The stereodivergent aziridination of allylic carbamates, amides and sulfonamides

Article abstract of DOI:10.1016/j.tet.2010.06.059

A stereodivergent protocol for the aziridination of a range of cyclic allylic amine derivatives has been developed. syn-Products can be obtained in >99:1 dr under H-bonded control and anti-products are obtained in >99:1 dr under steric control by judiciou

Full text of DOI:10.1016/j.tet.2010.06.059

Tetrahedron 66 (2010) 6806e6813
Contents lists available at ScienceDirect
Tetrahedron
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The stereodivergent aziridination of allylic carbamates, amides and sulfonamides
*
Stephen G. Davies , Kenneth B. Ling, Paul M. Roberts, Angela J. Russell, James E. Thomson,
Philip A. Woods
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 May 2010
Received in revised form 9 June 2010
Accepted 21 June 2010
Available online 25 June 2010
A stereodivergent protocol for the aziridination of a range of cyclic allylic amine derivatives has been
developed. syn-Products can be obtained in >99:1 dr under H-bonded control and anti-products are
obtained in >99:1 dr under steric control by judicious choice of the N-protecting groups.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Aziridine
Allylic amine
Substrate-directed reaction
Stereodivergent
1. Introduction
Me
O
Aziridines are the nitrogen analogues of epoxides and are useful
intermediates in organic synthesis. Several well-established methods
for the synthesis of aziridines from olefins are known,1 with 1,3-di-
polar cycloaddition of azide followed by decomposition of the in-
termediate triazoles,2 Michael addition of a nitrogen nucleophile
followed by expulsion of a leaving group,3 the addition of IN3 or INCO
followed by reductive or hydrolytic ring-closure,4 and the direct ad-
dition of a nitrene species or equivalent5,6 being amongst the most
popular. However, there are relatively few examples of stereo-
selective substrate-directed aziridination reactions known.7 Atkin-
son et al. have used this approach for the aziridination of both allylic
and homoallylic alcohols.8 For example, aziridination of 2-cyclo-
OH
O
NQ2
H
H
(i)
O
1
2
N
OH
Et
N
O
NQ2
3, 70%, 95:5 dr
NHOAc
Q2NHOA c 4
hexen-1-ol
1
with
C
(2)
-
ethyl substituted 3-acetoxy-
aminoquinazolinone (Q2NHOAc) 4 is reported to give syn-3 in 95:5 dr
and 70% isolated yield;9 a H-bonded transition state 2 (analogous to
that proposed by Bartlett for olefinic epoxidation)10 is postulated to
account for the high level of syn diastereoselectivity observed
(Scheme 1).11
Scheme 1. Reagents and conditions: (i) Q2NHOAc 4, CH2Cl2, rt.
Zn(CH2I)2 (the WittigeFurukawa reagent) or anti-7 upon treat-
ment with F3CCO2ZnCH2I (Shi’s carbenoid) in good yield and
>99:1 dr in both cases (Scheme 2).13d
Within the area of stereoselective substrate-directed reactions
O’Brien et al. have reported the stereoselective epoxidation of
a range of N-protected 2-cyclohexen-1-ylamines.12 Furthermore,
we have recently reported the chemo- and diastereoselective
epoxidation of allylic and homoallylic amines,13aec and the
cyclopropanation of allylic amines and carbamates.13dee For ex-
ample, the stereodivergent cyclopropanation of tert-butyl cyclo-
hex-2-en-1-ylcarbamate 5 gave either syn-6 upon treatment with
NHBoc
NHBoc
NHBoc
(i)
(ii)
syn-6, 67%
5
anti-7, 70%
>99:1 dr
>99:1 dr
Scheme 2. Reagents and conditions: (i) Et2Zn, CH2I2, CH2Cl2, rt, 1 h; (ii) Et2Zn, CH2I2,
TFA, CH2Cl2, rt, 1 h.
* Corresponding author. E-mail address: steve.davies@chem.ox.ac.uk (S.G. Davies).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.06.059

S.G. Davies et al. / Tetrahedron 66 (2010) 6806e6813
6807
We considered that this methodology may be extended to en-
compass the stereoselective substrate-directed aziridination of al-
lylic amine derivatives. A recent report by Kilic et al. concerning the
diastereoselective aziridination of chiral acyclic allylic alcohols14
has prompted us to publish our initial findings within this area,
which are delineated herein.
Atkinson et al. have also shown that the C(2)-trifluoromethyl
substituted 3-acetoxyaminoquinazolinone 11 (Q3NHOAc) is far
more resistant to decomposition than Q2NHOAc 4.19 Treatment of
carbamate 5 with 2.0 equiv of 11 for 24 h gave syn-aziridine 10 in
90% conversion as a single diastereoisomer (>99:1 dr). Employing
4.0 equiv of 11 promoted complete conversion to 10, although fur-
ther reaction optimisation revealed that treatment of 5 with only
2.0 equiv of 11 over an extended reaction time of 48 h is sufficient to
achieve full conversion: following reaction under these conditions
10 was isolated in 93% yield and >99:1 dr. The relative syn-config-
urationwithin aziridine 10 was assigned on the basis of 1H NMR NOE
analysis, which showed strong reciprocal enhancements between
the C(1)H and C(2)H protons, and also by analogy with related
substrates (vide infra). In accordance with Atkinson’s model 2 for
the aziridination of allylic alcohol 19 the high syn diaster-
eoselectivity observed upon aziridination of carbamate 5 is consis-
tent with H-bonded deliveryof the electrophile on the syn face of the
neighbouring olefin via a transition state such as 9 (Scheme 5).
2. Results and discussion
Ourinitial studiesfocused ontheaziridination of N-Boc protected
allylic amine 515 with 3-acetoxyaminoquinazolinone 4 (Q2NHOAc).9
A variety of reagents and conditions were screened in order to find
an effective combination to promote the formation of aziridine 8 in
good yield and with high diastereoselectivity.16 Treatment of car-
bamate 5 with 2.0 equivof 3-acetoxyaminoquinazolinone 4 at either
ꢀ23 ꢁC or 0 ꢁC returned only starting material, whereas reaction at
ambient temperature gave a single diastereoisomer of aziridine 8 in
35% conversion. In addition, it was found that the percentage con-
version after stirring for 24 h at ambient temperature was approx-
imately the same as that for stirring at 2.5 hat the same temperature.
This result was consistent with reports that 3-acetoxy-
aminoquinazolinone 4 is known to be stable at ꢀ23 ꢁC but not at
ambient temperature.6 In an attempt to improve the level of con-
version, aziridination of carbamate 5 with 4.0 and 8.0 equiv of
3-acetoxyaminoquinazolinone 4 gave aziridine 8 in 56 and 61%
conversion, respectively, and in >99:1 dr in each case (Scheme 3).17
The relative syn-configuration within 8 was tentatively assigned by
analogy to the H-bond directed aziridination of allylic alcohol 1.
Me
NHBoc
O
(i), (ii)
or (iii)
O
H
H
NQ 3
NBoc
5
9
N
N
NHBoc
NHBoc
NHBoc
1
2
F3C
O
NQ3
(i) or (ii)
NHOA c
Q3NHOAc 11
N
NQ2
10
Et
N
O
5
8, >99:1 dr
(i). 90% conv, >99:1 dr
(ii). >95% conv, >99:1 dr
(iii). >95% conv, 93%, >99:1 dr
NHOAc
Q2NHOAc 4
(i). 35% conv
(ii). 56% conv
(iii). 61% conv
Scheme 5. Reagents and conditions: (i) Q3NHOAc 11 (2.0 equiv), CH2Cl2, rt, 24 h; (ii)
Q3NHOAc 11 (4.0 equiv), CH2Cl2, rt, 24 h; (iii) Q3NHOAc 11 (2.0 equiv), CH2Cl2, rt, 48 h.
