Amines bearing tertiary substituents by tandem enantioselective carbolithiation-rearrangement of vinylureas

Article abstract of DOI:10.1021/ol3029324

In the presence of (-)-sparteine or a (+)-sparteine surrogate, organolithiums add to N-alkenyl-N'-arylureas to give benzylic organolithiums in an enantioselective manner. Under the influence of DMPU, these organolithiums undergo rearrangement with migrati

Full text of DOI:10.1021/ol3029324

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Amines Bearing Tertiary Substituents by
Tandem Enantioselective Carbolithiationꢀ
Rearrangement of Vinylureas
Michael Tait,† Morgan Donnard,† Alberto Minassi,† Julien Lefranc,† Beatrice Bechi,†
Giorgio Carbone,‡ Peter O’Brien,‡ and Jonathan Clayden*,†
School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, U.K.,
and Department of Chemistry, University of York, Heslington, York YO10 5DD, U.K.
clayden@man.ac.uk
Received October 25, 2012
ABSTRACT
In the presence of (ꢀ)-sparteine or a (þ)-sparteine surrogate, organolithiums add to N-alkenyl-N0-arylureas to give benzylic organolithiums in an
enantioselective manner. Under the influence of DMPU, these organolithiums undergo rearrangement with migration of the N0-aryl ring from N to
C, leading to the urea derivatives of enantiomerically enriched amines bearing tertiary substituents. Basic hydrolysis returns the functionalized
amine, providing a new synthetic route to compounds with quaternary stereogenic centers bearing nitrogen.
Chiral amines bearing tertiary substituents (tertiary
carbinamines) are widespread in naturally occurring and
synthetic bioactive molecules.1 Nonetheless, the synthesis
of the quaternary stereogenic center carrying a nitrogen
atom at the core of these molecules remains a challenge.2
Successful approaches include nucleophilic additions to
imines,3 stereospecific rearrangements of chiral precursors,2,5
or stereospecific functionalization of precursors containing
tertiary stereogenic centers.4,5 We have previously shown
that migration of an N-aryl substituent within a lithiated
urea (for example, 2Li to 3Li) allows the stereospecific
construction of quaternary centers bearing nitrogen.5
We have also shown that lithiated ureas such as 2Li may
be generated not only by deprotonation but also by
carbolithiation.6 We now report an asymmetric method
whereby amines bearing tertiary substituents may be
† University of Manchester.
‡ University of York.
(1) For selected reviews, see: (a) Ramon, D. J.; M. Yus, M. Curr. Org.
(4) (a) Faibish, N. C.; Park, Y. S.; Lee, S.; Beak, P. J. Am. Chem. Soc.
1997, 119, 11561. (b) Hara, O.; Ho, M.; Hamada, Y. Tetrahedron Lett.
1998, 39, 5537. (c) Hayes, C. J.; Sherlock, A. E.; Green, M. P.; Wilson,
C.; Blake, A. J.; Selby, M. D.; Prodger, J. C. J. Org. Chem. 2008, 73,
2041. (d) Bagutski, V.; Elford, T. G.; Aggarwal, V. K. Angew. Chem.,
Int. Ed. 2011, 50, 1080. For reviews, see: (e) Scott, H. K.; Aggarwal, V. K.
Chem.;Eur. J. 2011, 17, 13124. (f) O’Brien, P.; Bilke, J. L. Angew.
Chem., Int. Ed. 2008, 47, 2734.
(5) (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.
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(2) (a) Clayden, J.; Donnard, M.; Lefranc, J.; Tetlow, D. J. Chem.
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opments and Applications; Nugent, T. C., Ed.; Wiley-VCH: Weinheim,
2010. When the amine is a quaternary R-amino acid, many more possibilities
ꢀ
exist; for an overview, see: (c) Fletcher, S. P.; Sola, J.; Holt, D.; Brown, R. A.;
Clayden, J. Beilstein J. Org. Chem. 2011, 7, 1304.
