Asymmetric hetero-Diels-Alder reactions with heterocumulenes

Article abstract of DOI:10.1055/s-1999-2853

Chiral 2-alkenyloxazolines and 2-alkenylthiazolines react with isocyanates and ketenes to give formal hetero-Diels-Alder adducts with complete diastereocontrol. In each case an electron-rich double bond in the adduct is prone to a second addition of the heterocumulene. In the case of the oxazoline adducts the second addition is faster than the first, while with thiazolines the second addition is slower so that a different heterocumulene can be incorporated.

Full text of DOI:10.1055/s-1999-2853

LETTER
1379
Asymmetric Hetero-Diels-Alder Reactions with Heterocumulenes
Mark C. Elliott,* Alexandra E. Monk, Elbertus Kruiswijk, David E. Hibbs, Robert L. Jenkins, David V. Jonesa
Department of Chemistry, Cardiff University, PO Box 912, Cardiff CF10 3TB, UK
Fax: +44 (01222) 874030; E-mail: elliottmc@cardiff.ac.uk
aAmersham Pharmacia Biotech Ltd., Cardiff Laboratories, Forest Farm, Whitchurch, Cardiff, CF14 7YT, UK
Received 15 June 1999
lines and alkenylthiazolines with diphenylketene. The re-
actions of thiazolines with selected isocyanates have also
been investigated.
Abstract: Chiral 2-alkenyloxazolines and 2-alkenylthiazolines re-
act with isocyanates and ketenes to give formal hetero-Diels-Alder
adducts with complete diastereocontrol. In each case an electron-
rich double bond in the adduct is prone to a second addition of the
heterocumulene. In the case of the oxazoline adducts the second ad-
dition is faster than the first, while with thiazolines the second addi-
tion is slower so that a different heterocumulene can be
incorporated.
Ph
Ph
N
Ph
Ph
O
Ph
Ph
toluene
+
•
O
reflux, 3 h
N
Key words: Diels-Alder reactions, heterocycles, isocyanates,
S
S
ketenes, piperidines
4
5
Scheme 2
We have recently reported the reactions of alkenyloxazo-
lines 1 with isocyanates as a stereocontrolled entry into
the oxazolo[3,2-c]pyrimidine ring system (Scheme 1).1
Although stepwise,2 this reaction can formally be consid-
ered to be an aza-Diels-Alder reaction.3 In all cases thus
far reported, the initial adduct 2 undergoes a second, fast-
er, reaction with the isocyanate to give products 3. We
consider this to be a limitation of our methodology, and
sought ways to alleviate the problem. Also, asymmetric
hetero-Diels-Alder reactions involving carbon-carbon di-
enophiles would be more versatile. We now report an ex-
tension of our earlier work which addresses both of these
concerns.
Diphenylketene, prepared according to the procedure of
Taylor,5 was allowed to react with oxazolines 6 and 7. In
line with earlier results, this led to the formation of a sin-
gle stereoisomer of the double-addition products 86 and
9.7 These reactions were conducted in the minimum vol-
ume of chloroform to enable stirring of a homogeneous
solution. Reactions in the absence of solvent (which are
optimal with isocyanates) or in toluene (as reported by
Sakamoto with thiazoline 4) were much less satisfactory.
We have assigned the stereochemistry of 8 and 9 based on
our mechanistic model for the analogous reactions with
isocyanates, computational data and a single crystal X-ray
diffraction of compound 18 (vide infra). This therefore
represents a formal asymmetric aza-Diels-Alder reaction
involving a carbon-carbon dienophile.
R
R
O
R
N
H
NR'
R'N
H
NR'
R'NCO
O
N
N
O
O
O
O
R
N
O
R
N
Ph
Ph
Ph
O
Et
Et
Ph
Ph
Et
CHCl3, 3 h
+
•
O
1
2
3
Ph
O
O
Scheme 1
Et
Et
6, R = Me
7, R = Ph
8, R = Me, 62%
9, R = Ph, 26%
We reasoned that ketenes would be appropriate carbon-
carbon dienophiles since they are isoelectronic with iso-
cyanates. Also, since we might expect a stepwise reaction,
our mechanistic model leads us to expect high, if not com-
plete, diastereoselectivity. In 1979 Sakamoto reported the
reaction of an alkenylthiazoline with diphenylketene to
give a product in which only a single equivalent of the
ketene was incorporated (Scheme 2).4 We felt that this ap-
proach would open up significant possibilities, and have
therefore investigated the reactions of both alkenyloxazo-
Scheme 3
We conclude from this that it is the thiazoline component
rather than the ketene which leads to the formation of only
1:1 adducts in the work of Sakamoto. Compound 4 was
prepared by condensation of 2-methylthiazoline with ben-
zaldehyde,8 and allowed to react with diphenylketene to
give 5 as previously shown by Sakamoto (Scheme 2).
