Gold-Catalyzed Cycloisomerization of Alkyne-Containing Amino Acids: Controlled Tuning of C–N vs. C–O Reactivity

Article abstract of DOI:10.1002/ejoc.201600429

Versatile alkyne-containing amino acids were used as ambident precursors in the divergent synthesis of alkylidenelactones and 1-pyrrolines. Two gold-catalyzed protocols were applied for selective intramolecular O- and N-cycloisomerization reactions.

Full text of DOI:10.1002/ejoc.201600429

DOI: 10.1002/ejoc.201600429
Full Paper
Gold Catalysis
Gold-Catalyzed Cycloisomerization of Alkyne-Containing Amino
Acids: Controlled Tuning of C–N vs. C–O Reactivity
Noelia S. Medran,[a] Matías Villalba,[a] Ernesto G. Mata,[a] and Sebastián A. Testero*[a]
Abstract: Versatile alkyne-containing amino acids were used as applied for selective intramolecular O- and N-cycloisomeriza-
ambident precursors in the divergent synthesis of alkylidene-
lactones and 1-pyrrolines. Two gold-catalyzed protocols were
tion reactions.
Introduction
Homogenous gold catalysis has emerged as a powerful tool by
which to achieve a diverse range of chemical transforma-
tions.[1,2] Moreover, heteroatoms such as O, S or N can react
as nucleophiles with gold-activated alkyne moieties.[1a,3] In the
particular case of an intramolecular nucleophilic addition, cycli-
zation can occur in an endo or exo manner (5-endo-dig, 5-exo-
dig, 6-endo-dig and 6-exo-dig), thus generating five- or six-
membered heterocyclic rings.[4]
Figure 1. Possible modes of cycloisomerization of alkyne-containing amino
acids.
Alkyne-containing amino acids are versatile structures readily
available by a number of methods and are accessible using
very few transformations from economical starting materials.[5]
Some such amino acids are commercially attainable in enantio-
merically pure form. A variety of heterocycles have been pre-
pared from amino acid derivatives using gold-catalyzed reac-
tions.[6] As can be seen from the structure, alkyne-containing
amino acids are ambident nucleophiles.[7] These amino acids
have two well-positioned nucleophilic atoms – N and O – for
participation in gold-catalyzed intramolecular cycloisomeriza-
tions. With the appropriate use of protecting groups, the nu-
cleophilicities of the O and the N in the amino acid can be
modulated, and thus two different classes of heterocycles (O-
containing heterocycles and N-containing heterocycles)[8] can
be obtained from the same ambident intermediate (Figure 1).
In the case where the nucleophile is the oxygen atom of an
alkynoic acid, gold-catalyzed intramolecular cycloisomerization
generates the alkylidenelactone (Figure 1, path a).
of K2CO3 in order to generate the more reactive carboxylate
group. The same conditions were used by Marchal et al. to
transform o-alkynylbenzoic acids and 2-(2-ethynylphenyl)acetic
acids into the corresponding alkylidenelactones.[11] More re-
cently, a water-soluble AuIII–NHC complex,[12] dispersed thiol-
stabilized gold nanoparticles in the pores of siliceous mesocel-
lular foam[13] and a gold catalyst in combination with deep eu-
tectic solvents[14] were applied in the catalytic cycloisomeriza-
tion of γ-alkynoic acids. Nevertheless, the gold-catalyzed cyclo-
isomerization of alkyne-containing amino acids was scarcely ex-
plored.[5b,15]
In this regard, cycloisomerizations of alkyne-containing
amino acids gave γ-alkylidenelactones, which proved to be en-
zyme-activated irreversible inhibitors of serine proteases.[16] In
general, γ-alkylidenelactones display a variety of biological ac-
tivities that are based on the susceptibility of the enol ester
moiety to a nucleophilic attack, making this class of compounds
“suicide” substrates.[15,17]
In 2006 Genet et al. reported the first use of AuCl in MeCN,
without additives, for the intramolecular nucleophilic addition
of a carboxylic acid to gold-activated alkynes leading to γ-lact-
ones.[9] A few months later, Pale and co-workers[10] published a
similar cycloisomerization catalyzed by AuCl employing differ-
ent 4-pentynoic acids, but in this case adding catalytic amounts
On the contrary, if the nucleophile of these alkyne-contain-
ing amino acids is the nitrogen atom, a gold-catalyzed intra-
molecular cycloisomerization produces the corresponding
pyrrolines (Figure 1, path b).[18] The first example of gold-cata-
lyzed intramolecular hydroamination was Utimoto's 1987 semi-
nal report regarding the AuIII-catalyzed intramolecular hydro-
amination of 5-alkynylamines to form tetrahydropyridine deriv-
atives.[19] It is worth noting that other transition metals like pal-
ladium and silver have been used to achieve C–N and C–O func-
tionalization of alkynyl amino acids.[5b,18,20] Indeed, Rutjes has
[a] Instituto de Química Rosario – IQUIR (CONICET), Facultad de Ciencias
Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario
Suipacha 531, Rosario, S2002LRK, Argentina
E-mail: testero@iquir-conicet.gov.ar
http://www.iquir-conicet.gov.ar/eng/
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/ejoc.201600429.
Eur. J. Org. Chem. 0000, 0–0
1
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
reported several studies detailing the intramolecular hydro- argyl bromide (n = 1) in the presence of Cs2CO3 afforded inter-
amination of alkyne-containing amino acids (Scheme 1). The mediate 2 in excellent yield.[23] In contrast, alkylation of 1 using
first is a detailed report of several types of Pd-catalyzed cyclo- homopropargyl derivatives (n = 2, using both bromide and tos-
isomerization reactions of acetylene-containing amino acids us- ylate as the leaving groups) turned out to be quite difficult. Our
ing, in all cases, N-tosyl- or N-nosyl-protected amino acids to best result, after extensive optimization efforts, used tBuOK and
provide the corresponding cyclic enamides. The second report the homopropargyl tosylate in rigorously dried dioxane under
details the Pd-catalyzed cyclization of aniline containing acet- refluxing conditions.[5a] Unfortunately, the best yield attained
ylenic N-Boc-protected amino acids.[20a] This procedure is lim- by these efforts was only 30 %.[24]
ited in that the pyrrolines are obtained only in the presence of
an ortho-aniline nitrogen atom in the precursor. Without the
ortho-aniline group, the reaction does not proceed. The third
report involves an efficient AgOTf-catalyzed cyclization of aryl-
substituted acetylene-containing amino acids.[18] In this case,
the amino groups need to be unprotected to afford the pyrr-
olines. Finally, Osipov and co-workers used Brønsted acid cataly-
sis to cycloisomerize CF3-containing or phosphonate propargyl-
containing amines; this procedure works specifically for these
substrates.[21]
Scheme 2. (a) Base, solvent, X–(CH2)n–C≡ CH (n = 1: X = Br, Cs2CO3, MeCN,
room temp., 99 %; n = 2: X = OTs, tBuOK, dioxane, 100 °C, 30 %); (b) KOH,
MeOH/H2O, reflux, 4 h; (c) HCl (2 N) (n = 1, 77 %, two steps); (d) HCl (2 N),
reflux, 2 h (n = 1, 98 %).
