Intramolecular vinylation of secondary and tertiary organolithiums

Article abstract of DOI:10.1021/ja301591m

Deprotonation of benzylic ureas, carbamates, and thiocarbamates bearing N′-alkenyl substituents generates carbanions which undergo intramolecular migration of the alkenyl group to the carbanionic center. Solvolysis of the urea products generates α-alkenylated amines. With an enantiomerically pure starting urea, migration proceeds stereospecifically, generating in enantiomerically enriched form products containing allylic quaternary stereogenic centers bearing N. Computational and in situ IR studies suggest that the reaction, formally a nucleophilic substitution at an sp² carbon atom, proceeds by a concerted addition-elimination pathway.

Full text of DOI:10.1021/ja301591m

Communication
pubs.acs.org/JACS
Intramolecular Vinylation of Secondary and Tertiary Organolithiums
Julien Lefranc,† Anne M. Fournier,† Gaelle Mingat,† Simon Herbert,† Tommaso Marcelli,†,‡
̈
and Jonathan Clayden*,†
†School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, U.K.
‡Dipartimento di Chimica, Materiali e Ingegneria Chimica “Giulio Natta”, Politecnico di Milano, via Mancinelli 7, 20131 Milano, Italy
S
* Supporting Information
Scheme 1. Alkylidenation of Benzylic Ureas by Lithiation
and Rearrangement
ABSTRACT: Deprotonation of benzylic ureas, carba-
mates, and thiocarbamates bearing N′-alkenyl substituents
generates carbanions which undergo intramolecular
migration of the alkenyl group to the carbanionic center.
Solvolysis of the urea products generates α-alkenylated
amines. With an enantiomerically pure starting urea,
migration proceeds stereospecifically, generating in
enantiomerically enriched form products containing allylic
quaternary stereogenic centers bearing N. Computational
and in situ IR studies suggest that the reaction, formally a
nucleophilic substitution at an sp2 carbon atom, proceeds
by a concerted addition-elimination pathway.
any classes of electrophiles, including alkylating and
M
acylating agents, carbonyl compounds, and halogenating
agents, are compatible with organolithium chemistry.1 How-
ever, the direct arylation of organolithiums is a particular
challenge typically overcome by transmetalation with Cu or
Zn2,3 or by intramolecular aryl transfer.4−7 Vinylic electrophiles
likewise cannot normally be coupled directly with organo-
lithiums, and transmetalation is usually required to form new
position, providing 2a. A similar rearranged product 2b was
obtained from butadienyl urea 1b. Remarkably, even the simple
vinyl urea 1c underwent rearrangement, forming the ethyl-
idene-substituted 2c as its Z isomer. Likewise, vinyl migration
provided the Z-ethylidene substituted urea 2d from N-vinyl
tetrahydroisoquinolinyl urea 1d.
vinylic C−C bonds.2
d‑f
In this paper we present a new approach to the vinylation of
organolithium nucleophiles that allows new C−C bonds to be
formed by nucleophilic attack even on unactivated alkenes and
permits the stereospecific construction of functionalized
quaternary centers by vinylation of tertiary carbanions. We
had previously shown that when ureas5 or carbamates6 bearing
N′-aryl groups are lithiated, nucleophilic substitution at the ipso
position of the aryl group leads to intramolecular transfer of the
aryl substituent to the carbanion center.8 Given that this
intramolecular nucleophilic aromatic substitution is successful
even with electron-rich rings,5a it seemed plausible that the
migration of electron-rich alkenyl groups might also be feasible.
