Catalytic enantioselective aza-Diels-Alder reactions of unactivated acyclic 1,3-dienes with aryl-, alkenyl-, and alkyl-substituted imines

Article abstract of DOI:10.1039/c7cc03010j

A catalytic enantioselective aza-Diels-Alder reaction of unactivated acyclic dienes with aryl-, alkenyl-, and alkyl-substituted imines is described. With 5-10 mol% loadings of a new Br?nsted acid catalyst, the aza-Diels-Alder reaction of unactivated acyclic dienes proceeded to give the corresponding aza-Diels-Alder adducts in high yields (up to 98%) with excellent enantioselectivity (up to 98% ee). Preliminary DFT calculations suggest that the reaction proceeds through a chiral ion pair intermediate.

Full text of DOI:10.1039/c7cc03010j

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
first methanofullerene derivatives of Sc N@D5h-C80
=
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Catalytic Enantioselective Aza-Diels-Alder Reactions of
Unactivated Acyclic 1,3-Dienes with Aryl-, Alkenyl-, and Alkyl-
Substituted Imines†
Received 00th January 20xx,
Accepted 00th January 20xx
Yasuo Hatanaka*, Shuuto Nantaku, Yuhki Nishimura, Tomoyuki Otsuka, and Tohru Sekikaw
DOI: 10.1039/x0xx00000x
www.rsc.org/
Catalytic enantioselective aza-Diels-Alder reaction of unactivated dienes such as 1,3-dimethylbutadiene in catalytic asymmetric ADA
acyclic dienes with aryl-, alkenyl-, and alkyl-substituted imines is reaction is attributable to the lower HOMO energy level than that of
described. With 5-10 mol % loadings of new Brønsted acid activated electron-rich dienes such as Danishefsky’s diene (Scheme
catalyst, the aza-Diels-Alder reaction of unactivated acyclic dienes 1).6 The low HOMO energy level of the unactivated acyclic dienes
proceeded to give the corresponding aza-Diels-Alder adducts in leads to a large energy gap between the HOMO of dienes and the
high yields (up to 98%) with excellent enantioselectivity (up to LUMO of imine dienophiles.
98% ee). Preliminary DFT calculations suggest that the reaction
proceeds through a chiral ion pair intermediate.
Herein, we describe an enantioselective normal-electron
demand ADA reaction of unactivated acyclic dienes with aryl-,
alkenyl- and alkyl-substituted imines catalyzed by chiral
Brønsted acids to furnish tetrahydropyridines in good yields
with high enantioselectivities (Scheme 1a), whereas the
reaction of Danishefsky-type dienes with imine dienophiles
gives dihydropyridones as the products (Scheme 1b).4
The synthesis of chiral tetrahydropyridines and tetrahydropyridine-
derived piperidines has been in the focus of the research for new
pharmaceuticals, synthetic building blocks, and natural product
synthesis.1 The catalytic asymmetric aza-Diels-Alder reaction (ADA
reaction) is the most powerful and convergent strategies for the
enantioselective synthesis of tetrahydropyridine derivatives.2 The
ADA reactions are classified into two types: (a) the normal-electron
demand ADA reaction of 1,3-butadienes with imine dienophiles, and
(b) inverse-electron demand ADA reaction of aza-1,3-butadienes
with dienophiles (Scheme 1a and 1b).2e In contrast to the recent
great progress in the enantioselective inverse-electron demand ADA
reaction catalyzed by chiral Lewis acids and organocatalysts,3 there
remains a critical problem with the catalytic asymmetric normal-
electron demand ADA reaction. Thus, the highly enantioselective
normal-electron demand ADA reactions that have been reported so
far are mostly limited to the reaction of electron-rich dienes such as
Brassard’s diene and Danishefsky-type dienes activated by electron-
donating substituents, significantly limiting the scope of the
reaction.2,4 Although the catalytic asymmetric normal-electron
