Gold-catalyzed endo-cyclizations of 1,4-diynes to seven-membered ring heterocycles

Article abstract of DOI:10.1002/chem.200901702

"Chemical Equation Presented" endo-Ruie for gold: A highly endoselective gold-catalyzed cycloisomerization of 1,4-diynes was developed. By employing electron-rich phosphines and N-heterocyclic carbenes as ligands, a number of 1,4-diynes could be cyclized

Full text of DOI:10.1002/chem.200901702

COMMUNICATION
DOI: 10.1002/chem.200901702
Gold-Catalyzed endo-Cyclizations of 1,4-Diynes to Seven-Membered Ring
Heterocycles
Kristina Wilckens, Marcus Uhlemann, and Constantin Czekelius*[a]
Dedicated to Professor Hans-Ulrich Reißig on the occasion of his 60th birthday
In the context of complex natural product synthesis, the
preparation of saturated heterocyclic structures is of particu-
lar importance given the plethora of substances incorporat-
ing such structural motives. A significant amount of methods
Scheme 1. Cyclization of 1,4-diynes.
for the efficient preparation of five- and six-membered rings
are known and widely applied. In comparison, the selective
synthesis of seven-membered-ring heterocycles has evolved
a smaller array of methods for their preparation, despite the
fact that a number of biologically active targets incorporate
such scaffolds. Polyether marine natural products like breve-
toxin B[1] or maitotoxin,[2] and alkaloids like strychnine[3]
may serve as examples for which total syntheses and studies
towards are, without question, true landmarks in chemical
science.
sis of common-sized rings. In addition, such a cyclization
would lead to a desymmetrization of the molecule in the
case of three different substituents at the 3-position
(Scheme 1). Subsequent transformations are assumed to
occur in good diastereoselectivity given the small size of the
alkyne functional group.
We initiated our study with diynol 1 as starting material,
which is readily available. It should be noted that the cycli-
zation of related compounds has been reported by Schlosser
and co-workers.[9] Here, ring closure occurred under quite
harsh conditions (stoichiometric amounts of KOtBu at 858C
for 12 h). Furthermore, mixtures of exo- and endo-isomers
were obtained that required separation by preparative GC
methods in the majority of cases. For the cyclization of
diynol 1 we investigated gold and palladium catalysts
(Table 1). Palladium complexes[10] and gold chloro com-
plexes were not successful in this respect (entries 1–3).
When a cationic gold complex was prepared from [AuCl-
In recent years, gold-catalyzed processes have evolved as
very efficient methods for the functionalization of alkenes,
allenes, and alkynes.[4] Upon activation by the carbophilic
À
gold complex the C C multiple bonds can be attacked by
various O-,[5] N-,[6], or C-nucleophiles.[7] In most cases, reac-
tion occurs under very mild conditions and with high func-
tional-group tolerance. Although a wide range of compound
classes are accessible today by using gold catalysis, the cor-
responding enantioselective processes, in particular involv-
ing alkynes, remain limited in number.[8]
In this publication we would like to report our investiga-
tions in the context of gold-catalyzed intramolecular func-
tionalization of 3,3-disubstituted 1,4-diynes (Scheme 1). This
study was fueled by our interest in a synthetic method pre-
ferring endo- over exo-cyclization reactions, since the latter
are predominant in gold-catalyzed processes for the synthe-
ACHTUNGTRENN(NUG PPh3)] and AgSbF6 and submitted to the cyclization reac-
tion the desired endo-enol ether product could be isolated
in small amounts, but the reaction was rather sluggish. Since
the low yield could potentially stem from inefficient proto-
demetalation, protic additives were examined (entries 5–9).
