Sequential double α-arylation of N -allylureas by asymmetric deprotonation and N→C aryl migration

Article abstract of DOI:10.1021/ol102155h

On lithiation with lithium amides, N-allyl-N'-aryl ureas undergo rearrangement with transfer of the aryl ring from N to the allylic α carbon. From the α-arylated products, a further aryl transfer under the influence of a chiral lithium amide allows the en

Full text of DOI:10.1021/ol102155h

ORGANIC
LETTERS
2010
Vol. 12, No. 23
5442-5445
Sequential Double r-Arylation of
N-Allylureas by Asymmetric
Deprotonation and NfC Aryl Migration
Daniel J. Tetlow, Ulrich Hennecke, James Raftery, Michael J. Waring,
David S. Clarke, and Jonathan Clayden*
School of Chemistry, UniVersity of Manchester, Oxford Road, Manchester M13 9PL, U.K.,
and AstraZeneca Ltd., Alderley Park, Cheshire, SK10 4TG, U.K.
clayden@man.ac.uk
Received September 9, 2010
ABSTRACT
On lithiation with lithium amides, N-allyl-N′-aryl ureas undergo rearrangement with transfer of the aryl ring from N to the allylic r carbon. From
the r-arylated products, a further aryl transfer under the influence of a chiral lithium amide allows the enantioselective construction of 1,1-
diarylallylamine derivatives. Stereoselectivity in these reactions results from the enantioselective formation of a planar chiral allyllithium under
kinetic control.
The enantioselective formation of amine derivatives
bearing tertiary N-substituents is challenging,1 and the
most commonly used approaches involve addition of
nucleophiles to N-sulfinyl ketimines2 or reactions of
lithiated N-acyl benzylamine derivatives.3-5 In this paper,
we report a new approach to tertiary allylamines by
sequential double arylation R to nitrogen induced when
N-allyl-N′-aryl ureas are deprotonated with a lithium amide
base (LDA or its chiral analogues). In such cases, formation
of a planar-chiral allyllithium is followed by rapid rear-
rangement in which C-arylation (by intramolecular N-C aryl
transfer) of the allylamine results.
N-Allyl ureas 1a-j were deprotonated with LDA in THF
at -78 °C.6 DMPU (1,3-dimethylpropylideneurea) was
(3) (a) Beak, P.; Johnson, T. A.; Kim, D. D.; Lim, S. H. Top. Organomet.
Chem. 2003, 5, 139. (b) Faibish, N. C.; Park, Y. S.; Lee, S.; Beak, P. J. Am.
Chem. Soc. 1997, 119, 11561. (c) Hara, O.; Ito, M.; Hamada, Y. Tetrahedron
Lett. 1998, 39, 5537.
(1) (a) Riant, O.; Hannedouche, J. Org. Biomol. Chem. 2007, 5, 873.
(b) Shibasaki, M.; Kanai, M. Chem. ReV. 2008, 108, 2853. (c) Kobayashi,
S.; Ishitani, H. Chem. ReV. 1999, 99, 1069. (d) Bloch, R. Chem. ReV. 1998,
98, 1407.
(4) For arylation R to N by rearrangement, see: (a) Clayden, J.; Dufour,
J.; Grainger, D.; Helliwell, M. J. Am. Chem. Soc. 2007, 129, 7488. (b)
Clayden, J.; Hennecke, U. Org. Lett. 2008, 10, 3567. (c) Bach, R.; Clayden,
J.; Hennecke, U. Synlett 2009, 421. For a review of organolithium arylation,
see: O’Brien, P.; Bilke, J. L. Angew. Chem., Int. Ed. 2008, 47, 2734.
(5) Clayden, J.; Donnard, M.; Lefranc, J.; Minassi, A.; Tetlow, D. J.
J. Am. Chem. Soc. 2010, 132, 6624.
(2) (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.
