Nature of the intermediates in gold(I)-catalyzed cyclizations of 1,5-enynes

Article abstract of DOI:10.1002/chem.201101749

The carbene or carbocationic nature of the intermediates in the gold-catalyzed cycloisomerization of 1,5-enynes can be revealed, depending on the ligands on the gold catalysts. Gold complexes with highly electron-donating ligands promote reactions that proceed via intermediates with carbene-like character, leading to products with a bicyclo[3.1.0]hexene skeleton. The intermediate cyclopropyl endo-gold carbenes formed in this cyclization have been trapped, for the first time, to give biscyclopropane derivatives in a reaction that proceeds in a concerted fashion, according to DFT calculations.

Full text of DOI:10.1002/chem.201101749

DOI: 10.1002/chem.201101749
Nature of the Intermediates in Gold(I)-Catalyzed Cyclizations of 1,5-Enynes
Verꢀnica Lꢀpez-Carrillo,[a] Nfflria Huguet,[a] ngeles Mosquera,[a] and
Antonio M. Echavarren*[a, b]
Abstract: The carbene or carbocationic nature of the intermediates in the gold-cat-
alyzed cycloisomerization of 1,5-enynes can be revealed, depending on the ligands
on the gold catalysts. Gold complexes with highly electron-donating ligands pro-
Keywords: cyclization
functional theory · enynes · gold ·
reaction mechanisms
·
density
mote reactions that proceed via intermediates with carbene-like character, leading
to products with a bicyclo[3.1.0]hexene skeleton. The intermediate cyclopropyl
AHCTUNGTRENNUNG
endo-gold carbenes formed in this cyclization have been trapped, for the first time,
to give biscyclopropane derivatives in a reaction that proceeds in a concerted fash-
ion, according to DFT calculations.
Introduction
In contrast to 1,6-enynes, which usually react by 6-exo-dig
pathways with gold(I) catalysts,[1] 1,5-enynes 1 almost invari-
ably undergo 5-endo-dig cyclizations through intermediates
of type 2 to form derivatives 3,[1–9] since formation of inter-
mediates with a bicyclo
ACHTUNGTRENNUNG
able than formation of the strained bicyclo
AHCTUNGTRENNUNG
system resulting from exo cyclization (Scheme 1).[10,11,12]
Ligands play a major role in the control of the regio or
site selectivity in gold-catalyzed reactions of 1,6-eny-
nes.[1b,13,14] Thus, reactions of gold complexes with highly
electron-donating N-heterocyclic carbene (NHC) ligands
proceed via intermediates with more carbene-like character,
whereas reactions with phosphite–gold catalysts can be
better interpreted as proceeding via carbocationic inter-
mediates.[15,16,17,18] However, the role of ligands in cycliza-
tions of 1,5-enynes has not been examined systematically.
Herein, we report the results of a study on the effect of li-
gands in cyclizations of 1,5-enynes 1. Of particular mecha-
nistic relevance, we have found the first examples of intra-
molecular cyclopropanation of endo-gold carbenes formed
in the cyclization of 1,5-enynes to give products of type 5
(Scheme 1), which proceeded in a concerted manner, ac-
Scheme 1. Gold-catalyzed cyclization of 1,5-enynes via cyclopropyl
gold(I) carbenes 2.
cording to DFT calculations. We also report the intramolec-
ular opening of intermediates 2 by benzyl groups to give tri-
cyclic compounds 6.
Results and Discussion
DFT calculations on a series of 1,5-enyne models show that
the nature of intermediates 2 depends on the ligand on
gold(I) (Figure 1). For comparison, PtII intermediates 7 and
free carbocations 8a (R=H) and 8b (R=Me) are also in-
cluded for this study. Calculations show that metal-stabilized
intermediates are significantly different from single homoal-
[a] V. Lꢁpez-Carrillo, N. Huguet, ꢂ. Mosquera,+ Prof. A. M. Echavarren
Institute of Chemical Research of Catalonia (ICIQ)
Av. Paꢃsos Catalans 16, 43007 Tarragona (Spain)
Fax : (+34)977920225
E-mail: aechavarren@iciq.es
[b] Prof. A. M. Echavarren
lylic carbocations 8a,b. Intermediate 2 (L=PACTHNUGTRENUNG(OPh)3) shows
the longest bond length (1.688 ꢀ) of the AuI complexes, but
this distance is still 0.3 ꢀ shorter than a classic carbocation,
such as 8b (R=Me). In contrast, intermediate 2 with a
strongly electron-donating ligand, such as ClÀ, presents the
shortest bond (1.606 ꢀ), which corresponds more closely to
a cyclopropyl gold(I) structure. Although the effect is not
Departament de Quꢄmica Analꢄtica i Quꢄmica Orgꢅnica
Universitat Rovira i Virgili, C/Marcel·li Domingo s/n
43007 Tarragona (Spain)
[+] Summer Visiting Graduate Student from the Departamento de Quꢄ-
mica Fundamental, Universidade da CoruÇa (Spain).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201101749.
