Synergistic gold(I)/trimethylsilyl catalysis: Efficient alkynylation of N,O-acetals and related pro-electrophiles

Article abstract of DOI:10.1002/adsc.201400169

We report a unique mechanism-guided reaction that enhances and expands the chemical space that readily generated gold(I) acetylides currently operate in. Our strategy exploits the propensity of gold(I) carbophilic catalysts with specific counteranions (LAuX - X=triflate or triflimidate) to efficiently activate and desilylate trimethylsilylalkynes, thereby mediating the in situ formation of equal and catalytic quantities of a silyl Lewis acid (TMSX) of tunable strength and a nucleophilic gold(I) acetylide. This unprecedented manifold opens avenues for developing synergistic silyl-gold(I)-catalyzed alkynylation strategies of diverse pro-electrophiles which were heretofore unattainable, the proof of concept being principally exemplified herein with the first catalytic alkynylation of N,O-acetals. The reaction proceeds at low catalyst loading, employs mild reaction conditions, is easily scalable, and affords propargylic lactam products in good to excellent yields. Furthermore, it is fully amenable to a diverse array of structure and function substrates, and also expands to other pro-electrophiles beyond N,O-acetals. Control experiments have been carried out that strongly support our dual reaction mechanism proposal which, furthermore, itself outlines an inextricable link between the strength of the ancillary silyl Lewis acid (TMSOTf versus TMSNTf₂) and the coordinating ability of the gold counter anion employed. This underlying feature of our system underscores its significant potential and flexibility, which indeed manifests with the demonstration that by carefully selecting the gold counter ion, it is possible to manipulate the strength of the ancillary silyl Lewis acid so that it can be tailored to the ionizing ability of a particular pro-electrophile.

Full text of DOI:10.1002/adsc.201400169

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DOI: 10.1002/adsc.201400169
Synergistic Gold(I)/Trimethylsilyl Catalysis: Efficient
Alkynylation of N,O-Acetals and Related Pro-Electrophiles
Malina Michalska,a Olivier Songis,a Catherine Taillier,a Sean P. Bew,b
and Vincent Dallaa,*
a
URCOM, EA 3221, FR 3038, Facultꢀ des Sciences et Techniques de l’Universitꢀ du Havre, 25 rue Philippe Lebon, BP
540, F-76058 Le Havre, France
Fax : (+33)-2-3274-4391; phone: (+33)-2-3274-4401; e-mail: vincent.dalla@univ-lehavre.fr
School of Chemistry, University of East Anglia, Norwich Research Park, Norwich, NR47TJ, U.K.
b
Received: February 16, 2014; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400169.
Abstract: We report a unique mechanism-guided re- thermore, it is fully amenable to a diverse array of
action that enhances and expands the chemical space structure and function substrates, and also expands
that readily generated gold(I) acetylides currently to other pro-electrophiles beyond N,O-acetals. Con-
operate in. Our strategy exploits the propensity of trol experiments have been carried out that strongly
gold(I) carbophilic catalysts with specific counteran- support our dual reaction mechanism proposal
ions (LAuX – X=triflate or triflimidate) to efficient- which, furthermore, itself outlines an inextricable
ly activate and desilylate trimethylsilylalkynes, there- link between the strength of the ancillary silyl Lewis
by mediating the in situ formation of equal and cata- acid (TMSOTf versus TMSNTf2) and the coordinat-
lytic quantities of a silyl Lewis acid (TMSX) of tuna- ing ability of the gold counter anion employed. This
ble strength and a nucleophilic gold(I) acetylide. underlying feature of our system underscores its sig-
This unprecedented manifold opens avenues for de- nificant potential and flexibility, which indeed mani-
veloping synergistic silyl-gold(I)-catalyzed alkynyla- fests with the demonstration that by carefully select-
tion strategies of diverse pro-electrophiles which ing the gold counter ion, it is possible to manipulate
were heretofore unattainable, the proof of concept the strength of the ancillary silyl Lewis acid so that it
being principally exemplified herein with the first can be tailored to the ionizing ability of a particular
catalytic alkynylation of N,O-acetals. The reaction pro-electrophile.
