Gold(l)-catalyzed cascade cyclization reaction: Highly regio- and diastereoselective intermodular addition of water and alcohols to epoxy alkynes

Article abstract of DOI:10.1021/ol0713640

We have developed a novel access to ketal skeletons through a highly regio- and diastereoselective intermolecular addition of water and alcohols to alkynyl epoxides catalyzed by goid(l). This procedure involves a domino three-membered ring-opening, 6-exo-

Full text of DOI:10.1021/ol0713640

ORGANIC
LETTERS
2007
Vol. 9, No. 16
3191-3194
Gold(I)-Catalyzed Cascade Cyclization
Reaction: Highly Regio- and
Diastereoselective Intermolecular
Addition of Water and Alcohols to
Epoxy Alkynes
Lun-Zhi Dai, Ming-Juan Qi, Yong-Ling Shi, Xu-Guang Liu, and Min Shi*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai, China 200032
mshi@mail.sioc.ac.cn
Received June 8, 2007
ABSTRACT
We have developed a novel access to ketal skeletons through a highly regio- and diastereoselective intermolecular addition of water and
alcohols to alkynyl epoxides catalyzed by gold(I). This procedure involves a domino three-membered ring-opening, 6-exo-cycloisomerization,
and subsequent intra- or intermolecular nucleophilic addition to a double-bond sequence.
Cyclizations of epoxy alkynes have provided rapid access
to complex structures in an easy one-pot process in which a
wide range of metal salts can be used, either in a stoichio-
metric or a catalytic manner. For example, Marson reported
an efficient Sn(OTf)2- or SnBr4-induced alkyne-epoxy
alcohol cyclization leading to a seven-membered carbocyclic
ring; however, the reaction generally requires an excess
amount of metal reagents.1a Gansaser found that a catalytic
amount of Ti(III) complexes sufficed to implement radical
epoxide-alkyne cyclization in the presence of excess Mn
powder.1b In addition, McDonald described a W(CO)6-
catalyzed cyclization of R-ethynyl epoxides to give furans.1c
The first intermolecular alkyne-epoxide coupling was
recently reported by Jamison with the use of Ni(0)-PBu3
catalyst.1d Later on, Liu achieved a cascade alkyne-epoxide
cyclization of (o-ethynyl)phenyl epoxides catalyzed by Ru
complexes.1e Recently, a AuCl3-catalyzed isomerization of
alkynyl epoxides to furans under mild conditions was
reported by Hashmi.2 In the context of our ongoing efforts
to develop cascade reactions,3 we envisaged that the alkynyl
epoxides in the presence of various nucleophiles might
undergo a domino pathway consisting of three-membered
ring-opening, 6-exo-cycloisomerization, and subsequent nu-
cleophilic addition to a double bond to give ketal skeletons
(Scheme 1).
According to this mode, several problems should be taken
into consideration. (i) Choose a proper catalyst M to activate
the alkynyl group and the epoxy group as well as the
subsequently formed double bond. For example, previous
(1) (a) Marson, C. M.; Khan, A.; McGregor, J.; Grinter, T. J. Tetrahedron
Lett. 1995, 36, 7145. (b) Gansauer, A.; Bluhm, H.; Pierobon, M. J. Am.
Chem. Soc. 1998, 120, 12849. (c) McDonald, F. E.; Schultz, C. C. J. Am.
Chem. Soc. 1994, 116, 9363. (d) Molinaro, C.; Jamison, T. F. J. Am. Chem.
Soc. 2003, 125, 8076. (e) Madhushaw, R. J.; Lin, M.-Y.; Sohel, S. M. A.;
Liu, R.-S. J. Am. Chem. Soc. 2004, 126, 6895.
(2) Hashmi, A. S. K.; Sinha, P. AdV. Synth. Catal. 2004, 346, 432.
(3) Shi, M.; Liu, L.-P.; Tang, J. Org. Lett. 2006, 8, 4043.
10.1021/ol0713640 CCC: $37.00
© 2007 American Chemical Society
Published on Web 07/13/2007