Scheme 3. Reagents and conditions: (i) Q2NHOAc 4 (2.0 equiv), CH2Cl2, rt, 2.5 h; (ii)
Q2NHOAc 4 (4.0 equiv), CH2Cl2, rt, 2.5 h; (iii) Q2NHOAc 4 (8.0 equiv), CH2Cl2, rt, 2.5 h.
In order to test this hypothesis, and probe the role of the NH
proton in the reaction, aziridination of N-methyl carbamate 12 was
attempted. Carbamate 12 was synthesised in 69% yield by meth-
ylation of 5 with NaH and MeI. Subsequent treatment of 12 with
2.0 equiv of 11 for 48 h (i.e., under identical conditions to the re-
action of 5) proceeded to give 61% conversion to an approximately
50:50 ratio of diastereoisomers 13 and 14 (Scheme 6). The poor
diastereoselectivity and low reaction conversion observed in this
case is consistent with the proposed H-bond directed aziridination
of allylic carbamate 5 accelerating the reaction as well as being
responsible for the high diastereoselectivity.
It has previously been reported that the addition of hexa-
methyldisilazane (HMDS) to the reaction mixture gives improved
yields for aziridination products as the rate of decomposition of
3-acetoxyaminoquinazolinone 4 is decreased.18 Aziridination of
carbamate 5 with 2.0 equiv of 3-acetoxyaminoquinazolinone 4 in
the presence of 3.0 equiv of HMDS gave aziridine 8 in 30%
conversion and >99:1 dr. To determine if the lifetime of 3-ace-
toxyaminoquinazolinone 4 was now greater than 2.5 h, subsequent
reactions were run for 24 h and the effect of varying the number of
equivalents of 3-acetoxyaminoquinazolinone 4 in the presence of
HMDS was also investigated. Aziridination of carbamate 5 with 2.0
and 4.0 equiv of 3-acetoxyaminoquinazolinone 4 in the presence of
3.0 and 5.0 equiv of HMDS gave aziridine 8 in 55 and 74% conver-
sion, respectively, and in >99:1 dr in each case (Scheme 4).
NHBoc
NMeBoc
(i)
NHBoc
NHBoc
5
12, 69%
61% conv
50:50 dr
NMeBo c
(i), (ii)
or (iii)
(ii)
NQ2
NMeBo c
NQ 3
5
8, >99:1 dr
(i). 30% conv
NQ 3
(ii). 55% conv
(iii). 74% conv
13
14
Scheme 4. Reagents and conditions: (i) Q2NHOAc 4 (2.0 equiv), HMDS (3.0 equiv),
CH2Cl2, rt, 2.5 h; (ii) Q2NHOAc 4 (2.0 equiv), HMDS (3.0 equiv), CH2Cl2, rt, 24 h; (iii)
Q2NHOAc 4 (4.0 equiv), HMDS (5.0 equiv), CH2Cl2, rt, 24 h.
Scheme 6. Reagents and conditions: (i) NaH, THF, 0 ꢁC, 30 min then MeI, rt, 24 h; (ii)
Q3NHOAc 11 (2.0 equiv), CH2Cl2, rt, 48 h.

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S.G. Davies et al. / Tetrahedron 66 (2010) 6806e6813
The compatibility of this substrate-directed aziridination procedure
with various protecting groups was next investigated. Under our
optimised conditions, aziridination of sulfonamide 15, benzamide
17 and benzyl carbamate 19 gave aziridines 16, 18 and 20 in 90, 92
and 89% yield, respectively, and in >99:1 dr in each case (Scheme
7). The syn-relative configuration within benzamide 18 was un-
ambiguously proven by single crystal X-ray analysis (Fig. 1). The
relative configurations within 16 and 20 were thus assigned by
analogy to that of 18, and this analysis also supports the assigned
syn-configurations within 8 and 10.
was unambiguously proven by single crystal X-ray analysis (Fig. 2);
the relative configurations within 24 and 26 were thus assigned by
analogy.
NPhth
NP hth
(i)
(i)
(i)
NQ3
21
22, 73%
>99:1 dr
NHTs
NHTs
NTsBoc
NTsBoc
(i)
(i)
(i)
NQ3
NQ3
15
16, 90%
23
24, 75%
>99:1 dr
>99:1 dr
NHBz
NHBz
NTsCbz
NTsCbz
NQ3
NQ3
17
18, 92%
25
26, 65%
>99:1 dr
>99:1 dr
NHCbz
Scheme 8. Reagents and conditions: (i) Q3NHOAc 11 (2.0 equiv), CH2Cl2, rt, 48 h.
NHCbz
NQ3
19
20, 89%
>99:1 dr
Scheme 7. Reagents and conditions: (i) Q3NHOAc 11 (2.0 equiv), CH2Cl2, rt, 48 h.
Figure 2. Chem3D representation of the X-ray crystal structure of 22 (some H atoms
have been omitted for clarity).
3. Conclusion
In conclusion, a stereodivergent protocol for the aziridination of
a range of cyclic allylic amine derivatives with Atkinson’s C(2)-tri-
fluoromethyl substituted 3-acetoxyaminoquinazolinone reagent
has been developed. N-Protection as a carbamate, amide or sul-
fonamide leads to highly diastereoselective syn aziridination under
H-bonded substrate control. Conversely, protection of the nitrogen
atom with two bulky protecting groups leads to anti aziridination
under steric control. In each case the corresponding aziridines are
isolated in high yield as single diastereoisomers (>99:1 dr).
Figure 1. Chem3D representation of the X-ray crystal structure of 18 (some H atoms
have been omitted for clarity).
Subsequent studies were directed towards tuning the aziridi-
nation protocol to give anti-aziridines. It was anticipated that the
corresponding anti-aziridines may be obtained by removing the
H-bonding capacity of the substrate and providing a suitable steric
bias to favour anti aziridination. As N-methyl-N-Boc protected
carbamate 12 gives aziridines 13 and 14 in approximately 50:50 dr
upon treatment with 11, employing two bulky N-protecting groups
was expected to favour anti aziridination. Three substrates were
initially selected: imide 21 and sulfonyl carbamates 23 and 25.
Using the optimised conditions anti-aziridines 22, 24 and 26 were
obtained in 73, 75 and 65% yield, respectively, and in >99:1 dr in
each case (Scheme 8). The relative configuration within imide 22
4. Experimental
4.1. General experimental
All reactions involving organometallic or other moisture-sen-
sitive reagents were carried out under a nitrogen or argon

S.G. Davies et al. / Tetrahedron 66 (2010) 6806e6813
6809
atmosphere using standard vacuum line techniques and glassware
that was flame dried and cooled under nitrogen before use. Sol-
vents were dried according to the procedure outlined by Grubbs et
al.20 Water was purified by a Millipore ElixÒ UV-10 system. All
other solvents were used as supplied (analytical or HPLC grade)
without prior purification. Organic layers were dried over MgSO4.
Thin layer chromatography was performed on aluminium plates
coated with 60 F254 silica. Plates were visualised using UV light
(254 nm), iodine, 1% aq KMnO4, or 10% ethanolic phosphomo-
lybdic acid. Flash column chromatography was performed on
Kieselgel 60 silica.
