Lithiation and stereoselective transformations of 3-aroyl-2,2,4,4tetramethyloxazolidines (TMO amides), a new class of acid-labile atropisomeric amides

Article abstract of DOI:10.1055/s-2002-19748

Aromatic amides 4 (3-aroyl-2,2,4,4-tetramethyloxazolidines or TMO amides) derived by acylation of 2,2,4,4-tetramethyloxazolidine 6 undergo ortho- and lateral lithiation reactions. Given sufficient steric hindrance to bond rotation, they exhibit atropisomerism about the Ar-CO bond and the Ar-CO axis is able to control the atroposelective formation of new stereogenic centres. Unlike amides derived from hindered secondary amines such as diisopropylamine, the 3-aroyl-2,2,4,4-tetramethyloxazolidines are acid-sensitive, and treatment with methanesulfonic acid gives lactones or lactams by cyclisation onto the amide group.

Full text of DOI:10.1055/s-2002-19748

290
LETTER
Lithiation and Stereoselective Transformations of 3-Aroyl-2,2,4,4-
tetramethyloxazolidines (TMO Amides), a New Class of Acid-labile
Atropisomeric Amides
L
ithiationandstereose
a
lective
T
ran
r
sforma
t
k
ions of
T
MOAmid
A
es nstiss, Jonathan Clayden,* Alexander Grube, Latifa H. Youssef
Department of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, UK
Fax +44(161)2754939; E-mail: j.p.clayden@man.ac.uk.
Received 4 October 2001
the presence of triethylamine gave the TMO amides (3-
aroyl-2,2,4,4-tetramethyloxazolidines) 7–9 (Scheme 1,
Table 1).
Abstract: Aromatic amides 4 (3-aroyl-2,2,4,4-tetramethyloxazo-
lidines or TMO amides) derived by acylation of 2,2,4,4-tetrameth-
yloxazolidine 6 undergo ortho- and lateral lithiation reactions.
Given sufficient steric hindrance to bond rotation, they exhibit atro-
pisomerism about the Ar–CO bond and the Ar–CO axis is able to
control the atroposelective formation of new stereogenic centres.
Unlike amides derived from hindered secondary amines such as di-
isopropylamine, the 3-aroyl-2,2,4,4-tetramethyloxazolidines are
acid-sensitive, and treatment with methanesulfonic acid gives lac-
tones or lactams by cyclisation onto the amide group.
Key words: atropisomerism, lithiation, amides, stereoselectivity,
lactones
N,N-Diethylbenzamides and N,N-diisopropylbenzamides
1 have a history of powerful ortho-1 and lateral2 lithiation
chemistry, and during the last 20 years they have played a
central role in the regioselective synthesis of aromatic
compounds. Recently, we have highlighted the fact that
these amides also have stereochemical features – for ex-
ample, their 2,6-disubstituted derivatives exhibit atropi-
somerism about the Ar–CO bond which can both control
and be controlled by nearby stereogenic centres.3 Howev-
er, exploiting the potential of these hindered atropisomer-
ic aromatic amides for the stereoselective synthesis of
targets which lack the amide group is made difficult by the
extreme unreactivity of their C=O groups. Secondary
amides4,5 (for example, N-cumylbenzamides 2), some
functionalised6–8 or less hindered9 tertiary amides (N-me-
thyl-N-tert-butylbenzamides 3 for example) are more re-
active – particularly towards acid – but lack of steric
hindrance in 2 and 3 makes them unsuitable participants
in atroposelective reactions.
