Gold-catalyzed direct activation of allylic alcohols in the stereoselective synthesis of functionalized 2-vinyl-morpholines

Article abstract of DOI:10.1002/chem.201002606

Alcohol versus alcohol: A highly stereocontrolled synthesis of substituted morpholines is realized by means of gold-catalyzed dehydrative allylic cyclization of diols (see scheme for one example; segphos = 5,5′-bis[di(3, 5-di-tert-butyl-4-methyoxyphenyl)phosphine]-4,4′-bi-1,3-benzodioxole). The present methodology represents one of the few examples of enantioselective gold-catalyzed transformations involving unactivated alkenes. Copyright

Full text of DOI:10.1002/chem.201002606

DOI: 10.1002/chem.201002606
Gold-Catalyzed Direct Activation of Allylic Alcohols in the Stereoselective
Synthesis of Functionalized 2-Vinyl-Morpholines
Marco Bandini,* Magda Monari, Alessandro Romaniello, and Michele Tragni[a]
Dedicated to Professor Achille Umani-Ronchi for his life-long commitment to the advancement of organic synthesis
Gold catalysis has contributed remarkably to the develop-
ment of organic synthesis over the last few years, opening
access to a plethora of new chemical transformations in a
highly chemo-, regio-, and stereoselective manner.[1] In par-
ticular, the p acidity combined with the high functional
group tolerance of AuI/III species account for the successful
application of gold catalysis in the chemical manipulation of
unsaturated hydrocarbons with straightforward applications
in total synthesis.[2]
Interestingly, after the pioneering enantioselective gold-
Scheme 1. Stereoselective gold-catalyzed synthesis of heterocyclic com-
pounds with allylic alcohols: a) past work, b) present study.
catalyzed transformation reported by Ito et al. in the
1980s,[3] the chemical community did not recognize the great
synthetic potential of the methodology until recently, when
properly designed chiral biphenyl-type phosphine ligands
have started to be efficiently coupled with AuI species to
perform innovative asymmetric reactions.[4]
preparation of biologically relevant and stereochemically de-
fined heterocyclic compounds (Scheme 1b).[9,10]
Prompted by an interest in their pharmacological applica-
tions, we initiated our investigation with the diastereoselec-
tive synthesis of functionalized morpholines,[11] for which
catalytic stereoselective synthesis still remains relatively un-
explored.[12]
Readily available enantiomerically pure diol (R)-(Z)-1a
(see the Supporting Information) was elected as the model
substrate and a survey of reaction conditions[13] was per-
formed to optimize the chemical and optical outcome of the
intramolecular dehydrative coupling (Table 1).
As part of our ongoing research interests addressing the
stereoselective decoration of indolyl core,[5] we recently
documented the unprecedented direct activation of allylic
alcohols in Friedel–Crafts alkylations by chiral gold(I) com-
plexes (Scheme 1a).[6] Note that, despite intrinsic synthetic
availability and eco-friendliness, the use of allylic alcohols as
electrophilic agents in catalytic stereoselective transforma-
tions is still sporadic.[7,8] Low reactivity, the formation of car-
bocation intermediates, and undesirable release of water
during the catalytic cycle are some of the aspects that ac-
count for such a trend.
Interestingly, while [AuClACHTNUTRGNENG(U SMe2)] did promote the reac-
tion to a poor extent (yield=46%, d.r.=95:5; Table 1,
entry 1), the introduction of a stabilizing phosphane ligand
(e.g., PPh3) led to a net increase of the final yield (Table 1,
entry 2), however, a lower d.r. (83:17) value was recorded.
Analogously, the well-defined silver-free gold(I)-catalyst,
A,[14] induced intramolecular alkoxylation to a moderate
extent (62% yield), but with poor diastereoselection (80:20;
Table 1 , entry 3). After screening the reaction parameters,
we were delighted to find out that the chemical and stereo-
chemical outcome of the process improved remarkably by
adopting cationic dinuclear gold complexes deriving from li-
gands L2–L5. In particular, in situ formed [(AuOTf)2(L5)][15]
complex (2.5 mol%) produced the desired cis-2,5-disubsti-
To further validate the synthetic flexibility of the allylic
alcohol/chiral AuI catalyst combination, we envisioned that
such a methodology could be successfully applied to the
[a] Dr. M. Bandini, Prof. M. Monari, A. Romaniello, M. Tragni
Dipartimento di Chimica “G. Ciamician”
Alma Mater Studiorum - Universitꢀ di Bologna
via Selmi 2, 40126 Bologna (Italy)
Fax : (+39)51-2099456
E-mail: marco.bandini@unibo.it
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201002606.
