Transition Metal Free Cycloamination of Prenyl Carbamates and Ureas Promoted by Aryldiazonium Salts

Article abstract of DOI:10.1002/anie.201809323

Upon treatment with aryldiazonium salts, prenyl carbamates and ureas undergo redox-neutral azocycloamination. In general, N-aryl O-prenyl carbamates cyclize in a photocatalytic reaction with visible light and an organic dye. With electron-deficient diazonium salts, electronic matching with an electron-rich N-aryl substituent results in a reaction proceeding in the ground state, without either light or photocatalyst. Cyclic voltammetry suggests that this radical reaction is initiated by hydrogen-atom abstraction mediated by an aryl radical, followed by a radical addition cascade and proton-coupled hole propagation. The reaction proceeds at room temperature in short reaction times, and a range of functional groups is tolerated.

Full text of DOI:10.1002/anie.201809323

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Accepted Article
Title: Transition Metal-Free Cycloamination of Prenyl Carbamates and
Ureas Promoted by Aryldiazonium Salts
Authors: Roman Abrams, Quentin Lefebvre, and Jonathan Clayden
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201809323
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10.1002/anie.201809323
Angewandte Chemie International Edition
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Transition Metal-Free Cycloamination of Prenyl Carbamates and
Ureas Promoted by Aryldiazonium Salts
Roman Abrams+, Quentin Lefebvre+, and Jonathan Clayden*
Abstract: On treatment with aryldiazonium salts, prenyl carbamates
and ureas undergo redox-neutral azocycloamination. N-Aryl O-
prenyl carbamates in general cyclize in a photocatalytic reaction with
visible light and an organic dye. With electron-deficient diazonium
salts, electronic matching with an electron-rich N-aryl substituent the
amination reagents such as NFSI, O-acylhydroxylamines or the
Zhdankin reagent, which simultaneously act as two-electron
oxidants.
Knowles has shown that proton-coupled electron transfer
enables oxidation of amides, carbamates and ureas to
reaction to proceed in the ground state, without light or photocatalyst. electrophilic N-centered radicals. A weakly basic but strongly
Cyclic voltammetry suggests that this radical reaction is initiated by
hydrogen atom abstraction mediated by an aryl radical, followed by a
radical addition cascade and proton-coupled hole propagation. The
reaction proceeds at room temperature in short reaction times, and a
range of functional groups is tolerated.
hydrogen-bonding additive significantly lowers the oxidation
potential of the substrate, permitting the use of milder oxidants
such as excited-state iridium photocatalysts. However, this
approach was only applicable to hydro- or carbocycloamination
reactions when the intermediate nucleophilic radical was trapped
by hydrogen atom donors or electron-deficient olefins.[8]
Amination of olefins is an attractive approach to aliphatic
polyfunctionalized molecules, with allylic alcohols and allylic
amines being either feedstock chemicals or easily accessible
synthetically.[1] Intramolecular cyclization of carbamates and
ureas onto a pendent olefin is a convenient way of ensuring
selectivity. For example, treatment of allyl carbamates and ureas
with electrophilic halogen sources leads to regioselective
aminohalogenation of the olefin via a halonium intermediate.[2]
However, this approach is limited both by the lack of reactivity,
and by elimination side-reactions during functional group
interconversions of the halide substituents. Some of these
issues may be avoided using metal catalysts. Pd-catalyzed
carboamination of allyl carbamates and ureas, using aryl halides
as oxidants to form a palladium(II) species, promotes olefin
insertion into the amine-metal bond, followed by reductive
elimination to the arylated product.[3] Hypervalent iodine oxidants
widen the scope of this useful transformation, and enable the
formation of two heteroatom-carbon bonds, resulting in
aminoalkoxylation or aminofluorination of the pendent olefin.[4]
O
O
X = O, NR
R
Proton-coupled
oxidation
R
X
N
X
N
H
Ar
N
N
BH
B
Radical
addition
cascade
e
O
O
R
X
R
N
X
N
•
N
Ar
N
Ar
N
Reduction
N
Scheme 1. Mechanistic rationale for the redox-neutral diamination of allyl
carbamates and ureas with diazonium salts.