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FULL PAPER
Table 1. Cyclization of 1,5-enynes 9a–f with gold(I) and platinum(II)
metal catalysts.[a]
Entry R (enyne)
Cat.
T
t
Product (yield [%])
[8C]
[h]
1
H (9a)
A
23
16 10a+11a+12a’ (10:1:4,
74)
2
3
4
5
H (9a)
H (9a)
H (9a)
H (9a)
B
C
100[b] 0.3 12a’ (87)
23
1
12a’ (23)
AuCl3 80[c]
14 10a+11a (1:1, 51)
16 10a+11a+12a’ (10:2:1,
69)
D
23
Figure 1. Variation of distance, d [ꢀ], in gold intermediates 2 as a func-
tion of ligand L (NHC=N,N’-diphenylimidazolydene, Biph=biphenyl).
Platinum intermediate 7 and carbocations 8 are included for comparison.
The scale has originates at 1.4 ꢀ to highlight the relative differences
(DFT, B3LYP/6-31G**, LANL2DZ (Au)).
6
7
8
9
10
11
Me (9b)
Et (9c)
Ph (9d)
Ph (9d)
p-MeC6H4 (9e)
p-MeOC6H4
(9 f)
C
C
A
C
C
C
23
23
23
23
23
23
24 11b (80)
24 11c (52)
18 10d (50)
17 11d (67)+12d (25)
16 11e (58)+12e (21)
16 11 f (58)+12 f (28)
dramatic, the bond lengths increase along the series ClÀ <
N,N’-diphenylimidazolydene (NHC)<PMe2Biph<PPh3 <P-
12
p-AcC6H4 (9g)
C
23
18 11g (85)
[a] 5 mol% catalyst in CH2Cl2. [b] Microwave heating. [c] Reaction in tol-
uene.
ACHTUNGTRENNUNG
stituted enyne 9d gave rise to 10d with catalyst A (Table 1,
entry 8). The reaction of 9d with catalyst C led to 11d along
with 12d in 25% yield (Table 1, entry 9). Cyclopentadiene
12d was obtained as a single isomer that slowly equilibrated
to give a 3.6:1:1 mixture of three cyclopentadienes by 1,5-H
sigmatropic migration. Cyclization of enynes 9e,f in the
presence of catalyst C also gave mixtures of 1,4-dienes 11e,f
and cyclopentadienes 12e,f (Table 1, entries 10 and 11). In
contrast, cyclization of enyne 9g with catalyst C gave 11g
cleanly in 85% yield (Table 1, entry 12).
Vinyl-substituted enynes 9h,i were also studied. Cycliza-
tion of enyne 9h with catalyst B under microwave irradia-
tion led to the expected product 11h along with 13a as the
major product (Scheme 2). The product ratio was inverted
when the reaction was carried out with complex C as cata-
lyst at room temperature for 24 h. Tetrahydropentalene 13a
is formed via an intermediate of type 2 (see Scheme 1) and
not by gold(I)-catalyzed cyclization of 11h because heating
this triene with catalyst B at 1008C (microwave irradiation)
for 30 min failed to give 13a. Mechanistically, this annula-
tion is related to that occurring in the gold(I)-catalyzed
[4+2] cycloaddition of dienynes[13,21] and in the cyclization
of 1,8-dien-4-ynes,[8c] in which the pendant alkenes act as the
internal nucleophiles. Cyclization of enyne 9i in the pres-
ence of catalyst C resulted in the formation of 1.5:1 mixture
of bicyclic products 13b/13b’ in moderate yield.
