Dearomatizing disrotatory electrocyclic ring closure of lithiated N-benzoyloxazolidines

Article abstract of DOI:10.1002/1521-3773(20020315)41:6<1049::AID-ANIE1049>3.0.CO;2-7

Loss of aromaticity ensues when N-benzoyl oxazolidines are lithiated and undergo a 6π disrotatory electrocyclization (see scheme). The stereochemistry of the cyclization shows it to be a new example of an electrocyclic ring closure. The cis-tricyclic prod

Full text of DOI:10.1002/1521-3773(20020315)41:6<1049::AID-ANIE1049>3.0.CO;2-7

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8.28 (s, 1H, Ade-H8), 8.36, 8.37 (s, 1H, Ade-H2), 8.37, 8.46 (brs, 2H, Ade-
N6H2), 11.30 (s, 1H, Thy-N3H); MS: m/z: 562.0 [Pd(1)Cl] ; elemental
analysis (%) calcd for 2 ¥ 3H2O: C 28.99, H 4.12, N 13.92; found: C 28.13, H
3.97, N 13.14. A small quantity of crystals of 2 suitable for single-crystal
X-ray diffraction studies were grown by slow cooling of a hot aqueous
solution.[9]
unique (Rint ˆ 0.0451, q ꢀ 25.08); R ˆ 0.0829 (F values, F 2 > 2s), Rw ˆ
0.1771 (F 2 values, all data), GOF 1.312for 350 parameters, max./min.
residual electron density 2.58/ À 1.47 eäÀ3. b) Crystal data for 3:
C17H32ClF3N7O6.5PtS2Si0.5, Mr ˆ 804.20, monoclinic, space group I2/a,
a ˆ 24.4619(10), b ˆ 7.9190(3), c ˆ 29.1288(10) ä, b ˆ 98.073(2)8, Vˆ
5586.7(4) ä3, Z ˆ 8, 1calcd ˆ 1.912gcm À3, synchrotron radiation at Dare-
bury Laboratory station 9.8, l ˆ 0.6942ä, m ˆ 5.36 mmÀ1, Tˆ 160 K.
18024 measured reflections were corrected for absorption; 6866 were
unique (Rint ˆ 0.0360, q ꢀ 27.5 8); R ˆ 0.0388 (F values, F 2 > 2s), Rw ˆ
0.1053 (F 2 values, all data), GOF 1.185 for 350 parameters, max./min.
residual electron density 2.49/ À 1.19 eä3. c) The anion in both crystal
structures wass identified as SiF62À, generated by etching of the glass by
the aqueous BF4À ions. Detailed evidence is available from the authors.
d) Programs: standard Bruker AXS control and integration software
and SHELXTL. CCDC-170471 (2) and CCDC-170472( 3) contain the
supplementary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html
(or from the Cambridge Crystallographic Data Centre, 12Union Road,
Cambridge CB21EZ, UK; fax: (‡44)1223-336-033; or deposit@ccdc.
cam.ac.uk).
‡
3: Same procedure as for Pd analogue 2, except that K2[PtCl4] (0.074 g,
0.182mmol) in aqueous solution was used as starting material, and to this
was added dropwise a hot ethanolic solution of 1 (0.076 g, 0.182mmol), and
the mixture refluxed overnight. The cooled solution was taken to dryness
under reduced pressure, and the resultant solid residue dissolved in hot
water (50 mL). The mixture was filtered to remove undissolved solids and
concentrated to a minimum volume in vacuo. The addition of a saturated
aqueous solution of NaBF4 precipitated 3 as a white solid, which was
washed with water, ethanol, and diethyl ether and pump dried. Yield
0.093 g, 69.3%. 1H NMR ([D6]DMSO, TMS): d ˆ 1.78, 1.81 (s, 3H, Thy-
CH3), 2.13, 2.23 (m, 2H, H17), 3.04 (m, 1H, H16), 3.10 (m, 1H, H16), 3.22
(d, 1H, H13'), 3.36 (m, 1H, H14), 3.39 (m, 1H, H14'), 3.62(d, 1H, H13),
3.73 (m, 1H, H11'), 3.82(m, 1H, H11), 4.74 (m, 2H, H18), 4.81, 5.07 (d, 1H,
H10'), 5.13 (m, 1H, H10), 7.51, 7.53 (s, 1H, Thy-H6), 8.28, 8.29 (s, 1H, Ade-
H8), 8.41, 8.43 (s, 1H, Ade-H2), 8.47, 8.57 (brs, 2H, Ade-N6H2), 11.29 (s,
‡
1H, Thy-N3H); MS: m/z: 652.0 [Pt(1)Cl] ; elemental analysis (%) calcd
for 3 ¥ 2 H2O: C 26.35, H 3.51, N 12.65; found: C 27.07, H 3.98, N 12.71.
