Tandem β-alkylation-α-arylation of amines by carbolithiation and rearrangement of N -carbamoyl enamines (Vinyl Ureas)

Article abstract of DOI:10.1021/ja1007992

Organolithiums add in an umpolung fashion to the β-carbon of N-carbamoyl enamines (N-vinyl ureas). The reaction proceeds with syn diastereospecificity and provides urea-stabilized, configurationally defined organolithiums. Facilitated by coordinating solv

Full text of DOI:10.1021/ja1007992

Published on Web 04/22/2010
Tandem ꢀ-Alkylation-r-Arylation of Amines by Carbolithiation and
Rearrangement of N-Carbamoyl Enamines (Vinyl Ureas)
Jonathan Clayden,* Morgan Donnard, Julien Lefranc, Alberto Minassi, and Daniel J. Tetlow
School of Chemistry, UniVersity of Manchester, Oxford Road, Manchester M13 9PL, U.K.
Received February 8, 2010; E-mail: clayden@man.ac.uk
The construction of tertiary alkylamines1 is a synthetic challenge
exacerbated by the poor electrophilicity of imines.1e Umpolung2
approaches to the problem involving electrophilic attack on a nitrogen-
stabilized carbanion3 are a solution, and the use of nitroalkenes
allows tandem addition of substituents ꢀ and R to a nitrogen
function.4 In this paper, we report our discovery that N-carbamoyl
enamines (N-alkenyl ureas) likewise exhibit umpolung reactivity,
undergoing addition of organolithiums to their otherwise nucleophilic
ꢀ-carbons. The addition can be coupled with N f C aryl transfer within
the lithiated urea intermediate,5,6 allowing two new C-C bonds to
the R and ꢀ carbons of the alkene to be formed in a single pot.
Alkenyl urea 1a was treated with t-BuLi in THF for 1 h at -78
°C. After the reaction was quenched with methanol, a single addition
product 2a was obtained in 77% yield (Scheme 1); evidently,
regioselective carbolithiation of 1 occurs readily under these
conditions, presumably yielding initially a proposed benzylic
organolithium 3 (R ) t-Bu). Repeating the reaction with less
hindered organolithiums revealed further unconventional reactivity.
With n-butyllithium, the rearranged product 4a was obtained from
1 by N f C migration of the N-phenyl ring of 3.5 The product 4a
was straightforwardly converted to the tertiary alkyl amine 5a by
heating in n-BuOH for 2.5 h,7 indicating that this “alkylarylation”
of enamine 1a could constitute a useful new method for the
construction of multiply branched alkylamines.
made in two ways by exchanging Ar1 and Ar2, the alternative with
the more electron-rich Ar1 group was preferable. Unsaturated products
4i and 4j containing alkene or carbonyl functions were available by
addition of vinyllithium or ethoxyvinyllithium.
Table 1. Organolithium Additions to Vinyl Ureas 1
entry s.m.
Ar1
Ar2
R
4, yield (%)
1
2
3
4
5
6
7
8
1a Ph
Ph
Ph
Ph
Ph
Ph
Bu
4a, 72a
4b, 78b
4c, 74
4d, 74
4e, 77c
4f, 75
4g, 72
4f, 77
4g, 86
4h, 78
4i, 75
1a Ph
1a Ph
1a Ph
1a Ph
1b Ph
1c Ph
Me
i-Pr
s-Bu
Ph
p-MeOC6H4 i-Pr
p-ClC6H4
i-Pr
i-Pr
i-Pr
Ph
1d p-MeOC6H4 Ph
1e p-ClC6H4
1f p-FC6H4
1g p-Tol
1g p-Tol
9
Ph
Ph
Ph
Ph
10
11
12
-CH2dCH2
-CH(OEt)dCH2
4j, 96d
a Deprotected to yield amine 5a (82%). b Deprotected to yield amine
5b (76%). c Deprotected to yield amine 5e (74%). d Mixture of 4j and a
pyrimidinedione (see the Supporting Information).
Treating the propiophenimines 7 with aryl isocyanates gave vinyl
ureas 8 with >96:4 E/Z selectivity (Scheme 2).10 Methylation
returned the alkenyl ureas 9 also as >96% E isomer. The Z isomers
of 9 were available by a parallel route from allylamines 10,11 which
gave allylic ureas 11 upon treatment with aryl isocyanates.
