A base-catalysed one-pot three-component coupling reaction leading to nitrosubstituted pyrroles

Article abstract of DOI:10.1055/s-0028-1087991

Tosyl isocyanide and ethyl chloroformate react with nitrostyrenes to afford nitro-substituted pyrroles in good yield when a catch-and-release protocol was employed as a purification strategy. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1087991

PAPER
1485
A Base-Catalysed One-Pot Three-Component Coupling Reaction Leading to
Nitrosubstituted Pyrroles
S
ynthesi
a
s
of
N
itrosu
n
bstituted Pyrroles R. Baxendale, Christopher D. Buckle, Steven V. Ley,* Lucia Tamborini
Innovative Technology Centre for Advanced Chemical Synthesis, Department of Chemistry, University of Cambridge,
Lensfield Road, Cambridge, CB2 1EW, UK
Fax +44(1223)336442; E-mail: svl1000@cam.ac.uk
Received 22 December 2008
to undergo rapid polymerisation under many of the stan-
Abstract: Tosyl isocyanide and ethyl chloroformate react with ni-
trostyrenes to afford nitro-substituted pyrroles in good yield when a
catch-and-release protocol was employed as a purification strategy.
dard nitrating conditions. Furthermore, although proce-
dures exist for C–C bond formation at the 3-position, this
inevitably requires initial installation of a halogen or syn-
thetic equivalent which is not a straightforward transfor-
mation on this particular template. However, we
rationalised that a modification of the classical van
Leusen5 and Barton–Zard6 pyrrole syntheses might allow
direct access to the desired nucleus potentially as a se-
quential one-pot procedure (Scheme 1).
Key words: pyrroles, immobilized reagents, heterocycles, multi-
component
Pyrroles are one of nature’s most important building
blocks comprising the core scaffold of porphyrins such as
haem and the chlorophylls.1 They are also commonly en-
countered embedded within numerous other natural prod-
uct structures generating interesting architectures such as
the lamellarins and marinopyrroles.2 In addition, many
simple synthetic pyrroles display a significant range of
pharmacological activities (antibacterial, antiviral, anti-
inflammatory, antitumour, antioxidant and moderators as-
sociated with several neuropsychiatric diseases) as well as
having found utility in the material sciences as electrical
conductors.3
O
O2N
R1
1. base
S
NC
OR2
O
2. R2OCOCl
N
H
TosMIC
NO2
O
1
R1
3.
Scheme 1 Proposed synthetic scheme to pyrrole core 1
A series of bases were screened for the initial condensa-
tion reaction between ethyl chloroformate and toluene-
sulfonylmethyl isocyanide (TosMIC). Weak bases such as
triethylamine and Hünig’s base as well as the correspond-
ing immobilised forms proved ineffective, giving no no-
ticeable reaction after 24 hours at ambient temperature.
Employing stronger bases such as DBU and BEMP (or
their polymer-supported counterparts: PS-) also gave un-
satisfactory results, generating complex mixtures contain-
ing significant quantities of starting materials and
unidentified by-products. We considered the problem to
be one of ineffective deprotonation and the stability of the
resulting intermediate under the equilibrium conditions.
With this in mind we then carried out the reaction in THF
at 0 °C using two equivalents of n-BuLi or LiHMDS. Al-
though in both cases the starting materials were fully con-
sumed the build up of small quantities (8–12%) of an
additional adduct were also observed (later confirmed as
the 4,5-disubstituted oxazole 5; Figure 2). Reducing the
temperature below –40 °C completely suppressed this
side reaction giving smooth and quantitative conversion
to the lithio intermediate 4 in five minutes (although for
experimental convenience a temperature of –78 °C was
routinely used, maintaining a five minutes incubation
time). Interestingly, quenching the cold reaction mixture
containing intermediate 4 with a saturated solution of so-
dium chloride and leaving the aqueous component to
stand led to the formation of large transparent crystals of
oxazole 5 (79%, Figure 2) which resulted from intramo-
There already exists a large body of literature relating to
the synthesis and modification of these important hetero-
cyclic motifs.4 However, we wished to attain a pyrrole
unit with a unique substitution pattern (Figure 1; 1) as a
precursor to a series of 6-aminopyrrolizinone analogues 2
and a related family of 6-aminopiperazinopyrrolizine-2,6-
diones 3 for application in medicinal chemistry pro-
grammes (Figure 1).
R3 NH
R1
R3 NH
R1
O2N
R1
O
OR2
OH
R2
N
N
N
N
H
R2
O
O
1
2
3
O
Figure 1 Core template building block (1) and derivatives (2 and 3)
Compound 1, possessing a nitro group in the 4-position as
a masked amine and requiring substituent variation at the
3-position comprised a simple, compact and yet syntheti-
cally challenging target. Using current methods it is diffi-
cult to introduce the nitro functionality at a late stage due
to the intrinsic reactivity of the pyrrole and its propensity
SYNTHESIS 2009, No. 9, pp 1485–1493
x
x
.
x
x
.2
0
0
9
Advanced online publication: 06.03.2009
DOI: 10.1055/s-0028-1087991; Art ID: P14508SS
© Georg Thieme Verlag Stuttgart · New York

1486
I. R. Baxendale et al.
PAPER
results in parentheses). In certain cases a small amount of
a unidentified highly coloured material (red/dark orange)
was also displaced from the polymeric support but could
be readily removed from the sample by eluting the wash-
ings through a short plug of silica gel (pre-packed bond
elute cartridges11 were used).
O
O
C
S
S
N
N
O
O
O
4
5
OLi
EtO
EtO
Figure 2 Lithio intermediate 4 and cyclised oxazole 5
Although the products were attained in a higher overall
yield in a few cases (Figure 3) a secondary product was
also identified albeit as a minor component (3–6%). In
two cases chromatographic separation allowed the isola-
tion and characterisation of the species (i.e. Figure 4). In
each case the molecules had a different regioisomeric ar-
rangement and possessed the tosylate group in exchange
for the nitro functionality. The chemical structures were
elucidated from extensive NMR experimentation and
eventually confirmed by X-ray crystallography to be that
of the general structure 6 (Figure 4). We later also con-
firmed that these same compounds were present in the
previous reactions that were worked up using more tradi-
tional aqueous quenching and chromatography and are
therefore not an artefact of the isolation method. How-
ever, because of the much lower overall recovery of ma-
terial from the aqueous work-up they were originally
missed. Re-examination of the original work confirmed
their presence at 3–6% composition in the crude reaction
mixture but they were almost undetectable following the
aqueous work-up step.
lecular cyclisation. This compound was shown to match
the minor by-product previously detected in the condensa-
tion reactions performed at 0 °C as described above.
Using the optimised conditions for the formation of the
lithio derivative 4 (2 equiv n-BuLi, –78 °C in THF, 5 min)
a series of thirteen 10 mmol parallel reactions were set up
to prepare solutions of the anion of 4. To each reaction
was added a different nitrostyrene component (1 equiv)
and the reactions were allowed to warm to ambient tem-
perature with stirring. In each case a slow reaction over a
period of 2–4 days was observed to take place, generating
the desired pyrrole structure 1 as the main product in good
conversion according to crude 1H NMR and LC-MS anal-
ysis. Attempts to accelerate the reaction through various
modes of heating failed to give any improved results,
leading instead to product mixtures with significantly
lower purity profiles.
Isolation of the pure pyrrole products also proved chal-
lenging. A variety of aqueous quenching procedures ac-
companied by extensive organic extractions gave poor
recovery of the products. The best work-up conditions
were eventually found to be direct quenching of the reac-
tion mixture with a saturated solution of potassium car-
bonate and water, followed by extraction with ethyl
acetate and drying (Na2SO4). The organic extracts were
evaporated and the crude reaction mixture loaded onto a
Samplet Cartridge (Biotage FLASH EXP). Chromato-
graphic purification using a Biotage SP4 unit employing a
long gradient elution (hexane–Et2O) gave the best separa-
tion results enabling collection of highly pure products but
in only moderate final isolated yields (Figure 3).