7.43e7.50 (1H, m, Ar), 7.66e7.71 (1H, m, Ar), 7.72e7.79 (1H, m,
Ar), 8.25 (1H, d, J 7.9, Ar).
4.2.2. 2-Trifluoromethyl-3-aminoquinazolin-4-one.
N
F3C
N
O
NH2
Melting points were recorded on a Gallenkamp Hot Stage
apparatus and are uncorrected. Optical rotations were recorded
on a PerkineElmer 241 polarimeter with a water-jacketed 10 cm
cell. Specific rotations are reported in 10ꢀ1 deg cm2 gꢀ1 and
concentrations in grams per 100 mL. IR spectra were recorded on
a Bruker Tensor 27 FT-IR spectrometer. Selected characteristic
peaks are reported in cmꢀ1. NMR spectra were recorded on
Bruker Avance spectrometers in the deuterated solvent stated.
The field was locked by external referencing to the relevant
deuteron resonance. In cases where methylene protons of car-
bocyclic ring systems could not be unambiguously assigned to
Trifluoroacetic anhydride (60.8 mL, 437 mmol) was added
dropwise to a stirred suspension of anthranilic acid (20.0 g,
146 mmol) in CHCl3 (600 mL) and the mixture was then heated at
reflux for 1 h. The reaction mixture was then allowed to cool to rt
and concentrated in vacuo. Purification via recrystallisation from
60 ꢁC petrol gave 2-trifluoromethyl-benzo[1,3]oxazin-4-one as
a white crystalline solid (17.6 g, 56%); mp 48e49 ꢁC; {lit.19 mp
51e52 ꢁC}; dH (200 MHz, CDCl3) 7.71e7.42 (2H, m, Ar), 8.00e8.13
(1H, m, Ar), 8.19e8.30 (1H, m, Ar). 2-Trifluoromethyl-benzo[1,3]
oxazin-4-one (12.7 g, 59.0 mmol) was dissolved in EtOH (50 mL)
containing hydrazine monohydrate (3.15 mL, 64.9 mmol) and the
resultant mixture was stirred for 1 h at rt. The reaction mixture was
then concentrated in vacuo and the residue was dissolved in EtOAc
(100 mL). The resultant solution was washed with 2 M aq HCl
(100 mL) and brine (100 mL), then concentrated in vacuo. Purifi-
cation via flash column chromatography (eluent 30e40 ꢁC petrol/
Et2O, 4:1) to give 2-trifluoromethyl-3-aminoquinazolin-4-one as
a white crystalline solid (7.98 g, 59%);19 mp 146e148 ꢁC; {lit.19 mp
150e151 ꢁC}; dH (400 MHz, CDCl3) 4.92 (2H, s, NH2), 7.64e7.68 (1H,
m, Ar), 7.88e7.89 (2H, m, Ar), 8.35 (1H, d, J 7.7, Ar).
a
specific carbon atom, the descriptor ‘CH2’ is employed
throughout. Low-resolution mass spectra were recorded on ei-
ther a VG MassLab 20-250 or a Micromass Platform 1 spec-
trometer. Accurate mass measurements were run on either
a Bruker MicroTOF, which was internally calibrated with poly-
alanine, or a Micromass GCT instrument fitted with a Scientific
Glass Instruments BPX5 column (15 mꢂ0.25 mm) using amyl
acetate as a lock mass.
4.2. General procedure for aziridination
4.2.3. tert-Butyl cyclohex-2-en-1-ylcarbamate 5.
A solution of the requisite aminoquinazolinone (2.0e8.0 equiv)
in CH2Cl2 was added dropwise over a period of 30 min to a stirred
suspension of PhI(OAc)2 (2.0e8.0 equiv) in CH2Cl2 at ꢀ23 ꢁC. The
resultant mixture was stirred for a further 30 min and allowed to
warm to rt then a solution of the requisite olefin (1.0 equiv) in
CH2Cl2 was added dropwise over a period of 10 min. The reaction
mixture was then allowed to warm to rt and stirred for 2.5e48 h.
After this time, the reaction mixture was diluted with Et2O, washed
sequentially with 0.5 M aq KOH and H2O, then dried and concen-
trated in vacuo.
NHBo c
Sodium (2.29 g, 99.6 mmol) was added to a stirred solution of
naphthalene (12.8 g, 99.6 mmol) in THF (100 mL) at 0 ꢁC and the
resultant mixture was stirred for 30 min at rt. A solution of 23
(7.00 g, 19.9 mmol) in THF (100 mL) was then added to the reaction
mixture and the resultant solution was stirred for 2 h at rt. H2O
(100 mL) was then added and the aqueous layer was extracted with
Et2O (3ꢂ100 mL). The combined organic extracts were then dried
and concentrated in vacuo. Purification via flash column chroma-
tography (eluent 30e40 ꢁC petrol/Et2O, 4:1) gave 5 as a white solid
(2.00 g, 51%);12 mp 33e35 ꢁC; {lit.12 mp 32e34 ꢁC}; dH (400 MHz,
CDCl3) 1.46 (9H, s, CMe3), 1.49e1.57 (1H, m, CH2), 1.58e1.69 (2H, m,
CH2), 1.84e1.94 (1H, m, CH2), 1.95e2.03 (2H, m, CH2), 4.15 (1H, br s,
C(1)H), 4.52 (1H, br s, NH), 5.61 (1H, dd, J 9.9, 2.6, C(2)H), 5.77e5.86
(1H, m, C(3)H).
4.2.1. 2-Ethyl-3-aminoquinazolinone.
N
Et
N
O
NH2
A mixture of methyl 2-aminobenzoate (17.1 mL, 132 mmol)
and propionic anhydride (23.7 mL, 185 mmol) was heated
without solvent at 105 ꢁC for 30 min, then cooled to 75 ꢁC and
diluted with EtOH (50 mL). Hydrazine monohydrate (64.2 mL,
1.32 mol) was added in two portions at 5 min intervals and the
resultant mixture was then heated at reflux for 1 h, then allowed
to cool to rt and concentrated in vacuo. The residue was
dissolved in CH2Cl2 and the resultant solution was dried and
concentrated in vacuo. Purification via flash column chroma-
tography (eluent 30e40 ꢁC petrol/Et2O, 4:1) gave 2-ethyl-3-
aminoquinazolinone as a white crystalline solid (19.2 g, 77%);21
mp 125e127 ꢁC; {lit.21 mp 122e123 ꢁC}; dH (400 MHz, CDCl3)
1.41 (3H, t, J 7.4, CH3), 3.08 (2H, q, J 7.5, CH2), 4.86 (2H, s, NH2),
4.2.4. tert-Butyl [(1RS,2RS,6SR)-7-(20-ethyl-40-oxoquinazolin-30-yl)-
7-azabicyclo[4.1.0]hept-2-yl]carbamate 8.
