Intermolecular reaction of internal alkynes and imines: Propargyl tosylates as key partners in a gold-catalyzed [4 + 1] unusual cyclization leading to cyclopent-2-enimines

Article abstract of DOI:10.1021/ol8025523

Propargyl tosylates react with N-tosylaldimines to afford cyclopent-2-enimines in a gold-catalyzed process that involves a deep reorganization of both substrates. The formal [4 + 1] cyclization is initiated by a 1,2-migration of the tosylate that eventual

Full text of DOI:10.1021/ol8025523

ORGANIC
LETTERS
2009
Vol. 11, No. 1
13-16
Intermolecular Reaction of Internal
Alkynes and Imines: Propargyl
Tosylates as Key Partners in a
Gold-Catalyzed [4 + 1] Unusual
Cyclization Leading to
Cyclopent-2-enimines
Samuel Sua´rez-Pantiga,† Eduardo Rubio,† Carmen Alvarez-Ru´a,‡ and Jose´
M. Gonza´lez*,†
Instituto UniVersitario de Qu´ımica Organometa´lica “Enrique Moles”-Unidad
Asociada al C.S.I.C. and Departamento de Qu´ımica Orga´nica e Inorga´nica, and
SerVicio de Rayos X, SerVicios Cient´ıfico-Te´cnicos, UniVersidad de OViedo,
Julia´n ClaVeria, 8, 33006 OViedo, Spain
jmgd@unioVi.es
Received September 19, 2008
ABSTRACT
Propargyl tosylates react with N-tosylaldimines to afford cyclopent-2-enimines in a gold-catalyzed process that involves a deep reorganization
of both substrates. The formal [4 + 1] cyclization is initiated by a 1,2-migration of the tosylate that eventually generates a substituted 1,3-
diene. Subsequent interaction with the imine launches a series of reaction steps prior to a Nazarov-like cyclization to yield the final product.
The discovery of selective transformations associated with
basic functionalities is at the core of advances in synthetic
methodology. The reaction of internal alkynes with imines
has been scarcely reported, but significant transformations
have been described, among them, a vanadium-catalyzed
reaction of propargyl alcohols with imines furnishing Man-
nich adducts1 and an imidozirconocene-catalyzed carboami-
nation of imines across alkynes.2 Recent C-H activation-
based processses dealing with those functionalities are also
documented.3 Also, reactions of imines, with internal alkynes
and a third partner to furnish allyl amine derivatives, have
been disclosed.4 In general, these reactions take place through
an initial formation of an azametallacycle implying the imine
and the alkyne, which gives the product by catalytic ac-
tivation of the third component. Besides, the PMP aldimine
† Instituto Universitario de Qu´ımica Organometa´lica “Enrique Moles”-
Unidad Asociada al C.S.I.C. and Departamento de Qu´ımica Orga´nica e
Inorga´nica.
‡ Servicio de Rayos X.
(2) Ruck, R. T.; Zuckerman, R. L.; Krska, S. W.; Bergman, R. G. Angew.
Chem., Int. Ed. 2004, 43, 5372.
(1) (a) Trost, B. M.; Chung, C. K. J. Am. Chem. Soc. 2006, 128, 10358.
This result expands the scope of the oxovanadium-catalyzed aldol-type
reaction. For early work on aldol-type products by vanadium-catalyzed
addition of propargyl alcohol to aldehydes, see: (b) Trost, B. M.; Oi, S.
J. Am. Chem. Soc. 2001, 123, 1230.
(3) Selected examples: (a) Kuninobu, Y.; Tokunaga, Y.; Kawata, A.;
Takai, K. J. Am. Chem. Soc. 2006, 128, 202. (b) Yotphan, S.; Bergman,
R. G.; Ellman, J. A. J. Am. Chem. Soc. 2008, 130, 2452. (c) Colby, D. A.;
Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2008, 130, 3645.
