[4+2] Annulation of vinyl ketones initiated by a phosphine-catalyzed aza-Rauhut-currier reaction: A practical access to densely functionalized tetrahydropyridines

Article abstract of DOI:10.1002/chem.201201318

The first example of phosphine catalyzed aza-Rauhut-Currier reaction initiated [4+2] annulation of vinyl ketones with N-sulfonyl-1-aza-1,3-dienes has been disclosed. Under the ambient conditions, this protocol provides a practical access to valuable densely functionalized tetrahydropyridines in good to excellent yields and high diastereoselectivities (see scheme). Copyright

Full text of DOI:10.1002/chem.201201318

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DOI: 10.1002/chem.201201318
ACHTUNGTRENNUNG
Zugui Shi,[a, b] Qinjie Tong,[a, b] Wendy Wen Yi Leong,[a, b] and Guofu Zhong*[a, b]
Enolate represents a typical nucleophile in numerous clas-
strates scope. In 2003, Kwon and co-workers developed an
elegant protocol for the synthesis of highly functionalized
tetrahydropyridines, through a phosphine-catalyzed [4+2]
annulation reaction of 2-methyl-2,3-butadienoate with aldi-
mines (Scheme 1).[9,10] However, the usage of air sensitive
PBu3 as catalyst partly limited its scale-up potential. Thus,
the development of efficient, environmentally benign and
practical strategies for the construction of tetrahydropyri-
dines is highly desirable. Herein, we report the first example
of aza-Rauhut–Currier reaction initiated [4+2] annulation
of readily available vinyl ketones with N-sulfonyl-1-aza-1,3-
dienes under ambient atmosphere, which provides a practical
access to the synthesis of tetrahydropyridine derivatives
(Scheme 1).
À
sic C C bond formation reactions, but generally it inevitably
requires additional synthetic steps or stoichiometric base,
thus diminishes its synthetic importance. Direct usage of
enolate precursor as nucleophile would be of great synthetic
efficiency and atom-economy significance. Conceptually, the
Rauhut–Currier reaction and Morita–Baylis–Hillman reac-
tion are ideal models, in which activated alkenes are utilized
as latent enolate to coupling with Michael acceptor and car-
bonyl compounds, respectively.[1] Although the Rauhut–Cur-
rier reaction was discovered half a century ago, comparing
with the Morita–Baylis–Hillman reaction, it did not attract
enough attention until recent years, due to lack of selectivi-
ty.[2] In 2002, the groups of Krische[2a] and Roush[2b] inde-
pendently developed a synthetically useful intramolecular
Rauhut–Currier reaction to construct five- or six-membered
ring systems with high efficiency.[3] In 2007, Miller and Gla-
dysz realized the first intramolecular Rauhut–Currier reac-
tion in an asymmetric manner.[4] Recently, the achievements
of Miller, Ruszczycky, and Choi in their natural products
and bioactive compounds synthesis further proved the syn-
thetic efficiency of the intramolecular Rauhut–Currier reac-
tion.[5] However, up to date only sporadic intermolecular
Rauhut–Currier reactions were documented,[6] and there is
no report covering the aza-Rauhut–Currier reaction.
Scheme 1. Phosphine-catalyzed [4+2] annulation.
