Highly efficient access to Bi- and tricyclic ketals through gold-catalyzed tandem reactions of 4-acyl-1,6-diynes

Article abstract of DOI:10.1002/chem.200802304

The highly efficient, atom-economical, highly regio, and diasteroselective approach to polyfunctionalized fused bicyclic ketals and bridged tricyclic ketals through gold-catalyzed tandem reactions of 4-Acyl-1,6-diynes, was reported. When the reaction was

Full text of DOI:10.1002/chem.200802304

DOI: 10.1002/chem.200802304
Highly Efficient Access to Bi- and Tricyclic Ketals through Gold-Catalyzed
Tandem Reactions of 4-Acyl-1,6-diynes
Jia Meng, Yu-Long Zhao,* Chuan-Qing Ren, You Li, Zhu Li, and Qun Liu*[a]
In the past few years, reports on gold-catalyzed organic
transformations have increased substantially because various
organic transformations and several total syntheses of natu-
ral products have been accessible under facile conditions
with both high yields and chemoselectivity.[1] In gold-cata-
Scheme 1.
lyzed organic reactions, the cyclization reactions of alkynyl
ketones/aldehydes have emerged as a powerful strategy for
the construction of various cyclic ring systems.[1,2] These re-
actions are generally believed to proceed via an electrophilic
furylium (or pyrylium) ion, generated through intramolecu-
lar nucleophilic attack of the carbonyl-oxygen atom to the
cessible acetoacetanilide derivatives. Encouraged by these
results,[7,8] together with the significance of gold-catalyzed
reactions[1–3] and the synthetic versatility of functionalized
1,6-diynes,[9] we focused our attention on the metal-cata-
lyzed heteroannulation reactions of the readily available 4-
acyl-1,6-diynes 1 (Table 1) and 4 (Table 2). Herein, we wish
to report the highly efficient, atom-economical, highly regio-
and diastereoselective approach to polyfunctionalized fused
bicyclic ketals 3 and bridged tricyclic ketals 5 via AuCl3-cat-
alyzed multicomponent domino reactions of 4-acyl-1,6-
diynes 1 and 4 with H2O and alkanols, respectively.
ꢀ
Au-coordinated carbon carbon triple bond, which is trap-
ped by various nucleophiles to afford the corresponding
products. Recently, Michelet and GenÞt reported the synthe-
sis of strained bicyclic ketals via gold-catalyzed cycloisome-
rization of bis-homopropargylic diols with hydroxy oxygen
atom as internal nucleophile.[3] It was predicted that, based
on these reactions, a fused bicyclic ketal/acetal derivative,
which exists in many biologically active and structurally di-
verse natural products,[4,5] could be constructed in a domino
fashion if another tethered oxygen can be incorporated as
an internal nucleophile (Scheme 1). However, such an ap-
proach requires systematic evaluation.
In the initial experiment, the reactions of 1,6-diyne 1a
(obtained in 98% yield from the reaction of 3-oxo-N-phe-
Table 1. AuCl3-catalyzed synthesis of hexahydrofuroACTHNUTRGNEUNG
[2,3-b]furans 3.[a]
In chemistry, one-pot domino synthesis is a strategy to im-
prove the efficiency of a chemical reaction whereby multiple
bonds and stereocenters are formed in a single step without
the isolation of intermediates.[6] During our research focused
on transformations using relatively simple substrates to rea-
sonably complex products,[7] very recently, several routes
Entry
Substrate
R1
R2
t [h]
Yield[b] [%]
were developed for the synthesis of furoACTHNUTRGNEUNG
[2,3-b]quinolines[8a]
ꢁ
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1 f
1g
1h
1a
1b
1d
C6H5
CH2C CH
CH2C CH
CH2C CH
CH2C CH
CH2C CH
CH2C CH
CH2C CH
CH2C CH
4
4
4
4
4
4
4
4
4
4
4
3ca (93)
3cb (85)
3cc (90)
3cd (90)
3ce (92)
3cf (83)
3cg (90)
3ch (78)
3da (82)
3db (91)
3dd (88)
ꢁ
4-ClC6H4
2-ClC6H4
4-MeOC6H4
2-MeOC6H4
4-MeC6H4
4-EtOC6H4
H
C6H5
4-ClC6H4
4-MeOC6H4
and other quinoline derivatives[8b,c] starting from easily ac-
ꢁ
ꢁ
ꢁ
[a] Dr. J. Meng, Prof. Y.-L. Zhao, Dr. C.-Q. Ren, Dr. Y. Li, Dr. Z. Li,
Prof. Q. Liu
ꢁ
ꢁ
Department of Chemistry, Northeast Normal University
Changchun, 130024 (P.R. China)
Fax : (+86)431-8509-9759
ꢁ
9
10
11
CH2CH=CH2
CH2CH=CH2
CH2CH=CH2
E-mail: zhaoyl351@nenu.edu.cn
liuqun@nenu.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200802304.
