5-Endo-dig cyclisations of homopropargylic sulfonamides: A new route to 2,3-dihydropyrroles and β-iodopyrroles

Article abstract of DOI:10.1039/a806386i

5-endo-dig Iodocyclisations of the homopropargylic sulfonamides 12a-c and 13 give excellent yields of the iododihydropyrroles 14a-d and thence the β-iodopyrroles 15a-d, following base-catalysed elimination of sulfinic acid.

Full text of DOI:10.1039/a806386i

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5-endo-dig Cyclisations of homopropargylic sulfonamides: a new route to
2,3-dihydropyrroles and b-iodopyrroles
David W. Knight,*a† Adele L. Redferna and Jeremy Gilmoreb
a Chemistry Department, Cardiff University, PO Box 912, Cardiff, UK CF1 3TB
b Eli Lilly and Co. Ltd., Lilly Research Centre, Erl Wood Manor, Windlesham, Surrey, UK GU20 6PH
5-endo-dig Iodocyclisations of the homopropargylic sulfo-
namides 12a–c and 13 give excellent yields of the iododihy-
dropyrroles 14a–d and thence the b-iodopyrroles 15a–d,
following base-catalysed elimination of sulfinic acid.
We have recently reported that (E)-homoallylic tosylamides 1
(R1, R2 = alkyl, aryl) undergo highly efficient and stereoselec-
tive iodocyclisations to give the 2,5-trans iodopyrrolidines 2 in
the presence of a base such as K2CO3, seemingly via a well-
defined chair-like transition state conformation. In contrast, in
the absence of a base, the corresponding 2,5-cis diastereo-
isomers 3 are obtained exclusively by acid-catalysed isomeriza-
tion of the initial products 2 (Scheme 1).1 Although apparently
Scheme 3
Scheme 1
further elaboration; however, at the outset, we had no idea
whether these would be stable compounds. We were en-
couraged by the fact that, perhaps at first sight surprisingly and
in direct contrast to the 5-endo-trig mode, 5-endo-dig cyclisa-
tions are favoured under Baldwin’s rules.2 Herein, we report on
a first successful implementation of the approach shown in
Scheme 3.
The success of the pyrrolidine and pyrrole syntheses
(Schemes 1 and 2) naturally led us to choose as a first option the
toluene-p-sulfonyl (tosyl) group to mask the amine nitrogen; the
routes used to obtain representative substrates are shown in
Scheme 4. The benzophenone imine of methyl glycinate 96 was
5-endo-trig cyclisations, we do not regard these as exceptions to
Baldwin’s rules2 as the process is electrophile- rather than
nucleophile-driven; other aspects of our own studies and those
of other research groups appear to substantiate this principle.3
More recently, we have found that the method can be readily
extended to include preparations of both 2,5-trans and 2,5-cis
isomers of the substituted prolines 4 and that these undergo a
double elimination of both HI and toluene-p-sulfinic acid upon
warming with DBU in DMF, giving excellent yields of the
pyrrole-2-carboxylates 5 (Scheme 2).4
Scheme 2
While this is a useful route to such pyrroles and is related to
the established Kenner method, we felt that it was something of
a backward step to lose this degree of functionality during the
elimination, especially the iodine atom which could otherwise
provide a handle for further elaboration. It was with this in mind
that we wondered if it might be possible to effect similar
cyclisations of related homopropargylic amine derivatives,
inspired by our recent success in an approach to highly
substituted furans.5 The idea of working at this higher oxidation
state is outlined in Scheme 3. If a suitably protected propargylic
(prop-2-ynylic) amine 6 were to undergo a 5-endo-dig cyclisa-
tion, the resulting dihydropyrroles 7 might then be amenable to
elimination of the protecting group, leading to pyrroles 8, in
which the electrophilic species used to trigger cyclisation is
retained and hence would be available for additional reactions.
Further, the dihydropyrrole species 7 might well be useful for
Scheme 4 Reagents and conditions: i, propargyl bromide, K2CO3, Bu4Nl,
MeCN, reflux, 7 h; ii, 2 m aq. HCl, Et2O, 20 °C, ca. 1 h, then TsCl, Et3N,
DMAP (cat.), CH2Cl2, 20 °C, 15 h; iii, Arl, CuI (cat.), Pd(PPh3)4 (cat.),
Et2NH, 20 °C, ca. 3 h (TLC monitoring); iv, as i, using 1-bromopent-
2-yne
Chem. Commun., 1998
2207

