N-Heterocyclic olefins as efficient phase-transfer catalysts for base-promoted alkylation reactions

Article abstract of DOI:10.1039/c6cc03771b

N-Heterocyclic olefins (NHOs) have very recently emerged as efficient promoters for several chemical reactions due to their strong Br?nsted/Lewis basicities. Here we report the novel application of NHOs as efficient phase-transfer organocatalysts for synt

Full text of DOI:10.1039/c6cc03771b

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DOI: 10.1039/C6CC03771B
Chemical Communications
COMMUNICATION
N-Heterocyclic Olefins as Efficient Phase-Transfer Catalysts for
Base-Promoted Alkylation Reactions
Marcus Blümel,a,b Reece D. Crocker,a Jason B. Harper,a Dieter Endersb and Thanh V. Nguyen*,a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
N-Heterocyclic Olefins (NHOs) have very recently emerged as compounds to serve as an evolved class of organocatalysts
efficient promoters for several chemical reactions due to their with enhanced Brønsted/Lewis basicity for a wide range of
strong Brønsted/Lewis basicities. Here we report the novel chemical reactions.[8] We have recently established the use of
application of NHOs as efficient phase-transfer organocatalysts for NHOs as organocatalysts for transesterification reactions.[9] In
synthetically important alkylation reactions on a wide range of this article, we report another investigation for the
substrates, further demonstrating the great potential of NHOs in development of NHOs as promoters of organic chemical
organic chemistry.
transformations. Thus, NHOs and their azolium salt precursors
were employed as very efficient organocatalysts for solid-
liquid phase-transfer alkylation reactions.
In the last two decades, the utility of N-Heterocyclic carbenes
(NHCs) has evolved dramatically in many important areas,
most notably organometallic and organocatalytic chemistry.[1]
These intriguing chemical species have played critical roles in
the development of a wide range of transition metal-NHC
complexes with unusual stability and catalytic activity.[2] At the
same time, NHCs have been used extensively as
organocatalysts to promote fascinating chemical reactions.[1]
While NHC organocatalysts are mostly well-known for their
umpolung chemistry of carbonyl compounds via the formation
of the acyl anion intermediates,[3] their role as Brønsted/Lewis
base catalysts has been inadequately investigated due to
limitations in basicity and scope of reaction types.
N-Heterocylic Olefins (NHOs), previously known in the
literature as heterocyclic ketene aminal or ene-1,1-diamine
substrates used in several types of cycloaddition reactions,[4]
have lately emerged as an interesting class of ligands and
reaction promoters. These alkylidene derivatives of NHCs
possess an exocyclic carbon center with particularly high
electron density due to the electron donating effect of the two
conjugate heteroatoms and the partial aromatization of the
heterocycle. This nucleophilic carbon center can act as a very
strong Lewis basic site, resulting in several important
applications of NHO ligands in transition metal complexation
and catalysis.[5] Recent studies have also revealed interesting
catalytic activities of NHOs for CO2-sequestration[6] and ring-
opening polymerization reactions.[7] We postulated that with
suitable structural design, NHOs can overtake their parent NHC
Phase-transfer catalysis (PTC) has been widely used in
laboratory synthesis as well as the industrial production of fine
chemicals.[10] Apart from the host-guest cation transfer by
crown ethers,[11] phase-transfer catalysis has generally utilized
ammonium and phosphonium salts for physical anion transfer
catalysis (Scheme 1).[12] Recent developments have included
phase-transfer chemistry promoted by imidazolium,[13]
triazolium,[14]
cyclopropenium[10,15]
and
tetraamino-
phosphonium[16] salts. Although these salts can efficiently
facilitate numerous chemical transformations, a versatile
catalytic system with highly tunable structure, also with high
stability and easy accessibility on large scale at the same time,
has always been in high demand. Based upon our original
concept of utilizing NHOs as Brønsted base catalysts,[8] we
envisaged that NHOs or their azolium salt precursors could be
used cooperatively with a strong base in a ’chemically active’
fashion for solid/organic phase-transfer catalysis (Scheme 1).
