Gold(I)-catalyzed cycloisomerization of 1,6-diynes: Synthesis of 2,3-disubstituted 3-pyrroline derivatives

Article abstract of DOI:10.1002/anie.201006969

A novel synthetic protocol for the preparation of the title compounds has been developed from a gold-catalyzed cycloisomerization of 1,6-diynes containing propargylic ester and arene-yne units. The corresponding nitrogen-containing five-membered heterocyclic compounds have been obtained in moderate to good yields (see scheme; DCE=1,2-dichloroethane, Tf=triflate). A plausible reaction mechanism has been proposed on the basis of deuterium labeling experiments. Copyright

Full text of DOI:10.1002/anie.201006969

DOI: 10.1002/anie.201006969
Gold Catalysis
Gold(I)-Catalyzed Cycloisomerization of 1,6-Diynes: Synthesis of
2,3-Disubstituted 3-Pyrroline Derivatives**
Di-Han Zhang, Liang-Feng Yao, Yin Wei, and Min Shi*
Homogeneous catalysis mediated by gold complexes has
received considerable attention in recent years.[1] Among
these interesting reactions, gold-catalyzed cycloisomerization
of 1,6-enynes and 1,6-diynes[2,3] is one of the most important
strategies for the construction of functionalized cyclic struc-
tures (Scheme 1). In the context of our ongoing efforts to
diyne to give heterocyclic products (Z = N). Herein, we
À
report a novel C C bond formation along with cycloisome-
rization from 1,6-diyne-containing propargylic ester and
arene–yne (arenyne) units toward nitrogen-containing five-
membered heterocyclic rings such as 2,3-disubstituted 3-
pyrrolines,[4] which have been extensively used as synthetic
building blocks in organic synthesis and appear as structural
motifs in many natural products, thus exhibiting interesting
biological activities.[5]
Initial studies using propargylic acetate arenyne 1a
(0.2 mmol) as the substrate were aimed at determining the
reaction outcome and subsequently optimizing the reaction
conditions. The results are summarized in Table 1. We found
that an interesting 3-pyrroline derivative 2a was formed in
50% yield using [(PPh3)AuCl]/AgOTf as the catalyst
(5 mol%) in toluene at 808C (Table 1, entry 1). The structure
of compound 2a was confirmed by NMR spectroscopy and X-
ray crystal structure analysis (Figure 1).[6] Product 2a could be
Table 1: Optimization of reaction conditions for gold(I)-catalyzed
intramolecular cyclization.[a]
Scheme 1. Gold-catalyzed cycloisomerization of 1,6-enyne and
1,6-diynes. Nu=nucleophile.
develop gold-catalyzed tandem reactions, we realized that the
gold-catalyzed cascade transformation of 1,6-diynes to abnor-
mal five-membered cycloadducts has been less explored
(Scheme 1). Thus far, only one example has been reported, in
which a cycloisomerization of terminal 1,6-diynes catalyzed
