New regiocontrolled synthesis of functionalized pyrroles from 2-azetidinone-tethered allenols

Article abstract of DOI:10.1002/chem.200700788

A new one-pot approach to synthesize densely substituted racemic and enantiopure pyrroles from β-lactams has been developed. The approach relies on the regiocontrolled cyclization of β-allenamine intermediates derived from the ring opening of 2-azetidinon

Full text of DOI:10.1002/chem.200700788

FULL PAPER
DOI: 10.1002/chem.200700788
New Regiocontrolled Synthesis of Functionalized Pyrroles from 2-
Azetidinone-Tethered Allenols
Benito Alcaide,*[a] Pedro Almendros,*[b] Rocío Carrascosa,[a, b] and María C. Redondo[a]
Dedicated to Professor Miguel A. Yus on the occasion of his 60th birthday
Abstract: A new one-pot approach to synthesize densely substituted racemic and
enantiopure pyrroles from b-lactams has been developed. The approach relies on
the regiocontrolled cyclization of b-allenamine intermediates derived from the
ring opening of 2-azetidinone-tethered allenols. In this approach four points of di-
versity are introduced, one of which is the position of the allene moiety on the b-
lactam ring.
Keywords:
reactions
heterocycles · rearrangement
allenes
lactams
·
·
domino
nitrogen
·
Introduction
has been given to the use of the allenamine building block
for the synthesis of pyrroles.[6] Following our work on het-
Pyrroles constitute an important compound class owing to
their wide profile of biological activity.[1] Additionally, the
pyrrole nucleus is a useful building block for the synthesis of
heterocycles and natural products,[2] and this heterocyclic
core is widely used in materials science and molecular rec-
ognition.[3] Recently, organometallic transformations have
A
preparation of functionalized pyrroles from allene-b-lac-
tams.[8]
Results and Discussion
been pursued with renewed interest to achieve the elusive
[4]
À
addition reaction of the N H bond across allenes. In addi-
Precursors for pyrrole formation, a-allenols 2a–h and 5a–i,
were synthesized from 4-oxoazetidine-2-carbaldehydes 1a–f
(Scheme 1, Table 1) and azetidine-2,3-diones 4a–e
(Scheme 2, Table 2) through indium-mediated Barbier-type
carbonyl-allenylation reactions in aqueous media by using
our previously described methodologies.[9] a-Allenols 2 and
5 were protected as the corresponding methyl ethers 3 and 6
by treatment with dimethyl sulfate under phase-transfer
conditions.
tion to the key role that b-lactams have played in the fight
against pathogenic bacteria, the use of 2-azetidinones as
chiral building blocks in organic synthesis is now well estab-
lished.[5] Although much effort has been made in these
fields, the direct preparation of the pyrrole ring from b-lac-
tams has not yet been reported. Furthermore, little attention
[a] Prof. Dr. B. Alcaide, R. Carrascosa, Dr. M. C. Redondo
Departamento de Química Orgµnica I
Facultad de Química
With the a-allenol derivatives in hand, the next stage was
to carry out the b-lactam ring opening and the subsequent
key cyclization reactions. Treatment of allene-b-lactams 3a
Universidad Complutense de Madrid
28040 Madrid (Spain)
Fax : (+34)91-394-4103
E-mail: alcaideb@quim.ucm.es
[b] Dr. P. Almendros, R. Carrascosa
Instituto de Química Orgµnica General
Consejo Superior de Investigaciones Científicas
CSIC Juan de la Cierva 3
28006 Madrid (Spain)
Fax : (+34)91-564-4853
E-mail: iqoa392@iqog.csic.es
Scheme 1. Indium-mediated Barbier-type carbonyl allenylation of alde-
hydes 1 followed by protection of a-allenols 2 are precursors for the syn-
thesis of allene-b-lactams 3. Reagents and conditions: a) In, THF, NH4Cl
(aq. sat.), RT; b) Me2SO4, NaOH, TBAI, DCM-H2O, RT.
