Highly diastereoselective hetero-Diels-Alder reactions of alkenyldihydrooxazoles as an approach to novel pyrimidine derivatives

Article abstract of DOI:10.1039/a705571d

Chiral 2-alkenyldihydrooxazoIes react with two equivalents of aryl and arylsulfonyl isocyanates to give chiral non-racemic dihydropyrimidone derivatives in high yield and with complete diastereocontrol.

Full text of DOI:10.1039/a705571d

View Article Online / Journal Homepage / Table of Contents for this issue
Highly diastereoselective hetero-Diels–Alder reactions of
alkenyldihydrooxazoles as an approach to novel pyrimidine derivatives
Mark C. Elliott* and Elbertus Kruiswijk
Department of Chemistry, University of Wales Cardiff, PO Box 912, Cardiff, UK CF1 3TB
Chiral 2-alkenyldihydrooxazoles react with two equivalents
Me
O
Me
N
of aryl and arylsulfonyl isocyanates to give chiral non-
Ph
Ph
O
racemic dihydropyrimidone derivatives in high yield and
with complete diastereocontrol.
N
PhN
H
N
i
3
N
O
O
O
Despite the proven synthetic utility of the all-carbon Diels–
Alder reaction,1 the aza analogue has been much less investi-
gated.2,3 It offers the opportunity to prepare a wide range of
biologically interesting piperidines in a single step with control
over three stereogenic centres. We considered the possibility
that alkenyldihydrooxazoles 1 could act as aza-dienes,4 and
since these compounds are readily available in enantiopure form
from amino alcohols, an asymmetric aza-Diels–Alder reaction
as shown schematically in Scheme 1 is an attractive possibility.
To the best of our knowledge there is only one example of the
use of alkenyldihydrooxazoles as aza-dienes. However, the
reported infrared stretching absorption of the product (1760
cm21) seems inconsistent with the assigned structure 2 (Scheme
2).5 Since neither the yield nor reaction conditions were
reported, we felt it would be useful to investigate the reactions
of alkenyldihydrooxazoles with isocyanates as a prelude to a
broader study.6,7
Et
Et
8a
7
Scheme 4 Reagents and conditions: i, 2 equiv. PhNCO, 150 °C for 1 h or
25 °C for 24 h
obtained to which structure 8a was assigned on the basis of
spectroscopic data.†,‡ In fact, this reaction proceeds at room
temp. (24 h), and at either temperature only a single diastereo-
isomer was observed (Scheme 4). Presumably this reaction
proceeds via addition of a second molecule of phenyl isocyanate
to compound 7. The absence of any other products in the 1H and
13C NMR spectra of the crude reaction mixture conducted under
a wide range of stoichiometries lead us to conclude that this
process is faster than the hetero-Diels–Alder reaction. For a
such a small chiral directing group this selectivity is particularly
impressive.
To this end, dihydrooxazoles 3–6 were prepared as shown in
Scheme 3 from readily available (R)-2-aminobutan-1-ol.
When 3 was heated in a sealed tube (150 °C, 1 h) with 2
equiv. of phenyl isocyanate, an essentially pure 2 :1 adduct was
The reactions of 3–5 with five different isocyanates gave
similar results as shown in Table 1. In each case only a single
Table 1 Reactions of 3, 4 and 5 with selected isocyanates
R5
R5
R2
R
N
O
O
R
N
a R1 = Ph
R1
R4
R1
R4
R2
R3
R1
O
R1N
H
N
b R1 = 4-BrC6H4
c R1 = 4-O2NC6H4
d R1 = 4-MeOC6H4
e R1 = 4-MeC6H4SO2
i
N
N
R
O
O
O
R3
Et
Et
R
1
3 R = Me
4 R = Et
5 R = Ph
8 R = Me
9 R = Et
10 R = Ph
Scheme 1
Ph
Ph
O
N
•
Compound
N
R1
R2
Ph
t/h
T/°C
(yield %)a
N
O
N
O
O
Me
Me
Me
Me
Me
Et
Et
Et
Et
Et
Ph
Ph
Ph
Ph
Ph
48
24
21
120
0.5
1
25
25
25
25
25
150
150
150
—
8a (58)
8b (61)
8c (82)
8d (65)
8e (59)
9a (53)
9b (61)
9c (71)
9d (0)b
9e (90)
10a (76)
10b (59)
10c (74)
10d (10)c
10e (94)
4-BrC6H4
4-O2NC6H4
4-MeOC6H4
4-MeC6H4SO2
Ph
2
Scheme 2
R1
R1
R2
R2
4-BrC6H4
1
1
O
4-O2NC6H4
4-MeOC6H4
4-MeC6H4SO2
Ph
i
ii
—
0.5
1
1
1
R1
Cl
NH
Et
N
O
O
25
R2
150
150
150
150
25
Et
4-BrC6H4
HO
4-O2NC6H4
4-MeOC6H4
4-MeC6H4SO2
R1 = Me, R2 = H, 82%
R1 = Et, R2 = H, 75%
R1 = Ph, R2 = H, 62%
R1 = H, R2 = Me, 91%
3 R1 = Me, R2 = H, 74%
4 R1 = Et, R2 = H, 51%
5 R1 = Ph, R2 = H, 96%
6 R1 = H, R2 = Me, 68%
1
0.5
a Yields refer to pure isolated compounds, and are not optimised. b The 1H
NMR spectrum of the crude reaction mixture shows a small amount of the
c
Scheme 3 Reagents and conditions: i, (R)-2-aminobutan-1-ol, Na2CO3,
desired product. No dihydrooxazole remains unreacted. Not completely
CH2Cl2; ii, MeSO2Cl, Et3N, CH2Cl2
purified.
Chem. Commun., 1997
2311