NHBoc
NQ 2
Following the general procedure, 2-ethyl-3-aminoquinazolin-4-
one (348 mg, 2.00 mmol), PhI(OAc)2 (652 mg, 2.00 mmol) and 5
(50 mg, 0.25 mmol) were reacted in CH2Cl2 (10 mL) for 2.5 h at rt to
give, after purification via flash column chromatography (eluent
30e40 ꢁC petrol/Et2O, 2:1), 8 as a yellow solid (51 mg, 54%, >99:1

6810
S.G. Davies et al. / Tetrahedron 66 (2010) 6806e6813
dr); mp 91e93 ꢁC; nmax (KBr) 3390 (NeH), 2944, 1690 (C]O), 1685
(C]O), 1605; dH (400 MHz, CDCl3) 1.26e1.33 (1H, m, C(3)HA), 1.43
(3H, t, J 7.4, C(20)CH2CH3), 1.51 (9H, s, CMe3), 1.56e1.64 (1H, m, C(4)
HA), 1.93e2.14 (4H, m, C(3)HB, C(4)HB, C(5)H2), 2.58 (1H, app t, J 7.3,
C(6)H), 3.04 (2H, q, J 7.4, C(20)CH2CH3), 3.08e3.11 (1H, m, C(1)H),
3.90e3.94 (1H, m, C(2)H), 7.08 (1H, d, J 4.8, NH), 7.38e7.44 (1H, m,
Ar), 7.59e7.73 (2H, m, Ar), 8.20 (1H, d, J 8.1, Ar); dC (100 MHz, CDCl3)
10.1 (C(20)CH2CH3), 20.0 (C(4)), 21.6 (C(3)), 26.2 (C(5)), 28.1 (C(20)
CH2CH3), 28.6 (CMe3), 47.4 (C(2)), 47.6 (C(1)), 49.2 (C(6)), 79.0
(CMe3), 120.9 (C(50)), 126.3, 126.4, 126.8, 133.8 (C(4a0), C(70), C(80), C
m, C(3)H); dC (100 MHz, CDCl3) 21.4 (C(5)), 24.6 (C(4)), 28.5 (CMe3),
28.9 (C(6)), 29.1 (NMe), 36.8 (C(1)), 79.3 (CMe3), 90.1 (C(2)), 99.1 (C
(3)), 128.9 (C]O); m/z (ESIþ) 234 ([MþNa]þ, 80%); HRMS (ESIþ)
C12H21NNaOþ2 ([MþNa]þ) requires 234.1465; found 234.1464.
4.2.7. tert-Butyl (1RS,2RS,6SR)- and (1SR,2RS,6RS)-N-methyl-N-
[7-(20-trifluoromethyl-40-oxoquinazolin-30-yl)-7-azabicyclo[4.1.0]
hept-2-yl]carbamate 13 and 14.
NMeBoc
NQ3
NMeBoc
NQ3
t
(8a0)), 145.9 (C(60)), 156.0 (C(20)), 157.0 (CO2 Bu), 160.1 (C(40)); m/z
(ESIþ) 385 ([MþH]þ, 100%); HRMS (ESIþ) C21H28N4Oþ3 ([MþH]þ)
requires 385.2234; found 385.2234.
14
13
4.2.5. tert-Butyl [(1RS,2RS,6SR)-7-(20-trifluoromethyl-40-oxoquina-
zolin-30-yl)-7-azabicyclo[4.1.0]hept-2-yl]carbamate 10.
Following the general procedure, 2-trifluoromethyl-3-amino-
quinazolin-4-one (108 mg, 0.472 mmol), PhI(OAc)2 (152 mg,
0.472 mmol) and 12 (50 mg, 0.236 mmol) were reacted in CH2Cl2
(30 mL) at rt for 48 h to give a 38:31:31 mixture of 12/13/14.
Data for 13 and 14: dH (400 MHz, CDCl3) [selected peaks] 2.69
(3H, br s, NMe), 2.74 (3H, br s, NMe), 3.80 (2H, br s, C(1)H, C(2)H),
3.90 (2H, br s, C(1)H, C(2)H).
NHBoc
NQ3
Following the general procedure, 2-trifluoromethyl-3-amino-
quinazolin-4-one (458 mg, 2.0 mmol), PhI(OAc)2 (644 mg,
2.0 mmol) and carbamate 5 (197 mg, 1.0 mmol) were reacted in
CH2Cl2 (30 mL) at rt for 48 h to give, after purification via flash
column chromatography (eluent 30e40 ꢁC petrol/Et2O, 4:1), 10 as
a yellow solid (393 mg, 93%, >99:1 dr); mp 114e116 ꢁC; nmax (KBr)
3385 (NeH), 2940, 1695 (C]O), 1690 (C]O), 1605, 1160; dH
(400 MHz, CDCl3) 1.23e1.36 (2H, m, C(3)H2), 1.45 (9H, s, CMe3),
1.57e1.59 (1H, m, C(4)HA), 1.72e1.77 (1H, m, C(4)HB), 1.85e1.91 (2H,
m, C(5)H2), 3.81e3.84 (1H, m, C(6)H), 3.96e4.01 (1H, m, C(2)H),
4.03e4.08 (1H, m, C(1)H), 5.46 (1H, d, J 7.6, NH), 7.57e7.61 (1H, m,
Ar), 7.81e7.82 (2H, m, Ar), 8.21 (1H, d, J 8.1, Ar); dH (500 MHz, C6D6)
0.69e0.82 (1H, m, C(4)HA),1.10e1.20 (1H, m, C(4)HB),1.21e1.37 (3H,
m, C(3)HA, C(5)H2),1.47 (9H, s, CMe3),1.61 (1H, d, J 11.8, C(3)HB), 3.19
(1H, t, J 6.7, C(6)H), 3.89 (1H, dd, J 7.2, 4.0, C(1)H), 5.81 (1H, d, J 7.4,
NH), 6.91 (1H, t, J 7.5, Ar), 7.09 (1H, q, J 7.7, Ar), 7.48 (1H, d, J 8.0, Ar),
7.96e8.05 (1H, m, Ar); dC (100 MHz, CDCl3) 19.8 (C(4)), 21.8 (C(5)),
26.7 (C(3)), 28.4 (CMe3), 41.4 (C(1)), 42.0 (C(6)), 46.3 (C(2)), 79.3
(CMe3), 123.0 (C(50)), 126.6, 128.4, 129.2, 134.8 (C(4a0), C(70), C(80), C
4.2.8. N-Cyclohex-2-en-1-yl-toluenesulfonamide 15.
NHTs
TFA (2.64 mL, 35.6 mmol) was added to a stirred solution of 23
(2.50 g, 7.11 mmol) in CH2Cl2 (50 mL) and the resultant mixture was
stirred for 1 h at rt, then concentrated in vacuo. Purification via
flash column chromatography (eluent 30e40 ꢁC petrol/Et2O, 2:1)
gave 15 as a white crystalline solid (840 mg, 47%);12 mp 83e85 ꢁC;
{lit.12 mp 82e84 ꢁC}; dH (400 MHz, CDCl3) 1.49e1.67 (3H, m, CH2),
1.69e1.83 (1H, m, CH2), 1.94 (2H, br s, CH2), 2.44 (3H, s, C(40)Me),
3.82 (1H, br s, C(1)H), 4.43 (1H, d, J 7.7, NH), 5.35 (1H, d, J 9.6, C(2)H),
5.77 (1H, d, J 9.7, C(3)H), 7.31 (2H, d, J 7.7, C(30)H, C(50)H), 7.78 (2H, d,
J 7.7, C(20)H, C(60)H).
t
(8a0)), 143.9 (C(60)), 155.4 (CO2 Bu), 160.7 (C(40));22 m/z (ESIþ) 425
4.2.9. N-[(1RS,2SR,6RS)-7-(20-Trifluoromethyl-40-oxoquinazolin-
30-yl)-7-azabicyclo[4.1.0]-hept-2-yl]-toluenesulfonamide 16.