[a] Conditions: 1 (1.0 equiv), 3 mol% AuCl3 in alkanol/H2O (8.0 mL;
25:1). [b] Isolated yields.
1830
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Chem. Eur. J. 2009, 15, 1830 – 1834

COMMUNICATION
Table 2. AuCl3-catalyzed synthesis of tricyclic ketals 5.[a]
identical conditions as above,
when the reaction was carried
out in anhydrous EtOH, the
tetrahydrofuran 2ba was pro-
duced exclusively in 92% yield
(a mixture of mainly two diaste-
Entry
Substrate
R
R1
R2
t [h]
Yield[b] [%]
d.r.[d]
reoisomers, a major (2ba) and
ꢁ
1
2
3
4
4a
4b
4c
4d
4e
4a
4a
4a
2-ClC6H4
4-FC6H4
C6H5
3,4-CH2O2C6H3
2-ClC6H4
2-ClC6H4
2-ClC6H4
2-ClC6H4
4-EtOC6H4
4-EtOC6H4
4-EtOC6H4
4-EtOC6H4
C6H5
4-EtOC6H4
4-EtOC6H4
4-EtOC6H4
CH2C CH
10
10
10
10
10
10
10
10
5ca (52)
5cb (45)
5cc (43)
5cd (40)
5ce (44)
5aa (46)
5ba (42)
5da (50)
10:90 a minor product in a 7:3 ratio
1
ꢁ
CH2C CH
10:90
confirmed by H NMR, Table 3,
entry 9); whereas, when the re-
action was performed in EtOH/
ꢁ
CH2C CH
20:80
14:86
10:90
ꢁ
CH2C CH
ꢁ
5
CH2C CH
6[c]
7[c]
8
Me
Et
12:88
15:85
9:91
H2O, the hexahydrofuroACHTUNGTRENNUNG[2,3-
b]furan 3ba was obtained as
the major product in 70% yield
(Table 3, entry 10).
CH2CH=CH2
[a] Conditions: 4 (1.0 equiv), 5 mol% AuCl3 in alkanol/H2O (8.0 mL; 25:1). [b] Isolated yields. [c] Conditions:
4 (1.0 equiv), alkanols (3.0 equiv), H2O (5.0 equiv), 5 mol% AuCl3 in CH2Cl2 (8.0 mL). [d] Diastereomeric
Gratifyingly, when propargyl
alcohol was used as the external
1
ratios were determined by the H NMR spectra of 5.
nylbutanamide and propargyl bromide, see Supporting In-
formation) were examined in the presence of different
metal catalysts and solvents (Table 3). With anhydrous
Table 3. Experimental results of 1,6-diyne 1a.
MeOH as the solvent and PdCl2 (5 mol%) or PdACTHNUGTRENUNG(OAc)2
(5 mol%) as the catalyst, no reaction was observed at room
temperature for 24 h (Table 3, entries 1 and 2). To our de-
light, under otherwise identical conditions as above, the re-
action of 1a (1.0 mmol and 5.0 mL MeOH) could easily pro-
ceed to give exclusively the oxacyclization product 2aa
(Figure 1) in 95% yield (a mixture of mainly two diastereo-
2
3
Entry Catalyst (mol%) Solvent
t [h]
AHCTUNGTRENNUNG
1
2
PdCl2 (5)
Pd(OAc)2 (5)
MeOH
MeOH
24
24
4
4
4
4
4
4
4
–
–
–
–
N
3
4
5
6
7
8
9
10
AuCl3 (3)
AuCl3 (3)
AuCl3 (3)
AuCl3 (5)
AuCl3 (5)
AuCl3 (7)
AuCl3 (3)
AuCl3 (5)
MeOH
2aa (95) 3aa (0)
2aa (89) 3aa (8)
2aa (25) 3aa (60)
2aa (10) 3aa (75)
2aa (11) 3aa (72)
2aa (10) 3aa (73)
2ba (92) 3ba (0)
2ba (12) 3ba (70)
MeOH/H2O (50:1)
MeOH/H2O (15:1)
MeOH/H2O (15:1)
MeOH/H2O (10:1)
MeOH/H2O (15:1)
EtOH
EtOH/H2O (15:1)
4
[a] Isolated yields.
