Catalytic C-Alkylation of Pyrroles with Primary Alcohols: Hans Fischer's Alkali and a New Method with Iridium P,N,P-Pincer Complexes

Article abstract of DOI:10.1002/ejoc.201800146

Hydrogen-autotransfer alkylation (HAT or “borrowing-hydrogen” alkylation) of heteroaromatic compounds has been studied with a range of substrates recently, but pyrroles have been largely absent from such studies. The conditions for HAT alkylations of pyrroles were investigated under a variety of conditions and were found to take place under basic alcoholic conditions (Hans Fischer alkylation) in the absence of transition-metal catalysts; by means of a heterogeneous Pd/C catalyst in the presence of base; and finally by means of homogeneous transition-metal catalysis combining a base and iridium pincer complexes generated in situ that have not previously been used in HAT alkylations of heterocycles.

Full text of DOI:10.1002/ejoc.201800146

A Journal of
Accepted Article
Title: Catalytic C-Alkylation of Pyrroles with Primary Alcohols: Hans
Fischer's Alkali, and a New Spin with Iridium P,N,P-Pincer
Complexes
Authors: Sebastian Koller, Max Blazejak, and Lukas Hintermann
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800146
Link to VoR: http://dx.doi.org/10.1002/ejoc.201800146
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10.1002/ejoc.201800146
European Journal of Organic Chemistry
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Catalytic C-Alkylation of Pyrroles with Primary Alcohols: Hans
Fischer's Alkali, and a New Spin with Iridium P,N,P-Pincer
Complexes
Sebastian Koller,[a] Max Blazejak,[a] and Lukas Hintermann*[a]
Abstract: Hydrogen autotransfer alkylation (HAT or “borrowing
hydrogen” alkylation) of heteroaromatic compounds has been
studied with a range of substrates recently, but pyrroles have been
largely absent from such studies. The conditions for HAT-alkylations
of pyrroles were investigated under a variety of conditions and found
to take place a) under basic alcoholic conditions (Hans-Fischer-
alkylation) in the absence of transition metal catalysts; b) by means
of a heterogeneous Pd/C catalyst in the presence of base; c) and
finally by means of homogeneous transition metal catalysis
combining base and in situ generated iridium pincer complexes
introduced by Kempe and not previously used in HAT-alkylations of
heterocycles.
cores: with indoles, regioselective C-3-alkylation has been
realized using base and the catalysts [Cp*IrCl2]2,[3a,b,c]
RuCl2(PPh3)2/DPE-Phos,[3d] Pd/C,[3d] Pt nanoclusters;[4] for the
related case of indole HAT-alkylation with amines as alkylating
agents, the use of Shvo's catalyst[5a] or of a redox-active
anthraquinone/amine organocatalyst has been described.[5b,6]
NuH2
R1
R1
H
R2
OH
H
R2
Nu H
no direct reaction
A
D
[M]
[M]H2
Introduction
R1
R2
R1
R2
O
Nu
Catalytic reactions involving hydrogen autotransfer (HAT) from
starting materials to products (i.e., following the "borrowing
hydrogen principle") have recently become a useful tool for C–C
and C–N bond formation in organic chemistry.[1,2] Such
transformations generate water as sole stoichiometric byproduct
and, by virtue of their high atom-economy, can be important
contributors to green chemistry. The principle of HAT-alkylation
of a nucleophile (H2Nu; both hydrogens need not be attached at
the same nucleophilic center, since one may be in a tautomeric
position) with alcohol A is illustrated in Scheme 1: Catalyst-
mediated dehydrogenation of A gives carbonyl compound B and
reduced catalyst [M]H2; this is followed by spontaneous or bas-
catalyzed condensation of B with the nucleophile to give
unsaturated intermediate C; the latter is subsequently
hydrogenated by MH2 to give product D, thereby regenerating
catalyst [M] in the process. These reactions are typically
conducted with a transition-metal catalyst (viz. Ir, Ru) capable of
hydrogen-transfers, and a base co-catalyst for the condensation
step. Such methodology has been applied to C-alkylation via
activation of the acidified α-C(sp3)-H-bonds of carbonyl
compounds (ketones, esters, amides), nitriles or other
substrates.[2] However, C-alkylation with alcohols is also
possible at C(sp2)-centers of electron-rich (hetero)aromatic
H2O
NuH2
C
B
Scheme 1. General mechanistic sequence for a HAT-alkylation.
Recently, HAT-C-alkylations have also been realized with
phenols as examples of non-heterocyclic
arenes.[7]
Notwithstanding the success of such protocols, remarkably,
HAT-alkylation with alcohols and alkali base as sole catalyst
have been described, where hydride-transfers appear to
proceed via Cannizarro-type mechanisms.[8] Such transition-
metal free HAT-alkylations were described for ketones[9] and
electron-rich N-heterocycles including indoles.[10,11]
In contrast to numerous studies on indoles, HAT-alkylation of
pyrroles has been nearly absent; while our work was in progress,
an example of methylation of pyrroles by methanol (140 °C,
pressure tube) using [Cp*IrCl2]2 as catalyst was reported.[12]
However, we have become aware of work performed by Hans
Fischer and coworkers in 1912, describing remarkable
alkylations of simple pyrroles in alcoholic sodium alkoxide at
elevated temperature in sealed tubes (Scheme 2, a).[13] A table
with reaction examples reported by Fischer has been compiled
in the supporting information (Table S-1).
Hans Fischer’s lifework on the structure elucidation and
synthesis of pyrrole pigments was highlighted by the award of
the 1930 Nobel Prize of chemistry “for his researches into the
constitution of haemin and chlorophyll and especially for his
synthesis of haemin”.[14] He was a leading authority on the
chemistry of pyrroles, and a monograph, written with H. Orth and
A. Stern,[15] remained a key reference for many years, and
continues to be referenced in contemporary work.[16,17] The
alkoxide-mediated alkylation of pyrroles was among Fischer's
[a]
M.Sc. S. Koller, Dr. M. Blazejak, Prof. Dr. L. Hintermann,
Technische Universität München, Department Chemie,
Lichtenbergstr. 4, 85748 Garching bei München
and TUM Catalysis Research Center, Ernst-Otto-Fischer-Str. 1,
85748 Garching bei München
E-mail: lukas.hintermann@tum.de
http://www.oca.ch.tum.de
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201800146
European Journal of Organic Chemistry
FULL PAPER
earliest contributions to pyrrole chemistry and was immediately
applied for structural proof (through synthesis) of a series of
alkylated pyrroles, which had been obtained by degradation from
blood pigment.[18] The mechanism of this reaction was unknown
at the time of discovery[13a] and was still considered an unsolved
riddle 60 years later.[19,20] In view of recent developments in
HAT-alkylation chemistry with alkali bases, particularly the
related alkylation of indoles (Scheme 2, b)[10,11] or the base-
mediated alkylation of ketones,[9] a new interpretation of the
Hans-Fischer-alkylation as hydrogen autotransfer (HAT) reaction
recommended itself.
Table 1. Base-mediated pyrrole alkylation under microwave conditions.[a]
(2a)
Ph
Ph
Ph
Ph
Me
HO
base
+
Me
Me
N
H
Me
Me
3a
Me
N
N
Δ (µW)
H
H
1 h
1
4a
Base
BnOH
3a[b]
4a[b]
Entry
Solvent
T [°C]
(equiv.)