demand ADA reaction of cyclic dienes and unactivated acyclic
dienes with strongly electron-deficient dienophiles such as 2-
arylindol-3-ones and N-tosyl-α
-iminoesters have been reported,5 the
extension to more general ADA reaction of unactivated acyclic
dienes with aryl-, alkenyl- and alkyl-substituted imine dienophiles
seems to be difficult.2e The low reactivity of unactivated acyclic
Scheme 1. Normal-electron demand aza-Diels-Alder reactions
With the purpose of evaluating the catalytic activity of a
Department of Applied Chemistry, Osaka City University, Sumiyoshiku,
Sugimotocho, Sugimoto, Osaka 558-8585, Japan
E-mail: hatanaka@a-chem.eng.osaka-cu.ac.jp
series of (
BINOL-derived phosphoric acids,7 the catalytic asymmetric
ADA reaction of 2,3-dimethyl-1,3-butadiene 1a with -tosyl
R)-BINOL-derived N-triflylphosphoramides and (R)-
†
Electronic
DOI: 10.1039/x0xx00000x
Supplementary
Information
(ESI)
is
available:
see
N
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phenylimine
acid catalysts at room temperature. As shown in Table 1, (
BINOL-derived phophoric acid 4a failed to catalyze the (R)-3 in quantitative yield (99%) with 17% ee (entry 3). Catalyst
reaction, giving the corresponding Diels-Alder adduct ( )-
in 4d11a having sterically demanding 1-naphthyl substituents at the
very low yield (9%) with moderate enantiomeric excess (ee
(47% ee) (entry 1). The absolute configuration of the product
2
was examined at 10 mol % loading of Brønsted positions of BINOL moieties on the reaction. The use of catalyst
R
)- 4c11a bearing 2-naphthyl substituents at the 3,3’-positions afforded
R
3
)
3,3’-positions improved the ee (39% ee), whereas the yield dropped
3
considerably (75%). (entry 4). Since the addition of molecular sieve
was assigned by analogy with compound 3ai (Table 2, entry to reaction mixture often provides a better stereoselectivity of the
13).8
organocatalyzed asymmetric reaction, the 4d-catalyzed reaction was
carried out with MS 4Å (50 mg), but the ee considerably decreased
(entry 5). Introduction of electron-withdrawing substituents to the
3,3’-position of BINOL moiety resulted in a increase in reaction rate.
Table1. Catalytic aza-Diels-Alder Reaction between 1a and 2.a,b
For
example,
3,3’-[3,5-(CF3)2C6H3]2BINOL-derived
N-
triflylphosphoramide 4e11a exhibited higher catalytic activity to
accomplish the reaction within 10 h, giving (R)-3 in 75% yield,
while the enantioselectivity was low (19% ee) (entry 6). The
reaction catalyzed by 4f,11b which bears bulky 2,4,6-
tri(isopropyl)phenyl substituents at the 3,3’-position of the BINOL
moiety, gave (R)-3 with the highest ee (87% ee) in moderate yield
(67%) (entry 7). Next, we have synthesized catalyst 4g by
introducing strongly electron-withdrawing CF3 groups to the 6,6’-
positions of catalyst 4f. A significant improvement of catalytic
performance was observed by the employment of 4g in the reaction.
Even at 5 mol % loading of 4g, the ADA reaction between 1a and 2
smoothly took place to complete the reaction within 24 h, affording
adduct (R)-3 in 75% yield with good enantioselectivity (85% ee)
(entry 10). BINOL-derived N-triflylthiophosphoramide 4h,11c which
have stronger acidity than N-triflylphosphoramides,9 failed to
catalyze the reaction between 1a and 2, because of the H+-promoted
polymerization of diene 1a (entry 11).
Further investigation revealed that the N-protecting groups of
imines profoundly influence the enantioselectivity and the yields of
the 4g-catalyzed ADA reaction. By replacing N-tosyl group of
phenylimine 2 with N-SO2-2-naphthyl group, the enantioselectivity
and the yield of the aza-Diels-Alder adduct considerably increased.