10.1021/ol8025523 CCC: $40.75
Published on Web 12/01/2008
2009 American Chemical Society

of benzaldehyde reacts as a dipolarophile with a 1,4-dipole
arising from a gold-catalyzed rearrangement of 1-alkynyl-
1-acetylcyclopropanes.5
migration, the loss of a molecule of p-toluenesulfonic acid,
and the cleavage of the carbon-nitrogen imine bond are
among the changes in going from the starting compounds
to the product.
In this synthetic scenario, we investigated the conceivable
usefulness of alternative metal catalysts for the electrophilic
activation of alkynes. Moreover, a short screening for milder
reaction conditions was also undertaken. Representative
results are outlined in Table 1.
Herein, a new catalytic transformation arising from the
evolution of propargyl tosylates in the presence of different
N-tosylaldimines and a gold-based catalyst is reported. The
reaction promotes a moderate increase of molecular com-
plexity from the precursors and results in a selective assembly
of N-tosylimines derived from cyclopentenone scaffolds. The
overall process has been studied in detail, and it is shown to
comprise two well-defined cascade transformations that lead
to the cyclic frame, namely, an initial rearrangement of the
propargyl tosylate into a 2-tosyloxy-1,3-butadiene isomer and
a subsequent assembly of the cyclic frame that goes through
a multistep reaction sequence. Initial studies addressed the
search for proper propargyl partners and that of efficient
catalyst, with gold-based ones as an attractive choice due to
their potential in the electrophilic activation of unsaturated
carbon-carbon bonds.6,7 Early studies with alkynyl acetates
1 led to the well-documented product of self-condensation
3 without participation of the imine 2 (Scheme 1, eq 1).8
Table 1. Screening of Metal Complexes as Potential Catalysts
catalysta
(5 mol %)
T
time yieldb
entry
solvent (°C)
(h)
(%)
1
2
3
4
5
6
7
8
Ph3PAuNTf2
Au(DAVEPHOS)NTf2 DCE
Au(JOHNPHOS)NTf2 DCE
IPrAuCl/AgBF4
IPrAuCl/AgBF4
IPrAuCl/AgBF4
IPrAuNTf2
DCEc
60
60
60
60
40
rt
40
40
80
40
60
80
40
40
8
8
8
1
6
20
20
8
14
6
65
13
43
85
86
60
DCE
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
CH2Cl2
DCE
DCE
Scheme 1. Differential Behavior of Propargyl Acetates and
Tosylates toward Gold-Catalyzed Reaction with
Ph3PAuCl/AgBF4
51
68
83
19
N-Tosylaldimines
d
9
PtCl2
10
11
12
13
14
IPrAuCl/AgSbF6
AuCl3
2
d
Cu(MeCN)4BF4
48
21
20
d
AgBF4
CH2Cl2
CH2Cl2
26
-
none
a See the Supporting Information for references and description of the
catalysts structure and preparation. b Yield of isolated product after
chromatographic purification. c DCE ) 1,2-dichloroethane. d 7.5 mol %.
Although the reaction is feasible with metals such as Pt(II)
(entry 9) or Ag(I) (entry 13), several gold(I) precatalysts gave
We then checked the impact that the type of propargyl
ester being used might have over the reaction outcome as
an option to unveil other transformations. Interestingly, while
the use of phosphate esters gave no result at all, the switch
from carboxylic acid esters to related tosylates allowed an
alternative reaction path to occur and offered a simple way
for broadening the reactivity of the propargylic fragment.9
Thus, the reaction of imine 2a with tosylate 4a lead to the
isolation of the cyclopent-2-enimine 5a (see Scheme 1, eq
2, structure of 5a was established by X-ray analysis). The
formation of a cyclic structure, the ring size, a methyl
(6) For recent reviews, see, for instance: (a) Jime´nez-Nu´n˜ez, E.;
Echavarren, A. M. Chem. Commun. 2007, 333. (b) Gorin, D. J.; Toste,
F. D. Nature 2007, 446, 395. (c) Fu¨rstner, A.; Davies, P. W. Angew. Chem.,
Int. Ed. 2007, 46, 3410. (d) Hashmi, A. S. K. Chem. ReV. 2007, 107, 3180.
