Copper-catalysed C-H functionalisation gives access to 2-aminobenzimidazoles

Article abstract of DOI:10.1039/c9ob01651a

This paper describes the development, optimisation and exemplification of a copper-catalysed C-H functionalisation to form pharmaceutically relevant 2-aminobenzimidazoles from aryl-guanidines. High throughput screening was used as a tool to identify a catalytically active copper source, DoE was used for reaction optimisation and a range of aryl-guanidines were prepared and exposed to the optimum conditions to afford a range of 2-aminobenzimidazoles in moderate to good yields. The methodology has been applied to the synthesis of Emedastine, a marketed anti-histamine pharmaceutical compound, with the key cyclisation step performed on a gram-scale.

Full text of DOI:10.1039/c9ob01651a

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Copper-Catalysed C–H Functionalisation gives access to 2-aminobenzimidazoles
DOI: 10.1039/C9OB01651A
Peter R. Clark*a,b, Glynn D. Williamsa, Nicholas C. O. Tomkinsonb
This paper describes the development, optimisation and exemplification of
a copper-catalysed C–H
D’Received 00th January 20xx,
Accepted 00th January 20xx
functionalisation to form pharmaceutically relevant 2-aminobenzimidazoles from aryl-guanidines. High throughput
screening was used as a tool to identify a catalytically active copper source, DoE was used for reaction optimisation
and a range of aryl-guanidines were prepared and exposed to the optimum conditions to afford a range of
2-aminobenzimidazoles in moderate to good yields. The methodology has been applied to the synthesis of
Emedastine, a marketed anti-histamine pharmaceutical compound, with the key cyclisation step performed on a
gram-scale.
DOI: 10.1039/x0xx00000x
atmospheric oxygen as a terminal oxidant has not been reported for the
synthesis of 2-amino benzimidazoles.
Introduction
The direct functionalisation of aryl C–H bonds to form heterocycles
Figure 1. Emedastine and Albendazole: Important 2-aminobenzimidazoles.
presents the synthetic chemist with powerful method which
a
O
NH
overcomes the prelimitations encountered with more traditional
approaches.1 In recent years there has been a significant focus towards
developing robust methodologies which target the synthesis of
N
NMe
nPrS
OMe
N
N
N
N
H
pharmaceutically relevant heterocycles through
functionalisation approach.2-5
a
C–H
OEt
Albendazole, 1
Emedastine, 2
2-Aminobenzimidazole is a commercial material, which itself presents
opportunities to probe molecular space through substitution on the
carbon skeleton on either of the endocyclic or exocyclic nitrogen atoms.
Direct alkylation of this substrate with dimethylsulfate furnishes a
mixture of compounds baring varying degrees of alkylation on all three
nitrogen atoms.17 This highlights how using this heterocycle as a
feedstock for developing new classes of compounds is challenging.
Therefore, several methods have been developed for the synthesis of
this specific heterocycle (Scheme 2). One of the simplest retrosynthetic
disconnections to form this class of compound is an SNAr reaction of 2-
chlorobenzimidazole 3 with an amine (Method A, Scheme 2a). This has
been shown to furnish 2-aminobenzimidazoles,18 however, the
preparation of 2-chlorobenzimidazole represents an additional non-
trivial synthetic challenge. Other methods to prepare 2-
aminobenzimidazoles require the use of super-stoichiometric mercury
salts for the ring-closing of thiourea derivatives from 1,2-
diaminobenzenes (Method B Scheme 2a).19,20 Whilst effective, this
method has low atom-economy & utilises mercury which reduces the
feasibility of these reactions, particularly within larger scale synthesis.
Consequently, the starting materials for these reactions all bare 1,2-
diamine substitution on the arene scaffold, which are often unstable or
require pre-preparation.21 Methods which avoid the use of 1,2–
diaminobenzenes have been reported,22 which employ 1,2–
dihaloarenes (Method C, Scheme 2a) whose preparation again
represents a significant challenge in itself. Despite these methods,
there remains a clear, unmet need for direct heterocycle synthesis from
readily available feed-stock materials which take advantage of
contemporary C–H amination strategies in a more sustainable manner.
Efforts towards this have been achieved with a direct C–H amination
reported by Zhang et al using hypervalent iodine-based oxidants
(Method D, Scheme 2a)23, however, these hypervalent iodine-based
oxidants are relatively expensive and produce undesirable waste
streams. The ideal oxidant would need to be cheap, easy to handle and
produce minimal waste.
One of the major challenges with a transition-metal catalysed C–H
functionalisation is the requirement for an external oxidant to be present
to facilitate catalyst turnover. As such, there is an emerging interest in
developing reactions which utilise the oxidative capacity of molecular
oxygen as the terminal oxidant, owing to the environmental and
practical benefits with using air as a reagent.6-9 For example, seminal
work by the Buchwald group in 200810 described the synthesis of
benzimidazoles directly from aryl-amidines using a copper(II) source in
the presence of acetic acid under an oxygen atmosphere (Scheme 1).
This reaction class highlighted the potential for simple, unfunctionalised
starting materials to be efficiently and effectively manipulated into
important pharmaceutical building blocks.
Scheme 1. Benzimidazoles from aryl-amidines.
H
CuOAc (15 mol%)
AcOH (500 mol%)
H
N
N
Ar
R
Ar
R
DMSO, 100 °C
18 h, O2
NH
N
2-Amino benzimidazoles represent an important class of heterocycle
due to their antibacterial,11 immunosupressive,12 antidiabetic,13
antiviral14 and analgesic15,16 properties. For example, their use in the
treatment and prevention of parasitic worm infections (Albendazole 1)
and prevalence in second generation antihistamines (Emedastine 2,
Figure 1) highlight this. Given the importance of this heterocycle, it was
therefore surprising that a C–H functionalisation strategy which exploits
a.
API Chemistry, Product Development & Supply, GlaxoSmithKline, GSK Medicines
Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United
Kingdom
b. WestCHEM, Department of Pure and Applied Chemistry, Thomas Graham
Building, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, United
Kingdom
With these observations in mind, we envisaged that modification of the
conditions reported by Buchwald in 200810 (Scheme 1) could allow
access to this privileged heterocycle through the use of a guanidine
starting material. In addition, the transformation would use oxygen as
the terminal oxidant (Figure 2b). Within this paper we describe the
development of an optimised process for the synthesis of
Electronic Supplementary Information (ESI) available: [The Supporting Information
is available free of charge on the ACS Publications website. Copies of 1H, 19F, and
13C NMR spectra of all new compounds can be found, along with 1H of known
compounds. Results of a high throughput screen of copper sources, additives &
solvents, the kinetic isotope effect experiment and the Design of Experiment
optimisation procedure & the statistical model.
See DOI: 10.1039/x0xx00000x
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2-aminobenzimidazoles with robust conditions and apply a range of
aryl-guanidines to these conditions. We also discuss some mechanistic
experimentation and the preparation of the antihistamine, Emedastine
(2), on gram scale.
View Article Online
DOI: 10.1039/C9OB01651A
Scheme 2: Current synthetic approaches and the proposed aerobic C–H functionalisation to 2-amionobenzimidazoles
a) Current synthetic approaches
NH
HBr
H2N
A. From 2-halobenzimidazoles
N
C. From 1,2 dihaloarenes
NR2
X
CuI (15 mol%)
HNR2
R
Cl
R
DMEDA (30 mol%)
N
N
H
X
Cs2CO3 (400 mol%), DMAc
3
R
NR2
X = I, Br, Cl
D. From aryl-guanidines
N
H
B. From thioureas
Complex reactants
Toxic waste products
Accesibility issues
H
N
N
NR2
NH2
PhI(OCOCF3)2 (1.1 equiv)
NR2
HgO (2 equiv)
S8
R
R
S
H
NH2
b) This work: Aerobic 2-aminobenzimidazole synthesis from aryl-guanidines
H
H
N
[Cu] (catalyst)
Additive
N
NR2
R1
R1
NR2
N
Air (1 atm)
NH
H
conditions, we isolated 64% of the product 5 after 21 hours, with no
formation of 6 detected by HPLC analysis of the reaction mixture (Entry
9). Despite this encouraging result, we were interested in the possibility
of achieving a catalytic cyclisation & pursued further optimisation.
Results and discussion
At the outset of our studies we sought to optimise the cyclisation of 4 to
aminobenzimidazole 5. A high throughput screen consisting of 82
reactions examining catalyst, solvent and additives was conducted
under 6 bar of air. The elevated pressure for this screen was chosen to
increase the gas solubility in the solvents and reduce the variability that
is often associated with poor mixing in a two-phase system. Using the
Owing to the propensity of the reaction to form dimeric benzimidazole
6 when using a catalytic quantity of copper(I) acetate, we examined
alternative copper sources. High through-put screening of
precomplexed copper sources, additives and solvents was performed
(see Supporting Information for full details). Changing the solvent from
NMP to sulfolane (Entry 10) delivered 45% 5 with 30% aryl-guanidine
starting material remaining (cf. Entry 7, 42% 5, 15% aryl-guanidine).
Interestingly this also led to significantly reduced quantities of the
dimeric species 6 (5%). Using copper(II) ethyl acetoacetate (EAA, Entry
11, 54% 5) proved advantageous over copper(I) acetate and changing
pivalic acid for acetic acid (Entry 12) delivered reduced quantities of 5
(54% vs 49%). Entries 13–14 highlight how the use of sulfolane is
beneficial when compared to NMP or DMSO. Electron withdrawing
1,3-dicarbonyl ligands (hexafluoro acetylacetonate, acacF6) proved
significantly less effective in promoting the desired transformation
(Entry 15, 17% 5). Importantly, use of acetoacetate ligands also reduce
the amount of dimer 6 (<2%). Although the precise reason for this
observation is unclear, we propose that acetoacetate ligands restrict
coordination of multiple benzimidazole species to the catalyst.