([MþH]þ, 100%); HRMS (ESIþ) C20H23F3N4O3þ ([MþH]þ) requires
425.1795; found 425.1803.
NHTs
NQ3
4.2.6. tert-Butyl N-methyl-N-(cyclohex-2-en-1-yl)carbamate 12.
NMeBoc
Following the general procedure, 2-trifluoromethyl-3-amino-
quinazolin-4-one (183 mg, 0.801 mmol), PhI(OAc)2 (258 mg,
0.801 mmol) and sulfonamide 15 (100 mg, 0.400 mmol) were
reacted in CH2Cl2 (10 mL) at rt for 48 h to give, after purification via
flash column chromatography (eluent 30e40 ꢁC petrol/Et2O, 13:7),
16 as a yellow solid (169 mg, 85%, >99:1 dr); mp 49e51 ꢁC; nmax
(KBr) 3360 (NeH), 2950, 1685 (C]O), 1605, 1330 (SeN), 1160 (S]
O); dH (400 MHz, CDCl3) 1.20e1.26 (1H, m, C(4)HA), 1.40e1.46 (1H,
m, C(3)HA), 1.48e1.53 (1H, m, C(4)HB), 1.62e1.68 (1H, m, C(3)HB),
1.79e1.85 (2H, m, C(5)H2),1.96 (3H, s, C(400)Me), 3.70e3.75 (1H, m, C
(6)H), 3.75e3.80 (2H, m, C(1)H, C(2)H), 5.68 (1H, d, J 7.3, NH), 7.01
(2H, d, J 8.1, C(300)H, C(500)H), 7.56e7.66 (1H, m, Ar), 7.76 (2H, d, J 8.1,
C(200)H, C(600)H), 7.82e7.87 (2H, m, Ar), 8.14 (1H, d, J 7.8, Ar); dC
(100 MHz, CDCl3) 19.1 (C(4)), 21.0 (C(400)Me), 21.6 (C(5)), 27.7 (C(3)),
40.3 (C(1)), 42.0 (C(6)), 49.0 (C(2)), 123.0 (C(50)), 126.5 (Ar), 126.7 (C
(200), C(600)), 128.6 (Ar), 129.4 (Ar), 129.4 (C(300), C(500)), 135.0 (Ar),
138.6 (C(100)), 143.1 (C(400)), 143.7 (C(20)), 160.4 (C(40));22 m/z (ESIþ)
A solution of carbamate 5 (197 mg, 1.00 mmol) in THF (5 mL)
was added dropwise to a stirred suspension of NaH (60% dispersion
in mineral oil, 80 mg, 2.00 mmol) in THF (5 mL) at 0 ꢁC. After
30 min, MeI (0.16 mL, 2.50 mmol) was added and the resultant
mixture was stirred at rt for 16 h. MeOH (1 mL) was then added,
followed by H2O (1 mL) and satd aq NH4Cl (10 mL). The aqueous
layer was extracted with Et2O (3ꢂ20 mL) and the combined organic
extracts were washed with brine (20 mL), then dried and concen-
trated in vacuo. Purification via flash column chromatography
(eluent 30e40 ꢁC petrol/Et2O, 49:1) gave 12 as a colourless oil
(146 mg, 69%); nmax (film) 2930,1694 (C]O),1445,1396,1315,1255,
1150, 935, 885, 860, 775, 645; dH (400 MHz, CDCl3) 1.46 (9H, s,
CMe3), 1.62e1.65 (1H, m, C(5)HA), 1.77e1.82 (2H, m, C(4)H2),
1.97e1.99 (2H, m, C(5)HB, C(6)HA), 2.69e2.81 (4H, m, C(6)HB, NMe),
4.76 (1H, br s, C(1)H), 5.45 (1H, app d, J 9.9, C(2)H), 5.84e5.86 (1H,

S.G. Davies et al. / Tetrahedron 66 (2010) 6806e6813
6811
479 ([MþH]þ, 100%); HRMS (ESIþ) C22H22F3N4O3Sþ ([MþH]þ) re-
supplementary publication number CCDC 772458. Copies of the
data can be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK [fax: þ44 (0)1223 336033 or
e-mail: deposit@ccdc.cam.ac.uk].
quires 479.1359; found 479.1357.
4.2.10. (RS)-N-(Cyclohex-2-en-1-yl)benzamide 17.
NHBz
4.2.12. Benzyl (RS)-cyclohex-2-en-1-ylcarbamate 19.
NHCbz
A solution of 1 (980 mg, 10.0 mmol) in THF (5 mL) was added to
a
mixture of Bi(OTf)3 (328 mg, 0.500 mmol), KPF6 (92 mg,
A solution of 1 (980 mg, 10.0 mmol) in THF (5 mL) was added to
mixture of Bi(OTf)3 (328 mg, 0.500 mmol), KPF6 (92 mg,
0.500 mmol), benzamide (1.82 g,15.0 mmol) and MgSO4 (w1.5 g) in
THF (50 mL). The resultant mixture was stirred at rt for 16 h then
filtered through Celite (eluent Et2O). The filtrate was then concen-
trated in vacuo. Purification via flash column chromatography
(eluent 30e40 ꢁC petrol/EtOAc, 1:0 to 9:1 gradient elution) gave 17
as a white solid (570 mg, 28%);23 mp 96e98 ꢁC; {lit.23 mp
102e104 ꢁC}; nmax (KBr) 3300 (NeH), 2935(CeH),1635(C]O),1535,
1490, 1330, 1080, 695, 665; dH (400 MHz, CDCl3) 1.57e1.72 (3H, m,
CH2), 1.93e2.02 (3H, m, CH2), 4.64e4.70 (1H, m, C(1)H), 5.62e5.68
(1H, m, C(2)H), 5.85e5.90 (1H, m, C(3)H), 6.34 (1H, d, J 7.5, NH),
7.36e7.40 (2H, m, Ph), 7.44e7.48 (2H, m, Ph), 7.75e7.78 (2H, m, Ph).
a
0.500 mmol), benzyl carbamate (2.27 g, 15.0 mmol) and MgSO4
(w1.5 g) in THF (50 mL). The resultant mixture was stirred at rt for
16 h then filtered through Celite (eluent Et2O). The filtrate was then
concentrated in vacuo. Purification via flash column chromatogra-
phy (eluent 30e40 ꢁC petrol/EtOAc, 1:0 to 9:1 gradient elution)
gave 19 as a white solid (1.92 g, 83%);25 mp 65e67 ꢁC; dH (400 MHz,
CDCl3) 1.01e1.93 (3H, m, CH2), 1.45e1.64 (3H, m, CH2), 4.22 (1H, br
s, C(1)H), 5.02e5.09 (2H, m, OCH2Ph), 5.39 (1H, br s, NH), 5.58 (1H,
d, J 9.9, C(2)H), 5.74e5.79 (1H, m, C(3)H), 7.23e7.29 (5H, m, Ph).
4.2.13. Benzyl [(1RS,2RS,6SR)-7-(20-trifluoromethyl-40-oxaquinazo-
lin-30-yl)-7-azabicyclo[4.1.0]hept-2-yl]carbamate 20.
4.2.11. N-[(1RS,2RS,6SR)-7-(20-Trifluoromethyl-40-oxoquinazolin-
30-yl)-7-azabicyclo[4.1.0]hept-2-yl]benzamide 18.
