Geometry-selective synthesis of e or Z N -vinyl ureas (N -carbamoyl enamines)

Article abstract of DOI:10.1021/ol1027442

N-Vinyl ureas are emerging as a valuable class of compounds with both nucleophilic and electrophilic reactivity. They may be made by capturing the enamine tautomer of an imine with an isocyanate, a reaction which in general leads to the E isomer of the vi

Full text of DOI:10.1021/ol1027442

ORGANIC
LETTERS
2011
Vol. 13, No. 2
296-299
Geometry-Selective Synthesis of E or Z
N-Vinyl Ureas (N-Carbamoyl Enamines)
Julien Lefranc, Daniel J. Tetlow, Morgan Donnard, Alberto Minassi, Erik Ga´lvez,
and Jonathan Clayden*
School of Chemistry, UniVersity of Manchester, Oxford Road,
Manchester, M13 9PL, U.K.
clayden@man.ac.uk
Received November 12, 2010
ABSTRACT
N-Vinyl ureas are emerging as a valuable class of compounds with both nucleophilic and electrophilic reactivity. They may be made by
capturing the enamine tautomer of an imine with an isocyanate, a reaction which in general leads to the E isomer of the vinyl urea. Deprotonation
of such a vinyl urea, or of an allyl urea, generates a dipole stabilized Z-allyl anion which may be protonated to return the Z-vinyl urea.
Isomerization of an allyl urea with a Ru complex provides an alternative route to E-vinyl ureas.
Chemical interest in ureas as a compound class has typically
highlighted their structural and medicinal properties rather
than their reactivity: ureas are generally stable to acid and
base and have powerful hydrogen bonding abilities, making
them key functional components of foldamers1 and other
supramolecular structures,2 ligands or catalysts,3 and drugs.4
Recently, however, some new aspects of the reactivity of
ureas have come to the fore, particularly with regard to
amination chemistry5 and functionalization by selective
lithiation.6,7 We have reported that N-aryl ureas are valuable
starting materials for intramolecular arylation reactions.8,9
In parallel with these reports, it has also become evident that
ureas of certain classes undergo relatively mild solvolysis7,9,10
to reveal amines or isocyanates, further enhancing their
potential utility.
Ureas bearing N-alkenyl substituents 1 (i.e., N-vinyl
ureas, or N-carbamoyl enamines) display useful and
remarkable reactivity toward organolithiums and other
strong bases. They may be deprotonated to yield urea-
substituted allyllithiums,11 or they may undergo umpolung
carbolithiation by nucleophilic attack of the organolithium
on the (nominally nucleophilic) ꢀ-position of the enam-
(5) Bar, G. L. J.; Lloyd-Jones, G. C.; Booker-Milburn, K. I. J. Am. Chem.
Soc. 2005, 127, 7308. Morgen, M.; Bretzke, S.; Li, P.; Menche, D. Org.
Lett. 2010, 12, 4494.
(1) Clayden, J.; Lemie`gre, L.; Helliwell, M. J. Org. Chem. 2007, 72,
2302. Clayden, J.; Lemie`gre, L.; Morris, G. A.; Pickworth, M.; Snape, T. J.;
Jones, L. H. J. Am. Chem. Soc. 2008, 130, 15193. Clayden, J.; Pickworth,
M.; Jones, L. H. Chem. Commun. 2009, 547. Violette, A.; Averlant-Petit,
M. C.; Semetey, V.; Hemmerlin, C.; Casimir, R.; Graff, R.; Marraud, M.;
Briand, J.-P.; Rognan, D.; Guichard, G. J. Org. Chem. 2005, 127, 2156.
Guichard, G.; Fischer, L. Org. Biomol. Chem. 2010, 8, 3101. Fischer, L.;
Claudon, P.; Pendem, N.; Miclet, E.; Didierjean, C.; Ennifar, E.; Guichard,
G. Angew. Chem., Int. Ed. 2010, 49, 1067.
(6) Clayden, J.; Turner, H.; Pickworth, M.; Adler, T. Org. Lett. 2005,
7, 3147. Smith, K.; El-Hiti, G. A.; Hegazy, A. S. Synthesis 2010, 1371.
(7) Houlden, C. E.; Lloyd-Jones, G. C.; Booker-Milburn, K. I. Org. Lett.
2010, 12, 3090.