Alternatively, it is also possible that the ligand promotes
decomplexation of the product from the catalyst, thus preventing
dimerisation from occurring.
conditions reported by Buchwald (Entry
1 Table 1) gave 8%
benzimidazole 5 with 73% 4 remaining.10 Next, the amount of acetic
acid could be lowered to 1 equivalent (Entry 2) without a decrease in
yield (8%). Changing to pivalic acid as the additive (Entry 3) gave an
increase in benzimidazole formation (15%). Copper(I) acetate proved
to be more effective than copper(II) acetate (Entry 4, 31%). We next
examined alternative solvents in our optimisation process. Our
selection criteria for this necessitated that we considered solvents with
high flashpoints to minimise any risk associated with heating flammable
materials in an oxidative atmosphere (see the Supporting Information
for full details). NMP provided 41% product with 14% starting material
remaining by HPLC analysis with 15% catalyst loading at 100 °C (Entry
5). The major side product of the transformation was dimeric species 6
(10%). Lowering the temperature to 80 °C significantly reduced the
quantity of this impurity (Entry 6, 2%) whilst maintaining the yield of 5
(35%). The production of the dimeric species increased with the amount
of copper used, resulting in lower amounts of the desired product 5
being observed at higher copper loadings (Entries 6–8), with up to 25%
of the dimer observed when using one equivalent of copper(I) acetate
(Entry 8). We postulated that removing oxygen from the reaction media
would disfavour the formation of this dimeric species as the product
likely forms from a second oxidation event. When one equivalent of
copper(I) acetate was used in freeze-pump-thawed NMP under inert
2 | J. Name., 2012, 00, 1-3
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Table 1. Catalyst and solvent determination
View Article Online
DOI: 10.1039/C9OB01651A
X mol% [Cu]
RCO2H
MeO
N
N
MeO
N
NMe2
NH2
MeO
N
MeO
NMe2
NMe2
Solvent (0.3 M)
Y °C, 16 h, air
N
H
N
H
4
N
NMe2
5
6
Entry
Copper source
Acid
Solvent
X /
Y /
°C
5 Conversion*
6 *
mol%
15%
15%
15%
15%
15%
15%
50%
100%
100%
50%
50%
50%
50%
50%
50%
1
2
3
4
5
6
7
8
CuOAc2
CuOAc2
CuOAc2
CuOAc
CuOAc
CuOAc
CuOAc
CuOAc
CuOAc
CuOAc
Cu(EAA)2
Cu(EAA)2
Cu(EAA)2
Cu(EAA)2
Cu(acacF6)2
AcOH (5 equiv)
AcOH (1 equiv)
PivOH (1 equiv)
PivOH (1 equiv)
PivOH (1 equiv)
PivOH (1 equiv)
PivOH (1 equiv)
PivOH (1 equiv)
PivOH (1 equiv)
PivOH (1 equiv)
PivOH (1 equiv)
AcOH (1 equiv)
PivOH (1 equiv)
PivOH (1 equiv)
PivOH (1 equiv)
DMSO
DMSO
DMSO
DMSO
NMP
NMP
NMP
NMP
NMP
Sulfolane
Sulfolane
Sulfolane
NMP
DMSO
Sulfolane
100 °C
100 °C
100 °C
100 °C
100 °C
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
8% (73%)
8% (66%)
13% (53%)
31% (38%)
41% (14%)
35% (47%)
33% (25%)
20% (5%)
0%
0%
0%
-
10%
2%
13%
25%
0%
5%
2%
2%
< 1%
0%
9a,b
10
11
12
13
14
15
80%, 64%c (10%)
45% (30%)
54% (25%)
49% (31%)
43% (10%)
32% (41%)
17% (68%)
< 1%
All reactions run at 6 bar pressure of air in Cat96 pressure reactor, except entry 9 which was performed inerted in a Shlenk flask.
*HPLC peak area%. Yield in paranthesis refers to amount of starting material remaining (HPLC area).
a21 h reaction time. bfreeze-pump-thaw degassed NMP under nitrogen atmosphere in a Schlenk flask. cisolated yield after chromatography.
EAA = ethyl acetoacetate, acacF6 = hexafluoro acetylacetonate
Table 2: Design of Experiments optimisation.
From here we sought to further optimise this reaction using electron
deficient species 7 as the C–H activation step has been described as
being slower for electron deficient species,10 and so optimisation of a
more challenging trifluoromethyl substrate (7) was pursued. Having
observed a significant increase in conversion of 4 using Cu(EAA)2,
sulfolane and pivalic acid (table 1), we next switched to open-flask
conditions – as opposed to using a high-pressure of air – going forward
with our optimisation. This would make the presented chemistry
significantly more accessible. Statistical optimisation using design of
experiments (DoE) examining concentration, catalyst loading,
temperature and pivalic acid loading was performed. These
experiments were conducted at atmospheric pressure under open flask
conditions using the same equipment, stirring speed & reaction volume
to minimise any difference in mass-transfer of air to the system. Table
2 presents the experimental conditions and results observed by HPLC
analysis after a reaction time of 4 hours. †
Cu(EAA)2
PivOH
F3C
N
F3C
N
NMe2
NH2
NMe2
sulfolane
Temperature
1 atm air, 4 h
N
H
7
8
Entry Concn PivOH Catalyst Temp Conversion*
(M)
0.1
0.1
0.1
0.4
0.1
0.25
0.4
0.4
0.25
0.4
(equiv)
(mol%)
(°C)
100
130
130
130
100
115
100
100
115
130
(%)
1
2
3
4
5
6
7
8
9
1
1
2
2
2
1.5
2
1
1.5
1
5
25
5
25
25
15
5
25
15
5
9
74
23
74
60
74
23
67 (80%)a
75
10
26
A statistically significant model (R2 = 0.9735) was used to generate a
half-normal plot (see Supporting Information) to determine the most
important parameters for product formation. From this plot we saw that
maximising the loading of copper provides the most significant effect on
the reaction outcome. The most forcing conditions (Entries 2 and 4,
Table 2) used 25 mol% copper at 130 °C for 4 hours to give 74%
conversion to product. However, the same reactions at 21 hours
afforded the product in 52% and 32% conversion respectively,
indicating that under these conditions the product is unstable. Lowering
the temperature to 100 °C (Entry 8) afforded 67% of the product after 4
hours and 80% after 21 h, indicating that the product is more stable at
lower temperatures. With these observations in mind, we sought to
validate this result and isolated 54% of the product 8 after column
chromatography using the conditions shown in Entry 8 (0.4 M, 1 equiv
PivOH, 25 mol% catalyst, 100 °C, 24 h). It is worth noting that despite
entries 6 and 9 provide the highest yield at 4 hours, entry 8 provided a
higher yield (80%) at longer reaction times (24 h).
*HPLC area%. aresult at 24h gives 80 HPLC area%.
Having optimised the reaction conditions, we prepared a series of
N,N-dialkyl aryl-guanidines by addition of an aniline derivative to easily
accessible cyamides (Scheme 3). The isolated guanidines were then
reacted under our optimised reaction conditions. We were pleased to
discover that a range of functional groups were tolerated in the
transformation, including esters (11, 12), nitriles (13) and halogens (14–
18) which could be used in subsequent transformations. It is interesting
to note the tolerance of halogens on the arene backbone, in particular
bromine, as this shows the C–H functionalisation event is favoured over
Ullmann-type insertion of copper into the carbon-halogen bond under
the reaction conditions.24 We were unable to detect debromination of
meta or para substituted bromines of either product or starting material
under the reaction conditions. Products derived from meta-substituted
aryl-guanidines delivered mixtures of regioisomeric benzimidazole
products (15–20). Products 15:16 were obtained in a 3:1 ratio (35%
combined and isolated), whilst products 17:18 were obtained in a 4:1
ratio (90% combined and isolated). We attributed this change to the size
and steric bulk of the different halogen atoms in the substrates. It is
worth noting product
8 was obtained as a single regioisomer,
† See the supporting information for a full statistical analysis of the DoE
This journal is © The Royal Society of Chemistry 20xx
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presumably due to the increased size of a trifluoromethyl group over A range of commercial cyanamides were also used to prepare
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that of a chlorine or bromine, which disfavours insertion into the proton benzimidazoles 21–25 in moderate to good yields which suggests
DOI: 10.1039/C9OB01651A
ortho to the CF3 group. On considering products 19:20, a switch in N,N-dialkylcyanamides will provide effective substrates for the
selectivity to the more hindered position was observed in a 2:5 ratio. transformation. It is worth noting that product 26 was not observed
Nagasawa et al5 reported directed C–H insertions by copper to form under the optimised reaction conditions. The observed product was the
benzoxazoles, suggesting the direction into a hindered aryl C–H bond debrominated benzimidazole 24, presumably formed by oxidative
is facilitated by meta-substituted directing groups. In the case of 19– addition of copper into the ortho C–Br bond (as opposed to insertion
20, we suspect the switch in selectivity is driven by a directed C–H into the ortho C–H bond) and reductive elimination of the product, such
insertion by the pendant dioxole group into the more sterically hindered as previously reported by Evindar et al.25 Other 7-substituted
position.
benzimidazole products derived for an ortho-aniline were successfully
formed (9).
Scheme 3: Substrate scope of the developed cyclisation strategy
NR2
NaH
Cu(EAA)2 25 mol%
PivOH (1 equiv)
N
NH2
N
N
NR2
NH2
R1
NR2
R1
R1
Sulfolane 0.4 M
100 °C, Air (1 atm)
16-24 h
DMSO
N
H
F
N
F3C
N
N
N
N
NMe2
NMe2
NMe2
NMe2
NMe2
N
N
H
N
H
RO2C
N
R
H
N
H
H
11, R1 = Et, 63%
12, R1 = tBu, 53%
13, R = CN, 40%
14, R = Br, 58%
8, 54%
9, 46%
10, 65%
2NMe
N
Br
Cl
HN
Cl
Br
N
N
N
N
O
O
N
O
O
NMe2
NMe2
NMe2
NMe2
NMe2
N
H
N
H
N
H
N
H
N
H
17:18, 90%a, 4 : 1*
15:16, 35%, 3 : 1*
19:20, 81%, 2 : 5*
N
N
N
N
N
N
O
NEt2
N
NEt2
N
X
N
O
N
H
N
H
N
N
Br
Br
H
H
H
Br
21, 46 %
22, 74%
23, X = CH2, 41%
24, X = O, 52%
25, 59 %
26, 0 %
*relative HPLC peak areas of crude reaction mixture. Regioisomers (15–20) separated by chromatography and quoted yield is combined isolated yield. aProduct 18 was isolated as an impure
mixture of unknown impurities, however the regiochemistry was determined from this isolated material.