(equiv.)
[mol%]
[mol%]
1
2
3
4
5
6
7
8
NaH (2)
19
19
19
19
19
19
6
neat
250
51
36
52
27
31
8
19
18
10
0
a)
Me
Me
R
Me
Me
NaOR–ROH
KOH (2)
neat
250
Me
Me
N
H
210–220 °C
12 h
N
H
NaOH (2)
LiOBn[c] (2)
KOtBu (2)
KOtBu (4)
KOtBu (4)
KOtBu (4)
neat
250
R = Me, Et, nPr
neat
250
Me
Me
neat
250
54
60
19
21
Me
Me
Me
byproduct
NaOEt–EtOH
Me
250[d]
250[d]
240
Me
neat
Me
b)
Me
N
N
N
H
210–220 °C
8 h
+
H
H
toluene
toluene
61
48
60%
6
[a] Reaction scale: 1.0 mmol. [b] Analytical yield determined by qNMR against
internal standard. [c] Base was prepared in situ by dissolving Li metal in BnOH
at 70 °C. [d] Temperature was automatically reduced over reaction time to
prevent exceeding the reactor pressure limit (30 bar).
Ph
HO
Ph (3 equiv.)
KOH (1.3 equiv.)
xylene,
150 °C, 3 h
N
N
H
H
97%
Scheme 2. a) Pyrrole alkylations mediated by alcoholic alkoxide as performed
by Hans Fischer.[13] b) Base-induced HAT-alkylation of indole.[10]
KOtBu was in general superior (Table 1, entries 5–8) over
sodium (entries 1, 3) or lithium (entry 4) bases. A large excess of
benzyl alcohol (2a) – which also serves as the solvent – in
combination with KOtBu favors dialkylation (entries 5, 6), but a
sixfold excess of alcohol in toluene favors monobenzylated
product 3a (entries 7, 8). More polar solvents (dioxane, diglyme)
gave inferior results. The effect of hydrogen-transfer additives
(Ph2CO, Al(OiPr)3) on the reaction was negligible (Table S-2).
Yet, 1H NMR analyses of crude reaction mixtures consistently
revealed the presence of benzaldehyde (in the order of 2 mol%
or more) also in the absence of such additives, which supports
the importance of alcohol dehydrogenation in the process.
The temperature of 250 °C in the microwave experiments is
higher than in Fischer's sealed tube experiments (210–220 °C
over 12–14 h), in turn the reaction time could be reduced to 1 h.
In some of the screening reactions, internal overpressure (> 30
bar) built up that occasionally led to vial ruptures; the pressure is
presumably caused by evolution of hydrogen. By working at or
below 240 °C, and by using four or less equivalents of base,
such incidents were largely prevented. With the unsymmetrical
isopropyl-phenyl-pyrrole 5 (vide infra) as substrate, a mixture of
the monoalkylated regioisomers 6/7 in similar amounts emerged
(Scheme 3, a).
Our study aimed at addressing two key questions: first, to collect
evidence for the HAT-nature of the Hans-Fischer-alkylation, and
second, to take advantage of more recent knowledge of
transition metal-catalyzed HAT-alkylations to establish catalytic
HAT-C-alkylation protocols for pyrroles that will possibly proceed
under milder reaction conditions. In view of the importance of
pyrroles as structural motifs in pharmacologically active
compounds, an extension of the synthetic repertoire for pyrrole
alkylation by simple and atom-economic methods is highly
desirable.
Results and Discussion
Pyrrole alkylations according to Hans Fischer were performed in
sealed tubes ("Carius bomb tubes") and had a high incidence of
explosive bursts.[21] To simulate the original reaction conditions
in a reliable way we used microwave irradiation under adiabatic
conditions, and with high-boiling alcohols to limit pressure
buildup. Heating of 2,5-dimethylpyrrole (1) with benzyl alcohol
(2a) and base to 250 °C produced mono- (3a) as well as
dibenzylated (4a) product under a variety of conditions (Table 1).
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10.1002/ejoc.201800146
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a)
life. The standard synthesis of 8 proceeds from the air-stable
diester 11 via de-alkoxycarbonylation in strong base.[23] It would
BnOH
Bn
Ph
Bn
KOtBu
(4.0 equiv.)
be attractive to couple this base-mediated step with
a
Ph
N
Ph
N
consecutive alkylation, and in fact, 11 is alkylated with 2a under
basic conditions to give 4a in yields matching those of the
reaction starting with 8 (Scheme 3, c). This observation could
point to a general strategy for performing HAT-alkylations of
electron-rich heterocycles by way of their more stable ester
derivatives. The Fischer-type HAT-alkylation of 2,5-
dimethylpyrrole (1) was shortly tested with substituted benzyl
alcohols, and while the alkylation products 3 and 4 were
observed, it became evident that optimal results would require
individual optimization of the reaction conditions (Scheme 4).
N
neat,
230 °C (µW)
1 h
H
H
H
+
5
7 (34%)
6 (43%)
b)
Me
Me
Bn
Me
Bn
Bn
Me
BnOH
KOtBu
(4.0 equiv.)
Me
Me
N
N
H
N
H
H
+
250 °C (µW)
10a
9a
8
2%
54%
13%
10 min, neat
1 h, in toluene
38%
Me
(2)
R
R
R
Me
4
R
HO
base
c)
+
Me
Me
BnOH
N
H
Me
CO2Et
Me
Me
Bn
Bn
Me
Me
Me
Me
N
N
KOtBu
(6.0 equiv.)
Δ (µW)
H
H
1 h
1
3
EtO2C
Bn
Me
N
N
H
N
H
T (µW)
neat
H
+
OH
Cl
OH
3a
4a
OH
OH
HO
10 min, 250 °C
60 min, 230 °C
5–7%
3%
51–54%
58–61%
Cl
2b
2e (meta)
2f (para)
2c
2d
Scheme 3. a,b) Alkylation of 5 and 8 in the presence of base; "neat" reactions
use BnOH as solvent (2.0 mL per mmol), reactions in toluene use 6.0 equiv. of
BnOH. c) Direct alkylation of diester 11; analytical yield in mol% as determined
by qNMR against internal standard.
Pyrroles detected by qNMR:
3b (14 mol%)
4b (± 0 mol%)
3c (15 mol%)
4c (± 0 mol%) 4d (ca 10 mol%)
3d (ca 20 mol%)
decomp.
Scheme 4. Variation of benzylic alcohols in the base-mediated alkylation of 1.
With 2,4-dimethylpyrrole (8), dibenzylation to 10a was achieved
in very short time in neat alcohol, but monoalkylated 9a was the
dominant product in toluene at the hour mark (Scheme 3, b).
The higher reaction rate of 8 vs. 1 is in line with the established
higher nucleophilicity at the C-2/5 over the C-3/4 position in
pyrroles.[22] Those observations support an attack of the pyrrole
(or its anion) on an electrophile as a key step. Many alkylated
pyrroles including 8 are air-sensitive liquids with a limited shelf
A remarkable observation in attempted alkylations of pyrroles
with 3- and 4-methoxybenzyl alcohol (2g,h) was the generation
of methyl ethers by O-methylation of the benzylic alcohol, with
the methoxy group from the substrate either left intact (12), or
dealkylated (13). The pyrrole was unaffected in this reaction and
could be left out with no change in the result (Scheme 5, a).
a)
KOtBu (4 equiv.)