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Chem. Eur. J. 2010, 16, 14272 – 14277

COMMUNICATION
Table 1. Gold(I)-catalyzed diastereoselective synthesis of disubstituted
Table 2. Scope of the diastereoselective gold(I)-catalyzed synthesis of
morpholines.
morpholine 2a with allylic alcohol 1a.[a]
Entry[a]
R (1)
Product[b]
Yield [%][b]
d.r. [c]
1
Bn (1b)
Bn (1b)
Et (1c)
95
98
85
98:2
98:2
98:2
Entry
L or Cat. [%]
Yield [%][b]
d.r.[c]
95:5
83:17
80:20
95:5
95:5
94:6
>98:2
>98:2
98:2
1[d]
2[e]
3
4
5
–
46
95
62
92
89
86
93
92
70
91
2[d]
3
2b
L1 (10)
A (10)
L2 (5)
L3 (5)
L4 (5)
L5 (5)
L5 (2.5)
L5 (0.8)
L5 (2.5)
6
7
4
5
6
7
iPr (1d)
tBu (1e)
Me (1 f)
iBu (1g)
91
82
55
79
98:2[e]
98:2
97:3
8[f]
9[f]
10 [g]
97:3
[a] All of the reactions were carried out under nitrogen for 6 h, unless
otherwise specified. [b] Isolated yield after flash chromatography. [c] Dia-
stereomeric ratio (d.r.) was determined by GC analysis on the crude re-
action mixture. The relative configuration was established to be cis by
analogy to 2d (see below). [d] Ligand-free conditions. [e] Preformed
[AuCl
moisture restriction (reagent grade solvent, open-air vials with preformed
[(Au2Cl2)(dppf)] complex). [g] Insoluble silver salts were removed by fil-
ACHTUNGTRENNUNG(PPh3)] was used. [f] The reaction was carried out in the absence of
98:2
ACHTUNGTRENNUNG
tration. Dppm: bis(diphenylphosphino)methane; dppe: bis(diphenylphos-
phino)ethane; biphep: (biphenyl-2,2’-diyl)bis(diphenylposphine); dppf:
1,1’-bis(diphenylphosphino)ferrocene.
8[f]
– (1h)
(E)-1a
59
80
98:2
tuted morpholine 2a in nearly quantitative yield and 98:2
d.r., without the need for any moisture restriction. Finally,
[(Au2Cl2)(L5)] proved to be a competent precatalytic spe-
cies, even at a lower catalyst loading (up to 0.8 mmol%),
maintaining the stereoselection invariant (Table 1, entry 9).
Then, the role of the silver cocatalyst in the best operating
conditions was investigated by running control experiments
by removing insoluble silver salts and with AgOTf as the
catalytic system. Significantly, while in the first case, product
2a was isolated in 91% yield and with high cis diastereose-
lectivity (97:3; Table 1, entry 10), the absence of gold caused
the process to fail (see Table S2 in the Supporting Informa-
tion for details). These findings account for the essential
role of the cationic gold(I) species in triggering the catalytic
process.
9
63:37
[a] All of the reactions were carried out without moisture restriction (re-
agent grade solvent, open-air vial) for 6 h, unless otherwise specified.
[b] Isolated yield after flash chromatography. [c] Determined by GC anal-
ysis on the crude reaction mixture. [d] L4 was used as the ligand. [e] The
cis relative configuration of 2d was established unequivocally by means
of single-crystal X-ray crystallography (see the Supporting Information).
[f] Reaction time: 16 h.
thesis of enantiomerically pure 2,5,6-trisubstituted-tetrahy-
dro-1,4-oxazine (2h; Table 2, entry 8).
Preliminary mechanistic evidence was derived by subject-
ing (E)-1a to optimal ring-closing conditions (Table 2,
entry 9). Here, the lower stereoselection observed (d.r.
63:37) ruled out a cationic pathway,[10a] and accounted for
the combined effect of 1) catalyst, 2) substrate stereocenter,
and 3) substrate C=C configuration in determining the ste-
reochemical profile of the whole process.[16]
Encouraged by these results, we verified the generality of
the method by subjecting a series of enantiomerically pure
diols (1b–h) to dehydrative ring closure in the presence of
[(Au2Cl2)ACHTUNGTRENNUNG(dppf)]/AgOTf (2.5 mol%) as the catalytic system
(see Table 2).