Mechanistic studies
Mechanistic pathways A and B
N
R
Previous work to understand the formation of benzimidazoles from
amidines proposed a number of potential pathways, two of which are
presented in Figure 2.10 Pathway A involves an SEAr-type addition of
the arene onto the guanidyl unit, akin to an electrophillic source of
nitrogen, liberating a reduced copper species and forms the product
benzimidazole after rearomatisation. Pathway B involves attack of the
N
R
A
B
N
HN
R
Cu
NH
N
H
O
O
H
[Cu]
H
R
arene onto the copper centre to form
a
6-membered
Through measurement of the initial rate of consumption of
arylguanidine 27 and deuterated variant 28 we observed a small kinetic
isotope effect of 1.4 (Scheme 4). This small kinetic isotope effect lies
on the boundary between primary and secondary effects, indicating that
the cleavage of the C–H bond is unlikely to be fully rate-determining;
however, this result cannot rule out the possibility of a fourth potential
mechanism occurring, involving a concerted metalation-deprotonation
event (CMD).26 To examine the potential for a CMD mechanism, we
performed a screen of different acids examining steric and electronic
effects and found no acid surpassed the yield obtained with pivalic
acid.†
organometallocycle, which, after re-aromatisation, reductive elimination
and subsequent reoxidation of the copper closes the catalytic cycle and
forms the product. More recently a third potential pathway, involving the
formation of
a copper-nitrene intermediate has been ruled out
computationally by Fu et al.26
Figure 2. Previously proposed mechanistic pathways
† See the supporting information for an extensive screen of acids to examine this
effect. Acids with increased steric encumbrance offer increased yields of the desired
benzimidazole, with no acid surpassing the yield of pivalic acid
4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C9OB01651A
Scheme 4. Kinetic isotope effect
Finally, to exemplify the utility of this method we have developed a novel
synthesis of Emedastine 2 with the benzimidazole formation performed
on gram scale in good yield, isolating 1.7 g of the product 47 (Scheme
5). Treatment of prepared cyanamide 45 with aniline under basic
conditions afforded 46, which, upon exposure to re-optimised reaction
conditions gave benzimidazole 47 (71%). We were able to lower the
copper loading to 12.5% without a loss in yield, and the product was
isolated through precipitation from tBME (see supporting information).
Alkylation of 47 with alkyl iodide 48 allowed for preparation of the
N-alkylated benzimidazole 49 in an 89% yield. Final
deprotection/methylation furnished 2 in an 80% yield for the two steps.
rate1 = k1X
N
N
NMe2
NH2
NMe2
NMe2
Cu(EAA)2 25 mol%
PivOH (1 eq)
N
H
10
27
Sulfolane 0.4 M
100 °C, Air
N
N
NMe2
NH2
N
H
D4
29
D5
28
This route offers
a 34% yield over 5 steps to an important
pharmaceutical compound with aniline as the key starting material.
rate2 = k2X
K.I.E = rate1 / rate2 = 1.4
Scheme 5. Application of methodology to the synthesis of Emedastine
NBoc
NH2
NaH
N
On exposure of N–methyl and N–benzyl guanidyl derivatives (32 & 33
Figure 3) in which the N-alkylbenzimidazole product was expected to
be a more labile ligand (owing to the absence of an exchangeable N–H
in the product benzimidazole), we observed marked decomposition of
the substrate with negligible product formation. This could imply that
stabilisation of the guanidyl–copper intermediate 34 is important owing
to the presence of multiple tautomeric forms (which is less favourable
when R ≠ H). This result could further indicate that coordination of the
aniline nitrogen to the copper catalyst is a key artefact of the
mechanistic cycle which is inhibited by alkylating this position (Figure
3a). Secondly, this could indicate that reductive elimination from an sp3
nitrogen is more favourable when compared to the sp2 alternative
(Figure 3b. A final mechanistic point to note is that we observed the
formation of peroxide during the reaction by use of an enzymatic
peroxide detection kit. This is presumably formed as the by-product of
oxidation with air.
N
N
N
NBoc
NH2
67% 46
DMSO
45
Cu(EAA)2 (12.5% mol%)
pivalic acid (1 equiv.)
sulfolane 0.4 M
100 °C, Air (1 atm)
30 h
NaH
N
N
OEt
NBoc
I
N
N
NBoc
48
N
THF
N
H
89% 49
71% (1.7 g) 47
OEt
N
N
NMe
Figure 3. N–capped aryl-guanidines
N
1) HCl/EtOAc
R
R
N
2) H2CO, HCO2H
Cu(EAA)2 25 mol%
PivOH (1 equiv.)
N
NEt2
80% over two steps
Emedastine
2
NEt2
NH
OEt
N
Sulfolane 0.4 M
R = Me, Bn
100 °C, Air (1 atm)
16 h
32, 33
Experimental
(a) Stabilisation of guanidyl-copper intermediate
PhN
R2N
NH2
H
All catalysts and reagents were supplied by commercial sources and
used without further purification, unless otherwise stated. Sulfolane was
purchased from AlfaAesar and was melted in a buchi-path heated to 50
°C before use. When degassed solvent was required, a sample was
sealed in a microwave vial and frozen in a cardice/acetone bath at -78
PhHN
N
OPiv
PhN
N
OPiv
[Cu]
Cu
OPiv
NR2
NR2
Cu
34
(b) Disfavoured reductive elimination from sp2 nitrogen
R
°C, before being exposed to vacuum and warmed in
a room
R
- [Cun-2
]
N
temperature water bath. This process was repeated three times, or until
bubbles no longer form on melting of the sample. Reactions were
monitored using High Performance Liquid Chromatography (HPLC)
and Liquid Chromatography-Mass Spectrometry (LCMS) (high pH),
where the conditions are displayed in the SI. 1H, 13C and 19F NMR
spectra were recorded using a Bruker AV-400. HPLC was conducted
N
NEt2
NEt2
NEt2
N
N
[Cun]
vs.
- [Cun-2
N
]
N
NEt2
on
a Waters X-select CSH C18 column (XP). High-resolution
N
H
NH
[Cun]
electrospray mass spectra were recorded on a Thermo Exactive
orbitrap mass spectrometer equipped with a Waters Acquity UPLC
system, solvent gradient is recorded in the SI. Automated column
chromatography was performed on a Biotage SP4, Isolera 1 or Isolera
4 purification system monitored by UV (λ=200–400 nm, λ=254 nm and
220 nm) using, unless stated otherwise, Biotage® SNAP Ultra pre-
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Page 6 of 12
ARTICLE
Journal Name
packed cartridges or Biotage SNAP KP-NH cartridges. Reverse phase the desired carboxylic acid (0.22 mmol, 1 equiv) with sulfolane (0.5 mL).
View Article Online
column chromatography was performed on a CombiFlash automated The reaction was stirred and heated to 100 °C with a heating mantle
DOI: 10.1039/C9OB01651A
system using Biotage® SNAP KP-C18-HS pre-packed cartridge. and analysed by HPLC using the response factor calculations to
Chromatographic solvents were standard HPLC grade provided by determine the solution yield of benzimidazole 8 after the quoted time.
Honeywell, and when a modifier was required it was added in-house. The table in the SI summarises the solution yield of 8 using the internal
Melting points were measured on an OptiMelt melting point apparatus standard 4,4’-di-tertbutyl-1,1’-biphenyl.
and monitored manually. IR spectra were recorded using a Perkin
Elmer Spectrum One spectrometer and the data processed using
Synthesis of Guanidine Starting Materials (General Procedure
Perkim Elmer Spectrum software. Absorption frequencies (vmax) are 1).
reported in wavenumbers (cm-1) of the peaks with the larger numbers To a dry round-bottom flask was added a 60% suspension of sodium
away from the fingerprint region. The Mettler-Toledo Quantos QB5 or hydride (1.2 equiv) which was slurried in anhydrous DMSO (0.5
QX96 was used to weigh out desired solids for high throughput mL/mmol of NaH). The flask was exposed to vacuum and back-filled
screening in pre-loaded dispensing heads using the supplied with nitrogen for 3 cycles before cooling the flask to 0 °C and adding
dispensing algorithms. Guanidine synthesis is described in the the aniline derivative (1.0 equiv) dropwise as a solution in anhydrous
supporting information.
DMSO (0.33 mL/mmol of aniline). The reaction was stirred at 0 °C for
15 minutes before addition of the cyanamide (1.2 equiv), at which point
the reaction was allowed to warm to room temperature. After the stated
Solvent screen.
2-(3-methoxyphenyl)-1,1-dimethylguanidine (4) (95 mg, 0.5 mmol), time, the reaction was carefully quenched with water (~3 mL/mmol of
copper(I) acetate (9 mg, 0.074 mmol, 0.15 equiv) and pivalic acid (51 sodium hydride used) and extracted into tBME (3 washes of equal
mg, 0.5 mmol, 1 equiv) were placed in a 4 mL vial which was equipped volume of the water solution). The combined organic extracts were
with a stir-bar. Solvent (2 mL) was added and the vial fitted with a hole- washed with water (3 washes of 0.33 × total organic volume), brine (1
punched septum. The vial was placed in the Cat96 reactor and heated wash of 0.33 × total organic volume), dried over anhydrous MgSO4 and
to 100 °C under 6 bar of compressed air for 21 hr before being analysed concentrated in vacuo. The crude product was either purified by
by HPLC analysis. Data is presented in a table in the supporting crystallisation or chromatography to yield the desired guanidine
information.
product. See the supporting information for full experimental and
analytical data of guanidines.
