Facile synthesis of highly functionalized six-membered heterocycles via PPh3-catalyzed [4+2] annulations of activated terminal alkynes and hetero-dienes: Scope, mechanism, and application

Article abstract of DOI:10.1016/j.tet.2010.07.043

A novel [4+2] annulation between activated terminal alkynes and aza-dienes or oxo-dienes has been developed with the use of triphenylphosphine catalyst (20 mol %), which provides a facile method for synthesis of the corresponding highly functionalized dih

Full text of DOI:10.1016/j.tet.2010.07.043

Tetrahedron 66 (2010) 8095e8100
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Facile synthesis of highly functionalized six-membered heterocycles via
PPh3-catalyzed [4þ2] annulations of activated terminal alkynes
and hetero-dienes: scope, mechanism, and application
*
Qiongmei Zhang, Tong Fang, Xiaofeng Tong
Key Laboratory for Advanced Materials and Institute of Fine Chemicals, East China University of Science and Technology, Shanghai 200237, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 June 2010
Received in revised form 13 July 2010
Accepted 16 July 2010
Available online 6 August 2010
A novel [4þ2] annulation between activated terminal alkynes and aza-dienes or oxo-dienes has been
developed with the use of triphenylphosphine catalyst (20 mol %), which provides a facile method for
synthesis of the corresponding highly functionalized dihydropyridines or dihydropyrans in good to ex-
cellent yields. The reaction mechanism has also been established, consisting formal hetero-DielseAlder
reaction catalyzed by PPh3 and [1,3]-proton transfer, which exhibits a large isotopic effect.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
PPh3 Catalysis
Hetero-diene
[4þ2] Annulations
Heterocycle
H-Transfer
1. Introduction
became interested in extending this reactionprotocol to oxo-dienes 4.
Compounds4 are believed to bepossessedsimilarelectrophilicityand
Heterocycles form, by far, the largest of the classical divisions of
organic chemistry.1 Among heterocyclic compounds, hydro-
pyridines present ubiquitous structural motifs, which are fre-
quently found in natural products and in compounds of interest for
the pharmaceutical, agrochemical, and other chemical industries.2
As another type of six-membered heterocycles, hydropyrans are
also important core units within a multitude of biologically active
natural products.3 Although diverse synthetic approaches toward
hydropyridines and hydropyrans have been developed, versatile,
and flexible methodologies to construct these heterocycles with
selective control of substitution patterns using readily accessible
building blocks are still of pressing interest.
reactivity as those of aza-dienes 1. Thus we envisioned that similar
oxo-DielseAlder reaction of oxo-dienes 4 would also be promoted by
phosphine catalyst, and highly functionalized dihydropyrans [5]
would be produced consequently (part B, Scheme 1). This reaction
represents, to our knowledge, a novel reaction mode for phosphine
catalysis, although nucleophilic phosphine catalysis has been widely
developed for cycloaddition chemistry, which regio- and stereo-
selectively generates carbo- and heterocyclic motifs.6 In this Article,
we report the formal triphenylphosphine-catalyzed hetero-Dielse
Alder reactions7 between hetero-dienes and activated terminal
alkynes, as well as experiments for clarifying the mechanism of these
novel [4þ2] annulations.
Recently we have reported the phosphine-catalyzed [4þ2] annu-
lations between aza-dienes 1 and 1-phenylprop-2-yn-1-one 2b,
which provide
a
facile entry to highly functionalized 1,
2. Results and discussions
2-dihydropyridines 3 (part A, Scheme 1).4 Further investigations also
disclosed that 1,4-dihydropyridine [3] was a crucial intermediate for
this transformation, which could be recognized as the formal aza-
DielseAlder adduct from aza-dienes 1 and alkynes 2. As a continua-
tion of the study on the phosphine-catalyzed cycloadditions,5 we
NTs
O
OMe
NTs
20 mol% PPh3
PhMe, 80 oC
+
Ph
(1)
Ph
CO2Me
1aa
6a
2a (1.2 equiv.)
* Corresponding author. E-mail address: tongxf@ecust.edu.cn (X. Tong).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.07.043

8096
Q. Zhang et al. / Tetrahedron 66 (2010) 8095e8100
Part A: PPh3-catalyzed [4+2] annulations with aza-dienes as 4-atom unit
O
O
O
Ph
MeO2C
Ar
MeO2C
Ar
MeO2C
Ar
20 mol% PPh3
PhMe, reflux
H-Shift
Ph
Ph
+
NTs
N
N
Ts
[3]
Ts
3
1
2b
Part B: PPh3-catalyzed [4+2] annulations with oxo-dienes as 4-atom unit
R1
R1
O
O
Ph
E
20 mol% PPh3
E
E = Electron-withdrawing Groups
+
Ph
?
