α-Pyridylation of chiral amines via urea coupling, lithiation and rearrangement

Article abstract of DOI:10.1021/ol801332n

(Chemical Equation Presented) 2-, 3- and 4-Bromopyridine, along with other brominated electron-deficient arenes, undergo palladium-catalyzed coupling with ureas of structure RNMeCONHMe. Where R is a chiral, α-substituted benzyl group, treatment with LDA leads to a benzylic organolithium which undergoes rearrangement with stereospecific and regiospecific transfer of the pyridyl group, generating a quaternary stereogenic center with high enantioselectivity. Alcoholysis of the urea under neutral conditions reveals the pyridyl amine.

Full text of DOI:10.1021/ol801332n

ORGANIC
LETTERS
2008
Vol. 10, No. 16
3567-3570
r-Pyridylation of Chiral Amines via Urea
Coupling, Lithiation and Rearrangement
Jonathan Clayden* and Ulrich Hennecke
School of Chemistry, UniVesity of Manchester, Oxford Road,
Manchester M13 9PL, United Kingdom
clayden@man.ac.uk
Received June 12, 2008
ABSTRACT
2-, 3- and 4-Bromopyridine, along with other brominated electron-deficient arenes, undergo palladium-catalyzed coupling with ureas of structure
RNMeCONHMe. Where R is a chiral, r-substituted benzyl group, treatment with LDA leads to a benzylic organolithium which undergoes
rearrangement with stereospecific and regiospecific transfer of the pyridyl group, generating a quaternary stereogenic center with high
enantioselectivity. Alcoholysis of the urea under neutral conditions reveals the pyridyl amine.
Pyridines such as 1 bearing chiral substituents at various
positions of the ring form an important class of biologically
active compounds1 (including nicotine and its analogues1a)
and chiral ligands.2 Methods for the construction of a
stereogenic center adjacent to a pyridine ring3 typically
employ auxiliary (especially sulfinimine3b) controlled addi-
tion or cycloaddition to pyridyl aldehydes, ketones or
imines,3c asymmetric reduction of similar compounds,3d
asymmetric conjugate addition to electron-deficient pyridyl
alkenes,3e Pd-catalyzed coupling or protonation of a chiral
organometallic,3f or pyridine elaboration from a simple chiral
precursor.3g None of these methods is generally applicable
to the synthesis of pyridine-bearing quaternary centers.4
(3) (a) For reviews, see: Chelucci, G. Tetrahedron: Asymmetry 2005,
16, 2353. Ueinishi, J.; Aburatani, S. Yuki Gosei Kagaku Kyokaishi 2007,
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1996, 61, 2222. Kuduk, S. D.; DiPardo, R. M.; Chang, R. K.; Ng, C.; Bock,
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Kelly, P. M.; Pierres, C.; Savory, E. D.; Smith, A. D. J. Chem. Soc., Perkin
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Giacomelli, G. Synthesis 1992, 972. Cossu, S.; Conti, S.; Giacomelli, G.;
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Tetrahedron: Asymmetry 1994, 5, 1973.
(1) (a) Ullrich, T.; Krich, S.; Mereiter, K.; Anderson, D. J.; Meyer, M. D.;
Pyerin, M. J. Med. Chem. 2002, 45, 4047. (b) Lawson, E. C.; Hoekstra,
W. J.; Addo, M. F.; Andrade-Gordon, P.; Damiano, B. P.; Kauffman, J. A.;
Mitchell, J. A.; Maryanoff, B. E. Bioorg. Med. Chem. Lett. 2001, 11, 2619.
(c) Kawata, S.; Ashzawa, S.; Hirama, M. J. Am. Chem. Soc. 1997, 119,
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10.1021/ol801332n CCC: $40.75
Published on Web 07/22/2008
2008 American Chemical Society

