Gold(I)-catalyzed asymmetric cycloisomerization of eneallenes into vinylcyclohexenes

Article abstract of DOI:10.1002/anie.200701959

(Chemical Equation Presented) Coming around: Cycloisomerization of eneallenes by cationic gold(I) catalysts produces vinylcyclohexene derivatives in up to 77% ee, using [3,5-xylylbinap-(AuCl)₂] and AgOTf additive (see scheme; 3,5-xylyl-binap =

Full text of DOI:10.1002/anie.200701959

Communications
DOI: 10.1002/anie.200701959
Gold Catalysis
Gold(I)-Catalyzed Asymmetric Cycloisomerization of Eneallenes into
Vinylcyclohexenes**
Michael A. Tarselli, Anthony R. Chianese, Stephen J. Lee, and Michel R. GagnØ*
The use of gold(I) catalysts for organic synthesis continues to
be the subject of considerable attention, as unique reactivity
patterns are often observed.[1] Of the remarkably diverse
array of transformations catalyzed by AuI, the number that
have asymmetric variants remains low,[2–4] most likely as a
result of the enforced linear coordination geometry of gold(I),
which spatially separates ligand chirality fromthe reacting
substrate.[2]
ment, a preliminary screen of chiral phosphines was initiated.
Fromthis examination, [3,5-xylyl-binap(AuCl) 2] (3,5-xylyl-
binap = 2,2’-bis(di(3,5-xylyl)phosphino)-1,1’-binaphthyl) was
identified as a promising catalyst precursor, and additional
optimization studies were carried out with this complex.[14]
The regioselectivity was moderately dependent on solvent
polarity, though the enantioselectivities were strongly depen-
dent on this parameter (Table 1). Attempts to further
optimize these two parameters by modifying the counterion
were partially successful, but the counterion that delivered
the best regioselectivity for the formation of 2 (OTsÀ) was not
the same as that which provided the best enantioselectivity
(OTfÀ; Table 1).
The divergent reactivity of AuI catalysts came into view
during efforts to logically extend a project on diene cyclo-
isomerization[5] to 1,6-eneallenes. Although the initially tested
PtII catalysts were not effective, compound 1 was found to
react with 10 mol% of the catalyst generated from
[(Ph3P)AuCl] and AgOTf to give vinylcyclohexene 2,[6,7]
a
rare six-membered-ring product of eneallene cycloisomeriza-
tion [Eq. (1)]. Although numerous studies of eneallene
Table 1: Optimization of reaction conditions for the conversion of 1 to
2a,b using the [(R)-3,5-xylyl-binap(AuCl)2] precursor.[a]
Solvent
Activator
Regioselectivity 2a:2b
ee [%][e]
[b]
CH2Cl2
toluene
chlorobenzene
EtNO2
MeNO2
AgNTf2
2.5:1
1:2
2:1
3:1
4:1
30
29
51
42
65
cycloisomerization reactions have been reported (e.g. with
Rh,[8] Pd,[9] Ru,[10] Ni/Cr[11]), five-membered (typically) and
seven-membered (less common) rings are usually obtained,
and apparently, none of these reactions tolerates internal
substitution at the alkene.[12] This unknown selectivity for
cyclohexene derivatives was therefore pursued.[13]
Although the reaction rate was good and the PPh3-based
catalyst well-behaved, we decided to use this success as a
starting point for the discovery of heretofore unknown
enantioselective variants. Since the phosphine ligand pro-
vided the obvious point for creating a chiral catalyst environ-
AgNTf2
AgNTf2
AgNTf2
AgNTf2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
AgSbF6
AgBF4
4:3
57
30
50
65
72
incomplete conversion
10:1
9:1
AgOTs[c]
AgPF6
AgOTf[d]
4:1
[a] Reaction conditions: 5 mol% [(R)-3,5-xylyl-binap(AuCl)2], 15 mol%
AgX, 0.1 m 1,.RT, 16 h. The best regioselectivites and ee values are shown
in bold. [b] NTf2 =N(SO2CF3)2. [c] OTs=OSO2(4-MeC6H4). [d] OTf=
OSO2CF3. [e] The ee values are an average of 2a and 2b on chiral-
phase GC; see the Supporting Information.