All diols carrying sterically demanding substituents (1b,
d–e, g) and substrates with smaller side chains (1c, f) provid-
ed the desired cis-2,5-disubstituted morpholines in excellent
yields > 97:3 d.r. Moreover, a lower isolated yield, but ex-
cellent diastereomeric control was also recorded in the syn-
We next sought to verify the extent of the present allylic
substitution to the catalytic enantioselective synthesis of vi-
nylmorpholines, which has rarely been reported to date.[17]
To this aim, readily available compound (Z)-3a was elected
as the model substrate for intramolecular dehydrative allylic
alkylation. After an extensive survey of reaction conditions
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M. Bandini et al.
Table 3. Enantioselective gold(I)-catalyzed synthesis of heterocyclic aza-
compounds.
(see Table S3 in the Supporting Information), [(Au2Cl2){(R)-
3,5-tBu2-4-MeO-segphos}] (2.5 mol%; segphos=5,5’-
bis[di(3,5-di-tert-butyl-4-methyoxyphenyl)phosphine]-4,4’-bi-
1,3-benzodioxole), in combination with AgNTf2, emerged as
À
the best catalytic system and promoted C O bond-forming
processes. In particular, Ts-containing diol 3a gave the de-
sired product (4a) in 94% yield and 89% enantiomeric
excess (Table 3, entry 1).
The p-methylbenzenesulfonyl substituent (Ts) proved to
be crucial for efficient stereochemical translation. From an
inspection of entries 1–3 in Table 3 emerges that replacing
the tosyl group with (2-thienyl)sulfonyl (Ths) or mesitylsul-
fonyl (Mts) substituents (3b, c) leads to the corresponding
cyclic compounds 4b and c in high yields but lower ee
values (69–74%). Then, we set out to examine the scope of
the enantioselective gold-catalyzed process for the synthesis
of vinyl-substituted morpholines that would represent one
of the few examples of enantioselective gold(I)-catalyzed
transformations involving unactivated olefins.[18,19]
Entry[a] R/R1/X (3)
Product
Yield
ee of
of 4 [%][b] 4 [%][c]
1
2
3
H/H/Ts (3a)
H/H/Ths (3b)
H/H/Mts (3c)
94
91
78
89
69
74
A collection of representative results is reported in
Table 3. We were particularly pleased to verify the tolerance
of the method toward substitutions of the acyclic precursor.
In particular, it is worth mentioning that even highly steri-
cally congested tertiary alcohols reacted smoothly under op-
timal reaction parameters, providing 2-vinyl morpholines in
excellent yields (91–93%) and enantiomeric excesses up to
95% (Table 3, entries 5,7). The synthesis of more challeng-
ing seven-membered 1,4-oxazepanyl rings was also realized
by cyclizing diols 3h and i. In these cases, a higher catalyst
loading (5 mol%) was required to give the corresponding
products 4h[20a,b] and 4i[20c] in 74 and 80% ee, respectively
(Table 3, entries 8 and 9). Finally, N-phenyl morpholine 4j
was also obtained with an acceptable ee value (76%), but
with a low yield (41%) probably due to the undesired coor-
dination of the gold atoms by tethering tertiary amine 3j
(Table 3, entry 10).
4
Me/H/Ts (3d)
H/Me/Ts (3e)
92
93
79
91
55
92
92
84
95
74
5
À
À
6
H/ ACHTNGUTERNUN(G CH2)4 /Ts (3 f)
À
N
À
7
8[d]
3h
9[d]
10
3i
58
41
80
76
Mechanistically, several control experiments were carried
out to shed light on the operating activation mode of the al-
lylic alcohol unit by the cationic gold complex.[21]
H/H/Ph (3j)
First, as expected, a marked substrate control over stereo-
chemical translation was discovered by subjecting diastereo-
isomeric (Z)- and (E)-3a to the optimum conditions. In par-
ticular, inversion of stereoinduction was observed in the
morpholine 4a with the same catalyst (Table 4, entry 1 vs.
2), indicating (R)-DTBM-segphos/(Z)-3a as the matched
stereochemical combination.[22] Moreover, this inversion
calls for a tight anchoring of the C=C double bond to the di-
nuclear catalyst with a prominent role of the hydroxyl group
orientation.[23]
[a] All of the reactions were carried out under nitrogen, for 4 h, unless
otherwise specified. The gold complex was synthesized in situ by stirring
[AuClACHTNUGTRNENUG(SMe2)] and (R)-DTBM-segphos (L) in CH2Cl2. [b] Isolated yield
after flash chromatography. [c] Determined by HPLC analysis with a
chiral column. [d] 5 mol% of the catalyst was used at RT, reaction time
16 h. Mts: 2-mesitylsulfonyl, Ths=2-thienylsulfonyl. The absolute config-
uration of 4a was determined by comparison of the optical rotation value
with that of a known compound.[17a] Moreover, the stereochemistry of 4d
was confirmed by X-ray analysis (see the Supporting Information). Abso-
lute configuration of compounds 4b, c–e, g, j was assigned by analogy.
