Three-component reactions of isochromenylium tetrafluoroborates via non-classical [4+2]-intermediates: Mild one-step metal-free synthesis of functionalized dihydronaphthalenes and tetrahydronaphthalenes

Article abstract of DOI:10.1002/chem.201002317

Two novel types of elegant three-component reactions of stable isochromenylium tetrafluoroborates (ICTBs) have been developed under mild metal-free conditions in this work. Mechanistically, these reactions are commonly initiated by a [4+2]-cycloaddition between the non-classical isochromenylium diene and the aldehyde-enol, and terminated by the following addition of weak nucleophiles, including nitriles or the second equivalent of aldehydes, in a one-pot fashion. The developed methodologies exhibit excellent chemoselectivity, regioselectivity, and diastereoselectivity, and provide a new convenient access to functionalized dihydronaphthalenes and tetrahydronaphthalenes.

Full text of DOI:10.1002/chem.201002317

DOI: 10.1002/chem.201002317
Three-Component Reactions of Isochromenylium Tetrafluoroborates via
Non-Classical [4+2]-Intermediates: Mild One-Step Metal-Free Synthesis of
Functionalized Dihydronaphthalenes and TetrahydroACTHNUTRGENUGnN aphthalenes
Zhi-Long Hu,[a] Zhen-Yu Yang,[a] Shaozhong Wang,[b] and Zhu-Jun Yao*[a, b]
Abstract: Two novel types of elegant
three-component reactions of stable
chromenylium diene and the aldehyde–
enol, and terminated by the following
addition of weak nucleophiles, includ-
ing nitriles or the second equivalent of
aldehydes, in a one-pot fashion. The
developed methodologies exhibit excel-
lent chemoselectivity, regioselectivity,
and diastereoselectivity, and provide a
new convenient access to functional-
ized dihydronaphthalenes and tetrahy-
dronaphthalenes.
isochromenylium
tetrafluoroborates
(ICTBs) have been developed under
mild metal-free conditions in this work.
Mechanistically, these reactions are
commonly initiated by a [4+2]-cyclo-
addition between the non-classical iso-
Keywords: aldehydes · cascade re-
actions · cycloaddition · multicom-
ponent reactions · naphthalenes
Introduction
thetic community.[2] Recently, cascade multicomponent reac-
tions (CMCR) have emerged as powerful and efficient
bond-forming tools that allow the preparation of polycyclic
targets by connecting several components in one pot by effi-
cient sequential chemical reactions.[3] Compared with reac-
tions that use in situ generated metallic isochromenylium in-
termediates with metal catalysts or promoters,[4–12] ICTB-
based reactions have shown many significant differences in
their reaction behavior, products, and mechanisms. Such
unique properties of ICTBs definitely provide us with new
opportunities to discover novel useful chemical transforma-
tions. To further understand the ambiguous mechanisms in-
volving the reactive isochromenylium intermediates, reac-
tions of stable ICTBs with aldehydes (or their enol equiva-
lents) were thus investigated. Several previous studies have
shown that metallic isochromenylium-based reactions can
produce complex multiring frameworks[9a,10a] (Scheme 1a
and b) and naphthalene derivatives[5c–d] (Scheme 1c), but a
number of sensitive functional groups could not be tolerated
under such strong Lewis acid based conditions.[13] However,
up until now, direct reactions of stable ICTBs with electron-
rich compounds, as well as their further conversions, have
not been much explored. As a new type of stabilized reac-
tive agent, ICTBs are potentially useful for future industrial
applications, besides their value in mechanistic studies.
ICTB-based reactions usually do not need any metal cata-
lysts or promoters and can be carried out by direct treat-
ment with reaction partners at ambient temperatures. In this
article, we wish to report two new types of three-component
reactions of ICTBs under mild metal-free conditions
Isochromenylium tetrafluoroborates (ICTBs) are a type of
stabilized reactive intermediate recently developed by our
group,[1] and they can be used as regular reagents in the lab-
oratory. These crystalline materials are considerably stable
under air and moisture conditions, but retain high reactivi-
ties in organic media with various nucleophiles,[1c] olefins,
and electron-rich arenes.[1a–b] Many ICTB-based reactions
produce cascade reactions and can be carried out under
mild conditions without any assistance of metal catalysts
and promoters. These properties of ICTBs also make them
very useful for the development of new multistep transfor-
mations to construct complex frameworks. Rapid synthesis
of complex molecules in a single operation without isolation
of intermediates is one of the current concerns of the syn-
[a] Dr. Z.-L. Hu, Dr. Z.-Y. Yang, Prof. Dr. Z.-J. Yao
State Key Laboratory of Bioorganic and Natural Products Chemistry
EISU Chemical Biology Division, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences
345 Lingling Road, Shanghai 200032 (China)
Fax : (+86)215-492-5123
E-mail: yaoz@sioc.ac.cn
[b] Dr. S. Wang, Prof. Dr. Z.-J. Yao
Nanjing National Laboratory of Microstructures
School of Chemistry and Chemical Engineering
Nanjing University, 22 Hankou Road
Nanjing 210093, Jiangsu (China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201002317.