Methylation of 11 was accompanied by double-bond migration to
give the ureas 9 with 98:2 Z/E selectivity.12 (Z)-9 can alternatively
be made directly from (E)-9 by formation of a (Z)-allyl anion
represented as 12 (M ) Li; X ) Me): treatment of (E)-9a with
LDA followed by methanol led to some decomposition but gave
(Z)-9a with 98:2 Z/E selectivity.13
Scheme 1. Umpolung Carbolithiation of Vinyl Ureas
Scheme 2. Synthesis of (E)- and (Z)-Alkenyl Ureas
Other N-vinyl ureas 1b-g were made by N-carbamoylation of
imines 6 and alkylation of the resulting ureas (Scheme 1). Table 1
shows the results of treating these N-vinyl ureas 1 with a range of
organolithiums RLi in THF at -50 °C for 90 min.8 In each case,
carbolithiation followed by N-aryl migration resulted in tandem addition
of two carbon substituents, R and Ar2, across the electron-rich enamine
double bond. Yields were good to excellent, and a range including
methyl-, n- and sec-alkyl-, alkenyl-, and aryllithiums could be
successfully added to the ureas.9 Migration of a phenyl ring was
generally faster and cleaner8 than migrations of other (generally
electron-rich) substituted aryl groups, and where a product could be
In THF at -40 °C, alkyllithiums RLi underwent clean addition
to (E)-alkenyl ureas 9a-d (which have Ar2 ) Ph) and gave
carbolithiation-rearrangement products 13a-e as single diastere-
oisomers (Table 2, entries 1-5). Ureas 13a-e were readily
converted to single diastereoisomers of the amines 14 in refluxing
n-butanol (Scheme 3).7 The relative configuration of amine 14a
was confirmed by an X-ray crystal structure14 of its hydrochloride
salt 14a ·HCl (Scheme 3), which showed that 13 and hence 14 are
formed by syn addition of R and Ar2. As expected, transposition
of Ar1 and Ar2 within the starting material led to an inversion of
9
6624 J. AM. CHEM. SOC. 2010, 132, 6624–6625
10.1021/ja1007992  2010 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Organolithium Additions to Vinyl Ureas 9
Scheme 4. Proposed Mechanism
X in
Y in
13 or 15,
yield (%)
entry
s.m.
Ar1 ) C6H4X Ar2 ) C6H4Y
R
14, yield (%)
1
2
3
4
5
6
7
8
9
(E)-9a
(E)-9a
(E)-9b
(E)-9c
(E)-9d
(E)-9e
(E)-9f
(E)-9f
(Z)-9a
p-Cl
p-Cl
p-F
p-Me
p-MeO
H
H
H
p-Cl
Ph
Ph
H
H
H
H
i-Pra 13a, 81
n-Bua 13b, 70
i-Pra 13c, 69
i-Pra 13d, 60
i-Pra 13e, 76
14a, 66
14b, 73
14c, 75
14d, 70
14e, 70
H
tion of heavily substituted amines from four components: a ketone,
an amine, an isocyanate, and an organolithium.
p-MeO
i-Prb epi-13e, 60 epi-14e, 70
m-MeO i-Prb 13f, 60
14f, 69
-
m-MeO n-Bub 13g, 65
Acknowledgment. We thank the EPSRC for a research grant
and a studentship (to D.J.T.) and AstraZeneca for financial support
under the collaborative EPSRC Programme for Synthetic Organic
Chemistry with AZ-GSK-Pfizer.
H
i-Prb epi-13a, 75 epi-14a, 67
10 (Z)-9e
11 (E)-9e
12 (E)-9e
13 (Z)-9e
14 (E)-9f
15 (E)-9f
16 (E)-9f
p-MeO
p-MeO
p-MeO
p-MeO
i-Prb 13e, 54
i-Prc 15a, 85
n-Bud 15b, 85
i-Pra epi-15a, 44
14e, 70
Ph
Ph
Ph
Ph
m-MeO i-Prc 15c, 83
m-MeO n-Bud 15d, 85
m-MeO t-Bua 15e, 60
Supporting Information Available: Full experimental procedures,
characterization data for all compounds, and crystallographic data for
14a·HCl (CIF). This material is available free of charge via the Internet
at http://pubs.acs.org.
Ph
a THF, -40 °C, 3-6 h. b (1) Tol, -40 °C, 1 h; (2) DMPU, -40 to
+25 °C, 16 h. c Tol, -40 °C, 1-2 h. d Et2O, -40 °C, 90 min.
References
Scheme 3. Stereospecific Reactions of (E)- and (Z)-Alkenyl Ureas
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(2) Seebach, D. Angew. Chem., Int. Ed. 1979, 18, 239.
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(5) (a) Clayden, J.; Dufour, J.; Grainger, D.; Helliwell, M. J. Am. Chem. Soc.
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(c) Bach, R.; Clayden, J.; Hennecke, U. Synlett 2009, 421.
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(8) At-78 °C, yields were generally lower, and at least 2 h was required for
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within 2 h at-78 °C.
the relative configuration of the product (entries 5 and 6): the
products from (E)-9d and (E)-9e are epimeric. The migrations of
the more electron-rich rings of 9e and 9f were slower, and the best
yields of 13f and 13g were obtained by carrying out the carbo-
lithiation at -40 °C in toluene and adding DMPU to enforce
rearrangement after the carbolithiation was complete (entries
6-8).5a,15 Epimeric products were also formed when E starting
materials were replaced with their Z isomers (entries 9 and 10).
