Flexible gold-catalyzed regioselective oxidative difunctionalization of unactivated alkenes

Article abstract of DOI:10.1002/anie.201005763

Au^I/Au^III catalytic cycles can trigger three highly regioselective alkene difunctionalization processes that involve the formation of C(sp³)iO, C(sp³)iN, and C(sp³)iC(sp ²) bonds. The react

Full text of DOI:10.1002/anie.201005763

Communications
DOI: 10.1002/anie.201005763
Gold Catalysis
Flexible Gold-Catalyzed Regioselective Oxidative Difunctionalization
of Unactivated Alkenes
Teresa de Haro and Cristina Nevado*
Diols, diamines, and aminoalcohols are ubiquitous function-
alities in complex organic molecules. From the seminal work
of Sharpless and co-workers on the intermolecular osmium-
catalyzed asymmetric dihydroxylation and aminohydroxyla-
tion of alkenes,[1a,b] the development of alternative methods to
access these privileged motifs has become a priority for
synthetic organic chemists.[1c,d] In recent years, palladium
catalysts in combination with PhI(OAc)2 as oxidant have been
successfully used in the aminooxygenation and diamination of
unactivated alkenes both intra-[2] and intermolecularly.[3]
These transformations rely on the oxidation of PdII to PdIV
amination products. We also present a novel aminoamidation
process through an in situ gold-mediated activation of nitriles
and an intramolecular oxidative arylation to access cumbered
tricyclic benzazepine scaffolds, all based on AuI/AuIII catalytic
cycles.
Our study commenced with N-tosyl-4-pentenyl amine
(1a) as substrate using Selectfluor as stoichiometric oxidant
(Table 1).[11] The reaction in the absence of gold or with
neutral [(Ph3P)AuCl] returned the starting material (Table 1,
Table 1: Optimization of the gold-catalyzed aminohydroxylation.
[4,5]
À
species to facilitate the formation of C X bonds.
Copper-
catalyzed[6] and also metal-free[7] reactions have been
reported although the required acidic media in the later
processes might limit its potential application in more
elaborated settings [Eq. (1); TFA = trifluoroacetic acid].
Our research group has recently combined the unique
carbophilicity of gold complexes with the AuI/AuIII redox
catalytic cycles to design new transformations.[8,9] Surpris-
ingly, though, only one example of gold-catalyzed oxidative
diamination of alkenes from ureas has been reported up to
date.[10] We envisioned that highly oxidized gold(III) inter-
mediates generated in the presence of oxidants such as
Selectfluor or PhI(OAc)2 could trigger the selective oxidative
difunctionalization of alkenes [Eq. (2)].
Entry Modification of the standard
conditions[a]
Conv. [%][b] 2a/3a ratio
(Yield [%])
1
2
3
4
5
6
7
8
no gold, 12 h
[(Ph3P)AuCl], 12 h
0
0
–
–
[(Ph3P)AuSbF6], 2 h
as in entry 3, no base
[(Ph3P)AuNTf2], 2 h
[(IPr)AuNTf2], 12 h
[{(2,4-di-tBuC6H3O)3P}AuSbF6], 12 h
[(PhO)3PAuSbF6], 12 h
100
70
100
0
9:1 (78)
n.d.[c]
9:1
–
0
–
50
4:1
[a] Standard reaction conditions: [Au]: 5 mol%, Selectfluor (2 equiv),
NaHCO3 (1.1 equiv), CH3CN/H2O (20:1), 0.02m, 808C. [b] Measured by
1H NMR analysis. [c] n.d.: not determined. IPr=1,3-bis(2,6-diisopropyl-
phenyl)-imidazol-2-ylide, Tf=triflate, Ts=4-toluenesulfonyl.