[*] M. A. Tarselli, Dr. A. R. Chianese, Prof. M. R. GagnØ
University of North Carolina—Chapel Hill
Chapel Hill, NC 27599-3290 (USA)
Fax: (+1)919-962-6342
E-mail: mgagne@unc.edu
Dr. S. J. Lee
U.S. Army Research Office
P.O. Box 12211
Using the conditions providing optimum enantioselectiv-
ities with 3,5-xylyl-binap, a variety of chiral diphosphine
ligands were re-examined; however, none provided a better
enantioselectivity (Table 2). Interestingly, DTBM-SEG-
PHOS [(4,4’-bi-1,3-benzodioxole)-5,5-diylbis(di(3,5-di-tert-
butyl-4-methoxyphenyl)phosphine)], previously shown to be
optimum in related gold(I) allene chemistry,[15] was unreactive
in this system. Also intriguing was the reversed regioselec-
tivity in the [QUINAP(AuCl)] case, though the enantiose-
lectivity was poor.
Research Triangle Park, NC 27709 (USA)
[**] The authors thank Prof. Ross Widenhoefer (Duke) for a sample of
[(R)-tBu2MeO-BIPHEP(AuCl)2] and Prof. Wenbin Lin (UNC) for a
sample of 4,4’-(TMS)2binap. Postdoctoral funding from the
National Research Council (A.R.C.) and from the National Institutes
of General Medicine (GM-60578) is also greatly appreciated.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Chemie
Table 2: Chiral ligand screening for the conversion of 1 to 2a/2b.[a]
Table 3: Cycloisomerization catalyzed by [(R)-3,5-xylyl-binap(AuCl)2] and
AgOTf.[a]
Catalyst
ee [%][b]
Regioselectivity 2a:2b[c]
Substrate
Product
Yield [%][a]
ee [%][c]
72 (77)[d]
6
[(S,S)-DIOP(AuCl)2][d]
4
1:1
1:3
2.5:1
3.5:1
3:1
1:1.5
3.3:1
3.5:1
(isomer ratio)[b]
[(R)-QUINAP(AuCl)][e]
10
16
28
33
66
66
72
[(R)-xylyl-PHANEPHOS(AuCl)2][f]
[(R)-xylyl-SOLPHOS(AuCl)2][g]
[(R)-SYNPHOS(AuCl)2][h]
[(R)-4,4’-TMS-binap(AuCl)2]
[(R)-SEGPHOS(AuCl)2][i]
[(R)-3,5-xylyl-binap(AuCl)2]
83 (3.5:1)
82
[a] Only two products seen by GC after isolation; conversion monitored
by 1H NMR. The best regioselectivity and ee are shown in bold.
[b] Average of both regioisomers. [c] GC peak integration. [d] DIOP=
1,4-bis(diphenylphosphino)-1,4-dideoxy-2,3-O-isopropylidene-d-threitol.
[e] QUINAP=1-(2-diphenylphosphino-1-naphthyl)isoquinoline. [f] xylyl-
PHANEPHOS=4,12-bis[di(3,5-xylyl)phosphino]-[2.2]-paracyclophane.
[g] SOLPHOS=7,7’-bis[di(3,5-xylyl)phosphino]-3,3’,4,4’-tetrahydro-4,4’-
82
57[e]
dimethyl-8,8’-bi(2H-1,4-benzoxazine).
[h] SYNPHOS=[(5,6),(5’,6’)-
bis(ethylenedioxy)biphenyl-2,2’-diyl]bis(diphenylphosphine).
[i] SEG-
PHOS=4,4’-bi-1,3-benzodioxole-5,5’-diylbis(diphenylphosphine).