PhMe
OMe
OMe
OH
OH
+
HO
HO
+
MeO
MeO
250 °C, 1 h
2g (meta)
2h (para)
(pyrrole 1 present
or absent)
2e (meta)
2f (para)
12g (meta)
12h (para)
13g (meta)
13h (para)
b)
KOtBu (4 equiv.)
PhMe
HO
D3CO
D3CO
D3CO
HO
OCD3
OH
OCD3
OH
OH
+
+
+
250 °C, 1 h
(µW)
(CD3O)-2g
(CD3O)-2h
1,3'-(CD3O)2-12g (25%)
1-(CD3O)-13g (30%)
3'-(CD3O)-2g (8%)
4'-(CD3O)-2h (15%)
2e (6%)
2f (n.d.)
[20% isolated]
[31% isolated]
as above
c)
1,4'-(CD3O)2-12h (22%)
1-(CD3O)-13h (n.d.)
Scheme 5. a) Initial observation of transmethylations in attempted pyrrole alkylations. b) Base-induced alkyl transfer in deuterium labeled 3-(CD3O)-
methoxybenzylalcohol (2g) at high temperature. c) Base-induced transalkylation of 4-(CD3O)-methoxybenzyl alcohol (2h).
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10.1002/ejoc.201800146
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R
It was not immediately obvious if this alkyl transfer from an
aromatic methyl ether to a benzyl alcohol was due to a direct,
SN2-type substitution, or if a HAT-type process involving transfer
of a formaldehyde equivalent and hydride might be responsible.
Control experiments with deuterium labeled alcohols (CD3O)-2g
and (CD3O)-2h produced a mixture of di- (12) and mono-
methylated (13) methyl ethers in which all methoxy groups fully
retained their deuterium without scrambling (Scheme 5b, c). An
SN2-transfer by intermolecular attack of alkoxide on the methoxy
group of the aryl-ether is most plausible, and while we are not
aware of any literature precedent, the high reaction temperature
undoubtedly facilitates this SN2-transetherification.
L1: R = tBu, R' = Ph
L2: R = R' = Ph
L3: R = Ph, R' = iPr
N
N
O
N
P(t-Bu)2
HN
N
NH
Ir
H
R'2P
PR'2
Cl
14
L
Huang pincer
bis(phosphanylamino)triazines
(Kirchner, Kempe)
Figure 1. Structures of the Huang Ir-NCP pincer complex (14) and of Kirchner'
bis(phosphanylamino)triazine ligands (L) as precursors for Kempe's Ir-PNP
pincer catalysts.
Even if historically and conceptually important, the Hans-
Fischer-alkylation of pyrroles is limited in terms of substrate
range and by the harshness of reaction conditions, which can
lead to unexpected side-reactions such as transalkylation. Our
next aim was to realize pyrrole alkylations under milder
conditions taking advantage of recent developments in metal-
catalyzed HAT-alkylation. Very common, heterogeneous Pd/C-
catalysts have been applied for the HAT-alkylation of amines[24]
or indole[3d] with alcohols. Application of this catalyst system to
the alkylation of dimethylpyrrole 1 with benzyl alcohol are shown
in Scheme 6.
Ligands L have the advantage of a highly modular construction
principle based on on a combination of 6-substitued 1,3,5-
triazine-2,4-diamines and two equivalents of dialkylchloro-
phosphane (R2PCl; R = iPr, tBu). For the present work we
extended the ligand range to 6-tert-butyl substituted derivative
L1, whose synthesis takes advantage of our selective copper-
catalyzed tert-alkylation of multiply halogenated azines.[29]
Cyanuric chloride (15) was coupled with one equivalent of
tBuMgCl to give 16, which was aminated without isolation in the
same pot by adding ammonia and ammonium chloride for
solubilization of magnesium salts (Scheme 7). The new ligand
L1 was obtained by phosphanylation under basic conditions.
(2a)
Ph
HO
Bn
Me
Bn
Me
Bn
Me
(3.0 equiv.)
Pd/C (10 wt%)
KOH (0.2 equiv.)
NH4Cl,
H2N
N
NH2
tBuMgCl
Cl
N
Cl
Cl
N
Cl
Me
Me
Me
N
H
N
N
NH3 (aq)
CuI (cat.)
N
N
H
H
N
N
N
N
N
+
110 °C, 18 h
neat
60 °C,
19 h
1
3a (54%)
4a (2%)
THF, 0 °C
Cl
15
16
17 (73%)
Scheme 6. Pd/C-catalyzed HAT-alkylation of 2,5-dimethylpyrrole (1).
Analytical yield in mol-% as determined by qNMR against internal standard.
H
N
H
N
1. nBuLi
PPh2
PPh2
N
N
2. Cl-PPh2
The reaction proceeds under much milder thermal conditions
(110 °C) than the original Hans-Fischer-alkylation. Base additive
is still essential, but a substoichiometric quantity is sufficient.
KOH gave slightly better results than KOtBu. The reaction was
extended to 1-octanol (2i) as aliphatic alcohol, which gave 20%
of monoalkylated pyrrole (3i) at 160 °C. With 2,4-dimethylpyrrole
(8) and benzyl alcohol (2a), a 34% yield of monoalkylated 9a
was obtained (Table S-3).
Finally, we wished to investigate the potential of HAT-alkylation
of pyrroles with homogenous catalyst systems based on
established ruthenium catalysts, and a few selected iridium
pincer complexes (Figure 1).
The iridium NCP–pincer complex 14 of Huang et al has
previously been used in HAT-alkylations of esters at the acidified
α-C–H-position,[25] whereas iridacycles based on bis(phosphan-
ylamino)triazine ligands L[26] (Figure 1) were introduced by
Kempe et al for dehydrogenative condensation syntheses of
pyrroles or pyrimidines,[27] whereas their cobalt- or iron-
complexes have shown activity in HAT-alkylations of amines
with alcohols.[28]
L1 (52%)
Scheme 7. Synthesis of a new PNP-pincer ligand (L1) based on selective
copper-catalyzed tert-alkylation of cyanuric chloride.
Reaction screening started with the system Ru–DPEphos–
K3PO4, which had previously been successful in HAT-alkylation
of indoles.[3d] The catalyst system also showed activity for
pyrrole alkylation, but a stronger base was necessary for
achieving conversion at 110 °C (Table 2, entries 1 vs. 2). Iridium
pincer complex 14 did not show satisfactory activity in pyrrole
alkylation, and mono- vs dialkylation selectivity was low (entries
3, 4). Best results were eventually obtained with Kempe type
PNP-iridium-pincers, which were formed in situ from suitable
iridium precursors and bis(phosphinylamino)triazine ligands L1–
L3 (Figure 1) by allowing both components to pre-complex at
50 °C for 1 h.
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Table 2. Catalyst screening for the HAT-alkylation of 2,5-dimethylpyrrole (1).[a]
Ph
Me
Ph
Ph
catalyst, base
+
+
HO
Ph
Me
Me
N
H
Me
Me
Me
N
solvent or neat
24 h
N
H
H
1
2a
3a
4a
3a [%][b]
4a [%][b]
Precursor
(mol%)
Ligand
(mol%)
Base
(equiv.)
