Regioselective synthesis of functionalized pyrroles via gold(I)-catalyzed [3+2] cycloaddition of stabilized vinyl diazo derivatives and nitriles

Article abstract of DOI:10.1002/adsc.201300346

The reaction of nitriles with alkenyldiazo compounds in the presence of gold catalysts provides functionalized pyrrole derivatives in moderate to high yields. This formal [3+2] cyclization reaction takes place with complete regioselectivity. The observed regiochemical outcome suggests the attack of the nitrile to the terminal position of the alkenylgold carbenoid (vinylogous reactivity). A broad range of nitriles (including those bearing functional groups) is compatible with this cyclization reaction. Copyright

Full text of DOI:10.1002/adsc.201300346

COMMUNICATIONS
DOI: 10.1002/adsc.201300346
Regioselective Synthesis of Functionalized Pyrroles via
Gold(I)-Catalyzed [3+2]Cycloaddition of Stabilized Vinyl Diazo
Derivatives and Nitriles
Giacomo Lonzia and Luis A. Lꢀpeza,*
a
Instituto Universitario de Quꢁmica Organometꢂlica “Enrique Moles” and Departamento de Quꢁmica Orgꢂnica
e Inorgꢂnica, Universidad de Oviedo, c/Juliꢂn Claverꢁa 8, 33006 Oviedo, Spain
E-mail: lalg@uniovi.es
Received: April 22, 2013; Revised: May 31, 2013; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300346.
Abstract: The reaction of nitriles with alkenyldiazo
compounds in the presence of gold catalysts pro-
vides functionalized pyrrole derivatives in moderate
to high yields. This formal [3+2]cyclization reaction
takes place with complete regioselectivity. The ob-
served regiochemical outcome suggests the attack
of the nitrile to the terminal position of the alkenyl-
gold carbenoid (vinylogous reactivity). A broad
range of nitriles (including those bearing functional
groups) is compatible with this cyclization reaction.
available and, consequently, the development of such
approaches would be very interesting from a synthetic
point of view.
On the other hand, the significance of vinyldiazo
compounds as C3 synthons in metal-catalyzed synthe-
sis of nitrogen heterocyclic compounds is well estab-
lished.[6] In this regard, our group recently reported
the copper(I)-catalyzed regioselective [3+2]cycliza-
tion of pyridines toward vinyldiazoacetates leading to
functionalized indolizine derivatives (Scheme 1b).[7]
DFT calculations on this process support a reaction
pathway involving initial formation of a copper vinyl
carbenoid, which then would evolve via Michael-type
addition of the pyridine nitrogen. Subsequent cycliza-
tion followed by aromatization would afford the final
products.
Keywords:
ACHTUNGTRENNUNG[3+2]cyclization; diazo compounds;
gold catalysis; nitriles; pyrroles
Owing to their presence in several naturally occurring
compounds of biological importance and in many
pharmaceuticals, pyrroles represent one of the most
relevant classes of heterocycles.[1] For this reason, nu-
merous synthetic methodologies to access such com-
pounds have been described in the last decades in-
cluding classical condensation reactions as well as
most recently cyclization reactions based on the use
of transition metal promoters.[1,2] Despite these advan-
ces, the development of new regioselective ap-
proaches to the preparation of functionalized pyrrole
derivatives from easily available starting reagents still
remains an area of intense interest. Many of the
methods for preparing functionalized pyrroles, among
them the classical Hantzsch or Knorr synthesis, rely
on the use of [3+2]cyclocondensation reactions be-
tween appropriate substrates (Scheme 1a). Surprising-
ly, the reaction of simple nitriles toward C3 synthons
in [3+2]cyclization reactions has been little ex-
plored.[3–5] However, nitriles are especially attractive
as partners for formal [3+2]cycloaddtions because of
Scheme 1. a) [3+2]Cyclization approaches to the pyrrole
ring; b) copper(I)-catalyzed [3+2]cyclization of pyridines
the great number of nitriles that are commercially and vinyldiazo compounds.
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢃ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
ÞÞ
These are not the final page numbers!

