The triphenyl phosphite-chlorine reagent in the synthesis of pyrroles from N-allylamides

Article abstract of DOI:10.1055/s-2006-926365

A novel application of (PhO)₃P-Cl₂ chemistry to the synthesis of 2-substituted and 2,3-disubstituted pyrroles from N-allyl-amides is illustrated. A mild procedure is used to generate the imino chloride intermediates, which are subseq

Full text of DOI:10.1055/s-2006-926365

PAPER
995
The Triphenyl Phosphite–Chlorine Reagent in the Synthesis of Pyrroles from
N-Allylamides
T
riphenyl Phosphi
l
te–Chlo
b
rine Reagen
e
t
in the Syn
r
thesis of
t
Pyrrol
o
es Spaggiari, Daniele Vaccari, Paolo Davoli, Fabio Prati*
Dipartimento di Chimica, Università di Modena e Reggio Emilia, via Campi 183, 41100 Modena, Italy
Fax +39(059)373543; E-mail: prati.fabio@unimore.it
Received 6 September 2005; revised 10 November 2005
such an approach would also probe the validity of our
Abstract: A novel application of (PhO)3P–Cl2 chemistry to the syn-
thesis of 2-substituted and 2,3-disubstituted pyrroles from N-allyl-
amides is illustrated. A mild procedure is used to generate the imino
chloride intermediates, which are subsequently cyclized to pyrroles.
TPPCl2-promoted imino chloride protocol6a and broaden
its synthetic application. To this end, a representative set
of diversely substituted N-allylamides was chosen and
The products are smoothly obtained in moderate to good overall subjected to halogenation with TPPCl2, followed by treat-
yields.
ment with potassium tert-butoxide to achieve intramolec-
ular cyclization.
Key words: triphenyl phosphite, chlorine, pyrroles, allylamides,
cyclizations
N-Allylamides 1a–j (Table 1) were treated with freshly
prepared TPPCl2 in toluene at –25 °C in the presence of
triethylamine6a to afford the corresponding imino chlo-
rides. After rapid centrifugation to remove triethylamine
hydrochloride, the solvent was changed to THF and the
solution was used as such for the next cyclization step.
Treatment with potassium tert-butoxide in anhydrous
DMF at 0 °C resulted in a sudden color change to violet,
which indicated that the cyclization was taking place suc-
cessfully. The dark coloration persisted throughout the re-
action, which reached completion within 30 minutes (for
derivative 1f the reaction mixture remained colorless dur-
ing the cyclization step). Extraction followed by chro-
matographic purification allowed the removal of triphenyl
phosphate and phenol,9 and afforded pyrroles 2a–j in
moderate to good yields (25–78%). The results are sum-
marized in Table 1.
Since its first appearance in 1879,1 which was followed
five years later by the more famous and general Knorr ap-
proach,2 the construction of the pyrrole core has always
featured as a key topic in heterocyclic chemistry. In fact,
molecules containing the pyrrole skeleton as a structural
motif are still being used for a wide range of pharmaceu-
tical and industrial applications. Hence, much effort has
been devoted to the chemistry of substituted pyrroles,
which are endowed with anti-inflammatory and analgesic
properties3 and also represent a key unit in several biolog-
ically active compounds.4 Accordingly, a variety of syn-
thetic routes towards their synthesis have been
developed.5
In the course of our work with the halogenating reagent
(PhO)3P–Cl2 (TPPCl2) we had the opportunity to explore
the reactivity of imino chlorides as easily formed versatile
intermediates in the deacylation of amides to amines6 and
for the cyclocondensation to b-carbolines and isoquino-
lines.7 Compared to literature methods our TPPCl2-based
access to imino chlorides has resulted in easier experi-
mental protocols as these synthetic intermediates can be
smoothly prepared under mild conditions from the corre-
sponding amides.
R2
O
Cl
i
ii
R1
N
R2
R1
N
R2
R1
N
H
H
2a–j
1a–j
Scheme 1 General route from N-allylamides 1 to pyrroles 2.
Reagents and conditions: (i) (PhO)3P–Cl2, Et3N, toluene, –25 °C to
r.t.; (ii) t-BuOK, DMF–THF, 0 °C.
