Phosphite-gold(I)-catalyzed [2+2] intermolecular cycloaddition of enol ethers with N-allenylsulfonamides

Article abstract of DOI:10.1002/adsc.201200043

Addition of catalytic amounts of a phosphite-based gold(I) catalyst efficiently triggers the intermolecular [2+2] cycloaddition of allenes and alkenes substituted by electron-donor groups. The reaction is fast and furnishes cyclobutane derivatives in a st

Full text of DOI:10.1002/adsc.201200043

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DOI: 10.1002/adsc.201200043
Phosphite-Gold(I)-Catalyzed [2+2]Intermolecular Cycloaddition
of Enol Ethers with N-Allenylsulfonamides
Samuel Suꢀrez-Pantiga,a Cristina Hernꢀndez-Dꢁaz,a Marꢁa Piedrafita,a
Eduardo Rubio,a and Josꢂ M. Gonzꢀleza,*
a
Departamento de Quꢁmica Orgꢀnica e Inorgꢀnica and Instituto Universitario de Quꢁmica Organometꢀlica “Enrique
Moles” Universidad de Oviedo. C/Juliꢀn Claverꢁa 8, 33006 Oviedo, Spain
Fax : (+34)-98-510-3446; phone: (+34)-98-510-2980; e-mail: jmgd@uniovi.es
Received: January 16, 2012; Published online: June 5, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200043.
Abstract: Addition of catalytic amounts of a phos-
phite-based gold(I) catalyst efficiently triggers the
intermolecular [2+2]cycloaddition of allenes and
alkenes substituted by electron-donor groups. The
reaction is fast and furnishes cyclobutane deriva-
tives in a stereoselective manner using low catalyst
loadings. Besides, the same catalyst selectively af-
fords homodimerization products from the starting
allene, a process that may be conveniently fine
tuned by addition of norbornene.
Table 1 shows representative examples of an effi-
cient and selective assembly of cyclobutane frames
from both components, the allene and the alkene
having electron-rich natures, proving an hitherto elu-
sive intermolecular process.[7,12] The reaction of 4-
methyl-N-phenyl-N-(propa-1,2-dien-1-yl)-benzenesul-
fonamide 1a with an excess of 2,3-dihydrofuran 2a
was tested, as model system. Experiments were con-
ducted at room temperature, in CH2Cl2 under high di-
lution, using different excesses of the enol ether. The
addition of
a catalytic amount (entries 1–3) of
Keywords: alkenes; allenes; cycloaddition; cyclobu-
tanes; gold
IPrAuNTf2 3a (5 mol%) {IPr=(2,6-diisopropylphen-
yl)-1,3-imidazol-2-ylidene; NTf2 =bis[(trifluorometh-
AHCTUNGTREGaNNUN ne)sulfonyl]amide]} smoothly gave rise to the forma-
tion of the cycloadduct 4a in 73% isolated yield, re-
sulting from the [2+2]cocyclization of the electron-
rich alkene at the distal double bond of 1a. Remarka-
The allene functional group entails a unique reactivity bly, 4a was formed as a single regio- and stereoisomer,
and is a distinctive structural feature of some natural- showing cis-fusion at the assembled bicyclic junction
ly occurring products.[1] For selective organic synthe- and Z configuration for the exocyclic double bond.[13]
sis, it is a flexible building block[2] with further signifi-
cance for advancing gold catalysis.[3] Also, the synthe-
sis of the cyclobutane frame is a focus of current at-
tention as its chemistry keeps on expanding.[4] In this
context, allenes have emerged as unique partners for
cycloaddition with alkenes.[5]
The [2 +2]intermolecular process has been less re-
ported than the intramolecular one, but proved to be
feasible provided that a proper electronic matching of
the reagents is given.[6] However, the reaction involv-
ing both partners as electron-rich components is rare
(Scheme 1).[7–9] Gold catalysis has alreadly proven val-
uable in allenene cycloisomerization reactions leading
to cyclobutane bicyclic frames.[10,11] Now, we would
like to report our findings on intermolecular gold-cat-
alyzed [2+2]cycloaddition reactions of enol ethers
and N-allenylsulfonamides giving cyclobutane deriva-
tives (see Table 1).
