Amine-promoted asymmetric (4+2) annulations for the enantioselective synthesis of tetrahydropyridines: A traceless and recoverable auxiliary strategy

Article abstract of DOI:10.1002/anie.201300526

Gone, without a trace: The in situ reaction of 2-(acetoxymethyl)buta-2,3- dienoate and a secondary amine produces a 2-methylene-3-oxobutanoate equivalent that can be used in asymmetric [4+2] annulations with N-tosylimines to provide tetrahydropyridines in

Full text of DOI:10.1002/anie.201300526

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DOI: 10.1002/anie.201300526
Synthetic Methods
Amine-Promoted Asymmetric (4+2) Annulations for the
Enantioselective Synthesis of Tetrahydropyridines: A Traceless and
Recoverable Auxiliary Strategy**
Pengfei Hu, Jian Hu, Jiajun Jiao, and Xiaofeng Tong*
Substituted tetrahydropyridines and piperidines are common
six-membered heterocycles found in biologically active nat-
ural products and synthetic pharmaceuticals.[1] One of the
most versatile and reliable methods to prepare this class of
six-membered heterocycles is the aza-Diels–Alder reaction.[2]
Particularly, the recent development of dienamine catalysis[3]
has added a powerful dimension to the aza-Diels–Alder
reaction, which strongly relies on the formation of the
dienamines developed by the groups of Barbas,[4] Jørgensen,[5]
and Chen[5] by 1,2-addition of the amine catalyst to enone or
enal (Scheme 1). Despite extensive studies and noteworthy
dienoate (1; Scheme 1). Indeed, we have recently demon-
strated that 1 readily reacts with a Lewis base catalyst,
undergoing a continuous process, including Michael-addition
of the catalyst and 1,2-elimination of the acetate group, to
form a 1,n-bis electrophilic intermediate (n = 3,4).[8] Thus, we
envisioned that dienamine 2 would also result from the
reaction of 1 and secondary amines with the assistance of
a base by a similar addition–elimination process (Scheme 1).
Herein we report an amine-promoted asymmetric (4+2)
annulation of 1 with N-tosylimine for the enantioselective
synthesis of tetrahydropyridine. Furthermore, an analogue of
intermediate 2 was detected by 1H NMR spectroscopy, which
represents a novel type of push–pull dienamine,[9] and
provides a route to a 2-methylene-3-oxobutanoate equivalent
in dienamine chemistry.
We initiated our research by examining various chiral
secondary amines 4 as catalysts for the reaction of 1 (1 equiv)
and imine 3a (2 equiv) in toluene solution in the presence of
K3PO4·3H2O (1.2 equiv; Scheme 2). Commonly used amines
Scheme 1. Methods of dienamine formation. E=CO2R.
advances in this field, the utilization of 2-methylene-3-
oxobutanoate, a molecule potentially prone to polymeri-
zation,[6] as an enone-type substrate remains challenging. This
may be due to their competitive Michael addition,[7] which
renders the required dienamine intermediate 2 less likely to
be formed (Scheme 1).
We address this issue using an unprecedented and
alternative approach, namely a 2-methylene-3-oxobutanoate
equivalent formed through an addition–elimination reaction
between a secondary amine and 2-(acetoxymethyl)buta-2,3-
Scheme 2. Screening of chiral secondary amines. Bn=benzyl,
n.d.=not determined, Ts=p-toluenesulfonyl.
[*] P. Hu, J. Hu, Prof. J. Jiao, Dr. X. Tong
Key Laboratory for Advanced Materials and Institute of Fine
Chemicals, East China University of Science and Technology
Meilong Road No. 130, Shanghai, 200237 (China)
E-mail: tongxf@ecust.edu.cn
4a–4c were found to be inactive. This may be attributed to the
large steric hindrance around the secondary amine center,
which should strongly inhibit the Michael addition of amine
to substrate 1. Indeed, amine 4d, with the less steric benzyl
group, led to the desired (4+2) annulation product 5a very
slowly, but gave an encouraging 45% yield and 43% ee. We
then turned our attention to chiral morpholine derivatives
4e–4g, which are readily synthesized by a known procedure
from commercially available amino alcohols.[10] We were
delighted to find that 4e was the optimal one, resulting in the
[**] We are grateful for financial support from NSFC (21002025 and
21272066), NCET (12-0851), the Fundamental Research Funds for
the Central Universities, Shanghai Rising-Star Program
(11A1401700), and Fok Ying-Tong Education Foundation for Young
Teachers in the Higher Education Institutions of China (131011).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201300526.
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Table 1: Substrate scope for the one-pot reactions.[a]
isolation of 5a in 34% yield and 73% ee, although a very long
reaction time (15 days) was also required at room temper-
ature (Scheme 2).
Disappointingly, we failed to improve the catalytic
reaction through screening a variety of bases, solvents,
reaction temperature, and additives.[11] Thus, we made
recourse to an alternative strategy. We found that the reaction
of 1 (0.2 mmol) and 4e (0.24 mmol) in [D8]toluene solution in
the presence of K3PO4·3H2O (0.24 mmol) could go to
completion within 12 h, even at À108C (Scheme 3), and
Entry
3
5
Yield
[%][b]
ee
[%][c]
1
2
3
4
5
6
7
8
3a (R1 =H, R2 =H, R3 =CN)
3b (R1 =H, R2 =H, R3 =F)
