Gold-catalyzed 1,2-difunctionalizations of aminoalkynes using only N- and O-containing oxidants

Article abstract of DOI:10.1021/ja208150d

We report two viable routes for the 1,2-difunctionalization of aminoalkynes using only oxidants. In the presence of a gold catalyst, nitrones enable the oxoamination of aminoalkynes 1 to form 2-aminoamides 2. With a suitable gold catalyst, nitrosobenzenes implement an alkyne/nitroso metathesis of the same substrates to give 2-oxoiminylamides 3. These two novel oxidations also provide 1,2-aminoalcohols with opposite regioselectivity via NaBH₄ reduction in situ.

Full text of DOI:10.1021/ja208150d

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Gold-Catalyzed 1,2-Difunctionalizations of Aminoalkynes Using
Only N- and O-Containing Oxidants
Anupam Mukherjee, Ramesh B. Dateer, Rupsha Chaudhuri, Sabyasachi Bhunia, Somnath Narayan Karad,
and Rai-Shung Liu*
Department of Chemistry, National Tsing-Hua University, Hsinchu, Taiwan 30043, ROC
S Supporting Information
b
Scheme 1. 1,2-Difunctionalization of Aminoalkynes Using
Oxidants Only
ABSTRACT: We report two viable routes for the 1,2-
difunctionalization of aminoalkynes using only oxidants. In
the presence of a gold catalyst, nitrones enable the oxoamina-
tion of aminoalkynes 1 to form 2-aminoamides 2. With a
suitable gold catalyst, nitrosobenzenes implement an alkyne/
nitroso metathesis of the same substrates to give 2-oxoimi-
nylamides 3. These two novel oxidations also provide 1,2-
aminoalcohols with opposite regioselectivity via NaBH4
reduction in situ.
he generation of α-carbonyl carbenes via gold-catalyzed
T
intermolecular oxidation of alkynes represents a significant
advance in gold catalysis.1ꢀ3 This oxidation is promising to
generate new 1,2-difunctionalizations of alkynes, which are less
common than alkene oxidations.4 Scheme 1 shows one viable
route to access α-functionalized carbonyl II via a sequence of
oxidation/nucleophilic addition. The reported reactions focus
mainly on those alkynes tethered with a nucleophile, including
hydroxy and sulfinamide.5 Intermolecular alkyne oxidation with
external nucleophiles6 is a formidable task because most nucleo-
philes also attack alkynes, catalyzed by gold species, although gold
carbene is very reactive. Zhang recently reported the synthesis of
2,3-disubstituted oxazoles via a gold-catalyzed intermolecular
alkyne oxidation with external nitriles that served as solvents.7
We seek new oxidants X+ꢀOꢀ, the reduced form of which, i.e. X,
upon in situ generation, could serve as a nucleophile to immedi-
ately trap gold carbene I, giving α-functionalized carbonyl inter-
mediate IV. This new strategy inhibits the occurrence of
byproduct III with no participation of an external nucleophile.
Herein, we report two new 1,2-difunctionalizations of aminoalk-
ynes using only N- and O-containing oxidants. As shown in
Scheme 1, the use of nitrones8 enables oxoamination of these
alkynes, whereas nitrosobenzenes induce their oxoimination
reactions.9 These two oxidations introduce oxygen and nitrogen
functionalities onto alkynes with different regioselectivities. No-
tably, the two new products 2 and 3 can further provide two
distinct aminoalcohols 4 and 5 upon NaBH4 reductions in situ.10
Generation of four 1,2-difunctionalized compounds 2ꢀ5 from a
single substrate highlights the value of this new catalysis.
of aminoalkyne 1a with P(t-Bu)2(o-biphenyl)AuCl/AgSbF6
(5 mol %), 8-methylquinoline N-oxide (1.2 equiv), and aniline
(1.2 equiv) in dichloroethane (DCE, 25 °C, 8 h) produced
2-aminoamide 2a (48% yield), 1-aminoimine 6 (14%), and
2-oxoamide 7 (6%) at 100% conversion.
1-Aminoimine 6 arose from the gold-catalyzed hydroamina-
tion of aminoalkyne 1a;12 to circumvent this side reaction, we
employed N-benzylideneaniline oxide 8a as the oxidant.8 In this
new approach (eq 2), we expect that nitrone 8a enables the
oxidation of aminoalkyne 1a to generate gold carbenoid A that is
trapped with newly generated imine to form gold enolate B,
further giving 2-aminoamide 2a through hydrolysis. Indeed,
gold-catalyzed nitrone oxidation of aminoalkyne 1a in wet
DCE (25 °C, 10 h) delivered 2a in 81% yield after workup.