Crystallization by slow cooling of a hot aqueous solution of 3 yielded a few
single crystals, some of which were suitable for diffraction studies.[9]
Received: September 17, 2001
Revised: December 27, 2001 [Z17917]
Dearomatizing Disrotatory Electrocyclic Ring
Closure of Lithiated N-Benzoyloxazolidines**
Jonathan Clayden,* Savroop Purewal,
Madeleine Helliwell, and Simon J. Mantell
[1] a) G. M. Whitesides, E. E. Simanek, J. P. Mathias, C. T. Seto, D. N.
Chin, M. Mammen, D. M. Gordon, Acc. Chem. Res. 1995, 28, 37 44;
b) J. L. Sessler, B. Wang, A. Harriman, J. Am. Chem. Soc. 1993, 115,
10418 10419; c) A. D. Burrows, C.-W. Chan, M. M. Chowdhry, J. E.
McGrady, D. M. P. Mingos, Chem. Soc. Rev. 1995, 24, 351 358.
[2] a) I. Dieter-Wurm, M. Sabat, B. Lippert, J. Am. Chem. Soc. 1992, 114,
357 359; b) A. Schreiber, M. S. Luth, A. Erxleben, E. C. Fusch, B.
Lippert, J. Am. Chem. Soc. 1996, 118, 4124 4132; c) J. A. R. Navarro,
B. Lippert, Coord. Chem. Rev. 1999, 185, 653 667, and references
therein.
Aromatic amides–both naphthamides and benzamides–
can be dearomatized in a cyclization reaction triggered by a
benzylic lithiation a to the amide nitrogen.[1] The reaction has
been optimized for the synthesis of functionalized cyclo-
hexadienes 4 and cyclohexenones from amides 1, and both the
benzamide and naphthamide versions of the reaction
(Scheme 1) have been employed in the synthesis of important
members of the kainoid family of cyclic amino acids.[2]
Superficially, the mechanism of this cyclization appears to
be an intramolecular conjugate addition reaction[3] of the
benzylic anionic center into the electron-deficient ortho
position of the aromatic ring, with the product stereochem-
istry arising from the preference of the phenyl group for the
exo face of the forming bicyclic ring system. However, under
this interpretation, the cyclization of the lithiated benzamide 2
has at least some (Baldwin-disfavored) 5-endo-trig charac-
ter,[4] and the cyclization of a 2-naphthamide 2 (R1, R2 ˆ
benzo) rather more.
[3] Nucleic Acids in Chemistry and Biology (Eds.: G. M. Blackburn, J. M.
Gait), IRL Press, Oxford, 1990.
[4] a) C. Price, M. R. J. Elsegood, W. Clegg, A. Houlton, Chem. Commun.
1995, 2285 2286; b) C. Price, M. R. J. Elsegood, W. Clegg, N. H. Rees,
A. Houlton, Angew. Chem. 1997, 109, 1823 1825; Angew. Chem. Int.
Ed. Engl. 1997, 36, 1762 1764; c) M. A. Shipman, C. Price, A. E.
Gibson, M. R. J. Elsegood, W. Clegg, A. Houlton, Chem. Eur. J. 2000, 6,
4371 4378; d) M. A. Shipman, C. Price, M. R. J. Elsegood, W. Clegg,
A. Houlton, Angew. Chem. 2000, 112, 2450 2452; Angew. Chem. Int.
Ed. 2000, 39, 2360 2362; e) C. Price, M. A. Shipman, S. L. Gummer-
son, A. Houlton, W. Clegg, M. R. J. Elsegood, J. Chem. Soc. Dalton
Trans. 2001, 353 354; f) C. Price, M. A. Shipman, N. H. Rees, M. R. J.
Elsegood, A. J. Edwards, W. Clegg, A. Houlton, Chem. Eur. J. 2001, 7,
1194 1200.
[5] Synthetic nucleobase strands linked to flexible and rigid organic
framework have been reported previously: a) D. T. Browne, J. Eisinger,
N. J. Leonard, J. Am. Chem. Soc. 1968, 90, 7302 7312; b) J. L. Sessler,
R. Wang, J. Am. Chem. Soc. 1996, 118, 9808 9809; c) J. L. Sessler, R.
Wang, J. Org. Chem. 1998, 63, 4079 4091.
