A novel one-pot iridium-catalyzed alder-ene-murahashi sequence

Article abstract of DOI:10.1055/s-2007-970753

Yne allyl alcohols could be transformed under very mild conditions by a novel iridium-catalyzed one-pot cycloisomerization-Murahashi sequence in 43-77% yield. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-970753

LETTER
717
A Novel One-Pot Iridium-Catalyzed Alder–Ene–Murahashi Sequence
O
ne-Pot Iridium-Catal
a
yzed
A
lder
–
n
Ene–Murah
u
a
shi
S
equenc
e
e
la Kummeter, Christian M. Ruff, Thomas J. J. Müller*1
Organisch-Chemisches Institut der Ruprecht-Karls-Universität Heidelberg, Im Neuenheimer Feld 270, 69120 Heidelberg, Germany
Fax +49(211)8114324; E-mail: ThomasJJ.Mueller@uni-duesseldorf.de
Received 15 December 2006
Dedicated to Prof. Dr. Wolfgang Beck on the occasion of his 75th birthday
Abstract: Yne allyl alcohols could be transformed under very mild
conditions by a novel iridium-catalyzed one-pot cycloisomeriza-
tion–Murahashi sequence in 43–77% yield.
R
R
X
[M]
X
Key words: additions, alkynes, catalysis, condensations, ene reac-
tions, iridium
OH
OH
enol–keto
tautomerism
1
In recent years economically and ecologically benign
processes have become a playground for developing and
inventing new methodologies. In particular, the use of one
catalyst for more than one type of transformation in a one-
pot fashion, generally referred to as sequential catalysis,2
turns out to be catching two or more birds with one stone
as well as conceptual elegant and highly practical. Al-
though, among transition-metal-catalyzed sequences
sequentially palladium-catalyzed processes are well-de-
signed cascade reactions and experience quite recently an
increasing interest,3 for other metals this field has just
been opened.2,4
R
subsequent
reactions
X
O
2
Scheme 1 Alder–ene cycloisomerizations of yne allylalcohols 1 to
aldehydes 2 as an entry to sequential transformations
nation and subsequent reductive elimination, neither the
addition of an auxiliary carboxylic acid as for Pd(0) pre-
cursors nor the generation of air-sensitive cationic speci-
mens as for Rh(I) complexes is necessary. Hence, upon
reaction of yne allyl alcohols 1 in the presence of catalytic
amounts of [Ir(COD)Cl]2 in THF at room temperature the
heterocyclic enals 2 are isolated in good yields (Scheme 2,
Table 1).9,10
A group of transformations that are highly atom-econom-
ical are the transition-metal-catalyzed cycloisomeriza-
tions of enynes to generate cyclic dienes.5 In comparison
to palladium-,5a–c ruthenium-,5d,e and rhodium-cata-
lyzed5f–h Alder–ene cycloisomerizations (AEC), iridium
complexes5i,j are not that common, although, they have
just recently become attractive in allylic alkylation6 and
Murahashi condensation.7 The latter is a perfect example
for a base- and acid-free aldol-type condensation.
R
R
X
4.4 mol% [Ir(COD)Cl]2
X
As part of our program to design new sequences to
complex molecules initiated by intramolecular Alder–ene
cycloisomerizations of yne allyl alcohols to enals by
virtue of the tautomerism of the dienol intermediate
(Scheme 1),8 we are particularly interested in sequentially
catalyzed one-pot processes. Since Pd-catalyzed AEC re-
veal considerable drawbacks for aryl-substituted yne allyl
alcohols, we sought for an alternative catalyst system.
Here, we communicate a new sequential AEC–Murahashi
condensation in a one-pot fashion and under mild condi-
tions.