Scheme 1 Synthesis and lithiation of TMO amides. (i) CH2Cl2,
MeSO3H, ; (ii) ArCOCl, Et3N, CH2Cl2; (iii) 1. s-BuLi, THF, –78 °C;
2. E+
TMO amides 7–9 were lithiated with s-BuLi in THF at
–78 °C, and quenched with electrophiles (Scheme 1 and
Table 1) to give, straightforwardly, the ortho-functiona-
lised compounds 10–14. It was not necessary to add
Table 1 Synthesis and Lithiation of 7–9
En- SM R1, R2
try
yield E+
(%)
E
Prod- Yield
uct
10
11
12
13
(%)
In this paper, we report a class of amides 4 which are even
more sterically hindered than N,N-diisopropylbenza-
mides, and which react with comparable levels of atro-
poselectivity, but which have an Achilles’ heel: they are
readily hydrolysed in the presence of acid. The amides are
derivatives of 2,2,4,4-tetramethyloxazolidine 6 (“TMO”),
which is very easily made by refluxing commercially
available 2-amino-2-methylpropan-1-ol 5 with acetone.10
Acylation of 6 with 1-naphthoyl chloride, 2,3-methylene-
dioxybenzoyl chloride and 2-methoxybenzoyl chloride in
1
2
3
4
5
7
7
8
9
9
benzoa
70
MeI
Me
Et
65
EtI
EtI
75
OCH2Ob 70c
H, MeO 83
Et
53d
94
BrCH2CH2Br Br
n-C5H11I
n-C5H11 14
90
a 1-naphthamide.
b 2,3-methylenedioxybenzamide.
c Yield from 2,3-methylenedioxybenzoic acid, synthesised by the
method of Clark et al.11
Synlett 2002, No. 2, 01 02 2002. Article Identifier:
1437-2096,E;2002,0,02,0290,0294,ftx,en;D23101ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214
d TMEDA included in the lithiation step.

LETTER
Lithiation and Stereoselective Transformations of TMO Amides
291
TMEDA to get good yields in the ortholithiation of 7 and For these reactions, selectivities turned out to be rather
9,12 though TMEDA prevented a competing decomposi- closer to those previously obtained with the N,N-diethyla-
tion of 8.13
mides than with the more selective N,N-diisopropyla-
mides.16,17
In order to compare the stereoselectivity of atroposelec-
tive reactions of the TMO amides with that of N,N-dieth- All three sets of reactions were kept cold during work up
ylamides and we to prevent epimerisation of the products and to ensure the
N,N-diisopropylamides14,15
ortholithiated 7 and 9 and quenched the lithiated species isolated product ratios accurately represented the kinetic
with aldehydes (Scheme 2). In each case, two atropiso- ratio of products from the reaction mixture. We proved
meric diastereoisomers of the alcohols 15 and 16 were that this initial ratio was under kinetic control by subse-
isolated. The results of these reactions are presented in quent thermal epimerisation. Heating in toluene for 1 hour
Table 2, along with the results of equivalent reactions of at 100–110 °C equilibrated the atropisomers to give sig-
N,N-diethyl and N,N-diisopropylamides 18 and 19 to give nificantly changed ratios. As with their highly stereoselec-
the diastereoisomers of alcohols 20 and 21.14,15 In each tive formation, the pivalaldehyde adducts 15b, 20b and
case, the syn atropisomer was the major product, and the 21b showed exceptional selectivity in their thermody-
selectivity obtained typically lay between the selectivities namically controlled equilibration. The anti atropisomer
obtained with the N,N-diethylamides 18 and the N,N-di- was favoured by > 5:1 (20:1 for 15b) at equilibrium – a
isopropylamides 19.
complete reversal of the kinetic stereoselectivity of the ad-
dition reaction.18
The alcohols 15 may also be formed by diastereoselective
reduction of ketones 17. Swern oxidation of mixtures of The lithiation of 11 with s-BuLi, quenching with acetone
the diastereoisomeric alcohols gave good yields of the ke- or N-methylbenzaldimine, showed that lateral lithiations
tones 17, which were reduced back to the alcohols using of TMO amides (like their N-i-Pr2 analogues19–21) are also
either NaBH4 or LiBHEt3 (Scheme 2). Yields in all reduc- stereoselective. A single atropisomer (as indicated by 1H
tions were quantitative, and excellent selectivities were NMR spectroscopy) of the alcohol 24 and of the amine 25
obtained in favour of the anti diastereoisomer (Table 2). was obtained (Scheme 3).