F
H
N
CO2Et
47%
F
R =
F
(78%)
O2N
R
F
F
O2N
Cl
OCF3
F
39%
(63%)
31%
(68%)
59%
(70%)
30%
(77% + 3%)
By considering the potential acidity of the pyrrole NH
proton in these systems we determined that this might be
used as a handle to enable a more facile isolation. Conse-
quently it was shown that significantly improved yields
could be attained when a catch-and-release protocol7 was
employed as the purification strategy.8 Hence, using
strong immobilised bases such as the phosphazene re-
agent PS-BEMP9 or the DBU equivalent PS-TBD10 added
directly to the reaction mixture (no quenching or work-up
steps are required) enabled sequestering of the desired
product. Over the course of approximately four hours us-
ing PS-BEMP (PS-TBD was less effective requiring 12
hours) the pyrrole was completely removed from the reac-
tion mixture. The product was then recovered following a
washing step by treatment of the resin with a solution of
acetic acid (other acids including HCl in dioxane could
also be used). This procedure furnished the products in
much improved yields and avoided the requirement for an
aqueous work-up and column chromatography (Figure 3;
Cl
Br
OMe
Cl
35%
29%
34%
39%
(76% + 6%)
(66%)
(78%)
(88% + 3%)
O
O
O
F
O
Ph
28%
31%
(73%)
29%
24%
(71%)
(69% + 4%)
(63%)
Figure 3 Pyrrole products with isolated yields following chromato-
graphic purification; Yields in parentheses indicate the isolated mate-
rial attained using the polymer-supported reagent isolation procedure.
The second percentage values indicate an accompanying side-pro-
duct.
Synthesis 2009, No. 9, 1485–1493 © Thieme Stuttgart · New York

PAPER
Synthesis of Nitrosubstituted Pyrroles
1487
demonstrated that structures such as 6 can be attained
through the alternative nitro alkene precursor 8, these spe-
cies are themselves not readily available and require care
in their preparation because of the extreme accepting abil-
ity of the system. It would therefore be synthetically use-
ful to be able to redirect the product outcome through
more subtle changes in the nature of the residual ester
functionality.14 Also in a similar manner this conceptual
approach could in reverse be used to potentially complete-
Figure 4 General rearranged structural motif and crystal structure ly suppress the formation of 6 by reducing the propensity
of phenyl-substituted species
for addition into the ester grouping.
In conclusion, we have demonstrated a new way to prepare
We propose that this new motif is most likely generated
during the reaction through a competing pathway prior to
cyclisation, thereby leading to transposition of the ethoxy
carbonyl group as detailed in Scheme 2.12 Indeed, the to-
syl isocyanide would act as a reasonable leaving group
following intramolecular attack of the nitroalkane into the
ester functionality conducted through route B.13 In each
case the identity of the diversity group R would not be ex-
pected to change the natural selectivity of the system. It
also seems unlikely that there is any reversibility in the se-
quence following the cyclisation (Route A) or the ester
transfer (Route B). In order to help verifying this alterna-
tive pathway (Route B) we prepared the nitro alkene 8
(R = 4-methoxyphenyl) which following direct addition
of TosMIC should lead to the same initial intermediate 7
(Scheme 2, Route C). We were satisfied to discover that
indeed the cyclisation adduct 6 was formed and could be
isolated as the sole product in 81% yield using our previ-
ously described PS-BEMP work-up protocol (X-ray anal-
ysis was obtained on the crystalline product confirming
the structure).
specifically functionalised pyrroles via a one-pot three-
component coupling strategy. Furthermore, we have also
shown the advantage of using a polymer-assisted catch-
and-release work-up and purification protocol to maxi-
mise the yields and reduce the time needed to isolate these
building blocks. The origin and identity of a minor by-
product has been determined which could allow access to
this alternative structural motif via simple replacement of
the chloroformate component. Studies to this extent are
ongoing.
All solvents were distilled prior to use, petrol = petroleum ether
(40–60 °C). Melting points were determined using an OptiMelt au-
tomated melting point system available from Stanford Research
1
Systems and are calibrated against Phenacetin (mp 136 °C). H
NMR spectra were recorded on a Bruker Avance DPX-400 or
DRX-500 spectrometer with residual CDCl3 as the internal refer-
ence. 13C NMR spectra were also recorded in CDCl3 on the same
spectrometer with the central peak of the residual solvent as the in-
ternal reference using the deuterated solvent as internal deuterium
lock. COSY, DEPT 135 and HMQC spectroscopic techniques were
used to aid the assignment of signals in the 13C NMR spectra. IR
spectra were recorded on a Perkin-Elmer SpectrumOne FT-IR spec-
trometer neat. Letters in the parentheses refer to relative absorbency
of the peak: w, weak, <40% of the main peak; m, medium, 41–74%
of the main peak; s, strong, >74% of the main peak. LC/MS analysis
In our future work we are interested in the possibility of
favouring the alternative cyclisation pathway (route B) by
changing the electronics of the ester functionality to fur-
ther aid in the transfer process. Although we have already
NO2
NO2
NO2
NO2
R1
Ts
R1
R1
Ts
R1
– Ts
N
N
N
N
EtO2C
EtO2C
H
EtO2C
EtO2C
major product 1
Route A
NO2
R1
NO2
NO2
CO2Et
NO2
CO2Et
O2N
R1
Ts
CO2Et
R1
Ts
R1
Ts
R1
Ts
+
Route B
C
Ts
N
O
CO2Et
N
NC
NC
4
NC
7
EtO
Route C
Ts
NC
CO2Et
CO2Et
O2N
R1
R1
Ts
CO2Et
R1
+
CO2Et
– NO2
R1
N
N
N
Ts
Ts
H
NO2
8
minor product 6
Scheme 2 Proposed divergent pathway leading to the synthesis of the minor product 6 and the major product 1 (R = Et)
Synthesis 2009, No. 9, 1485–1493 © Thieme Stuttgart · New York

1488
I. R. Baxendale et al.
PAPER
was performed on an Agilent HP 1100 chromatograph (Luna Max
RP column) attached to an HPLC/MSD mass spectrometer. Elution
was carried out using a reversed-phase gradient of MeCN–water
with both solvents containing 0.1% formic acid. The gradient is de-
scribed in Table 1. For HRMS a LCT Premier Micromass spectro-
meter was used.
pound was obtained as a yellow crystalline solid. Yield: 4% (purity
90%) following silica chromatography (PE–Et2O, 12:1).
Data for Ethyl 4-Nitro-3-phenyl-1H-pyrrole-2-carboxylate
Mp 150.0–153.2 °C.
tR = 4.39; m/z = 259.90 (C13H12N2O4)–.
IR (neat): 3422.2 (w), 3214.9 (w), 2925.0 (w), 2199.9 (w), 1688.7
(m), 1598.0 (w), 1557.6 (w), 1503.6 (m), 1473.6 (w), 1445.9 (w),
1428.0 (w), 1372.1 (m), 1321.8 (m), 1280.4 (m), 1250.7 (m), 1226.1
(m), 1208.4 (s), 1166.6 (s), 1128.6 (s), 1094.0 (s), 1050.9 (s), 1041.5
(s), 1013.1 (s), 864.1 (w), 842.4 (w), 814.3 (m), 787.4 (m), 762.5
(m), 753.6 (m), 685.3 (s) cm–1.
1H NMR (500 MHz, CDCl3): d = 9.74 (s, 1 H, NH), 7.83 (d, J = 3.8
Hz, 1 H, H-Pyr), 7.39 (d, J = 0.8 Hz, 1 H, 4H-phenyl), 7.38 (d,
J = 2.6 Hz, 2 H, 3H-phenyl), 7.31 (m, 2 H, 2H-phenyl), 4.14 (q,
J = 7.1 Hz, 2 H, CH2), 1.04 (t, J = 7.1 Hz, 3 H, CH3).
13C NMR (125 MHz, CDCl3): d = 160.40 (C), 130.76 (C), 129.93
(CH), 129.88 (CH), 127.99 (CH), 127.49 (C), 127.27 (CH), 127.24
(CH), 126.16 (C), 122.39 (CH), 120.67 (C), 61.23 (CH2), 13.69
(CH3).
