Accessing skeletal diversity under iron catalysis using substrate control: Formation of pyrroles versus lactones

Article abstract of DOI:10.1002/adsc.201100049

2-Azetidinone-tethered alkynols and allen-Gols, readily prepared from a propanylidene β-lactam aldehyde, were used as starting materials for divergent ring expansion reactions catalyzed by iron(III) chloride. Worthy of note, in contrast to the iron-catalyzed reactions of β-lactam allenols which lead to γ-lactones, the reaction of β-lactam alkynols under identical conditions gives pyrroles. The gold-catalyzed 6-endo aminocyclization of these allenic γ-lactones formed fused dihydropyridines. The iron-catalyzed formation of pyrroles may proceed through a Meyer-Schuster rearrangement followed by β-lactam ring opening and cyclization by attack of the amino group to the ketone.

Full text of DOI:10.1002/adsc.201100049

FULL PAPERS
DOI: 10.1002/adsc.201100049
Accessing Skeletal Diversity under Iron Catalysis using Substrate
Control: Formation of Pyrroles versus Lactones
Benito Alcaide,a,* Pedro Almendros,b,* and M. Teresa Quirꢀsa
a
Grupo de Lactamas y Heterociclos Bioactivos, Departamento de Quꢁmica Orgꢂnica I, Unidad Asociada al CSIC, Facultad
de Quꢁmica, Universidad Complutense de Madrid, 28040 Madrid, Spain
Fax : (+34)-91-394-4103; e-mail: alcaideb@quim.ucm.es
Instituto de Quꢁmica Orgꢂnica General, Consejo Superior de Investigaciones Cientꢁficas, CSIC, Juan de la Cierva 3, 28006
b
Madrid, Spain
Fax : (+34)-91-564-4853; e-mail: Palmendros@iqog.csic.es
Received: January 19, 2011; Published online: March 4, 2011
Dedicated to Prof. Dr. Julio Alvarez-Builla on the occasion of his 65th birthday.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201100049.
Abstract: 2-Azetidinone-tethered alkynols and allen- tones formed fused dihydropyridines. The iron-cata-
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
chloride. Worthy of note, in contrast to the iron-cata- group to the ketone.
lyzed reactions of b-lactam allenols which lead to g-
lactones, the reaction of b-lactam alkynols under
identical conditions gives pyrroles. The gold-cata- Keywords: alkynes; allenes; iron; pyrroles; rear-
lyzed 6-endo aminocyclization of these allenic g-lac- rangement
Introduction
sis of the chemically and biologically relevant pyrrole
nucleus, as a convenient alternative to the existing
Iron is the most abundant transition metal on the face methodologies.[5] By using the same scaffold but re-
of the earth. In addition to playing a pivotal role in placing the alkyne by an allene moiety, the reaction
biological processes, iron salts have recently emerged proceeded in a different chemoselective fashion,[6] af-
as powerful alternatives to other transition metals in fording g-lactones.[7]
the field of catalysis in view of their inexpensiveness
and environmental friendliness.[1] On the other hand,
the usual strategies for the preparation of the majori- Results and Discussion
ty of heterocyclic systems start from the appropriate
alicyclic precursor, which after cyclization forms the Starting substrates, unsaturated alcohols 2 and 3, were
required heterocycle. An alternative strategy involv- prepared as inseparable syn/anti mixtures beginning
ing the preparation of heterocyclic compounds from from 4-oxoazetidine-2-carbaldehyde 1 through car-
smaller-sized heterocycles is very appealing,[2] because bonyl-addition reactions (Scheme 1). Alkynols 2a and
of the additional driving force liberated by strain re- 2b were prepared by the addition of magnesium or
duction in ring-enlargement reactions. The inherent lithium acetylides to carbaldehyde 1, using our previ-
strain and their convenient accessibility make b-lac- ous protocol (Scheme 1).[8] Terminal alkyne 2a was
tams an attractive substrate class. Indeed, b-lactams functionalized as its corresponding aryl alkynols 2c
have been recognized as versatile building blocks in and 2d by treatment with iodoarenes under Sonoga-
organic chemistry for the preparation of natural prod- shira conditions (Scheme 1). Allenols 3a–e were
ucts and medicinal reagents.[3] Following up on our achieved via metal-mediated Barbier-type allenylation
combined interest in the area of b-lactams and metal reactions of b-lactam aldehyde 1 in aqueous media
catalysis,[4] herein we report an iron-catalyzed synthe- following our previously described methodologies,[9]
Adv. Synth. Catal. 2011, 353, 585 – 594
ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
585

Benito Alcaide et al.
FULL PAPERS
Scheme 1. Synthesis of alkynols 2 and allenols 3. Reagents and conditions: i) Ethynylmagnesium bromide, THF, À788C, 18 h.
(PPh3)2Cl2, 2 mol% CuI, Et3N, DMSO, 408C, 3 h; 2c:
ii) Phenylacetylene, n-BuLi, THF, À788C, 5 h. iii) ArI, 1 mol% Pd
ACHTUNGTRENNUNG
ArI=4-iodoanisole; 2d: ArI=2-iodothiophene; 2e: ArI=1-bromo-4-iodobenzene. iv) Appropriate 1-substituted-3-bromo-
propyne, In, THF, NH4Cl (aqueous saturated), room temperature, 18 h. v) Ethyl 4-bromobut-2-ynoate, In, LiI, DMF, 408C,
69 h. vi) Propargyl bromide, SnCl2·2H2O, LiI·3H2O, DMF, room temperature, 48 h. PMP=4-MeOC6H4, Tph=2-thiophenyl.
Scheme 2. Chemodivergent iron-catalyzed reactions of enallenes 3a and 4. Reagents and conditions: i) 10 mol% FeCl3, DCE,
sealed tube, 808C, 1.5 h. PMP=4-MeOC6H4, DCE=1,2-dichloroethane.
while allenols 3f and 3g were prepared through Barbi- istry of the g-lactone 6a were determined by single
er-type protocols adopting modified literature meth- crystal X-ray diffraction analysis.[13] The single crystal
ods.[10]
structure analysis is in contrast to the structural as-
We have recently outlined the chemodifferentiation signment based on NMR data of this compound in
between and the alkene and allene moiety using iron ref.[11] which has been rectified in a corrigendum.[11]
catalysis in substrates of type 4 (Scheme 2).[11] To fur- Apparently, under the given reaction conditions, the
ther explore modes of reactivity of unsaturated hy- carbonyl group displays a more pronounced electro-
droxy-b-lactams under FeACTHUNTGRNEUNG(III) catalysis, we have philicity than the tetrasubstituted alkene moiety; af-
screened their reactions using a diverse set of sub- fording the g-lactone through N-1/C-2 amide bond
strates. With the requirement that iron salts be the cleavage with concomitant rearrangement.
catalytic metal source, we began to address the reac-
With the optimal reaction conditions established,
tivity of unsaturated alcohols 2 and 3 under FeCl3-cat- the scope of this rearrangement reaction was then
alysis. Enallene 3a was chosen as a model substrate. studied. Scheme 3 shows the results for six different
The outcome of this reaction is, however, unexpected, related enallenes, demonstrating that the transforma-
as the obtained product is not the expected b-lactam- tion from Scheme 2 is general under the chosen reac-
fused tetrahydrofuran 5, but rather its isomeric g-lac- tion conditions of iron catalysis, affording g-lactone
tone 6a (Scheme 2).[12] The structure and stereochem- derivatives 6b–g in moderate yields regardless of elec-
586
asc.wiley-vch.de
ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 585 – 594

Accessing Skeletal Diversity under Iron Catalysis using Substrate Control
Scheme 3. Iron-catalyzed preparation of g-lactones 6 from 2-azetidinone-tethered allenic alcohols 3. Reagents and conditions:
i) 10 mol% FeCl3, DCE, sealed tube, 808C, 6b: 2 h; 6c: 1.5 h; 6d: 1.5 h; 6e: 2 h; 6f: 2 h; 6g: 1 h. ii) NIS, acetone/H2O (3:1),
room temperature, 4 h. PMP=4-MeOC6H4, DCE=1,2-dichloroethane.
tronic and steric effects at the allene. Replacement of
the methyl group at the allene moiety by hydrogen or
aryl groups also afforded the corresponding products.