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
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637

and 3b with sodium methoxide at room temperature afford-
ed b-allenamines 7a and 7b in excellent yields. Most of the
previously reported metal-mediated cyclizations of aminoal-
lenes were not suitable for the cyclization of functionalized
b-allenamines 7, which results in a complex mixture of un-
Scheme 2. Indium-mediated Barbier-type carbonyl allenylation of ke-
tones 4 followed by protection of a-allenols 5 are precursors for the syn-
thesis of allene-b-lactams 6. Reagents and conditions: a) In, THF, NH4Cl
(aq. sat.), RT; b) Me2SO4, NaOH, TBAI, DCM-H2O, RT.
[4d]
identified products.[4] After extensive screening, AgNO3
in the presence of K2CO3 was found to be effective at pro-
moting aminocyclization in MeCN at room temperature, to
give pyrroles 8a and 8b, which
Table 1. Preparation of 2-azetidinone-tethered allenes 3.[a]
have a stereogenic center in the
Aldehyde
Allenol
Yield [%][b]
Protected allenol
Yield [%][b]
side chain (Scheme 3).[4m] Com-
pounds 8 can be considered as
hybrid scaffolds with a combi-
nation of the biologically and
synthetically relevant pyrrole
and a-hydroxy acid cores.[10]
However, despite the tendency
towards the development of
enantiomerically pure drugs, to
the best of our knowledge the
preparation of optically active
substituted (pyrrol-2-yl)acetic
acid esters has never been re-
ported.[11] Although complete
conversion was observed by
77
66
89
84
53
64
79
78
78
84
77
88
1
TLC and H NMR spectroscop-
ic analysis of the crude reaction
mixtures, some decomposition
was observed on sensitive pyr-
roles 8 during purification by
flash chromatography, which
may be responsible for the
moderate isolated yields.
One possible pathway for the
synthesis of pyrroles 8 may ini-
tially involve the formation of
p-complex 9 through coordina-
tion of silver nitrate to the 1,2-
diene moiety of b-allenamines
7.[12] Next, regioselective cycli-
zation to form species 10 fol-
lowed by demetallation and
proton transfer afforded inter-
mediates 11. Pyrrolines 11 were
assumed to be unstable and
could easily eliminate a meth-
78
76
80
60
[a] PMP=4-MeOC6H4. [b] Yield of pure, isolated product with correct analytical and spectral data.
AHCTREUNG
(Scheme 4).
According to the strategy outlined above, 2-azetidinone-
tethered phenyl allenes 3c–h were treated with sodium
methoxide at room temperature. To our delight, phenyl al-
lenes 3c–h did not give the expected b-allenamines, but in-
stead afforded the corresponding 1,2,3,5-tetrasubstituted
pyrroles 12 (Scheme 5). In all cases no other regioisomers
were observed. To obtain a reasonable yield of the corre-
sponding pyrrole derivative, the conversion of the allenol
precursor into its methyl ether is required. For example,
Abstract in Spanish: Se ha llevado a cabo una síntesis directa
de pirroles polisustituídos a partir de (a-alcoxialenil)-b-lacta-
mas por tratamiento con metóxido sódico en metanol, sin ne-
cesidad de utilizar metales de transición como catalizadores.
Esta reacción puede explicarse a travØs de un proceso
dominó sin precedentes que implica, en primer lugar, la aper-
tura del anillo de 2-azetidinona, seguido de aminociclación
con el grupo alØnico y aromatización del anillo formado.
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Regiocontrolled Synthesis of Functional Pyrroles
FULL PAPER
Table 2. Preparation of 2-azetidinone-tethered allenes 6.
allenes 3 gave nonisolable al-
lenic-b-amino esters 13, which
yielded pyrroles 12 after a total-
ly regioselective cyclization
onto the central carbon atom of
the neighboring allene under
the reaction conditions, fol-
lowed by aromatization of pyr-
rolines 14 (Scheme 6). Pyrrole
formation must be driven by
Ketone
Allenol
Yield [%][a]
Protected allenol
Yield [%][a]
74
97
63
98
forming
a more stable five-
membered ring, thereby reliev-
ing the strain associated with
the four-membered ring.
60
91
95
99
Another possible pathway
that involves a 5-endo process
and leads to an intermediate
stabilized benzylic anion may
also be considered (see the
Supporting Information).
Direct cyclization occurred
during the treatment of phenyl
allenes 3c–h (Scheme 5), as op-
posed to the sequential reac-
tions performed with methyl al-
lenes 3a and 3b (Scheme 3).
