Promotion of Appel-type reactions by N-heterocyclic carbenes

Article abstract of DOI:10.1039/c9cc02132a

N-Heterocyclic carbenes (NHCs) have been extensively used as a versatile class of catalysts and ligands in organocatalytic and organometallic chemistry. However, there are only a small number of synthetic applications where they act as reagents. Here we demonstrate that NHCs can be used as stoichiometric redox reagents for Appel-type halogenation reactions of alcohols. This new reactivity reveals a fresh and interesting aspect and enriches the chemistry of NHCs in an underexplored area. The potential of performing this chemical transformation at the catalytic level using an NHC-oxide derivative is also investigated.

Full text of DOI:10.1039/c9cc02132a

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Promotion of Appel-Type Reactions by N-Heterocyclic Carbenes
Mohanad A. Husseina and Thanh Vinh Nguyena,*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
N-Heterocyclic carbenes (NHCs) have been used extensively as a
versatile class of catalysts and ligands in organocatalytic and
reagent predominant role
catalyst
R
R
catalyst for
Appel reaction
(e.g. ref. 23)
organometallic chemistry. However, there are only
a small
R P
R P
O
R
number of synthetic applications where they act as reagents. Here
we demonstrate that NHCs can be used as stoichiometric redox
reagents for Appel-type halogenation reactions of alcohols. This
new reactivity reveals a fresh and interesting aspect and enriches
chemistry of NHCs in an underexplored area. The potential of
performing this chemical transformation at catalytic level using an
NHC-oxide derivative is also investigated.
R
phosphine - P(III)
phosphine oxide - P(V)
R1
R1
no known
synthetic
application
N
Z
N
Z
O
Y
Y
R2
R2
NHC
"NHC-oxide"
catalyst
reagent
underexplored
well studied
This work: NHC and NHC-oxide promoted Appel reaction
Since the isolation of the first stable N-Heterocyclic carbene
(NHC) by Arduengo,1 NHCs have been utilized extensively as
ligands and catalysts in organometallic2 and organocatalytic
chemistry.3 NHCs and phosphines share similar electronic
properties and reactivities, which are why they enjoy
widespread applications in transition metal complexation2,3e
and nucleophilic organocatalysis.3g With recent developments
in chemistry of NHC-derived compounds, the correlation has
become even more obvious (Figure 1). For example, NHC
azolium precursors showed similar phase-transfer catalytic
activity to phosphonium salts.4 Furthermore, N-heterocyclic
olefins (NHOs), alkylidene derivatives of NHCs, possess highly
polarized structures and chemical reactivity comparable to
those of phosphonium ylides.5 Due to their inherent
nucleophilicity and structurally tunability, NHCs would be able
to act as excellent stoichiometric reagents to promote
chemical reactions. However, there are only a small number of
synthetic applications of NHCs in this aspect,6 despite the fact
that the analogous phosphines have numerous uses as
stoichiometric reagents (Figure 1).
Figure 1. Underexplored synthetic applications of NHCs as reagents
the redox-condensation of alcohols.8 The reductive behaviour
of NHCs in Matsuoka’s studies was very intriguing given that
NHCs have shown to be relatively stable under oxidizing
conditions.3f,9 These literature examples in combination with
our recent works4a,5,10 have inspired us to investigate the NHC-
promoted dehydrative halogenation reactions of alcohols.11
Herein we demonstrate that NHCs can be used as
stoichiometric reagents for Appel-type halogenation reaction
of alcohols with various halogen sources. Arguably, the use of
NHCs in stoichiometric amount is not always favorable, as
these species are not that readily accessible like phosphines.
Therefore, we also demonstrated the potential of
implementing these Appel-type reactions with catalytic
amounts of a ‘NHC-oxide’ (Figure 1), opening up new
opportunities for this type of species in organic chemistry.