Synlett 1999, No. 9, 1379–1382 ISSN 0936-5214 © Thieme Stuttgart · New York

1380
M. C. Elliott et al.
LETTER
Clearly in this case the alkenylthiazoline reacts faster with to solid support, we elected to use a particularly bulky
the heterocumulene than does the product 5. However, protecting group to verify that it did not hinder the reac-
upon stirring 5 in toluene with tosyl isocyanate compound tion; also we felt that a less hindered protecting group
10 was formed in satisfactory yield. We can therefore in- might not withstand the conditions for the subsequent
troduce two different heterocumulenes, so that this chem- condensation with benzaldehyde (toluene, iodine, re-
istry has a significant advantage over our previously flux).8 In the event the chemistry proceeded smoothly, al-
reported work.
though the yield of the final step to give 17 was relatively
low (55%). However, carrying out this transformation in
a stepwise manner using LDA to deprotonate the 2-meth-
ylthiazoline followed by trifluoroacetic acid to effect
elimination12 gave more satisfactory results (80% over
two steps). The enantiomeric excess of 17 was shown by
chiral GC-MS to be 39.7%.
Ph
Ph
Ph
O
S
Ph
Ph
Ph
O
toluene, 25°C
TsN
H
+ TsNCO
4 h
N
O
N
S
10, 88%
5
CH3
HS
OEt
Scheme 4
Et3N, CH2Cl2
S
N
+
H3C
0°C
NH.HCl
EtO2C
NH2.HCl
CO2Et
14, 85%
Under similar conditions both single and double adducts
with tosyl isocyanate 11 and 12 have been isolated. Com-
pound 11 proved to be unstable and prone to a retro-Diels-
Alder reaction; however the addition of the second tosyl
group stabilised this compound. With the less reactive
phenyl isocyanate only a single addition product 13 was
obtained from 4 under a wide variety of conditions, opti-
mal being heating an equimolar mixture of starting mate-
rials neat (150°C, 15 h, 55 %).
NaBH4,
EtOH, H2O
CH3
N
CH3
TIPSOTf, Et3N
CH2Cl2
S
S
N
CH2OTIPS
16, 75%
CH2OH
15, 83%
Ph
N
Ph
N
LDA, PhCHO, THF then
CF3CO2H
1 eq. TsNCO
NTs
Ph
toluene, 25°C
O
S
S
11, 56%
4
S
N
2 eq. TsNCO
toluene, 25°C
CH2OTIPS
17, 80%
O
Ph
Ph
TsN
H
NTs
NPh
Scheme 6
N
O
N
O
S
S
We were then delighted to find that the reactions of 17
with diphenylketene and tosyl isocyanate proceed with to-
tal stereocontrol. Reaction with diphenylketene proceed-
ed smoothly to give compound 1813 as a single
diastereoisomer within the detection limits of 400 MHz
1H NMR. Subsequent reaction with tosyl isocyanate gave
19. Recrystallisation of compound 18 from pentane gave
crystals suitable for X-ray diffraction, although not sur-
prisingly the triisopropylsilyl group showed disorder.
