Synthesis of 1,2,3-Substituted Pyrroles from Propargylamines via a One-Pot Tandem Enyne Cross Metathesis-Cyclization Reaction

Article abstract of DOI:10.1021/acs.joc.5b00222

Enyne cross metathesis of propargylamines with ethyl vinyl ether enables the one-pot synthesis of substituted pyrroles. A series of substituted pyrroles, bearing alkyl, aryl, and heteroaryl substituents, has been synthesized in good yields under microwave irradiation. The reactions are rapid and procedurally simple and also represent a facile entry to the synthetically challenging 1,2,3-substituted pyrroles. The value of the methodology is further corroborated by the conversion of pyrroles into 3-methyl-pyrrolines and the derivatization of the 3-methyl-substituent arising from the metathesis reaction.

Full text of DOI:10.1021/acs.joc.5b00222

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Note
Synthesis of 1,2,3-substituted pyrroles from propargylamines via
a one-pot tandem enyne cross metathesis – cyclization reaction
Helene Chachignon, Nicolo Scalacci, Elena Petricci, and Daniele Castagnolo
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b00222 • Publication Date (Web): 21 Apr 2015
Downloaded from http://pubs.acs.org on April 27, 2015
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Synthesis of 1,2,3-substituted pyrroles from propargylamines via a one-pot
tandem enyne cross metathesis – cyclization reaction.
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Helene Chachignon,§,≠ Nicolò Scalacci,§,≠ Elena Petricci¥ and Daniele Castagnolo§,*
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§Department of Applied Sciences, Northumbria University Newcastle, Ellison Building, Ellison Place, NE1 8ST
¥
Newcastle upon Tyne, United Kingdom. Dipartimento di Biotecnologie, Chimica e Farmacia, Via A. Moro 2,
53100 Siena, Italy.≠These authors equally contributed to this work.
Corresponding Author: daniele.castagnolo@northumbria.ac.uk
ABSTRACT:
Enyne cross metathesis of propargylamines with ethylꢀvinyl ether enables the oneꢀpot
synthesis of substituted pyrroles. A series of substituted pyrroles, bearing alkyl, aryl and
heteroaryl substituents, has been synthesised in good yields under microwave irradiation. The
reactions are rapid and procedurally simple and also represent a facile entry to the
synthetically challenging 1,2,3ꢀsubstituted pyrroles. The value of the methodology is further
corroborated by the conversion of pyrroles into 3ꢀmethylꢀpyrrolines and the derivatization of
the 3ꢀmethylꢀsubstituent arising from the metathesis reaction.
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The occurrence of the pyrrole nucleus in many natural and synthetic biologically active
compounds represents an incentive toward the development of new synthetic methodologies
towards this important heterocycle.1 Metathesis reactions have been established as a powerful
and effective method for the construction of many functionalized heterocycles from acyclic
unsaturated precursors.1b Pioneering approaches to the synthesis of substituted pyrroles
through ring closing metathesis (RCM) were reported by Donohoe2 and Rutjes.3 These works
are based on the olefin RCM synthesis of 3ꢀpyrrolines starting from appropriate allylamines,
followed by an elimination step catalysed by acids. An evolution of this approach has been
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5b
the development of oneꢀpot RCMꢀaromatization sequences using RuCl3,4Pd/C,5a FeCl3 or
tBuOOH6 to promote the dehydrogenative step. More recently, Donohoe7 and Grela8
described an olefin crossꢀmetathesis (CM) approach for the synthesis of pyrroles. The alkyneꢀ
alkene (enyne) metathesis reaction offers advantages over the olefin version in terms of atom
economy and it has found large application in the synthesis of heterocyclic compounds as
well.9ꢀ10 However, to the best of our knowledge only one paper by Stevens and coworkers11
describes the synthesis of pyrroles via a ringꢀclosing enyne metahesisꢀaromatization
sequence, whilst no examples to access pyrroles via the enyne CM have been reported so far.
Herein, we describe the first approach to substituted pyrroles through a oneꢀpot tandem enyne
CM cyclization reaction starting from appropriate propargylamines and the cheap ethyl vinyl
ether (EVE) (Figure 1). In our early work, we demonstrated that EVE can be used as the
olefin synthetic equivalent of the acetaldehyde in enyne CM reactions, leading to the
formation of crotonaldehydes when reacted with terminal alkynes in the presence of the weak
Lewis acid CuSO4.12 Herein, we demonstrate that an analogous strategy is applicable to the
synthesis of pyrroles when propargylamines are used as substrates. Moreover, our CMꢀ
cyclization protocol offers an easy approach to the synthetically challenging pyrroles 3
unsubstituted at positions C4 and C5. Only few examples for the synthesis of 4,5ꢀ
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unsubstituted pyrroles have been reported so far, most of them relying on multistep synthetic
sequences.13
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Figure 1. Examples of pyrrole syntheses and the oneꢀpot tandem enyne cross metathesisꢀ
cyclization reaction
Our initial studies focused on the identification of the best reaction conditions (Table 1). The
Bocꢀprotected propargyl amine 4a was first reacted with EVE in the presence of
Grubbs’catalyst GꢀII under microwave irradiation according to our previous method.12 When
the reaction was carried out at 80 °C in an aqueous solution the desired pyrrole 6a was
obtained in 25ꢀ29% yield (entries 1ꢀ2), while a slightly higher amount (36%, entry 3) was
isolated when the reaction was run in degassed toluene. The use of a higher catalysts loading
(entry 2) did not lead to any improvement of the yield. Increasing the temperature to 120 °C
and the reaction time to 30 min proved to be beneficial and the yield rose up to 56% (entry 4).
When the reaction was performed under the same conditions and without CuSO4 the pyrrole
6a was not detected and the corresponding diene 5 was recovered in 41% yield (entry 5).On
the other hand the use of a stoichiometric amount of CuSO4 led to 6a in only 18% yield
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(entry 6). It is noteworthy that heating the diene intermediate 5 in refluxing toluene led to
pyrrole 6a in 24h, while in the presence of CuSO4 the reaction was completed in 6h. We
hypothesise that CuSO4 plays a crucial role in increasing the rate of the cyclization reaction
presumably by coordinating the ethoxy group.14
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Table 1.Optimization of the reaction conditions
GꢀII
T°C/
Time
Yield
%
Entry Solvent
CuSO4
2 eq.
2 eq.
2 eq.
2 eq.
ꢀ
a
mol%
H2O/
tBuOH
80°C/
20min
1
5
10
5
29%
25%
36%
56%
0%b
H2O/
tBuOH
80°C/
20min
2
80°C/
30min
3
4
5
6
7
8
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
120°C/
30min
5
120°C/
30min
5
120°C/
30min
5
1 eq.
2 eq.
18%
55%
56%
120°C/
30min
10
120°C/
30min
c
5
-
b
c
aIsolated yields. 41% diene 5 isolated. 2eq of Cu(OTf)2
were used.
No significant differences were observed when the reaction was carried out with 5mol% or
10mol% catalysts loading (entries 4 and 7). Finally, the use of a different copper source, the
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stronger Lewis acid Cu(OTf)2, did not lead to any improvement in the yield of the reaction
(entry 8). The influence of different amine group substituents on the outcome of the reaction
was then explored. A set of propargylamines 4b-e was synthesised according to Table 2.The
treatment of the tosyl derivative 4b with 10mol% of GꢀII led to desired 6b in 53% yield,
while a lower amount of 6b (25%) was recovered when 5mol% of catalyst was used (entry
1). The benzoyl compound 4d afforded the pyrrole 6d in moderate yield (entry 3). On the
other hand, the propargylaniline 4c afforded the phenylpyrrole 6c in good yield (entry 2),
while the benzylꢀderivative 4e was recovered unreacted from the reaction mixture and no
pyrrole 6e was observed (entry 4).
