Enantioselective gold-catalyzed functionalization of unreactive sp 3 Ci-H bonds through a redox-neutral domino reaction

Article abstract of DOI:10.1002/chem.201100019

Selectivity is golden: The first asymmetric redox-neutral domino reaction catalyzed by gold that results in the direct functionalization of unreactive sp³ Ci-H bonds has been reported. This method consists of a heterocyclization/1,5-hydride transfer/cyclization reaction and provides synthetically valuable azepines with high enantioselectivities and in high yields (Tf=triflate; see scheme).

Full text of DOI:10.1002/chem.201100019

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DOI: 10.1002/chem.201100019
Enantioselective Gold-Catalyzed Functionalization of Unreactive
3
À
sp C H Bonds through a Redox–Neutral Domino Reaction
Guanghua Zhou,[a] Feng Liu,[a] and Junliang Zhang*[a, b]
In memory of Xian Huang
The development of novel methods for the direct func-
(approach 1 in Scheme 1).[7b] Very recently, Kim and co-
workers developed the first elegant asymmetric organocata-
lytic redox–neutral domino reactions of (E)-3-(2-(dialkyl-
À
tionalization of relatively inactive C H bonds has received
much attention in the past decade,[1] thus offering an intrigu-
ing opportunity for the rapid buildup of synthetic methods
AHCTUNGTREGaNNNU mino)phenyl) acrylaldehyde, which leads to tetrahydro-
able to produce complex molecules. However, the direct
ACHTUNGTRENqNUNG uinolines with excellent enantioselectivity (approach 2 in
3
functionalization of sp C H bonds is still a particularly dif-
Scheme 1).[8]
À
3
À
ficult challenge, because of the strength of sp C H bonds
Our research group has recently demonstrated an alterna-
tive strategy of generating carbocations by a gold(I)-cata-
lyzed heterocyclization of 2-(1-alkynyl)-2-alken-1-ones,
which resulted in a further 1,5-hydride transfer and subse-
quent cyclization to produce furan[9]-fused tetrahydroaze-
pines[10] in moderate to excellent yields.[11] Encouraged by
our recent findings that the (R)-C1-TunePhos and (R)-MeO-
dtbm-biphep derived gold(I) complexes can catalyze the
asymmetric 1,3-dipolar cycloaddition of nitrones with 2-(1-
and because it can be difficult for the metal to reach steri-
cally hindered C H bonds. Recently, Sames and co-work-
ers as well as other research groups, developed a novel
redox–neutral strategy that addresses this issue and includes
[2]
À
À
the initial cleavage of a C H bond in the context of a 1,5-
hydride transfer and a subsequent ring closure.[3] On the
other hand, hundreds of gold-catalyzed reactions have been
well-explored and gold chemistry has been growing from in-
fancy to mature.[4] However, to the best of our knowledge,
there is no report about an asymmetric redox–neutral
domino reaction catalyzed by gold that involves the direct
3
[5]
À
functionalization of sp C H bonds. Herein, we report the
first example of asymmetric redox–neutral domino reactions
catalyzed by gold to achieve direct enantioselective func-
3
À
tionalization of inert sp C H bonds.
Seidel and co-workers recently reported an intriguing
domino 1,5-hydride transfer/cyclization reaction of N, N-dia-
lkyl-2-vinylanilines (tert-amino effect[6]) for efficient synthe-
sis of tetrahydroquinolines catalyzed by a Lewis acid.[7] In
2009, the same group achieved the asymmetric version of
this domino reaction using the Lewis acid [MgACTHUNRGTNEUNG(OTf)2]/
DBFox as the chiral catalyst, thus leading to ring-fused tet-
rahydroquinolines with high to excellent enantioselectivities
[a] G. Zhou, F. Liu, Prof. Dr. J. Zhang
Shanghai Key Laboratory of Green Chemistry and
Chemical Processes, Department of Chemistry
East China Normal University
3663 N. Zhongshan Road, Shanghai 200062 (P.R. China)
Fax : (+86)21-6223-5039
E-mail: jlzhang@chem.ecnu.edu.cn
[b] Prof. Dr. J. Zhang
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
354 Fenglin Road, Shanghai 200032, (P.R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201100019.
Scheme 1. Three different approaches to enantioselective redox–neutral
domino reactions. Tf=triflate.
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alkynyl)-2-alken-1-ones,[12] we envisaged that this catalyst
system may be applied to gold-catalyzed redox–neutral
domino reactions (approach 3 in Scheme 1).
With this hypothesis in mind, we first chose ketone 1a as
the model substrate to test a series of chiral ligands
(Table 1). Initial attempts to use (S)-binap as the ligand led
ties and the yields (Table 1, entries 12–14). When the silver
additive was used with AgBF4 instead of AgOTf, much
better ee values have been obtained by using L3 as the chiral