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(b) Shibasaki, M.; Kanai, M. Chem. Rev. 2008, 108, 2853. (c) Kobayashi,
S.; Ishitani, H. Chem. Rev. 1999, 99, 1069. (d) Cogan, D. A.; Ellman, J. A.
J. Am. Chem. Soc. 1999, 121, 268. (e) Bloch, R. Chem. Rev. 1998, 98, 1407.
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r
10.1021/ol3029324
XXXX American Chemical Society

constructed in enantiomerically enriched form from achiral
precursors by using a tandem carbolithiationꢀaryl migra-
tion in the presence of a chiral additive, forming two new
CꢀC bonds with control of absolute configuration.
Addition of (ꢀ)-sparteine to the addition in Et2O or
toluene gave, after protonation, mixtures of simple carbo-
lithiation product 2a and tandem carbolithiationꢀaryl
migration product 3a, complicating the analysis (entry 4).
With the aim of accelerating rearrangement of the carbo-
lithiation product 2aLi to 3aLi, the reactions were there-
fore terminated by addition of DMPU, an additive known
to accelerate the N to C aryl migration5,6 probably by
favoring the formation of solvated ion pairs.12 By adding
DMPU after 1 h at ꢀ78 °C, a carbolithiationꢀrearrangement
product was formed in moderate yield and in low er from
1a with n-BuLi and (ꢀ)-sparteine in toluene (entry 5).
However, on delaying the addition of DMPU to 6 h (entry 6),
the er was significantly improved. This suggested that
carbolithiation was still incomplete after 1 h and that
DMPU was promoting an unwanted rapid, racemic car-
bolithiation of any remaining unreacted alkyllithium.
We therefore sought conditions that would allow asym-
metric carbolithiation to reach completion fast enough to
avoid racemization or epimerization of the organolithium
product. Using i-PrLi, we were able to obtain 3b with
encouraging er’s in toluene after 1 h, but only with a large
excess of (ꢀ)-sparteine (entry 7). In cumene or in t-BuOMe,
similar er’s were obtained but without the need for a large
excess of (ꢀ)-sparteine (entries 8, 11), with cumene giving
the better yields. Interestingly, yields (but not er) improved
as the temperature was raised to ꢀ50 °C (entries 9 and 10),
perhaps because the increased rate of carbolithiation was
offset by the increased rate of racemization of 2Li. How-
ever, carbolithiationꢀrearrangement of 1a with i-PrLi in
cumene in the presence of (ꢀ)-sparteine gave the product
3b in high yield and in 92:8 er (entry 12). We ascribe the
exceptional performance of cumene to its resistance to
deprotonation at a temperature sufficiently high to allow
complete carbolithiation prior to addition of DMPU,
coupled with the high configurational stability of the
intermediate organolithium 2Li in such a noncoordinating
solvent.13 It was not possible to use (ꢀ)-sparteine cataly-
tically (entry 13) without statistical loss of er, but good
results were obtained with 2 equiv of alkyllithium and 1
equiv (ꢀ)-sparteine.
Styrenes, including those bearing R-N6,7 or -O8 substitu-
ents, undergo nucleophilic attack by organolithiums at
the β-position to generate benzyllithiums.9 The addition
of (ꢀ)-sparteine 4 to such carbolithiations may induce
enantioselectivity.10 By using 4 or a similar chiral lithium-
coordinating ligand, we proposed to impose enantioselec-
tivity on the carbolithiation of ureas such as 1a, generating a
configurationally stable, enantiomerically enriched orga-
nolithium 2Li which would be trapped in situ by stereo-
specific aryl migration to give 3Li and hence the tertiary
carbinamine derivatives 3 (Scheme 1).
