A general approach to polysubstituted pyrroles

Article abstract of DOI:10.1016/j.tetlet.2007.08.097

Exposure of a range of 3-hydroxy-2-sulfonylamino-4-alkynes to excess iodine delivers good yields of a series of iodopyrroles. Unexpectedly, the hydroxyl-dihydropyrroles, which were assumed to be the first-formed intermediates, turn out to be stable entities which have been isolated for the first time.

Full text of DOI:10.1016/j.tetlet.2007.08.097

Tetrahedron Letters 48 (2007) 7906–7910
A general approach to polysubstituted pyrroles
David W. Knight,* Heinz C. Rost, Christopher M. Sharland and Jirada Singkhonrat
School of Chemistry, Cardiff University, Main College, Park Place, Cardiff CF10 3AT, UK
Received 24 July 2007; accepted 21 August 2007
Available online 31 August 2007
Abstract—Exposure of a range of 3-hydroxy-2-sulfonylamino-4-alkynes to excess iodine delivers good yields of a series of iodo-
pyrroles. Unexpectedly, the hydroxyl-dihydropyrroles, which were assumed to be the first-formed intermediates, turn out to be
stable entities which have been isolated for the first time.
ꢀ 2007 Elsevier Ltd. All rights reserved.
When used in heterocyclic syntheses, halocyclisations1
are distinguished by the fact that not only is the hetero-
cycle formed in often excellent yield and, where relevant,
with often high levels of stereocontrol, but also that a
synthetically useful halogen atom is incorporated. This
is illustrated by an approach to b-iodofurans 3, which
we reported some time ago, wherein a series of 3-
alkyne-1,2-diols 1 undergo smooth overall 5-endo-dig
cyclisation to give good to excellent yields of the final
products 3, presumably via the initially formed
dihydrofurans 2 (Scheme 1).2 As all attempts to isolate
or even observe the latter intermediates failed, we as-
sume that the initial iodocyclisation is the rate determin-
ing step.
shown in Scheme 1 to examples having various modified
amino groups as the nucleophile, with a view to develop-
ing new pyrrole syntheses, along perhaps with other aza-
heterocycles. Certainly, such an idea is not completely
without precedent: in a remarkable and seemingly
unique contribution, Overhand and Hecht used a
mercury(II)-induced 5-endo-dig cyclisation of alkynone
4 to obtain heterocycle 5, the global reduction of which
led to the natural product Preussin 6 (Scheme 2).4
We had previously reported an approach to pyrrole-2-
carboxylates 8 by a double elimination of the elements
of hydrogen iodide and p-toluenesulfinic acid from
iodo-pyrrolidines 7,5 obtained from the corresponding
homoallylic sulfonamides by a 5-endo-trig iodocyclisa-
tion (Scheme 3).6 Arguably, this is one of the less useful
transformations involving these initial products 7, as the
two potentially useful functional groups are lost.
Of course, the iodine atom which is inevitably incorpo-
rated now provides the means for final homologations
to fully substituted furans by the application of one of
a plethora of coupling reactions now available, by halo-
gen–metal exchange or by radical formation. At the time
of our first foray into the area of 5-endo-dig cyclisations,
such reactions were somewhat obscure, but have
recently been shown capable of making a significant
contribution to heteroaromatic synthesis.3 We were
intrigued by the prospects of extending the chemistry
However, a combination of the successful Preussin
synthesis and a desire to access pyrroles more directly
led us to examine similar cyclisations of homopropar-
gylic sulfonamides, which proved successful as a rela-
tively general protocol for pyrrole synthesis.7 This
then set the stage for, potentially, the most direct route
to b-iodopyrroles, which would be to carry out such
5-endo-dig cyclisations on suitable nitrogen analogues
R2
HO R2
R1
I
R2
R1
I
HO
R3
I2
-H2O
O
R1
R3
R3
O
HgCl
C9H19
HO
Ph
OH
O
O
Hg2+
C9H19
1
2
3
NHBoc
Ph
C9H19
N
N
Boc
Me
Ph
Scheme 1.
4
5
6
*
Scheme 2.
