The reaction of nitrones with pyrroles and furan: An easy access to heteroaromatic hydroxylamines and bis(heteroaryl)alkanes

Article abstract of DOI:10.1016/j.tetlet.2005.10.061

N-Benzylnitrones react with heteroaromatic compounds such as pyrroles or furan in the presence of hydrogen chloride. Either heteroaromatic N-benzylhydroxylamines, symmetrical or unsymmetrical 2,2′-bis(heteroaryl) alkanes could be selectively produced depe

Full text of DOI:10.1016/j.tetlet.2005.10.061

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8653–8656
The reaction of nitrones with pyrroles and furan: an easy access to
heteroaromatic hydroxylamines and bis(heteroaryl)alkanes
*
*
´ ´
´
´
Christophe Berini, Frederic Minassian, Nadia Pelloux-Leon and Yannick Vallee
Laboratoire d’Etudes Dynamiques et Structurales de la Se´lectivite´, UMR 5616 CNRS/UJF, Institut de Chimie
Mole´culaire de Grenoble, FR-2607, Universite´ Joseph Fourier, Grenoble I, 301 rue de la Chimie, BP 53, 38041 Grenoble cedex 9, France
Received 6 September 2005; revised 13 October 2005; accepted 17 October 2005
Abstract—N-Benzylnitrones react with heteroaromatic compounds such as pyrroles or furan in the presence of hydrogen chloride.
Either heteroaromatic N-benzylhydroxylamines, symmetrical or unsymmetrical 2,20-bis(heteroaryl)alkanes could be selectively pro-
duced depending on the experimental conditions.
Ó 2005 Elsevier Ltd. All rights reserved.
The condensation of pyrrole derivatives with electro-
philes allows the preparation of important synthetic
intermediates for an access to natural alkaloids,1 as well
as other compounds of biological interest.2 Among the
various electrophiles, aldehydes have been considerably
employed for the synthesis of porphyrins and their core-
modified analogues.3 Mannich reaction has also been
widely described in order to prepare 2-aminomethylpyr-
roles.4 However, the direct preparation of 2-N-hydroxy-
aminomethylpyrroles from a convenient electrophile has
been mainly limited to the reaction between pyrrole and
acyclic oxyiminium cations.5
eroaromatic N-benzylhydroxylamines or 2,20-bis(hetero-
aryl)alkanes concisely.
We started our work with the selective preparation of
N-benzylhydroxylamines 3a–d. 2,3,4-Trisubstituted pyr-
roles 1a and 1b8 were used in order to limit the possible
pyrrole polymerization under acidic conditions. Con-
cerning the electrophilic partners, aldonitrones 2a and
2b have been chosen.9 Experiments were performed
using dry HCl in anhydrous methanol. Representative
results are shown in Table 1 (Scheme 1).
Reactions with pyrrole derivative 1a (with an acyl sub-
stituent) needed higher temperatures than reactions with
pyrrole derivative 1b which is indeed more electron-rich
Previous studies in our group have dealt with the reac-
tivity of nitrones as electrophiles.6 Among them, the
reaction of nitrones with various indoles has been
studied.7 Two types of products have been obtained
depending on the experimental conditions. Using chlo-
rotrimethylsilane as a promoter, the exclusive formation
of 3,30-bis(indolyl)alkanes was observed, whereas when
HCl was employed, 3-indolyl N-hydroxylamines were
formed as single products.
Table 1. Selective preparation of 2-pyrrolyl N-hydroxylamines 3a–d
Entry Pyrrole Nitrone Conditionsa
Ratio 3:4
Yield
(%)b
1
2
3
1a
1a
1a
2a
2a
2a
ꢀ20 °C, 2 h 100:0 (3a:4a) 20
ꢀ20 °C, 4 h 100:0 (3a:4a) 75
0 °C, 2 h 62:38 (3a:4a) 69
In this letter, we describe the first example of a reaction
between pyrroles or furan and nitrones in the presence
of HCl as the activating agent providing either 2-het-
4
5
1a
1a
2b
2b
ꢀ40 °C, 2 h 100:0 (3b:4b) 15
ꢀ40 °C, 24 h 100:0 (3b:4b) 55
6
7
1b
1b
2a
2a
ꢀ78 °C, 3 h 100:0 (3c:4c) 66
ꢀ78 °C, 4.5 h 83:17 (3c:4c) 68
Keywords: Nitrones; Pyrroles; Furan; Hydroxylamines; 2,20-Bis-
(heteroaryl)alkanes.
