Formal intermolecular [2 + 2] cycloaddition reaction of alleneamides with alkenes via gold catalysis

Article abstract of DOI:10.1021/ol202703a

An efficient method was developed to construct the densely functionalized cyclobuane adducts through formal intermolecular cycloaddition of alleneamides with electron-rich olefins via gold catalysis, in which vinyl ethers/amides and electron-rich styrenes

Full text of DOI:10.1021/ol202703a

ORGANIC
LETTERS
2012
Vol. 14, No. 2
436–439
Formal Intermolecular [2 þ 2]
Cycloaddition Reaction of Alleneamides
with Alkenes via Gold Catalysis
Xiao-Xiao Li,† Li-Li Zhu,† Wen Zhou,† and Zili Chen*,†,‡
Department of Chemistry, Renmin University of China, Beijing 100872, China, and
Laboratory of Molecular Sciences, CAS Key Laboratory of Molecular Recognition and
Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China
zilichen@ruc.edu.cn
Received October 10, 2011
ABSTRACT
An efficient method was developed to construct the densely functionalized cyclobuane adducts through formal intermolecular cycloaddition of
alleneamides with electron-rich olefins via gold catalysis, in which vinyl ethers/amides and electron-rich styrenes worked very well. In addition, a
series of alleneamide dimerization products were prepared from the same alleneamide substrates.
[2 þ 2] Cycloaddition presentsa straightforward method
for the synthesis of cyclobutanes and their derivatives.
However, thermal [2 þ 2] cycloaddition of two double
bonds is limited to some special substrates.1 On the other
hand, photochemical [2 þ 2] transformation is usually only
efficient in an intramolecular domain.2,3 Considering the
importance of this cyclobutane skeleton in natural prod-
ucts4 and in organic synthesis,5 exploring metal, especially
transition metal, catalyzed intra- or intermolecular [2 þ 2]
cycloaddition reactions would be of significant synthetic
utility.6
† Renmin University of China.
‡ Chinese Academy of Sciences.
(4) Dembitsky, V. M. J. Nat. Med. 2008, 62, 1.
(1) Some recent examples: (a) Feltenberger, J. B.; Hayashi, R.; Tang,
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Ogasawara, M.; Okada, A.; Nakajima, K.; Takahashi, T. Org. Lett.
2009, 11, 177. (c) Canales, E.; Corey, E. J. J. Am. Chem. Soc. 2007, 129,
12686. (d) Hiroaki Ohno, H.; Mizutani, T.; Kadoh, Y.; Aso, A.; Kumiko
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r
10.1021/ol202703a
Published on Web 12/27/2011
2011 American Chemical Society