Corresponding author. E-mail: knightdw@cf.ac.uk
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.08.097

D. W. Knight et al. / Tetrahedron Letters 48 (2007) 7906–7910
Table 1. Iodocyclisations of sulfonamides 11
7907
I
DBU
R
I
OH
CO2Et
I
R
CO2Me
R
CO2Me
OH
N
N
H
i)
ii)
Ts
R
R
CO2Et
N
N
7
8
TsHN
CO2Et
Ts
Ts
11
12
13
Scheme 3.
Entry
R
% yield 12
% yield 13
of 3-alkyne-1,2-diols 1, used in our furan synthesis
(Scheme 1). Herein, we report in preliminary form on
the successful outcomes of various versions of this idea,
which have led to the definition of a new, broadly
applicable pyrrole synthesis, as well as to an unex-
pected surprise—the isolation of the intermediate
hydroxy-dihydropyrroles as stable entities.
1
2
Ph
Bu
BzO(CH2)3
TBSO(CH2)3
TBSO(CH2)4
Cyclohex-2-en-1-ylethyl
tBu
Ph
93
93
96
91
92
86
51a
83
65
66
73
65
74
3
4
5
6
d
7
—
b
8
—
98
56
84e
c
9
10
Isopropenyl
Bu
—
Our first efforts were centred on the development of a
rapid route to 3-hydroxy-2-sulfonylamino-4-alkynoates
11, which we anticipated could be precursors of substi-
tuted pyrrole-2-carboxylates (cf. Scheme 1). These, we
found, could be prepared routinely in reasonable overall
yields from 1-alkynes 9 by sequential formylation using
the excellent protocol developed and explained by Jour-
net et al.8 and condensation of the resulting conjugated
ynals 10 with the tin(II) enolate derived from methyl N-
tosyl glycinate using the method developed by Kazmaier
(Scheme 4).9 Unexpectedly, the anti-diastereoisomers 11
turned out to be the major products.10
—
Reagents and conditions: (i) 3 equiv iodine, 3 equiv K2CO3, MeCN,
20 ꢁC, 2–16 h; (ii) 1.1 equiv MsCl, 2.2 equiv Et3N, CH2Cl2, 20 ꢁC, 16 h.
a The iodocyclisation was carried out in 1:1 MeCN–H2O at 20 ꢁC for
72 h.
b The crude product (78 mg) was left in chloroform solution for 24 h,
by which time it was completely converted into the iodopyrrole.
c Iodocyclisation was carried out using IBr (3 equiv) and NaHCO3
(3 equiv) in dichloromethane at 20 ꢁC for 2 h, which gave a 3:1
mixture of hydroxy-dihydropyrrole and pyrrole-2-carboxylates.
Immediate dehydration [MsCl, py, CH2Cl2, 0 ꢁC, 1 h] gave 56% yield
of the iodopyrrole.
d Dehydration using PPTS in hot toluene for 16 h gave only ca. 10–
15% yields of the deiodopyrrole.
e Iodocyclisation using 3 equiv each of IBr and NaHCO3 in MeCN for
16 h gave only the iodopyrrole.
We were very pleased to discover that exposure of a rep-
resentative series of such sulfonamides 11 to a typical set
of iodocyclisation conditions [3 equiv I2, 3 equiv K2CO3,
MeCN, 20 ꢁC] resulted in a controlled loss of the start-
ing material and the emergence of a single product.
Upon quenching the excess iodine using sodium sulfite
followed by a simple aqueous work-up, we were amazed
to find that the isolated products were in fact hydroxy-
dihydropyrroles 12 (Table 1, entries 1–6). While clearly
not pyrroles, these products were recognised by charac-
creation which would accrue upon dehydration to iodo-
pyrrole-2-carboxylates 13. To the best of our knowl-
edge, only one set of examples of this structural type
has been reported, from related studies in which sub-
strates 11 were cyclised using copper(I) catalysts.13
1
teristic resonances in their H NMR spectra, along with
To return to the central cyclisation (Table 1), this ap-
pears to be of a reasonably broad scope. Both simple
aryl and alkyl substituents are tolerated (entries 1 and
2), and there was no interference from the protected
hydroxyl groups in the hydroxypropyl derivatives
(entries 3 and 4; potential 5-exo- or 6-endo-dig) or in
the hydroxylbutyl analogue (entry 5; potential 6-exo-
dig). A relatively remote alkene group (entry 6) also
remained unmolested. However, problems did arise
when trying to form the rather crowded t-butyl deriva-
tive (entry 7) when somewhat different cyclisation condi-
tions had to be used; even then, the yield was much
lower than was typical, presumably due to extreme steric
hindrance.
other supportive spectroscopic and analytical data.11
Although not requiring any significant purification, all
these compounds proved stable to silica gel column
chromatography.