BnOH
[equiv.]
Entry
Solvent
T [°C]
1
RuCl2(PPh3)3 (1.25)
[Ru(p-cym)Cl2]2 (2.5)
14 (2.0)
DPE-Phos (1.25)
DPE-Phos (5.0)
-
K3PO4 (3.0)
KOtBu (5.0)
-
5
neat
165
110
150
150
105
110
110
110
110
110
110
110
110
110
110
110
40
12
2
2
10
3
toluene
neat
53
3
23
27
9
4
14 (2.0)
-
KOtBu (0.2)
KOtBu (2.0)
KOtBu (2.0)
KOtBu (2.0)
KOtBu (2.0)
KOtBu (2.0)
K3PO4 (2.0)
KOtBu (2.0)
KOtBu (2.0)
KOtBu (2.0)
KOtBu (2.0)
KOtBu (1.0)
KOtBu (2.0)
3
neat
26
5[c,d]
6[c]
[{IrOMe(cod)}2] (1.5)
[{IrOMe(cod)}2] (2.0)
[{Ir(cod)Cl}2] (2.0)
[{Ir(cod)Cl}2] (2.0)
[{Ir(cod)Cl}2] (2.0)
[{Ir(cod)Cl}2] (2.0)
[{Ir(cod)Cl}2] (1.0)
[{Ir(cod)Cl}2] (1.0)
[{Ir(cod)Cl}2] (0.5)
[{Ir(cod)Cl}2] (0.5)
[{Ir(cod)Cl}2] (0.5)
[{Ir(cod)Cl}2] (0.5)
L3 (3.0)
L1 (4.2)
L1 (4.2)
L3 (4.2)
L2 (4.2)
L2 (4.2)
L2 (2.1)
L3 (2.1)
L3 (1.05)
L3 (1.05)
L3 (1.05)
-
10
10
10
10
10
10
10
10
10
5
dioxane
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
26
1
57
3
7[c]
64
6
8[c]
70
6
9[c]
70
3
10[c]
11[c]
12[c]
13[c,d]
14[c,d]
15[c,d]
16[d]
44
1
62
3
71
7
70 (52)
51
4
5
10
10
61
2
34
3
[a] All reactions were performed with 1.0 mmol pyrrole. [b] Yields were determined by qNMR against 1,1,2,2-tetrachloroethane as internal standard. Isolated yields
are given in parenthesis. [c] Precomplexation of Ir-precursor and ligand for 1 h at 50 °C in the corresponding solvent. [d] 1.5 mmol pyrrole.
Up to 70% of 3a was obtained with such a catalyst, with high
selectivity over dialkylation (entries 5–16). L3 appeared to be the
most active ligand at lower catalyst loadings. Metal loading could
obtain the products in essentially the same yield (70% 3a + 6%
4a), with no need for a precomplexation phase. The optimal
catalyst system from the screening successfully realized the
be lowered to 1 mol% of iridium with no loss of activity (entry 13). alkylation of pyrroles 1 and 8 with some substituted benzylic
A sufficient excess of alcohol was required for achieving high
conversion (entry 14 vs 13). The reaction still proceeds in the
absence of ligand, but the yield was lower (entry 16). In
comparison to the base-catalyzed Hans-Fischer-alkylation, the
iridium-catalyzed process is active at much lower temperature
(110 vs 240 °C). The best conditions (entry 13) were also
reproduced by mixing all reaction components including the
metal precursor and ligand L3 at the outset of the reaction to
alcohols (2) in similar yields compared to 2a (Table 3, entries 1,
2).
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10.1002/ejoc.201800146
European Journal of Organic Chemistry
FULL PAPER
Table 3. Variation of the alcohol in the catalytic HAT-alkylation of pyrroles.[a]
H
[{Ir(cod)Cl}2] (0.5 mol%)
L3 (1.05 mol%)
Me
R
(R)2
(Me)2
(Me)2
+
or
+
KOtBu (2.0 equiv.)
N
H
N
Me
Me
HO
R
N
H
H
Me
N
H
monoalkylated
dialkylated
toluene, 110 °C, 24 h
2
1
8
(3 or 9)
(4 or 10)
Entry
Pyrrole
Alcohol
Monoalkylation product
Yield[b]
Dialkylation product
Yield[b]
OMe
OMe
MeO
OMe
HO
Me
Me
N
H
1
1
68
4
Me
Me
3g
Me
Me
N
N
H
2g
H
4g
Cl
Cl
Cl
HO
Me
Me
Me
N
H
1
2
3
69
21
3
3
Me
Me
3j
Me
N
Me
Cl
N
H
2j
H
4j
HO
Me
Me
N
H
1
Me
Me
Me
N
Me
N
2d
H
H
4d
3d
C7H15
Me
C7H15
C7H15
Me
N
H
1
nOctOH (2i)
BnOH (2a)
4
5
43
49
0
Me
Me
N
Me
N
H
H
4i
3i
Me
Me
Me
Me
20
Me
N
Me
N
N
H
10a
H
H
9a
8
Me
OMe
OMe
Me
Me
OMe
MeO
HO
Me
N
6
7
55
63
12
10
Me
H
N
Me
H
N
H
10g
9g
2g
8
Me
Me
Me
C7H15
Me
C7H15
C7H15
nOctOH (2i)
Me
Me
N
H
N
N
H
H
9i
8
10i
[a] All reactions were performed with 1.5 mmol pyrrole. Precomplexation of [{Ir(cod)Cl}2] and L3 in toluene for 1 h at 50 °C. [b] Yields were determined by qNMR
against 1,1,2,2-tetrachloroethane as internal standard.
The somewhat bulky 1-naphthylmethanol (2d) gave a low yield
of monosubstituted product 3d (entry 3). This can be attributed
to steric hindrance, which may be pronounced in the presumed
intermediary arylidene-azafulvene (vide infra). With an aliphatic
alcohol, the conversion was lower (entry 4). Pyrrole 8 gave
mixtures of mono- (9) and dialkylation (10) products under the
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10.1002/ejoc.201800146
European Journal of Organic Chemistry
FULL PAPER
catalytic alkylation conditions, with monoalkylation being favored. Starting from the general mechanism of HAT-alkylation (cf.
This underlines the higher reactivity of this substrate as a result
of having available a free α-position (entries 5–7). Consequently
the C-5-position is always alkylated first, whereas products of C-
3-monoalkylation have not been observed. Reactions with
secondary alcohols including isopropanol or 1-phenylethanol
were not successful.
As in case of the base-catalyzed pyrrole alkylation, the iridium-
pincer-catalyzed reaction could be performed with pyrrole
carboxylic esters[30] as starting material, which undergo
consecutive de-alkoxycarbonylation and alkylation (Scheme 8).