Giacomo Lonzi and Luis A. Lꢀpez
COMMUNICATIONS
On the basis of these results, we hypothesized that action to nitriles having a fused aryl or a heteroaryl
a related mechanistic scenario involving nitriles in- substituent proceeed successfully affording 2-(1-naph-
stead of pyridines might provide a direct entry to the thyl)- and 2-(2-furyl)pyrroles 3l and 3m in 56% and
pyrrole nucleus. Herein, we report the realization of 61%, respectively. Notably, a range of functionality in
this goal; specifically, we describe the gold(I)-cata- the nitrile component was compatible with this proto-
lyzed [3+2]cyclization of nitriles toward alkenyldiazo col. Thus, an ester function is well tolerated affording
compounds leading to a convenient method for the the pyrrole derivative 3n in moderate yield. a,b-Unsa-
preparation of functionalized pyrrole derivatives. Ni- turated nitriles were also found to be suitable re-
triles have previously been used as inert solvents in agents in this gold-catalyzed [3+2]cyclization reaction
reactions involving vinyl carbenoid intermediates,[8] affording efficiently the synthetically relevant 2-vinyl-
only a few gold-catalyzed reactions have ever been re- pyrrole derivatives 3o and 3p.[14] Interestingly, despite
ported to activate nitriles.[9]
the fact that a range of alkenes and alkynes was
For our exploratory studies we selected readily found to react with alkenyl diazo compounds in the
available ethyl 2-diazobut-3-enoate (1a) as substrate presence of gold catalysts,[12b] the reaction of diazo
and a series of transition metal catalysts (5 mol%) in compound 1a with nitriles bearing an alkene or
acetonitrile (2a) as solvent at room temperature (see alkyne function in a remote position takes place with
the Supporting Information for full details). Unfortu- complete chemoselectivity affording in good yields
nately, copper complexes, which proved to be compe- the pyrroles 3q and 3r resulting from the exclusive
tent catalysts in our previous research, did not afford participation of the nitrile function.
the expected pyrrole.[10] On the other hand, despite
We next investigated the scope of the diazo compo-
the fact that rhodium and silver complexes have been nent and found that this catalytic [3+2]cyclization is
widely used in the development of catalytic applica- not limited to diazo compounds bearing an alkoxycar-
tions of alkenyldiazo compounds, no desired product bonyl group. For example, it can be also applied to
was formed when the reaction was run in the pres- diazo derivatives with other stabilizing groups, like
ence of Rh2ACHTUNGTRENNUNG
(OAc)4 or AgNTf2. Next, we turned our phosphonate [diazo compound 1b; R1 =R2 =H,
attention to the use of gold catalysts. It should be EWG=POACTHNUTRGENUG(N OEt)2] and sulfonyl (diazo compound 1c;
noted that gold complexes have emerged in the last R1 =R2 =H, EWG=SO2Me) furnishing pyrrole deriv-
years as promising catalysts for the catalytic decom- atives 3s and 3t, respectively, in moderate yields. In
position of diazo compounds.[11,12] In this regard, we relation to the substitution on the vinyl moiety of the
were pleased to find that stirring overnight a mixture diazo component we observed that alkyl groups at the
of diazo compound 1a and IPr
(5 mol%) in acetonitrile at room temperature afford-
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
ed pyrrole derivative 3a in 80% after chromatograph- with benzonitrile under the standard reaction condi-
ic purification (see Table 1). Interestingly, a compara- tions affording the expected 2,3,4-trisubstituted pyr-
ble yield was observed when the reaction was con- role 3u in moderate yield (63%).[15] Conversely, b-sub-
ducted in dichloromethane, thus enabling not only the stituted diazoacetate 1e (R1 =H, R2 =Et, EWG=
use of non-volatile nitrile counterparts but also of COOEt) afforded the corresponding 2,3,5-trisubstitut-
a smaller excess of the nitrile. It should be noted that ed pyrrole derivative 3v in a diminished yield, thus in-
this formal [3+2]heterocyclization reaction takes dicating a deleterious effect of substitution at the Cb
place with total regioselectivity. The regioisomer position on the reaction.
formed suggests the attack of the nitrogen of the ni-
This gold-catalyzed [3+2]cyclization has been fur-
trile to the C-4 (vinylogous position) of the vinyldiazo ther extended to the synthesis of some deuterated
compound.[13]
pyrrole derivatives. Thus, the reaction of diazo com-
Next, we explored the scope of this gold-catalyzed pound 1a (R1, R2 =H, EWG=COOEt) with deuterat-
[3+2]cyclization reaction (Table 1). First, the reaction ed acetonitrile afforded in good yield 3a-D3. On the
of diazo compound 1a with an array of synthetically other hand, diazo compound 1a-D (R1 =D, R2 =H,
valuable nitriles was examined. Thus, good yields EWG=COOEt) was transformed into pyrroles 3a-D
were achieved with nitriles bearing alkyl groups of and 3f-D by treatment with acetonitrile and benzoni-
different nature (primary, secondary, tertiary or trile, respectively.
