by the introduction of TEMPO (0.5
equiv) to the copper(I)-catalyzed N-formylation of 1a under the
standard reaction conditions for 17 h, which was found to give 2a in
38% yield (entry 1). This was further corroborated by repeating the
control experiment of 1a with 1 or 2 equiv of the radical scavenger
and obtaining the N-carbaldehyde in lower yields of 25 and 19%
(entries 2–3). The role of air providing oxygen as the terminal oxidant
was supported by subjecting 1a to the CuBr-mediated standard
reaction conditions under a nitrogen or oxygen atmosphere (entries
4 and 5). Under a nitrogen atmosphere, this led to the recovery of
the α-silylamine in near quantitative yield based on 1H NMR
measurements. In contrast, the analogous control reaction under an
oxygen atmosphere was observed to produce 2a in 50% yield. In a
second set of control reactions, the CuBr-mediated control reaction
of 1a with 1,4-benzoquinone as an additive gave 2a in 12% yield,
which implied the presence of the superoxide radical anion (entry
6).18 With BHT (0.5 equiv) in place of 1,4-benzoquinone as the
additive, a similar outcome was found, giving a product yield of 17%
along with a derivative of the additive containing a molecule of
oxygen in 12 mg (entry 7). Although the structure of the latter could
not be elucidated by NMR measurements, it’s detection along with
the low product yield provided further evidence of the involvement
of the superoxide radical anion and a radical pathway.19
1
2
3
4
5
6
20
20
20
10
10
10
TEMPO (0.5 equiv)/air 38
TEMPO (1 equiv)/air
TEMPO (2 equiv)/air
N2 atmosphere
25
19
-
O2 atmosphere
50
1,4-benzoquinone (1 12
equiv)/air
7
10
BHT (0.5 equiv)/air
17c
a All reactions were performed with 0.2 mmol of 1a and CuBr at a catalyst
loading and reaction conditions stated in the Table in acetonitrile (0.5
b
mL) at room temperature for 17 h. 1H NMR product yield with 2-
c
(bromomethyl)naphthalene as the internal standard.
Unknown
structure of a BHT derivative containing a molecule of oxygen obtained
in 12 mg based on NMR measurements and mass spectrometry.
82% yield. Moreover, our hypothesis that the succeeding role of
air providing oxygen as part of the formylation reagent was
supported by repeating control reaction with 4 Å molecular
sieves (MS) in distilled acetonitrile and air pre-dried through a
plug of H2SO4, which afforded 2a and 3 in 43 and 46% yield
(entry 2). This was further augmented by performing the control
experiment for a third and fourth time in distilled acetonitrile
containing 1.25 or 10 equiv of H218O in place of 4 Å MS (entries
3 and 4).20 These tests gave 2a and 3 with no incorporation of
the isotope in respective yields of 57 and 48%, or no reaction,
which also indicated that the elimination of the silyl group was
unlikely to occur through nucleophilic attack by water.
Consistent with this are the product yields obtained in the Cu(I)-
catalyzed N-formylations of 1a in methanol, ethyl acetate,
Table 3 Control experiments with 1a
Scheme 4 Mechanistic investigation of the possible N-formylation reaction
Entry Reaction conditions
Yield (%)b
2a/2a‘ 3/3’
pathways.
1
2
3
airc
75/-
80 (82)d/-
4 Å MS (20 mg)/air (dried)
H218O
43/-
46/-
48/-
In a final set of control reactions, the proposed elimination
of the silyl motif as the silanol adduct on generation of the N-
formylated product was shown to be likely by subjecting the
PhMe2Si-substituted substrate 1 to the CuBr-mediated
standard reaction conditions for 17 h (Table 3, entry 1).
Monitoring the control experiment by 1H NMR analysis showed
the gradual formation of the N-formyl amine and PhMe2SiOH
3 in 75 and 80% yield, respectively, with the latter isolated in
(1.25
equiv)/air 57/-
(dried)
4
H218O (10 equiv)/air (dried)
-/-
-/-
a All reactions were performed with 0.2 mmol of 1 and 10 mol %
of CuBr under reaction conditions stated in the Table in distilled
acetonitrile (0.5 mL) at room temperature for 17 h. Air was dried by
passing it through conc. H2SO4 prior to use. b 1H NMR product yield
c
with 2-(bromomethyl)naphthalene as the internal standard.
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d
Reaction performed in non-distilled acetonitrile.
parenthesis denotes isolated product yield.