For this set of substrates, the reaction proceeded with
complete chemoselectivity in favour of g-lactone for-
mation. Noteworthy, the allenic group is kept unal-
tered under the reactions conditions. Curiously, the
anisyl group of g-lactone derivative 6a could be readi-
ly converted into a hydroxyphenyl moiety in g-lactone
7 by N-iodosuccinimide (NIS) treatment (Scheme 3).
Scheme 4. Gold-promoted preparation of tetrahydrofuro-
AHCTUNGTREG[NNUN 3,2-b]pyridin-2-ones 8 and chloroarenes 9 from 2-furanone-
tethered allenic amines. Reagents and conditions: i) 40 or
50 mol% AuCl3, CH2Cl2, sealed tube, 608C, 6a: 94 h; 6b:
97 h; 6g: 28 h. PMP=4-MeOC6H4.
Given their widespread applications as building
blocks in organic synthesis, allenes are of increasing
importance.[14] Among numerous synthetic utilities,
À
the hydroamination of the unsaturated C C bonds is
of fundamental significance.[15] Although allenes are
more reactive in metal-catalyzed hydroamination re-
actions than alkenes, regioselectivity problems are sig- be explained through a totally regioselective 6-endo-
nificant. The use of gold salts has gained a lot of at- trig allenic aminocyclization. More troublesome is the
tention in the recent times because of their powerful explanation for the obtention of chloroarene 9a. We
soft Lewis acidic nature.[16] In particular, gold activa- therefore speculated how the presence of a different
tion of allenes toward attacks by nitrogen nucleo- substituent at the allene moiety may influence the re-
[17]
À
philes is an important C N bond-forming reaction.
activity. Consequently, replacement of the methyl
However, effective gold-catalyzed protocols for free group at the allenic site by hydrogen or phenyl moiet-
amines have not yet been readily available,[18] because ies was studied. Thus, phenyl-substituted allene 6b
the high ligating ability of amines may cause deactiva- was exposed to goldACTHUNTGRNEUNG(III) reaction conditions. In this
tion of the catalyst by the basic amine. Despite the case, the reaction took place selectively, giving exclu-
anticipated difficulty, we decide to test the reactivity sively chloroarene 9b, but the reaction product could
of our allenic g-lactones under gold-catalyzed condi- only be obtained in reasonable yield using a higher
tions. The stage was thus set for the gold-catalyzed re- catalyst loading of 50 mol% (Scheme 4). Gratifyingly,
action of g-lactone allenamine 6a. Preliminary studies unsubstituted allene 6g was found to be the best part-
about the catalytic activity of gold(I) chloride com- ner of gold for the hydroamination reaction, because
plexes [AuCl, (Ph3P)AuCl] in the presence or absence its exposure to AuCl3 provided bicycle 8g as the sole
of different additives [AgOTf, pyridine] were frustrat- product (Scheme 4).
ing. Fortunately, under AuCl3 exposure the reaction
A possible pathway for the achievement of fused
took place, affording bicycle 8a in fair yield, using dihydropyridine derivatives 8 from b-allenamines 6
40 mol% loading (Scheme 4). However, when the may initially involve the formation of a complex 6-
loading of the catalyst was lowered to 10 mol%, only AuCl3 through coordination of the gold trichloride to
20% conversion was observed. Interestingly, along the distal allenic double bond. Next, regioselective 6-
with bicycle 8a, chloro derivative 9a was also obtained endo aminoauration forms zwitterionic species 10.
as by-product in the AuCl3-promoted reaction. The Loss of HCl followed by protonolysis of the carbon-
formation of fused dihydropyridine g-lactone 8a can gold bond of 11 affords bicycles 8 and regenerates the
Adv. Synth. Catal. 2011, 353, 585 – 594
ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
587

Benito Alcaide et al.
FULL PAPERS
AuCl3 is not restricted to a p-acidic gold catalyst, be-
cause it also acts as a reactant in this reaction.
It was envisaged that if the allene functionality is
replaced by an alkyne moiety, the analogous lactoni-
zation would give rise to amino-substituted alkyne de-
rivatives. We initially examined the iron-catalyzed re-
action of alkynol 2a. In the presence of FeCl3, the re-
actions conditions successfully used for the obtention
of allenic g-lactones 6, we found the reaction of 2a
proceeded smoothly. Surprisingly, the expected alkyn-
ic g-lactone 12a was obtained in just 9% yield. In ad-
dition, a chromatographically separable 1,2-disubsti-
tuted pyrrole 13a was also isolated in 44% yield
(Scheme 6). To shed light on the ring expansion, the
reaction of alkynol 2a was tested in the presence of
different Lewis acids. Different metallic halides
(HfCl4, BiCl3, etc.) gave g-lactone 12a without forma-
tion of any pyrrole derivative (Scheme 6). Only FeCl3
showed catalytic activity towards pyrrole obtention.
The a-vinylpyrrole substructure is the core of a
number of biologically relevant compounds, such as
sunitinib, a promising kinase inhibitor and antitumor-
al agent.[21] Besides, C-vinylated pyrroles are impor-
tant building blocks for forming porphyrins and relat-
Scheme 5. Mechanistic explanation for the Au-catalyzed
preparation of fused dihydropyridines 8. PMP=4-
MeOC6H4.
gold catalyst (Scheme 5). A conceivable mechanism ed nitrogen macrocycles as well as for serving as pre-
for the chlorination of the aromatic ring (obtention of cursors for photoactive polymeric materials.[22] As a
chloroarenes 9 from 6) could result from an electro- consequence, the unexpected skeletal reorganization
philic aromatic substitution,[19] in which the gold is to a-vinylpyrrole formation triggered our interest. As
highly Lewis acidic and the electron-rich aromatic revealed in Scheme 6 and Scheme 7, different b-
ring attacks gold-bound chloride.[20] The Au
ACTHNUTRGNEUNG(III) lactam alkynols were suitable for this transformation,
might be activated toward chloride donation by the affording pyrrole derivatives 13a–e in moderate to
substrate. In this mechanistic picture, the role of good yields regardless of electronic and steric effects.
Starting from non-terminal alkynes 2, 1,2,5-trisubsti-
Scheme 6. Diverse Lewis acid-catalyzed 2-azetidinone-tethered alkynol rearrangements. Reagents and conditions: i) 10 mol%
HfCl4, DCE, sealed tube, 858C, 2.5 h. ii) 10 mol% FeCl3, DCE, sealed tube, 858C, 1 h. PMP=4-MeOC6H4, DCE=1,2-di-
chloroethane.
Scheme 7. Iron-catalyzed ring expansion reaction of aryl-substituted 2-azetidinone-tethered alkynols 2b–e; synthesis of 1,2,5-
trisubstituted pyrroles 13b–e. Reagents and conditions: i) (a) 10 mol% FeCl3, DCE, sealed tube, 858C, 1 h; (b) DBU, MeI,
CHCl3, room temperature, 1.5 h. ii) 10 mol% FeCl3, DCE, sealed tube, 858C, 1 h. PMP =4-MeOC6H4, DCE=1,2-dichloro-
ethane, DBU=1,8-diazabicycloACHTUNTRGNEUNG[5.4.0]undec-7-ene.
588
asc.wiley-vch.de
ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 585 – 594

Accessing Skeletal Diversity under Iron Catalysis using Substrate Control
Scheme 8. Iron-catalyzed ring expansion reaction of bis(alkynyl-b-lactams) 14a and 14b; synthesis of bipyrroles 15a and 15b.
Reagents and conditions: i) Cu
858C, 1 h; (b) DBU, MeI, CHCl3, room temperature, 1.5 h. iii) 1,4-Diiodobenzene, 1 mol% Pd
DMSO, 408C, 2.5 h. PMP=4-MeOC6H4; DCE=1,2-dichloroethane, DBU=1,8-diazabicyclo[5.4.0]undec-7-ene.
