First thermal and transition metal catalysed intramolecular [4+2] cycloaddition reactions with N-tethered ynamides

Article abstract of DOI:10.1055/s-2003-38357

Cationic rhodium(I)-complexes generated from [RhCl(PPh₃)₃] and AgSbF₆ catalyse at room temperature the first examples of intramolecular [4+2] cycloaddition reactions with N-tethered ynamides and provide an efficient access

Full text of DOI:10.1055/s-2003-38357

708
LETTER
First Thermal and Transition Metal Catalysed Intramolecular [4+2]
Cycloaddition Reactions with N-Tethered Ynamides
I
ntramolecular [4
e
+2]
C
ycloa
r
ddition
n
w
i
h
th
N
-Tethere
a
d
Y
namide
r
s
d Witulski,* Jan Lumtscher, Uwe Bergsträßer
Fachbereich Chemie, Universität Kaiserslautern, Erwin-Schrödinger-Straße, 67663 Kaiserslautern, Germany
Fax +49(631)2053921; E-mail: witulski@rhrk.uni-kl.de
Received 6 January 2003
Abstract: Cationic rhodium(I)-complexes generated from
[RhCl(PPh3)3] and AgSbF6 catalyse at room temperature the first
i
examples of intramolecular [4+2] cycloaddition reactions with N-
tethered ynamides and provide an efficient access to synthetically
versatile tetrahydroindoles.
NH
R1
N
R1
R2
I+
-OTf
Ph
R2
1: R1 = Ts
2: R1 = CF3CO
3
3a: R2 = SiMe3
3b: R2 = Ph
Key words: ynamides, tetrahydroindoles, Diels–Alder reaction,
catalysis, alkynyliodonium salts
R2: 1,2~
ii
The intramolecular Diels–Alder reaction serves as an ex-
ceptionally useful ring forming transformation and has
long proven to be an invaluable aid in stereoselective syn-
theses of natural products and drug related targets.1 In-
tramolecular Diels–Alder reactions with N-functionalised
dienes or dienophiles are particularly interesting because
of their prospective use for approaches to alkaloids. Sev-
eral examples with either tethered dienamides or enam-
ides as cycloaddition partners allowing rapid assemblies
of nitrogen containing heterocycles were reported.2 How-
ever, intramolecular Diels–Alder reactions with N-substi-
tuted alkynes – ynamines or ynamides – as dienophilic
reagents remained unknown, albeit intermolecular inverse
electron demand [4+2] cycloadditions with electron rich
ynamines and electron deficient dienes served already for
the synthesis of aromatic and heteroaromatic systems.3
N
R1
R2
R2 = SiMe3
N
R1
R2
4: R1 = Ts; R2 = SiMe3 (80%)
5: R1 = CF3CO; R2 = SiMe3 (81%)
6: R1 = Ts; R2 = Ph (61%)
7: R1 = Ts; R2 = H (93%)
iii
8: R1 = Ts; R2 = nBu (63%)
Scheme 1 Reagents and conditions: (i) KHMDS, toluene, 0 °C,
then addition of 3 (1.3 equiv), 12 h, 20 °C; (ii) TBAF, THF, 0 °C, 15
min; (iii) KHMDS, THF, –78 °C to 0 °C, then addition of n-butyl
bromide.
alkynes 3 and the 1,3-butadiene moiety,6 nor an intramo-
lecular alkene cycloaddition of the intermediate alky-
lidene carbene was observed.7 Dienynes 4–6 were always
obtained as a single product. Desilylation of 4 with TBAF
in THF at 0 °C proceeded efficiently to give 7 with 93%
yield.8 Furthermore, dienyne 7 was alkylated with n-butyl
bromide to give 8 with 63% yield.
We have recently developed the first reliable and flexible
synthesis of N-functionalised ynamides (N-alkynyl-
amides),4 and as a part of our studies on their use as build-
ing blocks for novel pathways to nitrogen containing
heterocycles including natural product synthesis,5 we
report here our initial findings on their applicability in in-
tramolecular Diels–Alder reactions.
We initially chose to investigate the intramolecular [4+2]
cycloaddition reaction of these systems under standard
thermal activation (Scheme 2).
To examine the feasibility of ynamides in thermal and
transition metal catalysed intramolecular [4+2] cycloaddi-
tion reactions that would give synthetically versatile tet-
rahydroindoles otherwise difficult to obtain, the synthesis
of the dienynes 4–8 was attempted (Scheme 1).
80 °C
∆
benzene
DDQ
N
N
N
H
Ts
Ts
9 (54%)
Ts
10 (76%)
7
Scheme 2 Thermal intramolecular [4+2] cycloaddition reactions.
Deprotonation of diene 1 or 2 with KHMDS in toluene,
followed by addition of the alkynyliodonium salts 3a or
3b yielded 4–6 in 61–80%. Notably, this process of direct
N-ethynylation tolerated the presence of an adjacent 1,3-
diene moiety. Neither a concurrent Diels–Alder reaction
between the electron deficient and therefore activated
A series of trial reactions in a sealed NMR tube disclosed
that thermal intramolecular [4+2] cycloadditions with
tethered ynamides occurred only with dienynes bearing a
terminal alkyne moiety (i.e. 7: t1/2 = 2.5 h at 80 °C). The
silylated systems 4 and 5 proved less willing to participate
in these reactions and even under more forcing thermal
conditions only decomposition was observed. Reactions
on preparative scale with 7 gave the tetrahydroindole 9
Synlett 2003, No. 5, Print: 10 04 2003.
Art Id.1437-2096,E;2003,0,05,0708,0710,ftx,en;G00203ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
Intramolecular [4+2] Cycloaddition Reactions with N-Tethered Ynamides
709
with an isolated yield of 54%. However, purification of was not tolerated by this process (entry 2). Next, we
the cycloaddition product turned out to be troublesome, turned our attention to intramolecular cycloadditions me-
because partial aromatisation of the tetrahydroindole 9 to diated by Wilkinson’s catalyst [RhCl(PPh3)3], a catalyst
indoline 10 commenced slowly at 80 °C and the cycload- that was already exceptionally efficient in alkyne cyclo-
dition product 9 was always contaminated with small trimerisations with ynamides leading to indolines and car-
amounts of 10. However, indoline 10 could be obtained bazoles.5 Unfortunately, an intramolecular [4+2]
selectively by treatment of 9 with DDQ in toluene at cycloaddition reaction with dienyne 4 could not be effect-
110 °C with 76% yield.
ed by Wilkinson’s catalyst alone, neither in toluene nor in
polar solvents like CH2Cl2, THF or trifluoroethanol and
the starting material remained unconverted (entry 3).
