Efficient Syntheses of 2,5-Dihydropyrroles, Pyrrolidin-3-ones, and Electron-Rich Pyrroles from N-Tosylimines and Lithiated Alkoxyallenes

Article abstract of DOI:10.1002/ejoc.201700073

N-Tosylimines and lithiated alkoxyallenes afforded the corresponding allenyl N-tosylamines in good to excellent yields. The 5-endo-trig cyclizations of these intermediates to 2,5-dihydropyrrole derivatives were achieved under strongly basic conditions with potassium tert-butoxide or under milder conditions with either silver(I) or gold(I) catalysis. In general, gold chloride catalyzed reactions occurred with the lowest catalyst loadings and delivered the best yields. With phenyl-substituted 2,5-dihydropyrrole, we investigated typical reactions such as oxidative and reductive transformations. The acid-promoted hydrolysis of the enol ether moieties of three 2,5-dihydropyrroles furnished the corresponding pyrrolidin-3-ones, which were reduced to give 3-hydroxypyrrolidine derivatives in good yields. The aromatization of 2,5-dihydropyrroles to 3-methoxypyrrole derivatives was accomplished by base treatment, which caused the elimination of p-tolyl sulfinate. Electron-rich pyrrole derivatives were synthesized in good yields even on a large scale. All of the experiments illustrate the efficacy and flexibility of the alkoxyallene approach to pyrrole derivatives.

Full text of DOI:10.1002/ejoc.201700073

A Journal of
Accepted Article
Title: Efficient Syntheses of 2,5-Dihydropyrroles, Pyrrolidin-3-ones
and Electron-Rich Pyrroles from N-Tosylimines and Lithiated
Alkoxyallenes
Authors: Hans-Ulrich Reissig, Ghislaine Marlyse Okala Amombo,
Oliver Flögel, Scheghajeh Kord Daoroun Kalai, Stefan
Schoder, and Ulrike Warzok
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of the final Version of Record (VoR). This work is currently citable by
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the VoR from the journal website shown below when it is published
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700073
Link to VoR: http://dx.doi.org/10.1002/ejoc.201700073
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10.1002/ejoc.201700073
European Journal of Organic Chemistry
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Efficient Syntheses of 2,5-Dihydropyrroles, Pyrrolidin-3-ones and
Electron-Rich Pyrroles from N-Tosylimines and Lithiated
Alkoxyallenes
Ghislaine Marlyse Okala Amombo,[a] [b] Oliver Flögel,[a] Scheghajeh Kord Daoroun Kalai,[a] Stefan
Schoder,[a] Ulrike Warzok,[a] Hans-Ulrich Reissig*[a]
Dedicated to Professor Lutz F. Tietze on the occasion of his 75th birthday
Abstract: N-Tosylimines and lithiated alkoxyallenes afforded the
corresponding allenyl N-tosylamines in good to excellent yields. The
5-endo-trig cyclizations of these intermediates to 2,5-dihydropyrrole
derivatives were achieved under strongly basic conditions employing
potassium tert-butoxide or under milder conditions by either silver(I)
or gold(I) catalysis. In general, gold chloride-catalyzed reactions
occurred with the lowest catalyst loadings and delivered the best
yields. With the phenyl-substituted 2,5-dihydropyrrole we investigated
typical reactions such as oxidative and reductive transformations.
Acid-promoted hydrolysis of the enol ether moiety of three 2,5-
dihydropyrroles furnished the corresponding pyrrolidin-3-ones that
were reduced to give 3-hydroxypyrrolidine derivatives in good yields.
The aromatization of 2,5-dihydropyrroles to 3-methoxypyrrole
derivatives was accomplished by base treatment causing the
elimination of p-tolyl sulfinate. The electron-rich pyrrole derivatives
were synthesized in good yields even on large scale. All experiments
illustrate the efficacy and flexibility of the alkoxyallene approach to
pyrrole derivatives.
reactions were employed to prepare a variety of heterocycles that
are either of interest as intermediates for the synthesis of natural
products[6] and their analogs[7] or heteroaromatic compounds with
extended π-systems.[8] In a preliminary report, we described
additions of lithiated methoxyallene to imines leading to the
expected allenyl amines that were subsequently cyclized to 2,5-
dihydropyrrole derivatives.[9] Again, selected intermediates could
be employed in stereoselective natural product syntheses.[10] The
use of highly reactive N-tosylimines as electrophiles also provided
2,5-dihydropyrroles. In one example we demonstrated that by
elimination of p-tolyl sulfinate an aromatization occurred,
efficiently leading to electron-rich pyrrole derivatives.[9a] Since
only few methods[11] exist to approach this type of pyrroles, we
further investigated scope and limitations of this method. The
obtained pyrroles are of interest as precursors of specifically
substituted dipyrromethenes and of BODIPYs[12] or of
prodigiosine analogs.[13] In typical examples we also studied the
conversion of 2,5-dihydropyrrole derivatives into pyrrolidin-3-ones
and their subsequent reactions.
Introduction
In a series of publications we demonstrated that lithiated
alkoxyallenes are extremely valuable C3 building blocks for the
synthesis of heterocycles.[1] The required lithiated species is
easily generated by deprotonation with n-butyllithium as already
demonstrated in 1968 by Arens et al.[2] who also showed that
additions to carbonyl compounds and subsequent cyclizations
deliver 2,5-dihydrofuran derivatives.[3] We discovered that
addition to nitrones directly leads to 1,2-oxazine ring formation[4]
and that a three-component reaction with nitriles and carboxylic
acids provides highly substituted pyridine derivatives
(Scheme 1).[5] These useful and highly flexible cyclization
[a]
Dr. M. G. Okala Amombo, Dr. O. Flögel, S. Kord Daoroun Kalai, S.