Isolation of the major diastereoisomers 12 (typically
from a ca. 9:1 mixture of anti/syn-isomers10), while not
set up for E2 elimination, was unexpected, especially in
view of the failure to even observe the related intermedi-
ates 2, examples of which have been reported previ-
ously,12 in the furan synthesis (Scheme 1). This was, of
course, exacerbated by the driving force of aromaticity
R
R
i)
ii)
OH
As might be expected, the very stability of hydroxyl-
dihydropyrroles 12 did pose some problems in complet-
ing the projected syntheses of iodopyrrole-2-carboxyl-
ates 13. While the latter could be obtained using a
number of well established procedures, both acidic and
basic, in our hands a workable but perhaps not optimal
procedure was the elimination of the derived mesylates,
formed in situ without isolation. In this way, around
70% isolated yields of iodopyrrole-2-carboxylates 13
R
O
TsHN
CO2Et
9
10
11
Scheme 4. Reagents and conditions: (i) BuLi, ꢀ78 ꢁC, THF, then
DMF and reverse quench with NH4Cl (aq) [Ref. 8]; (ii)
TsHNCH2CO2Et, 2ÆLDA, THF, ꢀ78 ꢁC, 2ÆSnCl2, then 1 equiv 10
[Ref. 9].

7908
D. W. Knight et al. / Tetrahedron Letters 48 (2007) 7906–7910
Table 2. Iodocyclisation of precursors 15 with tertiary OH groups
could be routinely obtained (Table 1; entries 1–6). In the
case of the highly hindered t-butyl derivative (entry 7), a
pyrrole was only formed upon heating with pyridinium
p-toluenesulfonate (PPTS) in toluene which proved to
be a low yield of deiodinated material, again reflecting
both the extreme steric hindrance and the reversibility
of the iodocyclisation. In an isolated example with the
5-phenyl example (entry 8), essentially quantitative, pre-
sumably acid-catalysed, dehydration was observed for
an NMR sample left in CDCl3 overnight. However, de-
spite a number of attempts, this method was never satis-
factorily scaled up. In the case of the rather sensitive 2-
propenyl derivative (entry 9), cyclisation was carried out
using a combination of iodine monobromide and the
weaker base, sodium hydrogen carbonate, to give a mix-
ture of products, convertible to the final iodopyrrole
again using the mesyl chloride method. This same meth-
od when applied to the butyl-substituted precursor [11;
R = Bu] delivered the corresponding iodopyrrole-2-car-
boxylate [13; R = Bu] directly in very good yield (Entry
10). In other examples, the use of similar reagents and
conditions gave mixtures of the two products.
OH
R
I
I
R
i)
ii)
15
Ph
CO2Et
Ph
CO2Et
N
N
Ts
Ts
16
17
Entry
R
% yield 16
% yield 17
1
2
3
Me
C7H15
iPr
95a
71b
67
79
82c
c
—
Reagents and conditions: (i) 3 equiv iodine, 3 equiv K2CO3, see notes,
20 ꢁC, 2–16 h; (ii) 1.1 equiv MsCl, 2.2 equiv Et3N, CH2Cl2, 20 ꢁC, 16 h.
a The solvent was MeCN.
b The solvent was CH2Cl2.
c Iodocyclisation using 3 equiv IBr and 4 equiv NaHCO3 in CH2Cl2 at
ꢀ10 ꢁC for 2 h to give a 4:3 ratio of dihydropyrrole and pyrrole.