8
9
1b
1b
2b
2b
ꢀ78 °C, 3 h 100:0 (3d:4d) 41
ꢀ78 °C, 4.5 h 67:33 (3d:4d) 61
*
Corresponding authors. Tel.: +33 476 514 908; fax: +33 476 635 983;
e-mail addresses: frederic.minassian@ujf-grenoble.fr; nadia.pelloux-
leon@ujf-grenoble.fr
a In the presence of 1 equiv of HCl.
b Isolated yields.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.10.061

8654
C. Berini et al. / Tetrahedron Letters 46 (2005) 8653–8656
R2
R1
CH3
R1
CH3
H3C
CH3
-
+
N
O
R2
Ph
+
R1
R1
CH3
HCl
+
H3C
CH3OH
H3C
N
NH HN
H
R2
N
Ph
H
N
H
H3C
HO
3a-d
(R1 = Ac ; R2 = Et);
(R1 = R2 = Et);
1a (R1 = Ac)
1b (R1 = Et)
2a (R2 = Et)
2b (R2 = Ph)
4a-d
a
b
(R1 = Ac ; R2 = Ph)
c
d
(R1 = Et ; R2 = Ph)
Scheme 1.
(with only alkyl substituents) (Table 1, entries 1–5 vs 6–
9). In the case of 1a, formation of small amounts of 2,20-
bis(pyrrolyl)alkane 4a was observed when raising the
temperature (Table 1, entries 1 vs 3). An increase in
the reaction time improved the conversion to N-benz-
ylhydroxylamines 3a,b (Table 1, entries 1 vs 2 and 4
vs 5) while for 1b, competitive formation of 2,20-
bis(pyrrolyl)alkanes 4c,d occurred (Table 1, entries 6
vs 7 and 8 vs 9). For both pyrroles (1a,b), we found opti-
mized experimental conditions leading to the exclusive
formation of N-benzylhydroxylamines (3a–d; Table 1,
entries 2, 5, 6, and 8).
Et
Me
Me
Ph
Me
Me
HCl
CH3OH
O
Ph
Et
N
1a (1 eq.)
0 C, 1h
˚
NH HN
CH3
H
N
Me
Me
Ph
HO
3b
4e
Scheme 2.
R2
HCl, CH3OH
+
2a,b
1 eq.
-78 to -40˚C
24h
N
H
N
H
Ph
N
HO
5
6a (R2 = Et)
Furthermore, we took advantage of our initial observa-
tions in order to prepare 2,20-bis(pyrrolyl)alkanes 4a–d
selectively via simple modifications of the experimental
procedure. Our results are shown in Table 2. Highly
selective transformations were observed here by increas-
ing the relative amounts of pyrroles 1a,b and HCl to
2 equiv (nitrone/pyrrole/HCl: 1/2/2) and by running
the reactions at higher temperatures.
1 eq.
6b (R2 = Ph)
Scheme 3.
alkanes 4a–d (Table 2), or unsymmetrical 2,20-bis(pyrr-
olyl)alkane 4e (Scheme 2) with fair to excellent yields.
Encouraged by these results, we decided to turn our
attention to unsubstituted pyrrole (5), in order to pre-
pare the corresponding N-benzylhydroxylamines 6a,b
(Scheme 3). Such compounds would be valuable for fur-
ther ring functionalizations. Results are summarized in
Table 3. As expected, the reaction always occurred selec-
tively at the C-2 position of the pyrrole ring over 24 h at
ꢀ40 °C.15 Under this set of experimental conditions,
polymerization of pyrrole (5) was minimal.