R2
O
R2
O
[5]
4
2b
Scheme 1. Design plan for PPh3-catalyzed synthesis of dihydropyridines and dihydropyrans.
Very recently, we have discovered that aza-diene 1aa can be
Contrarily, compound 1ba would become favorable, accompa-
nied by 7ba (21% vs 14%) when the amount of 2b was reduced to be
1.0 equiv (Eq. 3, Scheme 2). When 3 equiv of 2b were used, com-
pound 7ba was found out to be the only product and 1ba was not
detected at all (Eq. 4, Scheme 2). These results strongly indicated
that 1ba probably worked as the intermediate for the formation of
7ba. In fact, 1ba smoothly reacted with 2b (1.2 equiv) in the pres-
ence of PPh3 (20 mol %) to afford 7ba in 81% yield although higher
reaction temperature was required (Eq. 5), which led us to discover
a novel phosphine-catalyzed [4þ2] annulations10 between aza-di-
enes 1ba and alkynes 2b.
readily obtained from methyl propiolate 2a (1.2 equiv) and imine
6a with 20 mol % PPh3 as catalyst (Eq. 1).8
Surprisingly, when 1-phenylprop-2-yn-1-one 2b rather than 2a
was used as the substrate, one unexpected compound 7ba was
obtained as major product with 53% isolated yield, while the cor-
responding aza-diene 1ba was isolated only in 36% yield (Eq. 2,
Scheme 2). The solid state structure of 7ba was further determined
by a single crystal X-ray diffraction analysis.9 Single crystals of
complex 7ba were obtained from CH2Cl2/petroleum ether at room
temperature. An ORTEP type view of 7ba is shown in Figure 1.
O
O
O
O
NTs
NTs
O
Ph
O
Ph
NTs
Ph
+
Ph
Ph
Ph
(5)
20 mol% PPh3
PhMe
20 mol% PPh3
+
+
Ph
Ph
PhMe, reflux
81%
Ph
N
Ph
N
Ph
COPh
1ba
COPh
1ba
Ts
7ba
Ts
7ba
6a (1 equiv.)
2b
2b
2 equiv. , 80 oC: 36%
53%
2b
(2)
(3)
1 equiv. , 80 oC: 21%
14%
75%
2b
2.1. [4D2] Annulations between aza-dienes and alkynes
2b
3 equiv. , reflux: <5%
(4)
Scheme 2. The relationship between 1ba and 7ba.
With these preliminary results in hand, we next examined the
generality of the phosphine-catalyzed [4þ2] annulations of aza-
dienes and alkynes and the results are presented in Table 1. This
Figure 1. X-ray crystallography of 7ba. Ellipsoids at 30% probability.

Q. Zhang et al. / Tetrahedron 66 (2010) 8095e8100
8097
transformation strongly depended on the activated group of ter-
minal alkyne. When methyl propiolate 2a was employed as two-
atom unit, no reaction occurred at all (entry 1, Table 1). Alkyl ketone
2e resulted in complicated reactions with some unidentified
products (entry 9, Table 1). However, aryl ketones 2bed readily
underwent [4þ2] annulations with a variety of aza-dienes to pro-
vide the corresponding 1,2-dihydropyridines 3 in good to excellent
yields (entries 2e8, Table 1). The substituents on the phenyl ring
seem to take some effects on the reaction performance although we
don’t have convincing explanations for these observations at this
stage.
Reconsidering the results presented in Scheme 2, it is easy to
identify that formal [2þ2þ2] annulation can be achieved between
2b and imine 6 when large excess of 2b (3 equiv) is used. Further
investigations of these novel [2þ2þ2] annulations were also un-
dertaken under similar conditions. It was a pleasure to disclose that
the [2þ2þ2] annulations proceeded smoothly with a range of
substrates and 1,2-dihydropyridines 7 could also be easily obtained
in good to excellent yields. The details are presented in Table 2.
Table 2
PPh3-catalyzed [2þ2þ2] annulations of alkyne 2b and imines 6a
O
O
O
Ph
+
NTs 20 mol% PPh3
Ph
Ph
Table 1
PPh3-catalyzed [4þ2] annulations of alkynes and aza-dienesa
PhMe, reflux
Ar
N
Ar
O
Ts
7
CO2R1
R
O
CO2R1
Ar
2b
6
20 mol% PPh3
PhMe, reflux
R
+
Entry
6 (Ar)
7
Yieldb (%)
TsN
Ar
N
1
2
3
4
5
6a (Ph)
7ba
7bb
7bc
7bd
7be
75
90
85
67
59
Ts
3
6b (4-MeO/C6H4)
6c (4-Br/C6H4)
6d (4-Cl/C6H4)
6e (4-Me/C6H4)
2a-e
1
Entry
2 (R)
1 (R1, Ar)
3/Yieldb (%)
1
2
3
4
5
6
7
8
9c
2a (OMe)
2b (Ph)
2b
1aa (Me, Ph)
1aa
1ab (Me, 4-MeO/C6H4)
1ac (Me, 4-Br/C6H4)
1ab
1ac
1ac
3aa (ND)d
3ba (59)
3bb (96)
3bc (86)
3cb (59)
3dc (60)
3cc (50)
3bf (63)
3ea (d)
a
Reaction conditions: the solution of 2b (1.5 mmol) in toluene (10 mL) was
slowly added to the mixture of 6 (0.5 mmol) and PPh3 (0.1 mmol) in toluene (10 mL)
at 120 ꢀC.