High throughput screen of copper sources, additives and
Cyclisation experiments
solvents for the cyclisation of 4.
To 0.5 mL glass vials were weighed the quoted masses (see SI) of
copper source and to the reactions containing basic additives added To
5-Methoxy-N,N-dimethyl-1H-benzo[d]imidazol-2-amine (5).
a
dry Schlenk tube was added 2-(3-methoxyphenyl)-1,1-
NaOAc/NaOPiv using the automated weighing platform Quantos QX96. dimethylguanidine (4) (97 mg, 0.5 mmol, 1 equiv), pivalic acid (50 mg,
To each vial was added 2-(3-methoxyphenyl)-1,1-dimethylguanidine (4) 0.5 mmol, 1.0 equiv), copper(I) acetate (60 mg, 48.9 mmol, 1.0 equiv)
(0.2 mL of a stock solution in the quoted solvent) such that each 0.2 mL and a stir bar. The Schlenk tube was fitted with a septum and the vessel
delivers 25 mg/0.13 mmol of substrate 4. To the reactions containing exposed to vacuum before being back-filled with nitrogen. This process
acidic additives was added a further 0.2 mL of a stock solution of the was repeated 3 times, and the reaction remained exposed to nitrogen.
desired acid in the quoted solvent such that the 0.2 mL delivers 1 To the Schlenk tube was added freeze-pump thawed degassed NMP
equivalent of the desired acidic additive with respect to 4. To the (2 mL). The sealed Schlenk tube was then placed in a silicone oil bath
remaining reactions in which the basic additive was added as a solid, a which had been preheated to 80 °C. After 21 h, the reaction was
further 0.2 mL of the quoted solvent was added to make the total removed from the oil bath and the septum taken out, allowing the
reaction volume up to 0.4 mL (0.32 M with respect to substrate 4). All solution to cool to room temperature. Water (10 mL) was added,
reactions were then stirred with a magnetic flea and heated to 80 °C causing a precipitate to form. On addition of tBME (10 mL) and EDTA(aq)
under 6 bar of compressed air in a CAT96 reactor for 16 hours before solution (6 mL, 0.1 M, 0.6 mmol, 1.2 equiv w.r.t copper(I) acetate), the
filtering and analysing by HPLC and LCMS. Displayed in the SI are the aqueous layer turns green and the precipitate dissolves in the organic
dispensed masses of solid reagents and the HPLC peak area % data layer, which turns brown. The aqueous layer was extracted a further
of starting material (4), product 5 and undesired dimeric product 6.
two times with tBME (2 × 15 mL) and the combined organic extracts
washed with water (2 × 15 mL) and brine (1 × 10 mL). The combined
water and brine washes were back-extracted with tBME (2 × 10 mL),
Design of Experiments Optimisation procedure.
To 4 mL glass tubes were added the masses of compounds highlighted and the five combined tBME extracts were concentrated in vacuo. The
table 1 in the SI, where the respective loading of each is shown, relative crude reaction mixture was purified by column chromatography (10 g
to the amount of 7. Each 4 mL glass tube was then fitted with a stir bar Biotage® SNAP Ultra) 0–10% MeOH/CH2Cl2 to yield 5-methoxy-N,N-
and sulfolane (1 mL). To minimise mass-transfer effects of air, constant dimethyl-1H-benzo[d]imidazol-2-amine (5) as a white solid. (62 mg, 0.3
volume experiments were designed, hence the varying quantity of 7. 25 mmol, 64%)
1H NMR (400 MHz, METHANOL-d4)  ppm 3.09 (6H, s), 3.77 (3H, s),
µL samples were taken and diluted into acetonitrile (500 µL), filtered
and analysed by HPLC/LCMS at 1 h, 1.5 h, 4 h and 21 h. Heating was
performed with a heating mantle set to the quoted temperature. Raw
HPLC data was then used to calculate HPLC area % which is then
shown in the main body of the text, displaying the 4 hour time-point
data, from which we fitted the statistical model (full details of statistical
model can be found in the SI)
6.60 (1H, dd, J = 8.6, 2.4 Hz), 6.82 (1H, d, J = 2.4 Hz), 7.08 (1H, d, J
= 8.6 Hz) 13C{1H} NMR (METHANOL-d4, 101MHz)  ppm 38.5, 56.5,
98.0, 108.5, 111.5, 118.0, 155.5, 156.0, 158.5. The spectroscopic
data is in agreement with those previously reported 27
5,6'-dimethoxy-N2,N2,N2',N2'-tetramethyl-3'H-[1,5'-
Reaction additive screening procedure.
bibenzo[d]imidazole]-2,2'-diamine (6).
To an HPLC vial was added 1,1-dimethyl-2-(3-(trifluoromethyl)phenyl)
guanidine (7) (50 mg, 0.22 mmol), 4,4’-di-tertbutyl-1,1’-biphenyl (13 mg,
0.05 mmol 0.23 equiv), Cu(EAA)2 (17 mg, 0.05 mmol, 0.25 equiv) and
To a vial containing 2-(3-Methoxyphenyl)-1,1-dimethylguanidine (4)
(1.00 g, 5.17 mmol, 1 equiv), copper(I) acetate (634 mg, 5.17 mmol, 1.0
equiv) & pivalic acid (529 mg, 5.17 mmol) was added NMP (17 mL).
6 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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ARTICLE
The reaction was heated to 80 °C in the CAT96 pressure reactor under Orbitrap) m/z: [M + H]+ Calcd for C10H11F3N3 [M + H]+ 230.0900, found
View Article Online
DOI: 10.1039/C9OB01651A
6 bar compressed air for 16 hours. On cooling to room temperature, the [M + H]+ 230.0893
solution was flushed through an SCX-2 ion exchange cartridge with
4-fluoro-N,N-dimethyl-1H-benzo[d]imidazol-2-amine (9).
MeOH (100 mL), followed by a 7N methanolic ammonia (50 mL). The Using general procedure 2 for benzimidazole formation was performed
methanolic ammonia solution was concentrated in vacuo and purified with 2-(2-fluorophenyl)-1,1-dimethylguanidine (51) (201 mg, 1.1 mmol),
by chromatography (0-10% MeOH/CH2Cl2 with 2% triethylamine Cu(EAA)2 (89 mg, 0.3 mmol, 0.25 equiv) and pivalic acid (114 mg, 1.1
modifier in the CH2Cl2) to yield 126 mg of a brown solid. The brown solid mmol, 1.0 equiv) for 19 hours to yield 4-fluoro-N,N-dimethyl-1H-
was then re-purified by reverse phase chromatography (15–55% benzo[d]imidazol-2-amine (9) as an off-white solid. (92 mg, 0.5 mmol,
MeCN/H2O, NH4HCO3 modifier at 0.1%), the volatiles removed under 46%)
reduced pressure, the aqueous extracted with CH2Cl2 (3 x 30 mL),
before drying over a hydrophobic frit and concentrating in vacuo to yield
5,6'-dimethoxy-N2,N2,N2',N2'-tetramethyl-3'H-[1,5'-
bibenzo[d]imidazole]-2,2'-diamine 6 as a white solid (63 mg, 0.17 mmol,
3%).
1H NMR (400 MHz, METHANOL-d4)  ppm 2.84 (6 H, s), 3.15 (6 H, s),
3.76 (3 H, s), 3.79 (3 H, s), 6.53 – 6.60 (2 H, m), 6.97 (1 H, d, J=1.2
Hz), 7.09 (1 H, s), 7.14 (1 H, s) 13C{1H} NMR (101 MHz, METHANOL-
d4)  ppm 37.2, 39.3, 54.9, 55.4, 96.5, 99.7, 107.5, 108.8, 118.3, 131.8,
141.6, 150.8, 156.0, 158.0, 158.4. Multiple signals missing from 13C
NMR. Refer to supporting information for full spectroscopic data (2D
NMRs) and structural elucidation. HRMS (ESI Orbitrap) m/z: [M + H]+
Calcd for C20H24N6O2 [M + H]+ 380.1960, found [M + H]+ 380.1963
Melting point: 232–234 °C FTIR νmax/cm-1 2921, 1634, 1578, 1509,
1
1415. H NMR (400 MHz, METHANOL-d4)  ppm 3.16 (6 H, s), 6.76 (1
H, ddd, J=10.9, 8.2, 0.6 Hz), 6.90 – 6.96 (1 H, m), 7.01 – 7.06 (1 H, m)
13C{1H} NMR (101 MHz, METHANOL-d4)  ppm 38.7, 107.6 (d, J=17.7
Hz), 107.9 (br), 121.2 (d, J=7.1 Hz), 129.1 (br), 141.0 (br), 151.6 (d,
J=243.2 Hz), 158.5 (br) 19F NMR (376 MHz, METHANOL-d4)  ppm -
135.4 HRMS (ESI Orbitrap) m/z: [M + H]+ Calcd for C9H11FN3 [M + H]+
180.0937, found [M + H]+ 180.0938.
N,N-dimethyl-1H-benzo[d]imidazol-2-amine(10).
Using general procedure 2 for benzimidazole formation was performed
with 1,1-dimethyl-2-phenylguanidine (27) (201 mg, 1.2 mmol),
Cu(EAA)2 (98 mg, 0.3 mmol, 0.25 equiv) and pivalic acid (125 mg, 1.2
mmol, 1.0 equiv) for 24 hours to yield N,N-dimethyl-1H-
benzo[d]imidazol-2-amine (10) as an off-white solid. (129 mg, 0.8 mmol,
65%)
General procedure
2
for aerobic copper catalysed
dehydrogenative cyclisation to form benzimidazoles.
