The Hydrazine–O2 Redox Couple as a Platform for Organocatalytic Oxidation: Benzo[c]cinnoline-Catalyzed Oxidation of Alkyl Halides to Aldehydes

Article abstract of DOI:10.1002/anie.201807134

An organocatalytic oxidation platform that capitalizes on the capacity of hydrazines to undergo rapid autoxidation to diazenes is described. Commercially available benzo[c]cinnoline is shown to catalyze the oxidation of alkyl halides to aldehydes in a novel mechanistic paradigm involving nucleophilic attack, prototropic shift, and hydrolysis. The hydrolysis and reoxidation events occur readily with only adventitious oxygen and water. A survey of the scope of viable substrates is shown along with mechanistic and computational studies that give insight into this mode of catalysis.

Full text of DOI:10.1002/anie.201807134

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Accepted Article
Title: The Hydrazine- O2 Redox Couple as a Platform for
Organocatalytic Oxidation. Benzo[c]cinnoline-Catalyzed
Oxidation of Alkyl Halides to Aldehydes.
Authors: Ilana B Stone, Janis Jermaks, Samantha N MacMillan, and
Tristan Hayes Lambert
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201807134
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10.1002/anie.201807134
Angewandte Chemie International Edition
COMMUNICATION
The Hydrazine- O2 Redox Couple as a Platform for
Organocatalytic Oxidation. Benzo[c]cinnoline-Catalyzed
Oxidation of Alkyl Halides to Aldehydes.
Ilana B. Stone,[a] Janis Jermaks,[b] Samantha N. MacMillan,[b] and Tristan H. Lambert*[a,b]
Abstract: An organocatalytic oxidation platform that capitalizes on
the capacity of hydrazines to undergo rapid autoxidation to diazenes
is described. Commercially available benzo[c]cinnoline is shown to
catalyze the oxidation of alkyl halides to aldehydes via a novel
mechanistic paradigm involving nucleophilic attack, prototropic shift,
and hydrolysis. The hydrolysis and reoxidation events occur readily
with only adventitious oxygen and water. A survey of the scope of
viable substrates is shown along with mechanistic and computational
studies that give insight into this mode of catalysis.
isomerization of the diazenium would then reveal a hydrazinium
intermediate (5), which would be prone to hydrolysis to furnish a
carbonyl product (6) along with the reduced catalyst (2). Finally,
facile autoxidation (2"1) would close the catalytic cycle. In this
Communication, we describe the first realization of this concept
in the context of an organocatalytic oxidation of organohalides to
aldehydes using benzo[c]cinnoline (BCC),
a commercially
available diazene known to be exceptionally difficult to maintain
in its reduced form (Figure 1C). [12,13]
The controlled oxidation of organic molecules is an essential
capability for chemical synthesis, and the development of
efficient and selective catalytic oxidation strategies is thus an
important goal. Catalytic oxidants that utilize molecular oxygen
as the stoichiometric electron sink are particularly desirable,
since O2 is free and the ultimate reduction by-product is water.
Indeed, a number of powerful O2-coupled oxidation platforms
have been developed that use transition metal catalysts (e.g. Cu,
Pd).[1] Oxidation platforms based on organic catalysts[2] are also
of high interest, both for reasons of mechanistic diversity and
because of the practical advantages that non-metal technologies
can offer.[3 ] Notable examples of organocatalytic O2-coupled
oxidants include quinones,[ 4 ] flavins,[ 5 ] nitroxyl radicals,[ 6 ]
hypervalent iodine, [7] and perguanidinylated arenes.[8] However,
because of the difficulties inherent in the direct oxidation of
organic molecules with molecular oxygen (autoxidation),[9] many
of these platforms rely on a metal co-catalyst to facilitate the
redox couple. Organocatalysts that achieve both substrate
oxidation and O2 reduction are relatively rare, and the
development of such platforms, especially those that operate via
unique mechanistic paradigms, is a compelling goal.