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Table 2. Synthesis of pyrroles 6b-e
Yield
%
Entry
Substrate
Pyrrole
Additive
a
1
53%
54%
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2
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3
4
39%
NOb
TsOH.H2O
(1.2 eq )
aIsolated yields were reported. b Product 6e was not observed
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It is reported that, contrary to the electron poorer anilines and tertiary hindered amines, the
aliphatic primary and secondary amines poison the Ruꢀcatalysts thus preventing the
metathesis reactions.15 The addition of a Brønsted acid to secondary amines makes the lone
pair unable to bind the ruthenium, allowing the metathesis reaction to occur.16 Amine 4e was
treated with a stoichiometric amount of pꢀtoluensulphonic acid (PTSA) and then reacted with
EVE under standard conditions. No pyrrole was observed and a mixture of side products was
recovered. The possibility to synthesise 1,2,3ꢀtrisubstituted pyrroles starting from the
appropriate 1ꢀsubstituted propargylamines and using this tandem metathesisꢀcyclization
protocol was explored. A first batch of arylꢀpropargylacetamides 8a-e was synthesised in
high yields from the appropriate propargylic alcohols (Scheme 1, Path a).17
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Scheme 1.Synthesis of propargylamine substrates
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Hydrolysis of 8a-b followed by Bocꢀ, Bz and Tsꢀprotections led to substrates 8f-h. Propargyl
alcohol 7 was acetylated to give 9 and in turn converted into the phenyl substrate 10 through
a copper mediated amination reaction.18 (Scheme 1, Path a). A multicomponent strategy19 was
used for the synthesis of aliphatic and heteroaryl derivatives 15a-d. The appropriate
aldehydes 11a-d were refluxed in toluene in the presence of pꢀtoluensulphonamide 12, TIPSꢀ
acetylene 13 and Cu(OTf)2 affording, after silylꢀdeprotection with TBAF, the terminal
alkynes 15a-d. (Scheme 1, path b). The alkynes 8, 10 and 15 were then converted into
pyrroles 6. Results are reported in Table 3. Acetamides 8a-e were first reacted with EVE and
GꢀII leading to the desired pyrroles 6f-j in high yields (59ꢀ76%). Only pyrrole 6i bearing a diꢀ
chloroꢀphenyl group was obtained in lower yield (38%) probably due to a combination of
steric and electronic factors. The pyrroles 6l and 6m, bearing the bulky groups Boc and Bz,
were obtained in lower yields than the acetyl analogue 6g. Similarly, the tosylpyrrole 6k was
isolated in lower yield than 6f. Reactions were performed using both a 5mol% and 10mol%
Grubbs’ cat. loading. However, in the case of 1ꢀsusbtituted propargylamines a lower catalyst
loading resulted into poorer yields. On the other hand, the aliphatic and the furyl Nꢀtosylꢀ
propargylamides 15a-d were converted into pyrroles 6o-r in excellent yields with the only
exception of the bulky cyclohexyl derivative 6p. Finally, the treatment of the substrate 10
with EVE and Grubbs’ cat. did not lead to the desired pyrrole 6n in significant amount.
Traces of 6n were detected only by GCꢀMS analysis of the crude reaction mixture. Attempts
to react the propargylamines with 2ꢀmethoxypropene, a substituted EVE analogue, proved to
be unsuccessful. Methoxypropene proved to be unreactive toward CM due to its steric
hindrance and propargylamines were recovered unreacted from the reaction mixtures. The
present methodology allows the synthesis in one synthetic step of pyrroles unsubstituted on
C4ꢀC5, which could be in turn further functionalised as described in Scheme 2. As an
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example, pyrrole 6f was hydrolysed affording the disubstituted 16 which was further
functionalised at C5 by VilsmeirꢀHaack reaction leading to aldehyde 17.
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Table 3.Synthesis of 1,2,3ꢀsubstituted pyrroles
Alkyne
8a
R
R1
Ac
Ac
Ac
Ac
Ac
Ts
Pyrrole
6f
Yielda
70%
72%
76%
38%
59%
38%
50%
64%
Tracesb
76%
43%
71%
69%
C6H5
8b
4ꢀClꢀC6H5
3ꢀFꢀC6H5
2,4ꢀClꢀC6H5
4ꢀPhꢀC6H5
C6H5
6g
8c
6h
6i
8d
8e
6j
8f
6k
6l
8g
4ꢀClꢀC6H5
4ꢀClꢀC6H5
C6H5
Boc
Bz
8h
6m
6n
6o
10
C6H5
Ts
15a
15b
15c
15d
2ꢀFuryl
CycHexyl
iPr
Ts
6p
6q
6r
Ts
iBu
Ts
aIsolated yields were reported. bObserved by GCꢀMS
All the pyrroles 6 have a methyl group at C3 deriving from the diene intermediate 5 of the
enyne metathesis reaction. Attempts to derivatize the methyl group through NBSꢀmediated
bromination20 or KMnO4 oxidation21 of 6 were unsuccessful due to the presence of the
reactive CH at positions C4 and C5, leading to a complex mixture of polymeric derivatives.
Nevertheless, pyrroles can be easily converted into 3ꢀpyrrolines, compounds endowed with
pharmaceutical properties and precursors in the synthesis of natural alkaloids.22,23 The
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pyrroles 6r and 6b were treated with NaCNBH3 in TFA leading respectively to pyrrolines 18ꢀ
20 which were in turn oxidized at the methyl group with SeO2 affording the aldehydes 19 and
21 in 65ꢀ56% yield (over twoꢀstep) respectively (Scheme 2). The aldehyde 21 can be
converted in a few steps into the alkaloid 22.22
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Scheme 2. Derivatization of pyrroles and synthesis of 3ꢀmethylꢀpyrrolines
In conclusion, a new approach for the synthesis of pyrroles based on an enyne cross
metathesisꢀcyclization cascade has been described. The present methodology represents the
first example of oneꢀpot synthesis of pyrroles via enyne crossꢀmetathesis reaction and it
constitutes a facile approach to the synthetically challenging 1,2,3ꢀsubstituted pyrroles.
Finally, the versatility of the method was shown through the synthesis of pyrroline analogues
as well as the derivatization of the methyl substituent at C3.
EXPERIMENTAL SECTION
General Methods. Nuclear Magnetic Resonance (NMR) spectra were recorded on a 400
1
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MHz spectrometer. H and C spectra were referenced relative to the solvent residual peaks
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and chemical shifts (δ) reported in ppm downfield of trimethylsilane (CDCl3 δ H: 7.26 ppm, δ
C: 77.0 ppm). Coupling constants (J) are reported in Hertz and rounded to 0.5 Hz. Splitting
patterns are abbreviated as follows: singlet (s), doublet (d), triplet (t), quartet (q), multiplet
(m), broad (br) or some combination of these. Positive and negative electrospray ionisation
spectrometry (ESIꢀMS) were conducted by direct injection. GCꢀMS analyses were performed
using aliquots of the compound dissolved in DCM (5 ꢁL) and injected onto a DBꢀ5MS (30 m
× 0.25 mm i.d. × 0.15 ꢁm film thickness) column at 250 °C. The oven temperature was set at
40 °C for 4 min and raised at 15 °C/min to 135 °C, then at 5 °C/min to 250 °C and held at
250 °C for 5 minutes. The carrier gas flow was 1.0 mL/min. The mass spectrometer was
operated in the full scan mode. The transfer line and ion source temperatures were 250 °C
and 200 °C, respectively. A LTQ Orbitrap XL instrument was used for the HRMS
measurements. Thin layer chromatography (TLC) was performed using commercially
available preꢀcoated plates and visualized with UV light at 254 nm; K2MnO4 or Ninhydrin
dips were used to reveal the products. Flash column chromatography was carried out using
Fluorochem Davisil 40ꢀ63u 60Å. All reactions were conducted under a nitrogen atmosphere
in ovenꢀdried glassware unless stated otherwise. Tetrahydrofuran was distilled under nitrogen
from sodium using a benzophenone indicator. Dichloromethane, toluene and diethyl ether
were obtained by distillation over calcium hydride under a nitrogen atmosphere. Petrol refers
to the fraction of light petroleum ether boiling between 40 and 65 °C. All other solvents and
commercially available reagents were used as received. All chemicals and solvents were used
as supplied, unless noted otherwise.
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Microwave irradiation experiments. Microwave irradiations were conducted using a CEM
Discover Synthesis Unit. The machine consists of a continuous focused microwave power
delivery system with operator, selectable power output from 0 to 300 W. The temperature of
the contents of the vessels was monitored using a calibrated infrared temperature control
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mounted under the reaction vessel. All the experiments were performed using a stirring
option whereby the contents of the vessel are stirred by means of rotating magnetic plate
located below the floor of the microwave cavity and a Teflon, coated magnetic stirring bar in
the vessel.
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Synthesis of monosubstituted propargylic amines.
tꢀButylꢀpropꢀ2ꢀynylcarbamate 4a. Lit24 A solution of (Boc)2O (436 mg, 2.00 mmol, 1.1
equiv) in DCM (5 mL) was added dropwise to a solution of propargylamine (100 mg, 1.81
mmol, 1 equiv) in DCM (5 mL), at 0 °C. The reaction mixture was then allowed to stir at
room temperature for 30 min. The solution was concentrated under reduced pressure. The
product (275 mg, 1.77 mmol) was obtained as a yellow oil.
1
Yield: 98%. H NMR (400 MHz CDCl3) δ 4.78 (bs, 1H), 3.88 (s, 2H), 2.18 (t, J = 2.8 Hz,
1H), 1.42 (s, 9H) ppm. LRMS m/z (ES+) m/z: 156 [M+H]+.