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Chem. Eur. J. 2011, 17, 1268 – 1274

FULL PAPER
attacks from proper nucleophiles inter- or intramolecularly.
Such inference prompts us to attempt to introduce some
heteroatom-based fucntionalities into the naphthalene skele-
ton. As a result, a variety of functionalized dihydronaphtha-
lene or tetrahydronaphthalene derivatives could be ob-
tained. Unfortunately, the C1 carbon of ICTBs 1 is highly
reactive in solution,[1c] and many regular nucleophiles, such
as free amino- and hydroxyl-containing substrates, are not
amenable to such one-pot cascade transformations. The de-
termination of suitable nucleophiles applicable to these
transformations is thus a crucial challenge in this work. With
our previous knowledge of ICTBs, we started our explora-
tion of novel three-component reactions of ICTBs with ni-
triles, a type of very weakly nucleophilic nitrogen source.
Three-component reactions of ICTBs with aldehydes and ni-
triles: First, the direct treatment of ICTB 1a (1.0 equiv)
with isobutyraldehyde (2d, 1.2 equiv) in dry acetonitrile at
room temperature was employed as the assessment and op-
timization platform. An unusual dihydronaphthalen-acet-
amide 3d was isolated in 37% yield after 48 h in our initial
experiment (Scheme 3). When the amount of aldehyde 2d
Scheme 1. Several representative reactions with an in situ generated [4+
2]-isochromenylium intermediate.
(Scheme 2). These newly developed cascade reactions pro-
vide a new convenient one-step entry to functionalized dihy-
dronaphthalenes and tetrahydronaphthalenes, which are
widely found as core structures in many bioactive natural
products and pharmaceutically important compounds,[14]
with high synthetic efficiency and excellent chemo-, regio-,
and diastereoselectivity.
Scheme 3. Reactions of ICTB 1a with isobutyraldehyde 2d in acetoni-
trile.
was increased to 4.0 equivalents, the yield of product 3d
could be improved up to 84%. The structure of 3d was as-
signed by the use of 1H and 13C NMR spectra and mass
spectrometry, and confirmed by comparison with another
product 3h (the structure of which was determined by X-ray
crystallographic analysis) in our further study (see Table 1
and Figure 1).[15] With these results, we believed that aceto-
nitrile did participate in this reaction as a nucleophile at-
tacking the C1 carbon of intermediate A at the second stage
of the cascade transformations (Scheme 2). Mechanistic
analysis also showed that the enol derived from aldehyde 2d
was the real reactant with the ICTB oxa-diene in the first
step.[5c] This mild one-step three-component procedure is
considerably useful for the introduction of nitrogenous func-
tionality into the dihydronaphthalene skeleton, especially
for compounds that are labile under metallic Lewis acid
based conditions.
Scheme 2. Outline of the three-component reactions in this work.
Results and Discussion
In our previous investigations, the Huckel aromatic pyryli-
um part of ICTBs 1 has shown typical properties as a non-
classical 2-oxonium 1,3-diene.[1a,b] The reactive [4+2]-adduct
(Scheme 2, A) was commonly thought to be generated upon
treatment with various olefins. We believe that the C1
carbon of this intermediate is the equivalent of a masked
carbocation, which should have the capability to receive the
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Z.-J. Yao et al.
Table 1. Reactions of ICTBs 1 with aldehydes 2 in acetonitrile.[a]
possible product resulting from a [4+2]-cycloaddition of 1a
with the non-enol C=C bond was not detected. An explana-
tion is that the enol C=C bond isomerized from aldehyde
2m is more electron-rich than the regular C=C bond, and
the reaction with the enol C=C bond proceeds preferentially
through a reverse-electron-demand Diels–Alder reaction.[17]
As far as we know, this is the first report of incorporating
both an aldehyde and a nitrile into the isochromenylium-in-
termediate-mediated cascade transformation. Therefore, our
findings present a new type of three-component cascade re-
action.