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
tuted pyrroles 13b–e were obtained as the sole isola- gave the best performance. Bis(alkynyl-b-lactam) 14b
ble products, except for 13b (69%) which was accom- was prepared by treatment of 2 equivalents of alkyne
panied by a small amount of lactone 12b (9%). 2- 2a with 1,4-diiodobenzene through a double Sonoga-
Azetidinone-tethered alkynol 2c containing an elec- shira coupling reaction (Scheme 8). As shown in
tron-donating group on the benzene ring (methoxy at Scheme 8, bis(alkynyl-b-lactams) 14a and 14b also
the para position) gave 53% yield of pyrrole 12c. participate in this chemistry, leading to bipyrroles 15a
Other heteroaromatic systems, such as thiophen-2-yl- and 15b upon sequential FeCl3 treatment and esterifi-
substituted alkynol 2d, could be employed in this re- cation. The reactions were so chemoselective that
action, and the corresponding pyrrolic product 12d signal for g-lactone protons were not observed in the
was obtained. Pyrrole 13e was isolated as the methyl 1H NMR spectra of the unpurified reaction mixtures.
ester due to the difficulty encountered in purifying Compounds 15 are remarkable since they bear a chal-
the high polar carboxylic acid. The formation of these lenging dimeric pyrrole structure.
pyrroles indicates an important feature, namely, it re-
Since reactions involving ironACHTGNUTERNNU(G III) trichloride may
veals that the nature of the unsaturated group at the generate HCl, the possibility exits that in situ generat-
carbinolic center does have an electronic influence on ed HCl may catalyze the rearrangement reaction.
the course of the ring expansion process, stressing the However, when 10 mol% of HCl was used as the cat-
importance of an alkyne versus allene group to drive alyst under identical conditions, no pyrrole product
the ring expansion towards pyrrole ring construction. was observed, thereby ruling out the possible HCl cat-
Fine-tuning of reactivity and selectivity by the substi- alysis. The role of the iron salt seems obvious, and a
tution of the parent compound is an important Brønsted acid catalysis for the ring expansion reaction
goal.[23]
seems very unlikely. Probably, FeCl3 enhances the re-
To demonstrate that the above protocol can be con- activity of the alkynol moiety through selective
sidered in complex synthetic planning, it was success- formal 1,3-hydroxy shift (Meyer–Schuster rearrange-
fully used for the double-ring expansion of bis(alkyn- ment).[26] A plausible mechanism based on a cascade
yl-b-lactams) 14a and 14b to bipyrroles 15a and 15b. rearrangement is outlined in Scheme 9. In the pres-
Bipyrroles are attractive structures not only because ence of FeCl3, a Meyer–Schuster intermediate 16 is
they are key subunits in important natural products produced from alkynols 2, which may generate the
but also are known for their conducting properties.[24] amino ketone species 17 after tautomerization and b-
To screen the reactivity of the bisACTHNUTRGNE(NUG alkynol) moiety, ho- lactam ring opening. The amine group of species 17
modimerization of alkyne 2a was studied in the pres- might then undergo nucleophilic attack to the ketone
ence of a copper promoter. The homodimerization re- moiety to affords species 18. Finally, dehydration fol-
action proceeded smoothly to afford the desired lowed by demetalation yield heterocycles 13 and re-
diyne 14a by using modified classical copper promot- generate the iron catalyst (Scheme 9). The pyrrole
ed conditions (Scheme 8).[25] Copper(II) acetate in formation must be driven by relief of the strain asso-
combination with potassium carbonate in acetonitrile
Adv. Synth. Catal. 2011, 353, 585 – 594
ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
589

Benito Alcaide et al.
FULL PAPERS
General Procedure for the FeACHTUNTRGNEUNG(III)-Catalyzed
Rearrangement of 2-Azetidinone-Tethered Allenic
Alcohols 3; Preparation of g-Lactones 6
FeCl3 (0.10 mmol) was added to a stirred solution of the cor-
responding allenol
3 (1.0 mmol) in 1,2-dichloroethane
(10 mL). The resulting mixture was heated at 808C in a
sealed tube until complete disappearance (TLC) of the start-
ing material. The reaction mixture was allowed to cool to
room temperature, and then was quenched with aqueous sa-
turated NH4Cl (1.0 mL). The mixture was extracted with
ethyl acetate (3ꢄ5 mL), and the combined extracts were
washed twice with brine. The organic layer was dried
(MgSO4) and concentrated under reduced pressure. Chro-
matography of the residue eluting with ethyl acetate/hex-
anes mixtures gave analytically pure g-lactones 6.[27]
g-Lactone 6a: From 100 mg (0.34 mmol) of 2-azetidinone-
tethered allenic alcohol 3a, and chromatography of the resi-
due using hexanes/ethyl acetate (3:1) as eluent gave com-
pound 6a as a colorless solid; yield: 87 mg (87%); mp 118–
Scheme 9. Proposed catalytic cycle for the iron-catalyzed
formation of pyrroles 13 from alkynyl-b-lactams 2.
1
1208C (hexanes/ethyl acetate); H NMR (300 MHz, CDCl3,
258C): d=6.81 and 6.57 (d, J=9.0 Hz, each 2H), 4.89 (m,
2H), 4.72 (br s, 1H), 4.62 (br s, 1H), 3.76 (s, 3H), 2.35 and
2.00 (s, each 3H), 1.77 (t, J=3.2 Hz, 3H); 13C NMR
(75 MHz, CDCl3, 258C): d=205.9, 169.1, 157.7, 152.9, 121.7,
115.2, 114.8, 98.1, 81.7, 77.2, 57.0, 55.8, 24.1, 20.5, 15.1; IR
(CHCl3): n=3367, 1958, 1743 cmÀ1; HR-MS (ES): m/z=
322.1420, calcd, for C18H21NNaO3 [M+Na]+: 322.1419.
g-Lactone 6b: From 85 mg (0.23 mmol) of 2-azetidinone-
tethered allenic alcohol 3b, and chromatography of the resi-
due using hexanes/ethyl acetate (3:1) as eluent gave com-
ciated with the four-membered ring on forming a
more stable five-membered ring.
Conclusions
In conclusion, an unprecedented and divergent route
to g-lactone and pyrrole derivatives via iron-catalyzed
tandem ring-opening/closing reactions of 2-azetidi-
none-tethered alkynols and allenols has been devel-
oped. This strategy offers a concise platform for the
construction of five-membered ring systems under
mild conditions with high atom economy. A further
gold-catalyzed access to fused dihydropyridines was
also developed. Further investigation on the range of
the current reaction is in progress.
1
pound 6b as a colorless oil; yield: 47 mg (56%); H NMR
(300 MHz, CDCl3, 258C): d=7.34 (m, 5H), 6.76 and 6.53 (d,
J=9.0 Hz, each 2H), 5.33 (m, 3H), 4.73 (br s, 1H), 3.75 (s,
3H), 2.34 and 1.98 (s, each 3H); 13C NMR (75 MHz, CDCl3,
258C): d=207.7, 166.7, 164.4, 153.0, 133.0, 128.6, 127.6,
126.6, 121.4, 115.1, 113.8, 105.6, 81.4, 77.2, 60.4, 55.7, 24.2,
20.5; IR (CHCl3): n=3364, 1955, 1741 cmÀ1; HR-MS (ES):
m/z=362.1752,calcd. for C23H24NO3 [M+H]+: 362.1756.
g-Lactone 6c: From 50 mg (0.13 mmol) of 2-azetidinone-
tethered allenic alcohol 3c, and chromatography of the resi-
due using hexanes/ethyl acetate (3:1) as eluent gave com-
1
pound 6c as a colorless oil; yield: 28 mg (55%); H NMR
(300 MHz, CDCl3, 258C): d=7.33 and 6.87 (d, J=9.0 Hz,
each 2H), 6.77 and 6.51 (d, J=9.0 Hz, each 2H), 5.30 (m,
2H), 5.23 (br s, 1H), 4.71 (br s, 1H), 3.81 (s, 3H), 3.74 (s,
3H), 2.34 and 1.98 (s, each 3H); 13C NMR (75 MHz, CDCl3,
258C): d=207.4, 159.1, 157.8, 152.9, 151.1, 128.0, 125.2,
121.7, 115.1, 115.0, 114.1, 105.2, 81.3, 78.8, 57.7, 55.7, 55.3,
24.1, 20.5; IR (CHCl3): n=3370, 1948, 1742 cmÀ1; HR-MS
(ES): m/z=392.1853, calcd. for C24H26NO4 [M+H]+:
392.1862.
