Synthesis of pyrroles through a 4π-electrocyclic ring-closure reaction of 1-azapentadienyl cations

Article abstract of DOI:10.1021/jo202477h

1-Azapenta-1,4-diene-3-ols 4a-m are easily accessible from 1-azapenta-1,4-dien-3-ones 3a-i and organolithium compounds. Treatment of the compounds 4a-m with strong acid (triflic acid) generates 1-azapentadienyl cations in situ upon protonation at the hydr

Full text of DOI:10.1021/jo202477h

Article
pubs.acs.org/joc
Synthesis of Pyrroles through a 4π-Electrocyclic Ring-Closure
Reaction of 1-Azapentadienyl Cations
Rishikesh Narayan,†,‡ Roland Frohlich,† and Ernst-Ulrich Wurthwein*,†
̈
̈
†Organisch-Chemisches Institut, Westfalische Wilhelms-Universitat, Corrensstrasse 40, D-48149 Munster, Germany
̈
̈
̈
‡Graduate School of Chemistry, University of Munster, Wilhelm-Klemm-Str. 10, D-48149 Munster, Germany
̈
̈
S
* Supporting Information
ABSTRACT: 1-Azapenta-1,4-diene-3-ols 4a−m are easily
accessible from 1-azapenta-1,4-dien-3-ones 3a−i and organo-
lithium compounds. Treatment of the compounds 4a−m with
strong acid (triflic acid) generates 1-azapentadienyl cations in
situ upon protonation at the hydroxyl oxygen atom and
subsequent water elimination. The intermediate cations
undergo facile 4π-electrocyclization under ambient condition
to give diversely substituted pyrroles 6a−m in moderate to
good yield. The product pyrrole 6k could be characterized by X-ray diffraction. Quantum chemical calculations were performed
to elucidate the mechanism of this reaction with respect to starting compounds, transition states, and products. They support the
proposed mechanism of a 4π-conrotatory Mobius-type electrocyclic ring-closure reaction.
̈
Whereas the products of a classical Nazarov cyclization are
INTRODUCTION
■
characterized by a cyclopentenone structure, the products of an
aza-Nazarov ring-forming reaction always contain a hydroxy
function in the 3-position, which in the case of pyrroles is the
reason for the substantial instability of such compounds. We
bypassed this problem by working up the reaction mixture
using acetic anhydride in order to isolate the much more stable
acetates instead of the hydroxy pyrroles (Scheme 2).
However, the formation of this 3-hydroxy- or 3-acetoxy
group may be regarded to be a certain limitation of this
cyclization method. Thus, a more general control in terms of
the substitution pattern at this position seemed to be desirable.
Substituent redundancy in the final product is also a common
problem with the multicomponent approach for the formation
of pyrroles.8
Pyrrole is a structural unit of immense importance occurring as
a building block of many physiologically important natural
products such as heme, chlorophyll, and vitamin B12 among
others.1 It has also been extensively used in the synthesis of a
variety of pharmaceutical agents2 along with its application in
the field of material science3 for conducting polymers,4
molecular optics,5 etc. Many substituted pyrroles have been
isolated mainly from marine sources, and they show important
biological properties.6 This general importance is still inspiring
synthetic chemists to find new ways to synthesize pyrrole and
its derivatives. There is a whole range of methods available for
the synthesis of pyrrole.1a,7 Multicomponent reactions8 and
metal-catalyzed reactions9 are two of the predominantly applied
strategies among others.
In order to circumvent this limitation we became interested
in the generation of 1-azapentadienyl cations 1 from 1-
azapenta-1,4-diene-3-ols 4 by use of strong Brønsted acids
(“super acid”,“superelectrophilic conditions”). This led us to
propose that compounds of type 4, with a hydroxyl group at the
3-position acting as leaving group upon protonation, might be
the substrate of choice (Scheme 3).
As part of a continuing project investigating the influence of
heteroatoms on the reactivity of positively and negatively
charged polyenyl species, we have been able to demonstrate
computationally and experimentally that 1-azapentadienyl
cations10 are quite reactive intermediates that stabilize
themselves by undergoing a facile conrotatory 4π-electro-
cyclization reaction to give pyrroles. 1-Azapentadienyl cations
might be considered to be vinylogous 1-azaallyl cations, which
were studied by Creary et al.11 For the generation of these
reactive intermediates 1 we used 1-azapentadienyl derivatives
(and also 1-oxapentadienyl cations for the corresponding
furans) with an appropriate leaving group (acetate) at the 5-
position (Scheme 1).12
Herein we report a highly versatile linear approach to form
pyrroles through a conrotatory 4π-electrocyclization reaction.
RESULTS
■
Synthesis of the Precursor and Model Reaction. We
envisaged 1-azapenta-1,4-diene-3-one 3a as a suitable precursor
for the synthesis of the required 1-azapenta-1,4-diene-3-ol 4a
from an 1,2-addition of an organometallic reagent, e.g.,
Later we also showed that 1-azapenta-1,4-diene-3-ones 3 can
be conveniently activated to undergo cyclization reactions upon
treatment with a strong Brønsted acid to give 1-aza-3-
hydroxypentadienyl cations, which cyclize to variably sub-
stituted hydroxy pyrroles (aza-Nazarov reaction,13 Scheme 2).14
Received: December 2, 2011
Published: February 1, 2012
© 2012 American Chemical Society
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Scheme 1. Cyclization of 1-Aza- or 1-Oxapentadienyl Cation 1 upon Cleavage of an Acetate Leaving Group from the 5-Position
of an Appropriately Substituted 1-Aza- or 1-Oxapenta-1,3-diene
Scheme 2. Cyclization of 1-Azapenta-1,4-diene-3-ones 3 to
Pyrroles upon Treatment with Strong Brønsted Acid
Scheme 4. Synthesis of the Cyclization Precursor, 1-
Azapenta-1,4-diene-3-ol 4a
methyllithium or others to the carbonyl group. As published
earlier, compound 3a was efficiently synthesized through a two-
step procedure involving condensation of a 1,2-diketone with a
substituted hydroxylamine or hydrazine followed by aldol
condensation with an aldehyde.14 The required starting
compound for the ring-closure reaction, 1-azapenta-1,4-diene-
3-ol 4a, was obtained in 68% yield by treatment of 3a with
MeLi (1.6 M in hexane) in THF at −78 °C (Scheme 4). This
reaction proceeded in high regio- and chemoselectivity as the
1,2-addition product of MeLi to the carbonyl group was
observed exclusively without any product of 1,4-addition or
addition to the CN bond.
Table 1. Optimization Attempts for the Cyclization of 4a
amount of
reaction
yield
(%)
a
entry
1
acid used
acid (equiv) conditions
product
concd H2SO4
1.2
CH2Cl2
CH2Cl2
intractable
mix.
2
PPA
excess
intractable
mix.
b
3
4
CH3COOH
CF3SO3H
1.2
1
CH2Cl2
CH2Cl2
(0.025 M)
no reaction
6a
32
c
5
6
7
CF3SO3H
CF3SO3H
CF3SO3H
2
2
5
CH2Cl2 (0.2 6a
<20
M)
CH2Cl2
6a
6a
40
(0.025 M)
This precursor 4a was screened with respect to a range of
Brønsted acids and reaction conditions for the intended
cyclization reaction (Table 1). The use of concd H2SO4 did
not give a clean reaction. The use of polyphosphoric acid
(PPA) also gave an intractable mixture of products.
Interestingly, CH3CO2H did not force any reaction even at
high temperature. Then we turned our attention to the “super
acid” triflic acid. We found that the alcohol 4a underwent a
clean reaction in 15 min at −10 °C when 1 or more than 1
equiv of triflic acid was used in dilute dichloromethane solution
to give 6a as the sole product in 20−40% yield (Schemes 5,
Table 1, entries 4−6). Best yields were obtained with 2 equiv of
acid in dilute solution (0.025 M) (entry 6). However, 5 equiv
of acid gave no detectable product (entry 7).
CH2Cl2
(0.025 M)
8
9
CF3COOH
CF3SO3H
1.2
0.4
CH2Cl2
7
7
67
53
CH2Cl2
a
b
All reactions were carried out at −10 °C. No reaction was observed
c
even at elevated temp; starting material could be recovered. The
product pyrrole 6a could not be purified completely in this case.
Scheme 5. Optimized Reaction Conditions for the Synthesis
of Pyrrole 6a from 4a
In the presence of 1.2 equiv of trifluoroacetic acid an
unexpected product 7 was obtained, containing formally two
molecules of 5a+ (Table 1, entry 8 and Scheme 6).
Substoichiometric amounts of triflic acid (0.4 equiv, entry 9)
also gave compound 7 as the only product. This can be
rationalized by the fact that at any point of time during the
reaction pyrrole 6a and uncyclized pentadienyl cation 5a+
coexist in the reaction medium and react to give 7 by
electrophilic aromatic substitution at C-4 position of the
pyrrole 6a.
We conclude from these optimization experiments that the
key to the success of this reaction is the availability of a
sufficient amount of protons in the reaction medium at any
time during the reaction in order to protonate all the substrate
molecules almost simultaneously. This condition can be assured
only in the presence of at least stoichiometric amounts of a very
strong acid.
Scheme 3. Synthesis of Pyrroles from 3-Hydroxy-1-aza-penta-1,4-dienes
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Scheme 6. Reaction of Precursor 4a with Trifluoroacetic Acid (TFA)
Scope of the Reaction. In order to study the scope of the
ring-forming reaction under these optimized reaction con-
ditions, we synthesized a large number of compounds 4b−m.
Different substituents R1, R2, and X were introduced by the
appropriate choice of the precursors 3a−i.14 Varying
substituents R3 came from the respective organometallic
species R3Li. All compounds 4b−m were efficiently obtained
in moderate to good yields exactly under the reaction condition
mentioned in Scheme 7 (Table 2).
Scheme 8. Acid-Promoted Cyclization Reaction of
Compounds 4a−m
4-position. It is worth noting that pyrroles having alkyl chains at
the 3-position are key units found in many functional organic
materials.15 The reaction worked with similar facility when
oximes (entries 1−10) or hydrazones were used (entries 11−
13). The yield was generally found to be higher in cases with
aryl groups (entries 8 and 10) at the C-3 position as compared
to those with an alkyl group at the same position. In the alkyl
cases we observed the formation of byproducts in larger
quantities compared to the aryl examples, possibly an indication
of competing polymerization.
Scheme 7. Synthesis of 1-Azapenta-1,4-diene-3-ols 4a−m
Upon protonation using 2 equiv of triflic acid in dilute
dichloromethane solution at −10 °C, all substrates 4a−m
reacted to give pyrroles in moderate to good yields (Scheme 8,
Table 3), thus allowing the controlled introduction of various
alkyl and aryl substituents at C2 and C3, of aryl and heteroaryl
groups at C5, and of alkoxy and amino groups at N1 of the
pyrrole skeleton. The aryl substituents R2 may carry either
electron-withdrawing or electron-donating groups in the 2- or
1
In general the pyrroles were easily identified by H (proton
at C4 at 6.0 to 6.8 ppm) and 13C NMR (C3, C4 at 100−110
ppm) spectroscopy. The structure of the compound 6k was
also confirmed by single crystal X-ray analysis (Figure 1).