Entry
1
2 (R1, R2)
3
Yield [%][b]
1[c]
2[d]
3
4
5
6
7
8
9
10
11
12[e]
13
14
15[f]
16[e]
17
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1a
1a
1a
2a (H, H)
3a
3b
3c
3d
3e
3 f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
69
79
81
84
83
81
78
80
2b (Me, H)
2c (Et, H)
2d (Me, Me)
Based on our observations, a mechanistic explanation is
proposed in Scheme 4. At first, an endo-[4+2]-cycloaddition
takes place between the isochromenylium oxa-diene 1a and
2e (CH
N
2 f (-(CH2)5-)
2g (AcOCH2CH2, H)
2h (ClCH2CH2, H)
2i (BnOCH2, H)
2j (BnOOCCH2, H)
2k (NO2CH2CH2, H)
2l (Ph, Me)
2m (allyl, H)
2d (Me, Me)
2o (BrCH
2p (allyl, Me)
2q (allyl, allyl)
64
72
71
77 (d.r. 5.4/1)
71
74
76
72 (d.r. 3/1)
75
(CH2)3, H)
[a] A mixture of 1 (0.5 mmol, 1.0 equiv) and 2 (2.0 mmol, 4.0 equiv) in
acetonitrile (10 mL) was stirred for 10 h at 258C. [b] Yields of the isolat-
ed, analytically pure products. [c] 20.0 equiv of 2a was used in a sealed
tube. [d] 10.0 equiv of 2b was used in a sealed tube. [e] The d.r. value
was determined by 1H NMR spectroscopy. [f] Propionitrile was used as
the solvent. Bn=benzyl.
Scheme 4. Proposed mechanisms for the reactions of ICTB 1a with alde-
hydes 2 in acetonitrile.
Figure 1. X-ray crystal structure of 3h.
Encouraged by the above results, a number of other
linear and cyclic aliphatic aldehydes containing halogen,
ether (as alcohol protecting groups), carboxylic acid ester,
or nitro functionalities were then examined (Table 1).
Under the optimized conditions (1.0 equiv of ICTBs 1 and
4.0 equiv of aldehydes 2 in dry acetonitrile at room tempera-
ture), all reactions provided the corresponding 1-acetamido-
1,2-dihydronaphthalenes 3 in satisfying yields. Excellent cis-
1,2-selectivities were observed in the products of this type of
three-component reaction.[16] Reactions of 1a with alde-
hydes 2m, 2p, and 2q (containing a C=C bond) afforded the
single products 3m, 3p, and 3q, respectively, and the other
the cis-enol (according to the cis-configuration of the 1,2-
substituents of products 3) converted from aldehyde 2,
giving a bridged oxonium intermediate, A (Scheme 4a, A).
This bridged [4+2]-adduct is immediately opened by the ni-
trogen of acetonitrile from the smaller steric direction and
converted into a new intermediate, B. At this stage, two
pathways might compete with each other. Through path 1,
an intramolecular nucleophilic addition and cyclization by
the free hydroxyl group to the carbocation of intermediate
B takes place, providing a new bridged intermediate, C.
Final proton elimination followed by bridge-opening afford-
ed the final product 3. The other possible pathway
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Three-Component Reactions of Isochromenylium Tetrafluoroborates
FULL PAPER
(Scheme 4a, path 2) proceeds with dehydration at first to
afford the intermediate, D, the carbocation of which is im-
mediately attacked by water to give the final product 3. To
determine the most likely pathway (path 1 or path 2), a mix-
ture of salt 1a (1.0 equiv), aldehyde 2d (1.0 equiv), and H2O
(1.0 equiv) in acetonitrile was treated for 24 h at room tem-
perature (Scheme 4b). Instead of the previously observed
product 3d, only the hydrolysis product 7 was observed.
With this evidence, we believe that dehydration did not
happen in this type of cascade reaction and that path 1 is
the more plausible route to give the products 3.
When 5.0 equivalents of aldehyde 2d were used, the yield of
product 5a could be improved to 78%, and the byproduct
6a decreased to 9% yield (Table 2). The use of 4.0 equiva-
Table 2. Reaction of ICTB 1a with isobutyraldehyde (2d) and 2-phenyla-
cetonitrile (4a).[a]
The so-formed products 3 could be applied to further syn-
theses. For example, a fused tricyclic compound 9 could be
synthesized from dihydronaphthalene 3o by oxidative aro-
matization and intramolecular nucleophilic substitution (2
steps, 86% yield). Using ring-closing metathesis (RCM) as
the cyclization method, tricyclic compounds 8 and 10 could
be smoothly prepared in good overall yields from dihydro-
naphthalenes 3p and 3m (87% yield in 2 steps; and 81%
yield in 3 steps), respectively (Scheme 5).