(8) Clayden, J.; Dufour, J.; Grainger, D.; Helliwell, M. J. Am. Chem.
Soc. 2007, 129, 7488. Bach, R.; Clayden, J.; Hennecke, U. Synlett 2009,
421.
(2) Steed, J. W. Chem. Soc. ReV. 2010, 39, 3686. Pinault, T.; Andrioletti,
B.; Bouteiller, L. Beilstein J. Org. Chem. 2010, 6, 869.
(9) Clayden, J.; Hennecke, U. Org. Lett. 2008, 10, 3567.
(10) Hutchby, M.; Houlden, C. E.; Ford, J. G.; Tyler, S. N. G.; Gagne,
M. R.; Lloyd-Jones, G. C.; Booker-Milburn, K. I. Angew. Chem., Int. Ed.
2009, 48, 8721.
(3) Connon, S. J. Synlett 2009, 354. Zhang, Z.; Schreiner, P. R. Chem.
Soc. ReV. 2009, 38, 1187.
(4) Dumas, J.; Smith, R. A.; Lowinger, T. B. Curr. Opin. Drug DiscoVery
DeV. 2004, 7, 600.
(11) Tetlow, D. J.; Hennecke, U.; Raftery, J.; Waring, M. J.; Clarke,
D. S.; Clayden, J. Org. Lett. 2010, 12, 5442.
10.1021/ol1027442  2011 American Chemical Society
Published on Web 12/17/2010

ine.12 This polarity inversion is clearly illustrated by the
comparison between the two reactions shown in Scheme
1. Electrophilic attack of bromine on N-vinyl urea 1a gives
Scheme 2. Synthesis of Vinyl Ureas via Imines
Scheme 1. Polarity-Promiscuous Additions to N-Vinyl Ureas
Table 1. Synthesis of N-Vinyl Ureas from Ketones 6 by
Trapping Imines 7 with Isocyanates (Scheme 2)
1
Ar1 )
Ar2 )
R ) yielda/% ratiob E/Z
1a Ph
1b Ph
1c Ph
1d Ph
1e p-MeOC6H4
1f p-ClC6H4
Ph
H
H
H
H
H
H
H
H
H
H
65
42
32
35
21
38
29
35
41
63
-
-
-
-
-
-
-
-
-
p-MeOC6H4
p-ClC6H4
o-BrC6H4
Ph
Ph
Ph
1g p-FC6H4
1h p-MeC6H4
initially the ꢀ-bromoenamine 2 as expected, with excess
bromine leading to further electrophilic substitution at the
N-aryl ring to yield 3. Remarkably, nucleophilic attack
on the self-same vinyl urea 1 by an organolithium takes
place at the same sites; initial carbolithiation at the ꢀ
carbon of the enamine to give 4 is followed by attack of
the resulting benzyllithium on the N-aryl ring of 4 to give
5 after rearrangement and protonation.12
The synthesis and reactivity of enamides in general has
received attention in recent years,13 but the synthetic
potential of vinyl ureas is not matched by the number of
methods for their synthesis. There are scattered reports
of addition of imines to isocyanates to yield vinyl ureas,14
but none of these reports address the issue of geometrical
isomerism in the product. In this paper we describe our
work on both general synthetic approaches to this
functional class and also on methods which allow the
synthesis of either geometric isomer of trisubstituted
alkenes bearing urea substituents.
N-Acyl enamides can in general be formed by acylation
of an imine in the presence of base.13,14 We found that when
N-methyl imines 7, formed quantitatively from the corre-
sponding acetophenones 6 (R ) H), were treated with aryl
isocyanates, N-vinyl ureas were formed in moderate to good
yield (Scheme 2). The products were isolated after methy-
lation at the carbamoyl nitrogen (see Scheme 1) to yield the
1,1-disubstituted vinyl ureas 1a-j (Table 1).