A. Hydrazine - dioxygen redox couple
2e–, 2H+
R
H
R
H
R
R
N
N
N
N
1
2
O2
rapid and
spontaneous
diazene
hydrazine
B. Blueprint for diazene-catalyzed oxidations
H2O2
(H2O)
R
R
N
R’
X
N
reoxidation
3
1
nucleophilic
attack
catalyst
O2
(H2O2)
R
R
R
+
R
H
X–
R'
N
N
H
N
H
N
2
4
R’
O
6
prototropic
shift
R
R
+
hydrolysis
X–
N
H
N
H2O
R'
5
Toward this goal, we took note of the fact that 1,2-
disubstituted hydrazines (2) are well known to undergo facile
autoxidation to generate diazenes (1, Figure 1A).[ 10 ] We
recognized that a process involving diazene–mediated oxidation
of a substrate[ 11] along with spontaneous re-oxidation of the
resulting hydrazine (2) would represent a novel and rare direct
organocatalytic O2-coupled oxidation. One blueprint for this type
of transformation is outlined in Figure 1B. Thus, diazene catalyst
(1) would be alkylated by an electrophilic substrate (3) to
C. This work: benzo[c]cinnoline-catalyzed oxidation of alkyl halides
catalytic
BCC
N
N
R’
R’
X
O
O2, H2O
3
6
Figure 1. A. Reduction of diazenes and the autoxidation of hydrazines as a
platform for catalytic oxidation. B. Generic blueprint for diazene-catalyzed
oxidation of electrophilic substrates. C. Organocatalytic, direct O2-coupled
oxidation of alkyl halides.
generate
a
diazenium intermediate (4).
Prototropic
[a]
[b]
I. B. Stone, Prof. T. H. Lambert
Department of Chemistry
The oxidation of alkyl halides to aldehydes has long been
Columbia University, New York, NY 10027, USA
E-mail: Tristan.lambert@cornell.edu
Dr. J. Jermaks, Dr. S. N. MacMillan, Prof. T. H. Lambert
Department of Chemistry and Chemical Biology
Cornell University, Ithaca, NY 14853, USA
]
achieved by a variety of stoichiometric oxidants.[14 ,15
For
example, the Kornblum oxidation employs simple and readily
available materials (DMSO, Et3N), but is therefore also limited
in its capacity for optimization.[15] In particular, the generation
of sulfide byproducts can complicate reaction mixtures, and
modification of the sulfoxide is impractical because of its
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201807134
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COMMUNICATION
stoichiometric nature. Alternative methods have been developed, conditions with 10 mol% catalyst, 30% conversion to
most notably with the use of hexamine and water (Sommelet
benzaldehyde was observed; however, the majority of the
substrate was converted to benzyl alcohol (68%) due to the
amount of water present in the reaction (7%). This result
suggests that H2O2 is indeed a viable oxidant for hydrazine
reoxidation, although it is slower than O2 under the current
conditions.
[14a,b]
oxidation)
or the use of trialkylamine N-oxides (Ganem
oxidation). [14c] However, catalysis of such oxidations has proven
to be very challenging. [16] We describe herein an organocatalytic
alkyl halide oxidation that proceeds via the catalytic cycle shown
in Figure 1B.
Under optimal conditions, treatment of benzyl bromide with
10 mol% BCC in DMF at 80 °C in an open flask resulted in full
conversion to benzaldehyde after 18 hours (Table 1, entry 1).
Notably, adventitious water and oxygen were sufficient to
achieve catalytic turnover. The effects of deviation from this
optimal procedure are shown in Table 1. Lower temperature
resulted in dramatically reduced conversion (entry 2), while
rigorous exclusion of water led to no reaction (entry 3), and
addition of significant amounts of water to the reaction mixture
was also detrimental (entries 4–6), primarily because of the
competing hydrolysis of the substrate to benzyl alcohol.
Importantly, no reaction was observed in the absence of BCC
(entry 7), and while reaction did occur with lower catalyst
loadings, conversion after 18 h was diminished accordingly
(entries 8–9). Strictly anaerobic conditions were also found to
prohibit catalyst turnover, with conversion limited to the amount
of BCC added (entry 10).
Because the reaction generates one equivalent of HBr, we
found it curious that the rate of product formation did not
diminish as the reaction progressed. In fact, addition of base
was detrimental to the reaction, although more hindered bases,
such as 2,6-di-tert-butyl-4-methylpyridine (dtbmp) and Hünig’s
base, still allowed for good conversion (entries 11–12). We
attribute this phenomenon to the fact that the pKa of protonated
BCC[12a,18] is similar to that of DMF itself; thus, the catalytically
active unprotonated BCC is presumably maintained in DMF
solution.[19 ] In other solvents, however, additional base was
necessary to achieve useful levels of conversion. For example,
in CH3CN without base, no turnover was observed (entry 13),
whereas addition of dtbmp or Hünig’s base led to catalytic
turnover, with the former providing optimal levels of conversion
(entries 14–15). Our subsequent substrate scope studies were
generally run in DMF under the optimized conditions shown in
entry 1; however, sensitive substrates were often more
amenable to the CH3CN/dtbmp conditions shown in entry 14.