Tetrahydropyridines are intriguing synthetic targets as
they can be readily converted into highly functionalized pyr-
idine or piperidine derivatives, which frequently occur in
natural products and biologically active compounds.[7] How-
ever, existing synthetic methods used to synthesize such
highly valuable heterocycles mainly rely on Lewis acid cata-
lyzed aza-Diels–Alder reactions,[8] which require harsh reac-
tion conditions and are limited by relatively narrow sub-
Initially, we tested the reaction of (E)-1,3-diphenyl-N-
(tosyl) prop-2-en-1-imine 2a with methyl vinyl ketone
(MVK) 1a in the presence of PPh3 (20 mol%) using di-
chloromethane as solvent. To our delight, the starting mate-
rials were consumed completely at room temperature within
24 h, and the desired product was isolated in good yield and
diastereoselectivity (Table 1, entry 1). The effects of various
sulfonyl protecting groups were subsequently investigated. It
was found that benzenesulfonyl (Bs) protected 1,3-azadiene
afforded the [4+2] adduct 3a with the highest yield and dia-
stereoselectivity (Table 1, entry 2). Subsequent catalyst
screening indicated that PPh3 was the best choice in terms
of its catalytic performance, low cost, and operational sim-
plicity. Other catalysts examined, such as DABCO, DMAP,
and PBu3 gave unsatisfactory results (Table 1, entries 5–
7).[11]
[a] Z. Shi, Q. Tong, W. W. Y. Leong, Prof. Dr. G. Zhong
College of Materials, Chemistry and Chemical Engineering
Hangzhou Normal University
Hangzhou 310036, Zhejiang (P. R. China)
Fax : (+86)571-28867899
E-mail: zgf@hznu.edu.cn
[b] Z. Shi, Q. Tong, W. W. Y. Leong, Prof. Dr. G. Zhong
Division of Chemistry and Biological Chemistry
Nanyang Technological University
21 Nanyang Link, Singapore 637371 (Singapore)
Solvent screening revealed that the solvent significantly
influenced the reaction outcome. A dramatic improvement
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201201318.
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tion time (Table 1, entry 9).[11] Notably, when 4-methoxyphe-
nol (30 mol%) was used, the reaction rate was further accel-
erated and afforded almost exclusive trans product in quan-
titative yield (Table 1, entry 10). A control reaction in ab-
sence of PPh3, was carried out and it was found that the re-
action did not proceed when only 4-methoxyphenol was
present (Table 1, entry 11). This ruled out the possibility of
a Diels–Alder reaction occurring between MVK and N-sul-
fonyl-1-aza-1,3-diene 2a catalyzed by phenol additive.[13]
Having established the optimized reaction conditions, the
generality of this reaction was then explored (Table 2). This
protocol possessed high tolerance to various substituents.
Ortho-substituted substrates, which usually lead to lower
yields or unsatisfactory stereocontrol due to steric hin-
drance, underwent this process to give products with com-
plete diastereoselectivities, and excellent yields were ob-
tained (Table 2, entries 2 and 3). In addition, meta-, and
para-substituted phenyl-N-sulfonyl-1-aza-1,3-dienes also
gave the corresponding products with good yields and dia-
stereoselectivities. Regardless of the electronic nature of the
phenyl rings, good to excellent chemical yields and diaste-
reomeric ratio (d.r.) values were obtained (Table 2, en-
tries 4–12). 2-Naphthyl and 2,3-dihydrobenzofuran-5-yl sub-
stituted aza-1,3-dienes were also well tolerated (Table 2, en-
tries 13 and 14). This protocol could be further extended to
heteroaryl N-sulfonyl-1-aza-1,3-dienes, although the sub-
strate bearing a 2-thienyl substituent gave a lower diastereo-
Table 1. Optimization of [4+2] annulation of vinyl ketones with N-sulfo-
nyl-1-aza-1,3-dienes.[a]
Entry PG
Cat.
Solvent
d.r.[b]
Yield
[%][c]
1
2
3
4
Ts
Bs
PPh3
PPh3
PPh3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
10:1 74
10:1 87
6:1 67
4-ClPhSO2
4-NO2PhSO2 PPh3
8:1 69
5
6
7
8
Bs
Bs
Bs
Bs
Bs
Bs
Bs
DABCO CH2Cl2
5:1 10
4:1 40
DMAP
PBu3
PPh3
PPh3
PPh3
–
CH2Cl2
CH2Cl2
CH2Cl2/MeOH (9:1)
CH2Cl2
CH2Cl2
20:1 20
18:1 81
16:1 91
>20:1 95
n.d. n.r.