Scheme 1. Optimization of Solvent and Conditions
Trial reactions were carried out using the vinylurea 1a.11
Treatment of 1a with n-BuLi in a range of solvents at
ꢀ78 °C resulted in rapid racemic carbolithiation, giving 2a
on protonation after 1 h in Et2O and a mixture of 2a and 3a
in THF (Table 1, entries 1 and 2). In toluene (entry 3), the
racemic reaction was slower, reaching only 35% comple-
tion in 6 h and therefore giving an opportunity for an
asymmetric ligand-accelerated reaction.
(7) (a) Gericke, R.; Harting, J.; Lues, I.; Schittenhelm, C. J. Med. Chem.
1991, 34, 3074. (b) Lepifre, F.; Cottineau, B.; Mousset, D.; Bouyssou, P.;
Coudert, G. Tetrahedron Lett. 2004, 45, 483. (c) Cottineau, B.; Gillaizeau,
I.; Farard, J.; Auclair, M. L.; Coudert, G. Synlett 2007, 1925.
€
(8) (a) Peters, J. G.; Seppi, M.; Frohlich, R.; Wibbeling, B.; Hoppe,
Withoptimizedconditionsinhand, arangeofvinylureas
111 were treated with commercially available organo-
lithiums in the presence of (ꢀ)-sparteineatꢀ50 °Cincumene
(Scheme 2). Both electron-rich and electron-poor aromatic
rings underwent the tandem additionꢀrearrangement reac-
tion in good yield and with good to excellent er. With
phenyllithium and with methyllithium (which underwent
carbolithiation only in THF), racemic products 3g and 3h
were formed.14
D. Synthesis 2002, 3, 381. (b) Superchi, S.; Sotomayor, N.; Miao, G.;
Joseph, B.; Campbell, M. G.; Snieckus, V. Tetrahedron Lett. 1996, 37,
6061. (c) Fournier, A. M.; Clayden, J. Org. Lett. 2012, 14, 142.
ꢁ
(9) Felkin, H.; Swierczewski, G.; Tambute, A. Tetrahedron Lett.
1969, 707. Kato, T.; Marumoto, S.; Sato, T.; Kuwajima, I. Synlett
1990, 671. Marumoto, S.; Kuwajima, I. Chem. Lett. 1992, 1421.
Marumoto, S.; Kuwajima, I. J. Am. Chem. Soc. 1993, 115, 9021. Wei,
X.; Taylor, R. J. K. J. Chem. Soc., Chem. Commun. 1996, 187. Wei, X.;
Taylor, R. J. K. Tetrahedron Lett. 1997, 38, 6467. Wei, X.; Taylor,
R. J. K. Tetrahedron Lett. 1996, 37, 4209. Wei, X.; Johnson, P.; Taylor,
R. J. K. J. Chem. Soc., Perkin Trans. 1 2000, 1109. Klein, S.; Marek, I.;
€
Normant, J. F. J. Org. Chem. 1994, 59, 2925. Muck-Lichtenfeld, C.;
With tert-butyllithium, only carbolithiation (without
tandem rearrangement) was observed, giving 2c. More
Ahlbrecht, H. Tetrahedron 1999, 55, 2609.
(10) (a) Klein, S.; Marek, I.; Poisson, J.-F.; Normant, J.-F. J. Am.
Chem. Soc. 1995, 117, 8853. (b) Norsikian, S.; Marek, I.; Poisson, J.-F.;
Normant, J.-F. J. Org. Chem. 1997, 62, 4898. (c) Wei, X.; Taylor, R. J. K.
Tetrahedron: Asymmetry 1997, 8, 665. (d) Norsikian, S.; Marek, I.;
Normant, J. F. Tetrahedron Lett. 1997, 38, 7523. (e) Norsikian, S.; Marek,
I.; Klein, S.; Poisson, J.-F.; Normant, J.-F. Chem.;Eur. J. 1999, 5, 2055. (f)
Norsikian, S.; Baudry, M.; Normant, J.-F. Tetrahedron Lett. 2000, 41,
6575. (g) Hogan, A.-M. L.; O’Shea, D. F. J. Org. Chem. 2008, 73, 2503.