(e) Shen, H. C. Tetrahedron 2008, 64, 3885. (f) Skouta, R.; Li, C.-J.
Tetrahedron 2008, 64, 4917. (g) Muzart, J. Tetrahedron 2008, 64, 5815.
(h) Shen, H. C. Tetrahedron 2008, 64, 7847.
(7) Selected examples of gold-catalyzed intermolecular annulations: (a)
Melhado, A. D.; Luparia, M.; Toste, F. D. J. Am. Chem. Soc. 2007, 129,
12638. (b) Barluenga, J.; Ferna´ndez-Rodr´ıguez, M. A.; Garc´ıa-Garc´ıa, P.;
Aguilar, E. J. Am. Chem. Soc. 2008, 130, 2764. (c) Gorin, D. J.; Watson,
I. D. G.; Toste, F. D. J. Am. Chem. Soc. 2008, 130, 3736. (d) Li, G.; Huang,
X.; Zhang, L. J. Am. Chem. Soc. 2008, 130, 6944. (e) Shapiro, N. D.; Toste,
F. D. J. Am. Chem. Soc. 2008, 130, 9244.
(4) Ni-catalyzed reactions with organoboron reagents: (a) Patel, S. J.;
Jamison, T. F. Angew. Chem., Int. Ed. 2003, 42, 1364. Iridium-catalyzed
processes with hydrogen incorporation: (b) Barchuk, A.; Ngai, M.-Y.;
Krische, M. J. J. Am. Chem. Soc. 2007, 129, 8432. For an asymmetric
version, see: (c) Ngai, M.-Y.; Barchuk, A.; Krische, M. J. J. Am. Chem.
Soc. 2007, 129, 12644. Titanium-mediated processes with CO2 fixation to
afford R,ꢀ-unsaturated γ-lactams: (d) McLaughlin, M.; Takahashi, M.;
Micalizio, G. C. Angew. Chem., Int. Ed. 2007, 46, 3912. Formally related
synthesis of allylamines involving alkyne hydrozirconation, transmetallation
to zinc and imine addition: (e) Wipf, P.; Kendall, C.; Stephenson, C. R. J.
J. Am. Chem. Soc. 2003, 125, 761. DABCO-mediated related three-
component reactions: (f) Matsuya, Y.; Hayashi, K.; Wada, A.; Nemoto, H.
(8) (a) Wang, S.; Zhang, L. J. Am. Chem. Soc. 2006, 128, 8414. (b)
Barluenga, J.; Riesgo, L.; Vicente, R.; Lo´pez, L. A.; Toma´s, M. J. Am.
Chem. Soc. 2007, 129, 7772.
(9) Recent work on propargyl tosylates: (a) Schwier, T.; Sromek, A. W.;
Yap, D. M. L.; Chernyak, D.; Gevorgyan, V. J. Am. Chem. Soc. 2007,
129, 9868. Revisions on the reactivity of propargyl esters: (b) Marion, N.;
Nolan, S. P. Angew. Chem., Int. Ed. 2007, 46, 2750. (c) Marco-Contelles,
J.; Soriano, E. Chem.sEur. J. 2007, 13, 1350. References not covered in
these reviews: (d) Yu, M.; Zhang, G.; Zhang, L. Org. Lett. 2007, 9, 2147.
(e) Amijs, C. H. M.; Lo´pez-Carrillo, V.; Echavarren, A. M. Org. Lett. 2007,
9, 4021. (f) Dudnik, A. S.; Schwier, T.; Gevorgyan, V. Org. Lett. 2008,
10, 1465. (g) Cordonnier, M. C.; Blanc, A.; Pale, P. Org. Lett. 2008, 10,
1569. (h) Correa, A.; Marion, N.; Fensterbank, L.; Malacria, M.; Nolan,
S. P.; Cavallo, L. Angew. Chem., Int. Ed. 2008, 47, 718.
J. Org. Chem. 2008, 73, 1987
(5) Zhang, G.; Huang, X.; Li, G.; Zhang, L. J. Am. Chem. Soc. 2008,
130, 1814
.
.