Table 1 LC-MS Conditions
Time
(min)
MeCN (%)
Flow rate
(mL⋅min–1)
0.00
3.00
5.00
5.50
8.00
5
1
1
1
1
1
95
95
5
5
HRMS: m/z calcd for C13H11N2O4: 259.0717; found: 259.0724.
Preparation of Pyrroles; General Procedures
Procedure A: To a solution of p-toluenesulfonylmethyl isocyanide
(1.95 g, 10 mmol, 1 equiv) dissolved in THF (75 mL) maintained at
–78 °C with stirring was added a solution of n-BuLi (20 mmol, 2
equiv, 1.6 M in hexanes). The reaction was stirred at –78 °C for 5
min and then a solution of ethyl chloroformate (10 mmol, 1 equiv)
in THF (50 mL) was added. After 10 min a solution of the appropri-
ate nitrostyrene (10 mmol, 1 equiv) in THF (50 mL) was added and
the mixture allowed to warm to ambient temperature with stirring.
After 2–4 d (reaction monitored by TLC), sat. K2CO3 (50 mL) and
H2O (100 mL) was added and the mixture was shaken for 1 h before
being separated. The aqueous layer was extracted with EtOAc
(2 × 100 mL) and the organic layers were combined, and dried over
Na2SO4. The solvents were removed in vacuo and the compounds
were purified using a Biotage SP4 EXP Automated Flash Chroma-
tography System. Compounds were pre-loaded onto 40M Samplet
Cartridge as a solution in CH2Cl2–MeOH (1:1) and then dried under
vacuum in a dessicator at 25 °C overnight. For elution gradient, de-
scribed in terms of column volumes (CV), see specific compound
preparations. The weak solvent was hexane and the strong solvent
was Et2O. Compounds were separated using the 40M silica column
and the elution solvent was collected in fractions of 27 mL.
Data for Ethyl 4-Phenyl-5-tosyl-1H-pyrrole-3-carboxylate
tR = 4.66; m/z = 368.79 (C20H18NO4S)–.
IR (neat): 3284.09 (w), 2984.1 (w), 2256.0 (w), 1703.6 (m), 1596.4
(w), 1541.1 (w), 1515.7 (w), 1445.3 (w), 1373.8 (m), 1318.4 (m),
1304.1 (m), 1271.8 (m), 1174.7 (m), 1141.9 (s), 1112.5 (m), 1083.0
(m), 1036.1 (m), 1018.9 (m), 985.6 (w), 909.4 (m), 813.4 (m), 763.0
(m), 728.7 (s), 697.1 (s), 663.1 (s) cm–1.
1H NMR (500 MHz, CDCl3): d = 10.16 (s, 1 H, NH), 7.56 (d,
J = 3.5 Hz, 1 H, H-Pyr), 7.29 (m, 5 H, phenyl), 7.11 (m, 2 H, tosyl),
7.04 (d, J = 8.2 Hz, 2 H, phenyl), 4.04 (q, J = 7.1 Hz, 2 H, CH2),
2.31 (s, 3 H, CH3), 1.03 (t, J = 7.1 Hz, 3 H, CH3).
13C NMR (125 MHz, CDCl3): d = 163.45 (C), 144.19 (C), 137.95
(C), 131.35 (C), 130.63 (C), 130.46 (CH), 129.95 (CH), 129.48
(CH), 129.33 (CH), 129.27 (CH), 128.27 (CH), 127.72 (CH),
127.39 (C), 127.22 (CH), 127.22 (CH), 126.41 (CH), 117.60 (C),
59.97 (CH2), 21.51 (CH3), 13.90 (CH3).
HRMS: m/z calcd for C20H20NO4S: 370.1113; found: 370.1108.
X-ray crystal structure file reference: CCDC 714239. Formula:
C20H19NO4S. Unit cell parameters: a = 6.8247(2), b = 10.8899(3),
c = 25.2730(7) Å; b = 91.4170(10)°. Space group: P21/c.
Procedure B: To a solution of p-toluenesulfonylmethyl isocyanide
(1.95 g, 10 mmol, 1 equiv) dissolved in freshly distilled THF (60
mL) maintained at –78 °C with stirring was added a solution of n-
BuLi (20 mmol, 2 equiv, 2.5 M in hexanes). The reaction was stirred
at –78 °C for 5 min and then a solution of ethyl chloroformate (956
mL, 10 mmol, 1 equiv) in THF (20 mL) was added. After 10 min a
solution of the appropriate nitrostyrene (10 mmol, 1 equiv) in THF
(20 mL) was added and the mixture allowed to warm to ambient
temperature with stirring. After 1–3 d (reaction monitored by TLC)
PS-BEMP (6.8 g, 2.2 mmol/g, 15 mmol, 1.5 equiv) was added to the
reaction mixture and the suspension shaken for 4 h. The immobil-
ised PS-BEMP was filtered off and washed with THF (3 × 25 mL).
Acetic acid (10 mmol) in THF (35 mL) was added to the polymer-
supported base and the resulting suspension shaken for 1 h. The PS-
BEMP was filtered off and the solvent was evaporated in vacuo to
obtain the desired product.
Ethyl 4-Nitro-3-(perfluorophenyl)-1H-pyrrole-2-carboxylate
General Procedure A: The Biotage separation used the elution 3 CV
25% Et2O, 9 CV 35% Et2O, 2CV 40% Et2O, 2 CV 60% Et2O to give
white crystals. Yield: 1.65 g, 47% (>95% purity). General Proce-
dure B: Yield: 2.73 g, 78%.
Mp 149–150 °C.
tR = 4.77; m/z = 349.01 (C13H7F5N2O4)–.
IR (neat): 3232.6 (w), 3145.8 (w), 1685.1 (m), 1529.1 (m), 1513.6
(s), 1503.8 (s), 1448.7 (w), 14354.0 (w), 1413.4 (w), 1381.3 (m),
1363.0 (m), 1332.0 (m), 1307.5 (s), 1258.9 (m), 1220.3 (m), 1175.8
(w), 1123.4 (m), 1052.0 (m), 998.1 (s), 973.6 (w), 865.0 (w), 855.7
(w), 838.8 (m), 792.0 (s), 751.1 (s) cm–1.
1H NMR (500 MHz, CDCl3): d = 10.30 (br s, 1 H, NH), 7.95 (d,
J = 3.8 Hz, 1 H, H-Pyr), 4.26 (q, J = 7.4 Hz, 2 H, CH2), 1.21 (t,
J = 7.4 Hz, 3 H, CH3).
13C NMR (125 MHz, CDCl3): d = 159.44 (C), 144.72 (C, dm,
JCF = 246.8 Hz), 141.38 (C, dm, JCF = 253.8 Hz), 137.28 (C, dm,
JCF = 250.4 Hz), 136.35 (C), 123.31 (CH), 122.21 (C), 108.57 (C),
106.55 (C, dt, JCF = 18.1, 4.1 Hz), 62.06 (CH2), 13.66 (CH3).
Ethyl 4-Nitro-3-phenyl-1H-pyrrole-2-carboxylate
The Biotage separation used the elution 1 CV 25% Et2O, 7 CV 35%
Et2O, 6 CV 40% Et2O, 5 CV 60% Et2O to give the title compound
as a light orange powder. Yield: 0.91 g, 35% (>95% purity). Using
procedure B the title compound was isolated in 76% with ethyl
4-phenyl-5-tosyl-1H-pyrrole-3-carboxylate (6%). The latter com-
Synthesis 2009, No. 9, 1485–1493 © Thieme Stuttgart · New York

PAPER
Synthesis of Nitrosubstituted Pyrroles
1489
HRMS: m/z calcd for C13H7F5N2O4: 350.0326; found: 350.0344.
1H NMR (500 MHz, CDCl3): d = 9.75 (s, 1 H, NH), 7.85 (d, J = 3.7
Hz, 1 H, H-Pyr), 7.47 (d, J = 8.3 Hz, 1 H, 4H-phenyl), 7.44 (d,
J = 2.0 Hz, 1 H, 1H-phenyl), 7.17 (dd, J = 8.3, 2.0 Hz, 1 H, 5H-phe-
nyl), 4.18 (q, J = 7.1 Hz, 2 H, CH2), 1.12 (t, J = 7.1, 3 H, CH3).