Dehydration using MsCl, py in CH2Cl2 at reflux for 16 h gave the
overall 82% yield.
sor synthesis, we used the two symmetrical alkenes 18
as starting materials (Scheme 6). Amino-hydroxyl-
ation14 gave good yields of the partly-protected amino-
alcohols 19, which were then oxidised to the correspond-
ing amino-ketone derivatives 20.15 Direct addition of a
lithio-acetylide then gave the necessary precursors 21
as stereoisomeric mixtures.
The viability of this type of cyclisation was also tested
on more highly substituted precursors with the aim of
obtaining fully substituted pyrroles. We were also intri-
gued to learn if such a sequence would result in a more
facile dehydration of the tertiary alcohol present. The
first few examples were prepared using our previously
developed methodology but starting with alkynones
14; perhaps surprisingly, the tin(II) enolate of methyl
N-tosyl glycinate was added with the same sense of ste-
reoselectivity to again give very largely the anti-isomers
15 (Scheme 5).10
That the carboxylate group had little influence on the
foregoing examples was established when it was found
that such precursors underwent equally smooth cyclisa-
tion to give the isolable hydroxy-dihydropyrroles 22 and
thence the fully substituted iodopyrroles 23 (Table 3).
The slightly lower yields of intermediate 22 reflect the
fact that some premature dehydration occurred, such
that these were isolated admixed with ca. 5–15% of iod-
opyrroles 23. Clearly, less symmetrical examples will be
readily accessed by starting with alternatives to the
amino-alcohols or -ketones 19 or 20.15
All these substrates underwent smooth iodocyclisation,
although the outcome was again dependent upon the
conditions: using potassium carbonate as the base al-
lowed for the isolation of the intermediate hydroxy-
dihydropyrroles 16 in good yields (Table 2). In contrast,
the use of sodium hydrogen carbonate led to extensive
dehydration, even under relatively mild conditions.
Once again, dehydration was carried out as a separate
step, by mesylation, and gave the final iodopyrroles 17
in ca. 80% purified yields. Hence, even though all these
examples contained a tertiary alcohol, dehydration, pre-
sumably via an E1cB mechanism, was just as demanding
as in previous, less substituted, examples.
A series of ‘pseudo’-symmetrical examples 27 were also
prepared in a final demonstration of the utility of this
methodology (Table 4). Thus, reaction between an N-
tosyl a-amino-ester 24 and an excess of a lithiated
1-alkyne led to good yields of the double addition prod-
ucts 25, which behaved well in the central cyclisation
reaction to give excellent yields of the hydroxy-dihydro-
pyrroles 26. In the valine-derived examples (entries 3
and 4), significant dehydration to the pyrroles 27 was
So far, all examples have contained an a-carboxylate
group, mainly for synthetic expedience in terms of pre-
cursor synthesis. To check whether the other types of
substrates were amenable to these cyclisations, and to
also demonstrate the viability of an alternative precur-
R1
R2
R2
R2
OH
R2
R2
O
OH
R2
i)
ii)
iii)
R2
TsHN
TsHN
R2
TsHN
Ph
OH
R
Ph
18
19
20
21
ref. 9
O
[Scheme 4]
Scheme 6. Reagents and conditions: (i) 3 equiv chloramine-T,
R
(DHQD)2-PHAL (cat.), K2OsO2(OH)2 (cat.), tBuOH–H2O (1:1),
TsHN
CO2Et
R = Me, C7H15, iPr
16 h, 20 ꢁC [75–85%]; (ii) 3.8 equiv PCC, 4 A mol. sieves, CH2Cl2,
˚
14
15
16 h, 20 ꢁC [85–90%]; (iii) 2.5 equiv 1-alkyne, add 2.5 equiv BuLi,
ꢀ30 ꢁC, THF, 1 h, then add 1 equiv 20, 16 h, 20 ꢁC [80–85%].
Scheme 5.

D. W. Knight et al. / Tetrahedron Letters 48 (2007) 7906–7910
7909
Ph
Ph
Table 3. Cyclisation of precursors 21 lacking a carboxylate group
OH
I
Ph
Ph
Ph
Ph
PhB(OH)2, Pd(PPh3)4
R2
MeOH, C6H6
R2
I
I
Ph
N
N
2M aq. Na2CO3, reflux, 16h
i)
ii)
Ts
Ts
30 [82%]
21
23 [R1, R2 = Ph]
R1
R2
R1
R2
N
N
Ts
Ts
Scheme 7.