4ꢀMethylꢀNꢀ2ꢀpropynꢀ1ꢀylꢀbenzenesulfonamide 4b. Lit25. Propargyl amine (0.17 mL, 2.69
mmol, 1 equiv), and triethylamine (0.45 mL, 3.23 mmol, 1.2 equiv) were added to a solution
of pꢀtoluenesulfonyl chloride (564 mg, 2.96 mmol, 1.1 equiv) in anhydrous DCM at 0 °C,
under N2 atmosphere. The reaction mixture was allowed to stir at room temperature for 6h,
and then it was quenched with a saturated NH4Cl solution. The aqueous layer was extracted
with DCM. The combined organic layers were dried over Na2SO4 and concentrated under
reduced pressure, giving the pure product (539 mg, 2.57 mmol) as yellow oil.
Yield: 96%. 1H NMR (400 MHz CDCl3) δ 7.69 (d, J = 8.2 Hz, 2H), 7.19 (d, J = 8.4 Hz, 2H),
3.69 (d, J = 2.8 Hz, 2H), 2.31 (s, 3H), 2.03 (t, J = 2.2 Hz, H) ppm.
Nꢀ2ꢀPropynꢀ1ꢀylꢀbenzenamine 4c. Lit.26 Aniline (0.46 mL, 5 mmol, 5 equiv) was added to a
solution of propargyl bromide (0.11 mL, 1 mmol, 1 equiv) in ethanol. The reaction mixture
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was stirred at room temperature for 2 days, and then concentrated under reduced pressure.
The crude product was purified by chromatography on silica gel, using hexane/EtOAc (9:1)
as eluent. The pure product (84 mg, 0.64 mmol) was obtained as a yellow oil.
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Yield: 64%. 1H NMR (400 MHz CDCl3) δ 7.21 (t, J = 7.6 Hz, 2H), 6.78 (t, J = 7.2 Hz, 1H),
6.68 (d, J = 7.6 Hz, 2H), 3.93 (s, 2H), 3.96 (bs, 1H), 2.20 (t, J = 2.4 Hz, 1H) ppm.
NꢀPropꢀ2ꢀynylbenzamide 4d.Lit.27 Benzoyl chloride (257 mg, 1.83 mmol, 1.01 equiv) and
triethylamine (0.30 mL, 2.21 mmol, 1.2 equiv) were added to a solution of propargylamine
(100 mg, 1.82 mmol, 1 equiv) in DCM (20 mL) at 0 °C. The reaction mixture was allowed to
stir at room temperature for 1 h, then it was quenched with 20 mL of 1M HCl solution, and
extracted with DCM. The combined organic layers were washed with brine, dried over
Na2SO4 and concentrated under reduced pressure. The crude mixture was purified by
chromatography on silica gel, using hexane/EtOAc (4:1) as eluent, affording 254 mg (1.60
mmol) of 4d.
Yield: 88%. 1H NMR (400 MHz CDCl3) δ 7.77 (d, J = 7.6 Hz, 2H), 7.48 (t, J = 7.2 Hz, 2H),
7.39 (t, J = 7.6 Hz, 2H), 6.64 (bs, 1H), 4.22 (dd, J = 2.8, 5.6 Hz, 2H), 2.25 (t, J = 2.8Hz, 1H)
ppm.
Nꢀbenzylꢀpropargylamine 4e. Lit.28 Benzylamine (1.1 mL, 10.08 mmol, 6 equiv) was added
to a solution of propargyl bromide (100 mg, 1.68 mmol, 1 equiv) in 1 mL of DCM. The
reaction mixture was stirred at room temperature for 2 days, and then concentrated under
reduced pressure. The crude product was purified by chromatography on silica gel, using
hexane/EtOAc (9:1) as eluent. Compound 4e (136 mg, 0.94 mmol) was obtained as a tan oil.
Yield: 56%. 1H NMR (400 MHz CDCl3) δ 7.35ꢀ7.25 (m, 5H), 3.85 (s, 2H), 3.40 (d, 2H), 2.25
(s, 1H) ppm.
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Synthesis of propargylamides 8a-e.General procedure. A solution of 96% H2SO4 (490 mg, 5
mmol) in dry acetonitrile (2 mL) was added to a stirred mixture of the appropriate
propargylalcohol17a (1 mmol) and anhydrous Na2SO4 (142 mg, 1 mmol) in dry acetonitrile
(3.1 mL) at 20 °C. The mixture was allowed to reach room temperature, and stirring was
continued for the required time. The mixture was concentrated, poured on ice, and extracted
with ether and dichloromethane. The combined organic layers were dried over Na2SO4,
filtered and concentrated. Flash chromatography, using ethyl acetate/ petroleum ether (1:1) as
eluent, afforded pure propargylamides 8a-e.
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Propragylamide 8d. Yield: 76% (183 mg, 0.76 mmol). H NMR (400 MHz CDCl3) δ 7.57ꢀ
7.55 (d, 1H, J = 8.2 Hz), 7.40 (s, 1H), 7.22ꢀ7.24 (m, 1H), 6.09 (br s, 1H), 6.08 (s, 1H), 2.46
(d, 1H, J = 1.8 Hz), 1.99 (s, 3H) ppm. 13C NMR (100 MHz CDCl3) δ 168.7, 135.0, 134.2,
134.1, 130.1, 127.5, 80.5, 73.3, 42.8, 23.0 ppm. IR ν max (film)/cmꢀ1 1676, 1497. LRMS m/z
(ES+) m/z: 242 [M+H]+, 264 [M+Na]+. HRMS (ESI): calcd for C11H10Cl2NO (M + H+)
242.0139, found 242.0137.
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Propragylamide 8e.Yield: 75% (186 mg, 0.74 mmol). H NMR (400 MHz CDCl3) δ 7.57ꢀ
7.55 (m, 6H), 7.45ꢀ7.41 (m, 2H), 7.36ꢀ7.33 (m, 1H), 6.06ꢀ6.04 (d, 1H), 6.00 (br d, 1H), 2.51
(s, 1H), 2.03 (s, 3H) ppm. 13C NMR (100 MHz CDCl3) δ 168.8, 141.4, 140.5, 137.3, 128.9,
127.6, 127.2, 81.7, 73.2, 44.3, 23.3 ppm. IR ν max (film)/cmꢀ1 1674, 1486. LRMS m/z (ES+)
m/z: 250 [M+H]+, 272 [M+Na]+. HRMS (ESI): calcd for C17H16NO (M + H+) 250.1232,
found 250.1227.
Spectroscopy data of propargylamides 8a-c were identical to those previously reported.16a
Synthesis of propargylacetate 9.32 Acetic anhydride (0.19 mL, 1.96 mmol, 1.3 equiv),
triethylamine (0.42 mL, 3.02 mmol, 2 equiv), and a catalytic amount of DMAP were added to
a solution of 1ꢀphenylꢀ2ꢀpropynol (200 mg, 1.51 mmol, 1 equiv) in DCM. The reaction
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mixture was stirred at room temperature for the indicated time, and then concentrated under
reduced pressure. The crude product was purified by chromatography on silica gel, using
hexane/EtOAc (9:1) as eluent.
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Yield: 77% (201 mg, 1.15 mmol). H NMR (400 MHz CDCl3) δ 7.53 (d, J = 6.8 Hz, 2H),
7.39 (m, 3H), 6.45 (d, J = 2.4 Hz, 1H), 2.66 (d, J = 2.4 Hz, 1H), 2.10 (s, 3H) ppm. LRMS m/z
(ES+) m/z: 197 [M+Na]+.
Synthesis of 1ꢀPhenylꢀ2ꢀpropynylamine S8.17a
A
suspension of Nꢀ(1ꢀphenylꢀ2ꢀ
propynyl)acetamide (0,76 mmol, 1 equiv) and 1.2M HCl (5 mL) was heated to 90 °C for 18h.
The reaction mixture was then cooled at room temperature, quenched with 20 mL of
saturated NaHCO3 solution, and diluted with Et2O (10 mL). The aqueous layer was extracted
twice with Et2O (20 mL). The combined organic layers were washed with brine, dried over
Na2SO4 and concentrated under reduced pressure. The crude 1ꢀphenylꢀ2ꢀpropynylamine was
purified by flash column chromatography (SiO2) using 1:1 EtOAc/hexanes as the eluent to
yield the desired 1ꢀphenylꢀ2ꢀpropynylamine as an oil.
1
Yield: 72 % (71 mg, 0.54 mmol). H NMR (400 MHz CDCl3) δ 7.75 (d, J = 8.4 Hz, 2H),
7.43 (d, J = 8.4 Hz, 2H), 7.32ꢀ7.22 (m,5H), 5.30 (d, J = 4.0 Hz, 1H), 5.06 (d, J = 4.0 Hz, 1H),
2.41 (s, 3H), 2.29 (d, J = 2.4 Hz, 1H) ppm. LRMS m/z (ES+) m/z: 132 [M+H]+.
Synthesis of 4ꢀmethylꢀNꢀ(1ꢀphenylpropꢀ2ꢀynꢀ1ꢀyl)benzenesulfonamide 8f.33 1ꢀPhenylꢀ2ꢀ
propynylamine S8 (0.35 mmol, 1 equiv) was added to a round bottom flask containing
pyridine (5 mL). Then pꢀtoluenesulphonic chloride (0.62 mmol, 1.77 equiv) was added at 0
°C to the solution previously obtained. The solution was allowed to stir at 100 °C for 18h.
