Gold-catalyzed tandem cyclizations of 1,6-diynes triggered by internal N- and O-nucleophiles

Article abstract of DOI:10.1021/jo100712d

(Figure presented) Investigations on gold-catalyzed tandem cyclization reactions of 1,6-diynes, tethered to nucleophilic functionalities such as amine, carboxylic acid, amide, and sulfonamide, are reported. The ability of such substrates to undergo tandem

Full text of DOI:10.1021/jo100712d

pubs.acs.org/joc
Gold-Catalyzed Tandem Cyclizations of 1,6-Diynes Triggered by Internal
N- and O-Nucleophiles
Christian A. Sperger and Anne Fiksdahl*
Department of Chemistry, Norwegian University of Science and Technology, 7491 Trondheim, Norway
anne.fiksdahl@chem.ntnu.no
Received April 16, 2010
Investigations on gold-catalyzed tandem cyclization reactions of 1,6-diynes, tethered to nucleophilic
functionalities such as amine, carboxylic acid, amide, and sulfonamide, are reported. The ability of
such substrates to undergo tandem cyclization, triggered by internal nucleophiles, has been
examined. Depending on the substrate, the catalytic system, and reaction conditions, different
regioisomers of monocyclic and bridged bicyclic products were obtained.
SCHEME 1. Cyclization Reaction of Diynes in Methanol
Introduction
Gold-catalyzed cyclization reactions involving alkynes
have emerged as an important and powerful tool for the
formation of carbo- and heterocyclic compounds.1 The
strong alkynophilic character of cationic gold complexes
allows these Lewis acids to selectively activate π-systems
toward nucleophilic attack. Thus, a number of different
intramolecular Au(I)- and Au(III)-catalyzed cyclizations of
alkynes bearing proximate C, O, and N nucleophiles have
provided a range of functionalized carbo- or heterocycles.
For instance, gold-catalyzed cycloisomerizations of 1,6-
enynes have been intensively investigated.2 Interesting
gold-catalyzed cyclization reactions involving indoles have
recently been reported.3 Cyclization reactions involving
heteroatoms have been developed for alkynyl sulfoxides,4
in situ generated enamine alkynes,5 acetylenic acids for the
formation of γ-lactones,6 for N-Boc-protected alkynylamines,7
N -propargylamides,8 for gem-difluorohomopropargylamines
to prepare 3-fluoropyrroles9 or for the formation of tetracyclic
indolines.10 In all of these intramolecular cyclization reactions,
the original triple bond is transformed into a double bond after
nucleophilic attack.
Our group has recently developed different Au(I)-cata-
lyzed cyclization reactions of symmetrically and unsymme-
trically substituted 1,6-diynes 1, triggered by an initial attack
of methanol (Scheme 1).11 We proposed the formation of an
intermediate alkylenol ether 2, acting as the nucleophile in
(1) (a) Skouta, R.; Li, C. J. Tetrahedron 2008, 64, 4917. (b) Shen, H. C.
Tetrahedron 2008, 64, 7847. (c) Stephen, A.; Hashmi, K. Chem. Rev. 2007,
107, 3180. (d) Arcadi, A. Chem. Rev. 2008, 108, 3266. (e) Sohel, S. M. A.; Liu,
R. S. Chem. Soc. Rev. 2009, 38, 2269. (f) Fuerstner, A. Chem. Soc. Rev. 2009,
38, 3208.
~
ꢀ
ꢀ
ꢀ~
(2) (a) Nieto-Oberhuber, C.; Munoz, M. P.; Lopez, S.; Jimenez-Nunez,
E.; Nevado, C.; Herrero-Gomez, E.; Raducan, M.; Echavarren, A. M.
ꢀ
Chem.;Eur. J. 2006, 12, 1677. (b) Zhang, L.; Sun, J.; Kozmin, S. A. Adv.
Synth. Catal. 2006, 348, 2271.
(3) (a) Zhang, L. J. Am. Chem. Soc. 2005, 127, 16804. (b) Ferrer, C.;
Amijs, C. H. M.; Echavarren, A. M. Chem.;Eur. J. 2007, 13, 1358.
4542 J. Org. Chem. 2010, 75, 4542–4553
Published on Web 05/28/2010
DOI: 10.1021/jo100712d
r
2010 American Chemical Society

Sperger and Fiksdahl
JOCArticle
SCHEME 2. Envisaged Tandem Cyclization Reactions
SCHEME 3. Preparation of Amine 9a
the final cyclization step. The cyclization proceeded regio-
and stereoselectively in a 5-exo-dig manner and provided
different Z-cyclopentylidene derivatives 3.
In the present investigation, we wanted to replace the
external methanol nucleophile with internal O- and N-
nucleophilic groups in order to trigger and enable tandem
cyclization reactions (Scheme 2). In the initial reaction step
the nucleophile could attack the activated alkyne moiety in
an exo- (a) or an endo-dig manner (b) to provide two possible
enyne intermediates 5 or 6. Depending on whether N- or
O-nucleophiles are involved, enamines, imines, enamides, or
vinyl esters are formed in the first cyclization step. These
alkene moieties, attached to a heteroatom, may then attack
the remaining, gold-activated triple bond, to give exo- (c) or
endo-dig cyclizations (d) to provide different bridged tandem
reaction products.
aConditions: (a) 1-bromo-2-butyne (2.2 equiv), NaH (2.2 equiv),
THF, 17 h, 50 °C, 79%. (b) LiAlH4 (2.0 equiv), Et2O, 1 h, 0 °C and
4.5 h, rt, 86%.
SCHEME 4. Preparation of Bispropargylic Carboxylic Acid 11
and Amides 12 and 14a
We now report the results of a series of gold-catalyzed
tandem cyclization reactions of various 1,6-diyne deriva-
tives, connected to different internal nitrogen or oxygen
nucleophilic groups. The aim of the investigation has been
to identify the ability of such substrates to undergo tandem
cyclization, triggered by internal nucleophiles. To study the
regioselectivity arising from different cyclization processes,
the effect of reaction conditions, including both gold-phos-
phine and gold-NHC catalysts and, in particular, the role of
the counterion, provided by anion exchange with the appro-
priate silver salt additives, have been examined.
aConditions: (a) KOH (1.1 equiv), MeOH, 48 h, rt, 80%. (b) C2O2Cl2
(1.25 equiv), cat. DMF, DCM, 1 h rt. (c) EtNH2 HCl (1.25 equiv), NEt3
(2.5 equiv), DMAP (0.05 equiv), DCM, 17 h, rt, 80%. (d) 1-Bromo-2-
butyne (2.2 equiv), NaH (2.2 equiv), THF, 23 h, rt, 83%.
3
Results and Discussion
pared in a two-step procedure from benzyl cyanide (7) by bis-
alkylation and subsequent nitrile reduction (Scheme 3).
The bispropargylic carboxylic acid 11 was obtained by
monosaponification of diethylmalonate derivative 10 in
basic methanolic medium in 80% yield.12 Treatment of car-
boxylic acid 11 with oxalylchloride provided the acyl chlor-
ide, which was subsequently transformed into the secondary
ethylamide 12 in 80% yield. Bis-alkylation of the monoamide
malonate 13 provided diyne 14 in 83% yield (Scheme 4).
Tosylamide 15 was synthesized from amine 9 and TsCl in
74% yield. Tosylation of benzylamine 16 afforded sulfon-
amide 17, which was further subjected to a standard Sono-
gashira reaction with the appropriate 1,6-diyne 1810 to give
diyne 19 in 50% yield (Scheme 5).
Preparation of Starting Materials. To investigate the en-
visaged tandem cyclization reactions, we synthesized a num-
ber of 1,6-diyne derivatives that included nucleophilic
groups, such as amine 9, carboxylic acid 11, amides 12, 14,
and 22, and sulfonamides 15 and 19. The amine 9 was pre-
(4) Shapiro, N. D.; Toste, F. D. J. Am. Chem. Soc. 2007, 129, 4160.
(5) Binder, J. T.; Crone, B.; Haug, T. T.; Menz, H.; Kirsch, S. F. Org. Lett.
2008, 10, 1025.
^
(6) (a) Genin, E.; Toullec, P. Y.; Antoniotti, S.; Brancour, C.; Genet, J. P.;
Michelet, V. J. Am. Chem. Soc. 2006, 128, 3112. (b) Harkat, H.; Dembele,
ꢀ
A. Y.; Weibel, J. M.; Blanc, A.; Pale, P. Tetrahedron 2009, 65, 1871. (c) Harkat,
H.; Weibel, J. M.; Pale, P. Tetrahedron Lett. 2006, 47, 6273.
(7) Robles-Machim, R.; Adrio, J.; Carretero, J. C. J. Org. Chem. 2006, 71,
5023.
(8) (a) Verniest, G.; England, D.; De Kimpe, N.; Padwa, A. Tetrahedron
2010, 66, 1496. (b) Verniest, G.; Padwa, A. Org. Lett. 2008, 10, 4379.
(9) Surmont, R.; Verniest, G.; De Kimpe, N. Org. Lett. 2009, 11, 2920.
(10) Liu, Y.; Xu, W.; Wang, X. Org. Lett. 2010, 12, 1448.
(11) Sperger, C.; Fiksdahl, A. Org. Lett. 2009, 11, 2449.
(12) Genin, E.; Toullec, P. Y.; Marie, P.; Antoniotti, S.; Brancour, C.;
^
Genet, J. P.; Michelet, V. ARKIVOK 2007, 5, 67.
J. Org. Chem. Vol. 75, No. 13, 2010 4543

Sperger and Fiksdahl
JOCArticle
SCHEME 5. Preparation of Sulfonamides 15 and 19a
aConditions: (a) TsCl (1.15 equiv), NEt3 (1.5 equiv), DCM, 4 h, rt, 74%. (b) TsCl (1.1 equiv), NEt3 (3.0 equiv), DCM, 19 h, rt, 95%. (c) 1,6-Diyne 18
(1.2 equiv), Pd(PPh3)2Cl2 (0.05 equiv), CuI (0.1 equiv), PPh3 (0.1 equiv), DMF/NEt3 = 1:1, 21 h, 80 °C, 81%.
SCHEME 7. Formation of pyrrolidines 25a and 25ba
Arylamide diyne 22 was prepared in two steps from
o-iodobenzoic acid (20). The iodoarylamide 21 was obtained
in 85% yield by reaction of the acid chloride with ethylamine.
Sonogashira cross-coupling of aryliodide 21 with 1,6-diyne
18 provided 1,6-diyne 22 in excellent yield (Scheme 6).
SCHEME 6. Preparation of Arylamide 22a
aConditions: (a) C2O2Cl2 (1.25 equiv), DCM, 4.5 h, rt. (b) EtNH2
HCl (1.5 equiv), NEt3 (3 equiv), DCM, 17 h, rt, 85%. (c) 1,6-Diyne 18
(1.2 equiv), Pd(PPh3)2Cl2 (0.05 equiv), CuI (0.1 equiv), PPh3 (0.1 equiv),
THF/NEt3 = 1:1, 19 h, rt, 98%.