14
Org. Lett., Vol. 11, No. 1, 2009

rise more efficiently to the desired transformation. Copper(I)
fails to produce the target transformation, and gold(III) is
quite inefficient for that purpose as it decomposes under the
reaction conditions. The counteranion ultimately associated
to the gold complex affects the reaction outcome; BF4 and
SbF6 yield better results than NTf2, probably because of the
more coordinating ability of the latter that could hamper the
reaction. This hypothesis is also consistent with the noticed
absence of reaction when the process was assayed using
acetonitrile rather than dichloromethane as solvent. Further-
more, the ligand present in the precatalyst and expected to
remain attached to gold offers another resort to improve the
reaction. Good results were obtained using a N-heterocycic
carbene (NHC) ligand.10 The best results were obtained using
the combination IPrAuCl/AgBF4 (entries 4-5)11 that fur-
nishes 5a in better yield than a similar reaction using
triphenylphosphine as ligand (see entries 5 and 8).12
Table 3. Screening of Propargyl Tosylatesa
Regarding the scope of the reaction, the transformation is
versatile for a representative set of substituents at the imine
carbon (Table 2). Thus, a variety of N-tosylimines could be
employed in this cyclization event, including aryl groups
other than phenyl (entries 2-5) and aliphatic ones (entries
6 and 7). The reaction is tolerant of both electron-rich (entries
2 and 4) and electron-deficient (entry 5) aromatic groups,
though the former gave higher yields. Interestingly, the nature
of the substituent at the imine nitrogen strongly affects the
feasibility of the process. Thus, when imines derived from
N-alkyl- or N-arylamines were employed rather than N-
tosylimines, the formation of the related cyclopent-2-enimine
derivatives of type 5 did not occur. No evidence could be
gathered for a significant evolution of the starting com-
pounds, probably speaking for a strong interaction of the
imine with the metal and resulting in the catalyst deactivation.
a The reactions were run in DCE or CH2Cl2 at 40-70 °C during a 20
min-10 h period (for full details, see the Supporting Information) with
imine 2a in the presence of 5 mol % of IPrAuCl/AgBF4. b After purification,
only the ketone was isolated.
carbon atom. Far from the case of 4a, with a linear alkyl
group attached at that position, the reaction is compatible
with other substitution patterns as benzyl or secondary alkyl
groups and even with some functional group at either alkyl
or aryl chains (entries 1-3 and 7). Moreover, the presence
of the tert-butyl group is not compulsory to push the
cyclization, which was proved compatible with secondary
alkyl substituents at that position (entries 4 and 5). Several
interesting structures were built including the spirane 5l and
the bicycle 5m arising from a selective ring-expansion
process.14
Table 2. Screening for N-Tosylimines: Modification of the
Substitution at the Imine Carbon Atom
entry
R
T (°C) time (h) product yielda (%)
In order to get insight into the mechanism of the reaction,
a clarifying result comes from the fact that the reaction of
alkyne 4g with the gold complex under the typical reaction
conditions yields the diene 6 as a 10:1 mixture of isomers.15
1
2
3
4
5
6
7
Ph
40
40
40
40
60
40
60
6
6
7
4
3
5a
5b
5c
5d
5e
5f
86
82
64
77
34
70
59
p-CH3(C6H4)
p-Cl(C6H4)
p-CH3O(C6H4)
p-NO2(C6H4)
Cy
(10) Overall view on NHC in synthesis: (a) N-Heterocyclic Carbenes
in Synthesis;Nolan, S. P., Ed.; Wiley-VCH: Weinheim, Germany, 2006.
Recent work on determination of stereoelectronic parameters associated with
NHC ligands, see: (b) D´ıez-Gonza´lez, S.; Nolan, S. P. Coord. Chem. ReV.
2007, 251, 874. (c) Kelly, R. A., III.; Clavier, H.; Giudice, S.; Scott, N. M.;
Stevens, E. D.; Bordner, J.; Samardjiev, I.; Hoff, C. D.; Cavallo, L.; Nolan,
S. P. Organometallics 2008, 27, 202.
10
1
n-C7H15
5g
a Yield of isolated product after chromatographic purification.