entries 1 and 2). Using a cationic [(Ph3P)AuSbF6] complex, we
were pleased to observe complete conversion of the starting
material into aminoalcohols 2a and 3a. The reaction was
highly regioselective favoring the 6-endo-cyclization product
in a 9:1 ratio (Table 1, entry 3). In the absence of base, the
reaction proved to be more sluggish (Table 1, entry 4). The
counteranion in the gold complex did not influence the
reaction outcome (Table 1, entry 5). In contrast, the size and
electronic nature of the ligand bound to gold seemed to play
an important role. Thus, the use of a bulky N-heterocyclic
ligand such as 1,3-bis(2,6-diiso-propylphenyl)-imidazol-2-
ylide or a more electrophilic tris-(2,4-di-tert-butylphenyl)-
phosphite ligand completely inhibited the reaction (Table 1,
entries 6 and 7). A less bulky triphenylphosphite not only
slowed down the reaction but also affected the regioselectiv-
ity of the process as compared to entry 3 (Table 1, entry 8).
Remarkably, under the optimized reaction conditions
(Table 1, entry 3), potentially competitive processes such as
protodemetalation to give 1-tosylpiperidine or b-hydrogen
Herein we report the successful realization of this concept
in a flexible alkene aminooxygenation reaction which allows
the introduction of alcohols, ethers, or esters into the hydro-
[*] T. de Haro, Prof. Dr. C. Nevado
Organic Chemistry Institute
Universitꢀt Zꢁrich (Switzerland)
Fax : (+41)44-635-6888
E-mail: nevado@oci.uzh.ch
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201005763.
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elimination to give 1-tosyl-1,2,3,4-tetrahydropyridine were
never detected. We then set out to explore the scope of this
endo-selective gold-catalyzed aminohydroxylation reaction
(Table 2). First, we examined the effect of substituents in the
backbone of the aminopentene substrates. N-Tosyl-(2,2-
diphenylpent-4-enyl) amine (1b) reacted efficiently under
through slight modifications of the reaction conditions. 2,2-
Dimethyl- and 2-cyclohexyl-substituted substrates 1c–d
afforded 1,3-aminoalcohols 2c–d in 85 and 80% yield,
respectively, as single regioisomers under the standard con-
ditions (Table 2, entries 5 and 8). The reaction of 1c in the
presence of EtOH afforded 4c’ in 77% yield whereas with
PhI(OAc)2 as oxidant aminoacetate 6c was isolated in 80%
yield (Table 2, entries 6 and 7). In the case of aniline 1e, an
unseparable 1.5:1 mixture of 6-endo and 5-exo aminohydrox-
ylation products 2e and 3e was obtained in 50% yield
(Table 2, entry 9). We then evaluated the influence of the N-
protecting groups in the reaction. N-methyl- and N-mesityl-
(2,2-dimethyl-pent-4-enyl) sulfonamides (1 f, 1g) were effi-
ciently converted into the corresponding 1,3-aminoalcohols in
good yields and complete regioselectivity (Table 2, entries 10
and 11) whereas substrate 1h bearing an o-nitro-benzenesul-
fonyl group failed to react (Table 2, entry 12). Interestingly,
the N-Cbz-protected substrate 1i reacted smoothly to give the
Table 2: Scope of the gold-catalyzed aminooxygenation reaction.
Entry React.
cond.[a]
Substrate, R, R1
Products
(Ratio)[b]
Yield
[%][c]
corresponding
1,3-aminoalcohol
2i
and
6,6-
1
2
3
4
5
6
7
8
A
A
B
C
A
B’
C
A
1a: R=Ts, R1 =H
2a/3a (9:1)
2b/3b (9:1)
4b/5b (9:1)
6b/7b (4:1)
2c
4c’
6c
2d
78[d]
85
87
76
85
77
80
80
dimethyltetrahydropyrrolo[1,2-c]oxazol-3(1H)-one (3i’’) in a
2:1 ratio and 82% yield (Table 2, entry 13).[13] Internal
substituted alkenes were efficiently transformed into the
corresponding tertiary acetates (Table 2, entry 14).