3
aConditions: (a) AuCl(PEt3) (2.5 mol %), AgSbF6 (2.5 mol %),
Dioxane, 2.5 h, rt, 94%. (b) NaBH4 (1.5 equiv), EtOH, 1.5 h, 0 °C and
15 h, rt, 77%. (c) LiAlH4 (1.5 equiv), THF, 1 h, 0 °C and 1.5 h, rt, 95%.
Cyclization of 1,6-Diynes. In the following cyclization
TABLE 1. Cyclization Reactions of Secondary Amines 25a and 25ba
experiments gold-phosphine catalysts (A-C), the gold-
NHC complex (D), and AuCl3 were screened (Figure 1).
The gold complexes B-D were used in combination with a
silver additive to provide counterion exchange, while the
commercially available catalyst A and AuCl3 were used
directly. The applied reaction conditions are specified in
the respective tables (Tables 1-5). Most of the cyclization
reactions created one or two new asymmetric centers.
yield (%)
ratio
entry substrate catalyst additiveb time (h) (26/27)c 26
27
1
2
3
4
5
25a
25a
25a
25b
25b
AuCl(PEt3) AgSbF6
AuCl(PEt3) AgNTf2
Ad,e
AuCl(PEt3) AgSbF6
Ae
2.5
2.5
23
2.5
18
33/67
27/73
4/96
23
12
43
54
63
53/47f
16/84f
70g
d56h
aReactions were run at [25] = 500 mM in DCM at room temperature
with 2.5 mol % catalyst loading. The reaction mixture was directly used
for column chromatography. b2.5 mol %. cAccording to GC before
column chromatography. d5.0 mol %. eSee Figure 1. fAccording to 1H
NMR spectroscopy before column chromatography. gIsolated as a
mixture 26b/27b = 51:49. hIsolated as a mixture 26b/27b = 10:90.
FIGURE 1. Applied gold catalysts.
Cyclization of Amine 9. The AuCl(PEt3) and AgSbF6 cata-
lytic system was applied to the cyclization of primary amine 9
(Scheme 7). Within 2.5 h at room temperature, the starting
material 9 was fully consumed, and the pyrrolidine derivative 23
was isolated in 94% yield. No subsequent reaction took place
either with the intermediate enamine 23 or with the imine moiety
in the isolated product 24. An additional attempt to achieve
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JOCArticle
TABLE 2. Cyclization Reactions of Bispropargylic Carboxylic Acid 11a
yield (%)
entry
catalyst
additiveb
time (h)
ratio (28/29/30)c
28
29
30
1
2
3
4
5
6
7
8
AuCl(PEt3)
AuCl(PEt3)
AuCl(PEt3)
AuCl(PEt3)
AuCl(PEt3)
AuCl(PPh3)
AuCl(PPh3)
AuCl(IMes)e, f
AuCl(IMes)
AuCl(IMes)
AuCl(IMes)
AuCl(IMes)
Af
AgSbF6
AgNTf2
AgBF4
20
20
21
20
20
1
38/15/47
20/5/75
53/29/18
61/0/39
90/10/0
100/0/0
23/7/70
100/0/0
42/7/51
24/11/65
55/9/36
85/15/0
55/9/36
50/49/1
17
12
39
d
d
d
AgOTf
AgBPh4
K2CO3
AgNTf2
K2CO3
AgSbF6
AgNTf2
AgOTf
AgBPh4
82
d
20
1
81
9
22
20
20
18
22
2
22
14
25
33
10
11
12
13
14
15
d
83
d
g
AuCl3
21
20
h
AgNTf2
20
aReactions were run at [11] = 500 mM in DCM at room temperature with 2.5 mol % catalyst loading. The reaction mixture was directly used for
c
e
column chromatography. b2.5 mol %. According to GC before column chromatography. dNot isolated. IMes =1,3-dimesitylimidazol-2-ylidene.
fSee Figure 1. g5 mol %. hNo reaction.
cyclization of amine 9 with catalyst A, performed in toluene at
90 °C, only afforded a quantitative conversion to the imine 24.
As the aim was to involve both triple bonds in a tandem
cyclization, a reduction of the imine 24 to a secondary amine 25
would give a more flexible heterocyclic system that could allow a
reaction with the remaining triple bond. The reduction of imine
24 was performed with either NaBH4 to yield 77% of a mixture
of both diastereomers 25a and 25b (diastereomeric ratio=54:46
according to GC) or LiAlH4 to provide 95% of a mixture of 25a
and 25b (diastereomeric ratio = 48:52 according to GC).
Stereoselective reductions of 2,3-dialkyl-3-chloro-1-pyrrolines
with metal hydrides have been observed before.13 The diastereo-
mers 25a and 25b were separated by flash chromatography.
Gold-catalyzed cyclization of pyrrolidine 25a gave the
bridged products 26a and 27a by 5-exo-dig and 6-endo-dig
processes, respectively. By applying AuCl(PEt3) as the gold
catalyst precursor and either AgSbF6 or AgNTf2, an ap-
proximately 1:2 mixture of the bicyclic products 26a and 27a
resulted, favoring the 6-endo-dig process (Table 1, entries
1 and 2). In contrast, when catalyst A was used, the azabi-
cyclo derivative 27a was almost exclusively formed, although
5 mol % catalyst loading and longer reaction times were
required (Table 1, entry 3).
(Table 1, entry 3) was observed. According to NOESY ex-
periments, all cyclization reactions selectively provided the
Z-isomers of 26a and 26b.
Cyclization of Bispropargylic Carboxylic Acid 11. Poten-
tial tandem cyclization reactions, triggered by a carboxylic
acid moiety, were also investigated (Table 2). When diyne 11
was treated with a number of different gold catalysts, three
main reaction products, 28, 29 and 30, were formed in
different ratios. Nucleophilic attack of the carboxylic acid
in a 5-exo-dig manner provided the five-membered lactone
derivative 28 selectively as the E-isomer. Once this dihydro-
furanone derivative 28 was formed, no subsequent cycliza-
tion took place. In contrast, when the tetrahydropyranone
29 was formed in the initial cyclization step, a second
reaction provided selectively the bridged product 30. The
alternative bridged bicyclic product, formed by a 5-exo-dig
cyclization, could not be detected. The lack of propensity of
28 to undergo a second cyclization might be explained by a
lower ring flexibility of the five-membered lactone 28 com-
pared with the corresponding six-membered compound 29,
preventing a nucleophilic attack of the 28 ethylidene moiety.
When the reaction was performed in the presence of either
AuCl(PEt3) or AuCl(IMes) and AgSbF6, all three main
cyclic products were detected, slightly favoring the 6-endo-
dig initial cyclization (Table 2, entries 1 and 9). By changing
Comparable results were obtained for the other diaster-
eomer 25b, and an almost 1:1 mixture of azabicyclo products
26b and 27b was formed in the presence of AuCl(PEt3) and
AgSbF6 (Table 1, entry 4). Correspondingly, the reaction
was shifted toward the 6-endo-dig cyclization when the gold
complex A was used (Table 1, entry 5). However, a slightly
reduced regioselectivity compared to the reaction of 25a
-
-
the counterion from SbF6 to NTf2 (bis(trifluoromethyl-
sulfonyl)imide), the first cyclization step shifted toward a
6-endo-dig process and thus to the formation of higher
amounts of tandem product 30 (Table 2, entries 2, 7, and
10). Alternative counterions, provided by AgBF4 or AgOTf
additives, afforded less effective catalytic systems for the
formation of the tandem product 30 (Table 2, entries 3, 4,
and 11). Catalyst A and AuCl3 slightly favored the formation
(13) Aelterman, W.; De Kimpe, N.; Tyvorskii, V.; Kulinkovich, O.
J. Org. Chem. 2001, 66, 53.
J. Org. Chem. Vol. 75, No. 13, 2010 4545

Sperger and Fiksdahl
JOCArticle
of the dihydrofuranone product 28 (Table 2, entries 13 and
14). An unexpected result was obtained by cyclization in the
presence of AgBPh4 and either AuCl(PEt3) or AuCl(IMes),
since the 5-exo-dig cyclization was strongly favored, as
shown by a ratio of approximately 9:1 (Table 2, entries 5
and 12).
The ability of AgNTf2 to catalyze one of the cyclization
reactions was tested, but no reaction took place under such
reaction conditions (Table 2, entry 15). According to the
cyclization attempts with gold-phosphine or gold-NHC
complexes (Table 2, entries 1-12), the regioselectivity of
the first cyclization step is mainly dependent on the counter-
-
-
The large, weakly nucleophilic BPh4 counterion shifted
ion. Thus, the weakly coordinating NTf2 anion showed a
high tendency to shift the initial cyclization reaction toward
the reaction toward the formation of the dihydrofuranone
derivative 28. Pale et al. reported a regioselective 5-exo-dig
cyclization of different 4-pentynoic acids in the presence of
catalytic amounts of AuCl and K2CO3.6b,c To investigate the
influence of K2CO3 on the regioselectivity, diyne 11 was tre-
ated with AuCl(PPh3) or AuCl(IMes) and K2CO3 (Table 2,
entries 6 and 8). It is conceivable that the carboxylate anion,
formed by carbonate deprotonation of the acidic moiety of
substrate 11, replaces the chlorine counterion of the gold
complex and thereby generates an active gold species.
As expected, the five-membered lactone 28 was obtained.
However, the selective formation of the E-isomer was a
surprising result as Pale et al. reported a 1:1 mixture of
Z- and E-stereoisomers when n-butyl substituted 4-penty-
noic acid was treated with AuCl in the presence of K2CO3,
although phenyl or bromine substituted derivatives provided
selectively the Z-isomers. The authors suggested the forma-
tion of two different intermediates Ia and Ib (Scheme 8).
Depending on the gold coordination site, the nucleophilic
addition of the carboxylate anion to intermediates Ia and Ib
proceeds in an anti or syn mode to provide the respective
vinylaurate intermediates IIa or IIb and, after protodeaura-
tion, the Z- and E-products, respectively.
the six-membered lactone 29 and further to the bridged
-
product 30. This trend decreased in the order NTf2
-
>
-
-
SbF6 > BF4 ≈ OTf- . BPh4 > COO- (from 11 and
K2CO3), thereby increasing the relative amount of product
28 formed by the 5-exo-dig process. Except for the BPh4
-
anion, these observations may be explained by increasing co-
ordination tendency of the counterions. It has been reported that
-
the BPh4 ion is prone to hydrolytic cleavage of one of the
boron-phenyl bonds and is relatively strongly coordinating.17
Cyclization of Bispropargylic Amides 12 and 14. Similar
tandem cyclization products were formed from propargylic
amides by intramolecular N-nucleophilic ring closure. The
diyne 12, bearing a secondary amido group, was treated with
a mixture of AuCl(PPh3) and AgSbF6 in refluxing DCM,
slow conversion having been observed at room temperature.