Table 2. Yields and Substitution Patterns of 1-Azapenta-1,4-diene-3-ols 4a−m from the Corresponding 1-Azapenta-1,4-diene-3-
ones 3a−i
entry
starting compound
product
X
R1
R2
R3
yield (%)
1
3a
3b
3c
3d
3e
3b
3b
3b
3f
4a
4b
4c
4d
4e
4f
OBn
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
Ph
Me
68
57
61
64
68
51
45
46
63
60
51
65
79
2
OBn
2-Br-Ph
2-OCH3-Ph
4-Cl-Ph
4-Me-Ph
2-Br-Ph
2-Br-Ph
2-Br-Ph
2-thienyl
4-Cl-Ph
Ph
Me
3
OBn
Me
4
OBn
Me
5
OBn
Me
6
OBn
n-Bu
i-Pr
Ph
7
4g
4h
4i
OBn
8
OBn
9
OBn
Me
10
11
12
13
3d
3g
3h
3i
4j
OBn
4-Me-Ph
Me
4k
4l
N(Me)Ph
N(Me)Ph
1-indolinyl
4-Me-Ph
Ph
Me
4m
Me
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Table 3. Yields and Structures of the Pyrroles 7a−m
Figure 1. Molecular structure of 6k as obtained by X-ray diffraction.
protonated in the presence of acid, and the H2O molecule is
eliminated to generate the delocalized 1-azapentadienyl cation
5+, the precursor for the cyclization. This cation has to undergo
several conformational changes through C−C bond rotation to
attain the required “U”-conformation, the active conformation
for the electrocyclization. Then this cation undergoes the 4π
conrotatory electrocyclization to form the pyrrolium cation 8,
which upon proton elimination with aromatization gives the
pyrrole 6.
This suggested mechanism is well supported by quantum
chemical calculation at the B3LYP/6-311G(d,p)//B3LYP/6-
311G(d,p) and the SCS-MP2/6-311G(d,p)//B3LYP/6-311G-
(d,p) level of theory.16−19 For the first step of the reaction
sequence, the gas phase protonation, quantum chemical
calculations indicate a preferred O-protonation over N-
protonation of the model substrate 4n (R1 = R3 = Me, R2 =
Ph, X = OCH3) by approximately 4 kcal/mol. This O-
protonated species is expected to lose easily a molecule of water
to generate the cation 5n+, the 1-azapentadienyl cation
(Scheme 9).
For the second reaction step, the electrocyclization, the W-
shaped conformer W-5n+ has to undergo two consecutive bond
rotations in order to attain the appropriate conformation
(Scheme 10). The rotational barrier from W-5n+ to the sickle-
shaped S-5n+ through rotation about C2−C3 (TS W-5n+-S-
5n+) was calculated to be 8.4 kcal/mol. S-5n+ then undergoes
the next conformational change through rotation about C3−C4
with a barrier of 19.4 kcal/mol to convert into the U-shaped
conformer U-5n+ (TS S-5n+-U-5n+) required for electro-
cyclization. The cyclization of this cation U-5n+ to pyrrolium
cation 8n+ was found to be highly exothermic (ca. 24 kcal/mol)
with a very low activation barrier of only 0.04 kcal/mol (TS U-
5n+-8n+) (Scheme 10). These calculated barriers correspond
well with the observed feasibility of the reaction and the
reaction conditions (−10 °C, short reaction times). The
calculated exothermicity of the reaction matches well with the
observations made earlier by us12 for the cyclization of 1-
azapentadienyl cation and calculations by Sorensen and Rauk
for the cyclization of pentadienyl cations (15−35 kcal/mol).20
Whereas the relative energies of the open-chain conformers
coincide well at both levels of theory, surprisingly large
differences are found for the relative energies of the transition
state and for the cyclic product.
The transition state TS U-5n+-8n+ of the cyclization is
nonplanar with dihedral angles of N1−C2−C3−C4 = 17.98°
and C2−C3−C4−C5 = 9.44° (Figure 2). The partially formed
C−N bond in the transition state TS has a length of 2.17 Å.
DISCUSSION
■
The proposed mechanism of the reaction is depicted in Scheme
9. The hydroxyl group of the 1-azapenta-1,4-diene-3-ol 4 gets
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Scheme 9. Proposed Reaction Mechanism for the Cyclization of Compounds 4 To Give Pyrroles 6
Scheme 10. SCS-MP2 Energy Profile for the Cyclization of Cation W-5n+ to Pyrrolium Cation 8n+
a
SCS-MP2/6-311G(d,p)//B3LYP/6-311G(d,p)+ZPE (kcal/mol).
b
B3LYP/6-311G(d,p)// B3LYP/6-311G(d,p)+ZPE (kcal/mol).
This indicates an early transition state, a characteristic feature
for the highly exothermic reactions according to Hammond’s
postulate. Houk et al. have reported that the conrotatory
electrocyclization of the pentadienyl cation to the cyclopentenyl
cation proceeds through a transition state with a partially
formed C−C bond (2.27 Å).21
The nature of the electrocyclization reaction was investigated
by analyzing the transition state U-5n+-8n+ with respect to
NBO charges at the termini of the 1-azapentadienyl cation and
to NICS values. The NBO charge separation between the
atoms N1 and C5 was found to be only 0.16 e, which indicates
little ionic character for the reaction. The lowest NICS value22
for the unsymmetrical transition state with respect to an axis
perpendicular to the plane of the ensuing heterocycle was
calculated to be −7.2 [(B3LYP/6-311G(d,p)], which is
Figure 2. Calculated transition state TS U-5n+-8n+ for the cyclization
(B3LYP/6-311G(d,p)).
strongly indicative of the Mobius type23 aromatic character
̈
(Figure 3). Upon comparing the optimized geometries of the
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Figure 3. Calculated NICS values for the transition structure TS U-5n+-8n+ (left). Measuring points are along an axis perpendicular to the center of
the developing cyclic moiety (right).
mmol) according to the general procedure. The subsequent
recrystallization from methanol gave the pure product (0.4 g, 1.3
mmol, 65%) as a pale yellow solid (mp 76−78 °C). H NMR (300
MHz, CD2Cl2): δ (ppm) 1.95 (s, 3H, CH3), 3.80 (s, 3H, OCH3), 5.25
(s, 2H, OCH2), 6.85−6.96 (m, 2H, CHar), 7.24−7.37 (m, 6H, CHar),
7.54 (dd, 1H, J = 7.8, 1.7 Hz, CHar), 7.61 (d, 1H, J = 16.2 Hz, CHol),
7.92 (d, 1H, J = 16.2 Hz, CHol). 13C NMR (75 MHz, CD2Cl2): δ
(ppm) 9.4 (CH3), 55.9 (OCH3), 77.9 (OCH2), 111.6 (CHar/ol), 121.0
(CHar/ol), 121.5 (CHar/ol), 124.3 (Cq), 128.6 (CHar/ol), 128.8 (CHar/ol),
128.84 (CHar/ol), 129.0 (CHar/ol), 132.1 (CHar/ol), 137.7 (Cq), 138.3
open chain, transition state, and cyclic structure, it can be seen
that the reaction is conrotatory in nature. We conclude that this
1
ring-forming reaction shows all of the features of a Mobius
̈
aromatic conrotatory 4π electrocyclic ring-closure reaction.
CONCLUSION
■
In summary we have been able to demonstrate for the first time
the synthetic use of 1-aza-3-hydroxy-penta-1,4-dienes 4 for the
preparation of variably substituted N-alkoxy- and N-amino
pyrroles 6. The starting compounds 4 are easily accessible by
treatment of 1-aza-penta-1,4-dien-3-ones 3 with various lithium
compounds attacking the carbonyl function of 3 in a strongly
chemoselective manner. Treatment of 4 with trifluorometha-
nesulfonic acid (triflic acid) yields the pyrroles 6 in moderate to
good yield upon aqueous workup. Mechanistically, we suggest
the intermediate formation of highly reactive 1-azapentadienyl
cations after protonation at the hydroxyl group of 4 by the
super acid and subsequent loss of water. Then, the 1-
azapentadienyl cations undergo a pericyclic ring-closure
reaction leading to the pyrroles 6 after proton loss and
aromatization. High level quantum chemical calculations have
been used to investigate the reaction mechanism theoretically.
They indicate a conrotatory 4π electrocyclic ring-closure
reaction. The calculated nonplanar transition state for the
(CHar/ol), 156.8 (Cq), 159.2 (CN), 187.1 (CO). IR (neat) ν
̃
:
3069 (w), 3055 (w), 2982 (w), 2873 (w), 1672 (vs), 1493 (s), 1457
(s), 1376 (s), 1232 (s), 1212 (s), 1134 (m), 1082 (s), 1027 (m), 968
(m), 875 (s), 866 (s), 726 (s), 717 (s), 673 (m), 664 (m), 652 (s), 623
(s). HRMS (ESI): calcd for C19H19NO3Na 332.1263; found 332.1257.
Anal. Calcd for C19H19NO3: C, 73.77; H, 6.19; N, 4.53. Found: C,
73.72; H, 6.18; N, 4.53.
(1E,4E)-4-((Benzyloxy)imino)-1-(4-chlorophenyl)-pent-1-en-3-one
3d. Compound 3d was obtained from 3-benzyloxyimino-butan-2-one
(0.382 g, 2 mmol) and 4-chlorobenzaldehyde (0.294 g, 2.1 mmol)
according to the general procedure. The subsequent recrystallization
from methanol gave the pure product 3d (0.363 g, 1.16 mmol, 58%) as
1
a white solid (mp 122−123 °C). H NMR (300 MHz, CDCl3): δ
(ppm) 1.98 (s, 3H, CH3), 5.26 (s, 2H, OCH2), 7.25−7.28 (m, 3H,
CHar), 7.31−7.33 (m, 4H, CHar), 7.43 (d, 2H, J = 8.6 Hz, CHar), 7.50
(d, 1H, J = 16.0 Hz, CHol), 7.57 (d, 1H, J = 16.0 Hz, CHol). 13C NMR
(75 MHz, CDCl3): δ (ppm) 9.4 (CH3), 77.6 (OCH2), 121.1 (CHar/ol),
128.29 (CHar/ol), 128.31 (CHar/ol), 128.5 (CHar/ol), 129.1 (CHar/ol),
129.7 (CHar/ol), 133.6 (CHar/ol), 136.2 (Cq), 136.9 (Cq), 141.6
cyclization possesses Mobius-type aromatic character as
̈
indicated by NBO charges and NICS calculations. Further
applications of this new methodology with regard to the use for
the preparation of more complicated pyrrole derivatives are
being currently investigated.
(CHar/ol), 156.4 (CN), 186.5 (CO). IR (neat) ν
̃
: 3073 (w), 3048
(w), 2933 (w), 2843 (w), 1676 (vs), 1482 (s), 1457 (s), 1365 (s),
1231 (s), 1214 (s), 1135 (m), 1091 (s), 1027 (m), 978 (m), 876 (s),
864 (s), 727 (s), 717 (s), 665 (m), 647 (m), 622 (s), 613 (s). HRMS
(ESI): calcd for C18H16NO2ClNa 336.0767; found 336.0762. Anal.
Calcd for C18H16NO2Cl: C, 68.90; H, 5.14; N, 4.46. Found: C, 68.86;
H, 5.18; N, 4.40.
EXPERIMENTAL SECTION
■
Melting points are uncorrected. 1H, 13C, GCOSY, GHSQC, GHMBC,
and 1D-NOE NMR spectroscopy: TMS (1H) (0.00 ppm) and CDCl3
(13C) (77.0 ppm) were used as internal references. When necessary,
the experiments were carried out with complete exclusion of moisture.
Compounds 3 were prepared according to a literature procedure.14
General Procedure for the Formation of (1E,4E)-4-(Alkox-
yimino)-1-aryl-pent-1-en-3-one 3. One equivalent of 3-benzylox-
yimino-butan-2-one14 was dissolved in the minimum amount of
methanol, and 0.5 equiv of KOH (30% in methanol) was added. To
this solution was added 1.1 equiv of aldehyde, and the mixture was
stirred at room temperature. Usually after some time, a solid
precipitated out of the solution. For completion, the reaction mixture
was left to stir overnight at room temperature. Then, the solid was
filtered off and washed with cold methanol to remove soluble
impurities. In case the precipitate was not formed, the reaction mixture
was cooled to 0 °C to allow precipitation. The crude products were
purified by recrystallization.