Table 2 Atroposelectivity in the Formation of Hydroxyamides by Addition to Aldehydes, by Reduction of Ketones and by Equilibration
Addition to
aldehyde
Oxidation to
ketone
Addition to
aldehyde
Reduction with Reduction with Equilibrated
NaBH4 LiBHEt3 mixture
Entry SM
R3
Product
Yield
(%)
Product
Yield
Ratio syn:anti Ratio syn:anti
Ratio syn:anti Ratio syn:anti
(%)
84
–
1
2
7
9
Et
15a
16a
20a
21a
15b
16b
20b
21b
16c
15c
20c
21c
16d
78
90
76a
79a
82
88
61
92
91
87
85a
89a
65
17a
–
85:15
77:23
78:22a
90:10a
81:19
76:24
89:11
89:11
60:40
63:37
51:49a
72:28a
67:33
22:78
–
12:88
–
Et
–
43:57
–
3
18
19
7
Et
–
–
14:86b
20:80b
15:85
–
12:88b
4
Et
–
–
7:93b
58:42c
4:96
13:87
25:75d
11:89
66:34e
–
5
t-Bu
t-Bu
t-Bu
t-Bu
n-Bu
Ph
17b
–
84
–
6:94
6
9
–
7
18
19
9
–
–
–
–
8
–
–
–
–
9
–
–
–
–
10
11
12
13
7
17c
22
23
–
71
–
13:87
14:86b
5:95b
–
< 3:> 97
7:93b
18
19
9
Ph
–
Ph
–
< 1:> 99b
–
36:64c
–
2-thienyl
–
a From ref.14 and ref.15 for comparison.
b From ref.16 and ref.17 for comparison.
c From ref.25 for comparison.
d Ratio after standing at r.t. for several days; contains 15% lactone. On heating in toluene, lactonisation occurs quantitatively.
e Contains 20% lactonised material.
Synlett 2002, No. 2, 290–294 ISSN 0936-5214 © Thieme Stuttgart · New York

292
M. Anstiss et al.
LETTER
the two geometrical conformers about the C–N bond (il-
lustrated for 13 in Figure 2). The two conformers of TMO
amides were typically present in a 2.5:1 ratio in solution,
but X-ray crystallography shows that crystals of 13 con-
tain only the cis conformer. A 1H NMR spectrum acquired
immediately after redissolving crystals of 13 in CDCl3
shows none of the minor conformer, indicating that the
major conformer in solution also has cis stereochemis-
try.23 Equilibrium between the major and minor conform-
ers was restored with a half-life of about 10 hours at 22 °C.
Using the Eyring equation, we calculate that there is a bar-
rier to C–N rotation in the major conformer of 13 of about
99 kJmol–1.24
Scheme 2 Atroposelective transformations. (i) 1. s-BuLi; 2.
R3CHO; (ii) Me2SO, (COCl)2, Et2N, CH2Cl2, –78 °C; (iii) NaBH4,
EtOH, 0 °C; (iv) LiBHEt3, THF, 0 °C; (v) 100–110 °C, toluene, 1 h.
Figure 1 X-ray crystal structure of syn-15c
Scheme 3 Atroposelective lateral lithiation–quench of TMO ami-
des. (i) 1. s-BuLi, THF, –78 °C; 2. acetone; (ii) 1. s-BuLi, THF, –78
°C; 2. PhCH=NMe, –78 °C.
Figure 2 C–N rotation and TMO amides
The stereochemistry of the reactions shown in Schemes 2
and 3 was assigned by analogy with the known stere-
ochemical course of similar reactions of other N,N-dialky-
lamides,14–17,19,25 and confirmed in the alcohol series by
the X-ray crystal structure of syn-15c (Figure 1). Curious-
ly, the polarities of the atropisomeric products, which are
a reliable guide15,17,22 to stereochemistry in the N,N-dieth-
yl and N,N-diisopropyl series (the syn hydroxyamides 20
and 21 are more polar than the anti), are inverted in the
TMO amides: syn-15 is always less polar than anti-15.