Schoder, U. Warzok, Prof. Dr. H.-U. Reissig
Institut für Chemie und Biochemie, Freie Universität Berlin
Takustr. 3, 14195 Berlin (Germany)
E-mail: hans.reissig@chemie.fu-berlin.de
Homepage: http://www.bcp.fu-berlin.de/en/chemie/chemie/for-
schung/OrgChem/reissig/index.html
[b]
Dr. G. M. Okala Amombo
Fachrichtung Chemie und Lebensmittelchemie, Technische
Universität Dresden, 01062 Dresden (Germany)
Scheme 1. Generation and reactions of lithiated alkoxyallenes with different
electrophiles leading to heterocyclic compounds.
Supporting information for this article is given via a link at the end of
the document.
1
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10.1002/ejoc.201700073
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Results and Discussion
Table 1. Addition of lithiated alkoxyallenes 1a-c to N-tosylimines 2a-h
leading to allenyl N-tosylamines 3-13.
The alkoxyallenes and N-tosylimines required for our study were
prepared according to literature methods (for details see
Supporting Information). In the additions, lithiated methoxyallene
1a was used in slight or large excess (up to five equivalents) since
the unconsumed portion can easily be removed by simple
evaporation after aqueous work-up. This protocol guarantees a
high degree of conversion of the imine and results in very good
yields that are often close to quantitative. The primary adducts
were in part not sufficiently stable to be purified and the crude
products were then used for the subsequent cyclization reactions.
As first imine benzaldehyde-derived N-tosylimine 2a was
combined with lithiated methoxyallene 1a (Scheme 2, Table 1,
entry 1) quantitatively providing the expected allenyl N-tosylamine
3 as very pure crude product; after crystallization a yield of 67 %
was obtained. The heteroaryl-substituted imines 2b-2e also gave
the corresponding primary addition products 4-7 in moderate to
excellent yields (entries 2-4). The syntheses of compound 3-5
were also performed on large scale without any erosion of yield
and purity, affording up to 8 g of the desired products.
Alkoxy-
allene
Pro-
duct
Entry
R1
Imine
R2
Yield[a]
1
2
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1c
Me
Me
2a
2b
2c
2d
2e
2f
Ph
3
4
67 %[b]
43 %
2-Thienyl
3-Thienyl
2-Pyrrolyl
2-Pyridyl
Styryl
3
Me
5
55 %
4
Me
6
quant.[c]
96 %[e]
80 %
5[d]
6[f]
7
Me
7
Me
8
Me
2g
2a
2c
2h
2c
t-Bu
9
92 %
8
Bn
Ph
10
11
12
13
quant.[g]
57 %
9
Bn
3-Thienyl
Hexyl
10
11[h]
Bn
quant.[g]
86 %
TMSE
3-Thienyl
[a] Yield of purified product; [b] Spectroscopically pure crude product
obtained quantitatively; [c] Purity ca. 90 %; [d] Reaction at -95 °C for
5 min; [e] Purity ca. 80 %; [f] Transmetalation with CeCl3, -40 °C to -20 °C,
1.5 h; [g] Crude product containing benzyloxyallene; [h] Reaction
at -78 °C for 2 h.
Scheme 2. Synthesis of allenyl N-tosylamines 3-13 by addition of lithiated
alkoxyallenes 1a-c to N-tosylimines 2a-h (for details see Table 1).
Allenyl N-tosylamines such as 3 are versatile starting materials for
synthetic applications. The reaction with iodine and nitriles leads
to the formation of highly substituted imidazole derivatives.[14]
Alternatively, the enol ether moiety can be hydrolyzed to generate
an enone or it can be cleaved by ozone to provide (racemic) α-
amino acid esters.[9a] Synthetically most valuable are the 5-endo-
trig cyclizations[15] of the allenylamines to 2,5-dihydropyrroles that
were investigated in this work employing different methods
(Scheme 3).
The highly reactive 2-pyridyl-substituted imine 2e rapidly
undergoes decomposition and side-reactions. Hence the addition
of 1a to 2e is best performed at -90 °C within 5 minutes affording
a good yield of compound 7 (entry 5). The styryl-substituted imine
2f provided adduct 8 under standard conditions only in ca. 50 %
yield. However, after transmetalation of lithiated methoxyallene
1a into the corresponding cerium(III) species,[3e] allenylamine 8
was isolated in 80 % yield (Table 1, entry 6). We assume that
lithiated methoxyallene 1a not only undergoes the expected 1,2-
addition to the α,β-unsaturated imine 2f but also 1,4-addition
resulting in product mixtures. The cerium species reacts more
selectively giving only 8. tert-Butyl-substituted N-tosylimine 2g
also smoothly reacted with 1a furnishing the allenylamine 9 in
excellent yield (entry 7).
Finally, two alkoxyallenes with different substituents R1 were
examined to demonstrate the flexibility with respect to this group
(Table 1, entries 8-11). Although the excess of the used
alkoxyallenes was more difficult to remove the additions of
lithiated benzyloxyallene 1b or of lithiated (2-trimethylsilyl)-
ethoxyallene 1c to N-tosylimines also provided the expected
addition products with high efficiency. Reaction of 1b with 2a
quantitatively provided allenyl amine 10 (entry 8). The addition
product 11 obtained from 1b and 3-thienyl-substituted imine 2c
was purified and isolated in 57 % yield (entry 9). The reaction of
1b with heptanal-derived N-tosylimine 2h demonstrates that
imines with unbranched alkyl groups are also suitable substrates
for this type of reaction (entry 10). Finally, lithiated (2-
trimethylsilyl)-ethoxyallene 1c was added to imine 2c to give the
3-thienyl-substituted product 13 in very good yield (entry 11).