The difference in reactivity be-
tween both types of allenic-b-
lactams can be explained by the
electron-withdrawing capacities
of phenyl substituents com-
pared with the electron-donat-
ing methyl groups. The pres-
ence of a Ph substituent in the
allene stabilizes intermediate
14; these conditions favor cycli-
zation over open-chain prod-
ucts.
76
62
72
72
62
76
80
85
The influence of the position
of the allene moiety at the b-
lactam ring for the one-pot syn-
thesis of the pyrrole nucleus
was investigated by stirring
methyl and phenyl quaternary
a-allenol derivatives 6 for 48 h
68
82
in
a mixture of MeONa in
[a] Yield of pure, isolated product with correct analytical and spectral data.
MeOH at room temperature.
After workup, the starting ma-
terials were recovered. Only
when the reaction was performed on unprotected a-allenol
(+)-2c, the sequence provided the desired product (À)-12a,
but in low yield (10%).
From a mechanistic point of view, our domino sequence
could be explained through a bond-cleavage process on the
four-membered lactam followed by allene cyclization with
after heating at reflux temperature, b-lactam a-allenic
ethers 6a–i reacted to form the corresponding heterocycles
(Scheme 7). New pentasubstituted pyrroles 15a–i were ob-
tained in fair yields by means of our one-pot procedure,[13]
without the concomitant formation of any regioisomer
(Scheme 7). Hydroxymethyl functionalities or aryl moieties
at the 2-position are structural features that are often associ-
ated with pronounced physiological activities of pyr-
À
concomitant aromatization. The selective N1 C2 bond
cleavage of the b-lactam nucleus in 2-azetidinone-tethered
Chem. Eur. J. 2008, 14, 637 – 643
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639

B. Alcaide, P. Almendros et al.
Scheme 3. Ring opening of b-lactams 3 followed by silver-catalyzed ami-
nocyclization reactions leads to the formation of b-allenamines 7 and pyr-
roles 8. Reagents and conditions: a) NaOMe, MeOH, RT, 8 h; b) 20
mol% AgNO3, K2CO3, MeCN, RT, 12 h.
Scheme 6. Mechanistic explanation for the direct formation of pyrroles
12 from phenyl allenes 3 through exo-cyclization.
Scheme 4. Mechanistic explanation for the silver-catalyzed aminocycliza-
tion of b-allenamines 7.
Scheme 7. One-pot synthesis of pyrroles 15 through domino b-lactam
ring-opening allene cyclization. Reagents and conditions: a) MeONa,
MeOH, reflux, 15a: 2 h; 15b: 12 h; 15c: 12 h; 15d: 6 h; 15e: 12 h; 15 f:
25 h; 15g: 3 4 h;15h: 54 h; 15i: 28 h.
roles.[14,15] Interestingly, compounds 15a–d are 2-(hydroxyal-
kyl)pyrroles, whereas compounds 15e–i are 2-arylpyrroles.
More vigorous conditions were required for tertiary allenol
derivatives 6. Nevertheless, a completely regioselective cycli-
zation was still observed in these cases. The reactivity differ-
ence between substrates 3 and 6 is striking and indicates a
Scheme 5. One-pot synthesis of pyrroles 12 through domino b-lactam
ring-opening allene cyclization. Reagents and conditions: a) MeONa,
MeOH, RT, 12a: 8 h; 12b: 24 h; 12c: 96 h; 12d: 96 h; 12e: 24 h; 12 f:
24 h.
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Regiocontrolled Synthesis of Functional Pyrroles
FULL PAPER
3H), 1.49 ppm (t, J=3.2 Hz, 3H); 13C NMR (75 MHz, CDCl3, 258C): d=
208.7, 172.3, 152.1, 141.4, 115.0, 114.4, 95.2, 82.6, 79.5, 73.7, 59.2, 58.8,
56.1, 55.6, 51.6, 12.8 ppm; IR (CHCl3): n˜ =1940, 1735 cmÀ1; MS (ES): m/z
(%): 336 (100) [M+H]+, 335 (15) [M]+; elemental analysis calcd (%) for
C18H25NO5: C 64.46, H 7.51, N 4.18; found: C 64.61, H 7.46, N 4.14.
strong influence of the steric properties of the substrate.