2b
b
Isolated yield.
2c (4-MeO/C6H4)
2d (4-Me/C6H4)
2c
2b
2.2. [4D2] Annulations between oxo-dienes and alkynes
1fb (Bn, 4-MeO/C6H4)
1aa
2e (n-C5H11
)
Upon the success of PPh3-catalyzed [4þ2] annulations of aza-
dienes 1 and 1-phenylprop-2-yn-1-one 2b, we would like to extend
this reaction protocol to oxo-dienes 4 (Eq. 6, Table 3). This extension
is conducted on the basis of the considerations that oxo-dienes 4
possess similar electrophilicity as that of aza-dienes 1 and might
perform similar reactivity toward 1-phenylprop-2-yn-1-one 2b in
the presence of PPh3 catalyst.
a
Reaction conditions: the solution of 2 (0.6 mmol) in toluene (6 mL) was slowly
added to the mixture of 1 (0.3 mmol) and PPh3 (0.06 mmol) in toluene (6 mL) at
120 ꢀC.
b
Isolated yield.
With unidentified products.
ND¼not detected.
c
d
In view of the conditions of Eq. 1 and Table 1, we found that
these two reactions shared almost common conditions except the
reaction temperature. This observation inspired us to explore the
possibility of preparing compounds 3 in one-pot strategy with first
step serving for the formation of aza-dienes 1 in situ and second
step for [4þ2] annulations with external 2b (Scheme 3). One-pot
tandem reactions are important for the efficient construction of
complex chemical structures and therefore are an active research
area in the synthetic community.11 Fortunately, this one-pot strat-
egy could be smoothly achieved through direct addition of com-
pounds 2b to the reaction systems, in which the compounds 1 were
thought to be firstly formed catalyzed by 20 mol % PPh3 with both
of 6b and propiolates as starting materials at 80 ꢀC. And the cor-
responding [2þ2þ2] annulation products 3bb and 3bf were
obtained in the yield of 58% and 53%, respectively. Obviously, these
numbers were some lower compared to the yields of the corre-
sponding products in Table 1. Furthermore, for better performance
of the one-pot strategy, both additional 20 mol % amount of PPh3
and elevated temperature (reflux) were required for the second
step (Scheme 3).
Table 3
Optimized conditions for PPh3-catalyzed [4þ2] annulations of 2b and oxo-dienes 4a
R1
R1
R1
O
Ph
E
E
Bz
20 mol% PPh3
solvent, temp.
E
Bz
+
(6)
+
R2
O
R2
O
R2
O
5
4
2b
[5]
: not observed
Entry
4 (R1, E, R2)
T (ꢀC)
Sol.
5/yieldb (%)
1
2
3
4
5
6
7
8
4a (Ph, CO2Et, Me)
4b (Ph, COMe, Me)
4c (Ph, CN, Ph)
4c (Ph, CN, Ph)
4c (Ph, CN, Ph)
4c (Ph, CN, Ph)
4c (Ph, CN, Ph)
4c (Ph, CN, Ph)
4c (Ph, CN, Ph)
4c (Ph, CN, Ph)
120
120
120
80
rt
rt
rt
rt
rt
PhMe
PhMe
PhMe
PhMe
PhMe
DMF
CH2Cl2
MeCN
acetone
MeCN
0 (5ba)
20 (5bb)
74 (5bc)
78 (5bc)
88 (5bc)
95 (5bc)
80 (5bc)
99 (5bc)
97 (5bc)
0 (5bc)
9
10c
rt
a
Reaction conditions: the solution of 2b (0.6 mmol) in toluene (10 mL) was
slowly added to the mixture of 4 (0.5 mmol) and PPh3 (0.1 mmol) in toluene (10 mL)
within 1.5 h.
b
Isolated yield.
Without PPh3 catalyst.
O
2b
c
O
R
COR
Ar
NTs
20 mol% PPh3
PhMe, 80 o
20 mol% PPh3
PhMe, reflux
Ph
+
C
Ar
To our disappointment, no reaction took place at 120 ꢀC in tol-
uene and 4a was recovered in 89% yield (entry 1, Table 3). We
suspected that the electrophilicity of 4a might be too weak relative
to aza-dienes. Therefore, we turned our attention to the com-
pounds 4b and 4c, which were activated by much stronger elec-
tron-withdrawing groups, keton- and cyano-, respectively. To our
N
Ts
2
6b
2a
2f
3bb yiled: 58%
3bf yield: 53%
R = OMe
R = OBn
Ar = 4-MeO-C6H4
Scheme 3. Synthesis of 3bb and 3bf in one-pot way.