Entry
4a [equiv]
Yield of 5a [%][b]
Yield of 6a [%][b]
1
2
3
4
5
1.0
2.0
3.0
4.0
5.0
29
39
58
76
78
44
38
25
11
9
[a] See the Supporting Information for details. [b] Yield of the isolated
product.
lents of nitrile 4a is necessary to reach a satisfactory yield of
product 5a. These results mention that the aldehyde
(through its carbonyl group) could compete with the nitrile
in the nucleophilic opening of bridged oxonium intermedi-
ate A (Scheme 4a) during the reaction. This finding also
prompted us to discover another type of three-component
reaction of ICTBs (see text below and Scheme 6 for the de-
tails).
Scheme 5. Several applications of 1-amino-1,2-dihydronaphthalenes 3;
DDQ=2,3-dichloro-5,6-dicyanobenzoquinone.
In the above reactions, acetonitrile takes part not only as
a reactant, but also as the solvent. To further understand the
stoichiometric relationship of the reactants, reactions with
stoichiometric amounts of nitriles in a non-nucleophilic sol-
vent 1,2-dichloroethane (DCE)[1b] were thus investigated.
The reaction of ICTB 1a (1.0 equiv) with isobutyraldehyde
(2d, 2.0 equiv), and 2-phenylacetonitrile (4a, 1.0 to
5.0 equiv) at room temperature for 24 h afforded the expect-
ed dihydronaphthalene 5a and an O,O-acetal byproduct 6a.
Scheme 6. Proposed mechanism for the reactions of ICTBs 1 with two
equivalents of aldehyde 2d.
The reaction conditions were optimized again during the
examination of substrate scope (Table 3). Mixing ICTB 1a
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Z.-J. Yao et al.
Table 3. Reaction of ICTBs 1 with propionaldehyde 2c or isobutyralde-
hyde 2d and nitriles 4.[a]
Because the cyclic O,O-acetals 6 represent a category of
useful tetrahydronaphthalene-1,3-diol building blocks,[20] op-
timization of this side reaction to a synthetically applicable
methodology was then attempted under nitrile-free condi-
tions. Again, dichloroethane was found to be the most suita-
ble solvent for this type of reaction (Table 4). Increasing the
Table 4. Optimization of the reaction of ICTB 1 with isobutyraldehyde
2d.[a]
Entry
1
4 (R1)
2
5 (%, R2)[b]
6 (%, R2)[b]
Entry
Solvent
1
2d [equiv]
6 [%][b]
1
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
4a (PhCH2)
4b (Ph)
4c (Me)
4d (Et)
4e (PhCH=CH)
4 f (NCCH2)
2d
2c
2d
2d
2d
2d
2d
2d
2d
2d
5a (76, Me)
5b (71, H)
5c (57, Me)
5d (51, Me)
5e (77, Me)
5 f (68, Me)
5g (81, Me)
5h (73, Me)
5i (57, Me)
5j (75, Me)
6a (11, Me)
6a (8, H)
1
2
3
4
5
6
7
THF
1a
1a
1a
1a
1a
1a
1b
2.4
2.4
2.4
2.4
1.2
3.6
2.4
6a (22)
6a (17)
6a (25)
6a (73)
6a (33)
6a (76)
6b (69)
2[c]
3
toluene
CH2Cl2
DCE
DCE
DCE
6a (15, Me)
6a (19, Me)
6a (6, Me)
6a (12, Me)
6a (6, Me)
6a (6, Me)
6a (32, Me)
6b (8, Me)
4
5
6
7
8
9
10
4g (ClACHTUNGTRENNUNG(CH2)3)
DCE
4h (EtO2CCH2)
4i (mNO2C6H4)
4d (Et)
[a] Reactions were stirred in the solvent at 258C for 48 h. [b] Yield of the
isolated product.
[a] A mixture of isochromenylium tetrafluoroborate 1 (1.0 mmol), nitrile
4 (4.0 mmol), and isobutyraldehyde 2d (2.0 mmol) in anhydrous DCE
(20 mL) was stirred at À788C to room temperature for 24 h (See the
Supporting Information for details). [b] Yield of the isolated product.
[c] Propionaldehyde 2c was used.
amount of aldehyde 2d from 2.4 equivalents to 3.6 equiva-
lents did not further improve the yield of the product
(Table 4, entries 4 and 6). Treatment of ICTB 1a (1.0 equiv)
with aldehyde 2d (2.4 equiv) in dry DCE at room tempera-
ture afforded the best results. Under such conditions, reac-
tion of ICTB 1b and isobutyraldehyde 2d also gave a satis-
fying yield of cyclic acetal 6b (Table 4, entry 7). Further
treatment of the representative acetal 6a with trifluoroacetic
acid (TFA) in dichloromethane at room temperature[21] gave
the corresponding 1,3-syn-diol 6a’ in a satisfactory yield
(Scheme 7).