(1E,4E)-4-(Phenoxyimino)-1-(thiophen-2-yl)-pent-1-en-3-one 3f.
Compound 3f was obtained from 3-benzyloxyimino-butan-2-one
(1.0 g, 5.24 mmol) and 2-thiophene carbaldehyde (0.59 g, 0.49 mL,
5.24 mmol) according to the general procedure. Pure product 3f
(0.863 g, 3.03 mmol, 58%) was obtained by recrystallization from
CH2Cl2 as a white solid (mp 84 °C). 1H NMR (400 MHz, CDCl3): δ
(ppm) 1.95 (s, 3H, CH3), 5.23 (s, 2H, OCH2), 6.95 (dd, 1H, J = 5.1,
3.7 Hz, CHar), 7.19−7.21 (m, 1H, CHar), 7.27−7.35 (m, 7H, CHar),
7.72 (d, 1H, J = 15.7 Hz, CHol). 13C NMR (100 MHz, CDCl3): δ
(ppm) 9.4 (CH3), 77.6 (OCH2), 119.8 (CHar/ol), 128.25 (CHar/ol),
128.29 (CHar/ol), 128.5 (CHar/ol), 128.55 (CHar/ol), 128.7 (CHar/ol),
131.8 (CHar/ol), 135.5 (CHar/ol), 136.9 (Cq), 140.7 (Cq), 156.2 (C
N), 186.4 (CO). IR (neat) ν
̃
: 3069 (w), 3057 (w), 2843 (w), 2361
(m), 1671 (vs), 1487 (s), 1446 (s), 1375 (m), 1245 (s), 1214 (m),
1163 (m), 1097 (s), 1046 (m), 978 (m), 863 (s), 747 (s), 717 (s), 664
(m), 642 (m), 639 (s), 616 (m). HRMS (ESI): calcd for
C16H15NO2SNa 308.0721; found 308.0718. Anal. Calcd for
C16H15NO2S: C, 67.34; H, 5.30; N, 4.91. Found: C, 67.12; H, 5.42;
N, 4.83.
(1E,4E)-4-((Benzyloxy)imino)-1-(2-methoxyphenyl)-pent-1-en-3-
one 3c. Compound 3c was obtained from 3-benzyloxyimino-butan-2-
one (0.382 g, 2 mmol) and 2-methoxybenzaldehyde (0.285 g, 2.1
1873
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Article
(1E,4E)-4-(2-Methyl-2-phenylhydrazono)-1-(p-tolyl)-pent-1-en-3-
one 3h. Compound 3h was obtained from the hydrazone (E)-3-(2-
methyl-2-phenylhydrazono)butan-2-one14 (1.0 g, 5.26 mmol) and 4-
methylbenzaldehyde (0.693 g, 5.78 mmol) according to the general
procedure. The subsequent recrystallization from methanol gave the
pure product as a yellow solid (mp 97−99 °C) in 44% yield. 1H NMR
(300 MHz, CD2Cl2): δ (ppm) 2.05 (s, 3H, CH3), 2.29 (s, 3H,
PhCH3), 3.44 (s, 3H, NCH3), 6.95−7.00 (m, 1H, CHar), 7.14 (d, 2H, J
= 8.1 Hz, CHar), 7.18−7.20 (m, 2H, CHar), 7.26−7.31 (m, 2H, CHar),
7.47 (d, 2H, J = 8.1 Hz, CHar), 7.56 (d, 1H, J = 16.0 Hz, CHol), 7.90
(d, 1H, J = 16.0 Hz, CHol). 13C NMR (75 MHz, CD2Cl2): δ (ppm)
15.0 (CH3), 21.6 (PhCH3), 43.6 (NCH3), 117.5 (CHar/ol), 120.9
(CHar/ol), 122.7 (CHar/ol), 128.7 (CHar/ol), 129.4 (CHar/ol), 129.9
(CHar/ol), 133.2 (Cq), 140.9 (Cq), 141.5 (CHar/ol), 149.7 (Cq), 150.0
COH), 76.1 (CH2), 126.6 (CHarom/olef), 127.7 (CHarom/olef), 127.8
(CHarom/olef), 128.2 (CHarom/olef), 128.4 (CH arom/olef), 128.5
(CHarom/olef), 129.4 (CHarom/olef), 132.8 (CH arom/olef), 136.6 (Cq),
̃
137.6 (Cq), 159.4 (CH3CN). IR (neat) ν: 3451 (M), 3063 (M), 3046
(M), 3030 (M), 2980 (M), 2930 (M), 2868 (M), 2361 (S), 2334 (S),
1497 (M), 1466 (M), 1454 (M), 1437 (M), 1368 (M), 1244 (M),
1207 (M), 1180 (M), 1109 (M), 1082 (M), 1022 (M), 968 (M), 881
(M), 866 (M), 822 (M), 746 (M), 714 (M), 696 (M), 677 (M), 652
(M), 611 (M), 586 (M), 581 (M), 573 (M), 552 (M), 542 (M), 536
(M), 527 (M). HRMS (ESI): calcd for C19H21NO2Na 318.1470;
found 318.1465.
(2E,4E)-5-(2-Bromophenyl)-3-hydroxy-3-methyl-pent-4-en-2-one
O-Benzyl Oxime (4b). This compound was obtained from the
corresponding ketone 3b (0.359 g, 1 mmol) and methyllithium (1.6 M
in Et2O) (0.7 mL, 1.1 mmol) according to the general procedure. The
subsequent chromatographic purification (Et2O/pentane, 1:3) gave
0.21 g (0.57 mmol, 57%) of 4b as a colorless oil. 1H NMR (300 MHz,
CDCl3): δ (ppm) 1.48 (s, 3H, CH3COH), 1.85 (s, 3H, CH3CN), 3.81
(s, br, 1H, OH), 5.06 (s, 2H, OCH2Ph), 6.07 (d, 1H, J = 15.9 Hz,
CHolef), 6.91 (d, 1H, J = 15.9 Hz, CHolef), 6.99−7.04 (m, 1H, CHarom,),
7.17 (t, 1H, J = 7.5 Hz, CHarom), 7.22−7.29 (m, 5H, CHarom), 7.39 (d,
1H, J = 7.8 Hz, CHarom), 7.46 (d, 1H, J = 8.0 Hz, CHarom); 13C NMR
(75 MHz, CDCl3): δ (ppm) 11.4 (CH3OH), 25.7(CH3CN), 74.7 (Cq,
COH), 76.3 (CH2), 123.9 (Cq), 127.2 (CHarom/olef), 127.4
(CHarom/olef), 127.9 (CH arom/olef), 128.2 (CHarom/olef), 128.4
(CHarom/olef), 128.6 (CH arom/olef), 129.0 (CHarom/olef), 132.9
(CHarom/olef), 136.1 (CH arom/olef), 136.7 (Cq), 137.6 (Cq), 159.0
(CN), 188.7 (CO). IR (neat) ν
̃
: 3061 (w), 3028 (w), 2918 (w),
1651 (m), 1593 (m), 1557 (m), 1491 (m), 1348 (w), 1306 (m), 1277
(m), 1206 (m), 1177 (m), 1103 (m), 1059 (m), 1028 (m), 997 (m),
874 (m), 806 (m), 743 (s). HRMS (ESI): calcd for C19H20N2ONa
315.1473; found 315.1468. Anal. Calcd for C19H20N2O: C, 78.05; H,
6.89; N, 9.58. Found: C, 77.99; H, 7.03; N, 9.55.
(1E,3E)-1-(Indolin-1-ylimino)-1,4-diphenyl-but-3-en-2-one 3i. To
a dry Schlenk flask was added t-BuOK (0.112 g, 1 mmol) was added
and dissolved in abs THF (10 mL). Then, the ketophosphonate (E)-
dimethyl(3-(indolin-1-ylimino)-2-oxo-3-phenylpropyl) phosphona-
te13h (0.372 g, 1 mmol) was dissolved in 2 mL of THF and added
to the base. This reaction mixture was stirred at RT for 1 h followed by
the addition of benzaldehyde (0.12 mL, 1.1 mmol), dissolved in 1 mL
of THF. The progress of the reaction was monitored by TLC. After
the completion of the reaction, the solvent was evaporated in vacuo.
The residue was then dissolved in CH2Cl2, washed with brine, dried
over MgSO4, and concentrated to obtain the crude product. The
subsequent recrystallization gave 0.25 g (0.72 mmol, 72%) of 3i as a
̃
(CH3CN). IR (neat) ν: 3451 (w), 3063 (w), 3046 (w), 3030 (w),
2980 (w), 2930 (w), 2868 (w), 2361 (S), 1466 (M), 1454 (M), 1437
(M), 1368 (S), 1244 (M), 1207 (M), 1180 (M), 1109 (M), 1082 (M),
1022 (VS), 968 (VS), 881 (M), 866 (M), 822 (M), 746 (VS), 714
(M), 696 (VS), 677 (M), 652 (M), 611 (M), 586 (M), 581 (M), 573
(M), 552 (M), 542 (M), 536 (M), 527 (M). HRMS (ESI): calcd for
C19H20BrNO2Na 396.0575; found 396.0563. Anal. Calcd for
C19H20BrNO2: C, 60.97; H, 5.39; N, 3.74. Found: C, 60.77; H,
5.78; N, 3.56
1
yellow solid (mp 127−128 °C). H NMR (300 MHz, CD2Cl2): δ
(ppm) 2.93 (t, 2H, J = 8.2 Hz, NCH2CH2), 3.22 (t, 2H, J = 8.2 Hz,
NCH2CH2), 6.92 (td, J = 7.4, 0.7 Hz, 1H, CHar), 7.06 (d, J = 7.3 Hz,
1H, CHar), 7.22−7.26 (m, 3H, CHar), 7.30−7.36 (m, 7H, CHar), 7.59
(d, J = 7.3 Hz, 2H, CHar), 7.63 (d, J = 16.0 Hz, 1H, CHol), 8.12 (d, J =
16.0 Hz, 1H, CHol). 13C NMR (75 MHz, CD2Cl2): δ (ppm) 26.9
(NCH2CH2), 52.4 (NCH2CH2), 110.2 (CHar/ol), 121.0 (CHar/ol),
122.1 (CHar/ol), 124.1 (CHar/ol), 126.5 (CHar/ol), 127.1 (CHar/ol),
127.21 (CHar/ol), 127.22 (CHar/ol), 127.5 (CHar/ol), 127.8 (CHar/ol),
128.7 (CHar/ol), 129.3 (Cq), 133.5 (Cq), 134.8 (Cq), 139.9 (CHar/ol),
(2E,4E)-3-Hydroxy-5-(2-methoxyphenyl)-3-methyl-pent-4-en-2-
one O-Benzyl Oxime (4c). This compound was obtained from
corresponding ketone 3c (0.309 g, 1 mmol) and methyllithium (1.6 M
in Et2O) (0.7 mL, 1.1 mmol) according to the general procedure. The
subsequent chromatographic purification (Et2O/pentane, 1:3) gave
0.19 g (0.61 mmol, 61%) of 4c as a colorless oil. 1H NMR (300 MHz,
CDCl3): δ (ppm) 1.47 (s, 3H, CH3COH), 1.84 (s, 3H, CH3CN), 3.76
(s, 3H, OCH3), 3.83 (s, br, 1H, OH), 5.06 (s, 2H, OC H2Ph), 6.18 (d,
1H, J = 16.2 Hz, CHolef), 6.79 (d, 1H, J = 8.2 Hz, CHarom), 6.85 (d, 1H,
J = 7.5 Hz, CHarom), 6.92 (d, 1H, J = 16.2 Hz, CHolef), 7.14 (d, 1H, J =
7.8 Hz, CH arom), 7.29−7.31 (m, 5H, CHarom), 7.34 (d, 1H, J = 7.7 Hz,
CHarom); 13C NMR (75 MHz, CDCl3): δ (ppm) 11.4 (CH3), 25.8
(CH3), 55.4 (OCH3), 74.9 (Cq, COH), 76.2 (OCH2Ph), 110.8 (CH
arom/olef), 120.6 (CHarom/olef), 125.5 (CHarom/olef), 126.9 (CH arom/olef),
127.8 (CHarom/olef), 128.1 (CHarom/olef), 128.3 (CH arom/olef), 128.7
(CHarom/olef), 133.3 (Cq), 137.6 (Cq), 156.8 (Cq), 159.5 (Cq). IR
̃
(neat) ν: 3449 (W), 3032 (W), 2978 (W), 2932 (W), 2837 (W), 1607
(S), 1578 (W), 1510 (VS), 1454 (W), 1368 (W), 1304 (W), 1246
(VS), 1175 (S), 1105 (S), 1030 (S), 972 (S), 930 (W), 851 (W), 816
(W), 741 (W), 698 (W), 608 (VS). HRMS (ESI): calcd for
C20H23NO3Na 348.1576; found 348.1574.