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Lilly and Co. Ltd and the EPSRC for financial support through
the CASE Scheme.
Notes and References
† E-mail: knightdw@cf.ac.uk
‡ All compounds reported herein gave satisfactory microanalytical and
spectroscopic data.
Scheme 5 Reagents and conditions: i, I2, K2CO3 (3 equiv. each), dry MeCN,
0–20 °C, 14 h; ii, DBU (2.1 equiv.), DMF, 20 °C, 14 h
1 A. D. Jones and D. W. Knight, Chem. Commun., 1996, 915.
2 J. E. Baldwin, J. Chem. Soc., Chem. Commun., 1976, 734 and 738.
3 S. H. Kang and S. B. Lee, Tetrahedron Lett., 1993, 34, 1955, 7579;
J. M. Barks, D. W. Knight, C. J. Seaman and G. G. Weingarten,
Tetrahedron Lett., 1994, 35, 7259; B. H. Lipshutz and T. Gross, J. Org.
Chem., 1995, 60, 3572; K. Chibale and S. Warren, J. Chem. Soc., Perkin
Trans. 1, 1996, 1935; M. B. Berry, D. Craig, P. S. Jones and
G. J. Rowlands, Chem. Commun., 1997, 2141; O. Andrey, L. Ducry,
Y. Landais, D. Planchenault and V. Weber, Tetrahedron, 1997, 53,
4339; B. H. Lipshutz and T. Gross, J. Org. Chem., 1995, 60, 3572 and
references cited therein in each.
4 D. W. Knight, A. L. Redfern and J. Gilmore, Synlett, 1998, 731.
5 S. P. Bew and D. W. Knight, Chem. Commun., 1996, 1007.
6 M. J. O’Donnell and R. L. Polt, J. Org. Chem., 1982, 47, 2663.
7 A. Lopez, M. Moreno-Manas, R. Pleixats, A. Roglans, J. Ezquerra and
C. Pedregal, Tetrahedron, 1996, 52, 8365.
Scheme 6
alkylated7 with propargyl bromide and the N-protecting group
of the resulting propargyl glycine 10 exchanged for a tosyl
group. Sonogashira coupling8 of the sulfonamide 11 so obtained
with representative iodides provided excellent yields of the
cyclisation substrates 12. An alkyl derivative 13 was obtained
using 1-bromopent-2-yne as the alkylating agent, followed by
protecting group exchange.‡ An alternative strategy involving
couplings between aryl iodides and the imine 10 was un-
successful. We were delighted to find that exposure of the
sulfonamides 12 and 13 to 3 equiv. of I2 and K2CO3 in dry
MeCN at ambient temperature resulted in slow but clean
cyclisation to give excellent isolated yields of the iododihy-
dropyrroles 14 (Scheme 5).9 The aryl derivatives 14a–c turned
out to be stable crystalline solids with sharp melting points,
whereas the alkyl derivative 14d was a somewhat sensitive oil
which nevertheless could be fully characterized.‡ Further, by
stirring these dihydropyrroles 14 with DBU in DMF at ambient
temperature, excellent yields of the corresponding iodopyrroles
15 were obtained by elimination of toluene-p-sulfinic acid
(Scheme 5).‡ It was important to use 2 equiv. of the base; if only
1 equiv. was used, then approximately 50% of the product was
the deiodopyrrole 16, along with the expected product 15
(Scheme 6). We assume that the released sulfinic acid is
responsible for this deiodination, perhaps by attack at iodine by
sulfur, leading to the sulfonyl iodide, a process greatly reduced
by the presence of an additional equivalent of base. Proton-
catalysed cycloreversion, with loss of iodine, cyclisation and
elimination is another possibility.
Both iodinated species 14 and 15 have potential for further
elaboration, especially using one of the many transition metal-
catalysed coupling procedures currently available. b-Io-
dopyrroles have recently been shown to undergo both Stille10
and Sonogashira couplings.11 In the present work we have
established that the iododihydropyrroles 14 are compatible with