proceeds at low catalyst loading, employs mild reac-
tion conditions, is easily scalable, and affords propar- Keywords: N-acyliminium ions; alkynylation; gold
gylic lactam products in good to excellent yields. Fur- acetylide; supersilyl Lewis acid; synergistic catalysis
Introduction
only two reports dedicated to the catalytic alkynyla-
tion of acetals.[2]
Despite the widespread exploitation and application
The first by Watson et al. is an asymmetric proto-
of the alkyne functional group the catalytic alkynyla- col, however it requires an excess quantity of both tri-
tion of highly electrophilic cationic intermediates, for methylsilyl trifluoromethanesulfonate (TMSOTf) and
example, carbenium, N-acyliminium and oxonium diisopropylethylamine (Scheme 1),[2b] while the
ions, is surprisingly a methodology that has thus far second contribution is a gold-catalyzed alkynylation
received only scant attention from the organic synthe- using terminal alkynes which, however, operates
sis community. This is quite revealing given the high under harsh reaction conditions.[2a] In the context of
synthetic ꢁvalueꢂ associated with functionalized prop- our ongoing research interests in catalytic N-acylimi-
argylic motifs. Thus only a handful of catalytic sys- nium ion chemistry,[3] we noted that the catalytic alk-
tems has been disclosed for the alkynylation of
ACHTUNGTRENyNGNU nylation of N,O-acetals is a synthesis methodology
(highly) p-activated alcohols and their derivatives; that has significant potential but has not yet been de-
see, for example, the recent report by Zhang et al. on veloped.[4] Thus, while the a-amidoalkylation of N,O-
the synthesis of arylated alkynes (Scheme 1).[1] Fur- acetals with traditional nucleophiles such as allylsi-
thermore, as far as the authors are aware, there are lanes, enol silanes, active methylene compounds, p-ar-
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Malina Michalska et al.
Scheme 1. Current state-of-the-art for catalytic alkynylation
of carbenium and oxonium ions.
omatics, has been widely documented,[3,5] the related
alkynylation reaction has not.[4] Thus, although a limit-
ed number of examples has been reported these often
require pre-formed metal alkynylides to be used, in
conjunction with harsh reaction conditions and, at
best, stoichiometric quantities of Lewis acid media-
tors, for example, BF3·OEt2, and TMSOTf. Of the dif-
ferent methods published on the alkynylation of N,O-
acetals the most appealing was that by Pilli et al.
(Scheme 2) who coupled terminal alkynes to N,O-ace-
Scheme 2. Current state-of-the-art for the C-alkynylation of
N-acyliminium ions.
tals using 2 equivalents of ZnACHTNUGRTNEUNG
(OTf)2.[4d]
Our preliminary attempts at developing an efficient
catalytic alkynylation of N,O-acetals using terminal al-
kynes (Scheme 3) were disappointing. In summary, al-
though the reaction would proceed using gold(I) cata-
lysts we were unable to achieve sufficiently high cata-
lytic turnovers that the starting material, for example
1A, was transformed into the desired product (3A) in
less than 24 h (Scheme 3).[6] For this reason we sought
to design an alternative strategy with a view to devel-
oping a more efficient and, importantly, faster reac-
tion process desirably amenable to structure and func-
tion diverse alkynes.
Scheme 3. Preliminary efforts towards generating a proce-
dure for the direct catalytic alkynylation of N,O-acetals.
acyliminium ion coupling targeted here. A generic
overview of the reaction as we envisaged it is outlined
in Scheme 4.
Design Plan
At the outset the reaction is initiated via the rapid
Inspired by previous reports of silylium catalysis[7] in- complexation of the carbon-carbon triple bond of
cluding our own contribution,[3a,b,d,e] we anticipated re- a trialkylsilylalkyne[8] with a cationic gold(I) salt. Sub-
storing the high catalytic activity desired in our alk- sequently an aurodesilylation event takes place which,
ACHTUNGTRENNUNGynylative a-amidoalkylation by developing an unpre- importantly, generates both a nucleophilic gold(I)
cedented catalytic gold/silyl synergistic approach, acetylide C[9,10] and a trimethylsilyl Lewis (super)acid
which is also expected to have the potential to be D.[7] This process is reminiscent of the well-known
a general alkynylative methodology beyond the N- protodesilylation of silicon-based nucleophiles by
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Synergistic Gold(I)/Trimethylsilyl Catalysis: Efficient Alkynylation of N,O-Acetals
Scheme 4. Design plan of our gold/silyl synergistic activation mode dedicated to the catalytic alkynylation of N,O-acetals.
Brønsted superacids.[7b,c] Critically, generating both in-
Bearing in mind the mechanistic considerations
termediates C and D sets the reaction up well for the outlined in Scheme 4 we consider our approach of in
initiation of the subsequent, and important, dual cat- situ generation of the catalytic agent to be superior to
alysis process that follows. Here D ꢁactivatesꢂ the ꢁexternalꢂ addition, we would for example anticipate
N,O-acetal B, generating a transient and highly reac- catalyst synthesis at source or where required to be
tive N-acyliminium intermediate E, which is, when significantly more efficient, direct and atom-economic
formed, immediately trapped by s-gold(I) complex C. than the alternative reaction employing terminal al-
ꢀ
This C C bond forming step releases the desired al- kynes and stochiometric quantities of Lewis acid (vide
kynylation product F, and regenerates the original supra). We also anticipate our conceptually new
gold(I) triflate catalyst which feeds back into the reac- mechanistic approach will have significant utility for
tion cycle affording substrate turnover.
the alkynylation of other structurally and functionally
Key to success in this strategy is the judicious diverse electrophiles including cationic precursors and
choice of gold counter anion. The counter anion must sp2 functionalities.