(2E,4E)-5-(4-Chlorophenyl)-3-hydroxy-3-methyl-pent-4-en-2-one
O-Benzyl Oxime (4d). This compound was obtained from the
corresponding ketone 3d (0.313 g, 1 mmol) and methyllithium (1.6 M
in Et2O) (1.1 mmol) according to the general procedure. The
subsequent chromatographic purification (Et2O/pentane, 1:3) gave
0.21 g (0.64 mmol, 64%) of 4d as a colorless oil. 1H NMR (300 MHz,
CDCl3): δ (ppm) 1.45 (s, 3H, CH3), 1.83 (s, 3H, CH 3), 3.85 (s, 1H,
COH), 5.06 (s, 2H, OC H2Ph), 6.14 (d, 1H, J = 16.0 Hz, CHolef), 6.54
(d, 1H, J = 16.0 Hz, CHolef), 7.20−7.29 (m, 9H, CHarom); 13C NMR
(75 MHz, CDCl3): δ (ppm) 11.4 (CH3), 26.0 (CH3), 74.6 (Cq,
COH), 76.3 (CH2Ph), 127.8 ( CHarom/olef), 127.9 (CH arom/olef), 128.2
(CHarom/olef), 128.4 (CHarom/olef), 128.7 (CH arom/olef), 133.4
(CHarom/olef), 133.5 (CHarom/olef), 135.1 (Cq), 137.5 (Cq), 159.2
140.5 (Cq), 146.9 (Cq), 187.4 (CO). IR (neat) ν
̃
: 3458 (m), 3421
(m), 2359 (w), 2180 (w), 2154 (w), 1653 (s), 1607 (s), 1547 (s),
1481 (m), 1325 (m), 1302 (s), 1269 (s), 1240 (m), 1163 (m), 1126
(m), 1115 (m), 1103 (s), 1065 (s), 1011 (m), 957 (s), 829 (s), 750
(m), 716 (m), 696 (m). HRMS (ESI): calcd for C24H20N2OH:
353.1654; found 353.1648.
General Procedure for the Preparation of (2E,4E)-5-(2-Aryl)-
3-hydroxy-3-alkyl-pent-4-en-2-one O-Benzyl Oxime (4). To a
clean dry Schlenk flask was transferred dry THF (10 mL per mmol).
To this was added 1-azapenta-1,4-diene-3-one 3 (1 equiv), and the
mixture was cooled to −78 °C. Then the corresponding organolithium
species (1.1 equiv) was added to the mixture dropwise. Then the
reaction mixture was stirred at the same temperature. The progress of
the reaction was monitored by TLC. Once the reaction was complete
the mixture was quenched with satd aq NH4Cl solution, diluted with
CH2Cl2, and washed three times with water. The combined organic
layers were dried with Na2SO4 and concentrated in vacuo. Finally, the
alcohol 4 was purified by column chromatography.
(2E,4E)-3-Hydroxy-3-methyl-5-phenyl-pent-4-en-2-one O-Benzyl
Oxime (4a). This compound was obtained from the corresponding
ketone 3a (0.279 g, 1 mmol) and methyllithium (1.6 M in Et2O) (0.7
mL, 1.1 mmol) according to the general procedure. The subsequent
chromatographic purification (Et2O/pentane, 1:3) gave 0.2 g (0.68
1
mmol, 68%) of 4a as a colorless oil. H NMR (300 MHz, CDCl3): δ
(ppm) 1.46 (s, 3H, CH3COH), 1.83 (s, 3H, CH3CN), 3.90 (s, br, 1H,
OH), 5.06 (s, 2H, OCH2Ph), 6.16 (d, 1H, J = 16.0 Hz, CHolef), 6.58
(d, 1H, J = 16.0 Hz, CHolef), 7.16−7.31 (m, 10H, CHarom); 13C NMR
(75 MHz, CDCl3): δ (ppm) 11.4 (CH3OH), 25.9(CH3CN), 74.4 (Cq,
1874
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Article
(Cq). IR (neat) ν
̃
: 3314 (W), 3037 (W), 2918 (W), 2862 (W), 1690
M in Et2O) (0.33 mL, 1.6 mmol) according to the general procedure.
The subsequent chromatographic purification (Et2O/pentane, 1:3)
gave 0.28 g (0.67 mmol, 46%) of 4h as a colorless oil. H NMR (300
MHz, CDCl3): δ (ppm) 1.76 (s, 3H, CH3), 4.26 (s, 1H, COH), 5.11
(s, 2H, OCH2Ph), 6.60 (d, 1H, J = 15.8 Hz, CHolef), 7.06 (d, 1H, J =
15.8 Hz, CHolef), 7.00−7.06 (m, 1H, CHarom), 7.16−7.31 (m, 11H,
CHarom), 7.46−7.48 (m, 2H, CHarom); 13C NMR (75 MHz, CDCl3): δ
(ppm) 11.4 (CH3), 12.9 (CH3), 76.4 (Cq, COH), 78.9 (CH2Ph), 126.8
( CHarom/olef), 127.9 (CH arom/olef), 128.2 (CHarom/olef), 128.4
(CHarom/olef), 129.0 (CH arom/olef), 132.8 (CHarom/olef), 136.0 (Cq),
(W), 1616 (W), 1504 (W), 1454 (W), 1368 (S), 1219 (W), 1179
(W), 1129 (S), 1008 (W), 969 (W), 813 (W), 779 (W), 698 (W).
HRMS (ESI): calcd for C19H20NO2ClNa 352.1080; found 352.1075.
(2E,4E)-3-Hydroxy-3-methyl-5-(p-tolyl)-pent-4-en-2-one O-Benzyl
Oxime (4e). This compound was obtained from the corresponding
ketone 3e (0. 293 g, 1 mmol) and methyllithium (1.6 M in Et2O) (0.7
mL, 1.1 mmol) according to the general procedure. The subsequent
chromatographic purification (Et2O/pentane, 1:3) gave 0.21 g (0.68
1
1
mmol, 68%) of 4e as a colorless oil. H NMR (300 MHz, CDCl3): δ
(ppm) 1.43 (s, 3H, CH3COH), 1.80 (s, 3H, CH3CN), 2.23 (s, 3H,
PhCH3), 3.81 (s, 1H, OH), 5.03 (s, 2H, OCH2Ph), 6.09 (d, 1H, J =
16.0 Hz, CHolef), 6.52 (d, 1H, J = 16.0 Hz, CHolef), 7.01 (d, 2H, J = 8.0
Hz, CHarom), 7.17 (d, 2H, J = 8.0 Hz, CHarom), 7.20−7.23 (m, 1H,
CHarom), 7.25−7.27 (m, 5H, CHarom); 13C NMR (75 MHz, CDCl3): δ
(ppm) 11.4 (CH3OH), 21.1 (PhCH3) 26.0(CH3CN), 74.7 (Cq,
COH), 76.2 (CH2), 126.6 (CHarom/olef), 127.9 (CHarom/olef), 128.2 (CH
arom/olef), 128.4 (CHarom/olef), 129.3 (CHarom/olef), 129.3 (CH arom/olef),
131.9 (CHarom/olef), 133.8 (Cq), 137.6 (Cq), 137.7 (Cq), 159.6 (Cq). IR
̃
137.6 (Cq), 159.3 (Cq). IR (neat) ν: 3478 (W), 2965 (W), 1466 (W),
1454 (W), 1369 (W), 1240 (W), 1204 (W), 1167 (W), 1022 (M), 972
(W), 932 (W), 750 (M),700 (M),658 (W), 631 (M),608 (W), 528
(VS), 509 (S). HRMS (ESI): calcd for C24H21BrNO2NaH 460.0711;
found 460.0710.
(2E,4E)-3-Hydroxy-3-methyl-5-(thiophen-2-yl)-pent-4-en-2-one
O-Benzyl Oxime (4i). This compound was obtained from the
corresponding ketone 3f (0.285 g, 1 mmol) and methyllithium (1.6
M in Et2O) (0.7 mL, 1.1 mmol) according to the general procedure.
The subsequent chromatographic purification (Et2O/pentane, 1:10)
̃
(neat) ν: 3304 (W), 3030 (W), 2928 (W), 2862 (W), 1690 (W), 1611
1
gave 0.19 g (0.63 mmol, 63%) of 4i as a colorless oil. H NMR (300
(W), 1514 (W), 1454 (W), 1368 (S), 1209 (W), 1179 (W), 1109 (S),
1018 (W), 974 (W), 802 (W), 743 (W), 698 (W). HRMS (ESI): calcd
for C20H23NO2Na 332.1626; found 332.1625.
MHz, C6D6): δ (ppm) 1.45 (s, 3H, CH3), 1.80 (s, 3H, CH3), 3.47 (br,
1H, COH), 5.11 (s, 2H, OCH2Ph), 6.29 (d, 1H, J = 15.7 Hz, CHolef),
6,76−6.82 (m, 1H, CHarom), 7.02 (d, 1H, J = 15.7 Hz, CHolef), 7.18−
7.27 (m, 4H, CHarom), 7.36−7.38 (m, 4H, CHarom); 13C NMR (75
MHz, C6D6): δ (ppm) 11.0 (CH 3), 26.3 (CH3), 74.7 (Cq, COH), 76.4
(CH2Ph), 122.8 (CHarom/olef), 124.5 (CH arom/olef), 126.4 (CHarom/olef),
127.6 (CHarom/olef), 128.1 (CH arom/olef), 128.6 (CHarom/olef), 128.6
(CHarom/olef), 133.2 (CH arom/olef), 138.2 (Cq), 142.3 (Cq), 159.8 (Cq).
(E)-3-((E)-2-Bromostyryl)-3-hydroxy-heptan-2-one O-Benzyl
Oxime (4f). This compound was obtained from the corresponding
ketone 3b (0.354 g, 1 mmol) and n-butyllithium (1.6 M in hexane)
(0.7 mL, 1.1 mmol) according to the general procedure. The
subsequent chromatographic purification (Et2O/pentane, 1:10) gave
0.19 g (0.51 mmol, 51%) of 4f as a colorless oil. 1H NMR (300 MHz,
CDCl3): δ (ppm) 0.81 (t, 3H, J = 7.2 Hz, CH2CH ), 0.98−1.10 (m,
̃
IR (neat) ν: 3447 (M), 3032 (M), 2980 (M), 2930 (M), 2872 (M),
3
1H, CH2CH2CH3), 1.24 (m, 2H, CH2CH2CH3), 1.33−1.40 (m, 1H,
1643 (M), 1454 (M), 1368 (M), 1179 (M), 1107 (M), 1018 (M), 959
(M), 856 (M), 737 (M), 696 (S), 631 (S), 538 (S), 527 (VS). HRMS
(ESI): calcd for C17H19NO2SNa 324.1034; found 324.1029. Anal.