An attractive alternative rationalization, illustrated in the
box in Scheme 1, is that the cyclization is pericyclic and
[6] AT bases have been attached to diazacrowns that can bind metal ions:
a) O. F. Schall, G. W. Gokel, J. Am. Chem. Soc. 1994, 116, 6089 6100;
b) O. F. Schall, G. W. Gokel, J. Org. Chem. 1996, 61, 1449 1458.
[7] a) C. Meiser, B. Song, E. Freisinger, M. Peilert, H. Sigel, B. Lippert,
Chem. Eur. J. 1997, 3, 388 398; b) Y. Lui, C. Pacifico, G. Natile, E.
Sletten, Angew. Chem. 2001, 113, 1266 1268; Angew. Chem. Int. Ed.
2001, 40, 1226 1228.
[*] Prof. J. Clayden, S. Purewal, Dr. M. Helliwell
Department of Chemistry
University of Manchester
Oxford Rd, Manchester M13 9PL (UK)
Fax : (‡44)161-275-4939
E-mail: j.p.clayden@man.ac.uk
Dr. S. J. Mantell
Pfizer Central Research
Sandwich, Kent CT13 9NJ (UK)
[8] a) Crystal data for 2: C17H32ClF3N7O6.5PdS2Si0.5, Mr ˆ 715.51, mono-
clinic, space group I2/a, a ˆ 24.3737(16), b ˆ 7.9006(5), c ˆ
29.2031(19) ä, b ˆ 97.894(2)8, Vˆ 5570.3(6) ä3, Z ˆ 8, 1calcd
ˆ
1.706 gcmÀ3, MoKa radiation, l ˆ 0.71073 ä, m ˆ 1.00 mmÀ1, Tˆ 160 K.
[**] We are grateful to Pfizer and to the EPSRC for a CASE studentship
(to S.P.).
18467 measured reflections were corrected for absorption; 4903 were
Angew. Chem. Int. Ed. 2002, 41, No. 6
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
1433-7851/02/4106-1049 $ 17.50+.50/0
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O
O
O
O
O
a)
a)
N
N
N
NtBu
NtBu
O
O
O
O
R1
R1
Li
6
R1
R1
Ar
R1
Ar
Li
Li
R2
R2
O
5
7
1
2
O
OLi
NtBu
E
H
E
b)
R1
Ar
or
N
O
N
O
N
O
OLi
NtBu
Ar
R2
R1
R1
H
O
b)
H
H
O
H
H
H
NtBu
Ar
8
9
c)
10 (from R1 = OMe)
R1
R1
c)
H
H
R2
R2
O
E
O
4
3
E
O
E
H
Scheme 1. Dearomatizing cyclization of lithiated N-aroyl benzylamines.
a) LDA, À78 ‡ 258C; b) NH4Cl.
N
N
O
N
R1
O
R1
O
H
H
H
13
H
HO
11
12
Scheme 2. Dearomatizing cyclization of lithiated N-benzoyl oxazolidines
5; a) Method A: sBuLi or tBuLi (1.5 equiv), DMPU (6 equiv), THF,
À788C, 30 min then 08C, 2h or Method B: tBuLi (1.5 equiv), DMPU
therefore is not subject to the usual stereoelectronic con-
straints adumbrated by Baldwin.[4] A disrotatory thermal
electrocyclic ring closure of 2 obeys the Woodward Hoff-
mann rules,[5] and will lead to the correct stereochemistry of 3,
provided that the aryl ring starts trans to the tert-butyl group.
Stereochemistry alone can therefore not distinguish between
the two mechanisms of cyclization in this case.
‡
(6 equiv), THF, À788C, 14 16 h; b) E ; c) 2m HCl, MeOH or Et2O.
However, when the nitrogen atom is within a ring, the
stereochemistry of the product is diagnostic of the reaction
mechanism. Herein, we describe the first dearomatizing
anionic cyclization of a non-benzyl substituted benzamide,
the stereochemistry of which gives strong evidence that the
cyclization is pericyclic.
The N-benzoyl oxazolidines 5 (R1 ˆ H and R1 ˆ OMe)[6]
were lithiated with tBuLi or sBuLi in the presence of 1,3-
dimethylhexahydro-2-pyrimidinone (DMPU) at À788C
(Scheme 2). The resulting deep orange organolithium com-
pounds were either warmed to 08C over 2h (method A) or
stirred at À 788C for 14 16 h (method B). From 5 (R' ˆ H) a
tricyclic product 9 was obtained as a single diastereoisomer in
moderate to good yield (Table 1).[7] Enones 10 were obtained
from 5 (R1 ˆ OMe) after work up with 1m HCl. The structure
of 9a was established by X-ray crystallography[8] (Figure 1a),
while evidence for the stereochemistry of 9b d, 10a and 10b
(Table 1) was gained from nuclear Overhauser enhancement
(NOE) studies (Figure 2and Table 1).