ligand. An excellent yield (98%) was achieved when the
silver additive AgSbF6 was used. However, the enantioselec-
tivity did not improve (88% ee; Table 1, entry 15).
With the optimal reaction conditions in hand, the scope of
this gold(I)-catalyzed enantioselective intramolecular cycli-
zation/1,5- hydride transfer/cyclization reaction was ex-
plored (Scheme 2). The gold(I)-catalyzed intramolecular
redox reaction of 1 proved to be a general approach for the
asymmetric synthesis of chiral azepines 2. When the sub-
stituent on the phenyl ring of substrate 1 was a convertible
group (Br) or even a triple bond (like phenylethynyl), the
azepines 2b and 2c have also been obtained in 97% and
87% ee, respectively. The absolute configuration of 2b was
confirmed by single-crystal X-ray diffraction analysis
(Figure 1).[13] In general, high to excellent enantioselectivi-
Table 1. Screening studies for the gold(I)-catalyzed asymmetric domino
reaction.[a]
AgY (x [mol%]) T [oC] Yield ([%ee])[b]
À
P P*
Entry
1
2
3
4
(S)-binap
AgOTf (10)
25
25
0
41 (12)
78 (74)
51 (65)
81 (60)
80 (55)
76 (42)
79 (96)
83 (34)
74 (52)
74 (81)
66 (49)
98 (91)
93 (96)
91 (98)
98 (88)
(R)-C1-TunePhos AgOTf (10)
(R)-C1-TunePhos AgOTf (10)
(R)-C1-TunePhos AgOTf (10)
(R)-C1-TunePhos AgOTf (10)
(R)-C1-TunePhos AgOTf (10)
(R)-C1-TunePhos AgOTf (5)
(R)-C2-TunePhos AgOTf (5)
(R)-C3-TunePhos AgOTf (5)
(R)-C4-TunePhos AgOTf (5)
40
25
25
25
25
25
25
25
25
25
25
25
5[c]
6[d]
7
8
9
10
11
12
13
14
15
L1
L2
L3
L3
L3
AgOTf (10)
AgOTf (5)
AgOTf (5)
AgBF4 (5)
AgSbF6
Figure 1. X-ray crystal structures of compound 2b.
[a] Reactions were performed on a 0.3 mmol scale in CH3CN (0.1m) and
the catalyst was produced in situ (see the Supporting Information for de-
tails). [b] Yield of isolated products and enantiomeric excesses deter-
mined by HPLC analysis on a chiral stationary phase. [c] Dichlorome-
thane (DCM) was used as the solvent. [d] 1, 2-Dichloroethane (DCE)
was used as the solvent.
ties can be obtained for a series of substrates containing aro-
matic units R2 with electron-donating and elelectron-with-
drawing substituents. Many of the functional groups that
easily undergo further functional group transformation, such
as carbonyl (2g), ester (2h), nitro (2i), and bromo (2j)
groups, were well-tolerated. Gratifyingly, a cyclohexenyl
unit could be readily introduced as R2, thus producing the
corresponding product 2l in 84% and 76% yields with
94% ee and 93% ee, respectively under the standard reac-
tion conditions or with AgBF4 as the silver additive. The in-
troduction of an aliphatic R2 (2m) on the alkyne moiety re-
sulted in some decrease in enantioselectivity and the yield
(in this case, the silver additive AgBF4 is better than
AgOTf). The methyl group on the ketone moiety (R1) can
be replaced by ethyl group and the desired product 2n can
be obtained in high yield with excellent enantioselectivity.
After studying morpholine derived substrates, piperidine de-
rived substrates were next examined and high enantioselec-
tivities were also achieved (2o–r). The reaction of phenyl
substituted (R1) substrate also worked well to give the cor-
responding product 2r in excellent yield (in this case the
silver additive AgBF4 was again better than AgOTf in enan-
tioselectivity). Next, we wondered whether this chemistry
could be applied to those substrates with acyclic tertiary
amines. Compound 1s was subjected to the standard condi-
to disappointing results (Table 1, entry 1). Next, (R)-Tune-
Phos ligands were examined (Table 1, entries 2–10). The re-
action indeed resulted in the desired product 2a in 78%
yield with 74% ee at room temperature in CH3CN by using
the combination of the (R)-C1-TunePhos derived gold com-
plex (5 mol%) and AgOTf (10 mol%) as the catalyst
(Table 1, entry 2). Next, the screening of the reaction in
other solvents and under different temperature failed to im-
prove the enantioselectivity (Table 1, entries 3–6). We were
pleased to find that a decrease in the loading of AgOTf
(5 mol%) resulted in an excellent enantioselectivity
(96% ee; Table 1, entry 7). Other C2À4-TunePhos ligands
were next screened to get better enantioselectivities and
yields but this attempt failed (Table 1, entries 8–10). The re-
placement of Cn-TunePhos ligands with (R)-MeO-biphep
(L1) led to even worse results. To our delight, it was found
that (R)-3, 5-di-CF3-biphep (L2) and (R)-MeO-dtbm-biphep
(L3), by introduction of bulky substituents on the phenyl of
the phosphine, dramatically increased the enantioselectivi-
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Chem. Eur. J. 2011, 17, 3101 – 3104

