Gold(I) catalyzes the intermolecular hydroamination of alkynes with imines and produces α,α′, N-triarylbisenamines: Studies on their use as intermediates in synthesis

Article abstract of DOI:10.1021/jo101674t

α,α′,N-Triarylbisenamines have been efficiently formed and isolated for the first time. The synthesis is based on an unprecedented gold(I)-catalyzed double intermolecular hydroamination between N-arylamines and aryl alkynes. This reaction constitutes a ne

Full text of DOI:10.1021/jo101674t

pubs.acs.org/joc
Gold(I) Catalyzes the Intermolecular Hydroamination of Alkynes
with Imines and Produces r,r0,N-Triarylbisenamines: Studies on Their
Use As Intermediates in Synthesis
ꢀ
Antonio Leyva-Perez,* Jose R. Cabrero-Antonino, Angel Cantın, and Avelino Corma*
ꢀ
´ ´
Instituto de Tecnologıa Quımica, Universidad Politecnica de Valencia-Consejo Superior de Investigaciones
Cientıficas, Avda. de los Naranjos s/n, 46022, Valencia, Spain
ꢀ
´
anleyva@itq.upv.es; acorma@itq.upv.es
Received August 26, 2010
R,R0,N-Triarylbisenamines have been efficiently formed and isolated for the first time. The synthesis
is based on an unprecedented gold(I)-catalyzed double intermolecular hydroamination between
N-arylamines and aryl alkynes. This reaction constitutes a new example of the intriguing behavior of
gold as catalyst in organic synthesis. The reactivity of these bisenamines for three different reactions,
leading to potentially useful intermediates, is also shown. In particular, hindered azabicycles [3.2.0],
which present excellent UVA and UVB absorption properties, are obtained by addition of triarylbis-
enamines to propiolates following an unexpected mechanism.
Introduction
Enamines are important molecules in organic synthesis1 and
constitute the key intermediates in organocatalysis.2 However,
bisenamines (Figure 1) are elusive compounds since the corre-
sponding imine form is generally more stable.3
FIGURE 1. Structure of bisenamines.
Bisenamines having a terminal vinyl group (R3 = R4 = H)
are particularly rare and only a few methods to form this kind
of compounds have been reported.4-6 These bisenamines present
a carbonyl-type group in the R position (R2=CO, CN), which
shifts the equilibrium toward the enamine by an electronic
withdrawing (EW) effect, and scarce examples of molecules
without this stabilizing effect can be found.7 Consequently, the
number of bisenamines reported to date is quite limited and
there are no general methods reported for their synthesis. To
this respect, the synthesis of bisenamines with substituents
other than carbonyl-type in the R position would open access
to new stable bisenamines.8
(1) Enamines: Synthesis, Structure and Reactions; Cook, A. G., Ed.;
Marcel Dekker Inc.: New York, 1988; p 717.
(2) (a) Beeson, T. D.; Mastracchio, A.; Hong, J.-B.; Ashton, K.; MacMillan,
Gold catalysis has emerged in the last years as a power-
ful tool in organic synthesis.9 The particular Lewis acidity
€
D. W. C. Science 2007, 316, 582. (b) Enders, D.; Huttl, M. R. M.; Grondal, C.;
Raabe, G. Nature 2006, 441, 861. For a review see: (c) Mukherjee, S.; Yang,
J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471.
(3) Lammertsma, K.; Prasad, B. V. J. Am. Chem. Soc. 1994, 116, 642.
(7) They have been described in some patents, where R1=R2=Me, as the
methyl quaternary ammonium salt or R1 = CO, R2 = alkyl or alkyl/aryl:
(a) Jpn. Kokai Tokkyo Koho, JP 59155366, 1984, p 14. (b) Martin, H.; Gysin,
H.; Zaeslin, H.; Margot, A.; 1948, US 2447196. (c) Shr, K.-Y.; Wu, J.-J.
Taiwan, TW 432092, 2001, p 2.
(8) We have found one example of phenyl groups as R-substituents in
bisenamines, obtained as byproducts, see: Volckaerts, E.; Geise, H. J.;
Daelemans, F.; Claereboudt, J. Bull. Soc. Chim. Belg. 1992, 101, 497.
(4) Thermal rearrangement of vinylaziridines (R1=H, R2=CO-, CN):
ꢁ
(a) Gelas-Mialhe, Y.; Mabiala, G.; Vessiere, R. J. Org. Chem. 1987, 52, 5395.
ꢁ
(b) Gelas-Mialhe, Y.; Touraud, E.; Vessiere, R. Can. J. Chem. 1982, 60, 2830.
(5) Reaction of thiazolidines with silver carbonate and DBU (R1 = H,
R2=CO2Me or CO2Et): Pinho e Melo, T. M. V. D.; Cabral, A. M. T. D. P.
V.; Gonsalves, A. M. d. A. R.; Beja, A. M.; Paixao, J. A.; Silva, M. R.; Alte da
Veiga, L.; Gilchrist, T. L. J. Org. Chem. 1999, 64, 7229.
ꢀ
(6) Reaction of methyl β-halo-R-aminopropionate hydrohalides with
bases (R1=H, R2=CO2Me): (a) Mitsuhashi, K. Asahi Garasu Kogyo Gijutsu
Shoreikai Kenkyu Hokoku 1973, 23, 355. Chem. Abstr. 1975, 82, 86591.
(b) Zaima, T.; Matsunaga, Y.; Mitsuhashi, K. J. Heterocycl. Chem. 1983, 20, 1.
(9) For reviews, see: (a) Ramon, R. S.; Gaillard, S.; Nolan, S. P. Strem
Chemiker 2009, 24, 11. (b) Hutchings, G. J.; Brust, M.; Schmidbaur, H. Chem.
Soc. Rev. 2008, 9, 1759. (c) Hashmi, A. S. K.; Hutchings, G. J. Angew. Chem.,
Int. Ed. 2006, 45, 7896.
DOI: 10.1021/jo101674t
r
Published on Web 10/25/2010
J. Org. Chem. 2010, 75, 7769–7780 7769
2010 American Chemical Society