The reaction mixture was then quenched with 10 mL of 1M HCl solution and washed with 10
mL of DCM. Then, 20 mL of saturated NaHCO3 solution was added to the aqueous layer and
this was extracted twice with DCM. The combined organic layers were washed with brine,
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dried over Na2SO4 and concentrated under reduced pressure. The crude compound was
purified by flash column chromatography (SiO2) using 1:4 EtOAc/hexanes as the eluent to
yield the desired 8f as an oil.
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Yield: 62 % (62 mg, 0.21 mmol). H NMR (400 MHz CDCl3) δ 7.65 (d, J = 8.4 Hz, 2H),
7.25 (d, J = 8.4 Hz, 2H), 4.78 (s,1H), 4.32 (d, J = 1.6 Hz, 2H), 2.38 (s, 3H), 1.92ꢀ1.85 (m,
1H), 1,56 (s, 3H), 1.48 (d, J = 1.8 Hz, 2H), 1.01 (d, J = 6.8 Hz, 3H), 0.88 (d, J = 6.8 Hz, 3H)
ppm. 13C NMR (100 MHz CDCl3) δ 143.7, 137.3, 137.0, 129.6, 128.8, 128.6, 127.5, 127.2,
80.5, 74.8, 49.0, 21.6 ppm. LRMS m/z (ES+) m/z: 308 [M+Na]+.
Nꢀ[1ꢀ(4ꢀchlorophenyl)ꢀ2ꢀpropynꢀ1ꢀyl]ꢀ 1,1ꢀdimethylethyl ester carbamic acid 8g. A solution
of (Boc)2O (183 mg, 0.84 mmol, 1 equiv) in DCM (5 mL) was added dropwise to a solution
of propargyl amine S8 (150 mg, 0.84 mmol, 1 equiv) in DCM (5 mL) and saturated
NaHCO3 solution (5 mL), at 0 °C. The reaction mixture was then allowed to stir at room
temperature for 2h. The solution was quenched with DCM. The aqueous layer was extracted
with DCM and EtOAc. The combined organic layers were dried over MgSO4 and
concentrated under reduced pressure. The obtained product was purified by silica gel
chromatography, using hexane/EtOAc (4:1) as eluent.
1
Yield: 60 % (132 mg, 0.5 mmol). H NMR (400 MHz CDCl3) δ 7.45 (d, J = 8.8 Hz, 2H),
7.33 (d, J = 8.8 Hz, 2H), 5.64 (d, J = 7.4 Hz, 1H), 5.06 (bs, 1H), 2.51 (d, J = 2.2 Hz, 1H),
1.46 (s, 6H) ppm. 13C NMR (100 MHz CDCl3) δ 154.7, 137.4, 134.0, 128.8, 128.3, 81.6,
80.6, 73.4, 45.6, 28.3 ppm. LRMS m/z (ES+) m/z: 288 [M+Na]+. HRMS (ESI): calcd for
C14H16ClNNaO2 (M + Na+) 288.0767, found 288.0765.
Nꢀ[1ꢀ(4ꢀchlorophenyl)ꢀ2ꢀpropynꢀ1ꢀyl]ꢀbenzamide 8h.Benzoyl chloride (0.07 mL, 0.57 mmol,
1.01 equiv) and triethylamine (0.09 mL, 0.67 mmol, 1.2 equiv) were added to a solution of
propargylic amine 5 (100 mg, 0.56 mmol, 1 equiv) in DCM (20 mL) at 0 °C. The reaction
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mixture was allowed to stir at room temperature for 1 h, and then quenched with 20 mL of
1M HCl solution, and extracted with DCM and EtOAc. The combined organic layers were
washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The obtained
product was purified by chromatography on silica gel, using hexane/EtOAc (4:1) as eluent.
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Yield: 65 % (98 mg, 0.36 mmol). H NMR (400 MHz CDCl3) δ 7.79 (d, J = 7.2 Hz, 2H),
7.51 (d, J = 6.4 Hz, 3H), 7.43 (t, J = 7.8 Hz, 2H), 7.33 (d, J = 8.2 Hz, 2H), 6.72 (d, J = 8.2
Hz, 1H), 6.21 (dd, J = 2.2, 8.4 Hz, 1H), 2.55 (d, J = 2.4 Hz, 1H) ppm. 13C NMR (100 MHz
CDCl3) δ 166.4, 136.9, 134.2, 133.4, 132.1, 128.9, 128.7, 128.6, 127.2, 81.2, 73.8, 44.4 ppm.
LRMS m/z (ES+) m/z: 270 [M+H]+. HRMS (ESI): calcd for C16H13ClNO (M + H+)
270.0686, found 270.0683.
Synthesis of Nꢀphenylꢀpropargylamine 10. Lit.29 Copper iodide (25 mg, 0.13 mg, 0.5 equiv)
was added to a solution of propargylic acetate 9 (45 mg, 0.26 mmol, 1 equiv) in MeOH at 0
°C, under N2 atmosphere. The reaction mixture was allowed to stir for 10 min before the
addition of aniline (0.05 mL, 0.52 mmol, 2 equiv) and triethylamine (0.15 mL, 1.04 mmol, 4
equiv). The mixture was then stirred at 0 °C, and allowed to reach room temperature
overnight. The reaction mixture was quenched with EtOAc and ammonia solution. The
aqueous layer extracted with EtOAc. The combined organic layers were dried over MgSO4
and concentrated under reduced pressure. The crude product was purified by chromatography
on silica gel, using hexane as eluent. The pure product was obtained as a tan oil (32 mg, 0.15
mmol).
Yield: 59%. 1H NMR (400 MHz CDCl3) δ 7.61 (d, J = 7.2 Hz, 2H), 7.43ꢀ7.35 (m, 3H), 7.21
(t, J = 7.2 Hz, 2H), 6.79 (t, J = 7.6 Hz, 1H), 6.74 (d, J = 7.8 Hz, 2H), 5.29 (s, 1H), 4.06 (bs,
1H), 2.47 (d, J = 2.4 Hz, 1H) ppm. LRMS m/z (ES+) m/z: 230 [M+Na]+.
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Synthesis of silylpropargylamines 14a-d.General procedure. The appropriate aldehyde (1.1
equiv) and triisopropylsilyl acetylene (1.5 equiv) were added to a solution of pꢀ
toluenesulfonamide (200 mg, 1.17 mmol, 1 equiv), sodium sulphate (1 equiv), cesium
carbonate (0.1 equiv) and copper triflate (0.1 equiv) in anhydrous toluene under N2
atmosphere. The reaction mixture was allowed to stir at 120 °C for 48 h. The reaction
mixture was then quenched with EtOAc and washed with a saturated NaHCO3 solution. The
combined organic layers were dried over MgSO4 and concentrated under reduced pressure.
The crude product was purified by chromatography on silica gel, using hexane/EtOAc (4:1)
as eluent.
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Nꢀ[1ꢀ(2ꢀfuranyl)ꢀ3ꢀ(triisopropylsilyl)ꢀ2ꢀpropynꢀ1ꢀyl]ꢀ4ꢀmethylꢀbenzenesulfonamide
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14a.Yield: 48% (242 mg, 0.56 mmol). H NMR (400 MHz CDCl3) δ 7.77 (d, J = 8.4 Hz,
2H), 7.31 (s, 1H), 7.25 (d, J = 8.4 Hz, 2H), 6.35 (d, J = 3.2 Hz, 1H), 6.27 (t, J = 2.2 Hz, 1H),
5.41 (d, J = 9.2 Hz, 1H), 5.21 (d, J = 8.4 Hz, 1H), 2.39 (s, 3H), 0.96 (m, 18H), 0.93ꢀ0.82 (m,
3H) ppm. 13C NMR (100 MHz CDCl3) δ 150.1, 143.5, 143.2, 137.5, 129.7, 127.2, 110.4,
108.4, 101.4, 87.0, 44.1, 21.6, 18.5, 11.0 ppm. LRMS m/z (ES+) m/z: 432 [M+H]+. HRMS
+
(ESI): calcd for C23H37SSiN2O3 (M+NH4 ) 449.2294, found 449.2284.
Nꢀ[1ꢀcyclohexylꢀ3ꢀ[tris(1ꢀmethylethyl)silyl]ꢀ2ꢀpropynꢀ1ꢀyl]ꢀ4ꢀmethylꢀbenzenesulfonamide
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14b.19 Yield: 45% (235 mg, 0.52 mmol). H NMR (400 MHz CDCl3) δ 7.74 (d, J = 8.4 Hz,
2H), 7.25 (d, J =8.4 Hz, 2H), 4.55 (d, J = 9.6Hz, 1H), 3.92 (dd, J = 5.6, 9.8Hz, 1H), 2.38 (s,
3H), 1.84ꢀ1.68 (m, 5H), 1.68ꢀ1.50 (m, 4H), 1.30ꢀ0.97 (m, 2H), 0.91 (d, J = 5.0 Hz, 18H),
0.88ꢀ0.81 (m, 3H) ppm. LRMS m/z (ES+) m/z: 448 [M+H]+.