nucleophile, the reaction of 1a could proceed smoothly with
complete product selectivity to give hexahydrofuro[2,3-
ACHTUNGTRENNUNG
b]furan 3ca. In the presence of 3 mol% of AuCl3 in prop-
argyl alcohol/H2O (8.0 mL; 25:1) at room temperature
under air for 4 h, 3ca was produced exclusively in 93% iso-
lated yield (Table 1, entry 1). Encouraged by these results,
the scope of the reaction was investigated further and the
results are summarized in Table 1. It is obvious that this
multicomponent domino reaction shows wide applicability
for various aryl substituents in diynes 1. All selected sub-
strates 1a–g, bearing an aryl group (with either electron-do-
nating or electron-withdrawing group on the phenyl ring) at
the nitrogen, could efficiently undergo the AuCl3-catalyzed
domino reaction to give the corresponding hexahydrofuro-
Figure 1. ORTEP drawing of 2aa.
isomers, a major (2aa) and a minor in a 6:4 ratio confirmed
1
by H NMR) in the presence of 3 mol% of AuCl3 for 4 h
(Table 3, entry 3).[10] Interestingly, when the reaction was
performed in wet methanol (MeOH/H2O 50:1), except 2aa
(in 89% yield), a fused bicyclic ketal, hexahydrofuroACHTUNTRGNEUNG[2,3-
b]furan 3aa was isolated in 8% yield (Table 3, entry 4). For-
tunately, the product selectivity could be controlled by the
MeOH/H2O ratio and catalyst loading. For example, 3aa
could be obtained as the major product in high yields and in
a regio- and diastereoselective manner by increasing the cat-
alyst loading and the ratio of H2O/MeOH (Table 3, entries 5
and 6). However, further increase of AuCl3 and the ratio of
H2O/MeOH did not improve the selectivity and the yield of
3aa (Table 3, entries 7 and 8). Similarly, under otherwise
AHCTUNGTREG[NNNU 2,3-b]furans 3ca–g in high to excellent yields under very
mild conditions (Table 1, entries 1–7). Notably, in the case
of 1h, the domino reaction also worked well, yielding the
desired product 3ch in 78% (Table 1, entry 8). Similarly, the
allyl alcohol prove to be an effective external nucleophile
Chem. Eur. J. 2009, 15, 1830 – 1834
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1831

Y.-L. Zhao, Q. Liu et al.
and the corresponding hexahydrofuro
G
oxygen atoms of the fused bicyclic ring system of 3 are gen-
erated from the two acetyl groups although the second
acetyl functionality is created from the intramolecular oxo-
assisted alkyne hydration (Scheme 2, B!C!D);[14] 2) both
water and the OH group of an alkanol play an important
but different role at different stages in the transformation
and 3dd were also obtained in high to excellent yields
(Table 1, entries 9–11).[11] In addition, according to H and
13C NMR spectroscopic data of hexahydrofuro
ACHTNUTRGNE[NUG 2,3-b]furans
3, it was found that the domino reaction proceeds in a
highly regio- and diastereoselective manner[12] and the struc-
ture of fused bicyclic ketals 3 was finally established by the
X-ray diffraction analysis of 3cd (Figure 2).[13]
process. Thus, tetrahydrofurans 2 and hexahydrofuroACHTUNGTRENNUNG[2,3-
b]furans 3 can be synthesized, respectively, by variation of
the ratio of water and alkanol. Following the success of the
evaluation (Tables 1 and 3; Schemes 1 and 2), we then
turned our focus towards a solution that would work for a
broad spectrum of substrates and lead to structures of high
molecular complexity from relatively simple starting materi-
als.[15] Therefore, the domino reactions of 1,6-diynes 4 (ob-
tained in 55–85% yields by the aldol reaction of 1,6-diynes
1 and aromatic aldehydes, see Supporting Information) with
H2O and alkanols were investigated.