ꢀ
Leyva-Perez et al.
JOCArticle
SCHEME 1. Mechanistic Pathways for the Gold(I)-Catalyzed Reaction of 1 with 2
of gold10 makes this metal unique as a catalyst, in terms of
reactivity and selectivity, and unexpected reaction path-
ways have been found. Up to now, gold salts,11 gold
complexes,12a,b gold metal-organic frameworks,12c or sup-
ported gold nanoparticles13 have been used as catalysts. In par-
ticular, highly acidic, bench-stable complexes of the general for-
tion to obtain 3, addition of the alkyne to the imine, and later
cyclization. When forcing the reaction conditions, a hydroar-
ylation occurs to form product 5.17,19 It has to be remarked
that a second hydroamination of 3 has not been observed since
the equilibrium imine-enamine (3-30) is mainly shifted toward
3. In fact, when using 13C-marked phenylacetylene, ∼17% of
enamine 30 with respect to imine can be observed by 13C NMR
spectroscopy in CDCl3 solution (see ahead imine 34). In our
case, when using AuSPhosNTf2 (7a) as catalyst, 6 is the main
product of the reaction (see Scheme 1). Product 6 was detected
by 1H and 13C NMR, and 4 and 5 were not present in the final
reaction mixture. This bisenamine 6 comes from the inter-
molecular hydroamination of 2with 30, as confirmed by isotopic
experiments (see Scheme S1 in the SI). To our knowledge,
this reaction has no precedent.
t
mula AuPR3NTf2 (R= phenyl, Bu, biphenyl-type, NTf2=
triflimide)14,15 have been shown to catalyze the addition of
water (hydration) and amines (hydroamination) to alkynes at
room temperature.14 Here, we report the first gold(I)-catalyzed
intermolecular hydroenamination of terminal alkynes to form
aryl bisenamines. The reactivity of these new bisenamines is
also studied, obtaining, for instance, new azobicycles with
photochemical properties.
Li and co-workers20 have reported a gold(III)-catalyzed
double-hydroamination of o-alkynylanilines with terminal
alkynes, in which they showed that the addition of the in situ
formed enamine to the alkyne occurs only intramolecularly.
In the work reported here, this addition is intermolecular and
bisenamine 6 is obtained in good yields under solventless
conditions at temperatures between 50 and 100 °C (Table 1,
entries 2-4). The cyclized products 4 and 5 are obtained in low
yields in all cases. Catalyst 7a could be recovered and reused
(entries 4 and 5). The use of gold(I) complex 7a as catalyst
rather than other gold(I) species seems to be preferable. As can
be seen in Table 1, the presence of the phosphine (compare
entries 2 and 9) and a low-coordinating counteranion (com-
pare entries 2 and 8 with 7) are necessary. Carbene gold(I) com-
plexes with noncoordinating counteranions also worked as
catalysts (entries 10-13) as well as AuPtBu3OTf (entry 14).
At this point, we prepared and studied the catalytic activity
of different gold(I)-NTf2 complexes where the nature of the
corresponding phosphine was varied (Table 2, phosphines are
roughly ordered from more to less donor from left to right).
It can be seen there that the better donor and hindered the
phosphine, the higher the activity is. Catalysts containing
Buchwald-type phosphines (7a,b, entries 1 and 2) or alkyl
phosphines (7c,d, entries 3-5) gave the best yields of 6. The
optimum result in terms of both activity and selectivity
was observed for complex 7c, which contains the bulky
Results and Discussion
Gold(I)-Catalyzed Synthesis of Aryl Bisenamines. In the
course of our work on hydroaminations,16 we have observed
that the addition of an excess of alkyne 2 to the amine 1 gives
the unexpected highly symmetric product 6 (Scheme 1).
Che and co-workers17 and Bertrand and co-workers18 have
reported the obtention of the 1,2-dihydroquinoline 4 by using
gold(I) carbene complexes at temperatures above 100 °C
(pathway A). The reaction sequence involves a hydroamina-
(10) Gorin, D. J.; Toste, F. D. Nature 2007, 446, 395.
(11) Hashmi, A. S. K.; Kurpejovic, E.; Frey, W.; Bats, J. W. Tetrahedron
2007, 63, 5879.
ꢀ
(12) (a) Marion, N.; Ramon, R. S.; Nolan, S. P. J. Am. Chem. Soc. 2009,
131, 448. (b) Staben, S. T.; Kennedy-Smith, J. J.; Toste, F. D. Angew. Chem.,
Int. Ed. 2004, 43, 5350. (c) Zhang, X.; Llabres i Xamena, F. X.; Corma, A.
J. Catal. 2009, 265 (2), 155.
(13) (a) Grirrane, A.; Corma, A.; Garcıa, H. Science 2008, 322, 1661.
(b) Zhang, X.; Corma, A. Angew. Chem., Int. Ed. 2008, 47, 4358. (c) Corma,
A.; Serna, P. Science 2006, 313 (5785), 332.
(14) (a) Leyva, A.; Corma, A. J. Org. Chem. 2009, 74, 2067. (b) Leyva, A.;
Corma, A. Adv. Synth. Catal. 2009, 351, 2876.
(15) Mezailles, N.; Ricard, L.; Gagosz, F. Org. Lett. 2005, 7, 4133.
(16) Forareviewongold(I)-catalyzedhydroaminations, see: (a)Widenhoefer,
R. A.; Han, X. Eur. J. Org. Chem. 2006, 4555. For a review on hydroaminations,
€
see: (b) Muller, T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada, M. Chem. Rev.
2008, 108, 3795.
(17) Liu, X.-Y.; Ding, P.; Huang, J.-S.; Che, C.-M. Org. Lett. 2007, 9, 2645.
(18) Zeng, X.; Frey, G. D.; Kinjo, R.; Donnadieu, B.; Bertrand, G. J. Am.
Chem. Soc. 2009, 131, 8690.
(19) For a silver-catalyzed reaction, see: (a) Luo, Y.; Li, Z.; Li, C.-J. Org.
Lett. 2005, 7, 2675. For a ruthenium-catalyzed reaction, see: (b) Yi, C. S.;
Yun, S. Y. J. Am. Chem. Soc. 2005, 127, 17000. (c) Yi, C. S.; Yun, S. Y.;
Guzei, I. A. J. Am. Chem. Soc. 2005, 127, 5782.
(20) Zhang, Y.; Donahue, J. P.; Li, C.-L. Org. Lett. 2007, 9, 627.
7770 J. Org. Chem. Vol. 75, No. 22, 2010

ꢀ
Leyva-Perez et al.
JOCArticle
TABLE 1. Formation of the Bisenamine 6 from p-Toluidine 1 and Phenylacetylene 2 under Different Conditions and Catalysts
entry
catalyst
2 (equiv)
T (°C)
1 (%, s.m.)a
3 (%)a
4 þ 5 þ others (%)a
6 (%)a
1
2
3
7a
7a
7a
7a
7a
7a
2
4
2
3.5
3.5
3.5
4
4
4
3.5
3.5
5
3.5
4
25
50
80
100
100
100
50
50
50
100
100
80
100
80
3
8
10
3
10
7
87
86
10
25
3
3
9
76
65
83
82
54
5
4
11
5b
6c
7
8
39
13
8
35
18
10
9
AuSPhosCl
AuSPhosOTfd
AuNTf2
8
9
2
10
5
5
5
90
e
65
f
10
11
12
13
14
IPrAuNTf2
77
85
86
IPrAuOTfg
IPrAuOTfh
IPrAuCl
65
30
35
5
AuPtBu3OTfi
65
aSee Scheme 1. For reaction conditions see Experimental Section. GC yield. bReuse of entry 4. cReuse of entry 5. dIsolated from AuSPhosCl and
AgOTf. eGenerated in situ from AuCl and AgNTf2. fGenerated in situ from chloro[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]gold(I) complex
and AgNTf2; see ref 17. gGenerated in situ from chloro[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]gold(I) complex and AgOTf; see ref 17. hUsing
a similar protocol to that in ref 17: CD3CN as solvent (1 M in 1), AgOTf (5 mol %), KPF6 (25 mol %). iGenerated in situ from AuPtBu3Cl and AgOTf,
CH3CN as solvent (1 M in 1).
TABLE 2. Catalyst Screening for the Formation of Bisenamine 6
tert-butylphosphine (entry 3, the corresponding triflate
derivative did not work so well, see entry 14 in Table 1).
On the contrary, catalysts containing EW phosphines (7e-g,
entries 6-8) gave mainly 3, which means that the reaction is still
in progress and uncompleted. The yield of the cyclized products
4 and 5 is low even for the most active catalysts and the
formation of one or another seems to depend on the nature of
the phosphine (compare entries 1-2 to 6-8).
The influence of the electronic density of the aniline ring
on the catalytic activity was also studied (Table S1, Support-
ing Information, SI). It was observed that electronically poor
rings improve the formation of the corresponding bisena-
mines (entries 1 and 2) while electronically rich aniline rings
hamper its formation (entry 4). The results are in agreement
with those found by Tanaka and co-workers on gold(I)-
catalyzed hydroamination of alkynes.21
Bisenamines containing different functionalities can be
formed in good to excellent yields (Table 3) including amides
(entry 2), R,β-unsaturated esters (entry 3), nitriles (entries 4
and 6), and halogens (entries 5 and 8-10). Isolation was not
trivial since the bisenamines decomposed largely on silica
(column or preparative TLC)22 and on neutral alumina. How-
ever, the purification was possible on basic alumina, affording
bisenamines 6, 9, 11, 13, and 18 in moderate to good yields after
column chromatography. Nonsymmetric bisenamines can also
be formed (entry 8). Amines having an o-substituent reacted
sluggishly (compare entry 7 to 4 and 6), possibly due to steric
effects (see X-ray diffraction, XRD, for 13 in the SI). The alkyl
alkyne 23 is also reactive, obtaining the R-substituted bisena-
mines 24 (entry 9) and 25 (entry 10) in high yields, as a mixture
of Z,Eisomers. Unfortunately, 24 decomposed under chromato-
graphic conditions and 25 after the workup. The only product
recovered from the decomposition of 25 was the corresponding
aromatic imine, which comes from the tautomerization of the
alkyl enamine functionality to the imine and subsequent hydro-
lysis. This degradation pathway confirms the results shown
in the isotopic experiments (see Scheme S1 in the SI). In those,
the bisenamines 59 and 60 were obtained as equimolecu-
lar mixtures of the Z/E isomers, coming from the rapid
entry
catalyst
ligand
1a
3a
4a
5a
6a
othersa
1
2
3
4
5
6
7
8
7a
7b
7c
7d
7db
7e
7f
A
B
C
D
Db
E
8
7
7
10
5
3
35
8
60
48
57
5
4
76
84
90
52
74
19
26
16
8
6
5
13
10
12
7
11
15
19
F
G
7g
aGC yield, in percentage. b10 mol % of catalyst.
imine-enamine equilibrium. This was assessed by GC-MS
(different isomers) and by H NMR spectroscopy (different
vinylic H peaks). Although the natural tendency of the
enamime to tautomerize to the imine form indeed occurs,
the triarylbisenamines here prepared are stable enough and
isolable.
Studies on the Reactivity of Aryl Bisenamines. The reactivity
of these novel compounds was explored. Bisenamine 6 was
chosen as substrate for three different reactions: a catalytic
hydrogenation, a palladium-catalyzed sp2 C-C coupling of
the two terminal double bonds, and an addition to propio-
lates. First, 6 was reduced with H2 over Pt/C to form the
corresponding racemic mixture of the diastereoisomers 26
and 27 (Scheme 2).
1
(21) Mizushima, E.; Hayashi, T.; Tanaka, M. Org. Lett. 2003, 5, 3349.
(22) However, the Rf values of the bisenamines could be calculated on
silica TLC plates.
J. Org. Chem. Vol. 75, No. 22, 2010 7771