indeed exhibit a subtle balance, being sufficiently sila-
Beside its doubtless synthetic utility as a novel alk-
AHCTUNGTREGyNNUN nylative methodology, this mechanism-guided design
philic to promptly mediate aurodesilylation,[11] and
also weakly coordinating thus enhancing its ability to strategy also manifests a conceptual interest since it
produce a suitable silicon-based Lewis acid which fa- can be regarded as an unprecedented approach where
cilitates and mediates the rapid ionization of the N,O- the incorporation of a single pre-catalyst (LAuX) me-
acetal group generating the N-acyliminium species, diates the initiation and in situ generation of two key
i.e., B!E (Scheme 4). With these general considera- catalytic species, namely a s-gold acetylide and
tions in mind, gold(I) triflate/triflimidate [LAuOTf/ a ꢁsuperꢂ silyl transfer reagent (TMSX), which when
NTf2] catalysts were assumed to hold the right bal- synergistically combined with the electrophilic reac-
ance of desirable chemical attributes to facilitate the tion partner promote the efficient formation of high-
efficient alkynylation of N,O-acetals.[3a–e,7,12] The for- value entities based on F (Scheme 4). When com-
mation of the ꢁsuperꢂ silyl transfer reagent trimethyl- pared to ꢁtraditionalꢂ synergistic catalysis, which sys-
silyl trifluoromethanesulfonate (TMSOTf) or trime- tematically promote reactions with the aid of two sep-
thylsilyl
bis(trifluoromethanesulfonyl)imide arate catalysts (Figure 1A),[13] our in situ approach to
(TMSNTf2), arising through a net trimethylsilyl trans- synergistic catalysis (Figure 1B) is arguably of signifi-
fer from the “protected” trimethylsilylalkyne, i.e., A cant synthetic value from an academic, economic,
to the triflate (or triflimidate) counter anion of the time and atom-efficiency point of view. In addition,
gold(I) salt, provides us with a highly convenient and our approach has particular value if the catalytic spe-
efficient method of generating in situ and ꢁat sourceꢂ cies and/or catalyst(s) to be generated are not trivial
catalytic quantities of the important naked Lewis to prepare and handle; as is the case here with s-
acid. The presence then of the trimethylsilyl group on gold(I) acetylides and the formation of extremely
the alkyne starting material is fundamentally important water-sensitive and highly reactive Lewis acids
and cannot be considered as a ꢀsuperfluousꢁ group.
TMSOTf and TMSNTf2.
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AHCTUNGTREGaNNUN cetylene 2A outperformed the direct variant using
terminal alkyne 2D (Table 1, entry 3 versus
Scheme 3).
(ii) Soft and rather carbophilic in nature, gold(I)
salts[15] stabilized with a ligand were superior to other
potential catalysts such as AuOTf, Au
ACHTUNGRTENUN(NG OTf)3, AgOTf,
CuI, Cu
AHCTUNGTRENNUNG
a net decrease in the reaction conversion rate was ob-
served as the steric bulk of the trialkylsilyl motif was
increased (see entry 3 versus entries 1 and 2, Table 1).
AHCTUNGTREG(NNUN iii) As anticipated from our mechanistic postulate,
a strong counter anion effect was observed (entry 3
versus entries 4–10). In particular and as anticipated
(videꢀ supra) Ph3PAuX (X=Clꢀ, Iꢀ, TsOꢀ BF4 and
ꢀ
SbF6 ) were at best moderately effective in promoting
the reaction.[12] Both Ph3PAuOTf and its triflimidate
analogue were expected to generate Me3SiOTf and
Me3SiNTf2, respectively, with the latter anticipated to
surpass the former in its ability to activate the N,O-
acetal.[3b,c,7b,16] The fact that both in situ generated
Gagosz pre-catalyst Ph3PAuNTf2 and its silver-free
commercially available analogue exhibited lower ac-
tivities than Ph3PAuOTf (compare entry 3 with en-
tries 9 and 10) reflects the higher nucleophilicity/sila-
philicity of the triflate anion over its triflimidate ana-
logue.[7b,16] This strongly suggests that the rate-deter-
mining step in our mechanistic proposal is the forma-
Figure 1. Conventional use of ꢁtwo separate catalystsꢂ (A)
versus our unprecedented ꢀin situꢁ synergistic catalysis acti-
vation protocol (B).
tion of the silyl Lewis acid catalyst
D (via
aurodesilylation, i.e., A to C) rather than generation
of the N-acyliminium ion (Scheme 4).[17,18] This, com-
Herein we report what we believe to be the first bined with the low conversions that were observed
prototype of this exciting synergistic catalysis concept. when more electrophilic gold catalysts such as
Preliminary results are exemplified principally via the (C6F5)3PAuOTf or AuOTf and AuACTHUNRTGNEUNG(OTf)3 (entries 17–
catalytic alkynylation of cyclic N,O-acetals but also 19) were employed, strongly support our dual syner-
with O,O-acetals, and the construction of the multicy- gistic gold/silyl catalysis concept rather than an oxo-
clic 5,11a-dihydro-1H-benzo[e]pyrrolo
3(2H)-one ring system.