cyclic) affording the corresponding pyrroles 3a–e. Ap-
On the basis of previous reports by us and
parently, the degree of steric hindrance near the reac- others,[12] a mechanistic proposal to rationalize the ob-
tive nitrile group was found not to have a dramatic tained results is depicted in Scheme 2.
impact on the efficiency of the reaction. Reactions
Thus, the initial reaction of the alkenyl diazo com-
with aromatic nitriles also proceeded smoothly to pound with the gold complex would afford a gold al-
afford 2-arylpyrroles 3f–3k, and those with both elec- kenyl carbenoid intermediate I which can be better
tron-rich and electron-deficient aryl groups gave the described as an allyl gold cation I’.[16,17] Next, regiose-
expected products in good yields. Extension of the re- lective nucleophilic attack of the nitrile to the C-3
2
asc.wiley-vch.de
ꢃ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

Regioselective Synthesis of Functionalized Pyrroles via Gold(I)-Catalyzed [3+2]Cycloaddition
Table 1. Scope of the Au-catalyzed [3+2]cyclization reaction of alkenyldiazo com-
pounds 1 and nitriles 2.[a]
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢃ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3
ÞÞ
These are not the final page numbers!

Giacomo Lonzi and Luis A. Lꢀpez
COMMUNICATIONS
Table 1. (continued)
[a]
Reaction conditions: 1 (0.5 mmol), 2 (5.0 mmol), IPrAuACHTUNTGRNENG(U MeCN)SbF6 (5 mol%),
CH2Cl2 (0.1M), room temperature, 14–24 h. Isolated yields after column chromatog-
raphy are given.
The nitrile was used as solvent.
[b]
[c]
[d]
Reaction run at 708C in 1,2-dichloroethane.
Small amounts (<5%) of a tetrasubstituted pyrrole were also obtained (see ref.[15]).
Scheme 2. Proposed mechanism for the Au(I)-catalyzed synthesis of pyrrole derivatives 3 from diazo compounds 1 and ni-
triles 2.
allyl cation would form the intermediate II,[9b] which lize the allyl gold cation resonance form I’ and favour
by cyclization would afford intermediate III. Final a carbenic pathway (participation of resonance form
tautomerism would lead to the pyrrole derivatives. In I). To test this hypothesis, we subjected vinyl diazo
contrast to the well documented protodeauration of compound 1f and benzonitrile to the standard reac-
the gold-carbon bond in alkenyl gold complexes,[18] tion conditions (Scheme 3). According to our expecta-
the transformation of intermediate II into III repre- tions this reaction did not lead to the corresponding
sents a less common case of attack of an alkenyl gold pyrrole derivative; instead, the oxazole derivative 4
intermediate to an electrophilic carbon center.[19,20]
was obtained in good yield (71%) after chromato-
According to our mechanistic hypothesis and graphic purification. This result would be consistent
taking into account that it is currently accepted that with a higher carbene character of the corresponding
the nature and, hence, the reactivity of alkenyl gold intermediate[21,22] and demonstrated that, in agree-
carbenoids depend largely on the substituents, we en- ment with previous studies,[17] the reactivity of vinyl
vision that an electron-withdrawing group at the vinyl gold carbenoids generated from diazo compounds can
moiety of the diazo component may help to destabi-
4
asc.wiley-vch.de
ꢃ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

Regioselective Synthesis of Functionalized Pyrroles via Gold(I)-Catalyzed [3+2]Cycloaddition
References
[1] Selected reviews: a) J. Bergman, T. Janosik, in: Modern
Heterocyclic Chemistry; (Eds.: J. Alvarez-Builla, J. J.
Vaquero, J. Barluenga), Wiley-VCH, Weinheim, 2011,
Vol. 1, p 269; b) A. S. Dudnik, V. Gevorgian, Transition
Metal-Catalyzed Synthesis of Monocyclic Five-Mem-
bered Aromatic Heterocycles, in: Catalyzed Carbon-
Heteroatom Bond Formation, (Ed.: A. K. Yudin),
Wiley-VCH, Weinheim, 2010, p 227, c) R. J. Sundberg,
in: Comprehensive Heterocyclic Chemistry II, (Eds.:
A. R. Katritzky, C. W. Rees, E. F. V. Scriven), Perga-
mon Press, Oxford, 1996, Vol. 2, p 119.