ꢀ
Leyva-Perez et al.
JOCArticle
TABLE 3. Formation of Different Bisenamines Catalyzed by 7c
aGC yield, isolated yield between brackets. b7b (5 mol %) as catalyst, 60 °C, solventless. c1H NMR yield of the crude. d20 mol % catalyst, 8 equiv of
alkyne, 48 h. eRoom temperature for 24 h, then 80 °C for 24 h. f60 °C, solventless; 24 decomposes under chromatographic purification. g7b (1 mol %),
60 °C for 24 h, then 7b (4 mol %), 60 °C for 24 h; 25 could be detected by GC-MS; the aromatic imine was the only product recovered after the workup.
7772 J. Org. Chem. Vol. 75, No. 22, 2010

ꢀ
Leyva-Perez et al.
JOCArticle
SCHEME 2. Catalytic Hydrogenation of 6
Gratifyingly, the syn and the anti isomers could be sepa-
rated on preparative TLC in quantitative yield. As far as we
know, these are the first examples of diastereopure compounds of
this kind and they could work as diastereoselective inductors in
basic and metal-catalyzed reactions. The enantioselective version
was then tried. Unfortunately, neither Noyori-Takaya’s ruthe-
nium catalyst23a nor Buchwald’s titanium complex23b (specific
for enamine hydrogenation) were active in our hands, under
standard conditions.
FIGURE 2. XRD structure of the azabicyclo 32 (N: purple, O: red,
C: gray; hydrogens omitted for clarity).
Second, the Pd-catalyzed Heck-Mizoroki coupling between
the terminal bonds in 6and PhI was attempted. To our surprise,
the product recovered in quantitative yield after separation of
biphenyl was the pyrrole 29, corresponding to the intramolec-
ular oxidative coupling of the double bonds (Scheme 3).24
It was checked that the presence of PhI as sacrificial
oxidant to form 30 is necessary, playing the role of hydroqui-
none or O2 in related reactions.24a This unusual C-C coupling
constitutes a new method to obtain 2,5-diarylpyrroles.25
Finally, the reaction between triarylbisenamine 6and dimethy-
lacetylenedicarboxylate (DMAD, 31), an excellent Michael-type
acceptor, was studied (Scheme 4).26
and alkyne would be desirable. In fact, 32 could be directly
obtained from p-toluidine (1) and phenylacetylene (2) (Table 4),
using AuPtBu3NTf2 (7c) as catalyst. After optimization of the
reaction conditions, an excellent atom economy was obtained,
since the excess of 2 can be recovered by distillation.
This cyclobutapyrroline system is quite unusual27 and may
present pharmacological activity.28 To shed light on the mech-
anism of this reaction, isotopic experiments were carried out.
First, bisenamine 35, having one of the vinyl carbons marked as
13C, was prepared and reacted with 2 under the optimized con-
ditions in Table 4 (Scheme 5).14
According to the nucleophilic nature of the enamime groups
in 6, we should expect a double addition to 31. However, asingle
isolated product whose structure corresponds to the highly
crowded compound 32 was obtained in good yields. XRD
analysis (Figure 2) confirmed this structure with four different
quaternary centers and a cyclobutane-pyrroline bicyclic ring.
Overall, four new C-C bonds are formed in the reaction, with
complete diastereoselectivity.
The degree of isotopic incorporation in each step was quan-
titative, as determined by GC-MS. It was found that the marked
carbon eventually appears in both CH2 of the cyclobutane ring,
equimolarly, thus giving two different isotopic products 36a and
36b. This can be clearly assessed by comparing the different 1H
and 13C NMR spectra of 32 and 36a þ 36b (see the SI). For the
sake of illustration, the DEPT spectra of 32 and 36a þ 36b are
compared in Figure 3, showing clearly how the two CH2s in
32 are now recorded as four different carbons in 36a þ 36b: one
more intense signal corresponding to the enriched 13C (intense
Given the inherent instability of bisenamines, a one-pot pro-
cedure to form the azabicycle from the corresponding amine
SCHEME 3. Pd-Catalyzed Intramolecular Oxidative Coupling of 6
SCHEME 4. Synthesis of the Azabicyclo 32 from Bisenamine 6 and DMAD (31)
J. Org. Chem. Vol. 75, No. 22, 2010 7773

ꢀ
Leyva-Perez et al.
JOCArticle
TABLE 4. One-Pot Formation of Azabicycle 32 from 1 and 2, Catalyzed by Gold(I) Complex 7c
entry
7c (mol %)
solventa (step 1)
T (step 1, °C)
31 (equiv)
T (step 2, °C)
32 (%)b
1
2
3
4
5
6
5
5
5
2
2
3
CH3CN
CH3CN
CH3CN
CH3CN
CH3CH2CN
CH3CN
80
80
80
80
95
80
4
80
80
rt
80
95
80
75
73
8
56
34
75
1.2
1.2
1.2
1.2
1.2
aDMF and 1,4-dioxane are also suitable solvents. bGC yield.
FIGURE 3. DEPT spectra of the azabicycles 32 (a) and 36a þ b (b); CH2s upside.
SCHEME 5. Formation of the Azabicycles 36a and 36b, Marked with 13
C
singlets) and other lesser intense signals corresponding to the
12C coupled with the neighboring 13C (doublets, J= 29.1 Hz).
A new isotopic experiment was carried out with deuterated
phenylacetylene 37 as the vinylating agent of 34 (Scheme 6).
It was found that scrambling of the deuterium atom occurs
in bisenamine 38,3 leading to the other three different
(23) (a) Mashima, K.; Kusano, K.; Sato, N.; Matsumura, Y.; Nozaki, K.;
Kumobayashi, H.; Sayo, N.; Hori, Y.; Ishizaki, T.; Akutagawa, S.; Takaya,
H. J. Org. Chem. 1994, 59, 3064. (b) Lee, N. E.; Buchwald, S. L. J. Am. Chem.
Soc. 1994, 116, 5985.
(25) Huerta, G.; Fomina, L.; Rumsh, L.; Zolotukhin, M. G. Polym. Bull.
2006, 57, 433.
(24) For a review see: (a) Beccalli, E. M.; Broggini, G.; Martinelli, M.;
Sottocornola, S. Chem. Rev. 2007, 107, 5318. For a related Pd-catalyzed
intramolecular cyclization of enaminones to obtain carbazoles see: (b) Iida,
H.; Yuasa, Y.; Kibayashi, C. J. Org. Chem. 1980, 45, 2938.
(26) (a) Berchtold, G. A.; Uhlig, G. F. J. Org. Chem. 1963, 28, 1459.
(b) Brannock, K. C.; Burpitt, R. D.; Goodlett, V. W.; Thweatt, J. G. J. Org.
Chem. 1963, 28, 1464.
(27) Acheson, R. M.; Procter, G. J. Chem. Soc., Perkin Trans. I 1977, 1924.
7774 J. Org. Chem. Vol. 75, No. 22, 2010