NHCbz
NHBz
NQ3
NQ3
Following the general procedure, 2-trifluoromethyl-3-amino-
quinazolin-4-one (458 mg, 2.0 mmol), PhI(OAc)2 (644 mg,
2.0 mmol) and carbamate 19 (231 mg, 1.0 mmol) were reacted in
CH2Cl2 (30 mL) at rt for 48 h to give, after purification via flash
column chromatography (eluent 30e40 ꢁC petrol/Et2O, 13:7), 20 as
a yellow solid (406 mg, 89%, >99:1 dr); mp 44e47 ꢁC; nmax (KBr)
3365 (NeH), 2945, 1695 (C]O), 1690 (C]O), 1605; dH (400 MHz,
CDCl3) 1.24e1.39 (2H, m, C(3)HA, C(4)HA), 1.56e1.62 (1H, m, C(4)
HB), 1.78e1.84 (1H, m, C(3)HB), 1.87e1.97 (2H, m, C(5)H2), 3.74e3.77
(1H, m, C(6)H), 3.97e4.02 (1H, m, C(1)H), 4.03e4.09 (1H, m, C(2)H),
5.09e5.15 (2H, m, CH2Ph), 5.91 (1H, d, J 7.6, NH), 7.25e7.38 (5H, m,
Ph), 7.56e7.60 (1H, m, Ar), 7.78e7.81 (2H, m, Ar), 8.20 (1H, d, J 7.8,
Ar); dC (100 MHz, CDCl3) 19.8 (C(4)), 21.7 (C(5)), 26.6 (C(3)), 41.8 (C
(1)), 43.0 (C(6)), 47.0 (C(2)), 66.6 (CH2Ph), 126.6, 128.4, 128.7, 129.3,
134.8 (C(4a0), C(50), C(70), C(80), C(8a0)), 128.0 (p-Ph), 128.1, 128.4 (o,
m-Ph), 136.7 (i-Ph), 143.8 (C(60)), 156.0 (CO2Bn), 160.6 (C(40));22 m/z
(ESIþ) 459 ([MþH]þ, 100%); HRMS (ESIþ) C23H21F3N4Oþ3 ([MþH]þ)
requires 459.1639; found 459.1641.
Following the general procedure, 2-trifluoromethyl-3-amino-
quinazolin-4-one (229 mg, 1.00 mmol), PhI(OAc)2 (322 mg,
1.00 mmol) and amide 17 (101 mg, 0.500 mmol) were reacted in
CH2Cl2 (15 mL) at rt for 48 h to give, after purification via flash col-
umn chromatography (eluent 30e40 ꢁC petrol/Et2O, 1:1), 18 as
a white solid (197 mg, 92%, >99:1 dr); mp 136e138 ꢁC; nmax (KBr)
3370(NeH), 2940,1685 (C]O),1655 (amideI),1605,1530 (amideII);
dH (400 MHz, CDCl3) 1.27e1.45 (2H, m, C(3)HA, C(4)HA), 1.56e1.70
(1H, m, C(4)HB),1.92e2.14 (3H, m, C(3)HB, C(5)H2), 3.40e3.51 (1H, m,
C(6)H), 3.58 (1H, dd, J 7.8, 3.4, C(1)H), 4.45 (1H, d, J 3.3, C(2)H),
7.39e7.53 (3H, m, Ar), 7.55e7.65 (1H, m, Ar), 7.76e7.86 (2H, m, Ar),
7.98 (2H, d, J 8.0, Ar), 8.16e8.30 (2H, m, Ar, NH); dC (100 MHz, CDCl3);
15.3 (C(4)),19.8 (C(5)), 26.1 (C(3)), 44.6 (C(1)), 46.4 (C(2)), 46.9 (C(6)),
122.5 (C(50)), 126.7 (Ar), 127.1 (o,m-Ph), 128.4 (Ar), 128.5 (o,m-Ph),
129.4 (Ar), 131.3 (p-Ph), 134.4 (i-Ph), 134.9 (Ar), 143.6 (C(60)),160.3 (C
(40)), 166.6 (PhCONH);22 m/z (ESIþ) 429 ([MþH]þ, 100%); HRMS
(ESIþ) C22H19F3N4Oþ2 ([MþH]þ) requires 429.1533; found 429.1529.
4.2.11.1. X-ray crystal structure determination for 18. Data were
4.2.14. N-(Cyclohex-2-en-1-yl)phthalimide 21.
collected using an Enraf-Nonius
k-CCD diffractometer with graph-
ite monochromated Mo K radiation using standard procedures at
a
NPhth
190 K. The structure was solved by direct methods (SIR92); all non-
hydrogen atoms were refined with anisotropic thermal parameters.
Hydrogen atoms were added at idealised positions. The structure
was refined using CRYSTALS.24
X-ray crystal structure data for 18 [C29.33H25.33F4N5.33O2.67]:
ꢀ
M¼428.41, monoclinic,spacegroup C 2/c, a¼42.5409(11) A, b¼6.8163
Phthalimide (3.00 g, 20.4 mmol), PPh3 (5.35 g, 20.4 mmol) and
DEAD (3.21 mL, 20.4 mmol) were added to a stirred solution of 1
(1.00 g, 10.2 mmol) in THF (75 mL) at rt. The resultant solution was
stirred at rt for 24 h then concentrated in vacuo. Purification via
flash column chromatography (eluent 30e40 ꢁC petrol/Et2O, 9:1)
gave 21 as a white crystalline solid (1.21 g, 52%);26 mp 109e111 ꢁC
{lit.26 mp 113e114 ꢁC}; dH (400 MHz, CDCl3) 1.70e1.78 (2H, m, CH2),
1.89e1.97 (2H, m, CH2), 2.06e2.23 (2H, m, CH2), 4.87e4.93 (1H, m, C
3
ꢀ
ꢀ
ꢀ
(2) A, c¼13.8366(5) A,
b
¼101.7744(9)ꢁ, V¼3927.8(2) A , Z¼6,
m
¼0.155 mmꢀ1
,
colourless
plate,
crystal
dimensions¼
0.1ꢂ0.2ꢂ0.3 mm3. A total of 4338 unique reflections were measured
for 5<q<27 and 2417 reflections were used in the refinement. The
final parameters were wR2¼0.040 and R1¼0.035 [I>3.0
s(I)].
Crystallographic data (excluding structure factors) has been
deposited with the Cambridge Crystallographic Data Centre as

6812
S.G. Davies et al. / Tetrahedron 66 (2010) 6806e6813
(1)H), 5.56 (1H, app d, J 10.2, C(2)H), 5.93e5.96 (1H, m, C(3)H),
7.69e7.72 (2H, m, C(30)H, C(40)H), 7.82e7.84 (2H, m, C(20)H, C(50)H).
10.2, C(2)H), 5.70e5.79 (1H, m, C(3)H), 7.31 (2H, d, J 8.0, C(30)H, C(50)
H), 7.82 (2H, d, J 8.4, C(20)H, C(60)H).
4.2.15. N-[(1SR,2RS,6RS)-7-(20-Trifluoromethyl-40-oxoquinazolin-
30-yl)-7-azabicyclo[4.1.0]hept-2-yl]phthalimide 22.
NPhth
4.2.17. tert-Butyl
N-tosyl-[(1RS,2RS,6RS)-7-(20-trifluoromethyl-
40-oxoquinazolin-30-yl)-7-azabicyclo[4.1.0]hept-2-yl]carbamate 24.