10.1021/ol102155h  2010 American Chemical Society
Published on Web 11/09/2010

added to enhance nucleophilicity of the resulting allyl-
lithium.7 An orange/red color resulted, and on quenching
with MeOH after 3 h at -78 °C, a product was recovered
which was identified in each case as the N-vinyl urea 2a-j
(Scheme 1) in which the N-aryl ring had migrated to the
deficient aryl bromides Ar2Br4b duly yielded Z-6, which on
treatment with LDA underwent rearrangement to the 1,1-
diarylallylureas 7 (Scheme 2).
Scheme 2. Amines Bearing Tertiary Substituents
Scheme 1. N to C Aryl Transfer in a Lithioallyl Urea
a Yield obtained on a 1-3 g scale. b Significant formation of an acyl
transfer product (red arrow on 3: see Supporting Information).
The amination of arenes by ureas10 (transformation of 2
to 6) was limited to electron-deficient coupling partners.
However, the N′-aryl-N-vinyl ureas could alternatively be
made straightforwardly by the other methods shown in
Scheme 2. Addition of vinyllithium11 to imine 9 gave the
allylic amine 10, which was converted to a urea and
N-methylated with concomitant double bond migration to
provide Z-6, presumably via the sodium Z-dianion.5 E-6 (4:1
E:Z) was available by formation of an allylic urea 11 using
a carbamoyl chloride followed by Ru-catalyzed double bond
migration.12
Z-Vinyl ureas 6 rearranged successfully on treatment with
base (LDA) to provide allyl ureas 7 with a variety of
substitution patterns and in good yield, as detailed in Table
1. Optimal yields required (a) lithiation in a coordinating
solvent (other solvents gave sluggish reactions and poor
yields), (b) addition of DMPU (omitting DMPU returned
poorer yields), and (c) an N-aryl enamine starting material,
which generally gave better yields than the analogous N-alkyl
enamines. Cleavage of the urea function to give 8 from the
acid-sensitive rearranged products 7 was achievable in
moderate yield by nitrosation and hydrolysis,4a carefully
avoiding exposure to acid.
R-carbon of the allylamine. We have previously reported a
related rearrangement of lithiated N-benzylureas,4,5 and it
appears that 2 is formed by N to C aryl transfer within the
lithio derivative 3 to yield 4, which undergoes a second
lithiation (optimal yields were obtained with a full 2 equiv
of LDA) to give a cinnamyllithium8,9 species 5. Protonation
γ to nitrogen yields 2 in generally good yield, whether the
migrating ring is electron deficient (2g,h,i) or electron-rich
(2d,e). With a p-MeOC6H4 migrating ring, some competing
attack of the allyllithium on the urea carbonyl group was
observed.
It seemed likely that, given a second N′-aryl substituent,
the cinnamyllithiums derived from 2 might also undergo
rearrangement upon lithiation, introducing a second aryl ring,
and hence a fully substituted stereogenic center, R to
nitrogen. N-Arylation of 2a-c by coupling with electron-
(6) Attempted deprotonations with alkyllithiums led to byproducts arising
from attack at the carbonyl group.
(7) We observe that DMPU commonly increases the nucleophilicity of
organolithiums, particularly those stabilized by delocalization. See: (a)
Clayden, J.; Knowles, F. E.; Menet, C. J. Tetrahedron Lett. 2003, 44, 3397.
(b) Clayden, J.; Knowles, F. E.; Menet, C. J. Synlett 2003, 1701. (c) Clayden,
J.; Parris, S.; Cabedo, N.; Payne, A. H. Angew. Chem., Int. Ed. 2008, 47,
5060. (d) Clayden, J.; Farnaby, W.; Grainger, D. M.; Hennecke, U.;
Mancinelli, M.; Tetlow, D. J.; Hillier, I. H.; Vincent, M. A. J. Am. Chem.
Soc. 2009, 131, 3410. (e) Fournier, A. M.; Brown, R. A.; Farnaby, W.;
Miyatake-Ondozabal, H.; Clayden, J. Org. Lett. 2010, 12, 2222.