Experimental Section
General Methods
1H NMR and 13C NMR spectra were recorded on a Bruker
AMX-500, Bruker Avance-300, Varian VRX-300S or Bruker
AC-200. NMR spectra were recorded in CDCl3 solutions,
except where otherwise stated. Chemical shifts are given in
ppm relative to TMS (1H, 0.0 ppm), or CDCl3 (13C,
77.0 ppm). Low- and high-resolution mass spectra were
taken on an Agilent 6520 Accurate-Mass QTOF LC/MS
spectrometer using the electronic impact (EI) or electro-
spray modes (ES) unless otherwise stated. IR spectra were
recorded on a Bruker Tensor 27 spectrometer. Specific rota-
tions [a]D are given in 10À1 deg cm2 gÀ1 at 208C, and the con-
centration (c) is expressed in g per 100 mL. All commercial-
ly available compounds were used without further purifica-
tion.
g-Lactone 6d: From 50 mg (0.14 mmol) of 2-azetidinone-
tethered allenic alcohol 3d, and chromatography of the resi-
due using hexanes/ethyl acetate (3:1) as eluent gave com-
1
pound 6d as a colorless oil; yield: 25 mg (49%); H NMR
(300 MHz, CDCl3, 258C): d=7.24 (dd, J=5.0, 1.3 Hz, 1H),
7.00 (m, 2H), 6.80 and 6.53 (d, J=9.0 Hz, each 2H), 5.35
(m, 2H), 5.17 (td, J=2.2, 1.0 Hz, 1H), 4.71 (br s, 1H), 3.75
(s, 3H), 3.34 (s, 3H), 2.34 and 1.99 (s, each 3H); 13C NMR
(75 MHz, CDCl3, 258C): d=206.9, 168.9, 158.1, 153.0, 136.6,
127.7, 125.4, 125.1, 121.4, 115.1, 113.9, 101.6, 82.0, 79.3, 57.7,
590
asc.wiley-vch.de
ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 585 – 594

Accessing Skeletal Diversity under Iron Catalysis using Substrate Control
55.7, 24.2, 20.6; IR (CHCl3): n=3364, 1951, 1743 cmÀ1; HR-
MS (ES): m/z=368.1304, calcd. for C21H22NO3S [M+H]+:
368.1320.
as eluent, 20 mg (45%) of the less polar compound 8a and
10 mg (20%) of the more polar compound 9a were ob-
tained.
1
g-Lactone 6e: From 50 mg (0.128 mmol) of 2-azetidinone-
tethered allenic alcohol 3e, and chromatography of the resi-
due using hexanes/ethyl acetate (3:1) as eluent gave com-
Bicycle 8a: Pale brown oil; H NMR (300 MHz, CDCl3,
258C): d=6.82 and 6.62 (d, J=9.0 Hz, each 2H), 5.76 (m,
1H), 4.74 (s, 1H), 4.41 (br s, 1H), 4.11 (m, 2H), 3.77 (s,
3H), 2.37 and 2.02 (s, each 3H), 1.70 (t, J=1.3 Hz, 3H);
13C NMR (75 MHz, CDCl3, 258C): d=169.1, 164.0, 147.8,
138.2, 124.6, 115.9, 115.1, 97.6, 77.2, 57.8, 55.7, 39.3, 24.4,
20.6, 11.6; IR (CHCl3): n=1752 cmÀ1; HR-MS (ES): m/z=
300.1594, calcd. for C18H22NO3 [M+H]+: 300.1600.
1
pound 6e as a colorless oil; yield: 28 mg (54%); H NMR
(300 MHz, CDCl3, 258C): d=7.34 (m, 5H), 6.77 and 6.60 (d,
J=9.0 Hz, each 2H), 5.04 (m, 2H), 4.94 (br s, 1H), 4.73 (br
s, 1H), 4.51 (s, 2H), 3.74 (s, 3H), 2.30 and 1.92 (s, each 3H);
13C NMR (75 MHz, CDCl3, 258C): d=206.8, 167.9, 157.8,
137.7, 128.6, 128.4, 127.8, 127.7, 126.9, 120.7, 115.2, 100.4,
78.8, 77.2, 72.4, 68.4, 60.4, 55.8, 24.1, 20.5; IR (CHCl3): n=
3364, 1954, 1744 cmÀ1; HR-MS (ES): m/z=406.2017, calcd.
for C25H28NO4 [M+H]+: 406.2018.
1
Chloro derivative 9a: Pale brown oil; H NMR (300 MHz,
CDCl3, 258C): d=6.93 (d, J=2.8 Hz, 1H), 6.77 (dd, J=9.0,
2.8 Hz, 1H), 6.56 (d, J=9.0 Hz, 1H), 4.89 (m, 2H), 4.68 (s,
1H), 4.64 (br s, 1H), 3.76 (s, 3H), 2.38 and 2.00 (s, each
3H), 1.78 (t, J=3.2 Hz, 3H); 13C NMR (75 MHz, CDCl3,
258C): d=205.9, 160.5, 158.5, 152.2, 136.2.121.4, 120.4, 115.8,
113.8, 112.6, 98.1, 82.1, 77.5, 56.7, 55.9, 24.2, 20.6, 15.1; IR
(CHCl3, cmÀ1): n 3370, 1954, 1740 cmÀ1; HRMS (ES): calcd.
for C18H21NClO3 [M + H]+: 334.1210; found: 334.1202.
Chloro derivative 9b: From 30 mg (0.09 mmol) of allenic
amine 6b, and chromatography of the residue using hex-
anes/ethyl acetate (4:1) as eluent gave compound 9b as a
pale brown oil; yield: 18 mg (52%); 1H NMR (700 MHz,
CDCl3, 258C): d=7.42 (d, J=7.7 Hz, 3H), 7.34 (t, J=
7.7 Hz, 2H), 6.93 (d, J=2.8 Hz, 1H), 6.65 (dd, J=9.0,
2.8 Hz, 1H), 6.39 (d, J=9.0 Hz, 1H), 5.35 (m, 2H), 5.24 (s,
1H), 4.75 (s, 1H), 3.74 (s, 3H), 2.38 and 1.98 (s, each 3H);
13C NMR (175 MHz, CDCl3, 258C): d=207.7, 168.8, 158.6,
152.3, 136.0, 133.1, 128.7, 127.8, 126.9, 121.3, 120.6, 115.8,
113.8, 113.0, 105.7, 81.6, 79.1, 57.4, 56.0, 24.2, 20.7; IR
(CHCl3, cmÀ1): n=3372, 1952, 1742 cmÀ1; HR-MS (ES): m/
z=396.1356, calcd. for C23H23NClO3 [M+H]+: 396.1366.
Bicycle 8g: From 45 mg (0.16 mmol) of allenic amine 6g,
and chromatography of the residue using hexanes/ethyl ace-
tate (4:1) as eluent gave compound 8g as a pale brown oil;
g-Lactone 6f: From 32 mg (0.09 mmol) of 2-azetidinone-
tethered allenic alcohol 3f, and chromatography of the resi-
due using hexanes/ethyl acetate (3:1) as eluent gave com-
1
pound 6f as a colorless oil; yield: 16 mg (49%); H NMR
(300 MHz, CDCl3, 258C): d=7.36 and 6.90 (d, J=9.0 Hz,
each 2H), 5.37 (t, J=1.5 Hz, 1H), 5.31 (m, 1H), 5.20 (dd,
J=1.5, 1.0 Hz, 1H), 4.44 (d, J=0.9 Hz, 1H), 4.24 (q, J=
7.0 Hz, 2H), 3.80 (s, 3H), 1.62 and 1.27 (s, each 3H), 1.31 (t,
J=7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3, 258C): d=
207.6, 179.2, 164.8, 158.1, 153.0, 125.1, 117.9, 114.6, 109.8,
94.4, 80.5, 77.2, 69.3, 60.7, 55.5, 24.2, 21.6, 14.1; IR (CHCl3):
n=3365, 1952, 1745, 1718 cmÀ1
; HR-MS (ES): m/z=
358.1652, calcd. for C20H24NO5 [M+H]+: 358.1654.
g-Lactone 6g: From 54 mg (0.19 mmol) of 2-azetidinone-
tethered allenic alcohol 3g, and chromatography of the resi-
due using hexanes/ethyl acetate (3:1) as eluent gave com-
1
pound 6g as a colorless oil; yield: 33 mg (60%); H NMR
(300 MHz, CDCl3, 258C): d=6.82 and 6.56 (d, J=9.0 Hz,
each 2H), 5.34 (q, J=6.3 Hz, 1H), 5.01 (m, 2H), 4.86 (dtd,
J=6.2, 2.5, 0.9 Hz, 1H), 4.53 (br s, 1H), 3.77 (s, 3H), 3.66
(br s, 1H), 2.36 and 2.02 (s, each 3H); 13C NMR (75 MHz,
CDCl3, 258C): d=207.9, 169.0, 158.6, 152.7, 139.6, 121.1,
115.1, 114.5, 90.3, 78.6, 78.5, 57.8, 55.7, 24.2, 20.5; IR
(CHCl3): n=3360, 1950, 1743 cmÀ1; HR-MS (ES): m/z=
286.1438, calcd. for C17H20NO3 [M+H]+: 286.1443.