Value in
alkene, and carboxylic ester. The potential usefulness of the
View Article Online
operationally straightforward synthetic DaOpIp: r10o.a10c3h9/wDa0GsCf0u1r2t4h2eDr
acetone and acetonitrile described in Table 1, entries 2–8. It
might be anticipated that an increase in substrate conversion or
product yield might be expected as the solubility of oxygen from
air increases on going from methanol ([O2]calc = 1.99 mM) to
ethyl acetate ([O2]calc = 2.06 mM) to acetone ([O2]calc = 2.55 mM)
to acetonitrile ([O2]calc = 2.60 mM).21
exemplified by the selective N-formylation of a symmetrical
bis(silyl)-substituted
substrate
and
the
late-stage
functionalization of a series of modified bioactive compounds
and natural products. Our studies additionally hint at the role of
oxygen from air in the aldehyde forming process to be that of
both the terminal oxidant and as part of the formylation
reagent, a mode of reactivity which has remained conspicuously
rare in copper catalysis. We envision that the present synthetic
method will not only provide a practical, sustainable and low-
cost tactic to install the N-formyl group that complements other
amine oxidation strategies to access the compound class but
also a non-photochemically-driven route to access α-amino
radical species as reactive intermediates.
On the basis of the above results, a tentative mechanism for
the present Cu(I)-mediated N-formylation of α-silylamines is
outlined in Scheme 5.11,15–17 This could involve the initial
oxidation of CuBr by molecular oxygen to give the higher
oxidation state [CuII] species along with singlet-state oxygen and
the superoxide radical anion. With 1a as a representative
example, a one-electron redox reaction of the ensuing posited
[CuII]-substrate complex Va via a SET pathway might produce
the nitrogen-centered radical cation Ia and regeneration of the
Cu(I) catalyst. For the analogous reactions catalyzed by CuBr2
and CuCl2 described in Table 1, entries 17 and 19, formation of
the Cu(I) catalyst might arise from coordination of the substrate
with the Cu(II) salt. Subsequent desilylative fragmentation of
this amine radical cation would afford the carbon-centered
Conflicts of interest
There are no conflicts of interest to declare.
Acknowledgements
radical species IIa and trimethylsilyl cation VIa, which can react This work was supported by a Discovery Project Grant
further with the superoxide radical anion to give the peroxysilyl (DP160101682) from the Australian Research Council (to P. W.
radical species IIIa. Coupling of this latter radical species with IIa H. C.) and a China Scholarship Council Visiting Scholar Award (to
would deliver the peroxide adduct IVa, which on deprotonation B. X.).
and desilylation, would provide the product 2a and release of a
molecule of trimethylsilanol 3a.
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Scheme 5 Proposed mechanism for the CuBr-mediated N-formylation of α-
silylamines represented by 1a.
Conclusions
4
5
In summary, we have exploited the intriguing reactivities of α-
silyl-substituted tertiary N-alkylamines in the presence of an
inexpensive copper(I) salt and oxygen from air to prepare N,N-
dialkyl formamides. Achieved under mild reaction conditions at
room temperature with a catalytic system that did not require
a
ligand or additives, the N-formylation protocol was
demonstrated to be chemoselective and tolerate substrates
containing a variety of functional groups such as an acetal,
6
P. G. M. Wuts, Greene’s Protective Groups in Organic
Synthesis, 5th ed., Wiley, Hoboken, NJ, 2014, p. 991.
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J. Name., 2013, 00, 1-3 | 5
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Green Chemistry
Page 6 of 6
ARTICLE
Journal Name
7
Selected examples: (a) L. Panella, A. M. Aleixandre, G. J.
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Synthesis 1996, 37–38.
substituted tertiary N-alkylamines and Cu(II)-Cu(I) systems
were reported to be E1/2 = ca. 0.4 to 0.8 and ca. 0.5 to 0.9 V vs
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8
Selected examples: (a) S. Nakai, T. Yatabe, K. Suzuki, Y.
Sasano, Y. Iwabuchi, J.-Y. Hasegawa, N. Mizuno and K.
Yamaguchi, Angew. Chem. Int. Ed. 2019, 58, 16651–16659 and
references therein; (b) W. Li, W. Liu, D. K. Leonard, J. Rabeah, 15 Selected reviews: (a) K. Nakajima, Y. Miyake and Y.
K. Junge, A. Bruckner and M. Beller, Angew. Chem. Int. Ed.
2019, 58, 10693–10697; (c) H. Yu, Z. Wu, Z. Wei, Y. Zhai, S. Ru,
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Chen and X.-H. Zhang, J. Org. Chem. 2018, 83, 12815–1282; 16 Selected examples: (a) Y. Cai, Y. Tang, L. Fan, Q. Lefebvre, H.
(e) M. R. Mutra, G. K. Dhandabani and J.-J. Wang, Adv. Synth.
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9
Selected examples: (a) X.-D. Li, S.-M. Xia, K.-H. Chen, X.-F. Liu,
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12 The measured oxidation potentials of a variety of amines and
their corresponding α-amino radical species were reported to
be E1/2 = ca. 0.70 to 2.40 and ca. 0.73 to –1.12 V versus the
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6 | J. Name., 2012, 00, 1-3
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