Scheme 1. ACTHNUTRGENUG[N 2+2]Allenene cycloadditions of electron-rich
partners.
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Samuel Suꢀrez-Pantiga et al.
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Table 1. Intermolecular [2+2] cycloaddition of allenamide 1a and enol ether 2a catalyzed by gold(I).
Entry[a]
2a (equiv.)
Solvent
Catalyst
Time[b]
Temperature [8C]
Yield[c] 4a, 4a’
1
2
3
4
5
6
7
8
5
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
PhMe
3a
3a
3a
–
7 h
4 h
1 h
24 h
24 h
24 h
48 h
5 min
5 min
4 h
20
20
20
20
20
20
20
20
52
61
73
–
21
10
15
15
10
10
10
5
1.5
1.5
1.5
1.5
1.5
3
[d]
3a
3a
3a
3b
3b
3b
3b
3b
3b
3b
3b
Et2O
26
12
MeCN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeCN
CH2Cl2
54, 31
34, 39
55[e]
60[e]
67[e]
66[e]
76[e]
86[e,f]
9
20
10
11
12
13
14
15
À55
À45
À35
À20
20
1 h
45 min
40 min
15 min
5 min
1.5
20
[a]
Typically 0.2 mmol of 1a were used for the optimization study and its concentration was 0.033M.
The reaction was quenched by addition of pyridine (10 mol%), unless otherwise specified.
Isolated yield of product after column chromatography.
Unaltered 1a was quantitatively recovered.
The reaction was quenched by addition of PPh3 (10 mol%), unless otherwise specified.
[b]
[c]
[d]
[e]
[f]
Amount of added catalyst 3b was lowered to 0.5 mol%.
It is also worthy of mention that the formation of affords clean crude reaction mixtures that contain 4a,
products arising from competitive allene dimerization without evidence for the formation of its stereoisomer
or hydroarylation reactions was not observed.[14] Ex- 4a’, as NMR inspection of those crudes revealed.
ploratory studies showed that the related phosphite- Column chromatography led to the isolation of the
based gold-catalyst 3b is very active in this transfor- cycloadduct 4a. The greater activity of 3b makes pos-
mation, in agreement with a likely electrophilic, step- sible the use of MeCN as solvent, although it requires
wise transformation that could be tuned through a higher charge of 2a to render the product in compa-
ligand variation.[15] However, now the cycloaddition rable yield in a short reaction time (entry 14). Gratify-
product was formed as a mixture of two stereoisomers ingly, lowering the amount of catalyst 3b loaded of-
around the double bond (4a/4a’), that could be sepa- fered a convenient and simple way to favor the cyclo-
rated and isolated upon column chromatography. The addition path versus competitive reactions and, after
ratio of these compounds was shown to be dependent reaction for five minutes at room temperature, it fur-
on the added excess of 2a, which can be safely dimin- nished 4a as a sole product, that can be isolated in
ished to 1.5 equiv. To explore the higher reactivity satisfactory 86% yield. Again, the reaction was
evidenced by the phosphite-gold complex and turn it quenched with triphenylphosphine to preclude any
into a synthetically useful procedure further experi- isomerization process to occur along the work-up, par-
mental conditions were assayed. The inherent reactiv- ticularly during the concentration step. With these
ity associated with 3b enables us to conduct reactions useful experimental conditions in hand, next the gen-
at low temperature (Table 1, entries 10–13). Quench- erality of the process was investigated (Scheme 2).
ing the reaction with PPh3, followed by simple filtra-
A summary of the synthesized compounds is de-
tion over silica gel and solvent removal under vacuum picted in Figure 1. The sulfonyl allenamide can be
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Phosphite-Gold(I)-Catalyzed [2+2]Intermolecular Cycloaddition of Enol Ethers
Scheme 2. Catalytic assemby of cyclobutane frames: [2+2]cycloaddition of N-sulfonylallenamides and enol ethers.