Therefore, as part of our ongoing investigations on the
synthetic potential of this reagent, we decided to assess
whether TPPCl2 could be successfully applied to the syn-
thesis of small-sized heterocycles such as pyrroles. In par-
ticular, we reasoned that allylamides could be used as
convenient substrates for an intramolecular cyclization to
pyrroles via imino chlorides (Scheme 1). Allyl derivatives
have been exploited in the past for the synthesis of substi-
tuted pyrroles, even though severe conditions and lengthy
procedures were generally employed.1,5a,8 In addition,
The presence of aryl or heteroaryl groups such as substi-
tuted phenyl rings, N-, O-, or S-containing heterocycles
were found to be compatible with the reaction conditions.
The highest yields were observed with N-allylamides
bearing electron-rich pentatomic heterocyclic groups,
such as furoyl-, thiophenyl-, and pyrrolylamides 1a–c,
whereas pyridylamide 1h bearing an electron-deficient
heteroaromatic moiety gave only a modest result. Such
dual behavior, though a priori foreseeable, is a bit surpris-
ing in its magnitude, and would suggest a remarkable
electronic influence by the pre-existing heterocyclic ring,
which may affect the stability of the chloroiminoyl carbon
atom and, consequently, its tendency to undergo intramo-
lecular attack.
SYNTHESIS 2006, No. 6, pp 0995–0998
x
x
.
x
x
.2
0
0
6
Advanced online publication: 27.02.2006
DOI: 10.1055/s-2006-926365; Art ID: T12005SS
© Georg Thieme Verlag Stuttgart · New York

996
A. Spaggiari et al.
PAPER
Table 1 Cyclization Products and Results
intermediates, which were subsequently cyclized to 2-aryl
and 2-heteroarylpyrroles with potassium tert-butoxide in
DMF. Although overall yields were comparable, the use
of TPPCl2 allows milder reaction conditions and offers a
somewhat greater ease of handling with respect to the
highly toxic phosgene.
Amide
Pyrrole
Yield (%)
78
O
O
H
N
N
H
O
S
2a
O
S
1a
In conclusion, our TPPCl2-based methodology represents
the mildest route available in the literature to access 2-
substituted and 2,3-disubstituted pyrroles from allyl-
amides. The short reaction times, the low temperatures
employed, and the lack of intermediate purifications ren-
der this approach a valuable option when targeting substi-
tuted pyrroles.
65
71
65
60
H
N
N
H
2b
1b
1c
O
H
N
N
H
N
N
2c
O
H
N
1H and 13C NMR spectra were recorded on a Bruker DPX 200 MHz
spectrometer in CDCl3. Chemical shifts are reported in ppm down-
field from TMS as internal standard and coupling constants (J) are
given in Hz. MS were determined on a Finnigan MAT SSQ A (EI,
70 eV), while elemental analyses were performed by means of a
Carlo Erba Elemental Analyzer 1110. IR spectra were recorded on
a Perkin-Elmer 1600 FTIR spectrophotometer. All organic solvents
were dried according to standard methods and glassware was oven-
dried at 120 °C for 4 h and assembled under an Ar stream. PE used
had a bp range 40–60 °C.
N
H
1d
2d
H
O
N
O
N
H
2e
1e
O
O
32
25
H
N
N
H
1f
2f
HN
O
N-Allylamides 1a–j
N-Allylamides 1a–j were prepared by reacting allylamine with a
suitable acyl chloride in the presence of Et3N in refluxing CH2Cl2,
according to standard procedures.10 All compounds gave satisfacto-
ry elemental analyses and had spectroscopic properties in perfect
agreement with literature data.