(11) Vinylureas were made by the method of ref 6 and: Lefranc, J.;
(12) Lefranc, J.; Fournier, A. M.; Mingat, G.; Herbert, S.; Marcelli,
T.; Clayden, J. J. Am. Chem. Soc. 2012, 134, 7286.
(13) For a discussion of the configurational stability of benzyl-
lithiums, see: Clayden, J. Organolithiums: Selectivity for Synthesis;
Pergamon: Oxford, 2002; pp 169ꢀ213.
(14) For the effect of THF on the action of diamine ligands, see: (a)
Carbone, G.; O’Brien, P.; Hilmersson, G. J. Am. Chem. Soc. 2010, 132,
15445. (b) Barker, G.; O’Brien, P.; Campos, K. R. Org. Lett. 2010, 12, 4176.
ꢁ
Tetlow, D. J.; Donnard, M.; Minassi, A.; Galvez, E.; Clayden, J. Org.
Lett. 2011, 13, 296.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Conditions for CarbolithiationꢀRearrangement of 1a
Scheme 2. Asymmetric CarbolithiationꢀRearrangement Using
(ꢀ)-Sparteine 4
4ꢀ7
DMPU
(equiv) solvent (°C)
temp yield of yield of er of
entry
R
(equiv)
2 (%)
3 (%)
3
1
2
3
4
5
6
7
8
9
n-Bu
n-Bu
n-Bu
n-Bu 4, 1
n-Bu 4, 1
n-Bu 4, 1
i-Pr 4, 6
i-Pr 4, 2
i-Pr 4, 2
0
0
0
0
0
0
0
THF
Et2O ꢀ78
tol
ꢀ78
ꢀ78
49
47
0, 35a
21
0
0
b
Et2O ꢀ78
32
0
0
0
0
0
0
0
0
0
0
0
0
0
12
10c
10d
10c
10e
10c
10c
10c
10c
10c
10c
10c
10c
10c
tol
tol
tol
ꢀ78
ꢀ78
ꢀ78
53 62:38
45 76:24
56 80:20
60 80:20
70 80:20
85 80:20
85 75:25
86 92:8
81 70:30
0
0
62 35:65
74 5:95
mtbe ꢀ78
mtbe ꢀ50
Et2O ꢀ50
cumf ꢀ78
cumf ꢀ50
cumf ꢀ50
10 i-Pr 4, 2
11 i-Pr 4, 1
12 i-Pr 4, 1
13 i-Pr 4, 0.5
14 i-Pr 6, 1
15 i-Pr 7, 1
16 i-Pr 5, 1
17 i-Pr 5, 1
b
tol
tol
ꢀ78
ꢀ78
b
cumf ꢀ78
THF
ꢀ78
a After 6 h. b Not determined. c Added after 1 h. d Added after 6 h.
e Added after 3 h. f cum = cumene = Phi-Pr.
generally, unrearranged products 2 could be isolated when
DMPU was not added to the reaction mixture: 2a was
formed in 65:35 er under these conditions and had [R]D =
þ12.8. Comparison with an authentic enantiomerically
pure sample of (S)-(ꢀ)-2a15 allowed us to confirm that
(ꢀ)-sparteine induces the formation of 2a with (R) abso-
lute configuration. Since both protonation and aryl migra-
tion are stereochemically retentive,16 and carbolithiation is
syn selective,6 we deduce that (ꢀ)-sparteine leads to aryl
migration to the Re face of the alkenyl group, the back face
as drawn, of vinylureas 1.
Despite the dominance of (ꢀ)-sparteine as a director of
asymmetric organolithium chemistry over the last 20 years,17
other lithium-complexing agents, especially the “(þ)-
sparteine surrogate” 5,18 show promising activity as alter-
native or improved ligands. We screened 5,18 BPox 6,19 and
trans-cyclohexanediamine 720 in the addition of i-PrLi to 1a.
a Reaction carried out in THF. b Without addition of DMPU.