In preliminary experiments, N-benzyl-N-alkenyl ureas 1 were
made in three steps from commercially available starting
materials.9 Styrenyl urea 1a was treated with sec-BuLi (2 equiv)
at −78 °C in THF and allowed to stir for 1 h before quenching
with MeOH (Scheme 1). Workup and purification yielded a
single Z geometrical isomer of the rearranged urea 2a in 60%
yield. We presume the reaction proceeds through deprotona-
tion of the urea α to N5a to give the benzyllithium 1Li, followed
by migration of the styrenyl group to the carbanionic center. A
second deprotonation α to N would give a Z-configured O-
chelated cinnamyllithium 2Li,5d which is quenched at its γ-
The second deprotonation (leading to 2Li) would be
avoided in any similar vinylation of tertiary carbanions10
because those products would lack a further proton at the
carbanion center. α-Alkylbenzylamine derivatives 3 (X = NH)
were converted into the N-vinyl ureas 4 by reaction with
commercially available vinyl isocyanate and, where necessary,
N-methylation (full details are provided in the Supporting
Information (SI)). When 4a (Ar = Ph, R1 = Me) was treated
with sec-BuLi in THF under the conditions reported in Scheme
1, only starting material was recovered. We have previously
noted that the lithium-coordinating cosolvent DMPU markedly
increases the reactivity of hindered organolithiums toward
nucleophilic attack on arenes and alkenes,5a,e probably by
favoring the formation of solvent-separated ion pairs.11 On
repeating the rearrangement of 4a using 10% DMPU as a
cosolvent the rearranged derivative 7a of a tertiary allylic amine
Received: February 27, 2012
Published: April 5, 2012
© 2012 American Chemical Society
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Communication
was obtained (Scheme 2), and when the rearrangement was
performed using an enantiomerically pure starting urea (S)-4a
Scheme 3. Conversion to α-Tertiary Amines and X-ray
Crystal Structure of (S)-10b•HCl
Scheme 2. Vinylation of Organolithiums α to N, O, or S
a
from α-Methylbenzyl Amine
group to give 7b, and hence presumably in other cases as well,
is stereochemically retentive.13
Other N-alkenyl ureas 4g−j were made from α-methyl-
benzylamine 3a either by reaction with the alkenyl isocyanates
(available by Curtius rearrangement of α,β-unsaturated
carboxylic acids) or carbamoyl chlorides or by isomerization
of an allylic or propargylic isomer (see SI for details). The
alkenyl ureas were lithiated with sec-BuLi in THF and DMPU
(Scheme 4). The cyclohexenyl group of (S)-4g rearranged
Scheme 4. Rearrangement and Cyclization of N-
a
Alkenylureas
a
Retention of stereochemistry proved for 7b (see below); absolute
configuration of other ureas 7 and of thiocarbamate 8 assumed by
analogy.
(>99:1 e.r.) the product 7a was obtained in enantiomerically
pure form. The intermediate benzyllithium must therefore be
configurationally stable12 over the time scale of the migration,
and the migration must occur with complete stereochemical
fidelity.13 Vinylation at the benzylic position α to nitrogen was
likewise observed on lithiation of other N-vinylureas 4 and
when enantiomerically pure starting materials were used, the
products were also obtained enantiomerically pure.
N-Vinyl thiocarbamate 5 and carbamates 6 were lithiated
under slightly modified conditions (with LDA) to minimize
attack of the base on their carbonyl groups.6 As with the ureas,
lithiation took place at their benzylic center to give a dipole
stabilized organolithium,14 which in every case underwent vinyl
migration to yield carbamoyl derivatives of the tertiary thiol 8
or tertiary alcohols 9a−c. Thiocarbamate 8 formed with 80:20
e.r. under these conditions (and was essentially racemic if
DMPU was used), and essentially racemic 9 was obtained
under all conditions attempted.12
a
Too unstable to purify. bIsolated in 60% yield. Absolute stereo-
c
chemistry not confirmed. Relative stereochemistry deduced by NOE.
The products 7 of the rearrangements of ureas are allylic
amines in protected form, and in many cases yields were
compromised by their acid sensitivity. Conversion of the
products to the α-tertiary allylic amine was achieved simply by
treatment of the urea with K2CO3 in refluxing n-BuOH5b
(Scheme 3). By combining into one operation the urea
formation, rearrangement, and deprotection, it was possible to
perform the direct stereospecific vinylation of the α-
methylbenzylamines 3 in a single reaction vessel without
purification of the acid-sensitive ureas. Treatment of 10b with
dry HCl yielded crystals of its hydrochloride salt, and single
crystal X-ray analysis allowed us to establish its absolute
configuration, thus confirming that the migration of the vinyl
cleanly and streospecifically to give (R)-7g in good yield.
Similarly, the propenyl group of (S)-4h rearranged to yield (R)-
7h without loss of e.r., but on attempted purification 7h
rearranged with partial stereospecificity to the urea 11. The
styrenyl urea 4i and the allenyl urea 4j both returned
imidazolidinones 12, presumably because migration of the
vinylic substituent in these cases is interrupted by the unusual
stability of the benzylic or vinylic intermediate anion (see below
for further mechanistic discussion). The benzyl-substituted
product 12i was obtained as a mixture of diastereoisomers,
while the vinyl-substituted 12j was isolated as a single
diastereoisomer, probably as a consequence of equilibration
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to the more stable epimer by deprotonation of the relatively
acidic allylic position α to N.
atom on the vinyl group (TS1) leads to the formation of a five-
membered ring (C′). Interestingly, for computational models
including either THF or DMPU, the lowest energy pathway
from lithiated 4a involves coordination of the lithium cation to
the π-system of the phenyl substituent rather than to the
benzylic carbon atom. In the transition state for C−C bond
formation, this lithium cation migrates to the terminal carbon
of the vinyl group in order to stabilize the developing negative
charge, leading to stereochemically retentive formation of the
new C−C bond, and with structure C′ having a syn
stereochemical relationship between the lithiomethyl group
and the phenyl ring. Structure C′ is predicted to be a shallow
local minimum on the potential energy surface.
