Asymmetric synthesis of 2-arylpyrrolidines by cationic cyclization

Article abstract of DOI:10.1055/s-0032-1317114

Homoallylic amines were prepared by asymmetric deprotonation of benzylamines using n-BuLi and (-)-sparteine to give chiral organolithiums to which were added prenyl bromide. Removal of the Boc protecting group gave anilines that were found to undergo Br?n

Full text of DOI:10.1055/s-0032-1317114

LETTER
▌2405
lAettserymmetric Synthesis of 2-Arylpyrrolidines by Cationic Cyclization
Pyrrolidines by Cationic Cyclization
Iain Coldham,*a Steven P. Robinson,a Carl A. Baxterb
a
Department of Chemistry, University of Sheffield, Brook Hill, Sheffield S3 7HF, UK
Fax +44(114)2229346; E-mail: i.coldham@sheffield.ac.uk
b
Global Process Chemistry, Merck Sharp and Dohme Research Laboratories, Hertford Road, Hoddesdon EN11 9BU, UK
Received: 28.06.2012; Accepted after revision: 24.07.2012
Beak and co-workers from the benzylamine 3a, although
it was converted directly into a carboxylic acid (using
O3/CrO3).6 Asymmetric deprotonation of the benzylamine
3a occurs in the presence of n-BuLi and (–)-sparteine, and
Abstract: Homoallylic amines were prepared by asymmetric de-
protonation of benzylamines using n-BuLi and (–)-sparteine to give
chiral organolithiums to which were added prenyl bromide. Remov-
al of the Boc protecting group gave anilines that were found to un-
dergo Brønsted acid catalyzed or iodine-mediated cyclization to the resulting organolithium species can be reacted with
give aryl-substituted pyrrolidine heterocyclic products with high
enantioselectivity.
prenyl bromide to give the product 4a. Isolation of com-
pound 4a and analysis by chiral stationary phase HPLC
Key words: amines, carbocation, cyclization, enantioselectivity,
heterocycles
showed that the reaction occurred enantioselectively as
expected [enantiomeric ratio (er) = 94:6].
Table 1 Asymmetric Deprotonation and Addition of Prenyl Bro-
mide
Recently, we reported that deprotection of the tert-
butoxycarbonyl (Boc) group from compound 1 by heating
with trifluoroacetic acid (TFA) in CH2Cl2 resulted in cy-
clization to give the product 2 (Scheme 1).1 The mecha-
nism is presumed to involve initial Boc removal then
protonation of the alkene and cyclization of the aniline
onto the intermediate carbocation. Normally, cationic cy-
clizations of alkylamines are inefficient due to the prefer-
ential protonation of the amine nitrogen atom. However,
there are examples of acid-mediated cyclizations of, in
particular, sulfonamides.2,3 After discovering the synthe-
sis of the product 2, we were interested to explore some of
the scope of the cyclization of anilines.4 Conjugation of
the nitrogen atom lone pair with the aromatic ring reduces
the propensity for protonation of the nitrogen atom and
could allow related cationic cyclizations to give other cy-
clic amine products.
Boc
Ar
N
n-BuLi, PhMe
(–)-sparteine
Boc
Ar
N
Br
OMe
OMe
Entry Starting
material
Ar
Product Yield er
(%)
1
2
3
4
5
3a
3b
3c
3d
3e
Ph
4a
4b
4c
4d
4e
80
65
54
34
64
94:6
91:9
91:9
98:2
94:6
4-MeC6H4
4-FC6H4
3,5-(F3C)2C6H3
4-MeOC6H4
TFA
N
N
Boc
CH2Cl2
heat, 1 h
In a similar way, the compounds 4b–e were prepared by
asymmetric deprotonation of 3b–e and addition of prenyl
bromide (Table 1). These included the p-methyl deriva-
tive 4b, two fluorinated derivatives 4c and 4d, and the p-
methoxy derivative 4e. The starting materials 3 were pre-
pared from N-Boc-p-methoxyaniline, sodium hydride,
and ArCH2Br.6
2
1
91%
Scheme 1 Cyclization of an indoline1
We chose initially to explore the acid-mediated Boc de-
protection and cyclization of compound 4a. This would
result in a novel synthesis of 1,2-diarylpyrrolidines. Aryl-
substituted pyrrolidines are present in natural products
(such as nicotine), potential pharmaceuticals (such as
ABT-418, RP-66803 and SIB-1508Y), and as chiral aux-
iliaries or catalysts.5 Compound 4a has been prepared by
Several acidic conditions were tested for the Boc deprot-
ection and cationic cyclization of these compounds. The
use of triflic acid (in CH2Cl2) or neat TFA resulted in de-
composition. However, by heating (under reflux) the car-
bamate 4a with a solution of TFA in CH2Cl2 (0.1 M,
16 h), a mixture of the pyrrolidine 5a and the secondary
amine 6a was formed in high overall yield (Scheme 2).