22
23
Entry
R1
R1
% yield 22
% yield 23
1
2
3
Bu
Ph
Bu
Ph
Ph
Me
80
73
71
88
93
91
It was shown some time ago that b-iodopyrroles in gen-
eral are suited to Suzuki coupling reactions and, hence,
probably to many other related homologations.16 In this
respect, the tosyl group and, where relevant, the 2-car-
boxylate groups, will play a useful role in reducing the
electron density of these otherwise electron-rich hetero-
cycles and, hence, aid such reactions by encouraging the
initial oxidation addition of Pd(0) to the C–I bond.
Other N-protecting groups were not tested, as the tosyl
function proved highly suitable throughout the precur-
sor syntheses and the central cyclisations. Significantly
and in contrast to many other types of sulfonamides,
such tosyl groups are readily removed from pyrrole
derivatives in general by reason of the latter’s relatively
low pKa values (ca. 17.5). However, the functionality is
not sufficiently delicate that it is lost in a standard
Suzuki coupling: homologation of iodopyrrole [23;
R1 = R2 = Ph] using phenylboronic acid and sodium
carbonate as base gave an unoptimised 82% yield of
the tetraphenylpyrrole 30 (Scheme 7).
Reagents and conditions: (i) 3 equiv iodine, 3 equiv K2CO3, CH2Cl2,
20 ꢁC, 16 h; (ii) 1.1 equiv MsCl, 2.2 equiv Et3N, CH2Cl2, 20 ꢁC, 16 h.
Table 4. Cyclisation of bis-alkynyl precursors 25
R1
R1
OH
R2
OH
I
CO2Me
R2
i)
ii)
TsHN
R1
R2
TsHN
R2
N
Ts
24
25
26
iii)
R1
I
R1
R2
N
Ts
27
In conclusion, we would suggest that the present
schemes represent generally useful and relatively efficient
routes to a large range of pyrroles. The unexpected iso-
lation of the various hydroxy-dihydropyrroles, also in
generally good yields, adds a further dimension to this
methodology, which we are at present exploring.
Entry
R1
R1
% yield 26
% yield 27
1
2
3
4
Bu
Ph
Bu
Ph
Me
Me
iPr
iPr
90
87
65
91
67
69
a
—
—
a
Reagents and conditions: (i) 3.5 equiv R1CCLi, THF, ꢀ78 ꢁC to 0 ꢁC
[ꢁ90%]; (ii), (iii) as Table 3, (i) and (ii).
a As a mixture with the corresponding iodopyrrole.
Acknowledgements
We are very grateful to the Erasmus scheme, to the gov-
ernment of Thailand and to the EPSRC for the financial
support.
observed. As in many of the foregoing examples, this fi-
nal dehydration step was satisfactory, if not exactly
spectacularly efficient. The intermediate dihydropyrroles
26 were isolated very largely as single diastereoisomers.
Although not proven, we speculate that the more
favourable conformation for the cyclisation step may
be that shown as formula 28, which benefits both from
an equatorial-like position of the substituent R2, as well
as intramolecular hydrogen bonding between the hydro-
xyl and sulfonamide groups. This implies that the result-
ing stereoisomers 29 would be the major products,
making their isolation all the more remarkable by rea-
son of the anti relationship between the a-protons and
the hydroxyl groups.
References and notes
1. Knight, D. W. Prog. Heterocycl. Chem. 2002, 14, 19–51;
French, A. M.; Bissmire, S.; Wirth, T. Chem. Soc. Rev.
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1996, 1007–1008; Evans, A. B.; El-Taeb, G. M. M.; Jones,
S.; Knight, D. W. Tetrahedron Lett. 2001, 42, 5945–5948.
3. For recent summaries of both 5-endo-dig cyclisations and
other related electrophile-driven heterocyclic syntheses,
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C. J. Org. Chem. 2007, 72, 1347–1353; Larock, R. C. Top.