Acetylenic malonate derivatives 2 and 3 were readily con-
verted into N-acetyl-protected alkynyl amino acids 4 and 5, re-
spectively, by base-promoted hydrolysis and subsequent de-
carboxylation. Removal of the acetyl group under acidic condi-
tions generated alkynyl amino acids 6 and 7, respectively.
The primary amine was protected using acetyl, Boc and tosyl
groups, whereas the acid was converted into the corresponding
methyl ester derivative. The terminal alkyne-containing pro-
tected amino acids 8 were subjected to Sonogashira cou-
pling[25] in order to increase the diversity of the final hetero-
cycles (Scheme 3).
Scheme 1. Other C–N functionalization reactions of alkyne-containing amino
acids.
In this context and as part of our research program concern-
ing the application of gold chemistry to the synthesis of hetero-
cycles,[22] we decided to explore the syntheses of γ-lactones
and 1-pyrrolines from alkyne-containing amino acids by means
of gold catalysis.
Results and Discussion
Scheme 3. (a) R3X, CuI, PPh3, Pd(PPh3)4, Et3N, DMF.
We prepared the cycloisomerization precursors, the alkyne-con-
taining amino acids, from commercially available diethyl acet-
With derivatives 8, 9 and 10 in hand, several gold-catalyzed
amidomalonate (1) (Scheme 2). Alkylation of 1 employing prop- conditions were evaluated with the aim of forming cyclic enam-
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
2
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
ides through C–N functionalization (Supporting Information;
Table 1). Even though there are numerous examples of gold-
catalyzed cyclizations of N-protected species in the literature,[26]
no C–N functionalization was observed in our system under any
of the conditions tested. However, N-deprotection afforded free
amine species that readily participated in gold-catalyzed cycloi-
somerizations to produce the 1-pyrroline scaffold (Scheme 4).
Of the gold catalysts examined, the most effective for this trans-
formation was AuCl3.[1h,1i,27]
Table 2. Gold-catalyzed C–O functionalization of alkynyl amino acids deriva-
tives.
Table 1. Gold-catalyzed C–N functionalization of alkynyl amino acids deriva-
tives.
[a] Isolated yield after the two steps of ester hydrolysis and gold-catalyzed
cycloisomerization.
[a] Overall isolated yield after flash column chromatography from the Boc-
protected compound (three steps: Boc removal, neutralization and gold-cata-
lyzed cycloisomerization).
methodologies have some limitations. The use of AuCl3 pro-
vides a broader scope and good yields for the cycloisomeriza-
tion of aryl-substituted alkynyl-containing amino acids en route
to 1-pyrrolines (Table 1). This conversion proceeds exclusively
by an AuIII-catalyzed 5-endo-dig N-cyclization. As can be seen
from Table 1, aryl-substituted alkynyl amino acids bearing elec-
tron-withdrawing groups provide excellent yields of the C–N-
functionalized product (Table 1, Entries 5 and 6). Reference
compounds such as phenyl- and naphthyl-modified derivatives
(Table 1, Entries 1 and 3) provide good yields of the desired
Scheme 4. Gold-catalyzed C–N functionalization.
Despite the fact that this transformation can be performed pyrrolines 11a and 11c (75 % and 71 %, respectively). Lower
using other transition metals[18,20a] and Brønsted acids,[21] these yields were obtained with derivatives carrying electron-donat-
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
3
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
ing groups (Table 1, Entries 2 and 4) showing that the efficiency N- and O-heterocycles making this methodology an excellent
of cycloisomerization is controlled, to some extent, by elec- alternative to the pre-existing strategies.
tronic factors. The reaction of the propargylglycine methyl ester
(Table 1, Entry 7) with a terminal alkyne failed to afford the
pyrroline.
Experimental Section
On the other hand, C–O functionalization can be achieved
General: Chemical reagents were purchased from commercial sour-
ces and were used without further purification unless noted other-
from the carboxylic acid derivatives of 8, 9 and 10 (R2 = H)
employing Pale's conditions[10] of catalytic AuCl and K2CO3 in
wise. Solvents were of analytical grade or were purified by standard
acetonitrile at room temp.; K2CO3 is necessary to obtain good procedures prior to use. 1H NMR spectra were recorded with a
Bruker Avance at 300 MHz spectrometer in CDCl3, in the presence
of TMS (δ = 0.00 ppm) as the internal standard unless otherwise
noted. 13C NMR assignments were made on the basis of chemical
shifts and proton multiplicities (from inverse HSQC spectra). High-
resolution mass spectra were recorded with a Bruker micrOTOF-
Q II spectrometer. Analytical thin-layer chromatography (TLC) was
carried out with silica gel 60 F254 pre-coated aluminum sheets. Flash
column chromatography was performed using silica gel 60 (230–
400 mesh).
Diethyl α-Acetamido-α-propargylmalonate (2):[5a] Propargyl
bromide (2.98 mL, 34.55 mmol) and Cs2CO3 (7.5 g, 23 mmol) were
added to a solution of diethyl acetamidomalonate (1) (5.0 g,
23 mmol) in CH3CN (50 mL). The resulting heterogeneous mixture
was stirred at room temp. for 18 h. Then, the reaction mixture was
yields of the enol-lactone product; the yield of product in its
absence is significantly lower than is the case when K2CO3 is
included. In order to explore the scope of this gold-catalyzed
cycloisomerization and to prepare a number of enol-lactones,
several alkyne-containing amino acids were subjected to cyclo-
isomerization conditions (Table 2). In general, the reactions
were complete in a short period of time and exhibited a high
5-exo-dig regioselectivity (n = 1). Despite the known reactivity
of enol-lactones,[5b] the isolated yields were excellent. In accord
with the anti intramolecular addition mechanism (Scheme 5),
in all cases the (Z)-γ-lactones were obtained. This stereochemis-
try was assigned on the basis of agreement between NOE ex-
periments and the chemical shift of the vinylic hydrogen signal
according to Pale's correlations (a chemical shift of δ ≈ filtered, concentrated, and the residue was dissolved in AcOEt. The
organic solution was washed with water, brine and dried with
Na2SO4. Evaporation of the solvent gave the crude product as a
yellowish white solid, which was purified by column chromatogra-
phy (AcOEt/hexane) to give 2 as a white solid (6.73 g, 99 %). 1H
NMR (300 MHz, CDCl3): δ = 1.27 (t, J = 7.1 Hz, 6 H), 1.98 (t, J =
2.6 Hz, 1 H), 2.07 (s, 3 H), 3.29 (d, J = 2.9 Hz, 2 H), 4.28 (qd, J = 7.1,
1.8 Hz, 4 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 13.9, 22.9, 23.8,
62.9, 65.2, 71.3, 78.2, 167, 169.2 ppm.
5.50 ppm for an anti-vinyl hydrogen atom facing the ring oxy-
gen atom, compared to a chemical shift for the syn-vinyl
hydrogen signal at δ ≈ 6.20 ppm).[15] In our examples, the
chemical shifts of this hydrogen signal ranged from δ = 5.57 to
5.95 ppm, confirming the (Z) stereochemistry.