by gold–phosphine gives the cyclopentene products in less
than 43% yield (Z = C; Scheme 1).[3f] We therefore antici-
pated that a new cascade process initiated by gold-induced
Entry Catalyst
[5 mol%]
Additive
(equiv)
Solvent
T
Yield of
[8C] 2a [%][b]
1
[(PPh3)AuCl]/AgOTf
–
toluene
toluene
toluene
80 50
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
[(PPh3)AuCl]/AgOTf
[(PPh3)AuCl]/AgOTf
[(PPh3)AuCl]/AgOTf
[(PPh3)AuCl]/AgOTf
[(PPh3)AuCl]/AgOTf
[(PPh3)AuCl]/AgOTf
[(PPh3)AuCl]/AgOTf
[(PPh3)AuCl]/AgOTf
[(PPh3)AuCl]/AgOTf
[(tBu3P)AuCl]/AgOTf H2O (1.0)
[(IPr)AuCl]/AgOTf H2O (1.0)
[(PMe3)AuCl]/AgOTf H2O (1.0)
[(tBu3P)AuCl]/AgSbF6 H2O (1.0)
[(tBu3P)AuCl]/AgBF4 H2O (1.0)
[(tBu3P)AuCl]/AgNTf2 H2O (1.0)
H2O (1.0)
H2O (2.0)
80 62
[c]
80
–
MeOH (2.0) toluene 100 complex
H2O (0.5)
H2O (1.0)
H2O (1.0)
H2O (1.0)
H2O (1.0)
H2O (1.0)
toluene
toluene
toluene 100 42
CH3CN
CH3NO2
DCE
DCE
DCE
DCE
DCE
80 52
60 40
À
C C bond formation along with cycloisomerization might be
achieved in a system in which a nitrogen atom connects 1,6-
80 NR
80 NR
80 65
80 83
80 26
[*] D.-H. Zhang, L.-F. Yao, Prof. M. Shi
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
80 40
80 NR
80 complex
80 complex
80 50
345 Lingling Road, Shanghai 200032 (China)
Fax: (+86)21-6416-6128
E-mail: mshi@mail.sioc.ac.cn
DCE
DCE
DCE
DCE
AgOTf
[(tBu3P)AuCl]
H2O (1.0)
H2O (1.0)
[**] We thank the Shanghai Municipal Committee of Science and
Technology (08dj1400100-2), the National Basic Research Program
of China (973)-2009CB825300, and the National Natural Science
Foundation of China for financial support (21072206, 20472096,
20872162, 20672127, 20821002, and 20732008).
80 NR
[a] All reactions were carried out using 1a (0.2 mmol), H2O (X equiv) in
the presence of catalyst (5 mol%) in various solvents (2.0 mL) unless
otherwise specified. [b] Yield of isolated product. [c] The product is a
ketone (see the Supporting Information). IPr=1,3-bis(2,6-diisopropyl-
phenyl)imidazol-2-ylidene, NR=no reaction.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201006969.
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Table 2: Substrate scope of the gold(I)-catalyzed cycloisomerization.[a]
Entry
1
X
R1 R2
R3
R4
Yield [%][b]
1
2
3
4
5
6
7
8
1b Ts Ac CH3CH2
CH3CH2
H
H
H
H
H
H
H
H
CH3
CH3
CH3
CH3
CH3
H
H
H
H
H
H
H
H
H
2b, 50
2c, 84
2c, 80
2d, 64
2d, 56
2e, 60
2e, 56
2 f, 63
2 f, 55
2g, 88
2h, 61
2i, 66
2j, 73
2k, 68
2l, 35
1c Ts Ac CH3CH2CH2
1d Ts Piv CH3CH2CH2
1e Ts Ac PhCH2CH2
1 f
Ts Piv PhCH2CH2
1g Ts Ac (CH3)2CH
1h Ts Piv (CH3)2CH
1i
1j
Ts Ac PhCH2
Ts Piv PhCH2
9
H
10
11
12
13
14
15
1k Ts Ac CH3
1l Ts Ac CH3
1m Ns Ac CH3
1n Bs Ac CH3
1o Ns Ac CH3
1p Ts Ac BnOCH2
CH3
Cl
H
H
CH3
H
Figure 1. ORTEP Drawing of 2a. Hydrogen atoms have been omitted
for clarity, ellipsoids are drawn at 30 % probability.