Interestingly, clear evidence for the direct engagement of
the hydroxyl group in determining the catalytically active
spatial arrangement, between starting diol and dinuclear
gold complex, came from the results obtained with (Z)-3a’
and 3k–m (Table 4, entries 3–6). In particular, while the fail-
ure recorded with sterically demanding 3a’ can be rational-
ized in terms of poor p activation of the C=C double bond,
the unsatisfactory stereochemical outcomes arising from 3k
and more reactive 3l and m emphasized further the impor-
tance of the allylic -OH to obtain high ee values. Moreover,
experimental evidence resulting from entries 5 and 6 in
Table 4 underline the complementarity of our gold-mediated
methodology with respect to classic Tsuji–Trost-like proto-
cols.[17,24]
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Gold-Catalyzed Direct Activation of Allylic Alcohols
COMMUNICATION
Table 4. Experimental evidence for substrate control over the chemical
and optical outcome of the reaction.
Entry[a] X/C=C
MX
4
Yield [%][b] ee [%][c]
1
2
3
H/Z (3a)
H/E (3a)
TBDMS/Z (3a’) AgNTf2
AgNTf2
AgNTf2
(S)-4a 94
(R)-4a 59
88
66
–
[d]
–
–
4
5
6
7
8
9
10
11
12[e]
Me/Z (3k)
Ac/Z (3l)
CO2Me/Z (3m)
H/Z (3a)
H/Z (3a)
H/Z (3a)
H/Z (3a)
H/Z (3a)
H/Z (3a)
AgNTf2
AgNTf2
AgNTf2
AgOTf
AgSbF6
AgBF4
NaBArF
AgOTs
AgNTf2
(S)-4a 19
8
–
7
68
50
23
–
26
82
[d]
–
–
(S)-4a 20
(S)-4a 69
(S)-4a 58
(S)-4a 80
–
trace
(R)-4a 22
(S)-4a 71
[a] All of the reactions were carried out under nitrogen at À108C for 4 h.
The gold complex was synthesized in situ by stirring [AuCl(SMe2)] and
AHCTUNGTRENNUNG
(R)-DTBM-segphos (L) in CH2Cl2. [b] Isolated yield after flash chroma-
Figure 1. View of one of the molecules of the dinuclear complex [Au2-
tography. [c] Determined by HPLC analysis with chiral column. [d] No
reaction. [e] Monocationic [(Au2Cl){(R)-3,5-tBu2-4-MeO-segphos}ACTHNUTRGEN(UNG NTf2)]
ACHUNTRGEN(NUG biphep)ACHTUNTGREN(NGUN NTf2)2]. Relevant bond lengths and angles are listed in Table S5
in the Supporting Information.[35]
complex was used.
The nature of the gold counterion was also investigated
by screening silver/sodium-based halide scavengers (Table 4,
entries 7–11).[19a,25] Here, the collected scattering results,
combined with the inversion of stereoinduction recorded
with AgOTs, call for a direct involvement of the XÀ species
in the stereodiscriminating event of the reaction. This aspect
is further corroborated by the comparable stereochemical
efficiency of monocationic [(Au2Cl){(R)-3,5-tBu2-4-MeO-
segphos}NTf2] in promoting the model allylic alkylation
(yield=71%, ee=82%; Table 4, entry 12).[26] Interestingly,
the chemical outcome of the reaction was also substantially
affected by the type of counterion utilized and this can have
reference to the well-known effect of anions over the final
hydrogen-transfer (protodeauration) step of gold catalysis.[27]
With the aim to shed some light on this intriguing behav-
range 2.222–2.230(2) ꢂ).[29] In addition in [Au
2ACTHNGUTERN(UNG biphep)-
AHCTUNTGRENN(GNU NTf2)2] the long Au···Au distances of 6.6818(6) ꢂ
(6.6829(5) ꢂ) rule out any kind of aurophilic interaction in
the solid state, which has been found in many analogous
digold complexes, for example, in [(Au2Cl2)ACTHNUTRGNE(NUG biphep)]
(Au···Au contact 3.0992(3) ꢂ).[30] It may be argued that the
À
NTf2 anion has a higher steric hindrance than the chloride
ion. However, a digold complex bridged by biphep and
having the AuI atoms coordinated by one oxygen atom of
the sterically demanding binaphthol-derived phosphate
anion was reported to present a short Au···Au contact