But-3-yn-1-yl 4-Methylbenzenesulfonate: Tosyl chloride (0.75 g,
3.96 mmol) was added to a solution of 3-butyn-1-ol (0.2 mL,
2.64 mmol) in anhydrous Et2O (7 mL) at 0 °C. The resulting mixture
was stirred for 15 min. After this time, KOH (0.44 g, 7.9 mmol) was
added, and the solution was stirred at room temp. overnight. The
resulting suspension was washed with HCl (5 %), dried with Na2SO4,
filtered and concentrated in vacuo. The crude product was purified
by column chromatography (AcOEt/hexanes) to yield 0.590 g (99 %)
of the desired product as colorless oil.
Diethyl α-Acetamido-α-homopropargylmalonate (3):[5a] Potas-
sium tert-butoxide (0.167 g, 1.48 mmol) was added to a diethyl
acetamidomalonate solution (0.3 g, 1.38 mmol) in dry dioxane
(6 mL) at 0 °C. The resulting suspension was stirred vigorously at
60 °C for 2 h. Then, but-3-yn-1-yl 4-methylbenzenesulfonate (0.3 g,
1.38 mmol) was slowly added, and the obtained mixture was re-
fluxed for 48 h. The resulting suspension was vacuum-filtered and
the residue washed with Et2O (3 × 5 mL). The filtrate was concen-
trated in vacuo to give a yellow oil, which was purified by column
chromatography (AcOEt/hexane) to yield 0.107 g (35 %) of product
as slightly yellow crystals. 1H NMR (300 MHz, CDCl3): δ = 1.26 (t, J =
7.1 Hz, 6 H), 1.92 (t, J = 2.7 Hz, 1 H), 2.03 (s, 3 H), 2.1 (m, 2 H), 2.61
(t, J = 7.4 Hz, 2 H), 4.16–4.33 (m, 4 H), 6.82 (br. s, 1 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 13.3, 13.9, 22.9, 30.8, 62.6, 65.7, 68.9, 82.6,
167.7, 169.2 ppm.
Scheme 5. Proposed reaction mechanism for gold-catalyzed cycloisomeriza-
tion.
Unlike the gold-catalyzed C–N functionalization of terminal
alkynes, the C–O functionalization of terminal alkynes provided
enol-lactones in very satisfactory yields (Table 2, Entries 1–3, 9).
Conclusions
Gold-catalyzed cycloisomerizations of alkyne-containing amino
acids result in C–O functionalization to give, through 5-exo-dig
cyclization, nine alkylidenelactones derived from amino acids
in excellent yields. In contrast, the corresponding amino esters
undergo gold-catalyzed intramolecular 5-endo-dig N-cyclo-
isomerizations to afford six pyrrolinecarboxylate esters derived
from amino acids in moderate to very good yields. Gold cataly-
N-Acetyl-2-aminopent-4-ynoic Acid (4):[5a] KOH (3.25 g, 58 mmol)
was added portionwise to a well-stirred suspension of 2 (6.73 g,
26.3 mmol) in MeOH/H2O (5:1) (600 mL). The mixture was heated
at reflux for 4 h. The solvents were evaporated to dryness, and the
sis is remarkably efficient for the synthesis of both of these residue was dissolved with AcOEt and treated with 2
N HCl to
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
4
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
pH = 1. The aqueous phase was extracted with AcOEt, the com-
was evaporated under reduced pressure, and the crude material
bined organic layers were dried with Na2SO4 and the solvents evap- was purified by flash column chromatography (hexane/AcOEt).
orated to obtain the crude compound. Recrystallization from EtOAc
Methyl 2-Acetylamino-4-pentynoate (8aa):[23] Yield 90 %. 1H NMR
afforded 2.8 g (70 %) of the desired N-acetyl-protected alkynyl
(300 MHz, CDCl3): δ = 2.03 (t, J = 2.6 Hz, 1 H), 2.06 (s, 3 H), 2.75–
amino acid 4. 1H NMR (300 MHz, [D4]methanol): δ = 2.01 (s, 3 H),
2.77 (m, 2 H), 3.79 (s, 3 H), 4.70–4.80 (m, 1 H), 6.4 (d, 1 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 22.4, 23.0, 50.6, 52.7, 71.5, 78.4, 169.8,
170.8 ppm.
2.36 (t, J = 2.4 Hz, 1 H), 2.62–2.77 (m, 2 H), 4.52–4.56 (m, 1 H) ppm.
13C NMR (75 MHz, [D4]methanol): δ = 22.5, 52.8, 72.2, 72.3, 80.3,
173.4, 173.5 ppm.
Methyl 2-[(tert-Butoxycarbonyl)amino]-4-pentynoate (8ba):[18]
N-Acetyl-2-aminohex-5-ynoic Acid (5):[5a] Compound 5 can be
1
Yield 96 %. H NMR (300 MHz, CDCl3): δ = 1.45 (s, 9 H), 2.04 (t, J =
prepared from 3 (0.107 g, 0.4 mmol) as described above. The prod-
uct was isolated as white crystals (0.585 g; 70 % yield). 1H NMR
(300 MHz, [D6]acetone): δ = 1.81–1.89 (m, 1 H), 1.93 (s, 3 H), 1.97–
2.04 (m, 1 H), 2.24–2.30 (m, 2 H), 2.34 (t, J = 2.7 Hz, 1 H), 4.47–4.54
(m, 1 H), 7.45 (s, 1 H) ppm. 13C NMR (75 MHz, [D6]acetone): δ =
15.8, 22.7, 31.7, 52.4, 70.8, 83.9, 171.3, 173.5 ppm.
2.5 Hz, 1 H), 2.65–2.77 (m, 2 H), 3.77 (s, 3 H), 4.47 (m, 1 H), 5.36 (d,
J = 7.4 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 22.9, 28.2, 51.9,
52.6, 71.6, 78.5, 80.2, 155.0, 171.1 ppm.
Methyl 2-[(4-Toluenesulfonyl)amino]-4-pentynoate (8ca):[5b]
1
Yield 94 %. H NMR (300 MHz, CDCl3): δ = 2.03 (t, J = 2.6 Hz, 1 H),
2.41 (s, 3 H), 2.58–2.75 (m, 2 H), 3.60 (s, 3 H), 4.11 (dt, J = 8.8, 5.1 Hz,
1 H), 5.55 (d, J = 8.8 Hz, 1 H), 7.29 (d, J = 8.2 Hz, 2 H), 7.73 (d, J =
8.2 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 21.0, 23.5, 52.4,
53.5, 71.8, 126.7, 129.2, 136.3, 143.3, 169.5 ppm.
2-Aminopent-4-ynoic Acid Hydrochloride (6):[5a] A solution of N-
acetyl-2-aminopent-4-ynoic acid (4, 0.199 g, 1.28 mmol) in HCl (2 N)
(4 mL) was stirred at reflux for 2 h. The solvent was evaporated in
vacuo to give 2-aminopent-4-ynoic acid hydrochloride (6) (0.187 g,
98 %), which was used without further purification. 1H NMR
(300 MHz, D2O): δ = 2.54 (td, J = 2.7, 0.9 Hz, 1 H), 2.92 (dt, J = 5.5,
2.8 Hz, 2 H), 4.22 (d, J = 5.5 Hz, 1 H) ppm. 13C NMR (75 MHz, D2O):
δ = 19.9, 51.3, 74.2, 76.5, 170.3 ppm.