Enantioselective Gold Catalysis
COMMUNICATION
to achieve excellent enantioselectivities. The stereochemical
model, (see Figure 2 in the Supporting Information), shows
a proposed transition state that accounts for the formation
of the major enantiomer. The formation of the minor enan-
tiomer would suffer from the severe interactions between
the substrate and the phenyl residue of the ligand.
In summary, we have presented the first example of enan-
tioselective redox–neutral domino reaction catalyzed by
gold(I) that results in the direct functionalization of unreac-
3
À
tive sp C H bonds. Furan-fused azepines derivatives have
been obtained in good to excellent yields with high enantio-
selectivities. Further investigations on gold-catalyzed asym-
metric domino reactions are under way.
Experimental Section
Synthesis of 2a: Under an atmosphere of nitrogen, the solution of the
ligand L3 (5 mol%) and [Au
ACTHNUTRGEN(NUG SMe2)Cl] (10 mol%) in anhydrous DCM
was stirred at room temperature for 2 h, then AgOTf or AgBF4
(5 mol%) and DCM were added and stirred at room temperature for an-
other 15 min. The solvent was then removed under reduced pressure.
Successively, ketone 1a (99.3 mg, 0.3 mmol) was added in anhydrous
CH3CN (3 mL) under an atmosphere of nitrogen, and the reaction was
carried out at room temperature until the complete consumption of the
substrate, which was determined by TLC analysis. After removal of the
solvent under reduced pressure, the resulting crude mixture was purified
by flash column chromatography on silica gel to afford the product 2a
(92.4 mg) in 93% yield with 96% ee. The enantiomeric excess was deter-
mined by HPLC with a Chiralpak OD-H column (hexanes/2-propanol=
90:10, 0.6 mLminÀ1, 230 nm); minor enantiomer tR =9.2 min, major enan-
tiomer tR =13.7 min; [a]D20 =À263.0 (c=0.84, CHCl3). 1H NMR
(400 MHz, CDCl3): d=7.57 (d, J=7.6 Hz, 2H), 7.36 (t, J=7.6 Hz, 2H),
7.30–7.10 (m, 4H), 7.01 (t, J=7.6 Hz, 1H), 4.42 (d, J=8.4 Hz, 1H), 4.26
(d, J=13.6 Hz, 1H), 4.04 (d, J=10.4 Hz, 1H), 3.95–3.75 (m, 2H), 3.65–
3.50 (m, 2H), 3.29 (d, J=13.6 Hz, 1H), 3.10 (d, J=11.6 Hz, 1H),
2.34 ppmACTHNUTRGNEUG(N s, 3H).
Acknowledgements
We are grateful to NSFC (20972054), the Ministry of Education of China
(20090076110007, NCET), STCSM (08dj1400100), and the 973 Program
(2009CB825300) for financial support.
À
Keywords: azepines · C H activation · enantioselectivity ·
furan · gold
À
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domino reactions. [a] Unless otherwise noted, reactions were performed
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details). The yields of the isolated products and the enantiomeric excess-
es were determined by HPLC analysis on a chiral stationary phase.
[b] AgBF4 was used as the silver additive.
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Received: January 4, 2011
Published online: February 15, 2011
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