Scheme 1. Gold Complexed Allene
Scheme 2. Allene Screening for Gold Catalyzed [2 þ 2] Cy-
cloaddition Reaction
Gold salts have recently been demonstrated to be excep-
tional reagents for the activation of CꢀC multiple bonds.7
As shown in Scheme 1, the reactivity of goldꢀallene
complexes I closely resembled that of the AuꢀC bond
functionalized allylic cation II (Scheme 1), which thereby
led to the realization of the gold catalyzed intramolecular
cycloaddition of the allenes with alkenes or dialkenes, to
give various [2 þ 2],8 [2 þ 3],9 [4 þ 2],10 and [4 þ 3]10b,11
cycloadducts.12 However, extending this strategy to an
intermolecular process remains less explored.13 We herein
will report the gold catalyzed intermolecular [2 þ 2] cycload-
dition of allene sulfonamides with electron-rich olefins, to
provide an efficient new approach to the multifunctional
cyclobutane derivatives. In addition, we also prepared a series
of allene sulfonamide dimerization products.
Inspired by the gold catalyzed intermolecular reactions
of allenes with amines,14 alcohols,15 and electron-rich aryl
groups,16 we reasoned that the enhanced olefin nucleophil-
icity might facilitate the suggested intermolecular [2 þ 2]
process. Electron-rich vinyl ether a was thus employed for
the initial investigation. At first, several allenes with dif-
ferent functionalities were investigated (Scheme 2, eq 1).
No reaction was found for alkyl allene 1, probably due to
its low reactivity. Alleneamides 2, 3, and 4 were tested.
Figure 1. X-ray chromatograph of compound 5a.
2 and 3 gave no reactions, while 2-oxazolidinone allene-
amide 4 afforded an inseparable mixture.16 Recognizing
that amide groups might coordinate and deactivate the
gold catalyst, alleneamide 5, which contains a low Lewis
basic sulfonamide group, was then explored.17 To our
delight, the reaction of 5 with vinyl ether a gave vinyl
cyclobutane 5a in 10% yield, and dimerization product
D-5 in 35% yield. The structure of5a, as shown in Figure 1,
was identified to be a vinylamide containing 2-oxabicyclo-
[4.2.0]octane by its X-ray chromatograph, in which vinyl-
amine oriented toward the oxygen atom selectively.18
Next, reactionoptimizations wereperformedtoimprove
(8) (a) Oh, C. H.; Kim, A. Synlett 2008, 777. (b) Luzung, M. R.;
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Mauleon, P.; Toste, F. D. J. Am. Chem. Soc. 2007, 129, 12402. (c)
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Bruneau, C. Angew. Chem., Int. Ed. 2005, 44, 2328. (g) Echavarren,
A. M.; Nevado, C. Chem. Soc. Rev. 2004, 33, 431.
(9) (a) Zhang, G.-Z.; Catalano, V. J.; Zhang, L.-M. J. Am. Chem.
Soc. 2007, 129, 11358. (b) Huang, X.; Zhang, L.-M. J. Am. Chem. Soc.
2007, 129, 6398.
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(10) (a) Mauleon, P.; Zeldin, R. M.; Gonzalez, A. Z.; Toste, F. D.
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J. Am. Chem. Soc. 2009, 131, 6348. (b) Alonso, I.; Trillo, B.; Lopez, F.;
Montserrat, S.; Ujaque, G.; Castedo, L.; Lledos, A.; Mascarenas, J. L.
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~
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J. Am. Chem. Soc. 2009, 131, 13020. (c) Gonzalez, A. Z.; Toste, F. D.
Org. Lett. 2010, 12, 200.
˚
ꢀ
~
(11) (a) Trillo, B.; Lopez, F.; Gulias, M.; Castedo, L.; Mascarenas,
ꢀ
5a’s yield. Addition of 4 A molecular sieve to remove the
residual moisture and lowering the reaction temperature
enhanced 5a’s yield (Table 1, entry 2, 80%).
J. L. Angew. Chem., Int. Ed. 2008, 47, 951. (b) Trillo, B.; Lopez, F.;
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Montserrat, S.; Ujaque, G.; Castedo, L.; Lledos, A.; Mascarenas, J. L.
~
Chem.;Eur. J. 2009, 15, 3336.
(12) Reviewfor[2þ 2] cycloaddition of allene: Alcaide, B.; Almendros, P.;
Aragoncillo, C. Chem. Soc. Rev. 2010, 39, 783.
In silver salt screening experiments, Ph3PAuCl/AgSbF6
performed better than other silver combinations (Table 1,
(13) An example of intermolecular [2 þ 2] cycloaddition of alkynes
ꢀ
with alkenes: Lopez-Carrillo, V.; Echavarren, A. M. J. Am. Chem. Soc.
2010, 132, 9292.
(17) Examples of the effect of sulfonamide’s Lewis basicity on the
reaction outcomes. (a) Schlummer, B.; Hartwig, J. F. Org. Lett. 2002, 4,
1471. (b) Rousseaux, S.; Gorelsky, S. I.; Chung, B. K. W.; Fagnou, K.
J. Am. Chem. Soc. 2010, 132, 10692. Hydrogen-bond basicity scale for
sulfonyl bases:(c) Chardin, A.; Laurence, C.; Berthelot, M.; Morrisb,
D. G. J. Chem. Soc., Perkin Trans. 2 1996, 1047.
(18) CCDC 838102 contains the supplementary crystallographic
data for compound 5a; CCDC 838101 contains the supplementary
crystallographic data for compound D-5. These data can be obtained
free of charge from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.Uk/ data_request/cif.
(14) (a) Kinder, R. E.; Zhang, Z.-B.; Widenhoefer, R. A. Org. Lett.
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Org. Lett., Vol. 14, No. 2, 2012
437