General Procedure for the Sonogashira Reaction: To a solution
of N-protected methyl propargylglycinate (0.6 mmol, 1 equiv.) in
N,N-dimethylformamide (DMF) (5 mL) were added p-iodotoluene
(0.8 mmol, 1.2 equiv.), triethylamine (0.11 mL) and Pd(PPh3)4
(0.04 mmol). The clear brown solution rapidly darkened when cop-
per(I) iodide (0.08 mmol) was added. The mixture was stirred under
nitrogen at room temp. overnight. The solvent was evaporated in
vacuo and the residue purified by chromatography (5 % AcOEt/hex-
ane).
N-Boc-Propargylglycine (8b):[5a] To a solution of 2-aminopent-4-
ynoic acid hydrochloride (6) (0.2 g, 1.34 mmol) in water (5 mL) and
dioxane (5 mL) was added Boc2O (434 mg, 1.99 mmol) and DIEA
(0.695 mL, 3.98 mmol). After stirring at room temp. for 3 h, the
solution was acidified to pH = 3 by addition of HCl (10 %), and
extracted with AcOEt. The combined organic layers were dried
(Na2SO4), filtered and concentrated, providing a yellow oil, which
was purified by column chromatography (AcOEt/hexane) to give
0.216 g (82 %) of the title compound. 1H NMR (300 MHz, CDCl3):
δ = 1.47 (s, 9 H), 2.09 (t, J = 2.4 Hz, 1 H), 2.72–2.77 (m, 2 H), 4.49–
4.54 (m, 1 H), 5.38 (d, J = 8.1 Hz, 1 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 22.5, 28.2, 51.7, 71.8, 80.6, 155.4, 174.7 ppm.
1
Compound 10aaa: Yield 99 %. H NMR (300 MHz, CDCl3): δ = 2.06
(s, 3 H), 2.97 (d, J = 5.0 Hz, 2 H), 3.80 (s, 3 H), 4.77–4.89 (m, 1 H), 6.37–
6.53 (m, 1 H), 7.24–7.40 (m, 5 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 23.1, 23.4, 51, 52.7, 83.6, 83.7, 122.8, 128.1, 120.2, 131.6, 169.8,
171.1 ppm. HRMS (ESI): calcd. for C14H16NO3 [M + H]+ 246.11247,
found 246.11318.
1
Compound 10aab: Yield 99 %. H NMR (300 MHz, CDCl3): δ = 2.07
(s, 3 H), 2.34 (s, 3 H), 2.97 (d, J = 5.0 Hz, 2 H), 3.81 (s, 3 H), 4.79–4.88
(m, 1 H), 7.10 (d, J = 8.1 Hz, 2 H), 7.27 (d, J = 8.1 Hz, 2 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 21.4, 23.2, 23.5, 51, 52.7, 82.8, 83.8, 119.7,
129, 131.5, 138.3, 169.8, 171.1 ppm. HRMS (ESI): calcd. for
C15H17NNaO3 [M + Na]+ 282.11006, found 282.11021.
N-Tosylpropargylglycine (8c):[5b] A mixture of 2-aminopent-4-yn-
oic acid hydrochloride (6) (441.7 mg; 2.95 mmol; 1 equiv.), Na2CO3
(650 mg; 6.12 mmol; 2.11 equiv.) and pTsCl (505.22 mg; 2.65 mmol;
0.9 equiv.) in p-dioxane/H2O (1:1; 8 mL) was stirred at room temp.
overnigt. The reaction mixture was concentrated, and the pH ad-
justed to 4.0 with 10 % HCl. The aqueous layer was extracted with
AcOEt (3 ×), dried with Na2SO4 and concentrated. The resulting
crude product was purified by recrystallization from chloroform/
hexane to give compound 8c in 95 % yield. 1H NMR (300 MHz,
CDCl3): δ = 2.06 (t, J = 2.6 Hz, 1 H), 2.43 (s, 3 H), 2.62–2.8 (m, 2 H),
4.14–4.20 (m, 1 H), 5.5 (d, J = 8.8 Hz, 1 H), 7.31 (d, J = 8.3 Hz, 2 H),
7.76 (d, J = 8.3 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 21.5,
23.8, 53.7, 72.7, 77.2, 127.2, 129.8, 144.1 ppm.
1
Compound 10aac: Yield 68 %. H NMR (300 MHz, CDCl3): δ = 2.10
(s, 3 H), 3.05 (d, J = 4.7 Hz, 2 H), 3.85 (s, 3 H), 4.84–4.9 (m, 1 H), 6.42
(d, J = 8.1 Hz, 1 H), 7.4–7.55 (m, 3 H), 7.74–7.81 (m, 3 H), 7.89 (s, 1
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 23.2, 23.6, 51.1, 52.8, 77.6,
84, 126.6, 126.6, 127.6, 127.7, 127.9, 128.5, 131.5, 169.9, 171.1 ppm.
HRMS (ESI): calcd. for C18H18NO3 [M + H]+ 296.12812, found
296.12764.
1
Compound 10baa:[18] Yield 99.4 %. H NMR (300 MHz, CDCl3): δ =
1.46 (s, 9 H), 2.87–3.03 (m, 2 H), 3.79 (s, 3 H), 4.47–4.62 (m, 1 H),
5.42 (d, J = 9.3 Hz, 1 H), 7.24–7.32 (m, 3 H), 7.34–7.42 (m, 2 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 23.8, 28.2, 52.2, 52.5, 80.1, 83.6, 83.8,
122.9, 128.1, 128.2, 131.6, 155.1, 171.3 ppm.
Compound 10bab: Yield 93.3 %. 1H NMR (300 MHz, CDCl3): δ =
1.47 (s, 9 H), 2.33 (s, 3 H), 2.86–3.03 (m, 2 H), 3.79 (s, 3 H), 4.51–4.62
(m, 1 H), 5.44 (d, J = 8.3 Hz, 1 H), 7.09 (d, J = 8.1 Hz, 2 H), 7.30 (d,
J = 8.1 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 21.3, 23.8, 28.2,
52.2, 52.4, 79.9, 82.9, 83.6, 119.8, 128.8, 131.5, 138.0, 155.0,
171.3 ppm. HRMS (ESI): calcd. for C18H23NO4 [M + H]+ 317.1626,
found 317.1627.
General Procedure for the Synthesis of Methyl Esters 8 and 9:
To a stirred solution of the N-protected amino acid (1 equiv.) in
methanol (50 mL) was added acetyl chloride (2.4 equiv.) at 0 °C.
The mixture was stirred at room temp. overnight, and the solvent
was evaporated under reduced pressure. The resulting crude prod-
uct was dissolved in AcOEt, washed with NaHCO3 (10 %) three times
and dried with Na2SO4. Concentration of the organic solution gave
the desired ester, which was purified by column chromatography
(5 % AcOEt in hexane). In the case of N-Boc-protected amino acids,
the ester was dissolved in CH2Cl2 and treated with an ethereal solu-
tion of diazomethane at 0 °C until a yellowish color persisted. The
reaction mixture was stirred for 30 min, and diazomethane was
Compound 10bac: Yield 98.9 %. 1H NMR (300 MHz, CDCl3): δ =
quenched by the addition of AcOH until discoloration. The solvent 1.49 (s, 9 H), 2.95–3.09 (m, 2 H), 3.82 (s, 3 H), 4.53–4.69 (m, 1 H),
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
5
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
5.51 (d, J = 8.1 Hz, 1 H), 7.36–7.53 (m, 3 H), 7.69–7.86 (m, 3 H), 7.92
(s, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 23.9, 28.2, 52.2, 52.5,
80.1, 83.9, 84.2, 120.2, 126.4, 126.5, 127.5, 127.6, 127.8, 128.4, 131.4,
132.6, 132.8, 155.1, 171.3 ppm. HRMS (ESI): calcd. for C21H23NNaO4
[M + Na]+ 376.15193, found 376.15106.