Nꢀ[1ꢀisobutylꢀ3ꢀ[tris(1ꢀmethylethyl)silyl]ꢀ2ꢀpropynꢀ1ꢀyl]ꢀ4ꢀmethylꢀbenzenesulfonamide 14c.
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Yield: 22% (105 mg, 0.25 mmol). H NMR (400 MHz CDCl3) δ 7.77 (d, J = 8.8 Hz, 2H),
7.28 (d, J = 8.8 Hz, 2H), 4.63 (d, J = 9.2 Hz, 1H), 3.95 (dd, J = 5.6, 9.6 Hz, 1H), 2.40 (s, 3H),
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2.00ꢀ1.88 (m, 1H), 1.00 (d, J = 6.8Hz, 6H), 0.92 (d, J = 5.0 Hz, 18H), 0.95ꢀ0.84 (m, 3H)
ppm. 13C NMR (100 MHz CDCl3) δ 143.4, 137.5, 129.7, 127.2, 104.0, 86.0, 52.3, 34.3, 21.5,
18.7, 18.5, 17.4, 11.0 ppm. LRMS m/z (ES+) m/z: 408 [M+H]+. HRMS (ESI): calcd for
9
+
C22H41SSiN2O2 (M+NH4 ) 425.2658, found 425.2645.
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Nꢀ[1ꢀ(3ꢀmethylbutyl)ꢀ3ꢀ[tris(1ꢀmethylethyl)silyl]ꢀ2ꢀpropynꢀ1ꢀyl]ꢀ4ꢀmethylꢀ
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benzenesulfonamide 14d. Yield: 56% (276 mg, 0.65 mmol). H NMR (400 MHz CDCl3) δ
7.77 (d, J = 8.4 Hz, 2H), 7.27 (d, J = 8.4 Hz, 2H), 4.49 (d, J = 9.6 Hz, 1H), 4.13 (q, J = 7.8
Hz, 1H), 2.40 (s, 3H), 1.96ꢀ1.83 (m, 1H), 1.60ꢀ1.44 (m, 2H), 0.93ꢀ0.79 (m, 27H) ppm. 13C
NMR (100 MHz CDCl3) δ 143.4, 137.6, 129.7, 127.2, 85.0, 46.6, 45.0, 24.8, 22.3, 22.0, 21.5,
18.5, 11.0 ppm. LRMS m/z (ES+) m/z: 422 [M+H]+.HRMS (ESI): calcd for C23H43SSiN2O2
+
(M + NH4 ) 439.2815, found 439.2804.
General procedure for the synthesis of propargylamides 15a-d. A TBAF solution 1M in THF
(1.1equiv) was added to a solution of compound 14 (0.25 mmol, 1 equiv) in THF at 0 °C. The
reaction mixture was stirred at room temperature for 1h30, then quenched with a saturated
NaHCO3 solution and extracted with EtOAc. The combined organic layers were washed with
brine, dried over MgSO4 and concentrated under reduced pressure. The crude product was
purified by chromatography on silica gel, using hexane/EtOAc (4:1) as eluent.
Nꢀ[1ꢀ(2ꢀfuranyl)ꢀ2ꢀpropynꢀ1ꢀyl]ꢀ4ꢀmethylꢀbenzenesulfonamide 15a.34 Yield: 82% (56 mg,
0.20 mmol). 1H NMR (400 MHz CDCl3) δ 7.75 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 1.2 Hz, 1H),
7.28 (d, J = 8.0 Hz, 2H), 6.33 (d, J = 3.2 Hz, 1H), 6.27 (t, J = 2.4 Hz, 1H), 5.37 (d, J = 2.4
Hz, 1H), 2.42 (s, 3H), 2.30 (d, J = 2.4 Hz, 1H) ppm. 13C NMR (100 MHz CDCl3) δ 149.0,
143.6, 143.1, 137.1, 129.4, 127.3, 110.4, 108.4, 78.3, 73.6, 43.1, 21.5 ppm. LRMS m/z (ES+)
m/z: 298 [M+Na]+.
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Nꢀ(1ꢀcyclohexylꢀ2ꢀpropynꢀ1ꢀyl)ꢀ4ꢀmethylꢀbenzenesulfonamide 15b.34 Yield: 99% (72 mg,
0.24 mmol). 1H NMR (400 MHz CDCl3) δ 7.75 (d, J = 6.8 Hz, 2H), 7.27 (d, J = 7.2 Hz, 2H),
4.69 (d, J = 7.4 Hz, 1H), 3.86 (m, 1H), 2.40 (s, 3H), 2.01 (s, 1H), 1.84ꢀ1.67 (m, 5H), 1.66ꢀ
146 (m, 4H), 1.33ꢀ0.99 (m, 2H). 13C NMR (100 MHz CDCl3) δ 143.4,132.2, 129.4, 127.3,
80.7, 73.1, 50.6, 42.8, 28.8, 25.7, 25.6, 21.5, 14.1 ppm. LRMS m/z (ES+) m/z: 314 [M+Na]+.
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Nꢀ(1ꢀisobutylꢀ2ꢀpropynꢀ1ꢀyl)ꢀ4ꢀmethylꢀbenzenesulfonamide15c.35 Yield: 95% (60 mg, 0.24
mmol). 1H NMR (400 MHz CDCl3) δ 7.78 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 7.8 Hz, 2H), 4.71
(d, J = 9.6 Hz, 1H), 3.90 (ddd, J = 2.2, 5.4, 10.0 Hz, 1H), 2.43 (s, 3H), 2.04 (d, J = 2.8 Hz,
1H), 1.91 (sex, J = 6.8 Hz, 1H), 0.98 (d, J = 6.8 Hz, 6H) ppm. 13C NMR (100 MHz CDCl3) δ
143.5, 137.2, 129.5, 127.3, 80.4, 73.1, 51.3, 33.5, 21.5, 18.5, 17.3 ppm. LRMS m/z (ES+)
m/z: 274 [M+Na]+.
Nꢀ(1ꢀmethylbutyl ꢀ2ꢀpropynꢀ1ꢀyl)ꢀ4ꢀmethylꢀbenzenesulfonamide 15d. Yield: 93% (66 mg,
0.23 mmol). 1H NMR (400 MHz CDCl3) δ 7.79 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.6Hz, 2H),
4.71 (d, J = 9.2Hz, 1H), 4.15ꢀ4.04 (m, 1H), 2.43 (s, 3H), 2.03 (d, J = 2.2 Hz, 1H), 1.89ꢀ1.77
(m, 1H), 1.53 (td, J = 7.6, 3.2 Hz, 2H), 0.89 (dd, J = 6.4, 3.0 Hz, 6H) ppm. 13C NMR (100
MHz CDCl3) δ 143.6, 137.3, 129.5, 127.5, 82.2, 72.4, 45.6, 44.0, 24.6, 22.2, 22.0, 21.6 ppm.
LRMS m/z (ES+) m/z: 288 [M+Na]+. HRMS (ESI): calcd for C14H19NNaO2S (M + H+)
288.1034, found 288.1008.
General procedure for the synthesis of 3ꢀmethylꢀpyrroles 6.Ethyl vinyl ether (9 equiv),
CuSO4 (2 equiv) and Grubbs’ catalyst 2nd generation (5ꢀ10mol%) were added to a microwave
vial containing a solution of the appropriate propargylamine derivative (50 mg, 1 equiv) in 3
mL of degassed toluene. The reaction mixture was heated at 120 °C under microwaves
irradiation (300W) for 2x10min. The maximum internal pressure observed during the
reaction was 44 psi. The reaction mixture was then quenched with 10 mL of saturated NH4Cl
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solution, 0.5 mL of NH4OH solution and 10 mL of Et2O. The aqueous layer was extracted
twice with Et2O. The combined organic layers were washed with brine, dried over Na2SO4
and concentrated under reduced pressure. All the crude products were purified by flash
column chromatography (SiO2) using 1:4 Et2O/hexanes as the eluent to yield the desired
pyrroles 6 as tan oils.
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tꢀButyl 3ꢀmethylꢀ1Hꢀpyrroleꢀ1ꢀcarboxylate 6a. Yield: 56% (33 mg, 0.18 mmol). H NMR
(400 MHz CDCl3) δ 7.12 (s, 1H), 6.95 (s, 1H), 6.04 (s, 1H), 2.04 (s, 3H), 1.56 (s, 9H) ppm.
13C NMR (100 MHz CDCl3) δ 149.0, 122.6, 120.0, 117.2, 114.1, 83.2, 28.1, 12.0 ppm. IR ν
max (film)/cmꢀ1 2924, 1730. GCꢀMS m/z (ES+) m/z: 181 [M]+, HRMS (ESI): calcd for
C10H16NO2 (M + H+) 182.1181, found 182.1173.