ACHTUNGTRENNUNG
efficiency was significantly enhanced in apolar sol-
vents,[14] this can be ascribed to a maximization of the
electrophilic properties associated with the cationic
gold(I) and the nucleophilic properties of the triflate
and triflimidate anions. Minimization of side effects
Results and Discussion
Alkynylation of N,O-Acetals: Optimization Study
In the first instance it was important to perform a fea- caused by silver might also be ascribed.[20] The solvent
sibility study that aimed to explore the possibility of effect was optimized when a,a,a-trifluorotoluene was
alkynylating the readily generated (ꢁ)-2-allyl-3-oxo- employed (compare entries 3 and 11), furthermore
ACHTUNGTRENNUNGisoindolin-1-yl acetate 1A with trialkylsilylphenylace- slightly warming the reaction to 408C established
tylene derivatives 2A–2C (Table 1). Gratifyingly, after a highly effective set of reaction conditions that al-
an extensive set of screening experiments had been lowed complete and efficient alkynylation to take
performed the results from this study strongly sup- place in only 15 min, employing a slight excess
ported our working hypothesis outlined in (1.2 equivalents) of 2A together with a low 3 mol%
Scheme 4.[14] Examples of the most important and loading of the gold(I) pre-catalyst Ph3PAuOTf
representative results from this preliminary study are (entry 12). The simplicity and mildness of our reaction
depicted in Table 1.
conditions are particularly noteworthy, and markedly
The following observations were particularly sup- contrast with the harsh reaction conditions,[1c–e] or the
portive of our mechanistic hypothesis: (i) As antici- high catalyst loading (viz. 10 mol%)[1f,g] applied in as-
pated, the coupling of 1A with trimethylsilylphenyl- sociation with extremely easily ionizable substrates
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Table 1. Optimization of the gold(I)-catalyzed amidoalkylation of phenylacetylene derivatives 2A–C with model N,O-acetal
1A.[a]
Entry
2
Equiv. Nu
Catalyst (n mol%)
Solvent
Time
Conversion [%][b]
1[c]
2[c]
3
4
5
6
7
8
9
10
11
12[c]
13
14
15
16[c]
17
18
19
19
2B
2C
2A
2A
2A
2A
2A
2A
2A
2A
2A
2A
2A
2A
2A
2A
2A
2A
2A
2A
1.2
1.2
1.5
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
Ph3PAuOTf (3)[d]
Ph3PAuOTf (3)[d]
Ph3PAuOTf (7)[d]
Ph3PAuCl (7)
CF3C6H5
CF3C6H5
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CF3C6H5
CF3C6H5
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
3 d
nr
16
100
nr
16
nr
nr
73
100
100
100
100[f]
44
100
100
43
5 h 40 min
45 min
3 d
5 h 40 min
24 h
30 h
4 h
4 h
1.5 h
15 min
15 min
30 min
30 min
30 min
30 h
22 h
20 h
20 h
20 h
Ph3PAuI (7)[d]
Ph3PAuOTs (7)[d]
Ph3PAuBF4 (7)[d]
Ph3PAuSbF6 (7)[d]
Ph3PAuNTf2 (7)[d]
Ph3PAuNTf2 (7)[e]
Ph3PAuOTf (7)[d]
Ph3PAuOTf (3)[d]
Ph3PAuOTf (3)[d]
L1AuOTf (3)[d]
IPrAuOTf (3)[d]
L2AuOTf (7)[d]
L3AuOTf (7)[d]
AuOTf (7)[d]
40
32
[g]
Au
Au
U
[g]
[a]
Unless otherwise indicated, the reactions were carried out at room temperature.
Yields have been estimated via H NMR.
The reaction was carried out at 408C.
Prepared by premixing commercially available gold(I) chloride with an equimolar amount of the silver salt.
Commercially available Gagosz (silver-free) catalyst was employed.
The isolated yield was 90%.
[b]
[c]
[d]
[e]
[f]
1
[g]
A complex mixture was obtained.
employed in the related catalytic alkynylation of p-ac-
tivated alcohols with alkynylsilanes.
Finally, it is worth noting that in our alkynylation
reaction turnover is virtually unaffected by the forma-
(v) Consistent with our mechanistic hypothesis, tion of the alkynylated product, this demonstrates the
analysis of the preliminary ꢁmodelꢂ reaction results[18] poor propensity of bulky product 3A to reversibly
using gold(I) triflates bound to an electron-rich phos- bind to the Au(I) center thus competing with the less
phine [p-MeO-(C6H4)3P] or a s-donor IPr ligand[21] in- hindered and more productive trimethylsilylalkyne
dicated that these ligands generated a superior cata- 2A.
lyst complex to that afforded with Ph3P (entries 13–
15), while sterically bulky triarylphosphines led to
a significant rate retardation (entry 16). Owing to in- Reaction Scope
creased atom economy and lower cost considerations,
triphenylphosphine was preferentially employed for Having established and optimized the best combina-
continuation of this work.[22]
tion of reaction partners, solvent, gold(I) salt catalyst
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Table 2. Scope of the gold(I)-catalyzed amidoalkylation of trimethylsilylacetylene derivatives 2A and 2E–K with N,O-acetals
1A–I and 4A–E.