Melting point: 202–204 °C FTIR νmax/cm-1 2918, 1634, 1603, 1575 (br),
1425, 1411. 1H NMR (400 MHz, METHANOL-d4)  ppm 3.08 - 3.25 (6
H, s), 6.99 (2 H, dd, J=5.8, 3.3 Hz), 7.24 (2 H, dd, J=5.8, 3.3 Hz) 13C{1H}
NMR (101 MHz, METHANOL-d4)  ppm 37.2, 111.2 (br), 119.8, 138.1
(br), 156.6 HRMS (ESI Orbitrap) m/z: [M + H]+ Calcd for C9H12N3 [M +
H]+ 162.1031, found [M + H]+ 162.1033. The spectroscopic data is in
agreement with those previously reported.22
Aryl guanidine, pivalic acid (1 equiv.) and copper(II) ethylacetoacetate
(0.25 equiv.) were placed in a round bottom flask fitted with a magnetic
stirring flea. Sulfolane was warmed using a heated water bath and the
desired volume was dispensed by syringe to make up to a reaction
concentration of 0.4 M. The reaction was stirred and heated to 100 °C
by heating mantle with the round bottom flask open to air. Reactions
were monitored by HPLC analysis (CSH method) and the reactions
were cooled to room temperature after the stated time. The reaction
mixture was loaded directly onto an SCX-2 ion-exchange cartridge and
homogenised with MeOH, after which the cartridge was flushed with a
further 15 column volumes of methanol. The cartridge was then flushed
with 2 column volumes of a 2 M methanolic ammonia solution to elute
the product, which was then concentrated in vacuo and purified by flash
column chromatography (0–4% MeOH in CH2Cl2 in most cases unless
stated otherwise) to yield the product.
Ethyl 2-(dimethylamino)-1H-benzo[d]imidazole-6-carboxylate
(11).
Using general procedure 2 for benzimidazole formation was performed
with ethyl 4-((amino(dimethylamino)methylene)amino)benzoate (52)
(50 mg, 0.2 mmol), Cu(EAA)2 (18 mg, 0.06 mmol, 0.27 equiv) and
pivalic acid (22 mg, 0.2 mmol, 1.0 equiv) for 14.5 hours to yield ethyl 2-
(dimethylamino)-1H-benzo[d]imidazole-6-carboxylate (11) as an off-
white solid. (31 mg, 0.13 mmol, 63%)
Melting point: 210–212 °C FTIR νmax/cm-1 3193, 2981, 1693, 1638,
1602, 1297. 1H NMR (400 MHz, METHANOL-d4)  ppm 1.27 (3 H, t,
J=7.1 Hz), 3.02 (6 H, s), 4.22 (2 H, q, J=7.1 Hz), 7.12 (1 H, d, J=8.2
Hz), 7.62 (1 H, dd, J=8.2, 1.5 Hz), 7.75 (1 H, d, J=1.5 Hz) 13C{1H} NMR
(101 MHz, METHANOL-d4)  ppm 14.8, 38.5, 61.7, 112.7 (br), 113.7,
123.0, 123.9, 138.5, 145.2, 159.6, 169.2 HRMS (ESI Orbitrap) m/z: [M
+ H]+ Calcd for C12H16N3O2 [M + H]+ 234.1237, found [M + H]+ 234.1227.
5-Trifluoromethyl-N,N-dimethyl-1Hbenzo[d]imidazol-2-amine
(8).
1-Dimethyl-2-(3-(trifluoromethyl)phenyl) guanidine (7) (370 mg, 1.6
mmol, 1 equiv), pivalic acid (163 mg, 1.6 mmol, 1.0 equiv) and
copper(II) 2-ethylacetoacetate (129 mg, 0.4 mmol, 0.25 equiv) were
placed in a round bottomed flask that was fitted with a stir bar. Sulfolane
(4 mL) was added, and the reaction heated to 100 °C. After 24 h, the
reaction was removed from the hotplate and allowed to cool to room
temperature, at which point water (20 mL), EDTA(aq) (5 mL, 0.1 M, 0.5
mmol, 1.2 equiv w.r.t copper.) and tBME (20 mL) was added. The
organic layer was separated, and the aqueous layer extracted a further
2 times (2 × 15 mL tBME), before the combined organic extracts were
washed with water (3 × 10 mL) and brine (1 × 20 mL). The water and
brine washes were then back-extracted with tBME (1 × 15 mL). The
combined organic extracts were then concentrated in vacuo and
purified by column chromatography (0–10% MeOH/CH2Cl2) to yield (8)
as an orange solid (196 mg, 0.9 mmol, 54%).
Melting point: 210–211 °C FTIR νmax/cm-1 3073 (br), 2925 (br), 1639,
1611, 1320. 1H NMR (400 MHz, METHANOL-d4)  ppm 3.15 (6 H, s),
7.24 – 7.33 (2 H, m), 7.45 (1 H, s) 13C{1H} NMR (101 MHz, METHANOL-
d4)  ppm 37.1, 108.2 (br.), 111.2 (br.), 116.9 (q, J=3.8 Hz), 121.9 (q,
J=31.3 Hz), 125.3 (t, J=270.1 Hz), 138.2 (br.), 141.1 (br.), 157.8 (br.)
19F NMR (376 MHz, METHANOL-d4)  ppm -61.8 (s) HRMS (ESI
2-(Dimethylamino)-1H-benzo[d]imidazole-6-carbo- nitrile (13).
Using general procedure 2 for benzimidazole formation was performed
with 2-(4-cyanophenyl)-1,1-dimethylguanidine (53) (292 mg, 1.6 mmol),
Cu(EAA)2 (115 mg, 0.4 mmol, 0.25 equiv) and pivalic acid (158 mg, 1.6
mmol, 1.0 equiv) for 24 hours to yield 2-(dimethylamino)-1H-
benzo[d]imidazole-6-carbonitrile (13) as a brown solid (114 mg, 0.61
mmol, 40%)
1H NMR (400 MHz, METHANOL-d4)  ppm 3.18 (6 H, s), 7.28 – 7.38 (2
H, m), 7.49 (1 H, s) 13C{1H} NMR (101 MHz, METHANOL-d4)  ppm
38.7, 103.0, 113.8, 121.9, 126.0, 139.1 (br), 140.2 (br), 159.9 HRMS
(ESI Orbitrap) m/z: [M + H]+ Calcd for C10H11N4 [M + H]+ 187.0978,
found [M + H]+ 187.0972. FTIR: 2978, 2210 (CN), 1639, 1599, 1574,
1470 cm-1. The spectroscopic data is in agreement with those previously
reported.28
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[M + H]+ 196.0645. Melting point: 245–247 °C The spectroscopic data
View Article Online
DOI: 10.1039/C9OB01651A
Tert-butyl
carboxylate (12).
2-(dimethylamino)-1H-benzo[d]-
imidazole-5- is in agreement with those previously reported30
Using general procedure 2 for benzimidazole formation was performed
with tert-butyl 4-((amino(dimethyl- amino)methylene)amino)benzoate
(54) (259 mg, 1.0 mmol), Cu(EAA)2 (81 mg, 0.25 mmol, 0.26 equiv) and
pivalic acid (102 mg, 1.0 mmol, 1.0 equiv) for 25 hours to yield tert-butyl
5-Bromo-N,N-dimethyl-1H-benzo[d]imidazol-2-amine (17) and
4-Bromo-N,N-dimethyl-1H-benzo[d]imidazol-2-amine (18).
Using general procedure 2 for benzimidazole formation was performed
with 2-(3-bromophenyl)-1,1-dimethylguanidine (57) (201 mg, 0.83
mmol), Cu(EAA)2 (67 mg, 0.21 mmol, 0.25 equiv) and pivalic acid (86
mg, 0.84 mmol, 1.0 equiv) for 18 hours. 5-bromo-N,N-dimethyl-1H-
benzo[d]imidazol-2-amine (17) was isolated as a brown solid (130 mg,
0.54 mmol, 66%). The fractions containing impure 4-bromo-N,N-
dimethyl-1H-benzo[d]imidazol-2-amine (18) were re-purified by
chromatography (3% MeOH/CH2Cl2, 10 g SNAP Ultra cartridge) to yield
4-bromo-N,N-dimethyl-1H-benzo[d]imidazol-2-amine (18) as a brown
foam (49 mg, 0.21 mmol, 25%). 5-Bromo-N,N-dimethyl-1H-
benzo[d]imidazol-2-amine (17)
Melting point: 244–246 °C FTIR νmax/cm-1 2921, 2859, 1628, 1603,
1578, 1459, 1409, 1278. 1H NMR (400 MHz, METHANOL-d4)  ppm
3.12 (6 H, s), 7.05 – 7.12 (2 H, m), 7.32 (1 H, d, J=1.1 Hz) 13C{1H}
NMR (101 MHz, METHANOL-d4)  ppm 38.6, 113.6, 113.8, 116.0,
123.9, 138.1, 141.8, 158.7 HRMS (ESI Orbitrap) m/z: [M + H]+ Calcd
for C9H11N3Br [M + H]+ 240.0131, found [M + H]+ 240.0143. The
spectroscopic data is in agreement with those previously reported29
4-Bromo-N,N-dimethyl-1H-benzo[d]imidazol-2-amine (18) 11H NMR
(400 MHz, METHANOL-d4)  ppm 3.18 (6 H, s), 6.89 (1 H, d, J=7.9
2-(dimethylamino)-1H-benzo[d]imidazole-5-carboxylate (12) as
a
brown solid. (137 mg, 0.52 mmol, 53%)
Melting point: 216–218 °C FTIR νmax/cm-1 2981, 1695, 1635, 1605, 1574.
1H NMR (400 MHz, METHANOL-d4)  ppm 1.61 (9 H, s), 3.15 (6 H, s),
7.23 (1 H, d, J=8.3 Hz), 7.69 (1 H, dd, J=8.3, 1.1 Hz), 7.83 (1 H, app. s)
13C{1H} NMR (101 MHz, METHANOL-d4)  ppm 167.1, 123.2, 122.3,
112.0, 111.0, 80.1, 37.1, 27.2 Not all signals are present by NMR. 1 ×
aliphatic carbon missing from spectra and 1 × quaternary carbon. NMR
sample was saturated (~100 mg in solution) and number of scans set
to 10,000. HRMS (ESI Orbitrap) m/z: [M + H]+ Calcd for C14H20N3O2 [M
+ H]+ 262.1550, found [M + H]+ 262.1539.