Our investigation started with a standard Appel-type reaction
setup in which 2,5-dimethoxy benzylalcohol (1a, Table 1) was
added to a pre-mixed solution of triazolylidene NHC 2a12 and
carbon tetrachloride in dichloromethane at room
temperature.13 This test reaction was promising as we
observed the formation of the chloride product (4a) in
moderate yield. The reaction also led to the formation of the
NHC-oxide 5a, which was also isolated as a by-product from
the previous studies by Matsuoka and co-workers.7-8 This NHC-
oxide14 is the equivalent of phosphorus oxide by-products in
reactions promoted by P(III)-P(V) redox process.15
While the area has been inadequately explored to date,6
Matsuoka and co-workers recently reported elegant studies in
which they confirmed the phosphine-like oxophilicity of NHCs
in promoting transhydrogenation reactions with water7 and
a. School of Chemistry, University of New South Wales, Sydney, Australia
E-mail: t.v.nguyen@unsw.edu.au
Electronic Supplementary Information (ESI) available: Experimental details,
analytical data and NMR spectra are provided. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 2019
Chem. Commun., 2019, 55, 1-4 | 1
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We subsequently used the optimized reaction conditions
developed to convert a wide range of alcohols to their
View Article Online
DOI: 10.1039/C9CC02132A
Table 1. Optimization of NHC-promoted Appel-type reactionsa
corresponding halogenated derivatives (Scheme 1). All tested
primary and secondary alcohols served as good substrates for
this type of reaction, producing halogenated derivatives 4a-s
and 4u-x in good to excellent yields. A tertiary alcohol
underwent very sluggish reaction with very poor yield of
product 4t. Chiral alcohol (R)-1-phenylethanol (98% ee) was
converted to (S)-bromide 4s with almost inverted
stereochemistry (92% ee), hinting that the reaction likely
proceeded in an SN2 fashion.8 We therefore hypothesized that
the reaction follows a mechanistic pathway similar to that of
the phosphine-promoted Appel reactions,22 as depicted in
Scheme 2 (right) for the reaction using NBS and NHC 2a
reagents. The structure of the proposed intermediate 6’ was
consistent with the 13C NMR spectrum of a mixture between
NHC 2a and NBS. (Scheme 2, left).
At this point in our study, we turned our attention to the
possibility of regenerating the by-product NHC oxide 5a to an
active reagent for the same Appel-type halogenation reaction.
As discussed earlier in Figure 1, NHC-oxides are analogous to
phosphine oxides; the latter has been well-known to catalyze
Appel-type reaction with a sacrificial halogenating reagent.23
Based on this and our previous experience with the similar
dehydrative chlorination reaction using tropone catalyst,11a,11c
we anticipated that NHC oxide 5a could be converted to
halotriazolium halide salt 8 (Scheme 3) using oxalyl chloride or
oxalyl bromide. Salt 8 would presumably possess the same
reactivity with the reactive intermediate 6/6’ in Scheme 2,
hence be able to halogenate the alcohol substrates.
Entry
1
2
3
4
5
6
7
8c
9
10
11
12
13
14
15
16
NHC
2a
2a
2a
2a
2a
2a
2b
2c-2jc
2a
2a
2a
2a
2a
2a
2a
-
[Hal] 3
CCl4
CBr4
NBS
NBS
NBS
NBS
NBS
NBS/CBr4
Br2
BrCH(CO2Et)2
NCS
CCl3CCl3
CCl3C(=O)CCl3
I2
Solvent
DCM
DCM
DCM
toluene
MeCN
THF
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
Time
18 h
6 h
6 h
6 h
6 h
6 h
6 h
6 h
6 h
6 h
6 h
6 h
6 h
6 h
6 h
48 h
Yieldb (%)
26
44
78
46
69
76
59
21-41
67
40
53
16
19
69
55
traces
NIS
all 3
a
Reaction conditions: NHC
2 (1.2 mmol, freshly prepared from the
corresponding azolium salts and KHMDS, see page S5 in the ESI), halide source
3 (1.2 mmol),16 alcohol 1a (1.0 mmol) in 10 mL solvent at rt for the indicated
time. Yield of isolated 4 after column chromatography.17 See page S3 in the
b
c
ESI for detailed reaction outcomes of NHC 2c-2j.