It is worth noting that the addition of alcohols, in particular
2-propanol, resulted in a cleaner conversion and higher iso-
lated yield (53%). This finding is in agreement with results
reported recently by Kirsch and co-workers.[11] More acidic
alcohols like CF3CH2OH or 2,6-di-tert-butylphenol inhibited
the reaction completely. Also addition of a base (i.e., 2,6-di-
tert-butylpyridine, entry 10) resulted in no conversion, sup-
porting the assumption that protodemetalation may be an
essential step for efficient turnover and preventing gold
[a] Dipl.-Chem. K. Wilckens, M. Uhlemann, Dr. C. Czekelius
Institut fꢀr Chemie und Biochemie, Freie Universitꢁt Berlin
14195 Berlin (Germany)
Fax : +49 (30)838 53625
E-mail: cczekeli@chemie.fu-berlin.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200901702.
Chem. Eur. J. 2009, 15, 13323 – 13326
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
13323

Table 1. Catalysts for the cyclization of diynols.
mechanism is supported by the
fact that electron-withdrawing
substituents as well as substitu-
ents in ortho-position (en-
tries 7–11) give only small
quantities of the rearranged
product. In the latter case, co-
planarity of the aromatic ring
with the benzylic sp2-center
would lead to significant A1,3-
Catalyst
AuCl3
Cat. loading
AHCTUNGTRENGN[UN mol%]
Additive
Solvent
Yield
[%]
1
2
3
20
20
20
5
–
–
–
–
MeOH
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
0
0
0
12
16
53
20
0
A
U
A
U
4
A
U
5
N
N
5
H2O (5 equiv)
strain.
Phenyl-substituted
6
N
N
5
iPrOH (5 equiv)
tBuOH (5 equiv)
CF3CH2OH (5 equiv)
2,6-di-tBu-phenol (1 equiv)
2,6-di-tBu-pyridine (0.5 equiv)
–
alkyne 24 (entry 12) gives pre-
dominantly the corresponding
rearranged 1,3-enyne product
25, forming an extended conju-
gated system. Since gold acety-
lide species may play a role in
7
N
N
5
8
N
N
5
9
N
N
5
0
0
53
10
11
U
N
5
5
vinyl species from undergoing deleterious side reactions.
Along these lines we also investigated gold complexes that
incorporate more electron-rich phosphine ligands and found
[AuClACHTUNGTRENNUNG(PCy3)]/AgBF4 to be equally effective even in the ab-
sence of alcohols (entry 11).
Optimization studies revealed that reactions in toluene
proceeded best among the solvents tested (MeOH, CH3CN,
THF, CH2Cl2, PhCH3). Furthermore, screening of different
silver salts (AgOTf, AgBF4, AgSbF6, AgO2CPh) showed
AgBF4 to be superior. At this point it should be noted that
appropriate control experiments were done to ensure that
neither [AuClACHTUNGTRENNUNG(PCy3)], AgBF4, nor simple Brønsted-acids
like p-TsOH alone would catalyze the reaction. It is worth
noting that AgBF4 did not catalyze the cyclization itself, but
had a detrimental effect on the enol ether product when
present for an extended period of time. Therefore, the gold
chloro complex was used in a small excess in the reaction.
At this point the substrate scope of the reaction was in-
vestigated (Table 2). By employing a catalyst prepared in
Scheme 2. Mechanistic proposal for the rearrangement of oxodiynols.
situ from [AuClACHTUNGTRENNUNG(PCy3)] (5 mol%) and AgBF4 (3 mol%),
substituted diynols were cyclized effectively.[12] For all sub-
strates investigated the exclusive formation of the corre-
sponding endo-enol ether was observed. This selectivity is
not limited to diynols, since also an alkynol related to 5
bearing an alkyne and an ethyl group instead of two alkyne
groups undergoes endo-cyclization selectively in limited
yield (10%, see Supporting Information).[13] Diynol sub-
strates with terminal alkyne groups and branched as well as
unbranched alkyl substituents are converted to the corre-
sponding endo-enol ethers (entries 1–5). In the case of an
unsubstituted phenyl group (11, entry 6) the desired product
12 was isolated in only 17% yield, together with acetal 13
(41% yield) formed by rearrangement. A mechanistic pro-
posal for this rearrangement is provided in Scheme 2.
an alternative pathway, compound 18 deuterated only at
ꢀ À
both alkyne moieties (C C D) was cyclized. Deuterium
was found exclusively at the 1-position of enol ether 19. In
contrast, cyclization of 18 deuterated only at the hydroxy
group (OD) provided the enol ether with D incorporation
solely at the 2-position. These results suggest that gold ace-
tylides are presumably not involved in the main pathway of
the reaction.