The ratio of the two products could be changed to favor
the pyrrolidine 5a by increasing the concentration of TFA
in CH2Cl2 to 1.0 M. After heating for 16 h under these
SYNLETT 2012, 23, 2405–2407
Advanced online publication: 24.08.2012
DOI: 10.1055/s-0032-1317114; Art ID: ST-2012-D0552-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

2406
I. Coldham et al.
LETTER
conditions the pyrrolidine 5a was isolated in 69% yield. compound 4e with MsOH did not give the same type of
Alternatively, by heating with methanesulfonic acid product but resulted in the formation of the diene 8, pre-
(MsOH) in THF (0.2 M, 1 h), only the amine 6a was iso- sumably by an E1-type mechanism due to the enhanced
lated. The er of the product 5a was determined by chiral stabilization of the carbocation by the methoxy group.
stationary phase HPLC (er = 94:6).
Treatment of the amines 6b–d with iodine gave the de-
Heating the amine 6a with TFA (1.0 M) in CH2Cl2 gave sired pyrrolidine products 7b–d (Scheme 4). In each case
the expected pyrrolidine product 5a (56% yield, er = a single diastereoisomer was formed, as shown by NMR
94:6). Hence the transformation of the carbamate 4a to the spectroscopy. The relative stereochemistry was deter-
1
pyrrolidine 5a proceeds through initial loss of the Boc mined using compound 7d by H NOESY experiments
group to give the amine 6a followed by acid-mediated cy- (3% enhancement of CHI on irradiating CHAr and vice
clization. These steps do not result in any loss of enantio- versa). No loss of enantioselectivity was assumed, due to
purity.
the high enantiomeric ratio of the analogues 6a and 7a.
I
H+
MsOH
I2
Ph
N
Ar
NH
Ph
NH
Ar
+
N
4a
4a–d
THF
MeCN
heat, 1 h
r.t., 24 h
OMe
OMe
OMe
OMe
Ar
4-MeC6H4
4-FC6H4
3,5-(CF3)2C6H3
91% 6b
95% 6c
97%* 6d
40% 7b
68% 7c
66% 7d
5a
6a
0.1 M TFA
CH2Cl2
38%
69%
0%
57%
1.0 M TFA
CH2Cl2
4%
MeO
0.2 M MsOH
THF
93%
8 (formed from 4e)
*using TFA
Scheme 2 Acid-catalyzed cyclization of substrate 4a
Scheme 4 Formation and cyclization of anilines 6b–d
As an alternative to the acid-mediated deprotection–cycli-
zation, we treated the amine 6a with iodine (Scheme 3).7
This gave the desired pyrrolidine product 7a as a single dia-
stereoisomer. The relative stereochemistry was assigned
by analogy, as described below. Hydrogenolysis of the
product 7a using a palladium catalyst gave the pyrrolidine
5a (er = 94:6). Hence, the iodine-mediated cyclization
proceeds without racemization.
Asymmetric deprotonation of the benzylamine 3a and ad-
dition of 3-methylcrotonaldehyde gave the product 9 as a
mixture of diastereoisomers (dr = 1:1) in low yield
(Scheme 5).8 Subsequent treatment with TFA gave the di-
hydropyrrole 10. The enantiomeric ratio of this product
was determined by chiral stationary phase HPLC (er =
95:5). Hence, in one pot the Boc and hydroxy groups are
removed to give an intermediate allyl cation that under-
goes cyclization without racemization.
I
In all the above cases we assume that the absolute config-
uration of the products is as shown, based on results by
Beak and co-workers, who showed that the intermediate
chiral organolithium undergoes stereoselective substitu-
tion with inversion of configuration.6
H2
I2
Ph
N
6a
5a
MeCN
r.t., 24 h
79%
Pd/C
THF, Et3N
60%
OMe
7a
HO
n-BuLi, PhMe
(–)-sparteine
TFA
Scheme 3 Cyclization of aniline 6a with iodine
Boc
3a
Ph
Ph
N
N
CH2Cl2
OHC
30%
heat, 16 h
We were disappointed to find that acid-catalyzed Boc-
deprotection of substituted derivatives 4b–e using TFA
was unsatisfactory, leading to decomposition or the isola-
tion of the amines 6 in variable yields. However, using
MsOH led to high yields of the amines 6b,c (6d was
formed in high yield using TFA) (Scheme 4). Treating
56%
OMe
OMe
9
10 er = 95:5
Scheme 5 Formation and cyclization of carbamate 9
Synlett 2012, 23, 2405–2407
© Georg Thieme Verlag Stuttgart · New York

LETTER
Pyrrolidines by Cationic Cyclization
2407
1705. (c) Faibish, N. C.; Park, Y. S.; Lee, S.; Beak, P.
J. Am. Chem. Soc. 1997, 119, 11561.
Finally, we have found that the p-methoxyphenyl group
can be removed in high yield from the product 5a using
ceric ammonium nitrate (CAN, Scheme 6). The specific
rotation of the product 11 {[α]D –10 (c 1.0, CHCl3)}
showed that racemization had not occurred, although the
enantiomeric ratio was not determined.
(7) For iodine-mediated cyclizations of sulfonamides, see:
(a) Amjad, M.; Knight, D. W. Tetrahedron Lett. 2006, 47,
2825. (b) Davis, F. A.; Song, M.; Augustine, A. J. Org.
Chem. 2006, 71, 2779.
(8) For a preference for conjugate addition of this
organolithium·(–)-sparteine complex with an enone, see:
Park, Y. S.; Weisenburger, G. A.; Beak, P. J. Am. Chem. Soc.
1997, 119, 10537.
(9) Procedure for the Acid-Mediated Cyclization
TFA (0.4 mL, 5.2 mmol) was added to the carbamate 4a
(200 mg, 0.52 mmol) in CH2Cl2 (0.5 mL), and the mixture
was heated under reflux. After 16 h, the mixture was cooled
to r.t., and H2O (5 mL) was added. The aqueous layer was
extracted with CH2Cl2 (3 × 10 mL). The organic layers were
combined, dried (MgSO4), and evaporated. Purification by
column chromatography on silica, eluting with PE–EtOAc
20
In summary, we have shown that chiral, highly enantio-
merically enriched 2-arylpyrrolidines can be prepared by
simple asymmetric deprotonation–electrophilic quench
followed by cationic cyclization, either with a Brønsted
acid or with iodine.9,10
CAN
Ph
N
Ph
N
H
MeCN, H2O
r.t., 24 h
20
(9:1), gave the pyrrolidine 5a (102 mg, 69%) as an oil; [α]D
+16.3 (c 6.5, CHCl3). IR: νmax = 2975, 2930, 1690, 1510 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.38–7.23 (5 H, m, Ph),
6.80–6.59 (4 H, m, Ar), 4.26 (1 H, t, J = 6.5 Hz, CH), 3.72
(3 H, s, CH3), 2.06–1.87 (2 H, m, CH2), 1.77–1.59 (2 H, m,
CH2), 1.52 (3 H, s, CH3), 1.51 (3 H, s, CH3). 13C NMR (100
MHz, CDCl3): δ = 156.0, 128.8, 127.7, 126.9, 115.8, 114.7,
113.9, 112.9, 88.6, 65.7, 55.6, 37.2 (2 × CH2), 25.5, 25.3.
HRMS (ES): m/z calcd for C19H24NO [MH+]: 282.1858;
found: 282.1854. Resolution between the enantiomers was
achieved using a Beckmann HPLC system fitted with a
Daicel Chiralcel OJ column (250 mm × 4.6 mm) as the
stationary phase with a mixture of hexane–i-PrOH (99:1 v/v)
as the mobile phase with a flow rate of 1 mL/min; ambient
temperature, detection by UV absorbance at λ = 254 nm.
Injection volume 25 μL of the sample prepared in a 2 g/L
solution of the eluent. Under these conditions the
90%
11
OMe
5a
Scheme 6 Removal of the PMP group from 5a
Acknowledgment
We would like to thank the EPSRC, the University of Sheffield, and
Merck Sharp & Dohme for funding.
References and Notes
(1) Leonori, D.; Coldham, I. Adv. Synth. Catal. 2009, 351, 2619.
(2) For a review of hydroaminations, see: Müller, T. E.;
Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada, M. Chem. Rev.
2008, 108, 3795.
(3) (a) Miura, K.; Hondo, T.; Nakagawa, T.; Takahashi, T.;
Hosomi, A. Org. Lett. 2000, 2, 385. (b) Schlummer, B.;
Hartwig, J. F. Org. Lett. 2002, 4, 1471. (c) Haskins, C. M.;
Knight, D. W. Chem. Commun. 2002, 2724. (d) Yin, Y.;
Zhao, G. Heterocycles 2006, 68, 23. (e) Baeza, A.; Nájera,
C. Synlett 2011, 631.
components were eluted at tR = 35.5 min (major) and tR =
48.5 min (minor), er 94:6.
(10) Procedure for the Iodine-Mediated Cyclization
Iodine (203 mg, 0.8 mmol) was added to the carbamate 6a
(75 mg, 0.26 mmol) in MeCN (0.9 mL) at r.t. After 24 h, sat.
aq Na2SO4 (5 mL) was added. After 30 min, the solvent was
evaporated, and Et2O (10 mL) was added. The organic layer
was washed with H2O (5 mL), dried (MgSO4), and
evaporated. Purification by column chromatography on
silica, eluting with PE–EtOAc (9:1), gave the pyrrolidine 7a
(86 mg, 79%) as an oil; [α]D20 +48.0 (c 1.0, CHCl3). IR:
νmax = 2970, 2920, 1605, 1505 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 7.29–7.24 (3 H, m, Ph), 6.92 (2 H, t, J = 8.5 Hz,
Ph), 6.84 (2 H, d, J = 9.0 Hz, Ar), 6.71 (2 H, d, J = 9.0 Hz,
Ar), 4.81 (1 H, dd, J = 9.5, 6.0 Hz, CH), 4.25 (1 H, dd, J =
12.0, 6.0 Hz, CH), 3.72 (3 H, s, CH3), 2.84 (1 H, dt, J = 12.0,
6.0 Hz, CH), 2.35 (1 H, td, J = 12.0, 9.5 Hz, CH), 1.70 (3 H,
s, CH3), 1.24 (3 H, s, CH3). 13C NMR (100 MHz, CDCl3):
δ = 138.6, 127.9, 122.3, 120.5, 118.3, 115.4, 115.1, 113.7,
64.2, 63.8, 55.3, 45.9, 36.0, 31.2, 24.5. HRMS (ES): m/z
calcd for C19H23INO [MH+]: 408.0819; found: 408.0817.
(4) (a) For photocyclization of anilines, see: Benali, O.;
Miranda, M. A.; Rormos, R.; Gil, S. J. Org. Chem. 2002, 67,
7915. (b) For acid-mediated cyclization of aminopyridines,
see: Métro, T.-X.; Fayet, C.; Arnaud, F.; Rameix, N.;
Fraisse, P.; Janody, S.; Sevrin, M.; George, P.; Vogel, R.
Synlett 2011, 684.
(5) Barker, G.; McGrath, J. L.; Klapars, A.; Stead, D.; Zhou, G.;
Campos, K. R.; O’Brien, P. J. Org. Chem. 2011, 76, 5936;
and references cited therein.
(6) (a) Park, Y. S.; Beak, P. J. Org. Chem. 1997, 62, 1574.
(b) Kim, B. J.; Park, Y. S.; Beak, P. J. Org. Chem. 1999, 64,
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2405–2407