Electrochemical Hofmann rearrangement mediated by NaBr: Practical access to bioactive carbamates

Article abstract of DOI:10.1039/c8ob01059e

An electrochemical Hofmann rearrangement is reported. With the mediation of NaBr, highly corrosive and toxic halogens are avoided. Moreover, this efficient and green approach is well compatible with a broad range of amides, including several commercial medicine derivatives, and provides direct access to synthetically useful carbamates. The synthetic utility of this method is also demonstrated by the preparation of ¹⁵N labeling carbamate and gram-scale synthesis of Amantadine.

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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Electrochemical Hofmann rearrangement mediated by NaBr: a
practical access to bioactive carbamates
Received 00th January 20xx,
Accepted 00th January 20xx
Lijun Li, Mengyu Xue, Xin Yan, Wenmin Liu, Kun Xu* and Sheng Zhang*
DOI: 10.1039/x0xx00000x
www.rsc.org/
Electrochemical Hofmann rearrangement is reported. With the appealing strategy to environmental-benign synthetic
promotion of NaBr, highly corrosive and toxic halogens are methods.6 As our ongoing work on the organic
avoided. Moreover, this efficient and green approach is well electrosynthesis,7 we envisioned that combination of anodic
compatible with a broad range of amides, including several oxidation and cathodic electro-generated base would enable
commercial medicines derivatives, and provides a direct access to an electrochemical Hofmann rearrangement with NaBr as the
synthetically useful carbamates. The synthetic utility of this mediator.8 Indeed, a broad spectrum of carbamates even
method is also demonstrated by the preparation of 15N labeling containing densely functional groups or stereocenters were
carbamate and gram-scale synthesis of Amantadine.
readily accessed with only 20 mol% loading (Scheme 1c).
Moreover, the scalability of reaction was also evidenced by the
Hofmann rearrangement as one of most synthetically useful
approaches,1 through which convert amides to amines or
carbamates, has attracted considerable attentions from
chemical industry and synthetic chemists.2 However, the
classical reaction commonly involves stoichiometric halogen
and sodium hydroxide. These highly corrosive and toxic
reagents significantly hamper its practical application.
Consequently, the modification on the reaction condition has
been extensively explored.3, 4, 5 For instance, various iodine (III)
species have been developed to replace bromine since the
pioneering work of Loudon (Scheme 1a).3 Additionally, N-
bromosuccinimide (NBS) has also been demonstrated as an
appealing alternative reagent in the Hoffmann reaction
(Scheme 1a).4 However, most of these works generally
requires equivalents of expensive oxidants. The ideal, but
challenging approach catalytic Hofmann rearrangement
receives far less attention and is considered as an illusive issue.
Very recently, a remarkable breakthrough in the catalytic
Hofmann rearrangement has been achieved by Miyamoto and
coworkers.5 In the novel method, excessive isobutyraldehyde
and nitriles are used to enable the aerobic iodoarene-
catalyzed reaction, and stepwise procedures are also required
to obtain the carbamates (Scheme 1b). In the past years, the
renaissance of organic electrochemistry has provided an
gram-scale synthesis of Amantadine.
a. Previous works on the modification of Hofmann reaction
O
stoichiometric PhIY2 / NBS + (base)
RCONH2
MeOH
RHN
OMe
b. Impressive work of Miyamoto - catalytic Hofmann rearrangement
O
ArI (10 mol%), i-PrCHO (3 eq.)
DCE-t-BuCN (9/1), O2
N
MeOH (20 eq.)