To expand the scope of the reaction further, gold-cata-
lyzed cyclizations of diynamides to the corresponding tetra-
hydrooxazepines were investigated (Table 3).[15] It was found
that cyclization of diyne sulfonamides occurred readily,
while carboxamides (i.e. benzamides and trifluoroacet-
If C(3)-O-bond cleavage is facilitated by the phenyl
group, the five-membered ring acetal is obtained through
either alkoxy allene B or oxonium intermediate C.[14] When
product 12 was isolated and resubmitted to the reaction con-
ditions no isomerization to 13 was detected. The proposed
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
13324
www.chemeurj.org
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 13323 – 13326

Gold Catalysis
COMMUNICATION
Table 2. Cyclization of diynols to dioxepine derivatives.[a]
Table 3. Cyclization of diynamides to tetrahydrooxazepine derivatives.[a]
Substrate
Product
t
Yield
[h] [%]
Substrate
Product
t
Yield
[%]
[h]
ACHTUNGTRENNUNG
(rsm)[c]
1
2
3
4
1
5
53
75
1
2
1
2
1.25
1.25
1.25
1.25
35 (55)
36 (29)
9 (81)
26
27
3
5
7
4
6
8
2.5 55
0.5 46
28
30
29
31
3[b]
4[b]
20 (60)
5
6
3
1
31
32
33
9
10
12
[a] Reactions were performed in toluene (0.1m) employing 10 mol%
[AuCl(PCy3)] and 10 mol% AgBF4. [b] Mes=2,4,6-trimethylphenyl.
[c] rsm=Yield of recovered starting material.
AHCTUNGTRENNUNG
17 (12)
41 (13)
11
13[b]
7
8
2.5 37
14
16
18
20
22
15
17
19
21
23
1
2
3
6
68
65
50
30
9
[AuClACHTNUGRTNEUNG
(NHCH)] incorporating a carbene ligand reported by
Herrmann and co-workers[16] performed well in the cycliza-
tion reaction leading to full conversion of diyne-sulfonamide
26 (Scheme 3).
10
11
Studies towards the enantioselective desymmetrization of
diynamides[6f,g,8] employing chiral gold complexes showed
that the use of optically pure NHCH ligand resulted in low
enantioselectivity (17% ee, Scheme 3).[17] It was demonstrat-
12
1
88
24
25
[a] Reactions were performed in toluene (0.1m) employing 5 mol%
[AuCl(PCy3)] and 3 mol% AgBF4. [b] The corresponding Z isomer was
formed in small quantities (<10%), but could not be isolated in pure
ACHTUNGTRENNUNG
Scheme 3. Synthesis of enantiomerically enriched oxazepine derivatives.
form.
Chem. Eur. J. 2009, 15, 13323 – 13326
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
13325

C. Czekelius et al.
S. D. Lee, R. A. Widenhoefer, J. Am. Chem. Soc. 2009, 131, 5372–
5373.
ed however that
[(AuCl)2MeOBIPHEP] and AgBF4
a
gold catalyst prepared from
[6d,f,18]
provided the corre-
[7] For selected examples, see: a) M. J. Johansson, D. J. Gorin, S. T.
Staben, F. D. Toste, J. Am. Chem. Soc. 2005, 127, 18002–18003; b) S.
Lꢃpez, E. Herrero-Gꢃmez, P. Pꢄrez-Galꢅn, C. Nieto-Oberhuber,
A. M. Echavarren, Angew. Chem. 2006, 118, 6175–6178; Angew.
Chem. Int. Ed. 2006, 45, 6029–6032; c) M. A. Tarselli, A. R. Chia-
nese, S. J. Lee, M. R. Gagnꢄ, Angew. Chem. 2007, 119, 6790–6793;
Angew. Chem. Int. Ed. 2007, 46, 6670–6673; d) M. R. Luzung, P.