1b: R=Ts, R1 =Ph
1b
1b
1c: R=Ts, R1 =Me
To our surprise, when scaling up the reaction of 1b, traces
of N-(5,5-diphenyl-1-tosylpiperidin-3-yl)acetamide (8b) were
detected in the mixture. In this case, the acetonitrile used as
solvent reacts as a nucleophile, followed by hydrolysis to the
corresponding amide. Due to the broad range of biological
activities reported for N-piperidin-3-yl carboxamides we
decided to further pursue this synthetically useful trans-
formation.[14] After an additional short screening of reaction
conditions, aminoamidation products could be selectively
obtained by reducing the amount of water in the reaction to
only 2 equivalents. With these new optimized conditions we
studied the scope of this transformation (Table 3). Substrate
1a afforded 1,3-aminoamide 8a in 68% yield (Table 3,
entry 1). 2,2-Diphenyl-, 2,2-dimethyl-, and 2-cyclohexyl-sub-
stituted substrates 1b–d were efficiently transformed under
these conditions into the corresponding cyclic 1,3-amino-
amidation products 8b–d in 72, 70, and 74% yield, respec-
tively (Table 3, entries 2, 3, and 6). Aminoamide 8c could be
crystallized, thus confirming the structure of these novel
derivatives (Figure 1b in the Supporting Information).
Propio- and butyronitrile could also be employed (Table 3,
entries 4 and 5). The reactions proved to be highly regiose-
lective except for aniline 1e which afforded a 1:1 mixture of
regioisomers 8e and 9e in 70% combined yield (Table 3,
entry 7). N-methyl and N-mesityl sulfonamides 1 f and 1g
afforded the corresponding products 8 f and 8g in 64 and 46%
yield, respectively, upon heating for 15 hours (Table 3,
entries 8 and 9).
1c
1c
1d: R=Ts, R1 =-(CH2)5-
9
A
2e/3e (1.5:1) 50[d]
10
11
A
A
1 f: R=Ms, R1 =Me
1g: R=mesitylsulfonyl,
R1 =Me
2 f
2g
80[e]
77[e]
12
13
14
A
A
C
1h: R=o-NO2C6H4,
–
–
R1 =Me
1i: R=Cbz, R1 =Me
2i/3i’’ (1:2)
82[13]
79
2j
15
A, B
–
–
[a] Reaction conditions A: Same as Table 1, entry 3; Cond. B: Selectfluor
(2 equiv), CH3CN/MeOH (20:1), 0.02m; Cond. B’: as B but with EtOH;
Cond. C: PhI(OAc)2 (2 equiv), DCE, 0.1m, 12 h. [b] Determined by
1H NMR analysis of the crude reaction mixture. [c] Yield of the isolated
major regioisomer. [d] Yield of the mixture of regioisomers. [e] Reaction
time: 12 h. Cbz=benzyloxycarbonyl.
the optimized conditions to give 1,3-amino alcohol 2b in 85%
yield (Table 2, entry 2).[12] When the reaction was performed
in a mixture of CH3CN/MeOH (20:1), the corresponding
aminomethoxylated product 4b could be obtained in 87%
yield (Table 2, entry 3).[2e] Switching to PhI(OAc)2 as stoi-
chiometric oxidant in 1,2-dichloroethane (DCE) as solvent,
the corresponding aminoacetoxylation product 6b was
obtained in 76% yield, although lower regioselectivity was
detected still favoring the piperidine product (4:1; Table 2,
entry 4).