Scheme 1) and taking into account the mechanism of base-
catalyzed HAT-alkylation of indoles,[10] we may assume that
alcohol B is deprotonated by a general base (abbreviated X–) to
give the alkoxide B' (Scheme 9, b), which is oxidized by β-
hydride elimination to the metal center (Ir, Ru; via their
alkoxides), thereby giving aldehyde C. The presence of
aldehyde in final reaction mixtures (and thus also during the
reaction) was proven by qNMR analysis. Next, electrophilic
aldehyde C is attacked either by free pyrrole A or its N-centered
anion as nucleophile, with H-X acting as general acid (Scheme 9,
b). This step is corroborated by the regioselectivity of the overall
reaction, which mirrors the known nucleophilicity pattern in
pyrroles. Addition product D will easily eliminate water to give
azafulvene E, which can be reduced to the final, alkylated
pyrrole F by hydride transfer from the metal hydride. In case of
the base-induced Hans-Fischer-alkylation, one may assume that
the reduction-step occurs as a conjugate 1,4-hydride transfer
from alkoxide B' (as in the Cannizarro-reaction,[8] or in hydride
2a
Ph
HO
O
[{Ir(cod)Cl}2]
(0.5 mol%)
EtO
Ph
Ph
Ph
Ph
N
H
L3 (1.05 mol%)
N
+
H
N
KOtBu (2 equiv.)
toluene
H
19 (50%)
20 (13%)
110 °C, 24 h
18
transfers from Hantzsch-esters[31]
) to azafulvene E, with
concomitant general acid catalysis by HX, which will usually be
alcohol B itself (Scheme 8, b). Azafulvene intermediates of
pyrroles are not particularly well known in the pure state, but the
Scheme 8. Iridium-pincer complex and base catalyzed consecutive de-
alkoxycarbonylation/HAT-alkylation of a pyrrole ester. Isolated yield is given
for 19, qNMR yield for 20.
related 3-benzylidene-3H-indole is
a
stable compound.[32]
Furthermore, azafulvenes related to pyrroles are postulated as
intermediates in the reduction of acyl- to alkylpyrroles by sodium
borohydride.[33]
The N-substituted substrate N-phenyl-2,5-dimethylpyrrole was
not alkylated by benzyl alcohol under those conditions; neither
did it react under the Pd/C–KOH conditions, or under the Hans-
Fischer-alkylation conditions with base as exclusive catalyst.
We can now propose a mechanistic scheme for this reaction and
its variations (Scheme 9, a).
Conclusions
In this project, we have explored the possibilities of HAT-
alkylations of simple model pyrroles. At the outset, we were
inspired by an early report from Hans Fischer, who described
pyrrole alkylation by alkali alkoxides in alcohols at elevated
temperature (210–220 °C, sealed tube conditions). The
mechanism of that reaction had been considered an unsolved
problem for many years.[13,19,20] By heating model pyrroles with
potassium tert-butoxide and benzyl alcohol in a microwave
reactor to 240–250 °C, we have been able to reproduce the
observations of Hans Fischer in that we obtained a range of
alkylated pyrroles. The similarity of the reaction conditions and
regioselectivity indicate that the early Hans-Fischer-alkylation is
mechanistically closely related to what is currently discussed as
"borrowing hydrogen" reaction or HAT-alkylation. In particular,
the chemistry is also related to recent work by Yus et al on the
base-catalyzed HAT-alkylation of indoles.[10] The Hans-Fischer-
alkylation of pyrroles requires harsh reaction conditions, which
also induce a remarkable SN2-transalkylation of a methyl group
from aromatic methyl ethers to primary alkoxides (Scheme 5).
Even if the chemoselectivity of the process is thus limited, it was
possible to obtain 50–60% of single, pure alkylation products in
suitable model reactions. Furthermore, we were able to realize
the reaction starting from pyrrole esters rather than free pyrroles
as substrates, because cleavage of the alkoxycarbonyl group
and C-alkylation are both induced by strong base. Considering
a)
R
+
R
OH
N
N
B
H
H
A
F
M+
X
X
X-H
R
X-H
M H
base-catalysis
+
R
O
- H2O
N
H
N
C
E
A
b)
R
O
H
H X
R
X
B'
O
OH
H
R
E1cb
R
B
C
+
F
- X
N
H
- HO
N
N
D
E
A
H X
X
Scheme 9. Proposed mechanisms for: a) metal-catalyzed, or; b) base-induced
HAT-alkylation of pyrroles with alcohols.
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10.1002/ejoc.201800146
European Journal of Organic Chemistry
FULL PAPER
temperature, a saturated solution of aq. NH4Cl (and optionally water to
dissolve solid residues) was added. The phases were separated and the
aqueous phase was extracted with Et2O (3x). The combined organic
phase was washed with water and brine and dried over MgSO4. Et2O
was removed in vacuum (≥500 mbar) and 1,1,2,2-tetrachloroethane
(20 µL, 0.191 mmol) was added as internal standard for qNMR.
that pyrroles tend to be quite unstable and cannot be stored for
prolonged time, this approach has practical advantages.
In the second part of this work we have modernized the
alkylation chemistry introduced by Hans Fischer in 1912 through
application of most recent tools from the field of transition-metal
catalyzed HAT-alkylations. The most successful catalyst
systems for HAT-alkylation of pyrroles identified in this work are
in-situ generated iridium-P,N,P-pincer-complexes based on
bis(phosphinalymino)triazine ligands, which Kempe et al had
earlier used in dehydrogenative condensation reactions.[27] We
now find that such complexes are suitable HAT-alkylation
catalysts which allow to carry out the HAT-alkylation of pyrroles
under fairly mild reaction conditions (110 °C, 24 h).
General procedure 2 for the Pd/C-catalyzed pyrrole alkylation (GP
2): A 10 mL Schlenk tube was charged with pyrrole (1.00 mmol), Pd/C
(10 wt.-% of catalyst, 5% Pd on carbon), alcohol and base under argon.
The tube was closed and the reaction mixture was heated for the
indicated time in an oil bath. After cooling to room temperature, the
mixture was filtered through celite; the celite was washed with Et2O. The
filtrate was evaporated in vacuum (≥500 mbar), and 1,1,2,2-
tetrachloroethane (20 µL, 0.191 mmol) was added as internal standard
for qNMR.
Experimental Section
General procedure 3 (GP 3) for the homogenously catalyzed pyrrole
alkylation without precomplexation (Table 2, entries 1–4+16): A
10 mL Schlenk tube was charged with 2,5-dimethylpyrrole (1), metal
complex, ligand, base, alcohol (2) and, if indicated, dry toluene
(1 mL/mmol) under argon. The tube was closed and the reaction mixture
was heated at the specified temperature for 24 h in an aluminum block.
After cooling to room temperature, Et2O and saturated NH4Cl aq. were
added. The phases were separated, the organic phase washed with
water and brine and dried over MgSO4. After filtration, Et2O was removed
in vacuum (≥500 mbar), and 1,1,2,2-tetrachloroethane was added as
internal standard for qNMR.
General Remarks: Chemicals: Unless otherwise specified, all reagents
and solvents were obtained from commercial suppliers and used without
further purification. 2,5-dimethylpyrrole (1),[34] 2,4-dimethylpyrrole (8),[23b]
2-isopropyl-5-phenylpyrrole (5),[35] diethyl 2,4-dimethylpyrrole-3,5-
dicarboxylate (11)[23a] and ethyl 2-phenylpyrrole-3-carboxylate (18)[30]
were prepared according to literature procedures. Ir-NCP pincer complex
14 and ligands L2, L3 were prepared according to refs.[35,25a,26]
Solvents for water-free reactions were dried by passing through a column
of Al2O3 and then kept over 3 Å molecular sieves under an argon
atmosphere.[36] The residual water content in dried solvents was analyzed
by coulometric Karl Fischer titration.