for the reaction of 5-methyl-2,3-dihydrofuran, but in
this case the use of an excess of 2d (2.5 equiv.) and
longer reaction time (2.5 h) were required, leading to
4f in only moderate yield, though 35% of the starting
allene 1b was recovered unaltered. Extending the re-
action time, to allow full conversion of 1b to occur,
did not result an increase of the yield for 4f. The
higher reactivity of the trisubstituted alkenyl ether
might lead to its competitive activation by the gold
catalyst and could launch alternative side pathways
for its consumption. Terminal enol ethers can be used
and reacted in fair yields, between 74% and 79%, to
give the corresponding cycloadducts, in agreement
with the lower reactivity of the alkene.[16] When the
1,2-disubstituted alkene 2e was used an interesting
observation was made. The vinyl ether was added as
nearly a 1:1 mixture of E/Z isomers. The reaction fur-
nished cyclobutane 4g as an inseparable 3:1 mixture
of diastereoisomers. Although isomerization of 2e
under the reaction conditions could not be safely
ruled out, the noticed stereoequilibration process may
additionally speak in favour of a stepwise cyclization
involving a cationic intermediate.
Figure 1. Allene-alkenyl ether cycloadducts from the phos-
In general, the reported examples highlight a regio-
phite-gold(I) catalyzed reaction (see Scheme 2).
selective transformation that takes place under mild
reaction conditions with a noteworthy control over
modified at the nitrogen atom (R1), resulting in the stereochemistry of the exocyclic double bond and
a robust process for aryl, alkyl or benzyl N-substitu- also that affecting to the bicyclic ring junction, if ap-
tion.
propriate. On this ground, considering the low cata-
For N-aryl derivatives, an intramolecular hydroary- lyst loading and the moderate excess of alkene re-
lation reaction could be a potential competitive path; quired in comparison with known [2+2]intermolecu-
however, it did not occur under the reported condi- lar cycloadditions, this process offers an attractive
tions, even for the moderately activated ring of 1e. In- choice to assemble functionalized cyclobutane frames
ternal allenes also enter this cycloaddition in a fast from convenient precursors. Thus, the reactivity of
and efficient manner.
further alternative substrates was screened with the
The reaction tolerates a wide array of enol ethers, aim to increase the scope of this catalytic transforma-
both cyclic and acyclic. For the former, a fast transfor- tion.
mation and the exclusive formation of the cis adduct
First, the reactivity of a silyloxy allenyl ether was
were noticed, establishing a stereoselective transfor- investigated in search for a cycloaddition mode that
mation for 2,3-dihydrofuran and 3,4-dihydro-2H- would be complementary to the [3+2]intermolecular
pyran cores in satisfactory isolated yields, ranging process
previously
described
by
Iwasawa
from 84% to 92%. The same selectivity was noticed (Scheme 1).[7] Interestingly, tert-butyl
(diphenyl)silyl
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not result in a higher yield for the desired dimer, as
the result of significant side oligomerization reactions,
and the use of a more coordinating solvent inhibited
the reaction. The catalyst loading can be safely dimin-
ished down to the level of 0.5 mol%. Interestingly, for
the case of the phosphite ligand, addition of norbor-
nene (15 mol%) determines a significant decrease of
the reaction time with concomitant increase of yield
for the homodimer 9b,[20] that was obtained as a single
stereoisomer.
Scheme 3. O-Silyl-substituted allene also undergoes selective
[2+2]cycloaddition.
(TBDPS) 1,2-propadienyl ether reacted with 2,3-dihy-
Larger amounts of the alkene, that is inactive in the
drofuran upon addition of the phosphite gold catalyst cocyclization process, did not improve the process.