This trend is also observed experimentally for 1,5-enynes
9a–g, with allylic sulfones, gold complexes A–C and plati-
num complex D as catalysts of different electrophilicity. The
reaction of 9a with catalyst A (5 mol%) in CH2Cl2 at room
temperature gave bicycloACTHNURGTNE[UNG 3.1.0]hexene 10a as the major
product (Table 1, entry 1), whereas more electrophilic cata-
lyst B led to cyclopentadiene 12a’ (Table 1, entry 2). Exten-
sive decomposition was observed with catalyst C, which led
to 12a’ in low yield (Table 1, entry 3). The reaction with
AuCl3 proceeded at 808C in toluene to give 51% of a 1:1
mixture of 10a and 11a (Table 1, entry 4). Platinum(II) com-
plex D also led to 10a as the major product (Table 1,
entry 5), whereas a complex mixture was observed with
[PtCl4]. The bicycloACHTUNGTRENNUNG[3.1.0]hexane derivatives did not under-
go isomerization through vinylcyclopropane rearrangements
under the reaction conditions.[19] The reaction of 9b and 9c
in the presence of catalyst C exclusively gave 1,4-dienes 11b
and 11c (Table 1, entries 6 and 7). As expected, phenyl-sub-
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A. M. Echavarren et al.
Table 2. Cycloaddition of enynes 9j–n with gold(I) catalysts.
Entry
R (enyne)
Cat.
t [h]
Product (yield [%])
1
2
3
4
5
6
7
8
H (9j)
H (9j)
p-MeO (9k)
p-MeO (9k)
p-MeO (9k)
p-Ph (9l)
p-Ph (9l)
p-Ph (9l)
2,3,4-(MeO)3 (9m)
2,3,4-(MeO)3 (9m)
m-MeO (9n)
m-MeO (9n)
B
C
A
B
C
A
B
C
B
C
B
C
14
12
3
3
2
14
14
0.2
14
0.2
14
14
16a (95)
16a (71)
16b (66)
16b (66)
16b (95)
16c (63)
16c (60)
16c (92)
16d (64)
16d (45)
16e (55)+16e’ (12)
16e (57)+16e’ (31)
9
10
11
12
cases, tricyclic compounds 16 were obtained as single stereo-
isomers. In general, good yields were obtained with electro-
philic catalysts B or C. Enyne 9n, substituted at the meta
position of the aryl ring, led to a mixture of regioisomeric
compounds 16e and 16e’ (Table 2, entries 11 and 12). In this
reaction, the aryl ring opens the intermediate cyclopropyl
gold(I) carbene in a process related to that occurring in the
gold(I)-catalyzed formal [4+2] cycloaddition of arylalkynes
with alkenes.[21]
Scheme 2. Gold(I)-catalyzed cyclization of dienynes 9h and 9i.
Enynes 14a–c, with different substitution patterns at the
alkene, also reacted with catalyst A at room temperature to
form tricyclic products 15a–c in good yields (Scheme 3).
1,5-Enyne 9o reacted smoothly with catalyst B at room
temperature to give cycloadduct 16 f in 95% yield, the struc-
ture of which was confirmed by X-ray diffraction
(Scheme 4).[22] Tricyclic compound 16 f possesses the tricyclic
skeleton of (+)-pycnanthuquinone C (17),[23,24] which is a
natural compound structurally related to pycnanthuquinone-
s A and B[25] and rossinone.[26]
Intermediates of cyclizations of 1,6-enynes have been
trapped by intra-[27] or intermolecular cyclopropanation;[18,28]
however, the trapping of intermediates 2 by alkenes in cycli-
zations of 1,5-enynes was unknown. Therefore, we decided
to trap these intermediates in reactions catalyzed by gold
complexes, such as A, with donating ligands that would en-
hance their carbene-like character. Thus, dienyne 18a,
which has two alkene groups in a 1,5-relationship to the
alkyne, reacted in the presence of catalyst A to give penta-
cyclic biscyclopropane derivative 19a in 76% yield
(Scheme 5). The relative configuration of 19a was assigned
by NOE experiments.