This system is distinguished from the other catalysts in that it
presumably proceeds through the deprotonation of the
azolium salt in the organic solution by the solid base, which
Scheme 1. Phase-transfer catalysis with N-Heterocyclic Olefins.
THIS WORK: PTC for anions with NHOs
PTC for anions with onium salts
solid phase (surface)
organic phase
R1
aqueous phase
organic phase
R
R2
BH
+
Me
N
N
CH2
X
PTC OH
X
H
Me
X
R3
X
R
R
+
Me
Me
X
CH3
N
R2
R1
B
N
OH
pKa ~ 24-28 [ref 9]
OH
PTC
X
R3
R
physical transfer of base
chemical transfer of base
This journal is © The Royal Society of Chemistry 2016
Chem. Commun., 2016, 52, 1-4 | 1
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Control reactions without catalyst (Table 1, entries 1a, 2a and
Table 1. Optimization of the NHO catalyzed phase-transfer alkylation reaction[a]
0]
icle Online
5a) gave lower yields with much longer reaction tiVmieewsA.r[t2
We subsequently turned our atDteOnI:t1io0n.103t9o/C6CdCif0fe3r7e71nBt
imidazolium-based NHO precursors (Table 2). The NHO
precursor B without methyl groups at C4-C5 catalyzed the
reaction with comparable results to its analogous catalyst A
(Table 2, entry 2). Therefore we assume that a deprotonation
at C4 or C5 of the imidazolium ring[8] was not taking place or
interfering with the phase-transfer catalysis. Sterically
demanding aryl groups in close proximity to the reactive
center had no impact on the efficiency of the reaction (catalyst
C, Table 2, entry 3). Presumably, due to the electronic
stabilization by the π-systems, the acidity of the C2-methyl
group is increased, which allows for an easier deprotonation to
the NHO. Indeed the acidity of these NHO precursor catalysts
was determined to be in agreement with this observation,[9]
which aligned well with the acidity trend for their
corresponding NHC precursors.[1b] C2-iPr substituted catalyst D
also afforded the alkylation product in excellent yield, albeit a
slightly prolonged reaction time was necessary (Table 2, entry
4). A similar observation on the effect of steric hindrance to
the reaction outcomes was also observed by other groups.[7]
Comparable yields could be achieved with decreased catalyst
loadings to 2, 1 and 0.5 mol % when using the most readily
available catalyst A (Table 2 entries 5-7); the reaction times,
however, predictably increased from 5 to 40 minutes. Thus, we
found the best balance between catalyst loading and reaction
time at 1 mol % catalyst (Table 2, entry 6).
1.2 equiv base, r.t.
O
O
O
O
Br
+
Me
OEt
OEt
Me
I
N
N
1a
2a
CH3
A
3a
Me
Me 5 mol %
Entry
Solvent
Base
Time [min][b]
Yield [%][c]
1
1a[d]
2
toluene
toluene
hexane
hexane
Et2O
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
K2CO3
K3PO4
KOH
30
4320
60
1440
60
10
5
210
94
77
93
80
93
92
94
86
16
28
89
80
66
2a[d]
3
4
THF
5
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
5a[d]
6
>1440[e]
>1440[e]
180
7
8
9
10
KH
5
KHMDS
>1440[e]
[a] The reactions were carried out with 1.0 mmol of 1a, 1.2 mmol of base,
and 1.25 mmol of BnBr (2a) in the presence 0.05 mmol NHO precursor A in
4 mL of solvent at ambient temperature. [b] Reactions were monitored
using TLC until complete consumption of starting material, unless
otherwise noted. [c] Yield of the isolated products. [d] Reaction without
catalyst. [e] The reaction was not completed after one day.
results in the free NHO as the active catalyst. This NHO catalyst
then promotes the reaction in the organic phase, in this
context being the alkylation reaction, to regenerate the
azolium salt for another catalytic cycle. Within seconds of
mixing suitable solid inorganic bases, such as KOtBu, and
organic solutions of imidazolium precursors, we observed the
immediate formation of NHOs,[17,18] which confirmed the
feasibility of our proposed phase-transfer catalytic system.