View Article Online
This new variation on the Diels–Alder reaction has con-
siderable potential in the provision of novel chiral nonracemic
compounds. This is, as far as we are aware, only the second
report of an asymmetric aza-Diels–Alder reaction of a chiral
1-azadiene.3 Detailed experimental and computational studies
are in progress to determine the mechanism and origin of
stereoselectivity with a view to realising the potential of this
reaction.
Me
N
Me
N
Me
N
+
Ph
O
Ph
O
Ph
O
N
N
N
8a
3
O
O
O
Et
11a
Et
Et
11b
We thank the University of Wales, Cardiff for financial
support of this research, Mrs A. Dams for microanalytical data
and Mr R. Jenkins for mass spectrometric data. The X-ray
crystallographic study of compounds 8c and 10e was carried out
by Professor M. B. Hursthouse, Mr D. E. Hibbs and Mr D. S.
Hughes of this department. Full details will be published
elsewhere.
Scheme 5
Ar
Me
O
Me
Ar
O
N
N
i
(a)
ArN
6
N
O
O
N
O
Et
Et
12a Ar = Ph
12b Ar = 4-BrC6H4
12c Ar = 4-MeOC6H4 70%
81%
Footnotes and References
* E-mail: elliottmc@cardiff.ac.uk
73%
† All compounds exhibit satisfactory spectroscopic and analytical data.
‡ Selected data for 8a: dH(400 MHz; CDCl3; J/Hz) 8.32 (1 H, s, NH), 7.47
(2 H, d, J 7.9, Ar-H), 7.33 (2 H, d, J 7.5, Ar-H), 7.28–7.20 (5 H, m, Ar-H),
7.00 (1 H, t, J 7.4, Ar-H), 4.89 (1 H, q, J 6.2, Me-CH), 4.60 (1 H, app. t, J
8.1, O-CH), 4.48 (1 H, dd, J 8.4 and 1.6, O-CH), 4.31 (1 H, m, HC-Et),
1.99–1.93 (1 H, m, one of CH2), 1.90–1.83 (1 H, m, one of CH2), 1.22 (3 H,
d, J 6.2, CH3), 0.87 (3 H, t, J 7.4, CH3); dC(100 MHz; CDCl3) 162.6 (CNO),
152.1 (CNO), 150.4 (CNC), 140.3 (C), 139.0 (C), 129.6 (CH), 129.3 (CH),
128.3 (CH), 127.0 (CH), 123.9 (CH), 120.2 (CH), 83.8 (CNC), 74.1
(O-CH2), 57.3 (CH), 56.2 (CH), 23.7 (CH2), 21.2 (CH3), 9.0 (CH3);
nmax(CHCl3)/cm21 3424, 1686, 1649, 1595, 1535.
§ Selected data for 12a (mixture of stereoisomers): dH(400 MHz; CDCl3;
J/Hz) 7.7–6.9 (10 H, m, aromatic H), 4.40–4.20 (1 H, m) 4.14–4.04 (2 H,
m), 3.95–3.85 (2 H, m), 1.58–1.46 (5 H, m, CH2 and CH3), 0.90 (3 H of
major isomer, t, J 7.4, CH3), 0.85 (3 H of minor isomer, t, J 7.5, CH3);
dC(100 MHz; [2H6]DMSO) 170.1 (CNO), 165.2 (CNO), 165.2 (CNO), 152.6
(C), 152.6 (C), 142.9 (C), 142.7 (C), 137.7 (C), 137.6 (C), 129.8 (CH), 129.7
(CH), 129.6 (CH), 129.5 (CH), 128.7 (CH), 127.3 (CH), 127.1 (CH), 126.3
(CH), 126.0 (CH), 73.1 (CH2), 72.9 (CH2), 67.7 (CH), 67.7 (CH), 53.6
(CH2), 53.1 (CH2), 45.1 (C), 45.1 (C), 29.1 (CH2), 28.6 (CH2), 18.4 (CH3),
18.0 (CH3), 10.6 (CH3), 10.2 (CH3); nmax(CHCl3)/cm21 3012, 2970, 1729,
1686 and 1498.
Scheme 6 Reagents and conditions: i, 2 equiv. ArNCO, 150 °C, 24 h
diastereoisomer was observed in the 1H and 13C NMR spectra of
the crude reaction mixture. The stereochemistry of 8c and 10e
were determined by single crystal X-ray diffraction. All other
compounds are assumed, on the basis of similar spectroscopic
data, to have the same stereochemistry.
There has been much debate about the concerted nature, or
lack thereof, in both normal8 and hetero9 Diels–Alder reactions.
Given the highly polarised nature of the reacting partners, the
initial interaction may be best represented as initial acylation of
the dihydrooxazole nitrogen as shown in Scheme 5.10 However,
the present results do not rule out a concerted (although
probably asynchronous) aza-Diels–Alder reaction.
The subsequent addition of the isocyanate may proceed either