Methyl 5-(Naphthyl)-3,4-dihydro-2H-2-pyrrolecarboxylate (11c):
Yield 71 %. H NMR (300 MHz, CDCl3): δ = 2.28–2.41 (m, 2 H), 3.00–
1
3.17 (m, 2 H), 3.19–3.36 (m, 1 H), 3.81 (s, 3 H), 4.98 (m, 1 H), 7.42–
7.58 (m, 2 H), 7.78–7.94 (m, 3 H), 8.11 (dd, J = 8.6, 1.9 Hz, 1 H), 8.21
(s, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 26.3, 35.3, 52.2, 74.5,
76.6, 124.6, 126.4, 127.3, 127.6, 128.1, 128.7, 128.7, 131.1, 132.7,
134.5, 173.3, 176.0 ppm. HRMS (ESI): calcd. for C16H16NO2 [M + H]+
254.11756, found 254.11804.
1
Compound 10bad: Yield 81 %. H NMR (300 MHz, CDCl3): δ = 1.44
(s, 9 H), 2.82–2.99 (m, 2 H), 3.77 (s, 6 H), 4.43–4.58 (m, 1 H), 5.42 (d,
J = 9.0 Hz, 1 H), 6.78 (d, J = 8.8 Hz, 2 H), 7.29 (d, J = 8.8 Hz, 2 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 23.4, 27.8, 51.9, 52.1, 54.8, 79.6,
81.7, 82.9, 113.4, 114.6, 132.6, 154.7, 158.9, 170.9 ppm. HRMS (ESI):
calcd. for C18H23NNaO5 [M + Na]+ 356.14601, found 356.14684.
Compound 10bae:[18] Yield 93 %. 1H NMR (300 MHz, CDCl3): δ =
1.45 (s, 9 H), 2.99 (d, J = 5.2 Hz, 2 H), 3.80 (s, 3 H), 4.55–4.60 (m, 1
H), 5.41 (d, J = 8.6 Hz, 1 H), 7.51 (d, J = 7.9 Hz, 2 H), 8.14 (d, J =
7.9 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 24.1, 28.2, 52.1,
52.7, 80.3, 81.8, 90.0, 123.4, 129.9, 132.4, 146.9, 155.0, 171.0 ppm.
Methyl 5-(4-Methoxyphenyl)-3,4-dihydro-2H-2-pyrrolecarbox-
ylate (11d): Yield 41 %. 1H NMR (300 MHz, CDCl3): δ = 2.19–2.35
(m, 2 H), 2.83–3.00 (m, 1 H), 3.02–3.13 (m, 1 H), 3.72 (s, 3 H) 3.82 (s,
3 H), 4.87 (ddt, J = 8.6, 6.6, 1.9, Hz, 1 H), 6.89 (d, J = 8.92 Hz, 2 H),
7.81 (d, J = 8.92 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 26.3,
35.2, 52.1, 55.2, 74.3, 113.6, 113.8, 126.5, 129.6, 161.7, 173.5,
175.2 ppm. HRMS (ESI): calcd. for C13H15NNaO3 [M
256.09441, found 256.09436.
+
Na]+
1
Compound 10baf: Yield 93 %. H NMR (300 MHz, CDCl3): δ = 1.46
Methyl 5-(4-Nitrophenyl)-3,4-dihydro-2H-2-pyrrolecarboxylate
(11e):[18] Yield 90 %. 1H NMR (300 MHz, CDCl3): δ = 2.29–2.45 (m, 2
H), 2.96–3.10 (m, 1 H), 3.13–3.27 (m, 1 H), 3.80 (s, 3 H), 4.94–5.02
(m, 1 H), 8.02–8.10 (m, 2 H), 8.24–8.35 (m, 2 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 26.3, 35.6, 52.4, 74.8, 123.6, 128.9, 139.3, 149.2,
172.7, 174.3 ppm. HRMS (ESI): calcd. for C12H13N2O4 [M + H]+
249.08698, found 249.08621.
(s, 9 H), 2.97 (d, J = 5.2 Hz, 2 H), 3.80 (s, 3 H), 3.91 (s, 3 H), 4.55–4.91
(m, 1 H), 5.40 (d, J = 7.6 Hz, 1 H), 7.43 (d, J = 8.9 Hz, 2 H), 7.96 (d,
J = 8.8 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 24.0, 28.3, 52.2,
52.7, 53.7, 80.3, 82.9, 87.2, 127.7, 129.4, 131.6, 155.0, 166.5,
171.2 ppm. HRMS (ESI): calcd. for C19H23O6 [M + Na]+ 384.14176,
found 384.14211.
1
Compound 10caa: Yield 97 %. H NMR (300 MHz, CDCl3): δ = 2.41
Methyl 5-[4-(Methoxycarbonyl)phenyl]-3,4-dihydro-2H-2-pyrr-
olecarboxylate (11f): Yield 87 %. 1H NMR (300 MHz, CDCl3): δ =
2.21–2.44 (m, 2 H), 2.93–3.06 (m, 1 H), 3.12–3.24 (m, 1 H), 3.78 (s, 3
H), 3.92 (s, 3 H), 4.87–4.99 (m, 1 H), 7.89–8.00 (m, 2 H), 8.02–8.10
(m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 26.3, 35.5, 52.2, 52.3,
74.7, 127.9, 129.6, 132.0, 137.6, 166.5, 172.9, 175.3 ppm. HRMS (ESI):
calcd. for C14H16NO4 [M + H]+ 262.10738, found 262.10792.
(s, 3 H), 2.90 (t, J = 5.1 Hz, 2 H), 3.64 (s, 3 H), 4.20 (dt, J = 9.1, 5.1 Hz,
1 H), 5.45 (d, J = 9.1 Hz, 1 H), 7.24–7.38 (m, 7 H), 7.76 (d, J = 8.3 Hz,
2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 21.5, 25, 52.9, 54.4, 82.7,
84.3, 122.7, 127.2, 128.2, 129.7, 131.7, 136.9, 143.8, 170.3 ppm.
HRMS (ESI): calcd. for C19H20NO4S [M + H]+ 358.10914, found
358.11076.
General Procedure for C–N Cycloisomerization; Synthesis of 1-
Pyrrolines: To a solution of compound 10ba (300 mg, 0.99 mmol)
Representative Experimental Procedure for the Synthesis of γ-
Lactones: The methyl ester derivatives were dissolved in THF/H2O
in EtOAc (5 mL), a 3
M solution of HCl in EtOAc (2 mL) was added
(6 mL, 2:1) and cooled to 0 °C. Then, a 1
M solution of LiOH (0.8 mL)
dropwise at room temp. The mixture was stirred at room temp.
and monitored by TLC. After complete conversion, the mixture was
concentrated in vacuo to afford the corresponding HCl salt. A solu-
tion of the HCl salt in dioxane/water (15 mL, 1:1 v/v) was treated
dropwise at room temp. with 25 % aqueous NH4OH until pH = 10.