(E/Z)ꢀtertꢀbutylꢀ(4ꢀethoxyꢀ2ꢀmethylenebutꢀ3ꢀenꢀ1ꢀyl)carbamate 5. Yield: 41% (30 mg, 0.13
mmol). Obtained as a 2:1 mixture of E/Z isomers as revealed by GCꢀMS. 1H NMR (400 MHz
CDCl3) major isomer E δ 6.63 (d, 1H, J = 12.8 Hz), 5.53 (d, 1H, J = 12.8 Hz), 4.85 (s, 1H),
4.80 (s, 1H), 4.59 (br s, 1H), 3.84ꢀ3.76 (m, 4H), 1.43 (s, 9H), 1.27 (t, 3H, J = 4.0 Hz) ppm;
peaks from minor isomer Z δ 5.96 (d, 1H, J = 6.9 Hz), 5.09 (s, 1H), 4.96 (s, 1H) ppm. 13C
NMR (100 MHz CDCl3) δ 155.8, 148.2, 140.9, 111.0, 106.2, 79.4, 65.8, 42.8, 28.4, 14.9
ppm; peaks from minor isomer δ 146.0, 113.6, 105.2, 69.0, 45.5, 27.4, 15.3 ppm. GCꢀMS m/z
(ES+) m/z: 227 [M]+, 171 [M–tBu]+, 154 [MꢀtBuOH]+. HRMS (ESI): calcd for C12H21NO3
(M +) 227.1516, found 227.1553.
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3ꢀMethylꢀ1ꢀ[(4ꢀmethylphenyl)sulfonyl]ꢀ1Hꢀpyrrole 6b.Yield: 53% (30 mg, 0.13 mmol). H
NMR (400 MHz CDCl3) δ 7.70 (d, 2H, J = 7.6 Hz), 7.25 (d, 2H, J = 7.6 Hz), 7.03 (s, 1H),
6.86 (s, 1H), 6.10 (s, 1H), 2.38 (s, 3H), 2.00 (s, 3H) ppm. 13C NMR (100 MHz CDCl3) δ
144.6, 136.2, 129.8, 126.7, 124.5, 120.8, 117.7, 115.7, 21.6, 11.8 ppm. IR ν max (film)/cmꢀ1
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1364, 1179. GCꢀMS m/z (ES+) m/z: 235 [M]+, HRMS (ESI): calcd for C12H14NO2S (M + H+)
236.0745, found 236.0738.
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3ꢀMethylꢀ1ꢀphenylꢀ1Hꢀpyrrole 6c. Lit.30 Yield: 54% (32 mg, 0.2 mmol). H NMR (400 MHz
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CDCl3) δ 7.40ꢀ7.35 (m, 4H), 7.19ꢀ7.18 (m, 1H), 6.98 (s, 1H), 6.86 (m, 1H), 6.16 (m, 1H),
2.16 (s, 3H) ppm. 13C NMR (100 MHz CDCl3) δ 140.8, 129.5, 125.1, 121.2, 120.0, 119.0,
117.2, 112.0, 12.0 ppm. GCꢀMS m/z (ES+) m/z: 157 [M]+, HRMS (ESI): calcd for C11H12N
(M + H+) 158.0970, found 158.0960.
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3ꢀMethylꢀ1ꢀbenzoylꢀ1Hꢀpyrrole 6d. Yield: 39% (23 mg, 0.12 mmol). H NMR (400 MHz
CDCl3) δ 7.71ꢀ7.70 (d, 2H, J = 7.3 Hz), 7.57ꢀ7.55 (m, 1H), 7.50ꢀ7.46 (m, 2H), 7.16 (s, 1H),
7.03 (s, 1H), 6.18 (s, 1H), 2.08 (s, 3H) ppm. 13C NMR (100 MHz CDCl3) δ 165.5, 132.0,
129.4, 128.4, 124.1, 121.4, 118.5, 115.6, 12.1 ppm. IR ν max (film)/cmꢀ1 1682, 1394, 1335.
GCꢀMS m/z (ES+) m/z: 185 [M]+, HRMS (ESI): calcd for C12H12NO (M + H+) 186.0919,
found 186.0906.
3ꢀMethylꢀ2ꢀphenylꢀ1ꢀacetylꢀ1Hꢀpyrrole 6f. Lit.31 Compound 6f was synthesised starting from
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200 mg (1.15 mmol) of 8a. Yield: 70% (160 mg). H NMR (400 MHz CDCl3) δ 7.42ꢀ7.30
(m, 3H,), 7.28(d, 1H, J = 3.6Hz), 7.27ꢀ7.23 (m, 2H), 6.16 (d, 1H, J = 3.6 Hz, ), 1.90 (s, 3H),
1.55 (s, 3H) ppm. 13C NMR (100 MHz CDCl3) δ 169.1, 133.7, 130.5, 130.2, 128.1, 126.8,
124.5, 120.2, 113.9, 25.0, 11.4 ppm. GCꢀMS m/z (ES+) m/z: 199 [M+H]+.
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3ꢀMethylꢀ2ꢀ(4ꢀchlorophenyl)ꢀ1ꢀacetylꢀ1Hꢀpyrrole 6g. Yield: 72% (40 mg, 0.17 mmol). H
NMR (400 MHz CDCl3) δ 7.35 (d, 2H, J = 8.4 Hz), 7.21 (d, 1H, J = 3.2 Hz), 7.17 (d, 2H, J =
8.4 Hz), 6.16 (d, 1H, J = 3.2 Hz), 2.29 (s, 3H), 1.89 (s, 3H) ppm. 13C NMR (100 MHz
CDCl3) δ 168.4, 133.5, 132.1, 131.5, 129.4, 128.3, 123.9, 120.7, 114.3, 24.6, 11.4 ppm. IR ν
max (film)/cmꢀ1 2925, 1721, 1305. GCꢀMS m/z (ES+) m/z: 233 [M]+, HRMS (ESI): calcd for
C13H13ClNO (M + H+) 234.0686, found 234.0677.
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3ꢀMethylꢀ2ꢀ(3ꢀfluorophenyl)ꢀ1ꢀacetylꢀ1Hꢀpyrrole 6h. Yield: 76% (43 mg, 0.2 mmol). H
NMR (400 MHz CDCl3) δ 7.36ꢀ7.29 (m, 1H), 7.21 (d, 1H, J = 3.2 Hz), 7.06ꢀ6.91 (m, 3H),
6.15 (d, J = 3.2 Hz), 2.27 (s, 3H), 1.90 (s, 3H) ppm. 13C NMR (100 MHz CDCl3) δ 168.4,
163.7, 161.2, 135.8, 135.7, 129.5, 129.4, 126.0, 124.1, 120.7, 117.2, 117.0, 114.6, 114.4,
114.3, 22.7, 14.2 ppm. IR ν max (film)/cmꢀ1 2924, 1730, 1367. GCꢀMS m/z (ES+) m/z: 217
[M]+, HRMS (ESI): calcd for C13H13FNO (M + H+) 218.0981, found 218.0975.
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3ꢀMethylꢀ2ꢀ(2,4ꢀdichlorophenyl)ꢀ1ꢀacetylꢀ1Hꢀpyrrole 6i. Yield: 38% (21 mg, 0.08 mmol). 1H
NMR (400 MHz CDCl3) δ 7.47ꢀ7.40 (m, 1H), 7.30ꢀ7.25 (m, 1H), 7.20 (d, 1H, J = 3.6 Hz),
6.20 (d, 1H, J = 3.6 Hz), 2.35 (s, 3H) 1.85 (s, 3H) ppm. 13C NMR (100 MHz CDCl3) δ 168.6,
136.0, 134.4, 132.6, 131.9, 129.3, 127.0, 126.4, 124.3, 102.6, 114.3, 23.6, 11.1 ppm. IR ν
max (film)/cmꢀ12926, 1725, 1474. GCꢀMS m/z (ES+) m/z: 267 [M]+, HRMS (ESI): calcd for
C13H12Cl2NO (M + H+) 268.0296, found 268.0285.
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3ꢀMethylꢀ2ꢀ(4ꢀphenylꢀphenyl)ꢀ1ꢀacetylꢀ1Hꢀpyrrole 6j. Yield: 59% (32 mg, 0.11 mmol). H
NMR (400 MHz CDCl3) δ 7.67ꢀ7.59 (m, 4H), 7.48ꢀ7.40 (m, 2H), 7.37ꢀ7.30 (m, 3H), 7.28 (d,
1H, J = 3.2 Hz), 6.18 (d, 1H, J = 3.2 Hz), 2.26 (s, 3H), 1.96 (s, 3H) ppm. 13C NMR (100
MHz CDCl3) δ 168.9, 140.7, 140.2, 132.6, 130.6, 130.2, 128.8, 127.4, 127.1, 126.8, 123.8,
120.5, 114.2, 25.0, 11.6 ppm. IR ν max (film)/cmꢀ12925, 1726, 1305. GCꢀMS m/z (ES+) m/z:
275 [M]+, HRMS (ESI): calcd for C19H18NO (M + H+) 276.1388, found 276.1380.