The barrier to interconversion of the atropisomeric diaste-
reoisomers of TMO amides – i.e. the barrier to Ar–CO ro-
tation – is evidently of a similar magnitude to that of N,N-
diisopropylamides: atropisomeric diastereoisomers are
stable at room temperature and may be separated, but in-
terconvert on heating in solution.25 By way of qualitative
illustration, samples of syn- and anti-15b in solution in
CDCl3 had not reached thermodynamic equilibrium even
after 18 weeks at 10–20 °C. Lineshape analysis of the
variable temperature NMR spectrum of 7 is complicated
by the possibility of correlation between Ar–CO and C–N
rotation,26 but simple analysis of coalescences27 indicates
The 1H NMR spectra of all amide derivatives of 6 feature
two sets of peaks because of the slow interconversion of
Synlett 2002, No. 2, 290–294 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Lithiation and Stereoselective Transformations of TMO Amides
293
Typical Synthesis of a TMO Amide: 3-(1 -Naphthoyl)-2,2,4,4-
tetramethyl-1,3-oxazolidine 7 from 5
barriers to both C–N and Ar–CO rotations of 73 3 kJ-
mol–1, similar to that of 19.25,28
A solution of 2-amino-2-methylpropanol 5 (9 g, 100 mmol), ace-
tone (11 mL, 150 mmol) and three drops of methanesulphonic acid
in CH2CH2 (60 mL) was heated to reflux under a Soxhlet extractor
for 70 h.10 After cooling, the mixture was washed with sat. K2CO3
(15 mL), dried (Na2SO4) and concentrated under reduced pressure
to give the oxazolidine 6 (11.9 g, 92%) as a colourless liquid, which
was used without further purification. 1-Naphthoyl chloride (13.6
mL, 90 mmol) was added dropwise over 15 min to a stirred solution
of 6 (11.5 g, 90 mmol) and triethylamine (18.8 mL, 135 mmol) in
CH2CH2 (50 mL) at 0 °C under nitrogen. The mixture was allowed
to warm to r.t. and left stirring for 3 days, diluted with CH2CH2,
washed with water and extracted with CH2CH2 (2 50 mL). The
combined organic fractions were washed 1 M HCl (2 50 mL),
dried (Na2SO4) and evaporated under reduced pressure to give a yel-
low solid. Recrystallisation from petrol/EtOAc gave the amide 7 as
white crystals, 17.8 g (70%), mp 169–170 °C; IR: max (film)/cm–1
Though highly resistant to the strongly basic conditions
of the lithiation reactions, TMO amides are sensitive to
acid. Treatment of mixtures of diastereoisomers of 15a–b,
16a–d and 24 with methanesulfonic acid in warm metha-
nol (refluxing ethanol for 24) gave, respectively, lactones
26a–b and 28a–d29 in good yield and 27 in moderate yield
(Scheme 4 and Table 3). Deprotection of the methyl
ethers of 28a and 28c with boron tribromide gave the nat-
ural products ( )-isoorchracein 29a30,31 and 29c, a metab-
olite of Penicillium vulpinum.32 Treatment of amine 25
with acid gave the amide 30 contaminated with the ester
arising from acyl transfer from N to O. The mixture was
cyclised to give lactam 31 by refluxing in pyridine.
1611 (C=O); 1H NMR (300 MHz; CD3SOCD3) (two rotamers):
=
8.0–7.3 (7 H, m, ArH), 3.8 (min.) and 3.7 (maj.) (2 H, s, OCH2),
1.78 (maj.), 1.77 (maj.), 1.35 (min.) and 0.70 (min.) (2 3 H, s,
(CH3)2C-2), 1.68 (min.), 1.60 (min.), 1.20 (maj.) and 0.45 (maj.)
(2 3 H, s, (CH3)2C-4); m/z (CI) (%) = 284 (100) [M + H]. Found:
M+, 283.1571, Cl8H21NO2 requires M, 283.1572.
Ortholithiation of a TMO Amide: (Ra*,S*)- and (Ra*,R*)-3-(2 -
(a-Hydroxybenzyl)-1 -naphthoyl)-2,2,4,4-tetramethyl-1,3-ox-
azolidine syn and anti-15c
sec-Butyllithium (3.0 mL of 1.3 M solution in cyclohexane, 3.9
mmol) was added to a stirred solution of amide 7 (0.500 g, 1.76
mmol) in dry THF (40 mL), under nitrogen at –78 °C. After 60 min
freshly distilled benzaldehyde (0.46 mL, 4.4 mmol) was added to
the yellow-sepia solution. The mixture was stirred for a further 60
min at –78 °C and allowed to warm to 0 °C. Sat. ammonium chlo-
ride was added (20 mL), then the mixture was diluted with water,
extracted with CH2CH2 (3 20 mL), dried (Na2SO4) and evaporat-
ed under reduced pressure at a temperature not exceeding 30 °C.