We chose a family of the readily available imidazolylidene-
derived NHO precursors[7,18] for an initial investigation of the
typical PTC benzylation reaction of a β-ketoester substrate
(Table 1). To our delight the reaction between β-ketoester 1a
and alkyl bromide 2a in the presence of base and the
pentamethyl NHO precursor A in toluene proceeded smoothly
to produce the desired product 3a in 94% yield within a short
reaction time of 30 minutes. Encouraged by this preliminary
result, we started the optimization of the reaction conditions
by firstly focusing on the solvent and base used (Table 1).
Excellent yields were obtained for all tested solvents,
irrespective of their polarity (Table 1, entries 1-4). However,
CH2Cl2 (Table 1 entry 4) was found to be superior to the other
solvents, including Et2O and THF (Table 1, entries 2, 3) due to
the significantly shorter reaction time. Therefore CH2Cl2 was
chosen for the subsequent screening of various bases.[19] In
accordance with our envisioned mechanism, K2CO3 and K3PO4
as weak inorganic bases gave poor conversions even after one
day (Table 1, entries 6,7). Better yields of 89%, 80%, and 66%
were observed for KOH, KH, and KHMDS, respectively (Table 1,
entries 7-9). With the exception of KHMDS, an increased
basicity correlates well to increased reactivity. However, the
use of KH and KHMDS resulted in lower yields than KOtBu.
With the optimized reaction conditions in hand we went
further to extend the scope of the NHO-catalyzed alkylation
reaction (Scheme 2). Activated electrophiles like allyl bromide,
dimethylallyl bromide, and propargyl bromide gave the
alkylation products in high to excellent yields (Scheme 2, 3b-d).
The use of inactivated alkyl halides usually resulted in no
conversion (Scheme 2, 3f). However, methyl iodide, with the
smallest alkyl group, gave the desired product 3e in 77% yield
within an hour. When the 1,3-dicarbonyl compound 2-acetyl
cyclopentanone was subjected to the PTC reactions, the
Table 2. Screening of different catalysts and loadings[a]
O
O
O
O
1.2 equiv KOtBu, cat.
r.t., CH2Cl2
Br
OEt
OEt
1a
+
2a
Ph
3a
Dipp
I
N
CH3
N
Dipp
Me
Me
Me
I
I
I
Me
Me
Me
Me
Me
N
N
Me
H
Me D
N
Dipp$=
cat. =
CH3
CH3
2,6)di(iPr)C H
₆
₃
N
Me
N
Me
N
Me
Me
B
C
A
Entry
Catalyst
Cat. [mol %]
Time [min] Yield [%][b]
1
2
3
4
5
6
7
A
B
C
D
A
A
A
5
5
5
5
2
5
10
5
15
10
20
40
94
95
93
94
95
94
93
1
0.5
[a] The reactions were carried out with 1.0 mmol of 1a, 1.2 mmol of KOtBu, and
1.25 mmol of BnBr (2a) in 4 mL of CH2Cl2. [b] Yield of the isolated products.
2 | Chem. Commun., 2016, 52, 1-4
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Figure 1. Comparative studies with other phase-transfer catalysts
alkylation products could be isolated in high yields (Scheme 2,
3g-i). In the same fashion, the cyclic β-ketoester 2-acetyl γ-
butyrolactone smoothly underwent the transformations
(Scheme 2, 3j-l). At this stage, we were interested in
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DOI: 10.1039/C6CC03771B
monitoring the selectivity of the reaction when
a 2-
unsubstituted β-ketoester was used (Scheme 2, 3m,n).