In this paper we show that diazonium salts constitute a
class of reagents capable of trapping such intermediate radicals
to form a new C–N bond (Scheme 1). Diazotization of anilines is
straightforward under either aqueous or anhydrous conditions,
making diazonium salts far more accessible than any other
Following
hydroaminations
aminofluorination reactions revealed
Nicolaou’s
of allyl
IBX-mediated
intramolecular
advances in
new mechanistic
carbamates,[5]
a
approach to the difunctionalization of these substrates.
Formation of an N-centred amidyl radical allows 5-exo-trig
cyclisation to an intermediate nucleophilic radical whose reaction
with fluorine atom donors provides aminofluorinated products.[6]
As an extension of this work, copper-mediated diamination
reactions exhibit interesting mechanistic behavior, at the
interface between free-radical chemistry and more standard
polar aminometalation.[7] Unfortunately, these reactions
generally rely on expensive or synthetically remote electrophilic
electrophilic
amination
reagent.
Most
diazonium
tetrafluoroborate salts are stable crystalline solids, indefinitely
stable in the fridge. Although free-radical addition onto
diazonium salts has been known for over 30 years, their full
potential as electrophilic amination reagents has been revealed
only recently. Their reduction requires only mild temperatures, in
the presence of nucleophilic bases, visible-light irradiation, or
weak reductants such as DABSO, and could initiate radical
reactions forming intermediates which would ultimately be
trapped by an additional equivalent of diazonium salt,
terminating the reaction.[9]
[*]
[+]
R. Abrams, Dr Q. Lefebvre, Prof J. Clayden
School of Chemistry, University of Bristol, Cantock’s Close, Bristol,
BS8 1TS, UK
E-mail: j.clayden@bristol.ac.uk
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document
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10.1002/anie.201809323
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COMMUNICATION
in the dark in the absence of photocatalyst gave 5 in an
improved 75% spectroscopic yield (entry 8). This led to the
conclusion that diazonium salts which are more electron-
deficient than the substrate promote direct oxidation or hydrogen
atom abstraction of 1a or 1b even in the ground state. We then
evaluated both sets of conditions using the related prenyl-
substituted urea 6c. Photocatalytic conditions in CH2Cl2 resulted
in low conversion without formation of the expected product 7b
(entry 9). In stark contrast, a 75% yield was obtained in DMSO
in the dark (entry 10). This unprecedented reactivity, apparently
arising from the interaction of the prenyl urea and the diazonium
salt in their electronic ground states, is remarkable, so we turned
to exploiting its generality.[11]
Table 1. Initial investigations using carbamates
Ar2
N
N
O
O
BF4 2 (2 equiv)
4DPAIPN (x mol%)
(NBu4)PO2(OBu)2 (2 equiv)
Ar1
O
N
H
O
N
Ar1
N
Ar2
CH2Cl2 (0.2 M), 15 h
blue LEDs
N
2a: Ar2 = p-MeOC6H4
2b: Ar2 = p-FC6H4
2c: Ar2 = p-CF3C6H4
1a: Ar1 = Ph
1b: Ar1 = p-MeOC6H4
3-5
Product,
Entry
Substrate
x mol% 4DPAIPN
Ar2
yield / % [a]
1
1a
6
p-CH3OC6H4
p-CH3OC6H4
p-CH3OC6H4
p-CF3C6H4
p-CF3C6H4
p-CF3C6H4
p-FC6H4
3, 74%
Table 2. Optimisation of the reaction conditions using urea substrates
O
0[b]
3, 47%
O
2
