Iridium-catalyzed X-H insertions of sulfoxonium ylides

Article abstract of DOI:10.1021/ol901298p

Image Persented The unique reactivity of sulfoxonium ylides as a carbene source is described for a variety of X-H bond insertions, taking advantage of a simple, commercially available iridium catalyst. This method has applications in both intra- and intermolecular reactivity, including a practical ring-expansion strategy for lactams. The safety and stability of sulfoxonium ylides recommend them as preferable surrogates to traditional diazo ketones and esters.

Full text of DOI:10.1021/ol901298p

ORGANIC
LETTERS
2009
Vol. 11, No. 16
3566-3569
Iridium-Catalyzed X-H Insertions of
Sulfoxonium Ylides
Ian K. Mangion,* Ikenna K. Nwamba, Michael Shevlin, and Mark A. Huffman
Department of Process Research, Merck and Co., Inc., P.O. Box 2000, Rahway,
New Jersey 07065
ian_mangion@merck.com
Received June 10, 2009
ABSTRACT
The unique reactivity of sulfoxonium ylides as a carbene source is described for a variety of X-H bond insertions, taking advantage of a
simple, commercially available iridium catalyst. This method has applications in both intra- and intermolecular reactivity, including a practical
ring-expansion strategy for lactams. The safety and stability of sulfoxonium ylides recommend them as preferable surrogates to traditional
diazo ketones and esters.
Metal-catalyzed insertion of organic diazo compounds into
X-H bonds (X ) C, N, O, S) has long been recognized as
a mild and efficient method for accessing an array of
important functionalized structural motifs.1 In particular,
R-diazocarbonyls have found broad utility as metal carbene
precursors and have been applied in a variety of intra- and
intermolecular bond insertion strategies.2 Despite the wide-
spread acceptance of R-diazocarbonyls in carbene methodol-
ogy, there are important limitations due to the safety issues
associated with their synthesis and the procedural inconve-
nience of their instability to extended storage.3 We took great
interest in a report from Baldwin et al.4 that demonstrated
the ability of ꢀ-keto sulfoxonium ylides to perform intramo-
lecular N-H insertions mediated by a rhodium(II) catalyst.
Rhodium carbenoids were invoked as intermediates in
analogy to known R-diazocarbonyl chemistry. Surprisingly,
no further applications of sulfoxonium ylides in carbene
chemistry have been reported, perhaps owing to the modest
yields reported or the limited substrate scope.5 Herein we
describe our initial findings of a more general approach for
generation of metal carbenes from sulfoxonium ylides.
We began investigations by treating ylide 1 with transition
metal catalysts in the presence of aniline to look for
intermolecular N-H insertion reactivity (Table 1).6 To our
delight, it was found that in the presence of Rh2(OAc)4 (5
mol %) the insertion product 2a could be obtained, albeit in
just 7% yield (entry 1).7 Use of Rh2(TFA)4 increased the
yield somewhat (22% yield, entry 2), but conversion of 1
consistently stalled, suggesting catalyst deactivation was
(1) (a) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds; Wiley-Interscience:
New York, 1998. (b) Regitz, M.; Maas, G. Diazo Compounds, Properties
and Synthesis; Academic Press: London, 1987.
(5) For the synthesis of metal carbenes from sulfonium ylides, see: (a)
Gandelman, M.; Rybtchinski, B.; Ashkenazi, N.; Gauvin, R. M.; Milstein,
D. J. Am. Chem. Soc. 2001, 123, 5372. (b) Gandelman, M.; Naing, K. M.;
Rybtchinski, B.; Poverenov, E.; Ben-David, Y.; Ashkenazi, N.; Gauvin,
R. M.; Milstein, D. J. Am. Chem. Soc. 2005, 127, 15265.
(2) (a) Doyle, M. P. Chem. ReV. 1987, 86, 919. (b) Doyle, M. P.; Forbes,
D. C. Chem. ReV. 1998, 98, 911. (c) Davies, H. M. L.; Beckwith, R. E.
Chem. ReV. 2003, 103, 2861. (d) Evans, P. A., Ed. Modern Rhodium-
Catalyzed Organic Reactions; Wiley-VCH: Weinheim, Germany, 2005.
(3) (a) Moore, J. A.; Reed, D. E. Org. Synth. 1973, 41, 1961. (b) Bio,
M. M.; Javadi, G.; Song, Z. J. Synthesis 2005, 19.
(6) For reviews on the reactivity of related donor/acceptor diazo
compounds, see :(a) Davies, H. M. L.; Antoulnakis, E. G. Org. React. 2001,
57, 1. (b) Davies, H. M. L.; Loe, Ø Synthesis 2004, 16, 2595. (c) Davies,
H. M. L.; Manning, J. R. Nature 2008, 451, 417.
(4) Baldwin, J. E.; Adlington, R. M.; Godfrey, C. R. A.; Gollins, D. W.;
Vaughan, J. G. J. Chem. Soc., Chem. Commun. 1993, 1434.
(7) In the absence of catalyst, no reaction was observed.
10.1021/ol901298p CCC: $40.75
Published on Web 07/20/2009
 2009 American Chemical Society