(1.0 equiv), isobutyraldehyde (2d, 2.0 equiv), or propional-
dehyde (2c, 2.0 equiv) and nitriles 4 (4.0 equiv) in DCE at
room temperature afforded the best results. All nitriles 4
could react smoothly with 1 and 2c or 2d, affording 1-
amido-1,2-dihydronaphthalenes 5 predominately. This type
of three-component reaction can tolerate a variety of func-
tional groups, including a double bond (Table 3, entry 5), a
halogen atom (entry 7), an ester (entry 8), and a nitro group
(entry 9). However, our attempt at a double-reaction with
the bis-nitrile 4 f failed. It stopped at the mono-reaction
stage under the above conditions, affording 5 f in 68% yield
(entry 6).
Three-component reactions of ICTBs with two molecules of
aldehydes (enol and aldehyde): As motioned above, the
cyclic O,O-acetals 6 were commonly identified as the minor
byproducts in the reactions carried out in dry DCE
(Table 3). The structure of the representative compound 6a
Scheme 7. Transformation of acetal 6a to 1,3-syn-diol 6a’.
Conclusion
1
was first assigned by the use of H and 13C NMR spectrosco-
py and mass spectrometry, and further confirmed by
2D NMR experiments (1H–1H COSY, NOESY, HMQC,
and HMBC).[19] According to the mechanisms of the above
three-component reactions, byproducts 6 might be generated
from the reaction of one equivalent of ICTB and two equiv-
alents of aldehyde (Scheme 6). After the [4+2]-cycloaddi-
tion between the isochromenylium oxa-diene 1 and the enol
(derived from the first molecule of aldehyde 2d), the C1
carbon of the resulting bridged oxonium intermediate A is
then attacked by the carbonyl oxygen of the second mole-
cule of aldehyde 2d, affording intermediate B. Finally, an in-
tramolecular addition of the exposed hydroxyl to the car-
bonyl equivalent of B gives the 1,3-syn-cyclic O,O-acetal 6.
Two types of novel three-component reaction of stable iso-
chromenylium tetrafluoroborates have been developed in
this work. These mild cascade reactions commonly begin
with a [4+2]-cycloaddition between the non-classic isochro-
menylium diene and the aldehyde–enol and is terminated by
the C1 addition of nitriles or aldehydes. Nitriles and alde-
hyde carbonyls were utilized as the nitrogen, and oxygen
sources in these reactions, respectively. The developed meth-
odology provides a convenient way to introduce new func-
tionality into dihydro- or tetrahydronaphthalene skeletons
in an atom- and step-economical way. Advantages of such
metal-free three-component cascade reactions also include
high diastereoselectivity and ease of operation in the synthe-
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Chem. Eur. J. 2011, 17, 1268 – 1274

Three-Component Reactions of Isochromenylium Tetrafluoroborates
FULL PAPER
turated aqueous NaHCO3 (20 mL) was added. The mixture was extracted
with ethyl acetate (20 mLꢂ3). The combined organic extracts were
washed with brine, dried over anhydrous Na2SO4, and concentrated. The
residue was purified by flash chromatography on silica gel (petroleum
ether/ethyl acetate=4:1) to give pure product 6a. 1H NMR (CD3OD,
500 MHz): d=8.02 (d, J=7.3 Hz, 2H), 7.66 (t, J=7.4 Hz, 1H), 7.56 (t,
J=7.4 Hz, 2H), 6.90 (s, 1H), 6.72 (s, 1H), 5.24 (d, J=5.0 Hz, 1H), 4.51
(d, J=4.3 Hz, 1H), 4.36 (s, 1H), 4.08 (d, J=4.1 Hz, 1H), 3.78 (s, 3H),
3.71 (s, 3H), 1.44–1.47 (m, 1H), 1.30 (s, 3H), 0.80 (s, 3H), 0.74 (d, J=
6.8 Hz, 3H), 0.64 ppm (d, J=6.9 Hz, 3H); 13C NMR (CDCl3, 125 MHz):
d=199.1, 148.2, 147.8, 137.2, 132.6, 128.6 (ꢂ2), 128.0 (ꢂ2), 127.0, 125.6,
113.0, 112.4, 91.7, 77.9, 76.2, 55.5, 55.4, 50.3, 34.3, 31.5, 23.8, 22.1, 16.9,
15.7 ppm; IR (KBr): v˜max =3048, 2253, 1685, 1518, 1272, 1056, 732,
sis of several functionalized dihydro- and tetrahydronaph-
thalene frameworks. In addition, the combinative use of
readily available reactants (aldehydes and nitriles) will allow
the incorporation of high levels of skeletal, functional, and
stereochemical diversity in dihydro- and tetrahydronaphtha-
lene synthesis with principles of diversity-oriented organic
synthesis. Further application of these reactions to natural
or unnatural product synthesis is currently underway in our
laboratories.