70 (1.5:1)
80 (5:1)
45
59
Eneallenes for examining the scope of this chemistry were
readily available[8,16] and enabled several structural variations
to be examined. Alkenes that were only monosubstituted at
the internal position were unreactive, though substitution at
the alkene terminus was tolerated. In the latter cases, this
tolerance provided sufficient bias to favor one product
regioisomer (10, 12, Table 3). In the case of methallyl- (1)
or phenallyl-substituted substrates (7) lacking this element, a
mixture of regioisomers was obtained. This result, however,
was not universal, as the sulfone and urea variants of the
methallyl substrate were quite regioselective for the 1,2-
product. Substitution at the internal allene hydrogen position,
on the other hand, led to lower yields and enantioselectivities,
along with competitive isomerization of starting material (not
shown).
70
65
64
77 (1:1)
[a] Catalyst generated in situ using standard reaction conditions, see the
Experimental Section. [b] 2,1:2,3 olefin isomer. [c] Major regioisomer.
[d] When cooled to À128C, 0.08m, 24 h. [e] Poor resolution (chiral-phase
supercritical fluid chromatography) limits the accuracy of this measure-
ment (Æ10%).
Enantioselectivities were found to be moderate for most
substrates, and a slight increase in ee was possible when the
reaction was run at À128C (77% ee for 2). Sulfone 3 was the
unusual case, as 4 was obtained in virtually racemic form.
Nevertheless, these results represent a significant subset of
the known gold-catalyzed asymmetric transformations of
allenes.
The skeletal divergence of AuI in this cycloisomerization
suggested a significantly different mechanism from that
typically found for Rh,[8] Pd,[9] and Ru[10] catalysts, which are
Scheme 1. Proposed mechanism for eneallene cycloisomerization. [Au]
À
prone to oxidative C C coupling processes and give exo,exo-
represents the active catalytic species.
cyclopentene products.[17] Our current mechanistic hypothesis
explaining the observed reactivity patterns involves the
electrophilic activation of the internal allene double bond
by AuI.[6,18] In this scenario, the alkene acts as a nucleophile to
generate putative carbeniumion A (Scheme 1); the catalytic
cycle is then completed by 2,3- or 2,1-elimination and
protodeauration. In cases where C1 and C2 are each
substituted, elimination to the more highly substituted
alkene product provides the observed major isomer (10 and
12). The role of the alkene as a nucleophile also explains why
internal disubstitution of the alkene is essential, since this
ensures the generation of a tertiary carbeniumion in the
putative intermediate. This mechanism is also consistent with
the observed regiochemical sensitivity to counterions, since
they can presumably act as a weak general bases in the b-
elimination step.
Since asymmetric induction in AuI-catalyzed processes is
relatively rare, we obtained a crystal structure of the dinuclear
catalyst precursor (Figure 1).[19,20] Interestingly, a key p–p
stacking interaction between two P-bound aryl groups (plane-
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Communications
ture was loaded directly onto a silica gel column for purification and
eluted with hexanes/ethyl acetate (8:1).
Received: May 3, 2007
Revised: May 31, 2007
Published online: July 27, 2007
À
Keywords: asymmetric synthesis · C C coupling · gold ·
homogeneous catalysis
.
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Figure 1. X-ray structure of [3,5-xylyl-binap(AuCl)2]; one of two mole-
cules in the asymmetric unit is shown; hydrogen atoms are omitted
for clarity.
to-plane distance of 3.7 Š) lends the structure of this
precursor a degree of rigidity and thus establishes a well-
defined chiral environment in the solid state. The same
conformational preference was observed in a tol-binap di-
gold structure (tol = tolyl),[3] which suggests that it may be a
common structural feature capable of sculpting the reactive
environment of a complex that is otherwise constrained to a
linear geometry.[21] Several observations that complicate the
identification of the active catalyst occurred while investigat-
ing the cyclization of 1 to 2 with an isolated catalyst. When
5 mol% isolated [(R)-3,5-xylyl-binap(AuOTf)2] was utilized
under the standard conditions, slow reactions and low
enantioselectivities were obtained (21% ee, more than 24 h
for completion), contrasting with studies of in situ generated
catalysts. Suspecting a role for Ag+ in these processes, we
repeated the reactions using 5 mol% [(R)-3,5-xylyl-binap-
(AuOTf)2] and a 15 mol% excess of AgOTf. Although a fast
rate returned, the enantioselectivity remained low (21%).