NTsBoc
NQ3
NQ3
Following the general procedure, 2-trifluoromethyl-3-amino-
quinazolin-4-one (458 mg, 2.00 mmol), PhI(OAc)2 (644 mg,
2.00 mmol) and 23 (352 mg, 1.00 mmol) were reacted in CH2Cl2
(30 mL) at rt for 48 h to give, after purification via flash column
chromatography (eluent 30e40 ꢁC petrol/Et2O, 3:1), 24 as a white
crystalline solid (434 mg, 75%, >99:1 dr); mp 138e140 ꢁC; nmax
(KBr) 2950, 1690 (C]O), 1680 (C]O), 1605, 1340 (SeN), 1165 (S]
O); dH (400 MHz, CDCl3) 1.41 (9H, s, CMe3), 1.53e1.58 (2H, m, C(5)
H2), 1.68e1.86 (3H, m, C(3)H2, C(4)HA), 2.18e2.23 (1H, m, C(4)HB),
2.33 (3H, s, C(400)Me), 3.88e3.94 (2H, m, C(1)H, C(6)H), 4.88 (1H, dd,
J 6.7, 11.5, C(2)H), 7.24 (2H, d, J 8.1, C(300)H, C(500)H), 7.58e7.65 (1H,
m, Ar), 7.82e7.83 (2H, m, Ar), 7.90 (2H, d, J 8.1, C(200)H, C(600)H), 8.20
(1H, d, J 8.1, Ar); dC (100 MHz, CDCl3) 15.2 (C(5)), 21.5 (C(400)Me), 22.5
(C(4)), 27.0 (C(6)), 28.0 (CMe3), 41.7, 44.2 (C(1), C(3)), 53.6 (C(2)),
84.6 (CMe3), 123.0 (C(50)), 126.5 (Ar), 128.1 (C(200), C(600)), 128.5 (Ar),
129.1 (Ar), 129.2 (C(300), C(500)), 134.7 (Ar), 137.4 (C(100)), 144.0, 144.1
Following the general procedure, 2-trifluoromethyl-3-amino-
quinazolin-4-one (458 mg, 2.00 mmol), PhI(OAc)2 (644 mg,
2.00 mmol) and imide 21 (227 mg, 1.00 mmol) were reacted in
CH2Cl2 (30 mL) at rt for 48 h to give, after purification via flash
column chromatography (eluent 30e40 ꢁC petrol/Et2O, 3:1), 22 as
a white crystalline solid (330 mg, 73%, >99:1 dr); mp 212e214 ꢁC;
nmax (KBr) 2945, 1770 (imide), 1710 (imide), 1705 (C]O), 1605; dH
(400 MHz, CDCl3) 1.52e1.62 (2H, m, C(4)H2), 1.71e1.77 (2H, m, C(3)
H2), 183e1.88 (1H, m, C(5)HA), 2.28e2.32 (1H, app d, J 14.2, C(5)HB),
3.76e3.80 (1H, m, C(6)H), 3.92e3.97 (2H, m, C(1)H, C(2)H),
7.52e7.56 (1H, m, Ar), 7.71e7.74 (2H, m, C(300)H, C(400)H), 7.77e7.79
(2H, m, Ar), 7.83e7.85 (2H, m, C(200)H, C(500)H), 8.14 (1H, d, J 7.8, Ar);
dC (100 MHz, CDCl3) 17.1 (C(4)), 22.5 (C(5)), 25.9 (C(3)), 41.6, 42.9 (C
(1), C(6)), 45.7 (C(2)), 122.9 (Ar), 123.3 (C(200), C(500)), 126.4, 128.4,
128.7, 129.1 (Ar), 131.9 (C(100), C(600)), 134.0 (C(300), C(400)), 134.6 (Ar),
143.9 (C(60)), 160.6 (C(40)), 167.7 (N(C]O)2);22 m/z (ESIþ) 455
([MþH]þ, 100%); HRMS (ESIþ) C23H17F3N4O3þ ([MþH]þ) requires
455.1326; found 455.1329.
(C(60), C(20)), 150.6 (CO2 Bu), 160.8 (C(40));22 m/z (ESIþ) 579
t
([MþH]þ, 100%); HRMS (ESIþ) C27H29F3N4O5Sþ ([MþH]þ) requires
579.1884; found 579.1883.
4.2.15.1. X-ray crystal structure determination for 22. Data were
4.2.18. Benzyl N-tosyl-(cyclohex-2-en-1-yl)carbamate 25.
collected using an Enraf-Nonius
k-CCD diffractometer with graph-
ite monochromated Mo K radiation using standard procedures at
a
NTsCbz
190 K. The structure was solved by direct methods (SIR92); all non-
hydrogen atoms were refined with anisotropic thermal parameters.
Hydrogen atoms were added at idealised positions. The structure
was refined using CRYSTALS.24
X-ray crystal structure data for 22 [C30.67H22.67F4N5.33O4]:
PPh3 (2.67 g, 10.2 mmol), 1 (500 mg, 5.09 mmol) and DEAD
(1.20 mL, 7.64 mmol) were added to a stirred solution of TsNHCbz
(2.33 g, 7.64 mmol) in THF (20 mL). The resulting mixture was
stirred at rt for 24 h then concentrated in vacuo. Purification via
flash column chromatography (eluent 30e40 ꢁC petrol/Et2O, 9:1)
gave 25 as a white solid (1.35 g, 69%); mp 68e70 ꢁC; nmax (KBr)
2940, 2360, 1731 (C]O), 1597, 1469, 1455, 1355, 1257, 1170, 1090; dH
(400 MHz, CDCl3) 1.65e1.77 (1H, m, C(5)HA), 1.85e1.90 (1H, m, C(5)
HB), 1.96e2.05 (3H, m, C(4)H2, C(6)HA), 2.16e2.26 (1H, m, C(6)HB),
2.41 (3H, s, C(40)Me), 5.07 (2H, s, OCH2Ph), 5.16e5.22 (1H, m, C(1)H),
5.51 (1H, app d, J 10.4, C(2)H), 5.73e5.76 (1H, m, C(3)H), 7.10e7.23
(5H, m, Ph), 7.32e7.34 (2H, m, C(30)H, C(50)H), 7.73 (2H, d, J 8.3, C(20)
H, C(60)H); dC (100 MHz, CDCl3) 21.6 (C(40)Me), 22.5 (C(5)), 23.9 (C
(4)), 28.2 (C(6)), 56.7 (C(1)), 68.7 (OCH2Ph),127.8,128.1,128.4, 128.5,
128.9, 129.3 (o,m,p-Ph, C(20), C(30), C(40), C(50), C(60),), 133.6þ(i-Ph),
134.5 (C(2)), 137.2 (C(3)), 144.2 (C(10)), 151.9 (C]O); m/z (ESI ) 408
([MþNa]þ, 100%); HRMS (ESIþ) C21H23NNaO4Sþ ([MþH]þ) requires
408.1240; found 408.1239.
ꢀ
M¼454.41, monoclinic, space group C 2/c, a¼21.6579(3) A, b¼16.3647
3
ꢀ
ꢀ
ꢀ
(3) A, c¼14.6212(3) A,
b
¼127.1892(7)ꢁ, V¼4128.30(13) A , Z¼6,
m
¼0.117 mmꢀ1
,
colourless
plate,
crystal
dimensions¼
0.2ꢂ0.2ꢂ0.3 mm3. A total of 4683 unique reflections were measured
for 5<q<27 and 2833 reflections were used in the refinement. The
final parameters were wR2¼0.050 and R1¼0.041 [I>3.0
s(I)].