Scheme 3. 5-endo-trig Cyclizations of allenyl N-tosylamines 3-13 to 2,5-
dihydropyrroles 14-24 by methods A (KOtBu, DMSO, 50 °C), B or B´ (AgNO3,
acetone, rt, or AgNO3, acetonitrile, K2CO3, rt), or C (AuCl, pyridine, CH2Cl2, rt)
(for details see Table 2); structure of side-products 25 and 26.
For allenylamine 3 we first tested the conditions that were
frequently applied for the related cyclizations of allenyl alcohols to
2,5-dihydrofuran derivatives,[3] employing potassium tert-butoxide
(0.15 to 1 equivalents) in DMSO at 50 °C. Despite the fairly harsh
2
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10.1002/ejoc.201700073
European Journal of Organic Chemistry
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conditions, the expected 2,5-dihydropyrrole derivative 14 was
isolated in very good yield (Table 2, entry 1). With substrate 3 we
also studied coin metal-catalyzed cyclizations using either silver
nitrate (27 mol % in acetone or acetonitrile)[16] or gold chloride (5
mol %, buffered by 0.15 equivalents of pyridine, in
dichloromethane), both methods under light exclusion.[17,6a] These
methods are considerably milder and furnished 14 in 93 % and
94 % yield, respectively (entries 2 and 3). Furthermore, we
studied the cyclization of allenylamine 3 promoted by Pd(PPh3)4
(5 mol %),[18] that gave 14 only in 56 % yield.[19]
The gold catalysis was also applied to allenylamines 4 and 5
affording the two isomeric thienyl-substituted 2,5-dihydropyrroles
15 and 16 in excellent yields (entries 4 and 5). Applying the
strongly basic conditions of method A, an acceptable yield of 56 %
was obtained for the conversion of 2-pyrrolyl-substituted
allenylamine 6 to 17 (entry 6). Unexpectedly, with gold chloride
(entry 7) not only compound 17 was formed but also the
elimination product 25 and the dihydroindole derivative 26
(Scheme 3) that could not be separated from the product mixture
(for a proposed mechanism[20] of the formation of 26 see
Supporting Information). The 2-pyridyl-substituted precursor 7, on
the other hand, required silver catalysis to isolate the expected
2,5-dihydropyrrole 18 in 80 % yield over two steps (entry 8).
With styryl- and tert-butyl-substituted allenylamines 8 and 9 only
methods A and B were examined[21] and gave only low to
moderate yields of the desired products 19 and 20 (entries 9-12).
The unpurified benzyloxy-substituted precursor 10 was subjected
to silver catalysis under slightly modified conditions (27 mol %
AgNO3, acetonitrile in the presence of K2CO3) affording the
desired 2,5-dihydropyrrole 21 in 82 % yield over two steps (entry
13). This method was also applied for the preparation of 23 (51 %
over two steps, entry 15). Allenyl amines 11 and 13 were exposed
to the gold chloride method C (entries 14 and 16) and afforded
the crude products 22 and 24 quantitatively that were further used
without purification (see below).
The experiments collected in Table 2 reveal that the gold-
catalyzed version of the cyclization works nicely in most cases
studied, converting the allenyl N-tosylamines into the desired 2,5-
dihydropyrrole derivatives under mild conditions and convenient
work-up. However, a few not well understood exceptions provided
better results under the strongly basic conditions of method A
(see entries 6 and 7).
From a mechanistic point of view, the metal-catalyzed processes
are easy to understand (Scheme 4): coordination of the silver or
gold ion to the central allene carbon generates a well stabilized
allyl cation A that is attacked by the amino group at the terminal
carbon to give the corresponding metallated 2,5-dihydropyrrole B.
Proto-demetallation of this intermediate affords the product and
regenerates the catalyst.[22]
Table 2. Cyclizations of allenyl N-tosylamines 3-13 to 2,5-dihydropyrrole
derivatives 14-24 (see Scheme 3).
Method
Time
(h)
Pro-
duct
Entry
1
R1, R2
Me, Ph
Yield[b]
84 %
(equiv.)[a]
A
(0.15)
3
3
1
3
14
14
14
15
16
17
17
18
19
19
20
20
21
22
23
24
B
(0.27)
2
Me, Ph
93 %
C
(0.05)
3
Me, Ph
3
12
12
12
3
94 %
C
(0.05)
4
Me, 2-Thienyl
Me, 3-Thienyl
Me, 2-Pyrrolyl
Me, 2-Pyrrolyl
Me, 2-Pyridyl
Me, Styryl
Me, Styryl
Me, t-Bu
4
quant.
95 %[c]
56 %
C
(0.05)
5
5
A
(0.5)
6
6
C
0.05
[d]
7
6
18
1
-
B
(0.24)
8
7
80 %
33 %
A
(0.5)
9
8
1
B
(0.27)
10
11
12
13
14
15
16
8
3
35 %
A
(1.0)
9
1
41 %
B
(0.27)
Me, t-Bu
9
3
51 %
B´
(0.27)
Bn, Ph
10
11
12
13
16
12
16
12
82 %
C
(0.05)
Bn, 3-Thienyl
Bn, Hexyl
quant.[c]
51 %
B´
(0.27)
Scheme 4. Possible mechanisms of 5-endo-trig cyclization of allenyl N-
tosylamines to 2,5-dihydropyrolles by silver(I) or gold(I) catalysts (Met) or by
potassium tert-butoxide.
TMSE,
3-Thienyl
C
(0.05)
quant.[c]
[a] A: KOtBu, DMSO, 50 °C; B: AgNO3, acetone, rt, light exclusion; B´:
AgNO3, K2CO3, CH3CN, rt, light exclusion; C: AuCl, pyridine, CH2Cl2, light
exclusion; [b] Purified products; [c] Crude product; [d] Quant.: mixture of 17,
25 and 26 (ca. 16:37:47).
