C O M M U N I C A T I O N S
Table 2. Stereospecific Aryl Migration
of 5 was generally recovered with a diminished enantiomeric ratio
(entries 9 and 19-22). When (R)-5b was lithiated and allowed to
stir at -78 °C for only 25 min before quenching with either CD3-
OD or (CD3)2SO, the small amount of 5b remaining was fully
deuterated but had only 42:58 or 74:26 er (R:S), respectively (entries
19 and 20). Deuteration of lithiated (R)-5l after only 5 min with
CD3OD or (CD3)2SO returned material with 89:11 or 88:12 er (R:
S) after accounting for incomplete lithiation (entries 21 and 22).
These observations suggest that, while rearrangement of 8 is
stereospecific, reprotonation of 8 is not, with stereospecificity
dependent on protonating agent: methanol protonates 8b with a
slight preference for inversion, while DMSO protonates with a 3:1
preference for retention.12
6, yield %
(5, %)a
6, er
7,
entry
5
R1
R2
R3
(5, er)a
yield %
1
2
3
4
5
6
7
8
9
5a
H
H
H
H
6a, 95b
6b, 82b
NOc 6b′, 65
-
72
(R)-5b 4-OMe
(()-5b 4-OMe
(()-5c 2-OMe
(S)-5d 3,4-OMe
(()-5e 2-F
(()-5f 3-F
(S)-5g 4-F
(S)-5h 4-Cl
H
H
H
H
H
H
H
H
97:3
-
82
-
-
-
-
-
-
H
H
H
H
H
H
6c, 84b
6d, 76
6e, 34b
6f, 40
6g, 34
6h, 51b
(17)
-
98:2
-
-
99:1
98:2
(50:50)
>99:1
97:3
95:5e
>97:3
>98:2
99:1
>97:3
>98:2
97:3
96:4
10 (S)-5i 3-Cl, 4-F
11 (S)-5j 2,3-benzo
12 (S)-5j 2,3-benzo
13 (S)-5k 3,4-benzo
H
H
H
H
MeO
MeO
MeO
H
6i, 69
75
-
68e
-
-
-
-
-
-
-
Med 6j, 88
Overall, the three-step sequence of urea synthesis, rearrangement,
and urea cleavage amounts to a stereospecific electrophilic arylation
of R-methylbenzylamines and thus provides a powerful way of
making otherwise inaccessible enantiomerically pure amines bearing
heavily substituted chiral substituents.
H
H
H
H
H
n/d
6k, 88
ent-6b, 73
6m, 64
6n, 79
14 (R)-5l
H
15 (S)-5m 2-Me
16 (S)-5n 4-Me
17 (R)-5o 2,3-benzo MeO Med 6o, 65
18 (R)-5p 2,3-benzo Cl
19 (R)-5b 4-OMe
Med 6p, 78
Hf
6b, 84
Acknowledgment. We are grateful to the EPSRC, the EU and
the Programme de Mobilite´ Internationale de la Re´gion Languedoc-
Roussillon for support, and to Mr. Saidul Islam for carrying out
rearrangements of 1b and 1c.
H
(16, >95% d)g (42:58)
6b, 95 95:5
20 (R)-5b 4-OMe
H
Hh
-
-
-
(5, >95% d)g (74:26)
21 (R)-5l
22 (R)-5l
H
H
MeO Hf
MeO Hh
ent-6b, <5
(95, 80% d)i
ent-6b, 6
(94, 92% d)i
n/d
(91:9)
n/d
Supporting Information Available: X-ray crystallography data for
10p. Experimental and spectroscopic data for all new compounds. This
(89:11)
a Remaining starting material. b Quenched after 2 h. c Quenched with
t-BuONO. d Quenched with MeI. e Yield over three steps from 5. Er is of
N-nitroso derivative. f Quenched with CD3OD. g Quenched after 25 min;
yields determined by NMR. h Quenched with (CD3)2SO. i Quenched after
5 min.
References
(1) (a) Schmidt, F.; Stemmler, R. T.; Rudolph, J.; Bolm, C. Chem. Soc. ReV.
2006, 35, 454. (b) Kobayashi, S.; Ishitani, H. Chem. ReV. 1999, 99, 1069.
(2) (a) Cabello, N.; Kizirian, J.-C.; Gille, S.; Alexakis, A.; Bernardinelli, G.;
Pinchard, L.; Caille, J.-C. Eur. J. Org. Chem. 2005, 4835 and references
therein. (b) Riant, O.; Hannedouche, J. Org. Biomol. Chem. 2007, 873.
(3) (a) Cogan, D. A.; Liu, G.; Ellman, J. Tetrahedron 1999, 55, 8883. (b)
Cogan, D. A.; Ellman, J. J. Am. Chem. Soc. 1999, 121, 268. (c) Ellman,
J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984. (d)
Tanuwidjaja, J.; Peltier, H. M.; Ellman, J. A. J. Org. Chem. 2007, 72,
626.
Scheme 3. Rearrangement of Ureas Derived from
R-Methylbenzylamines
(4) Clayden, J.; Turner, H.; Pickworth, M.; Adler, T. Org. Lett. 2005, 7, 3147.
(5) Clayden, J.; Dufour, J. Tetrahedron Lett. 2006, 47, 6945.
(6) Shaw, A. W.; deSolms, S. J. Tetrahedron Lett. 2001, 42, 7173.
(7) (a) Eisch, J. J.; Kovacs, C. A. J. Organomet. Chem. 1971, 30, C97. (b)
Eisch, J. J.; Dua, S. K.; Kovacs, C. A. J. Org. Chem. 1987, 52, 4437. (c)
Dannecker, W.; Fariborz, M. Z. Naturforsch. 1974, 29b, 578.
Scheme 4. Evidence for a Dearomatized Intermediate
(8) For a discussion of the effect of HMPA and DMPU on dearomatizing
cyclization reactions of benzyllithiums, see: (a) Ahmed, A.; Clayden, J.;
Yasin, S. A. Chem. Commun. 1999, 231. (b) Clayden, J.; Knowles, F. E.;
Menet, C. J. Synlett 2003, 1701.
(9) Comparison of Table 1, entries 2 and 3, shows that when both urea nitrogen
atoms bear an aryl substituent ring location and not ring substitution
determines which rearranges.
(10) Tertiary organolithiums R to nitrogen are generally configurationally stable
over periods of minutes to hours at -78 °C (Faibish, N. C.; Park, Y. S.;
Lee, S.; Beak, P. J. Am. Chem. Soc. 1997, 119, 11561) and acyl transfers
in R-methylbenzyl carbamates are stereospecific (Hara, O.; Ito, M.;
Hamada, Y. Tetrahedron Lett. 1998, 39, 5537). For a discussion, see:
Clayden, J. Organolithiums: SelectiVity for Synthesis; Pergamon: New
York, 2002; pp 193-194.
(11) Tertiary organolithiums R to nitrogen seem to alkylate with inversion but
acylate with retention (see ref 10a and ref 10c, pp 252-253). Although
the reaction we present here may be formalized as a kind of [1,4]-aza-
Wittig rearrangement, we have not pursued this interpretation first because
of evidence for a dearomatized intermediate 9 and second because Wittig
rearrangements usually proceed with inVersion at a chiral organolithium
center (see ref 10c, pp 247-249 and 346-360).
(12) Protonation/deuteration reactions of benzylic organolithiums are in general
retentive; see ref 10c, p 249, and: (a) Norsikian, S.; Marek, I.; Klein, S.;
Poisson, J.-F.; Normant, J.-F. Chem.sEur. J. 1999, 5, 2055. For related
examples of diastereoselectivity of protonation varying with proton source,
see: (b) Rein, K.; Goicoechea-Pappas, M.; Anklekar, T. V.; Hart, G. C.;
Smith, G. A.; Gawley, R. E. J. Am. Chem. Soc. 1989, 111, 2211. (c)
Meyers A. I.; Dickman, D. I. J. Am. Chem. Soc. 1987, 109, 1263. 8l has
a greater propensity to protonate with retention, but loss of er on
protonation is still significant.
of 5o and 5p to proceed for 2 h and then exposing the reaction
mixture to dry air. Oxidation of an intermediate presumed to be 9
yielded crystalline enones 10 in both cases: X-ray crystallography
confirmed the absolute stereochemistry of 10p and provides
evidence for stereochemically retentive (rather than invertive)
rearrangement.11
Interestingly, while the rearranged products were essentially
enantiomerically pure, starting material remaining after the reaction
JA071523A
9
J. AM. CHEM. SOC. VOL. 129, NO. 24, 2007 7489