9[d]
10[e]
11[f]
CH2Cl2
[a] Unless otherwise specified, reactions were performed using 2a
(0.1 mmol) and 1a (0.3 mmol) in dichloromethane (0.2 mL) at room tem-
perature in the presence of the catalyst (20 mol%) for 24 h. [b] d.r.=
1
trans/cis, determined by crude H NMR. [c]Yield of isolated trans isomer.
[d] 4-Methoxyphenol (20 mol%) was added. [e] 4-Methoxyphenol
(30 mol%) was added. [f] Reaction was conducted with 4-Methoxyphe-
nol (30 mol%), without PPh3. n.d.=not determined, n.r.=no reaction.
in diastereoselectivity was observed, when a mixture of di-
chloromethane and methanol (9:1) was examined for this
transformation (Table 1, entry 8). Inspired by this interesting
phenomenon, we envisioned that methanol may act as
proton source or hydrogen bond donor, which stabilizes the
enolate intermediate that is formed by nucleophilic addition
of PPh3 to MVK, thereby driving the reaction forward and
accelerating the reaction (Figure 1). A series of Brønsted
acids were then tested.[12] Among all the additives examined,
4-methoxyphenol afforded the product with the best yield
and diastereoselectivity and in a significantly shorter reac-
Table 2. Generality of [4+2] annulation of vinyl ketones with N-sulfonyl-
1-aza-1,3-dienes.[a]
Entry
2 (R2, R3)
3 (d.r.,[b] yield%[c]
)
1
2
3
4
5
6
7
8
2a (Ph, Ph)
3a (>20:1, 95)
3b (>20:1, 90)
3c (>20:1, 96)
3d (19:1, 95)
3e (13:1, 83)
3 f (18:1, 81)
3g (>20:1, 94)
3h (17:1, 75)
3i (13:1, 72)
3j (10:1, 89)
3k (>20:1, 83)
3l (18:1, 83)
3m (>20:1, 80)
3n (18:1, 87)
3o (19:1, 91)
3p (7:1, 87)
2b (2-FC6H4, Ph)
2c (2-Cl-5-NO2C6H4,Ph)
2d (3-BrC6H4, Ph)
2e (3-MeOC6H4, Ph)
2 f (3-MeC6H4, Ph)
2g (4-NO2C6H4, Ph)
2h (4-BrC6H4, Ph)
2i (4-MeC6H4, Ph)
2j (4-ClC6H4, Ph,)
2k (4-FC6H4, Ph)
2l (4-MeOC6H4, Ph)
2m (2-naphthyl, Ph)
2n (2,3-dihydrobenzofuran-5-yl, Ph)
2o (2-furyl, Ph)
2p (2-thienyl, Ph)
2q (styryl, Ph)
9
10
11
12
13
14
15
16
17
18
19
3q (>20:1, 75)
3r (>20:1, 92)
3s (20:1, 93)
2r (Ph, 4-IC6H4)
2s (Ph, styryl)
[a] Unless otherwise specified, reactions were performed using
2
(0.1 mmol) and 1a (0.3 mmol) in CH2Cl2 (0.2 mL) at room temperature
in the presence of PPh3 (0.02 mmol) and 4-methoxyphenol (0.03 mmol).
[b] d.r.=trans/cis, determined by crude 1H NMR. [c] Yield of isolated
trans isomer.
Figure 1. Proposed catalytic cycle of [4+2] annulation between vinyl ke-
tones and N-sulfonyl-1-aza-1,3-dienes.
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Practical Access to Densely Functionalized Tetrahydropyridines
COMMUNICATION
selectivity (Table 2, entry 16). Moreover, styryl and 4-iodo-
phenyl substituents on N-sulfonyl-1-aza-1,3-dienes, which
enabled their adducts more synthetic transformations, had
no influence on the reaction outcomes (Table 2, entries 17–
19).
