Gold(I)-catalyzed [4+2] cycloaddition of N-(hex-5-enynyl) tert-butyloxycarbamates

Article abstract of DOI:10.1016/j.jorganchem.2008.11.004

A study concerning the gold(I)-catalyzed transformation of N-(hex-5-enynyl) tert-butyloxycarbamates is described. The mild conditions employed allow the moderately efficient but stereoselective synthesis of a range of bicyclic carbamates following a forma

Full text of DOI:10.1016/j.jorganchem.2008.11.004

Journal of Organometallic Chemistry 694 (2009) 515–519
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Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Gold(I)-catalyzed [4+2] cycloaddition of N-(hex-5-enynyl) tert-butyloxycarbamates
Andrea Buzas a, Florin Istrate a, Xavier F. Le Goff b, Yann Odabachian a, Fabien Gagosz a,
*
a Laboratoire Syntheses Organiques, Ecole Polytechnique, CNRS, Route de Scaclay, F-91128 Palaiseau Cedex, France
b Laboratoire Heteroelements et Coordination, Ecole Polytechnique, CNRS, F-91128 Palaiseau Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 June 2008
Received in revised form 31 October 2008
Accepted 3 November 2008
Available online 7 November 2008
A study concerning the gold(I)-catalyzed transformation of N-(hex-5-enynyl) tert-butyloxycarbamates is
described. The mild conditions employed allow the moderately efficient but stereoselective synthesis of a
range of bicyclic carbamates following a formal [4+2] cycloaddition process.
Ó 2008 Elsevier B.V. All rights reserved.
Keywords:
Homogeneous catalysis
Gold complexes
Cycloaddition
Ynamides
1. Introduction
tetrahydroquinoline derivatives using electron-deficient ynamides
as the substrates [9].
During the past ten years, numerous organic synthetic chemists
have become attracted to the chemistry of electron-deficient
ynamines and ynamides. Such an interest may be explained by
the fact that these reactive species are easily accessible and possess
a high synthetic potential [1]. As a consequence, a wide variety of
methodologies have been developed involving ynamines, and yna-
mides, and leading to the formation of a plethora of cyclic and acy-
clic nitrogen containing structures. Among these transformations,
those using a metallic species as a catalyst remain predominant
since they allow a rapid increase in structural complexity while
working under generally mild reaction conditions. For instance
various cyclizations or [2+2], [4+2], [2+2+2] annelation reactions
have been described using Ru(II), Rh(I), Pt(II) or Pt(IV) based
catalysts [2]. Electron-deficient ynamides have also proved to be
suitable partners in a range of Pd(0)-catalyzed cross-coupling reac-
tions [3] or in RCM transformations [4].
The ongoing interest in gold catalysis [5] has also led to the
development of a few new transformations involving electron-
deficient ynamides. The first study in this domain was made by
Cossy and coworkers who described the gold(I)-catalyzed cycloiso-
merization of ene-ynamides into 2-azabicylco[3.1.0]hexanes [6].
Later on, the group of Hashmi [7] and our group [8] independently
reported that N-alkynyl tert-butyloxycarbamates 1 could be con-
verted in the presence of a gold(I) complex into a range of function-
alized oxazolones 2 (Scheme 1). More recently, Hashmi and
coworkers reported the elegant synthesis of dihydroindole and
Following this recent success in the chemistry of ynamides, we
envisaged to take advantage of this functionality to develop some
other new gold mediated transformations. We were particularly
keen to examine the cyclization of N-hex-5-enynyl tert-butyloxyc-
arbamates 3 into bicyclic compounds 4 (Scheme 2). This transfor-
mation could be a synthetically useful extension of one of our
previously reported transformations concerning the alkoxycylisa-
tion of 1,5-enynes [10].
We indeed recently reported that enynes of type 5 could be cy-
clized in the presence of an oxygen-containing nucleophile to ste-
reoselectively furnish cyclopentenes 7 (Scheme 3, Eq. (1)).
This transformation is proposed to involve the formation of an
intermediate 6 which is regio- and stereoselectively trapped by
an external nucleophile. Intermediate 6 would possess a pro-
nounced carbocationic character [11] and should be better de-
picted as a gold-stabilized homoallylic carbocation 6c rather than
cyclopropyl gold carbene 6a [12]. By analogy with this transforma-
tion, we surmised that substrates of type 3 possessing an ynamide
functionality could react in the presence of a gold(I) complex to
generate an analogous intermediate of type 8 (Scheme 3, Eq. (2)).