N
H
2g
1g
29
52
O
H
N
N
N
N
H
1h
2h
2i
Cyclization to Pyrroles 2a–j; General Procedure
O
Cl2 was bubbled through a glass septum into a cold solution
(–25 °C) of (PhO)3P (1.1 mmol) in anhyd toluene (20 mL) until a
bright yellow color appeared. Upon further addition of a few drops
of (PhO)3P the color faded to pale yellow. The amide 1 (1 mmol)
and anhyd Et3N (1.15 mmol) were then added. The mixture was
stirred for 3 h and left to warm to r.t. After centrifugation, the mix-
ture was washed with anhyd THF (3 × 10 mL), the combined organ-
ic layers were concentrated under reduced pressure, and the sticky
residue was finally dissolved in anhyd THF (20 mL). The solution
thus obtained was added dropwise to a cooled (0 °C) suspension of
t-BuOK (8 mmol) in anhyd DMF (30 mL). The reaction mixture im-
mediately turned dark purple to violet in color. After stirring for 30
min at the same temperature, the dark solution was poured into ice-
cold water (400 mL) and extracted with Et2O (3 × 150 mL). The
combined organic phases were washed with 10% NaOH (3 × 70
mL), dried over Na2SO4, and evaporated in vacuo to afford an oily
residue, which was purified by column chromatography on silica
gel (PE–Et2O, 80:20).
N
H
1i
HN
58
O
N
H
2j
1j
HN
Inevitably, application of the method is restricted to allyl-
amides lacking enolizable H atoms. Pivaloylamide 1f was
cyclized, albeit in moderate yield, which may be also due
to the high volatility of pyrrole 2f. In the case of cin-
namoyl amide 1g, the low yield might be explained by a
competing conjugate addition under the cyclization con-
ditions, since no inherent incompatibility of the cin-
namoyl residue with TPPCl2 can be invoked.6a Therefore,
R1 can be represented either by an aromatic ring or a qua-
ternary carbon atom, whereas no particular limitations are
required for R2. N-Cinnamyl and crotyl amides (1i and 1j,
respectively), for instance, were satisfactorily converted
into the corresponding 2,3-disubstituted pyrroles (2i and
2j).
2-Furan-2-yl-1H-pyrrole (2a)
Black crystals; mp 44 °C.
IR (KBr): 2932, 3116, 3401 cm–1.
1H NMR (200 MHz): d = 6.28 (dd, J = 2.7, 6.1 Hz, 1 H, H-4), 6.36
(d, J = 3.3 Hz, 1 H, H-3¢), 6.43–6.48 (m, 2 H, H-3, H-4¢), 6.81 (dt,
J = 1.5, 2.7 Hz, 1 H, H-5), 7.37 (d, J = 1.8 Hz, 1 H, H-5¢), 8.59 (br
s, 1 H, NH).
13C NMR (50 MHz): d = 102.2, 105.3, 109.7, 111.4, 118.2, 140.3,
148.4.
Similar results were described by Steglich,5a albeit on a
narrower set of compounds, using phosgene in DMF–tol-
uene at 40–50 °C for the preparation of the imino chloride
MS (EI): m/z (%) = 133 (M+, 100), 104 (85), 78 (17).
Synthesis 2006, No. 6, 995–998 © Thieme Stuttgart · New York

PAPER
Triphenyl Phosphite–Chlorine Reagent in the Synthesis of Pyrroles
997
Anal. Calcd for C8H7NO: C, 72.16; H, 5.30; N, 10.52. Found: C,
72.25; H, 5.32; N, 10.38.
1H NMR (200 MHz): d = 1.47 [s, 9 H, C(CH3)3], 6.13 (dq, J = 1.6,
2.7 Hz, 1 H, H-4), 6.31 (dd, J = 2.7, 5.9 Hz, 1 H, H-3), 6.81 (dt,
J = 1.6, 2.7 Hz, 1 H, H-5), 8.10 (br s, 1 H, NH).
2-Thiophen-2-yl-1H-pyrrole (2b)
Fine grey powder; mp 78–80 °C.
IR (KBr): 2932, 3366 cm–1.
1H NMR (200 MHz): d = 6.30 (dd, J = 2.6, 6.0 Hz, 1 H, H-4), 6.46
(dt, J = 1.5, 2.6 Hz, 1 H, H-3), 6.82 (dt, J = 1.5, 2.6 Hz, 1 H, H-5),
7.01–7.07 (m, 2 H, H-3¢, H-4¢), 7.17 (dd, J = 2.4, 3.8 Hz, 1 H, H-5¢),
8.31 (br s, 1 H, NH).