1
yield: 22 mg (49%); H NMR (300 MHz, CDCl3, 258C): d=
6.83 and 6.55 (d, J=9.0 Hz, each 2H), 6.07 (dt, J=9.1,
1.3 Hz, 1H), 4.98 (dd, J=9.1, 1.2 Hz, 1H), 4.40 (dd, J=2.5,
1.5 Hz, 2H), 4.36 (br s, 1H), 3.77 (s, 3H), 3.60 (br s, 1H),
2.38 and 2.03 (s, each 3H); 13C NMR (75 MHz, CDCl3,
258C): d=168.8, 159.5, 153.2, 139.2, 134.1, 120.8, 115.5,
115.3, 104.8, 85.6, 58.4, 55.8, 53.1, 24.4, 20.7; IR (CHCl3): n=
General Procedure for the Gold-Catalyzed Reaction
of 2-Furanone-Tethered Allenic Amines 6;
Preparation of Compounds 8 and 9
1750 cmÀ1
;
HR-MS (ES): m/z=286.1448, calcd. for
C17H20NO3 [M+H]+: 286.1443.
AuCl3 (0.4–0.5 mmol) was added to a stirred solution of the
corresponding 2-furanone-tethered allenic amine
6
General Procedure for the FeACHTUNTRGNEUNG(III)-Catalyzed
Rearrangement of 2-Azetidinone-Tethered Alkynols
2; Preparation of (Pyrrolyl)butenoic Acids 13
(1.0 mmol) in dichloromethane (10 mL) under argon. The
resulting mixture was heated at 608C in a sealed tube until
complete disappearance (TLC) of the starting material. The
reaction was then quenched with brine (2 mL), the mixture
was extracted with ethyl acetate (3ꢄ5 mL), and the com-
bined extracts were washed twice with brine. The organic
layer was dried (MgSO4) and concentrated under reduced
pressure. Chromatography of the residue eluting with ethyl
acetate/hexanes mixtures gave analytically pure adducts 8
and 9.
FeCl3 (0.10 mmol) was added to a stirred solution of the cor-
responding alkynol
2 (1.0 mmol) in 1,2-dichloroethane
(10 mL). The resulting mixture was heated at 858C in a
sealed tube until complete disappearance (TLC) of the start-
ing material. The reaction mixture was allowed to cool to
room temperature, and then was quenched with aqueous sa-
turated NH4Cl (1.0 mL). The mixture was extracted with
ethyl acetate (3ꢄ5 mL), and the combined extracts were
washed twice with brine. The organic layer was dried
(MgSO4) and concentrated under reduced pressure. Chro-
matography of the residue eluting with ethyl acetate/hex-
anes mixtures gave analytically pure pyrroles 13.
Preparation of Bicycle 8a and Chloro Derivative 9a
From 45 mg (0.15 mmol) of allenic amine 6a, and after chro-
matography of the residue using hexanes/ethyl acetate (4:1)
Adv. Synth. Catal. 2011, 353, 585 – 594
ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
591

Benito Alcaide et al.
FULL PAPERS
(2:1) as eluent gave compound 13d as a pale red solid;
yield: 33 mg (47%); mp 170–1728C (hexanes/ethyl acetate);
1H NMR (300 MHz, CDCl3, 258C): d=7.11 and 6.83 (d, J=
9.0 Hz, each 2H), 7.02 (dd, J=5.1, 1.0 Hz, 1H), 6.81 (dd, J=
5.1, 3.6 Hz, 1H), 6.51 (d, J=3.5 Hz, 2H), 6.15 (d, J=3.7 Hz,
1H), 3.81 (s, 3H), 2.10 and 1.82 (s, each 3H); 13C NMR
(75 MHz, CDCl3, 258C): d=171.2, 159.2, 157.0, 135.6, 132.0,
131.2, 129.9, 128.5, 126.8, 123.6, 123.4, 113.8, 109.9, 109.0, 55.3,
25.6, 22.6; IR (CHCl3): n=3228, 1704 cmÀ1; HR-MS (ES): m/
z=354.1167, calcd. for C20H20NO3S [M+H]+: 354.1164.
Preparation of g-Lactone 12a and Pyrrole 13a
From 42 mg (0.15 mmol) of alkynol 2a, and after chromatog-
raphy of the residue using hexanes/ethyl acetate (2:1) as
eluent, 4 mg (9%) of the less polar compound 12a and
19 mg (44%) of the more polar compound 13a were ob-
tained.
1
g-Lactone 12a: Colorless oil; H NMR (300 MHz, CDCl3,
258C): d=6.85 and 6.60 (d, J=9.0 Hz, each 2H), 4.94 (s,
1H), 4.66 (br s, 1H), 3.77 (s, 3H), 2.69 (d, J=2.2 Hz, 1H),
2.38 and 2.05 (s, each 3H), 1.60 (br s, 1H); 13C NMR
(75 MHz, CDCl3, 258C): d=159.9, 122.2, 119.9, 115.3, 114.0,
110.6, 108.4, 79.8, 70.9, 59.8, 55.7, 55.4, 24.4, 20.6; IR
(CHCl3): n=3392, 2125, 1748 cmÀ1; MS (EI): m/z (%)=271
(100) [M]+.
General Procedure for the Fe
ACHTUNGTRENNUNG
Rearrangement of Alkynol 2e and BisAHCUTNGTRENNUNG
Preparation of (Pyrrolyl)butenoates 13e and 15
Pyrrole 13a: Pale red solid; mp 160–1628C (hexanes/ethyl
1
acetate); H NMR (300 MHz, CDCl3, 258C): d=7.18 and 6.87
FeCl3 (0.10 mmol) was added to a stirred solution of the cor-
responding mono- or bis-alkynol 2e or 14 (1.0 mmol) in 1,2-
dichloroethane (10 mL). The resulting mixture was heated
at 858C in a sealed tube until complete disappearance
(TLC) of the starting material. The reaction mixture was al-
lowed to cool to room temperature, and then was quenched
with brine (2 mL). The mixture was extracted with ethyl
acetate (3ꢄ5 mL), and the combined extracts were washed
twice with brine. The organic layer was dried (MgSO4) and
concentrated under reduced pressure. The crude (pyrrolyl)-
butenoic acid was solved in chloroform (0.8 mL) and 1,8-
(d, J=9.0 Hz, each 2H), 6.85 (m, 1H), 6.30 (dd, J=3.2,
2.9 Hz, 1H), 6.16 (dd, J=3.4, 1.7 Hz, 1H), 3.82 (s, 3H), 2.11
and 1.66 (s, each 3H); 13C NMR (75 MHz, CDCl3, 258C): d=
171.3, 158.2, 156.4, 129.0, 126.3, 122.2, 120.5, 114.0, 110.6, 108.4,
55.4, 25.2, 22.6; IR (CHCl3: n=3210, 1705 cmÀ1; HR-MS (ES):
m/z=272.1281, calcd. for C16H18NO3 [M+H]+: 272.1287.