Upon full consumption of the starting material 12, three
products were identified, a pyrrolidone derivative 31 as the
single E-isomer and two major tandem cyclization products,
34 and 35 (Table 3, entry 1). The results show that no
subsequent cyclization of the five-membered lactam 31 took
place and are in accordance with the corresponding results
for the carboxylic acid 11 discussed above (Table 2). The tan-
dem cyclization products 34 and 35 would be formed from a
six-membered lactam 32 by a 5-exo-dig and a 6-endo-dig
cyclization, respectively. The putative lactam intermediate
32 was not observed. By changing the counterion from
SCHEME 8. Explanation for the Observed Regiochemistry
-
SbF6 to NTf2-, a comparable product ratio, but slightly
lower conversion, was observed (Table 3, entry 2). An en-
amide moiety is formed in the first cyclization step. Such
groups may possess latent nucleophilic character.
Only a few Pt(II)- and Ag(I)-catalyzed cycloisomeriza-
tions of enamides or enecarbamates, tethered to an electron-
deficient alkyne, are reported in the literature.18 It is
noteworthy that the presence of 5 mol % NEt3 in addition to
AuCl(PPh3) and different silver salts strongly favored the 5-exo-
dig monocyclization, providing lactam 31. Only traces of tandem
products 34 and 35 were detected (Table 3, entries 3-5). This
behavior might be explained by deprotonation of the secondary
amide moiety in 12, generating a more reactive nucleophile. In
contrast, applying 2.5 mol % of gold catalyst A and 2.5 mol %
NEt3, tandem cyclization was completely dominant. The starting
material 12 was fully consumed within 6 h, providing an
approximately 1:4 mixture of tandem products 34 and 35. In
contrast to the AuCl(PPh3)-catalyzed reactions (Table 3, entries
1 and 2), it is evident that catalyst A mainly activated 6-endo-dig
cyclizations (Table 3, entry 6).
Whereas the anti addition is also reported for gold-cata-
14
lyzed cyclization of N -propargylcarboxamides,
the syn
mode was calculated for gold-catalyzed addition of alcohols
to alkynes.15 The E-stereochemistry of 28 is based on
NOESY experiments as well as on chemical shift values of
similar compounds. 16 Only traces of the respective Z-isomer
28 were detected according to 1H NMR spectroscopy of the
crude reaction mixtures.
Thus, our gold-catalyzed reaction conditions afford
5-exo-dig cyclizations always with complete stereoselectivity
of the exocyclic double bond, as shown for E-isomers 28
(Table 2), 31 (Table 3), 38 (Scheme 9), and the previously
reported Z-products 311 (Scheme 1).
By replacing the secondary amide 12 by the primary amide
14 and performing the reaction in the presence of catalyst A,
one single tandem product 36 was isolated (Table 3, entry 7).
This bicyclic compound was formed by two subsequent
(14) Hashmi, A. S. K.; Weyrauch, J. P.; Frey, W.; Bats, J. W. Org. Lett.
2004, 6, 4391.
(15) Teles, J. H.; Brode, S.; Chababas, M. Angew. Chem., Int. Ed. 1998,
37, 1415.
(16) Chan, D. M. T.; Marder, T. B.; Milstein, D.; Taylor, N. J. J. Am.
Chem. Soc. 1987, 109, 6385.
(17) Krossing, I.; Raabe, I. Angew. Chem., Int. Ed. 2004, 43, 2066.
(18) (a) Harrison, T. J.; Dake, G. R. Org. Lett. 2004, 6, 5023. (b) Harrison,
T. J.; Patrick, O. B.; Dake, G. R. Org. Lett. 2007, 9, 367.
4546 J. Org. Chem. Vol. 75, No. 13, 2010

Sperger and Fiksdahl
JOCArticle
TABLE 3. Cyclization Reactions of Bispropargylic Amides 12 and 14a
entry
substrate
catalyst
additiveb
AgSbF6
AgNTf2
AgSbF6, NEt3
AgNTf2, NEt3
AgOTf, NEt3
NEt3
time (h)
ratio (12/31/34/35)c
yield (%)
d
d
1
2
3
4
5
6
7
8
9
10
12
12
12
12
12
12
14
14
14
14
AuCl(PPh3)
AuCl(PPh3)
AuCl(PPh3)
AuCl(PPh3)
AuCl(PPh3)
Ae
18
18
18
6
20
6
1/14/66/19
24/0/61/15
9/82/1/8
10/81/1/8
39/55/2/4
0/0/18/82
31 (59)
31 (55)
31( 35)
(34 þ 35) (88)f
A
4
36 (32)
g
AuCl(PPh3)
AuCl(IMes)e
AgNTf2
AgNTf2
AgNTf2
24
24
24
36 (6)
h
aReactions were run at [12] or [14] = 500 mM in refluxing DCM for [12] and rt for [14] with 2.5-5.0 mol % catalyst loading. The reaction mixture was
used directly for column chromatography. b2.5-5.0 mol %. cAccording to GC before column chromatography. dNot isolated. eSee Figure 1. fIsolated as
a mixture. For analytical purpose pure samples were obtained. gLow conversion. hNo reaction.
6-endo-dig cyclizations via intermediate 33, in accordance
with results above for substrate 12 and catalyst A (Table 3,
entry 6). In addition, a mixture of different byproducts was
formed, but the components could be neither separated nor
characterized. In contrast to the reaction of the secondary
amide 12, the cyclization took place at room temperature
within 4 h, probably due to the reduced steric hindrance
of the primary amide moiety. Further cyclization attempts
of 14 with AuCl(PPh3) or AuCl(IMes) in the presence of
AgNTf2 were less successful and showed only low conver-
sion (Table 3, entries 8 and 9). Only AgNTf2 as the catalyst
showed no activity under the applied reaction conditions
(Table 3, entry 10). The E- and Z-stereochemistry of 31 and
34, respectively, was determined by NOESY experiments.
Cyclization of Arylamides 22. Different results were ob-
tained by cyclization of the secondary arylamide 22, tethered
to a 1,6-diyne. On the basis of the results from the bispro-
pargyl amide substrates 12 and 14, we envisaged a nucleo-
philic attack of the amide nitrogen to provide isoindolin-1-
one or isoquinolin-1-one derivatives by the initial cycliza-
tion. These cyclic intermediates were expected to undergo a
subsequent cyclization with the remaining triple bond to
provide the respective tandem bicyclic products. However,
instead of the predicted transformations, an oxygen-nucleo-
philic attack took place. The reaction provided the imidate
37 as the single product by a regioselective 6-endo-dig
cyclization. An experiment applying catalyst A in refluxing
DCM, showed minor conversion after 18 h, according to 1H
NMR spectroscopy (Table 4, entry 1). As the addition of
catalytic amounts of a base might increase the reactivity of
the amide moiety by deprotonation, 5 mol % of NEt3 was
added to a reaction performed in DCE at 60 °C. Higher
conversion was obtained and the six-membered imidate 37
was isolated in 27% yield (Table 4, entry 2).
Improved results were obtained by performing the reac-
tion in toluene at 90 °C, providing full conversion of 22 in
21 h, and 59% yield of 37 was isolated (Table 4, entry 3).
Replacing catalyst A (Table 4, entry 3) by AuCl(PPh3) and
AgNTf2 gave comparable results (Table 4, entry 5). Since the
regioselectivity of the initial cyclization of amide 12 (Table 3)
was dependent on whether NEt3 was present, an additional
experiment with amide 22 in the absence of base, was carried
out (Table 4, entry 4). However, no other regioisomer was
detected, and only one-third of the diyne 22 was converted
into the imidate 37 after 20 h at 90 °C. An alternative
cyclization attempt with AuCl3 as the single catalyst gave
no reaction after 23 h (Table 4, entry 6). However, by adding
15 mol % AgNTf2, full conversion was observed (Table 4,
entry 7). A similar transformation with different silver cata-
lysts has recently been reported by Hong et al., synthesizing a
number of different (1H)-isochromen-1-imine derivatives.19
To investigate whether a silver salt may catalyze a tandem
cyclization, an experiment was performed with only 10 mol %
AgNTf2 in the absence of any gold complex (Table 4,
entry 8). Indeed, a silver-catalyzed cyclization of the diyne 22
was observed but provided only imidate 37 and no tandem
product was formed. Nevertheless, a potential requirement
of a silver salt additive for the cyclization of 22 can be
excluded, since the reaction proceeded with catalyst A in
the absence of any silver additive (Table 4, entries 2 and 3).
Since hardly soluble AgCl is formed by exchanging the
(19) Guannan, L.; Yu, Z.; Deju, Y.; Dengyou, Z.; Xiao, D.; Hualiang, J.;
Hong, L. Adv. Synth. Catal. 2009, 351, 2605.
J. Org. Chem. Vol. 75, No. 13, 2010 4547

Sperger and Fiksdahl
JOCArticle
TABLE 4. Cyclization Reactions of Arylamide 22a
entry
catalyst
Ad
A
A
additiveb
NEt3
NEt3
solvent
temp (°C)
time (h)
ratio 22/37c
yield 37 (%)
1
2
3
4
5
6
7
8
DCM
DCE
reflux
60
90
90
90
90
90
90
18
24
20
20
20
23
22
23
95/5
60/40
0/100
66/34
0/100
100/0
0/100
0/100
27
59
toluene
toluene
toluene
toluene
toluene
toluene
e
A
AuCl(PPh3)
AuCl3
AuCl3
AgNTf2/NEt3
57
f
AgNTf2g
AgNTf2
48
52
aReactions were run at [22] = 250 mM with 5 mol % catalyst loading. The reaction mixture was directly used for column chromatography. b5 mol %.
cAccording to 1H NMR after workup. dSee Figure 1. eNot isolated. f15 mol %. g10 mol %.
-
chlorine with a NTf2 counterion, the cyclizations in the
presence of AuCl(PPh3), AgNTf2, and NEt3 (Table 4, entry 5)
are likely to be catalyzed by a gold complex.
42. Final deutero-deauration releases the product d-38 and
enables cyclization of the active gold catalyst. According to
1H NMR spectroscopy, approximately 39% deuterium incor-
poration of the exocyclic alkene moiety and a 20% deuterium
incorporation of the endocyclic double bond had taken place.
The specific positions of both deuterium atoms can be rationa-
lized by the two deutero-deauration steps in the proposed
reaction mechanism.
Cyclization of Sulfonamides 15 and 19. The present inves-
tigations also included 1,6-diyne substrates with an adjacent
secondary sulfonamide functionality to act as the nucleo-
phile and thus trigger tandem cyclization reactions. The
diyne 15 was selectively converted into the tandem bicyclic
product 38 (72%) as the single E-isomer within 2 h in the
presence of 2.5 mol % AuCl(PEt3) and 2.5 mol % AgNTf2 at
room temperature (Scheme 9).
SCHEME 10. Proposed Mechanism for the Formation of 38
SCHEME 9. Cyclization of Sulfonamide 15
Based on an experiment with the N-deuterated diyne
amide d-15 (77% deuterium), prepared by proton abstrac-
tion with NaH and subsequent D2O workup, the following
reaction mechanism may be proposed (Scheme 10). One of
the triple bonds in substrate d-15 is activated by coordination
to the active gold catalyst followed by a 5-exo-dig attack of the
sulfonamide moiety to give the cationic vinylaurate intermediate
39. The pyrrolidine derivative 40 is formed by deutero-deaura-
tion (proto-deauration with deuterium) and regeneration of the
active gold catalyst. To explain the structure of the final product
d-38, we propose an isomerization of the exocyclic double bond
in 40, providing the more stable endocyclic enesulfonamide 41.