Breakage of the C−N bond adjacent to the lithiomethyl
group (TS2) completes the vinyl migration, leaving the negative
charge delocalized over the urea group. In the product structure
D′ both lithium cations are bound to the urea anion as well as
the methyl group, with one molecule of solvent coordinating
each metal atom. The calculated potential energy profile and
the optimized transition states are given in Figures 1 and 2,
respectively, and show that the proposed mechanism is
energetically feasible.
The vinyl migration is effectively a nucleophilic substitution
at a trigonal carbon atom, a reaction that is more commonly
observed when anion stabilizing substituents allow an
associative, addition−elimination mechanism to take place.15
Further details of the migration of the vinyl group in urea 4a
and carbamate 6a was provided by in situ IR spectroscopy
(React-IR).8,16 In order to avoid obscuring the carbonyl region
of the spectrum, experiments were carried out in either THF or
Et2O in the absence of DMPU. In THF at −78 °C, the urea 4a
displays two absorptions at 1660 and 1620 cm−1 which
disappear over a period of 30 s on treatment with sec-BuLi,
being replaced (with no identifiable intermediates) by an
absorption at 1575 cm−1 (Scheme 5). This peak can be
Scheme 5. Proposed Intermediates in the Rearrangement of
a
4a
a
X = DMPU or THF.
Figure 1. Calculated potential energy profile for the N→C vinyl
migration at the B3LYP/6-311+G(2d,2p)//B3LYP/6-31G(d,p) level
of theory.
assigned to rearranged structure D since the same spectrum is
generated by treating the rearranged product 7a with BuLi. A
similar reaction profile was observed for rearrangement of 6a in
THF.
Vinyl migration was much slower in Et2O. Addition of sec-
BuLi to 4a in Et2O in the absence or presence of LiCl gave a
transient absorption at 1646 cm−1 which gave way over a period
of seconds or minutes to a new intermediate with absorptions
at 1608 and 1593 cm−1. Quenching the reaction at this stage
returned starting material, so we assume that the transient
absorption arises from a prelithiated complex A16 which is
transformed into the intermediate lithiourea B. In the presence
of LiCl, slowly warming the reaction to rt promoted
rearrangement. At −25 °C the absorptions at 1608 and 1593
began to decrease in intensity, and at −15 °C, about 5 min
later, a new absorption appeared at 1575 cm−1, which we assign
to structure D already identified. The formation of
imidazolidinones from 4i and 4j points towards the
intermediacy of a cyclic structure C, but we were unable to
clearly identify absorptions corresponding to this proposed
structure.
Figure 2. Optimized transition states at the B3LYP/6-31G(d,p) level
of theory. Distances are in angstroms; hydrogen atoms have been
omitted for clarity.
The overall barriers for the computational models containing
THF and DMPU are 48.2 and 22.6 kJ/mol, respectively, in
qualitative agreement with the observed differences in
reactivity.
The cyclization of 4h and 4i arises because of the greater
stability of the benzylic or vinylic organolithium intermediate
corresponding to C and C′ from these starting ureas.
Nonetheless, successful migration of a styrenyl and a butadienyl
group in 1a and 1b suggests that relatively small changes in
structure can have a significant effect on the stability of any
cyclic intermediate. It is possible that ring opening of C and its
Density functional theory calculations5a,8 (for computational
details, see the SI) provided further illumination of the course
of the vinyl migration. We considered a system composed of
the lithiated derivative of 4a, with an additional molecule of
methyllithium coordinated to the urea carbonyl group and one
molecule of either DMPU or THF coordinating each lithium
atom, shown as structure B′ in Scheme 5.17 Starting from
structure B′, nucleophilic attack of the benzylic anionic carbon
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Journal of the American Chemical Society
Communication
congeners is reversible,18 and the successful migration of the
styrenyl and butadienyl groups in Scheme 1 is made possible
only by deprotonation of the final ring opened products,
displacing the equilibrium.