13C NMR (125 MHz, CDCl3): d = 159.89 (C), 136.10 (C), 132.28
(C), 132.12 (CH), 131.59 (C), 130.68 (C), 129.57 (CH), 129.52
(CH), 123.22 (C), 122.50 (CH), 120.93 (C), 61.55 (CH2), 13.78
(CH3).
X-ray crystal structure file reference: CCDC 714243. Formula:
C13H7F5N2O4. Unit cell parameters: a = 8.0224(1), b = 10.5196(2),
c = 16.6525(3) Å; a = 88.659(1), b = 79.068(1), g = 83.315(2)°.
Space group: P–1.
Ethyl 3-(3-Bromophenyl)-4-nitro-1H-pyrrole-2-carboxylate
General Procedure A: The Biotage separation used the elution 1 CV
25% Et2O, 7 CV 35% Et2O, 6 CV 40% Et2O, 5 CV 60% Et2O to give
an off white powder. Yield: 0.97 g, 29% (>95% purity). General
Procedure B: Yield: 2.24 g, 66%.
HRMS: m/z calcd for C13H10Cl2N2O4Na: 350.9909; found:
350.9910.
Mp 128.5–129.5 °C.
tR = 4.61; m/z = 339.74 (C13H11BrN2O4)–.
Ethyl 4-Nitro-3-(2-nitrophenyl)-1H-pyrrole-2-carboxylate
General Procedure A: The Biotage separation used the elution 3 CV
2% Et2O, 2 CV 35% Et2O, 7 CV 40% Et2O, 4 CV 60% Et2O to give
a yellow/brown powder. Yield: 1.80 g, 59% (purity >95%). General
Procedure B: Yield: 2.13 g, 70%.
IR (neat): 3276.6 (m), 3147.2 (w), 2986.6 (w), 1673.0 (s), 1600.0
(w), 1567.0 (w), 1553.0 (m), 1498.5 (s), 1472.4 (m), 1424.9 (m),
1366.2 (s), 1312.6 (s), 1312.6 (s), 1278.6 (s), 1230.7 (m), 1185.8 (s),
1146.0 (m), 1123.4 (m), 1075.3 (m), 1007.4 (m), 998.7 (m), 976.4
(w), 891.0 (w), 859.7 (m), 846.6 (w), 823.6 (m), 778.4 (m), 769.3
(s), 736.3 (s), 696.1 (s) cm–1.
1H NMR (500 MHz, CDCl3): d = 9.75 (s, 1 H, NH), 7.85 (d, J = 3.7
Hz, 1 H, H-Pyr), 7.51 (m, 1 H, 4H-phenyl), 7.48 (m, 1 H, 2H-phe-
nyl), 7.26 (m, 1 H, 6H-phenyl), 7.25 (m, 1 H, 5H-phenyl), 4.15 (q,
J = 7.1 Hz, 2 H, CH2), 1.08 (t, J = 7.1 Hz, 3 H, CH3).
Mp 151.9–153.7 °C.
tR = 4.32; m/z = 304.86 (C13H10N3O6)–.
IR (neat): 3252.9 (w), 1682.6 (s), 1507.9 (s), 1380.8 (m), 1350.7 (s),
1323.2 (m), 1279.0 (m), 1186.9 (m), 1115.3 (w), 1011.5 (w), 845.2
(w), 819.6 (m), 791.8 (m), 781.9 (m), 758.9 (s), 745.9 (m), 707.1
(m) cm–1.
1H NMR (500 MHz, CDCl3): d = 10.02 (s, 1 H, NH), 8.19 (dd,
J = 8.2, 1.0 Hz, 1 H, 6H-phenyl), 7.88 (d, J = 3.8 Hz, 1 H, H-Pyr),
7.65 (td, J = 7.5, 1.3 Hz, 1 H, 4H-phenyl), 7.58 (td, J = 8.2, 1.4 Hz,
1 H, 5H-phenyl), 7.36 (dd, J = 7.6, 1.5 Hz, 1 H, 3H-phenyl), 4.07
(q, J = 7.1 Hz, 2 H, CH2), 0.97 (t, J = 7.1 Hz, 3 H, CH3).
13C NMR (125 MHz, CDCl3): d = 159.74 (C), 148.43 (C), 136.1
(C), 132.70 (CH), 132.43 (CH), 129.14 (CH), 127.46 (C), 124.46
(CH), 122.67 (CH), 121.96 (C), 120.24 (C), 61.40 (CH2), 13.54
(CH3).
13C NMR (125 MHz, CDCl3): d = 160.20 (C), 133.04 (CH), 132.82
(C), 130.98 (CH), 128.00 (CH), 128.74 (CH), 124.15 (C), 122.42
(CH), 122.32 (C), 120.93 (C), 61.41 (CH2), 13.70 (CH3).
HRMS: m/z calcd for C13H12BrN2O4: 338.9980; found: 338.9965.
Ethyl 4-Nitro-3-[4-(trifluoromethoxy)phenyl]-1H-pyrrole-2-
carboxylate
General Procedure A: The Biotage separation used the elution 1 CV
25% Et2O, 7 CV 35% Et2O, 6 CV 40% Et2O, 5 CV 60% Et2O to give
a light orange powder. Yield: 1.07 g, 31% (>95% purity). General
Procedure B: Yield: 2.34 g, 68%.
HRMS: m/z calcd for C13H12N3O6: 306.0726; found: 306.0723.
Ethyl 3-(4-Fluorophenyl)-4-nitro-1H-pyrrole-2-carboxylate
General Procedure A: The Biotage separation used the elution 1 CV
25% Et2O, 7 CV 35% Et2O, 6 CV 40% Et2O, 5 CV 60% Et2O to give
a yellow/orange powder. Yield: 0.84 g, 30% (purity >95%). General
Procedure B: Yield: 2.13 g, 77%.
Mp 169.4–171.8 °C.
tR = 4.73; m/z = 343.79 (C14H10F3N2O5)–.
IR (neat): 3254.9 (w), 1687.1 (m), 1426.3 (w), 1361.4 (w), 1319.3
(m), 1283.3 (s), 1190.8 (m), 1155.6 (m), 1012.3 (w), 854.8 (w)
cm–1.
1H NMR (500 MHz, CDCl3): d = 9.79 (s, 1 H, NH), 7.84 (d, J = 3.8
Hz, 1 H, H-Pyr), 7.34 (m, 2 H, phenyl), 7.23 (m, 2 H, phenyl), 4.13
(q, J = 7.1 Hz, 2 H, CH2), 1.02 (t, J = 7.1 Hz, 3 H, CH3).
13C NMR (125 MHz, CDCl3): d = 160.24 (C), 149.01 (C, q, J = 1.6
Hz), 136.20 (C), 131.56 (CH), 129.54 (C), 124.53 (C), 122.50 (CH),
121.48 (C), 120.17 (CF3, q, J = 180 Hz), 119.98 (CH) 61.45 (CH2),
13.49 (CH3).
Mp 155.4–157.2 °C.
tR = 4.44; m/z = 277.85 (C13H10FN2O4)–.
IR (neat): 3268.1 (w), 2985.7 (w), 1702.2 (m), 1607.2 (w), 1518.3
(s), 1420.4 (w), 1368.1 (s), 1319.2 (m), 1275.4 (s), 1220.5 (m),
1117.2 (m), 1158.0 (m), 1097.3 (w), 1019.6 (w), 841.9 (m), 809.7
(w), 783.2 (m), 731.2 (w) cm–1.
1H NMR (500 MHz, CDCl3): d = 9.73 (s, 1 H, NH), 7.83 (d, J = 3.8
Hz, 1 H, H-Pyr), 7.28 (m, 2 H, phenyl), 7.07 (m, 2 H, phenyl), 4.14
(q, J = 7.1 Hz, 2 H, CH2), 1.07 (t, J = 7.1 Hz, 3 H, CH3).