We were pleased to find that 5 mol % loading of catalyst 4g
effectively promoted the reaction of N-SO2-2-naphthyl phenylimine
2a and 1,3-dimethylbutadiene 1a, furnishing the corresponding
adduct 3aa in high yield (87%) with high enantioselectivity (93% ee)
at room temperature (Table 2, entry 1). As a N-protecting group, N-
SO2-1-naphthyl was ineffective, making the reaction very sluggish.
Moreover, phenylimines having 4-MeOPh, PhCH2, Cbz, and BOC
Entry Catalyst Reaction time (h) Yield [%]c
Ee [%]d
47
9
1
2
4a
4b
4c
4d
4d
4e
4f
48
16
34
48
48
10
48
96
24
24
12
9
89
99
75
63
75
67
27
78
75
0
3
17
39
28
19
87
56
73
85
-
4
5e
6
7
8e
4f
9
4g
4g
4h
10f
11
aAbsolute configuration of
3ai (Table 2, entry 13). Reaction of 0.75 mmol of butadiene 1a and
3 was assigned by analogy with compound
b
0.25 mmol of N-tosylphenylimine 2 with 10 mol % loading of catalyst
4
was carried out in CHCl3 at room temperature unless otherwise noted. as N-protecting groups failed to undergo the 4g-catalyzed reaction
cIsolated yield. dObtained by chiral HPLC analysis. eReaction was
with 1a.
We then turned our attention to the substrate scope of the 4g-
f
conducted in the presence of 4 Å MS (50 mg). The reaction was
conducted with 5 mol % loading of 4g
catalyzed ADA reaction in chloroform at room temperature. Table 2
shows that 5-10 mol % loadings of catalyst 4g allowed the complete
conversion of aryl- and alkenyl-substituted imines in the reaction
with unactivated acyclic dienes (3 eq.), giving the corresponding
adducts in good yields with very high ee (entries 2-13). A series of
aromatic imines having aromatic rings substituted with Me, MeO,
and Cl smoothly reacted with 1,3-dimethylbutadiene 1a with 5
mol % of 4g, affording the corresponding adducts 3 in good yields
(70-81%) with high enantiomeric excess (85-96% ee) (entries 2-6).
Furthermore, sterically demanding 1-naphthylimine 2g effectively
underwent the 4g-catalyzed reaction with 1a, furnishing 3ag in 71%
yield with 98% ee (entry 7). It should be noted that the reaction of
The low catalytic activity of 4a can be ascribed to the weak
acidity of 4a (pKa = 12-14 in MeCN),9 indicating the role of 4a as a
chiral Brønsted acid reagent in this reaction.10
We have found that stronger Brønsted acids, (R)-BINOL-derived N-
triflylphosphoramide catalysts 4b-4g (pKa = 6-7 in MeCN),9 are
capable of promoting the asymmetric ADA reaction between 1a and
2 to afford aza-Diels-Alder adduct (R)-3 in moderate-to-high yields
(entries 2-10). Solvent screening indicated chloroform to be the
solvent of choice. Thus, with a 10 mol % of 4b, (R)-3 was obtained
in high yield (89%), but the ee was very low (9% ee) (entry 2). We
explored the effect of substutuents at the 3,3’-positions and 6,6’-
1,3-dimethylbutadiene 1a or isoprene 1b with (E)-β-phenylethenyl-
2 | J. Name., 2012, 00, 1-3
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substituted imine 2h took place selectively at the C=N bond of 2h
to afford the corresponding aza-Diels-Alder adducts 3ah and 3bh in
good yields (92% and 98%, respectively) with very high
enantioselectivities (96% ee and 97% ee, respectively) with no trace
of the Diels-Alder adducts (entries 8 and 12). The ADA reactions of
less reactive isoprene 1b with arylimines 2 needed 10 mol % loading
of 4g in addition to longer reaction time for the reaction completion
(140-300 h) (entries 9-12). However, the reactions exhibited the
very high level of enantioselectivities (83-97% ee), affording the
corresponding adducts 3ba, 3bb, and 3bh in moderate-to-high yields
(58-98%). Next, we examined the catalytic enantioselective ADA
reaction of unactivated diene 1a with in situ formed aliphatic imines.