Figure 1. a) X-ray crystal structure of 9a; b) X-ray crystal structure of 12c.
O
O
E
H
E
H
N
N
R1
NOE
R1
NOE
O
NOE
O
NOE
H
H
a%
c%
b%
d%
9
12
Figure 2. Stereochemistry of 9 and 12.
studies (Figure 2) confirmed the stereochemistry of 12b
d
and 13. Evidently the initial cyclization produces a cis-fused
tricyclic ring system which is significantly less stable than the
trans-fused system formed after epimerization under thermo-
dynamic control.
While an ionic cyclization of lithiated 5 would be expected
to generate directly a more stable trans tricyclic enolate epi-8,
and hence 12, thermal electrocyclic ring closure of lithiated 5
must be disrotatory and therefore has no alternative but to
form the enolate 8 with a cis tricyclic structure (Scheme 3).
The stereochemistry of the product strongly suggests that the
On stirring 9b d or 10b with acid (2m HCl in ether), a
clean isomerization took place to yield a diastereoisomer
12b d quantitatively (or enone 13 from 10b), presumably via
the acyliminium ion 11. An X-ray crystal structure[8] (Fig-
ure 1b) of 12c confirmed its stereochemistry, and NOE
Table 1. Yields and Stereochemistry.
‡
Entry
R1
E
E
Yield 9[a] or 10[b] [%]
NOE a%
NOE b%
Yield 12 or 13 [%]
NOE c%
NOE d%
1
2
3
4
5
6
7
H
H
H
H
H
MeO
MeO
NH4Cl
CD 3OD
MeI
BnBr
PBB-Br[e]
1m HCl
H
D
Me
Bn
PBB
H
9a 60
9b 60
20.0
13.217.3
14.6
22.3
11.2
12b 13[c]
12c 100
12d 99
2.2
2.3
4.1
2.5
1.8
2.9
9c 53[d]
9d 45
9e 41
10a 55
10b 48
14.9
12.5
13.5
13.8
MeI then 1m HCl
Me
13 100
3.7
2.6
[a] From 5 (R1 ˆ H) by method A. [b] From 5 (R1 ˆ OMe) by method B. [c] Major product is 19 (E ˆ H). [d] By NMR. [e] PBB ˆ p-BrC6H4CH2.
1050
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1433-7851/02/4106-1050 $ 17.50+.50/0
Angew. Chem. Int. Ed. 2002, 41, No. 6

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give monodeuterated 15 as a mixture of regioisomers
(Scheme 4).
6π disrotatory
electrocyclic
ring closure
OLi
OLi
O
N
O
N
O
Scheme 2summarizes all the key steps in the mechanism
that leads from 5 to 9 and 12 or 13 via the key electrocyclic
ring closure 7 !8. The tricyclic products, generated in two
steps from simple starting materials and are potentially very
versatile synthetic intermediates.
R1
R1
H
O
H
H
H
H
H
7
8
epi-8
not formed
Scheme 3. Mechanisms for ring closure of 7.
Received: November 7, 2001 [Z18174]
cyclization of 5 is indeed pericyclic, and we presume the same
for the cyclization of 1.
[1] A. Ahmed, J. Clayden, M. Rowley, Chem. Commun. 1998, 2 97; A.
Ahmed, J. Clayden, S. A. Yasin, Chem. Commun. 1999, 231; J.
Clayden, C. J. Menet, D. Mansfield, Org. Lett. 2000, 2, 42 2 9; J.
Clayden, K. Tchabanenko, S. A. Yasin, M. D. Turnbull, Synlett 2001,
302. For other related reactions, see J. K. Crandall, T. A. Ayers, J. Org.
Chem. 1992, 57, 2993; A. Padwa, M. A. Filipkowski, D. N. Kline, S. S.
Murphree, P. E. Yeske, J. Org. Chem. 1993, 58, 2061; V. K. Aggarwal,
To cyclize, 5 must be lithiated at the position a to the O and
to N atoms to give 7.[9] However, when 5 (R1 ˆ H) was lithiated
at À788C and quenched after 30 min with an electrophile
(CD3OD), only the ortho-deuterated product 14 was ob-
tained, in 95% yield. By repeating this step, both ortho
protons could be replaced to give 16 (Scheme 4). Presumably,
the sequence of events leading to cyclization involves firstly
formation of an ortho-lithiated compound 6,[10] which slowly
undergoes ™anion translocation∫[11] to give 7, which then
cyclizes. The powerful kinetic isotope effect typical of
low-temperature lithiations[12] can be used to hinder the
mechanism at either the 5 !6 or the 6 !7 step (Scheme 2).