8098
Q. Zhang et al. / Tetrahedron 66 (2010) 8095e8100
delight, both 4b and 4c reacted with 2b to give highly functional-
ized 2H-pyrans 5bb and 5bc in the yields of 20% and 74%,
respectively (entries 2 and 3, Table 3). These results indicated that
the electrophilicity of 4 played a determining role for the efficiency
of this transformation and the best results would be achieved by
applying oxo-dienes 4, which were activated by strongly electron-
withdrawing cyano-group. Even more, 4c worked well at room
temperature (entries 5e9, Table 3). It was noted that 4H-pyrane [5]
could not be detected in reaction mixture. Solvent screening also
disclosed that this transformation had little solvent effect; a wide
range of solvents could be employed to give excellent yields
(entries 5e9, Table 3). However, toluene solvent was found to be
the optimal one due to its more general substrate tolerance (vide
infra). Furthermore, control experiments shown that this reaction
did not occur at all without PPh3 catalyst (entry 10, Table 3).12
With the optimized conditions in hand, the scope of the PPh3-
catalyzed [4þ2] annulations of oxo-dienes 4 and 2b was further
investigated (Table 4). In general, various highly functionalized 2H-
pyrans were provided in good to excellent yields. Especially, hetero-
aryl motifs, such as furan (entries 2 and 8) and thiophene (entries 5, 7,
and 8) were successfully incorporated. Introduction of alkenyl was
also a particular feature of this method (entry 6). Interestingly, the
reaction of 2b with oxo-diene 4k, which attached a pentyl group on
the R1-position, offered not only the desired product 5bk but also the
compound 5bk-2 with a ratio of 1:1 (Eq. 7). Moreover, this method
Compared to aza-dienes 1, oxo-dienes 4 presented higher re-
activity toward 2b with much lower reaction temperature and
higher yields. Thus we envisioned that propiolates 2a and 2f could
react with oxo-dienes 4 to furnish [4þ2] annulations as a two-atom
unit (Table 5). We were delighted to find that the corresponding
products 5 with a carboxylate group on pyran rings could also be
obtained, although elevated temperature was required to complete
the reaction.
Table 5
PPh3-catalyzed [4þ2] annulations of propiolates with oxo-dienes 4a
R2
R2
O
O
OR
CN
R1
20 mol% PPh3
CN
R1
RO
+
PhMe, 80 o
C
O
O
2
4
5
Entry
2 (R)
4 (R1, R2)
5/Yieldb (%)
1
2
3
4
5
6
7
8
2a (Me)
2f (Bn)
2a
2a
2a
2a
2a
2a
4c (Ph, Ph)
4c
4e (Ph, 4-Br/Ph)
4f (Ph, 4-MeO/Ph)
4g (Ph, 2-thiophene)
4h (Ph, styrene)
4i (2-Thiophene, Ph)
4k (C5H11, Ph)
96 (5ac)
71 (5fc)
37 (5ae)
65 (5af)
69 (5ag)
51 (5ah)
71 (5ai)
63 (5ak)
a
Reaction conditions: the solution of 2 (1.0 mmol) in toluene (10 mL) was slowly
added to the mixture of 4 (0.5 mmol) and PPh3 (0.1 mmol) at 80 ꢀC in toluene
(10 mL) within 1.5 h.
could be extended to the
b-disubstituted oxo-dienes 4l and 4m,
affording the products 4,4-dialkyl-4H-pyrans 5bl and 5bm (Eq. 8). As
expected, the yields were much lower probably because the sub-
stituents at b-position reduced the electrophilicity of oxo-dienes for
b
Isolated yield.
both steric and electronic reasons.
2.3. Mechanistic considerations
Table 4
PPh3-catalyzed [4þ2] annulations of 2b with oxo-dienes 4a
A proposed mechanism for the PPh3-catalyzed annulations be-
tween 2 and hetero-dienes is depicted in Scheme 4. Addition of
PPh3 to activated terminal alkyne 2 generates intermediate A,13
which undergoes Michael-addition reaction with hetero-diene 1
or 4 to produce intermediate B. Then the formed hetero-atomic
anion of B undergoes 6-endo cyclization followed by elimination of
PPh3 to yield six-membered heterocycle D.14 In the end, the final
product can be obtained via [1,3]-proton transfer process.
O
R2
O
R2
O
Ph
CN
R1
20 mol% PPh3
PhMe, r.t.