Scheme 3. Gold(I)-catalyzed cyclization of eynes 14a–c and X-ray crystal
structure of 15b. Ellipsoids are drawn at the 50% probability level.[20]
Interestingly, in this case, the formation of 19a from 18a
could occur by two parallel pathways via intermediates 20a
and/or 20b, which would converge to form the same biscy-
clopropane derivative. Both intermediates are likely to be
formed in this transformation, since a similar gold(I)-cata-
lyzed reaction carried out in MeOH led to a 1:1.4 mixture
of adducts 21a and 21b. In the presence of catalyst C, the
methoxycyclization reaction gave a 1:5 mixture of 21a and
21b.
The reaction of enyne 14b was also carried out with catalyst
D to give 15b in 78% yield after 12 h at room temperature.
The structure of tricyclic compound 15b was confirmed by
single-crystal X-ray diffraction (Scheme 3).[20]
Benzyl-substituted 1,5-enynes 9j–n led to compounds 16
(Table 2) through intramolecular cycloaddition reactions
reminiscent to those of aryl-substituted 1,6-enynes.[21] In all
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Gold(I)-Catalyzed Cyclizations of 1,5-Enynes
FULL PAPER
Enyne 18b was also cyclized in the presence of catalyst A
to form biscyclopropane 19b. In contrast, enyne 20c gave
complex mixtures in the presence of catalyst A, whereas tet-
racyclic compound 22 (3:1 mixture of diastereomers) was
obtained in 86% yield using catalyst C, presumably via in-
termediate 23 (Scheme 6).
Scheme 6. Gold(I)-catalyzed cyclization of dienynes 18b and 18c.
The cyclopropanation of 1,5-dien-10-ynes proceeds
through transition states, such as 24 (Scheme 7), in which
the two carbon–carbon bonds are similarly formed (2.23 and
Scheme 4. Gold(I)-catalyzed cyclization of eyne 9o to give 16 f, which is
related to (+)-pycnanthuquinone C. Ellipsoids are drawn at the 50%
probability level.[22]
Scheme 7. Transition states 24 and 25 for the intra- and intermolecular
cyclization of 1,6-enynes with alkenes.
2.10 ꢀ).[27] We found that intermolecular cyclopropanation
can occur both in a concerted or in a stepwise fashion, de-
pending on the substituents present on the alkene. Thus,
whereas the reaction with ethylene and propene via transi-
tion states of type 25 (Scheme 7) is concerted (bond distan-
ces 2.1–2.5 ꢀ), cyclopropanation with more-polarized sty-
rene is stepwise.[18] However, in the latter case, formation of
À
the second C C bond required a very low barrier. As a con-
sequence, although formally stepwise, the cyclopropanation
of styrene is also stereospecific.
We studied the intramolecular cyclopropanation of inter-
mediates 26a,b theoretically to form tetracyclic products
27a,b with PMe3 and NHC (N,N’-dimethylimidazolydene) li-
gands as models, and for the intramolecular cyclopropana-
tions of 1,5-enynes (Figure 2). Cyclopropanation was found
to be concerted in both cases with activation energies of 17–
Scheme 5. Gold(I)-catalyzed cyclization of dienyne 18a to give 19a.
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A. M. Echavarren et al.
transition states TS26a-27a and TS26b-27b and, finally, LAu+
moves to C1 to form corner-metalated cyclopropanes 27a,b
À
(Au C distance 2.32–2.36 ꢀ) (Scheme 8).
Scheme 8. Mechanism for the conversion of 26a,b into 27a,b via transi-
tion state TS26a,b
.
As shown before in a more simple system,[16] the Au C
carbene bond (2.03 ꢀ) in intermediate 26b is shorter than
that between Au and the NHC ligand (2.08 ꢀ). Additionally,
À
À
although one of the cyclopropane C C bonds in intermedi-
ates 26a and 26b is longer than the other two (1.69–1.70 ꢀ
vs. 1.46–1.59 ꢀ), the internal angle (67.758 for 26a, 67.118
for 26b) is far more acute that the tetrahedral angle expect-
ed for an open carbocation.
Conclusion
Gold complexes with highly electron-donating N-heterocy-
clic ligands enhanced the carbene-like character of the inter-
mediates in cyclizations of 1,5-enynes in the same manner as
that observed before for 1,6-enynes.[13,15,18] These reactions
lead to products with a bicycloACTHNUTRGNEUGN[3.1.0]hexene skeleton that
retains the cyclopropane ring of the initial intermediate.