THF, 24 h
48–84%
O
OH
X = O, NTs
1
2
Scheme 2 Ir-catalyzed cycloisomerization of yne allyl alcohols 1 to
enals 2
Besides extensive spectroscopic analyses (1H NMR, 13C
NMR and DEPT, COSY, and HETCOR NMR experi-
ments, MS) the configuration of the double bond was
initially determined by a NOESY experiment and later
unambiguously confirmed by X-ray crystal structure anal-
ysis of the compound 2c (Figure 1).11
Therefore, we set out to test [Ir(COD)Cl]2 as previously
published for Alder–ene cycloisomerizations of enynes.5i,j
According to the tentative mechanistic rationale occurring
via an oxidative cyclization followed by b-hydride elimi-
Yne allyl alcohols with electronically variable aryl sub-
stituents can be transformed into the expected enalde-
hydes 2a–e in good yields (Table 1, entries 1–13).
However, aliphatic substituents even with variable steric
and electronic demand fail to give the desired products
SYNLETT 2007, No. 5, pp 0717–0720
1
6.
0
3.
2
0
0
7
Advanced online publication: 08.03.2007
DOI: 10.1055/s-2007-970753; Art ID: G36306ST
© Georg Thieme Verlag Stuttgart · New York

718
M. Kummeter et al.
LETTER
(Table 1, entries 12–15). With this regard the Pd-cata- With an Ir-catalyzed AEC in hand the stage is set for per-
lyzed cycloisomerization is fully complementary, where forming a second Ir-catalyzed step in a sequential fashion.
the yne allyl alcohols 1f–i can be efficiently trans- As the reaction medium is literally neutral we chose a se-
formed.8a Obviously, the presence of aryl substituents, quential combination of AEC and Murahashi reaction,7
presumably as a consequence of p-coordination regard- eventually both are iridium-catalyzed processes. There-
less of the electronic nature of the aryl ring, seems to be fore, after reacting the yne allyl alcohols 1 in the presence
essential for the transformation. Interestingly, indepen- of [Ir(COD)Cl]2 in THF for 24 hours a slight excess of
dent from the configuration of the double bond of the yne cyano acetates 3 was added to give after another 24 hours
allyl alcohol both diastereomers give the same yield cycloisomerization–condensation products in moderate to
(Table 1, entries 1 and 2). Other than Rh- or Pd-catalyzed good yields (Scheme 3, Table 2).8,12
AEC even the trans-configured yne allyl alcohol 1a can
be effectively transformed.
R
R
4.4 mol% [Ir(COD)Cl]2
X
THF
X
Table 1 Iridium-Catalyzed Cycloisomerization of Yne Allyl
Alcohols 1 to g,d-Enals 2a
CO2R2
OR2
(3)
then 1.5 equiv
NC
NC
O
Entry
1
X
R
Temp (°C) Product Yield (%)b
OH
43–76%
O
Ph
r.t.
r.t.
60
r.t.
60
r.t.
60
r.t.
60
r.t.
60
60
60
60
60
2a
2a
2a
2b
2b
2c
2c
2d
2d
2e
2e
2f
63
60
48
60
58
62
71
71
73
78
84
–
1
4
X = O, NTs
2c
3
O
Ph
Scheme 3 Ir-catalyzed cycloisomerization–Murahashi sequence
O
Ph
The structures of the sequence products were unambigu-
ously assigned by spectroscopic analyses and, in addition,
by an X-ray crystal structure analysis of the pyrrolidine 4e
(Figure 2).11
4
O
4-MeOC6H4
4-MeOC6H4
4-NO2C6H4
4-NO2C6H4
4-MeC6H4
4-MeC6H4
Ph
5
O
6
O
7
O
8
O
9
O
10
11
12
13
14
15
TsN
TsN
O
Ph
CH2OMe
Me
O
2g
2h
2i
–
O
CO2Me
TMS
–
O
–
Figure 2 Molecular structure of 4e (most hydrogen atoms have
been omitted for clarity)
a Reaction conditions: 1.0 equiv of the yne allyl alcohol 1, 0.044 equiv
of [Ir(COD)Cl]2, (0.2 M in THF).
b Yields refer to isolated yields of compounds 2 after flash chroma-
tography on dry silica gel.
The aldol condensation takes place as a purely iridium-
catalyzed process without addition of further bases or
acids. Indeed, the iridium catalyst is still active after the
initial AEC to catalyze a sequential Knoevenagel-type
condensation reaction. By coordination of the metal to the
nitrile the basicity of the metal and the acidity of the C–H
bond are concomitantly increased and the oxidative addi-
tion is simplified (Scheme 4).7 Thus, the metal–hydrido
complex can insert an electrophile, in this case an alde-
hyde that was formed in the previous AEC. Finally, reduc-
tive elimination regenerates the catalytic active species.
Besides water, no further by-products are produced.
c Starting from the trans-configured yne allyl alcohol.
Remarkably, in most cases room temperature is just suffi-
cient or even necessary to obtain better yields (Table 2,
entries 7 and 8). Due to the sensitivity of aliphatic alde-
Figure 1 Molecular structure of 2c (most hydrogen atoms have
been omitted for clarity)
Synlett 2007, No. 5, 717–720 © Thieme Stuttgart · New York

LETTER
One-Pot Iridium-Catalyzed Alder–Ene–Murahashi Sequence
719
Table 2 Alder-Ene Cycloisomerization–Murahashi Condensation Sequence Products 3a
Entry
1
X
R1
R2
Temp (°C)
Product 4
Yield (%)b
1
2
1a
1a
1b
1b
1c
1d
1e
1e
1b
1d
O
Ph
Me
60
r.t.
60
r.t.
r.t.
r.t.
60
r.t.
r.t.
r.t.
4a
4a
4b
4b
4c
4c
4e
4e
4f
74
73
61
69
43
70
17
72
50
76
O
Ph
Me
3
O
4-MeOC6H4
4-MeOC6H4
4-O2NC6H4
4-MeC6H4
Ph
Me
4
O
Me
5
O
Me
6
O
Me
7
TsN
TsN
O
Me
8
Ph
Me
9
4-MeOC6H4
4-MeC6H4
furfuryl
furfuryl
10
O
4g
a Reaction conditions: 1.0 equiv of the yne allyl alcohol 1, 0.044 equiv of [Ir(COD)Cl]2, (0.2 M in THF). After 24 h addition of 1.5 equiv of the
cyano acetate 3.
b Yields refer to isolated yield of compounds 4 after flash chromatography on silica gel.
R1
(3) For a review on sequentially Pd-catalyzed reactions, see:
Müller, T. J. J. Top. Organomet. Chem. 2006, 19, 149.
(4) (a) For a review on sequentially Ru-catalyzed reactions, see:
Bruneau, C.; Dérien, S.; Dixneuf, P. H. Top. Organomet.
Chem. 2006, 19, 296. (b) For a highlight on sequentially Rh-
catalyzed reactions, see: Körber, N.; Müller, T. J. J. Chim.
Oggi 2006, 24, 22.
R1
R1
E
R2
H
R2
M
H
R2
E
H
– M
insertion and
reductive
oxidative
addition
CN
M
CN
CN
elimination
Scheme 4 Mechanistic rationale by Murahashi
(5) For representative transition-metal-catalyzed Alder–ene
reactions, see for example Pd: (a) Trost, B. M. Acc. Chem.
Res. 1990, 23, 34. (b) Trost, B. M. Janssen Chim. Acta
1991, 9, 3. (c) Trost, B. M.; Krische, M. J. Synlett 1998, 1.
Ru: (d) Trost, B. M. Chem. Ber. 1996, 129, 1313. (e) Trost,
B. M.; Toste, F. D. Tetrahedron Lett. 1999, 40, 7739. Rh:
(f) Cao, P.; Wang, B.; Zhang, X. J. Am. Chem. Soc. 2000,
122, 6490. (g) Cao, P.; Zhang, X. Angew. Chem. Int. Ed.
2000, 22, 4104. (h) Lei, A.; He, M.; Zhang, X. J. Am. Chem.
Soc. 2002, 124, 8198. (i) Hashmi, A. S. K.; Haufe, P.; Rivas
Nass, A.; Bats, J. W. Adv. Synth. Catal. 2004, 346, 421.
(j) Hashmi, A. S. K.; Haufe, P.; Rivas Nass, A. Adv. Synth.
Catal. 2003, 345, 1237. (k) Hashmi, A. S. K.; Karch, R.;
Rivas Nass, A. Chem. Today 2006, 24, 16; supplement. Ir:
(l) Chatani, N.; Inoue, H.; Morimoto, T.; Muto, T.; Murai, S.
J. Org. Chem. 2001, 66, 4433. (m) Kezuka, S.; Okado, T.;
Niou, E.; Takeuchi, R. Org. Lett. 2005, 7, 1711. Ti:
(n) Sturla, S. J.; Kablaoui, N. M.; Buchwald, S. L. J. Am.
Chem. Soc. 1999, 121, 1976.
hydes, some of the yields of the products 4 are even higher
than for the corresponding AEC step itself (Table 2, en-
tries 1, 2, and 4).
In conclusion, based upon the iridium-catalyzed cyclo-
isomerization of yne allyl alcohols we have developed a
novel one-pot Alder–ene cycloisomerization–Murahashi
sequence that excels in its simplicity and diversity poten-
tial. Studies addressing scope and limitation of this novel
sequence are currently underway.
Acknowledgment
Financial support of the Deutsche Forschungsgemeinschaft (SFB
623) is gratefully acknowledged. We also cordially thank Dr. Frank
Rominger for performing the X-ray crystal structure analyses and
BASF AG for the generous donation of chemicals.
(6) (a) Bartels, B.; Helmchen, G. Chem. Commun. 1999, 8, 741.
(b) Schelwies, M.; Dübon, P.; Helmchen, G. Angew. Chem.
Int. Ed. 2006, 45, 2466.
References and Notes
(7) Murahashi, S.-I.; Takaya, H. Acc. Chem. Res. 2000, 33,
1855.
(1) New address: Lehrstuhl für Organische Chemie, Institut für
Organische Chemie und Makromolekulare Chemie der
Heinrich-Heine-Universität Düsseldorf, Universitätsstraße
1, 40225 Düsseldorf, Germany
(2) For reviews, see: (a) Wasilke, J.; Obrey, S. J.; Baker, R. T.;
Bazan, G. C. Chem. Rev. 2005, 105, 1001. (b) Ajamian, A.;
Gleason, J. L. Angew. Chem. Int. Ed. 2004, 43, 3754.
(c) Lee, J. M.; Na, Y.; Han, H.; Chang, S. Chem. Soc. Rev.
2004, 33, 302.
(8) (a) Kressierer, C. J.; Müller, T. J. J. Synlett 2004, 655.
(b) Kressierer, C. J.; Müller, T. J. J. Tetrahedron Lett. 2004,
45, 2155. (c) Kressierer, C. J.; Müller, T. J. J. Org. Lett.
2005, 7, 2237. (d) Kressierer, C. J.; Müller, T. J. J. Synlett
2005, 1721.
(9) All compounds have been fully characterized by
spectroscopic methods and by correct elemental analysis or
HRMS.
Synlett 2007, No. 5, 717–720 © Thieme Stuttgart · New York

720
M. Kummeter et al.
LETTER
(10) Typical Procedure of Compound 2c (Table 1, Entry 6).
To a solution of 30 mg (44 mmol) of [IR (COD)Cl]2 in 5 mL
of anhyd THF were added 252 mg (1.02 mmol) of 1c. The
reaction mixture was stirred at 60 °C for 24 h before it was
diluted with Et2O. After quick chromatography on dry silica
gel, 179 mg (71%) of 2c were obtained as a yellow solid; mp
61–66 °C. Rf = 0.40 (n-hexane–Et2O = 10:90, SiO2). 1H
NMR (300 MHz, CDCl3): d = 2.79 (dd, J = 8.4, 18.4 Hz, 1
H), 2.91 (dd, J = 5.1, 18.4 Hz, 1 H), 3.42 (m, 1 H), 3.61 (dd,
J = 5.6, 8.8 Hz, 1 H), 4.16 (dd, J = 6.7, 8.8 Hz, 1 H), 4.66 (s,
2 H), 6.46 (s, 1 H), 7.26 (d, J = 8.7 Hz, 2 H), 8.20 (d, J = 8.8
Hz, 2 H), 9.88 (s, 1 H). 13C NMR (75 MHz, CDCl3): d = 39.8
(CH), 47.3 (CH2), 69.9 (CH2), 72.4 (CH2), 119.8 (CH), 123.9
(CH), 128.4 (CH), 143.2 (Cquat), 146.1 (Cquat), 149.3 (Cquat),
199.9 (CH). MS (EI, 70 eV): m/z (%) = 247 (24) [M]+, 230
(38) [M – OH]+, 229 (33) [M – H2O]+, 204 (31) [M –
C2H3O]+, 203 (64) [M – C2H4O]+, 158 (22) [M – C4H10O]+.
HRMS (EI): m/z calcd: 247.0845; found: 247.0822. Anal.
Calcd for C13H13O4N (247.3): C, 63.15; H, 5.30; N 5.66.
Found: C, 62.99; H, 5.39; N, 5.52.
(12) Typical Procedure for 4e (Table 2, Entry 8).
To a solution of 30 mg (44 mmol) of [IR (COD)Cl]2 in 2.5
mL of anhyd THF were added 360 mg (1.01 mmol) of 1e.
The reaction mixture was stirred at r.t. for 24 h. Then 150 mg
(1.51 mmol) of cyanoacetate were added and the reaction
mixture was stirred for another 24 h at r.t. After dilution with
Et2O the crude product was chromatographed on silica gel to
give 319 mg (0.73 mmol, 72%) of 4e as a white crystalline
solid; mp 166–166.5 °C. Rf = 0.37 (n-hexane–Et2O = 10:90,
SiO2). 1H NMR (300 MHz, CDCl3): d = 2.42 (s, 3 H), 2.72
(m, 1 H), 2.85 (ddd, J = 6.1, 7.7, 13.9 Hz, 1 H), 2.99–3.11
(m, 2 H), 3.41 (ddd, J = 2.2, 8.2, 8.3 Hz, 1 H), 3.87 (s, 3 H),
4.23–4.05 (m, 2 H), 6.31 (s, 1 H), 7.14 (d, J = 8.4 Hz, 2 H),
7.43–7.21 (m, 5 H), 7.63 (dd, J = 7.9 Hz, 1 H), 7.72 (d,
J = 8.3 Hz, 2 H). 13C NMR (75 MHz, CDCl3): d = 21.5
(CH3), 35.1 (CH2), 43.4 (CH), 50.3 (CH2), 51.6 (CH2), 53.3
(CH3), 111.4 (Cquat), 113.3 (Cquat), 124.8 (CH), 127.6 (CH),
127.7 (CH), 128.2 (CH), 128.7 (CH), 129.9 (CH), 132.5
(Cquat), 135.7 (Cquat), 137.6 (Cquat), 144.0 (Cquat), 159.4 (CH),
161.2 (Cquat.). MS (EI, 70 eV): m/z (%) = 436 (18) [M]+, 312
(54) [M – C6H6NO2]+, 282 (25) [M –C7H6O2S]+, 281 (100)
[M – C7H7O2S]+, 157 (25), 149 (25), 156 (60) [C11H10N]+, 91
(35) [C7H7]+. Anal. Calcd for C24H24O4N2S (436.5): C,
66.04; H, 5.54; N, 6.42. Found: C, 65.95; H, 5.66; N, 6.35.
(11) CCDC-630817 (2c) and CCDC-630818 (4e) contain the
supplementary crystallographic data for this paper. These
data can be obtained free of charge via http://
www.ccdc.cam.ac.uk/conts/retrieving.html [or from the
Cambridge Crystallographic Data Center, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 (1223)336033; or
deposit@ccdc.cam.ac.uk].
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