(8) Weisenburger, G. A.; Faibish, N. C.; Pippel, D. J.; Beak, P. J. Am.
Chem. Soc. 1999, 121, 9522. Pippel, D. J.; Weisenburger, G. A.; Wilson,
S. R.; Beak, P. Angew. Chem., Int. Ed. Engl. 1998, 37, 2522. Weisenburger,
G. A.; Beak, P. J. Am. Chem. Soc. 1996, 118, 12218. Curtis, M. D.; Beak,
P. J. Org. Chem. 1999, 64, 299. Park, Y. S.; Weisenburger, G. A.; Beak,
P. J. Am. Chem. Soc. 1997, 119, 10537. Pippel, D. J.; Weisenberger, G. A.;
Faibish, N. C.; Beak, P. J. Am. Chem. Soc. 2001, 123, 4919. Lim, S. H.;
Curtis, M. D.; Beak, P. Org. Lett. 2001, 711. Whisler, M. C.; Beak, P. J.
Org. Chem. 2003, 68, 1207. Kim, D. D.; Lee, S. J.; Beak, P. J. Org. Chem.
Asymmetric lithiation of the achiral vinyl ureas 6 was
envisaged as a suitable potential route to enantiomerically
enriched amines 8. Beak has shown that N-acyl allyllithiums
may be deprotonated enantioselectively with alkyllithiums
in the presence of (-)-sparteine,8 and when Z-6i was treated
with s-BuLi in the presence of (-)-sparteine in cumene at
-40 °C, the product (S)-7i13 was obtained in 45% yield and
20:80 er.
We found that better er’s and yields of rearranged products
7 were obtained when lithiation/rearrangement conditions
2005, 70, 5376
.
(10) For examples of amination reactions with ureas, see ref 4b and
references therein.
(9) Our representations of the structure of the allyllithium species 3, 5,
and 14 are based on the structural work of Beak et al. (ref 8): their known
preference for the Z geometry is presumably due to intramolecular Li-O
coordination. N-Substituted allylithiums typically protonate in the γ-position
but react with other electrophiles to give diverse mixtures of R- and
γ-functionalized products. See: Gawley, R. E.; Coldham, I. In Chemistry
of Organolithium Compounds; Rappoport and Marek, Eds.; Wiley: New
York, 2004; pp 997-1053.
(11) Tomiuka, K.; Inoue, I.; Shindo, M.; Koga, K. Tetrahedron Lett.
1991, 32, 3095.
(12) Krompiec, S.; Pigulla, M.; Szczepankiewicz, W.; Bieg, T.; Kuznik,
N.; Leszczynska-Sajda, K.; Kubicki, M.; Borowiak, T. Tetrahedron Lett.
2001, 42, 7095. Krompiec, S.; Pigulla, M.; Kuznik, N.; Krompiec, M.;
Marciniec, B.; Chadyniak, D.; Kasperczyk, J. J. Mol. Catal. A: Chem. 2005,
225, 91.
Org. Lett., Vol. 12, No. 23, 2010
5443

salts 12·HCl or 13·HCl rather than from the free bases turned
out to be preferablespresumably a selectivity-enhancing
effect of the resulting LiCl.15 We found that the lithium salt
of N-isopropyl-R-methylbenzylamine 12a·Li performed best
among the bases tried, yielding the product ureas 7 in up to
93:7 er at -78 °C.
Table 1. Synthesis and Rearrangements of Ureas Z-6 with LDA
On optimizing the choice of solvent with 12a·Li, we found
that while THF was essential for reactivity improved yields
and er’s were obtained when this base was used without
DMPU, provided LiCl was present. Applying this optimal
combination of base and conditions to a range of starting
ureas Z-6 gave further enantioselective rearrangements with
selectivities lying between 84:16 and 92:8 er (Scheme 3).
We deduced the overall sense of asymmetric induction in
the rearrangement by single-crystal X-ray analysis of 7f
formed with (R)-12a (Figure 1) and precipitated from
chloroform; this was greatly assisted by the incorporation
of two molecules of chloroform in the unit cell, and with
the Flack parameter having a value of 0.0525 and an esd
0.1691, we can assign unequivocal S stereochemistry to this
product (Scheme 3).16 The same stereochemical course is
proposed for other rearrangements promoted by (R)-12·Li
and (R,R)-13·Li.
a Yield of deprotection. b Attempted deprotection led to cyclization of
the urea onto the pyridine ring in the yields quoted: see Supporting
Information. c N-Methyl (instead of N-PMP) analogue of the substrate.
d Reaction carried out at -60 °C; SM remained after 3 h at -78 °C. e No
DMPU added.
We assume, following previous related reactions,4a,5,7d,e
that these rearrangements occur by intramolecular attack of
the allyllithium on the distal aryl ring of the urea. Stere-
ochemically, two extreme mechanistic possibilities present
themselves:17 either the stereochemistry of the product is
determined by stereospecific rearrangement of a configura-
tionally stable planar chiral allyllithium 11 or it is the result
of a stereoselective reaction of configurationally unstable 11
under the kinetic or thermodynamic control of the associated
chiral amine 12a. To distinguish between these alternatives,
we used 12a·Li to rearrange the allyl urea (()-11 (Ar1 )
similar to those in Scheme 2 were used, but with LDA
replaced by a chiral lithium amide.14 Both enantiomers of a
range of suitable chiral amines 12·H and 13·H or their readily
handled hydrochloride salts are available commercially or
in a few steps from inexpensive starting materials. In a
preliminary screen, we treated Z-6b with a series of lithium
amides 12·Li or 13·Li in THF, adding DMPU to promote
rearrangement, and the results are shown in Table 2.
Formation of the lithium amides directly from the ammonium
Table 2. Enantioselectivity in the Lithiation and Rearrangement of 6
starting material
product
Ar1
Ar2
base
12aa
R1
Ph
R2
yield (%)
er (7:ent-7)
63b
72
8:92a b
,
Z-6b
7b
Ph
p-NCC6H4
i-Pr
8:92a
c d
,
11:89a c
,
s
Z-6b
Z-6b
Z-6b
Z-6b
Z-6b
Z-6b
Z-6b
Z-6b
Z-6b
7b
7b
7b
7b
7b
7b
7b
7b
7b
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
p-NCC6H4
p-NCC6H4
p-NCC6H4
p-NCC6H4
p-NCC6H4
p-NCC6H4
p-NCC6H4
p-NCC6H4
p-NCC6H4
12ba
Ph
cHx
Bn
Me
i-Pr
i-Pr
Me
Me
(CH2)2
i-Pr
71
sd
sd
66
58
72
sd
sd
91
10:90a
21:79a
36:64a
22:78a
8:92a
83:17
65:35
72:28
6:94a
29:71a
88:12
9:91a
88:12
84:16
92:8
12ca e
Ph
,
12da e
Ph
,
12ea
12fa
13a
1-Np
2-Np
Ph
13b
1-Np
Ph
Ph
13ce
12aa f
,
sd g
87
,
Z-6c
Z-6f
Z-6f
Z-6g
Z-6i
7c
7f
7f
7g
7i
Ph
6-MeOPy
p-NCC6H4
p-NCC6H4
6-MeOPy
p-ClC6H4
12af
Ph
Ph
Ph
Ph
Ph
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
12aa f
79
,
p-ClC6H4
p-ClC6H4
p-ClC6H4
Ph
e f
,
12a
54
12af
12af
88
78
c d
,
s
87:13c
92:8
86:14
50:50h
73:27j
64:36k
Z-6j
7j
Ph
Ph
Ph
Ph
m-FC6H4
12af
12af
12af
12af
Ph
Ph
Ph
Ph
i-Pr
i-Pr
i-Pr
i-Pr
86
Z-6k
(()-14
E-6bi
7k
7b
7b
m-MeOC6H4
p-NCC6H4
p-NCC6H4
63
sd
21j
41k
a (S)- or (S,S)-enantiomer of base used. b At -90 °C. c At -60 °C. d Not isolated: complete conversion to product by NMR. e LiCl not present. f Without
DMPU. g Et2O as solvent: no reaction was observed in cumene, and in toluene a very slow reaction gave 58:42 er. h Also (() with 0.5 equiv of base. i 4:1
mixture of E and Z isomers. j After 30 min. k After 60 min.
5444
Org. Lett., Vol. 12, No. 23, 2010

Racemic product was also formed slowly from E-6b (Table
2): rapid formation of a low (<25%) yield of enantiomerically
enriched 7b was observed from a 4:1 mixture of E- and Z-6b,
followed by a slower increase in yield and erosion of product
er.18 Enantioselective formation of an organolithium by a
chiral lithium amide other than by asymmetric deprotonation
of one of a pair of enantiotopic protons is apparently
unprecedented.14
Scheme 3. Asymmetric Lithiation-Arylation
The allyl urea products 7 are potentially intermediates for
the synthesis of allyl amines or, after oxidation, difficult to
obtain 1,1-diaryl R-amino acids. We are currently exploring
further applications of these versatile amine derivatives in
synthesis.
Acknowledgment. We thank the EPSRC for a studentship
(to D.J.T.), AstraZeneca for financial support under the
collaborative EPSRC Programme for Synthetic Organic
Chemistry with AZ-GSK-Pfizer, and the DAAD for a
postdoctoral fellowship (to U.H.).
Supporting Information Available: Experimental pro-
cedures and characterization of all new compounds. Crystal-
lographic data for 7f. This material is available free of charge
via the Internet at http://pubs.acs.org.
Ph; Ar2 ) p-NCC6H4). Complete conversion to racemic 7b
was observed (Table 2), despite the equivalence of allylithi-
ums formed from Z-6b and (()-11. The stereochemistry of
the product is therefore determined by stereoselective forma-
tion of the allyllithium and not its stereoselective reaction.
OL102155H
(13) Stereochemistry was deduced from the identity of the enantiomer
of 7i given both by s-BuLi-(-)-sparteine and by (S)-12a. It is not clear
however how this relates to the stereochemistry of the lithiated intermediate
formed by enantioselective deprotonation (ref 8) or whether the subsequent
rearrangement is stereochemically retentive (refs 4a, 5) or invertive (refs
7d, e).
(14) For an overview of the chemistry of chiral lithium amides, see: (a)
O’Brien, P. J. Chem. Soc., Perkin Trans. 1 1998, 1439. (b) Simpkins, N.;
Weller, M. D. Topics in Stereochemistry; Gawley, R., Ed.; 2010; Vol. 26,
p 1. (c) Clayden, J.; Menet, C. J.; Mansfield, D. J. Chem. Commun. 2002,
38. For a related asymmetric deprotonation of a carbamate, see: (d) Seppi,
M.; Kalkofen, R.; Reupohl, J.; Fröhlich, R.; Hoppe, D. Angew. Chem. Int.
Ed. 2004, 43, 1423.
(15) For a discussion of the beneficial effect of LiCl on many
organolithium reactions, see: Gupta, L.; Hoepker, A. C.; Singh, K. J.;
Collum, D. B. J. Org. Chem. 2009, 74, 2231, and references therein.
(16) The X-ray crystal data for 7f have been deposited with the
Cambridge Crystallographic Data Centre, deposition number 777622.
(17) Basu, A.; Thayumanavan, S. Angew. Chem., Int. Ed. 2002, 41, 716.
(18) The results from the 4:1 mixture of E- and Z-6b are consistent
with the rapid, enantioselective lithiation and rearrangement of Z-6b
followed by slow, racemic lithiation and rearrangement of E-6b.
Figure 1. X-ray crystal structure of (S)-7f (formed with (R)-12a).
Org. Lett., Vol. 12, No. 23, 2010
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