Chemo- and regioselective crossed alkyne cyclotrimerisation of 1,6-diynes with terminal monoalkynes mediated by Grubbs' catalyst or Wilkinson's catalyst

Article abstract of DOI:10.1039/b005636g

A novel protocol for crossed alkyne cyclotrimerisations mediated by Grubbs' catalyst [RuCl₂(=CHPh)(PCy₃)₂] allows the efficient synthesis of 4,6-substituted indolines with high regioselectivity, and it is complementary to

Full text of DOI:10.1039/b005636g

Chemo- and regioselective crossed alkyne cyclotrimerisation of 1,6-diynes with
terminal monoalkynes mediated by Grubbs’ catalyst or Wilkinson’s catalyst†
Bernhard Witulski,* Thomas Stengel and Jesús M. Fernández-Hernández
Fachbereich Chemie, Universität Kaiserslautern, Erwin Schrödinger Straße, D-67663 Kaiserslautern, Germany.
E-mail: witulski@rhrk.uni-kl.de
Received (in Liverpool, UK) 7th July 2000, Accepted 30th August 2000
First published as an Advance Article on the web
A novel protocol for crossed alkyne cyclotrimerisations
mediated by Grubbs’ catalyst [RuCl2(NCHPh)(PCy3)2] al-
lows the efficient synthesis of 4,6-substituted indolines with
high regioselectivity, and it is complementary to alkyne
cyclotrimerisations mediated by Wilkinson’s catalyst
[RhCl(PPh3)3] allowing the regioselective synthesis of the
corresponding 4,5-substituted isomers in many cases.
The transition metal catalysed cyclotrimerisation of alkynes has
been recognised as a versatile synthetic approach for highly
substituted benzenes.1 While the intramolecular version has
been established as an efficient synthetic method, the efficiency
of the conceptually more flexible crossed cyclotrimerisation of
tethered diynes with monoalkynes has to be evaluated by the
ability to gain control over the chemo- and regioselectivity of
this process.2 Only a few reports appear using differently
substituted diynes and monoalkynes in crossed cyclotrimerisa-
Scheme 1
tion reactions,2d,h,m,3 and in most cases the observed regio-
selectivity was either dependent on a reactivity preference of a
eq.) in the presence of 5 mol% A at 40 °C (Scheme 2, Table 1).
During a period of 10–20 h the starting material was consumed
giving the isoindolines 3a–d in 81–89% yield after chromatog-
raphy on silica gel (entries 1–4). Although in some cases the
amount of 2 could be reduced to 2 eq., best results were obtained
using 5 eq., which effectively suppressed a competitive co-
trimerisation of 1. In agreement with our mechanistic hypoth-
given substrate or limited by the use of sterically encumbered
substituents.
Recently, we reported a novel synthesis of indolines based on
a rhodium-catalysed crossed cyclotrimerisation with N-func-
tionalised alk-1-ynylamides, a process which provides flexible
access to 4-, or 7-, as well as to 4- and 7-substituted indolines.3
While servicing a number of objectives in indole synthesis, this
method has not yet been applicable for the regioselective
synthesis of indolines bearing substituents in the 4,6-, or
4,5-position—a feature of numerous compounds of synthetic
and medicinal interest.4 We propose below a solution to this
challenging issue by using either Grubbs’ catalyst
[RuCl2(NCHPh)(PCy3)2]
A
or Wilkinson’s catalyst
[RhCl(PPh3)3] B in crossed alkyne cyclotrimerisations.
At the outset of our studies we anticipated that a crossed
alkyne cyclotrimerisation based on a cascade of metathesis
steps could contribute to the above problem set, because
metathesis catalytic cycles usually begin with a regioselective
addition of the ylidene-transition metal complex to the less
hindered site of an olefinic or acetylenic substrate.5 Based on
the findings of Blechert and Roy, that the complex A caused a
fully intra- or intermolecular alkyne cyclotrimerisation,6 we
projected a catalytic cycle as outlined in Scheme 1. The
preferred addition of complex A to the least substituted alkyne
moiety of the 1,6-diyne should be supported by a coordination
of the remaining triple bond to the ruthenium complex, thus
causing the chemo- and regioselectivity of this process. A
cascade of intra- and intermolecular, as well as ring closing
metathesis steps, which are related to the well established enyne
and olefin metathesis,7 would finally result in the liberation of
the ruthenium benzylidene catalyst and in the preferred
formation of the corresponding meta-isomer.
Scheme 2
Table 1 Cycloaddition of 1 with 2a–d mediated by Grubbs’catalyst A or
Wilkinson’s catalyst B‡a
Catalyst
(mol%)
Entry
2
R1
Yield (%)b
meta+orthoc
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2a
2b
2c
2d
Ph
C3H7
CH2OH
(CH2)2OH
Ph
C3H7
CH2OH
(CH2)2OH
A (5)
A (5)
A (5)
A (5)
B (5)
B (5)
B (5)
B (5)
3a
3b
3c
3d
3a
3b
3c
3d
82
92
81
89
52
61
90
79
5+1
6+1
6+1
6+1
1+8
1+4
1+10
1+1.5
A first set of examples was obtained by the reaction of the
1,6-diyne 1 (0.02 M in CH2Cl2) with the monoalkynes 2a–d (5
a Reaction conditions: monoalkyne (5 eq.), reactions with catalyst A
[RuCl2(NCHPh)(PCy3)2] were run in CH2Cl2 at 40 °C in a sealed tube for
various reaction times (10–20 h), reactions with catalyst B [RhCl(PPh3)3]
were run in toluene at rt for various reaction times (10–15 h). b Yield after
purification by silica gel chromatography. c Determined by 1H-NMR.
† Electronic supplementary information (ESI) available: experimental
procedures and analytical data for 3, 4 and 5. See http://www.rsc.org/
suppdata/cc/b0/b005636g/
DOI: 10.1039/b005636g
Chem. Commun., 2000, 1965–1966
This journal is © The Royal Society of Chemistry 2000
1965