The 1,2-substitution pattern on the olefin seemed to be an
intrinsic limitation for these gold-catalyzed aminooxygena-
tion/amidation reactions (Table 2, entry 15 and Table 3,
entry 10). However, the reaction of 1k in the presence of a
phthaloyl-based iodosobenzene afforded tricyclic 3-benzaze-
pine 10k[15] in a diastereomerically pure form as a result of the
activation of one of the aromatic rings at the C2 position of the
pentene backbone (Scheme 1).[16] The reaction was extended
These results highlight the synthetic utility of this gold-
catalyzed process, since 1,3-aminoalcohols, ethers, or acetates
can be selectively obtained in a highly efficient manner
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Communications
Table 3: Scope of the gold-catalyzed aminoamidation reaction.
to related 1,2-disubstituted olefinic substrates 1l and 1m,
which were converted into the tricycles 10l and 10m in good
to moderate yields (Scheme 1). Compounds of type 10 largely
incorporate the carbon framework of aphanorphines, which
are marine natural compounds that resemble benzomorphane
analgesics such as pentazocine.[17]
To gain a deeper insight into the mechanism of these
transformations, deuterium-labeled alkenes (E)- and (Z)-1b-
d1 were prepared and subjected to the standard reaction
conditions (Table 1), thus affording trans-2b-d1 and cis-2b-d1,
respectively, as single diastereoisomers (Scheme 2).[18]
Entry
1
Products: R, R1, R2[a]
Yield
[%][b]
1
2
3
4
5
6
1a
8a: R=Ts, R1 =H, R2 =Me[c]
68[d]
72
70
60
68
1b 8b: R=Ts, R1 =Ph, R2 =Me
1c
1c
1c
8c: R=Ts, R1 =R2 =Me
8c’: R=Ts, R1 =Me, R2 =Et
8c’’: R=Ts, R1 =Me, R2 =Pr
1d 8d: R=Ts, R1 =-(CH2)5-, R2 =Me
74
7
1e
70[d]
8
9
10
1 f
1g
1k
8 f: R=Ms, R1 =R2 =Me
64[f]
46[f]
–
8g: R=mesitylsulfonyl, R1 =R2 =Me
–
[a] Determined by 1H NMR analysis of the crude reaction mixture.
[b] Yield of product isolated after column chromatography. [c] Regioiso-
meric mixture 9:1. [d] Yield of the isolated mixture of regioisomers.
[e] Regioisomeric mixture 1:1. [f] Reaction time: 15 h.
Scheme 2. Deuterium labeling experiments.
Based on these results, different mechanistic manifolds
can be outlined as shown in Scheme 3. First, gold(I) can
activate the alkene triggering the attack of the nitrogen in a 6-
endo fashion to form I upon deprotonation in the presence of
base in a reversible step (path a, red). The lack of reactivity of
[(Ph3P)AuCl] compared to cationic [(Ph3P)AuSbF6] supports
the hypothesis of a AuI-mediated trans-aminoauration of the
alkene as first step in this processes.[9d,19] In addition, the
failure of 1h to react seems to rule out the hypothesis of a
gold(III)–amido intermediate in contrast to copper-catalyzed
processes.[6,20] Alkyl–gold(I) complex I can then undergo
oxidation to give gold(III) intermediate II. If Selectfluor is
used, substitution of the fluorine ligand with a suitable
nucleophile such as water or alcohol delivers intermediate
Scheme 1. Gold-catalyzed synthesis of tricyclic 3-benzazepines.
Scheme 3. Mechanistic proposals.
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Angew. Chem. Int. Ed. 2011, 50, 906 –910

III.[21] Due to the highly electrophilic nature of the AuIII
center, acetonitrile can also react as a nucleophile[22a] being
hydrolyzed in the presence of water to give intermediate III
(Nu = NHCOMe).[22b–c,23] Upon reductive elimination in III
Received: September 14, 2010
Revised: December 1, 2010
Keywords: alkenes · amino alcohols · gold ·
3
3
3
.