Ph
1i
1j
m,p-diOMeC6H3 Ph
PhCH2)CH2-
Ph
-
1k Ph
1l Ph
1m Ph
1n Ph
1o Ph
1p Ph
1q Ph
1r Ph
m-MeOC6H4 Me 40
p-MeOC6H4 Me 50
94:6c
95:5
94:6
92:8
96:4
85:15
91:9
93:7c
90:10c
p-FC6H4
p-ClC6H4
p-MeC6H4
o-MeOC6H4
o-MeC6H4
1-naphthyl
Ph
Me 34
Me 20
Me 40
Me 37
Me 39 (42e)
Me 35
1s p-MeOC6H4
Me 55
95:5c d
,
1t
p-ClC6H4
Ph
Me 53
1u p-MeC6H4
1v p-FC6H4
1w p-ClC6H4
1x Ph
Ph
Ph
Me 45
92:8c
95:5c
92:8
Me 46 (50e)
p-MeOC6H4 Me 38 (40e)
p-MeC6H4
Ph 32
80:20
a Yield from ketone 6. b Ratio determined by NMR. c E geometry of
major isomer confirmed by NOE. d E geometry of major isomer confirmed
by X-ray crystallography.15 e Isolated yield of unmethylated urea 8.
ureas 1k-1x (Table 1).16 Yields are quoted with respect to
starting ketone 6 (R ) Me) and, over the three steps, were
moderate at best. However, no intermediate purification was
required, and the reaction could be carried out on a multigram
scale. In most cases, the conversion from the imine 7 to the
urea 1 was carried out as a one-pot operation, but the
intermediate urea 8 could also be isolated if required (Table
1 shows isolated yields for 8q, 8v, 8w).
In the case of the 1,1,2-trisubstituted ureas, we found that
the products were reliably formed as their E isomers,
generally with >90:10 selectivity. The ortho-substituted 1p
was formed with slightly lower selectivity, presumably due
to greater steric hindrance at the Ar2 ring, and selectivity
was also lower in the formation of the substituted stilbene
1x. Selectivity was confirmed in several cases by NOE
experiments and for 1t by X-ray crystallography15 (see
Scheme 3).
The reaction between imines and isocyanates was also
successful for the synthesis of 1,1,2-trisubstituted alkenyl
(12) Clayden, J.; Donnard, M.; Lefranc, J.; Minassi, A.; Tetlow, D. J.
J. Am. Chem. Soc. 2010, 132, 6624.
(13) For a review of related N-acyl enamines, see: Carbery, D. R. Org.
Biomol. Chem. 2008, 6, 3455. See also: Cottineau, B.; Gillaizeau, I.; Farard,
J.; Auclair, M.-C.; Coudert, G. Synlett 2007, 1925.
(14) Chupp, J. P.; Weiss, E. R. J. Org. Chem. 1968, 33, 2357. Goerdeler,
J.; Lindner, C. Chem. Ber. 1980, 113, 2499. Lenz, G. Tetrahedron 1984,
40, 4003. Schweim, H. G.; Ju¨rgens, S. Arch. Pharm. 1987, 320, 844. Tsuge,
O.; Hatta, T.; Kuwata, M.; Yamashita, T.; Kakehi, A. Heterocycles 1996,
43, 2083.
It was possible to isomerize the E isomer of 1t to its Z
isomer straightforwardly simply by treatment with LDA and
(15) X-ray crystallographic data for E-1t, Z-1t, 1y, and 17k have been
deposited with the Cambridge Crystallographic database, deposition numbers
CCDC 786909, 786910, 796730, and 796729.
(16) Tetrasubstituted products were formed only in very low yield and
were highly unstable to purification.
Org. Lett., Vol. 13, No. 2, 2011
297

Scheme 3
.
Conversion of the N-Vinyl Urea 1t from E to Z
Scheme 4. N-Vinyl Ureas from Allylamines
reprotonation with MeOH (Scheme 3). Both E- and Z-1t were
characterized by X-ray crystallography.15 LDA is known to
form allyllithiums from N-vinyl ureas,11 and allyllithiums
substituted with donor substituents generally adopt a Z
configuration to facilitate Li-donor interactions.17 Provided
conditions which promote orgonolithium rearrangement are
avoided, the γ-reprotonation of the allyllithium occurs with
retention of Z-geometry.18
iodide, with the best yields being obtained in DMF as
opposed to THF. In both cases the Z-vinyl ureas were
obtained (Table 2). Presumably, under the reaction condi-
Since the presumed allyl anion intermediate 911,19 in
this isomerization could in principle also be formed by
deprotonation of an allyl (rather than a vinyl) urea, we found
that a more direct route to the Z isomers could be realized
by starting from an allylamine rather than an imine (Scheme
4). The allyl amines 11 were made either by Overman
rearrangement of allyl alcohol 1020 (leading to primary amine
11a) or by addition of vinyllithium to imine 1221 (giving
PMP protected amine 11b).22 Addition of these amines to
aryl isocyanates gave the ureas 15a and 15b respectively.