13C NMR (125 MHz, CDCl3): d = 162.63 (CF, d, J = 250 Hz),
160.24 (C), 136.27 (C), 131.80 (CH, d, J = 8.3 Hz), 126.53 (C, d,
J = 3.4 Hz), 125.03 (C), 122.47 (C), 120.76 (CH), 114.57 (CH, d,
J = 22 Hz), 61.34 (CH2), 13.76 (CH3).
HRMS: m/z calcd for C14H12F3N2O5: 345.0698; found: 345.0767.
Ethyl 3-(3,4-Dichlorophenyl)-4-nitro-1H-pyrrole-2-carboxylate
General Procedure A: The Biotage separation used the elution 3 CV
35% Et2O, 7 CV 40% Et2O, 2 CV 50% Et2O, 6 CV 60% Et2O to give
a yellow/brown powder. Yield: 1.11 g, 34% (purity >95%). General
Procedure B: Yield: 2.56 g, 78%.
HRMS: m/z calcd for C13H12FN2O4: 279.0781; found: 279.0769.
Mp 155.3–158.0 °C.
tR = 4.74; m/z = 327.76 (C13H9Cl2N2O4)–.
Ethyl 3-(2-Chlorophenyl)-4-nitro-1H-pyrrole-2-carboxylate
General Procedure A: The Biotage separation used the elution 1 CV
25% Et2O, 7 CV 35% Et2O, 5 CV 40% Et2O, 6 CV 60% Et2O to give
a yellow/brown powder. Yield: 1.146 g, 39% (purity >95%). Gen-
eral Procedure B: Yield: 1.851 g, 63%.
IR (neat): 3258.1 (m), 3145.9 (w), 2986.5 (w), 1677.9 (s), 1562.1
(w), 1500.7 (s), 1472.0 (m), 1424.0 (m), 1382.9 (m), 1363.8 (s),
1314.1 (s), 1284.5 (s), 1230.9 (w), 1187.6 (m), 1136.2 (m), 1033.6
(m), 1021.9 (m), 1008.2 (m), 883.9 (w), 858.7 (w), 831.2 (m), 821.5
(m), 777.7 (s), 747.9 (m), 710.0 (m), 694.0 (m), 661.9 (m) cm–1.
Mp 158.2–160.5 °C.
tR = 4.47; m/z = 293.80 (C13H10ClN2O4)–.
Synthesis 2009, No. 9, 1485–1493 © Thieme Stuttgart · New York

1490
I. R. Baxendale et al.
PAPER
Ethyl 3-(2-Fluorophenyl)-4-nitro-1H-pyrrole-2-carboxylate
The Biotage separation used the elution 1 CV 25% Et2O, 7 CV 35%
Et2O, 5 CV 40% Et2O, 6 CV 60% Et2O to give an off white powder:
Yield: 0.81 g, 29% (purity >95%). Using procedure B the title com-
pound was isolated in 69% with ethyl 4-(2-fluorophenyl)-5-tosyl-
1H-pyrrole-3-carboxylate (4%). The latter compound was obtained
as a light brown solid. Yield: 2.5% (purity 90%) following silica
chromoatography (PE–Et2O, 10:1).
IR (neat): 3259.8 (w), 2983.7 (w), 1704.9 (m), 1573.6 (w), 1508.4
(s), 1474.7 (w), 1423.0 (w), 1374.1 (s), 1323.2 (m), 1285.7 (s),
1255.5 (m), 1227.8 (w), 1179.8 (m), 1156.5 (w), 1114.6 (w), 1067.4
(w), 1020.1 (w), 911.1 (w), 838.8 (w), 821.5 (w), 784.0 (w), 757.8
(m), 728.7 (m) cm–1.
1H NMR (500 MHz, CDCl3): d = 9.93 (s, 1 H, NH), 7.86 (d, J = 3.8
Hz, 1 H, H-Pyr), 7.44 (m, 1 H, phenyl), 7.30 (m, 3 H, phenyl), 4.13
(dq, J = 16.4, 7.1 Hz, 1 H, CH2), 4.10 (dq, J = 16.4, 7.1 Hz, 1 H,
CH2), 0.99 (t, J = 7.1 Hz, 3 H, CH3).
13C NMR (125 MHz, CDCl3): d = 160.26 (C), 136.35 (C), 133.91
(C), 131.30 (CH), 130.73 (C), 129.38 (CH), 128.92 (CH), 126.06
(CH), 122.70 (C), 122.39 (CH), 121.07 (C), 61.34 (CH2), 13.57
(CH3).
Data for Ethyl 3-(2-Fluorophenyl)-4-nitro-1H-pyrrole-2-car-
boxylate
Mp 125.0–126.2 °C.
tR = 4.38; m/z = 277.82 (C13H11FN2O4)–.
IR (neat): 3243.5 (w), 3141.8 (w), 2991.3 (w), 1683.3 (s), 1581.4
(w), 1505.9 (s), 1426.5 (w), 1373.2 (s), 1360.6 (s), 1322.7 (s),
1283.0 (s), 1262.9 (m), 1234.0 (m), 1222.7 (m), 1190.0 (m), 1152.9
(w), 1102.35(w), 1014.7 (m), 906.9 (w), 867.8 (w), 829.1 (m),
812.1 (m), 783.6 (m), 749.6 (s), 690.5 (w) cm–1.
1H NMR (500 MHz, CDCl3): d = 9.95 (s, 1 H, NH), 7.86 (d, J = 3.8
Hz, 1 H, H-Pyr), 7.37 (m, 1 H, phenyl), 7.30 (m, 1 H, phenyl), 7.16
(m, 1 H, phenyl), 7.10 (m, 1 H, phenyl), 4.15 (qd, J = 7.1, 2.4 Hz, 2
H, CH2), 1.05 (t, J = 7.1 Hz, 3 H, CH3).
13C NMR (125 MHz, CDCl3): d = 160.26 (C), 160.10 (CF, d,
J = 250 Hz), 135.10 (C), 132.00 (CH, d, J = 2.5 Hz), 130.13 (CH, d,
J = 8.3 Hz), 123.25 (CH, d, 3.5 Hz), 122.66 (CH), 121.17 (C),
119.13 (C), 118.92 (C, d, J = 16 Hz), 115.03 (CH, d, J = 22 Hz),
61.41 (CH2), 13.64 (CH3).
HRMS: m/z calcd for C13H12ClN2O4: 295.0486; found: 295.0478.
Ethyl 3-(1,3-Benzodioxol-4-yl)-4-nitro-1H-pyrrole-2-carboxy-
late
General Procedure A: The Biotage separation used the elution 1 CV
25% Et2O, 7 CV 35% Et2O, 6 CV 40% Et2O, 5 CV 60% Et2O to give
an orange/brown solid: Yield: 0.851 g, 28% (purity >95%). General
Procedure B: Yield: 2.16 g, 71%.
Mp 185.1–187.7 °C.
tR = 4.32; m/z = 303.87 (C14H12N2O6)–.
IR (neat): 3257.0 (w), 3141.2 (w), 1669.9 (m), 1500.0 (s), 1483.8
(m), 1422.0 (m), 1359.1 (m), 1341.0 (m), 1311.3 (s), 1283.8 (s),
1244.9 (s), 1220.1 (s), 1191.5 (m), 1147.3 (m), 1103.6 (m), 1037.0
(s), 1013.1 (m), 934.8 (m), 887.09(m), 868.7 (m), 845.5 (m), 812.9
(m), 781.8 (s), 753.0 (s), 678.1 (m) cm–1.
HRMS: m/z calcd for C13H11FN2O4: 278.2358; found: 278.2361.
1H NMR (500 MHz, CDCl3): d = 9.80 (s, 1 H, NH), 7.80 (d, J = 3.8
Hz, 1 H, H-Pyr), 6.81 (m, 3 H, aryl), 5.98 (s, 2 H, CH2), 4.17 (q,
J = 7.1 Hz, 2 H, CH2), 1.13 (t, J = 7.1 Hz, 3 H, CH3).
Data for Ethyl 4-(2-Fluorophenyl)-5-tosyl-1H-pyrrole-3-car-
boxylate
tR = 4.62; no mass observed.