Calcd for C17H 19NO2S: C, 67.74; H, 6.35; N, 4.65. Found: C, 67.81;
H, 6.17; N, 4.74.
COHCH2), 1.68−1.73 (m, 2H, COHCH2), 1.82 (s, 3H, CH CN),
3
3.97 (s, 1H, COH), 5.05 (s, 2H, OCH2Ph), 6.07 (d, 1H, J = 15.9 Hz,
CHolef), 6.94 (d, 1H, J = 15.9 Hz, CHolef), 7.00 (dd, 1H, J = 7.7, 1.2 Hz,
C Harom), 7.12−7.15 (m, 1H, CHarom), 7.18−7.23 (m, 2H, CHarom),
7.24−7.26 (m, 2H, CHarom), 7.37 (dd, 1H, J = 7.8, 1.4 Hz, C Harom),
7.44 (dd, 1H, J = 8.0, 1.2 Hz, C Harom); 13C NMR (75 MHz, CDCl 3):
δ (ppm) 11.5 (CH3), 14.1 (CH2CH3), 22.9 (CH2CH2), 25.3
(CH3CN), 37.8 (CH2COH), 76.2 (CH2OPh), 77.0 (CqOH), 123.9
(Cq), 127.2 (CHarom/olef), 127.4 (CHarom/olef), 127.8 (CH arom/olef),
128.1 (CHarom/olef), 128.4 (CHarom/olef), 128.7 (CH arom/olef), 128.8
(CHarom/olef), 132.9 (CHarom/olef), 135.6 (CH arom/olef), 136.9 (Cq),
(2E,4E)-5-(4-Chlorophenyl)-3-hydroxy-3-(p-tolyl)-pent-4-en-2-
one O-Benzyl Oxime (4j). This compound was obtained from the
corresponding ketone 3d and p-tolyl lithium. p-Tolyl lithium was
generated in situ by metal−halogen exchange of p-bromotoluene using
n-butyl lithium (1.6 M in hexane) by adding n-BuLi (0.7 mL, 1.1
equiv) to a solution of p-bromotoluene (0.188 g, 1.1 mmol,1.1 equiv)
in THF (10 mL) cooled to −78 °C. To this solution of p-tolyl lithium
in THF, ketone 3d (0.313 g, 1 mmol as a solution in THF) was added
dropwise. Then, the general procedure was followed with regard to the
monitoring of the progress and the work up of the reaction. The
subsequent chromatographic purification (Et2O/pentane, 1:3) gave
0.24 g (0.60 mmol, 60%) of 4j as a colorless oil. 1H NMR (300 MHz,
CDCl3): δ (ppm) 1.74 (s, 3H, CH3), 2.25 (s, 3H, tol-CH3), 4.22 (s,
1H, CH3OH), 5.11 (s, 2H, OCH2Ph), 6.62 (d, 1H, J = 15.8 Hz,
CHolef), 6.71 (d, 1H, J = 15.8 Hz, CHolef), 7.05 (d, 2H, J = 7.8 Hz,
CHarom), 7.15−7.30 (m, 11H, CHarom); 13C NMR (75 MHz, CDCl3):
δ (ppm) 12.8 (CH3), 21.1 (CH3), 76.3 (Cq, COH), 78.6 (OCH2Ph),
126.7 ( CHarom/olef), 127.9 (CH arom/olef), 127.9 (CHarom/olef), 128.2
(CHarom/olef), 128.4 (CH arom/olef), 128.7 (CHarom/olef), 129.2
(CHarom/olef), 129.2 (CH arom/olef), 131.4 (CHarom/olef), 133.3 (Cq),
135.3 (Cq), 137.6 (Cq), 137.7 (Cq), 139.6 (Cq), 158.7 (Cq). IR (neat)
137.6 (Cq), 158.3 (C N). IR (neat) ν
̃
: 3478 (W), 2955 (W), 2930
(W), 2870 (W), 2359 (W), 1497 (W), 1466 (M), 1454 (M), 1369
(M), 1209 (W), 1159 (W), 1022 (S), 970 (W), 916 (W), 750 (W),
698 (W), 631 (S), 538 (VS), 525 (VS). HRMS (ESI): calcd for
C22H26BrNO2Na 440.1024; found 440.1018.
(2E,4E)-5-(2-Bromophenyl)-3-hydroxy-3-isopropyl-pent-4-en-2-
one O-Benzyl Oxime (4g). This compound was obtained from the
corresponding ketone 3b (0.354 g, 1 mmol) and isopropyllithium (1.3
M in THF) (0.84 mL, 1.1 mmol) according to the general procedure.
The subsequent chromatographic purification (Et2O/pentane, 1:20)
1
gave 0.17 g (0.45 mmol, 45%) of 4g as a colorless oil. H NMR (300
MHz, CDCl3): δ (ppm) 0.7 (d, 3H, J = 6.5 Hz, CHCH3 ), 0.9 (d, 3H,
J = 6.7 Hz, CHCH3), 1.83 (s, 3H, CH3CN), 1.98 (h, 1H, J = 6.7 Hz,
CH(CH3)2), 3.95 (s, 1H, COH), 5.05 (s, 2H, OCH 2Ph), 6.07 (d, 1H,
J = 15.8 Hz, CHolef), 6.97−7.02 (m, 2H, CHarom/olef), 7.13−7.20 (m,
2H, CHarom), 7.37 (d, 2H, J = 7.7 Hz, CHarom), 7.45 (d, 2H, J = 8.0 Hz,
̃
ν: 3439 (M), 3030 (M), 2924 (M), 2870 (M), 1510 (M), 1491 (M),
1454 (M), 1368 M), 1179 (M), 1092 (M), 1013 (M), 974 (M), 905
(M), 858 (M), 818 (M), 752 (M), 725 (M), 698 (M), 631 (M), 608
(M). HRMS (ESI): calcd for C25H24NO2ClNa 428.1393; found
428.1388.
CHarom); 13C NMR (75 MHz, CDCl3): δ (ppm) 11.5 (CH(CH )2),
3
16.3 (CH3), 16.3 (CH3), 33.6 (CH3CN), 76.2 (CH2OPh), 79.3
(CqOH), 123.2 (Cq), 127.2 (CHarom/olef), 127.4 (CHarom/olef), 127.8
(CHarom/olef), 128.0 (CHarom/olef), 128.3(CH arom/olef), 128.7
(CHarom/olef), 129.3 (CHarom/olef), 132.9 (CH arom/olef), 135.0
(1E,4E)-3-Methyl-4-(2-methyl-2-phenylhydrazono)-1-phenyl-
pent-1-en-3-ol (4k). This compound was obtained from the
corresponding ketone 3g (0.278 g, 1 mmol) and methyllithium (1.6
M in Et2O) (0.7 mL, 1.1 mmol) according to the general procedure.
The subsequent chromatographic purification (Et2O/pentane, 1:3)
gave 0.15 g (0.51 mmol, 51%) of 4k as light yellow oil. 1H NMR (300
MHz, CDCl3): δ (ppm) 1.53 (s, 3H, CH3), 1.90 (s, 3H, CH3), 2.97 (s,
3H, CH3), 5.39 (br, 1H, OH), 6.23 (d, 1H, J = 16.0 Hz, CHolef), 6.71
(d, 1H, J = 16.0 Hz, CHolef), 6.79−6.86 (m, 3H, CHarom), 7.16−7.27
(CHarom/olef), 137.1 (Cq), 137.6 (Cq), 158.5 (C N). IR (neat) ν
̃
:
3478 (W), 2965 (W), 1466 (M), 1454 (M), 1369 (M), 1240 (W),
1163 (M), 1022 (S), 972 (S), 750 (S), 700 (M), 630 (S). HRMS
(ESI): calcd for C21H24BrNO2Na 424.0888; found 424.0875.
(2E,4E)-5-(2-Bromophenyl)-3-hydroxy-3-phenyl-pent-4-en-2-one
O-Benzyl Oxime (4h). This compound was obtained from the
corresponding ketone 3b (0.500 g, 1.45 mmol) and phenyllithium (1.9
1875
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The Journal of Organic Chemistry
Article
(m, 5H, CHarom), 7.32−7.35 (m, 2H, CHarom). 13C NMR (75 MHz,
CDCl3): δ (ppm) 14.5 (CH3), 26.0 (CH3), 43.1 (CH3), 75.1 (Cq,
COH), 115.9 (CHarom/olef), 120.8 (CHarom/olef), 126.7 (CHarom/olef),
127.8 (CHarom/olef), 128.6 (CHarom/olef), 128.9 (CHarom/olef), 129.9
(CHarom/olef), 132.8 (CHarom/olef), 136.7 (Cq), 151.1 (Cq), 171.7 (Cq).
(CH arom), 129.0 (CHarom), 129.7 (CHarom), 131.7 (Cq), 133.9 (Cq). IR
(neat) ν: 3063 (M), 3026 (M), 2914 (M), 2862 (M), 1601 (M), 1512
̃
(M), 1452 (M), 1383 (M), 1217 (M), 1177 (M), 1157 (M), 1119
(M), 1076 (M), 1030 (M), 982 (M), 964 (M), 949 (M), 908 (M), 847
(M), 789 (M), 748 (M), 735 (M), 692 (M), 652 (M). HRMS (ESI):
calcd for C19H19NONa 300.1364; found 300.1356. Anal. Calcd for
C19H19NO: C, 82.28; H, 6.90; N, 5.05. Found: C, 82.07; H, 7.23; N,
5.46.
̃
IR (neat) ν: 3387 (W), 3059 (W), 3026 (W), 2976 (W), 2926 (W),
1599 (VS), 1493 (VS), 1449 (S), 1368 (S), 1296 (S), 1182 (S), 1070
(S), 1028 (S), 970 (S), 746 (S), 692 (VS), 617 (VS). HRMS (ESI):
calcd for C19H22N2OH 295.1810; found 295.1797.
1-(Benzyloxy)-5-(2-bromophenyl)-2,3-dimethyl-pyrrole (6b). This
compound was obtained from 4b (0.2 g, 0.54 mmol) according to the
general procedure. The subsequent chromatographic purification
(Et2O/pentane, 1:10) gave 0.1 g (0.28 mmol, 53%) of 6b as a
colorless oil. 1H NMR (300 MHz, C6D6): δ (ppm) 2.08 (s, 3H, CH3),
2.14 (s, 3H, CH3), 4.50 (s, 2H, CH2), 6.47 (s, 1H, CHpyrrole.), 6.78−
6.83 (m, 1H, CHarom), 7.00−7.03 (m, 3H, CHarom), 7.08−7.11 (m, 3H,
CHarom), 7.62−7.67 (m, 2H, CHarom). 13C NMR (75 MHz, C6D6): δ
(1E,4E)-3-Methyl-4-(2-methyl-2-phenylhydrazono)-1-(p-tolyl)-
pent-1-en-3-ol (4l). This compound was obtained from the
corresponding ketone 3h (0.292 g, 1 mmol) and methyllithium (1.6
M in Et2O) (0.7 mL, 1.1 mmol) according to the general procedure.