Scheme 1. Projected Domino Reaction
Table 1. Scope of Gold(I)-Catalyzed Addition of Water to
Alkynyl Epoxidesa
entry
substrate
productb
1
2
3
4
5
6
1a: R1 ) H, X ) p-MeC6H4SO2N
1b: R1 ) H, X ) o-NO2C6H4SO2N
1c: R1 ) H, X ) p-BrC6H4SO2N
1d: R1 ) Me, X ) p-MeC6H4SO2N
1e: R1 ) CO2Et, X ) p-MeC6H4SO2N
1f: R1 ) SiMe3, X ) p-MeC6H4SO2N
2a (68%)
2b (56%)
2c (63%)
2d (38%)
2e (70%)
2a (50%)
reports have shown that gold salts are a kind of powerful
soft Lewis acid and can readily activate alkynes, allenes, and
olefins toward attacks by a variety of nucleophiles.4,5
Moreover, we have found that gold(I) can also be an efficient
catalyst for the rearrangement of oxirane. (ii) The rearrange-
ment of epoxy group should be suppressed. As we know,
the rearrangement of epoxides with a Lewis acid is a
common method in organic synthesis and has been broadly
studied.6 (iii) Once the catalyst M coordinates to the triple
bond and the epoxy group, the nucleophile should be used
to attack the epoxy group.6a
To probe the feasibility of this strategy, we initially focused
on the addition of water to the N-tethered alkynyl epoxide
compound 1a in the presence of various Lewis acids to
examine the formation of the fused bicyclic ketal 2a (see
the Supporting Information). The reaction, which was carried
out in 1,2-dichloroethane (DCE) using (Ph3P)AuCl/AgSbF6
as catalysts, gave the best result, and the desired product 2a
was obtained in 68% yield. The structure of compound 2a
was confirmed by X-ray diffraction study (see the Supporting
Information). Under the optimized conditions, the scope of
this domino approach from alkynyl epoxides to fused bicyclic
ketals was summarized in Table 1. Subjection of N-tethered
alkynyl epoxides 1b and 1c to the general protocol afforded
the expected fused bicyclic compounds 2b and 2c in
moderate yields respectively, indicating that the substituents
on the aryl ring did not have significant effect to this
transformation (Table 1, entries 2 and 3). The presence of
a Reactions were conducted with 0.30 mmol of substrate and 0.45 mmol
of water catalyzed by 5 mol % of (Ph3P)AuCl/AgSbF6 in 3 mL of DCE at
room temperature for 48-72 h. b All of the yields given in parentheses are
isolated yields.
an electron-withdrawing substituent on the alkyne appeared
to be more beneficial than the presence of an electron-
donating substituent (Table 1, entries 4 and 5). However,
the reaction could not tolerate the TMS group on the alkyne
in the substrate 1f (Table 1, entry 6).
By investigating the scope of the reaction, we surprisingly
found that the use of O-tethered alkynyl epoxide 3a led to
R,â-unsaturated carbonyl compound 4a in 80% yield instead
of fused bicyclic ketal (Scheme 2).
Scheme 2. Gold(I)-Catalyzed Addition of Water to 3a
We further tested the cascade reaction of epoxy alkyne
1a with methanol in DCE in the presence of 5 mol % of
(Ph3P)AuCl/AgSbF6, but the results were not satisfactory.
Gratifyingly, we discovered that treatment of 1a with 5 mol
% of (Ph3P)AuCl/AgSbF6 and 10 mol % of p-TsOH in 3.0
mL of methanol at room temperature afforded cleanly 2,6-
trans-substituted morpholine 6a in 75% yield with high
diastereoselectivity (see the Supporting Information).
Having demonstrated the efficient reaction between epoxy
alkyne and alcohol, we set out to explore the scope of this
cascade addition (Table 2). The corresponding 2,6-trans-
substituted morpholines 6b-d were obtained in 44-70%
yields by using (PPh3)AuCl/AgSbF6/p-TsOH in ethanol,
prop-2-en-1-ol, or propan-2-ol (Table 2, entries 2-4). Aryl
groups with substituents, including o-NO2, p-Br, were
allowed, and the corresponding morpholines 6e,f (Table 2,
entries 5 and 6) and 6g (Table 2, entry 7) were obtained in
moderate yields without the formation of by products. 1′,2′-
Disubstituted epoxide bearing a phenyl group was compatible
with this transformation, affording the corresponding product
(4) For selected recent reviews on gold-catalyzed reactions, see: (a)
Dyker, G. Angew. Chem., Int. Ed. 2000, 39, 4237. (b) Hashmi, A. S. K.
Gold Bull. 2003, 36, 3. (c) Echavarren, A. M.; Nevado, C. Chem. Soc.
ReV. 2004, 33, 431. (d) Hashmi, A. S. K. Angew. Chem., Int. Ed. 2005, 44,
6990. (e) Arcadi, A.; Di Giuseppe, S. Curr. Org. Chem. 2004, 8, 795. (f)
Hoffmann-Ro¨der, A.; Krause, N. Org. Biomol. Chem. 2005, 3, 387. (g)
Ma, S.; Yu, S.; Gu, Z. Angew. Chem., Int. Ed. 2006, 45, 200. (h) Nicolas,
M.; Steven, P. N. Angew. Chem., Int. Ed. 2007, 46, 2750. (i) Jime´mez-
Nu´n˜ez, E.; Echavarren, A. M. Chem. Commun. 2007, 333. (j) Fu¨rster, A.;
Davies, P. W. Angew. Chem., Int. Ed. 2007, 46, 3410. (k) Gorin, D. J.;
Toste, F. D. Nature 2007, 446, 395.
(5) For selected recent examples, see: (a) Brouwer, C.; He, C. Angew.
Chem., Int. Ed. 2006, 45, 1744. (b) Shi, Z.; He, C. J. Am. Chem. Soc. 2004,
126, 13596. (c) Guan, B.; Xing, D.; Cai, G.; Wan, X.; Yu, N.; Fang, Z.;
Yang, L.; Shi, Z. J. Am. Chem. Soc. 2005, 127, 18004. (d) Han, X.;
Widenhoefer, R. A. Angew. Chem., Int. Ed. 2006, 45, 1747. (e) Ferrer, C.;
Echavarren, A. M. Angew. Chem., Int. Ed. 2006, 45, 1105. (f) Genin, E.;
Toullec, P. Y.; Antoniotti, S.; Brancour, C.; Geneˆt, J.-P.; Michelet, V. J.
Am. Chem. Soc. 2006, 128, 3112. (g) Zhang, L.; Wang, S. J. Am. Chem.
Soc. 2006, 128, 1442. (h) Liu, Y.; Song, F.; Guo, S. J. Am. Chem. Soc.
2006, 128, 11332.
(6) For reviews on the Lewis acid mediated rearrangement of epoxides,
see: (a) Parker, R. E.; Isaacs, N. S. Chem. ReV. 1959, 59, 737. (b) Rickborn,
B. In ComprehensiVe Organic Synthesis, Carbon-Carbon Bond Formation;
Pattenden, G., Ed.; Pergamon: Oxford, 1991; Vol. 3, Chapter 3.3, p 733.
3192
Org. Lett., Vol. 9, No. 16, 2007