Similar behavior for methyl allenes 6a–d and phenyl allenes
6e–i occurred during these reactions, compared with the re-
actions performed with allenic b-lactams 3, probably be-
cause of the higher reaction temperature. The pathway for
the formation of products 15 is closely related to the pro-
posed pathway for the formation of pyrroles 12 (see the
Supporting Information).
General procedure for the silver-mediated cyclization of b-allenamines
7—preparation of pyrroles 8: Silver nitrate (68 mg, 0.40 mmol) and potas-
sium carbonate (550 mg, 3.98 mmol) were added to a stirred solution of
the corresponding b-allenamine 7 (2.0 mmol) in acetonitrile (10 mL) in
the absence of sunlight. The reaction was stirred at room temperature
until the starting material had disappeared (typically 12 h). Then, the re-
action mixture was filtered though a pad of Celite. Next, brine (2 mL)
was added to the filtrate and it was extracted with ethyl acetate (4”
5 mL). The organic extract was washed with brine, dried over MgSO4,
and the solvent was removed under reduced pressure. Chromatography
of the residue on deactivated silica gel (eluent: ethyl acetate/hexane)
gave analytically pure pyrroles 8.
No loss of enantiomeric purity of pyrroles 8, 12, and 15
1
was evident from the H NMR spectra of adducts (À)-8b,
(À)-12a, and (+)-15a, which were obtained with enantio-
meric excess (ee) values of >95%, in the presence of a
europium(III) chiral shift reagent. Typically, after the addi-
G
tion of the chiral shift reagent the signals for enantiopure
pyrroles moved downfield by approximately d=0.3ppm.
For racemates, after the addition of the chiral shift reagent,
the signals for both enantiomers in the 1H NMR spectra
could be differentiated by about d=0.4 ppm. In the
1H NMR spectra of the racemates after the addition of the
chiral shift reagent, the protons of the enantiomers not pre-
pared in this work were upfield of the analogous protons of
our enantiopure pyrrole derivatives.
Pyrrole (À)-8a: From the starting material b-allenamine (À)-7a (48 mg,
0.14 mmol), pyrrole (À)-8a was obtained as a colorless oil after purifica-
tion of the residue by column chromatography (hexane/ethyl acetate 2:1)
(20 mg, 47%). [a]D =À14.1 (c=0.3in CHCl 3); 1H NMR (300 MHz,
CDCl3, 258C): d=7.20–7.18 (m, 2H), 6.98–6.94 (m, 2H), 6.12 (s, 1H),
4.48 (s, 1H), 3.86 (s, 3H), 3.69 (s, 3H), 3.20 (s, 3H), 2.04 (s, 3H),
1.92 ppm (s, 3H); IR (CHCl3): n˜ =1740, 750 cmÀ1; MS (ES): m/z (%): 304
(100) [M+H]+, 303 (7) [M]+; elemental analysis calcd (%) for
C17H21NO4: C 67.31, H 6.98, N 4.62; found: C 67.44, H 6.93, N 4.66.
General procedure for the direct formation of pyrroles 12 or 15 from
phenyl allenes 3 or allenes 6: Sodium methoxide (0.6 mmol) was added
portionwise at 08C to a solution of the appropriate allenyl-b-lactam 3 or
6 (0.15 mmol) in methanol (3mL). The reaction was stirred at room tem-
perature or at reflux under an argon atmosphere until complete disap-
pearance of the starting material was observed by TLC and then water
was added (0.5 mL). The methanol was removed under reduced pressure,
the aqueous layer was extracted with ethyl acetate (5”3mL), the organic
layer was dried over MgSO4, and the solvent was removed under reduced
pressure. Chromatography of the residue on deactivated silica gel
(eluent: ethyl acetate/hexane) gave analytically pure pyrroles 12 or 15.