The subsequent chromatographic purification (Et2O/pentane, 1:10)
gave 0.20 g (0.65 mmol, 65%) of 4l as light yellow oil. 1H NMR (300
MHz, C6D6): δ (ppm) 1.22 (s, 3H, CH3), 1.37 (s, 3H, CH3), 1.81 (s,
3H, CH3), 2.42 (s, 3H, NCH3), 5.03 (br, 1H, OH), 6.03 (d, 1H, J =
15.9 Hz, CHolef), 6.53−6.59 (m, 1H, CHarom), 6.60−6.64 (m, 2H,
CHarom), 6.66−6.70 (m, 3H, CHarom/olef), 6.85−6.90 (m, 2H, CHarom),
6.94 (d, 2H, J = 8.2 Hz, CHarom); 13C NMR (75 MHz, C6D6): δ (ppm)
12.8 (CH3), 19.8 (CH3), 25.3 (CH3), 41.8 (CH3), 74.2 (Cq, COH),
114.9 (CHarom/olef), 119.6 (CHarom/olef), 125.6 (CHarom/olef), 127.8
(CHarom/olef), 128.2 (CHarom/olef), 128.5 (CHarom/olef), 131.3
(CHarom/olef), 133.2 (Cq), 136.1 (Cq), 150.4 (Cq), 170.9 (Cq). IR
(ppm) 8.7 (CH3), 11.4 (CH3), 80.8 (CH ), 108.7 (CHpyrrole.), 110.5
2
(Cq), 121.3 (Cq), 122.4 (Cq), 123.4 (Cq,), 125.9 (CHarom), 127.3
(CHarom), 127.4 (CHarom), 127.9 (CHarom), 128.5 ( CHarom), 131.3
(CHarom), 131.5 (Cq), 132.1 (CHarom), 132.8 (Cq). IR (neat) ν: 3063
̃
(w), 3032 (w), 2920 (w), 2862 (w), 1597 (w), 1558 (w), 1510 (w),
1454 (w), 1435 (w), 1379 (w), 1256 (w), 1213 (w), 1177 (w), 1119
(w), 1082 (w), 1043 (w), 1026 (m), 966 (w), 953 (w), 907 (w), 849
(w), 793 (w), 748 (S), 737 (m), 716 (w), 696 (m), 683 (w), 637 (w),
608 (w), 586 (w), 527 (w). HRMS (ESI): calcd for C19H18NOBrNa
378.0469; found 378.0464.
̃
(neat) ν: 3357 (W), 3064 (W), 3025 (W), 2976 (W), 2936 (W), 1601
(VS), 1492 (VS), 1459 (S), 1375 (S), 1296 (S), 1182 (S), 1070 (S),
1037 (S), 970 (S), 746 (S), 692 (VS), 620 (VS). HRMS (ESI): calcd
for C20H24N2ONa 331.1786; found 331.1781
1-(Benzyloxy)-5-(2-methoxyphenyl)-2,3-dimethyl-pyrrole (6c).
This compound was obtained from 4c (0.325 g, 1 mmol) according
to the general procedure. The subsequent chromatographic
purification (Et2O/pentane, 1:3) gave 0.1 g (0.29 mmol, 29%) of 6c
(1E,3E)-1-(Indolin-1-ylimino)-2-methyl-1,4-diphenyl-but-3-en-2-
ol (4m). This compound was obtained from the corresponding ketone
3i (0.17 g, 0.48 mmol) and methyllithium (1.6 M in Et2O) (0.28 mL,
0.53 mmol) according to the general procedure. The subsequent
chromatographic purification (Et2O/pentane, 1:10) gave 0.14 g (0.38
mmol, 79%) of 4m as light yellow oil. 1H NMR (300 MHz, CDCl3): δ
(ppm) 1.76 (s, 3H, CH3OH), 2.43 (t, J = 8.3 Hz, 2H, NCH2CH2),
2.68−2.88 (m, 2H, NCH2CH2), 5.25 (s, 1H, CH3OH), 6.57 (d, 1H, J
= 15.9 Hz, CHolef), 6.90−6.99 (m, 2H, CHarom), 7.06−7.16 (m, 5H,
1
as a colorless oil. H NMR (300 MHz, C6D6): δ (ppm) 1.97 (s, 3H,
CH3), 2.12 (s, 3H, CH3), 3.77 (s, 3H, OCH3), 4.63 (s, 2H, CH2), 6.07
(s, 1H, CHpyrrole), 6.88−6.95 (m, 2H, CHarom), 7.03−7.06 (m, 2H,
CHarom), 7.20−7.24 (m, 4H, CHarom), 7.55 (dd, 1H, J = 7.6, 1.7 Hz,
CHarom).13C NMR (75 MHz, C6D6): δ (ppm) 8.7 (CH 3), 11.4 (CH3),
55.5 (OCH3), 80.1 (CH2), 104.7 (CHpyrrole), 111. (Cq), 114.4
(CHarom), 122.3 (CH arom), 125.4 (Cq), 126.7 (CHarom), 127.9
(CHarom), 128.6 ( CHarom), 128.9 (CHarom),129.8 (CHarom), 134.7
CHarom), 7.19−7.26 (m, 5H, CHarom), 7.37−7.40 (m, 3H, CHarom); 13
C
NMR (75 MHz, CDCl3): δ (ppm) 27.7 (CH3), 28.1 (NCH2CH2),
54.6 (NCH2CH2), 75.8 (Cq, COH), 111.3 (CHarom/olef), 121.4
(CHarom/olef), 124.7 (CHarom/olef), 126.9 (CHarom/olef), 127.2
(CHarom/olef), 127.7 (Cq), 128.0 (CHarom/olef), 128.1 (CHarom/olef),
134.9 (Cq), 136.4 (Cq), 137.7 (Cq), 151.4 (Cq), 153.3 (Cq). IR (neat)
̃
(Cq), 158.7(Cq). IR (neat) ν: 3032 (w), 2936 (w), 2916 (w), 2835
(w), 1611 (m), 1572 (m), 1526 (v), 1454 (m), 1441 (m), 1377 (m),
1285 (M), 1246 (v), 1223 (w), 1177 (M), 1119 (w), 1105 (w), 1076
(w), 1032 (m), 966 (W), 951 (W), 908 (W), 831 (M), 808 (m), 781
(m), 754 (m), 737 (m), 696 (m), 621 (m), 604 (m), 590 (m). HRMS
(ESI): calcd for C20H21NO2Na 330.1470; found 330.1465.
̃
ν: 3391 (W), 3026 (W), 2972 (W), 2924 (W), 2858 (M), 1614 (M),
1593 (M), 1479 (VS), 1462 (M), 1371 (M), 1265 (M), 1207 (M),
1180 (M), 1153 (M), 1117 (M), 1072 (M), 1016 (M), 986 (M), 889
(M), 853 (M), 746 (VS), 704 (S), 691 (VS). HRMS (ESI): calcd for
C25H24N2ONa 391.1786; found 391.1781.
1-(Benzyloxy)-5-(4-chlorophenyl)-2,3-dimethyl-pyrrole (6d). This
compound was obtained from 4d (0.2 g, 0.61 mmol) according to the
general procedure. The subsequent chromatographic purification
(Et2O/pentane, 1:3) gave 0.06 g (0.2 mmol, 30%) of 6d as white
1
General Method for the Synthesis of Pyrroles 6a−m. To a
clean, dry Schlenk flask was added dry CH2Cl2 (40 mL per mmol of
the substrate), and the mixture was cooled down to −10 °C using
salt−ice mixture. Then CF3SO3H (2 equiv) was added followed by the
dropwise addition of the substrate 4 (1 equiv as a solution in DCM).
Usually the reaction mixture turned to brown or red after the addition
of the substrate. Soon this color slowly faded. The progress of the
reaction was monitored by TLC. After the completion, the reaction
mixture was quenched with satd aq NaHCO3 solution and washed a
couple of times with water. Then the organic phase was dried with
MgSO4 and concentrated in vacuo. The product pyrrole was purified
using silica gel column chromatography.
solid (mp 87−89 °C). H NMR (300 MHz, C6D6): δ (ppm) 2.07 (s,
3H, CH3), 2.11 (s, 3H, CH3), 4.49 (s, 2H, CH2), 6.16 (s, 1H,
CHpyrrole), 7.08−7.14 (m, 5H, CHarom), 7.24−7.27 (m, 2H, CHarom),
7.64−7.67 (m, 2H, CHarom). 13C NMR (75 MHz, C6D6): δ (ppm)
8.69 (CH3), 11.5 (CH3), 80.2 (CH2), 105.9 (CHpyrrole), 111.5 (Cq),
123.8 (Cq), 125.3 (Cq), 127.4 (CHarom), 128.6 (CHarom), 128.9
(CHarom), 129.1 (CHarom), 129.8 (CHarom), 130.9 (Cq), 131.7 (Cq),
̃
134.2 (Cq). IR (neat) ν: 3067 (W), 3032 (W), 2916 (W), 2862 (W),
1597 (W), 1512 (S), 1454 (W), 1414 (W), 1393 (W), 1377 (W),
1219 (W), 1177 (W), 1092 (S), 1013 (W), 964 (W), 951 (W), 908
(W), 833 (W), 785 (S), 760 (S), 745 (S), 735 (S), 696 (S), 631 (S).
HRMS (ESI): calcd for C19H18NOClH 312.1155; found 312.1150.
Anal. Calcd for C19H18NOCl: C, 73.19; H, 5.82; N, 4.49. Found: C,
73.14; H, 5.93; N, 4.49.
1-(Benzyloxy)-2,3-dimethyl-5-phenyl-pyrrole (6a). This com-
pound was obtained from 4a (0.295 g, 1 mmol) according to the
general procedure. The subsequent chromatographic purification
(Et2O/pentane, 1:10) gave 0.11 g (0.40 mmol, 40%) of 6a as a
1-(Benzyloxy)-2,3-dimethyl-5-(p-tolyl)-pyrrole (6e). This com-
pound was obtained from 4e (0.2 g, 0.65 mmol) according to the
general procedure. The subsequent chromatographic purification
(Et2O/pentane, 1:10) gave 0.06 g (0.23 mmol, 32%) of 6e as white
solid (mp 54−56 °C). 1H NMR (300 MHz, CDCl3): δ (ppm) 2.13 (s,
3H, CH3), 2.16 (s, 3H, CH3), 2.25 (s, 3H, CH3), 4.62 (s, 2H,
OCH2Ph), 6.52 (s, 1H, CHpyrrole), 7.13−7.18 (m, 7H, CHarom), 7.92
(d, 2H, J = 8.2 Hz, CHarom). 13C NMR (75 MHz, CDCl3): δ (ppm)
1
colorless oil. H NMR (300 MHz, CDCl3): δ (ppm) 2.11 (s, 3H,
CH3), 2.14 (s, 3H, CH ), 4.63 (s, 2H, CH2), 6.30 (s, 1H, CHpyrrole.),
3
7.15−7.18 (m, 6H, CHarom), 7.26−7.32 (m, 2H, CHarom), 7.95−7.98
(m, 2H, CHarom).13C NMR (75 MHz, CDCl3): δ (ppm) 8.7 (CH3),
11.2 (CH3), 80.1 (CH2), 104.7 (CHpyrrole.), 111.0 (Cq), 123.2 (Cq),
126.0 (CHarom), 126.2 (CHarom), 126.3 (Cq), 128.4 (CHarom), 128.5
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The Journal of Organic Chemistry
Article
8.7 (CH3), 11.6 (CH3), 21.1 (CH3), 80.0 (OCH2Ph), 105.2
(CHpyrrole), 111.1 (Cq), 122.9 (Cq), 126.4 (CHarom), 126.7, 128.6
(CHarom), 128.9 (CHarom), 129.6 (CHarom), 129.7 (CHarom), 129.9
1-(Benzyloxy)-2,3-dimethyl-5-(thiophen-2-yl)-pyrrole (6i). This
compound was obtained from 4i (0.18 g, 0.60 mmol) according to
the general procedure. The subsequent chromatographic purification
(Et2O/pentane, 1:20) gave 0.06 g (0.22 mmol, 36%) of 6i as yellow
̃
(Cq), 134.7 (Cq), 135.5 (Cq). IR (neat) ν: 3034 (W), 2913 (W), 2884
1
solid (mp 58−60 °C). H NMR (300 MHz, C6D6): δ (ppm) 2.03 (s,
(W), 2858 (W), 1524 (M) 1452 (M), 1375 (M), 1225 (W), 1207
(W), 1177 (W), 1107 (W), 988 (W), 964 (M), 947 (M), 910 (M),
851 (M), 822 (S) 783 (M) 754 (M) 737 696 (M). HRMS (ESI): calcd
for C20H21NOH 292.1701; found 292.1696.