Under the same cyclization conditions, 16 failed to lithiate
¬
M. Ferrara, Org. Lett. 2000, 2, 4107; I. Fernandez, F. L. Ortiz, B.
Tejerina, S. G. Granda, Org. Lett. 2001, 3, 1339.
[2] J. Clayden, K. Tchabanenko, Chem. Commun. 2000, 317; A. Ahmed,
R. A. Bragg, J. Clayden, K. Tchabanenko, Tetrahedron Lett. 2001, 42,
3407.
[3] 5-Exo-trig intramolecular Michael additions of organolithiums are
known, and Beak and co-workers have reported 5-exo-tet cyclizations
of lithiated N-benzyl groups. See D. L. Comins, Y.-m. Zhang, J. Am.
Chem. Soc. 1996, 118, 12248; S. Wu, S. Lee, P. Beak, J. Am. Chem. Soc.
1996, 118, 715.
[4] J. E. Baldwin, Chem. Commun. 1976, 734; J. E. Baldwin, J. Cutting, W.
Dupont, L. Kruse, L. Silberman, R. C. Thomas, Chem. Commun. 1976,
736.
[5] R. B. Woodward, R. Hoffmann, The Conservation of Orbital Symme-
try, Academic Press, New York, 1970; I. Fleming, Frontier Orbitals and
Organic Chemical Reactions, Wiley, New York, 1976.
[6] Compounds 5 were made in quantitative yield from commercially
available 4,4-dimethyloxazolidine and benzoyl chloride or p-methoxy-
benzoyl chloride under Schotten Baumann conditions (CH2Cl2,
NaOH, H2O).
(D)
O
D
O
H
a), b)
c)
5 (R1 = H)
N
N
O
(D)
O
H
14
15[a]
a), b)
D
O
[7] By using method A, the cyclization was accompanied by formation of
a by-product 19 in up to 50% yield, which may arise by decomposition
of the cyclized product or by an alternative cyclization mechanism
d)
d)
N
starting material 16[b]
O
O
D
O
16
involving lithiation a to N, a-elimina-
tion of alkoxide to form a carbene, and
O
O
O
À
insertion into an aromatic C H bond.
Formation of this by-product was
N
H2N
HO
R1
e), f)
N
D
N
E
avoided with method B, but instead up
to 50% remaining starting material was
recovered.
E
O
19
O
D
D
D
17
18[c]
[8] CCDC-173233 (9a) -173234 (12c) contains the supplementary crys-
tallographic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the
Cambridge Crystallographic Data Centre, 12, Union Road, Cam-
bridge CB21EZ, UK; fax: ( ‡44)1223-336-033; or deposit@ccdc.cam.
ac.uk).
Scheme 4. Establishing role of lithium: a) sBuLi, THF, À788C, 30 min;
b) CD3OD; c) method A (Scheme 2); d) method B (Scheme 2); e) CD2O,
D; f) PhCOCl, CH2Cl2, NaOH, H2O. [a] 34% 15, 19% 14 ‡ 20% addition
of sBuLi to benzamide ring; [b] 60% 16 ‡ 25% addition of sBuLi to
benzamide ring; [c] 62% 18 ‡ traces of cyclization products.
[9] N. Kise, T. Urai, Y.-i. Yoshida, Tetrahedron Asymmetry 1998, 9, 3125.
[10] V. Snieckus, Chem. Rev. 1990, 90, 879; M. Anstiss, J. Clayden, A.
Grube, L. H. Youssef, unpublished results.
[11] A. Ahmed, J. Clayden, M. Rowley, Tetrahedron Lett. 1998, 39, 6103.
[12] D. Hoppe, M. Paetow, F. Hintze, Angew. Chem. 1993, 105, 430; Angew.
Chem. Int. Ed. Engl. 1993, 32, 394; J. Clayden, J. H. Pink, N. Westlund,
F. X. Wilson, Tetrahedron Lett. 1998, 39, 8377; D. R. Anderson, N. C.
Faibish, P. Beak, J. Am. Chem. Soc. 1999, 121, 7553.
and predominantly starting material was returned. With 17, on
the other hand, ortho-lithiation occurred, but an inability to
form 7 meant that, on warming, the ortho-lithiated species
dimerized by intermolecular nucleophilic substitution to give
the ketone 18 in 62% yield. Monodeuterated 14 cyclized to
Angew. Chem. Int. Ed. 2002, 41, No. 6
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1433-7851/02/4106-1051 $ 17.50+.50/0
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