The potassium tert-butoxide-promoted cyclizations are
mechanistically still puzzling like those of the corresponding
allenyl alcohols[3]. A simple 5-endo-trig cyclization seems to be
3
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10.1002/ejoc.201700073
European Journal of Organic Chemistry
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forbidden according to Baldwin´s rules,[15] but it should be
considered that these rules were not designed for allenyl systems.
The flexible allene moieties bend easily[23] and hence the
nucleophilic attack of the deprotonated N-tosylamine group of C
to the terminal allene carbon seems to be geometrically feasible.
Nevertheless, this process generates a negative charge at the
alkenyl moiety of the resulting dihydropyrrole intermediate D.[24]
Although for the related allenyl alcohol cyclization to 2,5-
dihydrofurans electron-transfer processes were suggested as
alternative,[3c] when applied to the current system this mechanism
would still involve D as intermediate. We do not see strong
arguments for the electron-transfer mechanism in our examples
and speculate that the highly polar DMSO is not only coordinating
to the potassium counter ion, but that carbanion D is also
stabilized by this solvent either by hydrogen bonding or by full
proton transfer (in this case D would be a transition state and not
an intermediate).
In order to gain a more detailed understanding of the base-
promoted cyclizations, we performed
a
few additional
experiments with allenyl amine 3. First, we tried to directly use the
THF solution obtained by addition of lithiated methoxyallene 1a to
imine 2a delivering the lithium salt 3-Li (Scheme 5). Instead of
aqueous work-up this solution was heated to 50 °C for one hour
and then quenched with water. No cyclization was observed and
only allenylimine 3 was isolated in 98% yield.[25] On the other hand,
when the THF solution of 3-Li was concentrated in vacuo, the
residue dissolved in DMSO and heated to 50 °C for 1 h,
cyclization to 2,5-dihydropyrrole 14 occurred, but formation of 3-
methoxy-2-phenylpyrrole (27) was also observed (ratio ca. 2:1;
Scheme 5, equation 1). This result underscores the importance of
DMSO as highly polar solvent for the cyclization process.
Formation of 27 shows that the elimination of lithium p-tolyl
sulfinate from 14 occurs quite rapidly under these conditions
leading to aromatization (for details see Scheme 8 and discussion
below). A high conversion of allenyl imine 3 to pyrrole 27 was
achieved by use of 1.5 equivalents of potassium tert-butoxide in
DMSO (equation 2). Now a 12:88 mixture of 14 and 27 was
obtained and after chromatography, the two products were
isolated in 7 % and in 71 % yield, respectively. To achieve full
elimination, we performed reactions of 3 with even higher
amounts of potassium tert-butoxide. However, when 3.5
equivalents of base were used a mixture of 14 and 1,3-diene 28
was obtained. In DMSO the ratio was ca. 1:1 whereas in THF
essentially only 1,3-diene 28 was isolated (equation 3). Since the
formation of 27 requires the preceding cyclization to 14, this result
shows again that this process is disfavored in THF. The surprising
formation of 1,3-diene 28 in the presence of a high excess of base
may be explained by involvement of dianion E generated by
deprotonation at the amino group of 3 and (in equilibrium) at the
phenyl-substituted carbon. The reasonably stabilized dianion E
does not undergo the cyclization to 12 and by protonation the
conjugated diene 28 is formed.
Scheme 5. Base-promoted reactions of allenyl N-tosylamine 3 under different
conditions.
also operates as a base. Samarium diiodide is a versatile reagent
for the chemoselective reduction of many substrates,[28] often
including highly useful subsequent reactions.[29] Application of two
equivalents of SmI2 in a mixture of THF and HMPA (4:1)[30]
furnished the expected N-deprotected 2,5-dihydropyrrole 30 in
moderate yield, but it was accompanied by the acyclic enolether
31 (cis:trans ca. 1:2) in 11 % yield. The reductive cleavage of the
N-S bond of 14 obviously competes with that of the C-N bond,
generating an allylic radical, and after a second electron transfer
and protonation 31 is formed. With 2,5-dihydropyrrole derivative
23 we also examined the palladium-catalyzed hydrogenation.
However, a mixture of 3-benzyloxy- and 3-hydroxy-substituted
pyrrolidines and of the corresponding pyrrolidin-3-one was
isolated revealing the limited synthetic usefulness of this
reaction.[31]
To learn more about the reactivity of 2,5-dihydropyrroles such as
14, we explored typical transformations under oxidative, reductive
and acidic conditions. The oxidation of 14 with a large excess of
activated manganese dioxide[26] provided N-tosylpyrrole 29 in
moderate yield (Scheme 6). For the reductive removal of the N-
tosyl group of 14, we examined two methods. With sodium
naphthalenide in 1,2-dimethoxyethane,[27] the desired product 30
was isolated in 76 % yield, but the formation of the elimination
product 27 (10 %) could not be avoided, showing that the reagent
Scheme 6. Oxidation and reductions of 2,5-dihydropyrrole derivative 14.
4
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Heating of 2,5-dihydropyrroles 14, 19 and 20 with 10% aqueous
sulfuric acid provided the corresponding pyrrolidin-3-ones 32-34
(Scheme 7). The lower yield for 33 may be due to the sensitivity
of the styryl substituent. An alternative method was examined for
14 employing trimethylsilyl iodide (generated in situ from TMSCl
and sodium iodide in acetonitrile);[32] after aqueous work-up 32
was obtained in quantitative yield.
and subsequently of BODIPYs,[34] further 2,5-dihydropyrrole
derivatives were similarly treated with an excess of potassium
tert-butoxide in DMSO to induce the elimination of p-tolyl sulfinate.
The aromatization was not observed with the t-butyl-substituted
2,5-dihydropyrrole 20,[19] possibly due to the lower acidity of 2-H.