Conclusion
In conclusion, using a simple reagent we have successfully
accomplished an unprecedented domino lactam ring-open-
ing allene cyclization reaction for the construction of the
biologically relevant pyrrole frame, which offers clean and
synthetically competitive alternatives to existing methodolo-
gies.[16]
Pyrrole (À)-12a: From the starting material allene-b-lactam (+)-3c
(67 mg, 0.18 mmol), pyrrole (À)-12a was obtained as a colorless oil after
purification of the residue by column chromatography (eluent: hexane/
1
ethyl acetate 2:1; 52 mg, 77%). [a]D =À30.0 (c=0.4 in CHCl3); H NMR
Experimental Section
(300 MHz, CDCl3, 258C): d=7.44–7.20 (m, 6H), 7.04–7.00 (m, 3H), 6.45
(s, 1H), 4.52 (s, 1H), 3.88, 3.71 (2s, each 3H), 3.24 (s, 3H), 2.13 ppm (s,
3H); 13C NMR (75 MHz, CDCl3, 258C): d=170.6, 159.4, 136.7, 130.1,
129.8, 128.3, 128.0, 127.9, 127.5, 125.3, 121.7, 114.2, 114.1, 109.2, 74.7,
56.7, 55.5, 52.2, 12.0 ppm; IR (CHCl3): n˜ =1742, 750 cmÀ1; MS (ES): m/z
(%): 366 (100) [M+H]+, 365 (5) [M]+; elemental analysis calcd (%) for
C22H23NO4: C 72.31, H 6.34, N 3.83; found C 72.17, H 6.30, N 3.85.
General methods: 1H and 13C NMR spectra were recorded by using a
Bruker Avance-300, Varian VRX-300S, or Bruker AC-200 spectrometer.
NMR spectra were recorded in CDCl3 unless otherwise stated. Chemical
shifts are given in ppm relative to TMS (1H: 0.0 ppm), or CDCl3 (13C:
76.9 ppm). Low- and high-resolution mass spectra were recorded by
using an HP5989A spectrometer in electron impact (EI) or electrospray
modes (ES) unless otherwise stated. Specific rotation [a]D is given in
10À1 8cm2 gÀ1 at 208C, and the concentration (c) is expressed in g per
100 mL. All commercially available compounds were used without fur-
ther purification.
Pyrrole (À)-12 f: From the starting material allene-b-lactam (À)-3h
(28 mg, 0.07 mmol), pyrrole (À)-12 f was obtained as a colorless oil after
purification of the residue by column chromatography (eluent: hexane/
ethyl acetate 3:1; 16 mg, 57%). [a]D =À98.8 (c=1.2 in acetone);
1H NMR (300 MHz, [D6]acetone, 258C): d=7.36–7.28 (m, 4H), 7.14–7.12
(m, 2H), 6.96–6.90 (m, 3H), 6.18 (s, 1H), 5.69 (d, J=1.5 Hz, 1H), 4.44,
4.28 (2dd, J=12.5, 2.0 Hz, each 1H), 3.81, 3.35 (2s, each 3H), 2.00 (s,
3H), 1.76 ppm (d, J=1.7 Hz, 1H); 13C NMR (75 MHz, [D6]acetone,
258C): d=170.3, 159.3, 137.1, 135.6, 130.8, 130.7, 130.6, 128.2, 127.7,
127.5, 125.5, 124.9, 120.4, 113.5, 113.1, 108.9, 90.7, 73.4, 54.8, 50.9, 12.7,
11.2 ppm; IR (CHCl3): n˜ =1750, 747 cmÀ1; MS (EI): m/z (%): 403(4)
[M]+, 344 (100) [MÀ59]+; elemental analysis calcd (%) for C25H25NO4:
C 74.42, H 6.25, N 3.47; found C: 74.56, H 6.30, N 3.43.