The aqueous solution was extracted with EtOAc, and the combined
organic layers were dried with Na2SO4 and concentrated in vacuo.
The remaining crude amino ester was subsequently dissolved in
MeCN (10 mL), and AuCl3 (10 mol-%) was added. The mixture was
stirred at reflux temp. and monitored by TLC. Upon completion, the
reaction mixture was filtered and concentrated in vacuo. The crude
product was purified by chromatography (EtOAc/hexane) to afford
the corresponding 1-pyrroline.
was added. The mixture was stirred at room temp., and the reaction
was monitored by TLC. After complete conversion, the reaction mix-
ture was poured into a beaker with ice, and a solution of HCl (1 M)
was added until the pH was acidic. The aqueous solution was ex-
tracted with EtOAc, and the combined organic layers were dried
with Na2SO4 and concentrated in vacuo. The product was used in
the next step without further purification. AuCl (0.1 equiv.) and then
K2CO3 (0.1 equiv.) were added to a solution of the amino acid com-
pound (1 equiv.) in MeCN (3 mL/mmol) at room temperature. The
reaction mixture, initially a white suspension, turned into a dark
brown solution within minutes. After disappearance of the starting
material (TLC monitoring, usually 2 h), the reaction mixture was
filtered through a pad of Celite, and the filtrate was concentrated
under reduced pressure to give the crude product. Due to the insta-
bility of these enol-lactones, the compounds were purified by pas-
sage through a short pad of silica (eluent: EtOAc) as described in
the literature.[9,12]
Methyl 5-Phenyl-3,4-dihydro-2H-2-pyrrolecarboxylate (11a):[18]
1
Yield 75 %. H NMR (300 MHz, CDCl3): δ = 2.20–2.37 (m, 2 H), 2.89–
3.04 (m, 1 H), 3.08–3.23 (m, 1 H), 3.77 (s, 3 H), 4.86–4.97 (m, 1 H),
7.36–7.49 (m, 3 H), 7.81–7.94 (m, 2 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 26.3, 35.3, 52.2, 74.5, 127.9, 128.3, 130.8, 133.7, 173.3,
Compound 10aa: Yield 99.4 %. 1H NMR (300 MHz, [D4]methanol):
δ = 2.03 (s, 3 H), 2.93 (dd, J = 6.2, 4.0 Hz, 2 H), 4.64 (dd, J = 6.9,
5.5 Hz, 1 H), 7.25–7.41 (m, 5 H) ppm. 13C NMR (75 MHz, [D4]metha-
nol): δ = 22.5, 23.6, 53.1, 83.8, 85.9, 124.9 129.2, 129.5, 132.8, 173.5,
175.9 ppm. HRMS (ESI): calcd. for C12H13NNaO2 [M
226.08385, found 226.08451.
+
Na]+
Methyl
5-(4-Methylphenyl)-3,4-dihydro-2H-2-pyrrolecarbox-
ylate (11b): Yield 55 %. 1H NMR (300 MHz, CDCl3): δ = 2.21–2.35
(m, 2 H), 2.38 (s, 3 H), 2.88–3.02 (m, 1 H), 3.05–3.15 (m, 1 H), 3.77
(s, 3 H), 4.90 (dt, J = 6.9, J = 1.7 Hz, 1 H), 7.21 (d, J = 8.2 Hz, 2 H),
173.7 ppm. HRMS (ESI): calcd. for C13H13NNaO3 [M
254.07876, found 254.07927.
+
Na]+
1
7.77 (d, J = 8.2 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 21.4, Compound 10ab: Yield 90 %. H NMR (300 MHz, [D6]acetone): δ =
26.3, 35.3, 52.1, 74.4, 127.9, 129.0, 131.0, 141.2, 173.4, 175.8 ppm.
1.99 (s, 3 H), 2.31 (s, 3 H), 2.94 (d, J = 5.7 Hz, 2 H), 4.72 (m, 1 H),
HRMS (ESI): calcd. for C13H15NNaO2 [M + Na]+ 240.09950, found 7.14 (d, J = 8.1 Hz, 2 H), 7.26 (d, J = 8.1 Hz, 2 H) ppm. 13C NMR
240.09933.
(75 MHz, [D6]acetone): δ = 21.8, 23.2, 23.4, 52.6, 85.8, 121.9, 130.3,
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
6
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
132.8, 139.3, 170.8, 172.5 ppm. HRMS (ESI): calcd. for C14H15NNaO3
[M + Na]+ 268.09441, found 268.09429.
133.2, 134.6, 148.4, 170.6, 173.7 ppm. HRMS (ESI): calcd. for
C17H16NO3 [M + H]+ 282.11247, found 282.11310.
1
tert-Butyl (Z)-(5-Benzylidene-2-oxotetrahydrofuran-3-yl)carb-
amate (12g): Yield 90 %. H NMR (300 MHz, [D6]acetone): δ = 1.43
(s, 9 H), 3.11–3.20 (m, 1 H), 3.30–3.38 (m, 1 H), 4.61–4.7 (m, 1 H), 5.65
(s, 1 H), 7.17–7.57 (m, 5 H) ppm. 13C NMR (75 MHz, [D6]acetone):
δ = 1.5, 28.6, 33.9, 49.9, 80.2, 105, 127.4, 129.2, 129.3, 135.5, 147.6,
156.2, 174 ppm. HRMS (ESI): calcd. for C16H17NNaO4 [M + Na]+
312.12063 found 312.12065.
Compound 10ac: Yield 96 %. H NMR (300 MHz, [D6]acetone): δ =
1
2.01 (s, 3 H), 3.02 (d, J = 5.7 Hz, 2 H), 4.72–4.79 (m, 1 H), 7.49–7.63
(m, 3 H), 7.83–8.00 (m, 4 H) ppm. 13C NMR (75 MHz, [D6]acetone):
δ = 23.5, 24.4, 52.9, 84.5, 87.4, 122.6, 128.2, 129.2, 129.3, 129.6,
130.1, 132.7, 134.5, 134.8, 171.1, 172.8 ppm. HRMS (ESI): calcd. for
C
17H16NO3 [M + H]+ 282.11247, found 282.11195.
1
Compound 10ba: Yield 87 %. H NMR (300 MHz, [D6]acetone): δ =
1.46 (s, 9 H), 3.00 (br. s, 2 H), 4.61–4.63 (m, 1 H), 5.45 (d, J = 7.6 Hz,
1 H), 7.28 (br. s, 3 H), 7.39 (br. s, 2 H) ppm. 13C NMR (75 MHz,
[D6]acetone): δ = 23.5, 28.2, 52.1, 80.5, 83.6, 83.7, 122.9, 128, 128.1,
131.7, 155.4, 175.3 ppm. HRMS (ESI): calcd. for C16H18NNa2O4 [M +
Na]+ 334.10257, found 334.10297.