It was found that, under essentially the identical condi-
tions as above (Table 1), when the 1,6-diyne 4a was treated
with wet propargyl alcohol in the presence 5% AuCl3 at
room temperature for 10 h, the bridged tricyclic ketal 5ca
was obtained in 52% yield (Table 2, entry 1) along with the
recovery of 4a (36%). Under otherwise identical reaction
conditions, it was noted that, 1) increasing the amount of
AuCl3 (8 mol%) or reaction time (20 h) did not improve the
yield of 5ca (53 and 50%, respectively); 2) decreasing the
loading of AuCl3 (3 mol%) led to lower product yields
(35%); and 3) elevated temperatures (408C) resulted in the
formation of a complex mixture. All results indicate that
under the optimized reaction conditions (Table 2, entry 1),
the conversion yield of the domino reaction is high. With
these results in hand, similarly, under the optimized condi-
tions, the generality of the reaction was examined by select-
Figure 2. ORTEP drawing of 3cd.
On the basis of the above experimental results together
with the related reports,[1–3,14] a mechanism for the formation
ꢀ
of 3 involving five C O bond formation in a single step is
proposed (Scheme 2). Initially, the chemo- and regiospecific
attack of the acetyl carbonyl-oxygen of 1 on the electrophil-
ic p-alkyne moiety of gold complex A generates the electro-
philic furylium intermediate B, where the preferred intramo-
lecular oxo-assisted alkyne hydration (B!C!D)[14] leads to
the formation of dicarbonyl intermediate D. Then, the facili-
tated intramolecular cyclization of D followed by addition
of the alkanol in a stereospecif-
ic manner (induced by the
chiral center of intermediate D)
gives the intermediate auric ate
complex E. HexahydrofuroACTHNUTRGNE[UNG 2,3-
b]furans 3 are finally produced
via isomerization of E and fur-
ther alkanolysis. This explains
the excellent diastereoselectiv-
ity observed in the reaction se-
quence with four chiral centers,
which can possibly be rational-
ized by a series of the intramo-
lecular chiral inductions.
According to the mechanism
described above (Scheme 2), it
is obvious that, 1) under the re-
action conditions mentioned
above (Table 1 or 3), the car-
bonyl oxygen of the acetyl
group of 1 is more reactive than
the amide oxygen toward the
ꢀ
Au-coordinated carbon carbon
triple bond because the two Scheme 2. Proposed mechanisms for the formation of 3 and 5.
1832
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ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 1830 – 1834

Gold-Catalyzed Tandem Reactions
COMMUNICATION
ed 1,6-diynes 4 and the results are summarized in Table 2. It
was found that, the precursors 4 with either electron-donat-
ing or electron-withdrawing group on the phenyl ring (R=
Ar) could undergo efficiently AuCl3-catalyzed domino reac-
tion with H2O and propargyl alcohol in the presence 5%
AuCl3 to give the corresponding bridged tricyclic ketals
5ca–e in good yields (Table 2, entries 1–5). In addition to
propargyl alcohol, a variety of alcohols, such as methanol,
ethanol, and allyl alcohol, also worked well as external nu-
cleophiles, and the corresponding tricyclic ketals 5aa, 5ba
and 5da were obtained in good yields (Table 2, entries 6–8).
with the basic structure of either dioxabicyclo-
ACHUTNGRENNUG CAHTUNGTRENNUGN
[3.2.1]octane[5a–c,17–20] and hexahydrofuro[2,3-b]furan.[4,5d]
On the basis of the above experimental results together
with the related reports,[1–3,14] the formation of 5 is believed
to be similar to hexahydrofuro[2,3-b]furans 3 (Scheme 2).
AHCTUNGTRENNUNG
However, when the R substituent is ArCHOH, the attack of
intramolecular hydroxyl group of intermediate E from sub-
strates 4 would be more favorable than the corresponding
intermolecular mode (Scheme 2).
In conclusion, we have shown the novel gold-catalyzed
tandem reactions, that is, the cycloisomerization, intramolec-
ular oxo-assisted alkyne hydration, cycloisomerization, alka-
nolysis, isomerization, and alkanolysis (intermolecular or in-
tramolecular) sequence. These approaches allow the forma-
tion of either fused bicyclic ketals 3 or bridged tricyclic
ketals 5 in good to excellent yields. In addition, these new
transformations have the advantages of high regio- and dia-
stereoselectivity in a single reaction step under mild reaction
conditions and lead to structures of high molecular complex-
ity from simple starting materials in an atom economic way.