Aliphatic imines have been often problematic dienophiles even
in the asymmetric ADA reaction with reactive Danishefsky’s diene,
since aliphatic imines are enolizable and prone to decomposition.2e
Scheme 2. Three component aza-Diels-Alder reaction.
Thus, the three-component ADA reaction
of
aliphatic
aldehydes 5, 2-naphthalenesulfonamide 6, and diene 1a was carried
out with 10 mol % loading of catalyst 4g in chloroform, furnishing
the aza-Diels-Alder adducts 7 (Scheme 2).The ADA reaction of 2-
phenylethyl-substituted imine derived from
6
with 3-
phenylpropionaldehyde 5a gave 7a in 46% yield with 52% ee.
Under the same reaction conditions, the ADA reaction of hexyl-
substituted imine derived from heptanal 5b and 6 afforded 7b in
40% yield with 57% ee. Although the yields and enantioselectivities
of the reactions remain moderate, the present method is potentially
promising as a highly stereoselective route to chiral alkyl-substituted
tetrahydropyridines and piperidines, which are ubiquitous structural
feature of alkaloid natural products and drug candidates.1
Table 2. Aza-Diels-Alder reaction catalyzed by 4g.a,b
To shed light on the mechanism accounting for the
observed enantioselectivity of the 4g-catalyzed ADA reaction,
DFT calculations of the substrates and the catalyst-substrate
adduct were carried out. The mechanism of the activation of
imines by Brønsted acid catalysts has not been fully clarified.
Entry[b]
Diene
Imine
t (h)
Product
Yield [%][c]
Ee [%][d]
However, in view of the strong acidities of
triflylphosphoramids,9 it is reasonable to assume that 4g
catalyzed ADA reaction proceeds via complete protonation of
imine dienophile, which affordes ion pair consisting of chiral
amide anion and (
)-iminium cation (Scheme 3).12 The 19F
NMR spectra of the mixture of 4f and phenylimine 2a 4f 2a
1/10, CDCl3) indicated that the
(19F) of CF3 group of 4f is
N-
-
1
2
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1a
2a
2b
2c
2d
2e
2f
48
62
3aa
3ab
3ac
3ad
3ae
3af
87
70
81
76
74
71
71
92
58
68
50
98
64
93
89
85
96
87
94
98
96
94
83
95
97
89
A
Z
3
62
(
/
=
δ
4
96
shifted to -80.5 ppm from -78.3 ppm upon the addition of 2a
,
5
62
suggesting a variation of the local charge around CF3 group.
6
72
7
2g
2h
2a
2a
2b
2h
2i
91
3ag
3ah
3ba
3ba
3bb
3bh
3ai[g]
8
43
9[e]
10[e][f]
11[e]
12[e]
13
300
140
300
120
38
Scheme 3. Mechanism accounting for enantioselectivity.
aAbsolute configuration of product
3 was assigned by analogy with
b
compound 3ai (entry 13). Reaction of 0.75 mmol of butadienes 1 and 0.25
mmol of imines 2 was conducted with 5 mol % loading of 4g at room
temperature unless otherwise noted. cIsolated yield. dObtained by chiral
HPLC analysis. eReaction was conducted with 10 mol % of 4g. fReaction was
conducted at 50 oC. gAbsolute configuration of compound 3ai was
unequivocally determined by X-ray crystallographic analysis.
Approach of diene to the re-face of iminium cation takes place
to afford (R)-aza-Diels-Alder adduct. The si-face of the iminium
cation is considered to be shielded by the amide anion. (Z)-Iminium
cation is likely bound to the chiral amide anion by a hydrogen bond
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65, 141-599; (b) G. B. Rowland, E. B. Rowland, Q. Zhang and J.