CN
R1
R
+
O
2b
4
5
Entry
4 (R1, R2)
5/Yieldb (%)
1
2
3
4
5
6
7
8
4c (Ph, Ph)
4d (Ph, 2-furan)
4e (Ph, 4-Br/Ph)
4f (Ph, 4-MeO/Ph)
4g (Ph, 2-thiophene)
4h (Ph, styrene)
4i (2-Thiophene, Ph)
4j (2-Thiophene, 2-furan)
88 (5bc)
99 (5bd)
99 (5be)
83 (5bf)
90 (5bg)
89 (5bh)
99 (5bi)
84 (5bj)
X
R2
E
Ph3P
ROC
X
R2
E
Ph3P
ROC
R1
COR
1 or 4
2
R1
A
B
a
Reaction conditions: the solution of 2b (0.6 mmol) in toluene (10 mL) was
slowly added to the mixture of 4 (0.5 mmol) and PPh3 (0.1 mmol) in toluene (10 mL)
within 1.5 h.
X = O, NTs
PPh3
b
Isolated yield.
X
R2
E
X
R2
Ph3P
ROC
X
R2
E
[1,3]-H
ROC
2b
Ph
Ph
Ph
O
Bz
CN
Bz
CN
CN
20 mol% PPh3
PhMe, rt
93% overall
1:1 ratio
ROC
E
(7)
+
R1
3 or 5 or 7
R1
D
R1
C
O
5bk
C5H11
O
5bk-2
C5H11
C5H11
4k
Scheme 4. Proposed mechanism for PPh3-catalyzed [4þ2] annulations.
O
R
R
2b
On the basis of this proposed mechanism and the catalytic results
(Tables 1e5 and Eqs. 1e8), some features of this reaction protocol
have been observed and summarized as follows: (1) Intermediate A
works as nucleophile and its nucleophilicity seems to be strongly
determined by the activated groups of alkynes. When the activated
group is carboxylate, the corresponding intermediate A (R¼OMe,
CN
Ph
CN
Ph
20 mol% PPh3
PhMe, r.t.
(8)
O
O
Ph
4l
: R = Me
5bl: 39%
5bm
4m: R = Et
: 30%

Q. Zhang et al. / Tetrahedron 66 (2010) 8095e8100
8099
Scheme 4) is a too weak nucleophile to undergo Michael-addition
reaction with aza-dienes. Contrarily, the intermediate A (R¼Ph)
attaching benzoyl group shows higher reactivity toward hetero-di-
enes. We postulate that benzoyl group possiblyexhibits two positive
effects to stabilize the carboanion of intermediate A: one is the
stronger electron-withdrawing ability; the other is the larger con-
jugated systems afforded by phenyl group. However we do not have
further evidences to support this at present. (2) Hetero-dienes also
play important roles for Michael-addition step. The more electro-
philicity hetero-dienes exhibit, the more readily would Michael-
addition step occur. For example, oxo-diene 4a is inert for [4þ2]
annulations as two-atom unit, while oxo-dienes 4cej can smoothly
react with 2b even at room temperature. (3) The reaction pathway
involving intermediate D is possible, which is evidenced by the
isolation of some stable 4H-pyranproducts, such as 5bl and 5bm. (4)
[1,3]-Proton transfer process might be driven by the conjugating
requirement provided by aryl and/or cyano groups on dihydropyran
and dihydropyridine ring. This transfer process would be partially
inhibited in the case of 5bke2, whose alkyl substituent (n-pentyl) at
2-position is believed to partially reduce the conjugated effect.
readily obtained in moderate yield (Eq. 10, Scheme 6). In fact,
pyridine 8bc was also obtained in 43% yield through a one-pot
way, whereas the ammonium acetate reagent and acetic acid
solvent were directly added into the reaction systems after the
completion of PPh3-catalyzed annulations of 2b and 4c in aceto-
nitrile solvent (Eq. 11, Scheme 6).
Ar
Ar
2 equiv. AcONH4
AcOH, reflux, 24h
Bz
CN
Ph
Bz
CN
Ph
(10)
O
N
5bc: Ar = Ph
5bg: Ar = 2-furan
8bc: 71%
8bg: 47%
Ph
Bz
CN
Ph
MeCN
1) 20 mol% PPh3,
, rt
(11)
4c
2b +
2) 2.0 AcONH4, AcOH, reflux
yield: 43%
N
8bc
70%
D
D
2b
3
Scheme 6. Synthetic utility of 2H-pyrans.