An efficient preparation of these compounds usually
consists in reacting pyrroles and aldehydes under acidic
conditions.10 The assumed mechanism involves the
formation of an intermediate carbinol which is rarely
isolated.11,12 In our case, elimination of N-benzylhydr-
oxylamine from 3a–d under acidic conditions followed
by a second addition of pyrroles 1a,b leads to com-
pounds 4a–d.13 This hypothesis was confirmed by run-
ning a crossed reaction between N-hydroxylamine 3b
and 1 equiv of pyrrole 1a in the presence of 1 equiv of
HCl at 0 °C which gave unsymmetrical 2,20-bis(pyrr-
olyl)alkane 4e in 54% yield (Scheme 2).14
Formation of 2,20-bis(pyrrolyl)alkanes was never de-
tected, even under harsher experimental conditions. This
was probably due to the faster degradation of both pyr-
role (5) and hydroxylamines 6a,b than a second addition
step. Higher temperatures (Table 3, entries 2 vs 3, 4 vs 5
and 6) or a longer reaction time (65% in 36 h) afforded
To summarize, we have found experimental conditions
allowing selective access to either N-benzylhydroxyl-
amines 3a–d (Table 1), symmetrical 2,20-bis(pyrrolyl)-
Table 3. Selective formation of hydroxylamines 6a,b
Table 2. Selective preparation of 2,20-bis(pyrrolyl)alkanes 4a–d
Entry
Nitrone
Relative amount
of HCl (equiv)
N-Benzylhydroxylamine
6 (yield %)a
Entry Pyrrolea Nitrone Conditionsb
Ratio 3:4
Yield
(%)c
1
2
3
2a
2a
2a
1
2
2b
6a (65%)
6a (95%)
6a (50%)c
1
2
3
1a
1a
1b
2a
2b
2a
rt, 3 h
0:100 (3a:4a) 81
0:100 (3b:4b) 90
0:100 (3c:4c) 67
rt, 3.5 h
0 °C, 2 h
4
5
6
2b
2b
2b
2
6b (73%)
6b (50%)
6b (32%)c
2b
2d
4
5
1b
1b
2b
2b
ꢀ78 °C, 4.5 h 36:64 (3d:4d) 55
rt, 1 h 0:100 (3d:4d) 77
a Isolated yields.
a Two equivalents of pyrrole 1a,b were used.
b In the presence of 2 equiv of HCl.
c Isolated yields.
b Pyrrole (5) was added at ꢀ40 °C.
c 35% of nitrone was recovered.
d Reaction was performed at ꢀ20 °C.

C. Berini et al. / Tetrahedron Letters 46 (2005) 8653–8656
8655
Acknowledgement
-
+
N
O
10 eq. HCl
Ph
+
´
We are grateful to the Universite Joseph Fourier and
CH3OH, r.t., 5d
O
O
H
Et
Ph
the CNRS (UMR 5616, FR 2607) for financial support.
N
HO
7
2a
1 eq.
co-solvent
8
(68 %)
References and notes
Scheme 4.
´
´
1. (a) Sayah, B.; Pelloux-Leon, N.; Vallee, Y. J. Org. Chem.
´
2000, 65, 2824–2826; (b) Sayah, B.; Pelloux-Leon, N.;
-
Ph
+
O
´
Milet, A.; Pardillos-Guindet, J.; Vallee, Y. J. Org. Chem.
10 eq. HCl
Ph
N
´
2001, 66, 2522–2525; (c) Patel, J.; Pelloux-Leon, N.;
+
CH3OH, r.t., 2.5d
O
Minassian, F.; Vallee, Y. J. Org. Chem. 2005, 70, 9081–
´
O
O
H
Ph
9084.
2b
9
(49 %)
7
2. Ketcha, D. M. In Progress in Heterocyclic Chemistry;
Gribble, G. W., Gilchrist, T. L., Eds.; Pergamon: Oxford,
2002; Vol. 14, pp 114–121.
Scheme 5.
3. (a) Sakata, Y.; Hirano, Y.; Tatemitsu, H.; Misumi, S.;
Ochiai, H.; Shibata, H. Tetrahedron 1989, 45, 4717–4727;
(b) Srinivasan, A.; Furuta, H. Acc. Chem. Res. 2005, 38,
10–20, and references cited therein.