(11) (a) De Fre´mont, P.; Scott, N. M.; Stevens, E. D.; Nolan, S. P.
Organometallics 2005, 24, 2411. (b) De Fremont, P.; Stevens, E. D.; Fructos,
M. R.; D´ıaz-Requejo, M. M.; Pe´rez, P. J.; Nolan, S. P. Chem. Commun.
2006, 2045.
Studies aimed to prove the impact that the structure of
the propargyl tosylate counterpart could have over the scope
of the reaction were also conducted (Table 3).13
Preliminary results were obtained using as a model a
compound with a bulky tert-butyl group next to the tosylate
and modifying the substitution pattern at the other alkyne
(12) Improved gold-catalyzed reactions are realized when switching from
PPh3 to the NHC IPr ligand; see, for instance: (a) Marion, N.; D´ıez-
Gonza´lez, S.; de Fre´mont, P.; Noble, A. R.; Nolan, S. P. Angew. Chem.,
Int. Ed. 2006, 45, 3647. (b) Witham, C. A.; Mauleo´n, P.; Shapiro, N. D.;
Sherry, B. D.; Toste, F. D. J. Am. Chem. Soc. 2007, 129, 5838.
Org. Lett., Vol. 11, No. 1, 2009
15

Subsequent addition of the imine 2a and another charge of
the catalytic system provides the cyclopentene imine 5m in
64% yield (Scheme 2).
of the carbon-gold bond affording the 1,3-diene skeleton.17
Then, the intermediate 1,3-diene adds to the activated imine18
to form a strained azetine that, through an electrocyclic ring
opening in a formal metathesis process, opens up to a 1,4-
pentadiene.19 Again, the gold complex can activate this
intermediate to a “Nazarov-like” ring closure to the final
product.20 Also of interest, this fomal [4 + 1] annulation
mode expands the set of known reaction patterns for dienes
and imines, among them well established [4 + 2] cyclizations
or interesting vinylogous Mannich reactions.21 In short, a
new gold-catalyzed reaction cascade involving propargyl
derivatives and aldimines has been disclosed. The product
resulting from the overall transformation represents an
unprecedented coupling mode for these two partners. Fur-
thermore, the role of the 2-tosyloxy-1,3-butadiene scaffold
as intermediate for this process has been elucidated. A
subsequent reaction with the imine gave access to the final
cyclic compound through another selective combination of
steps, among them a well-documented Nazarov cyclization.
Further studies on the usefulness of the 1,2-shift of tosyl
group upon metal-catalyzed alkyne activation are in progress.
Scheme 2
.
Stepwise Elaboration of Cyclopent-2-Enenone Schiff
Base Derivatives
The successful assembly of the cyclopent-2-enimine scaf-
fold in the above-depicted stepwise process provides com-
pelling support to the involvement of related 2-tosyloxy-
1,3-butadienes in the one-pot approach previously described
that ultimately affords the same cyclic products. Thus, a
reasonable mechanistic proposal that accounts for the overall
reaction described from propargyl tosylates with N-to-
sylimines is outlined in Scheme 3 and involves a nicely
orchestrated combination of catalyzed reactions to gain access
to those elaborated cycles from readily available precursors.
Acknowledgment. We acknowledge the Spanish Govern-
ment for funding (Project CTQ2007-61048) and a FPU
fellowship (SSP).
Supporting Information Available: Experimental details,
X-ray data for 5a and 5i, and NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
Scheme 3
.
