Carbolithiation of N-alkenyl ureas and N-alkenyl carbamates

Article abstract of DOI:10.3762/bjoc.9.70

N-Alkenyl ureas and N-alkenyl carbamates, like other N-acyl enamines, are typically nucleophilic at their β-carbon. However, by incorporating an α-aryl substituent, we show that they will also undergo attack at the β-carbon by organolithium nucleophiles,

Full text of DOI:10.3762/bjoc.9.70

Carbolithiation of N-alkenyl ureas and
N-alkenyl carbamates
Julien Lefranc, Alberto Minassi and Jonathan Clayden*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 628–632.
School of Chemistry, University of Manchester, Oxford Road,
Manchester M13 9PL, UK
doi:10.3762/bjoc.9.70
Received: 14 January 2013
Accepted: 24 February 2013
Published: 28 March 2013
Email:
Jonathan Clayden* - clayden@man.ac.uk
* Corresponding author
This article is part of the Thematic Series "Carbometallation chemistry".
Guest Editor: I. Marek
Keywords:
carbamate; carbolithiation; carbometallation; organolithium;
stereospecificity; styrene; urea
© 2013 Lefranc et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
N-Alkenyl ureas and N-alkenyl carbamates, like other N-acyl enamines, are typically nucleophilic at their β-carbon. However, by
incorporating an α-aryl substituent, we show that they will also undergo attack at the β-carbon by organolithium nucleophiles,
leading to the products of carbolithiation. The carbolithiation of E and Z N-alkenyl ureas is diastereospecific, and N-tert-butoxy-
carbonyl N-alkenyl carbamates give carbolithiation products that may be deprotected in situ to provide a new connective route to
hindered amines.
Introduction
Enamines and N-acyl enamines are in general nucleophiles, O-carbamoyl enols [10-12]. The organolithium resulting from
reacting with electrophiles at the carbon atom β to the nitrogen the enamine carbolithiation is nucleophilic at the atom α to
atom [1,2]. The resulting intermediate iminium or N-acyl- nitrogen, and such carbolithiations have been used to generate
iminium ions are electrophilic, and may themselves trap a hindered organolithiums as intermediates for further rearrange-
nucleophile at the position α to the nitrogen substituent. How- ment reactions [13], for example intramolecular acylation [6],
ever, we [3,4] and others [5-7] have shown that this typical arylation [3,4] or vinylation [4]. In this paper, we now report
reactive polarity may be reversed when N-acylenamines (espe- our studies on the scope of the carbolithiation–protonation of
cially N-vinyl ureas [8]) meet organolithium nucleophiles. styrenes carrying α-acylamino substituents, namely N-alkenyl
N-Carbamoyl enamines bearing α-aryl substituents (in other ureas and N-alkenyl carbamates.
words, α-acylaminostyrenes), may undergo reaction as electro-
philes, with the carbon atom β to nitrogen succumbing to attack Results and Discussion
by organolithium nucleophiles in an enamine carbolithiation Simple N-alkenyl ureas 1 were prepared by a reported method
reaction [9]. Similar reactivity is observed with related [2] entailing N-acylation of an acetophenimine with an iso-
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Beilstein J. Org. Chem. 2013, 9, 628–632.
cyanate, followed by N-alkylation of the resulting urea. When t-BuLi, this time in toluene. As before, a noncoordinating
urea 1a was treated with t-BuLi or s-BuLi in THF at −78 °C for solvent was used to suppress rearrangement. In each case the
one hour, followed by protonation, carbolithiated products 2a addition product 4b–f was obtained in good yield always as a
and 2b were isolated in good yield (Scheme 1 and Table 1, single diastereomer (Table 2, entries 2–5 and 7). Styrenes with
entries 1 and 2). Similar reactivity was observed between urea substituents on the aromatic ring underwent carbolithiation irre-
1a and less hindered organolithiums such as iPrLi or n-BuLi spective of the electronic character of the ring: with electron-
[3], but in THF even at −78 °C a rearrangement [14-18] of the rich or electron-poor aromatic rings Ar1 carbolithiation was
intermediate benzyllithium reduces the yield of the simple complete in one hour.
