The diene-transmissive hetero-Diels-Alder reaction of 2-vinyl α,β-unsaturated aldimines: Stereoselective synthesis of hexahydroquinazolin-2-ones

Article abstract of DOI:10.1039/c4ob00224e

Stereoselective synthesis of hexahydroquinazolin-2(1H)-ones has been achieved through the application of the diene-transmissive hetero-Diels-Alder methodology to 2-vinyl-1-aza-1,3-butadienes. The cross-conjugated 1-azatriene underwent an initial hetero-Di

Full text of DOI:10.1039/c4ob00224e

Volume 12 Number 24 28 June 2014 Pages 4033–4266
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Takao Saito et al.
The diene-transmissive hetero-Diels–Alder reaction of 2-vinyl
α,β-unsaturated aldimines: stereoselective synthesis of
hexahydroquinazolin-2-ones

Organic &
Biomolecular Chemistry
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The diene-transmissive hetero-Diels–Alder
reaction of 2-vinyl α,β-unsaturated aldimines:
stereoselective synthesis of hexahydroquinazolin-
2-ones†
Cite this: Org. Biomol. Chem., 2014,
12, 4061
Received 29th January 2014,
Accepted 11th March 2014
DOI: 10.1039/c4ob00224e
Satoru Kobayashi, Kenji Kudo, Ai Ito, Satoru Hirama, Takashi Otani and Takao Saito*
www.rsc.org/obc
Stereoselective synthesis of hexahydroquinazolin-2(1H)-ones has [3]-1-azadendralenes (cross-conjugated 1-azatrienes) for the
been achieved through the application of the diene-transmissive first time.
hetero-Diels–Alder methodology to 2-vinyl-1-aza-1,3-butadienes.
Cross-conjugated azatriene 2 was prepared from the corres-
The cross-conjugated 1-azatriene underwent an initial hetero- ponding 2-vinyl α,β-unsaturated aldehyde 1 and amine by con-
Diels–Alder reaction on the 1-aza-1,3-butadiene system with tosyl densation with TiCl4 and Et3N; the product was used without
isocyanate to afford the [4 + 2] mono-cycloadduct pyrimidinone. isolation due to its instability under aqueous work-up con-
The second Diels–Alder reaction on the electron-rich 1-amino- ditions. N-Phenyl azatriene 2a, prepared in situ, reacted with
1,3-diene unit of the mono-cycloadduct with dienophiles provided tosyl isocyanate at 80 °C to afford the initial [4 + 2] cyclo-
hexahydroquinazolin-2(1H)-ones with high stereoselectivity.
adduct, dihydropyrimidinone 3a, in 97% yield as the sole
product (Scheme 1 and Table 1, entry 1). Similarly, azatrienes
2b–d reacted with tosyl isocyanate to produce [4 + 2] cyclo-
adducts 3b–d, respectively, in excellent to good yield (entries
2–4). Notably, the initial DA reaction with tosyl isocyanate took
place at the azadiene terminus with complete chemo- and
regioselectivity.11
The diene-transmissive Diels–Alder (DTDA) reaction is an
attractive method with which to construct polycyclic ring-fused
compounds in an efficient and stereocontrolled manner.1 The
reaction can be simply defined as two sequential Diels–Alder
(DA) cycloadditions of cross-conjugate trienes ([3]dendra-
lenes).2 Thus, the DTDA reaction consists of an initial DA reac-
tion of cross-conjugated triene or its equivalent (masked cross-
conjugated triene) with a dienophile, and a subsequent DA
reaction with a dienophile on the newly formed diene unit of
the mono-cycloadduct. The hetero-Diels–Alder (HDA) reaction
is one of the most useful and important tools available for the
synthesis of heterocyclic compounds because it can be used
for the straightforward construction of heterocycles with pre-
dictable chemo-, regio-, and stereoselectivities.3 Therefore, the
diene-transmissive hetero-Diels–Alder (DTHDA) methodology
would constitute an efficient and powerful tool for the con-
struction of polycyclic ring-fused heterocycles.4–10 Neverthe-
less, examples of this attractive method have so far been
limited to reactions with [3]-3-heterodendralenes (thia-,4 oxa-,5
and aza-6,7), [3]-1-heterodendralenes (oxa-8,9), and [3]-1,5-dioxa-
dendralenes,10 as shown in Fig. 1. Herein, we report the suc-
cessful implementation of the DTHDA methodology using
Because mono-cycloadduct 3 possesses a pyrimidinone ring
system incorporating a newly formed transmitted electron-rich
1-amino-1,3-diene unit, normal electron-demand DA reactions
were expected to occur. To examine the π-diastereofacial
selectivity of the second DA reaction of 3, a symmetrical and
reactive dienophile, tetracyanoethylene (TCNE), was selected.
The reaction of 3a with TCNE proceeded smoothly at room