by a direct [2ps + 2pa] cycloaddition followed by cleavage of
the b-lactam or by a stepwise enamine acylation.11 In fact, when
6 was subjected to similar reaction conditions (2 equiv. phenyl
isocyanate, 150 °C, 24 h) compound 12a was obtained§ as a
1.7:1 mixture of diastereoisomers (Scheme 6). Similar reac-
tions were observed with 4-bromophenyl and 4-methoxyphenyl
isocyanates. No product could be isolated from the reaction with
4-nitrophenyl isocyanate, presumably due to the ease of
hydrolysis of the corresponding b-lactam.
1 W. Carruthers, Cycloaddition Reactions in Organic Synthesis, Perga-
mon Press, Oxford, 1990.
2 Selected review articles: L. F. Tietze and G. Kettschau, Top. Curr.
Chem., 1997, 189, 1; D. L. Boger and S. M. Weinreb, Hetero Diels–
Alder Methodology in Organic Synthesis, Academic Press, New York,
1987.
3 Asymmetric hetero-Diels–Alder reactions of 1-azadienes: R.
Beaudegnies and L. Ghosez, Tetrahedron: Asymmetry, 1994, 5, 557;
A. Waldner, Tetrahedron Lett., 1989, 30, 3061.
4 Langlois has investigated the use of alkenyloxazolines as dienophiles in
asymmetric Diels–Alder cycloadditions: C. Kouklovsky, A. Poulihe`s
and Y. Langlois, J. Am. Chem. Soc., 1990, 112, 6672; Y. Langlois and
A. Poulihe`s, Tetrahedron: Asymmetry, 1991, 2, 1223.
5 W. Seeliger, E. Aufderhaar, W. Diepers, R. Feinauer, R. Nehring,
W. Thier and H. Hellmann, Angew. Chem., Int. Ed. Engl., 1966, 5,
875.
6 For a recent report of aza-Diels–Alder reactions of 1-azadienes with
isocyanates, see T. Saito, H. Kimura, T. Chonan, T. Soda and
T. Karakasa, Chem. Commun., 1997, 1013.
7 For the use of achiral dihydrothiazoles as azadienes, see M. Sakamoto,
K. Miyazawa, K. Kuwabara and Y. Tomimatsu, Heterocycles, 1979, 12,
231.
8 B. R. Beno, K. N. Houk and D. A. Singleton, J. Am. Chem. Soc., 1996,
118, 9984; J. W. Storer, L. Raimondi and K. N. Houk, J. Am. Chem.
Soc., 1994, 116, 9675.
9 M. A. McCarrick, Y.-D. Wu and K. N. Houk, J. Org. Chem., 1993, 58,
3330; L. F. Tietze, J. Fennen, H. Gießler, G. Schulz and E. Anders,
Liebigs Ann. Chem., 1995, 1681.
The structures of compounds 12 were assigned by analogy
with compounds 8–10, and are supported by extensive NOE
studies. Unfortunately we have been unable to assign the
stereochemistry of the major isomer. Furthermore, the quater-
nary carbon (a) in Scheme 6 is significantly deshielded (13C
resonance in 12, 152.6 ppm), which could be explained by the
contribution of a zwitterionic resonance form 13 to the overall
structure (Fig. 1). The existence of 12 as a full zwitterion seems
unlikely on the grounds of polarity. Rigorous purification of
12a–c proved difficult due to the lability of these compounds.
Chromatography over neutral alumina gave essentially pure
compounds, although traces of the diaryl urea, derived from the
isocyanate, could not be completely removed. To the best of our
knowledge this work represents the first synthesis of the
azeto[3A,2A: 5,6]pyrimido[6,1-b]oxazole ring system. We are
unable to consolidate our data with that of Seeliger et al.5
O
Me
(a)
Me
O
Ar
O
Ar
O
N
N
ArN
(a)
O
–
ArN
N
N
+
O
10 A recent computational study supports this mechanism: W. M. F. Fabian
and G. Kollenz, J. Phys. Org. Chem., 1994, 7, 1.
11 J. March, Advanced Organic Chemistry, Wiley Interscience, New York,
4th edn., 1992, p. 978.
Et
Et
12
13
Fig. 1
Received in Liverpool, UK, 31st July 1997; 7/05571D
2312
Chem. Commun., 1997