ꢀ
Leyva-Perez et al.
JOCArticle
SCHEME 6. Formation of the Azabicycles 42-45a and 42-45b, Marked with 13C and 2H
deuterated bisenamines 39-41 in equimolecular ratio. Com-
parison of the 1H NMR spectra of these bisenamines 38-41
and that corresponding to bisenamine 35 (see Scheme 5) clearly
shows the appearance of two different signals for each hydrogen
on both marked and unmarked carbons (Figure 4), indicating
one geminal deuterium by molecule. This is also con-
firmed by 13C NMR and DEPT (see the SI), since one 13CH2
and one 13CH signal are recorded in a similar ratio.
of the bisenamine 6. This implies that at least one vinyl CdC
bond is broken during the process.29 A plausible mechanism is
depicted in Scheme 7.
According to this mechanistic proposal, a first [2 þ 2]
cycloaddition occurs to form the cyclobutene adduct 47. Atthis
point, a second intramolecular addition to the formed alkene
does not occur but ring-opening forms 49. This fragmentation
has been well-reported for the addition of alkyl enamines from
ketones to 3126 and other propiolates.30 The failed intramolec-
ular addition of the second bisenamime group in 47 can be
explained by steric and electronic factors on the cyclobutene
ring, since a tertiary carbon must act as an electrophile.31 More-
over, the high steric hindrance in the hemiazacubane 48 would
also hamper this reaction pathway. But once 49 is formed, the
second intramolecular Michael-type addition can proceed with-
out steric impediments to form the seven-membered cycle adduct
50, which rapidly cyclizes back to form 32.30-32 The Michael-
type addition of 6 to acrylate esters only works intramolec-
ularly, since reaction of 6 with R-methyl acrylate or other
activated double bonds did not proceed under any experimen-
tal conditions tested, including metal catalyzed (see Scheme
S2 in the SI). The planarity of adduct 50 and the rigidity of the
bicylic ring in 32 forces the ester and the phenyl moieties to be in
the cis position, conferring complete diastereoselectivity to the
process. In fact, the trans diastereomer would be too unstable
to form. The proposed diionic nature33 of the intermediates
instead of a possible radical mechanism is supported by three
facts: (a) slight variations in the polarity of the solvent produce
FIGURE 4. Vinylic region of the 1H NMR spectra of the azabi-
cycles 35 (a) and 38-41 (b).
With the mixture 38-41 in hand, it was expected that reac-
tion with 31 would give a mixture of eight different azabicy-
cles 42-45a,b, according to the results in Scheme 5. Indeed, the
1H and13C NMR spectra of the isolated mixture confirmed the
presence of one deuterium per molecule bounded to the outer
carbons of the cyclobutane ring, having an equimolecular
mixture of 13C. For illustration, the 13C NMR spectra of 32,
36a,b, and 42-45a,b are compared in Figure 5, showing how
50% of the CH2s in 32 are marked as 13C in 36a,b (see also
Figure 3) and finally split again as triplet by deuterium incor-
poration in 50% of those; DEPT experiments confirmed that
the latest corresponds to a mixture of CH2sandCHs(seetheSI).
From these results it can be concluded that the carbons of the
cyclobutane ring in 32 are originally the terminal vinyl carbons
(29) Rearrangements are a cornerstone in organic synthesis since they
give access to carbon skeletons otherwise difficult to achieve: (a) Corey, E. J.
Angew. Chem., Int. Ed. 2002, 41, 1650. (b) Nicolaou, K. C.; Snyder, S. A.;
Montagnon, T.; Vassilikogiannakis, G. Angew. Chem., Int. Ed. 2002, 41,
1668. (c) Zimmerman, H. E.; Armesto, D. Chem. Rev. 1996, 96, 3065.
ꢀ
(d) Cantın, A.; Leiva, S.; Jorda, J. L.; Valencia, S.; Rey, F.; Corma, A. Stud.
Surf. Sci. Catal. 2007, 170A, 330. (e) Cantın, A.; Corma, A.; Leiva, S.; Rey,
F.; Rius, J.; Valencia, S. J. Am. Chem. Soc. 2005, 121, 560. Polycyclic
compounds, in particular those containing nitrogen, are ubiquitous in nature
and different rearrangements are used in their synthetic route: (f) Perreault,
S.; Rovis, T. Chem. Soc. Rev. 2009, 38, 3149. (g) Li, P.; Menche, D. Angew.
Chem., Int. Ed. 2009, 48 (28), 5078. (h) Singh, V.; Nedanthan, P.; Sahu, P. K.
Tetrahedron Lett. 2002, 43, 519.
(30) Brannock, K. C.; Burpitt, R. D.; Goodlett, V. W.; Thweatt, J. G.
J. Org. Chem. 1964, 29, 813–817.
(31) Brannock, K. C.; Bell, A.; Burpitt, R. D.; Kelly, C. A. J. Org. Chem.
1964, 29, 801.
(32) Brannock, K. C.; Bell, A.; Burpitt, R. D.; Kelly, C. A. J. Org. Chem.
1961, 26, 625.
(33) Smith, M. B.; March, J. In March’s Advanced Organic Chemistry:
Reactions, Mechanisms, and Structure. See [2 þ 2] cycloadditions, pp 1077-
1084; John Wiley and Sons: New York, 2001; p 2083.
€
€
(28) For related structures see: (a) Attia, M. I.; Guclu, D.; Hertlein, B.;
Julius, J.; Witt-Enderby, P. A.; Zlotos, D. P. Org. Biomol. Chem. 2007, 5,
2129. (b) Tang, P.; Lin, Z.; Yang, J.; Zhao, F.; Wang, Y.; Wang, Q. China,
WO2008148279 (A1), 2008.
J. Org. Chem. Vol. 75, No. 22, 2010 7775

ꢀ
Leyva-Perez et al.
JOCArticle
FIGURE 5. Part of the 13C NMR spectra of the azabicycles 32 (a), 36a,b (b), and 42-45a,b (c).
SCHEME 7. Proposed Mechanism for the Addition of DMAD (31) to Bisenamine 6
an important change in the reaction rate (Table 4, entries 4
and 5) and, in general, polar solvents are more suitable (see
footnote in Table 4); (b) the nucleophilicity of the bisenamine
and/or the electrophilicity of the Michael acceptor determines
dramatically the reaction yield (Scheme 8 and Scheme S2 in
the SI); and (c) addition of the radical AIBN (50 mol %) to the
reaction mixture does not stop the formation of 32, although a
slowdown in the reaction rate is observed.
As can be seen, the better donor the aryl ring of the bisenamine
(6) and the more electron acceptor the alkyne (31) are, the higher
the reaction yield. Although other factors such as the polymer-
ization rate of the alkyne and the stability of the bisenamine
under the reaction conditions cannot be overridden, these results
point to diionic charged intermediates in the reaction.
Azabicycles as UV Sunscreeners. UV sunscreen organic
chemicals are delocalized compounds such as p-octyl
7776 J. Org. Chem. Vol. 75, No. 22, 2010