medium (Table 1, entries 14ꢀ16). In the control experiments,
employing JohnphosAuCl and AgSbF6 separately gave no
desired products (Table 1, entries 17ꢀ18). When 5was treated
with 2 mol % of Ph3PAuCl/AgSbF6 as a sole reactant,
dimerization product D-5 was obtained in 90% yield.
Table 1. Condition Optimization for the Reaction of 5 with aa
Scheme 4. Unsuccessful Substrates for [2 þ 2] Cycloaddition
soln/temp (°C)
yieldb
catalyst (%)
/time (h)
5a/D-5 (%)
1c
2
Ph3PAuCl/AgSbF6 (5)
Ph3PAuCl/AgSbF6 (5)
Ph3PAuCl/AgBF4 (5)
Ph3PAuCl/AgOTf (5)
Ph3PAuCl/AgPF6 (5)
Ph3PAuCl/AgNTf2 (5)
IprAuCl/AgSbF6 (5)
DCM/rt/2
10/35
80/6
45/10
27/5
55/trace
70/15
71/0
70/0
NR
DCM/ꢀ10/2
DCM/ꢀ10/2
DCM/ꢀ10/2
DCM/ꢀ10/2
DCM/ꢀ10/2
DCM/ꢀ10/2
DCM/ꢀ10/2
DCM/ꢀ10/2
DCM/ꢀ10/2
DCM/25/2
3
4
5
We then turned to investigating the substrate scope. A
series of alleneamides with different substitution patterns
were tested. Butyl substituted alleneamide 6 gave 6a in
moderate yield, while its benzyl and phenyl analogs 7 and 8
afforded the desired products in relatively low yields
(Scheme 3).19 When trimethyl phenyl alleneamide 9 was
used as the reactant, cyclobutane adduct 9a was obtained
in 85% yield. Under the optimized conditions, 2-oxazoli-
dinone alleneamide 4 was also tested, which provided 4a in
82% yield. Similarly, 2,3-dihydrobenzo[d]isothiazole 1,
1-dioxide substituted cyclobutane product 10a was ob-
tained in 71% yield (Scheme 3). However, the reactions of
vinyl ether a with alleneamides 11 and 12 gave no desired
products even at a high temperature, possibly owing to the
improved steric hindrance (Scheme 4).
6
7
8
SIPrAuCl/AgSbF6 (5)
(PhO)3PAuCl/AgSbF6 (5)
JohnphosAuCl/AgSbF6 (5)
JohnphosAuCl/AgSbF6 (5)
JohnphosAuCl/AgSbF6 (2)
JohnphosAuCl/AgSbF6 (2)
JohnphosAuCl/AgSbF6 (2)
JohnphosAuCl/AgSbF6 (2)
JohnphosAuCl/AgSbF6 (2)
JohnphosAuCl (2)
9
10
11
12
13d
14
15
16
17
18
19e
85/0
87/0
86/0
81/0
75/0
66/0
NR
DCM/25/12
DCM/25/12
DCE/25/2
Toluene/25/24
THF/60/12
DCM/25/2
NR
AgSbF6 (2)
DCM/25/2
NR
Ph3PAuCl/AgSbF6 (2)
DCM/25/3
0/90
a Unless noted, all reactions were carried out at 0.1 mmol scale in
˚
2 mL of solvent with the addition of 5 mol % catalyst and 100 mg of 4 A
MS (5/a = 1/3). b Isolated yields. c No 4 A MS was added. d 2 equiv of
˚
compound a were added. e No compound a was added.
Table 2. [2 þ 2] Cycloaddition of Alleneamide 5 with Different
Alkenesa,b
entries 3ꢀ6). The catalyst’s ligands were then evaluated.
IprAuCl and SIPrAuCl showed moderate activities, while
(PhO)3PAuCl was totally inactive (Table 1, entries 7ꢀ9).
When JohnphosAuCl was utilized, 5a’s yield was im-
proved to 87%, even at an elevated temperature (Table 1,
entries 10ꢀ11). 2 mol % of JohnphosAuCl also gave 5a in
86% yield in 12 h (Table 1, entry 12). Addition of 2 equiv of
vinyl ether a led to a slight yield loss (Table 1, entry 13).
Solvent optimization proved DCM to be the best reaction
Scheme 3. [2 þ 2] Cycloaddition Reaction of Alleneamides with
Vinyl Ether aa,b
a Unless noted, all reactions were carried out at 0.1 mmol scale in
˚
a Unless noted, all reactions were carried out at 0.1 mmol scale in
2 mL of solvent with the addition of 5 mol % catalyst and 100 mg of 4 A
MS (5/N = 1/3). b Isolated yields. c The ratio was determined by 1H
NMR data.
˚
2 mL of solvent with the addition of 2 mol % catalyst and 100 mg of 4 A
MS (x/a = 1/3). bIsolated yields.
438
Org. Lett., Vol. 14, No. 2, 2012