General procedure 4 (GP 4) for the homogenously catalyzed pyrrole
alkylation with precomplexation of ligand and metal precursor
(Table 2, entries 5–15 and Table 3): A 10 mL Schlenk tube was
charged with iridium-precursor, ligand and dry solvent under argon. The
reaction mixture, which immediately turned red, was stirred at 50 °C for
1 h. The oil bath was removed and pyrrole, alcohol, base and additional
dry solvent were added. The tube was closed and the mixture was
heated at the specified temperature for 24 h in a metal heating block.
After cooling to room temperature, Et2O and a saturated solution of aq.
NH4Cl were added. The phases were separated, the organic phase was
washed with water and brine and dried over MgSO4. After filtration, Et2O
was removed in vacuum (≥500 mbar) and 1,1,2,2-tetrachloroethane was
added as internal standard for qNMR.
Chromatography: Column chromatography (CC) was performed on silica
gel 60 (35–70 µm particle size), usually as a flash chromatography with
0.2 bar positive air pressure. Thin layer chromatography was performed
on glass plates coated with silica gel 60 F254 and visualized with UV light
(254 nm), molybdenum stain (Mostain)[37] or anisaldehyde stain.[38]
Microwave reactions: Reactions with microwave heating were performed
in a mono-mode type microwave reactor (Anton Paar Monowave 300) at
a fixed target temperature (measured by IR sensor) with adaptive power
setting under adiabatic conditions. The reaction time indicated refers to
heating at target temperature without heating and cooling phases.
Deuterium labeling experiments on the base-induced alkyl-transfer
Syntheses of deuterated substrates:
Analytical data: NMR spectra were recorded at 300, 400, or 500 MHz
(1H) at ambient temperature (19–25 °C). Chemical shift δ is given in ppm.
1H NMR spectra were internally referenced to tetramethylsilane (TMS, δH
0.00) or residual solvent peaks; in CDCl3: δH 7.26; in (D6)-DMSO: δH 2.50.
13C NMR spectra were referenced to solvent peaks; CDCl3, δC 77.16;
(D6)-DMSO, δC 39.52.
((3-(D3)-Methoxy)phenyl)methanol ((CD3O)-2g): To a solution of 3-
hydroxybenzyl alcohol (2.00 g, 16.1 mmol, 1.00 equiv.) in DMF (10 mL)
was added powdered potassium carbonate (3.80 g, 27.5 mmol,
1.71 equiv.) and CD3I (1.25 mL, 20.0 mmol, 1.24 equiv.) under vigorous
stirring. The resulting suspension was stirred for 30 h at room
temperature. The reaction was quenched by addition of a water/brine
(1:1). After extraction with EtOAc (3x), the combined organic phases
were washed with water/brine (1:1, 4x) and dried over MgSO4. After
filtration, the solvent was removed by rotary evaporation and the crude
product was purified by column chromatography (hexane–EtOAc 3:1) to
give 1.93 g (85%) of (CD3O)-2g as colorless oil. Rf 0.20 (hexane–EtOAc
3:1). 1H NMR (400 MHz, CDCl3): δ 7.30–7.24 (m, 1H, Ar-H), 6.96–6.91
(m, 2H, Ar-H), 6.86–6.80 (m, 1H), 4.67 (s, 2H, CH2OH), 1.76 (br. s, 1H,
OH). 13C NMR (101 MHz, CDCl3): δ 159.98, 142.68, 129.73, 119.21,
113.40, 112.38, 65.40, 54.55 (sept, JC-D = 22 Hz). HRMS (EI): calcd for
C8H7D3O2+: 141.0864, found 141.0860.
Reaction component analysis by qNMR: Yield determinations by qNMR
were carried out by means of suitable internal standards and appropriate
pulse sequences, typically using a pulse repetition delay d1 of ≥20 sec,
see ref.[39]
General procedure 1 for the microwave-assisted, base-catalyzed
pyrrole alkylation (GP 1): Into a microwave glass vessel equipped with
a stirring bar (1 cm) were added pyrrole (1.00 mmol), alcohol (2 mL if
neat), base and, if indicated, additional solvent (2 mL). The reaction
mixture was heated in a microwave reactor using a temperature-driven
variable power setting. After the target temperature was reached, it was
kept constant for the indicated reaction time. Following cooling to room
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10.1002/ejoc.201800146
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((4-(OCD3)-Methoxy)phenyl)methanol ((CD3O)-2h): To a solution of 4-
hydroxybenzaldehyde (1.87 g, 15.3 mmol, 1.00 equiv.) in DMF (10 mL),
powdered potassium carbonate (3.60 g, 26.0 mmol, 1.70 equiv.) and
CD3I (1.25 mL, 20.0 mmol, 1.31 equiv.) were added under vigorous
stirring. The resulting suspension was stirred for 30 h at room
temperature. Ethanol (10 mL) was added to the mixture, followed by
sodium borohydride (0.30 g, 7.93 mmol, 0.52 equiv.) in portions. The
reaction mixture was stirred for 3 h at room temperature until aldehyde
was no longer detected by TLC. Ethanol was removed by rotary
evaporation and the residue was partitioned between water, EtOAc and
brine. The aqueous phase was extracted with EtOAc (2x). The combined
organic phases were washed with water/brine (1:1) and dried over
MgSO4. After filtration, the solvent was removed by rotary evaporation
and the crude product was purified by column chromatography (hexane–
EtOAc 3:1) to give 1.96 g (91%) of (CD3O)-2h as colorless oil. Rf 0.17
(hexane–EtOAc 3:1). 1H NMR (400 MHz, CDCl3): δ 7.29 (d, J = 7.9 Hz,
2H, Ar-H), 6.89 (d, J = 8.0 Hz, 2H, Ar-H), 4.61 (s, 2H, CH2OH), 1.67 (bs,
1H
NMR
analysis
of
reaction
mixture
from
(3-(D3)-
methoxyphenyl)methanol ((CD3O)-2g): 30 mol% HO-C6H4-CH2OCD3 (1-
(CD3O)-13g) (δH 4.39 (s), CH2OCD3), 25 mol% D3CO-C6H4-CH2OCD3
(1,3’-(CD3O)2-12g) (δH 4.45 (s), CH2OCD3), 6 mol% HO-C6H4-CH2OH
(2e) (δH 4.56 (s), CH2OH) and 8 mol% starting material ((CD3O)-2g) (δH
4.63 (s), CH2OH).
1H
NMR
analysis
of
reaction
mixture
from
(4-(D3)-
methoxyphenyl)methanol ((CD3O)-2h): 22 mol% D3CO-C6H4-CH2OCD3
(1,4’-(CD3O)2-12h) (δH 4.39 (s), CH2OCD3) and 15 mol% starting
material ((CD3O)-2h) (δH 4.61 (s), CH2OH).
Synthesis of Ligand L1
6-(tert-Butyl)-1,3,5-triazine-2,4-diamine (17):
1H, OH). 13C NMR (101 MHz, CDCl3): δ 159.33, 133.24, 128.77, 114.07,
Grignard-reagent: In a Schlenk flask under argon, Mg turnings (2.67 g,
110 mmol, 1.10 equiv.) were overlaid with dry THF. A crystal of iodine
and a small fraction of tert-butyl chloride (totally 11.0 mL, 100 mmol,
1.00 equiv.) were added. The mixture was slightly warmed until the color
of iodine vanished and the reaction started. The remaining chloride and
dry THF (totally 50 mL) were slowly added over 30 min, maintaining a
moderate boiling. The reaction mixture was then heated to 65 °C for 1 h.