[a]
The reaction was carried out on a 500-mg scale with 1 mol% of Ph3PAuOTf.
1.5 equiv. of the alkyne.
5 mol% of the catalyst with 2 equiv. of the alkyne.
7 mol% of the catalyst with 2 equiv. of the alkyne.
5 mol% of the catalyst.
10 mol% of Ph3PAuNTf2 with 2 equiv. of the alkyne.
[b]
[c]
[d]
[e]
[f]
and reaction time for a ꢁmodelꢂ reaction system (see bearing various structureally and functionally diverse
Table 1), we sought to further delineate and explore N-substituents was evaluated using trimethylsilylphe-
the reaction scope. With this in mind Table 2 outlines nylacetylene 2A (all the structures of the starting ma-
a representative selection of results that aim to dem- terials and substrates used throughout this study are
onstrate the broad applicability and generality of this given in the Supporting Information).
innovative synergistic gold/silyl catalyzed alkynylation
We were delighted to observe formation of the de-
reaction. A series of isoindolic acetoxylactame 1A–I sired alkynylated adducts 3B–F (Table 2) in consis-
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Synergistic Gold(I)/Trimethylsilyl Catalysis: Efficient Alkynylation of N,O-Acetals
tently fast reaction times (45 min to 3 h) as well as reaction protocol is fully tolerant of terminal alkynes
very good (76%) to excellent (97%) yields.[23] Further- in either of the reaction partners.
more this study also verified and substantiated the
Further analysis of the substrates that underwent
catalytic alkynylation reaction to be fully amenable reaction and in particular those affording 3F, 3H, 3J,
and highly effective when scaled-up, a fact that fur- 3K, and 5A–E allows us to conclude that the incorpo-
ther exemplifies the potential value of our synergistic ration of Lewis basic sites in either of the two starting
catalytic synthesis methodology. By way of an exam- materials is tolerated. Thus although the reaction
ple, in an excellent 97% yielding reaction, 550 mg of seems relatively insensitive to the presence of these
3B were isolated from 500 mg of the parent a-acet- Lewis bases in general the reaction rates were slower,
ACHTUNGTRENNUNG
We have established that trimethylsilylalkynes con- tant feature of this methodology lies in the fact that
taining diversely substituted aryl groups are viable the propargylic lactam products bearing various N-ar-
substrates in the alkynylation reaction. Thus electron- ylmethyl and N-heteroaryl methyl groups (3B, C, 3E,
rich para-tolylethynyltrimethylsilane 2E and trime- F, 3H–J and 3l) have the potential to undergo an in-
thylsilyl-p-methoxyphenylacetylene 2F afforded 3G tramolecular hydroarylation,[29] to our delight, howev-
and 3H in excellent 99% and 78% yields, respectively, er we found no evidence for this and the desired
they did however require an extended reaction time products were all isolated in good to excellent yields.
relative to the electronically neutral phenyl ring of
Further demonstrating the general applicability of
2A. It seemed that introducing a donor aryl group our synergistic gold/silyl-catalyzed alkynylation reac-
within the nucleophilic component had, as expected, tion, we sought to investigate the coupling of non-iso-
reduced the electrophilicity of the silicon center indolic N,O-acetals, i.e., 4A–E. Commercially avail-
within the gold p-alkyne complex. Thus the anticipat- able 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline
ed rate reduction associated with the aurodesilylation (EEDQ) 4A was alkynylated using trimethylsilylphe-
event manifests itself as an observable reduction in nylacetylene 2A, the desired propargylic N-carbamate
the reaction kinetics affording 3G and 3H.[24]
adduct 5A was afforded in an excellent 90% yield, al-
Perhaps most importantly, this methodology can be though the reaction rate was significantly slower in
extended to non-aryltrimethylsilylalkynes, thus incor- comparison to the isoindolic series. In spite of the ad-
porating 2G–K[25] afforded the corresponding propar- jacent steric bulk associated with the N-Cbz group
gylic amides, 3I–M in good 69%–75% yields. Further- and gem-dimethyl subunit that are close to its reactive
more, the successful application of trimethylsilylalk- center, the a-acetoxylactam-derived oxindole 4C re-
ACHTUNGTRENNUNGynes 2H and 2J appended with the acid- (OTBDPS) acted smoothly and efficiently affording, again, the
and base-sensitive (TMS) functional groups, respec- desired product 5C in a good yield. Exploring the po-
tively, is particularly noteworthy. Both reactions af- tential of the synergistic catalysis alkynylation meth-
forded 3J and 3l in good 75% and 73% yields, respec- odology in asymmetric synthesis, we were delighted
tively. More specifically the incorporation of bis(tri- that two a-acetoxylactams derived from (S)-malic
methylsilyl)alkyne 2J within our gold-catalyzed N,O- acid,[4e] afforded the expected adducts 5D and 5E in
alkynylation reaction is noteworthy for the fact that quantitative and excellent 94% yields, respectively.