À
À
À
the new C(sp ) OH, C(sp ) OR, and C(sp ) N bonds would
be formed (IV). If PhI(OAc)2 is used as oxidant, direct
reductive elimination in II would afford the observed amino-
acetoxylation products. This proposal allows to us explain the
relative configuration observed in the reactions shown in
Scheme 2. Thus, no competing SN2-type nucleophilic attack
by the nucleophile on II would be operating in these
reactions.[3,24]
homogeneous catalysis · oxidation
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In contrast, a 5-exo cyclization mode via intermediate V
(Scheme 3, path b, blue) that follows a similar oxidation
sequence would yield complex VI, thus accounting for the
formation of the five-membered ring products VII. In fact, for
1,2-disubstituted alkenes bearing an aromatic substituent in
the backbone, the aryl can behave as a nucleophile in VI to
produce tricyclic products 10 through nucleophilic substitu-
tion reaction.
However, an alternative mechanism to explain the
formation of IV from 5-exo intermediate VI can also be
outlined (Scheme 3, path c, pink). An aziridine intermediate
IX can be obtained from VI through intramolecular nucle-
ophilic attack of the N moiety with concomitant metal
departure.[25] Ring opening in the presence of an external
nucleophile would afford compounds IV, in line with the
relative configurations reported in Scheme 2. To test this
hypothesis, intermediate V-d1[19] was prepared and submitted
to the reaction conditions affording trans-2b-d1 and (E)-1b-d1
in a 2:1 ratio (Scheme 4).[11,26] Although the transformation of
V into 2b is not direct evidence of its participation in the
reactions described herein, it seems to indicate that several
pathways can coexist under the given reaction conditions, thus
explaining the formation of the observed products.
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[11] For further experimental details, please see the Supporting
Information.
[12] The structure of both regioisomers 2 and 3 could be assigned
based on the X-ray diffraction analysis of compound 2b (see
Figure 1a in the Supporting Information) and by comparison
with the analytical data reported for 3a respectively: K. Miura,
Katsukiyo, T. Hondo, T. Nakagawa, T. Takahashi, A. Hosomi,
Org. Lett. 2000, 2, 385 – 388. The structure of the remaining
products was assigned in analogy.
Scheme 4. Mechanistic studies.
In summary, the first gold-catalyzed aminooxygenation of
unactivated alkenes and a novel alkene aminoamidation by
gold activation of nitriles have been reported. The reactions
are highly regioselective, thus complementing 5-exo palla-
dium-catalyzed processes and expanding the scope of copper-
mediated reactions. The work described herein opens up
interesting mechanistic dichotomies of AuI/AuIII-catalyzed
transformations. In addition, tricyclic 3-benzazepines could
be efficiently obtained in a diastereomerically pure form as a
result of a gold-catalyzed oxidative arylation reaction.
Further studies to apply the latter process to the synthesis
of complex natural products are currently underway.
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Communications
[13] The formation of 3i’’ can be explained from the 5-exo product
[18] Similar results were obtained in the aminoacetoxylation reac-
tion, see the Supporting Information.
(3i).
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[23] A competition experiment was run with 1b under conditions of
Table 3 in the presence of 20 equivalents of ethyl amide. Only
product 8b was detected in the mixture, thus suggesting that
acetonitrile is the actual nucleophile being hydrolyzed to the
amide under the given reaction conditions.
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[15] In the presence of PhI(OAc)2 as oxidant, pyrrolidine 7k could be
isolated in 5% yield. The relative configuration of 7k was
confirmed by X-ray diffraction of alcohol 3k, obtained by
removal of the acetoxy group under basic conditions (see
Figure 1c in the Supporting Information). In addition, the
structure of 10k was also confirmed by X-ray diffraction analysis
(see Figure 1d in the Supporting Information).
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[25] Aziridine intermediates have been proposed to explain the
formation of 6-endo products in a palladium-catalyzed alkox-
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Org. Lett. 2010, 12, 5330 – 5333.
[16] A. Tessier, A. Salisbury, G. T. Giuffredi, L. E. Combettes, A. D.
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[26] We would like to thank one of the referees for suggesting this
insightful experiment.
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