Scheme 1
.
Chiral Amines by Rearrangement of
N-R-Methylbenzyl Ureas
Table 1. Coupling of Ureas with Aryl Bromidesd
In this paper, we now report a method which allows the
introduction of a pyridyl group to a preformed stereogenic
center and allows the formation of quaternary nitrogen-
carrying stereogenic centers. We envisaged making pyridyl
amines 1 by a modification of the urea rearrangement we
recently reported5 (Scheme 1) in which the aryl ring of urea
2undergoes stereospecific transfer from nitrogen to carbon
Scheme 2. Synthesis of Ureas by Palladium-Catalyzed Coupling
to yield 3. However, direct application of that method to
pyridine-containing compounds was prevented by the strongly
nucleophilic base needed to promote rearrangement and the
electrophilic conditions required for deprotection of the
product. Moreover, the synthesis of the starting pyridyl ureas
required an alternative approach because of the unreactivity
of appropriate pyridyl amines and/or unavailability of pyridyl
isocyanates. Our solutions to all three of these problems
permit for the first time the efficient enantioselective
synthesis of pyridines bearing an aminated quaternary
stereogenic center at the 2-, 3- or 4-position.
a 3 equiv aryl bromide used to ensure completion. b Hydrochloride salt
of 4-bromopyridine was used. c Microwave heating, 4 h at 140 °C.
d Conditions: urea (1 equiv), aryl bromide (1.5 equiv), NaOt-Bu (2 equiv),
Pd2(dba)3 (2.5 mol %) and xantphos (10 mol %) were heated in toluene at
110 °C for 14 h.
(4) For an isolated example, see: Shaw, A. W.; deSolms, S. J.
Tetrahedron Lett. 2001, 42, 7173.
(5) Clayden, J.; Dufour, J.; Grainger, D.; Helliwell, M. J. Am. Chem.
Soc. 2007, 129, 7488.
Bromopyridines are much more readily available than
pyridyl isocyanates, so we sought a new, coupling-based
route from these compounds to the urea starting materials.
Starting with the amines 4, treatment with triphosgene and
subsequently methylamine gave the urea 5 (Scheme 2). This
urea was coupled (Scheme 2) under the standard N-arylation
conditions reported for amides6 and simple unsubstituted
ureas7 (Pd2(dba)3, xantphos, toluene, NaOt-Bu) with a series
of bromopyridines, along with a further selection of electron-
deficient bromoarenes, to yield ureas 6 as detailed in Table 1.
The urea coupling was successful with all bromopyridines,
substituted bromopyridines, 3-bromoquinoline and 4-bro-
moisoquinoline, and could be extended to bromoarenes in
(6) Hartwig, J. F. Acc. Chem. Res. 1998, 31, 852.
(7) Sergeev, A. G.; Artamkina, G. A.; Beletskaya, I. Tetrahedron Lett.
2003, 44, 4719. Sergeev, A. G.; Artamkina, G. A.; Beletskaya, I. P. Russ.
J. Org. Chem. 2003, 39, 1741. For other urea arylations, see. Yin, J.;
Buchwald, S. L. Org. Lett. 2000, 2, 1101. Yin, J.; Buchwald, S. L. J. Am.
Chem. Soc. 2002, 124, 6043. Huang, X.; Anderson, K. W.; Zim, D.; Jiang,
L.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 6653.
Nandakumar, M. V. Tetrahedron Lett. 2004, 45, 1989. Popkin, M. E.;
Bellingham, R. K.; Hayes, J. F. Synlett 2006, 2716. Enguehard-Gueiffier,
C.; Therry, I.; Gueiffier, A.; Buchwald, S. L. Tetrahedron 2006, 62, 6042.
Hosseinzadeh, R.; Sarrafi, Y.; Mohadjerani, M.; Mohammadpourmir, F.
Tetrahedron Lett. 2008, 49, 840. Lee, C.-C.; Wang, P.-S.; Viswanath, M. B.;
Leung, M.-k. Synthesis 2008, 1359.
(8) For a related discussion, see: Shen, Q.; Hartwig, J. F. J. Am. Chem.
Soc. 2007, 129, 7734.
(9) Clayden, J.; Dufour, J. Tetrahedron Lett. 2006, 47, 6945.
3568
Org. Lett., Vol. 10, No. 16, 2008

general, but clearly performs best with more electron deficent
aryl bromide partners (see entries 10-12). 2- (Entries 1-4)
and 4- (entry 9) bromopyridines couple faster than 3-bro-
mopyridines (entries 5-7), which were used in excess to
ensure acceptable yields. Coupling is slow and low-yielding
with bromobenzene (entry 10), leading to incomplete reaction
even on microwave irradiation.8
Table 2. Ureas 7 and Aminopyridines 8 by Stereospecific
Rearrangement and Hydrolysis
The arylation shown in Scheme 1 involves nucleophilic
attack of an organolithium center on the N-aryl ring, and
given the electrophilicity of pyridines we hoped that a
corresponding rearrangement of N-benzyl-N′-pyridyl ureas
would be successful. However, under the conditions previ-
ously used for deprotonation (s-BuLi in THF), the products
isolated from the reaction of N-pyridyl-urea 6a contained
alkyl groups arising from nucleophilic attack on the pyridine
ring by the organolithium. Deprotonation of the urea by a
less nucleophilic base, LDA, was therefore attempted
(Scheme 3). The rearrangement now took place and yielded
Scheme 3. Rearrangement of an N-2-Pyridyl Urea
aProducts of nucleophilic attack on pyridyl ring observed by 1H NMR.
the urea 7a cleanly but with poor stereospecificity (er ) 60:
40), presumably because of extensive racemisation of the
intermediate benzyllithium10 before rearrangement. Adding
10% DMPU, which has been shown previously to accelerate
related rearrangements5 and cyclizations,11 to the THF
solvent increased both the rate and stereospecificity of
the pyridine transfer reaction, yielding the product 7a with
98:2 er.12
Using these conditions, the other pyridyl ureas 6a-e and
6i also underwent efficient rearrangement, yielding the
products 7 as shown in Table 2. When the starting materials
were enantiomerically pure, the rearrangement proceeded
with high stereospecificity, the product ureas 7 being obtained
in >96:4 er in every case where er was measurable. Previous
a Rearrangement conditions: LDA (2 equiv) in 10:1 THF/DMPU, -78
°C, 1-4 h. b Determined by HPLC on a chiral stationary phase. c Deprotection
conditions: 118 °C for 14 h in n-BuOH. d Determined after deprotection to
amine 8. e Estimated yield of impure material: oxidizes rapidly to 15 in
air.
related rearrangements of N-aryl ureas have proceeded with
retention of stereochemistry and we assume the same is the
case here. The rearrangement of quinoline substituted urea
6g (entry 7) showed minor side products but still gave 7g in
40% yield. The isoquinoline substituted urea 6h (entry 8)
failed to rearrange in good yield, but the only pyridyl urea
not to give the expected product was the 6-methoxy-
Scheme 4. “Deprotection” of the Product Ureas
(10) Clayden, J. Organolithiums: SelectiVity for Synthesis; Pergamon:
Oxford, 2002; pp 169-213.
(11) Clayden, J.; Knowles, F. E.; Menet, C. J. Synlett 2003, 1701.
Org. Lett., Vol. 10, No. 16, 2008
3569