13C NMR (125 MHz, CDCl3): d = 160.22 (C), 147.43 (C), 146.94
(C), 136.31 (C), 125.76 (C), 123.96 (C), 123.73 (CH), 122.39 (CH),
120.73 (C), 110.67 (CH), 107.63 (CH), 101.11 (CH2), 61.22(CH2),
13.86 (CH3).
IR (neat): 3233.1 (w), 3130.1 (w), 2989.8 (w), 1680.6 (m), 1623.0
(w), 1594.9 (w), 1547.0 (m), 1522.5 (m), 1492.2 (w), 1472.2 (w),
1448.2 (m), 1375.9 (m), 1357.2 8(w), 1342.3 (m), 1329.7 (m),
1290.9 (m), 1256.9 (m), 1222.8 (m), 1205.6 (m), 1187.0 (s), 1143.8
(s), 1099.6 (m), 1084.7 (m), 1036.4 (m), 1018.2 (m), 993.8 (w),
939.3 (w), 873.6 (w), 844.7 (w), 811.6 (m), 757.6 (s), 705.1 (m),
675.1 (s), 656.7 (s) cm–1.
1H NMR (500 MHz, CDCl3): d = 9.62 (s, 1 H, NH), 7.60 (d, J = 3.4
Hz, 1 H, 2H-pyr), 7.30 (m, 4 H), 7.14 (m, 3 H), 6.92 (m, 1 H), 4.07
(m, 2 H, CH2), 2.33 (s, 3 H, CH3-Ts), 1.03 (t, J = 7.1 Hz, 3 H, CH3-
Et).
13C NMR (125 MHz, CDCl3): d = 162.96 (C), 160.09 (CF, d,
J = 250 Hz), 144.41 (C), 137.58 (C), 132.78 (CH, d, J = 2.5 Hz),
130.01 (CH, d, J = 8.1 Hz), 129.42 (CH), 128.19 (C), 127.17 (CH),
125.79 (CH), 123.41 (C), 123.19 (CH, d, J = 3.5 Hz), 119.40 (C, d,
J = 16 Hz), 118.67 (C), 114.55 (CH, d, J = 22 Hz), 60.01 (CH2),
21.54 (CH3), 13.82 (CH3).
HRMS: m/z calcd for C14H13N2O6: 305.0774; found: 305.0788.
Ethyl 3-[2-(Benzyloxy)phenyl]-4-nitro-1H-pyrrole-2-carboxy-
late
General Procedure A: The Biotage separation used the elution 1 CV
25% Et2O, 7 CV 35% Et2O, 5 CV 40% Et2O, 6 CV 60% Et2O to give
an off white powder: Yield: 1.12 g, 31% (purity >95%). General
Procedure B: Yield: 2.67 g, 73%.
Mp 147.8–149.5 °C.
tR = 4.72; m/z = 365.79 (C20H17N2O5)–.
IR (neat): 2981.5 (w), 1725.5 (m), 1597.8 (m), 1555.8 (m), 1492.2
(m), 1452.4 (m), 1373.1 (m), 1321.2 (m), 1291.4 (m), 1242.4 (s),
1146.3 (s), 1081.6 (m), 1017.3 (m), 912.3 (m), 858.6 (w), 812.4 (m),
753.1 (s), 735.3 (s), 697.7 (m) cm–1.
HRMS: m/z calcd for C20H18FNO4S: 387.0941; found: 387.0955.
1H NMR (500 MHz, CDCl3): d = 9.57 (s, 1 H, NH), 7.73 (d, J = 3.8
Hz, 1 H, H-Pyr), 7.26 (m, 7 H, phenyl and benzyl), 6.98 (m, 2 H, 3-
and 5-phenyl), 4.99 (dd, J = 11.8, 17.3 Hz, 2 H, benzyl-CH2), 4.11
(dq, J = 41.8, 7.1 Hz, 1 H, CH2), 4.09 (dq, J = 41.8, 7.1 Hz, 1 H,
CH3), 1.02 (t, J = 7.1 Hz, 3 H, CH3).
13C NMR (125 MHz, CDCl3): d = 160.33 (C), 156.39 (C), 136.91
(CH), 136.90 (CH), 131.55 (CH), 129.62 (CH), 128.39 (CH),
127.69 (CH), 127.17 (CH), 122.44 (C), 122.19 (CH), 120.57 (C),
120.51 (C), 120.19 (CH), 111.99 (CH), 70.36 (CH2), 61.05 (CH2),
13.72 (CH3).
Ethyl 3-(4-Methoxyphenyl)-2-nitroacrylate
The title compound was prepared following the procedure of Forni-
cola et al.12 for the synthesis of the corresponding methyl 3-(p-
methoxyphenyl)-2-nitropropenoate being isolated in 82% yield (20
mmol scale) as a 1.1:1 mixture of isomers.
Isomer 1
1H NMR (400 MHz, CDCl3): d = 7.45 (s, 1 H, 1-H), 7.38 (d, J = 8.8
Hz, 2 H, 3H- and 5H-PhOMe), 6.91 (d, J = 8.8 Hz, 2 H, 2H- and 6H-
PhOMe), 4.36 (q, J = 7.3 Hz, 2 H, CH2-Et), 3.83 (s, 3 H, OCH3),
1.35 (t, J = 7.3 Hz, 3 H, CH3-Et).
HRMS: m/z calcd for C20H19N2O5: 367.1294; found: 367.1295.
Synthesis 2009, No. 9, 1485–1493 © Thieme Stuttgart · New York

PAPER
Synthesis of Nitrosubstituted Pyrroles
1491
13C NMR (100 MHz, CDCl3): d = 163.29 (C), 159.98 (C), 136.61
(C), 132.97 (CH), 132.55 (2 × CH), 121.75 (C), 115.31 (2 × CH),
63.16 (CH2), 55.88 (CH3), 14.45 (CH3).
1H NMR (500 MHz, CDCl3): d = 7.90 (m, 2 H, 2H-Ts), 7.33 (s, 1
H, CH), 7.31 (m, 2 H, 3H-Ts), 4.49 (q, J = 7.1 Hz, 2 H, CH2-Et),
2.41 (s, 3 H, CH3-Ts), 1.48 (t, J = 7.1 Hz, 3 H, CH3-Et).
13C NMR (125 MHz, CDCl3): d = 157.97 (C), 144.39 (C), 140.81
(CH), 138.23 (C), 129.72 (CH), 127.64 (CH), 114.88 (C), 70.94
(CH2), 21.61 (CH3), 14.89 (CH3).
Isomer 2
1H NMR (400 MHz, CDCl3): d = 8.02 (s, 1 H, 1-H), 7.48 (d, J = 8.8
Hz, 2 H, 3H- and 5H-PhOMe), 6.94 (d, J = 8.8 Hz, 2 H, 2H- and 6H-
PhOMe), 4.45 (q, J = 7.3 Hz, 2 H, CH2-Et), 3.86 (s, 3 H, OCH3),
1.37 (t, J = 7.3 Hz, 3 H, CH3-Et).
HRMS: m/z calcd for C12H13NO4S: 267.0565; found: 267.0553.
X-ray crystal structure file reference: CCDC 714241. Formula:
C12H13NO4S. Unit cell parameters: a = 11.8439(3), b = 7.5647(2),
c = 13.9630(4) Å; b = 101.1900(10)°. Space group: P21/n.
13C NMR (100 MHz, CDCl3): d = 163.66 (C), 162.14 (C), 140.16
(C), 136.94 (CH), 133.82 (CH), 121.70 (C), 115.31 (CH), 63.35
(CH2), 55.94 (CH3), 14.17 (CH3).
Ethyl 3-(Furan-2-yl)-4-nitro-1H-pyrrole-2-carboxylate
General Procedure A: The Biotage separation used the elution 2 CV
25% Et2O, 5 CV 35% Et2O, 6 CV 40% Et2O, 7 CV 60% Et2O to give
a brown solid. Yield: 0.60 g, 24% (purity >95%). General Proce-
dure B: Yield: 1.57 g, 63%.