3ꢀMethylꢀ2ꢀphenylꢀ1ꢀ[(4ꢀmethylphenyl)sulfonyl]ꢀ1Hꢀpyrrole 6k. Yield: 38 % (21 mg, 0.07
mmol). 1H NMR (400 MHz CDCl3) δ 7.38ꢀ7.18 (m, 7H), 7.08ꢀ7.05 (m, 3H), 6.18 (d, 1H, J =
3.2 Hz), 2.34 (s, 3H), 1.80 (s, 1H) ppm. 13C NMR (100 MHz CDCl3) δ 144.4, 135.9, 131.9,
131.2, 130.7, 129.3, 128.1, 127.4, 127.2, 123.8, 122.4, 114.2, 21.6, 11,6 ppm. IR ν max
(film)/cmꢀ1 1344, 1160. GCꢀMS m/z (ES+) m/z: 311 [M] , HRMS (ESI): calcd for
+
C18H18NO2S (M + H+) 312.1058, found 312.1047.
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tertꢀButyl 2ꢀ(4ꢀchlorophenyl)ꢀ3ꢀmethylꢀ1Hꢀpyrroleꢀ1ꢀcarboxylate 6l. Yield: 50% (27 mg,
0.093 mmol). 1H NMR (400 MHz CDCl3) δ 7.34 (t, J = 2.3 Hz, 1H), 7.32 (t, J = 2.3 Hz, 1H),
7.27 (d, J = 3.2 Hz, 1H), 7.17 (t, J = 1.6 Hz, 1H), 7.15 (t, J = 2.3 Hz, 1H), 6.10 (d, J = 3.7 Hz,
1H), 1.89 (s, 3H), 1.30 (s, 9H) ppm. 13C NMR (100 MHz CDCl3) δ 149.2, 133.0, 132.5,
131.6, 129.1, 127.2, 122.6, 121.3, 113.0, 83.3, 27.6, 11.6 ppm. IR ν max (film)/cmꢀ1 2922,
2357, 1739, 1458. GCꢀMS m/z (ES+) m/z: 291 [M]+, HRMS (ESI): calcd for C16H19ClNO2
(M + H+) 292.1104, found 292.1098.
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3ꢀMethylꢀ2ꢀ(4ꢀchlorophenyl) ꢀ1ꢀbenzoylꢀ1Hꢀpyrrole 6m. Yield: 64% (35 mg, 0.19 mmol). 1H
NMR (400 MHz CDCl3) δ 7.74 (d, J = 6.8 Hz, 2H), 7.56 (t, J = 7.2 Hz, 1H), 7.43 (t, J = 7.8
Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 8.8 Hz), 6.96 (d, J = 3.2 Hz, 1H), 6.18 (d, J =
3.2 Hz, 1H), 2.08 (s, 3H) ppm. 13C NMR (100 MHz CDCl3) δ 168.2, 133.6, 132.7, 131.4,
130.7, 130.2, 128.8, 128.4, 128.2, 128.0, 123.9, 123.7, 113.9, 11.6 ppm. IR ν max (film)/cmꢀ
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1681, 1330. GCꢀMS m/z (ES+) m/z: 295 [M]+, HRMS (ESI): calcd for C18H15ClNO (M +
H+) 296.0842, found 296.0836.
2ꢀ(Furanꢀ2ꢀyl)ꢀ3ꢀmethylꢀ1ꢀ[(4ꢀmethylphenyl)sulfonyl]ꢀ1Hꢀpyrrole 6o. Yield: 76% (41 mg,
0.13 mmol). 1H NMR (400 MHz CDCl3) δ 7.49 (d, J = 8.3 Hz, 2H), 7.46 (dd, J = 1.8, 0.9 Hz,
1H), 7.39 (d, J = 3.1 Hz, 1H), 7.22 (d, J = 8.2 Hz, 2H), 6.47 (dd, J = 3.1, 1.8 Hz, 1H), 6.38 (d,
J = 3.2 Hz, 1H), 6.19 (d, J = 3.2 Hz, 1H), 2.39 (s, 3H), 1.93 (s, 3H) ppm. 13C NMR (100
MHz CDCl3) δ 144.6, 143.1, 142.9, 136.0, 129.5, 127.7, 127.3, 123.5, 120.9, 113.9, 113.1,
110.7, 21.7, 11.8 ppm. IR ν max (film)/cmꢀ1 2917, 1368, 1172. GCꢀMS m/z (ES+) m/z: 301
[M]+, HRMS (ESI): calcd for C16H16NO3S (M + H+) 302.0851, found 302.0846.
2ꢀCyclohexylꢀ3ꢀmethylꢀ1ꢀ[(4ꢀmethylphenyl)sulfonyl]ꢀ1Hꢀpyrrole 6p. Yield: 43% (23 mg, 0.07
mmol). 1H NMR (400 MHz CDCl3) δ 7.64 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.1 Hz, 2H), 7.23
(d, J = 3.3 Hz, 1H), 6.03 (d, J = 3.0 Hz, 1H), 3.10 (dt, J = 11.9, 3.3 Hz, 1H), 2.42 (s, 3H),
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2.06 (s, 3H), 1.69ꢀ1.58 (m, 4H), 1.51ꢀ1.44 (m,4H), 1.34ꢀ1.27 (m, 2H) ppm. 13C NMR (100
MHz CDCl3) δ 144.5, 137.1, 134.4, 129.8, 126.8, 120.6, 120.3, 114.7, 36.0, 31.1, 29.7, 27.0,
26.0, 21.7, 13.2 ppm. IR ν max (film)/cmꢀ1 2222, 1368, 1145. GCꢀMS m/z (ES+) m/z: 317
[M]+, HRMS (ESI): calcd for C18H24NO2S (M + H+) 318.1528, found 318.1516.
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3ꢀMethylꢀ1ꢀ[(4ꢀmethylphenyl)sulfonyl]ꢀ2ꢀ(propanꢀ2ꢀyl)ꢀ1Hꢀpyrrole 6q. Yield: 71% (31 mg,
0.11 mmol). 1H NMR (400 MHz CDCl3) δ 7.60 (d, J = 8.3 Hz, 2H), 7.28 (d, J = 8.3 Hz, 2H),
7.21 (d, J = 3.3 Hz, 1H), 6.03 (d, J =2.9 Hz, 1H), 3.49 (s, J = 7.2 Hz, 1H), 2.41 (s, 3H), 2.04
(s, 3H), 1.04 (d, J = 6.7 Hz, 6H) ppm. 13C NMR (100 MHz CDCl3) δ 144.5, 137.1, 135.3,
129.9, 126.7, 120.6, 120.5, 114.9, 29.7, 25.4, 21.6, 21.2, 12.9 ppm. IR ν max (film)/cmꢀ1
2359, 1362, 1166. GCꢀMS m/z (ES+) m/z: 277 [M]+, HRMS (ESI): calcd for C15H20NO2S (M
+ H+) 278.1215, found 278.1207.
3ꢀMethylꢀ1ꢀ[(4ꢀmethylphenyl)sulfonyl]ꢀ2ꢀ(2ꢀmethylpropyl)ꢀ1Hꢀpyrrole 6r. Yield: 69 % (36
mg, 0.12 mmol). 1H NMR (400 MHz CDCl3) δ 7.58 (d, J = 8.2 Hz, 2H), 7.26 (d, J = 8.8 Hz,
2H), 7.20 (d, J = 3.2 Hz, 1H), 6.09 (d, J = 3.2 Hz, 1H), 2.46 (d, J = 7.3 Hz, 2H), 2.40 (s, 3H),
2.03ꢀ1.93 (m, 1H), 1.92 (s, 3H), 0.86 (d, J = 6.4 Hz, 6H) ppm. 13C NMR (100 MHz CDCl3) δ
144.4, 137.0, 130.9, 129.8, 126.4, 122,5, 121.8, 114.5, 34.1, 29.9, 22.7, 22.3, 21.6, 12.0 ppm.
IR ν max (film)/cmꢀ1 2170, 1371, 1170. GCꢀMS m/z (ES+) m/z: 291 [M]+, HRMS (ESI):
calcd for C16H22NO2S (M + H+) 292.1371, found 292.1364.
Synthesis of 3ꢀmethylꢀ2ꢀphenylꢀ1Hꢀpyrrole 16. The pyrrole 6f (90 mg, 0.452 mmol) was
added to a round bottom flask containing 2.5M NaOH solution (2 mL). The reaction mixture
was allowed to stir at r.t. for 3h. The reaction mixture was then diluted with 10 mL of water,
and 10 mL of DCM were added. The aqueous layer was extracted twice with DCM. The
combined organic layers were washed with brine, dried over Na2SO4 and concentrated under
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reduced pressure. The crude pyrrole16 was purified by flash column chromatography (SiO2)
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using 2:3 EtOAc/hexanes as the eluent.