PhOC
H
CO2Me
CO2Me
Ar
20 mol% PPh3
PhMe, reflux
30%
Ar = 4-MeO-C6H4
H
1
(9)
N
Ar
3. Conclusions
D
TsN
Ts
3bb-D
1ab-D
yield: 78%
In summary, we report a new PPh3-catalyzed [4þ2] annalution
of activated terminal alkynes and aza-dienes or oxo-dienes, which
allows the efficient construction of highly functionalized 2H-dihy-
dropyridines and dihydropyrans, respectively. The [4þ2] annula-
tions can also tolerate the dienes with
b-disubstituted alkenes
although the yields are somewhat lower. The reaction mechanism
has been proposed with two-step sequences, initial PPh3-catalyzed
[4þ2] annalution and subsequent [1,3]-proton transfer. In some
cases, the intermediated products from PPh3-catalyzed [4þ2]
annalution can be separately obtained. Deuterium labeling studies
also provide strong evidences to support the involving [1,3]-proton
transfer process, which exhibits a large isotopic effect in both
dihydropyridine and dihydropyran systems. The flexibility for di-
rect synthesis of pyridine derivatives in one-pot way through initial
PPh3-catalyzed [4þ2] annulations in acetonitrile solvent, followed
by the addition of ammonium acetate and acetate acid, has also
been demonstrated.
In order to get more details about the reaction mechanism, we
conducted some control experiments with the deuterium-labeled
substrates. When compound 1ab-D was subjected to the [4þ2]
annulations with 2b, the deuterium atom was found out to be fully
incorporated into the products 3bb-D with 30% D at C1 atom and
70% D at C3 atom (Eq. 9). These results strongly indicated that the
[1,3]-proton transfer process, with a KD:KH¼2.3 isotope effect, was
involved in the reaction pathway. Interestingly, when the deute-
rium-labeled oxo-diene 4f-D was employed, the distribution of
products shifted in favor of 4H-pyran [5]bf-D, which would be
completely transformed into 2H-pyran 5bf-D within 1 week
(Scheme 5). These results clearly showed that [1,3]-proton transfer
process in dihydropyran system took place much more slowly
relative to that in dihydropyridine, exhibiting a larger isotope effect
(KD:KH¼9).
4. Experimental section
4.1. General
1 week, 99%
Unless otherwise noted, all reactions were carried out under
a nitrogen atmosphere using a standard syringe, cannula, and septa
apparatus. The commercially available reagents were used without
further purification. NMR spectra were run at 400 (1H) or 100 MHz
PhMe, rt
Ar
Ar
O
D
Ar
Bz
D
CN
Ph
Bz
CN
Ph
CN
Ph
20 mol% PPh3
PhMe, r.t.
D
2b
+
+
(
13C) in CDCl3.
O
O
Ar = 4-MeO-C6H4
4f-D
5bf-D (9%)
[5]bf-D (81%)
4.2. Typical procedure for PPh3-catalyzed synthesis of 3ba
Scheme 5. Deuterium labeling studies.
Aza-diene 1aa (0.3 mmol), PPh3 (15.7 mg, 20 mmol %) were
added to toluene (6 mL) in there-neck bottle. The mixture was
stirred at 120 ꢀC under nitrogen atmosphere. To this reaction
mixture the solution of 1-arylpropynones 2b (0.6 mmol) in toluene
(6 mL) was slowly added within 1 h. The reaction mixture was
monitored by TLC. Once the reaction was finished, the reaction
mixture was cooled down to room temperature. The contents were
transferred to a round-bottom flask, and volatiles were removed in
vacuo. Then the mixture was directly subjected to silica gel column
2.4. Synthetic transformation
In order to demonstrate the synthetic utility of the present
method, we developed a procedure to synthesize 2,3,4,5-tetra-
substituent pyridine via the treatment of 2H-pyrans with 2 equiv
of ammonium acetate in acetic acid solvent.15 As a result, nic-
otinonitrile-like pyridine derivatives16 8bc and 8bg could be

8100
Q. Zhang et al. / Tetrahedron 66 (2010) 8095e8100
chromatography (petroleum ether/EtOAc 15:1 to 5:1 gradient) to
Supplementary data
give the product 3ba.
Supplementary data (copies of NMR spectra) associated with
this article can be found, in the online version, at doi:10.1016/
j.tet.2010.07.043.
4.3. Typical procedure for PPh3-catalyzed synthesis of 5bc
Oxo-diene 4c (0.5 mmol), PPh3 (26.2 mg, 20 mmol %) were
added to toluene (10 mL) in one-neck bottle. The mixture was
stirred at room temperature under nitrogen atmosphere. To this
reaction mixture the solution of terminal alkynes 2b (0.6 mmol) in
toluene (10 mL) was slowly added within 1.5 h. The reaction was
monitored by TLC. When the reaction was finished, the mixture was
directly subjected to silica gel column chromatography (petroleum
ether/EtOAc 30:1 to 10:1 gradient) to give the product 5bc.
References and notes
1. For reviews see: (a) Martins, M. A. P.; Frizzo, C. P.; Moreira, D. N.; Buriol, L.; Ma-
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N.; Zanatta, N.; Bonacorso, H. G. Chem. Rev. 2008, 108, 2015; (c) Druzhinin, S. V.;
Balenkova, E. S.; Nenajdenko, V. G. Tetrahedron 2007, 63, 7753; (d) Martins, M. A.