1a
ArN2BF4 2 (2 equiv)
base (2 equiv)
PMP
PMP
PMP
PMP
N
N
H
0, in the dark[b,c]
3, <10%
4, 62%
N
N
3
1a
N
N
Ar
DMSO (0.1 M)
r.t., time t
4
1a
6
6c
7
5
1a
0[b]
4, 69%
Product,
Entry
Ar
Base
t
yield / %[a]
6
1a
0, in the dark[b,c]
4, 38%
7
1b
3
5, (57%)[e]
5, (75%)[e]
No product
7b, 75%
1
p-CH3OC6H4
p-FC6H4
(NBu4)PO2(OBu)2
(NBu4)PO2(OBu)2
(NBu4)PO2(OBu)2
LiPO2(OBu)2
NaPO2(OBu)2
KPO2(OBu)2
Li3PO4
17 h
17 h
2 h
7a, < 30%
7b, 75%
7c, 77%
7c, 84%
7c, 84%
7c, 75%
7c, 72%
7c, 56%
7c, 83%[b]
7c, 67%
8
1b
0, in the dark, DMSO[b-d]
p-FC6H4
2
3
p-CF3C6H4
p-CF3C6H4
p-CF3C6H4
p-CF3C6H4
p-CF3C6H4
p-CF3C6H4
p-CF3C6H4
9
Urea 6c
Urea 6c
3
p-FC6H4
0, in the dark, DMSO[b-d]
p-FC6H4
4
30 min
30 min
30 min
17 h
10
5
[a] Reactions performed on 0.1 or 0.2 mmol scale (see supporting information).
Yields of isolated products. [b]No photocatalyst added. [c]No irradiation.
[d]DMSO as solvent instead of CH2Cl2. [e]Yields in brackets are spectroscopic
yields determined by 19F NMR using trifluorotoluene as internal standard.
4DPAIPN = 1,3-dicyano-2,4,5,6-tetrakis(N,N-diphenylamino)benzene.[10]
6
7
8
Na3PO4
17 h
9
NaPO2(OBu)2
15 min
30 min
We began our study by submitting N-phenyl O-prenyl
carbamate 1a to Knowles' photoredox catalysis conditions, in the
presence of a diazonium salt. Neutral organic dyes 4CzIPN (1,3-
dicyano-2,4,5,6-tetrakis(carbazole)-benzene) and 4DPAIPN
(1,3-dicyano-2,4,5,6-tetrakis(N,N-diphenylamino)-benzene) were
used as cheaper alternatives to iridium photocatalysts.[10] Upon
irradiation with blue LED, 1a and diazonium salt 2a gave the
coupling product 3 in 74% and 47% yield in the presence and
absence of photocatalyst, respectively (Table 1, entries 1 and 2).
There was almost no conversion in the dark and in the absence
of photocatalyst (entry 3). This shows that a purely photoinduced
reaction between the two substrates, without intervention of
4DPAIPN as redox mediator, is operative to some extent.
Very different results were obtained using the electron-
deficient diazonium salt 2c. Although best yields of product 4
were obtained on irradiation, with or without the photocatalyst
(entries 4-6), significant background reaction occurred even in
the dark. To further investigate this peculiar behavior, we used
electron-rich carbamate 1b in combination with an electron-
neutral diazonium salt 2b and obtained the expected product 5
in 57% spectroscopic yield under photocatalytic conditions (entry
7). Switching the solvent to DMSO and performing the reaction
[c]
[c]
10
p-CF3C6H4
NaPO2(OBu)2
[a]Isolated yield from reaction of 6c (0.1 mmol, 34 mg), diazonium salt (2
equiv., 0.2 mmol) and base (2 equiv., 0.2 mmol) under nitrogen in dry,
degassed DMSO (0.1 M, 1 mL). [b]Reaction carried out with starting material at
0.2 M concentration. [c]1.5 equiv. PMP = p-methoxyphenyl.
Upon treatment of 6c with 2a, 1H NMR gave evidence that
the triamine derivative 7a was formed (Table 2, entry 1), but only
in low yield even after 17 h. More electron-deficient partners 2b
and 2c coupled more successfully (entries 2 and 3). Screening a
series of bases (entries 4-8) established that the more soluble
sodium dibutylphosphate was optimal, and allowed the reaction
to be run at greater concentration. Full conversion of 2c to 7c
was achieved in only 15 min (83% isolated yield, entry 9).