ꢀ
Leyva-Perez et al.
JOCArticle
SCHEME 8. Influence of the Electronic Nature of Both Bisenamine and Alkyne in the Reaction
aGC yield.
methoxycinnamate and bisoctrizole. The azobicycles here
synthesized possess similar functionalities to those and, in
principle, they could absorb strongly in the whole range of the
UV-A and UV-B rays. The UV-vis spectra for compounds 32,
55, and 56 are shown in Figure 6.
Experimental Section
General. Glassware was dried in an oven at 175 °C before use.
Reagents and solvents were obtained from commercial sources
and were used without further purification unless otherwise
indicated. Gold(I) complexes 7a,14a 7c,14a and 7d15 were pre-
pared as previously reported. All the products obtained were char-
acterized by GC-MS, 1Hand13CNMR,andDEPT.Gaschromato-
graphic analyses were performed in an instrument equipped
with a 25 m capillary column of 5% phenylmethylsilicone. GC/
MS analyses were performed on a spectrometer equipped with the
same column as the GC and operated under the same conditions.
HRMS were performed with the electrospray ionization tech-
nique. 1H, 13C, DEPT, and 31P NMR were recorded in a 300 MHz
instrument with CDCl3 as solvent otherwise indicated, containing
TMS as internal standard. IR spectra of the compounds were re-
corded on a spectrophotometer by impregnating the windows with
a dichloromethane solution of the compound and leaving to evap-
orate before analysis. UV-visible measurements were recorded on
a spectrophotometer with CH2Cl2 as solvent. Elemental analyses
of the solids were determined by chemical combustion with a
CHNSO analyzer.
FIGURE 6. UV-vis spectra of p-octyl methoxycinnamate (A),
compound 32 (B), compound 55 (C), and compound 56 (D),
measured at 1 μM concentration in CH2Cl2.
Syntheses of Gold Catalysts. Synthesis of AuDavePhosCl. Tet-
rachloroauric acid trihydrate (394 mg, 1 mmol) was dissolved in
distilled water (1 mL) under nitrogen and the solution was cooled
in ice. Then, 2,20-thiodiethanol was slowly added over 45 min until
disappearance of the color (ca. 300 μL). After that, 20-dicyclohex-
ylphosphanylbiphenyl-2-yldimethylamine (DavePhos, 394 mg,
1 mmol) was added and then 3 mL of ethanol. The mixture was
stirred at rt for 3 h. Then, a NaHCO3 aqueous solution (ca. 20 mL)
was added to the clear solution until at pH ∼7 a white solid starting
precipitating. The solid was filtered off and redissolved in CH2Cl2,
extracted with brine, dried over MgSO4, and filtered. The solution
was concentrated to dryness to obtain AuDavePhosCl as a white
powder (500 mg, 0.80 mmol, 80%). IR (cm-1): 2931, 2854, 1446,
1327, 1203, 1142, 1057, 741. 1H NMR (δ, ppm; J, Hz): 7.60-7.40
(4H, mult), 7.36 (1H, ddd, J= 7.5, 4.1, 1.5), 7.06 (2H, mult), 6.97
(1H, dd, J=7.4, 1.7), 2.46 (6H, s), 2.30 (1H, qt, J= 11.8, 2.8), 2.00
(3H, mult), 1.85 (1H, mult), 1.80-1.50 (8H, mult), 1.40-1.05 (9H,
mult). 13C NMR (δ, ppm; JC-P, Hz): 151.1 (C), 148.5 (C, J=12),
134.6 (C), 133.35 (CH, J=8), 132.2 (CH, J=4), 131.4 (CH), 130.8
(CH, J=2), 129.3 (CH), 126.9 (CH, J=7), 125.4 (C, J=53), 121.9
(CH), 119.7 (CH), 43.7 (2CH3), 37.7 (CH, J=33), 35.6 (CH, J=
34), 30.7 (CH2, J=4), 30.2 (CH2, J=3), 29.9 (CH2), 28.8 (CH2),
26.9 (CH2), 26.6 (CH2, J=3), 26.5 (CH2, J=5), 26.4 (CH2), 25.6
(CH2, J = 2), 25.5 (CH2, J = 2). 31P NMR (δ, ppm): 39.4.
Elemental Anal. (calcd for C26H36AuClNP: C, 49.89; H, 5.80; N,
2.24) found: C 49.19, H 5.74, N 2.20. HRMS (ESI) [Mþ; calcd for
As can be seen, azobicycles 32, 55, and 56 indeed absorb in
the UVA and UVB ranges at similar concentrations as the
commercial p-octyl methoxycinnamate. Although, in general,
the latter absorbs stronger over the UVB region, the azobi-
cycles absorb more strongly in the UVA region and even in the
far UVB. These results indicate the potential interest of these
molecules for manufacturing sunscreen products.
Conclusions
In conclusion, the first intermolecular hydroamination of
alkynes with imines-enamines has been shown, AuPR3NTf2
complexes acting as catalysts. R,R0,N-Triarylbisenamines have
been formed and isolated for the first time. These novel com-
pounds could open new synthetic pathways to other chemicals.
As proof of reactivity, a catalytic hydrogenation, an intramo-
lecular oxidative C-C coupling, and an addition to propio-
lates have been performed, giving access to useful intermedi-
ates. In particular, the latter allows the synthesis of UV absorber
azabicycles [3.2.0], creating four new quaternary centers with
complete diastereoselectivity in a single step. The terminal
vinyl carbons of the bisenamine eventually form the cyclobu-
tane ring and this carbon rearrangement can be explained by
successive [2 þ 2] cycloaddition-cycloreversion reactions.
J. Org. Chem. Vol. 75, No. 22, 2010 7777