The tert-butyloxycarbonate moiety could perhaps play the role of
an internal nucleophile to stereoselectively trap this intermediate.
This would lead to the formation of the bicyclic compound 4 in
which the stereochemistry of one of the new stereocentres would
have been inverted by comparison with the previously reported
transformation. Moreover, the presence of the enamide functional-
ity in the cyclized products would be particularly useful to imple-
ment further transformations such as reduction, hydration or
oxidation.
* Corresponding author.
E-mail address: gagosz@dcso.polytechnique.fr (F. Gagosz).
0022-328X/$ - see front matter Ó 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2008.11.004

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A. Buzas et al. / Journal of Organometallic Chemistry 694 (2009) 515–519
2. Results and discussion
O
O
N
[(Ph3P)Au(NCMe)]SbF6
O
O
Enyne 11 was first chosen as a model substrate to validate our
approach. It was synthesized in two steps following the procedure
we previously reported (Scheme 4) [8]. Treatment of bromoalkyne
9 and tert-butyloxycarbamate 10 (1.2 equiv.) with CuSO4 Á 5H2O
(20 mol%), 1,10-phenanthroline (40 mol%) and K3PO4 (1.2 equiv.)
in toluene at 80 °C for 72 h led to the formation of the desired N-
alkynyl tert-butyloxycarbamates (11), which was isolated in 69%
yield [13].
N
R1
R2
or
R1
R2
(Ph3P)AuNTf2
1
2
R1= alkyl, alkenyl, aryl, silyl
R2= Boc, Piv, tosyl, aryl, benzyl
Scheme 1. Cyclization of N-alkynyl tert-butyloxycarbamates.
We were pleased to see that treating substrate 11 with 1 mol%
of the crystalline and air stable Ph3PAuNTf2 gold complex [14] in
dichloromethane at room temperature furnished the desired bicy-
clic compound 12 in 68% yield. The yield was improved to 78%
when the biphenylphosphine based gold complex 13 [14] was used
as the catalyst, even if the reaction time was longer in this case.
This new transformation, which can be described as a formal
[4+2] cycloaddition of an N-alkynyl tert-butyloxycarbamate with
an alkene [15], is remarkable from a synthetic point of view since
two cycles and one new stereocentre are created from a linear sub-
strate under mild reaction conditions. It is also noteworthy that the
R2
AcO
R3
R2
R3
O
H
Au(I)
?
O
N
O
AcO
N
O
R1
R1
4
3
Scheme 2. Proposal of N-hex-5-enynyl tert-butyloxycarbamates cyclization.
HOR4
R3
R2
R3
AcO
LAu
R2
R3
R2
R3
AcO
LAu
AcO
LAu
AcO
R2
H
OR4
(eq 1)
R
R
R
R
6a
6b
6c
7
Au(I)
inversion of
stereochemistry
R= alkyl, aryl
R2,R3 ≠ H
5
ou R2=H, R3=alkenyl
R2
R3
R2
AcO
Au
AcO
R3
H
H
R3
O
Au(I)
O
(eq 2)
O
AcO
R2
R
N
O
N
R1
8
R1
O
4
3
R=
N
O
internal nucleophilic attack
R1
Scheme 3. External nucleophilic addition versus internal nucleophilic addition.
AcO
AcO
AcO
H
CuSO4 5H2O
catalyst
Br
O
9
O
+
1,10-phenanthroline
K3PO4
CH2Cl2, RT
N
O
O
N
O
Bn
11
Bn
toluene, 80°C, 72 h
69%
HN
Bn
10
O
12
1 mol% Ph3PAuNTf 2
68%
78%
30 min
t-Bu
t-Bu
AuNTf2
13
P
1 h
1 mol%
AcO
14
1 mol% HNTf2
1 mol% AgNTf2
0%
15 min
30 min
Bn
N
O
O
<10%
(14: 85%)
Scheme 4. Formation and cyclization of enyne 11.