3b (Scheme 3) and gave the desired [2+2]cycload- Thus, adding 30 mol% slightly lowered the yield
duct 6a in a satisfactory 88% isolated yield, again as (73%, for a comparable reaction time 43 min), while
a single stereoisomer.[17]
addition of 100 mol% slowed down the reaction that
However, 1,1-di(4-methoxyphenyl)-1,2-propadiene took 80 min to go to completion, 9b being isolated in
failed to react under the standard conditions. Con- 78%, in this case. The influence of this additive over
versely, the alkene partner is not restricted to enol the reactivity and stability of the catalytic system is
ethers; the styrene derivative 7a was tested and fur- crucial to allow the synthesis of the corresponding
nished 8a in 94% isolated yield (Scheme 4).
dimer for the parent aromatic-substituted model com-
The assembly of the [2+2]cycloadduct from these pound 1a. In this case, a more sluggish process was
two types of electron-rich components is compatible noticed with most of the catalysts failing to provide
with a stepwise mechanism, in agreement with the lit- the dimer in acceptable yield, or even to react in the
erature precedents for gold-catalyzed addition reac- desired sense at any appreciable extent.[21] The phos-
tions to allenes.[18] Thus, an initial coordination of the phite-gold complex in combination with small
allene to gold determines its activation towards the amounts of norbornene and mild heating (entry 10)
attack of the nucleophilic alkene. The formed cationic results in a convenient way to assemble this cyclobu-
intermediate that is stabilized by lone pairs in the tane scaffold endowed of a 1,3-diamino motif. The
neighbouring oxygen atom or, alternatively, by an prepared compounds are depicted in Scheme 5. Far
electron-rich arene, would give rise to the formation from the benzylic system, two additional aryl-substi-
of the cyclobutane frame upon a cyclization.[19]
tuted compounds are given, illustrating that the reac-
In this context, it is reasonable and seems feasible tivity shows dependence on the substitution at the
that a second allene molecule could take part in a re- arene ring onto nitrogen.
lated cyclization process, simply by performing the
In summary, an efficient and selective catalytic [2+
role played by the alkene. In this regard, a selective 2]cycloaddition of N-allenylsulfonamides and enol
homodimerization transformation of the starting N-al- ethers is given. At the onset of this study this process
lenylsulfonamide takes place upon its exposure to was virtually lacking precedent. Studies concomitantly
a catalytic amount of gold(I). Different complexes conducted by Cheng and co-workers are now being
proved valuable for this purpose (see Table 2). Addi- disclosed. Our independently developed work shows
tional information concerning the optimization of the that the phosphite-gold catalyst 3b with the bis[(tri-
catalytic system is also detailed there. Thus, for the fluoromethane)sulfonyl]amide (NTf2) counter anion
case of aliphatic substitution at the nitrogen (1b) sev- provides a powerful and robust silver-free approach
eral complexes proved to be active at room tempera- to tackle this challenging cyclization for electron-rich
ture, using the standard 5 mol% catalyst loading (en- partners in an efficient and selective manner. Not
tries 1–4). Now the more electrophilic 3b, although it only terminal but internal allenyl sulfonamides enter
gave rise to full conversion of the starting allene, did the cyclization. This catalytic system works for other
Scheme 4. Cyclobutane derivative from cycloaddition of a substituted styrene and an allenylsulfonamide.
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Phosphite-Gold(I)-Catalyzed [2+2]Intermolecular Cycloaddition of Enol Ethers
Table 2. Catalytic dimerization of N-allenylsulfonamides.