Unfortunately, no selectivity to mono- or bis-alkylation could
be observed and the process gave a mixture of products.
Furthermore, the reaction with 2.5 equivalents of base and
benzyl bromide yielded only 56% of the bis-alkylated product
(Scheme 2, 3m). The synthetically interesting cyclization
reaction with a dibromo substrate successfully gave the 1,1-
disubstituted cyclopentane product 3n, albeit in a yield of only
37%. The substrate scope was further extended to the glycine
imine derivative (Scheme 2, 3o-r) with excellent outcomes. The
bis-alkylation reactions of the weakly acidic α-tetralone
(Scheme 2, 3s-u) also proceed smoothly to give the products in
high yields. The use of catalyst E for these transformations, in
addition to catalyst D in Table 2, proved that bulky
substituents on the exocyclic carbon of the NHO precursor
catalyst do not have a significant negative effect on the
catalytic activity. This is of importance for the strategic design
of improved NHO catalysts in the future.
In order to compare the efficiency of NHO-precursors with
other known PTC systems and provide evidence for our
proposed mechanism (Scheme 1), we conducted a series of
further control experiments. Firstly, we compared the results
of the NHO precursor A catalyzed process to those of other
typical PTCs such as (nBu)4NI and Ph4PBr, as well as the
reaction without any catalyst (Figure 1). A comparative
reaction with the parent imidazolium[13] NHC-precursor A’ as
phase-transfer catalyst was also carried out. For all tested
solvents the uncatalyzed reactions were found to be much
more sluggish than the ones with phase-transfer catalysts
(Figure 1). Catalyst A was more efficient with shorter reaction
times than the standard PTCs (nBu)4NI and Ph4PBr, particularly
in non-polar solvents. Interestingly, the structurally analogous
NHC precursor A’ was the least effective catalyst for this type
of chemical transformation.
We originally proposed that the deprotonation of the
imidazolium salt to the free NHO is the key step in the catalytic
cycle (Scheme 1). The alkylation reaction failed in the absence
of base, proving that the base is crucial. 1H NMR studies of the
PTC reactions confirmed the deprotonation of catalysts A and
C during the course of the reactions.[9,17] We then designed
three new experiments (Scheme 3) in order to provide more
evidence for this deprotonation step. In the first case, the free
NHO F, as a derivative of A, was used as catalyst with base as
well as a stoichiometric reagent without base. Both reactions
provided the same excellent results (Scheme 3a). In the second
reaction, we tested the imidazolium catalyst G with a blocked
reactive site, so that a deprotonation reaction to form the
NHO cannot occur (Scheme 3b). The dramatic increase in
reaction time in comparison to catalysts A, C, D and E shows
that at least one hydrogen atom at the C2-exocyclic carbon is
required for an efficient PTC. That the steric hindrance of the
tBu group was not the cause for this decrease in catalytic
activity was evidenced by the effectiveness of C, D and E, all
bearing bulky substituents in close proximity to the reactive
sites. At this point, however, we cannot completely rule out
the possibility of ”normal” phase-transfer catalysis occurring in
parallel with the deprotonation-to-NHO pathway. To further
underline the role of the hydrogen at the C2 exocyclic carbon,
we conducted the alkylation reaction with the deuterium-
labelled β-ketoester 1v and pre-catalyst A. We observed a
substantial amount of deuterium transfer to the C2-methyl
group of the pre-catalyst (d-A, Scheme 3c).[17] Similar results
were obtained with deuterated catalyst and protiated
Scheme 2. Substrate scope of the NHO-catalyzed alkylation reaction.[17]
Y
X
O
1.2 equiv KOtBu
CH2Cl2, r.t.