While alkyl bromides worked well under these conditions,
alkyl chlorides reacted very sluggishly if at all (eq 1). To remedy
this issue, we found that the addition of 1 equiv. of sodium iodide
resulted in efficient conversion of these substrates, undoubtedly
due to in situ conversion to the more reactive alkyl iodides.
Table 1. Catalyst optimization studies.a
catalytic BCC
Br
O
N
N
air, 18 h
BCC
10 mol%
entry
solvent
temp (ºC) mol% BCC
H2O (%)
baseb
conv (%)
N
N
1
NaI (equiv) conv. (%)
Cl
1
2
3c
4
5
6
7
8
80
50
80
80
80
80
80
80
80
80
80
80
80
80
80
80
10
10
10
10
10
10
0
-
-
-
-
-
-
-
-
-
-
99
17
0
80
65
6
0
50
12
10
30 (N2)
93
80
12
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
CH3CN
CH3CN
CH3CN
(1)
O
DMF
80 ºC, 18 h
0
1
6
96
F3C
F3C
0
4
10
20
-
-
-
-
7
-
-
-
-
-
7
8
Using the optimal conditions described above, we explored
5
1
the substrate scope of the catalytic Kornblum reaction (Table 2).
In addition to benzaldehyde (entry 1), 4-bromo- and 4-
fluorobenzaldehyde were produced with good efficiency (entries
2 and 3). A strongly electron-withdrawing 4-trifluoromethyl group
was well-tolerated (entry 4). Moreover, o-tolualdehyde was
generated in good yield (entry 5), demonstrating that at least
modest steric crowding can be accommodated. In general,
installation of halogens and nitro groups on the aromatic ring
resulted in high conversion and isolated yield (entries 6 and 7),
likely because these groups facilitate both the alkylation and
tautomerization events. Indeed, a wide range of aromatic and
heteroaromatic aldehydes was readily accessible from the
corresponding chloride and bromide precursors, including m-
methoxybenzaldehyde (entry 8), p-thiomethoxybenzaldehyde
(entry 9), thiophenyl aldehyde (entry 10), furanyl aldehydes
(entries 11 and 12), and naphthaldehyde (entry 13). Multiple
oxidations of the same substrate proved feasible, with the
formation of the 1,3,5-benzenetricarboxaldehyde occurring in
9
-
-
-
10d
11d,e
12
13
14
15
16
10
10
10
10
10
10
10
(N2)
(H2O2)
dtbmp
i-Pr2NEt
-
dtbmp
i-Pr2NEt
99
51
[a] Reactions in DMF were heated in small vials open to atmosphere, and
reactions in CH3CN were heated in roundbottom flasks fitted with reflux
condensers open to atmosphere. [b] For entries 12, 13, 15, and 16 one
equivalent of base was added. [c] Heated in a small, flame-dried vial under an
O2 balloon. [d] Heated in a small evacuated vial under a flow of N2. [e] 1
equivalent aqueous H2O2 was added, resulting in 7% H2O content.
In order to probe whether H2O2 is a viable oxidant in this
process – and thus whether the full O2 to H2O redox couple is
operative[17] – we ran an experiment wherein O2 was replaced
with
1 equivalent aqueous H2O2 (entry 11). Under these
moderate yield (entry 14).
An allylic substrate, cinnamyl
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10.1002/anie.201807134
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COMMUNICATION
bromide, was amenable to oxidation, leading to cinnamaldehyde
with good efficiency (entry 15). Other allylic substrates (e.g.
geranyl bromide), however, did not cleanly lead to aldehyde
products (not shown). Finally, hydrocinnamyl bromide
participated in this reaction, albeit without catalyst turnover
(entry 16). The fact that this substrate works to some extent
suggests that generalization to the more challenging aliphatic
class of substrates should be possible.
is therefore rate-limiting. Indeed, the success of the sodium
iodide experiment (eq 1) supports this notion. From this analysis,
it can be predicted that structural modifications to the catalyst
that facilitate the alkylation step (e.g. electron-donating
substituents) should accelerate the overall reaction rate.