Crystallographic data (excluding structure factors) has been
deposited with the Cambridge Crystallographic Data Centre as
supplementary publication number CCDC 772459. Copies of the
data can be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK [fax: þ44 (0)1223 336033 or
e-mail: deposit@ccdc.cam.ac.uk].
4.2.16. tert-Butyl N-tosyl-(cyclohex-2-en-1-yl)carbamate 23.
NTsBoc
4.2.19. Benzyl N-tosyl-[(1RS,2RS,6RS)-7-(20-trifluoromethyl-40-oxo-
quinazolin-30-yl)-7-azabicyclo[4.1.0]hept-2-yl]carbamate 26.
PPh3 (32.2 g, 123 mmol), 1 (6.03 g, 61.4 mmol) and DEAD (14.5 mL,
92.1 mmol) were added to a stirred solution of TsNHBoc (25.0 g,
92.1 mmol) in THF (125 mL). The resulting mixture was stirred at rt
for 24 h then concentrated in vacuo. Purification via flash column
chromatography (eluent 30e40 ꢁC petrol/Et2O, 9:1) gave 23 as
a white solid (18.8 g, 87%);12 mp 83e85 ꢁC; {lit.12 mp 84e86 ꢁC}; dH
(400 MHz, CDCl3) 1.35 (9H, s, CMe3), 1.66e1.80 (1H, m, CH2),
1.85e1.96 (1H, m, CH2), 1.97e2.12 (3H, m, CH2), 2.15e2.29 (1H, m,
CH2), 2.45 (2H, s, C(40)Me), 5.05e5.16 (1H, m, C(1)H), 5.52 (1H, d, J
NTsCbz
NQ3
Following the general procedure, 2-trifluoromethyl-3-amino-
quinazolin-4-one (458 mg, 2.00 mmol), PhI(OAc)2 (644 mg,

S.G. Davies et al. / Tetrahedron 66 (2010) 6806e6813
6813
Whitwood, A. C. Org. Biomol. Chem. 2008, 6, 4299; (g) Moore, S. P.; O’Brien, P.;
Whitwood, A. C.; Gilday, J. Synlett 2008, 237.
8. Atkinson, R. S.; Kelly, B. J.; McNicolas, C. J. Chem. Soc., Chem. Commun. 1989, 562.
9. Atkinson, R. S.; Kelly, B. J. J. Chem. Soc., Chem. Commun. 1988, 624.
10. Bartlett, P. D. Rec. Chem. Prog. 1950, 11, 47.
11. The geometry of the transition state for the hydroxyl-directed peracid epoxi-
dation has been open to debate. For an overview of the possible transition
states, see: Freccero, M.; Gandolfi, R.; Sarzi-Amadè, M.; Rastelli, A. J. Org. Chem.
2000, 65, 2030.
2.00 mmol) and 25 (386 mg, 1.00 mmol) were reacted in CH2Cl2
(30 mL) at rt for 48 h to give, after purification via flash column
chromatography (eluent 30e40 ꢁC petrol/Et2O, 3:1), 26 as a white
crystalline solid (398 mg, 65%, >99:1 dr); mp 124e126 ꢁC; nmax
(KBr) 2940, 1690 (C]O), 1685 (C]O), 1605, 1345 (SeN), 1160 (S]
O); dH (400 MHz, CDCl3) 1.35e1.57 (3H, m, C(3)HA, C(4)H2),
1.63e1.78 (1H, m, C(5)HA), 1.80e1.92 (1H, m, C(5)HB), 2.10 (1H, d, J
11.8, C(3)HB), 2.32 (3H, s, Me), 3.77 (1H, d, J 7.5, C(2)H), 3.87 (1H, d, J
7.5, C(1)H), 4.96 (1H, dd, J 11.4, 6.9, C(6)H), 5.11 (2H, s, CH2Ph), 7.15
(2H, d, J 8.0, Ar), 7.27 (2H, d, J 1.9, Ph), 7.35 (3H, d, J 2.3, Ph),
7.56e7.65 (1H, m, Ar), 7.78e7.88 (4H, m, Ar), 8.21 (1H, d, J 8.0, Ar); dC
(100 MHz, CDCl3) 17.1 (C(4)), 21.5 (C(400)Me), 22.2 (C(3)), 26.9 (C(5)),
42.0 (C(2)), 44.1 (C(1)), 53.8 (C(6)), 69.3 (CH2Ph), 123.0 (C(50)), 126.4
(Ar), 12.85, 128.6, 128.8, 129.3 (C(200), C(300), C(500), C(600), o,m-Ph),
128.5, 128.8, 129.2 (p-Ph, Ar), 134.2, 136.7 (C(100), i-Ph), 134.7 (Ar),
144.0 (C(60)), 144.5 (C(400)), 151.8 (CO2CH2Ph), 160.6 (C(40));22 m/z
(ESIþ) 613 ([MþH]þ,100%); HRMS (ESIþ) C30H27F3N4O5Sþ ([MþH]þ)
requires 613.1727; found 613.1727.
12. O’Brien, P.; Childs, A. C.; Ensor, G. J.; Hill, C. L.; Kirby, J. P.; Dearden, M. J.;
Oxenford, S. J.; Rosser, C. M. Org. Lett. 2003, 5, 4955.
13. (a) Aciro, C.; Claridge, T. D. W.; Davies, S. G.; Roberts, P. M.; Russell, A. J.;
Thomson, J. E. Org. Biomol. Chem. 2008, 6, 3751; (b) Aciro, C.; Davies, S. G.;
Roberts, P. M.; Russell, A. J.; Smith, A. D.; Thomson, J. E. Org. Biomol. Chem. 2008,
6, 3762; (c) Bond, C. W.; Cresswell, A. J.; Davies, S. G.; Fletcher, A. M.; Kurosawa,
W.; Lee, J. A.; Roberts, P. M.; Russell, A. J.; Smith, A. D.; Thomson, J. E. J. Org.
Chem. 2009, 74, 6735; (d) Davies, S. G.; Ling, K. B.; Roberts, P. M.; Russell, A. J.;
Thomson, J. E. Chem. Commun. 2007, 4029; (e) Csatayová, K.; Davies, S. G.; Lee,
J. A.; Ling, K. B.; Roberts, P. M.; Russel, A. J.; Thomson, J. E. Org. Lett. 2010. doi:10.
1021/o1101295t
14. Cakici, M.; Karabuga, S.; Kilic, H.; Ulukanli, S.; S¸ ahin, E.; Sevin, F. J. Org. Chem.
2009, 74, 9452.
15. 3-(N-tert-Butoxycarbonylamino)cyclohex-1-ene 5 was prepared in 44% overall
yield from cyclohex-2-enol according to the procedure of Henry, J. R.; Marein,
L. R.; McIntosh, M. C.; Scola, P. M.; Harris, G. D., Jr.; Weinreb, S. M. Tetrahedron
Lett. 1989, 30, 5709.
16. Both lead tetraacetate and iodosobenzene diacetate have been reported to ef-
fect the formation of 3-acetoxyaminoquinazolinone reagents from their parent
3-aminoquinazolinones, see: Koohang, A.; Stanchina, C. L.; Coates, R. M.
Tetrahedron 1999, 55, 9669. Both of these oxidants were found to be suitable in
this system, therefore all subsequent aziridinations utilised iodosobenzene
diacetate as the oxidant due to its reduced toxicity and ease of handling relative
to lead tetraacetate.
Acknowledgements
The authors would like to the Oxford Chemical Crystallography
Service for the use of their x-ray diffractometers.
References and notes
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