Reducing the amounts of diazonium salt and base below 2 equiv.
led to lower, but still synthetically useful, yields (entry 10).
Commercially available lithium phosphate is a more readily
available and scalable alternative (entry 7).
Having identified the optimal conditions for this redox-
neutral azocycloamination reaction, we explored its scope
(Table 3). Variation of the N-substituent of the N-aryl urea
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10.1002/anie.201809323
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showed that a range of para- and meta-, but not ortho-
substituents, were well tolerated (7c-n).[12] Halo-substituted
substrates gave the products 7f-h in good yields, as did nitriles,
esters and acetamides (7k, l, n), and the medicinally important
trifluoromethoxy group of 7j.
accessible 2-alkenyl benzamide 16 gave isoindolinone 17 in
good yield.[13]
O
O
p-CF3C6H4N2BF4 (2 equiv)
NaPO2(OBu)2 (2 equiv)
R
R
O
N
H
O
N
Ar
N
R1
R2
R1
DMSO (0.2 M)
30 min
N
R2
Table 3. Substrate scope of the diamination of ureas.
R3
4 Ar = p-CF3C6H4
R
O
R3
R4
O
p-CF3C6H4N2BF4 2c (2 equiv)
NaPO2(OBu)2 (2 equiv)
R
PMP
R
PMP
N
N
H
N
N
O
OMe
O
O
OMe
N
N
Ar
DMSO (0.2 M)
30 min
O
N
O
N
O
O
N
p-OMe: 8 67%
m-OMe: 9 57%
o,p-diOMe: 10 54%
6
7
11 49%
Ar
4 24%
N
N
N
Ar = p-CF3C6H4
Ar
Ar
N
N
N
Entry
1
Starting material, R
6c, p-CH3OC6H4
6d, C6H5
Product, yield / %[a]
7c, 83%
7d, 76%
7e, 87%
7f, 57%
O
O
OMe
O
O
N
N
PMP
O
OMe
N
N
N
2
N
X
HN Ar
N
3
6e, m-CH3C6H4
6f, p-FC6H4
X = CH2: 14 60%
X = O: 15 59%
CF3
HN
12 45%, 6:1 d.r.
13 49%
Ar
4
O
O
PMP
5
6g, p-ClC6H4
7g, 80%
7h, 76%
7i, 65%
p-CF3C6H4N2BF4 (2 equiv)
NaPO2(OBu)2 (2 equiv)
PMP
N
H
N
6
6h, p-BrC6H4
N
N
DMSO (0.2 M)
30 min
16
Ar
17 77%
7
6i, p-CH3SC6H4
6j, p-CF3OC6H4
6k, m-tBuO2CC6H4
6l, p-NCC6H4
Scheme 2. Extended substrate scope of the diamination. Yields of isolated
products. PMP = p-methoxyphenyl.
8
7j, 62%
9
7k, 59%
7l, 78%
10
11
12
13
14
15
Deprotection of the acid-sensitive products required stepwise
partial neutral reduction to the hydrazine followed by hydrazine
cleavage with acid (Scheme 3). 18, 20 and 21 were isolated
after a Boc- or Ts-protection. Basic hydrolysis of 18 gave the
diamino-alcohol 19; CAN-mediated deprotection of 21 gave the
urea 22.
