Coupling-isomerization-Claisen sequences - Mechanistic dichotomies in hetero domino reactions

Article abstract of DOI:10.1039/b609669g

A new coupling-isomerization-Claisen domino reaction starting from electron deficient halides and 1-(hetero)aryl propargyl trityl ethers dichotomizes in the concluding steps of the sequence and gives rise to the formation of tricyclo[3.2.1.0^2,7

Full text of DOI:10.1039/b609669g

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Coupling–isomerization–Claisen sequences – mechanistic dichotomies
in hetero domino reactions{{
Daniel M. D’Souza, Frank Rominger and Thomas J. J. Mu¨ller*
Received (in Cambridge, UK) 7th July 2006, Accepted 23rd August 2006
First published as an Advance Article on the web 12th September 2006
DOI: 10.1039/b609669g
A new coupling–isomerization–Claisen domino reaction start-
ing from electron deficient halides and 1-(hetero)aryl propargyl
trityl ethers dichotomizes in the concluding steps of the
sequence and gives rise to the formation of tricy-
clo[3.2.1.02,7]oct-3-enes, enones, 1H-isochromenes, or indans
as a consequence of minute differences of substituent effects.
The coupling–isomerization reaction1 (CIR) of electron deficient
Scheme 2
(hetero)aryl halides and (hetero)aryl propargyl alcohols under the
conditions of the Sonogashira coupling2 is a domino process3 and
ether substituent was conceived and should open new reactivity
furnishes 1,3-di(hetero)aryl propenones in good yields. In recent
profiles for the development of Pd-catalyzed sequential and
domino reactions.6 Here, we report a series of CI–pericyclic
years, this new chalcone synthesis has been elaborated into an
entry to consecutive one-pot syntheses of pharmaceutically
sequences and their mechanistic dichotomies with propargyl trityl
relevant heterocycles.1,4 Mechanistically, the CIR proceeds as a
ethers as substrates.
rapid palladium–copper catalyzed alkyne coupling followed by a
Initial attempts to isolate the proposed allenyl intermediates of
rate determining base catalyzed propargyl alcohol to enone
CIR as allenyl methyl or silyl ethers always led to the formation of
isomerization. Addressing the in situ generation of allenyl species
complex mixtures of cyclobutane stereoisomers arising from
we have discovered a new hetero domino reaction based upon a
[2 + 2]-cycloadditions. With the support of molecular modelling
CI–Diels–Alder sequence via a vinyl allenyl allyl ether intermediate
studies trityl ethers were identified to shield the cumulated double
that gives rise to the formation of spirocyclic benzofuranones and
indolones (Scheme 1).5
bonds of the generated allene most effectively from dimerizations.
However, upon submitting a whole series of electron deficient
Encouraged by this intriguing hetero domino reaction, the
(hetero)aryl halides 1 and (hetero)aryl propargyl trityl ethers 2 to
kinetic stabilization of an allenyl intermediate by a bulky propargyl
the conditions of the CIR, i.e. in a boiling 1 : 1 mixture of
butyronitrile and triethylamine and in the presence of catalytic
amounts of PdCl2(PPh3)2 and CuI, tricyclo[3.2.1.02,7]oct-3-enes
3§" are isolated in excellent yields (Scheme 2, Table 1). In this
process four new carbon–carbon bonds and a complex tricyclic
framework are formed with high efficiency.
The structures of tricyclo[3.2.1.02,7]oct-3-enes 3 were unambigu-
ously supported by spectroscopic (1H, 13C and DEPT, COSY,
Table 1 Coupling–isomerization–Claisen rearrangement–Diels–
Alder domino sequence to tricyclo[3.2.1.02,7]oct-3-enes 3a
Entry
Tricyclo[3.2.1.02,7]oct-3-ene 3 (yield)b
1
2
3
4
5
6
7
8
a
3a (R1 = 2-thiazolyl, R2 = Ph, 85%)
3b (R1 = p-O2NC6H4, R2 = Ph, 91%)
3c (R1 = p-F3CC6H4, R2 = Ph, 97%)
3d (R1 = p-F3CC6H4, R2 = p-anisyl, 98%)
3e (R1 = p-F3CC6H4, R2 = p-tolyl, 99%)
3f (R1 = p-F3CC6H4, R2 = p-ClC6H4, 99%)
3g (R1 = p-MeO2CC6H4, R2 = 2-thienyl, 92%)
3h (R1 = p-NCC6H4, R2 = 2-thienyl, 89%)
Scheme 1 CIR–Diels–Alder sequence to spirocyclic benzofuranones and
indolones.
Organisch-Chemisches Institut der Ruprecht-Karls-Universita¨t
Heidelberg, Im Neuenheimer Feld 270, D-69120 Heidelberg, Germany.
E-mail: Thomas.J.J.Mueller@oci.uni-heidelberg.de;
Fax: ++49(0)6221546579; Tel: ++49(0)6221546207
{ Electronic supplementary information (ESI) available: Experimental
procedures and characterization for compounds 3, 4, 6 and 7. See DOI:
10.1039/b609669g
Reaction conditions: 1.0 equiv. of the (hetero) aryl iodide 1,
1.1 equiv. of propargyl trityl ether (0.1 in butyronitrile–
triethylamine 1 : 1), 0.05 equiv. of PdCl2(PPh3)2 and 0.05 equiv. of
2
M
b
CuI were heated to reflux temp. for 16–72 h. Yields refer to
isolated yields of tricyclo[3.2.1.02,7]oct-3-enes
chromatography on silica gel and crystallization to be ¢ 95% pure
as determined by NMR spectroscopy and elemental analysis.
3
after flash
{ This work is dedicated to Prof. Dr. Dr. h.c. Rolf Gleiter on the occasion
of his 70th birthday.
4096 | Chem. Commun., 2006, 4096–4098
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Scheme 4 Coupling–isomerization–Claisen rearrangement–6p electrocy-
clization domino sequence to 1H-isochromenes 6 and indans 7.
ethers 2 were submitted to the reaction conditions of the
CI–Claisen sequence. Most interestingly, neither tricy-
clo[3.2.1.02,7]oct-3-enes
Fig. 1 Molecular structure of tricyclo[3.2.1.02,7]oct-3-ene 3a (protons
3 nor enones 4 are formed, but
were omitted for clarity, ORTEP: 50% probability).
1H-isochromenes 6 and indans 7 are isolated in good to excellent
yields (Scheme 4)." For both classes of compounds, the molecular
structures were corroborated by X-ray structure analyses of
1H-isochromene 6b and indan 7a (Fig. 3 and Fig. 4).I
NOESY, HETCOR and HMBC NMR experiments, IR, UV/Vis,
mass spectrometry) and combustion analyses. Additionally, the
molecular structure was corroborated by an X-ray structure
analysis of compound 3a (Fig. 1).I
With respect to the substitution pattern of the (hetero)aryl
halides 1 and (hetero)aryl propargyl trityl ethers 2 the domino
process appears to be quite general. However, upon reacting para-
cyanobenzonitrile (1e) with slightly electron rich (2b) or slightly
electron poor propargyl trityl ethers (2e) a completely different
outcome of the sequence is observed and the enones 4 are obtained
in moderate to good yields (Scheme 3)." Again, the molecular
structure was unambiguously supported by an X-ray structure
analysis of compound 4b (Fig. 2).I
In all four cases, tricyclo[3.2.1.02,7]oct-3-enes, enones,
1H-isochromenes, and indans, the product analyses readily
account for congruent and related initial steps followed by
mechanistic dichotomies in the conclusion of the sequences.
Mechanistically, these new CI hetero domino sequences can be
rationalized as follows (Scheme 5).
The CIR of electron deficient halides 8 and 1-(hetero)aryl
propargyl trityl ethers 2 furnishes in all cases allenyl trityl ethers 9
Obviously, this puzzling result is caused by minute electronic
substituent effects of the aryl halide and the propargyl trityl ether.
Hence, even stronger electron withdrawing groups, such as
carbonyl groups, directly linked to the isomerizing propargyl trityl
ether moiety should enhance the rate of the concluding pericyclic
step. Therefore, (hetero)aroyl chlorides 5 and propargyl trityl
Fig. 3 Molecular structure of isochromene 6b (protons and one molecule
of chloroform were omitted, ORTEP: 50% probability).
Scheme 3
Fig. 4 Molecular structure of indan 7a (most protons were omitted for
Fig. 2 Molecular structure of enone 4b (protons and one molecule of
clarity, ORTEP: 50% probability).
acetone were omitted for clarity, ORTEP: 50% probability).
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Chem. Commun., 2006, 4096–4098 | 4097

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der Chemischen Industrie. The authors also cordially thank Steffen
Wunderlich for experimental assistance.
Notes and references
§ All new compounds have been fully characterized spectroscopically and
by correct elemental analysis and HRMS.
" General procedure: To a deaerated mixture of 6 mL of butyronitrile and
6 mL of triethylamine in an oven dried screw capped vessel were added
successively 1.50 mmol of the electron deficient halide 8 (1 or 5), 1.65 mmol
of the 1-aryl propargyl trityl ethers 2, 53 mg (0.08 mmol) of PdCl2(PPh3)2,
and 14 mg (0.07 mmol) of CuI. The solution was stirred at room
temperature for 1 h, and then heated to reflux temperature for 16–72 h.
After work-up, chromatography on silica gel (hexane–ethyl acetate, 2 : 1)
and crystallization the products 3, 4, 6, or 7 were obtained as colorless
crystals.
I Crystallographic data: 3a. C34H29NO2S, M = 515.6, triclinic, space group
¯
P1, a = 10.7645(4), b = 10.8448(3), c = 13.3319(5) s, a = 78.687(1), b =
69.861(1), c = 68.875(1)u, V = 1358.37(8) s3, T = 200(2) K, Z = 2, r =
1.26 g cm23, crystal dimensions 0.25 6 0.13 6 0.10 mm3, Mo Ka
radiation, m = 0.15 mm21, l = 0.71073 s. Data were collected on a Bruker
Smart APEX diffractometer and a total of 5133 of the 12447 reflections
were unique [Rint = 0.0416]. Refinement on F2, wR2 = 0.096 (observed
reflections), R1 = 0.045 for [I . 2s(I)]. 4b. C35H24ClNO, M = 510.0,
¯
triclinic, space group P1, a = 9.1420(3), b = 11.3244(4), c = 14.2565(5) s,
a = 71.900(1), b = 89.355(1), c = 77.085(1)u, V = 1364.72(8) s3, T =
200(2) K, Z = 2, r = 1.24 g cm23, crystal dimensions 0.32 6 0.22 6
0.14 mm3, Mo Ka radiation, m = 0.17 mm21, l = 0.71073 s. Data were
collected on a Bruker Smart APEX diffractometer and a total of 6191 of
the 14158 reflections were unique [Rint = 0.0405]. Refinement on F2, wR2 =
0.107 (observed reflections), R1 = 0.049 for [I . 2s(I)]. 6b. C34H25Cl3O2S,
¯
M = 603.95, triclinic, space group P1, a = 8.9794(3), b = 11.1754(4), c =
Scheme 5 Mechanistic rationale of the CI–Claisen domino sequences.
14.8724(6) s, a = 87.793(1), b = 74.637(1), c = 88.191(1)u, V =
1437.67(9) s3, T = 200(2) K, Z = 2, r = 1.39 g cm23, crystal dimensions
0.30 6 0.22 6 0.08 mm3, Mo Ka radiation, m = 0.42 mm21, l = 0.71073 s.
Data were collected on a Bruker Smart APEX diffractometer and a total of
6549 of the 15088 reflections were unique [Rint = 0.0349]. Refinement on F2,
wR2 = 0.104 (observed reflections), R1 = 0.043 for [I . 2s(I)]. 7a.
C36H28O3, M = 508.58, monoclinic, space group P21/c, a = 8.905(4), b =
30.80(1), c = 10.012(5) s, a = 90, b = 99.91(1), c = 90u, V = 2705(2) s3, T =
200(2) K, Z = 4, r = 1.25 g cm23, crystal dimensions 0.24 6 0.14 6
0.10 mm3, Mo Ka radiation, m = 0.08 mm21, l = 0.71073 s. Data were
collected on a Bruker Smart APEX diffractometer and a total of 2777 of
the 14007 reflections were unique [Rint = 0.1048]. Refinement on F2, wR2 =
0.108 (observed reflections), R1 = 0.047 for [I . 2s(I)]. CCDC 610545–
610548. For crystallographic data in CIF or other electronic format see
DOI: 10.1039/b609669g
that undergo a [3,3]-sigmatropic rearrangement (allenyl–benzyl
Claisen rearrangement) to give 5-vinyl-1,3-cyclohexadiene as
common intermediates 10. The initial products 10 undergo
intramolecular cycloadditions7 for all electron deficient (hetero)aryl
substituents, except for para-cyanophenyl in combination with
modestly electron withdrawing and releasing aryl propargyl
derivatives. The sequence concludes with an intramolecular
[4 + 2] cycloaddition to give tricyclo[3.2.1.02,7]-oct-3-enes 3.
Cyano groups tend to stabilize radicals,8 therefore, for para-
cyanophenyl substitution and electron withdrawing and releasing
aryl propargyl substrates the resulting products are enones 4,
resulting from an aromatizing 1,3-H shift.
1 T. J. J. Mu¨ller, M. Ansorge and D. Aktah, Angew. Chem., Int. Ed., 2000,
39, 1253.
2 For lead reviews on Sonogashira couplings, see e.g.: (a) K. Sonogashira,
in Metal catalyzed Cross-coupling Reactions, Wiley-VCH, Weinheim,
1998, p. 203; (b) K. Sonogashira, J. Organomet. Chem., 2002, 653(1–2),
46.
3 For excellent reviews and classifications of domino reactions, see e.g.: (a)
L. F. Tietze and U. Beifuss, Angew. Chem., Int. Ed. Engl., 1993, 32, 131;
(b) L. F. Tietze, Chem. Rev., 1996, 96, 115.
4 See e.g. (a) R. U. Braun, K. Zeitler and T. J. J. Mu¨ller, Org. Lett., 2001, 3,
3297; (b) O. G. Dediu, N. A. M. Yehia, T. Oeser, K. Polborn and
T. J. J. Mu¨ller, Eur. J. Org. Chem., 2005, 1834; (c) O. G. Schramm, ne´e
Dediu, T. Oeser and T. J. J. Mu¨ller, J. Org. Chem., 2006, 71, 3494.
5 D. M. D’Souza, F. Rominger and T. J. J. Mu¨ller, Angew. Chem., Int. Ed.,
2005, 44, 153.
(Hetero)aroyl substituents are significantly stronger electron
withdrawing groups. As a consequence, deprotonation of 10
should readily furnish vinylogous enolates 11. Here, the electron
withdrawing capacity of the carbonyl group influences the
equilibrium 11/12. Stronger electron withdrawing aryl groups on
the carbonyl group favor the Z-isomer 11 leading to
1H-isochromenes 6 via a 6p electrocyclization of the heterotriene
moiety and protonation. On the other hand the electron rich anisyl
group favors the formation of the E-isomer 12. Now, 6p
electrocyclization of the pentadienide and protonation furnish
indans 7 with trans-configured acyl groups.
6 For recent reviews on transition metal assisted sequential processes, see
e.g.: (a) G. Kirsch, S. Hesse and A. Comel, Curr. Org. Synth., 2004, 1, 47;
(b) I. Nakamura and Y. Yamamoto, Chem. Rev., 2004, 104, 2127 and
references therein; (c) G. Balme, E. Bossharth and N. Monteiro, Eur. J.
Org. Chem., 2003, 4101; (d) G. Battistuzzi, S. Cacchi and G. Fabrizi, Eur.
J. Org. Chem., 2002, 2671.
7 See, e.g. S. M. Ng, C. M. Beaudry and D. Trauner, Org. Lett., 2003, 5,
1701 and references cited therein.
8 For the stabilization of benzyl radicals by the cyano group, see e.g.:
T. H. Fisher and A. W. Meierhoefer, J. Org. Chem., 1978, 43, 224.
In conclusion, we have discovered new domino reactions based
upon CI–Claisen–pericyclic sequences that are highly sensitive to
the electronic nature of the substitution pattern of the reactants.
Studies addressing the synthetic scope of these new domino
reactions and the elucidation of the electronic effects causing the
observed dichotomies are currently underway.
This
work
was
supported
by
the
Deutsche
Forschungsgemeinschaft (Graduate College 850), and the Fonds
4098 | Chem. Commun., 2006, 4096–4098
This journal is ß The Royal Society of Chemistry 2006