13C NMR (50 MHz): d = 106.8, 110.0, 118.5, 120.9, 122.7, 126.7,
127.6, 136.3.
13C NMR (50 MHz): d = 30.7, 31.4, 102.5, 107.9, 116.2, 142.0.
MS (EI): m/z (%) = 124 ([M + 1]+, 91), 108 (100), 68 (76), 57 (52).
Anal. Calcd for C8H13N: C, 77.99; H, 10.64; N, 11.97. Found: C,
78.00; H, 10.04; N, 11.89.
2-Styryl-1H-pyrrole (2g)
Green-brown fine powder; mp 123–124 °C.
IR (KBr): 2932, 3428 cm–1.
1H NMR (200 MHz): d = 6.38 (s, 1 H, H-4), 6.54 (s, 1 H, H-3), 6.68
(d, J = 16.5 Hz, 1 H, =CH), 6.82 (s, 1 H, H-5), 7.01 (d, J = 16.5
Hz, 1 H, =CHPh), 7.36 (m, 5 H, ArH), 8.34 (br s, 1 H, NH).
13C NMR (50 MHz): d = 109.2, 110.0, 119.0, 119.1, 123.4, 125.8,
126.2, 126.9, 128.7, 128.9.
MS (EI): m/z (%) = 149 (M+, 100), 121 (22), 104 (15).
Anal. Calcd for C8H7NS: C, 64.39; H, 4.73; N, 9.39; S, 21.49.
Found: C, 64.55; H, 4.81; N, 9.20; S, 21.50.
1-Methyl-1H,1¢H-[2,2¢]bipyrrole (2c)
Black crystals; mp 44–45 °C.
MS (EI): m/z (%) = 169 (M+, 100), 168 (87), 143 (72), 115 (48).
IR (KBr): 2924, 3112, 3362 cm–1.
Anal. Calcd for C12H11N: C, 85.17; H, 6.55; N, 8.28. Found: C,
85.17; H, 6.65; N, 8.33.
1H NMR (200 MHz): d = 3.74 (s, 3 H, NCH3), 6.25 (d, J = 2.2 Hz,
1 H, H-4), 6.28–6.33 (m, 2 H, H-3, H-4¢), 6.36 (dd, J = 2.7, 6.0 Hz,
1 H, H-3¢), 6.74 (d, J = 2.2 Hz, 1 H, H-5), 6.84 (dt, J = 1.5, 2.7 Hz,
1 H, H-5¢), 8.19 (br s, 1 H, NH).
13C NMR (50 MHz): d = 35.1, 106.8, 107.0, 107.6, 109.3, 117.7,
123.0, 124.4, 127.2.
2-(1H-Pyrrol-2-yl)pyridine (2h)
Brown solid; mp 90–91 °C.
IR (KBr): 3410 cm–1.
1H NMR (200 MHz): d = 6.31 (dt, J = 2.6, 3.6 Hz, 1 H, H-4¢), 6.74–
6.79 (m, 1 H, H-3¢), 6.87–6.95 (m, 2 H, H-3, H-5¢), 7.03 (dd, J = 2.0,
5.5 Hz, 1 H, H-5), 7.20–7.28 (m, 1 H, H-4), 8.33 (dd, J = 0.5, 5.5
Hz, 1 H, H-6), 10.21 (br s, 1 H, NH).
13C NMR (50 MHz): d = 109.2, 110.6, 118.6, 120.3, 120.6, 129.6,
129.9, 149.1, 156.4.
MS (EI): m/z (%) = 146 (M+, 100), 131 (23), 118 (19), 104 (16).
Anal. Calcd for C9H10N2: C, 73.94; H, 6.89; N, 19.16. Found: C,
73.80; H, 6.92; N, 19.12.
2-p-Tolyl-1H-pyrrole (2d)
Fine ivory powder; mp 152–153 °C.
MS (EI): m/z (%) = 144 (M+, 100).
IR (KBr): 3103, 3393 cm–1.
Anal. Calcd for C9H8N2: C, 74.98; H, 5.59; N, 19.43. Found: C,
74.74; H, 5.73; N, 19.37.
1H NMR (200 MHz): d = 2.39 (s, 3 H, CH3), 6.32 (dd, J = 1.5, 2.7
Hz, 1 H, H-4), 6.52 (dq, J = 2.7, 6.0 Hz, 1 H, H-3), 6.85 (dt, J = 1.5,
2.7 Hz, 1 H, H-5), 7.20 (d, J = 8.1 Hz, 2 H, ArH), 7.40 (d, J = 8.1
Hz, 2 H, ArH), 8.40 (br s, 1 H, NH).
13C NMR (50 MHz): d = 21.1, 105.4, 110.0, 118.4, 123.9, 129.6,
130.1, 132.3, 135.9.
3-Phenyl-2-p-tolyl-1H-pyrrole (2i)
Grey powder; mp 123–124 °C.
IR (KBr): 3029, 3336 cm–1.
1H NMR (200 MHz): d = 2.39 (s, 3 H, CH3), 6.46 (t, J = 2.7 Hz, 1
H, H-4), 6.88 (t, J = 2.7 Hz, 1 H, H-3) 7.12–7.44 (m, 9 H, ArH),
8.21 (br s, 1 H, NH).
MS (EI): m/z (%) = 157 (M+, 100), 128 (10).
Anal. Calcd for C11H11N: C, 84.04; H, 7.05; N, 8.91. Found: C,
83.90; H, 7.10; N, 9.00.
13C NMR (50 MHz): d = 21.2, 110.9, 117.8, 121.6, 125.6, 127.5,
128.2, 128.4, 129.4, 130.5, 132.1, 136.5, 136.8.
MS (EI): m/z (%) = 233 (M+, 100), 217 (15).
2-(4-Methoxyphenyl)-1H-pyrrole (2e)
Pale green solid; mp 145–147 °C.
IR (KBr): 2836, 2959, 3393, 3441 cm–1.
Anal. Calcd for C17H15N: C, 87.52; H, 6.48; N, 6.00. Found: C,
87.45; H, 6.53; N, 5.99.
1H NMR (200 MHz): d = 3.84 (s, 3 H, OCH3), 6.30 (dd, J = 2.7, 6.0
Hz, 1 H, H-4), 6.43 (dq, J = 1.5, 2.7 Hz, 1 H, H-3), 6.83 (dt, J = 1.5,
2.7 Hz, 1 H, H-5), 6.93 (d, J = 8.9 Hz, 2 H, ArH), 7.42 (d, J = 8.9
Hz, 2 H, ArH), 8.41 (br s, 1 H, NH).
13C NMR (50 MHz): d = 55.3, 104.9, 109.9, 114.4, 118.2, 125.3,
126.0, 132.1, 158.3.
3-Methyl-2-p-tolyl-1H-pyrrole (2j)
Reddish-grey glittering solid; mp 65–67 °C.
IR (KBr): 2862, 2923, 3423 cm–1.
1H NMR (200 MHz): d = 2.29 (s, 3 H, CH3), 2.40 (s, 3 H, p-CH3),
6.17 (s, 1 H, H-4), 6.77 (s, 1 H, H-5), 7.23 (d, J = 8.1 Hz, 2 H, ArH),
7.34 (d, J = 8.1 Hz, 2 H, ArH), 8.11 (br s, 1 H, NH).
13C NMR (50 MHz): d = 12.4, 21.1, 112.0, 116.8, 126.3, 126.4,
129.4, 130.7, 131.5, 135.6.
MS (EI): m/z (%) = 173 (M+, 97), 158 (100), 130 (30).
Anal. Calcd for C11H11NO: C, 76.28; H, 6.40; N, 8.09. Found: C,
76.50; H, 6.50; N, 8.01.
MS (EI): m/z (%) = 171 (M+, 94), 170 (100).
2-tert-Butyl-1H-pyrrole (2f)
Mint-scented waxy reddish-brown crystals; mp 40–42 °C.
IR (KBr): 2872, 2967, 3404 (br) cm–1.