6m, m,m’-diCH3OC6H3
6n, p-AcNHC6H4
6o, benzyl
7m, 67%
7n, 72%
7o, 61%
7p, 62%
7q, 56%
6p, n-butyl
O
6q, cyclopropyl
PMP
HO
HN
PMP
(iii)
O
N
Isolated yield from reaction of 6 (1 equiv., 0.2 mmol), p-trifluoromethylphenyl
diazonium tetrafluoroborate 2c (2 equiv., 0.4 mmol, 104 mg) and base (2
equiv., 0.4 mmol, 93 mg) under nitrogen in dry, degassed DMSO (0.2 M, 1
mL). PMP = p-methoxyphenyl.
NHTs
19 93%
X = O
(i), (ii)
NHTs
18 53%
O
O
N-Alkyl ureas were likewise cyclized successfully to the
triamine derivatives 7o-q, though yields were slightly lower, and
the products were acid-sensitive. Azocycloamination of
carbamates allows the use of allylic alcohols as precursors of
diamino alcohol derivatives, and a series of N-aryl O-prenyl
carbamates 1 were made and treated under the same reaction
conditions (Scheme 2). These carbamates also cyclized
successfully to products 4, 8, 9 and 10, with the best yields
being obtained from substrates with electron-rich N-substituents.
Cyclohexane-containing products 11 and 12 could be obtained
in moderate yields. Among mono- and disubstituted alkenes,
only α,α-disubstituted crotyl carbamates gave a product, as a
mixture of isomers. These isomerised to the single hydrazones
13-15 in acid. The carbamate linkage was not essential: easily
PMP
PMP
PMP
(i), (iv)
X
N
N
N
N
NHBoc
20 62%
Ar
N
O
O
X = NPMP
(i), (ii)
(v)
PMPN
HN
NPMP
NH
NHTs
NHTs
21 67%
22 63%
Scheme 3. Deprotection of the products, see supporting information for details.
(i) Pd/C, H2, MeOH, then HClaq; (ii) NEt3, TsCl, DCM; (iii) NaOH, EtOH; (iv)
K2CO3, Boc2O, DCM/H2O; (v) cerium ammonium nitrate, MeCN/H2O. PMP =
p-methoxyphenyl.
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10.1002/anie.201809323
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The mechanism of the reaction was investigated using the
reaction between 6c and 2c as a model (see full details in the
supplementary information). When the reaction in Table 3 entry
Radical addition of an amidyl radical onto an olefin, and
radical addition of a tertiary alkyl radical onto a diazonium ion
are both precedented, as discussed above. Remarkably, cyclic
voltammetry experiments showed that product 7c has a first
oxidation potential of 1.26 V, which is higher than that of 6c in
the absence or presence of base. Thus, 'hole catalysis' appears
to be responsible for the propagation of the reaction: a radical
cation intermediate resulting from the addition onto 2c oxidizes a
molecule of 6c to generate the product and an amidyl radical
intermediate ready for cyclization.[17] We therefore propose that
the reaction follows the mechanism depicted in Scheme 4.
1
was performed in the presence of 2 equiv. 2,2,6,6-
tetramethylpiperidine 1-oxyl (TEMPO), the only product was 1-
(2,2,6,6-tetramethylpiperidinyloxy)-4-trifluoromethylbenzene,
even in the absence of 6c. When dissolved in moist DMSO-d6,
2c slowly and cleanly decomposed to 4-trifluoromethylphenol
over 48 h. In contrast, with NaPO2(OBu)2, there was significant
decomposition of 2c to trifluorotoluene and its derivatives, with
only small amounts of 4-trifluoromethylphenol, within 3 h. This
reaction occurred even more rapidly in the presence of a urea
lacking an alkene (1,3-bis(4-methoxyphenyl)-1-methylurea: see
supporting information). These experiments are consistent with
the initiation step of the reaction being base-mediated
decomposition of 2c to the corresponding aryl radical, with the
diazonium salt and/or the aryl radical interacting with the urea,
by electron transfer, hydrogen atom abstraction or charge
transfer.