Unexpectedly, a control reaction using 5 mol% [(R)-3,5-
xylyl-binap(AuOTf)2] and added AgCl (15 mol%) increased
the ee to 34%. While we do not yet have an explanation for
these observations, the in situ protocol reproducibly provides
products with good selectivities.
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In conclusion, an enantioselective gold(I) catalyst has
been developed for the cycloisomerization of eneallenes into
vinylcyclohexene products. This carbon skeleton is unusual, as
five- and seven-membered-ring products are the norm with
other metal catalysts. The AuI catalyst is tolerant of functional
groups, it appears to selectively activate the allene over the
alkene, and it can be used to generate bicyclic products.
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Chem. Soc. 2006, 128, 10352 – 10353. See also footnote [6i].
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Experimental Section
In a glovebox charged with nitrogen, an oven-dried 1-dramvial was
charged with [(R)-3,5-xylyl-binap(AuCl)2] (5.0 mg, 4.2 mmol), silver
triflate (3.0 mg, 12.6 mmol), and nitromethane (0.8 mL). After
stirring the suspension for 5 min, 1 (20 mg, 84 mmol) was added. A
yellow color was usually noted within 10 min, and the reaction was
usually blue-gray upon completion. After consumption of the starting
material (determined by 1H NMR spectroscopy), the reaction mix-
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alcohols gave full conversion but low ee in the present system
(see footnote [6e]).
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b) S.-K. Kang, B.-S. Ko, D.-M. Lee, Tetrahedron Lett. 2002, 43,
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[11] B. M. Trost, J. M. Tour, J. Am. Chem. Soc. 1988, 110, 5231 – 5233.
[12] Itoh reported that internal alkene substituents completely
inactivate Rh-catalyzed eneallene cycloisomerizations, see foot-
note [8].
[13] Six-membered-ring products have been observed from Pauson–
Khand-type reactions and thermal [2+2] cyclizations of eneal-
lenes. See, for example: a) F. Inagaki, C. Mukai, Org. Lett. 2006,
8, 1217 – 1220; b) A. Padwa, M. Meske, S. S. Murphee, S. H.
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[17] For a discussion of cycloisomerization mechanisms, see: G. C.
Lloyd-Jones, Org. Biomol. Chem. 2003, 1, 215 – 236.
[18] A related ionic pathway is proposed for the AuI-catalyzed
asymmetric alkoxy cyclization of ene-ynes, see reference [3].
[19] For structural information, contact Dr. Peter White in the UNC–
Chapel Hill X-ray Facility (pswhite@email.unc.edu).
[20] Crystal data for [3,5-xylyl-binap(AuCl)2] at 100 K:
C52H48Au2Cl2P2, 1/2H2O, Mr = 1200.76 gmolÀ1, orthorhombic,
space group P212121, a = 12.6526(5), b = 19.0582(7), c =
38.1147(13) Š, V= 9190.8(6) Š3, Z = 8, 1calcd = 1.746 mgmÀ3
,
R1 = 0.0423 (0.0527), wR2 = 0.0933 (0.0996), for 4688 reflections
with I > 2s(I) (for 26863 reflections (Rint = 0.0604) with a total of
219861 measured reflections), goodness-of-fit on F2 = 1.029,
largest diff peak (hole) = 4.909 (À4.305 eŠÀ3).
[14] AgNTf2 has previously been utilized to generate reactive AuI
cations, see: N. MØzailles, L. Ricard, F. Gagosz, Org. Lett. 2005,
7, 4133 – 4136.
[15] The [xylyl-binap(Au(3,5-NO2-benzoate)2)] catalyst recently
reported for the cyclization of allenylsulfonamides was inactive
for the reactions described herein (20 h at 508C; see foot-
note [6f]). The tBu2MeO-BIPHEP digold catalyst reported by
Widenhoefer and co-workers for the cyclization of allenyl
[21] The L-AuI-L bond angle is typically in the 170–1808 range. See,
for example: a) A. A. Mohamed, J. Chen, A. E. Bruce, M. R. M.
Bruce, J. A. K. Bauer, D. T. Hill, Inorg. Chem. 2003, 42, 2203 –
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