(Z)-N-(5-Benzylidene-2-oxotetrahydrofuran-3-yl)-4-methyl-
benzenesulfonamide (12h): Yield 92 %. 1H NMR (300 MHz, [D6]
acetone): δ = 2.44 (s, 3 H), 2.87–2.97 (m, 1 H), 3.19–3.27 (m, 1 H),
4.7–4.76 (m, 1 H), 5.62 (s, 1 H), 5.63 (s, 1 H), 7.17–8.06 (m, 10 H)
ppm. 13C NMR (75 MHz, [D6]acetone): δ = 21.8, 35.5, 52.4, 106, 127.8,
128.2, 129.4, 129.5, 129.6, 130.8, 130.9, 134, 135.3, 139.8, 144.7,
146.8, 173.1 ppm. HRMS (ESI): calcd. for C18H17NNaO4S [M + Na]+
366.07705 found 366.07679.
Compound 10ca: Yield 94 %. 1H NMR (300 MHz, CDCl3): δ = 2.38
(s, 3 H), 2.91 (t, J = 4.7 Hz, 2 H), 4.18–4.27 (m, 1 H), 5.55 (d, J =
8.1 Hz, 3 H), 7.21–7.38 (m, 7 H), 7.76 (d, J = 8.3 Hz, 2 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 21.5, 24.7, 54.1, 82.4, 84.5, 122.5, 127.1,
128.2, 128.35, 129.8, 131.7, 136.7, 143.9, 173.5 ppm. HRMS (ESI):
calcd. for C18H17NNaO4S [M + Na]+ 366.07705, found 366.07624.
N-(6-Methylene-2-oxotetrahydro-2H-pyran-3-yl)acetamide
1
(12i): Yield 95 %. H NMR (300 MHz, [D6]acetone): δ = 1.93 (s, 3 H),
2.09 (s, 2 H), 2.54–2.62 (m, 1 H), 2.66–2.74 (m, 1 H), 3.31 (s, 1 H), 3.66
(s, 1 H), 3.37–4.46 (m, 1 H) ppm. 13C NMR (75 MHz, [D6]acetone):
δ = 22.7, 26.6, 39.8, 52.3, 94.1, 156.4, 168.5, 173.6 ppm. HRMS (ESI):
calcd. for C8H12NO3 [M + Na]+ 170.08161, found 170.08157.
N-(5-Methylene-2-oxotetrahydrofuran-3-yl)acetamide
(12a):
Yield 95 %. 1H NMR (300 MHz, CDCl3): δ = 2.06 (s, 3 H), 2.78–288
(m, 1 H), 3.29–3.37 (m, 1 H), 4.34 (br. s, 1 H), 4.58–4.67 (m, 1 H), 4.83
(br. s, 1 H), 6.28 (br. s, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 23.1,
33.8, 50.1, 91, 152.6, 170.9 ppm. HRMS (ESI): calcd. for C7H9NNaO3
[M + Na]+ 178.04746, found 178.04674.
Acknowledgments
This research has been supported by the Agencia Nacional de
Promoción Científica y Tecnológica (PICT-2011-0403) and the
Consejo Nacional de Investigaciones Científicas y Técnicas
(CONICET), Argentina. N. S. M. thanks CONICET for a fellowship.
The authors further gratefully acknowledge Dr. Jed F. Fisher,
University of Notre Dame, for critical discussions of the manu-
script.
tert-Butyl (5-Methylene-2-oxotetrahydrofuran-3-yl)carbamate
(12b): Yield 94 %. 1H NMR (300 MHz, CDCl3): δ = 1.46 (s, 9 H) 2.88–
2.92 (m, 1 H) 3.22–3.3 (m, 1 H) 4.41 (br. S, 2 H) 4.8 (br. s, 1 H) 5.21
(d, J = 5.5 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 28.2, 33.4,
50.5, 80.9, 90.4, 152.2, 173 ppm. HRMS (ESI): calcd. for C10H15NNaO4
[M + Na]+ 236.08933, found 236.08967.
4-Methyl-N-(5-methylene-2-oxotetrahydrofuran-3-yl)benzene-
1
sulfonamide (12c): Yield 97 %. H NMR (300 MHz, CDCl3): δ = 2.46
Keywords: Homogeneous catalysis · Nitrogen heterocycles ·
Oxygen heterocycles · Synthetic methods
(s, 3 H), 2.84–2.95 (m, 1 H), 3.25–3.33 (m, 1 H), 4.06–4.14 (m, 1 H),
4.47 (br. s, 1 H), 4.84 (br. s, 1 H), 5.16 (d, J = 3.8 Hz, 1 H), 7.36 (d, J =
8.1 Hz, 2 H), 7.80 (d, J = 8.1 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 21.6, 34.7, 52.1, 91.5, 127.3, 130, 135.6, 144.5, 151.6, 171.8 ppm.
HRMS (ESI): calcd. for C12H13NNaO4S [M + Na]+ 290.04575, found
290.04541.
[1] a) A. Arcadi, Chem. Rev. 2008, 108, 3266–3325; b) H. C. Shen, Tetrahedron
2008, 64, 3885–3903; c) H. C. Shen, Tetrahedron 2008, 64, 7847–7870; d)
J. Muzart, Tetrahedron 2008, 64, 5815–5849; e) M. Rudolph, A. S. K.
Hashmi, Chem. Soc. Rev. 2012, 41, 2448–2462; f) A. S. K. Hashmi, G. J.
Hutchings, Angew. Chem. Int. Ed. 2006, 45, 7896–7936; Angew. Chem.
2006, 118, 8064; g) J. H. Teles, S. Brode, M. Chabanas, Angew. Chem. Int.
Ed. 1998, 37, 1415–1418; Angew. Chem. 1998, 110, 1475; h) A. S. K.
Hashmi, L. Schwarz, J. H. Choi, T. M. Frost, Angew. Chem. Int. Ed. 2000,
39, 2285–2288; Angew. Chem. 2000, 112, 2382; i) A. S. K. Hashmi, T. M.
Frost, J. W. Bats, J. Am. Chem. Soc. 2000, 122, 11553–11554; j) S. P. Nolan,
Nature 2007, 445, 496–497; k) A. Corma, A. Leyva-Perez, M. J. Sabater,
Chem. Rev. 2011, 111, 1657–1712.
(Z)-N-(5-Benzylidene-2-oxotetrahydrofuran-3-yl)acetamide
(12d): Yield 96 %. 1H NMR (300 MHz, [D6]acetone): δ = 1.96 (s, 3 H),
3.09–3.18 (m, 1 H), 3.27–3.36 (m, 1 H), 4.66–4.75 (m, 1 H), 5.64 (s, 1
H), 7.19 (tt, J = 1.2, 7.4 Hz, 1 H), 7.32 (t, J = 7.4 Hz, 2 H), 7.56 (d, J =
7.4 Hz, 2 H) ppm. 13C NMR (75 MHz, [D6]acetone): δ = 22.5, 33.9,
49, 104.9, 127.3, 129.1, 129.2, 135.5, 147.8, 170.6, 173.6 ppm. HRMS
(ESI): calcd. for C13H13NNaO3 [M + Na]+ 254.07876, found 254.07867.
(Z)-N-[5-(4-Methylbenzylidene)-2-oxotetrahydrofuran-3-yl]acet-
[2] A. S. K. Hashmi, Angew. Chem. Int. Ed. 2010, 49, 5232–5241; Angew. Chem.
2010, 122, 5360.