Entry
1[a]
Catalyst[b] (loading)
Additive (loading)
Time[c]
Product 9/Yield [%][d]
1
2
3
1b
1b
1b
1b
1b
1b
1b
1b
1a
1a
3a (5 mol%)
3b (5 mol%)
3c (5 mol%)
3d (5 mol%)
3b (5 mol%)
3a (0.5 mol%)
3b (0.5 mol%)
3b (0.5 mol%)
3b (0.5 mol%)
3b (0.5 mol%)
–
–
–
–
–
–
1 h
2 h
2 h
2 h
3 h
5 h
40 min
3 h
55 min
30 min
9b/83
9b/53
9b/53
9b/70
–
9b/88
9b/86
9b/61
9b/30
9b/72
4
5[e]
6
7
8
norbornene (15 mol%)
–
norbornene (30 mol%)
norbornene (15 mol%)
9
10[f]
[a]
All reactions conducted in CH2Cl2 as solvent, at 208C, unless specified otherwise. 0.2 mmol of 1 were always used and its
concentration was 0.033M.
Catalyst 3 with the generic structure of LAuNTf2; 3a L=IPr; 3b L=(ArO)3P [Ar=2,4-(tBu)2C6H3]; 3c L=Ph3P; 3d L=
[b]
2-C6H5-C6H4PACHTUNGTRENNUNG(t-Bu)2 (JOHNPHOS).
[c]
[d]
[e]
[f]
Reaction time based on monitoring the consumption of 1. The reaction was quenched by addition of PPh3 (10 mol%).
Isolated yield of product after column chromatography. The structure of 9b was confirmed by X-ray analysis.
Reaction in 1,4-dioxane, unaltered 1b recovered (95%)
Reaction in ClCH2CH2Cl, at 508C.
tylphenyl)phosphite]gold
0.001 mmol, 0.5 mol%) in anhydrous dichloromethane (pre-
viously prepared dissolving 11.2 mg of the gold catalyst in
triflimidate
3b
(1.1 mg,
classes of alkenes and allenes. From a practical point
of view no additional chemicals are required to per-
form the reaction. Remarkably, with an olefin to
allene molar ratio of only 1.5 to 1, a catalyst loading
as low as 0.5 mol% gives rise to a very fast transfor-
mation under mild experimental conditions (values
up to 188 for TON and to 2256 hÀ1 for TOF were
found, as calculated for 8a). Besides, the [2+2]cyclo-
addition was also accomplished from tert-butyl-
ACHTUNGTRENNUNG(diphenyl)silyl 1,2-propadienyl ether nicely comple-
menting the known [3+2]cycloaddition mode. This
catalytic system also provides useful synthetic condi-
tions for accessing the attractive [2+2]homodimeriza-
tion reaction of the parent N-allenylsulfonamides, our
approach can be tuned to allow N-aryl-substituted
partners to dimerize in respectable yield. Further
mechanistic insights and additional studies of the im-
plications associated with this catalytic reaction are in
progress in our group.
Experimental Section
Representative Procedure for the Catalytic Synthesis
of [2+2]Cycloaduct 4a
The allene 1a (57.1 mg, 0.2 mmol, 1.0 equiv.) was dissolved
in 5.9 mL of anhydrous dichloromethane under an argon at-
mosphere. Then, the alkene 2a was added (23 mL, 0.3 mmol,
1.5 equiv.). Lastly, 100 mL of a solution of [tris(2,4-di-tert-bu-
Scheme 5. Phosphite-gold(I) complex 3b as catalyst for the
selective homodimerization of allenylsulfonamides.
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Samuel Suꢀrez-Pantiga et al.
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1.0 mL of dichloromethane) were charged. After 5 min,
once no starting material was observed (TLC), the reaction
was stopped by addition of 5.2 mg of PPh3 (0.02 mmol,
10 mol%). The mixture was concentrated under vacuum and
the residue was purified by a flash chromatography on neu-
tral alumina (hexane:AcOEt, 7:1), affording 4a as a white
solid; yield: 61.3 mg (86%).
Schuster, S. Litters, F. Rominger, M. Pernpointner,
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goncillo, Chem. Soc. Rev. 2010, 39, 783–816.
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examples: a) B. Alcaide, P. Almendros, C. Aragoncillo,
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Acknowledgements
We are grateful to MICINN (Grant CTQ-2010-20517-C02-
01) and the Principado de Asturias (Grant FC-11CO11-17).