While the crystal selected for analysis was found to be ra-
cemic, we were able to demonstrate by chiral HPLC on
the crude reaction mixture that no racemisation occurred
during the formation of 18. As expected from our previous
work,1 the phenyl group at the new stereogenic centre is
on the opposite side of the bicyclic ring system to the sub-
stituent on the thiazoline (Figure 1).14
12, 46%
13
Scheme 5
With these results in hand, we needed to verify that the re-
actions with thiazolines also proceed with good diastereo-
control. A suitable thiazoline was prepared from cysteine
as shown in Scheme 6. Cysteine ethyl ester hydrochloride
was allowed to react with ethyl acetimidate hydrochloride
to give ethyl 2-methylthiazoline-4-carboxylate 14.9 While
this reaction is known to proceed with partial racemisa-
tion,10 conditions leading to single enantiomers, while
marginally less convenient, are known.11 Sodium borohy-
dride reduction was followed by protection as the triiso-
propylsilyl ether. Since this chemistry should be amenable
Synlett 1999, No. 9, 1379–1382 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Asymmetric Hetero-Diels-Alder Reactions with Heterocumulenes
1381
Ph
Ph
Ph
Ph
N
Ph
Ph
O
1 eq. TsNCO
NTs
Ph
Ph
toluene,
+
•
O
toluene, 25°C
N
O
S
N
S
N
S
reflux, 12 h
S
CH2OTIPS
20
CH2OTIPS
18, 52%
CH2OTIPS
CH2OTIPS
17
17
TsNCO,
2 eq. TsNCO
25°C, 4 h
toluene, 25°C
O
S
Ph
Ph
Ph
O
Ph
TsN
H
TsN
H
NTs
N
O
N
O
S
CH2OTIPS
CH2OTIPS
21, 25%
19, 68%
Scheme 8
Scheme 7
cation of the products. These reactions are currently under
investigation and will be reported in due course.
Acknowledgement
We would like to thank EPSRC (AEM) and Cardiff University (EK)
for project studentships, and the EPSRC National Mass Spectrome-
try Centre at the University of Wales Swansea for accurate mass da-
ta.
References and Notes
(1) Elliott, M. C.; Kruiswijk, E. Chem. Commun., 1997, 2311;
Elliott, M. C.; Hibbs, D. E.; Hughes, D. S.; Hursthouse, M. B.;
Kruiswijk, E.;Malik, K. M. A. J. Chem. Cryst., 1998, 28, 663.
(2) Elliott, M. C.; Kruiswijk, E.; Willock, D. J. Tetrahedron Lett.,
1998, 39, 8911.
(3) Tietze, L.; Kettschau, G. Top. Curr. Chem., 1997, 189, 1.
(4) Sakamoto, M; Miyazawa, K.; Kuwabara K.; Tomimatsu, Y.
Heterocycles, 1979, 12, 231.
(5) Taylor, E. C.; McKillop, A.; Hawks, G. H. Org. Synth. Coll.
Vol. VI, 1988, 549.
Figure 1 Solid state structure of compound 18. Isopropyl carbons
(6) Selected spectroscopic data for 8: dH (400 MHz; CDCl3) 7.56
(2 H, dd, J 8.2, 1.0, aromatic CH), 7.34 (2 H, apparent t, J 7.7,
aromatic CH), 7.26 – 6.88 (14 H, m, aromatic CH), 6.66 (2 H,
dd, J 7.2, 1.4, aromatic CH), 5.97 (1 H, s, Ph2CH), 4.62 (1 H,
apparent dq, J 1.1, 6.5, CH-N), 3.93 (1 H, dd, J 8.6, 1.1, one
of CH2O), 3.77 (1 H, dd, J 8.6, 6.5, one of CH2O), 3.67 (1 H,
q, J 6.8, CHMe), 1.75 – 1.64 (2 H, m, CH2CH3), 0.97 (3 H, t,
J 7.4, CH3) and 0.95 (3 H, d, J 6.8, CH3).
(7) Selected spectroscopic data for 9: dH (400 MHz; CDCl3) 7.67
(2 H, d, J 7.4, aromatic CH), 7.33 (2 H, apparent t, J 7.6,
aromatic CH), 7.22 – 6.85 (19 H, m, aromatic CH), 6.65 (2 H,
d, J 7.1, aromatic CH), 6.06 (1 H, s, Ph2CH), 4.78 (1 H, s,
PhCH), 4.54 (1 H, apparent dq, J 1.2, 6.5, CH-N), 3.69 (1 H,
dd, J 8.7, 1.4, one of CH2O), 3.61 (1 H, dd, J 8.7, 6.3, one of
CH2O), 1.67 – 1.59 (2 H, d, CH2CH3) and 0.94 (3 H, t, J 7.4,
CH3).
omitted for clarity
Reaction of 17 with tosyl isocyanate also gave a single
stereoisomer of the single adduct 20, but this compound,
like the analogous compound 11, proved to be unstable
and prone to a retro-Diels-Alder reaction. Once again
though, the double-addition product 2115 proved to be
much more stable, the low yield being due more to diffi-
culties encountered in purification.