carbolithiation product. However, by lowering the temperature
to −85 °C rearrangement occured to only a limited extent, and
the addition product 2c was obtained in 53% yield (Table 1,
entry 3). Rearrangement was also suppressed if the substituent
Ar2 was replaced by either a p-chlorophenyl or a p-methoxy-
phenyl ring, and even with n-BuLi the carbolithiation–protona-
tion product may be obtained in moderate yield from 1b and 1c
(Table 1, entries 4 and 5).
Scheme 2: Diastereospecific carbolithiation of ureas 3.
Table 2: Organolithium additions to ureas 3.
Scheme 1: Carbolithiation of ureas 1.
Entry SM
Ar1
Ar2
R
4, yield (%)
Table 1: Organolithium addition to ureas 1.
1
2
3
4
5
6
7
8
9
10
E-3a Ph
3-MeOC6H4 n-Bu 4a, 85
E-3b 4-F-C6H4
E-3c Ph
Ph
s-Bu 4b, 70a
iPr 4c, 78
t-Bu 4d, 63
Entry SM
Ar1
Ar2
R
2, yield (%)
4-MeC6H4
E-3d 4-MeC6H4 Ph
1
2
3
4
5
1a
1a
1a
1b
1c
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
t-Bu
s-Bu
iPr
2a, 77a
2b, 74b
2c, 53c
2d, 61
2e, 47
E-3e 4-ClC6H4
Z-3e 4-ClC6H4
E-3f Ph
Ph
Ph
iPr
iPr
4e, 81
epi-4e, 80
4-MeOC6H4 n-Bu 4f, 85
4-MeOC6H4 n-Bu
4-ClC6H4 n-Bu
E-3f Ph
4-MeOC6H4 iPr
4-MeOC6H4 iPr
4-MeOC6H4 iPr
4g, 85b
Z-3f Ph
epi-4g, 85b
4h, 60
aReported in ref [3]; bmixture of diastereoisomers; creaction carried out
at −85°C.
E-3g 4-ClC6H4
a2:1 mixture of diastereoisomers; breaction reported in ref [3] but yield
now improved.
β-Substituted vinyl ureas 3 are available as either E or Z
geometrical isomers according to the method of synthesis:
N-acylation of a propiophenimine typically generates an When the reaction was performed using the Z-isomer of the
E-alkenylurea, but deprotonation and reprotonation of the urea starting materials, Z-3e and Z-3f (Scheme 2 and Table 2, entries
inverts its geometry to Z [2], probably via an intramolecularly 6 and 8), the other diastereomer of the product urea epi-4 was
chelated urea-substituted allyl anion [17]. Urea E-3a was obtained selectively: the carbolithiation–protonation is com-
treated with n-BuLi in Et2O (the less-coordinating solvent pletely diastereospecific. Both geometrical isomers of 3
suppresses rearrangement of the product [4]) at −40 °C: it presented similar reactivity and the products 4 were obtained in
underwent clean carbolithiation of the double bond, and on similar yields under the same reaction conditions.
protonation urea 4a was obtained as a single diastereomer in
85% yield (Scheme 2 and Table 2, entry 1). Other E-alkenyl To avoid possible contamination of the carbolithiation products
ureas bearing a range of substituted aromatic rings E-3b–f were by compounds arising from tandem carbolithiation–rearrange-
likewise treated with alkyllithium reagents s-BuLi, iPrLi and ment, we were also keen to explore the possibility of carbo-
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Beilstein J. Org. Chem. 2013, 9, 628–632.