An alternative but less versatile approach to 15a involved
vinylation of the sulfone 14,23 itself available from urea 13.
Methylation of 15b and dimethylation of 15a both
required the same conditions, sodium hydride and methyl
Table 2. Synthesis of N-Vinyl Ureas from Allylamines 11 by
the Methods of Scheme 4
1 or
17
yielda b ratio
/%
,
via
Ar1 )
Ar2 )
R )
E/Zd
1k
1l
1n
1y
1z
10, 11a Ph
10, 11a Ph
10, 11a Ph
10, 11a Ph
10, 11a Ph
m-MeOC6H4 Me
43c
75
67
49
75
74
94
72
89
75
75c
85
97
56
73
75c
55c
67
81
20
<5:95f
2:98f
<5:95f
<5:95g
5:95
<5:95
<5:95
<5:95
<5:95
<5:95
<5:95
5:95
p-MeOC6H4
p-ClC6H4
o-FC6H4
p-CNC6H4
Ph
Me
Me
Me
Me
Me
PMP
1aa 13, 14 Ph
17a 12, 11b Ph
17b 12, 11b Ph
17c 12, 11b Ph
17d 12, 11b Ph
17e 12, 11b Ph
17f 12, 11b Ph
17g 12, 11b Ph
17g 11b, 16 Ph
17h 12, 11b Ph
17i 12, 11b Ph
m-FC6H4
2,6-diMeC6H3 PMP
m-MeOC6H4 PMP
(17) Schlosser, M.; Desponds, O.; Lehmann, R.; Moret, E.; Rauch-
schwalbe, G. Tetrahedron 1993, 59, 10175. Margot, C.; Maccaroni, P.;
Leroux, F.; Schlosser, M. Tetrahedron 1998, 54, 12853. For synthetically
useful N-substituted Z-allyllithiums, see: 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.
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. 2005, 70, 5376. Ahmed, A.; Clayden, J.;
Rowley, M. Synlett 1999, 1954. Clayden, J.; Turnbull, R.; Pinto, I. Org.
Lett. 2004, 6, 609. Clayden, J.; Turnbull, R.; Helliwell, M.; Pinto, I. Chem.
Commun. 2004, 2430.
o-MeC6H4
p-ClC6H4
p-MeC6H4
p-CNC6H4
p-CNC6H4
m-CF3C6H4
Ph
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
<5:95
80:20
5:95
5:95
17j 12, 11b p-ClC6H4 Ph
<5:95
6:94g
<5:95
<5:95
17k 12, 11b p-ClC6H4 p-MeC6H4
17l 12, 11b p-ClC6H4 p-CNC6H4
17m 12, 11b p-CNC6H4 Ph
a From 11a, 11b, or 16. b Alkylation of 15 carried out in DMF unless
otherwise stated. c Alkylation of 15 carried out in THF. d Determined by
NMR. e Final product treated with silica to induce isomerization (see below).
f Geometry of major isomer confirmed by comparison with E-1. g Geometry
of major isomer confirmed by X-ray crystal structure.15
(18) Resek, J. E.; Beak, P. Tetrahedron Lett. 1993, 34, 3043.
(19) Gawley, R. E.; Coldham, I. R-Amino organolithium compounds.
In The Chemistry of Organolithium Compounds; Rappoprt, Z., Marek, I.,
Eds.; Wiley: New York, 2004; pp 997-1053.
(20) Overman, L. E. J. Am. Chem. Soc. 1974, 96, 597. Schmidt, A. M.;
Eilbracht, P. J. Org. Chem. 2005, 70, 5528.
(21) Tomiuka, K.; Inoue, I.; Shindo, M.; Koga, K. Tetrahedron Lett.
1991, 32, 3095.
tions, an allyl anion forms at least to some extent, which
is then protonated in the γ position to return the Z isomer
of the product. It is interesting to note that the same
(22) Comparable additions to N-methyl imines failed to provide good
yields of allyl amines.
(23) Mecozzi, T.; Petrini, M. J. Org. Chem. 1999, 64, 8970.