5-Bromo-N,N-dimethyl-1H-benzo[d]imidazol-2-amine (14).
Using general procedure 2 for benzimidazole formation was performed
with 2-(4-bromophenyl)-1,1-dimethylguanidine (55) (174 mg, 0.72
mmol), Cu(EAA)2 (59 mg, 0.18 mmol, 0.25 equiv) and pivalic acid (74
mg, 0.72 mmol, 1.0 equiv) for 14.5 hours to yield 5-bromo-N,N-
dimethyl-1H-benzo[d]imidazol-2-amine (14) as an off-white solid. (100
mg, 0.42 mmol, 58%)
Melting point: 244–245 °C FTIR νmax/cm-1 2981, 1630, 1602, 1568, Hz), 7.15 (1 H, dd, J=7.9, 0.8 Hz), 7.18 (1 H, dd, J=7.9, 0.8 Hz 13C{1H}
1459, 1408. 1H NMR (400 MHz, METHANOL-d4)  ppm 3.13 (6 H, s), NMR (101 MHz, METHANOL-d4)  ppm. Low sample quantity and
7.06 – 7.14 (2 H, m), 7.34 (1 H, s) 13C{1H} NMR (101 MHz, METHANOL- rapid tautomerisation meant multiple peaks were missing from the 13C
NMR. HRMS (ESI Orbitrap) m/z: [M + H]+ Calcd for C9H11N3Br [M + H]+
240.0131, found [M + H]+ 240.0144.
d4)  ppm 38.6, 113.6, 113.8, 116.0, 123.9, 138.1, 141.8, 158.7 HRMS
(ESI Orbitrap) m/z: [M + H]+ Calcd for C9H11N379Br [M + H]+ 240.0131,
found [M + H]+ 240.0121. The spectroscopic data is in agreement with
those previously reported29
N,N-dimethyl-5H-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]imidazol-6-
amine (19) and N,N-dimethyl-8H-[1,3]dioxolo[4',5':3,4]benzo[1,2-
d]imidazol-7-amine (20).
Using general procedure 2 for benzimidazole formation was modified to
90 °C but otherwise identical with 2-(benzo[d][1,3]dioxol-5-yl)-1,1-
dimethylguanidine (58) (50 mg, 0.24 mmol), Cu(EAA)2 (19 mg, 0.06
mmol, 0.25 equiv) and pivalic acid (25 mg, 0.24 mmol, 1.0 equiv) for
12 hours. The products were purified by chromatography using the
5-Chloro-N,N-dimethyl-1H-benzo[d]imidazol-2-amine (15) and
4-Chloro-N,N-dimethyl-1H-benzo[d]imidazol-2-amine (16).
Using general procedure 2 for benzimidazole formation was performed
with 2-(3-chlorophenyl)-1,1-dimethylguanidine (56) (203 mg, 1.02
mmol), Cu(EAA)2 (82 mg, 0.25 mmol, 0.25 equiv) and pivalic acid (104
mg, 1.02 mmol, 1.0 equiv) for 22 hours. The reaction was worked-up as
described general procedure 2, and purified by chromatography using
a SNAP KP-NH 28g column (60% EtOAc / Heptane  EtOAc) to isolate
5-chloro-N,N-dimethyl-1H-benzo[d]imidazol-2-amine (15) as a white
solid (61 mg, 0.31 mmol, 30%). The fractions containing impure 4-
chloro-N,N-dimethyl-1H-benzo[d]imidazol-2-amine (16) were re-
purified by chromatography (3% MeOH/CH2Cl2, 10 g SNAP Ultra
cartridge) to yield 4-chloro-N,N-dimethyl-1H-benzo[d]imidazol-2-amine
(16) as a white solid (10 mg, 0.05 mmol, 5%)
standard
method
to
yield
N,N-dimethyl-5H-
[1,3]dioxolo[4',5':4,5]benzo[1,2-d]imidazol-6-amine (19) as an off-white
solid (14 mg, 0.07 mmol, 28%) and N,N-dimethyl-8H-
[1,3]dioxolo[4',5':3,4] benzo[1,2-d]imidazol-7-amine (20) as an off white
solid (26 mg, 0.13 mmol, 53%)
N,N-dimethyl-8H-[1,3]dioxolo[4',5':3,4]benzo[1,2-d]imidazol-7-amine
(20) Melting point: 110–112 °C FTIR νmax/cm-1 3357, 3126 (br), 1664,
1622, 1603, 1463. 1H NMR (400 MHz, METHANOL-d4)  ppm 2.99 (6
H, s), 5.80 (2 H, s), 6.43 (1 H, d, J=8.2 Hz), 6.55 (1 H, d, J=8.2 Hz)
13C{1H} NMR an informative 13C spectra could not be obtained due to
the low sample quantity and multiple peaks were not present in the
spectra. All of the available material was loaded into the NMR tube,
despite this, the signals were not detectable above the baseline, even
when increasing the number of scans to 8192. HRMS (ESI Orbitrap)
m/z: [M + H]+ Calcd for C10H12N3O2 [M + H]+ 206.0924, found [M + H]+
206.0916. N,N-dimethyl-5H-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]imidazol-
6-amine (19) Melting point: > 400 °C FTIR νmax/cm-1 2981, 2867, 1623,
1601, 1496, 1463, 1423. 1H NMR (400 MHz, METHANOL-d4)  ppm
2.96 (6 H, s), 5.73 (2 H, s), 6.64 (2 H, s) 13C{1H} an informative 13C
spectra could not be obtained due to the low sample quantity and
multiple peaks were not present in the spectra. Sample saturation was
performed (as above) in an attempt to afford a more informative
4-Chloro-N,N-dimethyl-1H-benzo[d]imidazol-2-amine (16)
1H NMR (400 MHz, METHANOL-d4)  ppm 3.15 (6 H, s), 6.91 (1 H, d,
J=8.0 Hz), 6.97 (1 H, dd, J=8.0, 1.1 Hz), 7.12 (1 H, dd, J=8.0, 1.1 Hz)
13C{1H} NMR (101 MHz, METHANOL-d4)  ppm 39.1, 121.4 – 122.1
(br), 159.0 Multiple signals missing from spectra. Broad signal at 121–
122 ppm is at least two signals. It is likely that the quaternary carbons
are the non-observable signals and the lack of material meant a more
resolved spectrum was not obtained. HRMS Calculated for C9H11N3Cl
[M + H]+ 196.0636, found [M + H]+ 196.0646.
5-Chloro-N,N-dimethyl-1H-benzo[d]imidazol-2-amine (15) 1H NMR
(400 MHz, METHANOL-d4)  ppm 3.11 (6 H, s), 6.94 (1 H, dd, J=8.4,
1.9 Hz), 7.13 (1 H, d, J=8.4 Hz), 7.17 (1 H, d, J=1.9 Hz) HRMS (ESI
Orbitrap) m/z: [M + H]+ Calcd for C9H11N3Cl [M + H]+ 196.0636, found
8 | J. Name., 2012, 00, 1-3
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ARTICLE
spectrum. HRMS (ESI Orbitrap) m/z: [M + H]+ Calcd for C10H12N3O2 [M
+ H]+ 206.0924, found [M + H]+ 206.0915.
4-(6-bromo-1H-benzo[d]imidazol-2-yl)morpholineV(i2ew5)A.rticle Online
Using general procedure 2 for benzimidazole formation was performed
DOI: 10.1039/C9OB01651A
with N'-(4-bromophenyl)morpholine-4-carboximidamide (63) (269 mg,
0.95 mmol), Cu(EAA)2 (78 mg, 0.24 mmol, 0.26 equiv) and pivalic acid
(99 mg, 0.97 mmol, 1.0 equiv) for 21 hours to yield (25) as a brown
solid. (157 mg, 0.56 mmol, 59%)
N,N-diethyl-1H-benzo[d]imidazol-2-amine (21).
Using general procedure 2 for benzimidazole formation was performed
with 1,1-diethyl-2-phenylguanidine (59) (256 mg, 1.34 mmol), Cu(EAA)2
(108 mg, 0.34 mmol, 0.25 equiv) and pivalic acid (139 mg, 1.36 mmol,
1.0 equiv) for 19 hours to yield N,N-diethyl-1H-benzo[d]imidazol-2-
amine (21) as a pale orange solid. (118 mg, 0.62 mmol, 46%)
Melting point: 202–204 °C FTIR νmax/cm-1 2964, 2871, 1625, 1599,
1567. 1H NMR (400 MHz, METHANOL-d4)  ppm 1.24 (6 H, t, J=7.0
Hz), 3.51 (4 H, q, J=7.0 Hz), 6.97 (2 H, dd, J=5.5, 3.2 Hz), 7.22 (2 H,
dd, J=5.5, 3.2 Hz) 13C{1H} NMR (101 MHz, METHANOL-d4)  ppm
12.3, 42.6, 111.2, 119.7, 138.2 (br), 155.1 HRMS (ESI Orbitrap) m/z:
[M + H]+ Calcd for C11H16N3 [M + H]+ 190.1339, found [M + H]+ 190.1331.
Melting point: 235–236 °C FTIR νmax/cm-1 3476 (br), 2976, 2842, 1626,
1
1557, 1441. H NMR (400 MHz, METHANOL-d4)  ppm 3.48 – 3.55 (4
H, m), 3.79 – 3.87 (4 H, m), 7.09 – 7.19 (2 H, m), 7.39 (1 H, app. s)
13C{1H} NMR (101 MHz, CHLOROFORM-d)  ppm 46.6, 66.1, 113.8,
123.9, 156.4. 4 signals are missing from the spectra, presumably the
quaternary carbons. HRMS (ESI Orbitrap) m/z: [M + H]+ Calcd for
C11H13BrN3O [M + H]+ 282.0237, found [M + H]+ 282.0233.
Emedastine synthesis
2-(Piperidin-1-yl)-1H-benzo[d]imidazole (23).
4-cyano-1,4-diazepane-1-carboxylate (45).