In order to provide experimental evidence in support of the
proposed mechanism, we conducted the series of reactions
shown in Scheme 1. Thus, BCC and benzyl chloride were
mixed in dry, oxygen-free CH2Cl2 in the presence of AgOTf,
during which time the solution changed from light to dark yellow.
The production of N-benzyl benzocinnolinium triflate (25) was
confirmed by X-ray analysis. Subsequent treatment of 25 in
DMF with Hünig’s base resulted in a deep purple solution.
Although the in situ 1H NMR spectrum of this mixture was
complicated, we attribute this dramatic color change to the
formation of the 1,3-dipole 26.[21] Addition of 1N HCl to this
solution caused a change in color from dark purple to clear
orange with the accompanying formation of benzaldehyde and
dihydro-BCC (2). This progression through the intermediate
stages of the reaction pathway in a stepwise fashion offers
substantial evidence in favor of the proposed mechanism and
underscores the extent to which water and oxygen fuel the
catalytic cycle.
Table 2. Scope studies for benzo[c]cinnoline-catalyzed Kornblum oxidation.a
10 mol% BCC
R
R
X
O
N
N
80 ºC, solvent, air
conditionsa–c
BCC
(1)a,d
(2)a,d
(3)b,d
(4)b,d
O
O
O
O
F
Br
F3C
9
10
11
8
99% conv
62% yield
98% conv
80% yield
98% conv
89% yield
97% conv
82% yield
(5)b,d
(6)b,e
(7)b,d
(8)a,e
Me
O2N
Cl
MeO
O
O
O
O
Cl
12
90% conv
82% yield
13
14
15
98% conv
85% yield
96% conv
87% yield
84% conv
78% yield
(10)b,e
(11)b,e
(12)c,e
(9)a,e
H
+25.5 kcal/mol
N
N
Br
Ph
S
O
O
O
Cl
MeO2C
O2N
H
O
O
O
19
83% conv
MeS
24
16
90% conv
87% yield
17
18
82% conv
60% yield
78% conv
64% yield
80% yield
+ H2O
(13)a,e
(14)a,e
O
(15)c,e
(16)c,e
Br–
Ph
+12.5 kcal/mol
N
+
N
26
H
O
O
O
+14.9 kcal/mol
O
O
20
21
22
23
35% conv
31% yield
92% conv
87% yield
66% conv
52% yield
69% conv
63% yield
HBr
N
N
2
H
H
0.0
+ PhCHO
[a] X = Br; Reactions run in DMF without additional base. [b] X = Cl; Reactions
were run in DMF with 1 equiv. NaI. [c] X = Br: Reactions were run in CH3CN
with 1 equiv. dtbmp. In many cases, aldehyde isolation and purification can
lead to significant loss of material, so both conversion and yield are reported in
this table. Conversion of the halide was determined by NMR using an internal
standard, while yield was determined by either [d] isolation of the acetal
following addition of ethylene glycol or [e] isolation of the aldehyde product.
–2.0 kcal/mol
+ BnBr
N
N
BCC
Br–
Ph
+
N
H
N
25
Figure 2. Gibbs free energy change for presumed reaction pathway.
Calculations were performed at the B3LYP/6-311++G**/PCM(DMF) level of
theory.
To gain further insight into the energetics of this catalysis,
we calculated the free energy change for each of the presumed
steps of our catalytic cycle using benzyl bromide as the
substrate (Figure 2). Alkylation to form the benzocinnolinium
intermediate 25 was found to be nearly thermoneutral, although
the activation energy for this step was significant (25.5 kcal/mol).
Tautomerization to the hydrazinium 26 was calculated to be
endothermic by 12.5 kcal/mol, and the subsequent hydrolysis to
generate dihydro-BCC 2 required a small further energy input.
Because of the numerous pathways by which the
tautomerization and hydrolysis events might occur, it is difficult
to calculate with confidence the activation energies for these
steps.[ 20 ] Nevertheless, we suspect that under the reaction
conditions both are relatively facile, and that the alkylation step
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10.1002/anie.201807134
Angewandte Chemie International Edition
COMMUNICATION
18, 5174-5177; e) A. E. Wendlandt, S. S. Stahl, J. Am. Chem. Soc.
2014, 136, 506-512.
BnCl
AgOTf
N
N
[5]
For selected examples of flavin-catalyzed aerobic oxidations, see: a) H.