Gratifyingly, a more reactive cationic rhodium(I)-species
generated in situ from Wilkinson’s catalyst10 became the
catalyst of choice for intramolecular [4+2] cycloadditions
with ynamides. Addition of 5 mol% AgSbF6 (0.05 M so-
lution in dichloroethane) to a toluene solution containing
5 mol% [RhCl(PPh3)3] and 4 (0.01 M in toluene) pro-
duced a cationic Rh(I)-species, that efficiently effected
the rapid conversion of 4 to tetrahydroindole 11 in 89%
yield (entry 4). Importantly, this cationic rhodium species
worked comparable well for terminal as well as non termi-
nal ynamides giving the tetrahydroindoles 9 and 12–14 al-
ways at room temperature in isolated yields of 70–89%
(entries 5–8).11 Side products caused by subsequent iso-
merisation or aromatisation being always present in the
thermally induced Diels–Alder reaction were not formed
under these mild conditions. On the basis of these results
the synthesis of 12 was accomplished in 86% yield and its
structure and connectivity was unequivocally evidenced
by X-ray analysis (Figure 1).12
To overcome the difficulties of the standard thermal acti-
vated Diels–Alder reaction – elevated reaction tempera-
tures and poor selectivities – the transition metal catalysed
versions of these cycloaddition reactions were investigat-
ed. Nickel(0)-, as well as rhodium(I)-catalysts seemed to
be promising candidates for this endeavour. Reports of
Wender’s and Livinghouse’s group evidenced, that these
catalysts are capable to effect intramolecular [4+2] cy-
cloadditions between electronically similar dienes and di-
enophiles under mild conditions through a multistep
mechanism.9,10
Indeed, treatment of dienyne 4 with 20 mol% Ni(COD)2
and 60 mol% tris-ortho-biphenylphosphite [P(O-o-bi-
Ph)3] in THF at 40 °C afforded tetrahydroindole 11, that
could not be obtained in the uncatalysed reaction, in 73%
yield (Table 1, entry 1). However, the applicability of the
nickel(0)-catalysed reaction for the synthesis of tetrahy-
droindoles was still restricted to both, elevated reaction
temperatures and a high catalyst load of 20 mol%. Fur-
thermore, the dienyne 7 with a terminal alkyne moiety
Table 1 Transition Metal Catalysed Intramolecular [4+2] Cyclo-
additions with Dienynes 4–812
Ni(0)- or Rh(I)-catalyst
N
R2
N
R2
R1
R1
Entry Di-
enynea
R1
R2
Catalyst Prod-
and Con- uct
ditionsb
Yield
(%)c
1
2
3
4
5
6
7
8
4
Ts
Ts
Ts
Ts
Ts
SiMe3
H
A
A
B
C
C
C
C
C
11
9
73
0d
7
4
4
7
5
6
8
SiMe3
SiMe3
H
11
11
9
0
89
83
86
70
79
Figure 1 Solid state structure of tetrahydroindole 12.12 Selected
bond lengths [Å] : N1–C2 1.488 (3), N1–C10 1.344 (3), N1–C9 1.440
(3), C2– C31.510 (4), C3–C4 1.519 (4), C4–C5 1.487 (4), C4–C9
1.502 (3), C5–C6 1.309 (4), C6–C7 1.488 (4), C8–C9 1.328 (3).
CF3CO SiMe3
12
13
14
Ts
Ts
Ph
In conclusion, we have successfully accomplished the
first intramolecular Diels–Alder reactions with ynamides
leading to synthetically versatile tetrahydroindoles. It was
also demonstrated, that best results were obtained when a
cationic rhodium(I)-species, prepared in situ from
equimolar amounts of [RhCl(PPh3)3] and AgSbF6, was
used as catalyst. Further studies along this line including
applications of this strategy to the synthesis of alkaloids
are in progress.
n-Bu
a 0.01 M solution.
b Method A: 20 mol% Ni(COD)2, 60 mol% P(O-o-biPh)3, THF,
40 °C; P(O-o-biPh)3 = tris-ortho-biphenylphosphite. Method B:
5 mol% [RhCl(PPh3)3], toluene, 20 °C up to 100 °C. Method C:
5 mol% [RhCl(PPh3)3], 5 mol% AgSbF6, toluene, 20 °C.
c Yield after purification by Alox III/N column chromatography.
d Decomposition.
Synlett 2003, No. 5, 708–710 ISSN 0936-5214 © Thieme Stuttgart · New York

710
B. Witulski et al.
LETTER
Soc. 1989, 111, 6432. (b) Wender, P. A.; Smith, T. E. J.
Org. Chem. 1996, 61, 824. (c) Wender, P. A.; Smith, T. E.
Tetrahedron 1998, 54, 1255. (d) DiMauro, E. F.;
Acknowledgement
Financial support of this work by the Deutsche Forschungsgemein-
schaft (Wi-1969) and by Boehringer Ingelheim, Pharma KG is
gratefully acknowledged.
Kozlowski, M. C. J. Chem. Soc., Perkin Trans. 1 2002, 439.
(10) Rhodium(I)- and cationic rhodium(I)-catalysed
intramolecular [4+2] cycloaddition reactions: (a) Jolly, R.
S.; Luedtke, G.; Sheehan, D.; Livinghouse, T. J. Am. Chem.
Soc. 1990, 112, 4965. (b) Wender, P. A.; Jenkins, T. E.;
Suzuki, S. J. Am. Chem. Soc. 1995, 117, 1843.
References
(1) (a) Corey, E. J. Angew. Chem. Int. Ed. 2002, 41, 1650.
(b) Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.;
Vassilikogiannakis, G. E. Angew. Chem. Int. Ed. 2002, 41,
1701. (c) Fringuelli, F.; Taticchi, A. The Diels-Alder
Reaction; Wiley and Sons: Chichester, 2002.
(2) (a) Fearnley, S. P.; Market, E. Chem. Commun. 2002, 438.
(b) Padwa, A.; Bur, S. K.; Danca, D. M.; Ginn, J. D.; Lynch,
S. M. Synlett 2002, 851. (c) Oppolzer, W.; Flaskamp, E.;
Bieber, L. W. Helv. Chim. Acta 2001, 84, 141. (d) Boger,
D. L.; Wolkenberg, S. E. J. Org. Chem. 2000, 65, 9120.
(e) Magnus, P.; Cairns, P. M. J. Am. Chem. Soc. 1986, 108,
217. (f) Martin, S. F.; Tu, C.; Kimura, M.; Simonsen, S. H.
J. Org. Chem. 1982, 47, 3634. (g) Stork, G.; Morgans, D. J.
Jr. J. Am. Chem. Soc. 1979, 101, 7110.
(3) (a) Genet, J. P.; Ficini, J. Tetrahedron Lett. 1979, 1499.
(b) Iwamoto, K.; Fukuta, H.; Suzuki, S.; Maruyama, J.;
Oishi, E.; Miyashita, A.; Higashino, T. Heterocycles 1996,
43, 2409. (c) Barluenga, J.; Ferrero, M.; Peláez-Arango, E.;
López-Ortiz, F.; Palacios, F. J. Chem. Soc., Chem. Commun.
1994, 865. (d) Padwa, A.; Gareau, Y.; Harrison, B.;
Rodriguez, A. J. Org. Chem. 1992, 57, 3540. (e) Boger, D.
L.; Dang, Q. Tetrahedron 1988, 44, 3379. (f) Himbert, G.;
Brunn, W. Liebigs Ann. Chem. 1986, 1067. (g) For Hetero
Diels–Alder reactions with ynamines, see: van Elburg, P. A.;
Honig, G. W. N.; Reinhout, D. N. Tetrahedron Lett. 1987,
28, 6397. (h) See also: Vilsmaier, E.; Baumheier, R. Chem.
Ber. 1989, 122, 1285.
(c) McKinstry, L.; Livinghouse, T. Tetrahedron 1994, 50,
6145. (d) O’Mahony, D. J. R.; Belanger, D. B.; Livinghouse,
T. Synlett 1998, 443. (e) Gilbertson, S. R.; Hoge, G. S.;
Genov, D. G. J. Org. Chem. 1998, 63, 10077. (f)Paik,S.-J.;
Son, S. U.; Chung, Y. K. Org. Lett. 1999, 1, 2045.
(11) Experimental Procedure: [RhCl(PPh3)3] (9.3 mg, 0.01
mmol) was added to a solution of ynamide 4–8 (0.20 mmol)
in dry toluene (10 mL) under argon. After stirring for 5 min
at r.t., AgSbF6 (0.01 mmol, 0.2 mL of a 0.05 M solution in
1,2-dichloroethane) was added and the reaction mixture was
stirred at r.t. The reaction mixture was filtered through a
small plug of celite, the solvent was evaporated and the
resulting crude product was purified by column
chromatography (Al2O3 III/N, hexanes–EtOAc = 8:2) to
afford 9, 11–14.
Compound 9: Mp 87–88 °C. 1H NMR (400 MHz, CDCl3):
d = 7.72 (d, J = 8.4 Hz, 2 H), 7.28 (d, J = 8.4 Hz, 2 H), 5.76
(m, 2 H), 5.66 (m, 1 H), 3.76 (m, 1 H), 3.33 (m, 1 H), 2.77
(m, 2 H), 2.54 (m, 1 H), 2.41 (s, 3 H), 2.02 (m, 1 H), 1.49 (m,
1 H). 13C NMR (100 MHz, CDCl3): d = 143.6, 137.9, 134.8,
129.5, 127.2, 126.5, 125.3, 103.1, 48.9, 38.0, 28.7, 26.9,
21.5. MS (EI, 70 eV): m/z (%) = 275 (43) [M+], 91 (100).
Anal. Calcd for C15H17NO2S: C, 65.43; H, 6.22; N, 5.09.
Found: C, 65.15; H, 6.06; N, 5.31. Compound 11: Mp 74–
75 °C. 1H NMR (400 MHz, CDCl3): d = 7.70 (d, J = 8.3 Hz,
2 H), 7.27 (d, J = 8.3 Hz, 2 H), 5.79 (m, 1 H), 5.64 (m, 1 H),
3.46 (m, 2 H), 2.96–2.81 (m, 2 H), 2.47 (s, 3 H), 1.89 (m, 2
H), 1.34 (m, 1 H), 0.35 (s, 9 H). 13C NMR (100 MHz,
CDCl3): d = 145.2, 143.6, 134.8, 129.5, 128.1, 125.9, 125.8,
125.7, 47.2, 36.9, 29.8, 28.7, 21.5, 0.0. MS (EI, 70 eV): m/z
(%) = 347 (3) [M+], 99 (100). Anal. Calcd for
(4) Witulski, B.; Stengel, T. Angew. Chem. Int. Ed. 1998, 37,
498.
(5) (a) Witulski, B.; Alayrac, C. Angew. Chem. Int. Ed. 2002,
41, 3281. (b) Witulski, B.; Stengel, T.; Fernández-
Hernández, J. M. Chem. Commun. 2000, 1965.
(c) Witulski, B.; Buschmann, N.; Bergsträßer, U.
Tetrahedron 2000, 56, 8473. (d) Witulski, B.; Gößmann, M.
Synlett 2000, 1793. (e) Witulski, B.; Stengel, T. Angew.
Chem. Int. Ed. 1999, 38, 2426. (f) Witulski, B.; Gößmann,
M. Chem. Commun. 1999, 1879. (g) For other contributions
to the chemistry of ynamides, see: Hoffmann, R. W.;
Brückner, D. New J. Chem. 2001, 25, 369. (h) Rainier, J.
D.; Imbriglio, J. E. J. Org. Chem. 2000, 65, 7272.
(i) Mulder, J. A.; Hsung, R. P.; Frederick, M. O.; Tracey, M.
R.; Zificsak, C. A. Org. Lett. 2002, 4, 1383. (j) Wei, L.-L.;
Mulder, J. A.; Xiong, H.; Zificsak, C. A.; Douglas, C. J.;
Hsung, R. P. Tetrahedron 2001, 57, 459. (k) Saito, N.;Sato,
Y.; Mori, M. Org. Lett. 2002, 4, 809.
C18H25NO2SSi: C, 62.21; H, 7.25; N, 4.03. Found: C, 61.98;
H, 7.35; N, 3.93. Compound 13: Mp 121–122 °C. 1H NMR
(400 MHz, CDCl3): d = 7.52 (m, 2 H), 7.44 (m, 2 H), 7.32
(m, 2 H), 7.22 (m, 3 H), 5.77 (m, 1 H), 5.70 (m, 1 H), 3.54
(m, 2 H), 3.38 (m, 1 H), 2.78 (m, 1 H), 2.40 (s, 3 H), 2.23 (m,
1 H), 2.11 (m, 1 H), 1.55 (m, 1 H). 13C NMR (100 MHz,
CDCl3): d = 143.4, 141.0, 134.1, 129.4, 128.0, 127.6, 125.4,
125.3, 124.8, 47.7, 38.0, 33.3, 29.3, 21.6. Compound 14: Oil.
1H NMR (400 MHz, CDCl3) d = 7.67 (d, J = 8.2 Hz, 2 H),
7.27 (d, J = 8.2 Hz, 2 H), 5.67 (m, 1 H), 5.54 (m, 1 H), 3.42
(m, 2 H), 2.89 (m, 1 H), 2.60 (m, 2 H), 2.41 (s, 3 H), 2.34 (m,
1 H), 1.87 (m, 2 H), 1.52 (m, 1 H), 1.38 (m, 3 H), 1.28 (m, 1
H), 0.93 (t, J = 7.2 Hz, 3 H). 13C NMR (100 MHz, CDCl3)
d = 143.5, 134.6, 131.8, 129.5, 128.5, 127.8, 125.7, 124.8,
47.9, 36.8, 32.0, 31.0, 29.6, 29.4, 22.9, 21.5, 14.0.
(6) (a) Kitamura, T.; Kotani, M.; Yokoyama, T.; Fujiwara, Y.;
Hori, K. J. Org. Chem. 1999, 64, 680. (b) Murch, P.; Arif,
A. M.; Stang, P. J. J. Org. Chem. 1997, 62, 5959.
(c) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2002, 102,
2523.
(12) Crystal data for 12: C13H18NOF3Si, triclinic, space group
P1 (No. 2), a = 8.896 (2), b = 9.643 (2), c = 9.830 (2) Å,
a = 102.38 (3)°, b = 115.97 (3)°, g = 92.73 (3)°, V = 730.8
(3) Å3, Z = 2, Dc = 1.315 g cm–3, F(000) = 304,
(7) Feldman, K. S.; Mareska, D. A. J. Am. Chem. Soc. 1998,
120, 4027.
m (Mo-Ka) = 1.85 cm–1. 6235 reflections collected, 2650
independent [R(int) = 0.0449], which were used in all
calculations. 172 parameters, R1 = 0.0457, wR2 = 0.1129 for
observed reflections [F2>2s(F2)] and R1 = 0.0597,
(8) Spectral data for dienyne 7: 1H NMR (400 MHz, CDCl3):
d = 7.80 (m, 2 H), 7.35 (m, 2 H), 6.23 (m, 1 H), 6.07 (m, 1
H), 5.55 (m, 1 H), 5.11 (d, J = 16.1 Hz, 1 H), 5.01 (d, J = 9.1
Hz, 1 H), 3.38 (m, 2 H), 2.78 (s, 1 H), 2.43 (s, 3 H), 2.39 (m,
2 H). 13C NMR (100 MHz, CDCl3): d = 144.7, 136.6, 133.8,
130.0, 129.8, 127.6, 134.6, 116.3, 75.8, 59.5, 50.6, 30.9,
21.6.
wR2 = 0.1217 for all reflections, GoF (on F2) = 0.871. Max.
and min. residual electron densities: 0.285 and –0.231 eÅ–3.
Data were collected on a STOE-IPDS at r.t., the structure
was solved by direct methods using SHELXS-97 and refined
using SHELXL-97. CCDC: 194177.
(9) Nickel(0)-catalysed intramolecular [4+2] cycloaddition
reactions: (a) Wender, P. A.; Jenkins, T. E. J. Am. Chem.
Synlett 2003, No. 5, 708–710 ISSN 0936-5214 © Thieme Stuttgart · New York