Diastereoselective aziridination of cyclic dienes with 3-acetoxyaminoquinazolin-4(3H)-ones: Competitive formation of insertion products from cyclohexadienes

Article abstract of DOI:10.1016/S0040-4039(00)01328-9

Aziridination of cyclopentadiene and cycloheptadiene with 3-acetoxyamino-2-[(S)-1-hydroxy-2,2-dimethylpropyl]quinazolin-4(3H)-one 1 in the presence of titanium(IV) tert-butoxide gave the corresponding vinyl aziridines highly diastereoselectively: the corresponding aziridination product of cyclohexa-1,3-diene is formed less diastereoselectively and is accompanied by a by-product 9 from formal insertion into an allylic C-H bond, a previously unobserved reaction type for 3-acetoxyaminoquinazolinones. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01328-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 7769–7772
Diastereoselective aziridination of cyclic dienes with
3-acetoxyaminoquinazolin-4(3H)-ones: competitive formation
of insertion products from cyclohexadienes
Robert S. Atkinson* and Christopher K. Meades
Department of Chemistry, Leicester University, Leicester LE1 7RH, UK
Received 24 June 2000; revised 28 July 2000; accepted 1 August 2000
Abstract
Aziridination of cyclopentadiene and cycloheptadiene with 3-acetoxyamino-2-[(S)-1-hydroxy-2,2-
dimethylpropyl]quinazolin-4(3H)-one 1 in the presence of titanium(IV) tert-butoxide gave the correspond-
ing vinyl aziridines highly diastereoselectively: the corresponding aziridination product of cyclohexa-
1,3-diene is formed less diastereoselectively and is accompanied by a by-product 9 from formal insertion
into an allylic CꢀH bond, a previously unobserved reaction type for 3-acetoxyaminoquinazolinones.
© 2000 Elsevier Science Ltd. All rights reserved.
3-Acetoxyaminoquinazolinones QNHOAc are versatile aziridinating agents for alkenes of
widely different p-electron availability.1 Reaction of cyclopentadiene with the enantiopure
3-acetoxyaminoquinazolinone 1 (Q1NHOAc) (Scheme 1) in the presence of titanium(IV)
tertbutoxide2 (TTB) gave the aziridine 3a (25%) as a single diastereoisomer whose relative and
therefore absolute configuration3 was determined by X-ray crystallography (Fig. 1).4
Scheme 1. Reagents: (i) Ti(OBut)4, CH2Cl2; (ii) cyclopentadiene
* Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01328-9

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Figure 1. Molecular structure of 3a. Displacement parameters are shown at the 30% probability level, H atoms are
omitted for clarity
From the crystal structure of aziridine 3a it is clear that the Q1 group is cis to the
cyclopentadiene ring residue. On heating at 60°C for 1 h, thermodynamic equilibration to give
a 1:1 mixture of aziridine N-invertomers 3a and 3b occurs and accordingly 3a is the expected
kinetically-formed product.1
The sense of diastereoselectivity in formation of aziridine 3a is consistent with a titanium-
coordinated and chelated complex of Q1NHOAc 1, which undergoes reaction with the cyclopen-
tadiene from the less-hindered face as in transition state (tsc) 2 (Scheme 1) with the expected
endo-orientation of the cyclopentadiene giving rise to the N-invertomer 3a.2
Reaction of cycloheptadiene with Q1NHOAc 1 and TTB gave aziridine 4 (30%) as the major
product whose NMR spectrum indicated that it was a single diastereoisomer5 (Scheme 2).
Reaction of the 2-isopropyl analogue 5 (Q2NHOAc) with cycloheptadiene in the presence of
HMDS6 gave the corresponding aziridine 6 (45%).
Scheme 2.
Reaction of cyclohexa-1,3-diene with Q1NHOAc 1 and TTB gave both diastereoisomers of
aziridine 7 (dr 10:1)7 together with a mixture of tert-butoxyaminoquinazolinone 8, (a known
reaction product of Q1NHOAc 1 with titanium(IV) tert-butoxide)2 and dienylamine 9, an
apparent CꢀH insertion product of cyclohexa-1,3-diene (Scheme 3).