1
amide (12e): Yield 85 %. H NMR (300 MHz, [D6]acetone): δ = 1.96
(s, 3 H), 2.30 (s, 3 H), 3.09–3.16 (m, 1 H), 3.25–3.34 (m, 1 H), 4.66–
4.75 (m, 1 H), 5.58 (s, 1 H), 7.14 (d, J = 8.2 Hz, 2 H), 7.43 (d, J =
8.2 Hz, 2 H) ppm. 13C NMR (75 MHz, [D6]acetone): δ = 21.6, 22.9,
34.2, 49.4, 105.3, 129.5, 130.3, 132.7, 137.3, 147.3, 170.9, 174.1 ppm.
HRMS (ESI): calcd. for C14H15NNaO3 [M + Na]+ 268.09441, found
268.09470.
[3] a) E. Jimenez-Nunez, A. M. Echavarren, Chem. Commun. 2007, 333–346;
b) M. Rudolph, A. S. K. Hashmi, Chem. Commun. 2011, 47, 6536–6544.
[4] a) H. C. Shen, T. H. Graham, Drug Discovery Today Technol. 2013, 10, e3–
e14; b) A. Arcadi, in Gold Catalysis: A Homogeneous Approach (Eds.: F. D.
Toste, V. Michelet), Imperial College Press, London, 2014, pp. 175–224.
[5] a) R. J. Brea, M. P. Lopez-Deber, L. Castedo, J. R. Granja, J. Org. Chem.
2006, 71, 7870–7873; b) L. B. Wolf, K. Tjen, H. T. ten Brink, R. H. Blaauw,
H. Hiemstra, H. E. Schoemaker, F. Rutjes, Adv. Synth. Catal. 2002, 344, 70–
83.
(Z)-N-[5-(Naphthalen-2-ylmethylene)-2-oxotetrahydrofuran-3-
yl]acetamide (12f): Yield 71 %. 1H NMR (300 MHz, [D6]acetone):
δ = 1.28 (s, 3 H), 3.15–3.26 (m, 1 H), 3.32–3.42 (m, 1 H), 5.78 (s, 1
H), 7.7–8.16 (m, 7 H) ppm. 13C NMR (75 MHz, [D6]acetone): δ = 22.5,
33.9, 49, 104.9, 126.6, 127.1, 127.5, 127.7, 128.3, 128.5, 128.8, 130.3,
[6] a) D. Kadzimirsz, D. Hildebrandt, K. Merz, G. Dyker, Chem. Commun. 2006,
661–662; b) D. D. Vachhani, M. Galli, J. Jacobs, L. Van Meervelt, E. V.
Van der Eycken, Chem. Commun. 2013, 49, 7171–7173.
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
7
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
[7]
[8]
[19] Y. Fukuda, K. Utimoto, H. Nozaki, Heterocycles 1987, 25, 297–300.
[20] a) B. C. J. van Esseveldt, F. L. van Delft, R. de Gelder, F. Rutjes, Org. Lett.
2003, 5, 1717–1720; b) T. Yasuno, T. Ohe, K. Takahashi, S. Nakamura, T.
Mashino, Bioorg. Med. Chem. Lett. 2015, 25, 3226–3229.
[21] M. A. Zotova, T. P. Vasil'eva, S. N. Osipov, Russ. Chem. Bull. 2013, 62, 792–
796.
[22] A. La-Venia, S. A. Testero, M. P. Mischne, E. G. Mata, Org. Biomol. Chem.
2012, 10, 2514–2517.
[23] S. Kotha, D. Goyal, N. Thota, V. Srinivas, Eur. J. Org. Chem. 2012, 1843–
1850.
[24] N. Li, R. K. V. Lim, S. Edwardraja, Q. Lin, J. Am. Chem. Soc. 2011, 133,
15316–15319.
[25] G. T. Crisp, Y. L. Jiang, P. J. Pullman, C. DeSavi, Tetrahedron 1997, 53,
17489–17500.
[26] a) N. Gouault, M. Le Roch, C. Cornee, M. David, P. Uriac, J. Org. Chem.
2009, 74, 5614–5617; b) G. Verniest, A. Padwa, Org. Lett. 2008, 10, 4379–
4382; c) F. M. Istrate, F. Gagosz, Org. Lett. 2007, 9, 3181–3184; d) C. Shu,
M. Q. Liu, S. S. Wang, L. Li, L. W. Ye, J. Org. Chem. 2013, 78, 3292–3299;
e) N. Gouault, M. Le Roch, A. Cheignon, P. Uriac, M. David, Org. Lett. 2011,
13, 4371–4373.
I. I. Strambeanu, M. C. White, J. Am. Chem. Soc. 2013, 135, 12032–12037.
a) J. M. Weibel, A. Blanc, P. Pale, Chem. Rev. 2008, 108, 3149–3173; b)
N. T. Patil, R. D. Kavthe, V. S. Shinde, Tetrahedron 2012, 68, 8079–8146.
E. Genin, P. Y. Toullec, S. Antoniotti, C. Brancour, J. P. Genet, V. Michelet,
J. Am. Chem. Soc. 2006, 128, 3112–3113.
H. Harkat, J. M. Weibel, P. Pale, Tetrahedron Lett. 2006, 47, 6273–6276.
E. Marchal, P. Uriac, B. Legouin, L. Toupet, P. van de Weghe, Tetrahedron
2007, 63, 9979–9990.
a) E. Tomas-Mendivil, P. Y. Toullec, J. Diez, S. Conejero, V. Michelet, V.
Cadierno, Org. Lett. 2012, 14, 2520–2523; b) E. Tomas-Mendivil, P. Y. Toul-
lec, J. Borge, S. Conejero, V. Michelet, V. Cadierno, ACS Catal. 2013, 3,
3086–3098.
[9]
[10]
[11]
[12]
[13] K. Eriksson, O. Verho, L. Nyholm, S. Oscarsson, J. E. Backvall, Eur. J. Org.
Chem. 2015, 2250–2255.
[14] M. J. Rodriguez-Alvarez, C. Vidal, J. Diez, J. Garcia-Alvarez, Chem. Com-
mun. 2014, 50, 12927–12929.
[15] H. Harkat, A. Y. Dembele, J. M. Weibel, A. Blanc, P. Pale, Tetrahedron 2009,
65, 1871–1879.
[16] M. J. Sofia, P. K. Chakravarty, J. A. Katzenellenbogen, J. Org. Chem. 1983,
48, 3318–3325.
[27] Y. Fukuda, K. Utimoto, Synthesis 1991, 975–978.
[17] M. I. Konaklieva, B. J. Plotkin, Mini-Rev. Med. Chem. 2005, 5, 73–95.
[18] B. C. J. van Esseveldt, P. W. H. Vervoort, F. L. van Delft, F. Rutjes, J. Org.
Chem. 2005, 70, 1791–1795.
Received: April 5, 2016
Published Online: ■
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
8
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Gold Catalysis
N. S. Medran, M. Villalba,
E. G. Mata, S. A. Testero* ................. 1–9
Gold-Catalyzed Cycloisomerization
of Alkyne-Containing Amino Acids:
Controlled Tuning of C–N vs. C–O
Reactivity
A gold-catalyzed C–N and C–O func- disclosed here enables the divergent
tionalization of alkyne-containing synthesis of alkylidenelactones and 1-
amino acids is described. The strategy pyrrolines derived from amino acids.
DOI: 10.1002/ejoc.201600429
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
9
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim