α-arylation of cyclic amines by aryl transfer in lithiated ureas

Article abstract of DOI:10.1055/s-0028-1087543

Treatment with base of N′-aryl urea derivatives of hetero-or carbocyclic amines with benzylic nitrogen atoms promotes rearrangement with transfer of the aryl ring from N to C, giving rise to α-arylated products. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1087543

LETTER
421
a-Arylation of Cyclic Amines by Aryl Transfer in Lithiated Ureas
a
-Arylation of Cy
e
clic
A
mine
n
s
aud Bach, Jonathan Clayden,* Ulrich Hennecke
School of Chemistry, University of Manchester, Oxford Rd., Manchester M13 9PL, UK
Fax +44(161)2754939; E-mail: clayden@man.ac.uk
Received 22 October 2008
heteroaryl ring from N to C leads to 4 by stereospecific
arylation of the intermediate lithiourea 3 (Scheme 1).3
The products may be converted to arylated amines 5 by
simply heating in ethanol or n-butanol.3b
Abstract: Treatment with base of N¢-aryl urea derivatives of het-
ero- or carbocyclic amines with benzylic nitrogen atoms promotes
rearrangement with transfer of the aryl ring from N to C, giving rise
to a-arylated products.
Key words: arylation, amines, heterocycles, lithiation, ureas
In this Letter, we report our studies on the application of
this arylation reaction to cyclic amines (both heterocyclic
and carbocyclic) and we outline the classes of cyclic
amine which may be arylated by this method.
Metallation of amide, carbamate, and amidine derivatives
of cyclic amines has provided a series of important meth-
ods for the synthesis of biologically active heterocyclic
compounds.1 Reactions of their organometallic deriva-
tives with electrophiles, or coupling reactions with halide
coupling partners, gives a range of valuable functionalised
amine derivatives.2
Pyrrolidine undergoes enantioselective deprotonation by
sec-BuLi in the presence of (–)-sparteine when its nitro-
gen atom is protected as an O-tert-butyl carbamate.4 Ureas
are also known to promote lithiation a to nitrogen,5 and
we made a small group 7a–e of urea derivatives of pyrro-
lidine 6a and 2-phenylpyrrolidine 6b6 either by addition to
the available isocyanates or by formation of the N¢-methyl
urea 8 and palladium-catalysed coupling3b with electron-
deficient pyridyl bromides (Scheme 2).
We recently reported that urea derivatives 2 of amines 1
may be lithiated a to nitrogen, and that if the urea is N¢-
aryl or N¢-heteroaryl substituted, migration of the aryl or
urea
O
O
Li
s-BuLi or LDA
formation
Ar2
Ar2
MeHN
Ar1
N
N
Ar1
N
N
Ar1
THF or Et2O
–78 °C
Me
Me
Me
Me
1
2
3
Ar2
MeHN
O
Ar2
1. DMPU or 20 °C
2. MeOH
n-BuOH, Δ
Ar1
MeHN
N
Ar1
Me
4
5
stereospecific
aryl migration
Scheme 1 Stereospecific arylation of acyclic ureas
R
1. ArNCO, CH2Cl2
2. NaH, MeI
N
Me
N
O
R
N
H
Ar
6a (R = H)
6b (R = Ph)
7a (R = H; Ar = Ph) 85%
1. Cl3COCO2CCl3
Et3N
2. MeNH2
7b (R = H; Ar = 4-MeOC6H4) 88%
7c (R = Ph; Ar = 4-MeOC6H4) 85%
ArBr,
XantPhos
7d (R = Ph; Ar = 2-pyridyl) 90%
7e (R = Ph; Ar = 3-pyridyl) 96%
R
Pd2(dba)3,
NaOt-Bu
toluene
N
MeHN
O
8 (R = Ph) 78%
Scheme 2 Synthesis of N¢-aryl urea derivatives of pyrrolidine
SYNLETT 2009, No. 3, pp 0421–0424
x
x.
x
x.
2
0
0
9
Advanced online publication: 21.01.2009
DOI: 10.1055/s-0028-1087543; Art ID: D36908ST
© Georg Thieme Verlag Stuttgart · New York

422
R. Bach et al.
LETTER
OMe
N
Me
LDA
N
O
N
THF, DMPU
–78 °C, 5 h
Me
N
O
H
7c
9c 89%
OMe
N
N
Me
N
1. Δ, n-BuOH
LDA
O
THF, DMPU
–78 °C, 5 h
2. HCHO
NaBH3CN
MeOH
N
N
N
N
Me
Me
N
O
H
7d
10 62%
9d 70%
Scheme 3 Arylation of the pyrrolidine ring by rearrangement
Under standard lithiation conditions [either s-BuLi or
LDA in Et2O or THF, and in the presence or absence of ei-
ther DMPU7 or (–)-sparteine], 7a and 7b failed to lithiate
a to nitrogen.8 However, when treated with LDA in THF–
DMPU (10:1) both 7c and 7d underwent clean aryl trans-
fer from N to C to yield, on workup, the quaternary arylat-
ed pyrrolidines9 9c and 9d in excellent yield (Scheme 3).
Pyrrolidine 9d was crystalline and Figure 1 shows its X-
ray crystal structure.10 It has an alkaloid-like structure and
it was efficiently deprotected by heating in n-butanol and
methylated under reductive amination conditions to give
10, an arylated regioisomer of nicotine (Scheme 3).11 Un-
fortunately, the 3-pyridyl isomer 7e failed to rearrange.12
Figure 1 X-ray crystal structure of 9d10
Building on the observation that successful lithiation and
rearrangement occurred at a site that was both adjacent to
nitrogen in a ring and also benzylic, urea derivatives 12,
14, and 15 were prepared from the isoindoline 11 and tetra-
hydroisoquinoline 13 (Scheme 4). Compound 15 was
formed from 14 by lithiation and methylation in THF in
the absence of DMPU at low temperature. These condi-
tions avoid rearrangement, and in general the presence or
absence of DMPU allows control over whether such an
organolithium rearranges or may be quenched by an elec-
trophile.
Tetrahydroisoquinoline 14 was lithiated with s-BuLi, and
under the standard conditions (lithiation in THF–DMPU)
underwent rearrangement to 16 in only 37% yield. How-
Me
N
NH
NH
N
O
12 91%
1. PhNCO
CH2Cl2
2. NaH, MeI
11
O
O
1. s-BuLi, THF
–78 °C, 15 min
2. MeI
N
N
N
N
Me
Me
15
14 96%
13
s-BuLi, THF
–78 to 20 °C
s-BuLi, THF, DMPU
O
O
N
NH
Me
N
NH
Me
17 66%
16 78%
Scheme 4 Rearrangement of tetrahydroisoquinolines
Synlett 2009, No. 3, 421–424 © Thieme Stuttgart · New York

LETTER
a-Arylation of Cyclic Amines
423
O
Me
NH2
s-BuLi, THF,
N
1. ArNCO, CH2Cl2
2. NaH, MeI
DMPU (19b–d)
N
R
Me
or LDA, THF,
DMPU (19a,e)
n
n
18a (n = 2)
19a (n = 2; R = H) 79%
18b (n = 1)
19b (n = 1; R = H) 96%
19c (n = 1; R = 2,3-benzo) 62%
19d (n = 1; R = 2,6-dimethyl) 96%
19e (n = 1; R = 4-Cl) 96%
NHMe
Me
MeHN
O
N
n-BuOH, Δ
n-BuOH, Δ
R
21a 71%
n
20a (n = 2; R = H) 81%
20b (n = 1; R = H) 66%
20c (n = 1; R = 2,3-benzo) 70%
20d (n = 1; R = 2,6-dimethyl) 78%
20e (n = 1; R = 4-Cl) 55%
Cl
MeHN
21e 61%
Scheme 5 Arylation of aminoindane and aminotetralin
ever, in this case the yield was improved greatly to 78% if arylated at the benzylic position. After deprotection of the
lithiation was carried out in the absence of DMPU and re- products, the reaction provides amines bearing fully sub-
arrangement was promoted by warming to room tempera- stituted, doubly benzylic substituents. This rearrange-
ture. Nonetheless methylated tetrahydroisoquinoline 15 ment, unlike those of acyclic N-a-methylbenzylureas,3 is
gave 17 cleanly when DMPU was employed as a cosol- not stereospecific, and current work is aimed at introduc-
vent. Isoindoline 12 failed to rearrange under the usual ing enantioselectivity, as well as widening the scope of the
conditions: colour changes suggested that lithiation is fol- rearrangement to other compound classes.
lowed by rapid decomposition of the a-lithio intermedi-
ate.
N,N¢-Dimethyl-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-N¢-phenyl-
urea (19a)
1,2,3,4-Tetrahydronaphthalen-1-ylamine (18a; 0.43 mL, 3.0 mmol)
was dissolved in CH2Cl2 (10 mL), and phenylisocyanate (0.32 mL,
3.0 mmol) was added. The mixture was stirred at r.t. for 14 h. The
solvent was removed under reduced pressure, and the residue was
dissolved in THF (10 mL). Sodium hydride (60% in mineral oil, 360
Finally, a group of carbocyclic compounds was made with
the nitrogen in an exocylic benzylic position. Aminotetra-
lin 18a and aminoindane 18b were converted to the ureas
19a–e by the standard methods shown in Scheme 5. All
five ureas rearranged successfully on treatment with ei-
ther s-BuLi or LDA in a THF–DMPU mixture, to yield
the arylated products 20a–e in good to excellent yield. mg, 9.0 mmol) was added, and the suspension was stirred for 30 min
at r.t. Then MeI (0.65 mL, 10.5 mmol) was added, and the suspen-
sion was stirred for 14 h at r.t. Ammonium chloride solution was
Deprotection of the ureas 20a and 20e was achieved by
warming to 118 °C in n-butanol for 48 hours. 1-Methyl-
added, the mixture was extracted twice with EtOAc, the organic
amino-1-phenyltetralin (21a) and 1-methylamino-1-(4-
phases were combined, washed with brine, dried over MgSO4, and
chlorophenyl)indane (21e) were formed in good yield,
completing an overall three-step a-arylation (and N-methy-
lation) of the starting amines 18.
the solvent was removed under reduced pressure. The crude product
was purified by flash chromatography (SiO2; PE–EtOAc, 2:1) to
give the title compound (700 mg, 2.4 mmol, 79%) as a colourless
oil.
Rearrangements of related acyclic ureas give rise to enan-
tiomerically enriched products because the aryl transfer is
stereospecific and retentive.3 However, in no case could
we observe stereospecific rearrangement starting with a
cyclic amine: rearrangements carried out with enantio-
merically enriched 7c, 7d, or 19e6,13 all yielded racemic
product. It is notable that the rearrangements of these ureas
are slower than those in the acyclic series, probably due to
the more constrained bicyclic transition state for aryl
transfer. Presumably rearrangement competes poorly
against racemisation of the organolithium intermediate
(even though cyclic organolithiums themselves racemise
more slowly than acyclic ones).1
Rf = 0.86 (PE–EtOAc, 1:1). IR (CHCl3): nmax = 1644 (C=O) cm–1.
1H NMR (400 MHz, CDCl3): d = 7.39–7.33 (m, 2 H), 7.20–7.03 (m,
7 H), 5.45 (dd, 1 H, J = 10.6, 5.4 Hz), 3.28 (s, 3 H), 2.74–2.68 (m,
2 H), 2.24 (s, 3 H), 1.96–1.85 (m, 2 H), 1.78–1.53 (m, 2 H). 13C
NMR (125 MHz, CDCl3): d = 162.9, 147.1, 138.4, 136.0, 129.4,
129.0, 127.2, 126.5, 126.0, 124.7, 124.5, 56.0, 40.3, 31.8, 29.5,
26.9, 22.0. MS (ES+): m/z = 317 [M + Na+], 295 [MH+]. HRMS
(ES+): m/z calcd for C19H23N2O [MH+]: 295.1805; found: 295.1796.
N,N¢-Dimethyl-N-(1-phenyl-2,3,4-trihydronaphthalen-1-yl)-
urea (20a)
Urea 19a (110 mg, 0.37 mmol) was dissolved in THF (8 mL) and
DMPU (0.8 mL). The solution was cooled to –78 °C, and LDA
(freshly prepared 1 M solution in THF–hexanes, 0.75 mL, 0.75
mmol) was added dropwise. The resulting orange solution was
stirred at –78 °C for 5 h. Methanol (0.5 mL) was added, and the re-
action was poured into NH4Cl solution. The mixture was extracted
In summary, heterocyclic and carbocyclic amines con-
taining a benzylic nitrogen within or a to a ring may be
Synlett 2009, No. 3, 421–424 © Thieme Stuttgart · New York

424
R. Bach et al.
LETTER
Soc. 1994, 116, 405. (e) Anderson, D. R.; Faibish, N. C.;
Beak, P. J. Am. Chem. Soc. 1999, 121, 7553. (f) Meigh,
J.-P.; Álvarez, M.; Joule, J. A. J. Chem. Soc., Perkin Trans.
1 2001, 2012. (g) Llopart, C. C.; Ferrer, C.; Joule, J. A. Can.
J. Chem. 2004, 82, 1649.
twice with EtOAc, the organic phases were combined, washed with
brine, dried over MgSO4, and the solvent was removed under re-
duced pressure. The crude product was purified by flash chromatog-
raphy (SiO2; PE–EtOAc, 1:1) to give the title compound (89 mg,
0.30 mmol, 81%) as a colourless oil.
(6) 2-Phenylpyrrolidine was made in enantiomerically enriched
form (er = 92:8 by GC) by the method of: Verdaguer, X.;
Lange, U.; Reding, M. T.; Buchwald, S. L. J. Am. Chem.
Soc. 1996, 118, 6784.
(7) DMPU promotes reactions involving dearomatising addition
of organolithiums to aromatic rings. See: (a) Clayden, J.;
Knowles, F. E.; Menet, C. J. Synlett 2003, 1701.
Rf = 0.70 (EtOAc). IR (CHCl3): nmax = 3353 (NH), 1636 (C=O),
1522 cm–1. 1H NMR (400 MHz, DMSO-d6): d = 7.31–7.25 (m, 2 H),
7.21–7.12 (m, 3 H), 7.10–7.06 (m, 2 H), 7.04–6.98 (m, 1 H), 6.67
(d, 1 H, J = 7.8 Hz), 6.18 (br q, 1 H, J = 4.4 Hz), 3.31–3.22 (m, 1
H), 2.84–2.77 (m, 2 H), 2.56 (s, 3 H), 2.52 (d, 3 H, J = 4.4 Hz),
2.19–2.11 (m, 1 H), 1.77–1.66 (m, 1 H), 1.63–1.52 (m, 1 H). 13C
NMR (100 MHz, DMSO-d6): d = 158.7, 146.3, 141.6, 137.3, 129.0,
128.8, 127.6, 127.1, 126.8, 125.9, 125.1, 66.8, 35.8, 35.6, 28.0,
27.1, 18.1. MS (ES+): m/z = 317 [M + Na+], 295 [MH+], 207, 177.
HRMS (ES+): m/z calcd for C19H23N2O [MH+]: 295.1805; found:
295.1804.