(2.9937(2) ꢂ). The formation of intramolecular p–p stacking
interactions (centroid–centroid distance 3.78 ꢂ) between
phenyl rings bound to two different P atoms (see dotted line
À
in Figure 1) can therefore explain the lack of Au Au con-
ior, we first synthesized [Au
complex, (83% yield, see the Supporting Information for
details). Suitable crystals of [Au2A(biphep)(NTf2)2] for an X-
C
R
tacts generated by the consequent loss of flexibility of the
phosphine ligand. In fact, p–p stacking interactions between
P-bound aryl rings have already been observed in
[(AuCl)2(3,5-xylyl-binap)] (3,5-xylyl-binap = 2,2’-bis(di(3,5-
xylyl)phosphino)-1,1’-binaphthyl) and an analogous digold–
tol–binap (tol–binap = 2,2’-bis(di-p-tolylphosphino)-1,1’-bi-
C
ACHTUNGTRENNUNG
ray analysis were obtained by slow evaporation from a
dilute solution of CD2Cl2 (48C, Figure 1). Two slightly differ-
ent half molecules are present in the asymmetric unit
around crystallographic C2 axes passing through the mid-
naphthyl) complex.[31] In both cases no Au Au interactions
À
À
point of the C C bond connecting the two twisted phenyl
have been found. Finally, a further stabilization of the struc-
À
rings of the biphenyl unit (twist angle between phenyl rings
74.1(1)8). The two gold(I) atoms maintain the usual linear
geometry and are coordinated by one P atom of the bridg-
ing biphep and by a N atom of the anionic Tf2NÀ ligand (P-
ture of the digold complex is given by two weak C H···p in-
teractions involving one hydrogen of the second phenyl ring
(C(14)-H(14)···pACTHNUTRGNEUNG(centroid) distance 3.03 ꢂ) and the phenyl
ring bound to the same P atom already engaged in p–p
stackings. The geometry of the diphosphine-bridged digold
complexes seems to be dominated by a subtle balance of
noncovalent interactions that include aurophilic interactions,
intramolecular p–p stacking, and ligand–ligand repulsion in
addition to the flexibility of the diphosphine ligands.[32]
With the isolated complex in hand, a variable-temperature
NMR spectroscopic investigation was carried out in the
À
Au-N 172.4 and 174.3(1)8). The Au N (Au(1)-N(1) 2.114(4)
À
and 2.105(4) ꢂ) and Au P (Au(1)-P(1) 2.227(1) and
2.225(1) ꢂ) distances are comparable to those found in the
À
related mononuclear [Au
G
G
[28]
À
Au P 2.2306(7) ꢂ) and the Au N bonds are longer than
those reported for [Au{N
(PPh3)] (R=Me, p-
À
À
C6H4Cl, p-C6H4NO2, F) (Au N range 2.074-2.083 ꢂ, Au P
Chem. Eur. J. 2010, 16, 14272 – 14277
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14275

M. Bandini et al.
Umani-Ronchi), Wiley-VCH, Weinheim, 2009; c) M. Bandini, A.
Eichholzer, Angew. Chem. 2009, 121, 9786–9824; Angew. Chem. Int.
Ed. 2009, 48, 9608–9644.
presence of model substrate 3n (see the Supporting Infor-
mation). Here, although the interaction between the digold
complex and 3n was established by 31P/13C NMR spectro-
scopic analysis, attempts to unambiguously localize both
[6] M. Bandini, A. Eichholzer, Angew. Chem. 2009, 121, 9697–9701;
Angew. Chem. Int. Ed. 2009, 48, 9533–9537; see also: M. Bandini,
A. Eichholzer, A. Gualandi, T. Quinto, D. Savoia, ChemCatChem
2010, 2, 661–665.
counterions and hydroxyl groups in the [Au
2ACHTUNGTRENN(UNG biphep)-
ACHTUNGTRENNUNG
[7] a) B. M. Trost, J. Quancard, J. Am. Chem. Soc. 2006, 128, 6314–
6315; b) C. Defieber, M. A. Ariger, P. Moriel, E. M. Carreira,
Angew. Chem. 2007, 119, 3200–3204; Angew. Chem. Int. Ed. 2007,
46, 3139–3143; c) M. Rueping, B. J. Nachtsheim, S. A. Moreth, M.
Bolte, Angew. Chem. 2008, 120, 603–606; Angew. Chem. Int. Ed.
2008, 47, 593–596; d) S. Tanaka, T. Seki, M. Kitamura, Angew.