4. Zhang, C.; Dong, J.; Cheng, T.; Li, R. Tetrahedron Lett.
2001, 42, 461–463, and references cited therein.
5. Grigg, R.; Rankovic, Z.; Thoroughgood, M. Tetrahedron
2000, 56, 8025–8032.
indeed products 6a,b in lower yields. We also found that
the use of 2 equiv of HCl was optimal (Table 3, entries 1
vs 2). By this way, 2-pyrrolyl N-benzylhydroxylamines
6a and 6b could be isolated in one step with good to
excellent yields (Table 3, entries 2 and 4).
This study was then extended to furan (7). Under the
previous conditions, no reaction was observed. How-
ever, significant results were obtained using furan as a
cosolvent, by increasing the relative amount of HCl, at
higher reaction temperature, and with a longer reaction
time (Schemes 4 and 5). This weaker reactivity corre-
lated well with some studies attributing a lower nucleo-
philicity to furan (7) than to pyrrole (5).16 In the case of
nitrone 2a, we observed the formation of the 2-furyl N-
benzylhydroxylamine 8 as a single product in 68% iso-
lated yield (Scheme 4). As in the pyrrole series, reaction
occurred only at the C-2 position. Interestingly, with nit-
rone 2b, 2,20-bis(furyl)alkane 9 was preferentially ob-
tained (Scheme 5) in 49% yield (not optimized) under
similar conditions.17,18 This difference was probably
due to the increased resonance stabilization of the possi-
ble intermediate 2-alkylidene-2H-furylium cation which
could therefore easily react with a second equivalent of
furan (7).
6. (a) Pandya, S. U.; Garc¸on, C.; Chavant, P. Y.; Py, S.;
´
Vallee, Y. Chem. Commun. 2001, 1806–1807; (b) Pinet, S.;
´
Pandya, S. U.; Chavant, P. Y.; Ayling, A.; Vallee, Y. Org.
Lett. 2002, 4, 1463–1466; (c) Patel, S. K.; Murat, K.; Py,
´
S.; Vallee, Y. Org. Lett. 2003, 5, 4081–4084.
7. Chalaye-Mauger, H.; Denis, J.-N.; Averbuch-Pouchot,
´
M.-T.; Vallee, Y. Tetrahedron 2000, 56, 791–804, and
references cited therein.
8. 3-Ethyl-2,4-dimethylpyrrole 1b was prepared by LAH-
mediated reduction from commercially available com-
pound 1a in a 81% isolated yield.
9. For the preparation of nitrones, see: for 2a: (a) Dondoni,
´
A.; Franco, S.; Junquera, F.; Merchan, F.; Merino, P.;
Tejero, T. Synth. Commun. 1994, 24, 2537–2550; for 2b:
(b) Murahashi, S.-I.; Mitsui, H.; Shiota, T.; Tsuda, T.;
Watanabe, S. J. Org. Chem. 1990, 55, 1736–1744.
10. See for example: Sakata, Y.; Hirano, Y.; Tatemitsu, H.;
Misumi, S.; Ochiai, H.; Shibata, H. Tetrahedron 1989, 45,
4717–4727.
11. First isolation of indol-30-ylcarbinols under acidic clay-
catalyzed conditions has been recently described: Chakra-
barty, M.; Karmakar, S.; Harigaya, Y. Heterocycles 2005,
65, 37–48.
12. Isolable pyrrole-based carbinols have been obtained from
electron deficient aldehydes: (a) Blinn, R. C.; Gunther, F.
A.; Metcalf, R. L. J. Am. Chem. Soc. 1954, 76, 37–39; (b)
Bishop, J. E.; OÕConnell, J. F.; Rapoport, H. J. Org.
Chem. 1991, 56, 5079–5091.
Finally, all attempts involving thiophene as the nucleo-
philic species under these experimental conditions were
unsuccessful, either recovery or degradation of the start-
ing material being observed.