View Online
stitued indolines.§ Under these conditions the products 5e and
5b were obtained in 54 and 67% yield with excellent
selectivities of meta+ortho = 1+10, and 1+20, respectively
(entries 5 and 6). However, only a moderate preference for the
ortho-isomer of 5b (meta+ortho = 1+3) was found in the
reaction of 4a (R2 = CH3) with but-3-yn-1-ol 2d, and the
reaction of 4b (R2 = Ph) with 2c occurred without a significant
selectivity. Obviously crossed alkyne cyclotrimerisation cata-
lysed by complex B are more sensitive to steric hindrance and
the substitution pattern of the alkynes, than those catalysed by
A.
In conclusion, we have achieved a new protocol for chemo-
and regioselective crossed alkyne cyclotrimerisations mediated
by Grubbs’ complex A, which is most likely based on a cascade
of metathesis steps. This novel catalytic protocol offers an
efficient, flexible and highly regioselective access to 4,6-substi-
tuted indolines. Moreover, in many cases the regioselectivity of
the alkyne cyclotrimerisation could be switched affording the
corresponding 4,5-substituted indolines, when Wilkinson’s
catalyst B was used. Notably, both catalysts are commercially
available and tolerate a wide range of functionalities.
Scheme 3
Table 2 Cycloaddition of 4a–b with 2b–e mediated by Grubbs’ catalyst A
or Wilkinson’s catalyst B‡a
Catalyst
Entry
4
R2
2
R1
(mol%) Yield (%)b meta+orthoc
1
2
3
4
5
6
7
8d
4a CH3 2c CH2OH
4a CH3 2d (CH2)2OH
4a CH3 2e (CH2)3OH
A (5)
5a
70
51
57
60
54
67
66
70
9+1
9+1
A (10) 5b
A (10) 5c
A (10) 5d
9+1
4b Ph
4a CH3 2b C3H7
2c CH2OH
9.5+1
1+10
1+20
1+3
B (5)
B (5)
B (5)
B (5)
5e
5a
5b
5f
4a CH3 2c CH2OH
4a CH3 2d (CH2)2OH
Financial support of this work by the Deutsche For-
schungsgemeinschaft (Wi-1696) is gratefully acknowledged.
4b Ph
2c CH2OH
1+1
a Reaction conditions: monoalkyne (5 eq.), reactions with catalyst A
[RuCl2(NCHPh)(PCy3)2] were run in CH2Cl2 at 40 °C in a sealed tube for
various times (10–20 h), reactions with catalyst B [RhCl(PPh3)3] were run
in toluene at rt for various reaction times (10–15 h). b Yield after
purification by silica gel chromatography. c Determined by 1H-NMR.
d Reaction run at 100 °C.
Notes and references
‡ All new compounds exhibited satisfactory spectra and elemental analyses.
The regioisomers could be separated by simple flash chromatography on
silica gel.
§ Regioselectivities of crossed alkyne cyclotrimerisations using catalyst B
were solvent dependent. Best selectivities were obtained with non-polar
solvents like toluene. A detailed discussion on the solvent-dependency of
this process will be presented in the full account of this study.
esis, well pronounced selectivities were observed with ratios of
meta+ortho = 5+1 and 6+1 for 3a and 3b–d, respectively.‡
Most strikingly, when the same set of compounds was treated
with 5 mol% Wilkinson’s catalyst B in toluene at 20 °C, the
regioselectivities of the above reactions could be reversed
giving the ortho-isomers of 3a–d as major products with ratios
of meta+ortho = 1+8, 1+4, 1+10, and 1+1.5, respectively (Table
1, entries 5–8).§ However, in the case of complex B—a catalyst
that is assumed to operate through rhodacyclooligoolefins as
intermediates in alkyne cyclotrimerisations—the outcome of
regioselectivity was markedly dependent on the substituent of
the monoalkyne 2.
Finally, we applied our findings to the regioselective
synthesis of 4,6- and 4,5-substituted indolines using either
complex A or B as catalyst and the 1,6-diynes 4a (R2 = Me) or
4b (R2 = Ph) together with the monoalkynes 2b–e (Scheme 3,
Table 2).8 When complex A was applied in CH2Cl2 at 40 °C the
indolines 5a–d were obtained in 51–70% yield, and once again
with excellent meta-selectivities of meta+ortho = 9+1 and
9.5+1 for 5a–c and 5d, respectively (entries 1–4). However, a
higher catalyst load of 10 mol% A was in some cases necessary
for the completion of the reaction. Notably, nearly uniform
isomer ratios were observed being independent of the substitu-
tion pattern of the alkynes used. These uniform ratios and
comparably higher selectivities for the formation of the
4,6-substituted indolines meta-5a–d should be attributed to the
electron richness of the alk-1-ynylamide moiety in 4a and 4b
causing a clear and distinct preference for the addition of the
electrophilic ruthenium benzylidene complex A to this electron
rich triple bond and thus underlying our mechanistic hypoth-
esis.
1 D. B. Grotjahn in Comprehensive Organometallic Chemistry II, ed. L. S.
Hegedus, E. W. Abel, F. G. A. Stone and G. Wilkinson, Pergamon,
Oxford, 1995, vol. 12, p. 741; N. E. Shore, in Comprehensive Organic
Synthesis: Selectivity, Strategy, and Efficiency in Modern Organic
Chemistry, ed. B. M. Trost and I. Fleming, Pergamon, Oxford, 1991, vol.
5, p. 1129.
2 (a) E. Müller, Synthesis, 1974, 761; (b) R. Grigg, R. Scott and P.
Stevenson, Tetrahedron Lett., 1982, 23, 2691; (c) R. L. Hillard III, C. A.
Parnell and K. P. C. Vollhardt, Tetrahedron, 1983, 39, 905; (d) K. P. C.
Vollhardt, Angew. Chem., Int. Ed. Engl., 1984, 23, 539; (e) R. Grigg, R.
Scott and P. Stevenson, J. Chem. Soc., Perkin Trans. 1, 1988, 1357; (f) P.
Bahataran and E. H. Smith, J. Chem. Soc., Perkin Trans 1, 1992, 2163;
(g) D. F. Taber and M. Rahimizadeh, Tetrahedron Lett., 1994, 35, 9139;
(h) F. E. McDonald, H. Y. H. Zhu and C. R. Holmquist, J. Am. Chem.
Soc., 1995, 117, 6605; (i) D. M. Duckworth, S. Lee-Wong, A. M. Z.
Slawin, E. H. Smith and D. J. Williams, J. Chem. Soc., Perkin Trans. 1,
1996, 815; (j) Y. Sato, K. Ohashi and M. Mori, Tetrahedron Lett., 1999,
40, 5231; (k) R. Grigg, V. Sridharan and J. Zhang, Tetrahedron Lett.,
1999, 40, 8277; (l) A. Bradley, W. B. Motherwell and F. Ujjainwalla,
Chem. Commun., 1999, 917; (m) Y. Yamamoto, R. Ogawa and K. Itoh,
Chem. Commun., 2000, 549.
3 B. Witulski and T. Stengel, Angew. Chem., Int. Ed., 1999, 38, 2426.
4 R. J. Sundberg in Indoles, Academic Press, London, 1996; G. W. Gribble,
J. Chem. Soc., Perkin Trans. 1, 2000, 1045.
5 W. J. Zuercher, M. Scholl and R. H. Grubbs, J. Org. Chem., 1998, 63,
4291; S.-H. Kim, N. Bowden and R. H. Grubbs, J. Am. Chem. Soc., 1994,
116, 10 801.
6 J.-U. Peters and S. Blechert, Chem. Commun., 1997, 1983; S. K. Das and
R. Roy, Tetrahedron Lett., 1999, 40, 4015.
7 R. H. Grubbs and S. Chang, Tetrahedron, 1998, 54, 4413; M. Mori, Top.
Organomet. Chem., 1998, 1, 133; S. K. Armstong, J. Chem. Soc., Perkin
Trans. 1, 1998, 371; M. Schuster and S. Blechert, Angew. Chem., Int. Ed.
Engl., 1997, 36, 2036.
Gratifyingly, when the 1,6-diyne 4a and the monoalkynes
2b,c were treated with 5 mol% Wilkinson’s catalyst B in
toluene at 20 °C, again a switch in regioselectivity was
observed, allowing the regioselective synthesis of 4,5-sub-
8 For the synthesis of alky-1-ynylamides see: B. Witulski and M.
Gößmann, Chem. Commun., 1999, 1879; B. Witulski and T. Stengel,
Angew. Chem., Int. Ed., 1998, 37, 489; and ref. 3.
1966
Chem. Commun., 2000, 1965–1966