It is also noteworthy that the scope of vinyl ketones was
not strictly limited to MVK (Table 3). Ethyl vinyl ketone 1b
could also successfully undergo the [4+2] annulation to gen-
erate the desired product 3t in 86% yield and with excellent
diastereocontrol. Under the standard reaction conditions,
vinyl ketones 1c, 1d, 1e, and 1 f only gave moderate yields
(50–70%) due to significant homocoupling. Fortunately, this
side reaction can be easily suppressed by the slow addition
of a solution of 1c–f in dichloromethane to 2a through a sy-
ringe pump, and the [4+2] annulations adducts could be ob-
tained in good yields and excellent diastereoselectivities
(Table 3, entries 2–6).
confirmed the structure of the product established by NMR
spectroscopy.[14]
Hydrobenzo[h]quinoline is a core substructure which is
frequently found in many biologically active natural prod-
ucts, such as sanguinarine, chelerythrine, tetrahydroberber-
ine,[15] and corynoline.[16] To highlight the synthetic utility of
this method, this molecular complex was efficiently assem-
bled in a single step using the reaction of N-sulfonyl-1-aza-
1,3-dienes 2t with methyl vinyl ketone. Alternatively, hydro-
1H-indenoACTHNUTRGENUG[N 1,2-b]pyridine derivatives, which are potent anti-
spermatogenic agents,[17] were also synthesized through this
protocol, with excellent diastereoselectivity and 84% yield
(Scheme 3).
Table 3. Scope of vinyl ketones.[a]
Scheme 3. Synthesis of backbone of bioactive compounds.
Entry
1
3 (d.r.,[b] yield%[c]
)
The synthetic utility of this method was further demon-
strated (Scheme 4). Deprotection of the benzenesulfonyl
group was readily carried out under mild reaction conditions
to give imine product 4, which led to highly substituted pyri-
dine 5 in 88% yield, by oxidation with 2,3-dichloro-5,6-di-
cyanobenzo-quinone. Furthermore, reduction of imine inter-
mediate 4 with sodium cyanoborohydride afforded piperi-
dine adduct 6 in almost quantitative yield and modest dia-
stereoselectivity.
1
1b
1c
1d
1e
1 f
1g
3t (>20:1, 86)
3u (10:1, 85)
3v (>20:1, 92)
3w (>20:1, 90)
3x (>20:1, 89)
3y (>20:1, 94)
2[d]
3[d]
4[d]
5[d]
6[d]
[a] Unless otherwise specified, reactions were performed using 2a
(0.1 mmol) and 1 (0.3 mmol) in CH2Cl2 (0.2 mL) at room temperature in
the presence of PPh3 (0.02 mmol) and 4-methoxyphenol (0.03 mmol).
[b] d.r.=trans/cis, determined by crude 1H NMR. [c] Yield of isolated
trans isomer. [d] 1c–g (0.3 mmol) in CH2Cl2 (0.2 mL) was added to
0.1 mL of a solution of 2a (0.1 mmol) and 4-methoxyphenol (0.03 mmol)
CH2Cl2 during 6 h through a syringe pump.
To demonstrate the ease and feasibility of scaling-up this
reaction, this reaction was carried out using 5 mmol of 2a.
The pure crystalline product (3a, 1.92 g, 92% yield and
>20:1 d.r.) was obtained after single recrystallization from
hexane/acetone (8:1), hence proving its scale-up potential
(Scheme 2). X-ray crystallographic analysis of 3a further
Scheme 4. Synthesis of pyridine and piperidine from tetrahydropyridine
adduct 3a. a) TFA/thioanisole, p-TSA·H2O, RT, 5 h, 88% yield. b) DDQ,
CH2Cl2, RT, 2 h, 70% yield. c) NaBH3CN, RT, 0.5 h, 95% yield, 4:1 d.r.
To better understand the reaction pathway, preliminary
mechanistic investigations were carried out (Scheme 5). Sur-
prisingly, when deuterium labeled 1g’ (>99% D) was used
Scheme 2. Preparative-scale synthesis of tetrahydropyridine.