16
1q
2m, 71
obtained in 62% yield in the presence of H2O (1.0 equiv;
Table 1, entry 2). On the other hand, the addition of H2O
(2.0 equiv) to the reaction system led to the formation of a
ketone product rather than 2a (see product 7a in the
Supporting Information) and replacing H2O with methanol
(2.0 equiv) resulted in a complex mixture at 1008C (Table 1,
entries 3 and 4). Using 0.5 equivalents of water did not
increase the yield of 2a either (Table 1, entry 5). Reducing the
reaction temperature to 608C or elevating the temperature to
1008C did not improve the reaction outcome in the presence
of H2O (1.0 equiv; Table 1, entries 6 and 7). Carrying out the
reaction in CH3NO2 or CH3CN did not facilitate the
formation of 2a (Table 1, entries 8 and 9). When 1,2-dichloro-
ethane (DCE) was used as a solvent, the yield of 2a could be
improved up to 65% (Table 1, entry 10). In the presence of
[(tBu3P)AuCl], 2a could be obtained in 83% yield and
[(PMe3)AuCl] as well as [(IPr)AuCl] were not effective gold
catalysts in this reaction (Table 1, entries 11–13). Further
examination of silver salts revealed that AgOTf was the best
choice for the reaction (Table 1, entries 14–16). Control
experiments indicated that using AgOTf alone as the catalyst
gave 2a in 50% yield and using [(tBu3P)AuCl] alone as the
catalyst did not promote the reaction (Table 1, entries 17 and
18). Therefore, the optimal reaction conditions were found
when the reaction was carried out in DCE at 808C using
[(tBu3P)AuCl]/AgOTf (5 mol%) as the catalyst in the pres-
ence of H2O (1.0 equiv).
17
18
1r
NR
1s
3a, 71
[a] All reactions were carried out using 1 (0.2 mmol), H2O (1.0 equiv) in
the presence of [(tBu3P)AuCl]/AgOTf (5 mol%) in DCE (2.0 mL) at 808C
for 24 h. [b] Yield of isolated product. Bn=benzyl, Bs=4-bromobenze-
nesulfonyl, Ns=4-nitrobenzenesulfonyl, Ts=4-toluenesulfonyl.
group on the benzene ring (R4 = CH3) and R2 and R3 were
methyl groups, the corresponding product 2g was formed in
88% yield (Table 2, entry 10). Substrate 1l having an
electron-withdrawing chloro atom on the benzene ring
(R4 = Cl) gave the desired product 2h in 61% yield
(Table 2, entry 11). In the case of other N-sulfonated amines
(X = Ns or Bs), the reactions also proceeded smoothly to give
the corresponding cycloadducts 2i–2k in 66–73% yields, thus
indicating a broad substrate scope for this reaction (Table 2,
entries 12–14). Further examination of substrate 1p (R2 =
CH2OBn) revealed that the desired product 2l could be
obtained in 35% yield (Table 2, entry 15). The aromatic
group of 1 could also be a naphthyl group (1q), thereby giving
the corresponding cycloadduct 2m in 71% yield (Table 2,
entry 16). As for substrate 1r having a methyl group at the
terminal of alkyne moiety, no reaction occurred under the
standard conditions (Table 2, entry 17). When the terminal of
alkyne moiety is a hydrogen atom (1s), the corresponding
enone 3a could be formed in 71% yield rather than the
cyclized product (Table 2, entry 18). The product structures of
2a–2m were determined by NMR spectroscopic analysis,
mass spectrometry (MS), and HRMS (see the Supporting
Information).
We next examined the substrate generality of the reaction
under the optimized conditions and the results are shown in
Table 2. When both R2 and R3 were ethyl groups, 3-pyrroline
derivative 2b was formed in 50% yield (Table 2, entry 1). For
various propargylic esters in which both R3 and R4 were
hydrogen atoms, the corresponding cycloadducts 2c–2 f could
be obtained in 55–84% yields under the standard conditions
(Table 2, entries 2–9). As for substrate 1k having a methyl
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Angew. Chem. Int. Ed. 2011, 50, 2583 –2587

On the other hand, in the case of oxygen-tethered 1,6-
diynes containing propargylic ester and arenyne such as
substrates 1t and 1u, the reactions produced the correspond-
ing 2,5-dihydrofuran derivative 4a (normal cyclization) in
62% and 61% yield at room temperature (208C), respec-
tively (Scheme 2).
(1.0 equiv) led to the corresponding product [D2]-2a in 90%
yield along with 72% and 33% deuterium incorporation at its
olefinic carbon atoms.
Plausible mechanisms for this reaction are outlined in
Scheme 5 on the basis of the above deuterium labeling
experiments. Two cationic AuI complexes A first coordinate
Scheme 2. Gold(I)-catalyzed cycloisomerization of 1t and 1u. Piv=
pivaloyl, Tf=triflate.