Y
X
Hal
O
R4
+
R3
R1
R3
R1
2
R4
R2
R2
1
3
X = C or N; Y = O or CR2
O
O
O
O
O
O
Me
N
O
O
Me
Me
OEt
I
OEt
OEt
OEt
CH3
Me
Me
N
Me
1 mol % A
3a, 20 min, 94%
3b, 20 min, 95%
3c, 20 min, 70%
3d, 20 min, 90%
O
O
O
O
O
O
O
O
O
O
Me
OEt
Me
Me
Me
OEt
Me
Me
3f, no reaction
even with alkyl iodide
3e, 60 min, 77%
(with MeI)
3g, 1 h, 88%
3h, 1 h, 84%
3i, 3 h, 83%
O
O
O
O
OO
O
O
O
O
Me
Me
Me
OMe
O
Me
O
O
Me
Ph
OMe
Ph
3n, 3 d, 37%
substrate.[17]
This
indicates
repeated
protonation/
3m, 3 h, 56%
3j, 30 min, 84%
3k, 30 min, 83%
3l, 3 h, 85%
O
O
O
Me
Me
deprotonation events, which is consistent with our proposed
phase-transfer mechanism (Scheme 1). The distribution ratios
of deuterated products d-A were very close to the theoretical
values, suggesting that even if there was any ”normal” phase-
transfer catalysis occurring, the chemically active NHO catalytic
pathway is still predominant. This type of catalytic activity is
conceptually significant to the advancement of PTC in a similar
I
Ph
N
Ph
N
Ph
N
H
OtBu
N
OtBu
OtBu
Ph
Ph
Ph
N
Me
Ph
Me
Me
3o, 3 h, 95%
3p, 1 h, 71%
3q, 1 h, 75%
Me
2 mol % E
O
O
O
O
Ph
Me
Ph
N
Me
OtBu
Ph
Ph Me
3r, 1 h, 78%
3s, 20 min, 84%
3t, 20 min, 84%
3u, 20 min, 87%
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Fuerstner, M. Alcarazo, R. Goddard, C. W. Lehmann, Angew.
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Chem. Int. Ed., 2008, 47, 3210; e) S. M. Ibrahim Al-Rafia, A. C.
Scheme 3. Mechanistic studies
DOI: 10.1039/C6CC03771B
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(a) NHO as base
1.2 equiv KOtBu
O
O
5 mol % free NHO cat. F
Me
N
OEt
O
O
Me
Me
CH2Cl2, r.t.
Br
CH2
+
OEt
N
Me
CH2Cl2, r.t.
F
100 mol % free NHO cat. F
no base
top: 10 min, 93%
bottom: 5 min 96%
(b) Blocking the reactive site
O
O
O
O
1.2 equiv KOtBu, 5 mol % cat.
solvent, r.t.
OEt
Br
+
OEt
Me
Dipp
Me
I
Me
N
Me
I
I
Me
Me
Me
Me
Me
I
H
Me
Me
N
Me
Me
Me
N
Me
Me
I
N
Me
H
Me
N
CH3
6
7
CH3
N
Me
N
N
Me
N
Dipp
Me
N
Me
Me
Me
A
C
Me E
D
G
tol: 30 min, 92%
CH2Cl2: 15 min 94%
toluene: 30 min, 94% tol: 30 min, 95%
CH2Cl2: 5 min 94% CH2Cl2: 5 min 93%
tol: 30 min, 90%
CH2Cl2: 10 min 92%
tol: 6 h, 89%
CH2Cl2: 30 min 94%
(c) Deuterium labelling
O
O
I
I
Br
8
9
R. D. Crocker, T. V. Nguyen, T. V. Chem. Eur. J., 2016, 22,
2208.
M. Blümel, J-M. Noy, D. Enders, M. H. Stenzel, T. V. Nguyen,
Org. Lett., 2016, 18, 2208.
O
O
Me
N
Me
N
Me
Me
Me
H
H
H/D
H/D
H/D
OEt
OEt
H/D
H
+
+
CH2Cl2, r.t.
