Intramolecular carbolithiation reactions for the synthesis of 2,4-disubstituted tetrahydro-quinolines: Evaluation of TMEDA and (-)-sparteine as ligands in the stereoselectivity

Article abstract of DOI:10.1021/ol900066c

The preparation of 4-substituted 2-phenyltetrahydroquinolines from N-alkenylsubstituted 2-iodoanilines via intramolecular carbolithiation reactions has been investigated. The stereochemical outcome of the carbolithiation reactions depends on the nature of organolithium employed to perform the lithium-halogen exchange, the solvent, or the use of additives, for example, TMEDA or chiral bidentated ligands such as (-)-sparteine. Thus, the 2,4-disubstituted tetrahydroquinolines are obtained with moderate diastereoselectivities (up to 77:23) and with ee up to 94% when Weinreb amide derivatives are used (R) CONMe(OMe)).

Full text of DOI:10.1021/ol900066c

ORGANIC
LETTERS
2009
Vol. 11, No. 6
1237-1240
Intramolecular Carbolithiation Reactions
for the Synthesis of 2,4-Disubstituted
Tetrahydro-quinolines: Evaluation of
TMEDA and (-)-Sparteine as Ligands in
the Stereoselectivity†
Unai Mart´ınez-Est´ıbalez, Nuria Sotomayor, and Esther Lete*
Departamento de Qu´ımica Orga´nica II, Facultad de Ciencia y Tecnolog´ıa,
UniVersidad del Pa´ıs Vasco/Euskal Herriko Unibertsitatea, Apdo. 644. 48080 Bilbao,
Spain
esther.lete@ehu.es
Received January 13, 2009
ABSTRACT
The preparation of 4-substituted 2-phenyltetrahydroquinolines from N-alkenylsubstituted 2-iodoanilines via intramolecular carbolithiation reactions
has been investigated. The stereochemical outcome of the carbolithiation reactions depends on the nature of organolithium employed to
perform the lithium-halogen exchange, the solvent, or the use of additives, for example, TMEDA or chiral bidentated ligands such as (-)-
sparteine. Thus, the 2,4-disubstituted tetrahydroquinolines are obtained with moderate diastereoselectivities (up to 77:23) and with ee up to
94% when Weinreb amide derivatives are used (R ) CONMe(OMe)).
The intramolecular carbolithiation1 of alkenes and alkynes
has recently emerged as an interesting approach for the
synthesis of functionalized five-member carbocyclic and
heterocyclic systems. The attraction of this methodology lies
inthehighregio-andstereoslectectivitywhenacarbon-carbon
bond is formed and in the possibility of trapping the resulting
cyclized organolithium with various electrophiles to introduce
diverse functionality into the cyclized products. Although
many of these carbolithiations involve alkyl or alkenyllithi-
ums,2 there are also some examples of cycloisomerization
of alkenyl substituted aryllithiums generated by metal-halogen
exchange.3 Thus, an intramolecular carbolithiation reaction
of unsaturated aryllithiums is particularly well suited for the
(2) For some representative examples, see: (a) Chamberlin, A. R.; Bloom,
S. H.; Cervini, L. A.; Fotsch, C. H. J. Am. Chem. Soc. 1988, 110, 4788–
4796. (b) Funk, R. L.; Bolton, G. L.; Brummond, K. M.; Ellestad, K. E.;
Stallman, J. B. J. Am. Chem. Soc. 1993, 115, 7023–7024. (c) Bailey, W. F.;
Jiang, X.-L.; McLeod, C. E. J. Org. Chem. 1995, 60, 7791–7795. (d) Krief,
A.; Kenda, B.; Remacle, B. Tetrahedron 1996, 52, 7435–7463. (e) Coldham,
I.; Hufton, R; Price, K. N.; Rathmell, R. E.; Snowden, D. J.; Vennall, G. P.
Synthesis 2001, 1523–1531. (f) Deng, K.; Bensari, A.; Cohen, T. J. Am.
Chem. Soc. 2002, 124, 12106–12107. (g) Sanz, R.; Ignacio, J.; Rodr´ıguez,
M. A.; Fan˜an´as, F. J.; Barluenga, J. Chem.-Eur. J. 2007, 13, 4998–5008.
The procedure has also been extended to the corresponding alkyne
derivatives; see, for instance: (h) Wu, G.; Cederbaum, F. E.; Negishi, E.
Tetrahedron Lett. 1990, 31, 493–496.
† Dedicated to Prof. Josep Font on the occasion of his 70th birthday.
(1) For reviews, see: (a) Marek, I. J. Chem. Soc., Perkin 1 1999, 535–
544. (b) Mealy, M. J.; Bailey, W. F. J. Organomet. Chem. 2002, 646, 59–
67. (c) Clayden, J. Organolithiums: SelectiVity for Synthesis; Pergamon
Press: New York, 2002; pp 282-335. (d) Normant, J. F. Top. Organomet.
Chem. 2003, 287–310. (e) Fan˜ana´s, F. J.; Sanz, R. In The Chemistry of
Organolithium Compounds; Patai Series: The Chemistry of Functional
Groups, Vol. 2; Rappoport, Z., Marek, I., Eds.; Wiley: Chichester, 2006;
Chapter 4, pp 295-379.
10.1021/ol900066c CCC: $40.75
Published on Web 02/17/2009
2009 American Chemical Society

construction of five-membered rings through a 5-exo-trig
cyclization process, as it has been shown in the synthesis of
carbocyclic4 and heterocyclic compounds,5 even in a dia-
stereoselective6 or enantioselective fashion.7,8 However,
some limitations have precluded the general applicability of
this method. In fact, the above-cited examples consist of
intramolecular carbolithiations to five-membered rings and
it remains unclear whether cyclization to six-membered
cycles would provide the same degree of stereo- and
regiochemical efficiency. Only a few examples of 6-exo
cyclization process via intramolecular carbolithiations in-
volving alkyl or alkenyllithiums have been reported.9 Re-
garding aryllithiums, Pedrosa10 et al. have described the
synthesis of enantiopure 4-substituted tetrahydroisoquinolines
Via a diastereoselective 6-exo carbolithiation of unactivated
double bonds in chiral (-)-8-aminomenthol derived perhy-
dro-1,3-benzoxazines. Recently, we have also reported11 the
synthesis of the pyrrolo[1,2-b]isoquinoline system through
MesLi-mediated intramolecular carbolithiation reactions of
N-(o-iodobenzyl)pyrroles, though in our case the alkene is
required to be substituted with an electron withdrawing
group.
Scheme 1
.
Synthesis of N-Alkenyl Substituted o-Iodoanilines
2a,b and 3a,b
with different substitution patterns as internal electrophiles.
We have also examined the effect of bidentate ligands, such
as TMEDA and (-)-sparteine, in the stereoselectivity of these
carbolithiation reactions.
Therefore, in connection with our work12 on Parham-type
cyclizations,13 we decided to investigate the intramolecular
carbolithiation for the synthesis of 2,4-disubstituted tetrahy-
droquinolines. Herein we describe the cyclization of the
aryllithiums generated from N-alkenyl substituted o-iodoa-
nilines to the tetrahydroquinoline derivatives, using alkenes
To test the carbolithiation reactions, we first prepared the
N-alkenyl substituted o-iodoanilines 2 and 3 by standard
methodologies (Scheme 1). Condensation of o-iodoaniline
and benzaldehyde, followed by addition of allylmagnesium
chloride led to secondary amine 2a, which was alkylated
with LDA and MeI, thus affording amine 2b.14 Oxidative
cleavage of the alkene double bond with OsO4/NaIO4 led to
the corresponding aldehyde, whose in situ olefination was
was achieved via Wittig reaction with the corresponding
phosphorus ylides to afford N-alkenyl substituted o-iodoa-
nilines 3a,b15 in good overall yields (Scheme 1).
We first studied the carbolithiation reactions of o-iodoa-
niline 2a with t-BuLi (Table 1), starting under standard
conditions (2 equiv of RLi, THF, -78 °C). However,
although iodine-lithium occurred efficiently, since dehalo-
genated amine was always isolated (entries 1 and 2),
intramolecular carbolithiation did not take place. We next
tried the addition of a bidentate ligand as TMEDA, which
(3) (a) Wakefield, B. J. The Chemistry of Organolithium Compounds,
2nd ed.; Pergamon Pres: New York, 1990. (b) Rappoport, Z., Marek, I.,
Eds. The Chemistry of Organolithium Compounds; Patai Series: The
Chemistry of Functional Groups, Vol. 1; Rappoport, Z., Ed.; Wiley:
Chichester, 2004. (c) Gribble, G. W. In Science of Synthesis [Houben-Weyl
Methods of Molecular Trnasformations]; Majewski, M., Snieckus, V., Eds.;
Georg Thieme Verlag: Sttutgart; 2006; Vol. 8a, pp 357-426.
(4) (a) Ross, G. A.; Koppang, M. D.; Bartak, D. E.; Woolsey, N. F.
J. Am. Chem. Soc. 1985, 107, 6742–6743. (b) Harrowven, D. C. Tetrahedron
Lett. 1992, 33, 2879–2882. (c) Bailey, W. F.; Daskapan, T.; Rampalli, S.
J. Org. Chem. 2003, 68, 1334–1338.
(5) For some representative examples, see: Indoles: (a) Barluenga, J.;
Sanz, R.; Granados, A.; Fan˜ana´s, F. J. J. Am. Chem. Soc. 1998, 120, 4865–
4866. Indolines: (b) Bailey, W. F.; Jiang, X.-L. J. Org. Chem. 1996, 61,
2596–2597. (c) Zhang, D.; Liebskind, L. J. Org. Chem. 1996, 61, 2594–
2595. Azaindolines: (d) Bailey, W. F.; Salgaonkar, P. D.; Brubaker, J. D.;
Sharma, V. Org. Lett. 2008, 10, 1071–1074.
(6) (a) Bailey, W. F.; Mealy, M. J.; Wiberg, K. B. Org. Lett. 2002, 4,
791–794. (b) Fresigne´, C.; Girard, A.-L-; Durandetti, M.; Maddaluno, J.
Angew. Chem., Int. Ed. 2008, 41, 891–893. (c) Fresigne´, C.; Girard, A.-L.;
Durandetti, M.; Maddaluno, J. Chem.-Eur. J. 2008, 14, 5159–5167.
(7) (a) Comins, D. L.; Zhang, Y.-m. J. Am. Chem. Soc. 1996, 118,
12248–12249. (b) Nishiyama, H.; Sakata, N.; Sugimoto, H.; Motoyama,
(12) For representative examples of our synthetic work in this area, see:
(a) Ruiz, J.; Sotomayor, N.; Lete, E. Org. Lett. 2003, 5, 1115–1117. (b)
Osante, I.; Lete, E.; Sotomayor, N. Tetrahedron Lett. 2004, 45, 1253–1256.
(c) Gonza´lez-Temprano, I.; Osante, I.; Lete, E.; Sotomayor, N. J. Org. Chem.
2004, 69, 3875–3885. (d) Ruiz, J.; Ardeo, A.; Ignacio, R.; Sotomayor, N.;
Lete, E. Tetrahedron 2005, 61, 3311–3324. (e) Ruiz, J.; Sotomayor, N.;
Lete, E. Tetrahedron 2006, 62, 6182–6189. (f) Abdullah, M. N.; Arrasate,
S.; Lete, E.; Sotomayor, N. Tetrahedron 2007, 64, 1329–1332.
(13) For reviews, see: (a) Parham, W. E.; Bradsher, C. K. Acc. Chem.
Res. 1982, 15, 300–305. (b) Gray, M.; Tinkl, M.; Snieckus, V. In
ComprehensiVe Organometallic Chemistry II; Abel, E. W., Stone, F. G. A.,
Wilkinson, G., Eds.; Pergamon Press: Exeter, 1995; Vol. 11, pp 66-92.
(c) Ardeo, A.; Collado, M. I.; Osante, I.; Ruiz, J.; Sotomayor, N.; Lete, E.
In Targets in Heterocyclic Systems; Atanassi, O., Spinelli, D., Eds.; Italian
Society of Chemistry: Rome, 2001; Vol. 5, pp 393-418. (d) Sotomayor,
N.; Lete, E. Curr. Org. Chem. 2003, 7, 275–300. (e) Na´jera, C.; Sansano,
J. M.; Yus, M. Tetrahedron 2003, 59, 9255–9303. See also ref 1.
(14) All attempts to prepare 2b by quenching the addition reaction with
MeI failed.
Y.; Wakita, H.; Nagase, H. Synlett 1998, 930–932
.
(8) (a) Bailey, W. F.; Mealy, M. J. J. Am. Chem. Soc. 2000, 122, 6787–
6788. (b) Sanz, G.; Groth, U. M. J. Am. Chem. Soc. 2000, 122, 6789–
6790. (c) Barluenga, J.; Fan˜ana´s, F. J.; Sanz, R.; Marcos, C. Org. Lett.
2002, 4, 2225–2228. (d) Mealy, M. J.; Luderer, M. R.; Bailey, W. F.;
Sommer, M. B. J. Org. Chem. 2004, 69, 6042–6049. (e) Barluenga, J.;
Fan˜an´; as, F. J.; Sanz, R.; Marcos, C. Chem.-Eur. J. 2005, 11, 5397–
5407. (f) Groth, U.; Ko¨ttgen, P.; Langenbach, P.; Lindenmaier, A.; Schu¨tz,
T.; Wiegand, M. Synlett 2008, 1301–1304
.
(9) (a) Bailey, W. F.; Nurmi, T. T.; Patricia, J. J.; Wang, W. J. Am.
Chem. Soc. 1987, 109, 2442–2448. (b) Bailey, W. F.; Ovaska, T. V.
Tetrahedron Lett. 1990, 31, 627–630. (c) Coldham, I.; Vennall, G. P. Chem.
Commun. 2000, 1569–1570. (d) Ashweek, N. J.; Coldham, I.; Snowden,
D. J.; Vennall, G. P. Chem.-Eur. J. 2002, 8, 195–207.
(10) Pedrosa, R.; Andre´s, C.; Iglesias, J. M.; Pe´rez-Encabo, A. J. Am.
Chem. Soc. 2001, 123, 1817–1821.
(15) Attempts to introduce the electron withdrawing group directly on
2b by cross metatethesis with acryl amides in the presence of 1st and 2nd
generation Grubbs’ catalysts failed, leading only to dimeric product derived
from 2b. Besides, addition of functionalized allyl organomagnesium reagents
to imine 1 also faliled.
(11) Lage, S.; Villaluenga, I.; Sotomayor, N.; Lete, E. Synlett 2008,
3188–3192.
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Org. Lett., Vol. 11, No. 6, 2009

Table 1. Carbolithiation Reactions of o-Iodoaniline 2b
Table 2. Carbolithiation Reactions of o-Iodoanilines 3a,b
t-BuLi TMEDA
(equiv) (equiv)
temp (°C)
time
prod yield (%)
1
2
3
4
5
6
7
2.2a
2.2a
1.1b
2.2b
2.2b
1.1d
2.2d
-
-
1.1
2.2
2.2
1.1
2.2
-78
3 h
7 h
4a
4a
4ac
5a
4a
4ae
5a
80
65
60
60
95
20
80
additive
2.2 equiv
temp time yield
-78 to rt
-78 to 0
-78 to 0
-78
-78 to 45
-78 to 45
subs
RLi
(°C)
(min) (%) dr 6:7
40 min
40 min
30 min
45 min
45 min
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
3a
3a
3a
3a
3a
3a
3a
3a
3b
3b
3b
3b
3b
3b
3b
t-BuLi
t-BuLi
t-BuLi
t-BuLi
t-BuLi
n-BuLi
-
-78
-78
-78
-95
-105
-105
-105
-105
-105
-105
-105
-95
50
60
10
8
5
5
5
5
5
5
73
58:42
TMEDA
-
-
TMEDA
-
60a 55:45
74
81
55:45
56:44
64b 61:39
a Solvent THF. b Solvent: n-pentane/Et2O (9:1). c N-methylaniline
80
81
58:42
77:23
(<5%) was isolated. d Solvent: n-heptane/t-Bu2O (9:1). e N-methylaniline
(20%) was also isolated.
n-BuLi TMEDA
n-BuLi TMEDA
60c 71:29
t-BuLi
t-BuLi
t-BuLi
t-BuLi
t-BuLi
n-BuLi
-
66
-
-
-
-
29:71
TMEDA
TMEDA
TMEDA
TMEDA
-
has been shown to facilitate and accelerate the rate of
carbolithiation reactions.16 The use of equimolecular amounts
of t-BuLi/TMEDA in a less coordinating solvent system
(pentane/Et2O 9:1) also resulted in reductive dehalogenation
and deiodinated amine 4b was isolated (entry 3) when the
reaction was allowed to reach 0 °C. When 2 equiv of t-Buli
were employed under the same conditions, addition of t-Buli
to the unsubstituted alkene in 2b was competitive with
cyclization, isolating 5a (Table 1, entry 4). This side reaction
could be avoided quenching the reaction at -78 °C, though
4a was again the only reaction product (entry 5). It has been
shown that the rate of carbolithiation reactions can be
increased performing the reactions at higher temperatures,17
so the reaction mixtures were warmed to 45 °C, using
n-heptane/t-Bu2O (9:1) as solvent to avoid protonation of
the intermediate aryllithium (entries 6 and 7), but similar
results were obtained, isolating also decomposition products,
as N-methylaniline.
Therefore, we studied the carbolithiation reactions on 3a
(Table 1, entries 1-8). Thus, the introduction of an electron
withdrawing group on the alkene (R1 ) CONEt2) allowed
the cyclization, affording efficiently the corresponding tet-
rahydroquinolines 6a and 7a at -78 °C, although with almost
no diastereoselectivity (entry 1). The addition of TMEDA
did not improve the results (entry 2).18 Different reaction
conditions were tested to improve the yield and the stereo-
selectivity. In fact, the cyclization reaction was quite fast
and was completed just in 10 min, even in the absence of
TMEDA (entry 3). Lowering the temparature to -95 °C did
60
60
120
5
-45
-105
-105
68
40:60
n-BuLi TMEDA
a Solvent: Toluene. b Conversion: 93%. c Solvent: Et2O. d Conversion:
73%.
5
74d 59:41
not improve the selectivity (entry 4). The addition of
TMEDA allows the reaction to be carried out at -105 °C in
5 min with an improved diastereoselectivity in favor of the
cis product 6a (entry 5). However, the best results were
obtained using n-BuLi as metalating agent, yielding 6a with
a reasonable diastereoselectivity (77:23, entry 7). A change
in the solvent to Et2O resulted in lower yield and loss of
diastereoselectivity (entry 8).
When the amide 3b was used as substrate, the cyclization
took place efficiently at -105 °C, even in the absence of
TMEDA, although with opposite diastereoselectivity, obtain-
ing mainly the trans product 7b (entry 9). In the presence
of TMEDA, the reaction did not take place under various
conditions (entries 10-13). When n-BuLi was used an
increased formation of the cis product 6a was observed (entry
14), which was the major product in the presence of TMEDA
(entry 15), although with almost no diastereoselectivity.
We next studied the posibility of performing the carbo-
lithiation reactions in an enantioselective fashion in the
presence of a chiral bidentate ligand such as (-)-sparteine.19
(16) See, for instance refs 2c,g, 5b, and 9. See also: Coldham, I.;
Ferna´ndez, J C.; Price, K. N.; Snowden, D. J. J. Org. Chem. 2000, 65,
3788–3795.
(19) For reviews of the use of sparteine as chiral ligand, see: (a) Beak,
P.; Basu, A.; Gallagher, D. J.; Park, Y. S.; Thayumanavan, S. Acc. Chem.
Res. 1996, 29, 552–560. (b) Hoppe, D.; Hense, T. Angew. Chem., Int. Ed.
Engl. 1997, 36, 2283–2316. (c) Beak, P.; Anderson, D. R.; Curtis, M. D.;
Laumer, J. M.; Pippel, D. J.; Weisenburger, G. A. Acc. Chem. Res. 2000,
33, 715–727. (d) Hoppe, D.; Christoph, G. In The Chemistry of Organo-
lithiums Compunds; Rappoport, Z., Marek, I., Eds.; John Wiley and Sons:
New York, 2004; Chapter 17, p 1055.
(17) Bailey, W. F.; Daskapan, T.; Rampalli, S. J. Org. Chem. 2003, 68,
1334–1338.
(18) The addition of TMEDA has been reported to influence not only
the rate of the carbolithiation, but also the stereochemical outcome. See,
for instance: Bailey, W. F.; Jiang, X. Tetrahedron 2005, 61, 3183–3194.
Org. Lett., Vol. 11, No. 6, 2009
1239

Thus, 3a,b were added over a solution of the alkyllithium
(t-BuLi or n-BuLi) and (-)-sparteine, using toluene as
solvent to allow the coordination of the organolithium with
the amine. As can be seen in Table 3, the stereochemical
outcome was opposite to that observed with TMEDA,
affording the trans tetrahydroquinolines 7a,b as the major
diastereomer. A similar reversal of the stereochemical
outcome when (-)-sparteine is used instead of TMEDA has
been observed in alkylation reactions, 20 although the change
in the solvent from THF, that may bind to the lithium cation,
to toluene may also play a role.21 First, 3a was treated with
t-BuLi/(-)-sparteine under the same conditions used with
TMEDA (Table 3, entry 1), but the mixture of tetrahydro-
quinolines 7a and 6a was obtained with poor diastereose-
lectivity and each of the diastereomers with low enantiomeric
excess.22 Several attempts were made to improve both the
diastereo and the enantioselectivity, but the use of n-BuLi
at lower temperature, reduced reaction time, or inverse
addition conditions slightly improved the distereoselectivity,
but not significantly the ee (entries 2-5). However, we were
pleased to find that when the Weinreb amide 3b was used
as substrate, the cyclization proceeded with reasonable
diastereoselectivty (entry 6) and, when n-BuLi is used (entry
7), with excellent ee for each of the isolated diastereomers
(6, 92% ee and 7, 94% ee).23 Thus, this result indicates that
in the presence of (-)-sparteine, one of the enantiomers
would react more rapidly leading to the mayor stereoisomer.
In summary, it has been shown that the intramolecular
carbolithiation of o-iodoanilines affords 2-phenyltetrahyd-
roquinolines diastereoselectively. The use of TMEDA as
Table 3. Carbolithiation Reactions of o-Iodoanilines 3a,b in the
Presence of (-)-Sparteine
entry subs
RLi
conditionsa yield (%) dr 6/7 ee (%) 6/7
1
2
3
4
5
6
7
3a
3a
3a
3a
3a
3b
3b
t-BuLi
n-BuLi
n-BuLi
-78, 60
-95, 40
-95, 5
91
59
63
33
53
31
48
42:58
38:62
27:73
40:60
42:58
30:70
33:67
17/5
5/13
17/33
5/10
7/15
8/2
n-BuLib -95, 5
n-BuLib -95, 5
t-BuLi
n-BuLi
-95, 10
-95, 10
92/94
a Conditions: temperature (°C), time (min). b n-BuLi was added over
a solution of 3a,b and (-)-sparteine.
additive not only increases the rate of the cyclization but
also favors the formation of the cis adducts 6. Besides, the
use of (-)-sparteine allows the enantioselective synthesis of
tetrahydroquinolies. The use of the Weinreb amide derivative
3b and n-BuLi as base turned out to be crucial to obtain
tetrahydroquinolines 6 and 7 in high ee and dr.
Acknowledgment.FinancialsupportfromMEC(CTQ2006-
01903), Gobierno Vasco (GIC07/92-IT-227-07) and UPV/
EHU is gratefully acknowledged.
(20) Arrasate, S.; Lete, E.; Sotomayor, N. Tetrahedron: Asymmetry 2002,
13, 311–316.
(21) Liu, H.; Deng, K.; Cohen, T.; Jordan, K. D. Org. Lett. 2007, 9,
1911–1914.
Supporting Information Available: Experimental pro-
cedures and characterization data of compounds 1-7. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(22) The enantiomeric excess for each diastereomer was determined by
comparison with the racemic mixture in all cases by CSP HPLC (Chirlacel
OJ, 2% hexane/i-propanol). See Supporting Information.
(23) The absolute configuration of each diastereomer was assigned by
comparison with the results obtained performing the carbolithiation reaction
with a substrate that incorporates a (R)-(-)-4-phenyl-2-oxazolidinone as
chiral auxiliary. See Supporting Information.
OL900066C
1240
Org. Lett., Vol. 11, No. 6, 2009