This isomerization step seems to be crucial for a successful sec-
ond cyclization. The spatial alkene-alkyne proximity is not
present in the previous five-membered imine 24 (Scheme 7),
lactone 28 (Table 2), and lactam 31 (Table 3) products and may
explain their lack of further cyclization. Subsequent activation
of the remaining alkyne moiety followed by a nucleophilic
attack of the enamide double bond, once more in a 5-exo-dig
manner, leads to the formation of a cationic gold intermediate
Gold-catalyzed tandem cyclization reaction of another
bispropargyl sulfonamide 19 with a fundamentally different
structure was studied. In contrast to substrate 15, the diyne
moiety of sulfonamide 19 is directly connected to an aryl
system. In a cyclization performed with catalyst A in DCM,
the starting material 19 was fully consumed after 23 h,
4548 J. Org. Chem. Vol. 75, No. 13, 2010

Sperger and Fiksdahl
JOCArticle
providing only the dihydroisoquinoline monocyclization
product 43 in 72% yield (Table 5, entry 1). No second
tandem cyclization, triggered by the sulfonyl enamide unit,
occurred.
Experimental Section
General Experimental. All reactions were performed under
argon atmosphere. Commercial grade reagents were used as
received. AuCl(IMes) was prepared according to a literature
procedure.20 Dry solvents were collected from a solvent purifi-
cation system. All reactions were monitored by GC and thin-
layer chromatography (TLC) using silica gel 60 F254 (0.25 mm
thickness). Flash chromatography was carried out using silica
gel 60 (0.040-0.063 mm). High throughput flash purification
TABLE 5. Cyclization Reactions of Sulfonamide 19a
(HPFP) was performed on prepacked cartridges. H and 13C
1
NMR spectra were recorded using a 300 or 400 MHz spectro-
meter. Chemical shifts are reported in ppm (δ) downfield from
tetramethylsilane (TMS) as internal standard. Coupling con-
stants (J) are reported in hertz (Hz). The attributions of the
chemical shifts were determined by means of COSY, HMQC,
HMBC, and NOESY experiments. Melting points (mp) were
determined using a Stuart apparatus and are uncorrected. High
resolution mass spectra (HRMS) were obtained using ESI
ionization. IR spectra were obtained using a Smart Endurance
reflection cell. Diynes 10 and 18 were prepared according to a
literature procedure.21
Preparation of Starting Materials. 2-(But-2-ynyl)-2-phenyl-4-
ynenitrile (8). To an ice-cold suspension of NaH (180 mg, 7.52
mmol, 2.5 equiv) in THF (30 mL) was added a solution of nitrile
8 (353 mg, 3.01 mmol) and 1-bromo-2-butyne (1.0 g, 7.52 mmol,
0.66 mL, 2.5 equiv) in THF (3 mL). The cooling bath was
removed, and the suspension was heated in a 50 °C hot oil bath
for 17 h. After the addition of water (40 mL) the aqueous layer
was extracted with EtOAc (3 ꢀ 50 mL). The combined organic
layers were washed with brine (40 mL), dried (Na2SO4), and
evaporated to dryness. The residue was purified by flash chro-
matography (n-hexane/EtOAc 15:1) to yield 8 (526 mg, 79%) as
a colorless solid. Rf=0.49 (n-hexane/EtOAc 4:1); mp 93-94 °C;
1H NMR (300 MHz, CDCl3) δ 1.77 (t, J = 2.5 Hz, 6 H, CH3),
2.86 (dq, J=16.6/2.5 Hz, 2 H, CH2), 2.96 (dq, J=16.6/2.5 Hz,
2 H, CH2), 7.32-7.43 (m, 3 H, Harom), 7.47-7.51 (m, 2 H, Harom);
13C NMR (100 MHz, CDCl3) δ 3.5 (2 ꢀ CH3), 29.9 (2 ꢀ CH2),
46.9 (CCN), 72.8 (2 ꢀ Calkyne), 80.6 (2 ꢀ Calkyne), 121.6 (CN), 126.2
(2 ꢀ CHarom), 128.3 (CHpara.), 128.7 (2 ꢀ CHarom), 137.3 (Carom);
IR (neat, cm-1) 2925, 2359, 2244, 1448; HRMS (ESI) calcd for
C16H15NNa 244.1102, obsd 244.1100.
entry
catalyst
Ac
AuCl(PPh3) AgNTf2 DCM
AuCl(PEt3) AgNTf2 DCM
additiveb solvent temp (°C) time (h) yield (%)
1
2
3
4
DCM
rt
rt
23
24
19
20
72
d
d
e
rt
100
A
toluene
aReactions were run at [19] = 500 mM with 5 mol % catalyst loading.
The reaction mixture was directly used for column chromatography.
b5 mol %. cSee Figure 1. dTraces according to 1H NMR. e36% conver-
sion according to 1H NMR.
In contrast to the initial cyclization product 41 (Scheme 10),
the enamide double bond in 43 is conjugated to an aryl
system that may reduce the reactivity of the alkene moiety,
thus preventing a second cyclization. A conjugated alkene
moiety is similarly present in isochromen imine 37, obtained
from arylamide 22 (Table 4), and may likewise explain the
lack of a tandem reaction. As we observed a selective tandem
transformation of bispropargyl sulfonamide 15 into the
bicyclic product 38 in the presence of AuCl(PEt3) and
AgNTf2 (Scheme 9), two further sulfonamide (19) reactions
were performed, using AuCl(PPh3) and AuCl(PEt3) with the
-
NTf2 counterion (Table 5, entries 2 and 3). By applying
similar reaction conditions as used for 15 (Scheme 9), only
traces of product 43 were detected after 19 and 24 h, ac-
cording to 1H NMR spectroscopy. Thus, another attempt at
tandem cyclization of 19 was performed in toluene at 100 °C
with gold complex A (Table 5, entry 4). Rather than increas-
ing the yield of the dihydroisoquinoline 43 or forming
tandem cyclization products, only a reduced conversion of
36% into 43 was observed, according to 1H NMR spectra of
the crude reaction mixture.
2-(But-2-ynyl)-2-phenylhex-4-yn-1-amine (9). To an ice-cold
suspension of LiAlH4 (151 mg, 3.98 mmol, 2.0 equiv) in Et2O (5
mL) was added a solution of 8 (440 mg, 1.99 mmol) in Et2O (5
mL). The gray suspension was stirred for 1 h at 0 °C and for an
additional 4.5 h at room temperature. After cooling to 0 °C a
NaOH solution (10 mL, 1 N) was added followed by the
addition of water (20 mL). The aqueous layer was extracted
with Et2O (3 ꢀ 50 mL), and the combined organic layers were
dried (Na2SO4) and evaporated to dryness. The residue was
purified by flash chromatography (DCM/methanol 97:3) to
yield 9 (386 mg, 86%) as a colorless oil. Rf = 0.32 (DCM/
Conclusion
The results from a series of tandem cyclization reactions of
various 1,6-diyne substrates are reported. The reactions were
triggered by internal O- and N-nucleophiles, such as amine,
carboxylic acid, amide, and sulfonamide functionalities.
Bicyclic bridged reaction products were obtained by success-
ful tandem cyclizations of carboxylic acid 11, secondary and
primary amides 12 and 14, and sulfonamide 15. Tandem
cyclization of amine 9 was obtained after reduction of the
monocyclization imine product 24. Arylamide substituted
diynes 19 and 22 failed to undergo tandem cyclization, and
only monocyclization products were formed. The regioselec-
tivity of the reactions with carboxylic acid diyne 11 and amide
diyne 12 was more closely investigated. The applied counterion
turned out to be crucial for the formation of bicyclic products.
All of the reported tandem reactions were successfully per-
formed with the NTf2- and SbF6- counterions.
1
methanol 9:1); H NMR (300 MHz, CDCl3) δ 0.93 (bs, 2 H,
NH2), 1.73 (t, J = 2.4 Hz, 6 H, CH3), 2.66 (q, J = 2.4 Hz, 4 H,
CH2), 3.06 (s, 2 H, CH2NH2), 7.19-7.27 (m, 1 H, Hpara),
7.31-7.38 (m, 4 H, Harom); 13C NMR (100 MHz, CDCl3)
δ 3.5 (2 ꢀ CH3), 26.4 (2 ꢀ CH2), 46.2 (CH2NH2), 49.6 (PhC),
75.7 (2 ꢀ Calkyne), 78.1 (Calkyne), 126.4 (CHpara), 126.8 (2 ꢀ
CHarom), 128.3 (2 ꢀ CHarom), 143.1 (Carom); IR (neat, cm-1
)
2917, 2854, 761; HRMS (ESI) calcd for C16H20N 226.1596, obsd
226.1595.
2-But-2-ynyl)-2-(methoxycarbonyl)hex-4-ynoic acid (11). The
acid was prepared according to a procedure described by
~
(20) Nieto-Oberhuber, C.; Munoz, M. P.; Lopez, S.; Jimenez-Nunez, E.;
Nevado, C.; Herrero-Gomez, E.; Raducan, M.; Echavarren, A. M. Chem.;
ꢀ
ꢀ
ꢀ~
ꢀ
Eur. J. 2006, 12, 1677.
(21) Sperger, C.; Fiksdahl, A. Org. Lett. 2009, 11, 2449.
J. Org. Chem. Vol. 75, No. 13, 2010 4549

Sperger and Fiksdahl
JOCArticle
Michelet et al.22 from diyne 10 (80 mg, 0.34 mmol) and KOH
(20.9 mg, 0.37 mmol, 1.1 equiv) in methanol (500 μL). The acid
11 was obtained as a colorless solid (60.2 mg, 80%), mp 112-
114 °C; 1H NMR (300 MHz, CDCl3) δ 1.76 (t, J=2.6 Hz, 6 H,
CH3), 2.88-2.92 (m, 4 H, CH2), 3.79 (s, 3 H, OCH3), 10.55 (bs,
1 H, COOH); 13C NMR (100 MHz, CDCl3) δ 3.5 (2 ꢀ CH3),
23.1 (2 ꢀ CH2), 53.1 (2 ꢀ OCH3), 57.1 (COCCO), 72.8 (2 ꢀ
Calkyne), 79.3 (2 ꢀ Calkyne), 169.6 (COOH), 174.7 (COOMe); IR
(neat, cm-1) 2958, 2920, 1748, 1710, 1434, 1202; HRMS (ESI)
calcd for C12H15O4 223.0970, obsd 223.0969.
Methyl 2-(But-2-ynyl)-2-(ethylcarbamoyl)hex-4-ynoate (12).