Table 1. Catalyst Development for N-H Insertion of Aniline
with Sulfoxonium Ylide 1a
Table 2. X-H Insertion Reactions of Ylide 1a
entry
R
X
product
yield (%)b
entry
catalyst
Rh2(OAc)4
mol %b
solvent
yield (%)c
1
2
3
4
5
6
7
8
9
Ph
NH
NH
NH
NH
NMe
NH
O
O
O
S
2a
2b
2c
2d
2e
2f
2g
2h
2i
91
93
76
85
89c
82
p-FC6H4
p-MeOC6H4
p-CF3C6H4
Ph
2-naphthyl
Et
i-Pr
TMSCH2CH2
Ph
1
2
3
4
5
6
7
8
9
10
11
12
13
5
5
2
2
2
2
1
1
1
1
1
1
1
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
DMF
CH2Cl2
DCE
CH2Cl2
CH2Cl2
7
22
12
55
66
59
85
79
77
91
90
84
78
Rh2(TFA)4
[Ru(cym)Cl2]2
RuCl2(PPh3)3
RuCl2(Cp)(PPh3)2
RuCl2(DMSO)4
[Ir(COD)Cl]2
[Ir(COD)Cl]2
[Ir(COD)Cl]2
[Ir(COD)Cl]2
[Ir(COD)Cl]2
Ir(COD)2BF4
86d e
,
63f
73d
80
10
2j
a All reactions conducted at 0.1 M at 23 °C for 4-18 h in degassed
CH2Cl2 under nitrogen using 2.0 equiv of nucleophile except where noted.
b Isolated yield. c Reaction conducted at 70 °C using DCE as solvent.
d Reaction conducted at 35 °C. e Performed in neat EtOH. f Performed in
neat i-PrOH at 80 °C.
Ir(COD) BArF
2
a All reactions conducted at 0.1 M at 23 °C for 10 h in degassed solvent
under nitrogen. b Catalyst loading. c Isolated yield.
insertion of substituted anilines (76-93% yield, entries 2-4).
A secondary aniline also afforded good yield of the desired
R-amino ester (2e, entry 5), though only with elevated
temperature.12 Alcohols perform well in analogous O-H
insertions; surprisingly, these reactions can be performed in
neat alcohol as solvent for optimal conversion (63-86%
yield, entries 7-9). S-H insertion was also demonstrated
in high yield with thiophenol (80% yield, entry 10). In a
similar fashion, ꢀ-keto sulfoxonium ylide 3 can engage in
N-H or O-H insertion processes (eq 1).
occurring. We suspected that DMSO, the byproduct of
sulfoxonium ylide decomposition, was inhibiting rhodium
catalysis.8 This idea was confirmed by control experiments
in which addition of 25 mol % DMSO was sufficient to
suppress reactivity in reactions catalyzed by Rh2(OAc)4 or
Rh2(TFA)4. To overcome this deactivation pathway, we
began screening a variety of metals to find a more robust
catalyst system.9 Ruthenium-based catalysts afforded higher
yields at a lower loading (12-66% yield, entries 3-6).10
Notably, RuCl2(DMSO)4 was a competent catalyst, perhaps
supporting the idea that resistance to DMSO deactivation is
key to ruthenium activity. Surprisingly, even better results
were obtained with an iridium catalyst, [Ir(COD)Cl]2, in
noncoordinating solvents such as CH2Cl2 (91% yield, entry
10). Alternative iridium(I) catalysts afforded comparable