In summary, the reactions of unsaturated oxazolines with
diphenylketene follow a similar course to our previously-
reported reactions of oxazolines with isocyanates.1 How-
ever, the reactions of unsaturated thiazolines with isocy-
anates and with diphenylketene allow the introduction of
two different heterocumulenes in a controlled manner,
and therefore open up many opportunities for the modifi-
(8) Wehrmeister, H. L. J. Org. Chem., 1962, 27, 4418.
(9) Barton, M. A.; Kenner, G. W.; Sheppard, R. C. J. Chem. Soc.
C, 1966, 1061.
Synlett 1999, No. 9, 1379–1382 ISSN 0936-5214 © Thieme Stuttgart · New York

1382
M. C. Elliott et al.
LETTER
1.194 gcm-3, Mo-Ka radiation, l = 0.71073 Å, 2.24 ≤ 2q ≤
26.31°. 6633 reflections were collected of which 6354 were
unique. 3239 reflections having I > 2.0s(I) were used for
refinement (429 parameters), converging to R = 0.0820 and Rw
= 0.2135. The isopropyl groups of the protecting group were
heavily disordered. Full data have been deposited with the
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK (Fax: (+44) 1223 336033. Email:
deposit@ccdc.cam.ac.uk).
(10) Meyers, A. I.; Whitten, C. E. Heterocycles 1976, 4, 1687;
Fantin, G.; Fogagnolo, M.; Medici, A.; Pedrini, P.
Heterocycles 1993, 36, 473.
(11) C. D. J. Boden, G. Pattenden and T. Ye, Synlett 1995, 417; F.
Almqvist, D. Guillaume, S. J. Hultgren and G. R. Marshall,
Tetrahedron Lett., 1998, 39, 2293.
(12) Meyers, A.I.; Durandetta, J. L.; Munavu, R. J. Org. Chem.
1975, 40, 2025; Meyers, A. I.; Smith, R. K.; Whitten, C. E. J.
Org. Chem. 1979, 44, 2250.
(13) Selected spectroscopic data for 18: dH (400 MHz; CDCl3) 7.57
- 7.53 (2 H, m, aromatic CH), 7.35 - 7.32 (3 H, m, aromatic
CH), 7.09 (1 H, d, J 7.4, aromatic CH, 7.03 (2 H, apparent t, J
7.2, aromatic CH), 6.97 (1 H, d, J 7.3, aromatic CH), 6.90 (2
H, apparent t, J 7.6, aromatic CH), 6.70 (2 H, d, J 7.2, aromatic
CH), 6.56 (2 H, d, J 7.8, aromatic CH), 5.43 (1 H, d, J 6.0,
alkene CH), 4.92 - 4.87 (1 H, m, CH-N), 4.09 (1 H, d, J 6.0,
CHPh), 3.47 (1 H, dd, J 9.6, 3.9, one of CH2S), 3.40 (1 H, dd,
J 11.3, 6.4, one of CH2O), 3.28 (1 H, d, J 11.3, one of CH2O),
2.91 (1 H, apparent t, J 9.6, one of CH2S) and 1.0 - 0.9 (21 H,
m, iPr3Si).
(15) Selected spectroscopic data for 21: dH (400 MHz; CDCl3) 7.72
(2 H, d, J 8.2, aromatic CH), 7.36 - 7.33 (6 H, m, aromatic CH
+ NH), 7.28 (2 H, d, J 8.3, aromatic CH), 7.19 (2 H, d, J 8.0,
aromatic CH), 7.02 (2 H, d, J 8.2, aromatic CH), 6.12 (1 H, s,
CHPh), 4.56 - 4.51 (1 H, m, CH-N), 3.64 (1 H, dd, J 9.1, 3.5,
one of CH2O), 3.49 (1 H, apparent t, J 9.1, one of CH2O), 3.29
(1 H, d, J 11.4, one of CH2S), 3.17 (1 H, dd, J 11.4, 7.1, one
of CH2S), 2.34 (3 H, s, CH3), 2.27 (3 H, s, CH3) and 0.93 (21
H, m, iPr3Si).
(14) Selected crystallographic data for 18: C35H43NO2SSi (Mr
569.85), monoclinic, P21/a, a = 13.311(2), b = 16.811(3), c =
14.525(2) Å. b = 102.73(3)°, Z = 4, V = 3170.4(9) Å3, Dc =
Article Identifier:
1437-2096,E;1999,0,09,1379,1382,ftx,en;L09699ST.pdf
Synlett 1999, No. 9, 1379–1382 ISSN 0936-5214 © Thieme Stuttgart · New York