Preparation of g-Lactone 12b and Pyrrole 13b
From 73 mg (0.21 mmol) of alkynol 2b, and after chromatog-
raphy of the residue using hexanes/ethyl acetate (2:1) as
eluent, 7 mg (9%) of the less polar compound 12b and 51 mg
(69%) of the more polar compound 13b were obtained.
diazabicycloACHTUNTRGNEUNG[5.4.0]undec-7-ene (304 mg, 2.0 mmol) was
slowly added at 08C under argon atmosphere. The reaction
mixture was stirred for 30 min at room temperature and
then was recooled at 08C. Methyl iodide (2.8 mmol) was
added and the mixture was stirred for 1 h at room tempera-
ture. The reaction was then quenched with aqueous saturat-
ed NH4Cl (1.0 mL), the mixture was extracted with ethyl
acetate (3ꢄ5 mL), and the combined extracts were washed
twice with brine. The organic layer was dried (MgSO4) and
concentrated under reduced pressure. Chromatography of
the residue eluting with ethyl acetate/hexanes mixtures gave
analytically pure pyrroles 13e and 15.
1
g-Lactone 12b: Colorless oil; H NMR (300 MHz, CDCl3,
258C): d=7.50 (m, 2H), 7.36 (m, 3H), 6.86 and 6.64 (d, J=
9.0 Hz, each 2H), 5.16 (d, J=1.0 Hz, 1H), 4.73 (br s, 1H),
3.78 (s, 3H), 2.40 and 2.07 (s, each 3H); 13C NMR (75 MHz,
CDCl3, 258C): d=168.6, 159.5, 153.0, 139.3, 131.9, 129.1,
128.4 (2CH Ph), 121.6, 120.4, 115.3, 114.5, 87.8, 84.9, 71.9,
60.0, 55.8, 24.4, 20.6; IR (CHCl3): n=3385, 1750 cmÀ1; HR-
MS (ES): m/z=348.1594, calcd. for C22H22NO3 [M+H]+:
348.1600.
Pyrrole 13b: Pale red solid; mp 160–1628C (hexanes/ethyl
acetate); 1H NMR (300 MHz, CDCl3, 258C): d=7.13 (m,
5H), 7.02 and 6.77 (d, J=9.0 Hz, each 2H), 6.45 (d, J=
3.5 Hz, 1H), 6.19 (d, J=3.7 Hz, 1H), 3.77 (s, 3H), 2.09 and
1.76 (s, each 3H); 13C NMR (75 MHz, CDCl3, 258C): d=
172.0, 158.4, 156.2, 134.4, 133.3, 131.9, 131.8, 129.2, 128.0,
127.9, 125.8, 121.2, 113.7, 110.0, 109.1, 55.3, 25.5, 22.6; IR
(CHCl3): n=3214, 1704 cmÀ1; HR-MS (ES): m/z=348.1596,
calcd. for C22H22NO3 [M+H]+: 348.1600.
Pyrrole 13e: From 32 mg (0.075 mmol) of alkynol 2e, and
chromatography of the residue using hexanes/ethyl acetate
(3:1) as eluent gave compound 13e as a pale red oil; yield:
17 mg (52%); 1H NMR (300 MHz, CDCl3, 258C): d=7.28
and 6.93 (d, J=9.0 Hz, each 2H), 6.94 and 6.80 (d, J=
9.0 Hz, each 2H), 6.44 (d, J=3.6 Hz, 1H), 6.17 (d, J=
3.6 Hz, 1H), 3.81 (s, 3H), 3.45 (s, 3H), 2.10 and 1.85 (s, each
3H); 13C NMR (75 MHz, CDCl3, 258C): d=167.4, 158.5,
153.3, 132.9, 132.6, 132.2, 131.5, 131.1, 129.3, 129.1, 121.4,
119.7, 113.8, 110.5, 109.4, 55.3, 51.3, 25.1, 22.5; IR (CHCl3):
Pyrrole 13c: From 70 mg (0.20 mmol) of alkynol 2c, and
chromatography of the residue using hexanes/ethyl acetate
(2:1) as eluent gave compound 13c as a pale red solid; yield:
37 mg (53%); mp 179–1818C (hexanes/ethyl acetate);
1H NMR (300 MHz, CDCl3, 258C): d=7.01 and 6.76 (d, J=
9.0 Hz, each 2H), 7.00 and 6.71 (d, J=9.0 Hz, each 2H),
6.36 (d, J=3.5 Hz, 1H), 6.17 (d, J=3.5 Hz, 1H), 3.77 (s,
3H), 3.75 (s, 3H), 2.08 and 1.74 (s, each 3H); 13C NMR
(75 MHz, CDCl3, 258C): d=171.5, 158.3, 157.8, 155.7, 134.3,
131.9, 131.1, 129.3, 129.2, 126.0, 121.4, 113.7, 113.4, 109.8,
n=1718 cmÀ1
C23H23BrNO3 [M+H]+: 440.0861.
Bis(pyrrole) 15a: From 66 mg (0.14 mmol) of bisACTHNGUTRENNU(G alkynol)
; HR-MS (ES): m/z=440.0884, calcd. for
G
14a, and chromatography of the residue using hexanes/ethyl
acetate (3:1) as eluent gave compound 15a as a red solid;
yield: 41 mg (60%); mp 136–1388C (hexanes/ethyl acetate);
1H NMR (300 MHz, CDCl3, 258C): d=6.56 and 6.42 (d, J=
9.0 Hz, each 4H), 6.34 (d, J=3.5 Hz, 2H), 6.04 (d, J=
3.5 Hz, 2H), 3.74 (s, 6H), 3.33 (s, 6H), 2.04 and 1.70 (s, each
6H); 13C NMR (75 MHz, CDCl3, 258C): d=167.3, 157.7,
153.0, 131.7, 130.3, 127.7, 125.9, 121.6, 113.0, 111.3, 109.7,
55.3, 51.1, 24.8, 22.4; IR (CHCl3): n=1714 cmÀ1; HR-MS
(ES): m/z=569.2640, calcd. for C34H37N2O6 [M+H]+:
569.2652.
108.2, 55.3, 55.1, 25.4, 22.5; IR (CHCl3): n=3220, 1700 cmÀ1
;
HR-MS (ES): m/z=378.1701, calcd. for C23H24NO4 [M+
H]+: 378.1705.
Pyrrole 13d: From 71 mg (0.14 mmol) of alkynol 2d, and
chromatography of the residue using hexanes/ethyl acetate
592
asc.wiley-vch.de
ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 585 – 594

Accessing Skeletal Diversity under Iron Catalysis using Substrate Control
Bis
G
E
[4] See, for instance: a) B. Alcaide, P. Almendros, R. Car-
rascosa, M. R. Torres, Adv. Synth. Catal. 2010, 352,
1277; b) B. Alcaide, P. Almendros, A. Luna, M. R.
Torres, Adv. Synth. Catal. 2010, 352, 621; c) B. Alcaide,
P. Almendros, C. Aragoncillo, Chem. Eur. J. 2009, 15,
9987; d) B. Alcaide, P. Almendros, T. Martꢁnez del
Campo, M. T. Quirꢀs, Chem. Eur. J. 2009, 15, 3344;
e) B. Alcaide, P. Almendros, R. Carrascosa, T. Martꢁnez
del Campo, Chem. Eur. J. 2009, 15, 2496; f) B. Alcaide,
P. Almendros, R. Carrascosa, M. C. Redondo, Chem.
Eur. J. 2008, 14, 637; g) B. Alcaide, P. Almendros, T.
Martꢁnez del Campo, Angew. Chem. 2007, 119, 6804;
Angew. Chem. Int. Ed. 2007, 46, 6684; h) B. Alcaide, P.
Almendros, T. Martꢁnez del Campo, Angew. Chem.
2006, 118, 4613; Angew. Chem. Int. Ed. 2006, 45, 4501.
[5] The search for new syntheses of pyrroles is of interest
because of the biological activity of these molecules.
Pyrroles are also being used as valuable intermediates
in organic synthesis and they are widely used in materi-
als science and molecular recognition. For selected ref-
erences on the use of these heterocycles in a multitude
of applications, see: a) S. Thirumalairajan, B. M.