Mauleꢃn, D. F. Toste, J. Am. Chem. Soc. 2007, 129, 12402–12403;
e) A. S. K. Hashmi, L. Schwarz, J.-H. Choi, T. M. Frost, Angew.
Chem. 2000, 112, 2382–2385; Angew. Chem. Int. Ed. 2000, 39, 2285–
2288; f) C. Ferrer, A. M. Echavarren, Angew. Chem. 2006, 118,
1123–1127; Angew. Chem. Int. Ed. 2006, 45, 1105–1109; g) N.
Marion, S. Dꢆez-Gonzꢅlez, P. de Frꢄmont, A. R. Noble, S. P. Nolan,
Angew. Chem. 2006, 118, 3729–3732; Angew. Chem. Int. Ed. 2006,
45, 3647–3650; h) A. S. K. Hashmi, S. Schꢁfer, M. Wçlfle, C. D. Gil,
P. Fischer, A. Laguna, M. C. Blanco, M. C. Gimeno, Angew. Chem.
2007, 119, 6297–6300; Angew. Chem. Int. Ed. 2007, 46, 6184–6187.
[8] For a recent review, see: R. A. Widenhoefer, Chem. Eur. J. 2008, 14,
5382–5391.
sponding product with 60% ee, albeit in lower yield due to
limited catalyst lifetime. Studies addressing the synthesis of
sterically more encumbered, chiral NHC ligands and their
application in enantioselective gold-catalyzed reactions are
currently under investigation.
In summary, a gold-catalyzed cyclization of 1,4-diynes has
been developed by employing cationic gold complexes. The
cyclization occurs exclusively in an endo-fashion under mild
conditions and provides access to dihydrodioxepines and tet-
rahydrooxazepines. Cyclizations of diynamides with sulfona-
mide protecting groups and optically active gold complexes
allowed the preparation of enantiomerically enriched N-pro-
tected tetrahydrooxazepines.
Acknowledgements
[9] H.-x. Wei, M. Schlosser, Chem. Eur. J. 1998, 4, 1738–1743.
[10] PdCl2, [PdCl
were tested.
2CAHTUNTGERNNGU(PPh3)2], PdCl2/AgBF4, and [PdCl2AHCTUNGTREN(NUGN PPh3)2]/AgBF4
This work was generously supported by the Fonds der Chemischen Indus-
trie e.V. by a Liebig fellowship and by the DFG in the context of the
Emmy-Noether program (CZ 183/1-1).
[11] a) S. F. Kirsch, J. T. Binder, B. Crone, A. Duschek, T. T. Haug, C.
Liꢄbert, H. Menz, Angew. Chem. 2007, 119, 2360–2363; Angew.
Chem. Int. Ed. 2007, 46, 2310–2313; b) H. Menz, J. T. Binder, B.
Crone, A. Duschek, T. T. Haug, S. F. Kirsch, P. Klahn, C. Liꢄbert,
Tetrahedron 2009, 65, 1880–1888.
[12] Apart from the enol ether, other products could not be identified.
The enol ether was shown to be stable towards work-up and purifi-
cation conditions.
Keywords: alkynes · asymmetric catalysis · gold · nitrogen
heterocycles · oxygen heterocycles
[13] The low yield is presumably due to the potential of the starting ma-
terial to form a carbocation under the reaction conditions, since a
byproduct was isolated (8%) which could be explained by such an
intermediate.
[1] a) K. C. Nicolaou, Angew. Chem. 1996, 108, 644–664; Angew. Chem.
Int. Ed. Engl. 1996, 35, 588–607.
[2] a) T. Nonomura, M. Sasaki, N. Matsumori, M. Murata, K. Tachiba-
na, T. Yasumoto, A. DeMattei, J.-P. Wu, J. J.-W. Duan, L. R. Cook,
H. Oinuma, Y. Kishi, J. Am. Chem. Soc. 1996, 118, 7946–7968.
[3] J. Bonjoch, D. Sol, Chem. Rev. 2000, 100, 3455–3482.