In conclusion, we have shown that the reaction of nitro-
nes with heteroaromatic compounds such as pyrrole or
furan is an efficient, simple, and unprecedented method
for the synthesis of 2-pyrrolyl19a and 2-furyl N-hydrox-
ylamines.20 The former molecules were never prepared
so far, while the latter were previously obtained via
addition of the corresponding 2-lithiofuran to nitro-
nes.21 They would be valuable building blocks for the
elaboration of new drug candidates. Our method allows
supplementary access to symmetrical 2,20-bis(hetero-
aryl)alkanes.19b Furthermore, it represents a straightfor-
ward preparation of unsymmetrical 2,20-bis(hetero-
aryl)alkanes.14 Studies concerning new extensions of this
methodology and applications to the synthesis of bio-
active compounds are in progress.
13. Similarly to the indole series, the second pyrrole would
add onto intermediate 2-alkylidene-2H-pyrrolium cations.
See Ref. 7.
14. Unsymmetrical 2,20-bis(pyrrolyl)alkanes are often pre-
pared: (a) from pyrroles and aldehydes using statistical
approaches, sometimes requiring tedious chromatographic
separation: Lee, C.-H.; Li, F.; Iwamoto, K.; Dadok, J.;
Bothner-By, A. A.; Lindsey, J. S. Tetrahedron 1995, 51,
11645–11672, and references cited therein; (b) from 2-
acetoxymethylpyrroles: Jackson, A. H.; Pandey, R. K.;
Rao, K. R. N.; Roberts, E. Tetrahedron Lett. 1985, 26,
793–796.
15. Clayden, J.; Greeves, N.; Warren, S.; Wothers, P. In
Organic Chemistry; Oxford University Press: Oxford,
2001; p 1157.

8656
C. Berini et al. / Tetrahedron Letters 46 (2005) 8653–8656
16. Mayr, H.; Kempf, B.; Ofial, A. R. Acc. Chem. Res. 2003,
36, 66–77.
17. Compound 9 was previously obtained from benzaldehyde
in 33% yield and used for the syntheses of core-modified
porphyrins. See: Cho, W.-S.; Lee, C.-H. Bull. Korean
Chem. Soc. 1998, 19, 314–319.
(ESI) m/z (%) = 230.9 [M+H]+ (20), 124.0 (100), 108.1
(68). Anal. Calcd (%) for C14H18N2O: C, 73.01; H, 7.88;
N, 12.16. Found (%): C, 72.63; H, 7.93; N, 11.98.; (b)
Typical experimental procedure for the preparation of 2,20-
bis(pyrrolyl)alkane 4a: Anhydrous acetyl chloride
(157 mg; 2 mmol) was added dropwise at 0 °C to anhy-
drous methanol (5 mL) in a 10 mL round-bottomed flask
and the mixture was stirred for 15 min under argon.
Nitrone 2a (163 mg; 1 mmol) and pyrrole 1a (137 mg;
2 mmol) were then added at 0 °C. Stirring was continued
for 3 h. Subsequent work-up procedure was performed as
described above and purification by flash silica gel
chromatography (pre-treated with 2.5% w/w of triethyl-
amine; eluent: pentane/ethyl acetate: 6/4) led to pure 4a as
a white powder (129 mg; 81% yield). Mp 207–208 °C. IR
(KBr): m = 3301, 3030, 2961, 2924, 2870, 1629, 1583, 1517,
18. For the preparation 2,20-bis(furyl)alkanes or 2,20-bis(thi-
enyl)alkanes using aldehydes under acidic conditions and
their synthetic applications, see: (a) Riad, A.; Mouloun-
gui, Z.; Delmas, M.; Gaset, A. Synth. Commun. 1989, 24,
2571–2576; (b) Skouta, M.; Lesimple, A.; Le Bigot, Y.;
Delmas, M. Synth. Commun. 1994, 24, 2571–2576; (c)
Ancerewicz, J.; Vogel, P. Helv. Chim. Acta 1996, 79, 1393–
1414.