A. Buzas et al. / Journal of Organometallic Chemistry 694 (2009) 515–519
517
AcO
AcO
H
AcO
1 mol% 13
CuSO4 5H2O
O
Br
O
9
+
N
R
O
CH2Cl2, RT
1,10-phenanthroline
K3PO4, toluene, 80°C
N
R
O
O
HN
R
O
17
18
68%
65%
R=Me
15
16
(16%)
R=CH2COOEt (51%)
Scheme 5. Formation and cyclization of enynes 15 and 16.
previously reported 5-endo cyclization of the tert-butyloxycarba-
mate on the alkyne (Scheme 1) [7,8] did not significantly compete
with this new transformation. The nucleophilic addition of the al-
kene moiety on the activated gold-alkyne complex seems to be a
more favored process and only traces of oxazolones 14 could be
observed when a gold complex was used as the catalyst. A control
experiment led to the conclusion that HNTf2 was not a suitable cat-
alyst for this transformation. The reaction only furnished degrada-
tion products in this case. In contrast, the use of AgNTf2 led to the
rapid and clean conversion of enyne 11. However, the desired bicy-
clic compound 12 was formed in a very low yield (<10%) and oxa-
zolone 14 was surprisingly the major compound (85%) produced
during the reaction.
The transformation was compatible with substrates bearing
other groups on the nitrogen atom (Scheme 5).
The copper-catalyzed formations of enynes 15 and 16, possess-
ing either a methyl group or an ester group, were less efficient.
However, they reacted comparably during the gold-catalyzed
Fig. 2. Molecular structure of 20a. Hydrogen atoms are omitted for clarity.
Fig. 3. Molecular structure of 21a. Hydrogen atoms are omitted for clarity.
Fig. 1. Molecular structure of 17. Hydrogen atoms are omitted for clarity.
R2
R2
R1
O
R2
AcO
AcO
R1
AcO
H
CuSO4 5H2O
Br
1 mol% 13
R1
O
9
+
1,10-phenanthroline
K3PO4, toluene, 80°C
CH2Cl2, RT
N
O
O
N
O
R3
R3
HN
R3
O
R3=Bn (E)-19a
R3=Me (E)-19b
61%
38%
20a 63%
20b
R1= Me, R2=
61%
R3=Bn (Z)-19a
45%
37%
21a 57%
21b
R1=
, R2= Me
(Z)-19b
R3=Me
56%
Scheme 6. Formation and cyclization of enynes (Z)-19a–b and (E)-19a–b.

518
A. Buzas et al. / Journal of Organometallic Chemistry 694 (2009) 515–519
cyclisation to produce bicyclic compounds 17 and 18 in respec-
tively 68% and 65% yield. As noted in our previous study, the reac-
tions were highly stereoselective, leading to the formation of single
isomers [10]. The cis relationship between the acetoxy group and
the hydrogen at the ring junction was determined by NMR analysis
and confirmed by X-ray crystallography of compound 17 (Fig. 1).
The reaction could also be applied to substrates possessing di-
versely substituted alkenes. A complete transfer of the chiral infor-
mation from the cis or trans alkene to the final product was
observed in the case of enynes (Z)-19a–b and (E)-19a–b with the
stereoselective formation of two new contiguous stereocenters
(Scheme 6). Bicycles 20a–b and 21a–b were thus obtained as single
isomers in yields ranging from 56% to 63%.
The relative configuration of the new stereocentres were deter-
mined by NMR analysis and confirmed by X-ray crystallography of
compound 20a and 21a (Figs. 2 and 3).
The [4+2] cycloaddition could also be performed with a disub-
stituted alkene possessing cation-stabilizing substituents on the
alkene moiety, as attested by the reaction of substrate 22 derived
from cinnamaldehyde (Scheme 7). The transformation was how-
ever less stereoselective and a diastereoisomeric mixture of com-
pounds 23a and 23b was obtained. In the case of a trisubstituted
Ph
H
H
O
AcO
Ph
N
O
AcO
Bn
AcO
Ph
Br
CuSO4 5H2O
3 mol% 13
23a
+
1,10-phenanthroline
K3PO4, toluene, 80˚C
Boc
CH2Cl2, RT
O
N
Ph
H
Bn
AcO
HN
Bn
O
H
47%
(23a:23b = 1.9:1)
O
(31%)
22
N
O
Bn
23b
R2
R1
O
AcO
H
R2
R1
O
Ot-Bu
AcO
H
N
Bn
O
N
AuL
Bn
24ax
R2
AcO
Au+
R1
or/and
Boc
N
R2
R1
R2
O
R1
AcO
Ot-Bu
H
H
Bn
O
N
AcO
Bn
N
O
AuL
24eq
Bn
Scheme 7. Formation and cyclization of enyne 22.