tection was slow under these conditions, but replacing ethanol
by n-butanol, and heating to 118 °C overnight served to
accomplish the transformation cleanly and reliably (Scheme
4 and Table 2).
Scheme 5. Proposed Mechanism for the Rearrangement of 6a
The rearrangement presumably proceeds by the mechanism
shown in Scheme 5: deprotonation at the benzylic position9
generates an organolithium 10 which (given the er’s of the
products) is evidently configurationally stable on the time
scale of the reaction. Ipso attack of this organolithium center
on the pyridyl ring gives a dearomatised intermediate 11
which then collapses with regeneration of aromaticity to
provide lithiourea 12.
The lack of regioisomeric pyridine products shows that
even the 3-pyridyl substituents are attacked R to the urea
nitrogen, overriding the usual regiochemistry of nucleophilic
attack on a pyridine ring. However, when electron-density
is loaded onto the 3-position by incorporation of a 6-methoxy
substituent, an alternative pathway takes over. The product
of attempted rearrangement of 6f was identified as a
diastereoisomeric mixture of the unstable 3,4-dihydropyridine
9, which must arise by attack of organolithium 13 at the
4-position of the pyridine (Scheme 6). The dearomatized
product 14 now has no possibility to regain aromaticity by
elimination of the urea nitrogen: instead it remains in the
reaction mixture until trapped by protonation, and rearoma-
tises by oxidation in air to give 15.14 Treatment of 9 with
DDQ yields 15 in 24% yield from 6f.
substituted13 6f (entry 9) whose cyclization product 9 is
discussed below. Demonstrating that these new rearrange-
ment conditions are more generally applicable to other
functionalized ureas, starting materials 6k carrying an N-p-
cyanophenyl group also rearranged under these conditions,
although the p-nitrophenyl-substituted 6l failed to rearrange
cleanly.
Removal of the -CONHMe substituent carried by the urea
products of the rearrangement has been accomplished either
by reductive cleavage or, more generally, hydrolysis of the
ureas’ N-nitroso derivatives.5 However, the electrophilicity
of the pyridine ring and the nucleophilicity of its nitrogen
atom posed problems with these methods. We therefore
developed an alternative method for urea cleavage. We found
that simply heating the urea product 7a to reflux in neutral
ethanol over a period of several days led to clean elimination
of methyl isocyanate (which is presumably trapped by the
alcohol solvent) to return the secondary amine 8a. Depro-
In summary, a simple four-step sequence from 4 to 8
provides functionalized aminopyridines containing a fully
substituted quaternary stereogenic center adjacent to the
pyridine ring.
Acknowledgment. We are grateful to the Leverhulme
Trust for financial support and to the DAAD (Deutscher
Akademischer Austauschdienst) for a fellowship (to U.H.)
within the postdoctoral program.
Scheme 6. Cyclisation of 6fa
Supporting Information Available: Full experimental
details and characterization data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL801332N
(12) For the reasons put forward by Gawley (Gawley, R. E. J. Org.
Chem. 2006, 71, 2411), we prefer the term “enantiomeric ratio” to
“enantiomeric excess”.
(13) The difficulty of attacking an aromatic ring para to a methoxy group
with an organolithium is noted in ref 11.
(14) Clayden, J.; Hamilton, S. D.; Mohammed, R. T. Org. Lett. 2005,
7, 3673. Arnott, G.; Clayden, J.; Hamilton, S. D. Org. Lett. 2006, 8, 5325.
aAr ) p-ClC6H4-.
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