298
Org. Lett., Vol. 13, No. 2, 2011

reaction conditions evidently fail to generate this allyl
anion from the isomeric vinyl ureas 7 (R ) Me), since
methylation of this compound leads to the E vinyl urea
(Scheme 2). This must be a kinetic effect, with R-depro-
tonation being faster than γ-deprotonation.24
romethane overnight gave Z-1k quantitatively. We presume
that trapping of the acylenamine as a cyclic cation (Scheme
6) is involved in this isomerization, since this pathway is
The route to Z-1 and Z-17 shown in Scheme 4 allowed
the synthesis of N-vinyl ureas bearing either aryl or alkyl
groups on the enamine nitrogen. However, we found that
the synthesis of E-17 in a manner analogous to the synthesis
of E-1 shown in Scheme 2 was not applicable to the N-aryl
subclass of vinyl ureas. No reaction was observed between
N-arylimines and isocyanates (Scheme 5). We were however
Scheme 6
.
Isomerisation and Cyclization of N′-3-Methoxy Vinyl
Ureas
Scheme 5. Synthesis of an E-Vinyl Urea from an Azaenolate
uniquely favorable with a 3-methoxyphenyl urea. Evidence
that a cyclic intermediate is involved came from treatment
of E-1k trifluoromethanesulfonic acid: a cyclic product 20a
was formed in 89% yield by intramolecular Friedel-Crafts
alkylation of the methoxy-substituted ring. A related product
was formed when the allyl anion derived from E-1k was
treated with methyl triflate. After neutral workup, the cyclic
urea 20b was obtained, presumably by cyclization of the first-
formed vinyl urea in the triflic acid generated on workup
(Scheme 6).
In conclusion, we show that simple N-alkyl vinyl ureas
may be made from imines by N-acylation with isocyan-
ates. Where geometrical isomerism is possible, these are
formed predominantly as their E isomers but can be
isomerized to their Z isomers by treatment with a strong
base. Alternatively the Z isomers may be formed by
methylation and isomerization of the corresponding allyl
ureas.
able to make such an E N-vinyl urea in one case by first
treating the imine 18 with potassium hexamethyldisilazide
to form the potassium azaenolate, which was then N-acylated
with a carbamoyl chloride to form, directly, the E-vinyl urea
19 in 77% yield.
Nonetheless, the lack of nucleophilicity at nitrogen in
N-aryl imines left us without a general route to E-vinyl
ureas bearing an aryl substituent on the enamine nitrogen.
We therefore explored alternative methods for the isomer-
ization of the allyl ureas 9 which would avoid the
Z-selective formation of an allyl anion. N-Acyl allyl
amines may be isomerized to N-acylenamines not only
with base but also with the Ru complex RuCl(CO)-
H(PPh3)3.25 We therefore converted the allyl urea 11b
directly to the fully N-alkylated allyl urea 16, avoiding
the use of base to prevent isomerization, and treated it
with RuCl(CO)H(PPh3)3 in refluxing toluene to induce
migration of the double bond to the vinylic position. The
product 17g was formed with E selectivity complementary
to that seen with the method employing base.
This last method works equally for the synthesis of Z-N-
aryl vinyl ureas, but the unreactivity of N-arylimines
toward isocyanates means that the E isomers must be made
by Ru-catalyzed isomerization of the corresponding allyl
ureas.
In most cases the E- and Z-vinyl ureas were stable to
isomerization during workup and purification or on standing.
However, a notable exception was presented by the urea 1k
carrying a 3-methoxyphenyl substituent, which isomerized
readily on contact with silica during purification. For
example, stirring E-1k in a suspension of silica in dichlo-
Acknowledgment. We are grateful to the EPSRC for
research grants and to AstraZeneca and the EPSRC for
support under the EPSRC-Pharma Synthesis Studentships
scheme with AZ-GSK-Pfizer.
(24) For a discussion of the structure of sodium aza-allyl species, see:
Koutsaplis, M.; Andrews, P. C.; Bull, S. D.; Duggan, P. J.; Fraser, B. H.;
Jensen, P. Chem. Commun. 2007, 3580.
Supporting Information Available: Full experimental
and characterization details for all compounds; X-ray crystal-
lographic data for E- and Z-1t, 1y, and 17k. This material is
available free of charge via the Internet at http://pubs.acs.org.
(25) 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.
OL1027442
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