The Grignard-solution was titrated against salicylic aldehyde
phenylhydrazone.[40]
+
65.15, 54.61 (sept, JC-D = 22 Hz). HRMS (EI): calcd for C8H7D3O2
:
141.0864, found 141.0861. Known compound, CAS 14629-71-1.
Alkyl-transfer experiments:
Preparative run with (3-(OCD3)-methoxyphenyl)methanol:
A
microwave vial was charged with (3-(OCD3)-methoxyphenyl)methanol
((CD3O)-2g; 706 mg, 5.00 mmol, 1.00 equiv.), potassium tert-butoxide
(561 mg, 5.00 mmol, 1.00 equiv.) and toluene (2 mL). The reaction
mixture was heated in a microwave reactor at 250 °C for 1 h. After
cooling to room temperature, a saturated solution of aq. NH4Cl (5 mL)
and EtOAc (20 mL) was added. After separation of the phases, the
organic layer was washed with water (5 mL) and brine (5 mL) and dried
over NaSO4. The solvent was evaporated and the crude product mixture
was purified by column chromatography (hexane–EtOAc 20:1 → 4:1) to
afford 1-(CD3O)-13g (218 mg, 31%) and 1,3’-(CD3O)2-12g (156 mg, 20%)
as colorless oils.
Coupling/amination:[29] In
a Schlenk flask under argon atmosphere,
cyanuric chloride (15; 7.03 g, 38.1 mmol, 1.00 equiv.) and CuI (362 mg,
1.90 mmol, 0.05 equiv.) were suspended in dry THF (25 mL) and cooled
to –20 °C. A solution of tert-butyl magnesium chloride (93 mL; 0.43 m in
THF, 40.0 mmol, 1.05 equiv.) was added dropwise over 40 min. After
warming to 0 °C and stirring for 30 min, the content of the flask was
poured into 25% aq. NH3 (400 mL). The mixture was heated to 60 °C and
stirred for 19 h. Saturated aq. NH4Cl was added to dissolve magnesium
salts. The mixture was basified with 25% NH3 (aq.) and extracted with
EtOAc (3 x). The organic phases were washed with water and brine.
After drying over MgSO4 and filtration, evaporation in vacuum gave 6-
(tert-butyl)-1,3,5-triazine-2,4-diamine (17; 4.67 g, 73%) as colorless solid.
The compound can be recrystallized from dichloromethane. Rf 0.30
(hexane–EtOAc 1:2). M.p. 168–170 °C (lit.:[41] 169–171 °C). 1H NMR (400
MHz, CDCl3): δ 5.02 (br s, 4H, NH2), 1.26 (s, 9H, CH3). 13C NMR
(101 MHz, CDCl3): δ 186.23, 167.38, 38.56, 28.70. Analysis calcd for
C7H13N5 (167.22): C 50.28, H 7.84, N 41.88; found C 50.01, H 7.80, N
41.91. Known compound, CAS 35841-84-0.
(3-(D3)-methoxymethyl)phenol (1-(CD3O)-13g): 1H NMR (500 MHz,
CDCl3): δ 7.21 (t, J = 7.8 Hz, 1H, Ar-H), 6.88 (d, J = 7.5 Hz, 1H, Ar-H),
6.85–6.82 (m, 1H, Ar-H), 6.76 (dd, J = 8.1, 2.5 Hz, 1H, Ar-H), 5.13 (bs,
1H, OH), 4.43 (s, 2H, CH2OCD3). 13C NMR (101 MHz, CDCl3): δ 156.21,
139.53, 129.79, 120.08, 115.08, 114.81, 74.48, 57.15 (sept, JC-D = 22 Hz).
HRMS (EI): calcd for C8H7D3O2+: 141.0864, found 141.0862.
(1-(D3)-methoxy)-3-(OCD3)-(methoxymethyl))benzene
(1,3’-(CD3O)2-
12g): 1H NMR (500 MHz, CDCl3): δ 7.29–7.23 (m, 1H, Ar-H), 6.94–6.87
(m, 2H, Ar-H), 6.83 (dd, J = 7.9, 1.9 Hz, 1H, Ar-H), 4.44 (s, 2H,
CH2OCD3). 13C NMR (101 MHz, CDCl3): δ 159.90, 140.01, 129.53,
(6-tert-Butyl)-N2N4-bis(diphenylphosphino)-1,3,5-triazine-2,4-diamine
(L1): Synthesis performed in analogy to refs. [26,27a] A Schlenk flask under
argon atmosphere was charged with 6-(tert-butyl)-1,3,5-triazine-2,4-
diamine (17; 500 mg, 2.99 mmol, 1.00 equiv.) and dry THF (20 mL). After
120.03, 113.50, 112.98, 74.63, 57.26 (sept, JC-D = 22 Hz), 54.54 (sept,
+
JC-D
=
22 Hz). HRMS (EI): calcd for C9H6D6O2
:
158.1208, found
158.1203.
cooling to –20 °C (NaCl/ice), n-BuLi (4.02 mL, 1.5
m in hexane,
6.13 mmol, 2.05 equiv.) was added dropwise. The resulting white
suspension was warmed to r.t. and stirred for 30 min.
Chlorodiphenylphosphine (1.10 mL, 5.98 mmol, 2.00 equiv.) was added
dropwise at ca. –10 °C and the resulting clear solution was warmed and
stirred overnight at r.t. The solvent was removed in vacuum and the
slightly yellow, foamy residue was suspended in CH2Cl2. Filtration
removed most of the LiCl-precipitate. The solvent was removed in
vacuum and the crude product was purified by column chromatography
(in air, hexane–EtOAc 10:1) to afford L1 (828 mg, 52%) as white,
crystalline solid. Rf 0.20 (hexane–EtOAc 10:1). 1H NMR (500 MHz, C6D6):
δ 7.46–7.20 (m, 8H, Ar-H), 7.09–6.89 (m, 12H, Ar-H), 5.62 (br s, 2H, NH),
1.41 (s, 9H, CH3). 13C NMR (126 MHz, C6D6): δ 185.93, 168.23, 139.58
(d, J = 16.1 Hz), 131.59 (d, J = 22.1 Hz), 128.90, 128.39 (d, J = 6.6 Hz),
Analytical runs with (CD3O)-2g and (CD3O)-2h: A microwave vial was
charged with deuterium labeled methoxybenzyl alcohol (CD3O)-2g or
(CD3O)-2h (141 mg, 1.00 mmol, 1.00 equiv., 100 mol%), potassium tert-
butoxide (112 mg, 1.00 mmol, 1.00 equiv.) and toluene (2 mL). The
reaction mixture was heated in a microwave reactor at 250 °C for 1 h.
After cooling to room temperature, a solution of sat. NH4Cl aq (3 mL) and
EtOAc (15 mL) was added. After separation of the phases, the organic
layer was washed with water (5 mL) and brine (5 mL) and dried over
MgSO4. After filtration, the solvent was removed in vacuum. The residue
was dissolved in CDCl3 and 1,1,2,2-tetrachloroethane (20 µL,
0.191 mmol) was added as internal standard for qNMR.