A solution of the acid 11 (150 mg, 0.675 mmol) in DCM (1.8 mL)
and DMF (1 μL) was cooled to 0 °C, and oxalylchloride (107 mg,
0.844 mmol, 71.4 μL, 1.25 equiv) was added dropwise. After stirring
for 10 min the cooling bath was removed, and the reaction mixture
was stirred for 1 h at room temperature. The solvent and excess
oxalylchloride were removed under reduced pressure, and the oily
residue was dissolved in DCM (4.8 mL). After cooling again to 0 °C,
NEt3 (171 mg, 1.69 mmol, 235 μL, 2.5 equiv), DMAP (4.30 mg,
Hz, 4 H, CH2), 3.30 (d, J=6.6 Hz, 2 H, CH2NH), 4.32 (t, J=6.6
Hz, 1 H, NH), 7.20-7.34 (m, 7 H, Harom), 7.67 (t, J=8.4 Hz, 1 H,
H
arom);13CNMR(100MHz, CDCl3) δ3.5 (2 ꢀ CH3), 21.5(CH3),
26.9 (2 ꢀ CH2), 44.4(CH2NH), 50.3 (COCCO), 74.8 (2 ꢀ Calkyne),
79.0 (2 ꢀ Calkyne), 126.5 (2 ꢀ CHarom), 127.1 (CHarom), 127.2 (2 ꢀ
CHarom), 128.6 (2 ꢀ CHarom), 129.6 (2 ꢀ CHarom), 136.5 (Carom),
141.2 (Carom), 143.4 (Carom); IR (neat, cm-1) 3274, 1315, 1160.
HRMS (ESI) calcd for C23H26NO2S 380.1679, obsd 380.1685.
N-(2-Bromobenzyl)-4-methylbenzenesulfonamide (17).24 To a
suspension of benzylaminehydrochloride 16 (300 mg, 1.35 mmol)
in DCM (10 mL) were successively added NEt3 (410 mg,
4.05 mmol, 565 μL, 3.0 equiv) and solid TsCl (283 mg, 1.49 mmol,
1.1 equiv). After 19 h at room temperature HCl (30 mL, 1 M) was
added, and the aqueous layer was extracted with EtOAc (3 ꢀ
50 mL). The combined organic layers were washed with brine
(40 mL), dried (Na2SO4), and evaporated to dryness. The
residue was purified by flash chromatography (n-hexane/EtOAc
4:1) to provide 17 (438 mg, 95%) as a colorless solid. The melting
point (mp 72-73 °C, lit. 73.5 °C) and the 1H NMR data are in
accordance with the literature.
0.034 mmol, 5.0 mol %) and EtNH2 HCl (68.8 mg, 0.844 mmol,
3
Dimethyl 2-(But-2-ynyl)-2-(3-(2-((4-methylphenylsulfonamido)-
methyl)phenyl) Prop-2-ynyl)malonate (19). The reaction was per-
formed with 17 (130 mg, 0.382 mmol), diyne 18 (102 mg,
0.458 mmol, 1.2 equiv), Pd(PPh3)2Cl2 (13.4 mg, 0.019 mmol,
0.05 equiv), CuI (7.3 mg, 0.038 mmol, 0.1 equiv), and PPh3 (10.0 mg,
0.038 mmol, 0.01 equiv) in a mixture of DMF/NEt3=1:1 (2 mL)
at 80 °C for 21 h. The reaction mixture was filtered through a
pad of Celite, and the filtrate was evaporated to dryness. The
residue was purified by flash chromatography (n-hexane/EtOAc
3:1) to provide 19 (149 mg, 81%) as a yellow oil. Rf = 0.41
1.25 equiv) were subsequently added. The reaction mixture was
stirred for 5 min at 0 °C and for 17 h at room temperature before
a HCl solution (20 mL, 0.5 N) was added. The aqueous layer was
extracted with EtOAc (3 ꢀ 35 mL), and the combined organic
layers were washed with a satd NaHCO3 solution (20 mL), dried
(Na2SO4), and evaporated to dryness. The residue was purified
by flash chromatography (n-hexane/EtOAc 4:1) to yield 12
(134.3 mg, 80%) as a colorless solid, mp 113-114 °C; Rf =
0.47 (n-hexane/EtOAc 1:1); 1H NMR (400 MHz, CDCl3) δ 1.15
(t, J=7.4 Hz, 3 H, CH2CH3), 1.75 (t, J=2.6 Hz, 6 H, CH3), 2.78
(dq, J=16.7/2.6 Hz, 2 H, CH2), 2.89 (dq, J=16.7/2.6 Hz, 2 H,
CH2), 3.33 (qd, J = 7.4/5.7 Hz, 2 H, CH2CH3), 3.77 (s, 3 H,
OCH3), 6.60 (bs, 1 H, NH); 13C NMR (100 MHz, CDCl3) δ 3.6
(2 ꢀ CH3), 14.6 (CH2CH3), 24.6 (2 ꢀ CH2), 34.7 (CH2CH3), 52.8
(OCH3), 57.1 (COCCO), 73.8 (2 ꢀ Calkyne), 78.9 (2 ꢀ Calkyne),
168.2 (CONH), 172.2 (COOMe); IR (neat, cm-1) 3323, 2923,
1740, 1635; HRMS (ESI) calcd for C14H20NO3 250.1443, obsd
250.1443.
1
(n-hexane/EtOAc 1:1); H NMR (300 MHz, CDCl3) δ 1.78 (t,
J = 2.6 Hz, 3 H, CH3), 2.39 (s, 3 H, CH3), 2.90 (q, J = 2.6 Hz,
2 H, CH2), 3.16 (s, 2 H, CH2), 3.78 (s, 6 H, OCH3), 4.23 (d, J=
6.4 Hz, 2 H, CH2NH), 5.41 (t, J=6.4 Hz, 1 H, NH), 7.10-7.23
(m, 5 H, Harom), 7.25-7.29 (m, 1 H, Harom), 7.68 (d, J=8.3 Hz,
2 H, Harom); 13C NMR (100 MHz, CDCl3) δ 3.5 (CH3), 21.4
(CH3), 23.5 (CH2CCCH3), 24.0 (CCCH2), 46.1 (CH2NH), 53.2
(2 ꢀ OCH3), 56.9 (COCCO), 72.6 (Calkyne), 79.7 (Calkyne), 81.2
(Calkyne), 89.2 (Calkyne), 122.1 (Carom), 127.0 (2 ꢀ CHarom), 127.5
(CHarom), 128.3 (CHarom), 129.0 (CHarom), 129.4 (2 ꢀ CHarom),
132.6 (CHarom), 137.7 (Carom), 138.3 (Carom), 142.9 (Carom),
169.7 (2 ꢀ CO); IR (neat, cm-1) 3294, 2954, 2923, 1735, 1435,
1156; HRMS (ESI) calcd for C26H28NO6S 482.1637, obsd
482.1646.
Methyl 2-(But-2-ynyl)-2-carbamoylhex-4-ynoate (14).23 To an
ice-cold suspension of NaH (90.2 mg, 3.76 mmol, 2.2 equiv) in
THF (10 mL) was added a solution of methyl malonate mono-
amide (13) (200 mg, 1.71 mmol) and 1-bromo-2-butyne (500 mg,
3.76 mmol, 329 μL, 2.2 equiv) in THF (3 mL). The cooling bath
was removed, and the suspension was stirred for 23 h at room
temperature. After the addition of water (40 mL) the aqueous
layer was extracted with EtOAc (3 ꢀ 50 mL). The combined
organic layers were dried (Na2SO4) and evaporated to dryness.
The residue was purified by flash chromatography (n-hexane/
EtOAc 1:2) to yield 14 (312 mg, 83%) as a colorless solid. Rf =
0.29 (EtOAc); mp 133-134 °C (lit. 128-130 °C).
N-(2-(But-2-ynyl)-2-phenylhex-4-ynyl)-4-methylbenzenesulfo-
namide (15). To a solution of the amine 9 (50 mg, 0.222 mmol) in
DCM (3 mL) were successively added NEt3 (33.7 mg, 0.333 mmol,
46.2 μL, 1.5 equiv), DMAP (1.36 mg, 0.01 mmol, 5 mol %), and
TsCl (48.6 mg, 0.255 mmol, 1.15 equiv) at 0 °C. The cooling bath
was removed, and stirring was continued for 4 h. The mixture was
poured into a HCl solution (10 mL, 1 N), and the aqueous layer
was extracted with EtOAc (3 ꢀ 25 mL). The combined organic
layers were washed with a saturated NaHCO3 solution (15 mL)
and dried (Na2SO4). The solvent was evaporated, and the residue
was purified by flash chromatography (n-hexane/EtOAc 4:1) to
provide 15 (62.6 mg, 74%) as a colorless solid, mp 165-166 °C;
Rf =0.84 (n-hexane/EtOAc 1:1); 1H NMR (300 MHz, CDCl3) δ
1.68 (t, J=2.5 Hz, 6 H, CH3), 2.43 (s, 3 H, CH3), 2.63 (q, J=2.5
N-Ethyl-2-iodobenzamide 21. The acid 20 (500 mg, 2.02 mmol)
was suspended in DCM (5 mL) and DMF (2 μL). After the
addition of oxalylchloride (320 mg, 2.52 mmol, 213 μL, 1.25 equiv),
stirring was continued for 4.5 h at room temperature. The solvent
and excess oxalylchloride were removed under reduced pressure,
and the solid yellow residue was dissolved in DCM (15 mL). After
cooling again to 0 °C, NEt3 (613 mg, 6.06 mmol, 845 μL, 3.0 equiv)
and EtNH2 HCl (247 mg, 3.03 mmol, 1.5 equiv) were subse-
3
quently added. The reaction mixture was stirred for 5 min at 0 °C
and for 17 h at room temperature before a HCl solution (40 mL,
1 N) was added. The aqueous layer was extracted with EtOAc (3 ꢀ
50 mL), and the combined organic layers were washed with a satd
NaHCO3 solution (50 mL), dried (Na2SO4), and evaporated to
dryness. The residue was purified by flash chromatography (n-
hexane/EtOAc 2:1) to yield 21 (474 mg, 85%) as a colorless solid.
The melting point (mp 117-118 °C, lit. 114-116 °C) and the 1H
NMR data are in accordance with the literature.25
Dimethyl 2-(But-2-ynyl)-2-(3-(2-(ethylcarbamoyl)phenyl)prop-
2-ynyl) Malonate (22). The reaction was performed with 21
(103 mg, 0.375 mmol), diyne 18 (100 mg, 0.450 mmol, 1.2 equiv),
Pd(PPh3)2Cl2 (13.1 mg, 0.019 mmol, 0.05 equiv), CuI (7.1 mg,
(22) Genin, E.; Toullec, P. Y.; Marie, P.; Antoniotti, S.; Brancour, C.;
^
Genet, J. P.; Michelet, V. ARKIVOK 2007, 5, 67.
(23) Liu, C.; Widenhoefer, R. A. Organometallics 2002, 21, 5666.
(24) Gao, F.; Deng, M.; Qian, C. Tetrahedron 2005, 61, 12238.
(25) Beak, P.; Musick, T. J.; Chen, C. J. Am. Chem. Soc. 1988, 110, 3538.