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G. Zhong et al.
in good to excellent yields (up to 96%) and excellent diaste-
reoselectivities (up to >20:1) using the easily accessible
PPh3 as catalyst. The operation simplicity, broad substrate
generality, and low cost of this process apparently proved its
potential for industrial application. Preliminary mechanistic
study showed this reaction followed an aza-Rauhut–Currier
reaction/intramolecular proton transfer/aza-conjugate addi-
tion sequence. Additional investigations on the application
of this method to construct biologically active molecular
complex and its asymmetric manner are currently underway
in our laboratory.
Experimental Section
General procedure: Vinyl ketone (1, 0.3 mmol) was added to a stirred so-
lution of N-sulfonyl-1-aza-1,3-diene (2, 0.1 mmol), PPh3 (5.24 mg,
0.02 mmol), and 4-methoxyphenol (3.72 mg, 0.03 mmol) in CH2Cl2
(0.2 mL). After completion of the reaction (monitored by TLC), the re-
action mixture was directly applied to column chromatography on silica
gel (acetone/hexane 10:1 to 8:1 as eluent) to give the crystalline product
3.
Scheme 5. Preliminary mechanistic investigation.
there was 40% of the deuterium incorporated at the 5-posi-
tion of 3y’ (experiment a). This interesting phenomenon
suggested that a carbanion at the 5-position might be gener-
ated during the course of reaction. This hypothesis was fur-
ther proved by experiment b. When deuterium labeled N-
sulfonyl-1-aza-1,3-diene 2a’ (>99% D) was subjected to the
standard reaction conditions, as predicted, similar incorpora-
tion of deuterium at the 5-position was observed (experi-
ment b). The erosion of deuterium content probably result-
ed from the presence of adventitious H2O and additives. To
elucidate our speculation, a reaction between 1g and 2a was
conducted in the presence of D2O (10 equiv) under the stan-
dard conditions. The reaction proceeded smoothly to deliver
the product with similar chemical outcomes, in which 69%
deuterium incorporation occurred at the 3-position of 3y’’,
accompanied with 44% deuterium incorporation at the 5-
position (experiment c).
Acknowledgements
Research support from Hangzhou Normal University in China and the
Ministry of Education in Singapore (ARC12/07, No. T206B3225) is grate-
fully acknowledged. We also thank Dr. Yongxin Li for the X-ray crystal-
lographic analysis.
Keywords: annulation · diene ligands · Rauhut–Currier
reaction · tetrahydropyridines · vinyl ketones
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Based on the above observations, a rational mechanism
was proposed (Figure 1). The reaction is initiated by the ad-
dition of PPh3 to the vinyl ketone to generate enolate inter-
mediate 7, which subsequently undergoes the aza-Rauhut–
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In summary, the first example of the aza-Rauhut–Currier
reaction initiated [4+2] annulation between vinyl ketones
and N-sulfonyl-1-aza-1,3-dienes has been developed. This
protocol furnishes highly functionalized tetrahydropyridines
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Received: April 18, 2012
Published online: && &&, 0000
Chem. Eur. J. 2012, 00, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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G. Zhong et al.
Annulation Reactions
Z. Shi, Q. Tong, W. W. Y. Leong,
G. Zhong* ..................... &&&& — &&&&
ACHTUNGTRENNUNG[4+2] Annulation of Vinyl Ketones
Initiated by a Phosphine-Catalyzed
Aza-Rauhut–Currier Reaction: A
Practical Access to Densely Function-
alized Tetrahydropyridines
The first example of phosphine cata-
lyzed aza-Rauhut–Currier reaction ini-
tiated [4+2] annulation of vinyl
ketones with N-sulfonyl-1-aza-1,3-
dienes has been disclosed. Under the
ambient conditions, this protocol pro-
vides a practical access to valuable
densely functionalized tetrahydropyri-
dines in good to excellent yields and
high diastereoselectivities (see
scheme).
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www.chemeurj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!