lithiating vinyl ureas incapable of rearrangement, either because
they lack the N’-aryl substituent or because the remote nitrogen
is protected from attack by existing as an anion. Urea 5a, which
was available as an intermediate from the synthesis of 3a, was
treated with n-BuLi, using an additional equivalent of the
organolithium to allow for deprotonation of the urea NH
(Scheme 3) and in THF since a competing rearrangement is not
a problem. Despite the carbolithiation now requiring an anion to
act as an electrophile, the corresponding carbolithiated and
protonated product 6a was obtained as a single diastereoisomer
in excellent yield without chromatography (Table 3, entry 1)
after one hour in THF at −40 °C. With urea 5b primary
(n-BuLi), secondary (iPrLi) and also tertiary (t-BuLi) alkyl-
lithium reagents were added successfully in excellent yields
(Table 3, entries 2–4), and no chromatography was needed.
Figure 1: X-ray crystal structure of urea 6c.
butyloxycarbonyl-substituted carbamates would give more
readily manipulated carbamate products bearing a standard Boc
protecting group, providing they too could be carbolithiated and
trapped without rearrangement. Related carbamates are reactive
towards carbolithiation–rearrangement reactions [6]. Thus, Boc-
protected carbamates 9–11 were synthesised by acylation
of the imines 7 and 8 with di-tert-butyl dicarbonate or with
(−)-menthylchloroformate (Scheme 4). The N-alkenylcarba-
mates 10 and 11 were formed exclusively as their E isomers,
and the X-ray crystal structure of E-10 is shown in Figure 2.
Scheme 3: Diastereospecific carbolithiation of ureas 5.
Table 3: Carbolithiation of urea 5.
Entry SM
Ar1
Ph
Ar2
R
6, yield (%)
1
2
3
4
5a
5b
5b
5b
4-MeOC6H4 n-Bu
6a, 80
6b, 87
6c, 98
6d, 98
4-ClC6H4 4-MeOC6H4 n-Bu
4-ClC6H4 4-MeOC6H4 iPr
4-ClC6H4 4-MeOC6H4 t-Bu
The relative configuration of the carbolithiation products 6 was
established by X-ray crystallography of urea 6c (Figure 1). The
stereochemical outcome of the reaction is consistent with syn-
addition of the organolithium across the double bond (as is
typical for carbolithiation [9,19]) followed by retentive protona-
tion.
Scheme 4: Synthesis of N-alkenyl carbamates 9–11.
The relative configuration of the carbolithiation products 4 was
likewise confirmed by methylation (NaH, MeI) of 6d to provide Vinyl carbamate 9 was treated with primary, secondary or
a single diastereoisomer of urea 4g in 60% yield, which was tertiary alkyllithium reagents at −78 °C in THF for one hour
spectroscopically identical with the compound obtained by (Scheme 5), and after protonation the addition products 12a–c
treating urea E-3g with iPrLi (Table 2, entry 9). Again, the were isolated in good yields (Table 4, entries 1–3) . Substituted
stereochemical outcome is consistent with syn-carbolithiation carbamate 10 also reacted with primary, secondary or tertiary
followed by retentive protonation.
alkyllithium reagents under similar conditions, and in this case
the carbamates were deprotected by treatment with CF3CO2H in
In principle, the urea products 2, 4 and 6 could be solvolysed to a one-pot process, to provide the amines 13a–c in good yields
liberate free amines, as has been demonstrated for related com- over the two steps (Table 4, entries 4–6). In every case, the
pounds [4,15,20]. However, we reasoned that the related tert- amine 13 was obtained as a single diastereomer, which we
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Beilstein J. Org. Chem. 2013, 9, 628–632.
Table 4: Organolithium addition to vinyl carbamates.