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Yield: 90 % (64 mg, 0.4 mmol). H NMR (400 MHz CDCl3) δ 8.13 (brs, 1H), 7.45ꢀ7.37 (m,
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4H), 7.25ꢀ7.21 (m, 1H), 6.76 (t, J = 2.7 Hz, 1H), 6.14 (t, J = 2.7 Hz, 1H), 2.27 (s, 3H) ppm.
13C NMR (100 MHz CDCl3) δ 133.7, 128.7, 128.6, 128.3, 128.0, 126.4, 126.0, 117.3, 116.1,
112.2, 14.2 ppm. GCꢀMS m/z (ES+) m/z: 157 [M]+.
Synthesis of pyrrole 17. DMF (0.11 mmol) and phosphorus oxychloride (0.10 mmol) were
added to a round bottom flask containing DCM (2 mL). The solution was allowed to stir for
15 minutes at room temperature. Then the solution was cooled down at 0 °C and 3ꢀmethylꢀ2ꢀ
phenylꢀ1Hꢀpyrrole 16 (16 mg, 0.10 mmol) in 1 mL of DCM was added to the solution
previously obtained. The solution was allowed to stir at room temperature for 1 h. The
reaction mixture was then quenched with 10 mL of 1M Na2CO3 solution. The aqueous layer
was extracted twice with DCM. The combined organic layers were washed with a NaHCO3
saturated solution, brine and dried over Na2SO4 and concentrated under reduced pressure.
The crude pyrrole was purified by flash column chromatography (SiO2) using 1:4
EtOAc/hexanes as the eluent to yield the 17 as an oil.
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Yield: 86 % (16 mg, 0.08 mmol). H NMR (400 MHz CDCl3) δ 9.44 (s, 1H), 9.22 (bs, 1H),
7.51ꢀ7.43 (m, 4H), 7.38ꢀ7.34 (m, 1H), 6.84 (d, J = 2.29 Hz 1H), 2.27 (s, 3H) ppm. 13C NMR
(100 MHz CDCl3) δ 178.6, 136.9, 131.6, 131.4, 129.0, 128.3, 127.2, 123.7, 119.5, 12.5 ppm.
IR ν max (film)/cmꢀ1 1634, 1418, 1261. GCꢀMS m/z (ES+) m/z: 185 [M] +, HRMS (ESI):
calcd for C12H12NO (M + H+) 186.0919, found 186.0912.
General procedure for the synthesis of pyrroles 18 and 20. Sodium cyanoborohydride (0.38
mmol, 3 equiv) was added to a round bottom flask containing trifluoroacetic acid (2 mL). The
solution was allowed to stir for 20 minutes at room temperature. Then the appropriate pyrrole
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6b or 6r (0.127 mmol, 1 equiv), was added to the solution previously obtained. The solution
was allowed to stir at room temperature for 1 h. The reaction mixture was then quenched with
10 mL of water, and 10 mL of DCM. The aqueous layer was extracted twice with DCM. The
combined organic layers were washed with a NaHCO3 saturated solution, brine, dried over
Na2SO4 and concentrated under reduced pressure. The crude pyrrolines 18 and 20 proved to
be pure enough to be used in the next synthetic step without any further purification.
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2ꢀisobutylꢀ3ꢀmethylꢀ1ꢀ[(4ꢀmethylphenyl)sulfonyl]ꢀ2,5ꢀdihydroꢀ1Hꢀpyrrole 18. H NMR (400
MHz CDCl3) δ 7.65 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.4 Hz, 2H), 4.78 (s,1H), 4.32 (d, J = 1.6
Hz, 2H), 2.38 (s, 3H), 1.92ꢀ1.85 (m, 1H), 1,56 (s, 3H), 1.48 (d, J = 1.8 Hz, 2H), 1.01 (d, J =
6.8 Hz, 3H), 0.88 (d, J = 6.8 Hz, 3H) ppm. 13C NMR (100 MHz CDCl3) δ 149.4, 138.6,
137.5, 129.6, 127.5, 118.9, 68.4, 42.4, 33.9, 24.3, 23.8, 23.2, 14.1 ppm. LRMS m/z (ES+)
m/z: 294.
3ꢀmethylꢀ1ꢀ[(4ꢀmethylphenyl)sulfonyl]ꢀ2,5ꢀdihydroꢀ1Hꢀpyrrole 20. 1H NMR (400 MHz
CDCl3) δ 7.69 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 5.22 (s, 1H), 4.04 (d, J = 4.0 Hz,
2H), 3.94 (s,2H), 2.40 (s, 3H), 1.63 (s, 3H) ppm. 13C NMR (100 MHz CDCl3) δ 143.4, 135.1,
134.2, 129.8, 127.5, 119.1, 57.7, 55.2, 21.5, 14.1 ppm. LRMS m/z (ES+) m/z: 238.
General procedure for the synthesis of aldehydes 19 and 21.The appropriate pyrroline 18 or
20 (0.076 mmol, 1 equiv) was added to a round bottom flask containing anhydrous dioxane
(2 mL). Then SeO2 (0.076 mmol, 1 equiv) was added to the solution previously obtained. The
solution was allowed to stir at reflux for 1 h under N2 atmosphere. The reaction mixture was
then cooled at room temperature, quenched with 10 mL of water, and 10 mL of DCM were
added. The aqueous layer was extracted twice with DCM. The combined organic layers were
washed with a NaHCO3 saturated solution and brine, dried over Na2SO4 and concentrated
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under reduced pressure. The crude aldehydes were purified by flash column chromatography
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(SiO2) using 2:3 EtOAc/hexanes as the eluent to yield the desired 19 and 21 as an oils.
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1ꢀ(2ꢀisobutylꢀ1ꢀ[(4ꢀmethylphenyl)sulfonyl]ꢀ2,5ꢀdihydroꢀ1Hꢀpyrrolꢀ3ꢀyl)ethanone 19. Yield:
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65 % (25 mg, 0.08 mmol). H NMR (400 MHz CDCl3) δ 9.53 (s, 1H), 7.65 (d, J = 8.4 Hz,
2H), 7.25 (d, J = 8.2 Hz, 2H), 6.53 (s, 1H), 4.78 (d, J = 1.3 Hz, 1H), 4.34ꢀ4.32 (m, 2H), 2.41
(s, 3H), 1.92ꢀ1.85 (m, 1H) 1.48(d, J = 2.0 Hz, 2H), 1.01(d, J = 6.8 Hz, 3H), 0.88(d, J = 6.8
Hz, 3H) ppm. 13C NMR (100 MHz CDCl3) δ 186.5, 146.1, 143.9, 143.4, 134.3, 129.5,
127.5, 63.7, 54.9, 43.1, 28.3, 28.1, 24.4, 23.8, 22.4, 21.6 ppm. IR ν max (film)/cmꢀ1 1682,
1165. LRMS m/z (ES+) m/z: 308 [M+H]+, HRMS (ESI): calcd for C16H22NO3S (M + H+)
308.1320, found 308.1308.
1ꢀ[(4ꢀmethylphenyl)sulfonyl]ꢀ2,5ꢀdihydroꢀ1Hꢀpyrroleꢀ3ꢀcarbaldehyde 21. Yield: 56 % (18
mg, 0.07 mmol). 1H NMR (400 MHz CDCl3) δ 9.53 (s, 1H), 7.65 (d, J = 8.4 Hz, 2H), 7.25 (d,
J = 8.4 Hz, 2H), 4.78 (s,1H), 4.32 (d, J = 1.6 Hz, 2H), 2.38 (s, 3H), 1.92ꢀ1.85 (m, 1H), 1.48
(d, J = 1.8 Hz, 2H), 1.01 (d, J = 6.8 Hz, 3H), 0.88 (d, J = 6.8 Hz, 3H), ppm. 13C NMR (100
MHz CDCl3) δ 186.5, 144.1, 142.4, 141.7, 130.0, 127.5, 55.5, 51.9, 21.6 ppm. IR ν max
(film)/cmꢀ1 1681, 1344, 1163. LRMS m/z (ES+) m/z: 252 [M+H]+, HRMS (ESI): calcd for
C12H14NO3S (M + H+) 252.0694, found 252.0686.
ASSOCIATED CONTENT
Supporting Information: Copies of Hꢀ and 13CꢀNMR spectra. Conversion of 5 into 6a.This
1
material is available free of charge via the Internet at http://pubs.acs.org/.
AUTHOR INFORMATION
Corresponding Author
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*daniele.castagnolo@northumbria.ac.uk
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ACKNOWLEDGMENT
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We gratefully acknowledge the EPSRC UK National Mass Spectrometry Facility (Swansea)
for providing the mass spectrometry data. H. C. thanks the European School of Chemistry,
Polymers and Materials Science (ECPM) of Strasbourg for her Placement Leave.
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