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Scheme 3. Reagents: (i) Ti(OBut)4; (ii) cyclohexa-1,3-diene (2 equiv.); (iii) p-ClC6H4SH, CH2Cl2, 90°C; (iv) H2O2–
HOAc; (v) D, CCl4
1
From its H NMR spectrum, this dienylamine 9 appeared to be a single diastereoisomer and
this conclusion was supported by analysis of the NMR spectrum of the product from Swern
oxidation of the alcohol group in the quinazolinone 2-substituent followed by sodium borohy-
dride reduction of the resulting ketone: the additional resonances were assignable to a new
diastereoisomer of 9 (dr ꢀ1:1). Chemical correlation between the major aziridine diastereoiso-
mer 7 and dienylamine 9 was carried out (Scheme 3) by SN2% ring-opening8 of the aziridine 7
with p-chlorothiophenol to give arylsulfide 10 followed by thermolysis of the derived sulfoxide.
Thus, the configuration at the cyclohexadienyl ring carbon in dienylamine 9 corresponds to that
at C-6 in aziridine 7 and is R, assuming that aziridine 7 is formed by a tsc analogous to 2.
A relatively larger proportion of insertion to aziridine product was obtained in the reaction of
cyclohexa-1,4-diene with Q1NHOAc and with Q2NHOAc (Scheme 4).
Scheme 4.
Completely stereoselective insertion into CꢀH bonds is a reaction characteristic of reactive
singlet nitrenes and is competitive with aziridination when alkenes are used as substrates.9
However, products from direct insertion into CꢀH bonds have not previously been observed
using 3-acetoxyaminoquinazolinones or their corresponding nitrenes.10,11
When the reaction of Q2NHOAc 5 with cyclohexa-1,4-diene (Scheme 4) was carried out by
first adding triethylamine, conditions known to bring about aziridination of alkenes via the
corresponding N-nitrene,9 the yield of the insertion product, dienylamine 14 (4%) was greatly
reduced relative to that of the aziridine 13 (60%). It therefore seems unlikely that N-nitrenes are
the intermediates mediating the formation of these dienylamines in Schemes 3 and 4.

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Aziridines 3, 4 and 7 are potentially useful sources of chirons by ring-opening of the
three-membered ring and the removal of the Q1 group. Thus, aziridine 7 (dr 5:1) was ring-opened
by aqueous acetonitrile containing toluene p-sulfonic acid with complete retention of
configuration12 to give the diastereoisomeric alcohols 15 and 16 (Scheme 5). Separation of these
alcohols and reaction of each with carbonyl diimidazole followed by reduction with samarium
diiodide gave the corresponding enantiomeric chirons 17 mp 85–86°C and 18 mp 87–88°C (lit.13
mp 86–88°C) whose optical rotations were close in magnitude but opposite in sign.
Scheme 5.
Acknowledgements
We thank Dr. J. Fawcett and Dr. D. R. Russell for the X-ray crystal structure determination.
References
1. Atkinson, R. S. Tetrahedron 1999, 55, 1519.
2. Atkinson, R. S.; Ayscough, A. P.; Gattrell, W. T.; Raynham, T. M. J. Chem. Soc., Perkin Trans. 1 1998, 2783.
3. Q1NHOAc 1 is prepared from (S)-tert-leucine.
4. Crystal data for 3a: C18H21N3O2, M=311.18, monoclinic, space group P21, a=8.789(2), b=11.035(3), c=
3
9.229(4) A, i=111.20(4)°, U=834.5(5) A , T=190 K, Z=2, v(Mo Ka)=0.082 mm−1, crystal 0.56×0.44×0.16
mm, 1764 reflections measured, 1662 unique (Rint=0.034). The final R1[F2>2|(F2)]=0.0415, ꢀR2 (all data)=
0.111 for 208 parameters. Crystals of 3a were obtained from diethyl ether.
,
,
5. The configuration shown in 4 is assigned by analogy with that of 3a.
6. Atkinson, R. S.; Barker, E.; Ulukanli, S. J. Chem. Soc., Perkin Trans. 1 1998, 583.
7. Occasionally the dr was lower at 4:1 for reasons not as yet clear.
8. A by-product in this reaction was the allyl aryl thioether from SN2 ring-opening (10%).
9. Mishra, A.; Rice, S. N.; Lwowski, W. J. Org. Chem. 1968, 33, 481; Lwowski, W. In Nitrenes and Azides,
Reactivity and Utility; Scriven, E. F. V., Ed.; Academic: New York, 1984, pp. 205–246.
10. Atkinson, R. S.; Barker, E. J. Chem. Soc., Chem. Commun. 1995, 819.
11. Insertion also occurs into a CHH bond of 9,10-dihydroanthracene with Q1NHOAc 1 in the presence of Ti(OBut)4
(12% yield) and into a CHH bond of xanthene with Q2NHOAc 5 (12% yield).
12. Atkinson, R. S.; Ayscough, A. P.; Gattrell, W. T.; Raynham, T. M. Tetrahedron Lett. 1998, 39, 4377.
13. Knapp, S.; Kukkola, P. J.; Sharma, S.; Murali Dhar, T. G.; Naughton, A. B. J. J. Org. Chem. 1990, 55, 5700:
the reported NMR spectrum is very similar to those of 17 and 18.