Using general procedure 2 for benzimidazole formation was performed To an ice-cooled solution of cyanogen bromide (3.147 g, 29.7 mmol, 1
with N-phenylpiperidine-1-carboximidamide (60) (263 mg, 1.29 mmol), equiv) in chloroform (10 mL) under a nitrogen atmosphere was added
Cu(EAA)2 (101 mg, 0.32 mmol, 0.25 equiv) and pivalic acid (137 mg, tert-butyl 1,4-diazepane-1-carboxylate (6.17 g, 30.8 mmol, 1.05 equiv)
1.34 mmol, 1.0 equiv) for 24 hours to yield 2-(piperidin-1-yl)-1H- and diisopropylethylamine (4.00 g, 30.9 mmol, 1.05 equiv) both as a
benzo[d]imidazole (23) as a pale orange solid. (108 mg, 0.54 mmol, solution in chloroform (20 mL). The reaction was slowly allowed to warm
41%)
to rt. After 4 h, the reaction was quenched with 2M NaOH (50 mL) and
Melting point: 276–278 °C FTIR νmax/cm-1 2947, 2849, 1625, 1565, 1542. extracted with CH2Cl2 (3 x 40 mL). The combined organic extracts were
1H NMR (400 MHz, METHANOL-d4)  ppm 1.65 – 1.77 (6 H, m), 3.47
dried over anhydrous MgSO4, concentrated in vacuo and purified by
chromatography (20% ethyl acetate in heptane) to yield 45 as a
colourless oil (4.668 g, 20.7 mmol, 70%).
– 3.58 (4 H, m), 6.99 (2 H, dd, J=5.6, 3.1 Hz), 7.23 (2 H, dd, J=5.6, 3.1
Hz) 13C{1H} NMR (101 MHz, METHANOL-d4)  ppm 23.9, 25.0, 47.0,
111.7 (br.), 120.0, 156.5 One 13C signal is missing. HRMS (ESI
Orbitrap) m/z: [M + H]+ Calcd for C12H16N3 [M + H]+ 202.1339, found [M
+ H]+ 202.1329. The spectroscopic data is in agreement with those
previously reported31
1H NMR (400 MHz, CHLOROFORM-d)  ppm 3.34 – 3.48 (m, 4 H), 3.19
– 3.25 (m, 2 H), 3.12 – 3.18 (m, 2 H), 1.79 – 1.91 (m, 2 H), 1.37 (s, 9
H). 13C NMR (101 MHz, CHLOROFORM-d)  ppm 27.6, 28.3, 46.0,
47.5, 50.3, 52.0, 80.1, 117.7, 154.6. Observed as a mixture of rotomers.
The spectroscopic data is in agreement with those previously reported32
4-(1H-Benzo[d]imidazol-2-yl)morpholine (24).
Using general procedure 2 for benzimidazole formation was performed
with N-phenylmorpholine-1-carboximidamide (61) (250 mg, 1.22
Tert-butyl4-(N'-phenylcarbamimidoyl)-1,4-diazepane-1
mmol), Cu(EAA)2 (98 mg, 0.31 mmol, 0.25 equiv) and pivalic acid (126 carboxylate (46).
mg, 1.23 mmol, 1.0 equiv) for 24 hours to yield 4-(1H-benzo[d]imidazol- To a stirred suspension of 60% sodium hydride (0.620 g, 15.5 mmol,
2-yl)morpholine (24) as an off-white solid. (129 mg, 0.64 mmol, 52%) 1.1 equiv) in DMSO (10 mL) was added aniline (1.33 g, 14.3 mmol, 1
Melting point: 286–287 °C FTIR νmax/cm-1 2981, 2848, 1625, 1560, equiv) as a solution in DMSO (9 mL) dropwise. After 15 minutes, tert-
1
butyl 4-cyano-1,4-diazepane-1-carboxylate 45 (3.00 g, 13.3 mmol, 0.93
equiv) was added as a solution in DMSO (10 mL) and the reaction
stirred at room temperature for 24 hours, at which point a further portion
of tert-butyl 4-cyano-1,4-diazepane-1-carboxylate 45 (0.500 g, 2.2
mmol, 0.16 equiv) was added as a solution in DMSO (5 mL). After a
further 60 minutes, the reaction was quenched with water (50 mL) and
extracted into tBME (3 × 50 mL). The combined organic extracts were
washed with water (3 × 50 mL) and brine (1 × 30 mL) before being
purified by chromatography (SNAP Ultra, 50% EtOAc/Heptane 
EtOAc with 2% triethylamine in the EtOAc portions) to yield an off white
solid (3.17 g, 9.6 mmol, 96.7% purity by HPLC analysis, 67.4% based
on aniline). The off-white solid was recrystallised from tBME to yield
2.65 g of analytically pure material of > 99% purity by HPLC analysis
which was used in the subsequent dehydrogenative cyclisation.
Melting point: 107–108 °C FTIR νmax/cm-1 3485, 3395, 2979, 1680,
1618, 1575. 1H NMR (400 MHz, METHANOL-d4)  ppm 1.52 (9 H, s),
1.87 – 1.98 (2 H, m), 3.49 (2 H, t, J=5.9 Hz), 3.55 (2 H, t, J=5.9 Hz),
3.60 – 3.67 (4 H, m), 6.91 (2 H, d, J=7.6 Hz), 7.01 (1 H, t, J=7.6 Hz),
7.29 (2 H, t, J=7.6 Hz) Observed as a mixture of rotomers. 13C{1H} NMR
(101 MHz, DMSO-d6)  ppm 27.1, 28.6, 45.8, 46.2, 46.6, 46.8, 47.1,
47.4, 48.2, 48.6, 78.8, 78.9, 120.5, 123.5, 129.3, 151.2, 151.3, 151.9,
154.9. HRMS (ESI Orbitrap) m/z: [M + H]+ Calcd for C17H27N4O2 [M +
H]+ 319.2129 found [M + H]+ 319.2116.
1451. H NMR (400 MHz, METHANOL-d4)  ppm 3.44 – 3.54 (4 H, m),
3.76 – 3.85 (4 H, m), 7.03 (2 H, dd, J=5.3, 3.2 Hz), 7.28 (2 H, dd, J=5.3,
3.2 Hz) 13C{1H} NMR (101 MHz, METHANOL-d4)  ppm 46.3, 65.9,
112.0, 120.4, 137.6 (br), 156.3 (br) HRMS (ESI Orbitrap) m/z: [M + H]+
Calcd for C11H14N3O [M + H]+ 204.1131, found [M + H]+ 204.1121. The
spectroscopic data is in agreement with those previously reported22
6-Bromo-N,N-diethyl-1H-benzo[d]imidazol-2-amine (22).
Using general procedure 2 for benzimidazole formation was performed
with 2-(4-bromophenyl)-1,1-diethylguanidine (62) (217 mg, 0.80
mmol), Cu(EAA)2 (66 mg, 0.20 mmol, 0.25 equiv) and pivalic acid (84
mg, 0.82 mmol, 1.0 equiv) for 18 hours to yield 6-bromo-N,N-diethyl-
1H-benzo[d]imidazol-2-amine (22) as an off-white solid. (159 mg, 0.59
mmol, 74%)
Melting point: 190–192 °C FTIR νmax/cm-1 2971, 2929, 1625, 1560,
1463. 1H NMR (400 MHz, METHANOL-d4)  ppm 1.27 (6 H, t, J=7.1
Hz), 3.54 (4 H, q, J=7.1 Hz), 7.04 - 7.13 (2 H, m), 7.33 (1 H, d, J=1.0
Hz) 13C{1H} NMR (101 MHz, METHANOL-d4)  ppm 12.2, 42.7, 111.8,
112.2, 114.3, 122.2, 155.7 Two signals missing from spectra. HRMS
(ESI Orbitrap) m/z: [M + H]+ Calcd for C11H1579BrN3 [M + H]+ 268.0444,
found [M + H]+ 268.0445.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 9
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Journal Name
155.5, 158.8, 159. HRMS (ESI Orbitrap) m/z: [M + VHiew]+ ACrticallecOdnlfinoer
C21H33N4O3 [M + H]+ 389.2547, found [M + H]+ 389.2534
DOI: 10.1039/C9OB01651A
Tert-butyl
carboxylate (47).
To round bottom flask was added tert-butyl 4-(N- (50).
4-(1H-benzo[d]imidazol-2-yl)-1,4-diazepane-1-
2-(1,4-Diazepan-1-yl)-1-(2-ethoxyethyl)-1H-benzo[d]imidazole
a
phenylcarbamimidoyl)-1,4-diazepane-1-carboxylate (46) (2415 mg, 7.6 To a dry round bottomed flask containing tert-butyl 4-(1-(2-ethoxyethyl)-
mmol, 1 equiv), Cu(EAA)2 (303 mg, 0.94 mmol, 0.12 equiv) and pivalic 1H-benzo[d]imidazol-2-yl)-1,4-diazepane-1-carboxylate (50) (1.397 g,
acid (776 mg, 7.6 mmol, 1.03 equiv) prior to the addition of a stir bar 3.6 mmol, 1.0 equiv) was added HCl as a solution in EtOAc (1 M, 20
and sulfolane (20 mL). The reaction was heated to 100 °C for 30 hours mL, 20 mmol, 5.6 equiv). The reaction was stirred at room temperature
at which point it was then cooled to room temperature. The resultant for 64 hours before quenching with saturated sodium bicarbonate (50
solid was suspended between water (100 mL) and tBME (100 mL) mL) and diluting with CH2Cl2 (30 mL). The organic layer was separated
before addition of EDTA(aq) (20 mL, 0.1 M). The organic portion was and the resultant aqueous portion washed a further 2 times with CH2Cl2
separated and the aqueous washed with further tBME (3 × 75 mL). The (2 x 10 mL). The combined organics were washed with brine (10 mL),
resultant aqueous solution (~100 mL) was then saturated with NaCl and dried over a hydrophobic frit and concentrated in vacuo to yield 2-(1,4-
then extracted with tBME (1 × 50 mL). The combined organic extracts diazepan-1-yl)-1-(2-ethoxyethyl)-1H-benzo[d]imidazole (50a) as
a
were then washed with water (5 × 50 mL), the water washes back- pale-yellow oil (962 mg, 3.3 mmol, 93%).
extracted with tBME (2 × 50 mL) and the combined organic portions FTIR νmax/cm-1 3400 (br), 2970, 2872, 1528, 1464, 1408, 1285. 1H NMR
washed with brine. The brown organic solution was reduced in volume
to ~30 mL at which point a white solid precipitated. The mixture was
cooled in an ice bath and the solid was filtered to yield a white solid
(1.410 g). The organic solution was then purified by chromatography
(SNAP Ultra, 0–3 % MeOH/CH2Cl2) to yield 305 mg of a white solid.