4550 J. Org. Chem. Vol. 75, No. 13, 2010

Sperger and Fiksdahl
JOCArticle
0.038 mmol, 0.1 equiv), and PPh3 (9.8 mg, 0.038 mmol, 0.01
equiv) in a mixture of THF/NEt3 = 1:1 (2.4 mL) at room
temperature for 19 h. The reaction mixture was filtered through
a pad of Celite, and the filtrate was evaporated to dryness. The
residue was purified by flash chromatography (n-hexane/EtOAc
2:1 f 1:1) to provide 22 (135 mg, 98%) as a yellow oil. Rf=0.23
provide 25a (141.5 mg, 42%), 25b (87.6 mg, 26%), and a
mixture of both diastereomers (40.5 mg, 12%). 25a: Rf =
0.15 (DCM/methanol 9:1); 1H NMR (300 MHz, CDCl3)
δ 1.00 (t, J = 7.5 Hz, 3 H, CH2CH3), 1.51-1.78 (m, 2 H,
CH2CH3), 1.74 (t, J=2.6 Hz, 3 H, CH3), 1.83 (dd, J=13.6/9.0
Hz, 1 H, H-3), 2.40 (dd, J=13.6/7.5 Hz, 1 H, H-3), 2.53 (q, J=
2.6 Hz, 2 H, CH2), 3.08-3.21 (m, 1 H, H-2), 3.31 (d, J = 11.5
Hz, 1 H, H-5), 3.44 (d, J = 11.5 Hz, 1 H, H-5), 4.49 (bs, 1 H,
NH), 7.19-7.26 (m, 1 H, Harom), 7.27-7.38 (m, 4 H, Harom);
13C NMR (75 MHz, CDCl3) δ 3.4 (CH3), 11.6 (CH2CH3), 28.8
(CH2CH3), 32.6 (CH2), 43.2 (C-3), 50.7 (C-4), 56.8 (C-5), 61.1
(C-2), 76.3 (Calkyne), 77.8 (Calkyne), 126.3 (2 ꢀ CHarom), 126.5
1
(n-hexane/EtOAc 1:1); H NMR (300 MHz, CDCl3) δ 1.28 (t,
J=7.2 Hz, 3 H, CH2CH3), 1.77 (t, J=2.6 Hz, 3 H, CH3), 2.97 (q,
J = 2.6 Hz, 2 H, CH2), 3.25 (s, 2 H, CH2), 3.50-3.60 (m, 2 H,
CH2CH3), 3.78 (s, 6 H, OCH3), 7.23 (bs, 1 H, NH), 7.34-7.46
(m, 3 H, Harom), 7.99 (dd, J=7.2/2.3 Hz, 1 H, Harom); 13C NMR
(100 MHz, CDCl3) δ 3.5 (CH3), 14.8 (CH2CH3), 23.5
(CH2CCCH3), 24.0 (CH2), 34.9 (CH2CH3), 53.1 (2 ꢀ OCH3),
56.9 (COCCO), 72.6 (Calkyne), 79.6 (Calkyne), 82.1 (Calkyne), 90.7
(Calkyne), 119.2 (Carom), 128.6 (CHarom), 129.8 (CHarom), 130.2
(CHarom), 133.9 (CHarom), 135.9 (Carom), 166.1 (CONH), 169.4
(2ꢀCO); IR (neat, cm-1) 3301, 2954, 1736, 1645, 1529, 1435, 1292;
HRMS (ESI) calcd for C21H24NO5 370.1654, obsd 370.1667.
Cyclization Reactions. General Procedure. The gold catalyst
and, if needed, a silver additive were placed in a Schlenk flask under
an argon atmosphere, and a solution of the substrate in the given
solvent was added. The reaction mixture was stirred at the appro-
priate temperature for the given time. If not stated otherwise, the
reaction mixtures were used directly for flash chromatography.
3-(But-2-ynyl)-5-ethyl-3-phenyl-3,4-dihydro-2H-pyrrole (24).
The title compound was prepared according to the general
procedure from AuCl(PEt3) (7.82 mg, 22.3 μmol, 2.5 mol %),
AgSbF6 (7.62 mg, 22.2 μmol, 2.5 mol %), and 9 (200 mg, 0.888
mmol) in DCM or dioxane (1.8 mL). Flash chromatography (n-
hexane/EtOAc 1:1) after 2.5 h at room temperature yielded 24
(187.8 mg, 94%) as a colorless oil. Rf = 0.20 (n-hexane/EtOAc
(CHpara), 128.2 (2 ꢀ CHarom), 146.1 (Carom); IR (neat, cm-1
)
2958, 2872, 1445. HRMS (ESI) calcd for C16H22N 228.1752,
obsd 228.1748. 25b: Rf=0.15 (DCM/methanol 9:1); 1H NMR
(300 MHz, CDCl3) δ 0.95 (t, J = 7.5 Hz, 3 H, CH2CH3),
1.35-1.60 (m, 2 H, CH2CH3), 1.67 (dd, J = 13.2/9.0 Hz, 1 H,
H-3), 1.72 (t, J = 2.6 Hz, 3 H, CH3), 2.31 (bs, 1 H, NH), 2.42
(dd, J=13.2/6.8 Hz, 1 H, H-3), 2.47 (q, J=2.6 Hz, 2 H, CH2),
3.20-3.38 (m, 1 H, H-2), 3.21 (d, J=10.9 Hz, 1 H, H-5), 3.33
(d, J = 10.9 Hz, 1 H, H-5), 7.17-7.36 (m, 5 H, Harom); 13C
NMR (75 MHz, CDCl3) δ 3.5 (CH3), 11.6 (CH2CH3), 30.1
(CH2CH3), 31.3 (CH2), 43.5 (C-3), 51.4 (C-4), 56.6 (C-5), 59.7
(C-2), 76.5 (Calkyne), 77.7 (Calkyne), 126.1 (CHpara), 126.9 (2 ꢀ
CHarom), 128.0 (2 ꢀ CHarom), 147.0 (Carom); IR (neat, cm-1
)
N
2957, 2917, 2857, 1445. HRMS (ESI) calcd for C16H22
228.1752, obsd 228.1751.
(Z)-(()-2-Ethyl-6-ethylidene-4-phenyl-1-azabicyclo[2.2.1]heptane
(26a) and (()-7-Ethyl-2-methyl-5-phenyl-1-azabicyclo[3.2.1]oct-
2-ene (27a). Representative Procedure. (Table 1, entry 1) The
title compounds were prepared according to the general proce-
dure from AuCl(PEt3) (1.54 mg, 4.4 μmol, 2.5 mol %), AgSbF6
(1.51 mg, 4.4 μmol, 2.5 mol %), and 25a (40 mg, 0.176 mmol) in
DCM (c = 500 mM). Flash chromatography (DCM/ethanol
96:4) after 2.5 h at room temperature provided 26a (9.2 mg,
23%) as a yellow oil and 27a (17.1 mg, 43%) as a colorless oil.
26a: Rf = 0.61 (DCM/methanol 4:1); 1H NMR (300 MHz,
CDCl3) δ 0.96 (t, J = 7.5 Hz, 3 H, CH2CH3), 1.18 (ddd, J =
11.8/6.0/2.2 Hz, 1 H, CH2, H-3), 1.28-1.44 (m, 1 H, CH2CH3),
1.62-1.80 (m, 1 H, CH2CH3), 1.75 (dt, J = 6.8/1.9 Hz, 3 H,
CH3), 2.08 (ddd, J=11.8/8.3/3.1 Hz, 1 H, H-3), 2.13-2.21 (m,
1 H, H-5), 2.44-2.51 (m, 1H, H-5), 2.81 (dd, J=9.0/2.2 Hz, 1 H,
H-7), 2.97 (dd, J = 9.0/3.1 Hz, 1 H, H-7), 3.18-3.31 (m, 1 H,
H-2), 5.14 (qt, J = 6.8/2.0 Hz, 1 H, CH), 7.17-7.37 (m, 5 H,
1
1:1); H NMR (400 MHz, CDCl3) δ 1.19 (t, J = 7.6 Hz, 3 H,
CH2CH3), 1.72 (t, J=2.5 Hz, 3 H, CH3), 2.39 (q, J=7.6 Hz, 2 H,
CH2CH3), 2.42 (q, J=2.5 Hz, 2 H, CH2CC), 2.85 (dt, J=17.1/
2.0 Hz, 1 H, H-4), 2.97 (dt, J=17.1/1.2 Hz, 1 H, H-4), 4.01 (dq,
J=15.2/2.0 Hz, 1 H, H-2), 4.19 (dq, J=15.2/1.2 Hz, 1 H, H-2),
7.18-7.24 (m, 3 H, Harom), 7.28-7.35 (m, 2 H, Harom); 13C NMR
(75 MHz, CDCl3) δ 3.5 (CH3), 10.5 (CH2CH3), 27.2 (CH2CH3),
32.4 (CH2CC), 48.9 (C-4), 50.0 (C-3), 71.6 (C-2), 76.1 (CH2C),
77.8 (CCH3), 126.2 (CHpara.), 126.7 (2 ꢀ CHarom), 128.2 (2 ꢀ
CHarom), 146.5 (Carom), 178.6 (C-5); IR (neat, cm-1) 2971, 2917,
1643; HRMS (ESI) calcd for C16H20N 226.1596, obsd 226.1599.
(()-4-(But-2-ynyl)-2-ethyl-phenylpyrrolidine (25a) and (()-
4-(But-2-ynyl)-2-ethyl-phenylpyrrolidine (25b). Method A. To
an ice-cold solution of the imine 24 (137 mg, 0.608 mmol) in
ethanol (2.8 mL) was added NaBH4 (31.7 mg, 0.837 mmol, 1.5
equiv) in small portions. The dark brown solution was stirred
for 1.5 h at 0 °C and an additional 15 h at room temperature.
After the addition of a satd NaHCO3 solution (20 mL), the
aqueous layer was extracted with DCM (3 ꢀ 40 mL). The
combined organic layers were dried (Na2SO4) and evaporated
to dryness. The residue was purified by flash chromatography
(DCM/methanol 9:1) to yield a mixture of both diastereomers
25a and 25b (97.2 mg, 77%) as a colorless oil. The mixture was
further purified by using a VersaFlash purification system (23ꢀ
110 mm, 23 g SiO2, DCM/methanol 97:3) to yield 25a (45.5 mg,
36%) as a colorless oil and 25b (34.4 mg, 27%) as a colorless oil.