temperature to afford the [4 + 2] cycloadduct hexahydroquina-
zolin-2(1H)-one 4a in 90% yield as the sole product (Scheme 2
and Table 2, entry 1). Similarly, the reactions of 3b and 3c with
TCNE produced 4b and 4c, respectively, in 97 and 85% yield.
The stereochemistry of bis-cycloadduct 4 was determined
based on the results of 1H NMR spectroscopic analysis.
Nuclear Overhauser effects (NOE) were observed between H-6
and H-8a, and H-5 and H-6 but, as anticipated, not between
H-8a and H-4. These observations and the structural infor-
mation (trans-relationship between H-8a and H-4) obtained
from X-ray crystallographic analysis of compound 6b
(vide infra) suggest that the dienophile (TCNE) attacks the
diene π-face from the less hindered back H-4 side of 3, avoid-
ing the more bulky phenyl substituent at the 4-position.12
To examine the endo/exo selectivity as well as the
π-diastereofacial selectivity in the second DA reaction of 3, the
reaction with N-phenylmaleimide (N-PhMI) was carried out.
Department of Chemistry, Faculty of Science, Tokyo University of Science,
Kagurazaka, Shinjuku, Tokyo 162-8601, Japan. E-mail: tsaito@rs.kagu.tus.ac.jp;
Fax: +81 (0)3-5261-4631
†Electronic supplementary information (ESI) available: Experimental details and
other electronic format. CCDC 981131. For ESI and crystallographic data in CIF
or other electronic format see DOI: 10.1039/c4ob00224e
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Fig. 1 Reported [3]heterodendralenes used in the DTHDA reaction.
Scheme 1 Imination of 2-vinyl α,β-unsaturated aldehyde 1 and initial cycloaddition of azatriene 2 with tosyl isocyanate.
Table 1 Initial cycloaddition of azatriene 2 with tosyl isocyanate
Entry Azatriene R1
R2
Time (h) Product Yield (%)
1
2
3
4
2a
2b
2c
2d
Ph
Ph
5
4
3
2
3a
3b
3c
3d
97
98
97
60
p-Tol Ph
Bn
Bn
Ph
CO2Me
Scheme 3 The second cycloaddition of 3 with N-phenylmaleimide.
Table 3 The second cycloaddition of 3 with N-phenylmaleimide
Time
(h)
Yield
Product (%)
Entry Diene R1
R2
endo/exoa
Scheme 2 The second cycloaddition of 3 with tetracyanoethylene.
Table 2 The second cycloaddition of 3 with tetracyanoethylene
1
2
3
4
3a
3b
3c
3d
Ph
p-Tol Ph
Bn
Bn
Ph
10
18
10
5a
5b
5c
5d
88
96
98
90
>99 : 1
>99 : 1
>99 : 1
>99 : 1
Ph
CO2Me 10
Entry
Diene
R1
Product
Yield (%)
a Ratio was determined by 1H-NMR spectroscopic analysis. Ratio >99 : 1
denotes that no exo-isomer was detected.
1
2
3
3a
3b
3c
Ph
p-Tol
Bn
4a
4b
4c
90
97
85
The reaction proceeded in toluene at reflux to afford bis-cyclo-
adduct 5 as a single diastereomer in good to excellent yield
with complete π-diastereofacial and endo selectivities. Thus, N-
PhMI cycloadded from the less hindered back H-4 side of the
diene π-face in the endo arrangement (Scheme 3 and Table 3).
Finally, the reaction of mono-cycloadduct 3 with methyl
vinyl ketone was performed to examine the regioselectivity in
addition to the endo/exo and π-diastereofacial selectivities in
the second DA reaction. When diene 3 in toluene was heated
Scheme 4 The second cycloaddition of 3 with methyl vinyl ketone.
to reflux with methyl vinyl ketone (MVK; an excess amount) for nately, Lewis acid TMSOTf (20 mol%) was found to effectively
70 h in a sealed tube, the reaction resulted either in the for- catalyze the desired DA reaction to afford 6a as a single cyclo-
mation of complex mixtures without any cycloadduct adduct in 53% yield, with no other isomers being detected in
(Scheme 4 and Table 4, entry 1) or in the production of 6d in the crude reaction mixture (entry 3).13 TMSOTf also worked
low yield (17%) with an endo/exo ratio of 3 : 1 (entry 2). Fortu- effectively in the reactions of 3b–d to give 6b–d in moderate to
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Table 4 The second cycloaddition of 3 with methyl vinyl ketone
Entry
Diene
R1
R2
Solvent
TMSOTf (mol%)
Temp. (°C)
Time (h)
Product
Yield (%)
endo/exoa
1
2
3
4
5
6
3a
3d
3a
3b
3c
3d
Ph
Bn
Ph
p-Tol
Bn
Ph
CO2Me
Ph
Ph
Ph
Toluene
Toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
—
—
20
20
20
20
113b
70
50
3.6
1
22
46
6a
6d
6a
6b
6c
6d
0
—
113b
17c
53
3 : 1
−20 to 0
−20 to 0
−20 to 0
−20 to rt
>99 : 1
>99 : 1
>99 : 1
>99 : 1
63
56
Bn
CO2Me
43d
a Ratio was determined by 1H NMR spectroscopic analysis. Ratio >99 : 1 denotes that no exo-isomer was detected. b Reaction conducted in a
sealed tube. c 34% recovery of 3d. d 37% recovery of 3d.