the second trimethylsilyl group was retained in the Unfortunately, although these reactions were ex-
product 3l. The stability of the alkynyl appended tri- tremely efficient there was little diastereocontrol,
methylsilyl group to the reaction conditions employed even in the presence of a para-methoxybenzyl or
further demonstrates the exceptional mildness of our bulky adamantyl ester groups, poor trans-/cis-diaste-
synergistic catalysis methodology.[26] Moreover with reocontrol was observed (see Table 2).
this trimethylsilyl group in place, the possibility of un-
Triphenylphosphine gold(I) triflate (Ph3PAuOTf)
ꢀ
dertaking a second Csp Si activation further exempli- consistently displayed greater reactivity than
fies the significant potential that our new methodolo- Ph3PAuNTf2 in the alkynylation of highly reactive
gy has in the synthesis arena. Use of trimethylsilylace- N,O-acetals such as a-acetoxylactams, this was attrib-
tylene 2K afforded exclusively and as anticipated ter- uted to the fast formation of a gold(I) acetylide inter-
minal alkyne 3M in a good yield. This result lends mediate (see Scheme 4). In contrast, we considered
credence to our proposed mechanism (Scheme 4) and, the possibility that this situation could be reversed
more specifically, also indicates a quite unusual and when a less reactive N-acyliminium ion precursor was
ꢀ
selective mode of Csp Si activation for trimethylsilyl- engaged in the reaction and would, in fact, require
acetylene.[27,28] This result is further substantiated by a stronger silyl Lewis acid activator to be employ-
the successful inclusion of N-propargylated a-acetoxy- ed.[10b,17] Testing for this assumption we were immedi-
lactam 1D that afforded adduct 3D. That 3D and 3M ately rewarded with the alkynylation of the challeng-
are both generated in good yields confirms that our ing N,O-acetal carbamate 4B that is equipped with
two neighbouring and deactivating ester groups.[3e]
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Scheme 5. Synthesis of 7 via the dual synergistic gold(I)/silyl
alkynylation of O-methoxy acetal 6.
Scheme 6. Mechanistic ꢁmodelꢂ experiment that supports our
dual synergistic gold(I)/silyl catalysis hypothesis.
Exposure of 4B to our standard alkynylation protocol
in the presence of Ph3PAuOTf resulted in poor con-
version, possibly due to the inability of in situ gener-
ated TMSOTf to efficiently generate, under such mild
reaction conditions, the required N-acyliminium ion.
[30]
ꢂ
Ph3PAuC CPh, it was our aim to mimic within the
However, switching to Ph3PAuNTf2 as an in situ reaction medium the key catalytic components consid-
source of TMSNTf2 we were delighted that a signifi- ered to undertake critical roles viz. C and D and
cant rate enhancement was observed when 10 mol% which we assumed were generated in the mechanism
of the Gagosz pre-catalyst was employed and 5B was outlined in Scheme 4. To our delight, and as anticipat-
afforded in an excellent 88% yield.
ed, we restored the high reactivity exhibited in our
optimized synergistic reaction procedure (see Table 1,
entry 12). Substrate 1A was transformed in a clean, ef-
ficient and quantitative process into alkynylated prod-
uct 3A in only 15 min. This result strongly corrobo-
rates our working mechanistic hypothesis (Scheme 4)
Expanding the Substrate Scope of the Alkynylation
Reaction: Evaluating Alternative Pro-Electrophiles
Our gold-initiated synergistic silyl/gold catalysis alk- that the critical formation of two synergistic gold(I)/
ACHTUNGTRENNUNGynylation concept could, in principle, be extended to silyl species is required for the efficient alkynylation
the inclusion of a wide variety of alternative electro- of N,O-acetals.
philic substrates related to the reported a-amidoalky-
lation reaction. As a preliminary research effort to-
wards probing this goal we were delighted to observe Synthetic Utility of the Alkynylation Products:
that the isochroman O-methoxy acetal 6[2b] was fully Efficient Multicyclic Ring Synthesis
compliant and engaged successfully in the catalytic al-
kynylation methodology. Thus, the desired 1-alkynyl- A preliminary study was undertaken to explore the
ACHTUNGTRENNUNGisochroman 7 (Scheme 5) was afforded from 6 in potential of our methodology for the synthesis of mul-
a similar reaction time and yield as observed for the ticyclic ring systems via a two-step, one-pot alkynyla-
previously generated a-amidoalkylation adducts (see tion/hydroarylation sequence of reactions. Gratifying-
Table 1 and Table 2).