699 cmÀ1
;
MS (ESI): m/z: 433 [M+Na+]; HRMS (ESI) calcd for
Experimental Section
C25H30O5Na [M+Na+]: 433.1991; found: 433.1999.
General methods: All reactions were conducted using oven-dried glass-
ware. Acetonitrile, dichloromethane, and 1,2-dichloroethane were dis-
tilled from CaH2, and tetrahydrofuran and toluene were distilled from
Na prior to use. Petroleum ether and ethyl acetate were obtained from
commercial suppliers and used without further distillation. IR spectra
were recorded on an FTIR instrument. 1H NMR spectra were recorded
at 300 or 400 MHz, and 13C NMR spectra were recorded at 100 MHz,
and assigned in parts per million (d). Reference peaks for chloroform in
Acknowledgements
This project is co-supported by MOST (2010CB832200), MOH
(2009ZX09501), NSFC (20672128, 20921091, and 21032002), and
SHMCST (08JC1422800). Y.Z.J. is a principle investigator of the e-Insti-
tute of Shanghai Universities Chemical Biology Division.
1
the H NMR and 13C NMR spectra were set at d=7.27 and 77.0 ppm, re-
spectively. For [D6]DMSO, the reference peaks in the 1H NMR and
13C NMR spectra were set at d=2.50 and 40.0 ppm, respectively. Crystal-
lographic structures were determined on a 1000 diffractometer, MoKa ra-
diation (l=0.71073 ꢁ), at 120 K. Flash column chromatography was per-
formed on silica gel H (10–40 m).
[1] a) Z.-L. Hu, W.-J. Qian, S. Wang, S.-Z. Wang, Z.-J. Yao, Org. Lett.
2009, 11, 4676–4679; b) Z.-L. Hu, W.-J. Qian, S. Wang, S.-Z. Wang,
Z.-J. Yao, J. Org. Chem. 2009, 74, 8787–8793; c) Z.-L. Hu, W.-J.
Qian, Z.-J. Yao, Sci. China Ser. B: Chem. 2010, 53, 869–876; d) W.-
G. Wei, Z.-J. Yao, J. Org. Chem. 2005, 70, 4585–4590; e) Y.-S. Yao,
Z.-J. Yao, J. Org. Chem. 2008, 73, 5221–5225.
[2] a) L. F. Tietze, Chem. Rev. 1996, 96, 115–136; b) D. Enders, C.
Grondal, M. R. Huttl, Angew. Chem. 2007, 119, 1590–1601; Angew.
Chem. Int. Ed. 2007, 46, 1570–1581.
[3] a) A. Dçmling, I. Ugi, Angew. Chem. 2000, 112, 3300–3344; Angew.
Chem. Int. Ed. 2000, 39, 3168–3210; b) L. F. Tietze, T. H. Evers, E.
Topken, Angew. Chem. 2001, 113, 927–929; Angew. Chem. Int. Ed.
2001, 40, 903–905; c) A. Dçmling, Chem. Rev. 2006, 106, 17–89.
[4] a) D. Hojo, K. Noguchi, K. Tanaka, Angew. Chem. 2009, 121, 8273–
8276; Angew. Chem. Int. Ed. 2009, 48, 8129–8132; b) K. Tanaka, Y.
Hagiwara, K. Noguchi, Angew. Chem. 2005, 117, 7426–7429;
Angew. Chem. Int. Ed. 2005, 44, 7260–7263; c) K. Tanaka, Y. Hagi-
wara, M. Hirano, Eur. J. Org. Chem. 2006, 3582–3595; d) K.
Tanaka, Y. Hagiwara, K. Noguchi, Angew. Chem. 2006, 118, 2800–
2803; Angew. Chem. Int. Ed. 2006, 45, 2734–2737.
