Gold (I) catalysis of X-H bond insertions

Article abstract of DOI:10.1016/j.tetlet.2010.08.038

The utility of gold catalysis for carbene X-H bond insertion chemistry is described for the first time, taking advantage of the unique reactivity of sulfoxonium ylides as metal carbene precursors.

Full text of DOI:10.1016/j.tetlet.2010.08.038

Tetrahedron Letters 51 (2010) 5490–5492
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Tetrahedron Letters
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Gold (I) catalysis of X–H bond insertions
⇑
Ian K. Mangion , Mark Weisel
Department of Process Research, Merck and Co., Inc., PO Box 2000, Rahway, NJ 07065, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The utility of gold catalysis for carbene X–H bond insertion chemistry is described for the first time, tak-
ing advantage of the unique reactivity of sulfoxonium ylides as metal carbene precursors.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 19 July 2010
Revised 5 August 2010
Accepted 12 August 2010
Available online 17 August 2010
Transition metal-catalyzed reactions of
a
-diazocaronyls have
catalysis are certainly not unprecedented. The utility of Au and
Pt in forming transient carbene species has been examined in sev-
eral synthetic contexts.9 Indeed, an Au(I) catalyst was recently
demonstrated by Nolan to be effective in carbene transfer from
ethyl diazoacetate in cyclopropanations and X–H insertions.6a
However, we are interested in expanding the scope and under-
standing of the reactivity of sulfoxonium ylides through gold catal-
ysis to complement existing methods. Therefore we examined the
X–H insertions of 1 with a variety of nitrogen and oxygen nucleo-
philes (Table 2). As in the related Ir(I) system, a range of anilines all
been widely explored, with numerous applications encompassing
a variety of bond formations.1 Notably, copper,2 rhodium3 and
ruthenium4 catalysts occupy a privileged place among transition
metals in mediating carbene reactions. Recently, however, there
has been a growing interest in new applications of gold catalysis,5
including reactions intercepting gold carbene intermediates.6 Pre-
vious work in our labs has shown sulfoxonium ylides to be safe
alternatives to
a
-diazocaronyls as metal carbene precursors,7 and
we sought to further develop their use in the synthesis through
the development of new, differentiated catalyst systems. Herein,
we describe our findings of simple gold catalysts that promote car-
bene transformations.
Table 1
N–H insertion of 1 with aniline using different metal catalystsa
Based on our earlier finding that iridium catalysts efficiently
mediate carbene transformations of sulfoxonium ylides, we further
examined the utility of iridium in the prototypical reaction of 1 with
NH2
O
O
O
8
*
aniline (Table 1). It was found that [Ir(Cp )Cl2]2 reacted in compara-
ble efficiency to [Ir(COD)Cl]2 (Table 1, entry 2), a result that was sur-
prising given the failure of other Ir(III) catalysts (Table 1, entries 3
and 4). In surveying Group 11–12 metals, it was observed that sim-
ple Pt(II), Au(I), and Au(III) catalysts are all capable of mediating the
reaction with good efficiency (Table 1, entries 6–13). Within the gold
and platinum catalysts tried, AuCl(SMe2) was found to provide the
best yield at a low catalyst loading (Table 1, entry 12), whereas re-
lated phosphine complexes gave poor reactivity (entries 10 and
11). AuCl (Table 1, entry 9) gave poorer reactivity than the DMS com-
plex but this is attributed in part to its limited solubility. This result
is consistent with our previous observations that Ir(I) catalysts re-
quire a weakly coordinating ligand such as COD to be both soluble
and active. Indeed, addition of phosphine ligands was found to sup-
press reactivity in otherwise viable catalyst systems, suggesting the
importance of a labile ligand for high conversion (Table 1, entries 6
and 14).
OMe
OMe
catalyst
S
HN
2a
1
Ph
Entry
Catalyst
Mol %b
% Yieldc
1
2
3
4
5
6
7
8
9
10
11
12
13
14
[Ir(COD)Cl]2
[Ir(Cp )Cl2]2
IrCl3
Ir(acac)3
AgCN
Pt(PPh3)2Cl2
Pt(COD)Cl2
PtCl4
1
3
3
3
3
5
3
5
1
1
1
1
1
1
91
88
0
0
24
0
81
3
30
0
12
94
78
6d
*
AuCl
Au(PPh3)Cl
Au(PEt3)Cl
AuCl(SMe2)
AuCl3
AuCl(SMe2)
The high catalytic efficiency of Au(I) in the above transforma-
tion demanded further investigation, though gold carbenes in
a
All reactions conducted in 0.2 M degassed CH2Cl2 under nitrogen at 23 °C with
1.5 equiv of aniline.
b
Catalyst loading.
Isolated yield.
2 mol % PPh3 added.
c
⇑
Corresponding author. Tel.: +1 732 594 5443; fax: +1 732 594 1499.
E-mail address: ian_mangion@merck.com (I.K. Mangion).
d
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.08.038