The optimization of reaction conditions identified
dichloromethane as the best solvent for this transformation
(entries 3-6, Table 1).17 NHC 2a, coincidentally, acted as the
best promoter out of ten NHCs we screened (2a-j).17
Triazolylidenes 2a and 2b are the most suitable frameworks for
this type of reaction, which was in agreement with Matsuoka’s
studies.7-8 The ‘oxophilicity’ or the tendency to form stable
‘oxides’ of these NHCs somehow correlated to trends of NHC
reactivity reported by Smith and O'Donoghue,18 Lupton,19
Mayr,20 and our group10b where triazolylidene derivatives are
generally considered the least nucleophilic NHCs.
Various halide sources for the Appel reaction were also
investigated (Table 1).16 The dehydrative halogenation
processes went smoothly with elemental bromine and
diethylbromomalonate, albeit with lower yields than reactions
with NBS. Elemental iodine gave better results than NIS for
iodination reactions (entries 14-15). On the other hand,
reactions with NXS21 (entries 3, 11 and 15, Table 1) were
generally cleaner than ones with perhalogenated reagents
1
(entries 1-2 and 12-13, Table 1), as monitored by TLC and H
NMR spectroscopy. Control experiments with no NHC reagent
(entry 16, Table 1) did not lead to any significant amounts of
halogenated products even after prolonged reaction time.17
Scheme 1. NHC-promoted Appel-type reactions of alcohols.
2 | Chem. Commun., 2019, 55, 1-4
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Indeed, a test reaction with alcohol 1a, 20 mol% NHC-oxide 5a hinted that the catalytic reaction might be less effective to the
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DOI: 10.1039/C9CC02132A
and the slow addition of oxalyl chloride over 24 hours gave non-activated alcohols.
very promising result with the formation of product 4a in high In comparative studies on performance of 5a against similar
yield. The addition rate was calculated such that the local catalytic systems, our experimental protocol gave similar
concentration of oxalyl chloride at any one point is lower than results to previous catalytic systems such as phosphine
that of the NHC-oxide catalyst loading. The optimized reaction oxide,23 cyclopropenone,24 sulfoxides,25 formamides26 and our
conditions were developed with just 10 mol% catalyst 5a and previous studies on tropone.11a,11c Using the same catalyst
10 hours slow addition time, which were applied to convert loadings and oxalyl halides on four different substrates
several alcohols to their corresponding chlorides and bromides (Scheme 3b), it was shown that 5a was slightly less effective
using oxalyl chloride and bromide, respectively (Scheme 3a). than phosphine oxide but comparable to cyclopropenone and
The efficiency of this catalytic system is similar to that of the better than tropone (which normally require elevated
stoichiometric NHC-mediated reactions in Scheme 2, with the temperature). Thus, these Appel reactions with catalytic
only exception of product 4w. The low yield of this aliphatic amount of NHC-oxide as promoter open up new opportunities
product in comparison to other benzylic products in Scheme 3 for this type of chemical species in organic synthesis.
13C NMR (400 MHz, CD2Cl2, 25 °C): NBS
Ph
Ph
O
N
N
N
N
Br
O
Br
R
N
O
R
N
N
Ph
Ph
O
7
Ph
Ph
R'
N
Br
3
6
R'
OH
1
O
- succinimide
Ph
Ph
N
N
N
Br
R
Br
N
13C NMR (400 MHz, CD2Cl2, 25 °C): mixture NBS + NHC 2a
O
N
O
O
N
Ph
N
Ph
Ph
6'
Ph
6'
Ph
7'
R'
N
N
Br
N
O
O
N
Ph
SN2
R'
Ph
Ph
Ph
O
R
N
N
+
N
N
N
Br
-
O
Br
N
N
Ph
4
Ph
O
3
Ph
2a
Ph
5a
Scheme 2. (right) Proposed mechanism for the NHC-promoted Appel reaction with NBS; (left) 13C NMR spectra of a 1 : 1 mixture of NHC 2a and NBS (bottom-left) in CD2Cl2 at 25 C
after 20 minutes in comparison to pure NBS (top-left).