Ethyl 4-(4-Methoxyphenyl)-5-tosyl-1H-pyrrole-3-carboxylate
Procedure B: To a solution of p-toluenesulfonylmethyl isocyanide
(1.95 g, 10 mmol, 1 equiv) dissolved in freshly distilled THF (55
mL) maintained at –78 °C with stirring was added a solution of n-
BuLi (10 mmol, 1 equiv, 1.6 M in hexanes). The reaction was stirred
at –78 °C for 5 min and then a solution of the ethyl 3-(4-methox-
yphenyl)-2-nitroacrylate (10 mmol, 1 equiv) in THF (15 mL) was
added and the mixture allowed to warm to ambient temperature
with stirring. After 36 h (reaction monitored by TLC) PS-BEMP
(6.8 g, 2.2 mmol/g, 15 mmol, 1.5 equiv) was added to the reaction
mixture and the suspension shaken for 4 h. The immobilised PS-
BEMP was filtered off and washed with THF (3 × 25 mL). Acetic
acid (10 mmol) in THF (35 mL) was added to the polymer-support-
ed base and the resulting suspension shaken for 1 h. The PS-BEMP
was filtered off and the solvent was evaporated in vacuo to obtain
the desired product in 81% yield.
tR = 4.16; m/z = 249.95 (C11H9N2O5)–.
IR (neat): 3238.4 (w), 1675.7 (s), 15.43.6 (w), 15.04 (s), 1426.7 (w),
1365.1 (m), 1359.2 (m), 1318.2 (s), 1278.8 (s), 1197.5 (m), 113.82
(m), 1010.1 (m), 1001.1 (s), 903.1 (w), 816.7 (m), 780.4 (m), 736.8
(m), 727.7 (s) cm–1.
1H NMR (400 MHz, CDCl3): d = 10.12 (s, 1 H, NH), 7.82 (d,
J = 3.8 Hz, 1 H, 2H-pyr), 6.65 (d, J = 3.2 Hz, 1 H, furyl), 6.53 (dd,
J = 3.2, 1 Hz, 1 H, furyl), 4.38 (q, J = 7.3 Hz, 2 H, CH2-Et), 1.21 (t,
J = 7.3 Hz, 3 H, CH3-Et).
13C NMR (100 MHz, CDCl3): d = 160.22 (C), 142.85 (CH), 142.34
(C), 122.72 (CH), 121.72 (C), 114.80 (C), 112.44 (CH), 110.99
(CH), 61.70 (CH2), 13.99 (CH3).
Mp 172.0–173.3 °C.
tR = 4.62; m/z = 398.54 (C21H20NO5S)–.
HRMS: m/z calcd for C11H11N2O5: 251.0668; found: 251.0661.
IR (neat): 3261.2 (w), 2867.3 (w), 2233.9 (w), 1716.4 (m), 1530.7
(w), 1521.6 (m), 1289.7 (s), 1049.5 (m), 1009.8 (m), 985.2 (w),
693.2 (m) cm–1.
1H NMR (400 MHz, CDCl3): d = 10.13 (s, 1 H, NH), 7.56 (d,
J = 3.3 Hz, 1 H, H-Pyr), 7.29 (d, J = 8.4 Hz, 2 H, 3H- and 5H-
PhOMe), 7.09 (m, 4 H, tosyl), 6.85 (d, J = 8.4 Hz, 2 H, 2H- and 6H-
PhOMe), 4.10 (q, J = 7.1 Hz, 2 H, CH3-Et), 3.87 (s, 3 H, OMe), 2.34
(s, 3 H, CH3-Ts), 0.97 (t, J = 7.1 Hz, 3 H, CH3-Et).
13C NMR (100 MHz, CDCl3): d = 163.78 (C), 159.77 (C), 144.56
(C), 138.62 (C), 132.18 (CH), 131.07 (C), 129.76 (CH), 127.78 (C),
127.62 (CH), 126.83 (CH), 123.86 (C), 118.06 (C), 113.18 (CH),
60.32 (CH2), 55.66 (CH3), 21.92 (CH3), 14.47 (CH3).
Ethyl 3-(4-Methoxyphenyl)-4-nitro-1H-pyrrole-2-carboxylate
General Procedure A: The Biotage separation used the elution 1 CV
25% Et2O, 7 CV 35% Et2O, 5 CV 40% Et2O, 6 CV 60% Et2O to give
a light orange solid. Yield: 1.13 g, 39% (purity >95%). General Pro-
cedure B: Yield: 2.55 g (88%) with ethyl 4-methoxy-5-tosylpyrrole-
3-carboxylate (3%).
Mp 152.0–153.5 °C.
tR = 4.38; m/z = 289.08 (C14H14N2O5)–.
IR (neat): 3265.7 (m), 3234.3 (m), 3147.0 (w), 1667.8 (s), 1610.8
(w), 1518.8 (s), 1497.8 (s), 1467.2 (m), 1424.2 (m), 1359.0 (s),
1317.9 (m), 1281.0 (s), 1253.0 (s), 1208.8 (m), 1176.9 (s), 1109.7
(m), 1032.3 (m), 1009.4 (m), 863.2 (w), 847.9 (m), 830.4 (m), 822.4
(m), 781.4 (s), 753.7 (s) cm–1.
1H NMR (500 MHz, CDCl3): d = 10.15 (br s, 1 H, NH), 7.85 (d,
J = 3.7 Hz, 1 H, H-Pyr), 7.26 (d, J = 8.8 Hz, 2 H, PhOMe), 6.92 (d,
J = 8.8 Hz, 2 H, PhOMe), 4.15 (q, J = 7.3 Hz, 2 H, CH2), 3.86 (s, 3
H, OMe), 1.08 (t, J = 7.1 Hz, 3 H, CH3).
HRMS: m/z calcd for C21H21NNaO5S: 422.1038; found: 422.1021.
X-ray crystal structure file reference: CCDC 714240. Formula:
C21H21NO5S.
Unit
cell
parameters:
a = 18.2420(2),
b = 11.22880(10), c = 19.4059(2) Å. Space group: Pbca.
5-Ethoxy-4-tosyl-1,3-oxazole (5)
13C NMR (125 MHz, CDCl3): d = 161.14 (C), 159.87 (C), 136.61
(C), 131.76 (2 × CH), 126.66 (C), 123.34 (C), 123.16 (CH), 120.89
(C), 113.42 (2 × CH), 61.71 (CH2), 55.65 (CH3), 14.23 (CH3).
A solution of n-BuLi (20 mmol, 12.5 ml, 1.6 M in hexanes) was
added to p-toluenesulfonylmethyl isocyanide (1.96 g, 10 mmol) dis-
solved in THF (100 mL) with stirring at –78 °C. To this mixture was
added via a cannular ethyl chloroformate (10 mmol, 0.96 mL) dis-
solved in THF (75 mL). The mixture was allowed to warm to ambi-
ent temperature and quenched with a sat. K2CO3 solution (25 mL)
and H2O (75 mL), and extracted. The aqueous fraction was left to
stand for 3 d and the oxazole product collected by filtration yielded
colourless needle-shaped crystals. Yield: 1.94 g (72%).
HRMS: m/z calcd for C14H14N2O5: 290.0903; found: 290.0916.
X-ray crystal structure file reference: CCDC 714242. Formula:
C14H14N2O5. Unit cell parameters: a = 10.7326(3), b = 11.4430(3),
c = 12.8689(4) Å; a = 81.253(2), b = 74.532(2), g = 64.739(2)°.
Space group: P1.
tR = 4.12; m/z = 268.88 (C12H13NO4S)+.
Ethyl 5-Tosylpyrrole-1H-3-carboxylate
General Procedure A: The Biotage separation used the elution 3 CV
25% Et2O, 4 CV 35% Et2O, 4 CV 40% Et2O, 8 CV 60% Et2O to give
a white crystalline solid. Yield: 0.211 g, 7% (purity >90%).
IR (neat): 3378.9 (m), 1618.8 (m), 1192.7 (s), 1132.6 (m), 1050.1
(m), 1015.3 (m), 814.2 (m), 693.1 (s), 665.2 (s) cm–1.
tR = 4.29; m/z = 294.71 (C14H16NO4S)–.