C. Antilla, J. C., Curr. Org. Chem. 2006, 10, 981-1005; (c) V. V.
Kouznetsov, Tetrahedron 2009, 65, 2721-2750; (d) P. R.
to oxygen atom of SO2 moiety of the amide anion (charges of two
oxygen atoms: -0.53 for O---H and -0.65; Mulliken charges
calculated at B3LYP/6-31G(d) level). Although nitrogen atom of
the amide anion (-0.67) and oxygen atom of O=P moiety (-0.55) bear
large negative charges, hydrogen bond formation of iminium cation
with amide nitrogen as well as oxygen of O=P moiety seems to be
difficult due to steric repulsion (Figure 1). It is probable that the
iminium cation involved in ion pair A has (Z)-geometry, because
linear (E)-iminium cation is too bulky in sterically congested
environment of the amide anion (Figure 1). With these assumptions
in mind, we optimized the simplified structure of chiral ion pair A at
B3LYP/6-31G(d) level. The results of the theoretical calculations are
in fair agreement with the speculated reaction mechanism. The
optimization of simplified structure of A discloses that a hydrogen
bond between the iminium cation and oxygen atom of SO2 moiety of
amide anion is formed so as to avoid the steric repulsion between the
i-Pr group on BINOL and N-tosyl group of the (Z)-iminium cation.
H-Bond length (1.56 Å) as well as the N-H-O angle (172°) indicate
the formation of a fairly strong H-bond,13 suggesting that the ion pair
A is effectively stabilized by the H-bonding. The i-Pr substituent on
the BINOL shields the si-face of the iminium cation. The addition
of diene to the iminium cation takes places at the exposed re-face of
the iminium cation, predicting the sense of asymmetric induction.
In conclusion, in the presence of new Brønsted acid catalyst,
unactivated acyclic dienes react with aryl- and alkeny-substituted
imines to give the ADA-adducts in good yields with high
enantioselectivities.14 However, the reaction of alkyl-substituted
imines remained moderate ee and moderate yields.
Girling, T. Kiyoi and A. Whiting, Org. Biomol. Chem, 2011, 9,
3105-3121; (e) G. Masson, C. Lalli, M. Benohoud and G.
Dagousset, Chem. Soc. Rev. 2013, 42, 902-923; (f) K. Ishihara,
A. Sakakura, in Comprehensive Organic Synthesis II, ed. P.
Knochel and G. A. Molander, Elsevier, Amsterdam, 2014, pp.
409-465.
For recent review, see: (a) X. Jiang and R. Wang, Chem. Rev.
2013, 113, 5515-5546. For selected recent reports, see: (b) B.
Chen, Z. Wang, G. Wang and J. Z. Sun, Angew. Chem. Int. Ed.
2013, 52, 2027-2031; (c) Y. Deng, L. Liu, R. G. Sarkisian and K.
Wheeler, Angew. Chem. Int. Ed. 2013, 52, 3663-3667; (d) Y.
Watanabe, T. Washio, J. Krishnamurthi, M. Ando and S.
Hashimoto, Chem. Commun. 2012, 48, 6969-6971; (e) X.
Feng, Z. Zhou, C. Ma, X. Yin, R. Li, L. Dong, and Y. –C. Chen,
3
4
5
Angew. Chem. Int. Ed. 2013, 52, 14173-14176; (f) V.
Eschenbrenner-Lux, P. Küchler, S. Ziegler, K. Kumar and H.
Waldmann, Angew. Chem. Int. Ed. 2014, 53, 2134-2137.
For selected recent reports of the asymmetric normal-
electron demand ADA reactions of activated dienes, see: (a)
V. I. Maleev, T. V. Skrupskaya, L. V. Yashkina, A. F.
Mkrtchyan, A. S. Saghyan, M. M. Il‘ii and D. A. Chusov,
Tetrahedron. Asym. 2013, 24, 178-183; (b) H. Zheng, X. Liu, C.