Synthesis of compound 3d: Isobutyraldehyde 2d (2.0 mmol) was added
to a solution of 1a (0.5 mmol) in dry CH3CN (10 mL) at room tempera-
ture. After the starting material was consumed, saturated aqueous
NaHCO3 (15 mL) was added. The mixture was extracted with ethyl ace-
tate (15 mLꢂ3). The combined organic extracts were washed with brine,
dried over anhydrous Na2SO4 and concentrated. The residue was purified
by flash chromatography on silica gel (petroleum ether/ethyl acetate=
1:2) to give pure product 3d. 1H NMR (CDCl3, 300 MHz): d=7.86 (d,
J=7.2 Hz, 2H), 7.63 (t, J=7.5 Hz, 1H), 7.50 (t, J=7.5 Hz, 2H), 6.92 (s,
1H), 6.88 (s, 1H), 6.05 (s, 1H), 5.77 (d, J=9.6 Hz, 1H), 4.94 (d, J=
9.6 Hz, 1H), 3.91 (s, 3H), 3.78 (s, 3H), 1.97 (s, 3H), 1.20 (s, 3H),
1.19 ppm (s, 3H); 13C NMR (CDCl3, 100 MHz): d=196.9, 169.4, 149.2,
148.3, 143.8, 137.9, 135.4, 133.1, 129.9 (ꢂ2), 128.5 (ꢂ2), 128.3, 122.0,
111.6, 109.4, 56.0, 55.9, 55.2, 36.9, 25.1, 23.4, 23.2 ppm; IR (KBr): v˜max
=
3350, 2964, 1654, 1513, 1269, 1058, 733 cmÀ1
; MS (ESI): m/z: 402
[M+Na+]; HRMS (ESI) calcd for C23H25NO4Na [M+Na+]: 402.1681;
found: 402.1678.
Synthesis of compound 5a:
A solution of isobutyraldehyde 2d
[5] a) N. Asao, K. Takahashi, Y. Yamamoto, J. Am. Chem. Soc. 2002,
124, 12650–12651; b) N. Asao, T. Nogami, S. Lee, Y. Yamamoto, J.
Am. Chem. Soc. 2003, 125, 10921–10925; c) N. Asao, H. Aikawa, Y.
Yamamoto, J. Am. Chem. Soc. 2004, 126, 7458–7459; d) N. Asao, H.
Aikawa, J. Org. Chem. 2006, 71, 5249–5253; e) G. Dyker, D. Hilde-
brandt, J. H. Liu, Angew. Chem. 2003, 115, 4536–4538; Angew.
Chem. Int. Ed. 2003, 42, 4399–4402; f) N. T. Patil, Y. Yamamoto,
Chem. Rev. 2008, 108, 3395–3442; g) A. Arcadi, Chem. Rev. 2008,
108, 3266–3325; h) Z. G. Li, C. Brouwer, C. He, Chem. Rev. 2008,
108, 3239–3265; i) T. N. Jin, Y. Yamamoto, Org. Lett. 2007, 9, 5259–
5262; j) H. C. Shen, Tetrahedron 2008, 64, 7847–7870; k) G. T. Li,
X. G. Huang, L. M. Zhang, Angew. Chem. 2008, 120, 352; Angew.
Chem. Int. Ed. 2008, 47, 346–349; l) N. Kim, Y. Kim, W. Park, D.
Sung, A. K. Gupta, C. H. Oh, Org. Lett. 2005, 7, 5289–5291.
[6] a) N. Asao, T. Kasahara, Y. Yamamoto, Angew. Chem. 2003, 115,
3628–3630; Angew. Chem. Int. Ed. 2003, 42, 3504–3506; b) J. Ez-
querra, C. Pedregal, C. Lamas, J. Org. Chem. 1996, 61, 5804–5812;
c) K. Hiroya, S. Itoh, T. Sakamoto, J. Org. Chem. 2004, 69, 1126–
1136.
(1.0 mmol) and 2-phenylacetonitrile 4a (2.0 mmol) at room temperature
was added to a solution of 1a (0.5 mmol) in dry (CH2Cl)2,725 mL). After
the starting material was consumed, saturated aqueous NaHCO3 (20 mL)
was added. The mixture was extracted with ethyl acetate (20 mLꢂ3). The
combined organic extracts were washed with brine, dried over anhydrous
Na2SO4, and concentrated. The residue was purified by flash chromatog-
raphy on silica gel (petroleum ether/ethyl acetate=3:1) to give pure
product 5a. 1H NMR (CDCl3, 300 MHz): d=7.73 (d, J=4.8 Hz, 2H),
7.58 (t, J=4.5 Hz, 1H), 7.44 (t, J=4.5 Hz, 2H), 7.24–7.34 (m, 5H), 6.92
(s, 1H), 6.76 (s, 1H), 5.96 (s, 1H), 5.75 (d, J=5.7 Hz, 1H), 5.00 (d, J=
6.0 Hz, 1H), 3.82 (s, 3H), 3.71 (s, 3H), 3.61 (d, J=9.6 Hz, 1H), 3.57 (d,
J=9.3 Hz, 1H), 1.13 (s, 3H), 0.99 ppm (s, 3H); 13C NMR (CDCl3,
100 MHz): d=196.5, 170.3, 149.0, 148.1, 143.2, 137.8, 135.3, 134.8, 132.9,
129.7 (ꢂ2), 129.1, 128.9 (ꢂ2), 128.4 (ꢂ2), 128.0, 127.3 (ꢂ2), 122.2, 110.8,
109.5, 55.9, 55.8, 55.3, 43.9, 36.7, 25.2, 22.1 ppm; IR (KBr): v˜max =3300,
2935, 1735, 1653, 1513, 1269, 1058, 734 cmÀ1
; MS (ESI): m/z: 478
[M+Na+]; HRMS (ESI) Calcd for C29H29NO4Na [M+Na+]: 478.1994;
Found: 478.1988.