These intermediates can be opened by aryl groups in sub-
strates 9j–o in a process that is mechanistic and synthetically
similar to the formal [4+2] cycloaddition of dienynes 28 to
form tricyclic derivatives 29 (Scheme 9).[21]
The intermediate cyclopropyl endo-gold carbenes can be
trapped to form biscyclopropane derivatives, which is in
agreement with cyclopropanations observed in gold(I)-cata-
lyzed cyclization of vinyl allenes, which proceed through
similar intermediates.[29] According to DFT calculation, this
intramolecular cyclopropanation from 1,5-enynes proceeds
by a concerted process similar to that found before for the
Figure 2. Top: Reaction coordinate (DFT, B3LYP, 6-31G(d) (C, P, H),
and SDD (Au) in CH2Cl2) for the intramolecular cyclopropanation of
26a to form corner-metalated 27a. Bottom: Reaction coordinate (DFT,
B3LYP, 6-31G(d) (C, N, H), and SDD (Au) in CH2Cl2) for the intramo-
lecular cyclopropanation of 26b to form corner-metalated 27b. Free ener-
gies in kcalmolÀ1 (ZPE-corrected potential energies are in parentheses).
18 kcalmolÀ1 (free energy in CH2Cl2), which were about
twice as high as that found for the intermolecular cyclopro-
panation of a model 1,6-enyne with propene.[18] Transition
À
states TS26a-27a and TS26b-27b are asynchronous and the C C
bond between the carbene carbon and C1 is more advanced
(2.07–2.10 ꢀ) than that of C2 (2.32–2.34 ꢀ). The reaction
proceeds very similarly with [AuACTHNUTRGENNUG CAHTUNGTRENNUGN
(PMe3)]+ and [Au(NHC)]+,
although the activation energy is higher for 26b, as expected
for an intermediate in which the electrophilicity of the car-
bene is reduced by the more donating NHC ligand. Transi-
tion states leading to anti-biscyclopropane derivatives were
not found.
À
As the cyclopropanation progresses, the C Au bond elon-
gates from 2.03–2.05 ꢀ in carbenes 26a,b to 2.11–2.12 ꢀ in
Scheme 9. Comparison between the intramolecular arylation of 1,5-
enynes (9) with that of 1,6-enynes (28).
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Gold(I)-Catalyzed Cyclizations of 1,5-Enynes
FULL PAPER
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Experimental Section
General procedure for the cyclization of 1,5-enynes: The starting enyne
was dried before being used in the reaction by repeated evaporation of a
solution of the compound in toluene (10 mgmLÀ1, 3ꢇ) under vacuum. A
solution of the 1,5-enynes in CH2Cl2 (0.5–1 mL) was added to a solution
of gold(I) complexes A–C (5 mol%) in CH2Cl2 (0.5 mL) and stirred at
room temperature until full conversion (as determined by TLC). The
crude reaction mixture was filtered through Celite and the solvent was
evaporated under reduced pressure. The residue was purified by column
chromatography on silica gel to provide the cyclized products.
Computational details: Calculations were performed with the Gaussi-
an 09 series of programs.[30] The geometries of all complexes were opti-
mized at the DFT level using the B3LYP functional.[31] The LANL2DZ
basis set, which included the relativistic effective core potential (ECP) of
Hay and Wadt and employed a split-valence (double-z) basis set, was
used for Au.[31]
[11] The 5-exo-dig process has been observed in a few examples of
gold(I)-catalyzed cyclization of 1-alkynyl-2-alkenylbenzenes, see: T.
Shibata, Y. Ueno, K. Kanda, Synlett 2006, 0411–0414.
Acknowledgements
[12] For a theoretical study of AuI-catalyzed cycloisomerizations of cy-
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We thank the MICINN (CTQ2010-16088/BQU, Consolider Ingenio 2010
grant CSD2006-0003), the MEC (FPU predoctoral fellowships to V.L.-C.
and N.H.), the AGAUR (2009 SGR 47), and the ICIQ Foundation for
support. We also thank Dr. M. Besora for her helpful advice with the
computations.
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