(b) Clayden, J.; Parris, S.; Cabedo, N.; Payne, A. H. Angew.
Chem. Int. Ed. 2008, 47, 5060.
(8) Alongside remaining starting material, byproducts from this
reaction included those arising from ortholithiation of the
aryl ring followed by anionic ortho-Fries rearrangement (see
Sibi, M. P.; Snieckus, V. J. Org. Chem. 1983, 48, 1935).
Quenching the reaction mixture with TMSCl yielded no
products of silylation a to nitrogen.
(9) For recent synthesis of pyrrolidines containing quaternary
centres, see: (a) Calaza, M. I.; Cativiela, C. Eur. J. Org.
Chem. 2008, 3427. (b) Makosza, M.; Sulikowski, D.;
Maltsev, O. Synlett 2008, 1711.
(1-Phenyl-2,3,4-trihydronaphthalen-1-yl)methylamine (21a)
Urea 20a (42 mg, 0.14 mmol) was dissolved in n-BuOH and heated
under reflux (118 °C) for 2 d. The solvent was removed, and the
crude product was purified by flash chromatography (SiO2; PE–
EtOAc, 2:1) to give the title compound (24 mg, 0.10 mmol, 71%) as
a colourless oil.
Rf = 0.26 (PE–EtOAc, 1:1). IR (CHCl3): nmax = 3338 (w, NH), 2937,
756, 702 cm–1. 1H NMR (400 MHz, CDCl3): d = 7.27–7.12 (m, 8 H),
7.05–7.01 (m, 1 H), 2.87–2.81 (m, 2 H), 2.28–2.21 (m, 1 H), 2.27
(s, 3 H), 2.02–1.94 (m, 1 H), 1.87 (br s, 1 H), 1.85–1.75 (m, 1 H),
1.70–1.58 (m, 1 H). 13C NMR (100 MHz, CDCl3): d = 149.5, 139.9,
139.0, 129.0, 128.7, 127.7, 127.7, 126.4, 126.3, 125.6, 63.0, 36.0,
30.0, 29.9, 19.5. MS (ES+): m/z = 238 [MH+], 227, 207. HRMS
(ES+): m/z calcd for C17H20N [MH+]: 238.1590; found: 238.1595.
(10) The X-ray crystallographic data for 9d has been deposited
with the Cambridge Crystallographic Database, deposition
number 706267.
(11) For a review of the chemistry of nicotine analogues, see:
(a) Wagner, F.; Comins, D. L. Tetrahedron 2007, 63, 8065.
Conformationally constrained analogues of nicotine are of
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Horenstein, N. A.; Dwoskin, L. P.; Crooks, P. A. Bioorg.
Med. Chem. Lett. 2005, 15, 3874. (c) Luo, S.; Fang, F.;
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S.; Binder, D.; Mereiter, K.; Anderson, D. J.; Meyer, M. D.;
Pyerin, M. J. Med. Chem. 2002, 45, 4047. (j) Xu, R.;
Dwoskin, L. P.; Grinevich, V.; Sumithran, S. P.; Crooks,
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D.; Pyerin, M. Tetrahedron Lett. 2002, 43, 177. (l) Ferretti,
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Acknowledgment
We are grateful to the Deutscher Akademischer Austauschdienst for
a postdoctoral fellowship (to UH), and to the Leverhulme Trust and
the Erasmus programme of the EU for support. We acknowledge
the contribution of Dr. Damian Grainger for the synthesis and rear-
rangement of 15.
References and Notes
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(12) In THF, decomposition products suggest that lithiation is
followed by intra- and/or intermolecular addition to the 2- or
4-position of the pyridyl ring, rather than the 3-position.
(13) Compound 19e was made by standard methods from
commercially available material.
(5) (a) Clayden, J.; Dufour, J. Tetrahedron Lett. 2006, 47, 6945.
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