Heck reactions of quinoline-derived nonaflates

Article abstract of DOI:10.1055/s-2006-948197

An efficient synthesis of a series of quinolyl-substituted ketones or ketone precursors via the Heck reaction of 6- or 8-quinolyl nonaflates with an appropriate selection of olefins is presented. These ketones are useful building blocks for the diastereoselective construction of azapolycycles via SmI ₂-induced intramolecular cyclization of (het)aryl-substituted ketones. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-948197

LETTER
2993
Heck Reactions of Quinoline-Derived Nonaflates
Heck
R
eaction
r
s
of
Q
ui
a
noline
D
eri
n
vative
s
cesca Aulenta, Hans-Ulrich Reissig*
Institut für Chemie und Biochemie, Freie Universität Berlin, Takustr. 3, 14195 Berlin, Germany
Fax +49(30)83855367; E-mail: hans.reissig@chemie.fu-berlin.de
Received 4 April 2006
Dedicated to Professor Richard Heck
low cost and less toxic olefins compared to the other
cross-coupling reactions (Stille, Suzuki, Kumada, Negishi
reactions) and therefore, explains for its exceptional
utility.
Abstract: An efficient synthesis of a series of quinolyl-substituted
ketones or ketone precursors via the Heck reaction of 6- or 8-
quinolyl nonaflates with an appropriate selection of olefins is
presented. These ketones are useful building blocks for the dia-
stereoselective construction of azapolycycles via SmI2-induced
intramolecular cyclization of (het)aryl-substituted ketones.
Among possible quinolines, 6-hydroxyquinoline (5) and
8-hydroxyquinoline (3) have been selected because of
their low cost, high stability and commercial availability.
These compounds are readily transformed into the corre-
sponding aryl nonaflates (nonafluorobutanesulfonates) 6
and 74 (Scheme 2) by treating the sodium salt of the
hydroxy quinolines with nonafluorobutanesulfonyl
fluoride (2 equiv) in dry THF. Although not yet widely
explored in cross-coupling reactions,5 aryl nonaflates
show similar reactivities compared to the corresponding
triflates,5f but with the advantage of being rather stable
and easily purifiable by crystallization or column chroma-
tography. They can be smoothly prepared6 using the
commercially available, non-toxic and cost-effective
nonafluorobutanesulfonyl fluoride.
Key words: Heck coupling, Pd catalysis, nonaflate, samarium(II)
iodide, quinoline
In continuation of our program focused on the synthesis of
polycycles with steroid-like frameworks via SmI2-in-
duced cyclization of (het)aryl-substituted ketones,1 we
aimed at the construction of dihydroquinoline-containing
tri- and tetracycles from quinolyl-substituted ketones.
Azasteroids are receiving much attention,2 due to the
presence of the nitrogen atom which confers interesting
biological properties. In order to achieve efficiently the
synthesis of these azapolycyclic frameworks
1
(Scheme 1) a short and reliable synthesis of ketones 2 –
used as substrate for the SmI2-induced reductive coupling
– was required. Suitable starting materials for precursors
2 should be quinoline derivative 3 and olefins 4.
NfO
HO
1. NaH, THF, r.t.
2. NfF, r.t., 73%
N
N
N
N
6
5
1. NaH, THF, r.t.
2. NfF, r.t., 73%
n
n
N
O
OH
ONf
N
OH
3
7
SmI2
1
2
Scheme 2 Synthesis of quinolyl nonaflates 6 and 7.
Pd-catalyzed
coupling
With 6 and 7 in hand, the next step was to investigate and
optimize the Heck reactions of these substrates. When
electron-deficient olefins such as methyl acrylate 8 or
methyl vinyl ketone 9 were employed in the presence of
LiCl, triethylamine and 5 mol% of Pd(OAc)2 in DMF, the
couplings proceeded smoothly affording products 10 and
11 as single isomers in excellent yields (Scheme 3).
OH
N
+
X
4
3
Scheme 1 Retrosynthetic analysis for the synthesis of azasteroids 1
via quinolyl-substituted ketones 2.
These encouraging results prompted us to test more
challenging homoallylic alcohols (Table 1), in which the
olefin moiety is not activated by an electron-withdrawing
group. We expected that, under the coupling conditions,
migration of the double bond would occur, leading
(ultimately upon final work-up) to the desired quinolyl-
substituted ketones.7 With this goal in mind, nonaflate 7
and the acyclic homoallylic alcohol 12 were subjected
to the conditions reported above. However, rather dis-
appointingly, the reaction failed to afford any coupling
As a method of choice, we decided to investigate the
palladium-catalyzed arylation (Heck reaction)3 of a series
of selected olefins. This powerful carbon–carbon bond-
forming process has the advantage of employing stable,
SYNLETT 2006, No. 18, pp 2993–2996
0
3
.1
1
.2
0
0
6
Advanced online publication: 04.08.2006
DOI: 10.1055/s-2006-948197; Art ID: S05606ST
© Georg Thieme Verlag Stuttgart · New York

2994
F. Aulenta, H.-U. Reissig
LETTER
Table 1 Heck Reactions of the Quinolyl Nonaflates (QO-NF) 7 and 6 with Different Homoallylic Alcoholsa
Entry
QO-Nf
Olefin (3–4 equiv)
Product
Yield (%)
N
OH
1
7
30
O
12
13
OH
N
N
15: 75
16: 8
2
7
HO
O
14
15
16
OH
N
N
3
7
18 + 19: 69
HO
HO
17
18
19
N
20: 8
O
20
HO
N
4
5
7
6
89
95
N
Boc
HO
21
NBoc
22
OH
OH
N
14
23
a Conditions: DMF, NaHCO3 (3–4 equiv), BnEt3N+Cl– (1.2–2 equiv), 6–20 mol% Pd(OAc)2, 90 °C, 48 h.7b
product. Switching to modified Jeffery conditions7b,8 and (entries 2,3). Formation of a mixture of products in the
prolonging the reaction time, succeeded in delivering the case of secondary allylic or homoallylic alcohols is due to
desired ketone 13, albeit in moderate 30% yield (entry poor regioselectivity in the b-hydride elimination step and
1).
similar results have already been reported by other
authors.9 However, in our case, the fact that a mixture of
products was obtained did not represent a real problem,
since the desired ketones were always easily separable by
column chromatography from the alcohols. The two
The coupling of cyclic homoallylic alcohols 14 and 17
with nonaflate 7 under these optimized conditions, pro-
vided a mixture of allylic and homoallylic alcohols, as
well as the corresponding ketones in good overall yields
Synlett 2006, No. 18, 2993–2996 © Thieme Stuttgart · New York

LETTER
Heck Reactions of Quinoline Derivatives
2995
chelated to the nearby nitrogen and therefore, preventing
the next step of the catalytic cycle.11 On the contrary, in
the case of the 6-substituted quinoline derivative 6 the ni-
trogen cannot interfere and the coupling reaction proceeds
as expected. Complete lack of reactivity of nonaflate 7
was also observed when a Suzuki–Miyaura coupling was
tried using an alkenyl boronic acid in the presence of
PdCl2, dppf, BnEt3NBr and K3PO4 as the base.12
Pd(OAc)2, LiCl, Et3N,
DMF, 100 °C, 94%
O
+
N
N
O
ONf
8
7
O
O
10
Pd(OAc)2, LiCl, Et3N,
DMF, 100 °C, 88%
+
N
N
O
With the range of alcohols and ketones obtained in a
reliable and efficient fashion from Heck reactions, the
synthesis of the desired aza-containing polycyclic skele-
tons was only few steps away. An example of the results
obtained so far is described in Scheme 5. In the case of
compound 22, hydrogenation of the double bond in the
presence of Pd/C in EtOH, followed by oxidation of the
alcohol moiety by Py·SO3 in DMSO afforded the desired
ketone 25 in 75% yield for the two steps. Precursor 25 was
then subjected to the SmI2-induced coupling reaction pre-
viously developed in our group.1,13 Under standard condi-
tions, ketone 25 furnished the expected cyclized product
26 in 50% yield as a single diastereomer. The relative con-
figuration of this tetracyclic diazasteroid derivative 26
was confirmed by NOESY NMR analysis.
ONf
9
7
O
11
Scheme 3 Heck reactions leading to quinoline derivatives 10
and 11.
regioisomeric alcohols were not separated, but con-
veniently converted into the corresponding ketones in a
two-step procedure (as an example see Scheme 5). In the
case of cyclic homoallylic alcohols, it is also plausible to
assume that the presence of the cyclic framework may
hinder the formation of the syn,syn conformation required
in the b-hydride elimination step, which would lead to the
double-bond isomerization. Such hypothesis might ex-
plain the very low yield obtained for ketones 16 and 20
and the complete lack of isomerization when olefin 21
was used. However, in this latter case, the yield of the
coupled alcohol 22 was excellent.10
1. H2, 10 mol% Pd/C,
EtOH, r.t., 82%
N
N
A very pleasing result was also obtained for the coupling
of 6-quinolyl nonaflate 6 with alcohol 14 (entry 5). The
reaction only afforded the homoallylic alcohol 23 in 95%
yield.
2. Py·SO3 (1.7 equiv), Et3N (2 equiv),
HO
O
DMSO, r.t., 92%
NBoc
NBoc
22
25
SmI2, HMPA, t-BuOH,
Led by the curiosity to establish whether these quinolyl
nonaflates would also be good coupling substrates in other
typical Pd-catalyzed cross-couplings such as the
Sonogashira reaction, we treated 6 and 7 in the presence
of phenylacetylene under several coupling conditions
(Scheme 4). With great surprise, we observed that while
nonaflate 6 afforded the expected coupling product 24 in
excellent 95% yield, nonaflate 7 constantly failed to pro-
vide the expected disubstituted alkyne, affording instead
only the homocoupled acetylene and unreacted starting
material 7. A plausible explanation to elucidate this result
is that the oxidative insertion of Pd(0) would lead to a
rather inert intermediate, in which the metal is strongly
THF, r.t., 50%
H
H
NBoc
N
H
OH
26
Scheme 5 Synthesis of diazasteroid derivative 26 from homoallylic
alcohol 22 via SmI2-induced cyclization of ketone 25.
In conclusion, the use of quinolyl nonaflates as aryl
components in Heck reactions proved to be an efficient,
reliable and cost-effective method for the synthesis of a
wide range of quinolyl-substituted homoallylic alcohols
and ketones. Such compounds have found application in
the diastereoselective synthesis of complex azapolycyclic
skeletons, which resemble steroid structures with un-
natural cis,cis-junction of rings B–C–D.
Ph
NfO
Ph (2 equiv)
Pd(OAc)2 (0.2 equiv),
CuI (0.4 equiv),
i-Pr2NH, DMF, r.t., 95%
N
N
N
24
6
Ph
only homocoupling
several conditions
Acknowledgment
ONf
This work was generously supported by the European Community
(Marie Curie Intra European Fellowship for F.A.), the Deutsche
Forschungsgemeinschaft, the Fonds der Chemischen Industrie and
the Schering AG.
7
Scheme 4 Attempted Sonogashira couplings of nonaflates 6 and 7
with phenylacetylene.
Synlett 2006, No. 18, 2993–2996 © Thieme Stuttgart · New York

2996
F. Aulenta, H.-U. Reissig
LETTER
(10) Typical Procedure for the Heck Reaction of 7 and 21
References and Notes
Leading to 22.
(1) (a) Berndt, M.; Hlobilová, I.; Reissig, H.-U. Org. Lett. 2004,
6, 957. (b) Review: Berndt, M.; Gross, S.; Hölemann, A.;
Reissig, H.-U. Synlett 2004, 422.
A high-pressure tube was loaded with NaHCO3 (0.285 g,
3.40 mmol), triethylbenzylammonium chloride (0.389 g,
1.71 mmol), quinolin-8-yl 1,1,2,2,3,3,4,4,4-nonafluoro-
butane-1-sulfonate (7, 0.362 g, 0.85 mmol), Pd(OAc)2 (39
mg, 0.17 mmol) and DMF (3 mL). The suspension was
stirred at r.t. under argon for 10 min, then a solution of
rac-tert-butyl (3S,4R)-3-hydroxy-4-vinylpyrrolidine-1-
carboxylate (21, 0.729 g, 3.42 mmol) in DMF (1 mL) was
added, the vessel was sealed and heated to 90 °C for 48 h.
The vessel was then cooled to r.t., distilled H2O was added
and the phases were separated. The product was extracted in
CH2Cl2 (3 × 5 mL), the combined organic layers were
washed with brine (2 × 5 mL), dried over MgSO4 and the
solvent was removed under reduced pressure to leave the
crude product, which was purified by column
(2) For recent reviews on azasteroids see: (a) Senthilkumar, S.
P. Curr. Org. Chem. 2004, 8, 1521. (b) Burbiel, J.; Bracher,
F. Steroids 2003, 68, 587 . For selected publications:
(c) Oumzil, K.; Ibrahim-Ouali, M.; Santelli, M. Synlett 2005,
1695. (d) Dolle, R. E.; Allaudeen, H. S.; Kruse, L. I. J. Med.
Chem. 1990, 33, 877. (e) Brandt, M.; Levy, M. A.
Biochemistry 1989, 28, 140. (f) Gandiha, A.; Marshall, G.;
Paul, D.; Singh, H. J. Pharm. Pharmacol. 1974, 26, 871.
(3) (a) Heck, R. F.; Nolley, J. P. Jr. J. Org. Chem. 1972, 37,
2320. (b) Mizoroki, T.; Mori, K.; Ozaki, A. Bull. Chem. Soc.
Jpn. 1971, 44, 581. Reviews: (c) Beletskaya, I. P.;
Cheprakov, A. V. Chem. Rev. 2000, 100, 3009. (d) de
Meijere, A.; Meyer, F. E. Angew. Chem., Int. Ed. Engl. 1994,
33, 2379; Angew. Chem. 1994, 106, 2473. (e) For a scope
of reaction conditions, see: Bräse, S.; de Meijere, A. Cross-
Coupling of Organyl Halides with Alkenes: the Heck
Reaction, In Metal-Catalyzed Cross-Coupling Reactions; de
Meijere, A.; Diederich, F., Eds.; Wiley-VCH: Weinheim,
1998, 217.
chromatography on silica gel (eluent: hexane–EtOAc from
4:1 to 1:1) to afford tert-butyl 3-hydroxy-4-[(E)-2-quinolin-
8-ylvinyl]pyrrolidine-1-carboxylate (22) as a colorless oil
(0.259 g, 89% yield). Two distinct rotamers were visible
from NMR analysis at r.t. 1H NMR (500 MHz, CDCl3):
d = 1.47 (s, 9 H, t-Bu), 3.01–3.07 (m, 1 H, 4-H), 3.30–3.36
(m, 2 H, 2-H, 5-H), 3.54 (br d, 3J = 16.2 Hz, 1 H, OH), 3.72–
3.80 (m, 2 H, 2-H, 5-H), 4.24–4.26 (m, 1 H, 3-H), 6.23 (mc,
1 H, 1¢-H), 7.37 (mc, 1 H, Ar–H), 7.45–7.48 (m, 1 H, Ar–H),
7.67–7.70 (m, 1 H, Ar–H), 7.73–7.77 (m, 2 H, 2¢-H, Ar-H),
8.10 (d, 3J = 7.7 Hz, 1 H, Ar-H), 8.92 (m, 1 H, Ar-H) ppm.
13C NMR (126 MHz, CDCl3): d = 28.5 (q, t-Bu), 49.6, 49.8
(2 t, C-5), 50.3, 50.6 (2 d, C-4), 52.0, 52.2 (2 t, C-2), 70.4,
70.5 (2 d, C-3), 79.4 (s, t-Bu), 121.2 (d, C–Ar), 125.9 (s, C–
Ar), 126.5 (d, C-2¢), 127.4, 128.4 (2 d, C–Ar), 128.6 (s, C–
Ar), 130.2, 135.4, 136.4 (3 d, C–Ar), 145.1 (s, C–Ar), 149.5
(d, C-1¢), 154.6 (s, CO) ppm. IR (KBr): n = 3380–3200
(OH), 3050–3005, 2970, 2940, 2880 (=CH, C–H), 1695
(C=O) cm–1. MS (EI, 80 eV, 160 °C): m/z (%) = 340 (16)
[M]+, 283 (8) [M – C4H9]+, 239 (8) [M – C5H9O2]+, 154 (46)
[M – C8H15O]+, 57 (100) [C4H9]+. HRMS (80 eV, 160 °C):
m/z calcd for C20H24N2O3: 340.17868; found: 340.17944.
(11) Formation of a stable dimeric complex would also be
plausible.
(4) For the synthesis of 7 see also: Martinez, A. G.; Fernandez,
A. H.; Alvarez, R. M. M. Synthesis 1984, 481.
(5) (a) Tundel, R. E.; Anderson, K. W.; Buchwald, S. L. J. Org.
Chem. 2006, 71, 430. (b) Gavryushin, A.; Kofink, C.;
Manolikakes, G.; Knochel, P. Org. Lett. 2005, 7, 4871.
(c) Flögel, O.; Dash, J.; Brüdgam, I.; Hartl, H.; Reissig, H.-
U. Chem. Eur. J. 2004, 10, 4283. (d) Dash, J.; Lechel, T.;
Reissig, H.-U. unpublished results. (e) Denmark, S. E.;
Sweis, R. F. Org. Lett. 2002, 4, 3771. (f) Rottländer, M.;
Knochel, P. J. Org. Chem. 1998, 63, 203. (g) Roth, G. P.;
Fuller, C. E. J. Org. Chem. 1991, 56, 3493.
(6) Subramanian, L. R.; Bentz, H.; Hanack, M. Synthesis 1973,
293.
(7) (a) Dyker, G.; Kadzimirsz, D. Eur. J. Org. Chem. 2003,
3167. (b) Padwa, A.; Zanka, A.; Harris, J. M. Tetrahedron
2003, 59, 4939. (c) Dyker, G.; Thöne, A. J. Prakt. Chem.
1999, 341, 138. (d) Jeffery, T. Tetrahedron Lett. 1990, 31,
6641.
(8) (a) Jeffery, T. Tetrahedron 1996, 52, 10113. (b) Jeffery, T.
J. Chem. Soc., Chem. Commun. 1984, 1287.
(9) (a) Littke, A. F.; Fu, G. C. J. Am. Chem. Soc. 2001, 123,
6989. (b) Kang, S.-K.; Jung, K.-Y.; Park, C.-H.; Namkoong,
E.-Y.; Kim, T.-H. Tetrahedron Lett. 1995, 36, 6287.
(12) Beletskaya, I. P.; Gamina, O. G.; Tsvetkov, A. V.; Fedorov,
A. Y.; Finet, J.-P. Synlett 2004, 2797.
(13) (a) Gross, S.; Reissig, H.-U. Org. Lett. 2003, 5, 4305.
(b) Gross, S.; Reissig, H.-U. Synlett 2002, 2027. (c) Berndt,
M.; Reissig, H.-U. Synlett 2001, 1290. (d) Nandanan, E.;
Dinesh, C. U.; Reissig, H.-U. Tetrahedron 2000, 56, 4277.
(e) Dinesh, C. U.; Reissig, H.-U. Angew. Chem. Int. Ed.
1999, 38, 789; Angew. Chem. 1999, 111, 874.
Synlett 2006, No. 18, 2993–2996 © Thieme Stuttgart · New York