Addition of a THF solution of NaBH4 (2.2 equiv) in an equal
volume to this wet DCE solution containing 2a gave
Equation 1 shows our attempts to realize the oxoamination of
aminoalkyne 1a according to an oxidation/nucleophilic addition
sequence. The corresponding intramolecular oxoamination was
recently reported by Zhang and co-workers.5c Aminoalkynes are
selected because of their high electrophilicity, activated by a gold
complex, to generate α-carbonyl gold carbenoids.6,11 The treatment
Received: August 29, 2011
Published: September 09, 2011
r
2011 American Chemical Society
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Table 1. Scope for Gold-Catalyzed Oxoaminations and
Aminohydroxylations
Scheme 2. Control Experiments Confirming Gold Carbe-
noids (Ar = 4-MeOC6H4)
compatible with varied p-phenyl substituents, as in substrates
1bꢀ1f, including fluoro, chloro, bromo, methyl, and methoxy;
their corresponding oxoamination products 2gꢀ2k were
obtained in 66ꢀ73% yields (entries 6ꢀ10). Similarly, amino-
alcohols 4gꢀ4j were produced in 62ꢀ69% yields following the
same reduction sequence. In entry 10, we were unable to obtain
pure aminoalcohol 4k; its production (98% yield) relied on the
NaBH4 reduction of 2-aminoamides 2k. The scope of this
catalysis is further expanded to alkyne substrates 1g and 1h
bearing 2- and 3-thienyl that gave desired products 2l and 2m in
71ꢀ74% yields; the reduction in situ gave 4l and 4m in 65ꢀ70%
yields (entries 11 and 12). For substrates 1i and 1j bearing
alterable amino substituents, the same reaction sequence deliv-
ered aminoamides 2n and 2o in 62ꢀ78% yields, further giving
2-aminoalcohols 4a in 55ꢀ69% yields.
a [1] = 0.12 M, [Au] = P(t-butyl)2(o-biphenyl)AuSbF6. b [Nitrone] =
1.3 equiv. c Product yields are reported after purification from silica
column. d This yield corresponds to NaBH4 reduction of purified 2k.
2-aminoalcohol 4a in 73% yield (eq 3). Efforts to improve this
alkyne oxoamination were unsuccessful using other gold cata-
lysts: PPh3AuSbF6 (2a, 43%; 7, 13%), P(t-Bu)2(o-biphe-
nyl)AuNTf2 (2a, 26%; 7, 38%), and IPrAuSbF6 (2a, 41%; 7,
10%; IPr = 1,3-bis(diisopropylphenyl)imidazol-2-ylidene).
Among various organic oxides, only pyridine-based oxides are
confirmed to generate α-carbonyl carbenoid A from alkyne
oxidations.5,6 Scheme 2 shows crucial results to confirm the
participation of α-carbonyl carbenoid A using nitrone. Treat-
ment of 1-amino-2-(n-butyl)ethyne 1k with nitrone 8a and
P(t-Bu)2(o-biphenyl)AuSbF6 (5 mol %) in DCE (25 °C, 8 h)
gave enamide 10 (E/Z = 1.3) in 67% yield through a 1,2-hydride
shift of gold carbenoid A. We also found evidence for an
intermolecular arylation of gold carbenoid A via treatment of
1-amino-2-(tert-butyl)ethyne 1l with nitrone 8a under the same
conditions, which produced α-arylamide 11a and γ-lactam 11b
in 68% and 15% yields, respectively. Acid-catalyzed hydrolysis of
11a gave 11b in 96% yield. We performed crossover experiments
to understand further the hypothetical α-carbonyl carbenoid A.
As shown in Scheme 2, treatment of aminoalkyne 1a with nitrone
8a (1.3 equiv), N-benzylidene-4-methoxyaniline (1.3 equiv) and
gold catalyst in DCE (25 °C, 10 h) produced only aminoamide
2a in 64% yield, with the other analogue 2f in a negligible
amount. A subsequent experiment also revealed that nitrone 8f is
the source for both the amino and oxo groups of the resulting
aminoamide 2f.