[4] a) A. Arcadi, Chem. Rev. 2008, 108, 3266–3325; b) Z. Li, C. Brouw-
er, C. He, Chem. Rev. 2008, 108, 3239–3265; c) A. S. K. Hashmi,
Chem. Rev. 2007, 107, 3180–3211; d) D. J. Gorin, B. D. Sherry, F. D.
Toste, Chem. Rev. 2008, 108, 3351–3378.
[5] For selected examples, see: a) Y. Fukuda, K. Utimoto, J. Org. Chem.
1991, 56, 3729–3731; b) S. Antoniotti, E. Genin, V. Michelet, J.-P.
GenÞt, J. Am. Chem. Soc. 2005, 127, 9976–9977; c) V. Belting, N.
Krause, Org. Lett. 2006, 8, 4489–4492; d) Z. Zhang, R. A. Widen-
hoefer, Angew. Chem. 2007, 119, 287–289; Angew. Chem. Int. Ed.
2007, 46, 283–285; e) R. Zriba, V. Gandon, C. Aubert, L. Fenster-
bank, M. Malacria, Chem. Eur. J. 2008, 14, 1482–1491; f) C.-Y.
Yang, G.-Y. Lin, H.-Y. Liao, S. Datta, R.-S. Liu, J. Org. Chem. 2008,
73, 4907–4914; g) G. L. Hamilton, E. J. Kang, M. Mba, F. D. Toste,
Science 2007, 317, 496–499.
[6] For selected examples, see: a) J. Zhang, C.-G. Yang, C. He, J. Am.
Chem. Soc. 2006, 128, 1798–1799; b) C. Brouwer, C. He, Angew.
Chem. 2006, 118, 1776–1779; Angew. Chem. Int. Ed. 2006, 45, 1744–
1747; c) N. Nishina, Y. Yamamoto, Angew. Chem. 2006, 118, 3392–
3395; Angew. Chem. Int. Ed. 2006, 45, 3314–3317; d) R. L. LaLonde,
B. D. Sherry, E. J. Kang, F. D. Toste, J. Am. Chem. Soc. 2007, 129,
2452–2453; e) I. Nakamura, U. Yamagishi, D. Song, S. Konta, Y. Ya-
mamoto, Angew. Chem. 2007, 119, 2334–2337; Angew. Chem. Int.
Ed. 2007, 46, 2284–2287; f) Z. Zhang, C. F. Bender, R. A. Widen-
hoefer, J. Am. Chem. Soc. 2007, 129, 14148–14149; g) Z. Zhang,
[14] a) N. Marion, P. Carlqvist, R. Gealageas, P. de Frꢄmont, F. Maseras,
S. P. Nolan, Chem. Eur. J. 2007, 13, 6437–6451; b) A. Correa, N.
Marion, L. Fensterbank, M. Malacria, S. P. Nolan, L. Cavallo,
Angew. Chem. 2008, 120, 730–733; Angew. Chem. Int. Ed. 2008, 47,
718–721; c) K. Kato, R. Teraguchi, T. Kusakabe, S. Motodate, S. Ya-
mamura, T. Mochida, S. Yamamura, T. Mochida, H. Akita, Synlett
2007, 0063–0066; d) C. H. Oh, S. Karmakar, J. Org. Chem. 2009, 74,
370–374.
[15] For an example of silver-catalyzed hydroamination of aminodiynes,
see: J. M. Carney, P. J. Donoghue, W. M. Wuest, O. Wiest, P. Hel-
quist, Org. Lett. 2008, 10, 3903–3906.
[16] D. Baskakov, W. A. Herrmann, E. Herdtweck, S. D. Hoffmann, Or-
ganometallics 2007, 26, 626–632.
[17] Desymmetrization of diynol 5 using optically pure NHCH–gold cata-
lyst provided the product in <5% ee.
[18] The catalyst was prepared using 10 mol% [(AuCl)2MeOBIPHEP]
and 10 mol% AgBF4.
Received: June 20, 2009
Published online: November 6, 2009
13326
www.chemeurj.org
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 13323 – 13326