Scheme 3. Au-catalyzed reaction of diazo compound 1f and
benzonitrile: synthesis of oxazole derivative 4.
[2] For a recent review on the transition metal-mediated
synthesis of monocyclic aromatic heterocycles, see:
A. V. Gulevich, A. S. Dudnik, N. Chernyak, V. Ge-
vorgyan, Chem. Rev. 2013, 113, 3084.
[3] For the Lewis acid-promoted [3+2]reactions of nitriles
and donor-acceptor cyclopropanes, see: a) M. Yu, B. L.
Pagenkopf, Org. Lett. 2003, 5, 5099; b) M. Yu, G. D.
Pantos, J. L. Sessler, B. L. Pagenkopf, Org. Lett. 2004,
6, 1057.
be modified by the adequate selection of the substitu-
ents on the vinyl moiety.
In summary, we have developed a general and effi-
cient approach to the pyrrole nucleus from easily
available diazo compounds and nitriles. This process
represents one of the few cases of the involvement of
nitriles in gold-catalyzed reactions as well as a new
application of diazo compounds in gold catalysis.
Moreover, the reported method represents an unusual
example of transition metal-catalyzed [3+2]cycliza-
tion approach to pyrroles involving nitriles as reaction
partners. A broad range of nitriles (including those
bearing functional groups) is compatible with this cyc-
lization reaction. In agreement with previous reports,
the regioselectivity pattern of the process (vinylogous
attack) can be explained in terms of the formation of
a gold-vinyl carbenoid with a high electrophilic char-
acter at the terminal position. Further applications of
this new gold-catalyzed heterocyclization are current-
ly being studied in our group.
[4] For the galliumACTHUNRGTENN(UG III) and indiumACHUTNGTRENN(UNG III) halide-mediated
reactions of nitriles and cyclopropenes yielding pyrrole
derivatives, see: S. Araki, T. Tanaka, S. Toumatsu, T.
Hirashita, Org. Biomol. Chem. 2003, 1, 4025.
[5] While writing this manuscript the synthesis of pyrroles
by silver-catalyzed cycloaddition of vinylogous diazo
esters and nitriles has been reported: R. J. Billedeau,
K. R. Klein, D. Kaplan, Y. Lou, Org. Lett. 2013, 15,
1421.
[6] For a selection of relevant contributions on the applica-
tion of vinyldiazoacetates in the synthesis of four- to
seven-membered nitrogen heterocycles, see: a) N. S. Y.
Loy, A. Singh, X. Xu, C.-M. Park, Angew. Chem. 2013,
125, 2868; Angew. Chem. Int. Ed. 2013, 52, 2212; b) X.
Xu, P. Y. Zavalij, W. Hu, M. P. Doyle, J. Org. Chem.
2013, 78, 1583; c) X. Xu, P. Y. Zavalij, M. P. Doyle,
Angew. Chem. 2012, 124, 9967; Angew. Chem. Int. Ed.
2012, 51, 9829; d) J. Qian, X. Xu, X. Wang, P. Y. Zava-
lij, W. Hu, M. P. Doyle, Angew. Chem. 2012, 124, 6002;
Angew. Chem. Int. Ed. 2012, 51, 5900; e) J. Barluenga,
L. Riesgo, G. Lonzi, M. Tomꢂs, L. A. Lꢀpez, Chem.
Eur. J. 2012, 18, 9221; f) X. Xu, P. Y. Zavalij, W. Hu,
M. P. Doyle, Chem. Commun. 2012, 48, 11522; g) X.
Xu, M. O. Ratnikov, P. Y. Zavalij, M. P. Doyle, Org.
Lett. 2011, 13, 6122; h) R. Manning, H. M. L. Davies, J.
Am. Chem. Soc. 2008, 130, 8602; i) R. P. Reddy,
H. M. L. Davies, J. Am. Chem. Soc. 2007, 129, 10312;
j) M. P. Doyle, M. Yan, W. Hu, L. S. Gronenberg, J.
Am. Chem. Soc. 2003, 125, 4692; k) M. P. Doyle, W.