3H, CH3), 2.08 (s, 3H, CH3), 4.72 (s, 2H, OCH2Ph), 6.34 (s, 1H,
CHarom), 6.90 (s, 1H, CHarom), 6.91 (d, 1H, J = 1.4 Hz, CHarom), 7.16
(d, 1H, J = 2.1 Hz, CHarom), 7.18−7.19 (m, 2H, CHarom), 7.24−7.26
(m, 2H, CHarom), 7.43 (dd, 1H, J = 2.9, 1.4 Hz, CHarom). 13C NMR (75
MHz, C6D6): δ (ppm) 8.6 (CH3), 11.4 (CH3), 80.1 (OCH2Ph), 105.2
(CHarom), 111.4 (Cq), 121.2 (Cq), 122.4 (CHarom), 122.8 (CHarom),
122.9, 127.5 (CHarom), 128.6 (CHarom), 128.9 (CHarom), 129.6
1-(Benzyloxy)-5-(2-bromophenyl)-3-butyl-2-methyl-pyrrole (6f).
This compound was obtained from 4f (0.19 g, 0.46 mmol) according
to the general procedure. The subsequent chromatographic
purification (Et2O/pentane, 1:20) gave 0.09 g (0.23 mmol, 50%) of
6f as oil. 1H NMR (300 MHz, C6D6): δ (ppm) 1.03 (t, 3H, J = 7.3 Hz,
CH3CH2), 1.43−1.55 (m, 2H, CH2), 1.65−1.75 (m, 2H, CH2), 2.10
(s, 3H, CH3), 2.56 (t, 2H, J = 7.5 Hz, CH2CH2), 4.51 (s, 2H, CH2),
6.53 (s, 1H, CHpyrrole), 6.78−6.83 (m, 1H, CHarom), 6.99−7.03 (m, 3H,
̃
(CHarom), 134.2 (Cq), 134.6 (Cq). IR (neat) ν: 3105 (M), 3069
(M), 3038 (M), 2945 (M), 2918 (M), 2882 (M), 2858 (M), 1528
(M), 1499 (M), 1481 (M), 1464 (M), 1452 (M), 1398 (M), 1366
(M), 1335 (M), 1227 (M), 1215 (M), 1196 (M), 1175 (M), 1113
(M), 1078 (M), 1030 (M), 982 (M), 972 (M), 951 (S), 926 (M), 908
(S), 843 (S), 814 (S), 777 (S), 768 (S), 758 (S), 745 (S), 735 (S), 692
(S), 637 (M), 602 (M). HRMS (ESI): calcd for C17H17NOSH
284.1109; found 284.1104.
CHarom), 7.09−7.11 (m, 3H, CHarom), 7.63−7.69 (m, 2H, CHarom). 13
C
NMR (75 MHz, C6D6): δ (ppm) 8.8 (CH3), 14.3 (CH3CH2), 22.8
(CH2), 26.4 (CH2), 33.7 (CH2), 80.7 (CH2OPh), 107.8 (CHpyrrole),
115.9 (Cq), 122.3 (Cq), 123.7 (Cq), 124.5 (Cq), 127.1 (CHarom), 128.2
(CHarom), 128.5 (CHarom), 128.9 (CHarom), 129.9 (CHarom), 132.6
1-(Benzyloxy)-5-(4-chlorophenyl)-2-methyl-3-(p-tolyl)-pyrrole
(6j). This compound was obtained from 4j (0.18 g, 0.45 mmol)
according to the general procedure. The subsequent chromatographic
purification (Et2O/pentane, 1:20) gave 0.11 g (0.29 mmol, 64%) of 6j
̃
(CHarom), 133.3 (Cq), 133.6 (CHarom), 134.5 (Cq). IR (neat) ν: 3063
(w), 3032 (W), 2955 (W), 2926 (W), 2855 (W), 1595 (W), 1558
(W), 1454 (W), 1377 (W), 1213 (W), 1161 (W), 1119 (W), 1084
(W), 1026 (W), 959 (W), 907 (W), 849 (W), 799 (W), 750 (m),716
(W), 694 (m), 637 (m), 611 (m), 511 (w), 501 (m), 492 (m), 476
(M). HRMS (ESI): Calcd. for C22H24NOBrNa 420.0939; found
420.0935. Anal. Calcd for C22H24NOBr: C, 66.33; H, 6.07; N, 3.52.
Found: C, 67.07; H, 6.05; N, 3.46.
1
as white solid (mp 123−124 °C). H NMR (300 MHz, C6D6): δ
(ppm) 2.29 (s, 3H, CH3), 2.34 (s, 3H, CH3), 4.49 (s, 2H, OCH2Ph),
6.56 (s, 1H, CHpyrrole), 7.08−7.14 (m, 5H, CHarom), 7.26−7.29 (m, 5H,
CHarom), 7.55 (d, 2H, J = 8.0 Hz, CHarom), 7.67 (d, 2H, J = 8.0 Hz,
CHarom). 13C NMR (75 MHz, C6D6): δ (ppm) 10.0 (CH3), 21.2
(CH3), 80.4 (OCH2Ph), 104.4 (CHpyrrole), 118.7 (Cq), 123.9 (Cq),
126.2 (Cq), 127.8 (CHarom), 127.9 (CHarom), 128.7 (CHarom), 129.0
(CHarom), 129.2 (CHarom), 129.6 (CHarom), 129.9 (CHarom), 130.5
1-(Benzyloxy)-5-(2-bromophenyl)-3-isopropyl-2-methyl-pyrrole
(6g). This compound was obtained from 4g (0.16 g, 0.4 mmol)
according to the general procedure. The subsequent chromatographic
purification (Et2O/pentane, 1:20) gave 0.045 g (0.14 mmol, 30%) of
̃
(Cq), 132.2 (Cq), 133.9 (Cq), 134.3 (Cq), 135.2 (Cq). IR (neat) ν:
3073 (W), 3032 (W), 2920 (W), 2887 (W), 1616 (W), 1597 (W),
1585 (W), 1562 (W), 1524 (W), 1499 (S), 1476 (M), 1456 (M), 1429
(M), 1408 (M), 1381 (M), 1238 (M), 1213 (M), 1180 (M), 1148
(M), 1105 (M), 1090 (M), 1028 (M), 1011 (M), 991 (M), 978 (M),
951 (M), 914 (M), 849 (M), 833 (S), 824 (S), 781 (VS), 772 (S), 750
(S), 737 (VS), 698 (S), 677 (M), 642 (M), 613 (M), 600 (M). HRMS
(ESI): calcd for C25H22NOClNa 410.1288; found 410.1284. Anal.
Calcd for C25H22NOCl: C, 77.41; H, 5.72; N, 3.61. Found: C, 77.46;
H, 5.84; N, 3.35.
1
6g as oil. H NMR (300 MHz, C6D6): δ (ppm) 1.37 (d, 6H, J = 6.9
Hz, CH(CH3)2), 2.10 (s, 3H, CH3), 2.90 (hept, 1H, J = 6.9 Hz,
CH(CH3)2), 4.49 (s, 2H, OCH2Ph), 6.54 (s, 1H, CHpyrrole), 6.80 (ddd,
1H, J = 8.0, 7.4, 1.7 Hz, CHarom), 6.98−7.03 (m, 3H, CHarom), 7.07−
7.11 (m, 3H, CHarom), 7.65 (ddd, 2H, J = 7.9, 4.0, 1.4 Hz, CHarom). 13
C
NMR (75 MHz, C6D6): δ (ppm) 8.7 (CH3), 24.2 (CH3), 26.0
(CH(CH3)2), 80.7 (CH2OPh), 104.9 (CHpyrrole), 121.2 (Cq), 122.3
(Cq), 123.7 (Cq), 124.4 (Cq), 127.1 (CHarom), 128.2 (CHarom), 128.5
(CHarom), 128.9 (CHarom), 129.9 (CHarom), 132.6 (CHarom), 133.4
2,3-Dimethyl-5-phenyl-pyrrol-1-methylphenylamine (6k). This
compound was obtained from 4k (0.12 g, 0.41 mmol) according to
the general procedure. The subsequent chromatographic purification
(Et2O/pentane, 1:10) gave 0.06 g (0.22 mmol, 54%) of 6k as a white
̃
(Cq), 133.6 (CHarom), 134.5 (Cq). IR (neat) ν: 3059 (W), 3030 (W),
2957 (M), 2922 (W), 2866 (W), 1589 (M), 1508 (M), 1456 (S), 1381
(M), 1211 (M), 1161 (M), 1024 (M), 957 (M), 901 (S), 802 (M),
750 (VS), 731 (M), 700 (M), 683 (M), 637 (M), 610 (M). HRMS
(ESI): calcd for C21H22NOBrH 386.0943; found 386.0938.
1
solid (mp 77−78 °C). H NMR (300 MHz, C6D6): δ (ppm) 1.87 (s,
3H, CH3), 2.16 (s, 3H, CH3), 2.88 (s, 3H, NCH3), 6.43 (s, 1H,
CHpyrrole), 6.51−6.54 (m, 2H, CHarom), 6.79−6.85 (m, 1H, CHarom),
7.04−7.09 (m, 2H, CHarom), 7.16−7.21 (m, 3H, CHarom), 7.63−7.67
(m, 2H, CHarom). 13C NMR (75 MHz, C6D6): δ (ppm) 9.4 (CH3),
11.6 (CH3), 39.6 (NCH3), 108.5 (CHpyrrole), 111.6 (CHarom), 114.6
(Cq), 119.0 (CHarom), 126.4 (CHarom), 126.6 (Cq), 127.0 (CHarom),
128.7 (CHarom), 129.8 (CHarom), 131.4 (Cq), 133.0 (Cq), 149.4 (Cq).
1-(Benzyloxy)-5-(2-bromophenyl)-2-methyl-3-phenyl-pyrrole
(6h). This compound was obtained from 4h (0.24 g, 0.55 mmol)
according to the general procedure. The subsequent chromatographic
purification (Et2O/pentane, 1:20) gave 0.19 g (0.45 mmol, 83%) of
1
6h. H NMR (300 MHz, C6D6): δ (ppm) 2.27 (s, 3H, CH3), 4.50 (s,
2H, OCH2Ph), 6.80 (s, 1H, CHpyrrole), 6.80−6.86 (m, 1H, CHarom),
6.98−7.05 (m, 3H, CHarom), 7.07−7.11 (m, 3H, CHarom), 7.20−7.26
(m, 1H, CHarom), 7.40 (t, 2H, J = 7.6 Hz, CHarom), 7.62−7.67 (m, 4H,
CHarom). 13C NMR (75 MHz, C6D6): δ (ppm) 10.4 (CH3), 80.9
(OCH2Ph), 107.1 (CHpyrrole), 117.6 (Cq), 123.0 (Cq), 124.0 (Cq),
125.7 (CHarom), 127.1 (CHarom), 128.0 (CHarom), 128.6 (CHarom),
128.7 (CHarom), 128.8 (CHarom), 129.1 (CHarom), 129.9 (CHarom),
132.7 (CHarom), 132.8 (Cq), 133.6 (CHarom), 134.1 (Cq), 137.3 (Cq).
̃
IR (neat) ν: 3014 (W), 2898 (W), 2869 (W), 1609 (M), 1526 (M),
1493 (S), 1477 (W), 1293 (W), 1264 (W), 1190 (W), 1164 (W),
1103 (W), 1022 (W), 989 (W), 874 (W), 869 (W), 820 (W), 804 (S),
756 (S), 692 (M), 664 (W), 644 (W). HRMS (ESI): calcd for
C19H20N2Na 299.1524; found 299.1519.