H
1 mol% 13
CH2Cl2, RT
Br
CuSO4 5H2O
O
+
1,10-phenanthroline
K3PO4, toluene, 80°C
Boc
N
O
O
N
R
R
HN
R
O
26a-d
25a-d
R=
25a
25b
25c
25d
26a 40%
Ph
56%
25%
29%
68%
26b 43% (dr= 1:1.3)
26c 41% (dr= 1:1.2)
26d 41% (dr= 1:1.4)
Ph
Ph
Naphth
Scheme 8. Formation and cyclization of enynes 26a–d.

A. Buzas et al. / Journal of Organometallic Chemistry 694 (2009) 515–519
519
[2] (a) For selected examples, see: N. Riddell, K. Villeneuve, W. Tam, Org. Lett. 7
(2005) 3681–3684;
alkene (R1, R2 – H), the reaction was stereospecific due to a strong
steric interaction between the acetoxy group and R1 which disfa-
vored the formation of an intermediate such as 24ax. The lack of
a similar interaction for substrate 22 (R1 = H) makes the transfor-
mation less selective since it allows the competitive formation of
two intermediates of types 24ax and 24eq.
(b) B. Witulski, C. Alayrac, Angew. Chem., Int. Ed. 41 (2002) 3281–3284;
(c) B. Witulski, J. Lumtscher, U. Bergstraesser, Synlett (2003) 708–710;
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Mulder, R.P. Hsung, Org. Lett. 6 (2004) 2209–2212;
We finally attempted to develop an asymmetric version of this
[4+2] cycloaddition. We hoped that the presence of a chiral frag-
ment on the nitrogen atom of substrates 25b–d might induce some
stereoselectivity in the reaction (Scheme 8). The reaction of sub-
strate 25a, bearing a simple benzyl group on the nitrogen atom,
furnished the corresponding cyclized product 26a in a moderate
40% yield. The yields were not improved when optically pure sub-
strates 25b–d were used (41–43%). Moreover, the results were
highly disappointing since bicyclic compounds 26b–d were ob-
tained with a very poor selectivity.
(b) S. Couty, B. Liegault, C. Meyer, J. Cossy, Tetrahedron 62 (2006) 3882–3895;
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(2006) 3843–3855.
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Rameshkumar, J.A. Mulder, T.P. Grebe, Org. Lett. 4 (2002) 2417–2420;
(b) N. Saito, Y. Sato, M. Mori, Org. Lett. 4 (2002) 803–806.
[5] (a) For recent reviews on gold and platinum catalysis, see: Z. Li, C. Brower, C.
He, Chem. Rev. 108 (2008) 3239–3245;
(b) A. Arcadi, Chem. Rev. 108 (2008) 3266–3325;
(c) E. Jimenez-Nunez, A.M. Echavarren, Chem. Rev. 108 (2008) 3326–3350;
(d) D.J. Gorin, F.D. Toste, Chem. Rev. 108 (2008) 3351–3378;
(e) A.S.K. Hashmi, M. Rudolph, Chem. Soc. Rev. 37 (2008) 1766–1775;
(f) A.S.K. Hashmi, Chem. Rev. 107 (2007) 3180–3211;
(g) A. Fürstner, P.W. Davies, Angew. Chem., Int. Ed. 46 (2007) 3410–3449;
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3. Summary
(i) E. Jimenez-Nunez, A.M. Echavarren, Chem. Commun. (2007) 333–346;
(j) A.S.K. Hashmi, G.J. Hutchings, Angew. Chem., Int. Ed. 45 (2006) 7896–7936;
(k) L. Zhang, J. Sun, S.A. Kozmin, Adv. Synth. Catal. 348 (2006) 2271–2296.
[6] S. Couty, C. Meyer, J. Cossy, Angew. Chem., Int. Ed. 45 (2006) 6726–6730.
[7] A.S.K. Hashmi, R. Salathé, W. Frey, Synlett (2007) 1763–1766.
[8] F. Istrate, A. Buzas, I. Dias Jurberg, Y. Odabachian, F. Gagosz, Org. Lett. 10 (2008)
925–928.
[9] A.S.K. Hashmi, M. Rudolph, J.W. Bats, W. Frey, F. Rominger, T. Oeser, Chem. Eur.
J. (2008) 6672–6678.
[10] A. Buzas, F. Istrate, F. Gagosz, Angew. Chem., Int. Ed. 46 (2007) 1141–1144.
[11] (a) Based on recent investigations by Fürstner and coworkers: A. Fürstner, L.