24 h
RCONH2
R
C
O
RHN
OMe
c. Our work
O
15NHCOOMe
NaBr
NHCOOMe
Br
RCONH2
O
C2H4NHCOOMe
NHCOOMe
√ Lower catalyst loading
√ External oxidant-free
√ Good-scalability
H
H
H
O
O
√ Broad substrate scope
H
35 examples, up to 94% yield
Combination of anodic oxidation and cathodic electro-generated base
Scheme 1. Modifications on the Hofmann reaction
On the outset, benzamide 1a was selected as the pilot
substrate to study the electrochemical Hoffmann
rearrangement. We commenced our study using 20 mol%
NaBr as the mediator in an undivided cell under constant
current conditions (Table 1). Screening on the supporting
electrolyte showed that n-Bu4NBF4 was the optimal one giving
the product 2a with 80% yield (Entries 1-4). Lowering reaction
a.College of Chemistry and Pharmaceutical Engineering, Nanyang Normal
University, Nanyang, 473061 P. R. China
E-mail: xukn@nynu.edu.cn; shengzhang@nynu.edu.cn
† Footnotes relaꢀng to the ꢀtle and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
temperature to 25 ºC resulted in diminished yield (Entry 5). It
was found that changing platinum electodes to graphite
caused a significant decrease of yield (Entry 6). To our delight,
a relative satisfactory yield (79%) was observed with 40 mol%
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loading, which provided a possibility for practical application precusors (2ac-2ad) of the best-selling drugs Amantadine and
(Entry 7). To simplify the reaction conditions, NaBr was added Memantine were readily accessed with reasonable yields.
as a sole additive functioned as both mediator and electrolyte.
Notably, 50 mol% loading is enough to maintain good
conductivity for the electrolysis, as well as to achieve a
excellent yield (88%).
Table 2. Substrate scope of electrochemical Hofmann rearrangement.a
Pt(+)-Pt(-)
O
O
NaBr
R
Me
N
O
CH3CN/MeOH
R
NH2
H
CCE, undivided cell
1
2
Table 1. Optimization of electrochemical Hoffmann rearrangementa
H
H
H
H
N
OMe
N
OMe
N
OMe
N
OMe
O
O
O
O
F
Br
N
Cl
2a, 88% (80%)b
2b, 67% (61%)b
2c
, 92% (81%)b
2d, 86% (74%)b
n
H
N
O
S
H
Pr
OMe
N
OMe
NH
n
O
Pr
O
O
O
F3C
MeOOC
MeO
2f, 84% (70%)b
2g, 68% (63%)b
2e, 80% (76%)b
Entry
X
SE
Electrode
Pt-Pt
Pt-Pt
Pt-Pt
Pt-Pt
Pt-Pt
C-C
T (ºC)
50
Yield (%)b
80
H
N
H
H
H
1
2
3
4
5
6
7
8c
20
20
20
20
20
20
40
50
n-Bu4NBF4
n-Bu4NClO4
n-Bu4NPF6
LiClO4
OMe
N
OMe
N
OMe
N
OMe
50
76
O
O
O
O
tBu
nBu
Et
50
78
2h, 71% (62%)b
, 75% (68%)b
2j
, 92% (85%)b
2k, 82% (74%)b
2i
50
66
H
H
F
H
N
N
OMe
N
OMe
H
OMe
n-Bu4NBF4
n-Bu4NBF4
n-Bu4NBF4
-
25
trace
49
N
OMe
O
O
50
O
O
MeO
C-C
50
79
Cl
2m,
2n, 93% (83)b
Ph
2o, 92%, (87%)b
92% (85%)b
2l, 87% (79%)b
Br
Pt-Pt
50
88
a Reaction conditions: undivided cell, electrodes (1.5 × 1.5 cm2, J = 6.7 mA/cm2),
1a (1 mmol), CH3CN/MeOH (9/1 mL, v/v), NaBr (0.2 mmol) and supporting
H
H
H
H
Cl
N
OMe
N
OMe
N
OMe
N
OMe
O
O
O
O
b
c
electrolyte (1 mmol) for 8 h, 4.5 F. Isolated yield. Reaction conditions:
undivided cell, electrodes (1.5
1.5 cm2, 6.7 mA/cm2), 1a (1 mmol),
2s, 60% (51%)b
2r, 82%, (74%)b
2q, 93%, (79%)b
2p, 87%, (83%)b
Cl
×
J =
F
H
N
H
H
CH3CN/MeOH (10/2 mL, v/v), NaBr (0.5 mmol) at 50 ºC for 6 h, 3.4 F.