Iida, Y. Imada, S. I. Murahashi, Org. Biomol. Chem. 2015, 13, 7599-
7613; b) S. Chen, F. W. Foss, Jr., Org. Lett. 2012, 14, 5150-5153; c) Y.
Imada, T. Kitagawa, T. Ohno, H. Iida, T. Naota, Org. Lett. 2010, 12, 32-
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4986-4989; e) R. Ohkado, T. Ishikawa, H. Iida, Green Chem. 2018, 20,
984-988.
CH2Cl2
rt
BCC
25
54% yield
(DMF)
1N HCl
i-Pr2NEt
DMF
rt
N N
+
N
N –
H
H
26
Ph
2
[6]
[7]
[8]
[9]
M. Shibuya, Y. Osada, Y. Sasano, M. Tomizawa, Y. Iwabuchi, Y. J. Am.
Chem. Soc. 2011, 133, 6497-6500.
+
PhCHO
For example: A. Maity, S.-M. Hyun, D. C. Powers, Nature Chem. 2018,
10, 200-204.
Scheme 1. Stepwise progression through the intermediates of the catalytic
cycle.
U. Wild, F. Schön, H.-J. Himmel, Angew. Chem. 2017, 129, 16330-
16333; Angew. Chem. Int. Ed. 2017, 56, 16410-16413.
a) W. T. Borden, R. Hoffmann, T. Stuyver, B. Chen, J. Am. Chem. Soc.
2017, 139, 9010-9018; b) M. Filatov, W. Reckien, S. D. Peyerimhoff, S.
Shaik, J. Phys. Chem. A. 2000, 104, 12014-12020.
In conclusion, we have introduced a platform for catalytic O2-
coupled oxidation that makes use of a novel mechanistic
paradigm. The ability of BCC to undergo nucleophilic attack,
1,3-prototropic shift, and hydrolysis has enabled the
development of a mechanistically-unique catalytic oxidation of
alkyl halides. We expect that this organocatalytic oxidation
strategy should be applicable to a variety of transformations
involving other electrophiles. More generally, the heretofore
underutilized autoxidation of hydrazines may prove to be a
useful platform for controlled oxidation.
[10] For example, see: a) M. G. Lazzara, J. J. Harrison, M. Rule, E. F.
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Trans. I 1998, 3917-3920. b) S. Polanc J. Heterocyc. Chem. 2005, 42,
401-412.
Acknowledgements
Financial support for this work was provided by the National
Science Foundation (CHE-0953259). IBS thanks Professor
Xavier Roy for mentorship and helpful conversations. We thank
Rebecca Wilson for assistance in the preparation of the
manuscript.
[12] a) J. W. Barton, Benzo[c]cinnolines Advances in Heterocyclic
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is reported as E1/2 = +0.05 V vs. SCE in THF. Y. Mugnier, E. Laviron, J.
Org. Chem. 1988, 53, 5781-5783.
Keywords: oxidation • organocatalysis • Kornblum oxidation •
benzo[c]cinnoline • diazene
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50, 4524-4543.
[3]
[4]
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[19]
A
reviewer noted that dimethylamine, which is formed from the
[16] This example achieves the overall conversion of a benzylic halide to an
aldehyde or ketone via hydrolysis of the halide followed by TEMPO-
catalyzed oxidation: Q. Liu, M. Lu, F. Yang, W. Wei, F. Sun, Z. Yang, S.
Huang, Synth. Commun. 2010, 40, 1106-1114.
decomposition of DMF, could also be responsible for this behavior.
[20] The intramolecular proton shift was calculated to be >+60 kcal/mol. The
pathways that we believe are most likely, either a concerted or stepwise
solvent-mediated proton shift, have thus failed to return viable transition
states.
[17] The use of hydrogen peroxide for the oxidation of hydrazines has been
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[21] Attempts to verify formation of dipole 26 by trapping with a dipolarophile
were unsuccessful. However, the analogous dipole formed from a-
bromoacetophenone was successfully trapped with norbornene. See
Supporting Information for details.
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Ilana B. Stone, Janis Jermaks,
Samantha N. MacMillan, Tristan H.
Lambert
R
Br
H2O
+
N
N
H2O
benzo[c]cinnoline
rapid and
spontaneous
1/2 O2
Page No. – Page No.
R
O
N
N
H
Title
H
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