On the other hand, the expected 2-heteroaryl-3-methoxypyrroles
37-41 were isolated in good yields (Table 3, entries 2-7). The 2-
pyridyl-substituted 2,5-dihydropyrrole 18 also afforded the
expected product 39 in 57 % yield under the standard conditions.
However, in this case we also examined an alternative basic
system for the elimination process, consisting in exposure of 18
to 2.5 equivalents of LDA in THF at -78 °C and warm-up to -20°C
during 7 h. These considerably milder conditions furnished 39 in
an improved yield of 87 % (compare entries 4 and 5). The
precursors 22 and 24 were used as unpurified crude products and
delivered the 3-thienyl-substituted pyrroles 40 and 41 with
differing alkoxy groups in 45 % and 53 % yield (entries 6 and 7).
These yields over two steps are quite satisfying and demonstrate
that our route to sensitive electron-rich pyrroles is efficient.
Scheme 7. Acid-promoted hydrolysis of the enol ether moiety of 2,5-
dihydropyrroles 14, 19 and 20 to pyrrolidin-3-ones 32-34 and stereoselective
reductions to pyrrolidine derivatives 35 and 36.
The carbonyl groups of 32 and 34 were stereoselectively reduced
with sodium borohydride delivering the 3-hydroxypyrrolidine
derivatives 35 and 36 in good yields. By analogy to literature
results,[33] we assume that the major isomers are cis-configured.
The transformations shown in Scheme 7 illustrate that 2,5-
dihydropyrroles obtained by the alkoxyallene route are versatile
intermediates for the syntheses of simple, but useful building
blocks. Other transformations involving the enol ether moiety of
the 2,5-dihydropyrroles (e.g. stereoselective hydroboration[10b]) or
the carbonyl group of pyrrolidin-3-ones are conceivable.
Scheme 8. Potassium tert-butoxide-promoted p-tolyl sulfinate elimination
converting 2,5-dihydropyrroles 14-16, 18, 22 and 24 into 3-alkoxypyrroles 27
and 37-41 and proposed reaction mechanism.
In Scheme 5 (equation 2) we already described the base-
promoted formation of 3-methoxy-2-phenylpyrrole (27) from the
primary adduct 3 with 2,5-dihydropyrrole 14 as intermediate. As
probable mechanism (Scheme 8), we assume the deprotonation
at C-2 of 14 to generate an allylic anion F that is additionally
stabilized by the 2-phenyl group and possibly by the electron-
withdrawing N-tosyl moiety. Subsequent displacement of the p-
tolyl sulfinate anion affords the corresponding 2H-pyrrole G that
immediately undergoes a proton shift to the aromatic 1H-pyrrole
27; a concerted deprotonation and elimination (E2 mechanism)
directly leading to G cannot be excluded.
Although a one-pot procedure to 2-aryl-3-methoxypyrroles as
described for 27 in Scheme 5 (equation 2) is possible, it was more
efficient to isolate the 2,5-dihydropyrrole derivatives and treat
these subsequently with 2.5 equivalents of potassium tert-
butoxide. This procedure results in full conversion into the
aromatic products. Hence, 14 gave 27 in 98 % yield after
purification by chromatography (Table 3, entry 1). It should be
mentioned that these electron-rich pyrroles are fairly sensitive to
oxygen and rapidly turn brownish. To avoid major decomposition,
they should be used shortly after their synthesis. To investigate
the scope of the aromatization process and to gain access to the
starting materials for the planned syntheses of dipyrromethenes
Table 3. Eliminations leading to 3-alkoxypyrroles 27 and 37-41 by
potasium tert-butoxide or LDA (2.5 equiv. in all entries).
Pre-
cursor
Time
(h)
Pro-
duct
Entry
R1
R2
Yield[a]
1
2
14
15
16
18
18
22
24
Me
Me
Ph
17
2.5
17
2.5
7
27
37
38
39
39
40
41
98 %
73 %
54 %
57 %
87 %[c]
45 %
53 %
2-Thienyl
3-Thienyl
2-Pyridyl
2-Pyridyl
3-Thienyl
3-Thienyl
3
Me
4
Me
5[b]
6
Me
Bn
2.5
2.5
7
TSME
[a] Purified products; [b] 2.5 equiv. LDA, -78 to -20 °C in THF; [c] crude
product (purity > 95 %).
We also examined the possibility to directly access 3-methoxy-
substituted pyrroles bearing alkyl groups at the nitrogen. For this
purpose, a one-pot three-component reaction employing lithiated
5
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10.1002/ejoc.201700073
European Journal of Organic Chemistry
FULL PAPER
vacuo to provide crude 3 (2.15 g, quant.) as brownish solid. By washing
the sample with diethyl ether pure 3 (1.44 g, 67 %) was obtained as a
yellow solid. In large scale experiments up to 7 g of 3 were prepared in
95 % yield. M.p. 100–101 °C. 1H NMR (CDCl3, 300 MHz): δ = 2.41 (s, 3 H,
Me), 3.15 (s, 3 H, OMe), 5.06 (dbr, J = 9.2 Hz, 1 H, 1-H), 5.15 (d, J = 9.2
Hz, 1 H, N-H), AB part of ABX system (δA = 5.32, δB = 5.36, JAB = 8.0 Hz,
JAX = 1.0 Hz, JBX = 1.2 Hz, 1 H each, 4-H), 7.23–7.32 (m, 7 H, Tos, Ph),
7.74 (d, J = 8.3 Hz, 2 H, Tos) ppm. 13C NMR (CDCl3, 75.5 MHz): δ = 21.4
(q, Me), 56.3 (q, OMe), 58.3 (d, C-1), 92.6 (t, C-4), 127.2, 127.5, 127.8,
128.4, 129.7 (5 d, Tos, Ph), 131.8, 137.8, 138.4, 143.1 (4 s, Ph, Tos, C-2),
197.3 (s, C-3) ppm. IR (KBr): ṽ = 3400–3120 (N-H), 3080–3000 (=C-H),
3000–2820 (C-H), 1955 (C=C=C), 1630 (C=C), 1350–1310, 1160–1120
(SO2) cm-1. C18H19NO3S (329.4): calcd. C 65.63, H 5.81, N 4.25, S 9.73;
found C 65.99, H 5.88, N 4.36, S 9.40.