OMe
H
F
N
OMe
N
OMe
N
OMe
O
O
O
O
F
F
With the identified conditions in hand, various amides
were investigated in the electrochemical Hofmann
rearrangement (Table 2). The electronic property of
substitution was studied using para-substituted benzamide as
F
2t, 42%c (38%)d
2u, 93% (85%)b
2w, 43%c (37%)d
2v, 75%c (68%)d
MeO
H
H
N
H
N
OMe
OMe
N
OMe
Bn
NHCOOMe
O
O
iPr
O
N
substrates (2a-2l). As shown on the table, the substituents
2y, 94% (87%)b
2z,
81% (73%)b
2x, 58%c (57%)d
2aa, 68%c (60%)d
marignally affected the performance of reaction, thereby
giving carbamates with good to excellent yields. Specifically,
the pharmaceutical Probenecid derived amide was readily
converted to the product 2g. Additionally, the strongly electro-
donating group OMe is well-tolerated in this method delivering
the product with 87% yield, which is difficult to obtain with
previous approaches due to the undesired oxidation of the
electron-rich product 2l. Subsequently, we examined the
effect of substitution pattern on the reaction and uniformly
excellent results were detected for the meta- or ortho-
O
C2H4NHCOOMe
NHCOOMe
NHCOOMe
H
H
H
O
2ad, 87% (76%)b
O
2ab, 63%c (54%)d
2ac, 85%, (78%)b
H
a Reaction condition A: undivided cell, platinum plate electrodes (1.5 × 1.5 cm2, J
= 6.7 mA/cm2), 1 (1 mmol), CH3CN/MeOH (10/2 mL, v/v), NaBr (0.5 mmol) at 50
ºC for 6 h, 3.4 F. b Reaction condition B: undivided cell, platinum plate electrodes
(1.5 × 1.5 cm2, J = 6.7 mA/cm2), 1 (1 mmol), CH3CN/MeOH (9/1 mL, v/v), NaBr (0.2
c
mmol), n-Bu4NBF4 (1 mmol) at 50 ºC for 8h, 4.5 F. Higher temperature 60 ºC is
required in condition A. d Higher temperature 60 ºC is required in condition B.
substitution (2m-2r). Mutiple substituted benzamides even
including pentafluorobenzamide proved to be amenable
substrates give a direct access to a broad range of cabamates
Having constructed structurally diverse carbamates from
amides, the moiety of ester group was also studied with other
alcohols. In the cases of ethanol and trifluoroethanol, the
(
2s
-2v). This electrochemical method also compatiable with
fused and heterocycles, albeit with lower yields (2w
-2x). To
corresponding carbamates (2ae-2af) were readily obtained
further expand the scope of this transformation, alphatic
amides bearing chiral centers and functional groups were
synthesized and employed in the reaction. It is particularly
with modification of the solvent (Scheme 2a). By contrast, only
3 equivalents of benzyl alcohols was required to furnish the
products (2ag-2ah) using n-Bu4NBr as the mediator (Scheme
noteworthy that
a high retention of configuration was
2a). To demonstrate the synthetic utility of this
electrochemical approach, the preparation of 15N labeling
product (15N-2d) and the gram-scale reaction were performed.
From commercially accessible 15N-ammonium chloride, 4-
bromobenzoic acid was transformed into the isotope labeling
carbmates through sequential steps. The practically gram-scale
synthesis of Amantadine was studied using graphite as
detected for the cases of 2z and 2aa (Naproxen derived
carbamate). Moreover, the bioactive dehydrocholic acid
derived amides with densely functional groups (ketones)
proceed smoothly to afford the products 2ab without any
observation of bromination of ketones. More importantly, the
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electrodes. With NaBr as mediator, 7.7 g adamantyl carbamate significant increase of anodic (ipa) peak current was observed
was produced, which underwent a hydrolysis affording 4.8 g when we treated the mediator NaBr with substrate 1a (curve c
Amantadine
.
vs curve d). Moreover, further introducing base MeONa led to
a higher anodic (ipa) peak current (curve c vs curve e). The
increase of ipa associates with the regeneration of bromide,
which suggests that NaBr serves as a mediator during the
reaction. In addition, the electrogenerated base can further
facilitate the promotion process.