Hu, D. J. Timmons, Org. Lett. 2001, 3, 3741; l) for alter-
native pathways to these intermediates and subsequent
cycloadditions, see: W. Yang, T. Wang, Y. Yu, S. Shi, T.
Zhang, A. S. K. Hashmi, Adv. Synth. Catal. 2013, 355,
1523.
Experimental Section
Representative Procedure for the Synthesis of
Pyrrole 3a
To a solution of 1a (70 mg, 0.5 mmol) in acetonitrile (5 mL)
was added IPrAuACHTUNRGTNEUNG(MeCN)SbF6 (21.6 mg, 0.025 mmol,
5 mol%). The mixture was stirred 14 h at room temperature
(disappearance of 1a checked by TLC). The solvent was re-
moved under reduced pressure and the resulting residue was
purified by flash chromatography (SiO2, 3:1 hexanes/ethyl
acetate) to afford 3a as a yellow oil; yield: 61 mg (80%).
Acknowledgements
We are grateful to the Ministerio de Economꢀa y Competitivi-
dad of Spain (MINECO) (Grant CTQ2010-20517-C02-01).
G. L. thanks the MINECO and European Union (Fondo
Social Europeo) for a predoctoral grant. We wish also to
thank Prof. Josꢁ Barluenga for his constant encouragement
and support and Prof. Miguel Tomꢂs and Prof. Josꢁ M. Gon-
zꢂlez for many helpful discussions.
[7] J. Barluenga, G. Lonzi, L. Riesgo, L. A. Lꢀpez, M.
Tomꢂs, J. Am. Chem. Soc. 2010, 132, 13200.
[8] a) A. S. K. Hashmi, T. M. Frost, J. W. Bats, J. Am.
Chem. Soc. 2000, 122, 11553; b) A. S. K. Hashmi, M.
Rudolph, H.-U. Siehl, M. Tanaka, J. W. Bats, W. Frey,
Chem. Eur. J. 2008, 14, 3703.
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢃ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
5
ÞÞ
These are not the final page numbers!

Giacomo Lonzi and Luis A. Lꢀpez
COMMUNICATIONS
[9] a) R. S. Ramꢀn, N. Marion, S. P. Nolan, Chem. Eur. J.
2009, 15, 8695; b) for the gold-catalyzed synthesis of
amides from alcohols and nitriles involving the genera-
tion of a carbocation and subsequent attack of the ni-
trile, see: N. Ibrahim, A. S. K. Hashmi, F. Rominger,
Adv. Synth. Catal. 2011, 353, 461.
[14] C-vinylpyrroles have been extensively used in organic
synthesis as convenient building blocks for the con-
struction of complex pyrrole systems. For a review on
this topic, see: B. A. Trofimov, L. N. Soberina, A. P. De-
menev, A. I. Mikhaleva, Chem. Rev. 2004, 104, 2481.
[15] In this case, in addition to pyrrole 3u, small amounts
(<5%) of the corresponding tetrasubstituted pyrrole
derivative resulting from the reaction of 3u with
a second equivalent of the vinylcarbenoid were also ob-
tained. For related arylation reactions of alkenyldiazo
[10] Only products resulting from the decomposition of the
starting diazo compound were observed.
[11] For a seminal contribution on gold-catalyzed carbene
transfer from ethyl diazoacetate to unsaturated sub-
strates, see: a) M. R. Fructos, T. R. Belderrain, P. de
Frꢄmont, N. M. Scott, S. P. Nolan, M. M. Dꢁaz-Requejo,
P. J. Pꢄrez, Angew. Chem. 2005, 117, 5418; Angew.
Chem. Int. Ed. 2005, 44, 5284. For additional examples
on gold-catalyzed transformations of diazocompounds
with unsaturated substrates, see: b) J. F. Briones,
H. M. L. Davies, J. Am. Chem. Soc. 2012, 134, 11916;
c) M. Delgado-Rebollo, A. Beltrꢂn, A. Prieto, M. M.
Dꢁaz-Requejo, A. M. Echavarren, P. J. Pꢄrez, Eur. J.
Inorg. Chem. 2012, 1380; d) P. J. Pꢄrez, M. M. Dꢁaz-Re-
quejo, I. Rivilla, Beilstein J. Org. Chem. 2011, 7, 653;
e) I. Rivilla, P. Gꢀmez-Emeterio, M. R. Fructos, M. M.