1
In addition, according to H and 13C NMR data of tricyclic
ketals 5, it was found that the domino reaction proceeds in a
highly regio- and diastereoselective manner (Table 2) and
the structure of 5 was finally established by the X-ray dif-
fraction analysis of 5ca (Figure 3).[16]
Experimental Section
General procedure for the synthesis of 3: AuCl3 (9.1 mg, 0.03 mmol) was
added in one portion to a stirred solution of 1a (253 mg, 1.0 mmol) in
propargyl alcohol/H2O (8.0 mL, 25:1). The reaction mixture was stirred
for 4 h at room temperature. After 1a was consumed (monitored by
TLC), the reaction mixture was poured into water (30 mL) and extracted
with CH2Cl2 (10 mL ꢁ3). The combined organic extracts were dried over
anhydrous MgSO4, filtered and concentrated under reduced pressure to
yield the corresponding crude product, which was purified by silica gel
chromatography (diethyl ether/hexane 1:12) to give 3ca (356 mg, 93%)
as a white solid. M.p. 79–818C; 1H NMR (CDCl3, 500 MHz): d=1.53 (s,
3H), 1.55 (s, 3H), 1.65 (s, 3H), 2.16 (d, J=13.0 Hz, 1H), 2.38 (s, 1H),
2.40 (s, 1H), 2.83 (d, J=14.0 Hz, 1H), 2.96 (d, J=14.5 Hz, 1H), 3.17 (d,
J=13.5 Hz, 1H), 4.20–4.42 (m, 4H), 7.10 (d, J=7.0 Hz, 1H), 7.31 (t, J=
8.0 Hz, 2H), 7.67 (d, J=8.5 Hz, 2H), 9.66 ppm (s, 1H); 13C NMR
(CDCl3, 125 MHz): d=21.7, 22.1, 23.8, 47.8, 49.5, 49.7, 49.8, 63.1, 73.4,
74.8, 79.4, 80.6, 108.8, 109.5, 119.8, 119.9, 121.0, 123.9, 128.5 (2C), 138.3,
169.8 ppm; IR (KBr): n˜ =3286, 2924, 2156, 1686, 1555, 1446, 1378, 1212,
1177, 1049, 953 cmꢀ1; MS (ESI) m/z: 406 [M+23]+; elemental analysis
calcd (%) for C22H25NO5: C 68.91, H 6.57, N 3.65; found: C 68.74, H
6.51, N 3.53.
Figure 3. ORTEP drawing of 5ca.
It should be noted that fused bicyclic ketal/acetal deriva-
tives, especially dioxabicycloACTHNUGRTNEUNG[3.2.1]octanes, exist in many
biologically active and structurally diverse natural prod-
ucts.[17] General synthetic methods for dioxabicyclo-
ACHTUNGTRENNUNG[3.2.1]octanes involve mainly the intramolecular acetaliza-
tion of ketodiols,[5a,17] and ketalization/ring-closing metathe-
sis of diene diol and alkenyl ketones developed recently.[18]
Additionally, alternative strategies have been explored, for
example, the intramolecular double alkoxylation of alkyne
diols in the presence of transition-metal complexes, includ-
ing Pt[5b] and Pd.[19] Recently, Shi and co-workers reported
the gold(I)-catalyzed cycloisomerization of propargylic alco-
hols with oxirane to fused bicyclic ketals,[20] whereas, the re-
action needs to be performed in the presence of co-catalysts.
Undoubtedly, the above AuCl3-catalyzed domino reactions
(Tables 1 and 2) provide a facile and efficient access to
fused bicyclic ketals 3 and bridged tricyclic ketals 5 from
readily available starting materials under mild reaction con-
ditions. Moreover, to the best of our knowledge, products 5
show the first example of the novel bridged tricyclic ketals
Acknowledgements
Financial support from the National Natural Sciences Foundation of
China (20602006), the Department of Science and Technology of JLSDG
(20080548 and 20082212) and Training Fund of NENU’S Scientific Inno-
vation Project (NENU-STC07017 and NENU-STB07007).
Keywords: asymmetric synthesis
reactions · gold
· cyclization · domino
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Received: November 6, 2008
Published online: January 8, 2009
1834
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