We examined the scope of this new oxoamination on various
aminoalkynes 1aꢀ1j and nitrones 8aꢀ8f; one-pot syntheses of
2-aminoalcohols are also depicted in Table 1. Entries 1ꢀ5 show
the oxoaminations of aminoalkyne 1a using varied nitrones
8bꢀ8f bearing fluoro, chloro, bromo, methyl, and methoxy
groups at the aniline moiety, producing the desired 2-aminoa-
mides 2bꢀ2f in 71ꢀ83% yields, with the methoxy-containing
nitrone 8f giving the best efficiency. Reduction of the above
DCE solution in situ with a THF solution of NaBH4
(2.2 equiv) delivered the expected 2-aminoalcohols 4bꢀ4f in
67ꢀ76% yields. The 1,2-difunctionalizations of alkynes are also
The control experiments ambiguously verify the intermediacy
of gold carbenoids, which are trapped instantly by imine in the
inner sphere. To rationalize this behavior, we propose that the
newly generated gold carbenoids form a strong dipoleꢀdipole
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Scheme 3. Proposed Mechanism for Gold-Catalyzed Oxoa-
mination Reactions
Table 2. Gold-Catalyzed Oxoimination Reactions
interaction with imine to prevent its diffusion to the outer sphere,
as depicted in state A or its resonance form A0. This complex pair
facilitates the addition of imine at gold carbenoid to give species
B0 or its enolate form B, ultimately generating observed product
2 through hydrolysis (Scheme 3).
Using the same aminoalkyne 1a and gold catalysts, to our
delight, we discover a distinct 1,2-difunctionalization using
nitrosobenzene (9a) as the oxidant. As depicted in Table 2,
various gold complexes implemented efficiently this unprece-
dented alkyne/nitroso metathesis, giving the oxoimination pro-
duct 3a. As shown in entries 1 and 2, P(t-Bu)2(o-biphenyl)AuCl/
AgX (X = SbF6 and NTf2) gave 2-oxoiminylamide 3a in 86ꢀ88%
yields. IPrAuCl/AgSbF6 and IPrAuCl/AgNTf2 showed pro-
nounced activities to give the desired 2-oxoiminylamides 3a in
excellent yields (90ꢀ91%, entries 3 and 4); herein, we also
performed the NaBH4 reduction of their parent DCE solution
(25 °C, 12 h), producing 2-aminoalcohols 5a in 71ꢀ74% yields.
In contrast, PPh3AuCl/AgSbF6 and AuCl3 gave the desired 3a in
only 55ꢀ58% yields. In this novel metathesis reaction, we
envisage that nitrosobenzene attacks the π-aminoalkyne 1a via
its nitrogen, giving intermediate C, further giving gold carbenium
species D. Intramolecular cyclization of species D is expected to
give 4H-oxazet-2-ium species E that will lose its gold fragment to
facilitate the ring cleavage to give observed 3a.
a L = P(t-Bu)2(o-biphenyl), IPr = 1,3-bis(diisopropylphenyl)imidazol-2-
ylidene), [1] = 0.12 M. b Product yields are reported after purification
from silica column.
Table 3. Gold-Catalyzed Oxoiminations and
Aminohydroxylations
We examined the scope of this alkyne/nitroso metathesis on
aminoalkynes 1aꢀ1o and nitroso benzene 9aꢀ9d; one-pot
syntheses of 2-aminoalcohols 5aꢀ5n are also summarized in
Table 3. All catalytic operations were done with 5 mol %
IPrAuCl/AgNTf2 in dry DCE at 25 °C. In entries 1ꢀ5, this
new metathesis works satisfactorily with aminoalkynes 1bꢀ1f
bearing p-phenyl substituents including fluoro, chloro, bromo,
methyl, and methoxy; their oxoimination products 3bꢀ3f were
obtained in 69ꢀ90% yields. NaBH4 reduction of these 2-oxoi-
minylamides in situ delivered the desired 2-aminoalcohols 5bꢀ5f
in 64ꢀ88% yields. The reactions were also extensible to ami-
noalkynes 1g,1h, which delivered the desired 2-oxoiminylamides
3g,3h and 2-aminoalcohols 5g,5h in 80ꢀ85% and 75ꢀ77%
yields, respectively (entries 6 and 7). Entries 8 and 9 show our
reactions with new aminoalkynes 1l,1m bearing aliphatic sub-
stituents (R1 = cyclopropyl and tert-butyl), which gave good
yields of both 2-oxoiminylamides 3i,3j (89ꢀ93%) and aminoal-
cohols 5i,5j (78ꢀ86%). The molecular structure of 3j was
confirmed by X-ray diffraction.13 As shown in entry 10, we
obtained moderate yields of 2-oxoiminylamide 3k (48%)
and aminoalcohol 5k (41%), derived from starting 1n bearing
R1 = isopropyl, because of unknown components that were
inseparable. This metathesis reaction also works well for nitro-
sobenzenes 9bꢀ9d, giving the desired oxoimination products
a [Au] = lPrAuCl/AgNTf2, [1] = 0.12 M. b Product yields are reported
after purification from silica column. c Unknown mixtures were formed
and difficult to purify in entry 10.