O
Pt(+)-Pt(-)
a.
R: Et, 2ae, 64%
H
Br- (50 mol %)
N
R: CH2CF3, 2af, 67%
NH2
COOR
+
ROH
CH3CN
CCE, undivided cell
2ag
R: Bn,
, 49%
2ah
p
Br
Br
R: CH2 Tolyl,
, 42%
1d
b. Synthetic utility:
O
According to these observations and previous reports,3
a
O
Pt(+)-Pt(-)
15NHCOOMe
NaBr(50 mol %)
15NH4Cl
15NH2
OH
catalytic cycle is proposed (Figure 2). Intially, cathodic
reduction of MeOH produces H2 and base MeO-. With the
assistance of in-situ generated base, the anodic generated
bromine is intercepted by the amide, thereby forming the
active N-Br sepcies. This intermediate proceeds through the
CH3CN/MeOH (5/1)
CCE, undivided cell
Br
Br
Br
15N-2d
15N-1d
COOMe
HN
O
NH2
NH2
C(+)-C(-), CH3CN/MeOH = 9/1
KOH, MeOH
reflux
CCE: 750 mA, 8 h
NaBr (40 mol %), 50 oC
classical Hofmann rearrangement and
a
sequential
1ac, 9.0 g
Amantadine
86%, 4.8 g
2ac, 73%, 7.7 g
nucleophilic reaction with MeO- to afford the desired
carbamates.
Scheme 2. Investigation on the alcohol substrate and synthetic utility.
To get insight of the reaction mechanism, some control
experiments were conducted in a divided cell (Scheme 3).
When the electrochemical Hofmann reaction was performed
in the anodic cell, no any product was detected, which
suggested a crucial role of cathodic electro-generated base
MeO-. To verify this postulation, 1 equivalent of MeONa was
added to the anodic cell and the desired product was obtained
with 62% yield. On basis of these results, both anodic oxidation
and cathodic electro-generated base are considered to be
essential for this reaction.
O
NH2
Br2
1a
2MeO- + H2
O
MeO-
NH
Br-
3
Br
2MeOH
2a
=
MeO-
MeO-
Ph
Br-
N
C
O
nucleophilic attack
4
cathode
anode
Figure 2. Proposed mechanism.
Pt(+)-Pt(-)
O
Conclusions
O
NaBr (50 mol%)
Me
Ph
N
O
In conclusion, an electrochemical Hofmann rearrangement is
developed with the promotion of NaBr. This efficient and
green approach exhibits high atom-economy, good fuctional-
group tolerance, operational simplicity under external oxidant-
and transition-metal-free conditions. More importanly, the
practicability of the method are evidenced by the derivazation
of pharmacetucials Probenecid, Naproxen, dehydrocholic acid
and the gram-scale synthesis of Amantadine.
CH3CN/MeOH
Ph
NH2
H
15 mA, divided cell
1a
2a
no additive,
additive: MeONa, 62% yield
N.R.
Scheme 3. Control experiments.
To further elucidate the role of NaBr, cyclic voltammetric
experiments were performed. As shown in the Figure 1, a
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We are grateful to the Natural Science Foundation of China
(21702113, 21602119, U1504208) and acknowledged the
financial support from Nanyang Normal University (ZX2017016,
QN2017037).
Notes and references
1
For reviews of Hofmann rearrangemant, see: (a) A. W.
Hofmann, Chem. Ber., 1881, 14, 2725; (b) H. E. Baumgarten,
Figure 1. Cyclic voltammograms of NaBr and related compounds: (a) background,
(b) 1a (5 mmol/L), (c) NaBr (5 mmol/L), (d) NaBr (5 mmol/L) and 1a (10 mmol/L),
(e) NaBr (5 mmol/L), 1a (10 mmol/L) and MeONa (10 mmol/L).
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