General procedure for the preparation of b-allenamines 7: Sodium meth-
oxide (0.6 mmol) was added portionwise at 08C to a solution of the ap-
propriate allenyl-b-lactam 3 (0.15 mmol) in methanol (3mL). The reac-
tion was stirred at room temperature under an argon atmosphere for 8 h
and then water was added (0.5 mL). The methanol was removed under
reduced pressure, the aqueous layer was extracted with ethyl acetate (5”
3mL), the organic layer was dried over MgSO 4, and the solvent was re-
moved under reduced pressure to give b-allenamines 7. Spectroscopic
and analytical data for a representative form of compounds 7 follow.[17]
Pyrrole (+)-15a: From the starting material allenyl-b-lactam (+)-6a
(50 mg, 0.14 mmol), compound (+)-17a was obtained as a colorless oil
after purification of the residue by column chromatography (eluent:
hexane/ethyl acetate 5:1; 30 mg, 60%). [a]D =+72.0 (c=0.6 in CHCl3);
1H NMR (300 MHz, CDCl3, 258C): d=7.17, 7.06 (2d, J=9.5 Hz, each
1H), 6.93(dd, J=7.5, 1.5 Hz, 2H), 5.81 (dd, J=8.9, 6.7 Hz, 1H), 4.02 (t,
J=7.0 Hz, 1H), 3.85, 3.84 (2s, each 3H), 3.70 (dd, J=8.9, 7.5 Hz, 1H),
b-Allenamine (À)-7a: From the starting material b-lactam (+)-3a
(75 mg, 0.25 mmol), compound (À)-7a was obtained as a colorless oil
(78 mg, 93%). [a]D =À16.0 (c=0.3in CHCl 3); 1H NMR (300 MHz,
CDCl3, 258C): d=6.68 (d, J=9.0 Hz, 2H), 6.50 (d, J=9.0 Hz, 2H), 4.62–
4.58 (m, 2H), 4.24 (d, J=2.2 Hz, 1H), 3.88 (dd, J=10.0, 2.9 Hz, 1H),
3.72 (d, J=10 Hz, 1H), 3.70 (s, 3H), 3.54 (s, 3H), 3.49 (s, 3H), 3.29 (s,
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B. Alcaide, P. Almendros et al.
2.19 (s, 3H), 1.80 (s, 3H), 1.26, 0.93ppm (2s, each 3H); 13C NMR
(75 MHz, CDCl3, 258C): d=166.4, 159.4, 131.6, 130.8, 129.3, 128.9, 115.9,
114.2, 113.9, 113.4, 108.6, 70.6, 68.3, 55.5, 50.8, 25.5, 25.0, 11.2, 10.2 ppm;
IR (CHCl3): n˜ =1699 cmÀ1; MS (EI): m/z (%): 359 (19) [M]+, 152 (100)
[MÀ207]+; elemental analysis calcd (%) for C20H25NO5: C 66.83, H 7.01,
N 3.90; found: C 66.97, H 7.05, N 3.86.
na, Y. Yamamoto, Tetrahedron Lett. 2006, 47, 4749; j) N. Morita, N.
Krause, Eur. J. Org. Chem. 2006, 4634; k) P. H. Lee, H. Kim, K. Lee,
M. Kim, K. Noh, H. Kim, D. Seomoon, Angew. Chem. 2005, 117,
1874; Angew. Chem. Int. Ed. 2005, 44, 1840; l) R. K. Dieter, N.
Chen, H. Yu, L. E. Nice, V. K. Gore, J. Org. Chem. 2005, 70, 2109;
m) the exposure of b-allenamine (À)-7b to a system of hot MeONa/
MeOH resulted in a complex mixture that contained pyrrole (À)-8b
(7%), as determined by 1H NMR spectroscopic analysis of the
crude material.
Pyrrole 15e: From the starting material allenyl-b-lactam (Æ)-6c (86 mg,
0.25 mmol), compound 17e was obtained as a colorless solid after purifi-
cation of the residue by column chromatograpy (eluent: dichlorometh-
ane; 48 mg, 54%). M.p. 161–1628C; 1H NMR (300 MHz, CDCl3, 258C):
[5] For selected reviews, see: “b-Lactams: Synthesis, Stereochemistry,
Synthons and Biological Evaluation”: a) Curr. Med. Chem. 2004, 11,
1813–1964 (special issue); b) B. Alcaide, P. Almendros, Synlett 2002,
381; c) C. Palomo, J. M. Aizpurua, I. Ganboa, M. Oiarbide, Synlett
2001, 1813; d) B. Alcaide, P. Almendros, Chem. Soc. Rev. 2001, 30,
226; e) I. Ojima, F. Delaloge, Chem. Soc. Rev. 1997, 26, 377; f) M. S.