Thus, addition of i-PrLi to the Z isomer of 9e yielded 13e, which
is epimeric with epi-13e derived from (E)-9e and identical to that
produced from the “ring-transposed” (E)-9d.
Carbolithiation and rearrangement of 9 is slower than that of 1.
With 9e and 9f, the electron-rich aryl rings failed to migrate in the
absence of DMPU,15 and it was possible to isolate products 15 resulting
from carbolithiation without rearrangement, even in THF (entries
11-16). Epimeric products were produced from (E)- and (Z)-9f.
Evidently, both the carbolithiation and aryl migration steps are
stereospecific,16 since either inverting the double-bond geometry in
the starting material or exchanging the substituents Ar1 and Ar2 changes
the configuration of the products. The crystal structure of 14a indicates
that the addition-migration process is mechanistically suprafacial. We
propose that the reactions proceed by umpolung carbolithiation17,18
of 9 (Scheme 4) to give a substituted benzyllithium 16 that is
configurationally stable19 on the time scale of the reaction. With
electron-rich Ar2, 16 may be trapped as 15 by retentive protonation.17c,18a
In general, however, benzyllithium 16 undergoes retentive5a,20 N f
C aryl migration by attack of the organolithium center on the N-aryl
ring Ar2 (17), transferring Ar2 to the position R to N and yielding
lithiourea 18 and hence 13 upon protonation.
(9) Furyllithium and alkynyllithiums failed to add to 1. Phenyllithium and
vinyllithium, which added cleanly to 1, failed to add to 9.
(10) A review of enamides: Carbery, D. Org. Biomol. Chem. 2008, 6, 3455.
(11) Allylamines 10 were made by Overman rearrangement of the cinnamyl
alcohols (see the Supporting Information).
(12) We ascribe both the double-bond isomerization and the Z selectivity to
deprotonation R to nitrogen by NaH to yield allyl anions represented as 12
(M ) X ) Na), which prefer a Z configuration. See: (a) Price, C. C.; Snyder,
W. R. Tetrahedron Lett. 1962, 3, 69. (b) Beak, P.; Lee, B. J. Org. Chem.
1989, 54, 458. (c) Katritzky, A. R.; Piffl, M.; Lang, H.; Anders, E. Chem.
ReV. 1999, 99, 665. Presumably, γ-deprotonation to give the same dianion
from 8 is slower.
(13) The alkene geometry was confirmed in each case by NOE studies and, for
(E)- and (Z)-9a, by X-ray crystallography.
(14) The X-ray crystallographic data has been deposited with the Cambridge
Crystallographic Data Centre under deposition number 762201.
(15) The coordinating cosolvent DMPU typically accelerates nucleophilic attack
of organolithiums on aromatic rings. See: Clayden, J.; Parris, S.; Cabedo, N.;
Payne, A. H. Angew. Chem., Int. Ed. 2008, 47, 5060, and references therein.
(16) In the sense of Zimmerman (see: Zimmerman, H. E.; Singer, L.;
Thyagarajan, B. S. J. Am. Chem. Soc. 1959, 81, 108).
(17) (a) Hogan, A.-M. L.; O’Shea, D. F. Chem. Commun. 2008, 3891, and
references therein. (b) Clayden, J. Organolithiums: SelectiVity for Synthesis;
Pergamon: Oxford, U.K., 2002; pp 273-281; (c) Norsikian, S.; Marek, I.;
Klein, S.; Poisson, J.-F.; Normant, J. F. Chem.sEur. J. 1999, 5, 2055.
(18) For related carbolithiations of acylated enols and enamines, see: (a) Peters,
J. G.; Seppi, M.; Fro¨hlich, R.; Wibbeling, B.; Hoppe, D. Synthesis 2002,
381. (b) Cottineau, B.; Gillaizeau, I.; Farard, J.; Auclair, M.-C.; Coudert,
G. Synlett 2007, 1925. (c) Lepifre, F.; Cottineau, B.; Mousset, D.; Bouyssou,
P.; Coudert, G. Tetrahedron Lett. 2004, 45, 483.
(19) Basu, A.; Thayumanavan, S. Angew. Chem., Int. Ed. 2002, 41, 716.
(20) By application of “Ockham’s razor” (Hoffmann, R. Bull. Soc. Chim. Fr. 1996,
133, 117), we discount an alternative combination of anti carbolithation
followed by invertive rearrangement (ref 6). See: Clayden, J.; Helliwell, M.;
Pink, J. H.; Westlund, N. J. Am. Chem. Soc. 2001, 123, 12449.
This new reaction allows the “1,2-alkylarylation” of a urea-
substituted alkene and provides a valuable method for the construc-
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