3c (R1 =H, R2 =H, R3 =Cl)
3d (R1 =H, R2 =H, R3 =Br)
3e (R1 =H, R2 =H, R3 =CF3)
3 f (R1 =H, R2 =H, R3 =Me)
3g (R =H, R –R = OCH2O )
3h (R1 =H, R2 =H, R3 =H)
3i (R1 =H, R2 =NO2, R3 =H)
3j (R1 =Br, R2 =H, R3 =H)
3k (R1 =NO2, R2 =H, R3 =H)
3l (R1 =CO2Me, R2 =H, R3 =H)
3m (X=S)
5a
5b
5c
5d
5e
5 f
5g
5h
5i
5j
5k
5l
5m
5n
5o
90
94
94
91
81
85
53
86
88
91
53
94
64
80
51
91
92
92
94
88
90
90
87
80
95
95
95
92
70
85
1
2
3
À
À
9
10
11
12
13
14
15
3n (X=O)
3o
[a] Reaction conditions: 1 (0.2 mmol), 4e (1.2 equiv), 3 (2 equiv), and
K3PO4·3H2O (1.2 equiv), toluene (2 mL), À108C, 24 h, then aqueous
HCl (6n, 5 mL) and THF (5 mL), RT, 6 h. [b] Yield of isolated product.
[c] Determined by HPLC analysis on a chiral stationary phase.
Bn=benzyl, Ts=p-toluenesulfonyl.
Scheme 3. Stoichiometric Reactions. E=CO2Bn.
1H NMR analysis clearly demonstrated the formation of
dienamine 2e (Supporting Information, Figure S1). This
result strongly implied that the corresponding addition–
elimination process would be a fast step (Scheme 3). A
relatively rapid and complete conversion of 2e into the (4+2)
annulation intermediate 6, which was detected by ESI-HRMS
analysis (Figure S2), was also observed when imine 3a
(0.4 mmol) was subsequently added (Scheme 3). To our
surprise, neither product 5a nor catalyst 4e were detected,
even when the reaction mixture was stirred at room temper-
ature for 15 days. This observation may be attributed to the
fact that enamine intermediate 6 is so stable that its hydrolysis
is sluggish under these conditions,[12] which may be an intrinsic
obstruction to the development of an optimal catalytic
version. However, simple treatment of the reaction mixture
with aqueous hydrochloric acid (6n) allowed the isolation of
5a in 72% yield with 90% ee. Furthermore, amine 4e was also
easily recovered in quantitative yield without column chro-
matography (Scheme 3).[13] In this way, amine 4e acts as
a traceless and recoverable auxiliary.[14]
These results notwithstanding, we continued our pursuit
of a synthetically useful 2-methylene-3-oxobutanoate equiv-
alent for the enantioselective synthesis of tetrahydropyridines
using dienamine 2e. In view of the inefficiency of the catalytic
reaction, we chose to focus on the development of a strategy
utilizing a traceless and recoverable auxiliary. Ultimately, we
identified a one-pot method: slow addition of 1 into a toluene
solution of 4e (1.2 equiv), 3d (2 equiv), and K3PO4·3H2O
(1.2 equiv) at À108C, and subsequent acidic workup by the
addition of aqueous hydrochloric acid (6n) and THF after
completion of the [4 + 2] annulation, could afford product 5a
in 90% yield and 91% ee (Table 1).[11]
As illustrated in Table 1, this one-pot method can be
applied to an array of aryl N-tosylimines, affording the
desired products in excellent yields and enantioselectivities.
Generally, the aromatic ring can be ortho-, meta-, or para-
substituted. It can also bear an electron-withdrawing or an
electron-donating group, although the latter case gives
slightly worse results with respect to the reaction yield and
enantioselectivity. Some other heteroaromatic N-tosylimines,
such as 3m and 3n, were also tested, both of which worked
well to give the corresponding products in good yields and
enantioselectivities. The substrate trans-styrenyl N-tosylimine
smoothly undergoes (4+2) annulation to deliver 5o in 51%
yield and 85% ee. In all cases, quantitative amounts of amine
4e were recovered with > 95% purity.
The absolute configuration of 5d was determined to be S
by X-ray crystal structure analysis.[18] The stereochemistry of
all other products is assigned by analogy. The observed
enantioselectivity can be explained by the proposed transi-
tion-state model shown in Scheme 4. Because the bottom face
of dienamine 2e is blocked by its benzyl group, tosylimine 3d
approaches from the upper side to furnish the Diels–Alder
reaction in an endo fashion, delivering the observed (S)-5d
(Scheme 4).
Furthermore, cyclic imine 3p reacted well with 1 under
the standard conditions, affording product 5p in 90% yield,
albeit with very low ee [Eq. (1)]. This low enantioselectivity is
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resulting dienamine intermediate 2e is shown to readily
undergo aza-Diels–Alder reaction with tosylimine. Although
the 4e-catalyzed reaction provides unsatisfying results, the
stoichiometric version affords substituted tetrahydropyri-
dines in good to excellent yields and enantioselectivities.
Amine 4e can be recovered quantitatively through a simple
workup, thus serving as a traceless and recoverable auxiliary.
Further studies regarding the development of other (4+2)
annulations and applications of this method are ongoing and
will be reported in due course.
Scheme 4. Proposed transition state model. Thermal ellipsoids set at
20% probability.
Received: January 21, 2013
Revised: February 19, 2013
Published online: April 9, 2013
Keywords: cycloaddition · dienamine · elimination ·
.
nucleophilic addition · tetrahydropyridine
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tion with N-tosylimine.
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