Many other mono- and disubstituted olefins were also
examined. As shown in Table 2, cyclic vinyl ethers worked
very well. 2,3-Dihydrofuran c gave 5c in 89% yield, while
2-methoxy-3,4-dihydro-2H-pyran e afforded 5e in 79%
yield (Table 2, entries 3, 5). Two cyclic vinyl amines were
explored, which afforded 5b and 5d in good yields (Table 2,
entries 2, 4). We then investigated the linear vinyl ether’s
reactions. The reactions of 5 with ethoxy ethene f and
butoxy ethene g occurred, giving 5f and 5g in 73% and
80% yields (Table 2, entries 6ꢀ7). The reaction of 1,1-
disubstituted vinyl ether h gave 5h in 69% yield, while 1,2-
disubstituted ether i afforded 5i in 84% yield (Table 2,
entries 8ꢀ9). Although alkyl olefins and electron-poor
styrenes did not work in this transformation, styrenes
bearing electron-donating groups, such as ethoxy, methyl,
tert-butyl, etc., can be employed in this reaction and gave
the desired products in moderate to good yields (Table 2,
entries 10ꢀ12). Disubstituted (E)-1-(p-methoxyphenyl)-
1-propene E-n was then tested, which provided polyfunc-
tional cyclobutane derivative trans-5n in good yield
(Table 2, entry 13). However, the reaction of Z-n gave no
desired product (Scheme 4). To determine the Z-olefin’s
stereochemistry, deuterated substrateo was investigated. It
was found that deuterium ratio Ha/Hb in 5owaslower than
that in substrate o (Table 2, entry 14).
Scheme 6. A Plausible Mechanism for Gold Catalyzed [2 þ 2]
Cycloaddition Reaction and the Dimerization Reaction of
Alleneamides
alleneamide 5 generated intermediate A.20 Trapping A with
vinyl ether a afforded intermediate B (step I), which under-
went intramolecular cyclization through nucleophilic addi-
tion of vinylamine onto the ketonium carbon (step II), giving
cyclobutane iminium intermediate C. Deauration via elim-
ination then provided formal [2 þ 2] cycloaddition product
5a and regenerated the cationic gold catalyst. Isomerization
occurred in the reaction of a Z-styrene substrate (Table 2,
entry 14). In intermediate B and C, The steric hindrance
between the sulfonamide group and the gold catalyst deter-
mined the configuration of the formed vinylamine in 5.
Similarly, in the absence of olefin reactants, trapping A with
the second alleneamide molecule 5, followed by intramolec-
ular cyclization and deauration, would provide dimeriza-
tion product D-5 and regenerate the gold catalyst.
Scheme 5. Gold Catalyzed Dimerization of Alleneamidesa,b
In summary, we have developed an efficient method to
construct the densely functionalized cyclobuane adducts
through the formal intermolecular cycloaddition reactions
of alleneamides with electron-rich olefins via gold catal-
ysis. Vinyl ether, amine, and electron-rich styrenes reacted
smoothly with alleneamides at rt. Importantly, a series of
allene amide dimerization products were also prepared
from these alleneamide substrates in the absence of al-
kenes. Efforts to extend this reaction and broaden its
application are still underway in this laboratory.
a Unless noted, all reactions were carried out at 0.1 mmol scale in
˚
2 mL solvent with the addition of 5 mol % catalyst and 100 mg 4 A MS.
bIsolated yields.
Using these alleneamide substrates, a series of dimeriza-
tion products were also prepared. As shown in Scheme 5,
butyl and benzyl substituted alleneamide 6 and 7 gave D-6
and D-7 in moderate yields, while phenyl analog8 afforded
D-8 in low yield. Steric 2-naphthalene methyl alleneamide
9 provided cyclobutane adduct D-9 in 71% yield. 2-
Oxazolidinone alleneamide 4 was also tested, which gave
D-4in 56% yield. Similarly, 2,3-dihydrobenzo[d]isothiazole 1,
1-dioxide substituted alleneamide 10 provided D-10 in 73%
yield (Scheme 5).
Acknowledgment. Support of this work by the grant
from National Sciences Foundation of China (Nos.
20872176 and 21072224), by the Fundamental Research
Funds for the Central Universities, and by the Research
Funds of Renmin University of China (11XNI003) is
gratefully acknowledged.
Supporting Information Available. Experimental pro-
cedures and data for all new compounds. This material
is available free of charge via the Internet at http://pubs.
acs.org.
A plausible mechanism was then proposed. As shown in
Scheme 6, Complexation of the cationic gold catalyst with
(20) Two types of complexation have been suggested, in which
coordination of the gold catalyst to the double bond of the vinylamide
was presumed to be favorable. See ref 16.
(19) The low 7 and 8 yields were due to their FriedelꢀCrafts type
intramolecular cyclization reaction.
Org. Lett., Vol. 14, No. 2, 2012
439