methoxyallene 1a, N-tosyl imine 2a and iodomethane was
performed (Scheme 9). Addition of 1a to 2a under standard
conditions followed by solvent exchange to DMSO and heating
with 2.5 equivalents of potassium tert-butoxide generated the
potassium salt of 27. By treatment with an excess of iodomethane,
this intermediate was directly converted into N-methyl-substituted
3-methoxypyrrole 42 isolated in an overall yield of 46 %.
Compounds of this type are available by O-alkylation of pyrrol-3-
ones, however, this reaction is fairly unselective.[35] The simple
and direct method for the synthesis of N-substituted electron-rich
pyrroles reported here should be extendable to other SN2 reactive
alkyl halides.
3-Methoxy-2-phenyl-1-tosyl-2,5-dihydro-1H-pyrrole (14): To a solution
of allenylamine 3 (7.26 g, 22.0 mmol) in dichloromethane (50 mL) were
added pyridine (0.261 g, 3.30 mmol) and AuCl (0.256 g, 1.10 mmol). The
resulting mixture was stirred at room temperature under light exclusion for
12 h and filtered through a pad of Celite (elution with dichloromethane).
After removal of the solvent, crude 14 (6.81 g, 94 %) was obtained as
yellow solid that was analytically pure. M.p. 155–157 °C. 1H NMR (CDCl3,
300 MHz): δ = 2.38 (s, 3 H, Me), 3.50 (s, 3 H, OMe), 4.25–4.30 (m, 2 H, 5-
H), 4.57 (q, J = 1.6 Hz, 1 H, 2-H), 5.22–5.25 (m, 1 H, 4-H), 7.18 (d, J = 8.2
Scheme 9. Three-component synthesis of N-methyl-substituted 3-methoxy-
pyrrole 42 starting from 1a, 2a and iodomethane.
Hz, 2 H, Tos), 7.26 (mc, 5 H, Ph), 7.51 (d, J = 8.2 Hz, 2 H, Tos) ppm. 13
C
NMR (CDCl3, 75.5 MHz): δ = 21.5 (q, Me), 52.3 (t, C-5), 57.3 (q, OMe),
67.3 (d, C-3), 89.0 (d, C-4), 127.3, 127.6, 128.0, 128.3, 129.4 (5 d, Tos,
Ph), 135.4, 139.4, 143.1 (3 s, Ph, Tos), 156.6 (s, C-3) ppm. IR (KBr): ṽ =
3100–3000 (=C-H), 3000–2840 (C-H), 1670–1600 (C=C), 1350–1310,
1160–1120 (SO2) cm-1. C18H19NO3S (329.4): calcd. C 65.63, H 5.81, N
4.25, S 9.73; found C 65.73, H 5.89, N 4.27, S 9.48.
Conclusions
Due to the importance of pyrrole derivatives, their synthesis with
specific substitution patterns is a permanent challenge for organic
chemists.[36-38] The results enclosed here show that the [3+2]
route employing alkoxyallenes and N-tosylimines provides new
options to prepare this important class of heterocycles. The
primary allenyl N-tosylamines 3-13 were converted into the
corresponding 2,5-dihydropyrroles 14-24 by various cyclization
methods in good efficacy. The optimal conditions for this step
depend on the structure of the precursor compounds. The enol
ether moiety of the intermediate 2,5-dihydropyrrole derivatives
was used for functionalizations, e.g. for acid-induced hydrolysis
furnishing pyrrolidin-3-ones such as 32-34. By treatment with
strong base, the 2,5-dihydropyrroles were aromatized by p-tolyl
sulfinate elimination to afford 3-alkoxypyrroles 27 and 37-41.
However, this transformation seems to be restricted to precursors
with an (hetero)aryl group at C-2. A one-pot three-component
protocol directly delivered trisubstituted pyrrole derivative 42.
Other reactions were performed to study the cyclization process
to 2,5-dihydropyrroles and the reactivity of these key
intermediates.
3-Methoxy-2-phenylpyrrole (27): A solution of 14 (0.300 g, 0.91 mmol),
KOtBu (0.255 g, 2.28 mmol) in DMSO (5 mL) was heated for 17 h to give
after aqueous work-up and purification by chromatography (alumina III,
hexanes/ethyl acetate 8:1) 27 (0.155 g, 98 %) as dark brown oil.[39] 1H NMR
(300 MHz, CDCl3): δ = 3.84 (s, 3 H, OMe), 6.07, 6.61 (2 t, J = 3.0 Hz, 1 H
each, 4-H, 5-H), 7.10–7.60 (m, 5 H, Ph), 8.00 (sbr, 1 H, NH) ppm. 13C NMR
(100 MHz, CDCl3): δ = 58.4 (q, OMe), 97.9 (d, C-4), 114.7 (s, C-2), 115.8
(d, C-5), 124.8, 126.7, 129.0, 132.1 (3 d, s, Ph), 145.9 (s, C-3) ppm.