Method B. LiAlH4 (83.9 mg, 2.21 mmol, 1.5 equiv) was
suspended in THF (5 mL) and cooled to 0 °C. Imine 24
(332 mg, 1.47 mmol) in THF (5 mL) was then added dropwise,
and the brown solution was stirred for 1 h at 0 °C before the
cooling bath was removed. After an additional 1.5 h at room
temperature a Na2SO4 solution (25 mL, 1 M) was added, and
the aqueous layer was extracted with EtOAc (3ꢀ50 mL). The
combined organic layers were dried (Na2SO4) and evaporated
to dryness providing a mixture of both diastereomers 25a and
25b as a yellow oil (335 mg, 95%). The diastereomers were
separated by two HPFP (DCM/methanol/iPrOH 95:4:4) to
H
arom); 13C NMR (100 MHz, CDCl3) δ 11.9 (CH2CH3), 13.4
(CH3), 26.1 (CH2CH3), 43.3 (C-3), 45.1 (C-5), 54.0 (C-4), 65.2
(C-7), 67.9 (C-2), 113.4 (CH), 126.3 (CHpara), 126.6 (2ꢀCHarom),
128.4 (2 ꢀ CHarom), 142.7 (Carom), 146.2 (C-6); IR (neat, cm-1
)
3027, 2959, 2932, 1497, 1446; HRMS (ESI) calcd for C16H22N
228.1752, obsd 228.1751. 27a: Rf = 0.55 (DCM/methanol 4:1);
1H NMR (300 MHz, CDCl3) δ 0.98 (t, J = 7.5 Hz, 3 H,
CH2CH3), 1.39-1.56 (m, 1 H, CH2CH3), 1.61 (dd, J = 12.4/
8.3 Hz, 1 H, CH2, H-3), 1.81-1.83 (m, 3 H, CH3), 1.81-1.97 (m,
1 H, CH2CH3), 2.02-2.12 (m, 1 H, H-5), 2.27 (ddd, J=12.4/8.3/
1.9 Hz, 1 H, H-3), 2.34-2.44 (m, 1 H, H-5), 3.15 (d, J=10.5 Hz,
1 H, H-8), 3.23 (dd, J = 10.5/1.9 Hz, 1 H, H-8), 3.24-3.37 (m,
1 H, H-2), 5.24-5.28 (m, 1 H, CH), 7.20 (tt, J=6.8/2.2 Hz, 1 H,
H
para), 7.24-7.37 (m, 4 H, Harom); 13C NMR (100 MHz, CDCl3)
δ 12.3 (CH2CH3), 24.3 (CH3), 25.6 (CH2CH3), 44.6 (C-5), 45.0
(C-4), 45.7 (C-3), 62.7 (C-8), 72.3 (C-2), 114.7 (CH), 125.9
(CHpara), 126.1 (2 ꢀ CHarom), 128.3 (2 ꢀ CHarom), 146.7 (C-6),
148.1 (Carom); IR (neat, cm-1) 3024, 2959, 2875, 1495, 1445;
HRMS (ESI) calcd for C16H22N 228.1752, obsd 228.1751.
(Z)-(()-2-Ethyl-6-ethylidene-4-phenyl-1-azabicyclo[2.2.1]heptane
(26b) and (()-7-Ethyl-2-methyl-5-phenyl-1-azabicyclo[3.2.1]oct-
2-ene (27b). Representative Procedure. (Table 1, entry 5) The
title compounds were prepared according to the general proce-
dure from catalyst A (5.95 mg, 7.7 μmol, 5.0 mol %) and 25b
J. Org. Chem. Vol. 75, No. 13, 2010 4551

Sperger and Fiksdahl
JOCArticle
(35 mg, 0.154 mmol) in DCM (c = 500 mM) for 18 h. Flash
chromatography (DCM/ethanol 96:4) provided a mixture of
26b and 27b (19.5 mg, 56%, 26b/27b 10:90) as a pale yellow oil.
26b and 27b: Rf=0.67 (DCM/methanol 4:1). As it was not pos-
sible to separate 26b and 27b, detailed analytical data could not
be obtained. (See 1H NMR and NOESY spectra of mixture).
(E)-(()-Methyl 3-(But-2-ynyl)-5-ethylidene-2-oxotetrahydro-
3-carboxylate (28), Methyl 3-(But-2-ynyl)-6-methyl-2-oxo-3,4-
dihydro-2H-pyran-3-carboxylate (29), and (()-Methyl 6-Ethyli-
dene-4-methylene-2-oxo-3-oxabicyclo[3.2.1]octane-1-carboxylate
(30). Representative Procedure I. (Table 2, entry 10) The title
compounds were prepared according to the general procedure
from AuCl(IMes) (2.42 mg, 4.5 μmol, 2.0 mol %), AgNTf2
(1.75 mg, 4.5 μmol, 2.0 mol %) and 11 (50 mg, 0.225 mmol) in
DCM (c=500 mM) for 18 h. Flash chromatography (n-hexane/
EtOAc 12:1) provided 28 (7.1 mg, 14%) as a colorless oil and 30
(16.3 mg, 33%) as a colorless oil.
from catalyst A (2.32 mg, 3.0 μmol, 2.5 mol %), NEt3 (0.30 mg,
3.0 μmol, 0.42 μL, 5.0 mol %), and 12 (30 mg, 0.120 mmol) in
refluxing DCM (c = 500 mM) for 6 h. Flash chromatography
(n-hexane/EtOAc 4:1) provided a mixture of 34 and 35 (26.3 mg,
88%, 34/35 18:82) as a colorless oil. A pure sample of 35 was
obtained by HPFP (23 ꢀ 110 mm, 23 g SiO2, n-hexane/EtOAc
10:1).
1
31: Rf = 0.26 (n-hexane/EtOAc 1:1); H NMR (300 MHz,
CDCl3) δ 1.13 (t, J=7.2 Hz, 3 H, CH2CH3), 1.68 (dt, J=6.9/
1.1 Hz, 3 H, CH3), 1.70 (t, J=2.6 Hz, 3 H, CH3), 2.76-2.80 (m,
2 H, CH2), 2.79-2.89 (m, 1 H, H-4), 3.04-3.13 (m, 1 H, H-4),
3.39-3.52 (m, 1 H, CH2CH3), 3.57-3.70 (m, 1 H, CH2CH3),
3.74 (s, 3 H, OCH3), 4.78 (qt, J = 6.8/2.3 Hz, 1 H, CH); 13C
NMR (100 MHz, CDCl3) δ 3.5 (CH3), 11.7 (CH2CH3), 11.9
(CH3), 24.7 (CH2), 31.9 (C-4), 35.2 (CH2CH3), 53.0 (C-3), 54.0
(OCH3), 73.5 (Calkyne), 78.3 (Calkyne), 95.0 (CH), 136.2 (C-5),
171.2 (CO), 171.5 (CO); IR (neat, cm-1) 2954, 1744, 1707, 1677,
1417, 1250; HRMS (ESI) calcd for C14H20NO3 250.1443,
Representative Procedure II. (Table 2, entry 14) The title
compounds were prepared according to the general proced-
ure from AuCl3 (2.05 mg, 6.8 μmol, 5.0 mol %) and 11 (30 mg,
0.135 mmol) in DCM (c=500 mM) for 2 h. The crude reaction
mixture was purified using a VersaFlash purification system
(23 ꢀ 110 mm, 23 g SiO2, n-hexane/EtOAc 12:1) to yield 28
(6.3 mg, 21%) as a colorless oil and 29 (6.0 mg, 20%) as a
colorless oil.
1
obsd 250.1440. 34: Rf = 0.35 (n-hexane/EtOAc 1:1); H NMR
(300 MHz, CDCl3) δ 1.09 (t, J = 6.8 Hz, 3 H, CH2CH3),
1.66-1.73 (m, 3 H, CH3), 1.94 (dd, J = 11.5/4.9 Hz, 1 H,
H-8), 2.36 (dd, J = 11.5/1.9 Hz, 1 H, H-8), 2.70-2.79 (m, 1 H,
H-7), 2.84-2.95 (m, 1 H, H-7), 2.57-3.75 (m, 3 H, CH2CH3 þ
H-5), 3.78 (s, 3 H, OCH3), 4.19 (s, 2 H, CCH2), 5.43 (qm, J=6.8
Hz, 1 H, CH). As a pure sample of 34 could not be obtained only
1
1
28: Rf = 0.56 (n-hexane/EtOAc 1:1); H NMR (300 MHz,
the H NMR datas are given. 35: Rf = 0.35 (n-hexane/EtOAc
1
CDCl3) δ 1.71 (dt, J=6.8/1.9 Hz, 3 H, CH3), 1.75 (t, J=2.6 Hz,
3 H, CCH3), 2.80-2.85 (m, 2 H, CH2C), 3.09-3.18 (m, 1 H,
H-4), 3.18-3.27 (m, 1 H, H-4), 3.78 (s, 3 H, OCH3), 4.70 (qt, J=
6.8/1.9 Hz, 1 H, CH); 13C NMR (75 MHz, CDCl3) δ 3.4 (CH3),
10.4 (CH3), 24.3 (CH2), 34.6 (C-4), 53.4 (C-3), 54.6 (OCH3), 72.4
(Calkyne), 79.7 (Calkyne), 99.9 (CH), 145.4 (C-5), 169.0 (CO),
171.9 (CO); IR (neat, cm-1) 2954, 1738, 1716, 1435, 1198.
HRMS (ESI) calcd for C12H15O4 223.0970, obsd 223.0967. 29:
Rf = 0.52 (n-hexane/EtOAc 1:1); 1H NMR (300 MHz, CDCl3)
δ 1.77 (t, J = 2.6 Hz, 3 H, CH3), 1.86-1.89 (m, 3 H, CH3),
2.56-2.67 (m, 1 H, H-4), 2.69-2.81 (m, 2 H, CH2, H-4 þ
CH2CC), 2.86 (dq, J = 16.6/2.6 Hz, 1 H, CH2CC), 3.76 (s,
3 H, OCH3), 4.98-5.04 (m, 1 H, H-5); 13C NMR (75 MHz,
CDCl3) δ 3.6 (CH3), 18.4 (CH3), 24.8 (CH2), 27.5 (C-4), 52.2
(OCH3), 53.2 (C-3), 73.1 (Calkyne), 79.3 (Calkyne), 99.1 (C-5),
149.8 (C-6), 166.8 (CO), 170.0 (CO); IR (neat, cm-1) 2955, 2923,
1796, 1772, 1737, 1716, 1435, 1146; HRMS (ESI) calcd for
C12H15O4 223.0970, obsd 223.0969. 30: Rf = 0.51 (n-hexane/
EtOAc 1:1); 1H NMR (300 MHz, CDCl3) δ 1.74-1.78 (m, 3 H,
CH3), 1.98 (dd, J = 12.4/3.5 Hz, 1 H, H-9), 2.47 (dd, J = 12.4/
2.3 Hz, 1 H, H-9), 2.53-2.65 (m, 1 H, H-8), 2.74-2.85 (m, 1 H,
H-8), 2.97 (dd, J = 3.5/2.3 Hz, 1 H, H-5), 3.78 (s, 3 H, OCH3),
4.36 (d, J=1.6 Hz, 1 H, CCH2), 4.64 (d, J=1.6 Hz, 1 H, CCH2),
5.53-5.59 (m, 1 H, H-7); 13C NMR (75 MHz, CDCl3) δ 21.0
(CH3), 30.2 (C-9), 34.7 (C-8), 38.7 (C-5), 50.2 (C-1), 53.0
(OCH3), 92.7 (CH2), 121.1 (C-7), 132.6 (C-6), 155.9 (C-4),
168.4 (CO), 170.9 (CO); IR (neat, cm-1) 2954, 1741, 1658,
1271, 1225, 1054; HRMS (ESI) calcd for C12H15O4 223.0970,
obsd 223.0967.