S.S.-P.and M.P. thank the Ministerio de Educaciꢀn and the
European Union (Fondo Social Europeo) for predoctoral fel-
lowships. C.H.-D. thanks the Ministerio de Ciencia e Innova-
ciꢀn for a predoctoral fellowship.
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[8] A related cyclization manifold was noticed for intramo-
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of propargyl indole-3-acetates. An initial 3,3-rearrange-
ment of the propargyl to the allenyl ester was assumed.
Then, depending on the catalyst, the allene enters
À
a [2+2] or [3+2]process with the C-2 C-3 bond of
indole. In terms of the electron-rich nature of both
partners, it represents a gold(I)-catalyzed intramolecu-
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[9] 3-Sulfonyl derivatives of the 4-vinylideneoxazolidin-2-
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thermal [2+2]cycloaddition reactions with alkenes and
alkynes leading, respectively, to cyclobutane and cyclo-
butene derivatives. However, for the case of alkenes
bearing electron-donating substituents (i.e., enol
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clobutanes and a different reaction occurs, giving tetra-
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[10] Intramolecular gold-catalyzed [2+2]cycloaddition re-
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1656
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ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 1651 – 1657

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[12] The intermolecular [2+2]cyclization mode has been
recently reported as a side reaction in gold-catalyzed
intermolecular [4+2]cycloaddition of allenamides and
acyclic 1,3-dienes, see: a) H. Faustino, F. Lꢄpez, L. Cas-
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While writing this manuscript a paper by other authors
has appeared describing a related study that prompted
us to immediately disclose our results, see: b) X.-X. Li,
L.-L. Zhu, W. Zhou, Z. Chen, Org. Lett. 2012, 14, 436–
439. In terms of the nature of catalytic system, catalyst
loading, efficiency, time, insights for reaction tuning
and other practical aspects our system shows significant
differences.
[13] The stereochemistry was established on the basis of ex-
tensive NMR bidimensional studies on compounds 3,
and further confirmed by X-rays analysis of 4l.
[14] The use of dilute conditions (1a 0.033M in dichlorome-
thane) in combination with the excess of alkene may
preclude allene dimerization to take place.
[15] For a review on ligand effects in gold catalysis, see:
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[19] The cyclobutane is isolated as single stereoisomer pro-
vided that the reaction is quenched with triphenylphos-
phine before the solvent is removed to furnish the
crude reaction. If not, the highly active phosphite cata-
lyst 3b gives rise to isomerization around the double
bond (see Table 1, entries 8 and 9 and 15). This sug-
gests a kinetic preference behind the formation of the
noticed stereoisomer. Its nature is yet to be firmly es-
tablished. However, assuming some active role for the
carbon-gold bond in the second step of the ring-form-
ing process (see ref.[10a] in this manuscript), a reasonable
proposal would imply the participation of a cationic in-
termediate featuring the sulfonamide and the metal
within a cis-vinylic disposition, as postulated for addi-
tion reactions to related allenamides, see: a) M. C.
Kimber, Org. Lett. 2010, 12, 1128–1131; b) A. W. Hill,
M. R. J. Elsegood, M. C. Kimber, J. Org. Chem. 2010,
75, 5406–5409; and also to alkyl-substituted allenes,
see: c) K. L. Toups, G. T. Liu, R. A. Widenhoefer, J.
Organomet. Chem. 2009, 694, 571–575.
[20] CCDC 862672 (4l) and CCDC 862201 (9b) contain 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. The X-ray crystal
data have been summarized in the Supporting Informa-
tion.
[17] NMR inspection of the crude reaction mixture showed
the exclusive formation of cyclobutane 6a without any
evidence for the presence of a cyclopentene derivative
arising from an alternative [3+2]cyclization.
[21] M. Piedrafita, Ph. D. Dissertation, University of
Oviedo, Spain, 2010.
Adv. Synth. Catal. 2012, 354, 1651 – 1657
ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
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