Anal. Calcd for C12H13N: C, 84.17; H, 7.65; N, 8.18. Found: C,
84.11; H, 7.71; N, 8.20.
Synthesis 2006, No. 6, 995–998 © Thieme Stuttgart · New York

998
A. Spaggiari et al.
PAPER
Sire, B.; Wendeborn, F.; Zard, S. Z. Chem. Commun. 2002,
2214. (f) Quiclet-Sire, B.; Quintero, L.; Sanchez-Jimenez,
G.; Zard, S. Z. Synlett 2003, 75. (g) Padmavathi, V.; Reddy,
B. J. M.; Padmaja, A. J. Heterocycl. Chem. 2005, 42, 333.
(h) Banik, B. K.; Banik, I.; Renteria, M.; Dasgupta, S. K.
Tetrahedron Lett. 2005, 46, 2643.
Acknowledgment
We thank MIUR (Ministero dell’Istruzione, dell’Università e della
Ricerca) for financial support (COFIN 2003). The authors are gra-
teful to Centro Interdipartimentale Grandi Strumenti (CIGS) at the
Università di Modena e Reggio Emilia for valuable assistance in
NMR acquisition and mass spectrometric determinations, and to
Prof. Franco Ghelfi (Dipartimento di Chimica, Università di Mode-
na e Reggio Emilia) for providing chlorine delivery facilities at his
laboratory. A.S. thanks Fondazione Cassa di Risparmio di Modena
for a post-doctoral grant.
(6) (a) For details on the mechanism of TPPCl2, see: Spaggiari,
A.; Blaszczak, L. C.; Prati, F. Org. Lett. 2004, 6, 3885.
(b) Spaggiari, A.; Blaszczak, L. C.; Prati, F. Ars Pharm.
2005, 46, 167.
(7) Spaggiari, A.; Davoli, P.; Blaszczak, L. C.; Prati, F. Synlett
2005, 661.
(8) Gluud, W. J. Chem. Soc. 1913, 940.
References
(9) While triphenyl phosphate originated as a by-product of the
halogenation step,6a transesterification of triphenyl
phosphate during the base-promoted cyclization would
furnish phenol.
(10) (a) Billman, J. H.; Rendall, J. L. J. Am. Chem. Soc. 1944, 66,
540. (b) McManus, S. P.; Carroll, J. T. J. Org. Chem. 1970,
35, 3768. (c) Balsamo, A.; Crotti, P.; Lapucci, A.; Macchia,
B.; Macchia, F. J. Med. Chem. 1981, 24, 525. (d) Harvey,
D. F.; Sigano, D. M. J. Org. Chem. 1996, 61, 2268.
(e) Fürstner, A.; Gastner, T.; Weintritt, H. J. Org. Chem.
1999, 64, 2361. (f) Krompiec, S.; Pigulla, M.; Krompiec,
M.; Baj, S.; Mrowiec-Białoń, J.; Kasperczyk, J. Tetrahedron
Lett. 2004, 45, 5257.
(1) Königs, W. Ber. Dtsch. Chem. Ges. 1879, 12, 2344.
(2) Knorr, L. Ber. Dtsch. Chem. Ges. 1884, 17, 1635.
(3) Dannhard, G.; Kiefer, W.; Kramer, G.; Maehrlein, S.; Nowe,
U. Eur. J. Med. Chem. 2000, 35, 499.
(4) (a) Jones, A. R. Pyrroles; Wiley: New York, 1990.
(b) Fürstner, A. Angew. Chem. Int. Ed. 2003, 42, 3582.
(5) For some examples, see: (a) Engel, N.; Steglich, W. Angew.
Chem., Int. Ed. Engl. 1978, 17, 676. (b) Cohnen, E.;
Dewald, R. Synthesis 1987, 566. (c) Quiclet-Sire, B.;
Thévenot, I.; Zard, S. Z. Tetrahedron Lett. 1995, 36, 9469.
(d) Katritzky, A. R.; Huang, T. B.; Voronkov, M. V.; Wang,
M.; Kolb, H. J. Org. Chem. 2000, 65, 8819. (e) Quiclet-
Synthesis 2006, No. 6, 995–998 © Thieme Stuttgart · New York