The synthesis of quaternary centers bearing heteroatoms is in
many cases challenging,10 and the ability to deliver alkenyl
substituents to such centers fills a useful gap in the synthetic
repertoire.
Miyatake-Ondozabal, H.; Clayden, J. Org. Lett. 2010, 12, 2222.
(c) Fournier, A. M.; Clayden, J. Org. Lett. 2012, 14, 142.
(7) MacLellan, P.; Clayden, J. Chem. Commun. 2011, 3395.
(8) For a study of the mechanism of the arylation, see: Grainger, D.
M.; Campbell Smith, A.; Vincent, M. A.; Hillier, I. H.; Wheatley, A. E.
H.; Clayden, J. Eur. J. Org. Chem. 2012, 731.
(9) For a survey of routes to vinyl ureas, see: Lefranc, J.; Tetlow, D.
J.; Donnard, M.; Minassi, A.; Gal
13, 296.
́
vez, E.; Clayden, J. Org. Lett. 2011,
(10) (a) Clayden, J.; Donnard, M.; Lefranc, J.; Tetlow, D. J. Chem.
Commun. 2011, 4624. (b) Clayden, J.; MacLellan, P. Beilstein J. Org.
Chem. 2011, 7, 582.
ASSOCIATED CONTENT
■
S
* Supporting Information
(11) (a) Sikorski, W. H.; Reich, H. J. Am. Chem. Soc. 2001, 123, 6527.
(b) Mukhopadhyay, T.; Seebach, D. Helv. Chim. Acta 1982, 65, 385.
(12) Dipole-stabilized benzylic organolithiums α to O or S are less
configurationally stable than those α to N. See ref 1, pp 169−213.
(13) The X-ray crystal structure of (S)-10b•HCl has been deposited
with the Cambridge Crystallographic Database, deposition number
861577. Related intramolecular arylations of ureas (ref 5a, 5e) and
thiocarbamates (ref 6) proceed with retention of configuration, while
arylations of carbamates (ref 5) proceed with inversion. In general,
benzyllithiums react stereospecifically, but with the sense of retention
or inversion being strongly dependent on conditions and the
electrophile. For a discussion, see: References 1, pp 241−258, and 4.
Also see: (a) Gawley, R. E. Tetrahedron Lett. 1999, 40, 4297.
(b) Gawley, R. E.; Low, E.; Zhang, Q.; Harris, R. J. Am. Chem. Soc.
2000, 122, 3344.
(14) α-O- and α-N-substituted organolithiums stabilized by
carbamates and α-S-substituted organolithiums stabilized by thio-
carbamates are well-established carbanion equivalents (ref 1). The
equivalent ureas have risen to prominence only recently: (a) Clayden,
J.; Dufour, J. Tetrahedron Lett. 2006, 47, 6945. (b) Clayden, J.; Turner,
H.; Pickworth, M.; Adler, T. Org. Lett. 2005, 7, 3147. (c) Clayden, J.;
Turner, H.; Helliwell, M.; Moir, E. J. Org. Chem. 2008, 73, 4415. For
an overview, see: (d) Volz, N.; Clayden, J. Angew. Chem., Int. Ed. 2011,
50, 12158.
1
Full experimental and characterization data, including H and
13C NMR spectra, for all new compounds. Computational and
React IR data. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
clayden@man.ac.uk
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the EPSRC. We thank
GlaxoSmithKline for a CASE award (to A.M.F.) and SASOL
for a postdoctoral fellowship (to S.H.). Tommaso Marcelli
acknowledges the MIUR (Rientro dei Cervelli 2008) and the
Politecnico di Milano for financial support. We are indebted to
CILEA for the generous allocation of computer time. J.C. is the
recipient of a Royal Society Wolfson Research Merit Award.
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Chemistry, 6th ed.; Wiley: NJ, 2007; pp 473−5. (c) Vinylic
substitution may be achieved by 1,2-metallate rearrangement; see:
Kocienski, P.; Barber, C. Pure Appl. Chem. 1990, 62, 1933.
(16) Full details of the in situ IR studies are provided in the
Supporting Information. For recent studies of organolithium reactions
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Campos, K. R.; Coldham, I.; Sanderson, A. J. Am. Chem. Soc. 2010,
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O’Brien, P.; Coldham, I. J. Am. Chem. Soc. 2012, 134, 5300. Several of
these studies have noted transient species with reduced carbonyl
stretching frequencies identified as ‘pre-lithiation complexes’ between
the alkyllithium base and the substrate.
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