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5. Jones, A. D.; Knight, D. W.; Hibbs, D. E. J. Chem. Soc.,
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R1
R1
R1
HO
N
I
NHTs
R1
R2
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O
H
H
Ts
6. Knight, D. W.; Redfern, A. L.; Gilmore, J. J. Chem. Soc.,
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28
29

7910
D. W. Knight et al. / Tetrahedron Letters 48 (2007) 7906–7910
7. Knight, D. W.; Redfern, A. L.; Gilmore, J. J. Chem. Soc.,
3.45–3.55 (1H, br s, OH), 3.89 (2H, q, J = 7.1 Hz, OCH2),
4.02–4.08 (1H, app. br s, 2-H), 4.29–4.34 (1H, app. br s,
3-H), 7.26 (2H, d, J = 8.3 Hz, 2 · ArH), 7.68 (2H, d,
J = 8.3 Hz, 2 · ArH); dC (CDCl3, 100 MHz) 14.2 (Me),
14.4 (Me), 22.1 (ArMe), 22.6 (CH2), 29.9 (CH2), 30.1
(CH2), 62.8 (OCH2), 70.1 (CH), 79.5 (4-C–I), 80.6 (CH),
128.1 (2 · ArCH), 130.4 (2 · ArCH), 134.5 (ArC), 144.2
(ArC), 170.2 (C@O); m/z (ES) 494 (M+H+, 45%), 476
(M+H+ꢀH2O, 100). [Found: M+H+, 494.0499.
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11. A typical procedure is as follows: (2SR,3RS)-Ethyl 5-
butyl-3-hydroxy-4-iodo-1-(4-toluenesulfonyl) 2,3-dihydro-
pyrrole-2-carboxylate 12; entry 2, Table 1: To a vigorously
stirred mixture of (2SR,3SR)-ethyl 2-(4-toluenesulfonyl-
amino)-3-hydroxynon-4-ynoate 11 (0.50 g, 1.36 mmol)10
and finely ground anhydrous potassium carbonate
(0.55 g, 4.1 mmol) in dry acetonitrile (12 ml) cooled in an
ice-water bath was slowly added a solution of iodine
(1.04 g, 4.1 mmol) in dry acetonitrile (20 ml). The resulting
purple suspension was stirred without further cooling for
16 h, then quenched by the addition of saturated aqueous
sodium thiosulfate, until the iodine colouration disap-
peared. The organic layer was separated and the aqueous
layer extracted with dichloromethane (3 · 15 ml). The
combined organic solutions were washed with brine
(20 ml), then dried (MgSO4), filtered through a plug of
silica gel and evaporated to leave essentially a pure
hydroxy-dihydropyrrole 12, entry 2, as a yellow oil
(0.625 g, 93%) which showed mmax (film) 3490, 1735,
12. For very early examples, see: Denss, R.; Girod, E.;
Hafliger, F.; Eugster, C. H. Helv. Chim. Acta 1959, 42,
1191–1193; More recent examples include: Gomez, A. M.;
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J. C.; Townsend, L. B. J. Org. Chem. 2003, 68, 4170–4178;
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L. A.; Gold, B. J. Am. Chem. Soc. 2005, 127, 12657–
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13. Knight, D. W.; Sharland, C. M. Synlett 2004, 119–121.
14. Fokin, V. V.; Sharpless, K. B. Angew. Chem., Int. Ed.
2001, 40, 3455–3457, and references cited therein; Muniz,
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2544–2548; For a direct method, see: Villar, A.; Ho¨vel-
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1628, 1597, 1457, 1354, 1166, 1090, 1028, 912, 666 cmꢀ1
;
16. Wang, J. J.; Scott, A. I. Tetrahedron Lett. 1995, 36, 7043–
7046; For a general overview of this type of chemistry, see:
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dH (CDCl3, 400 MHz) 0.86 (3H, t, J = 7.2 Hz, 40-Me),
1.06 (3H, t, J = 7.1 Hz, OCH2Me), 1.27 (2H, hextet,
J = 7.2 Hz, 30-CH2), 1.41 (2H, quintet, J = 7.2 Hz, 20-
CH2), 2.33 (3H, s, ArMe), 2.56–2.66 (2H, m, 10-CH2),