3-Methoxy-2-phenyl-1-tosylpyrrole (29): A mixture of allenyl amine 14
(0.359 g, 1.10 mmol) in THF (50 mL) and MnO2 (3.83 g, 44.0 mmol) was
heated under reflux for 2.5 h and then the same amount of MnO2 was
added again. After further heating the mixture was cooled to room
temperature and filtered through a pad of Celite. Evaporation in vacuo
provided a residue that was dissolved in dichloromethane (50 mL) and
extracted with 1N HCl (10 mL) and water (10 mL), dried (Na2SO4) and
concentrated in vacuo. The crude product (0.309 g) was purified by
chromatography (alumina III, hexanes/ethyl acetate 4:1) to provide 29
(0.209 g, 58 %) as pale yellow solid. M.p. 113–114 °C. 1H NMR (300 MHz,
CDCl3): δ = 2.28 (s, 3 H, Me), 3.56 (s, 3 H, OMe), 6.16 (d, J = 3.8 Hz, 1 H,
4-H, 7.01–7.26 (m, 10 H, Ph, Tos). 13C NMR (75.5 MHz, CDCl3): δ = 21.6
(q, Me), 58.4 (s, OMe), 103.3 (d, C-4), 121.8 (d, C-5), 127.1, 127.3, 127.7,
129.3, 131.5 (5 d, Ph, Tos), 118.2, 129.2, 135.2, 144.5, 148.5 (5 s,C-2, C-
3, Ph, Tos) ppm. IR (KBr): ṽ = 3100–3000 (=C-H), 2960–2840 (C-H), 1760
(C=O), 1600 (C=C), 1370 (SO2) cm-1. UV-Vis (CH3CN, lg ε): λ = 266 (sh,
3.96), 226 (4.17), 203 (4.33) nm. C18H17NO3S (327.4): calcd. C 66.03, H
5.23, N 4.27, S 9.78; found C 65.87, H 5.39, N 4.32, S 9.55.
Experimental Section
For general information and all experimental details see Supporting
Information.
N-(2-Methoxy-1-phenylbuta-2,3-dienyl)-p-toluene sulfonamide (3):
Lithiated methoxyallene 1a was generated from methoxyallene (0.687 g,
9.80 mmol) and n-butyllithium (4.00 mL, 8.80 mmol of 2.2 M solution in
hexanes) in THF (20 mL) at -40 °C. After 5 min, a solution of imine 2a (1.70
g, 6.54 mmol) in THF (6.5 mL) was added and the mixture was allowed to
warm-up to -20 °C within 2 h. It was then hydrolyzed with ice water (20 mL)
and after warm-up to room temperature the organic phase was separated
and the aqueous phase was extracted with diethyl ether (3 x 20 mL). The
combined organic phases were dried (Na2SO4), filtrated and evaporated in
3-Methoxy-2-phenyl-2,5-dihydropyrrole (30):
A solution of sodium
naphthalenide (2.87 mL of a 1 M solution in 1,2-dimethoxyethane,
prepared according to ref. 27) was added to a solution of 14 (0.322 g, 0.98
mmol) in 1,2-dimethoxyethane (9 mL) at -78 °C. After 40 min the mixture
was quenched with water (5 mL) and concentrated in vacuo. The residue
was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20
mL). The combined organic phases were dried (Na2SO4), filtered and
evaporated in vacuo. The residue (0.363 g) was purified by
6
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10.1002/ejoc.201700073
European Journal of Organic Chemistry
FULL PAPER
chromatography (alumina III, hexanes/ethyl acetate 1:0 to 1:1) to give 27
(0.017 g, 10 %) as purple oil and 30 (0.128 g, 75 %) as yellow oil. 1H NMR
(CDCl3, 300 MHz): δ = 2.41 (sbr, 1 H, N-H), 3.61 (s, 3 H, OMe), 3.82 (td, J
= 2.4, 12.4 Hz, 1 H, 5-H), 3.95 (ddd, J = 1.8, 4.6, 12.4 Hz, 1 H, 5-H), 4.76
(q, J ≈ 2 Hz, 1 H, 2-H), 4.81–4.84 (m, 1 H, 4-H), 7.20–7.37 (m, 5 H, Ph)
ppm. 13C NMR (CDCl3, 75.5 MHz): δ = 50.5 (t, C-5), 57.4 (q, OMe), 66.5
(d, C-3), 92.6 (d, C-4), 127.2, 127.5, 128.6, 142.9 (3 d, s, Ph), 159.9 (s, C-
3) ppm. IR (KBr): ṽ = 3400–3430 (N-H), 3080–3000 (=C-H), 2960–2840
(C-H), 1650 (C=C) cm-1. C11H13NO (175.2): calcd. C 75.40, H 7.48, N 7.99;
found C 75.61, H 7.54, N 7.94.
give pure 42 (0.109 mg, 46 %) as yellow oil. The NMR data of 42 agree
with those reported in the literature. [35]
Acknowledgements
Generous support of this work by the Deutsche
Forschungsgemeinschaft, the Fonds der Chemischen Industrie,
the Arzneimittelwerk Dresden and Bayer HealthCare is most
gratefully acknowledged. We thank Prof. J. Fabian (Technische
Universität Dresden) and Dr. M. Domínguez (Universidad de
Santiago de Chile) for calculations on the cyclizations of allene
derivatives.
2-Phenyl-1-tosylpyrrolidin-3-one (32): Dihydropyrrole 14 (0.100 g, 0.303
mmol) in THF (5 mL) and 10% aqueous sulfuric acid (5 mL) were heated
under reflux for 3 h. After cooling to room temperature the mixture was
neutralized with saturated aqueous NaHCO3 solution. The organic phase
was separated and dried (MgSO4), filtered and evaporated in vacuo to give
crude 32 (0.121 g) as brownish solid. Recrystallization from hexanes/ethyl
acetate 5:1 furnished 32 (0.094 g, 98 %) as pale yellow solid. M.p. 123 °C.