Proposed Mechanism: Main Steps Involved in the
One-Pot Approach
OL8025523
(15) For related intramolecular gold-catalyzed diene formation, see: (a)
Wang, S.; Zhang, L. Org. Lett. 2006, 8, 4585. (b) Buzas, A. K.; Istrate,
F. M.; Gagosz, F. Org. Lett. 2007, 9, 985. (c) Li, G.; Zhang, G.; Zhang, L.
J. Am. Chem. Soc. 2008, 130, 3740.
(16) For 1,2-alkyl migration in π-acid catalyzed reactions: (a) Crone,
B.; Kirsch, S. F. Chem.sEur. J. 2008, 14, 3514. For ligand effects on
migration of propargyl esters, see: (b) Gorin, D. J.; Sherry, B. D.; Toste,
F. D. Chem. ReV. 2008, 108, 3351. For a recent example of substrate design
to facilitate 1,2-shifts in activation of propargyl alcohol derivatives, see:
(c) Zhang, G.; Zhang, L. J. Am. Chem. Soc. 2008, 130, 12598.
(17) The rearrangement shows the chemoselectivity of [1,2]-shifts with
or without the occurrence of electron sextets. Bruckner, R. AdVanced
Organic Chemistry; Hartcourt/Academic: San Diego, 2002; pp 438-466.
(18) NMR monitoring of the reaction showed a deshielding of the imine
proton upon mixing equimolecular amounts of the reagents providing
evidence for the formation of an imine-gold complex. A gold(III)-catalyzed
addition of arenes to imines has been reported in Luo, Y.; Li, C.-J. Chem.
Commun. 2004, 1930. An alternative pathway involving straightforward
addition of the C-Au σ-bond in the complex with the dienesprior to its
protonationscannot be rigorously ruled out at present.
Upon coordination of the catalyst to the alkyne, an initial
isomerization of the propargyl tosylate occurs that leads to
a diene similar to 6. The isomerization process comprises a
1,2-tosyl rearrangement inducing a vicinal alkyl migration16
and a further elimination step that enables the protonation
(19) One of the reviewers suggested that the formation of the azetine is
a high energy pathway and proposed a plausible alternative that involves
the elimination of TsNH2 to form a pentadienone with Ts attached to the
carbonyl oxygen and further exchange of TsOH by TsNH2.
(13) The consumption of the propargyl tosylate was noticed for all of
the reactions depicted in Tables 2 and 3, with the exception of 5c (21% of
4a was recovered; extended reaction times did not improve the yield). As
a rule, NMR inspection of the reaction crude revealed conversion of starting
materials into the corresponding product 5 as the only noticeable major
reaction path. The standard column chromatographic purification process
was difficult, and partial hydrolysis of compounds 5 occurs to give the
related ketone easily, as noticed previously in the obtention of related
unsaturated imines; see: Boger, D. L.; Corbett, W. L. J. Org. Chem. 1992,
57, 4777. This fact accounts for the moderate isolated yields obtained for
some of the unsaturated imines reported.
(20) A carbonyl metathesis followed by a Nazarov cyclization has been
invoked in: (a) Jin, T.; Yamamoto, Y. Org. Lett. 2008, 10, 3137. For alkyne
carbonyl metathesis, see: (b) Jin, T.; Yamamoto, Y. Org. Lett. 2007, 9,
5259. Recent studies on the Nazarov cylization: (c) Marcus, A. P.; Lee,
A. S.; Davis, R. L.; Tantillo, D. J.; Sarpong, R. Angew. Chem., Int. Ed.
2008, 47, 6379. (d) Cavalli, A.; Pacetti, A.; Recanatini, M.; Prandi, C.;
Scarpi, D.; Occhiato, E. G. Chem.sEur. J. 2008, 14, 9292. (e) Basak, A. K.;
Tius, M. A. Org. Lett. 2008, 10, 4073. Metal-catalyzed asymmetric
approaches: (f) Liang, G.; Trauner, D. J. Am. Chem. Soc. 2004, 126, 954.
(g) Walz, I.; Togni, A. Chem. Commun. 2008, 4315.
(21) (a) Giera, D. S.; Sickert, M.; Schneider, C. Org. Lett. 2008, 10,
4259. (b) Salvador Gonza´lez, A.; Go´mez Arraya´s, R.; Rodr´ıguez Rivero,
M.; Carretero, J. C. Org. Lett. 2008, 10, 4335.
(14) To date, under the standard conditions, primary substituents at that
position fail to yield a clean transformation producing related cycles.
16
Org. Lett., Vol. 11, No. 1, 2009