Dꢁaz-Requejo, P. J. Pꢄrez, Organometallics 2011, 30,
2855; f) A. Corma, M. Iglesias, F. X. Llabrꢄs i Xamena,
F. Sꢂnchez, Chem. Eur. J. 2010, 16, 9789; g) A. Prieto,
M. R. Fructos, M. M. Dꢁaz-Requejo, P. J. Pꢄrez, P.
Pꢄrez-Galꢂn, N. Delpont, A. M. Echavarren, Tetrahe-
dron 2009, 65, 1790; h) M. R. Fructos, M. M. Dꢁaz-Re-
quejo, P. J. Pꢄrez, Chem. Commun. 2009, 5153; i) J. A.
Flores, H. V. R. Dias, Inorg. Chem. 2008, 47, 4448; j) L.
Ricard, F. Gagosz, Organometallics 2007, 26, 4704;
k) Z. Li, X. Ding, C. He, J. Org. Chem. 2006, 71, 5876;
l) M. R. Fructos, P. de Frꢄmont, S. P. Nolan, M. M.
Dꢁaz-Requejo, P. J. Pꢄrez, Organometallics 2006, 25,
2237.
[12] a) The gold-catalyzed reactions of nitrosobenzenes and
alkenyldiazo esters have been recently reported: V. V.
Pagar, A. M. Jadhav, R.-S. Liu, J. Am. Chem. Soc. 2011,
133, 20728; b) the gold-catalyzed reactions of alkenyl-
diazo compounds with unsaturated hydrocarbons have
been recently reported by our group: J. Barluenga, G.
Lonzi, M. Tomꢂs, L. A. Lꢀpez, Chem. Eur. J. 2013, 19,
1573.
[13] The reactivity of the carbene carbon versus the vinylo-
gous carbon in metal-stabilized vinylcarbenoids has
been extensively studied by the group of Davies. For
a selection of contributions on this field, see: a) D. Val-
ette, Y. Lian, J. P. Haydek, K. I. Hardcastle, H. M. L.
Davies, Angew. Chem. 2012, 124, 8764; Angew. Chem.
Int. Ed. 2012, 51, 8636; b) D. Morton, A. R. Dick, D.
Ghosh, H. M. L. Davies, Chem. Commun. 2012, 48,
5838; c) Y. Lian, H. M. L. Davies, Org. Lett. 2012, 14,
1934; d) J. H. Hansen, H. M. L. Davies, Chem. Sci.
2011, 2, 457; e) Y. Lian, H. M. L. Davies, Org. Lett.
2010, 12, 924; f) Y. Sevryugina, B. Weaver, J. Hansen, J.
Thompson, H. M. L. Davies, M. A. Petrukhina, Orga-
nometallics 2008, 27, 1750; g) H. M. L. Davies, B. Hu,
E. Saikali, P. R. Bruzinski, J. Org. Chem. 1994, 59,
4535; h) H. M. L. Davies, E. Saikali, W. B. Young, J.
Org. Chem. 1991, 56, 5696; i) H. M. L. Davies, E. Saika-
li, T. J. Clark, E. H. Chee, Tetrahedron Lett. 1990, 31,
6299. For additional examples, see ref.[6]
substrates see ref.[12b]
.
[16] The preference for the 1,3-dipole resonance form relat-
ed to I’ in alkenyl gold intermediates bearing an elec-
tron-withdrawing group at the carbene center has been
recently reported: G. Zhang, L. Zhang, J. Am. Chem.
Soc. 2008, 130, 12598.
[17] The actual nature (gold-stabilized carbenes vs. allyl
gold carbocations) of alkenylgold carbenoids has, until
recently, been a matter of discussion. For some interest-
ing contributions on this topic, see: a) A. S. K. Hashmi,
Angew. Chem. 2010, 122, 5360; Angew. Chem. Int. Ed.
2010, 49, 5232; b) G. Seidel, R. Mynott, A. Fꢅrstner,
Angew. Chem. 2009, 121, 2548; Angew. Chem. Int. Ed.
2009, 48, 2510; c) A. S. K. Hashmi, Angew. Chem. 2008,
120, 6856; Angew. Chem. Int. Ed. 2008, 47, 6754; d) D.
Benitez, N. D. Shapiro, E. Tkatchouk, Y. Wang, W. A.
Goddard III, F. D. Toste, Nat. Chem. 2009, 1, 482;
e) R. B. Dateer, K. Pati, R.-S. Liu, Chem. Commun.