ly using Ph3PAuOTf (10 mol%) the intended cascade
alkynylation/hydroarylation reaction sequence was
observed with the desired tetracyclic compound 8
generated in an acceptable, unoptimized 34% yield
(Scheme 7). Otherwise, examination of an array of or-
Mechanistic Considerations
Confident that our reaction protocol was robust, we dinary hydroarylation gold(I) catalysts was investigat-
opted to initiate a preliminary study aimed at gaining ed for the cyclization of pre-isolated product 3E in
an insight into the reaction mechanism. Attempting a,a,a-trifluorotoluene, in a view of possibly improving
the model reaction outlined in Table 1 using trime- the one-pot alkynylation/hydroarylation sequence by
thylsilylacetylene 2A with 3 mol% trimethylsilyl tri- a two-gold catalysts approach.[3f] Unfortunately, the
flate as an ꢁexternally addedꢂ Lewis acid catalyst re- cyclization was invariably complicated by several side
sulted, as anticipated, in a slow conversion rate to the reactions and the desired compound 8 could not be
alkynylated product 3A (34% conversion after 5 h re- isolated in yields greater than 55%, which did not en-
action time), this suggests that trimethylsilylalkynes courage us to pursue with the two reactions sequence.
are probably insufficiently nucleophilic to efficiently Future efforts within our laboratory will be dedicated
mediate
this
catalytic
alkynylation
process at improving the efficiency of this sequence by testing
(Scheme 6). However, repeating the reaction in additional substrates and gold catalysts or applying
the presence of 3 mol% of both trimethylsilyl triflate recent methodological[31] and technological advan-
and the easily prepared s-gold(I) alkynylide ces.[32]
8
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Synergistic Gold(I)/Trimethylsilyl Catalysis: Efficient Alkynylation of N,O-Acetals
Scheme 7. Two-stage, one-step catalytic alkynylation/intramolecular hydroarylation sequence for the synthesis of multicyclic
8.
Conclusions
Experimental Section
In summary, we have developed the first catalytic al- Representative Procedure for the Gold(I)-Catalyzed
kynylation of N,O-acetals. The reaction employs read- Alkynylation of N,O-Acetals with TMS Alkynes
ily synthesised trimethylsilylalkynes as nucleophilic
partners and, typically, low pre-catalyst loadings, i.e.,
To a solution of Ph3PAuOTf (0.01–0.1 equiv.) in situ formed
by mixing Ph3PAuCl and AgOTf (1/1 mixture) in a,a,a-tri-
1–5 mol% of LAuOTf. The reaction operates under
mild reaction conditions, exhibits high chemical effi-
ciency and diverse applicability. This reaction has
been engineered via a design mechanism which pro-
ceeds via an unprecedented synergistic silyl–gold(I)
catalysis approach which is initiated from a single
readily available gold(I) pre-catalyst. Furthermore,
our protocol has the practical advantage of generating
in situ the air and moisture-sensitive super silyl trans-
fer reagents, i.e., TMSOTf/TMSNTf2, which act as
critical components within the catalytic cycle that we
have proposed and consolidated by means of control
experiments. To the best of our knowledge, this is the
first report of a synergistic catalytic system that pro-
ceeds via the simultaneous in situ synthesis of both
key catalytic components. We have briefly demon-
strated the potential flexibility and applicability of
this protocol with its extension to pro-electrophilic
substrates related to N,O-acetals such as acetals
(Scheme 5), and their transformation into new multi-
cyclic and heterocyclic ring systems (Scheme 7). Per-
haps more importantly, we have also shown that with
the careful selection of the gold counter ion, it is pos-
sible to manipulate the strength of the ancillary silyl
Lewis acid so that it complements the inherent reac-
tivity, viz. the ionizing ability, of a particular pro-elec-
trophilic substrate. We are currently exploring the in
situ approach for synergistic catalysis in other sub-
strate studies, which we anticipate will open up new
directions in gold chemistry and stimulate the discov-
ery of new reactions in the synthesis arena.[33,34]
fluorotoluene ([substrate]=0.48 mol/L) in a round-bottom
flask with a Teflon stirring bar, was added a solution of the
nucleophile (1.2–2 equiv.) and the acetoxy- or alkoxylactam
(1 equiv.) [substrate]=0.8 mol/L)]. The reaction mixture
was then stirred at 408C in an oil bath. At the end of the re-
action (1H NMR or TLC monitoring), the reaction mixture
was directly purified by flash column chromatography on
silica gel (cyclohexane/ethyl acetate) to afford the corre-
sponding alkynylated products.
Further experimental details of the experimental proce-
dures, optimization studies, characterization along with
1
copies of H and 13C NMR spectra of all new isolated com-
pounds are available in the Supporting Information.
Acknowledgements
The authors would like to thank the European Community
for the financial support for the project IS:CE-Chem in the
framework of INTERREG IVA France-(Manche)–England
(project 4061). OS gratefully acknowledges the Rꢂgion Haute
Normandie for a post-doctoral fellowship.
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ed a-amidoalkylation of silicon-based nucleophiles (see
refs.[3a–d]); Au(I) cations ꢀpaired to non-nucleophilic
ꢀ
anions such as BF4 , SbF6 and BARF are also consid-
ered to be unsuitable as we assume they will not or
may but only poorly mediate aurodesilylation.