Cyclic voltammetry in DMSO using Bu4NPF6 as electrolyte
revealed that NaPO2(OBu)2 is not redox active within the
solvent’s electrolysis range, and diazonium salt 2c has a
reduction potential of –0.33 V vs Ag+/Ag (0.170 V open circuit
potential) which does not change upon addition of base. The
urea starting material 6c has an oxidation potential of 1.21 V,
decreasing to 1.06 V in the presence of 3.8 equivalents of base,
in line with Knowles’ previous reports.[8]
O
O
initiation
R
R
X
N
H
ArN2BF4
X
N
B–
O
R
X
N
proton-coupled
hole catalysis
product
O
O
R
X
N
H
R
X
N
ArN2BF4
+•N
N
Ar
B–
Scheme 4. Proposed reaction mechanism
In conclusion, the use of diazonium salts as both oxidants
and radical acceptors leads to a new transition metal-free
azocycloamination reaction of prenyl carbamates and ureas by
intramolecular radical attack of an amidyl radical on an alkene.
The diamination tolerates a range of functional groups, and
generally proceeds in high yields, provided the amidyl radical
bears an N-p-methoxyphenyl substituent. The reaction is atom-
efficient and easy to perform, and the products are obtained in
short reaction times under concentrated conditions. Cyclic
voltammetry identified a likely reaction mechanism involving
proton-coupled hole catalysis, with a visible light-promoted
diamination reaction providing an alternative method for
otherwise unreactive substrates. Further ground state electron-
transfer promoted reactions involving ureas are under
investigation and will be reported in due course.
Figure 1. Overlaid cyclic voltammograms of 6c (▲, 3.0 mM), a mixture of 6c
and NaPO2(OBu)2 (♦, 3.0 mM and 11.5 mM respectively) and 7c (■, 2.0 mM)
in DMSO containing 0.1 M NBu4PF6. Ag reference electrode, glassy carbon
working electrode, Pt mesh counter electrode were used. Scan rate: 0.1 V/s.
Oxidation of 6c by 2c is therefore thermodynamically
unfavorable in the ground state, even in the presence of base.
Additionally, the fact that the reaction proceeds in the dark, in a
highly polar and dissociating solvent, further suggests a ground
state reactivity.[14] We therefore propose that the reaction is
initiated by decomposition of 2c to an aryl radical, which
Acknowledgements
We thank Gaël Gobaille-Shaw and Prof. David Fermin for
assistance with cyclic voltammetry experiments. The work was
supported by the Deutsche Forschungsgemeinschaft (research
fellowship LE 3853/1-1 to QL), and the EPSRC Centre for
Doctoral Training in Catalysis.
abstracts
a
hydrogen atom from 6c.[15] Electron-deficient
diazonium salts decompose simply in the presence of base,[9f]
while electron-rich diazonium salts require additional activation
by light.[16]
Keywords: amination • carbamate • diazonium salt • radical
chemistry • urea
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10.1002/anie.201809323
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[13]
A
diastereoselective cyclisation was achieved using
a sulfinamide
auxiliary: see supporting information..
[14] The formation of a charge-transfer complex was difficult to investigate
by UV-Vis spectroscopy due to the formation of highly colored
unidentified decomposition products derived from 2c.
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10.1002/anie.201809323
Angewandte Chemie International Edition
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
Arenediazonium salts promote the
azocycloamination of prenyl
carbamates and ureas by acting both
as oxidant and radical trap in a mild,
metal-free and redox-neutral
cascade sequence.
Roman Abrams, Quentin
Lefebvre, and Jonathan Clayden*
O
O
R
X
N
X
N
R
Page No. – Page No.
Transition Metal-Free
Cycloamination of Prenyl
Carbamates and Ureas
Promoted by Aryldiazonium
Salts
N2
Hydrogen Atom
Transfer
Amination
F3C
O
O
R
X
X = O, NR
X
N
N
R
H
N
Ar
Metal free • mild • room temp
>20 examples
N
This article is protected by copyright. All rights reserved.