the absence of (Ph3P)AuCl/AgSbF6 only resulted in the
formation of oxirane-opened product 7a in 92% yield. Then,
treatment of 7a in prop-2-en-1-ol under these optimized
conditions afforded morpholine 8a in 93% yield (Scheme
3).
Table 2. Scope of Gold- and Acid-Catalyzed Diastereospecific
Addition of Alcohols to Alkynyl Epoxidesa,b
To gain some mechanistic insight into the function of
p-TsOH in this reaction, a control experiment was carried
out. We treated 7a with (Ph3P)AuCl/AgSbF6 in prop-2-en-
1-ol for 4.5 h in the absence of p-TsOH and found that the
reaction proceeded smoothly to give 8a in 76% yield, which
was lower than that of the reaction in the presence of p-TsOH
(Scheme 4). Therefore, according to the results shown in
Scheme 4. Gold-Catalyzed Addition of Prop-2-en-1-ol to 7a
at Room Temperature
Table 2 and Schemes 3 and 4, we believed that p-TsOH was
beneficial to both ring-opening of oxirane and hydroalkoxy-
lation of double bond.7
Additionally, subjecting ketal 6b to the reaction conditions
in prop-2-en-1-ol resulted in ketal exchange to give ketal
8a in 95% yield (Scheme 5).
a Reactions were conducted with 0.30 mmol of substrate catalyzed by 5
mol % of (Ph3P)AuCl/AgSbF6 and 10 mol % of p-TsOH in 3 mL of alcohol
at room temperature for 6-24 h. b All of the yields given in parentheses
are isolated yields. c The reaction was carried out at 45 °C, and 50% of
starting material was recovered.
Scheme 5. Gold and p-TsOH-Catalyzed Ketal Exchange
6h in 72% yield under identical conditions (Table 2, entry
8). The epoxy alkyne with a substituent on the end of alkynyl
group gave 65% yield of morpholine product 6i (Table 2,
entry 9). The structures of 6a-i were assigned by NMR
spectroscopic analysis and by the X-ray diffraction deter-
mination of 6g (see the Supporting Information).
Remarkably, the foregoing experiment showed that the
reaction of 1a with ethanol using 10 mol % of p-TsOH in
Possible reasons for this highly diastereoselective forma-
tion of 2,6-trans-substituted morpholines are shown in
Scheme 6. Taking the reaction of epoxyalkyne 1a with
alcohol as an example, the pivotal intermediate of substituted
2-methylenemorpholine was formed through a three-mem-
bered ring-opening8 and 6-exo-cycloisomerization9 sequence.
If gold(I) was an effective catalyst in this transformation,
Scheme 3. Stepwise Synthesis of 8a from 1a
(7) Belting, V.; Krause, N. Org. Lett. 2006, 8, 4489.
(8) A direct nucleophilc addition of an aryl-Au to epoxide has been
reported by He. In this work, we believe that gold(I) works just as a Lewis
acid to activate epoxides; see: Shi, Z.; He, C. J. Am. Chem. Soc. 2004,
126, 5964.
(9) (a) Hashmi, A. S. K.; Frost, T. M.; Bats, J. W. J. Am. Chem. Soc.
2000, 122, 11553. (b) Hashmi, A. S. K.; Schwarz, L.; Choi, J.-H.; Frost, T.
M. Angew. Chem., Int. Ed. 2000, 39, 2285. (c) Staben, S. T.; Kennedy-
Smith, J. J.; Toste, F. D. Angew. Chem., Int. Ed. 2004, 45, 5350. (d)
Kennedy-Smith, J. J.; Staben, S. T.; Toste, F. D. J. Am. Chem. Soc. 2004,
126, 4526. (e) Gorin, D. J.; Davis, R. N.; Toste, F. D. J. Am. Chem. Soc.
2005, 127, 11260. (f) Corkey, B. K.; Toste, F. D. J. Am. Chem. Soc. 2005,
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Org. Lett., Vol. 9, No. 16, 2007
3193