conversion (78-84% yield, entries 12 and 13). This repre-
sents a rare instance of iridium catalysis in carbene catalysis
and the first instance we have found where iridium has been
shown to mediate an N-H bond insertion.11
Efforts were then dedicated toward demonstrating other
carbene transformations such as C-H insertion and cyclo-
propanation.13 Ylides 1 and 3 were subjected to a range of
alkanes and alkenes with known reactivity in R-diazocarbonyl
chemistry.14 However, neither of the desired transformations
was ever observed. To simplify the problem, ꢀ-keto sul-
foxonium ylide 5 was synthesized to probe for intramolecular
reactivity. It was expected that the comparative lability of
A range of nucleophiles was evaluated in the iridium-
catalyzed decomposition of 1 (Table 2). Both electron-
withdrawing and -donating groups are tolerated in the N-H
(8) Modulation of metal carbene reactivity by coordinating solvents has
been observed previously. See, for example: Nelson, T. D.; Song, Z. J.;
Thompson, A. S.; Zhao, M.; DeMarco, A.; Reamer, M. A.; Huntington,
M. F.; Grabowski, E. J. J.; Reider, P. J. Tetrahedron Lett. 2000, 41, 1877.
(9) Production of DMSO during the reaction was confirmed by 1H
NMR.
(12) Aliphatic amines did not react under these conditions and suppressed
catalyst activity for other substrates.
(13) For C-H insertion of iridium complexes, see: (a) Liu, F.; Goldman,
A. S. Chem. Commun. 1999, 2273. (b) Kawamura, K.; Hartwig, J. F. J. Am.
Chem. Soc. 2001, 123, 8422. (c) Whited, M. T.; Grubbs, R. H. J. Am. Chem.
Soc. 2008, 130, 5874. (d) Romero, P. E.; Whited, M. T.; Grubbs, R. H.
Organometallics 2008, 27, 3422. (e) Boebel, T. A.; Hartwig, J. F. J. Am.
Chem. Soc. 2008, 130, 7534.
(10) For Ru-based carbene catalysis, see: (a) Nishiyana, H.; Itoh, Y.;
Matsumoto, H.; Park, S.-B.; Itoh, K. J. Am. Chem. Soc. 1994, 116, 2223.
(b) Del Zotto, A.; Baratta, W.; Rigo, P. J. Chem. Soc., Perkin Trans. 1
1999, 3079. (c) Deng, Q.-H.; Xu, H.-W.; Yuen, A. W.-H.; Xu, Z.-J.; Che,
C.-M. Org. Lett. 2008, 10, 1529.
(14) (a) Doyle, M. P.; Protopopova, M. N. Tetrahedron 1998, 54, 7919.
(b) Nishiyama, H.; Itoh, Y.; Sugawara, Y.; Matsumoto, H.; Aoki, K.; Itoh,
K. Bull. Chem. Soc. Jpn. 1995, 68, 1247. (c) Kennedy, M.; McKervey,
M. A.; Maguire, A. R.; Roos, G. H. P. J. Chem. Soc., Chem. Commun.
1997, 983.
(11) For Ir-catalyzed cyclopropanation or polymerization, see also: (a)
Kanchiku, S.; Suematsu, H.; Matsumoto, K.; Uchida, T.; Katsuki, T. Angew.
Chem., Int. Ed. 2007, 46, 3889. (b) Xiao, X.-Q.; Jin, G.-X. J. Organomet.
Chem. 2008, 693, 3363.
Org. Lett., Vol. 11, No. 16, 2009
3567