Pearce, A. Thompson, Chem. Commun. 2010, 46, 1797;
b) M. Gonidec, F. Luis, ꢆ. Vꢁlchez, J. Esquena, D. B.
Amabilino, J. Veciana, Angew. Chem. 2010, 122, 1667;
Angew. Chem. Int. Ed. 2010, 49, 1623; c) N. A. Trofi-
mov, N. A. Nedolya, in: Comprehensive Heterocyclic
Chemistry III, (Eds.: A. R. Katritzky, C. A. Ramsden,
E. F. V. Scriven, R. J. K. Taylor), Elsevier, Oxford,
2008, Vol. 3, pp 45–268; d) M. G. Banwell, T. E. Good-
win, S. Ng, J. A. Smith, D. J. Wong, Eur. J. Org. Chem.
2006, 3043; e) Heterocyclic Antitumor Antibiotics, in:
Topics in Heterocyclic Chemistry, (Ed.: M. Lee),
Springer-Verlag: Berlin, 2006, chap. 2; f) A. Fꢅrstner,
Angew. Chem. 2003, 115, 3706; Angew. Chem. Int. Ed.
2003, 42, 3582; g) P. A. Jacobi, L. D. Coults, J. S. Guo,
S. I. Leung, J. Org. Chem. 2000, 65, 205; h) A. Fꢅrstner,
Synlett 1999, 1523; i) D. L. Boger, C. W. Boyce, M. A.
Labrili, C. A. Sehon, Q. Jin, J. Am. Chem. Soc. 1999,
121, 54; j) S. Higgins, Chem. Soc. Rev. 1997, 26, 247;
k) G. W. Gribble, in: Comprehensive Heterocyclic
Chemistry II, (Eds.: A. R. Katritzky, C. W. Rees, E. F.
Scriven), Pergamon Press, Oxford, 1996, Vol. 2, p 207;
l) A. Gossauer, Die Chemie der Pyrrole, Springer-
Verlag: Berlin, 1974.
14b, and chromatography of the residue using hexanes/ethyl
acetate (6:1) as eluent gave compound 15b as a pale red oil;
yield: 35 mg (54%); H NMR (700 MHz, CDCl3, 258C): d=
6.90 and 6.75 (d, J=9.0 Hz, each 4H), 6.86 (s, 4H), 6.41 (d,
J=3.6 Hz, 2H), 6.14 (d, J=3.6 Hz, 2H), 3.79 (s, 6H), 3.42
(s, 6H), 2.08 and 1.84 (s, each 6H); 13C NMR (175 MHz,
CDCl3, 258C): d=167.5, 158.3, 153.0, 133.9, 132.0, 131.9,
130.5, 129.1, 127.3, 121.6, 113.6, 110.4, 108.9, 55.3, 21.3, 25.0,
22.5; IR (CHCl3): n=1710 cmÀ1
645.2997, calcd. for C40H41N2O6 [M+H]+: 645.2965.
Acknowledgements
Support for this work by the DGI-MICINN (Project
CTQ2009-09318), Comunidad Autꢀnoma de Madrid (Project
S2009/PPQ-1752) and UCM-BSCH (Project GR58/08) are
gratefully acknowledged. M. T. Q. thanks the MEC for a pre-
doctoral grant.
References
[1] For reviews, see: a) C. Bolm, J. Legros, J. Le Paih, L.
Zani, Chem. Rev. 2004, 104, 6217; b) D. D. Dꢁaz, P. O.
Miranda, J. I. Padrꢀn, V. S. Martin, Curr. Org. Chem.
2006, 10, 457; c) A. Fꢅrstner, B. D. Sherry, Acc. Chem.
Res. 2008, 41, 1500; d) A. Correa, O. Garcꢁa-MancheÇo,
C. Bolm, Chem. Soc. Rev. 2008, 37, 1108; e) Iron Catal-
ysis in Organic Chemistry, (Ed.: B. Plietker), Wiley-
VCH, Weinheim, 2008; f) E. B. Bauer, Curr. Org.
Chem. 2008, 12, 1341; g) A. Fꢅrstner, Angew. Chem.
2009, 121, 1390; Angew. Chem. Int. Ed. 2009, 48, 1364.
[2] Forming two or more bonds in one pot, and avoiding
the purification procedures of intermediates greatly en-
hances synthetic efficiency. For selected papers, see:
a) P. R. Ullapu, S.-J. Min, S. L. Chavre, H. Choo, J. K.
Lee, A. N. Pae, Y. Kim, M. H. Chang, Y. S. Cho,
Angew. Chem. 2009, 121, 2230; Angew. Chem. Int. Ed.
2009, 48, 2196; b) J.-R. Chen, C.-F. Li, X.-L. An, J.-J.
Zhang, X.-Y Zhu, W.-J. Xiao, Angew. Chem. 2008, 120,
2523; Angew. Chem. Int. Ed. 2008, 47, 2489; c) Q.-G.
Wang, X.-M. Deng, B.-H. Zhu, L.-W. Ye, X.-L. Sun, C.-
Y. Li, C.-Y. Zhu, Q. Shen, Y. Tang, J. Am. Chem. Soc.
2008, 130, 5408; d) L.-W. Ye, X.-L. Sun, Q.-G. Wang, Y.
Tang, Angew. Chem. 2007, 119, 6055; Angew. Chem.
Int. Ed. 2007, 46, 5951; e) D. Enders, M. R. M. Hꢅttl, C.
Grondal, G. Rabbe, Nature 2006, 441, 861.
[6] For a review on chemoselectivity and the curious reac-
tivity preferences of functional groups, see: A. K.
Yudin, N. A. Afagh, Angew. Chem. 2010, 122, 270;
Angew. Chem. Int. Ed. 2010, 49, 262.
[7] One of the key elements of successful diversity-orient-
ed synthesis is efficient use of chemical reactions to in-
crease diversity and complexity: a) T. E. Nielsen, S. L.
Schreiber, Angew. Chem. 2008, 120, 52; Angew. Chem.
Int. Ed. 2008, 47, 48; b) S. L. Schreiber, Nature 2009,
457, 153. Furthermore, such synthetic strategies are
more valuable if they allow scaffold diversity rather
than compound diversity.
[3] For selected reviews, see: a) B. Alcaide, P. Almendros,
C. Aragoncillo, Chem. Rev. 2007, 107, 4437; b) B. Al-
caide, P. Almendros, Curr. Med. Chem. 2004, 11, 1921;
c) A. R. A. S. Deshmukh, B. M. Bhawal, D. Krishnasw-
amy, V. V. Govande, B. A. Shinkre, A. Jayanthi, Curr.
Med. Chem. 2004, 11, 1889; d) B. Alcaide, P. Almen-
dros, Synlett 2002, 381; e) C. Palomo, J. M. Aizpurua, I.
Ganboa, M. Oiarbide, Synlett 2001, 1813; f) B. Alcaide,
P. Almendros, Chem. Soc. Rev. 2001, 30, 226; g) I.
Ojima, F. Delaloge, Chem. Soc. Rev. 1997, 26, 377;
h) M. S. Manhas, D. R. Wagle, J. Chiang, A. K. Bose,
Heterocycles 1988, 27, 1755.
[8] B. Alcaide, P. Almendros, J. M. Alonso, J. Org. Chem.
2004, 69, 993.
[9] B. Alcaide, P. Almendros, C. Aragoncillo, M. C. Redon-
do, M. R. Torres, Chem. Eur. J. 2006, 12, 1539.
Adv. Synth. Catal. 2011, 353, 585 – 594
ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
593

Benito Alcaide et al.
FULL PAPERS
[10] a) T. Seiser, N. Cramer, Angew. Chem. 2008, 120, 9435;
Angew. Chem. Int. Ed. 2008, 47, 9294; b) C. Park, P. H.
Lee, Org. Lett. 2008, 10, 3359.
[11] B. Alcaide, P. Almendros, T. Martꢁnez del Campo,
Chem. Eur. J. 2008, 14, 7756; B. Alcaide, P. Almendros,
T. Martꢁnez del Campo, Chem. Eur. J. 2011, 17, 1074
(for a correction of the originally assigned structure for
compounds 6).
g) Z. Zhang, C. F. Bender, R. A. Widenhoefer, J. Am.