19. (a) Typical experimental procedure for the preparation of
N-benzylhydroxylamine 6a: Distilled acetyl chloride
(157 mg; 2 mmol; 0.2–0.5 M in methanol) was added
dropwise at 0 °C to anhydrous methanol (5 mL) in a
10 mL round-bottomed flask and the mixture was stirred
for 15 min under argon. Nitrone 2a (163 mg; 1 mmol) was
then added and the mixture was cooled to ꢀ78 °C before
the addition of pyrrole 5 (67 mg; 1 mmol). Reaction
temperature was then set to ꢀ40 °C and stirring was
continued until complete disappearance of starting mate-
rial (followed by TLC with UV detection, alkaline
KMnO4 or TTC22 staining). The mixture was treated with
saturated aqueous NaHCO3 solution until pH 8–9. The
aqueous layer was then extracted with dichloromethane,
the combined organic layers were washed with brine, and
dried over anhydrous sodium sulfate. After filtration and
evaporation of the solvents under vacuum, the crude
product was purified by flash silica gel chromatography
(pre-treated with 2.5% w/w of triethylamine; eluent:
pentane/ethyl acetate: 8/2). Compound 6a was isolated
as a colorless oil (219 mg; 95% yield). IR (film): m = 3454,
1442, 1414, 1381, 1252 cmꢀ1
.
1H NMR (300 MHz,
CDCl3): d = 8.43 (br s, 2H), 4.00 (t, J = 7.3 Hz, 1H),
2.42 (s, 6H), 2.41 (s, 6H), 2.22 (s, 6H), 1.89–1.99 (m, 2H),
0.89 (t, J = 7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3):
d = 196.8, 134.9, 128.6, 121.1, 115.2, 33.7, 31.0, 27.2, 15.2,
12.4, 12.0. MS (DCI, NH3+isobutane) m/z (%) = 315
[MH+] (63), 178 (100), 138 (63). Anal. Calcd (%) for
C19H26N2O2: C, 72.58; H, 8.33; N, 8.91. Found (%): C,
72.36; H, 8.35; N, 8.52.
20. Compound 8: Colorless oil. IR (film): m = 3240, 3034,
1
2967, 2926, 2870, 1498, 1455, 1324, 1152 cmꢀ1. H NMR
(300 MHz, CDCl3): d = 7.43–7.44 (m, 1H), 7.22–7.32 (m,
5H), 6.37–6.39 (m, 1H), 6.26–6.27 (m, 1H), 5.92 (br s, 1H),
3.62 (ABq, JAB = 13.2 Hz, dA ꢀ dB = 46.1 Hz, 2H), 3.60
(dd, J = 5.7, 9.3 Hz, 1H), 1.75–2.00 (m, 2H), 0.81 (t,
J = 7.5 Hz, 3H). 13C NMR (75 MHz, CDCl3): d = 153.1,
141.9, 137.9, 129.7, 128.2, 127.2, 110.1, 109.1, 65.9, 60.7,
23.9, 11.0. MS (ESI, additive LiCl) m/z (%) = 237.9
[M+Li]+ (20), 231.9 [M+H]+ (22). Anal. Calcd (%) for
C14H17NO2: C, 72.71; H, 7.41; N, 6.06. Found (%): C,
72.53; H, 7.54; N, 5.95.
3222, 3023, 2957, 2932, 2874, 1497, 1451, 1401, 1269 cmꢀ1
.
1H NMR (300 MHz, CDCl3): d = 8.66 (br s, 1H), 7.24–
7.33 (m, 5H), 6.77–6.79 (m, 1H), 6.14–6.17 (m, 1H), 6.04
(br s, 1H), 5.89 (br s, 1H), 3.56 (dd, J = 6.0, 9.0 Hz, 1H),
3.55 (ABq, JAB = 13.2 Hz, dA ꢀ dB = 45.2 Hz, 2H), 1.82–
1.96 (m, 1H), 1.67–1.80 (m, 1H), 0.88 (t, J = 7.4 Hz, 3H).
13C NMR (75 MHz, CDCl3): d = 137.9, 129.8, 129.7,
128.2, 127.3, 117.6, 108.3, 107.2, 65.5, 60.2, 25.3, 11.4. MS
´
21. Dondoni, A.; Junquera, F.; Merchan, F. L.; Merino, P.;
Scherrmann, M.-C.; Tejero, T. J. Org. Chem. 1997, 62,
5484–5496.
22. Alkaline 2,3,5-triphenyltetrazolium chloride gives bright
red coloration with hydroxylamines. Metz, H. Naturwis-
senchaften 1961, 48, 569–570.