I. K. Mangion, M. Weisel / Tetrahedron Letters 51 (2010) 5490–5492
5491
Table 2
O
1 mol%
catalyst
O
O
S
Gold-catalyzed X–H insertions of ylide 1a
AuCl(Me2S): 7% yield
[IrCl(COD)]2: 82% yield
1 mol%
AuCl (SMe2)
O
O
R
NBoc
6
º
NHBoc
DCE, 70 C
5
OMe
OMe
X
S
X
1
2a-n
R
H
Scheme 1. Comparison of catalysts for intramolecular N–H insertion.
O
Entry
R
X
Product
% Yieldb
robust to steric influence of the amino acid side chain (Table 3, en-
tries 1–3), while the yield of O–H insertions became slightly more
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Ph
NH
NH
NH
NH
NH
NH
NH
NH
NH
NMe
O
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
94
87
82
93
91
89
87
80
92
p-BrC6H4
p-CNC6H4
p-CF3C6H4
o-ClC6H4
p-MeOC6H4
p-tBuC6H4
o-MeC6H4
2-Naphthyl
Ph
modest with
a-branching in the side chain (Table 3, entries 4–6).
Notably, in the absence of catalyst no reaction was observed in
all cases.
In contrast to [Ir(COD)Cl]2, AuCl(SMe2) does not efficiently
mediate the N–H insertion of carbamates, a weaker nucleophile.
As shown in Scheme 1, intramolecular N–H insertion of 5 proceeds
in only 7% yield with 1 mol % AuCl(SMe2). This result may suggest
that the gold carbene presumably generated during the course of
the reaction is not sufficiently electrophilic to initiate attack of
the carbamate. However, the addition of chloride-abstracting
agents such as AgSbF6 did not improve the efficiency of this
reaction.
Efforts to demonstrate the intermediacy of a gold carbene in a
catalytic cycle for the reactions described herein have not yet been
successful. Following the proposed mechanism in Scheme 2, gold
should liberate DMSO from sulfoxonium ylide (1), generating a
gold carbene complex (7). This process is expected to be reversible
based on previous reports that DMSO can react with carbenes and
carbenoids to generate sulfoxonium ylides,14 and the empirical
observation that elevated concentrations of DMSO suppress con-
version to 10.15 It was hoped that intermediate 7 might be obser-
vable by NMR, as had been the case during our research on
[Ir(COD)Cl]2 and related catalysts.16 However, this intermediate,
if generated,17 appears not to have a sufficient lifetime for NMR
observation at low temperature. Therefore support for a carbene
mechanism, as opposed to an alternative mechanism such as Lewis
acid activation, currently relies on empirical observations; most
notably the sensitivity of the reaction to atmospheric oxygen, or
the inability of simple Lewis acids to effect conversion of 1 in the
absence of a transition metal catalyst.18 Attack of 7 with a nucleo-
phile is thought to first generate a zwitterionic intermediate (8),
which can undergo proton transfer and then elimination of the me-
tal to yield product 10 and regenerate the catalyst.19
84c
89d
82d
76d
69e
Et
TMSCH2CH2
Bn
i-Pr
O
O
O
a
All reactions conducted in 0.2 M degassed CH2Cl2 under nitrogen at 23 °C with
1.5 equiv of nucleophile unless otherwise noted.
b
Isolated yield.
Reaction conducted at 70 °C using DCE as solvent.
Reaction conducted at 40 °C using 4 equiv of alcohol.
Reaction conducted at 80 °C in neat i-PrOH.
c
d
e
Table 3
X–H insertions of amino acid derived sulfoxonium ylidesa
1 mol%
O
O
S
O
AuCl (SMe2)
PGHN
PGHN
X
R2
R1
R1
R2-XH
3a-c
4a-h
Entry
Ylide
PG
R1
R2
X
Product
% Yieldb
1
2
3
4
5
6
7
8
3a
3b
3c
3a
3b
3c
3a
3a
Cbz
Cbz
Boc
Cbz
Cbz
Boc
Cbz
Cbz
Me
iPr
Bn
Me
iPr
Bn
Ph
Ph
Ph
Bn
Bn
Bn
p-CF3C6H4
o-MeC6H4
NH
NH
NH
O
4a
4b
4c
4d
4e
4f
90
87
80
81c
73c
60c
91
O
O
Me
Me
NH
NH
4g
4h
84
a
All reactions conducted in 0.2 M degassed CH2Cl2 under nitrogen at 23 °C with
O
O
R
1.5 equiv of nucleophile unless otherwise noted.
Ph
Ph
b
OMe
Isolated yield.
Reaction conducted at 40 °C using 4 equiv of alcohol.
OMe
c
S
X
O
1
10
Au(L)n
O
S
reacted to provide the corresponding N–H insertion product in
high yield (Table 2, entries 1–10).10 Electron-withdrawing substit-
uents on the aromatic ring were well tolerated furnishing high
yield of the N–H insertion product (entries 3 and 4). Electron-
donating substituents (entries 6 and 7) were also well tolerated
as well as increased steric demand from either the ylide or the
nucleophile (entries 8–10). Likewise, alcohols were found to pro-
vide the O–H insertion products in good yield (Table 2, entries
11–14), though higher temperature was found to be necessary
for optimal conversion.11
Similarly, a variety of sulfoxonium ylides derived from commer-
cial amino acids were found to be excellent substrates for catalytic
X–H insertions (Table 3). Following the method of Nugent,12 ylides
3a–c were synthesized without loss of stereochemical integrity,
and likewise were found to undergo N–H and O–H insertions with-
out racemization.13 It was found that N–H insertion of anilines was
H
O
O
Ph
Ph
Au(L)n
OMe
OMe
X
Au(L)n
7
R
9
O
X
Ph
R
H
OMe
H
X
Au(L)n
R
8
Scheme 2. Proposed mechanistic cycle for Au catalysis.