ꢀ
Leyva-Perez et al.
JOCArticle
C26H36AuClNP: 625.1939] found m/z 625.1936; [(M - Cl)þ,
major peak ; calcd for C26H36AuNP: 590.2251] found m/z
590.2232.
1264, 1207, 1136, 952, 739. 1H NMR (δ, ppm; J, Hz): 7.44 (6H,
t, J=7.7), 7.34 (3H, tq, J=7.6, 1.3), 7.20 (6H, mult). 13C NMR
(δ, ppm; JC-P, Hz): 148.8 (3C, d, J=5.0), 130.6 (6C, d, J=2.2),
127.1 (3C, d, J=2.2), 121.1 (6C, d, J=6.0). 31P NMR (δ, ppm):
103.7.
Synthesis of AuDavePhosNTf2 (7b). AuDavePhosCl (350 mg,
0.56 mmol) and AgNTf2 (217 mg, 0.56 mmol) were placed in a
round-bottomed flask. Air evacuation-nitrogen refilling cycles
were carried out and a rubber septum was rapidly fitted after the
last nitrogen refilling, a nitrogen balloon additionally coupled
through a needle. Then, dry CH2Cl2 (15 mL) was added and the
mixture was magnetically stirred at rt for 30 min. Then, the white
solid formed (AgCl) was filtered off over Celite and the clear filtrates
were concentrated to dryness to obtain AuDavePhosNTf2 as a
yellow-bright crystalline powder (490 mg, quantitative). Crystals
can be obtained by dissolving the solid in the minimum amount of
CH2Cl2 and adding hexane until blurring is observed, then leaving
the mixture into a fridge at -14 °C overnight and filtering the
crystal thus obtained. IR (cm-1): 2931, 2854, 1342, 1196, 1142,
1057. 1H NMR (δ, ppm; J, Hz): 7.64-7.38 (5H, mult), 7.11 (2H, t,
J=7.7), 6.99 (1H, d, J=7.0), 2.46 (6H, s), 2.28-2.00 (4H, mult),
1.86-1.62 (8H, mult), 1.48-1.18 (10H, mult). 13C NMR (δ, ppm;
JC-P,otherwise indicated, Hz): 151.2 (C), 148.1 (C), 133.4 (CH), 132.4
(CH), 131.6 (2 ꢀ CH), 129.3 (CH), 127.3 (CH), 124.0 (C), 123.3
(C,), 122.2 (CH), 119.4 (C, JC-F = 323), 119.1 (CH), 43.4 (2 ꢀ
CH3), 37.4 (CH, J = 34), 36.3 (CH, J = 34), 31.0 (CH2), 29.6
(CH2), 26.6 (CH2), 26.5 (2 ꢀ CH2), 26.4 (CH2), 26.3 (CH2), 25.6
(CH2), 25.5 (2 ꢀ CH2). 31P NMR (δ, ppm): 39.1. Elemental Anal.
(calcdforC28H36AuF6N2O4PS2: C, 38,63; H, 4,17; N, 3,22; S, 7,37)
found: C, 39,53; H, 4,32; N, 3,24; S, 7,43. HRMS (ESI) [(M - Cl)þ,
major peak; calcd for C26H36AuNP: 590.2251] found m/z
590.2258.
Synthesis of AuP(trisCF3-phenyl)3NTf2 (7g). The title com-
pound was obtained by following the same procedure as for 7c
but with AuP(trisCF3-phenyl)3Cl complex (200 mg, 0.28 mmol)
as gold precursor (slightly purple-white solid, 265 mg, 71%). IR
(cm-1): 1396, 1327, 1203, 1134, 1057, 956, 833, 710, 601.
1H NMR (δ, ppm; J, Hz): 7.87 (3H, ddt, J = 8.1, 2.3, 0.6), 7.84
(3H, ddt, J=13.4, 8.1, 0.6). 13C NMR (δ, ppm; JC-P, Hz): 134.6
(3C, d, J=14.9), 126.9 (3C, dq, J=12.4, 3.2), 135.9-112.9 (23C,
mult). 31P NMR (δ, ppm): 30.7. HRMS (ESI) [Mþ þ Hþ; calcd
for C29H7AuF33NO4PS2: 1351.8691] found m/z 1352.0453.
Reaction Procedures. General Double-Hydroamination Procedure
(Bisenamine 6). Complex 7b (22 mg, 5 mol%) and p-toluidine (1)
(54 mg, 0.5 mmol) were placed into a vial. Then, dry CH3CN
(0.25 mL) and phenylacetylene (2) (220 μL, 2 mmol) were sequen-
tially added (alternatively, the reaction can be run without solvent).
The vial was sealed and the mixture was magnetically stirred in a
preheated oil bath at 80 °C for 24 h. After cooling, an aliquot was
taken for GC analysis. The CH3CN was removed in vacuo and
CH2Cl2 (1 mL) was added to redissolve the mixture. Then, n-hexane
(10-20 mL) was added and the mixture was vigorously stirred for
15 min and filtered over Celite. The resulting filtrates were concen-
trated under reduced pressure and analyzed by NMR. The crude
was purified by column chromatography on basic alumina (2-5%
AcOEt in n-hexane) to achieve bis(1-phenylvinyl)-p-tolylamine
(6) as a yellow oil (140 mg, 0.45 mmol, 90%). This oil solidifies in
a fridge at -14 °C as yellow crystals, which were washed with
n-hexane and dried.
Hydrogenation Procedure for Bisenamine 6 and Isolation of the
Corresponding Tertiary Amines 26 and 27. Pt/C (3 wt%, 12 mg,
Pt: 15 mol%) and bisenamine 6 (39 mg, 0.125 mmol) were placed
into a 2 mL thin double-walled vial having a pressure controller
and an H2 inlet/outlet. Dry THF (1 mL) was added and the vial
was sealed, purged three times with H2 (8-10 atm), and finally
loaded with H2 (12 atm, 0.13 mmol, 5 equiv). The mixture was
magnetically stirred in a preheated oil bath at 50 °C for 6 h.
Progressive loss of the yellow color of the solution was observed.
After cooling, the remaining H2 was removed and the mixture
was filtered. The resulting solution was analyzed by GC and
GC-MS and the amines were quantitatively separated and
purified by TLC on silica (2% AcOEt in hexane). After extrac-
tion from the silica with neat AcOEt and removal of the solvents,
18 mg of each amine was obtained as a white oil (>95% yield).
Pd-Catalyzed Intramolecular Oxidative Coupling of 6. Pd-
(OAc)2 (2.2 mg, 20 mol%), bisenamine 6 (15.6 mg, 0.05 mmol),
and NaHCO3 (12.6 mg, 3 equiv) were placed into a vial. Dry
DMF (0.25 mL) and PhI (16.7 μL, 3 equiv) were added and the
vial was sealed and magnetically stirred in a preheated oil bath at
140 °C for 20 h. After cooling, the resulting solution was ana-
lyzed by GC and GC-MS and the product was purified by TLC
on silica (2% AcOEt in hexane). After extraction from the silica
with neat AcOEt and removal of the solvents, 15 mg of pyrrole
29 was obtained (>95% yield). The spectroscopic data of 29 fit
those previously reported.
Synthesis of Au(PtBu3)NTf2 (7c).14a Au(PtBu3)Cl (435 mg,
1 mmol) and AgNTf2 (388 mg, 1 mmol) were mixed in dry
dichloromethane (25 mL). The mixture was stirred at rt under
nitrogen for 30 min and filtered over Celite. The solution was
concentrated to dryness to obtain Au(PtBu3)NTf2 as a white
solid (675 mg, 0.99 mmol, quantitative). Crystals can be obtained
by dissolving the solid in the minimum amount of CH2Cl2 and
leaving to evaporate at room temperature. IR (cm-1): 3437, 2951,
1398, 1205, 1134, 958. 1H NMR (δ, ppm; J, Hz): 1.52 (27H, d, J=
14.3). 13C NMR (δ, ppm; J, Hz): 119.3 (2C, q, JC-F = 323.0),
39.8 (3C, d, JC-P = 11.9), 32.1 (9C, d, JC-P = 3.8). 31P NMR
(δ, ppm): 90.9. FABþ [Mþ; calcd for C14H27AuF6NO4PS2: 679]
found m/z 399 (Mþ - N(SO2CF3)2), 833 (PtBu3AuClAuPtBu3).
Synthesis of Au(PEt3)NTf2 (7d). The title compound was
obtained by following the same procedure as for 7c but with Au
(PEt3)Cl (200 mg, 0.57 mmol) as gold precursor (gray solid, 340
mg, quantitative). IR (cm-1): 3511, 2928, 1342, 1200, 1140,
1057. 1H NMR (δ, ppm; J, Hz): 1.90 (4H, dq, JH-P =10.6, J=
7.8), 1.21 (6H, dt, JH-P = 19.7, J = 7.7). 13C NMR (δ, ppm):
119.3 (2C, q, JC-F=322.7), 38.4 (3C, d, JC-P=38.4), 9.2 (3C, d,
J
C-P = 1.7). 31P NMR (δ, ppm): 32.6.
Synthesis of AuP(OPh)3Cl. Tetrachloroauric acid trihydrate
(394 mg, 1 mmol) was dissolved in distilled water (1 mL) under
nitrogen and the solution was cooled in ice. Then, 2,20-thio-
diethanol was slowly added over 45 min until disappearance of
the color (ca. 300 μL). After that, triphenylphosphite (236 μL,
1 mmol) was added and then 3 mL of ethanol. The mixture was
stirred at rt for 3 h. The solid was filtered off and washed with
methanol, redissolved in dry dichloromethane, and filtered
again. The solution was concentrated to dryness to obtain
Addition of Bisenamine 6 to DMAD (31). Bisenamine 6 (15.6 mg,
0.05 mmol) was placed into a vial. Dry DMF (0.25 mL) and
DMAD (24.6 μL, 4 equiv) were added and the vial was sealed and
magnetically stirred in a preheated oil bath at 140 °C for 20 h.
After cooling, the resulting solution was analyzed by GC and GC-
MS and the product was purified by TLC on silica (10% AcOEt in
hexane). After extraction from the silica with neat AcOEt and
removal of the solvents, 19 mg of 32 was obtained (85% yield).
Yellow crystals were obtained by redissolving in CH2Cl2 and slow
evaporation. GC-MS (m/z): 453 (Mþ•, 3%), 425 (100%), 394
1
AuP(OPh)3Cl as a white solid. H NMR (δ, ppm; J, Hz): 7.32
(6H, t, J=8.0), 7.17 (9H, mult). 13C NMR (δ, ppm; JC-P, Hz):
149.3 (3C, d, J=4.9), 130.5 (6C, d, J=1.7), 126.7 (3C, d, J=1.6),
121.1 (6C, d, J=5.6). 31P NMR (δ, ppm): 109.7.
Synthesis of AuP(OPh)3NTf2 (7f). The title compound was
obtained by following the same procedure as for 7c but with
AuP(OPh)3Cl (130 mg, 0.24 mmol) as gold precursor (white solid,
100 mg, 54% yield). IR (cm-1): 3054, 2981, 1590, 1486, 1404,
7778 J. Org. Chem. Vol. 75, No. 22, 2010