Morency, Angew. Chem., Int. Ed. (2008) 5030–5033;
(b) See also:A.S.K. Hashmi, Angew. Chem., Int. Ed. (2008) 6754–6756.
[12] Formula 6a–c in Scheme 3 are mesomeric forms of the same intermediate.
[13] (a) These reactions conditions are slightly modified compared to those
previously reported by Hsung and coworkers, see: X. Zhang, Y. Zhang, J.
Huang, R.P. Hsung, K.C.M. Kurtz, J. Oppenheimer, M.E. Petersen, I.K.
Sagamanove, L. Shen, M.R. Tracey, J. Org. Chem. 71 (2006) 4170–4177;
(b) Y. Zhang, R.P. Hsung, M.R. Tracey, K.C.M. Kurtz, E.L. Vera, Org. Lett. 6 (2004)
1151–1154;
In summary, we have shown that N-(hex-5-enynyl) tert-butyl-
oxycarbamates could be cyclized into functionalized bicyclic car-
bamates under mild conditions by using a gold(I) complex as the
catalyst. This transformation can be described as a formal [4+2]
cycloaddition between an N-alkynyl tert-butyloxycarbamate and
an alkene. Even if the yields are moderate (41–78%), the transfor-
mation is generally strereoselective and allows a rapid increase
in structural complexity with the formation of two cycles and up
to two new asymmetric centers. Further studies related to the con-
version of the bicyclic carbamates thus obtained into more valu-
able compounds as well as studies concerning the development
of other gold-catalyzed transformation of N-alkynyl carbamates
are underway.
(c) For other leading references dealing with the Cu(II) catalyzed coupling of
bromoalkynes with carbamates, see:M.O. Frederick, J.A. Mulder, M.R. Tracey,
R.P. Hsung, J. Huang, K.C.M. Kurtz, L. Shen, C.J. Douglas, J. Am. Chem. Soc. 125
(2003) 2368–2369;
(d) J.R. Dunetz, R.L. Danheiser, Org. Lett. 5 (2003) 4011–4014;
(e) J.R. Dunetz, R.L. Danheiser, J. Am. Chem. Soc (2005) 5776–5777;
(f) A.L. Kohnen, X.Y. Mak, T.Y. Lam, J.R. Dunetz, R.L. Danheiser, Tetrahedron
(2006) 3815–3822;
Supplementary material
CCDC 687781, 687782 and 687783 contains the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
(g) K. Villeneuve, N. Riddell, W. Tam, Tetrahedron (2006) 3823–3836;
(h) R.L. Danheiser, A.L. Kohnen, J.R. Dunetz, Org. Synth. (2007) 88–101.
[14] N. Mezailles, L. Ricard, F. Gagosz, Org. Lett. 7 (2005) 4133–4136.
[15] (a) For gold catalyzed [4+2] cycloadditions of polyenynes, see: C. Nieto-
Oberhuber, P. Péres-Galan, E. Herreo-Gomez, T. Lautenbach, C. Rodriguez, S.
Lopez, C. Bour, A. Rosellon, D.J. Cardenas, A.M. Echavarren, J. Am. Chem. Soc.
130 (2008) 269–279;
Acknowledgements
The authors wish to thank Prof. S.Z. Zard for helpful discussions
and Rhodia Chimie Fine for a generous gift of HNTf2.
(b) C. Nieto-Oberhuber, S. Lopez, A.M. Echavarren, J. Am. Chem. Soc. 127
(2005) 6178–6179;
(c) A. Fürstner, C.C. Stimson, Angew. Chem., Int. Ed. 46 (2007) 8845–8849;
(d) For [4+2] cycloadditions involving furans, see:A.S.K. Hashmi, T.M. Frost,
J.W. Bats, J. Am. Chem. Soc. 122 (2000) 11553–11554;
(e) A.S.K. Hashmi, T.M. Frost, J.W. Bats, Org. Lett. 4 (2002) 3769–3771;
(f) A.S.K. Hashmi, M. Rudolph, J.P. Weyrauch, M. Wölfle, W. Frey, J.W. Bats,
Angew. Chem., Int. Ed. 44 (2005) 2798–2801.
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[1] (a) For recent reviews on ynamines and ynamides chemistry, see: R.P. Hsung,
C.A. Zificsak, J.A. Mulder, C. Rameshkumar, L.-L. Wei, Tetrahedron 57 (2001)
7575–7606;
(b) J.A. Mulder, K.C.M. Kurtz, R.P. Hsung, Synlett (2003) 1379–1390.