the benzylic C-H bonds would allow for facile cyclopen-
tanone formation as seen with the analogous diazo com-
pound.15 Surprisingly, only dimerization was observed in a
range of solvents and concentrations (eq 2). However,
formation of dimer 6 could be avoided with the presence of
an appropriate X-H nucleophile such as thiophenol (eq 3).
lactam into a ꢀ-amino ketone. In this way, a range of cyclic
ꢀ-amino ketones might be accessible while circumventing
more stepwise traditional synthetic approaches.
This strategy was applied in practice for several different
ring sizes (Table 3).18 Sulfoxonium ylide 8a (derived from
Table 3. Intramolecular N-H Insertions for ꢀ-Amino Ketones
C-H insertion appears to be too slow to compete with
dimerization. This undesired reactivity may stem from
nucelophilic attack of a sulfoxonium ylide onto an iridium
carbene followed by elimination of DMSO and regeneration
of the iridium catalyst (Scheme 1). The enhanced propensity
Scheme 1. Proposed Dimerization Pathway
a All reactions conducted at 0.05 M at 70 °C for 8-18 h in degassed
DCE with 1 mol % [Ir(COD)Cl]2 under nitrogen. b Isolated yield.
of sulfoxonium ylides to dimerize relative to diazo com-
pounds could then be ascribed to a greater carbanion
character16 leading to faster nucleophilic attack. Ylide
dimerization was also observed to be the exclusive product
in the presence of Rh2(OAc)4 or Rh2(TFA)4, both of which
have been applied successfully in C-H insertion applications.
This result further suggests that dimerization of 5 is driven
by mechanistic considerations particular to sulfoxonium
ylides.
the lactam)19 was designed as an optimal case in which N-H
insertion should be favored over intermolecular processes
due to the structural proximity of the reacting functionalities.
At room temperature there was no reaction, perhaps due to
the attenuated nucleophilicity of the t-Bu carbamate. Switch-
ing solvents to DCE and elevating the reaction temperature,
however, allowed for good conversion (74% yield, entry 1).
More challenging cases, such as six- and seven-membered
ring formation, also proceeded smoothly in good yield
(67-90% yield, entries 2-5).
We began to focus on intramolecular N-H insertion as a
ring-forming strategy (Scheme 2). A lactam (or ester) can
To highlight the differential reactivity of carbamates
compared with anilines in N-H insertion, ylide 8a reacted
cleanly with aniline providing 10 without any measurable
competing ring formation (eq 4). Despite the entropic cost
Scheme 2. Lactam Ring Expansion Strategy
(15) Kennedy, M.; McKervey, M. A.; Maguire, A. R.; Tuladhar, S. M.;
Twohig, M. F. J. Chem. Soc., Perkin Trans. 1 1990, 1047.
(16) For a study on the nucleophilicity of diazo compounds, see: Bug,
T.; Hartnagel, M.; Schlierf, C.; Mayr, H. Chem.sEur. J. 2003, 9, 4068.
(17) (a) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353.
(b) Wang, D.; Schwinden, M. D.; Radesca, L.; Patel, B.; Kronenthal, D.;
Huang, M.-H.; Nugent, W. A. J. Org. Chem. 2004, 69, 1629.
(18) Applying this strategy to lactones was unsuccessful because of
spontaneous relactonization of hydroxy sulfoxonium ylides.
be converted into a ꢀ-keto sulfoxonium ylide by treatment
with the methylide resulting from reaction of a trimethyl-
sulfoxonium halide with a strong base.17 A subsequent N-H
insertion would effect a net ring expansion of the starting
(19) See Supporting Information for details.
3568
Org. Lett., Vol. 11, No. 16, 2009

of the intermolecular process, N-H insertion of aniline
occurs at room temperature, allowing for a chemoselective
N-H insertion process.
preferable for large scale processing. Identification of a
relatively inexpensive, commercially available iridium cata-
lyst greatly enhances the practicality of this system. Efforts
are currently underway to identify chiral ligands to promote
asymmetric X-H bond insertions.
Acknowledgment. The authors would like to thank Dr.
Abbas Walji (Merck) for helpful discussions.
Sulfoxonium ylides offer promise as alternatives to
traditional diazo compounds for the development and ap-
plication of metal carbene chemistry. These ylides are
typically crystalline, stable to chromatography, and stable
for months on benchtop storage. Moreover, they do not
produce gas or rapid exotherms during reaction, making them
Supporting Information Available: Experimental pro-
cedures and characterization data for compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL901298P
Org. Lett., Vol. 11, No. 16, 2009
3569