1.0 equiv KOtBu
N
Me
N
Me
(75% D)
1v (1 equiv)
Me
d-A
A (1 equiv)
10 J. S. Bandar, A. Tanaset, T. H. Lambert, Chem. Eur. J., 2015,
21, 7365.
11 D. Landini, F. Montanar, F. M. Pirisi, J. Chem. Soc. Chem.
Commun., 1974, 879.
Experimental: CH3:CDH2:CD2H:CD3 = 1.0:0.51:0.10:0
Theoretical: CH3:CDH2:CD2H:CD3 = 1.0:0.69:0.16:0.01
d-A
12 a) R. A. Jones, Quaternary Ammonium Salts: Their Use in
Phase Transfer Catalysis, Academic Press, London, 2001; b) S.
Shirakawa, K. Maruoka, Angew. Chem. Int. Ed., 2013, 52,
4312.
13 a) S. Muthusamy, B. Gnanaprakasam, Tetrahedron Lett.,
2015, 46, 635; b) S. Okamoto, K. Takano, T. Ishikawa, S.
Ishigami, A. Tsuhako, Tetrahedron Lett., 2006, 47, 8055.
14 a) K. Ohmatsu, M. Kiyokawa, T. Ooi, J. Am. Chem. Soc., 2011,
133, 1307; b) K. Ohmatsu, M. Kiyokawa, T. Ooi, J. Am. Chem.
Soc., 2011, 133, 1307.
way to the elegant H-bonding tetraalkylammonium salt
systems reported by Shirakawa, Maruoka and co-workers
recently.[21]
In conclusion, the novel application of NHOs as phase-
transfer organocatalysts for synthetically important alkylation
reactions was successfully developed. NHOs and their
azoliumsalt precursors were employed as very efficient
organocatalysts for solid-liquid phase-transfer alkylation
reactions. The work illustrates the great potential of NHO
organocatalysts in organic synthesis and will certainly
stimulate further interest in N-heterocyclic olefin chemistry.
We are currently working on other types of NHO-
organocatalyzed chemical transformations and will report
these studies in due course.
15 R. Mirabdolbaghi, T. Dudding, T. Stamatatos, Org. Lett.,
2014, 16, 2790.
16 For the first study on tetraamino-phosphonium salts, see: a)
D. Uraguchi, S. Sakaki, T. Ooi, J. Am. Chem. Soc., 2007, 129,
12392; for other examples, see recent reviews: b) D. Enders,
T. V. Nguyen, Org. Biomol. Chem., 2012, 10, 5327; b) H.
Krawczyk, M. Dziegielewski, D. Deredas, A. Albrecht, L.
Albrecht, Chem. Eur. J., 2015, 21, 10268.
17 See Supporting Informations for more details.
18 K. Powers, C. Hering-Junghans, R. McDonald, M. J. Ferguson,
E. Rivard, Polyhedron, 2016, 108, 8.
The project was supported by the Australian Research
Council (Grant DE150100517). M. B. thanks the DAAD for
funding the research exchange to UNSW.
19 Control studies confirmed that there was no deprotonation
of the CH2Cl2 solvent under these reaction conditions.
20 Control reaction with 1.0 equiv KOtBu, 1.0
Notes and references
Me
Br/I
Me
H
N
equiv BnBr, 1.0 equiv catalyst A and no β-
ketoester substrate in DCM after 180
minutes gave yield to the benzylated
1
For recent reviews on NHCs, see: a) M. N. Hopkinson, C.
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H
Bn
N
Me
Me
imidazolium salts (confirmed by ESI-MS as [M-Br/I]+ = 229.3).
These nucleophilic substitution products confirmed the
formation of NHO F and also agreed with our prediction (see
ref 8) that NHOs are strong nucleophiles. See Supporting
Informations for more details.
2
3
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4 | Chem. Commun., 2016, 52, 1-4
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