palladium catalysts. Thus, a rapid Sonogashira coupling
between dihydropyrrole 14a and phenylacetylene [CuI (0.2
equiv.), Pd(PPh3)4 (0.1 equiv.), Et2NH, 20 °C, 2 h] delivered an
82% isolated yield of the enyne 17, suggesting that they will
prove to be useful synthetic intermediates. These aspects and
further studies of the scope and limitations of this chemistry are
currently being pursued.
8 K. Sonogashira, Comp. Org. Synth., 1991, 3, 521.
9 Typical experimental procedure for 14b: The tosylamide 12b (70 mg,
0.20 mmol) was stirred in dry MeCN (1 ml) containing anhydrous
K2CO3 (84 mg, 0.61 mmol) and cooled in an ice bath. I2 (153 mg, 0.61
mmol) in MeCN (0.6 ml) was added dropwise and the resulting
suspension stirred overnight without the addition of further coolant.
Saturated aq. sodium thiosulfate was then added until the excess I2 was
decolourized and the organic layer separated. The aqueous layer was
extracted with CH2Cl2 (2 3 5 ml) and the combined organic solutions
dried (MgSO4) and evaporated. Column chromatography of the residue
(6:1 hexane–EtOAc) gave 14b (74 mg, 78%) as a pale yellow solid, mp
88–92 °C, nmax/cm21 2953, 1742, 1597, 1437, 1361, 1212, 1170, 1089,
1017; dH(CDCl3; 400 MHz) 2.45 (3H, s, Ar-CH3), 2.59 (1H, dd, J 17.1
and 9.7, 3-Ha), 2.85 (1H, dd, J 17.1 and 2.4, 3-Hb), 3.82 (3H, s, OCH3),
4.83 (1H, dd, J 9.7 and 2.4, 2-H), 6.50 (1H, dd, J 3.4 and 1.8, 4A-H), 6.89
(1H, d, J 3.4, 3A-H), 7.31 (2H, d, J 8.2, 2 3 Ar-H), 7.47 (1H, app. br s,
5A-H), 7.60 (2H, d, J 8.2, 2 3 Ar-H); dC(CDCl3; 100 MHz) 21.6 (Ar-
CH3), 43.5 (3-CH2), 53.1 (OCH3), 62.2 (2-CH), 77.6 (4-C), 111.0
(4A-CH), 113.9 (3A-CH), 127.8 (2 3 Ar-CH), 129.6 (2 3 Ar-CH), 133.5
(C), 135.8 (C), 143.1 (5A-CH), 144.6 (C), 144.8 (C) and 170.6 (CO); m/z
(EI) 473 (M+, 27%), 318 (17), 191 (88), 159 (51), 132 (56), 104 (55), 91
(100) [Found: C, 42.8; H, 3.4; N, 3.1. C17H16INO5S requires C, 43.1; H,
3.4; N, 3.0%]. For elimination of toluene-p-sulfinic acid: To a stirred
solution of the 14 (1 mmol) in dry DMF (5 ml) at ambient temperature,
DBU (0.3 ml, 2.1 mmol) was added dropwise and the elimination
followed by TLC. Upon completion (ca. 12 h), 2 m HCl (5 ml) was
added and the resulting mixture extracted with hexane (4 3 20 ml). The
combined extracts were dried (MgSO4) and concentrated, then passed
through a short silica plug; evaporation of the filtrate left the pure
iodopyrrole 15. Selected data for 15b: pale yellow solid, mp
120–124 °C; nmax/cm21 3282, 2951, 1697, 1508, 1437, 1395, 1317,
1262, 1203; dH(CDCl3; 400 MHz) 3.88 (3H, s, OCH3), 6.53 (1H, dd, J
3.5 and 1.6, 4A-H), 7.07 (1H, d, J 2.7, 3-H), 7.21 (1H, d, J 3.5, 3A-H), 7.47
(1H, d, J 1.6, 5A-H), 9.45 (1H, br s, NH); dC(CDCl3; 100 MHz) 5.19
(OCH3), 65.2 (4-C), 107.8, 111.8, 124.5 (all Ar-CH), 129.0, 136.0,
140.5 (all Ar-C), 142.0 (Ar-CH), 162.5 (CO); m/z (EI) 317 (M+, 79%),
285 (59), 130 (70), 76 (79), 57 (100) [Found: M+, 316.9551. C10H8INO3
requires M, 316.9551].
10 J. J. Wang and A. I. Scott, Tetrahedron Lett., 1995, 36, 7043. See also
J. J. Wang and A. I. Scott, Tetrahedron Lett., 1996, 37, 3247.
11 A. Alvarez, A. Guzman, A. Ruiz, E. Velarde and J. M. Muchowski,
J. Org. Chem., 1992, 57, 1653; P. A. Jacobi, J. S. Guo, S. Rajeswari and
W. J. Zheng, J. Org. Chem., 1997, 62, 2907 and references cited
therein.
We thank the EPSRC Mass Spectrometry Centre, Swansea
University, for the provision of high resolution MS data and Eli
Received in Liverpool, UK, 2nd August 1998; 8/06386I
2208
Chem. Commun., 1998