should be a favorable path in this reaction.12 Based on the
result shown in Scheme 5, the formed 2,6-cis-substituted
morpholine would be transformed to the energetically
favorable 2,6-trans-substituted morpholine through ketal
exchange. Moreover, path II was less favorable because of
the existence of double diaxial interactions.
Scheme 6. Proposed Reasons for Diastereospecific Attacks of
the Double Bond by Various Alcohols
In summary, we have developed a novel access to ketal
skeletons13 that are found in a number of biologically active
natural products through highly regio- and diastereoselective
intermolecular addition of water and alcohols to alkynyl
epoxides catalyzed by gold(I). This procedure involves a
domino three-membered ring-opening, 6-exo-cycloisomer-
ization, and subsequent intra- or intermolecular nucleophilic
addition to a double-bond sequence.14 Additionally, the high
regio- and diastereoselectivities and mildness of these
reaction conditions should make this reaction a valuable tool
for synthesis of 2,6-trans-substituted morpholines.
Acknowledgment. We thank the Shanghai Municipal
Committee of Science and Technology (04JC14083,
06XD14005), Chinese Academy of Sciences (KGCX2-210-
01), and the National Natural Science Foundation of China
for financial support (20472096, 203900502, and 20672127).
the following intermolecular nucleophilic addition of the
double bond10 of 2-methylene morpholine by another mol-
ecule of alcohol was believed to proceed through a chairlike
transition state. The cationic gold complex coordinated to
the double bond from the less steric orientation forming
transition state A (transition state B is disfavored), and the
remaining alcohol attacked the double bond from the opposite
direction to give 2,6-trans-substituted morpholine.11 If p-
TsOH was an effective catalyst,7 the success of this highly
diastereoselective transformation relied on both stereoelec-
tronic and steric control. Considering the half-chair confor-
mation C resulting from protonation of 2-methylenemor-
pholine, energetically favorable perpendicular attack by
alcohol could occur from either of two directions, for
example, path I or path II. Path I attack would lead to chair
conformation D having the new group axial to the ring. Path
II attack would adopt a twist-boat conformation E which
could undergo conformational change to give 2,6-cis-
substituted morpholine. Because the chairlike transition state
had lower energy than the twist-boat alternative, the path I
Supporting Information Available: Spectroscopic data
of all new compounds, detailed descriptions of experimental
procedures, and X-ray data for compounds 2a (CCDC no.
633797) and 6g (CCDC n. 645277). This material is available
free of charge via the Internet at http://pubs.acs.org.
OL0713640
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