The crude products were separated by f1ash chromatography (9:1
petrol–EtOAc) to give (Ra*,S*)-3-(2'-( -hydroxybenzyl)-l'-naph-
thoyl)-2,2,4,4-tetramethyl-1,3-oxazolidine syn-15c (0.371 g, 55%)
Scheme 4 Cyclisation–deprotection. (i) MeSO3H, MeOH, , 10–
240 min; (ii) BBr3, CH2Cl2, –78 °C; (iii) 6 M HCl, ; (iv) pyridine,
60 h.
,
as a white solid, mp 116–120 °C; Rf (c 0.34, 5:1 petrol–EtOAc); IR:
1
(film)/cm–l 3416 (OH), 1594 (C=O); H NMR (300 MHz;
max
CDC13): = 8.00–7.00 (11 H, m, ArH), 6.15 (l H, d, CHOH), 4.00–
3.70 (2 H, m, OCH2), 2.03 (maj.), 1.95 (maj.), 1.42 (min.), 1.08
(min.) (2 3 H, s, (CH3)2C-2), 1.92 (min.), 1.85 (min.), 1.15 (maj.),
0.96 (maj.) (2 3 H, s, (CH3)2C-4); 13C NMR (75 MHz; CDC13):
= 168.8 (C=O), 141.0, 138.5, 134.3, 132.6, 130.0 ,129.2, 129.0,
128.4, 128.1, 128.0, 127.6, 127.5, 126.9, 126.8, 126.4, 126.3, 126.0,
125.9, 125.0, 125.0 (Ar), 98.6, 95.9 (OCH2), 75.6, 73.9, 73.6
(CHOH) and (NC-2), 63.9, 61.3 (NC-4), 27.8, 27.6, 26.8, 25.7,
25.3, 24.5, 24.2 (CH3 4); m/z (CI) (%) = 390 (22) [M + H], 374
(100) and 372 (98). Found: M+, 389.1995, C25H27NO3 requires M,
389.1991. Also obtained was (Ra*,R*)-3-(2'-( -hydroxybenzyl)-l'-
naphthoyl)-2,2,4,4-tetramethyl-1,3-oxazolidine anti-15c (0.222 g,
Table 3 Deprotection of 15 and 16
Entry SM
R3
Cyclised Yield Deprotected Yield
product
(%)
62
77
29
89
88
81
60
product
(%)
1
2
3
4
5
6
7
15a
15b
24
Et
26a
–
–
t-Bu
–
26b
27
–
–
–
–
16a
16b
16c
16d
Et
28a
29aa
–
77
–
32%) as a white solid, mp 183–185 °C; Rf (c 0.17, 5:1 petrol–
t-Bu
n-Bu
2-thienyl
28b
28c
1
EtOAc); IR:
(film)/cm–l 3430 (OH), 1600 (C=O); H NMR
max
(300 MHz; CDC13): = 7.90–7.20 (11 H, m, ArH), 6.08 (l H, d,
J = 4 Hz, CHOH), 3.90 (min.), 3.80 (maj.) (2 H, s, OCH2), 2.50 (l
H, d, J = 4 Hz, OH), 2.03 (maj.), 1.98 (maj.), 1.28 (min.), 0.75
(min.) (2 3 H, s, (CH3)2C-2), 1.90 (min.), 1.85 (min.), 1.48 (maj.),
0.95 (maj.) (2 3 H, s, (CH3)2 C-4); 13C NMR (75 MHz; CDCl3):
= 166.8 (C=O), 143.6, 136.8, 132.6, 132.5, 130.0, 129.5, 129.3,
128.4, 127.9, 127.4, 126.5, 126.3, 126.2, 125.7, 123.7 (Ar), 98.3
(OCH2), 75.6, 73.2, 73.1 (CHOH) and (NC-2), 60.9 (NC-4), 27.9,
27.6, 26.3, 26.0, 25.6, 25.1, 24.6, 24.4 (CH3 4); m/z (CI) (%) = 390
(15) [M+, H] and 374 (100). Found: M, 389.1996, C25H27NO3 re-
quires M, 389.1991.