Synthesis of compound 6a:
(1.2 mmol) in dry (CH2Cl)2 (25 mL) was ,added at room temperature, to
a solution of 1a (0.5 mmol) After the starting material was consumed, sa-
A
solution of isobutyraldehyde 2d
[7] a) N. Asao, T. Nogami, K. Takahashi, Y. Yamamoto, J. Am. Chem.
Soc. 2002, 124, 764–765; b) J. J. Li, G. W. Gribble, Palladium in Het-
erocyclic Chemistry, Pergamon New York, 2000; c) J. Barluenga, H.
Chem. Eur. J. 2011, 17, 1268 – 1274
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1273

Z.-J. Yao et al.
Vꢃzquez-Villa, A. Ballesteros, J. M. Gonzꢃlez, Org. Lett. 2003, 5,
4121–4123.
[15] Crystal sample of 3h for X-ray single crystallographic study was ob-
tained from a mixed solvent of acetonitrile and petroleum ether.
CCDC-802482 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
[8] a) A. B. Beeler, S. Su, C. A. Singleton, J. A. Porco, Jr., J. Am. Chem.
Soc. 2007, 129, 1413–1419; b) P. Pale, J. Chuche, Eur. J. Org. Chem.
2000, 1019–1025; c) N. T. Patil, N. K. Pahadi, Y. Yamamoto, J. Org.
Chem. 1998, 63, 4564–4565; d) S. Kotha, S. Misra, S. Halder, Tetra-
hedron 2008, 64, 10775–10790.
[9] a) Y. C. Hsu, C. M. Ting, R. S. Liu, J. Am. Chem. Soc. 2009, 131,
2090–2091; b) J.-M. Tang, T.-A. Liu, R.-S. Liu, J. Org. Chem. 2008,
73, 8479–8483.
[10] C. H. Oh, J. H. Lee, S. J. Lee, J. I. Kim, C. S. Hong, Angew. Chem.
2008, 120, 7615–7617; Angew. Chem. Int. Ed. 2008, 47, 7505–7507.
[11] a) D. Fischer, H. Tomeba, N. K. Pahadi, N. T. Patil, Z. B. Huo, Y.
Yamamoto, J. Am. Chem. Soc. 2008, 130, 15720–15725.
[12] N. Isono, M. Lautens, Org. Lett. 2009, 11, 1329–1331.
[13] a) W. D. Wulff, T. S. Powers, J. Org. Chem. 1993, 58, 2381–2393;
b) W. R. Roush, S. E. Hall, J. Am. Chem. Soc. 1981, 103, 5200–5202;
c) D. A. Evans, K. T. Chapman, J. Bisaha, J. Am. Chem. Soc. 1988,
110, 1238–1240.
[16] Diastereomers were not observed by 1H NMR spectroscopy meth-
ods.
[17] a) N. Asao, K. Sato, Y. Yamamoto, J. Org. Chem. 2005, 70, 3682–
3685; b) Y. Yamamoto, J. Org. Chem. 2007, 72, 7817–7831; c) S.
Yamabe, T. Dai, T. Minato, J. Am. Chem. Soc. 1995, 117, 10994–
10997.
[18] The selectivity was determined by 1H NMR spectroscopic analysis.
[19] See the Supporting Information.
[20] K. Chen, J. M. Richter, P. S. Baran, J. Am. Chem. Soc. 2008, 130,
7247–7249.
[21] A. M. Riley, M. F. Mahon, B. V. L. Potter, Angew. Chem. 1997, 109,
1583–1585; Angew. Chem. Int. Ed. Engl. 1997, 36, 1472–1474.
[14] D. F. P. Leite, C. A. L. Kassuya, T. L. Mazzuco, A. Silvestre, V. M.
Rumjanek, J. B. Calixto, Planta Med. 2006, 72, 1353–1358.
Received: August 13, 2010
Published online: December 8, 2010
1274
www.chemeurj.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 1268 – 1274