1:1); H NMR (400 MHz, CDCl3) δ 1.08 (t, J = 7.1 Hz, 3 H,
CH2CH3), 1.70-1.73 (m, 3 H, CH3), 1.90 (dd, J=12.1/3.4 Hz,
1 H, H-9), 2.42-2.47 (m, 1 H, H-9), 2.50-2.59 (m, 1 H, H-7),
2.66-2.74 (m, 1 H, H-7), 2.86-2.90 (m, 1 H, H-5), 3.72 (q, J=
7.1 Hz, 2 H, CH2CH3), 3.75 (s, 3 H, OCH3), 4.30 (d, J=1.1 Hz,
1 H, CCH2), 4.32 (d, J=1.1 Hz, 1 H, CCH2), 5.44-5.49 (m, 1 H,
H-7); 13C NMR (100 MHz, CDCl3) δ 11.6 (CH2CH3), 21.0
(CH3), 31.0 (C-9), 33.7 (C-8), 37.5 (CH2CH3), 41.9 (C-4), 50.8
(OCH3), 52.5 (C-1), 91.0 (CH2), 120.8 (C-7), 133.4 (C-6), 144.8
(C-4), 169.1 (CON), 172.7 (CO); IR (neat, cm-1) 2956, 1739,
1673, 1620, 1230; HRMS (ESI) calcd for C14H20NO3 250.1443,
obsd 250.1436.
(()-Methyl 6-Methyl-4-methylene-2-oxo-3-azabicyclo[3.3.1]-
non-6-ene-1-carboxylate (36). Representative Procedure. (Table 3,
entry 7) The title compound was prepared according to the general
procedure from catalyst A (8.73 mg, 11.3 μmol, 5 mol %) and 14
(50 mg, 0.226 mmol) in DCM (c = 500 mM) for 4 h at room
temperature. Flash chromatography (n-hexane/EtOAc 1:1) pro-
vided 36 (16.2 mg, 32%) as a colorless solid. Rf =0.24 (n-hexane/
EtOAc 1:1); mp 123-126 °C; 1H NMR (300 MHz, CDCl3)
δ 1.72-1.75 (m, 3 H, CH3), 1.94 (dd, J = 12.6/3.4 Hz, 1 H,
H-9), 2.41-2.48 (m, 1 H, H-9), 2.48-2.59 (m, 1 H, H-8), 2.71-2.82
(m, 1 H, H-8), 2.83-2.89 (m, 1 H, H-5), 3.76 (s, 3 H, OCH3), 4.19
(s, 1 H, CCH2), 4.23 (s, 1 H, CCH2), 5.44-5.50 (m, 1 H, H-7), 7.69
(s, 1 H, NH); 13C NMR (100 MHz, CDCl3) δ 21.1 (CH3), 30.6
(C-9), 33.0 (C-8), 39.4 (C-5), 49.6 (OCH3), 52.6 (C-1), 90.8 (CH2),
120.5 (C-7), 133.2 (C-6), 142.7 (C-4), 170.5 (CONH), 172.2 (CO);
IR (neat, cm-1) 3180, 1739, 1655, 1234; HRMS (ESI) calcd for
C12H16NO3 222.1130, obsd 222.1123.
(E)-Methyl 3-(But-2-ynyl)-1-ethyl-5-ethylidene-2-oxopyrroli-
dine-3-carboxylate (31), (Z)-Methyl 3-Ethyl-6-ethylidene-4-methy-
lene-2-oxo-3-azabicyclo[3.2.1]octane-1-carboxylate (34), and Methyl
3-Ethyl-6-methyl-4-methylene-2-oxo-3-azabicyclo[3.3.1]non-6-ene-
1-carboxylate (35). Representative Procedure I. (Table 3, entry
6) The title compounds were prepared according to the general
procedure from AuCl(PPh3) (3.72 mg, 8.0 μmol, 5.0 mol %),
AgNTf2 (3.11 mg, 8.0 μmol, 5.0 mol %), NEt3 (0.81 mg, 8.0 μmol,
1.12 μL, 5.0 mol %), and 12 (40 mg, 0.160 mmol) in refluxing
DCM (c=500 mM) for 6 h. Flash chromatography (n-hexane/
EtOAc 4:1) yielded 31 (21.8 mg, 55%) as a colorless oil.
Dimethyl 2-(But-2-ynyl)-2-((1-(ethylimino)-1H-isochromen-3-
yl)methyl)malonate (37). Representative Procedure. (Table 4,
entry 3) The title compound was prepared according to the
general procedure from catalyst A (3.14 mg, 4.1 μmol, 5 mol %)
and 22 (30 mg, 0.08 mmol) in toluene (c=250 mM) at 90 °C for
20 h. Flash chromatography (n-hexane/EtOAc 4:1) provided 37
(17.7 mg, 59%) as a colorless oil. Rf = 0.35 (n-hexane/EtOAc
1
1:1); H NMR (300 MHz, CDCl3) δ 1.26 (t, J = 7.5 Hz, 3 H,
CH2CH3), 1.80 (t, J=2.6 Hz, 3 H, CH3), 2.86 (q, J=2.6 Hz, 2 H,
CH2), 3.20 (s, 2 H, CH2), 3.45 (q, J=7.5 Hz, 2 H, CH2CH3), 3.76
(s, 6 H, OCH3), 5.99 (s, 1 H, CH), 7.11 (dd, J=7.9/1.1 Hz, 1 H,
Representative Procedure II. (Table 3, entry 6) The title
compounds were prepared according to the general procedure
H
arom), 7.25-7.32 (m, 1 H, Harom), 7.38-7.44 (m, 1 H, Harom),
8.03-8.13 (m, 1 H, Harom); 13C NMR (75 MHz, CDCl3) δ 3.5
4552 J. Org. Chem. Vol. 75, No. 13, 2010

Sperger and Fiksdahl
JOCArticle
(CH3), 16.0 (CH2CH3), 23.4 (CH2CCCH3), 36.1 (CH2), 40.6
(CH2CH3), 53.0 (2ꢀOCH3), 56.6 (COCCO), 73.2 (Calkyne), 79.5
(Calkyne), 105.0 (CH), 123.9 (Carom), 124.8 (CHarom), 126.5
(CHarom), 127.8 (CHarom), 131.4 (CHarom), 132.4 (Carom),
Dimethyl 2-(But-2-ynyl)-2-((2-tosyl-1,2-dihydroisoquinolin-3-
yl)methyl) Malonate (43). The title compound was prepared
according to the general procedure from catalyst A (4.01 mg,
5.2 μmol, 5 mol %) and 19 (50 mg, 0.104 mmol) in DCM (c =
500 mM) for 23 h at room temperature. Flash chromatography
(n-hexane/EtOAc 4:1) provided 43 (35.9 mg, 72%) as a colorless
solid. Rf = 0.53 (n-hexane/EtOAc 1:1); mp 168-170 °C; 1H
NMR (300 MHz, CDCl3) δ 1.80 (t, J=2.6 Hz, 3 H, CH3), 2.16
(s, 3 H, CH3), 2.77 (q, J=2.6 Hz, 2 H, CH2), 3.56 (s, 2 H, CH2),
3.83 (s, 6 H, OCH3), 4.54 (s, 2 H, CH2N), 6.39 (s, 1 H, CH), 6.63
(d, J=7.5 Hz, 1 H, Harom), 6.80 (d, J=8.1 Hz, 2 H, Harom), 6.86
(d, J = 7.5 Hz, 1 H, Harom), 6.89-6.96 (m, 1 H, Harom), 6.97-
7.04 (m, 1 H, Harom), 7.30 (d, J=8.1 Hz, 1 H, Harom); 13C NMR
(100 MHz, CDCl3) δ 3.5 (CH3), 21.2 (CH3), 23.0 (CH2CCCH3),
38.5 (CH2), 50.3 (CH2N), 52.9 (2 ꢀ OCH3), 56.7 (COCCO),
73.4 (Calkyne), 79.4 (Calkyne), 124.6 (CHarom), 125.0 (CH), 125.2
(CHarom), 126.9 (CHarom), 127.4 (2 ꢀCHarom), 127.8 (CHarom),
128.2 (2 ꢀ CHarom), 129.9 (C), 130.3 (C), 134.1 (C), 135.7 (C),
143.1 (C), 170.5 (2 ꢀ CO); IR (neat, cm-1) 2953, 1730, 1343,
1156; HRMS (ESI) calcd for C26H28NO6S 482.1637, obsd
482.1642.
149.7 (OCCH), 151.0 (NCO), 170.0 (2 ꢀ CO); IR (neat, cm-1
)
2955, 1736, 1671, 1650, 1435; HRMS (ESI) calcd for C21H24NO5
370.1654, obsd 370.1659.
(()-(E)-1-Ethylidene-6-methyl-3a-phenyl-2-tosyl-1,2,3,3a,4,6a-
hexahydrocyclo Penta[c]pyrrole (38). The title compound was
prepared according to the general procedure from sulfonamide
15 (25.0 mg, 0.066 mmol), AuCl(PEt3) (0.60 mg, 1.7 μmol, 0.025
equiv), and AgNTf2 (0.63 mg, 1.7 μmol, 0.025 equiv) in DCM
(136 μL) for 2 h at room temperature. Flash chromatography
(n-hexane/EtOAc 4:1) provided 38 (18 mg, 72%) as a colorless
oil that solidified upon standing. Rf = 0.60 (n-hexane/EtOAc
1:1); mp 109-111 °C, 1H NMR (300 MHz, CDCl3) δ 1.27-1.31
(m, 3 H, CCH3), 1.76 (d, J=7.2 Hz, 3 H, CHCH3), 2.40 (s, 3 H,
CH3), 2.61-2.67 (m, 2 H, CH2CH), 3.65 (d, J = 9.8 Hz, 1 H,
NCH2), 3.86 (bs, 1 H, CH), 4.00 (d, J = 9.8 Hz, 1 H, NCH2),
5.18-5.24 (m, 1 H, CHCH2CH), 5.85 (qd, J=7.2/1.1 Hz, 1 H,
CH), 7.11-7.28 (m, 7 H, Harom), 7.59 (d, J=8.3 Hz, 2 H, Harom);
13C NMR (100 MHz, CDCl3) δ 14.5 (CH3), 14.7 (CH3), 21.5
(CH3), 42.5 (CH2CH), 53.0 (PhC), 59.2 (CH), 63.6 (NCH2),
103.2 (CH), 123.8 (CH), 125.9 (2 ꢀ CHarom), 126.3 (CHarom),
127.5 (2 ꢀ CHarom), 128.6 (2 ꢀ CHarom), 129.1 (2 ꢀ CHarom),
134.8 (C), 138.9 (C), 140.7 (C), 143.5 (C), 145.5 (C); IR (neat,
cm-1) 2914, 2859, 1336, 1159; HRMS (ESI) calcd for
C23H26NO2S 380.1684, obsd 380.1688.
Acknowledgment. We thank the Norwegian Research
Council for financial support.
1
Supporting Information Available: Copies of H and 13C
NMR spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 13, 2010 4553