ꢀ
Leyva-Perez et al.
JOCArticle
(39%), 194 (17%). 1H NMR (δ, ppm; J, Hz): 7.44 (2H, dd, J =
8.5, 1.7), 7.38 (2H, mult), 7.29 (4H, mult), 7.20 (2H, mult), 6.65
(2H, dd, J=8.6, 0.7), 6.35 (2H, dt, J=8.5, 2.1), 3.50 (3H, s), 3.22
Compound 13. The reaction was run at 2 mmol scale. The
crude was purified by column chromatography on basic alumina
(0-10% AcOEt in hexane) to achieve 4-[bis(1-phenylvinyl)-
amino]benzonitrile (13) as a yellow oil (152 mg, 47%). The
product was dissolved in the minimum amount of hexane and
kept overnight in a fridge at -14 °C to obtain yellow crystals,
which were washed with cold n-hexane and dried. Rf (10%
AcOEt in hexane): 0.61%. GC-MS (m/z): 322 (Mþ•, 86%), 294
(10%), 245 (12%), 205 (100%). IR (cm-1): 3062, 3024, 2918, 2852,
2221, 1600, 1500, 1317, 1206. 1H NMR (CD3CN, δ, ppm; J, Hz):
7.61 (4H, mult), 7.43 (2H, dt, J = 9.0, 2.3), 7.31 (6H, mult), 7.09
(2H, dt, J=8.8, 2.3), 5.28 (2H, d, J=0.6), 4.95 (2H, d, J=0.6).
13C NMR (CD3CN, δ, ppm): 151.8 (2C), 151.7, 138.6 (2C), 133.6
(2C), 129.5 (2C), 129.3 (4C), 127.8 (4C), 124.7 (2C), 119.8, 109.7
(2C), 105.1. HRMS (ESI) [M þ Hþ; calcd for C23H19N2:
323.15548] found m/z 323.1555.
(3H, s), 3.19-2.94 (3H, mult), 2.43 (1H, mult), 2.05 (3H, s). 13
C
NMR (δ, ppm): 171.3, 161.8, 137.0, 136.4, 136.3, 133.8, 131.7,
129.6, 129.0, 128.8 (2C), 128.6, 128.0 (2C), 127.8, 127.7 (2C),
127.4, 127.0, 125.2 (2C), 105.7, 77.6, 62.1, 51.5, 50.5, 29.2, 27.6,
20.7. HRMS (ESI) [M þ Hþ; calcd for C29H28NO4: 454.2018]
found m/z 454.1956.
Isotopic Experiments (Schemes 5 and 6). p-Toluidine (1) (21.
4 mg, 0.2 mmol) and AuSPhosNTf2 (7a) or AuPtBu3NTf2 (7c)
(1 mol%) were placed into a vial equipped with a magnetic bar.
Then, CD3CN (0.4 mL, 0.5 M solution) and 13C-marked phe-
nylacetylene (2) (24 μL, 1.1 equiv) were sequentially added and
the vial was sealed. The solution was magnetically stirred at
room temperature for 24 h. Then, AuPtBu3NTf2 (7c) (17 mg,
5 mol %) and phenylacetylene (2) or d1-phenylacetylene (37)
(63 μL, 3 equiv) were added and the mixture was magnetically
stirred in a preheated oil bath at 80 °C for 24 h. After this time,
DMAD (31) (30 μL, 1.2 equiv) was added and the mixture was
magnetically stirred at 80 °C for an additional 20 h. The resulting
solution was analyzed by GC and GC-MS and the product was
purified by TLC on silica (10-20% AcOEt in hexane). After extrac-
tion from the silica with neat AcOEt and removal of the solvents,
21 mg of 36a,b (23%) or 30 mg of 42-45a,b (35%) was obtained.
All the intermediates were analyzed by in situ NMR and GC-MS.
UV Measurements. A 1 μM DCM solution of the compounds
was prepared as follows: 32 (2.26 mg, 0.005 mmol) was diluted
in 5 mL of DCM and then 25 μL of this solution was diluted in
25 mL of DCM. The same procedure was followed for 55 (2.32 mg,
0.005 mmol), 56 (2.40 mg, 0.005 mmol), and p-octylmethoxycinna-
mate (1.45 μL, 0.005 mmol).
Compound 16. The reaction was run at 0.5 mmol scale (1H
NMR yield, 58%). The crude was purified by column chroma-
tography on basic alumina (0-5% AcOEt in hexane) to achieve
bis[1-(4-chlorophenyl)vinyl](4-iodophenyl)amine (16). Rf (5%
AcOEt in hexane): 0.77. 1H NMR (ppm; J, Hz): 7.37 (4H, mult),
7.19 (4H, mult), 7.17 (2H, dt, J=8.8, 2.1), 6.71 (2H, dt, J=8.2,
2.1), 5.01 (2H, d, J = 0.8), 4.64 (2H, d, J = 0.8). 13C NMR
(δ, ppm): 150.0 (2C), 146.2, 137.8 (2C), 136.6 (2C), 134.0 (2C),
128.6 (4C), 127.9 (4C), 126.8 (2C), 107.6 (2C), 86.8.
Compound 18. The reaction was run at 1 mmol scale. The
crude was purified by column chromatography on basic alumi-
na (0-15% AcOEt in hexane) to achieve 3-[bis(1-phenylvinyl)-
amino]benzonitrile (18) as a yellow oil (306 mg, 95%). Rf (10%
AcOEt in hexane): 0.52%. IR (cm-1): 3059, 3033, 2954, 2925,
1
2229, 1686, 1602, 1485, 1437, 1318, 1276. H NMR (δ, ppm;
J, Hz): 7.47 (4H, mult), 7.24-7.14 (8H, mult), 7.09 (1H, td, J=
7.7, 0.5), 7.03 (1H, dt, J=7.6, 1.4), 5.10 (2H, s), 4.98 (2H, s). 13
C
Product Characterization. Compound 6. The yellow oil, after
column chromatography, solidifies in a fridge at -14 °C as
yellow crystals, which were washed with n-hexane and dried.
Rf (10% AcOEt in hexane): 0.69. GC-MS (m/z): 311 (Mþ•, 100%),
283 (14%), 194 (100%). IR (cm-1): 3034, 2924, 1611, 1505, 1321,
NMR (δ, ppm): 150.8 (2C), 147.6, 137.6 (2C), 129.4, 128.7, 128.4
(4C), 128.3, 127.4 (2C), 126.7 (4C), 125.8, 118.7, 112.6, 108.1
(2C). HRMS (ESI) [Mþ; calcd for C23H19N2: 323.1548] found
m/z 323.1553.
Compound 20. The reaction was run at 0.25 mmol scale for 48
h, using 20 mol % of 7c (34 mg) as catalyst and 8 equiv of
phenylacetylene 2 (220 μL). The crude was analyzed by GC, GC-
1
1258, 773, 702. H NMR (δ, ppm; J, Hz): 7.49 (4H, mult), 7.11
(6H, mult), 6.89(2H, d, J=8), 6.82 (2H, d, J=8), 4.91(2H, s), 4.54
(2H, s), 2.08 (3H, s). 13C NMR (δ, ppm): 151.7, 144.4 (2C), 138.9,
132.5 (2C), 129.3 (2C), 128.1 (2C), 127.9 (2C), 126.7 (4C), 125.2
(2C), 125.2 (2C), 106.1 (2C), 20.7. HRMS (ESI) [Mþ; calcd for
C23H21N: 311.1674] found m/z 311.1674.
MS, 1H, 13C NMR, and DEPT. GC-MS (m/z): 322 (Mþ•
,
100%), 294 (5%), 245 (10%), 205 (68%).
Compound 24. The reaction was run at 1 mmol scale. After
24 h, hexane (10-20 mL) was added and precipitated solid was
filtered off. After removal of the volatiles under vacuum, 24 was
obtained as an orangish red oil (417 mg, 95%). GC-MS (m/z,
Compound 9. The reaction was run at 1 mmol scale. The crude
was purified by column chromatography on basic alumina (0-3%
MeOH in AcOEt) to achieve 4-[bis(1-phenylvinyl)amino]benz-
amide (9) as a yellowish orange solid (190 mg, 56%). GC-MS
(m/z): 340 (Mþ•, 100%), 312 (7%), 223 (100%). IR (cm-1): 3353,
three different peaks, major isomer shown here): 439 (Mþ•
,
12%), 382 (40%), 368 (100%), 354 (33%), 298 (29%), 244
(79%). 1H and 13C NMR: see spectra.
1
3207, 2921, 2855, 2304, 2200, 1806, 1708, 1494, 1371. H NMR
Compound 25. The reaction was run at 1 mmol scale. The first
imine with phenylacetylene (2) (121 μL, 1.1 equiv) was formed at
60 °C for 24 h, using 7b (9 mg, 1 mol %) as catalyst. Then,
additional catalyst (36 mg, 4 mol %) was added together with
1-octyne (444 μL, 3 equiv) and the mixture was reacted at 60 °C
for 24 h, and analyzed by GC-MS. After the reaction was
completed, volatiles were removed under vacuum and hexane
(10-20 mL) was added to precipitate the catalyst. The solid was
filtered off and, after removal of the solvents, an orange solid,
corresponding to the aromatic imine, was recovered (225 mg,
70% yield). GC-MS of 25 (m/z, two peaks, major isomer shown
here): 431 (Mþ•, 46%), 416 (48%), 374 (100%), 354 (13%), 298
(6%), 244 (31%).
(δ, ppm; J, Hz): 7.48 (6H, mult), 7.20-7.17 (6H, mult), 6.97 (2H,
dt, J=8.7, 1.9), 5.80(2H, brs), 5.12(2H, s), 4.81 (2H, s). 13CNMR
(δ, ppm): 169.0, 151.0 (2C), 150.3, 138.0 (2C), 128.3 (4C), 128.2
(2C), 128.1 (2C), 126.7 (4C), 126.5, 123.6 (2C), 108.2 (2C). HRMS
(ESI) [M þ Hþ; calcd for C23H21N2O: 341.1654] found m/z
341.1665.
Compound 11. The reaction was run at 1 mmol scale. The
crude was purified by column chromatography on basic alumina
(1-5% AcOEt in hexane) to achieve 3-{4-[bis(1-phenylvinyl)
amino]phenyl}acrylic acid ethyl ester (11) as a yellow oil (304 mg,
77%). Rf (5% AcOEt in hexane): 0.23. IR (cm-1): 3057, 3032,
2977, 1706, 1624, 1600, 1505, 1315, 1265, 1171. 1H NMR (δ, ppm;
J, Hz): 7.61 (6H, mult), 7.29 (7H, mult), 7.06 (2H, dt, J=8.6, 2.1),
6.28 (1H, d, J = 16.0), 5.20 (2H, s), 4.89 (2H, s), 4.26 (2H, q,
J = 7.1), 1.33 (3H, t, J = 7.2). 13C NMR (δ, ppm): 167.2, 151.0
(2C), 148.9, 144.2, 138.2 (2C), 128.6 (2C), 128.5, 128.3 (4C), 128.2
(2C), 126.7 (4C), 124.3 (2C), 116.1, 107.9 (2C), 60.2, 14.3. HRMS
(ESI) [Mþ; calcd for C27H26NO2: 396.1964] found m/z 396.1955.
Compound 32. Rf (20% AcOEt/hexane): 0.24. GC-MS (m/z):
1
453 (Mþ•, 3%), 425 (100%), 394 (39%), 194 (17%). H NMR
(δ, ppm; J, Hz): 7.46 (2H, dd, J=8.5, 1.7), 7.40 (2H, mult), 7.31
(4H, mult), 7.22 (2H, mult), 6.67 (2H, dd, J=8.6, 0.7), 6.37 (2H,
dt, J=8.5, 2.1), 3.52 (3H, s), 3.24 (3H, s), 3.21-2.96 (3H, mult),
2.45 (1H, mult), 2.07 (3H, s). 13C NMR (δ, ppm): 171.3, 161.8,
J. Org. Chem. Vol. 75, No. 22, 2010 7779