1H NMR (300 MHz, CDCl3): δ = 2.42 (s, 3 H, Me), 2.45–2.48, 2.50–2.65 (2
m, 1 H each, 4-H), 3.66–3.76, 3.90–4.57 (2 m, 1 H each, 5-H), 4.60 (s, 1
H, 2-H), 7.26–7.33 (m, 7 H, Ph, Tos), 7.62 (d, J = 8.2 Hz, 2 H, Tos) ppm.
13C NMR (75.5 MHz, CDCl3): δ = 21.5 (q, Me), 29.4, 35.8 (2 t, C-5, C-4),
67.2 (d, C-2), 126.9, 127.7, 128.3, 128.7, 129.9 (5 d, Ph, Tos), 133.8, 135.5,
144.2 (3 s, Ph, Tos), 208.1 (s, C-3) ppm. IR (KBr): ṽ = 3100–3000 (=C-H),
3000–2800 (C-H), 1760 (C=O), 1660-1600 (C=C), 1340 (SO2) cm-1.
C17H17NO3S (315.4): calcd. C 64.74, H 5.43, N 4.44, S 10.16; found C
64.84, H 5.52, N 4.51, S 10.02.
Keywords: allenes • cyclizations • gold catalysis • imines •
pyrroles • pyrrolidines
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2-Phenyl-1-tosylpyrrolin-3-ol (35): To a solution of sodium borohydride
(0.071 mg, 1.86 mmol) in ethanol (2 mL) was added 32 (0.294 g, 0.93
mmol). After stirring at room temperature for 18 h 2N HCl was added until
the gas evolution ceased and the colorless precipitate dissolved. The
mixture was extracted with diethyl ether (5 x 2 mL) and the combined
organic phases were washed with saturated aqueous NaHCO3 solution,
dried (Na2SO4), filtered and evaporated in vacuo. Crude 35 (0.306 mg)
was obtained as brownish solid and purified by recrystallized from
hexanes/ ethyl acetate 5:1 to furnish 35 (0.209 g, 71 %, cis:trans = 89:11)
as pale yellow solid. M.p. 125–126 °C. IR (KBr): ṽ = 3580 (O-H), 3100–
3000 (=C-H), 3000–2900 (C-H), 1350–1310 (SO2) cm-1. C17H19NO3S
(317.4): calcd. C 64.33, H 6.03, N 4.41, S 10.10; found C 64.27, H 6.10, N
4.39, S 9.90.
Data of the cis-31: 1H NMR (300 MHz, CDCl3): δ = 1.27 (dbr, J = 5.0 Hz, 1
H, OH), 1.66–1.77, 1.80–1.90 (2 m, 1 H each, 4-H), 2.42 (s, 3 H, Me),
3.56–3.64, 3.67–3.80 (2 m, 1 H each, 5-H), 4.18 (q, J = 5.0 Hz, 1 H, 3-H),
4.70 (d, J = 5.6 Hz, 1 H, 2-H), 7.26–7.37 (m, 7 H, Ph, Tos)*, 7.65 (d, J =
8.2 Hz, 2 H, Tos) ppm; 13C NMR (75.5 MHz, CDCl3): δ = 21.4 (q, Me)*,
32.3, 47.0 (2 t, C-5, C-4), 67.5, 73.5 (2 d, C-2, C-3), 127.4, 127.7, 127.8,
128.5, 129.6 (5 d, Ph, Tos), 134.9, 136.5, 143.5 (3 s, Ph, Tos) ppm; *
signals of both isomers.
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Data of trans-31: 1H NMR (300 MHz, CDCl3): δ = 2.41 (s, 3 H, Me), 4.12–
4.15 (m, 1 H, 3-H), 4.65 (sbr, 1 H, 2-H) 7.72 (d, J = 8.2 Hz, 2 H, Tos) ppm;
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C-2, C-3), 126.2, 127.5, 127.9, 128.4, 129.4 (5 d, Ph, Tos), 143.4 (s, Tos)
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3-Methoxy-1-methyl-2-phenylpyrrole (42): Lithiated methoxyallene 1a
was generated from methoxyallene (0.133 g, 1.90 mmol) and n-
butyllithium (0.74 mL, 1.71 mmol of 2.3 M solution in hexanes) in THF (10
mL) at -40 °C. After 5 min. a solution of imine 2a (0.328 g, 1.26 mmol) in
THF (2.5 mL) was added and the mixture was allowed to warm-up to room
temperature within 2 h. The solvent was evaporated in vacuo and replaced
by DMSO (10 mL). After heating the mixture to 50 °C for 1 h, KOtBu
(0.353g, 3.15 mmol) was added and the heating was continued to 50 °C
was continued for another 1 h. Then iodomethane (0.716 mg, 5.04 mmol)
was added and the mixture was stirred at room temperature for 1 h. After
aqueous work-up crude 42 (0.35 g) was obtained as brownish oil that was
purified by chromatography (alumina III, hexanes/ethyl acetate 10:1) to
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8
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10.1002/ejoc.201700073
European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents
FULL PAPER
Pyrrole Derivatives
G. M. Okala Amombo, O. Flögel, S.
Kord Daoroun Kalai, S. Schoder, U.
Warzok, H.-U. Reissig*
Page No. – Page No.
Two components, two steps: addition of lithiated alkoxyallenes to N-tosylimines
followed by base-, silver- or gold-promoted cyclization of the primary addition
products efficiently provides 2,5-dihydropyrroles that are excellent substrates for
further transformations. Acid causes hydrolysis of the enol ether moiety to deliver
pyrrolidin-3-ones and base promotes aromatization to the elusive class of 3-
alkoxypyrroles.
Efficient Syntheses of 2,5-
Dihydropyrroles, Pyrrolidin-3-ones
and Electron-rich Pyrroles from N-
Tosylimines and Lithiated
Alkoxyallenes
9
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