29c
–
79
–
28db
a ( )-Isoorchracein.
b Methyl ether of ( )-chrycolide.
Synlett 2002, No. 2, 290–294 ISSN 0936-5214 © Thieme Stuttgart · New York

294
M. Anstiss et al.
LETTER
(15) Bowles, P.; Clayden, J.; Helliwell, M.; McCarthy, C.;
Tomkinson, M.; Westlund, N. J. Chem. Soc., Perkin Trans.
1 1997, 2607.
(16) Clayden, J.; Westlund, N.; Wilson, F. X. Tetrahedron Lett.
1996, 37, 5577.
Acknowledgement
We are grateful to the EPSRC and EU (Erasmus/Socrates) for sup-
port, and to Dr. Madeleine Helliwell for determining the X-ray cry-
stal structures of 13 and of syn-16c.
(17) Clayden, J.; Westlund, N.; Beddoes, R. L.; Helliwell, M. J.
Chem. Soc., Perkin Trans. 1 2000, 1351.
(18) High selectivity under thermodynamic control is a feature of
amides with adjacent stereogenic centres bearing well-
contrasted small, medium and large groups. For further
discussion, see ref.3 and ref.19
(19) Clayden, J.; Pink, J. H. Tetrahedron Lett. 1997, 38, 2561.
(20) Clayden, J.; Darbyshire, M.; Pink, J. H.; Westlund, N.;
Wilson, F. X. Tetrahedron Lett. 1997, 38, 8587.
(21) Clayden, J.; Westlund, N.; Wilson, F. X. Tetrahedron Lett.
1999, 40, 3331.
References
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(23) Presumably, stereoelectronics favour antiperiplanarity of C–
O
* and the more electron-rich C4-N bond.
(24) (a) Stewart, W. H.; Siddall, T. H. Chem. Rev. 1970, 70, 517.
(b) Rate–Energy interconversions are conveniently carried
out using the applet at http://www.ch.cam.ac.uk/magnus/
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(28) These relatively high barriers to Ar–CO rotation are
gratifying, given that ground-state destabilisation in some
analogous tetramethylpiperidine-derived amides results in
extremely low (ca. 25 kJ mol–1) barriers to C–N (and,
presumably therefore, Ar–CO) rotation, see: Lunazzi, L.;
Macciantelli, D.; Tassi, D.; Dondoni, A. J. Chem. Soc.,
Perkin Trans. 2; 1980, 717.
(29) Lactone 28d is the ( )-methyl ether of the plant-growth
inhibitor chrycolide, see: Tada, M.; Chiba, K. Agric. Biol.
Chem.; 1984, 48, 1367.
(8) Comins, D. L.; Brown, J. D. J. Org. Chem. 1986, 51, 3566.
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(10) Hoppe introduced base-stable, acid-labile carbamate
derivatives of oxazolidine 6 as powerful promoters of
lithiation to oxygen: (a) Hintze, F.; Hoppe, D. Synthesis
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Chem., Int. Ed. Engl. 1989, 102, 1457.
(11) 2,3-Dihydroxybenzoic acid was esterified (EtOH, H2SO4,
and treated with CH2Br2 and KF in DMF. Hydrolysis
returned 2,3-methylenedioxybenzoic acid: Clark, J. H.;
)
Holland, H. L.; Miller, J. M. Tetrahedron Lett.; 1976, 3361.
(12) Although it is standard practice to perform ortholithiations in
the presence of TMEDA (see ref.1), we have found that
TMEDA is generally unnecessary in lithiations of N,N-
diisopropylamides, though it is required to avoid formation
of ketones by “dimerisation” of N,N-diethylamides.
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Synlett 2002, No. 2, 290–294 ISSN 0936-5214 © Thieme Stuttgart · New York