Manhas, D. R. Wagle, J. Chiang, A. K. Bose, Heterocycles 1988, 27,
1755.
d=6.99 (d, J=1.5 Hz, 4H), 6.93, 6.77 (2d, J=9.0 Hz, each 2H), 3.78,
3.64 (2s, each 3H), 2.30, 2.27 (2s, each 3H), 1.98 ppm (s, 3H); 13C NMR
(75 MHz, CDCl3, 258C): d=158.7, 136.7, 131.1, 130.8, 129.6, 129.5, 128.0,
127.3, 116.2, 113.8, 55.3, 50.4, 21.2, 11.1, 10.6 ppm; IR (CHCl3): n˜ =
1690 cmÀ1; MS (ES): m/z (%): 350 (100) [M+H]+, 349 (24) [M]+; ele-
mental analysis calcd (%) for C22H23NO3: C 75.62, H 6.63, N 4.01; found:
C 75.74, H 6.60, N 4.03.
[6] To the best of our knowledge, only two reports are available:
a) R. K. Dieter, H. Yu, Org. Lett. 2001, 3, 3855; b) M. O. Amombo,
A. Hausherr, H.-U. Reissig, Synlett 1999, 1871; the preparation of
pyrroles from allenimines is somewhat more developed, for exam-
ples, see: c) L. Peng, X. Zhang, J. Ma, Z. Zhong, J. Wang, Org. Lett.
2007, 9, 1445; d) O. Flçgel, J. Dash, I. Brüdgam, H. Hartl, H.-U. Re-
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Pyrrole 15i: From the starting material allenyl-b-lactam (Æ)-6i (72 mg,
0.18 mmol), compound 17i was obtained as a pale yellow oil after purifi-
cation of the residue by column chromatography (eluent: hexane/ethyl
acetate 5:1; 49 mg, 68%). 1H NMR (300 MHz, CDCl3, 258C): d=7.35–
7.31 (m, 5H), 7.16, 6.92 (2d, J=9.0 Hz, each 2H), 6.02 (d, J=3.1 Hz,
1H), 5.85 (dd, J=3.1, 1.0 Hz, 1H), 3.85, 3.59 (2s, each 3H), 2.16,
1.98 ppm (2s, each 3H); 13C NMR (75 MHz, CDCl3, 258C): d=165.8,
159.3, 151.7, 143.0, 135.5, 131.1, 130.1, 129.3, 127.7, 126.2, 122.8, 116.2,
114.0, 111.9, 106.6, 55.4, 51.0, 13.4, 11.4 ppm; IR (CHCl3): n˜ =1694 cmÀ1
;
MS (EI): m/z (%): 401 (100) [M]+; elemental analysis calcd (%) for
C25H23NO4: C 74.79, H 5.77, N 3.49; found: C 74.67, H 5.74, N 3.52.
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Acknowledgements
Support for this work by the DGI-MEC (project CTQ2006–10292) and
CAM-UCM (grant GR69/06) is gratefully acknowledged. R.C. thanks
MEC for a predoctoral grant and CSIC for a studentship. M.C.R. thanks
MEC for a predoctoral grant.
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class of a-chymotrypsin inhibitors, as well as central analgesics. For
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642
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Chem. Eur. J. 2008, 14, 637 – 643

Regiocontrolled Synthesis of Functional Pyrroles
FULL PAPER
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[16] Preliminary studies concerning the oxidative N-deprotection of N-
PMP pyrroles resulted in a complex process. Further investigations
into ruthenium-catalyzed N-allyl cleavage are in progress in our lab-
oratories. All of these results will be reported in due course.
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[17] Full spectroscopic and analytical data for compounds not included
in the Experimental Section are described in the Supporting Infor-
mation. It contains compound characterization data, experimental
procedures for compounds 2a–h, (R)- and (S)-O-acetylmandelates
of compounds (+)-2g, 3a–h, 5a–h, 6a–h, (À)-7b, (À)-8b, 12b–e,
15b–d, and 15 f–h, mechanistic explanation for the direct formation
of pyrroles 12 from phenyl allenes
3 through endo-cyclization
(Scheme S8), and rationalization for the direct formation of pyrroles
15 from allenes 6 (Scheme S9).
Received: May 24, 2007
Published online: October 23, 2007
Chem. Eur. J. 2008, 14, 637 – 643
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