X-ray Crystal Structure Analysis of 6k. Formula C19H20N2, MW =
276.37, colorless crystal 0.30 × 0.13 × 0.07 mm3, a = 18.0934(3) Å, b
= 8.1573(2) Å, c = 21.2642(4) Å, α = 90.000, β = 99.461(2), γ =
90.000, V = 3095.76(11) Å3, ρcalc = 1.186 g cm−3, μ = 0.07 mm−1,
empirical absorption correction (0.979 ≤ T ≤ 0.995), Z = 8,
monoclinic, space group C2/c (No. 15), λ = 0.71073 Å, T = 223(2) K,
ω and j scans, 11067 reflections collected (( h, k, l), [(sin θ)/λ] =
0.59 Å−1, 2683 independent (Rint = 0.045 and 2291 observed
reflections [I > 2σ(I)], 193 refined parameters, R = 0.052, Rw2 = 0.138,
max (min) residual electron density 0.24 (−0.19) e Å−3, hydrogen
atoms calculated and refined as riding atoms.
̃
IR (neat) ν: 3032 (W), 2943 (W), 2882 (W), 1603 (S), 1560 (W),
1520 (W), 1491 (S), 1454 (S), 1379 (W), 1364 (W), 1258 (W), 1229
(W), 1213 (W), 1173 (W), 1152 (W), 1119 (W), 1070 (W), 1045
(W), 1026 (S), 984 (W), 951 (M), 907 (M), 849 (W), 804 (W), 758
(VS), 748 (VS), 739 (VS), 719 (W), 694 (VS), 683 (W), 629 (W),
611 (W), 542 (W), 530 (W), 519 (W), 500 (W). HRMS (ESI): calcd
for C24H20NOBrNa 440.0626; found 440.0611. Anal. Calcd For
C24H20NOBr: C, 68.91; H, 4.82; N, 3.35. Found: C, 68.80; H, 5.06; N,
3.32.
1877
dx.doi.org/10.1021/jo202477h | J. Org. Chem. 2012, 77, 1868−1879

The Journal of Organic Chemistry
Article
2,3-Dimethyl-5-(p-tolyl)-pyrrol-1-methylphenylamine (6l). This
compound was obtained from 4l (0.2 g, 0.65 mmol) according to
the general procedure. The subsequent chromatographic purification
(Et2O/pentane, 1:20) gave 0.11 g (0.43 mmol, 67%) of 6l as a yellow
ASSOCIATED CONTENT
* Supporting Information
Spectral characteristics of the synthesized compounds; H and
13C spectra for the new compounds; Cartesian coordinates and
SCS-MP2/6-311G(d,p)//B3LYP/6-311G(d,p)+ZPE energies
for the calculated structures and thermal ellipsoid plots for
the crystal structure (50% ellipsoid probability). This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
1
1
solid (mp 82−84 °C). H NMR (300 MHz, C6D6): δ (ppm) 1.49 (s,
3H, CH3), 1.75 (s, 3H, CH3), 1.78 (s, 3H, CH3), 2.51 (s, 3H, CH3),
6.02 (s, 1H, CHpyrrole), 6.12−6.15 (m, 2H, CHarom), 6.40−6.44 (m, 1H,
CHarom), 6.59 (d, 2H, J = 8.0 Hz, CHarom), 6.76−6.82 (m, 2H,
CHarom), 7.16 (d, 2H, J = 8.0 Hz, CHarom). 13C NMR (75 MHz,
C6D6): δ (ppm) 8.0 (CH3), 10.3 (CH3), 19.6 (CH3), 38.2 (N-CH3),
106.6 (CHpyrrole), 110.7 (CHarom), 113.0 (Cq), 117.6 (CHarom), 124.8
(Cq), 125.7 (CHarom), 128.0 (CHarom), 128.3 (Cq), 128.9 (Cq), 130.2
AUTHOR INFORMATION
Corresponding Author
*E-mail: wurthwe@uni-muenster.de.
■
(Cq), 134.4 (Cq), 148.1 (Cq). IR (neat) ν
̃
: 3024 (W), 2918 (W), 2860
(W), 1599 (M), 1526 (M), 1499 (S), 1477 (W), 1294 (W), 1254 (W),
1190 (W), 1155 (W), 1113 (W), 1032 (W), 989 (W), 874 (W), 839
(W), 820 (W), 800 (S), 746 (S), 692 (M), 656 (W), 642 (W), 583
(W), 546 (W). HRMS (ESI): calcd for C20H22N2Na 313.1681; found
313.1675. Anal. Calcd for C20H22N2: C, 82.72; H, 7.64; N, 9.65.
Found: C, 82.27; H, 7.86; N, 9.35
ACKNOWLEDGMENTS
This work was supported by the NRW Graduate School of
■
Chemistry Munster, the Deutsche Forschungsgemeinschaft
̈
(DFG, Bad Godesberg) and the Fonds der Chemischen
Industrie (Frankfurt). Dedicated to Prof. Dr. Herbert Mayr on
the occasion of his 65th birthday.
1-(3-Methyl-2,5-diphenyl-pyrrol-1-yl)indoline (6m). This com-
pound was obtained from 4m (0.13 g, 0.35 mmol) according to the
general procedure. The subsequent chromatographic purification
(Et2O/pentane, 1:20) gave 0.04 g (0.12 mmol, 33%) of 6m as a
1
light yellow oil. H NMR (300 MHz, C6D6): δ (ppm) 2.28 (s, 3H,
REFERENCES
■
CH3), 2.34−2.48 (m, 2H, NCH2CH2), 3.35−3.50 (m, 2H,
NCH2CH2), 6.52 (s, 1H, CHpyrrole), 6.66 (d, 1H, J = 7.8 Hz, CHarom),
6.73−6.78 (m, 1H, CHarom), 6.84 (d, 1H, J = 7.8 Hz, CHarom), 7.03−
7.10 (m, 3H, CHarom), 7.10−7.13 (m, 2H, CHarom), 7.18−7.23 (m, 2H,
CHarom), 7.37−7.40 (m, 2H, CHarom), 7.70−7.73 (m, 2H, CHarom).13C
NMR (75 MHz, C6D6): δ (ppm) 12.3 (CH3), 27.4 (NCH2CH2), 53.9
(NCH2CH2), 108.6 (CHpyrrole), 109.9 (Cq), 117.2 (CHarom), 119.8
(CHarom), 125.1 (CHarom), 126.3, 126.9 (CHarom), 127.3 (CHarom),
127.8 (CHarom), 128.1 (CHarom), 128.2 (CHarom), 128.6 (CHarom),
131.1(CHarom), 132.5 (Cq), 132.7(Cq), 133.2(Cq), 134.6(Cq),
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̃
152.6(Cq). IR (neat) ν: 3051 (M), 2928 (M), 2870 (M), 1601
(VS), 1489 (VS), 1468 (M), 1458 (M), 1443 (M), 1327 (M), 1271
(S), 1233 (M), 1171 (M), 1097 (M), 1074 (M), 916 (M), 812 (M),
793 (M), 748 (VS), 729 (M), 694 (VS), 675 (M), 642 (M), 619 (M),
611 (M), 513 (S). HRMS (ESI): calcd for C25H22N2H 351.1861;
found 351.1856.
(2E,3E)-5-(1-(Benzyloxy)-4,5-dimethyl-2-phenyl-pyrrol-3-yl)-3-
methyl-5-phenyl-pent-3-en-2-one O-Benzyl Oxime (7). This com-
pound was obtained from alcohol 4a according to the general
procedure for the cyclization. To a clean dry Schlenk flask was
transferred 40 mL of dry CH2Cl2. This was cooled to −10 °C, and
then CF3CO2H (0.15 mL, 2 mmol) was added. To this solution
alcohol 4a (0.295 g, 1 mmol) was added dropwise as a solution in dry
CH2Cl2. The reaction was stirred for 1 h and then quenched with satd.
NaHCO3 solution. Then the phases were separated, and the organic
phase was washed twice with H2O, dried with MgSO4, and
concentrated in vacuo. The product was purified using column
chromatography (Et2O/pentane 1:10) to give 0.185 g (67%) of 7 as a
colorless oil. 1H NMR (300 MHz, C6D6): δ (ppm) 1.90 (s, 3H, CH3),
1.99 (s, 3H, CH3), 2.03 (s, 3H, CH3), 2.10 (s, 3H, CH3), 4.49 (s, 2H,
OCH2Ph), 5.22 (s, 2H, OCH2Ph), 5.52 (d, 1H, J = 9.3 Hz, CH), 6.56
(dq, 1H, J = 9.3, 1.4 Hz, CH), 6.95−6.98 (m, 2H, CHarom), 7.06−7.12
(m, 5H, CHarom), 7.15−7.22 (m, 5H, CHarom), 7.31 (t, 2H, J = 7.5 Hz,
CHarom), 7.38 (d, 2H, J = 6.8 Hz, CHarom), 7.51 (d, 2H, J = 8.0 Hz,
CHarom), 7.63 (d, 2H, J = 6.9 Hz, CHarom). 13C NMR (75 MHz,
C6D6): δ (ppm) 8.5 (CH3), 10.5 (CH3), 10.6 (CH3), 12.6 (CH3), 40.7
(CH), 76.1 (OCH2Ph), 79.8 (OCH2Ph), 109.4 (CHarom), 117.3 (Cq),
122.5 (Cq), 125.5 (Cq), 126.0 (CHarom), 126.8 (CHarom), 127.5
(CHarom), 127.8 (CHarom), 128.2 (CHarom), 128.3 (CHarom), 128.4
(CHarom), 128.7 (CHarom), 129.6 (CHarom), 130.0 (CHarom), 134.3
(CHarom), 133.4 (Cq), 134.19 (Cq), 134.22 (Cq), 138.58 (Cq), 144.6
̀ ́
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(e) Enders, D.; Maaßen, R.; Han, S.-H. Liebigs Ann. 1996, 1565−1574.
̃
(Cq), 156.4 (Cq). IR (neat) ν: 3065 (W), 3028 (W), 2926 (W), 2862
(M), 1692 (M), 1603 (M), 1530 (M), 1447 (M), 1373 (M), 1329
(M), 1209 (M), 1016 (M), 980 (S), 953 (M), 905 (M), 883 (S), 766
(M), 750 (VS), 716 (M), 698 (VS), 608 (M). HRMS (ESI): calcd for
C38H38N2O2Na 577.2831; found 577.2837.
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̈
1878
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The Journal of Organic Chemistry
Article
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(16) All computations in this study have been performed using the
Gaussian 03 suite of programs.17 The Becke three-parameter exchange
functional and the correlation functional of Lee, Yang, and Parr
(B3LYP) with the 6-311G(d,p) basis set were used to compute the
geometries and the normal mode vibration frequencies of the starting
cation, the corresponding transition structure, and the product. For
single-point energy calculations on DFT-optimized geometries the
SCS-MP2 method was used.18 The transition structures were localized
starting with AM1 reaction pathway calculations using the MOPAC
2007 program.19 The transition structures were further optimized at
the DFT level with the Gaussian 03 package of programs using the
option “mndofc” (opt) (ts, noeigentest, mndofc)), applying the
B3LYP/6-311G(d,p) basis set. In order to verify the character of the
stationary points, they were subjected to frequency analyses. In the
discussion, E (0 K) energies are used, which contain zero-point
corrections. The vibration related to the imaginary frequency
corresponds to the nuclear motion along the reaction coordinate
under study. Intrinsic reaction coordinate (IRC) calculations were
performed in order to unambiguously connect transition structure
with reactant and product. Bond orders and atomic charges were
calculated with the natural bond orbital (NBO) method as
implemented in the Gaussian 03 program.
(17) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A.; Vreven, T., Jr.;
Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.;
Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.;
Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.;
Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao,
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1879
dx.doi.org/10.1021/jo202477h | J. Org. Chem. 2012, 77, 1868−1879