Chem. Soc. 2007, 129, 14148; h) 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.
[18] a) N. Morita, N. Krause, Eur. J. Org. Chem. 2006, 4634;
b) Z. He, A. K. Yudin, Angew. Chem. 2010, 122, 1651;
Angew. Chem. Int. Ed. 2010, 49, 1607.
[12] For a synthesis of simple allenic lactones, see: C. Made-
laine, V. Valerio, N. Maulide, Angew. Chem. 2010, 122,
1628; Angew. Chem. Int. Ed. 2010, 49, 1583. For a two-
step synthesis of g-lactones from b-lactams, see: M. Ta-
kahashi, J.-i. Atsumi, T. Sengoku, H. Yoda, Synthesis
2010, 3282. a-exo-Methylene-g-butyrolactone deriva-
tives have attracted a great deal of attention due to the
range of biological activities they show. For selected ex-
amples including cytotoxic, anti-inflammatory, phyto-
toxic, and antimicrobial properties, see: a) A. Albrecht,
[19] A less conventional mechanism for the achievement of
chloroarenes 9 from compounds 6 suggests a stepwise
mechanism and can be rationalized through initial par-
ticipation of an amine-AuCl3 complex and further acti-
vation of the aromatic ring. For this purpose, the for-
À
mation of a CAr Au bond through direct auration of a
À
CAr H bond at the ortho position is necessary. The so
formed bimetallic species may evolve by intramolecular
chloride shift from the amine-AuCl3 complex to the
À
CAr Au bond, which finally gives chloroarenes 9 after
ˆ
M. Rꢀyalski, U. Krajewska, A. Janecka, K. Studzian, T.
deauration. For the gold-catalyzed halogenation of aro-
matics by N-halosuccinimides, see: F. Mo, J. M. Yan, D.
Qiu, F. Li, Y. Zhang, J. Wang, Angew. Chem. 2010, 122,
2072; Angew. Chem. Int. Ed. 2010, 49, 2028.
Janecki, New J. Chem. 2010, 34, 750; b) R. R. A.
Kitson, A. Millemaggi, R. J. K. Taylor, Angew. Chem.
2009, 121, 9590; Angew. Chem. Int. Ed. 2009, 48, 9426;
c) J.-P. Lepoitteniv, V. Berl, E, Gimꢇnez-Arnau,
Chem. Rec. 2009, 9, 258; d) M. T. Lindenmeyer, A.
Hrenn, C. Kern, V. Castro, R. Murillo, S. Muller, S.
Laufer, J. Schulte-Monting, B. Siedle, I. Merfort,
Bioorg. Med. Chem. 2006, 14, 2487; e) Y.-L. Chen, C.-
M. Lu, S.-J. Lee, D.-H. Kuo, I. Chen, T.-C. Wang, C.-C.
Tzeng, Bioorg. Med. Chem. 2005, 13, 5710.
À
[20] For a precedent with regard to C H activation using
Au(III), see: T. de Haro, C. Nevado, J. Am. Chem. Soc.
G
2010, 132, 1512.
[21] a) C. Le Tourneau, E. Raymond, S. Faivre, Ther. Clin.
Risk Manage. 2007, 3, 341; b) A. Millemaggi, R. J. K.
Taylor, Eur. J. Org. Chem. 2010, 4527.
[22] For reviews, see: a) B. A. Trofimov, L. N. Sobenina,
A. P. Demenev, A. I. Mikhaleva, Chem. Rev. 2004, 104,
2481; b) S. Cacchi, G. Fabrizi, Chem. Rev. 2005, 105,
2873. For a recent selected reference, see: c) T. D.
Lash, S. A. Jones, G. M. Ferrence, J. Am. Chem. Soc.
2010, 132, 12786.
[23] Substrate-directable reactions are an important class of
selective organic transformations, and understanding
their mechanism of direction is paramount to their util-
ity, see: A. H. Hoveyda, D. A. Evans, G. C. Fu, Chem.
Rev. 1993, 93, 1307.
[24] For selected references, see: a) G. Cafeo, H. M. Colqu-
houn, A. Cuzzola, M. Gattuso, F. H. Kohnke, L. Valen-
ti, A. J. P. White, J. Org. Chem. 2010, 75, 6263; b) D. M.
Pinkerton, M. G. Banwell, A. C. Willis, Org. Lett. 2007,
9, 5127; c) G. W. Gribble, D. H. Blank, J. P. Jasinski,
Chem. Commun. 1999, 2195; d) J. Simonet, J. R. Ber-
thelot, Prog. Solid State Chem. 1991, 21, 1.
[13] The ORTEP drawing (Figure S1) and experimental
crystallographic details for compound 6a are shown in
the Supporting Information section.
[14] For selected reviews, see: a) M. Brasholz, H.-U. Reis-
sig, R. Zimmer, Acc. Chem. Res. 2009, 42, 45; b) S. Ma,
Chem. Rev. 2005, 105, 2829; c) Modern Allene Chemis-
try, (Eds.: N. Krause, A. S. K. Hashmi), Wiley-VCH,
Weinheim, 2004; d) R. W. Bates, V. Satcharoen, Chem.
Soc. Rev. 2002, 31, 12; e) R. Zimmer, C. U. Dinesh, E.
Nandanan, F. A. Khan, Chem. Rev. 2000, 100, 3067;
f) A. S. K. Hashmi, Angew. Chem. 2000, 112, 3737;
Angew. Chem. Int. Ed. 2000, 39, 3590.
[15] T. E. Mꢅller, K. C. Hultzsch, M. Yus, F. Foubelo, M.
Tada, Chem. Rev. 2008, 108, 3795.
[16] For selected reviews, see: a) B. Lipshutz, Y. Yamamoto,
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
2008, 37, issue 9; c) N. Bongers, N. Krause, Angew.
Chem. 2008, 120, 2208; Angew. Chem. Int. Ed. 2008, 47,
2178; d) G. J. Hutchings, Chem. Commun. 2008, 1148;
e) J. Muzart, Tetrahedron 2008, 64, 5815; f) A. S. K.
Hashmi, Chem. Rev. 2007, 107, 3180.
[25] a) C. Glaser, Ber. Dtsch. Chem. Ges. 1869, 2, 422; b) G.
Eglinton, A. R. Galbrait, Chem. Ind. (London) 1956,
737; c) A. S. Hay, J. Org. Chem. 1962, 27, 3320.
[26] For recent selected references, see: a) D. A. Engel,
G. B. Dudley, Org. Biomol. Chem. 2009, 7, 4149; b) M.
Stefanoni, M. Luparia, A. Porta, G. Zanoni, G. Vidari,
Chem. Eur. J. 2009, 15, 3940; c) V. Cadierno, J. Francos,
J. Gimeno, Tetrahedron Lett. 2009, 50, 4773; d) L.-F.
Yao, M. Shi, Chem. Eur. J. 2009, 15, 3875.
[27] Experimental procedures as well as full spectroscopic
and analytical data for compounds not included in this
Experimental Section are described in the Supporting
Information. It contains compound characterization
data and experimental procedures for compounds 2a–e,
3a–g, 7, 12a, 14a, and 14b. It contains as well copies of
NMR spectra for all new compounds.
[17] For a review, see: a) R. A. Widenhoefer, X. Han, Eur.
J. Org. Chem. 2006, 4555. For recent selected referen-
ces, see: b) R. L. LaLonde, Z. J. Wang, M. Mba, A. D.
Lackner, F. D. Toste, Angew. Chem. 2010, 122, 608;
Angew. Chem. Int. Ed. 2010, 49, 598; c) A. W. Hill,
M. R. J. Elsegood, M. C. Kimber, J. Org. Chem. 2010,
75, 5406; d) C. Winter, N. Krause, Angew. Chem. 2009,
121, 6457; Angew. Chem. Int. Ed. 2009, 48, 6339; e) H.
Li, R. A. Widenhoefer, Org. Lett. 2009, 11, 2671;
f) A. C. Breman, J. Dijkink, J. H. Van Maarseveen, S. S.
Kinderman, H. Hiemstra, J. Org. Chem. 2009, 74, 6327;
594
asc.wiley-vch.de
ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 585 – 594