[13] A. E. Allen, D. W. C. MacMillan, Chem. Sci. 2012, 3,
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[14] Our full optimization study including catalysts and sol-
vents screening is provided in Tables S1 to S3 in the
Supporting Information.
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prone to ionization, or if other oxygen electrophiles
which are known to be much better activated by silyl
triflimidates than by silyl triflates[10] were used.
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utes to form a weak [Au]+/triflate ion-pair which is
easier to dissociate. The tighter ion-pairing resulting
from the use of more electrophilic gold salts with no
ligand or electron-poor triarylphosphines, probably re-
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Synergistic Gold(I)/Trimethylsilyl Catalysis: Efficient Alkynylation of N,O-Acetals
duces silaphilicity of the triflate anion and then retards
the overall reaction rate.
6704; b) V. Gudla, R. Balamurugan, Chem. Asian J.
2013, 8, 414.
[19] The use of 2,6-di-tert-butylpyridine inhibited the reac-
tion in the case of an in situ generated Ph3PAuOTf.
Furthermore while the reaction catalyzed by IPrAuOTf
was significantly retarded it did almost reach comple-
tion but only after a 24h reaction time. These results
are amazing and remain unclear at this stage, as they
fully contradict the mechanism proposal that we have
consolidated (see Scheme 7) – more work will be re-
quired to clarify this point.
[20] D. Wang, R. Cai, S. Sharma, J. Jirak, S. K. Thummana-
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reaction scope partly depicted in Table 2.
[27] Under transition metal catalysis conditions, chemose-
ꢀ
lective C H activation of TMS-acetylene is generally
followed. Some illustrative examples can be found in
the two following reviews: a) B. M. Trost, A. H. Weiss,
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Nꢆjera, Chem. Soc. Rev. 2011, 40, 5084.
[28] a) For selected examples of chemoselective gold-cata-
ꢀ
lyzed Csp H activation of TMS-acetylene in the pres-
ence of an amine component, please see: refs.[10h–j]
;
ꢀ
b) For a quite rare example of chemoselective Csp
SiMe3 activation of TMS-acetylene, see ref.[1f]
[29] For one paper reporting examples of gold-catalyzed in-
tramolecular 7-endo-dig hydroarylation of indole-ary-
lalkynes easily proceeding at the temperature range
used in our alkynylation, see: Y. Lu, X. Du, X. Jia, Y.
Liu, Adv. Synth. Catal. 2009, 351, 1517.
[30] For the preparation of LAu alkynylide using a lithium
base and LAuCl, see: a) H. Werner, H. Otto, T. Ngo-
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wave irradiation, see: a) X.-Y. Liu, P. Ding, J.-S. Huang,
C.-M. Che, Org. Lett. 2007, 9, 2645; b) S. Pascual, C.
Bour, P. de Mendoza, A. M. Echavarren, Beilstein J.
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[33] During the preparation of this manuscript, we became
aware of an excellent paper by Gonzꢆles and co-work-
ers who describe the bis-alkynylation of aryl aldehydes
with TMS-alkynes catalyzed by gold triflimidate salts.
The mechanistic investigations described by these au-
thors fully support our own synergistic gold/silyl activa-
tion mode. B. Rubial, A. Ballesteros, J. M. Gonzꢆlez,
Adv. Synth. Catal. 2013, 355, 3337–3343.
[23] The reaction times presented in Table 2 are for reac-
tions exceeding 2–3 h, are unoptimized and are more
than likely less than indicated.
[24] The alkynylation of silylacetylenes with an electron-de-
ficient aryl group was not studied for the following
ꢀ
reason: their direct C H coupling was evaluated under
the optimal reaction conditions, and around 90% con-
versions were reached with p-NO2- and p-CF3-phenyla-
cetylene. This enhancement of the conversion reflected
our assumption that the location of an electron-with-
drawing substituent on the nucleophile may increase
the acidity of the terminal alkynyl proton and therefore
accelerate its deprotonation thus facilitating gold(I)
acetylide formation. Unfortunately, the alkynylation
products appeared to be particularly sensitive and par-
tial decomposition was observed during chromatogra-
phy purification on silica gel.
[25] The nature of the R2 substituents within TMS-alkynes
2E–H is seen in the accordant propargylic lactams 3G–
M depicted in Table 2.
[26] For selected examples of gold-catalyzed processes of
TMS-alkynes that proceed with extensive or partial de-
silylation, see: a) J. Zhang, H. G. Schmalz, Angew.
Chem. 2006, 118, 6856; Angew. Chem. Int. Ed. 2006, 45,
[34] Our work is fully independent from that of the previ-
ous reference, and had been initially submitted else-
where for publication on July 5th, 2013.
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12 Synergistic Gold(I)/Trimethylsilyl Catalysis: Efficient
Alkynylation of N,O-Acetals and Related Pro-Electrophiles
Adv. Synth. Catal. 2014, 356, 1 – 12
Malina Michalska, Olivier Songis, Catherine Taillier,
Sean P. Bew, Vincent Dalla*
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