2012, 48, 7200; f) V. Lꢀpez-Carrillo, N. Huguet, A.
Mosquera, A. M. Echavarren, Chem. Eur. J. 2011, 17,
10972. For recent reviews on the generation of dipolar
species related to intermediate I, see: g) D. Garayalde,
C. Nevado, ACS Catal. 2012, 2, 1462; h) F. Lꢀpez, J. L.
MascareÇas, Beilstein J. Org. Chem. 2011, 7, 1075. For
similar results on the higher homologues of such carbe-
noids, see: i) M. M. Hansmann, F. Rominger, A. S. K.
Hashmi, Chem. Sci. 2013, 4, 1552; j) M. M. Hansmann,
M. Rudolph, F. Rominger, A. S. K. Hashmi, Angew.
Chem. 2013, 125, 2653; Angew. Chem. Int. Ed. 2013, 52,
2593.
[18] For recent studies on the isolation and protodeauration
of vinyl gold intermediates, see: a) A. S. K. Hashmi,
A. M. Schuster, F. Rominger, Angew. Chem. 2009, 121,
8396; Angew. Chem. Int. Ed. 2009, 48, 8247; b) C. M.
Krauter, A. S. K. Hashmi, M. Pernpointner, Chem-
CatChem 2010, 2, 1226; c) A. S. K. Hashmi, Gold Bull.
2009, 42, 275.
[19] For related cyclization reactions involving alkenyl gold
intermediates and carbenium-type electrophiles, see:
a) E. Jimꢄnez-NfflÇez, C. K. Claverie, C. Nieto-Ober-
huber, A. M. Echavarren, Angew. Chem. 2006, 118,
5578; Angew. Chem. Int. Ed. 2006, 45, 5452; b) L.
Zhang, J. Am. Chem. Soc. 2005, 127, 16804; c) A. S. K.
Hashmi, T. Häffner, W. Yang, S. Pankajakshan, S. Schä-
fer, L. Schultes, F. Rominger, W. Frey, Chem. Eur. J.
2012, 18, 10480; d) A. S. K. Hashmi, S. Pankajakshan,
M. Rudolf, E. Enns, T. Bander, F. Rominger, W. Frey,
Adv. Synth. Catal. 2009, 351, 2855; e) A. S. K. Hashmi,
M. Bꢅhrle, R. Salathꢄ, J. W. Bats, Adv. Synth. Catal.
2008, 350, 2059. See also ref.[12]
[20] It should be mentioned that, although the cationic
mechanism depicted in Scheme 2 accounts well for the
6
asc.wiley-vch.de
ꢃ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

Regioselective Synthesis of Functionalized Pyrroles via Gold(I)-Catalyzed [3+2]Cycloaddition
results, we cannot rule out an alternative pathway pro-
ceeding via Lewis acid activation of the nitrile, fol-
lowed by attack of the diazocompound to the corre-
sponding nitrilium ion and subsequent cyclization with
cently reported: W. He, C. Li, L. Zhang, J. Am. Chem.
Soc. 2011, 133, 8482.
[22] The geometries of oxazole 4 and the isomeric pyrrole
(diethyl 5-phenyl-1H-pyrrole-2,4-dicarboxylate) were
fully optimized at the B3LYP/6–31G* level of theory.
From these calculations, oxazole 4 is predicted to be
28.4 kcalmolÀ1 less stable than the pyrrole isomer. Con-
sequently, the oxazole 4 seems to be the kinetically fav-
oured product.
loss of nitrogen. Some common Lewis acids [Cu
ACHTUNGERTN(NUNG OTf)2,
Zn(OTf)2, BF3OEt2, AlCl3, TiCl4, SnCl4] were tested to
ACHTUNGTRENNUNG
gain insight into the mechanism of the reaction. No de-
sired pyrrole derivative was detected in these reactions
(see the Supporting Information for details).
[21] The formation of oxazoles in the reaction of a-oxo
gold carbene intermediates with nitriles has been re-
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢃ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
7
ÞÞ
These are not the final page numbers!

COMMUNICATIONS
8 Regioselective Synthesis of Functionalized Pyrroles via
Gold(I)-Catalyzed [3+2]Cycloaddition of Stabilized Vinyl
Diazo Derivatives and Nitriles
Adv. Synth. Catal. 2013, 355, 1 – 8
Giacomo Lonzi, Luis A. Lꢀpez*
8
asc.wiley-vch.de
ꢃ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!