P.; Cunico, W.; Pereira, C. M. P.; Flores, A. F. C.; Bonacorso, H. G.; Zanatta, N. Curr.
Org. Synth. 2004, 1, 39.
2. For reviews see: (a) Progress in Heterocyclic Chemistry; Gribble, G. W., Joule, J. A.,
Eds.; Elsevier: Oxford, 2008; Vol. 20; (b) Lavilla, R. J. Chem. Soc., Faraday Trans.
2002, 1141; (c) Simon, C.; Constantieux, T.; Rodriguez, J. Eur. J. Org. Chem. 2004,
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3. For reviews see: (a) Faulkner, D. J. Nat. Prod. Rep. 2000,17, 7; (b) Larrosa, I.; Romea,
P.; Urpi, F. Tetrahedron 2008, 64, 2683; (c) Clarke, P. A.; Santos, S. Eur. J. Org. Chem.
2006, 2045; (d) Nakata, T. Chem. Rev. 2005, 105, 4314; (e) Wong, H. N. C.; Yu, P.;
Yick, C. Y. Pure Appl. Chem. 1999, 71, 1041; (f) Kuthan, J.; Sebek, P.; Boehm, S. Adv.
Heterocycl. Chem. 1995, 62, 19.
4. Liu, H.; Zhang, Q.; Wang, L.; Tong, X. Chem. Commun. 2010, 312.
5. Zhang, Q.; Yang, L.; Tong, X. J. Am. Chem. Soc. 2010, 132, 2550.
6. For reviews, see: (a) Lu, X.; Zhang, C.; Xu, Z. Acc. Chem. Res. 2001, 34, 535; (b)
Methot, J. L.; Roush, W. R. Adv. Synth. Catal. 2004, 346, 1035; (c) Lu, X.; Du, Y.; Lu,
C. Pure Appl. Chem. 2005, 77, 1985; (d) Nair, V.; Menon, S. R.; Sreekanth, A. R.;
Abhilash, N.; Biji, A. T. Acc. Chem. Res. 2006, 39, 520; (e) Ye, L.; Zhou, J.; Tang, Y.
Chem. Soc. Rev. 2008, 37, 1140; (f) Kwong, C. K.; Fu, M. Y.; Lam, C. S.; Toy, P. H.
Synthesis 2008, 2307.
4.4. Typical procedure for synthesis of 8bc
2H-Pyran 5bc (0.2 mmol), ammonium acetate (30.8 mg,
0.4 mmol), and acetic acid (3 mL) was added into one-necked
bottle. The reaction mixture was heated and reflux for 24 h. The
mixture then was cooled down to room temperature. Water
(30 mL) and CH2Cl2 (30 mL) were added. The organic layer was
separated and dried over Na2SO4. The solvent was removed under
vacuum to obtain a liquid, which was purified via FCG to give
product 8bc.
Spectral data of compounds 3aa, 5bc, and 8bc are listed below.
Other spectral data and copies of the 1H and 13C NMR spectra of all
compounds are given in the Supplementary data.
7. For reviews see: (a) Weinreb, S. M.; Scola, P. M. Chem. Rev. 1989, 89, 1525; (b)
Reymond, S.; Cossy, J. Chem. Rev. 2008, 108, 5359; (c) Behforouz, M.; Ahmadian,
M. Tetrahedron 2000, 56, 5259; (d) Takao, K.-I.; Munakata, R.; Tadano, K.-I.
Chem. Rev. 2005, 105, 4779.
8. Liu, H.; Zhang, Q.; Wang, L.; Tong, X. Chem.dEur. J. 2010, 16, 1968.
9. CCDC 739301 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.
10. For representative examples of phospine-catalyzed [4þ2] cycloadditions, see:
(a) Zhu, X.-F.; Lan, J.; Kwon, O. J. Am. Chem. Soc. 2003, 125, 4716; (b) Wurz, R. P.;
Fu, G. C. J. Am. Chem. Soc. 2005, 127, 12234; (c) Tran, Y. S.; Kwon, O. J. Am. Chem.
Soc. 2007, 129, 12632.
11. For reviews, see: (a) Bruggink, A.; Schoevaart, R.; Kieboom, T. Org. Process Res.
Dev. 2003, 7, 622; (b) Ajamian, A.; Gleason, J. L. Angew. Chem., Int. Ed. 2004, 43,
3754; (c) Wasilke, J.-C.; Obrey, S. J.; Baker, R. T.; Bazan, G. C. Chem. Rev. 2005,
105, 1001; (d) Pellissier, H. Tetrahedron 2006, 62, 1619; (e) MacMillan, D. W. C.;
Walji, A. M. Synlett 2007, 1477; (f) Chapman, C. J.; Frost, C. G. Synthesis 2007, 1.