5492
I. K. Mangion, M. Weisel / Tetrahedron Letters 51 (2010) 5490–5492
García-Cuadrado, D.; Pérez-Galán, P.; Raducan, M.; Bour, C.; Echavarren, A. M.;
In conclusion, we have found that a simple gold catalyst can
Espinet, P. Organometallics 2010, 29, 951.
mediate X–H insertion chemistry of sulfoxonium ylides. Sulfoxoni-
um ylides merit attention as safe alternatives to traditional diazo
compounds for the development and application of metal carbene
chemistry. Their bench and thermal stability make them particu-
larly attractive for large scale chemical processing. Moreover, we
have demonstrated a surprising preference of these ylides to en-
gage with late transition metals that are arguably underdeveloped
in carbene catalysis. Continued exploration of sulfoxonium ylides
may reveal further discoveries of novel reactivity.
7. Mangion, I. K.; Nwamba, I. K.; Shevlin, M.; Huffman, M. A. Org. Lett. 2009, 11,
3566.
8. For preparation of 1 see: Dost, F.; Gosselck, J. Tetrahedron Lett. 1970, 58, 5091.
9. For applications of Pt in carbene transformations see: (a) Bertani, R.; Michelin,
R. A.; Mozzon, M.; Traldi, P.; Seraglia, R.; da Silva, M.; Pombeiro, A. J. L.
Organometallics 1995, 14, 551; (b) Cave, G. W. V.; Hallett, A. J.; Errington, W.;
Rourke, J. P. Angew. Chem., Int. Ed. 1998, 37, 3270; (c) Martín-Matute, B.;
Nevado, C.; Cárdenas, D. J.; Echavarren, A. M. J. Am. Chem. Soc. 2003, 125, 5757;
(d) Ishida, K.; Kusama, H.; Iwasawa, N. J. Am. Chem. Soc. 2010, 132, 8842.
10. Typical procedure for catalytic X–H insertions: To a mixture of 300 mg of 1
(1.33 mmol), and 3.90 mg of AuCl(SMe2) (0.013 mmol, 0.01 equiv) under a
nitrogen atmosphere was added 6.6 mL of degassed CH2Cl2 (sparged 30 min
with nitrogen). To the resulting suspension was added 285 mg 2-
aminonaphthalene (1.99 mmol, 1.5 equiv). The resulting solution was stirred
for 4 h, at this time TLC analysis indicated completion, so the reaction was
concentrated and the resulting residue purified via silica gel column
chromatography (9:1 hexanes/EtOAc), affording 355 mg (92% yield) of 2i as a
white solid. 1H NMR (CDCl3, 400 MHz) d 7.70 (t, J = 5.2 Hz, 2H), 7.61 (m, 3H);
7.38 (m, 4H); 7.23 (m, 1H), 7.01 (dd, J = 8.8, 2.3 Hz), 6.72 (s, 1H), 5.28 (d,
J = 6 Hz, 1H), 5.20 (d, J = 6 Hz, 1H), 3.81 (s, 3H); 13C NMR (CDCl3, 100 MHz) d
172.32, 143.6, 137.4, 134.9, 129.1, 128.4, 127.8, 127.6, 127.3, 126.3, 126.1,
122.4, 118.0, 105.8, 60.8, 52.9.
Acknowledgments
The authors would like to thank Dr. Mark Huffman (Merck) for
helpful discussions.
References and notes
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substrates.
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15. 10% v/v DMSO was sufficient to suppress conversion.
16. Dormer, P. G.; Mangion, I. K. unpublished results; for direct observation of a
gold carbene complex see for example: (a) Wang, H. M. J.; Chen, C. Y. L.; Lin, I. J.
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Chem. 2009, 1, 482.
18. Lewis acid derivatives of Zn, Mg, Sc, La and Yb were found not to provide
conversion in the reaction of 1 with aniline.
19. For a detailed mechanistic discussion of polar X–H bond insertions of metal
carbenes see Ref. 1a, Chapter 8 and: Davis, F. A.; Yang, B.; Deng, J. J. Org. Chem.
2003, 68, 5147.
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