Chem. 2009, 121, 9110–9113; Angew. Chem. Int. Ed. 2009, 48, 8948–
8951; e) K. Namba, Y. Kaihara, H. Yamamoto, H. Imagawa, K.
Tanino, R. M. Williams, M. Nishizawa, Chem. Eur. J. 2009, 15, 6560–
6563; f) P. Mukherjee, R. A. Widenhoefer, Org. Lett. 2010, 12, 1184–
1187; g) K. Korber, F. Rominger, T. J. J. Muller, Synlett 2010, 782–
786; h) M. Roggen, E. M. Carreira, J. Am. Chem. Soc. 2010, 132,
11917–11919.
crystallography). As a consequence, we can only speculate
that the second gold atom could act either as a mere specta-
tor, perhaps stabilizing the gold intermediates through auro-
philic interactions or, alternatively, being involved in a
À
À
bridged arrangement through the OH···X network, capa-
ble of bringing steric as well as electronic diversity near the
reaction site.[33]
In conclusion, we have accounted for an innovative intra-
molecular gold(I)-catalyzed asymmetric nucleophilic alkoxy-
lation of allylic alcohols for the synthesis of vinyl-substituted
six-/seven-membered heterocycles in
a straightforward
[8] For general review in the use of p activated alcohols in catalytic
Friedel–Crafts alkylations, see: a) M. Bandini, M. Tragni, Org.
Biomol. Chem. 2009, 7, 1501–1507; b) N. Ljungdahl, N. Kann,
Angew. Chem. 2009, 121, 652–654; Angew. Chem. Int. Ed. 2009, 48,
642–644.
manner. Computational investigations are currently under-
way to clarify both activation geometry and organogold in-
termediates.[34]
[9] Asymmetric Synthesis of Nitrogen Heterocycles (Ed.: J. Royer),
Wiley-VCH, Weinheim, 2009.
[10] For efficient metal-catalyzed synthesis of racemic substituted tetra-
hydropyranes, tetrahydrofuranes, and piperidines through dehydra-
tive cyclization of diols see: a) A. Aponick, C.-Y. Li, B. Biannic,
Org. Lett. 2008, 10, 669–671; b) A. Aponick, B. Biannic, Synthesis
2008, 3356–3359; c) A. Guꢃrinot, A. Serra-Muns, C. Gnamm, C.
Bensoussan, S. Reymond, J. Cossy, Org. Lett. 2010, 12, 1808–1811.
[11] For a general review, see: R. Wijtmans, M. K. S. Vink, H. E. Schoe-
maker, F. L. van Delft, R. H. Blaauw, F. P. J. T. Rutjes, Synthesis
2004, 641–662.
[12] M. L. Leathen, B. R. Rosen, J. P. Wolfe, J. Org. Chem. 2009, 74,
5107–5110, and references therein. See also: a) H. Ito, Y. Ikeuchi, T.
Taguchi, Y. Hanzawa, M. Shiro, J. Am. Chem. Soc. 1994, 116, 5469–
5470; b) M. K. Ghorai, D. Shukla, K. Das, J. Org. Chem. 2009, 74,
7013–7022.
[13] A number of different Lewis acids were tested in the model reac-
tion, but 2a was always obtained to a lower extent in comparison
with gold(I) catalysis, see Table S2 in the Supporting Information.
[14] a) C. Nieto-Oberhuber, S. Lòpez, A. M. Echavarren, J. Am. Chem.
Soc. 2005, 127, 6178–6179; b) E. Herrero-Gómez, C. Nieto-Ober-
huber, S. López, J. Benet-Buchholz, A. M. Echavarren, Angew.
Chem. 2006, 118, 5581–5585; Angew. Chem. Int. Ed. 2006, 45, 5455–
5459.
Acknowledgements
We would like to thank the MIUR (Rome), the Universitꢀ di Bologna,
and the Fondazione del Monte di Bologna e Ravenna. We also thank Dr.
Stefano Grilli for NMR analysis.
Keywords: alcohols · asymmetric synthesis · gold catalysis ·
heterocycles · stereoselectivity
[1] For general reviews on gold-catalyzed organic transformations, see:
a) A. S. K. Hashmi, G. J. Hutchings, Angew. Chem. 2006, 118, 8064–
8105; Angew. Chem. Int. Ed. 2006, 45, 7896–7936; b) A. S. K.
Hashmi, Chem. Rev. 2007, 107, 3180–3211; c) A. S. K. Hashmi,
Catal. Today 2007, 122, 211–214; d) E. Jimꢃnez-NfflÇez, A. M. Echa-
varren, Chem. Commun. 2007, 333–346; e) H. C. Shen, Tetrahedron
2008, 64, 3885–3903; f) R. Skouta, C.-J. Li, Tetrahedron 2008, 64,
4917–4938; g) A. Arcadi, Chem. Rev. 2008, 108, 3266–3325; h) Z.