Xu, Y. Xia, Y., L. Lin and X. Feng, Angew. Chem. Int. Ed. 2015,
54, 10958-10962; (c) H. Hu, C. Meng, Y. Dong, X. Li and J. Ye,
ACS Catal. 2015,
5, 3700-3704; (d) M. P. Lalonde, M. A.
McGowan, N. S. Rajapaksa and E. N. Jacobsen, J. Am. Chem.
Soc. 2013, 135, 1891-1894; (e) C. Beceño, T. Krappitz, G.
Raabe and D. Enders, Snthesis 2015, 47, 3813-3821.
(a) M. Rueping and S. Raja, Bielstein J. Org. Chem. 2012,
1819-1824; (b) S. Yao, S. Saaby, R. G. Hazell and K. A.
Jørgensen, Chem. Eur. J. 2000, , 2435-2448; (c) J. –X. Liu. Q.
8.
6
This work has been supported by a Grant-in-Aid for Scientific
Research (C) (17K05865) from JSPS.
–Q. Zhou, J. –G. Deng and Y. –C. Chen, Org. Biomol. Chem.
2013, 11, 8175-8178.
See Supporting Information for details.
For recent reviews on the asymmetric Brønsted acid-
catalyzed reactions, see: (a) M. Terada, Synthesis 2010, 1929-
1982; (b) P. S. Bhadury and Z. Sun, Curr. Org. Chem. 2014,
18, 127-150 (c) C. M. R. Volla, I. Atodiresei and M. Rueping,
M. Chem. Rev. 2014, 114, 2390-2431.
6
7
8
9
Configuration of compound 3ai was unequivocally
determined by X-ray crystallographic analysis: CCDC
1508051.
K. Kaupmees, N. Tolstoluzhsky, S. Raja, M. Rueping and I.
Leito, Angew. Chem. Int. Ed. 2013, 52, 11569-1157.
10 Asymmetric normal-electron demand ADA reaction of
unactivated dienes promoted by silicon Lewis acid: K. U.
Tambar, S. K. Lee and J. L. Leighton, J. Am. Chem. Soc. 2010,
132, 10248-10250.
11 (a) M. Rueping, B. J. Nachtsheim, J. Bors, S. A. Moreth and M.
Bolte, Angew. Chem. Int. Ed. 2008, 47, 593-596; (b) D.
Nakashima and H. Yamamoto, H. J. Am. Chem. Soc. 2006,
128, 9626-9627; (c) N. D. Shapiro, V. Rauniyar, G. L.
Figure 1. Simplified structure of chiral ion pair A optimized at B3LYP/6-31G(d)
level. Hydrogen atoms without polar one are omitted for clarity.
Hamilton, J. Wu, F. D. Toste, Nature, 2011, 470, 245-250.
12 (a) M. Fleischmann, D. Drettwan, E. Sugiono, M. Rueping and
R. M. Gschwind, Angew. Chem. Int. Ed. 2011, 50, 6364-6369;
(b) M. Rueping, U. Uria, M. –Y. Lin and I. Atodresi, J. Am.
Chem. Soc. 2011, 133, 3732-3735.
Notes and references
13 G. A. Jeffrey, An Introduction to Hydrogen Bonding, Oxford
University Press, New York, 1997, pp. 11-16.
1
For reviews, see: (a) P. M. Weintraub, J. S. Sabol, J. M. Kane
and D. R. Borcherding, Tetrahedron. 2003, 59, 2953-2989; (b)
M. G. P. Buffat, Tetrahedron 2004, 60, 1701-1729; (c) C.
14 Under the same conditions, cyclopentadiene failed to
undergo the ADA reaction with phenylimine because of the
polymerization of cyclopentadiene. Cyclohexadines reacted
with phenylimine, giving the corresponding adducts (86%,
endo/exo = 50/50. 43% ee (endo), 12% ee (exo).
Escolano, M. Amat and J. Bosch, Chem. Eur. J. 2006, 12
8198-8207.
,
2
For selected recent reviews, see: (a) G. R. Heintzelman, I. R.
Meigh, Y. R. Mahajan and S. M. Weinreb, Org. React. 2005,
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