The two solids were combined, homogenised with MeOH and
evaporated to give tert-butyl 4-(1H-benzo[d]imidazol-2-yl)-1,4-
diazepane-1-carboxylate (47) as a white solid (1.715 g, 5.4 mmol, 71%)
Melting point: 219–220 °C. FTIR νmax/cm-1 2970 (br), 1686, 1626, 1597,
1566, 1461. 1H NMR (400 MHz, METHANOL-d4)  ppm 1.30 (5 H, s),
1.38 (4 H, s), 1.88 – 2.08 (2 H, m), 3.38 – 3.48 (2 H, m), 3.63 – 3.81 (6
H, m), 6.95 – 7.02 (2 H, m), 7.19 – 7.26 (2 H, m) Observed as a mixture
of rotomers. 13C{1H} NMR (101 MHz, METHANOL-d4)  ppm 22.3, 26.1,
26.2, 27.0, 27.2, 27.3, 45.5, 45.9, 46.2, 46.5, 47.9, 48.3, 48.6, 50.6,
79.8, 111.6, 119.9, 154.7, 155.4, 155.6 HRMS (ESI Orbitrap) m/z: [M
+ H]+ Calcd for C17H25N4O2 [M + H]+ 317.1972, found [M + H]+ 317.1867.
(400 MHz, CHLOROFORM-d)  ppm 1.15 (3 H, t, J=7.0 Hz), 1.94 (2 H,
quin, J=5.9 Hz), 2.30 (1 H, br. s), 3.04 – 3.08 (2 H, m), 3.10 – 3.15 (2
H, m), 3.47 (2 H, q, J=7.0 Hz), 3.59 – 3.64 (4 H, m), 3.79 (2 H, t, J=6.0
Hz), 4.20 (2 H, t, J=6.0 Hz), 7.08 – 7.20 (2 H, m), 7.24 – 7.29 (1 H, m),
7.52 – 7.57 (1 H, m) 13C{1H} NMR (101 MHz, CHLOROFORM-d)  ppm
15.1, 31.1, 44.7, 48.2, 49.8, 52.7, 55.8, 66.9, 68.3, 109.1, 117.6, 120.8,
121.7, 135.5, 141.7, 159.2 HRMS (ESI Orbitrap) m/z: [M + H]+ Calcd for
C16H25N4O [M
+ +
H]+ 289.2023, found [M H]+ 289.2012 The
spectroscopic data is in agreement with those previously reported33
2-(4-Methyl-1,4-diazepan-1-yl)-1-(2-ethoxyethyl)-1H-
benzo[d]imidazole, Emedastine (2).
To a dry round bottomed flask containing 2-(1,4-diazepan-1-yl)-1-(2-
ethoxyethyl)-1H-benzo[d]imidazole (50) (915 mg, 3.2 mmol, 1.0 equiv)
was added formaldehyde (13.0 mL, 37 wt% aq, 175.0 mmol, 55 equiv)
and formic acid (1.80 g, 1.50 mL, 39.1 mmol, 12.3 equiv). The reaction
was stirred and heated to 80 °C for 30 minutes before diluting into water
Tert-butyl 4-(1-(2-ethoxyethyl)-1H-benzo[d]imidazol-2-yl)-1,4- (50 mL), basifying with NaOH to pH 10 (2 M aq) and extracting with
diazepane-1-carboxylate (49). CH2Cl2 (5 x 40 mL). The combined organic extracts were washed with
To suspension of tert-butyl 4-(1H-benzo[d]imidazol-2-yl)-1,4- brine (20 mL), dried over a hydrophobic frit and concentrated in vacuo
a
diazepane-1-carboxylate (47) (1.320 g, 4.2 mmol, 1.0 equiv) in THF (30 to yield an orange oil, which was purified by chromatography (0-10%
mL) was added 60% sodium hydride suspension (0.220 g, 5.5 mmol, MeOH / CH2Cl2 w/ 1% Et3N in the CH2Cl2 portion) to yield 2-(4-methyl-
1.3 equiv) in 5 separate portions over a period of 15 minutes. The 1,4-diazepan-1-yl)-1-(2-ethoxyethyl)-1H-benzo[d]imidazole
resultant solution was stirred for 15 minutes before addition of 1-(2- (Emedastine, 2) as a pale yellow oil (824 mg, 2.7 mmol, 86%).
iodoethoxy)ethane (48) (1.155 g, 5.8 mmol, 1.4 equiv) as a solution in FTIR νmax/cm-1 2910, 2803, 1611, 1532, 1470. 1H NMR (400 MHz,
THF (2 mL). The reaction was heated to reflux for 18 hours under
nitrogen before a second addition of 1-(2-iodoethoxy)ethane (48)
(0.162 g, 0.81 mmol, 0.2 equiv). After a further 60 minutes the reaction
was cooled to room temperature, quenched with water and the volatiles
removed under reduced pressure. The resultant aqueous was
extracted into CH2Cl2 (3 × 30 mL), the combined organic portions
washed with brine, dried over a hydrophobic frit and concentrated in
vacuo. The crude material was purified by chromatography (SNAP
Ultra, 40% EtOAc/heptane  EtOAc) to yield tert-butyl 4-(1-(2-
ethoxyethyl)-1H-benzo[d]imidazol-2-yl)-1,4-diazepane-1-carboxylate
(49) as a colourless oil (1.443 g, 3.7 mmol, 89%)
CHLOROFORM-d)  ppm 1.17 (3 H, t, J=7.0 Hz), 2.06 (2 H, br. s.), 2.45
(3 H, s), 2.79 (4 H, m), 3.48 (2 H, q, J=6.9 Hz), 3.67 (2 H, t, J=6.2 Hz),
3.71 (2 H, m), 3.80 (2 H, t, J=6.0 Hz), 4.21 (2 H, t, J=6.0 Hz), 7.15 (2 H,
m), 7.26 (1 H, s) 7.55 (1 H, m) 13C{1H} NMR (101 MHz, CHLOROFORM-
d)  ppm 15.1, 28.0, 44.9, 46.8, 51.9, 57.6, 58.6, 66.9, 68.3, 77.2, 109.1,
110.0, 117.5, 120.7, 121.7, 135.6, 141.8 HRMS (ESI Orbitrap) m/z: [M
+ H]+ Calcd for C17H27N4O [M + H]+ 303.2179, found [M + H]+ 303.2173
Spectroscopic data is in agreement with the literature.34
Conclusions
FTIR νmax/cm-1 2971, 2871, 1688, 1527, 1436, 1408. 1H NMR (400 MHz,
CHLOROFORM-d)  ppm 1.16 (3 H, t, J=6.9 Hz), 1.49 (4.5 H, s), 1.50
(4.5 H, s) 1.91 – 2.08 (2 H, m), 3.47 (3 H, q, J=6.9 Hz), 3.53 – 3.64 (5
H, m), 3.64 – 3.75 (2 H, m), 3.81 (2 H, t, J=5.8 Hz), 4.21 (2 H, t, J=5.8
Hz), 7.10 – 7.23 (2 H, m), 7.26 – 7.33 (1 H, m), 7.52 – 7.61 (1 H, m)
In summary, we have developed conditions for the direct formation of
2-aminobenzimidazoles from aryl guanidines under base-metal
catalytic conditions using air as the terminal, green oxidant.
Stabilisation of the catalytically active species is required using an
electron donating 1,3-dicarbonyl ligand to avoid dimerisation of the
benzimidazole product. The substrate scope of the reaction allows for
a range of functional groups to be tolerated, and a selection of amine
groups have been shown to be compatible with the reaction to afford
substituted 2-aminobenzimidazoles that may have an application within
Observed as
a
mixture of rotomers. 13C{1H} NMR (101 MHz,
CHLOROFORM-d)  ppm 15.1, 28.2, 28.5, 28.6, 44.6, 45.4, 44.7, 45.9,
47.7, 48.3, 52.7, 53.1, 54.2, 54.5, 66.9, 68.2, 68.3, 79.5, 79.6, 109.3,
117.8, 117.8, 121.0, 121.1, 121.8, 135.3, 135.4, 141.5, 141.6, 155.3,
10 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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Journal Name
ARTICLE
medicinal chemistry. Finally, we have shown how products of significant
pharmaceutical interest can be prepared using this method through the
Tamir, R.; Wang, X.; Xi, N.; Xu, S.; Zhu, D.; Gavva, N. R.; Treanor,
View Article Online
J. J. S.; Norman, M. H. J. Med. Chem. 200D6O, 4I:91,03.1701399./C9OB01651A
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marketed second-generation
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Conflicts of interest
There are no conflicts to declare.
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Correspondoing author
*Email: peter.r.clark@gsk.com
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Acknowledgements
We thank GlaxoSmithKline (GSK) for a PhD studentship (PRC), for
financial support and chemical resources. We thank the EPSRC for
funding via Prosperity Partnership EP/S035990/1. We thank J.
McKnight and D. Valette for initial scoping, S. Davies for DoE, P.
Rushworth & K. Wheelhouse for screening.
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DOI: 10.1039/C9OB01651A
N
N
NR2
Cu(II) cat, PivOH
R1
R1
NR2
H
N
N
2
H
2O2
O2
H
H
.
Copper-catalysed C–H functionalisation
.
Air/O2 as a terminal oxidant
.
Gram-scale synthesis of pharmaceutical compound