Li, C. Brouwer, C. He, Chem. Rev. 2008, 108, 3239–3265; i) “Gold
Catalysis—New Perspectives for Homogeneous Catalysis”, special
issue: J. Organom. Chem. 2009, 649 by A. S. K. Hashmi; j) “Recent
Developments in Gold Catalysis”, Symposia-in-print: Tetrahedron
2009, 65, Issue 9 by F. Gagosz; k) N. D. Shapiro, F. D. Toste, Synlett
2010, 675–691; l) S. Wang, G. Zhang, L. Zhang, Synlett 2010, 692–
706.
[2] a) A. S. K. Hashmi, M. Rudolph, Chem. Soc. Rev. 2008, 37, 1766–
1775; see also: b) K. Molawi, N. Delpont, A. M. Echavarren,
Angew. Chem. 2010, 122, 3595–3597; Angew. Chem. Int. Ed. 2010,
49, 3517–3519; c) Q. Zhou, X. Chen, D. Ma, Angew. Chem. 2010,
122, 3591–3594; Angew. Chem. Int. Ed. 2010, 49, 3513–3516.
[3] Y. Ito, M. Sawamura, T. Hayashi, J. Am. Chem. Soc. 1986, 108,
6405–6406.
[15] T. V. Segapelo, I. A. Guzei, J. Darkwa, J. Organomet. Chem. 2008,
693, 701–708.
[16] See Figure S1 in the Supporting Information for a pictorial represen-
tation of transition states accounting for the cis diastereoselection.
[17] For previous examples of asymmetric Pd-catalyzed synthesis of mor-
pholines through single and double alkylation with allylic acetates/
carbonates, see: a) Y. Uozumi, A. Tanahashi, T. Hayashi, J. Org.
Chem. 1993, 58, 6826–6832; b) C. Thorey, J. Wilken, F. Hꢃnin, J.
Martens, T. Mehler, J. Muzart, Tetrahedron Lett. 1995, 36, 5527–
5530; c) M. Massacret, R. Lakhmuri, P. Lhoste, C. Nguefack, F. B. B.
Abelouahab, R. Fadel, D. Sinou, Tetrahedron: Asymmetry 2000, 11,
3561–3568; d) M. C. Wilkinson, Tetrahedron Lett. 2005, 46, 4773–
4775.
[18] a) M. J. Johansson, D. J. Gorin, S. T. Steven, F. D. Toste, J. Am.
Chem. Soc. 2005, 127, 18002–18003; b) Z. Zhang, S. D. Lee, R. A.
Widenhoefer, J. Am. Chem. Soc. 2009, 131, 5372–5373; c) I. D. G.
Watson, S. Ritter, F. D. Toste, J. Am. Chem. Soc. 2009, 131, 2056–
2057.
[4] a) R. A. Widenhoefer, Chem. Eur. J. 2008, 14, 5382–5391; b) D. J.
Gorin, B. D. Sherry, F. D. Toste, Chem. Rev. 2008, 108, 3351–3378;
c) N. Bongers, N. Krause, Angew. Chem. 2008, 120, 2208–2211;
Angew. Chem. Int. Ed. 2008, 47, 2178–2181; d) S. Sengupta, X. Shi,
ChemCatChem 2010, 2, 609–619.
[5] a) M. Bandini, A. Melloni, A. Umani-Ronchi, Angew. Chem. 2004,
116, 560–566; Angew. Chem. Int. Ed. 2004, 43, 550–556; b) Catalytic
Asymmetric Friedel–Crafts Alkylations (Eds.: M. Bandini, A,
[19] For gold(I)-catalyzed intramolecular enantioselective hydroamina-
tion and hydroalkoxylation of allenes, see: a) R. L. LaLonde, B. D.
14276
www.chemeurj.org
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 14272 – 14277

Gold-Catalyzed Direct Activation of Allylic Alcohols
COMMUNICATION
Sherry, E. J. Kang, F. D. Toste, J. Am. Chem. Soc. 2007, 129, 2452–
2453; b) Z. Zhang, C. F. Bender, R. A. Widenhoefer, Org. Lett.
2007, 9, 2887–2889; c) Z. Zhang, R. A. Widenhoefer, Angew. Chem.
2007, 119, 287–289; Angew. Chem. Int. Ed. 2007, 46, 283–285; d) Z.