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3lꢀ3n in 82ꢀ91% yields and further generating 2-aminoalcohols
5lꢀ5n in situ in good yields (73ꢀ76%, entries 11ꢀ13). For
aminoalkynes 1i, 1j, and 1o14 bearing different amino groups, the
same reaction sequence afforded 2-oxoiminylamides 3oꢀ3q in
83ꢀ87% yields, further producing 2-aminoalcohol 5a in
71ꢀ81% yields (entries 14ꢀ16).
compounds: Xu, C.-F.; Xu, M.; Jia, Y.-X.; Li, C.-Y. Org. Lett. 2011,
13, 1556 and references therein.
(5) Gold-catalyzed alkyne oxidations using external oxidants to give
enones and four-membered heterocycles: (a) Ye, L.; Cui, L.; Zhang, G.;
Zhang, L. J. Am. Chem. Soc. 2010, 132, 3258. (b) Ye, L.; He, W.; Zhang,
L. J. Am. Chem. Soc. 2010, 132, 8550. (c) Ye, L.; He, W.; Zhang., L.
Angew. Chem., Int. Ed. 2011, 50, 3236. (d) Vasu, D.; Hung, H.-H.;
Bhunia, S.; Gawade, S. A.; Das, A.; Liu, R.-S. Angew. Chem., Int. Ed. 2011,
50, 6911.
(6) Gold-catalyzed oxidation of aminoalkynes: (a) Li, C.-W.; Pati,
K.; Lin, G.-Y.; Abu Sohel, S. M.; Hung, H.-H.; Liu, R.-S. Angew. Chem.,
Int. Ed. 2010, 49, 9891. (b) Davies, P. W.; Cremonesi, A.; Martin, N.
Chem. Commun. 2011, 47, 379. (c) Li, C.; Zhang, L. Org. Lett. 2011,
13, 1738.
(7) He, W.; Li, C.; Zhang, L. J. Am. Chem. Soc. 2011, 133, 8482.
(8) Gold-catalyzed intramolecular cyclization of nitrone/alkynes
was first studied by Shin and co-workers, but no oxoamination products
2 were formed therein: Yeom, H.-S.; Lee, J.-E.; Shin, S. Angew. Chem., Int.
Ed. 2008, 47, 7040.
(9) In the presence of AuCl, the reaction of nitrosobenzenes with
phenylacetylenes produced 3-arylindoles, rather than oxoimination
products 3 as described in this work: Murru, S.; Gallo, A. A.; Srivastava,
R. S. ACS Catal. 2011, 1, 29.
(10) Selected examples of metal-catalyzed synthesis of 2-aminoalco-
hols from alkenes and metal-catalyzed aminohydroxylation of unfunc-
tionalized alkenes: (a) Sharpless, K. B.; Chong, A. O.; Oshima, J. J. Org.
Chem. 1976, 41, 177. (b) Desai, L. V.; Sanford, M. S. Angew. Chem., Int.
Ed. 2007, 46, 5737. (c) Liu, G.; Stahl, S. J. Am. Chem. Soc. 2006,
128, 7179. (d) Michaelis, D. J.; Shaffer, C. J.; Yoon, T. P. J. Am. Chem.
Soc. 2007, 129, 1866. (e) Williamson, K. S.; Yoon, T. J. Am. Chem. Soc.
2010, 132, 4570. (f) Alexanian, E. J.; Lee, C.; Sorenson, E. J. J. Am. Chem.
Soc. 2005, 127, 7690.
(11) Chemistry of ynamides: (a) DeKorver, K. A.; Li, H.; Lohse,
A. G.; Hayashi, R.; Lu, Z.; Zhang, Y.; Hsung, R. P. Chem. Rev. 2010,
110, 5064. (b) Evano, G.; Coste, A.; Jouvin, K. Angew. Chem., Int. Ed.
2010, 49, 2840.