Synthesis 2009, No. 9, 1485–1493 © Thieme Stuttgart · New York

1492
I. R. Baxendale et al.
PAPER
(4) For a selection of the most generic methods see: (a) De
IR (neat): 3272.12 (m), 3142.07 (w), 2982.76 (w), 1687.44 (s),
1593.65 (w), 1552.28 (m), 1479.51 (w), 1437.97 (m), 1413.29 (m),
1387.88 (s), 1369.05 (w), 1337.42 (m), 1312.02 (s), 1302.43 (s),
1288.77 (m), 1256.65 (s), 1201.62 (s), 1140.13 (s), 1120.66 (m),
1092.66 (s), 1072.95 (m), 1022.58 (m), 966.34 (m), 950.79 (m),
913.19 (w), 875.41 (w), 842.77 (m), 832.01 (w), 814.49 (m), 776.34
(s), 733.98 (w), 704.97 (m), 676.99 (s) cm–1.
1H NMR (500 MHz, CDCl3): d = 10.30 (s, 1 H, 1H-pyr), 7.77 (m, 2
H, tosyl), 7.50 (q, J = 1.7 Hz, 1 H, 5H-pyr), 7.24 (d, J = 8.3 Hz, 2
H, tosyl), 7.09 (m, 1 H, 3H-pyr), 4.27 (q, J = 7.1 Hz, 2 H, CH2), 2.35
(s, 3 H, CH3), 1.29 (t, J = 7.1 Hz, 3 H, CH3).
Kimpe, N.; Abbaspour, T. K.; Stevens, C.; De Cooman, P.
Tetrahedron 1997, 53, 3693; and references cited therein.
(b) Crawley, M. L.; Goljer, I.; Jenkins, D. J.; Mehlmann,
J. F.; Nogle, L.; Dooley, R.; Mahaney, P. E. Org. Lett. 2006,
8, 5837. (c) Martin, R.; Rivero, M. R.; Buchwald, S. L.
Angew. Chem. Int. Ed. 2006, 45, 7079. (d) Larionov, O. V.;
de Meijere, A. Angew. Chem. Int. Ed. 2005, 117, 5809.
(e) Gorin, D. J.; Davis, N. R.; Toste, F. D. J. Am. Chem. Soc.
2005, 127, 11260. (f) Aydogan, F.; Demir, A. S.
Tetrahedron 2005, 61, 3019. (g) Chien, T.-C.;Meade, E. A.;
Hinkley, J. M.; Townsend, L. B. Org. Lett. 2004, 6, 2857.
(h) Ramanathan, B.; Keith, A. J.; Armstrong, D.; Odom,
A. L. Org. Lett. 2004, 6, 2957. (i) Trofimov, B. A.; Zaitsev,
A. B.; Schmidt, E. Y.; Vasil’tsov, A. M.; Mikhaleva, A. I.;
Ushakov, I. A.; Vashchenko, A. V.; Zorina, N. V.
13C NMR (125 MHz, CDCl3): d = 160.53 (C), 143.77 (C), 139.73
(C), 129.76 (CH), 127.26 (C), 126.98 (CH), 125.53 (CH), 124.84
(C), 114.02 (CH), 61.26 (CH2), 21.49 (CH3), 14.22 (CH3).
X-ray crystal structure file reference: CCDC 714244. Formula:
C29H31Cl3N2O8S2 (two molecules per unit with one molecule of
CHCl3). Unit cell parameters: a = 10.4955(2), b = 12.0180(3),
c = 14.0496(4) Å; a = 79.975(1), b = 76.909(1), g = 79.572(1)°.
Space group: P1.
Tetrahedron Lett. 2004, 45, 3789. (j) Almerico, A. M.;
Montalbano, A.; Diana, P.; Barraja, P.; Lauria, A.;
Cirrincione, G.; Dattolo, G. ARKIVOC 2001, (vi), 129.
(k) Trofimov, B. A.; Markova, M. V.; Morozova, L. V.;
Mikhaleva, A. I. ARKIVOC 2001, (ix), 24. (l) Trofimov,
B. A.; Tarasova, O. A.; Mikhaleva, A. I.; Kalinina, N. A.;
Sinegovskaya, L. M.; Henkelmann, J. Synthesis 2000, 1585.
(5) (a) Van Leusen, A. M.; Siderius, H.; Hoogenboom, B. E.;
van Leusen, D. Tetrahedron Lett. 1972, 52, 5337.
(b) ten Have, R.; Leusink, F. R.; van Leusen, A. M. Synthesis
1996, 871.
(6) (a) Barton, D. H. R.; Zard, S. Z. J. Chem. Soc., Chem.
Commun. 1985, 1098. (b) Barton, D. H. R.; Kervagoret, J.;
Zard, S. Z. Tetrahedron 1990, 21, 7587. (c) Bergman, J.;
Rehn, S. Tetrahedron 2002, 58, 9179.
(7) (a) Cohen, B. J.; Kraus, M. A.; Patchornik, A. J. Am. Chem.
Soc. 1977, 99, 4165. (b) Cainelli, G.; Contento, M.;
Manescalchi, F.; Regnoli, R. J. Chem. Soc., Perkin Trans. 1
1980, 2516. (c) Cohen, B. J.; Kraus, M. A.; Patchornik, A.
J. Am. Chem. Soc. 1981, 103, 7620. (d) Bergbreiter, D. E.
Chem.-Tech. 1987, 17, 686. (e) Brown, S. D.; Armstrong,
R. W. J. Am. Chem. Soc. 1996, 118, 331. (f) Wentworth, P.;
Janda, K. D. Chem. Commun. 1999, 1917.
Acknowledgment
We gratefully acknowledge financial support from the EPSRC (to
IRB), and the University of Milan (to LT). We also wish to make a
special thank you to Dr. J. E. Davis for determining the crystal
structures of the compounds and the EPSRC for a financial contri-
bution toward the purchase of the diffractometer.
References
(1) (a) Davies, D. T. Aromatic Heterocyclic Chemistry; OUP:
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(8) For selected reviews and application articles see:
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(b) Bhattacharyya, S. Mol. Diversity 2005, 9, 253.
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Baxendale, I. R.; Ley, S. V. Chem.–Eur. J. 2004, 10, 2529.
(d) Kirschning, A.; Wittenberg, R. In Merging Solid-Phase
and Solution-Phase Synthesis - The “Resin-Capture-
Release” Hybrid Technique, Organic Synthesis Highlights
V; Wiley-VCH: Weinheim, 2003, 265–279. (e) Ley, S. V.;
Baxendale, I. R. Chem. Rec. 2002, 2, 377. (f) Ley, S. V.;
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Synthesis 2009, No. 9, 1485–1493 © Thieme Stuttgart · New York

PAPER
(9) PS-BEMP refers to 2-tert-butylimino-2-diethylamino-1,3-
Synthesis of Nitrosubstituted Pyrroles
1493
products following addition to the nitrostyrene were
dimethylperhydro-1,3,2-diazaphosphorine on polystyrene
2% DVB, loading 2.2 mmol/g. Commercially available from
Aldrich Cat No. 20026-XXG where XX is the quantity in
grams.
conducted using sub-stoichiometric quantities to quench the
original TosMIC anion. These reactions gave comparable
crude mixtures accompanied by the components from the
standard Barton–Zard condensation. The possibility that the
TosMIC could still act as a leaving group and consequently
as an ethyl formate transfer agent can still not be excluded.
(14) The reaction between the lithio enolate 4 and ethyl acrylate
gave only a mixture of products from which only 7% of a
rearrangement product (ethyl 5-tosylpyrrole-1H-3-
(10) PS-TBD refers to 1,5,7-triazabicyclo[4.4.0]dec-5-ene–
polystyrene cross-linked with 2% DVB, loading 1.33 mmol/
g. Commercially available from Biotage Cat. No. 800422.
(11) Available from Varian Inc. named as Bond Elut silica
packed cartridges.
(12) Fornicola, R. S.; Oblinger, E.; Montgomery, J. J. Org. Chem.
1998, 63, 3528.
carboxylate) could be isolated. 1H NMR and X-ray analysis
was used to confirm the structure.
(13) Experiments to try and exclude the possibility of excess
ethyl chloroformate being responsible for the secondary
Synthesis 2009, No. 9, 1485–1493 © Thieme Stuttgart · New York