12. This result convincingly rules out the other mechanistic consideration, con-
sisting DielseAlder reaction of oxo-diene with alkyne and [1,3]-proton transfer.
13. (a) Larpent, C.; Meignan, G.; Patin, H. Tetrahedron Lett. 1991, 32, 2615; (b) Lu, C.;
Lu, X. Org. Lett. 2002, 4, 4677; (c) Trost, B. M.; Li, C. J. J. Am. Chem. Soc. 1994, 116,
3167; (d) Trost, B. M.; Li, C. J. J. Am. Chem. Soc. 1994, 116, 10819; (e) Trost, B. M.;
Dake, G. R. J. Org. Chem. 1997, 62, 5670; (f) Dake, G. R.; Trost, B. M. J. Am. Chem.
Soc. 1997, 119, 7595; (g) Dureen, M. A.; Stephan, D. W. J. Am. Chem. Soc. 2009,
131, 8396.
14. Guo, H.; Xu, Q.; Kwon, O. J. Am. Chem. Soc. 2009, 131, 6318.
15. (a) Reinhoudt, D. N.; Dijkstra, P. J. Pure Appl. Chem. 1988, 60, 477; (b) Shibuya, J.;
Nabeshima, M.; Nagano, H.; Maeda, K. J. Chem. Soc., Perkin Trans. 2 1988, 1607;
(c) Dijkstra, P. J.; Hertog, H. J.; Eerden, J.; Harkema, S.; Reinhoudt, D. N. J. Org.
Chem. 1988, 53, 375.
16. (a) Katritzky, A. R.; Denisenko, A.; Arend, M. J. Org. Chem. 1999, 64, 6076; (b)
Palacios, F.; Alonso, C.; Rubiales, G. J. Org. Chem. 1997, 62, 1146; (c) Reich, S. H.;
Melnick, M.; Pino, M. J.; Fuhry, M. A. N.; Trippe, A. J.; Appelt, K.; Davies, J. F., II;
Wu, B. W.; Musick, L. J. Med. Chem. 1996, 39, 2781; (d) Katsuyama, I.; Ogawa, S.;
Yamaguchi, Y.; Funabiki, K.; Matsui, M.; Muramatsu, H.; Shibata, K. Synthesis
1997, 1321.
4.4.1. Compound 3ba. 1H NMR (400 MHz, CDCl3):
10H), 7.31 (d, J¼7.2 Hz, 2H), 7.19 (d, J¼8.0 Hz, 2H), 6.89 (s, 1H), 4.91
(s, 2H), 3.45 (s, 3H), 2.36 (s, 3H); 13C NMR (100 MHz, CDCl3):
192.5,
167.1, 150.7, 144.6, 137.3, 135.3, 135.2, 131.9, 130.7, 130.0, 129.7, 128.7,
128.3, 127.9, 127.0, 126.7, 120.3, 51.8, 45.6, 21.5; MS (EI-m/z): 473
(Mþ); HRMS calcd for C27H23NO5S 473.1297. Found 473.1296.
d 7.53e7.38 (m,
d
4.4.2. Compound 5bc. Yellow solid, mp: 102e103 ꢀC. 1H NMR
(400 MHz, CDCl3):
7.56e7.53 (m, 4H), 7.31e7.23 (m, 3H), 7.17e7.14 (m, 5H), 5.24 (s,
2H); 13C NMR (100 MHz, CDCl3):
194.9, 170.4, 141.1, 137.1, 134.2,
d 8.10e8.08 (m, 2H), 7.63e7.60 (m, 1H),
d
133.0, 132.5, 130.7, 129.9, 129.8, 129.5, 129.1, 128.8, 128.2, 128.0,
119.3, 117.6, 90.8, 69.3. MS (m/z): 363 (Mþ); HRMS calcd for
C25H17NO2 363.1259. Found 363.1260.
4.4.3. Compound 8bc. 1H NMR (400 MHz, CDCl3):
8.03e8.00 (m, 2H), 7.64e7.56 (m, 5H), 7.48e7.47(m, 1H), 7.36e7.30
(m, 7H); 13C NMR (100 MHz, CDCl3):
194.4, 163.4, 153.6, 150.9,
d 8.92 (s, 1H),
d
137.0, 136.3, 134.0, 133.8, 133.3, 130.7, 129.9, 129.7, 129.3, 129.1,
128.7, 128.6, 128.5, 116.4, 107.9. MS (m/z):360 (Mþ); HRMS calcd for
C25H16N2O 360.1263. Found 360.1261.
Acknowledgements
This work is supported by the Fundamental Research Funds for
the Central Universities. Special gratitude also goes to Prof. Xingyi
Wang and Ms. Shuzhen Jiang for their support.