Before this work, very few instances of gold-catalyzed oxida-
tive 1,2-difunctionalizations of alkynes with external nucleophiles
were reported.47 Herein, we have developed two indepen-
dent routes for gold-catalyzed 1,2-difunctionalizations of amino-
alkynes15 using only external oxidants. In the presence of
P(t-Bu)2(o-biphenyl)AuSbF6, nitrones enable the oxoamination
of aminoalkynes 1 to form 2-aminoamides 2 that are then sub-
jected to NaBH4 reduction in situ to deliver 2-aminoalcohols 4.
Control experiments confirm the occurrence of α-carbonyl
carbenoids that are trapped instantly by the released imine in
the inner sphere. We subsequently discovered that nitrosobenzene
implements a novel gold-catalyzed alkyne/nitroso metathesis
to give 2-oxoiminylamides 3, and subsequent NaBH4 reduction
in situ delivered 2-aminoalcohols 5 with opposite regioselec-
tivity. With two oxidants, selective production of diversified 1,
2-difunctionalized products from a single substrate highlights
the significance of these catalytic reactions.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures, char-
b
acterization of new compounds, and X-ray crystallographic data
of 3j. This material is available free of charge via the Internet at
http://pubs.acs.org.
’ AUTHOR INFORMATION
(12) Kramer, S.; Dooleweerdt, K.; Lindhardt, A. T.; Rottl€ander, M.;
Skrydstrup, T. Org. Lett. 2009, 11, 4208.
Corresponding Author
rsliu@mx.nthu.edu.tw
(13) Crystallographic data of 3j are provided in the SI.
(14) For alkynyloxazolidinone 1o, its gold-catalyzed oxidation with
nitrone 8a gave dicarbonyl compound 12 exclusively (76%) via a
secondary oxidation of gold carbenoid A.4 Spectral data of 12 are
provided in the SI.
(15) For 1-hexyne and phenylacetylene, we exclusively recovered
these two alkynes for both nitrone and nitrosobenzene oxidations in
dichloroethane at room temperature, whereas we obtained a messy
mixture of products when the reactions were performed at 80 °C. These
results indicate that the amino group activates the oxidation of alkynes
with external oxidants.
’ ACKNOWLEDGMENT
The authors thank the National Science Council, Taiwan, for
supporting this work.
’ REFERENCES
(1) Recent review for α-carbonyl gold carbenoids: Xiao, J.; Li, X.
Angew. Chem., Int. Ed. 2011, 50, 7226.
(2) Reviews for gold catalysis: (a) Das, A.; Abu, S. M. A.; Liu, R.-S.
Org. Biomol. Chem. 2010, 8, 960. (b) Sohel, S. M. A.; Liu, R.-S. Chem. Soc.
Rev 2009, 38, 2269. (c) Arcadi, A. Chem. Rev. 2008, 108, 3266. (d)
Jimꢀenez-Nꢀu~nez, E.; Echavarren, A. M. Chem. Rev. 2008,
108, 3326–3350. (e) Gorin, D. J.; Sherry, B. D.; Toste, F. D. Chem.
Rev. 2008, 108, 3351. (f) Hashmi, A. S. K. Chem. Rev. 2007, 107, 3180.
(3) Selected examples of intramolecular redox reactions of alkynes:
(a) Shapiro, N. D.; Toste, F. D. J. Am. Chem. Soc. 2007, 129, 4160. (b) Li,
G.; Zhang, L. Angew. Chem., Int. Ed. 2007, 46, 5156. (c) Davies, P. W.;
Albrecht, S. J.-C. Chem. Commun. 2008, 238. (d) Cuenca, A. B.;
ꢀ
ꢀ
Montserrat, S.; Hossain, K. M.; Mancha, G.; Lledοs, A.; Medio-Simοn,
M.; Ujaque, G.; Asensio, G. Org. Lett. 2009, 11, 4906. (e) Cui, L.; Zhang,
G.; Peng, Y.; Zhang, L. Org. Lett. 2009, 11, 1225. (f) Cui, L.; Peng, Y.;
Zhang, L. J. Am. Chem. Soc. 2009, 131, 8394. (g) Jadhav, A. M.; Bhunia,
S.; Liao, H.-Y.; Liu, R.-S. J. Am. Chem. Soc. 2011, 133. (h) Yeom, H.-S.;
Lee, Y.; Jeong, J.; So, E.; Hwang, S.; Lee, J.-E.; Lee, S. S.; Shin, S. Angew.
Chem., Int. Ed. 2010, 49, 1611.
(4) In intermolecular processes, metal-catalyzed oxidative 1,2-di-
functionalizations of alkynes were only reported for dicarbonyl
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