good yields. In all cases, the Lewis acid-catalyzed DA reaction hindered H-4 side of 3. The X-ray crystallographic analysis also
proceeded with complete regio- and stereoselectivity.
confirmed the regio- and endo selectivities determined by NOE
The structure of bis-cycloadduct 6 was determined based measurements. We believe that the π-diastereofacial selectivity
on 1H NMR spectroscopic analysis. An endo transition-state (from the less hindered H-4 side of 3) is always the same in
model of the second DA reaction between 3 and MVK to form the second DA cycloaddition with dienophiles.
bis-cycloadduct 6 is depicted in Fig. 2. An NOE was observed
for 6 between H-8 and H-8a, H-7 and H-8a, and between CH3
protons of the acetyl group and H-7′, which is consistent with
the predicted arrangement of MVK (endo and orientation).
However, NMR spectroscopic techniques were not sufficient to
Conclusions
clearly prove the π-facial selectivity of the second DA reaction
(relationship between H-4 and H-8a or H-8a and Ph-H at the
4-position). In contrast, X-ray crystallographic analysis of 6b14
proved unambiguously the trans relationship between H-4 and
H-8a (Fig. 3), suggesting that the π-diastereofacial selectivity
occurs when MVK cycloadds to the diene from the less
The DTHDA reaction of 2-vinyl α,β-unsaturated aldimine has
been developed. The reaction, including aza DA reaction with
tosyl isocyanate in the initial cycloaddition, provides an
efficient new synthetic route to quinazoline derivatives with
high regio- and stereoselectivities.
Notes and references
1 For reviews on cross-conjugated oligoenes (dendralenes)
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Fig. 2 Endo transition-state model and stereochemistry of 6.
Fig. 3 Molecular structure of compound 6b as an ORTEP plot.14
Thermal ellipsoids are shown at the 30% probability level. Hydrogen
atoms on the p-tolyl, phenyl, and methyl groups have been omitted for
clarity.
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2 The term “Diels–Alder” reaction used here refers to a
formal Diels–Alder-type [4 + 2] cycloaddition, and does not
imply a concerted or stepwise reaction mechanism.
T. Takahashi, S. Yoshida, K. Dai, T. Otani and T. Saito,
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7 Very recently, an asymmetric variant of the DTHDA reaction
of [3]-3-azadendralene was reported, see: Z. Jin, R. Yang,
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8 For the DTHDA reaction of [3]-1-oxadendralenes, see:
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227.
11 We concluded that the reaction proceeds in a stepwise
fashion because whereas tosyl isocyanate, with a highly
electrophilic cumulenic center, reacted efficiently, tetra-
cyanoethylene, which is much more reactive than tosyl iso-
cyanate based on the frontier molecular orbital
calculations (lower LUMO), did not react with azatriene 2
under even harsher reaction conditions.
5 For the DTHDA reaction of [3]-3-oxadendralenes, see:
(a) O. Tsuge, T. Hatta, H. Yoshitomi, K. Kurosaka, 12 The observed π-diastereofacial selectivity is consistent with
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41, 225; (b) O. Tsuge, T. Hatta, T. Fujiwara, T. Yokohari and
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6 For the DTHDA reaction of [3]-3-azadendralenes, see:
(a) T. Saito, H. Kimura, T. Chonan, T. Soda and
T. Karakasa, Chem. Commun., 1997, 1013; (b) T. Saito,
our previous study.6 For selected other precedents of selec-
tive π-diastereofacial Diels–Alder reactions of vinyl cyclo-
hexenes, see: (a) J. Franzén, J. Löfstedt, J. Falk and
J.-E. Bäckvall, J. Am. Chem. Soc., 2003, 125, 14140;
(b) H. W. Sünnemann, A. Hofmeister, J. Magull,
M. G. Banwell and A. de Meijere, Org. Lett., 2007, 9, 517.
S. Kobayashi, M. Ohgaki, M. Wada and C. Nagahiro, Tetra- 13 The reaction of 3a catalyzed by other Lewis acids such as
hedron Lett., 2002, 43, 2627; (c) S. Kobayashi, T. Furuya,
T. Otani and T. Saito, Tetrahedron Lett., 2008, 49, 4513;
TiCl4 (20 mol%) and BF3·OEt2 (20 mol%) did not produce
6a.
(d) S. Kobayashi, T. Furuya, T. Otani and T. Saito, Tetra- 14 CCDC 981131 contains the supplementary crystallographic
hedron, 2008, 64, 9705; (e) S. Kobayashi, T. Semba, data for this communication.†
4064 | Org. Biomol. Chem., 2014, 12, 4061–4064
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