Further transformations of products 2 are shown in
Scheme 3. The benzenesulfonyl group and 4-nitrobenzene-
sulfonyl group could be easily removed by treatment with
sodium naphthalene agent[7] or thiophenol in the presence of
K2CO3,[8] respectively, thus giving the corresponding pyrrole
derivatives 5a and 5b in good yields.
Scheme 3. Further transformations of products 2c and 2k.
To elucidate the cycloisomerization mechanism, deute-
rium labeling experiments were performed as shown in
Scheme 4. Propargylic acetate [D]-1a containing CD2 pro-
duced cycloadduct [D]-2a in 70% yield with > 99% deute-
rium incorporation at its alkyl carbon center. Carrying out the
reaction of propargylic acetate 1a in the presence of D2O
Scheme 5. A plausible reaction mechanism. L=ligand.
to the two alkyne moieties of 1a, respectively, to give
intermediate B, which undergoes a gold-catalyzed [3,3]-
sigmatropic rearrangement[9] to give the corresponding car-
boxyallene intermediates C. The resulting oxonium inter-
mediate D[9,10] undergoes hydrolysis to give enone E. Alter-
natively, based on
a
Meyer–Schuster-like rearrange-
ment,[10b,11] the nucleophilic attack of water on the alkyne
moiety of intermediate B affords allenol C’ along with the
release of AcOÀ, and which can also further tautomerize to
the conjugated enone E. The enone E undergoes a Lewis acid
catalyzed enolization to give intermediate F. Activation of the
remaining alkyne moiety by the gold complex induces a 5-
endo-dig cycloaddition to give intermediate G.[9h] The hydro-
lysis of intermediate G produces cycloadduct 2a and regen-
erates the AuI complex A to complete the catalytic cycle. To
verify the proposed mechanism, we also synthesized alkynyl
Scheme 4. Isotopic labeling experiments.
Angew. Chem. Int. Ed. 2011, 50, 2583 –2587
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Communications
enone 6a,[12] which is the intermediate E in the catalytic cycle.
Experimental Section
In the control experiment, we found that upon treatment of
6a with [(tBu3P)AuCl]/AgOTf (5 mol%) in DCE at 808C for
5 hours, 2a could be obtained in 84% yield, therefore
suggesting that intermediate E is the real key species in the
catalytic cycle (Scheme 6).
General procedure for gold-catalyzed cyclization of propargylic ester-
arenyne: Propargylic ester arenyne 1 (0.2 mmol, 1.0 equiv) was
dissolved in 1,2-dichloroethane (2.0 mL, 0.1m) in an Schlenk tube
under ambient atmosphere, [(tBu3P)AuCl] (5 mol%) and AgOTf
(5 mol%) were added followed by H2O (3.6 mL, 1.0 equiv). The
reaction mixture was stirred at 808C until the reaction was complete.
Then, the solvent was removed under reduced pressure and the
residue was purified by a flash column chromatography (SiO2) to give
the corresponding product 2 in moderate to good yields.
Received: November 6, 2010
Published online: February 15, 2011
Keywords: cycloisomerization · gold · homogeneous catalysis ·
.
Scheme 6. Gold(I)-catalyzed cyclization of alkynyl enone 6a.
isotopic labeling · pyrroles
As mentioned above, oxygen-tethered 1,6-diynes under-
went a different reaction, thereby affording normal cycliza-
tion adducts. We hypothesized that the pKa value of a protons
with respect to the carbonyl group in oxygen-tethered 1,6-
diynes is larger than that of a protons with respect to the
carbonyl group in nitrogen-tethered 1,6-diynes, which may
make the proton transfer step (shown in Scheme 5) difficult to
occur for the reaction involving oxygen-tethered 1,6-diynes.
We chose two simplified model compounds I and II, and
calculated the pKa value of the a protons with respect to the
carbonyl group in aqueous solution at CPCM/UAHF/
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Scheme 7. pKa value of compound I and compound II on the basis of
DFT calculation.
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argylic ester and arenyne to provide an easy access to 3-
pyrroline or pyrrole derivatives in good yields upon heating at
808C. The reaction mechanism has been proposed on the
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