Entry
SM
R
Product, yield (%), (dr)
1
2
3
4
5
6
7a
8
9
n-Bu
iPr
12a, 61
9
12b, 61
9
t-Bu
n-Bu
iPr
12c, 80
E-10
E-10
E-10
Z-10
11
13a, 70 (>95:5)
13b, 80 (>95:5)
13c, 81 (>95:5)
epi-13b, 50 (80:20)
14, 60 (50:50)
t-Bu
iPr
iPr
a24 h reaction time.
Figure 2: X-ray crystal structure of carbamate E-10.
mediate organolithium during the 24 h before the reaction is
assume, by analogy with the reactions of the equivalent ureas, quenched.
to be that shown, arising from syn-carbolithiation and retentive
protonation.
Related vinylureas will undergo enantioselective carbo-
lithiation in the presence of (−)-sparteine or a (+)-sparteine
surrogate [4], but enantioselective carbolithiation of carbamate
9 in the presence of (−)-sparteine led to product with only 60:40
er. The use of a chiral auxiliary in the form of a (−)-menthylcar-
bamate (11) also failed to induce selectivity, reacting with iPrLi
to yield a carbolithiated product 14 in 60% yield as a 50:50
mixture of diastereoisomers (Table 4, entry 8).
Conclusion
In conclusion, we have demonstrated that electron-rich double
bonds of vinyl ureas and carbamates may undergo carbo-
lithiation with primary, secondary and tertiary organolithium
reagents. N-tert-butoxycarbonyl vinylcarbamates may be carbo-
lithiated, protonated and deprotected in a one-pot synthesis of
amines employing this unusual umpolung nucleophilic β-alkyl-
ation. With β-substituted vinylureas, the carbolithiation is
diastereospecific, with (E) and (Z)-isomers of the ureas giving
different diastereoisomers of the products; (E)-N-alkenylcarba-
mates react with complete diastereospecificity. The overall syn-
relative configuration of the reaction products, which probably
arises from syn-carbolithiation followed by retentive protona-
tion, was confirmed by X-ray crystallography.
Scheme 5: Umpolung carbolithiation of carbamates 9 and 10.
E-10 was isomerised to Z-10 by treatment with LDA and repro-
tonation (presumably, like the equivalent ureas [2,3], via an Experimental
intramolecularly coordinated Z-allyllithium [21,22]), giving 1-(4-Methoxyphenyl)-1,3-dimethyl-3-[(1R*,2R*)-2-methyl-1-
Z-10 in excellent yield (Scheme 4). However, in contrast to phenylhexyl]urea (4f): To a solution of urea 3f (0.086 g,
Z-alkenyl ureas, Z-10 was rather less reactive than its E-isomer. 0.28 mmol, 1 equiv) in dry toluene (0.1 M) cooled to −40 °C,
The carbolithiation with iPrLi (Scheme 5) was slower, and had n-BuLi (2 equiv) was added slowly. After 1 h at −40 °C, the
to be performed for 24 hours instead of 1 hour. After deprotec- reaction was quenched slowly with MeOH and a saturated
tion with trifluoroacetic acid, the amine epi-13b was obtained in aqueous solution of NH4Cl. The resulting solution was
lower yield (50%) and as a 8:2 mixture of diastereomers extracted with EtOAc, dried with MgSO4, concentrated under
(Table 4, entry 7). The loss of diastereospecificity may be reduced pressure and purified by flash chromatography on silica
explained by the long reaction time: we assume that syn-carbo- gel (eluting with petroleum ether/EtOAc 9:1). The title com-
lithiation is followed by a partial epimerisation of the inter- pound 4f (0.086g, 85%) was obtained as a colourless oil. Rf 0.5
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Beilstein J. Org. Chem. 2013, 9, 628–632.
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Supporting Information
Supporting Information File 1
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Acknowledgements
License and Terms
We are grateful to the EPSRC for funding this work, to Alistair
Holdsworth for carrying out some preliminary reactions, and to
Madeleine Helliwell for determining the X-ray crystal struc-
tures of 6c and E-10.
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(http://creativecommons.org/licenses/by/2.0), which
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