Zhang, C. F. Bender, R. A. Widenhoefer, J. Am. Chem. Soc. 2007,
129, 14148–14149; e) G. L. Hamilton, E. J. Kang, M. Mba, F. D.
Toste, Science 2007, 317, 496–499; f) R. L. LaLonde, Z. J. Wang, M.
Mba, A. D. Lackner, F. D. Toste, Angew. Chem. 2010, 122, 608–611;
Angew. Chem. Int. Ed. 2010, 49, 598–601.
2009, 11, 4962–4965; d) D. Zuccaccia, L. Belpassi, F. Tarantelli, A.
Macchioni, J. Am. Chem. Soc. 2009, 131, 3170–3171.
[26] The complex was synthesized in situ by mixing [(Au2Cl2){(R)-3,5-
tBu2-4-MeO-segphos}] and AgNTf2 in a 1:1 ratio.
[27] G. Kovµcs, G. Ujaque, A. Lledós, J. Am. Chem. Soc. 2008, 130, 853–
864.
[28] M. Mꢃzailles, L. Ricard, F. Gagosz, Org. Lett. 2005, 7, 4133–4136.
[29] P. G. Jones, A. Blaschette, J. Lautner, C. Thçne, Z. Anorg. Allg.
Chem. 1997, 623, 775–779.
[20] a) L. Banfi, A. Basso, G. Guanti, N. Kielland, C. Repetto, R. Riva,
J. Org. Chem. 2007, 72, 2151–2160; b) S. K. Das, A. K. Srivastava,
G. Panda, Tetrahedron Lett. 2010, 51, 1483–1485, and references
therein; c) H. Stadtmueller, A. Baum, G. Boehmelt, H. Engelhardt,
J. Quant, F. Solca, M. Steegmaier, Z. Martin, K. Stephan, PCT Int.
Appl., WO 2007096351, 2007.
[30] K. Aikawa, M. Kojima, K. Mikami, Angew. Chem. 2009, 121, 6189–
6193; Angew. Chem. Int. Ed. 2009, 48, 6073–6077.
[31] a) M. A. Tarselli, A. R. Chianese, S. J. Lee, M. R. Gagnꢃ, Angew.
Chem. 2007, 119, 6790–6793; Angew. Chem. Int. Ed. 2007, 46, 6670–
6673; b) M. Paz MuÇoz, J. Adrio, J. C. Carretero, A. M. Echavarren,
Organometallics 2005, 24, 1293–1300.
[21] H. Schmidbaur, A. Schier, Organometallics 2010, 29, 2–23, and ref-
erences therein.
[32] D. V. Partyka, J. B. Updegraff III, M. Zeller, A. D. Hunter, T. G.
Gray, Dalton Trans. 2010, 39, 5388–5397.
[22] Opposite behavior was documented in the Tsuji–Trost-type ap-
proach for the preparation of 4a, see reference [17a].
[33] As a partial support to the latter hypothesis, the suitability of labile
counterions (i.e., OTfÀ) to establish a “strong hydrogen bond with
the OH from the nucleophile” in gold-catalyzed addition of phenols
to olefins has been demonstrated, see: G. Kovµcs, A. Lledós, G.
Ujaque, Organometallics 2010, 29, 3252–3260.
[34] For a recent review dealing with characterized intermediates in gold
catalysis, see: A. S. K. Hashmi, Angew. Chem. 2010, 122, 5360–5369;
Angew. Chem. Int. Ed. 2010, 49, 5232–5241.
[35] CCDC-789888 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
[23] Z olefins have been demonstrated to bind more tightly to cationic
gold(I) complexes containing sterically demanding phosphine li-
gands than that the corresponding E isomers, see: T. J. Brown, M. G.
Dickens, R. A. Widenhoefer, Chem. Commun. 2009, 6451–6453.
[24] S. Porcel, V. Lopez-Carrillo, C. García-Yerba, A. M. Echavarren,
Angew. Chem. 2008, 120, 1909–1912; Angew. Chem. Int. Ed. 2008,
47, 1883–1886.
[25] For representative examples highlighting the role of silver salts as
gold cocatalysts in organic transformations, see: a) M. Reetz, K.
Sommer, Eur. J. Org. Chem. 2003, 3485–3496; b) C. Ferrer, A. M.
Echavarren, Angew. Chem. 2006, 118, 1123–1127; Angew. Chem.
Int. Ed. 2006, 45, 1105–1109; c) D. Weber, M. R. Gagnꢃ, Org. Lett.
Received: September 9, 2010
Published online: November 18, 2010
Chem. Eur. J. 2010, 16, 14272 – 14277
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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