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10.1002/ejoc.201800146
European Journal of Organic Chemistry
FULL PAPER
38.93, 28.65. 31P NMR (203 MHz, C6D6): δ 28.45 (br s, 62%), 25.68 (br s,
38%; tautomers?). HRMS (EI) calcd for C31H31N5P2+: 535.2049, found
535.2052.
Keywords: alkylation • borrowing hydrogen • homogeneous
catalysis • iridium • pyrrole
[1]
a) T. D. Nixon, M. K. Whittlesey J. M. J. Williams, Dalton Trans. 2009,
753–762; b) G. Guillena, D. J. Ramón, M.Yus, Angew. Chem. Int. Ed.
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Isolated pyrrole alkylation products
3-Benzyl-2,5-dimethylpyrrole (3a): The product was synthesized
according to GP 4. A 10 mL Schlenk tube was charged with [Ir(cod)Cl]2
(5.0 mg, 7.5 µmol, 0.5 mol%), ligand L3 (6.6 mg, 15.8 µmol, 1.05 mol%)
and dry toluene (0.2 mL) under argon. The reaction mixture, which
immediately turned red, was stirred at 50 °C for 60 min. The oil bath was
removed and 2,5-dimethylpyrrole (1; 153 µL, 1.50 mmol, 1.00 equiv.),
benzyl alcohol (1.55 mL, 15.0 mmol, 10.0 equiv.), potassium tert-
butoxide (337 mg, 3.00 mmol, 2.00 equiv.) and dry toluene (1.3 mL) were
added. The tube was tightly closed and the mixture was heated at 110 °C
for 24 h in an aluminium heating block. After cooling to room temperature,
Et2O (20 mL) and sat. aq. NH4Cl (7 mL) were added. The phases were
separated; the organic phase was washed with water (5 mL) and brine
(5 mL) and dried over MgSO4. After filtration, the solvent was removed in
vacuum and the crude product was purified by Kugelrohr distillation
(115 °C, 0.15 mbar) to give 3a (144 mg, 52%) as white crystalline solid.
The compound is not very stable and slowly decomposes, even if stored
under argon at 4 °C, under exclusion of light. 1H NMR (400 MHz, CDCl3):
δ 7.42 (bs, 1H, NH), 7.29–7.24 (m, 2H, Ar-H), 7.23–7.19 (m, 2H, Ar-H),
7.18–7.13 (m, 1H, Ar-H), 5.62 (d, J = 2.7 Hz, 1H, Ar-H), 3.72 (s, 2H,
CH2), 2.19 (s, 3H, CH3), 2.17 (s, 3H, CH3). 13C NMR (101 MHz, CDCl3):
δ 142.86, 128.55, 128.37, 125.58, 125.24, 122.23, 118.25, 107.30, 32.46,
13.11, 11.20. HRMS (EI): calcd for C13H15N+: 185.1199, found 185.1199.
[2]
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2-Benzyl-5-phenylpyrrole (19): The product was synthesized according
to the GP 4. A 10 mL Schlenk tube was charged with [Ir(cod)Cl]2 (5.0 mg,
7.5 µmol, 0.5 mol%), ligand L3 (6.6 mg, 15.8 µmol, 1.05 mol%) and dry
toluene (0.2 mL) under argon. The reaction mixture, which immediately
turned red, was stirred at 50 °C for 60 min. The oil bath was removed
and 2-phenylpyrrole-3-carboxylate (18; 323 mg, 1.50 mmol, 1.00 equiv.),
benzyl alcohol (1.55 mL, 15.0 mmol, 10.0 equiv.), potassium tert-
butoxide (337 mg, 3.00 mmol, 2.00 equiv.) and dry toluene (1.3 mL) were
added. The tube was closed and the mixture was heated at 110 °C for
24 h in an aluminium heating block. After cooling to room temperature,
Et2O (20 mL) and a saturated solution of aq. NH4Cl (7 mL) were added.
The phases were separated, the organic one was washed with water
(5 mL) and brine (5 mL) and dried over MgSO4. After filtration, the solvent
was removed in vacuum and the crude product was purified by column
chromatography (hexane–EtOAc = 20:1) to give 176 mg (50%) of 19 as a
slightly pink solid. Rf 0.52 (hexane–EtOAc 4:1). 1H NMR (300 MHz,
CDCl3): δ 8.00 (bs, 1H, NH), 7.40–7.20 (m, 9H, Ar-H), 7.17–7.10 (m, 1H,
Ar-H), 6.45–6.41 (m, 1H, Ar-H), 6.06–6.02 (m, 1H, Ar-H), 4.01 (s, 2H,
CH2). 13C NMR (75 MHz, CDCl3): δ 139.39, 132.93, 132.12, 131.64,
128.92, 128.83, 128.80, 126.69, 125.96, 123.59, 108.76, 106.24, 34.39.
Known compound, CAS 905971-72-4.
[6]
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Acknowledgements
We thank the Hans-Fischer-Gesellschaft for financial support.
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10.1002/ejoc.201800146
European Journal of Organic Chemistry
FULL PAPER
[19] A. Treibs, Das Leben und Wirken von Hans Fischer, Hans-Fischer-
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Pyrrolarbeiten ist die Alkylierungsreaktion mit Alkoholaten zu höher
substituierten, besonders Tetraalkylpyrrolen ... , Sie erfordert scharfe
Bedingungen und steht ziemlich ohne Analogien da, ihr Mechanismus
hat noch keine Erklärung gefunden.“ („A remarkable success of
[Fischer's] ... initial work on pyrroles is the alkylation reaction with
alcoholates that provides more highly substituted, especially
tetraalkylpyrroles... It requires harsh conditions and is quite without
analogies, its mechanism has not yet found any explanation.")
[21] While not mentioned in the original reports (ref. [13]), this information
was conveyed by Alfred Treibs (ref. [19]), who wrote: "Die Methode war
bei der Bearbeitung der Wolff-Kishner-Reaktion gefunden worden; man
ließ sich nicht davon abschrecken, daß 3/4 aller Bombenröhren
explodierten." ("The [pyrrole alkylation] method had been found during
studies of the Wolff-Kishner-reaction; one was not deterred by the fact
that three out of four sealed tubes exploded.")
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H2O (200 mL) and conc. H2SO4 (12 mL; added last with stirring).
[38] Prepared from acetic acid (100 mL), conc. H2SO4 (2 mL) and
anisaldehyde (1 mL).
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European Journal of Organic Chemistry
FULL PAPER
FULL PAPER
Hydrogen-Autotransfer-Alkylation
Sebastian Koller, Max Blazejak, Lukas
Hintermann*
Page No. – Page No.
Catalytic C-Alkylation of Pyrroles with
Primary Alcohols: Hans Fischer's
Alkali, and a New Spin with Iridium
P,N,P-Pincer Complexes
The alkylation of pyrroles with primary alcohols and alkali base at 220 °C was
realized by Hans Fischer one hundred years ago. However, this hydrogen
autotransfer (borrowing hydrogen) alkylation proceeds under much milder
conditions in the presence of iridium P,N,P-pincer-complex catalysts.
This article is protected by copyright. All rights reserved.