(b) comparative studies 5a vs phosphine oxide, cyclopropenone and tropone
Ph
5a
10% catalyst, DCM, rt, 16 h
N
R
10 mol%
R
N
O
(COHal)2
1.2 equiv
slow addition over 10 h
R'
OH
R'
Hal
R
N
(COHal)2 1.2 equiv, slow addition over 10 h
Ph
4
1
Ph
R'
R'
Hal
4
OMe
OMe
DCM, rt, 16 h
Ph
Cl
Br
Cl
4a
Br
nC20H41
R
4f
4b
4w
cat.
5a
CO + CO2
Hal
Hal
N
OMe
OMe
64%
OH
N
1
82%
73%
78%
42%
74%
N
Ph
Hal = Cl or Br
Ph
8
90%
87%
Ph3P=O
O
(a) with 5a catalyst
80%
74%
55%
71%
50%
33%
Ph
Ph
Cl
Br
Br
Br
O
O2N
69%
51%
Ph
O2N
4q, 90%
4e, 61%
4f, 55%
4k, 71%
Scheme 3. (a) Catalytic Appel reaction with NHC-oxide 5a and oxalyl halides; (b) Comparative studies between 5a and other known catalytic systems.
In conclusion,
a new method employing N-heterocyclic to phosphines. Furthermore, NHC-oxides could be used as
carbenes as reagents for the Appel-type halogenation reaction promoters for these reactions in a catalytic manner with
of alcohols was developed. NHCs could be used as suitable sacrificial halogenating agents. The promotion of
stoichiometric reagents for these reactions in a similar fashion Appel-type reactions by NHCs is a conceptually different
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Chemical Communications
11. (a) T. V. Nguyen and A. Bekensir, Org. Lett., 2014, 16, 1720-
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Effers and J. H. Teles, Angew. Chem. Int. Ed., 2010, 49, 7120-
7124; (b) A. Berkessel and S. Elfert, Adv. Synth. Catal., 2014,
356, 571-578.
15. H. A. van Kalkeren, F. L. van Delft and F. P. J. T. Rutjes,
ChemSusChem, 2013, 6, 1615-1624.
16. All halogen-source reagents were distilled or recrystallized
before use.
17. See the Supporting Information for more details.
18. R. S. Massey, C. J. Collett, A. G. Lindsay, A. D. Smith and A. C.
O’Donoghue, J. Am. Chem. Soc., 2012, 134, 20421-20432.
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50, 6915-6919.
21. That the reaction did not proceed partly or totally through free
radical halogenation with NCS or NBS was confirmed by control
reactions with BHT additive as a radical scavenger, which
worked and led to similar outcomes.
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application of NHCs in synthetic organic chemistry, which will
not only enrich the chemistry of these versatile species but
also define a new area of research for future investigations.
The authors acknowledge the Australian Research Council
(grants DE150100517 and FT180100260 to TVN) for financial
support. MAH is grateful to the Iraqi HCED for sponsoring his
Ph.D. scholarship. The authors thank A/Prof Jason Harper
(UNSW Sydney) for helpful discussions.
Notes and references
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4 | Chem. Commun., 2019, 55, 1-4
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DOI: 10.1039/C9CC02132A
N-Heterocyclic carbenes are found to mediate Appel-type dehydrative
halogenation reaction
NHC-mediated Appel reaction
Ph
N
N
NXS
N
Ph
R
R
Ph
R'
Hal
R'
OH
DCM, rt, 6 h