No carbolithiation was observed using 6 or 7 in toluene
(Table 1, entries 14 and 15), but in a test reaction with 5 the
product 3b was obtained in excellent er, even in THF
(Table 1, entries 16 and 17).14
When applied to a wider range of substrates 1 (Scheme 3),
carbolithiation with organolithiums in the presence of the
(þ)-sparteine surrogate 5 behaved distinctively differently
from reactions using (ꢀ)-sparteine 4 as the chiral ligand.
As expected, the products had the opposite absolute con-
figuration using 5 in place of 4. The reactions also per-
formed best in THF. In general, carbolithiation and
rearrangement proceeded with good er using i-PrLi. How-
ever, with n-BuLi the products 3j and 3l were close to
racemic.21 Other noncommercial organolithiums gave vary-
ing results: p-methoxyphenyllithium led to racemic 3m, while
cyclopentyllithium resulted in only slight enantioenrichment
in 3n. An attempted reaction employing in situ halogenꢀ
lithium exchange of (Z)-1-iodohex-3-ene resulted in the
formation of 3o in good yield, evidently via ethylation of
t-BuLi by ethylene generated on decomposition of THF.22
Ureas related to 3 are readily converted to amines 8
bearing tertiary substituents by solvolysis under neutral or
basic conditions.5b Thus, treatment of 3k with ethanolic
sodium hydroxide gave the amine 8k in excellent yield
(Scheme 4) and without loss of enantiomeric purity.
(15) (S)-(ꢀ)-2a ([R]D = ꢀ59.7) was made using the method of: Liu,
G.; Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1997, 119, 9913. See
the Supporting Information.
(16) Protonation of benzyllithiums is almost always retentive; for a
discussion, see: Clayden, J.; Helliwell, M.; Pink, J. H.; Westlund, N.
J. Am. Chem. Soc. 2001, 123, 12449 and also ref 12 of ref 5a. Aryl
migrations in ureas (refs 5a and 6) and thiocarbamates are retentive:
MacLellan, P.; Clayden, J. Chem. Commun. 2011, 3395. In carbamates
they are, however, invertive: 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. Fournier, A. M.; Brown, R. A.;
Farnaby, W.; Miyatake-Ondozabal, H.; Clayden, J. Org. Lett. 2010, 12,
2222. Fournier, A. M.; Nichols, C. J.; Vincent, M. A.; Hillier, I. H.;
Clayden, J. Chem. Eur. J., 2012, 18, 16478.
(17) Hoppe, D.; Hense, T. Angew. Chem., Int. Ed. 1997, 36, 2282–2316.
(18) O’Brien, P. Chem Commun, 2008, 655. For the use of 5 in
asymmetric carbolithiation, see: Dearden, M. J.; McGrath, M. J.;
O’Brien, P. J. Org. Chem. 2004, 69, 5789. Although 5 is commercially
available, best results were with material synthesized from cytisine (itself
extracted from Laburnum anagyroides seeds) by the method of: Dixon,
A. J.; McGrath, M. J.; O’Brien, P. Org. Synth. 2006, 83, 141.
(21) Increasing the concentration of the reaction mixture from 0.1 to
0.3 M made a marginal improvement to the er of 3j, suggesting that the
coordination of 5 to n-BuLi in THF may be concentration dependent.
Concentration-dependent values for er have been observed in other
lithiations using n-BuLi þ 5 in THF. Nonetheless, NMR indicated
coordination between n-BuLi þ 5 in THF even at 0.07 M: Carbone, G.;
O’Brien, P. Unpublished results.
€
(19) Lange, H.; Bergander, K.; Frohlich, R.; Kehr, S.; Nakamura, S.;
Shibata, N.; Toru, T.; Hoppe, D. Chem. Asian J. 2008, 3, 88.