ꢀ
Leyva-Perez et al.
JOCArticle
137.0, 136.4, 136.3, 133.8, 131.7, 129.6, 129.0, 128.8 (2C), 128.6,
128.0 (2C), 127.8, 127.7 (2C), 127.4, 127.0, 125.2 (2C), 105.7,
77.6, 62.1, 51.5, 50.5, 29.2, 27.6, 20.7. HRMS (ESI) [M þ Hþ;
calcd for C29H28NO4: 454.2018] found m/z 454.1956.
50.7, 29.7, 27.5. HRMS (ESI) [M þ Hþ; calcd for C29H27N2O5:
483.1920] found m/z 483.1879.
Acknowledgment. This work is dedicated to Prof. Steven V.
Ley on the occasion of his 65th birthday. A.L-P. thanks CSIC
for a contract under the JAE-doctors program. Financial
support by the PLE2009 project from MCIINN and PRO-
METEO from Generalitat Valenciana are also acknowledged.
We thank Dr. I. Andreu for discussions on UV results. The
continuous support from the ITQ’s NMR team is also parti-
cularly appreciated.
1
Compound 55. Rf (25% AcOEt/hexane): 0.21. H NMR (δ,
ppm; J, Hz): 7.44-7.35 (2H, mult), 7.10 (2H, d, J=9), 6.39 (2H,
d, J = 9), 3.53 (3H, s), 3.24 (3H, s), 3.18 (2H, mult), 2.98 (1H,
mult), 2.47 (1H, mult). 13C NMR (δ, ppm): 170.5, 165.0, 159.0,
143.1, 135.8, 132.1 (2C), 130.9, 130.7, 129.7 (2C), 129.4, 128.5
(2C), 128.3 (2C), 128.2, 127.0 (2C), 123.5 (2C), 118.7, 109.5,
105.8, 62.2, 51.7, 50.8, 29.7, 27.3. HRMS (ESI) [M þ Hþ; calcd
for C29H25N2O4: 465.1814] found m/z 465.1802.
Compound 56. Rf (75% AcOEt/hexane): 0.23. 1H NMR
(δ, ppm; J, Hz): 7.60-7.10 (12H, mult), 6.35 (2H, d, J = 9),
5.85-5.15 (2H, br s), 3.90-3.40 (3H, mult), 3.52 (3H, s), 3.24
(3H, s), 3.15 (1H, mult). 13C NMR (δ, ppm): 171.1, 168.4, 165.2,
159.9, 142.5, 136.2, 131.2, 129.5, 129.4, 128.3 (2C), 128.1 (4C),
128.0, 127.6, 127.5 (2C), 127.2 (2C), 123.6 (2C), 108.3, 62.2, 51.7,
Supporting Information Available: General methods, reac-
tion procedures and compound characterization in detail, as
well as additional schemes, tables, and figures, XRD structure
1
for compounds 6, 7c, 13, and 32, and copies of H, 13C, and
DEPT spectra of compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
7780 J. Org. Chem. Vol. 75, No. 22, 2010