(20) Cabello, N.; Kizirian, J.-C.; Alexakis, A. Tetrahedron Lett. 2004,
45, 4639.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 3. Asymmetric CarbolithiationꢀRearrangement Using
(þ)-Sparteine Surrogate 5
Scheme 5. Asymmetric CarbolithiationꢀVinylation
a In THF (ꢀ78 °C, 90 min then ꢀ30 °C, 90 min) with neither 4 nor 5.
b 4, cumene, ꢀ35 °C, 2 h. c 5, Et2O, ꢀ45 °C, 4 h.
Scheme 6. Trapping a Dearomatized Intermediate
lithium attacks one enantiotopic face of the alkene (Re for
4; Si for 5) to form a stereodefined organolithium formed
under kinetic control. We know from other work that such
urea-stabilized organolithiums are configurationally stable
onthetimescaleof therearrangement,5,13 so it seems unlikely
that asymmetry is induced by any form of equilibration of the
organolithium.23 Migration of the aromatic ring then occurs
via an intramolecular nucleophilic aromatic substitution
whose mechanism has been discussed elsewhere24 and which
may or may not involve a dearomatized intermediate. In the
case of the 1-naphthyl migration to form 3f, a dearomatized
intermediate5a may, however, be trapped to give the enone 12
by allowing dry air into the reaction flask (Scheme 6).
In summary, carbolithiation in the presence of chiral
diamines of vinylic ureas bearing an N-aryl group leads to
tandem formation of two new CꢀC bonds and allows
the formation of amines bearing R-tertiary substituents in
good enantiomeric ratios.
a Enantiomeric ratio not determined. b At 0.1 M. c At 0.3 M.
Scheme 4. Solvolysis of the Product Urea To Liberate the Amine
Lithiated ureas will not only trap N-aryl groups by
intramolecular migration but also N-alkenyl groups.12
In THF, the N-alkenylurea 9 underwent regioselective
carbolithiation followed by vinyl migration to yield 10,
whose isolation was complicated by a strong tendency to
undergo rearrangement to 11 in acid. However, both 4 and
5 induced asymmetric carbolithiationꢀvinylation to give
10 in enantiomerically enriched form (Scheme 5).
Acknowledgment. This workwas fundedby the EPSRC
(Grant No. EP/F069103/1) and by AstraZeneca. We are
grateful to Dr. Sam Butterworth of AstraZeneca for many
helpful discussions and to Lucy Salmon and Jennifer
Whittle for assistance with the synthesis of 5.
We assume that the reactions begin with an asymmetric
carbolithiation, in which the diamine-complexed organo-
Supporting Information Available. Full experimental
details and characterization of new compounds.This
material is available free of charge via the Internet at
http://pubs.acs.org.
(22) Clayden, J.; Yasin, S. A. New J. Chem. 2002, 26, 191. For
instances of ethylene insertion into organolithiums, see: Maercker, A.;
Theysohn, W. Liebigs Ann. Chem. 1971, 747, 70. Spialter, L.; Harris,
C. W. J. Org. Chem. 1966, 31, 4263. Krief, A.; Kenda, B.; Barbeaux, P.;
Guittet, E. Tetrahedron 1994, 50, 7177. Bartlett, P. D.; Friedman, S.;
Stiles, M. J. Am. Chem. Soc. 1953, 75, 1771.
(23) For an overview of the mechanisms by which asymmetry may be
induced by chiral ligands complexed to organolithiums, see: Beak, P.;
Basu, A.; Gallagher, D. J.; Park, Y. S.; Thayumanavan, S. Acc. Chem.
Res. 1996, 29, 552. Basu, A.; Thayumanavan, S. Angew. Chem., Int. Ed.
2002, 41, 716. Beak, P.; Anderson, D. R.; Curtis, M. D.; Laumer, J. M.;
Pippel, D. J.; Weisenburger, G. A. Acc. Chem. Res. 2000, 33, 715.
(24) Grainger, D. M.; Campbell Smith, A.; Vincent, M. A.; Hillier,
I. H.; Wheatley, A. E. H.; Clayden, J. Eur. J. Org. Chem. 2012, 731.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX