Lanthanide-Catalyst-Mediated Tandem Double Intramolecular Hydroalkoxylation/Cyclization of Dialkynyl Dialcohols: Scope and Mechanism

Article abstract of DOI:10.1002/chem.200903027

Lanthanide-organic complexes of the general type [Ln{N-(SiMe ₃)₂}₃] (Ln = La, Sm, Y, Lu) serve as effective precatalysts for the rapid, exo-selective, and highly regioselective tandem double intramolecular hydroalkoxylation/cyclization of primary and secondary dialkynyl dialcohols to yield the corresponding bi-exocyclic enol ethers. Conversions are highly selective with products distinctly different from those generally produced by conventional transition metal or other catalysts, and the turnover frequencies with some substrates are too large to determine accurately. The rates of terminal alkynl alcohol hydroalkoxylation/cyclization are significantly more rapid than those of internal alkynyl alcohols, arguing that steric demands dominate the cyclization transition state. The hydroalkoxylation/cyclizations of internal dialkynyl dialcohols afford excellent E selectivity. The rate law for dialkynyl dialcohol hydroalkoxylation/ cyclization is first-order in [catalyst] and zero-order in [alkynyl alcohol], as is observed for the organolanthanide-catalyzed hydroamination/cyclization of aminoalkenes, aminoalkynes, and aminoallenes, and the intramolecular single-step hydroalkoxylation/cyclization of alkynyl alcohols. An ROH/ROD kinetic isotope effect of 0.82(0.02) is observed for the tandem double hydroalkoxylation/ cyclization. These mechanistic data implicate turnover-limiting insertion of C-C unsaturation into the Ln-O bond, involving a highly organized transition state, with subsequent, rapid Ln-C protonolysis.

Full text of DOI:10.1002/chem.200903027

DOI: 10.1002/chem.200903027
Lanthanide-Catalyst-Mediated Tandem Double Intramolecular
Hydroalkoxylation/Cyclization of Dialkynyl Dialcohols: Scope and
Mechanism
SungYong Seo and Tobin J. Marks*[a]
Abstract: Lanthanide-organic com-
plexes of the general type [Ln{N-
ACHTUNGTRENNUNG(SiMe3)2}3] (Ln=La, Sm, Y, Lu) serve
as effective precatalysts for the rapid,
exo-selective, and highly regioselective
tandem double intramolecular hydro-
alkynl alcohol hydroalkoxylation/cycli-
zation are significantly more rapid than
those of internal alkynyl alcohols, argu-
ing that steric demands dominate the
cyclization transition state. The hydro-
alkoxylation/cyclizations of internal di-
alkynyl dialcohols afford excellent E
selectivity. The rate law for dialkynyl
dialcohol hydroalkoxylation/cyclization
is first-order in [catalyst] and zero-
order in [alkynyl alcohol], as is ob-
served for the organolanthanide-cata-
lyzed hydroamination/cyclization of
aminoalkenes, aminoalkynes, and ami-
noallenes, and the intramolecular
single-step hydroalkoxylation/cycliza-
tion of alkynyl alcohols. An ROH/
ROD kinetic isotope effect of
ACHTUNGTRENNUNGalkoxylation/cyclization of primary and
secondary dialkynyl dialcohols to yield
the corresponding bi-exocyclic enol
ethers. Conversions are highly selective
with products distinctly different from
those generally produced by conven-
tional transition metal or other cata-
lysts, and the turnover frequencies with
some substrates are too large to deter-
mine accurately. The rates of terminal
ACHUTNGREN0NUG .82ACHTUNGTRENN(UGN 0.02) is observed for the tandem
double hydroalkoxylation/cyclization.
These mechanistic data implicate turn-
ꢀ
over-limiting insertion of C C unsatu-
Keywords: heterogeneous cataly-
ꢀ
ration into the Ln O bond, involving a
sis
· hydroalkoxylation · lantha-
highly organized transition state, with
subsequent, rapid Ln–C protonolysis.
nides · oxygen heterocycles · paral-
lel reactions
Introduction
tramolecular variants of this reaction would provide
straightforward and atom-efficient approaches to numerous
Oxygen-containing heterocycles are important structural
motifs in many naturally occurring and pharmacologically
active organic molecules (e.g., okadaic acid, prostacyclin,
and monensin A).[1] For this reason, the constraints of tradi-
tional heterocycle synthetic methodologies have stimulated
great interest in the development of new, more efficient and
selective homogeneous catalytic approaches to important
heterocyclic frameworks.[2] In principle, many important and
useful oxygen-containing organic structures should be acces-
sible via catalytic hydroalkoxylation of alkenes or alkynes
using transition metal or other catalysts,[3] and effective in-
[a] Dr. S. Seo, Prof. Dr. T. J. Marks
Department of Chemistry, Northwestern University
Evanston, Illinois 60208 (USA)
E-mail: t-marks@northwestern.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200903027: Complete experi-
1
mental procedure and spectral data for all synthetic compounds; H
and 13C NMR spectra of representative compounds.
5148
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Chem. Eur. J. 2010, 16, 5148 – 5162

FULL PAPER
oxygen-containing heterocycles. However, while catalytic
hydroalkoxylation offers many attractions versus traditional
heterocycle synthetic pathways, efficient catalytic transfor-
mations present many challenges due to several factors, such
ꢀ
as the relatively large bond enthalpies of typical O H bonds
and the modest reactivity of electron-rich olefins with nu-
A
ACHTUNGTRENNUNGphiles.
cy is not limited simply to high yields but is, in fact, multi-
faceted.[4] Over the past several years, significant research
activity has focused on developing new bond-forming meth-
odologies which enhance synthetic efficiency and atom
economy.[5] Among these, tandem reactions which promote
formation of several new bonds in a single sequence from
readily available starting materials are of particular inter-
est.[6] Processes that form multiple carbon–carbon or
carbon–heteroatom bonds in a sequence of events without
inefficient isolation of intermediates represent a powerful
means to approach this ideality. In this context, concurrent
tandem reactions provide a means to improve synthetic effi-
ciency and chemoselectivity. In terms of hydrofunctionaliza-
tion, there has therefore been great interest in developing
more efficient and selective single-site hydroalkoxylation
catalysts to mediate such challenging transformation sequen-
ces.[7–10]
ꢀ
cient and selective hydroamination/C C bond formation se-
quences have been reported [e.g., Eq. (6)].[32c]
There have been growing efforts to develop catalysts for
tandem hydroalkoxylation. Most of these transformations
produce cyclic or bicyclic acetals using transition-metal cata-
lysts via intermolecular or intramolecular pathways. Tandem
intermolecular hydroalkoxylation processes include the for-
mation of cyclic acetals from alkynyl alcohols and another
alcohol such as MeOH or EtOH using AuCl3,[11] [AuCl-
A
ACHTUNGTRENNUNG(cod)Cl}2] catalysts [e.g., Eqs. (1) and
cyclic acetals from alkynyl dialcohols using [AuCl
(Ph3P)],[14]
We recently reported a detailed study of the scope, kinet-
ics, and mechanism of the catalytic intramolecular single hy-
droalkoxylation/cyclization of a broad series terminal and
internal monoalkynyl alcohols.[33] In that work we showed
that internal alkynyl alcohols are transformed exclusively to
exo-enol ethers as shown in Scheme 1 with thermodynamic
considerations.[34] Herein we report a detailed scope/kinetic/
mechanistic study aimed at determining whether and with
what scope, catalytic dialkynyl dialcohol tandem double hy-
droalkoxylation processes can be effected [Eq. (7)]. Al-
Rh,[15] or Ir catalysts [Eq. (3)].[16] For example, Leyꢁs and De
Brabanderꢁs groups used PtCl4 [Eq. (4)][17] and [{Pt-
ACHTUNGTRENNUNG
(CH2CH2)Cl2}2] [Eq. (5)][18] catalysts to produce fused bicy-
clic acetals from alkynyl dialcohols. However, to the best of
ꢀ
our knowledge, tandem intramolecular C O fusion process-
es using two alkynyl groups and two alcohol functionalities
have never been reported.
Organolanthanide complexes are known to be highly
active hydrofunctionalization catalysts.[19–21] Among such cat-
alysts, easily prepared homoleptic [Ln{NACHTNUGTRNE(UNG SiMe3)2}3] amido
complexes (Ln=lanthanide, Y)[22] are versatile agents for a
variety of organic transformations, which can be either inter-
molecular or intramolecular in character. Successful inter-
molecular transformations include ynone synthesis,[23] cross-
aldol reactions,[24] coupling of isocyanides with terminal al-
kynes,[25] dimerization of terminal alkynes,[26] guanylation of
amines,[27] hydrosilylation,[28] hydroboration,[29] Tishchenko
aldehyde dimerization,[30]and amidations.[31] Intramolecular
transformations include hydroelementation processes, such
as hydroamination,[32,30b] hydrophosphination,[20b] and hydro-
alkoxylation.[33] In regard to organolanthanide-mediated
tandem hydrofunctionalization processes, several very effi-
though the catalytic synthesis of such target structures has
never been reported, these structures should be very useful
scaffolds, with a variety of applications in natural and phar-
maceutical product synthesis. Note that structurally similar
Chem. Eur. J. 2010, 16, 5148 – 5162
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5149

T. J. Marks and S. Seo
400 MHz, 1H; 100 MHz, 13C), or Inova-500 (500 MHz, 1H; 125 MHz, 13C,
2
1
2
76.7 MHz, H) instrument. Chemical shifts (d) for H, H, and 13C are ref-
erenced to internal solvent resonances and reported relative to SiMe4.
NMR experiments on air-sensitive samples were conducted in Teflon
valve-sealed J. Young tubes. Mass spectra data were obtained on a
Varian 1200 Quadrupole Mass Spectrometer and Micromass Quadro II
Spectrometer. Elemental analyses were performed by Midwest Micro-
labs, Indianapolis, IN.
1-(2,5-Diethynyl-4-(hydroxymethyl)phenyl)ethanol
(11):
1H NMR
(400 MHz, CDCl3): d=7.67 (s, 1H), 7.54 (s, 1H), 5.28 (q, J=6.3 Hz, 1H),
4.77 (s, 2H), 3.39 (s, 2H), 1.94 (br, 2H), 1.47 ppm (d, J=6.3 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=147.38, 141.85, 131.56, 129.33, 119.97,
83.83, 83.49, 80.78, 67.79, 63.09, 23.97 ppm; elemental analysis calcd (%)
for C13H12O2: C 77.98, H 6.04; found: C 77.88, H 6.08.
1,1’-(2,5-Diethynyl-1,4-phenylene)diethanol (13): 1H NMR (400 MHz,
CDCl3): d=7.64 (s, 2H), 5.26 (q, J=6.3 Hz, 2H), 3.39 (s, 2H), 2.03 (s,
2H), 1.47 ppm (d, J=6.3 Hz, 6H); 13C NMR (100 MHz, CDCl3): d=
148.24, 129.68, 115.71, 83.89, 68.02, 24.16 ppm; elemental analysis calcd
(%) for C14H14O2: C 78.48, H 6.59; found: C 78.24, H 6.78.
(4,6-Diethynyl-1,3-phenylene)dimethanol (15): 1H NMR (400 MHz,
[D6]DMSO): d=7.71 (s, 1H), 7.41 (s, 1H), 5.37 (t, J=5.9 Hz, 2H), 4.59
(d, J=5.5 Hz, 4H), 4.38 (s, 2H), 2.26 (t, J=5.5 Hz, 2H), 2.04 ppm (t, J=
2.8 Hz, 1H); 13C NMR (100 MHz, [D6]DMSO): d=145.69, 135.36, 124.56,
117.71, 85.94, 80.41, 61.37 ppm; elemental analysis calcd (%) for
C12H10O2: C 77.40, H 5.41; found: C 77.25, H 5.31.
Scheme 1. Catalytic cycle for lanthanide-mediated single hydroalkoxyla-
tion/cyclization of internal alkynyl alcohols.
1,1’-(4,6-Diethynyl-1,3-phenylene)diethanol (17): 1H NMR (400 MHz,
CDCl3): d=7.67 (s, 1H), 7.48 (s, 1H), 5.20 (m, 2H), 3.25 (s, 2H), 2.83
(br, 2H), 1.41 ppm (d, J=3.9 Hz, 6H); 13C NMR (100 MHz, CDCl3): d=
152.26, 152.19, 139.74, 139.55, 123.63, 123.42, 120.52, 85.00, 84.90, 82.88,
70.62, 70.43, 26.56 ppm; elemental analysis calcd (%) for C14H14O2: C
78.48, H 6.59; found: C 77.98, H 6.67.
(3,6-Diethynyl-1,2-phenylene)dimethanol (19): 1H NMR (400 MHz,
CDCl3): d=7.44 (s, 2H), 5.00 (d, J=6.3 Hz, 4H), 3.37 (s, 2H), 2.84 ppm
(t, J=6.3 Hz, 2H); 13C NMR (100 MHz, CDCl3): d=142.15, 132.57,
123.38, 83.00, 81.08, 61.03 ppm; elemental analysis calcd (%) for
C12H10O2: C 77.40, H 5.41; found: C 77.40, H 5.50.
structures such as O,O-spiroacetals,[35] omaezakianol,[36] and
gymnocin A[37] are prevalent in natural products. In this ac-
count, substrate synthetic routes, reaction scope, stereoselec-
tivity, metal ion effects, and reaction kinetics and mecha-
nism are examined in detail and compared/contrasted with
previously characterized intramolecular hydroalkoxylation/-,
intramolecular hydroamination/-, and hydrophosphination/
cyclization processes.
2-(But-2-ynyl)-2-(prop-2-ynyl)propane-1,3-diol (21): 1H NMR (400 MHz,
CDCl3): d=3.68 (d, J=5.5 Hz, 4H), 2.42 (t, J=5.5 Hz, 2H), 2.31 (d, J=
2.3 Hz, 2H), 2.24 (m, 2H), 2.01 (t, J=2.7 Hz, 1H), 1.76 ppm (t, J=
2.3 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=80.79, 78.82, 74.84, 71.20,
66.95, 42.39, 22.37, 21.98, 3.74 ppm; elemental analysis calcd (%) for
C10H14O2: C 72.26, H 8.49; found: C 72.02, H 8.49.
Experimental Section
Materials and methods: All manipulations of air-sensitive materials were
carried out with rigorous exclusion of oxygen and moisture in flame- or
oven-dried Schlenk-type glassware on a dual-manifold Schlenk line, inter-
faced to a high-vacuum line (10ꢀ6 Torr), or in a nitrogen-filled vacuum at-
mospheres glove box with a high capacity recirculator (<1 ppm of O2).
Argon (Airgas, prepurified) was purified by passage through a MnO
oxygen-removal column and a Davison 4 ꢂ molecular sieves column.
Pentane was dried using activated alumina columns according to the
method described by Grubbs.[38] Et2O and THF were distilled from
sodium/benzophenone. Benzene was dried by vacuum-transfer from Na/
K alloy immediately prior to use if employed for catalyst synthesis or cat-
alytic reactions. D2O (Cambridge Isotope Laboratories; all 99+ atom%
D) was used directly as received. [D6]-Benzene and [D10]-o-xylene (Cam-
bridge Isotope Laboratories; all 99+ atom% D) used for NMR reactions
and kinetic measurements were stored in vacuo over Na/K alloy in re-
sealable bulbs and were vacuum-transferred immediately prior to use.
Substrates 1,[39] 7,[40] 9,[41] 27[42] and 29[41,42] were prepared as reported in
the literature. All liquid substrates were dried twice as solutions in [D6]-
benzene over freshly activated Davison 4 ꢂ molecular sieves and were
degassed by freeze–pump–thaw methods. They were then stored in
vacuum-tight storage flasks. Solid substrates were sublimed under high-
vacuum and stored in the glove box before use. The lanthanide com-
2-(Prop-2-ynyl)-2-(3-(trimethylsilyl)prop-2-ynyl)propane-1,3-diol
(22):
1H NMR (400 MHz, CDCl3): d=3.72 (d, J=4.7 Hz, 4H), 2.34 (s, 4H),
2.25 (q, J=5.5 Hz, 2H), 2.02 (t, J=2.7 Hz, 1H), 0.13 ppm (s, 9H);
13C NMR (100 MHz, CDCl3): d=80.42, 71.40, 71.37, 66.91, 66.74, 42.37,
23.61, 22.10, 21.91, 0.23 ppm; elemental analysis calcd (%) for
C12H20O2Si: C 64.24, H 8.98; found: C 67.55, H 8.48.
2-(3-Phenylprop-2-ynyl)-2-(prop-2-ynyl)propane-1,3-diol (23): 1H NMR
(400 MHz, CDCl3): d=7.37 (m, 2H), 7.26 (m, 3H), 3.78 (d, J=6.3 Hz,
4H), 2.55 (s, 2H), 2.41 (d, J=3.1 Hz, 2H), 2.26 (t, J=5.5 Hz, 2H),
2.04 ppm (t, J=2.8 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=131.81,
128.49, 128.18, 123.51, 85.78, 83.57, 80.62, 71.43, 67.06, 42.75, 23.02,
22.15 ppm; elemental analysis calcd (%) for C15H16O2: C 78.92, H 7.06;
found: C 79.10, H 7.16.
1-(4-(Hydroxymethyl)-2,5-bis(phenylethynyl)ethanol
(33):
1H NMR
(400 MHz, [D6]DMSO): d=7.66 (s, 1H), 7.57 (s, 1H), 7.40 (m, 4H), 7.27
(m, 6H), 5.18 (m, 1H), 4.93 (m, 2H), 4.71 (d, J=5.5 Hz, 2H), 1.37 ppm
(d, J=6.3 Hz, 3H); 13C NMR (100 MHz, [D6]DMSO): d=147.62, 142. 15,
131.44, 131.34, 129.76, 128.63, 128.58, 128.55, 128.39, 122.94, 120.53,
119.88, 95.22, 87.49, 87.20, 66.72, 61.64, 24.97 ppm; elemental analysis
calcd (%) for C25H20O2: C 85.20, H 5.72; found: C 83.44, H 5.97.
1,1’-(2,5-Bis(phenylethynyl)-1,4-phenylene)diethanol
(35):
1H NMR
plexes [Ln{NACHTUNGTRENNUNG(SiMe3)2}3] (Ln=La, Nd, Sm, Y, and Lu), were prepared ac-
cording to published procedures.[22] Details of substrate syntheses and
characterization are provided in the Supporting Information.
(400 MHz, [D6]DMSO): d=7.66 (m, 2H), 7.55 (m, 4H), 7.42 (m, 6H),
5.35 (m, 2H), 5.14 (br, 2H), 1.37 ppm (m, 6H); 13C NMR (100 MHz,
[D6]DMSO): d=150.75, 149.68, 135.42, 134.38, 133.91, 132.14, 131.97,
125.76, 125.26, 123.21, 122.59, 114.27, 98.24, 92.20, 90.22, 87.44, 69.11,
Physical and analytical measurements: NMR spectra were recorded on a
Varian Gemini 300 (300 MHz, 1H; 75 MHz, 13C), Mercury-400 (FT,
5150
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Double Intramolecular Hydroalkoxylation/Cyclization
FULL PAPER
67.19, 33.50, 28.00 ppm; elemental analysis calcd (%) for C26H22O2: C
85.22, H 6.05; found: C 84.92, H 6.32.
6.3 Hz, 1H), 4.71 (s, 2H), 4.70 (s, 1H), 4.67 (s, 1H), 4.48 (s, 1H), 4.44 (s,
1H), 1.12 ppm (d, J=6.3 Hz, 3H); 13C NMR (100 MHz, C6D6): d=
164.10, 163.03, 147.90, 143.38, 137.66, 115.94, 115.66, 82.72, 81.21, 81.11,
75.41, 23.75 ppm; HRMS-ESI: m/z: calcd for C13H13O2: 201.0916; found:
201.0908 [M+H+].
A
(37):
1H NMR
(400 MHz, CDCl3): d=7.68 (s, 1H), 7.62 (s, 1H), 7.46 (m, 4H), 7.30 (m,
6H), 4.87 (s, 4H), 3.74 ppm (s, 2H); 13C NMR (100 MHz, CDCl3): d=
143.47, 135.20, 131.51, 128.54, 125.34, 122.82, 119.80, 94.33, 85.97,
63.14 ppm; elemental analysis calcd (%) for C24H18O2: C 85.18, H 5.36;
found: C 79.82, H 5.33.
1,5-Dimethyl-3,7-dimethylene-1,5-dihydrofuroACTHNUTRGENUG[N 3,4-f]isobenzofuran (14):
1H NMR (400 MHz, C6D6): d=6.75 (d, J=4.7 Hz, 2H), 5.12 (q, J=
5.5 Hz, 2H), 4.68 (s, 2H), 4.48 (s, 2H), 1.13 ppm (t, J=5.5 Hz, 6H);
13C NMR (100 MHz, C6D6): d=160.42, 145.42, 135.02, 113.11, 113.09,
80.09, 78.47, 21.10 ppm; HRMS-ESI: m/z: calcd for C14H15O2: 215.1072;
found: 215.1062 [M+H+].
1,1’-(4,6-Bis(phenylethynyl)-1,3-phenylene)diethanol
(39):
meso/d,l:
1H NMR (400 MHz, CDCl3): d=7.66 (s, 1H), 7.50 (m, 2H), 7.45 (m,
3H), 7.35 (m, 2H), 7.29 (m, 4H), 5.37 (m, 2H), 3.26 (br, 2H), 1.54 ppm
(m, 6H); 13C NMR (100 MHz, CDCl3): d=148.23, 148.09, 135.86, 135.55,
131.46, 128.61, 128.46, 128.34, 123.02, 121.19, 119.33, 118.91, 94.62, 94.42,
86.17, 86.08, 68.57, 68.49, 24.20, 24.01 ppm; elemental analysis calcd (%)
for C26H22O2: C 85.22, H 6.05; found: C 80.62, H 5.86.
3,5-Dimethylene-1,7-dihydrofuro
[3,4-f]isobenzofuran
(16):
1H NMR
(400 MHz, C6D6): d=7.33 (s, 1H), 5.97 (s, 1H), 4.69 (s, 6H), 4.48 ppm (s,
2H); 13C NMR (100 MHz, C6D6): d=163.86, 144.13, 136.94, 116.51,
115.02, 81.15, 75.29 ppm; HRMS-ESI: m/z: calcd for C12H11O2: 187.0759;
found: 187.0747 [M+H+].
A
(41):
1H NMR
3,5-Dimethyl-1,7-dimethylene-3,5-dihydrofuroACTHNUTRGENUG[N 3,4-f]isobenzofuran (18):
(400 MHz, CDCl3): d=7.52 (m, 4H), 7.50 (s, 2H), 7.34 (m, 6H), 5.08 (d,
J=6.3 Hz, 4H), 2.94 ppm (t, J=6.3 Hz, 2H); 13C NMR (100 MHz,
CDCl3): d=144.12, 134.71, 134.29, 131.39, 131.10, 126.62, 125.36, 97.68,
89.73, 64.05 ppm; elemental analysis calcd (%) for C24H18O2: C 85.18, H
5.36; found: C 82.50, H 5.30.
1H NMR (400 MHz, C6D6): d=7.35 (s, 1H), 6.16 (s, 1H), 5.10 (m, 2H),
4.67 (s, 2H), 4.48 (s, 2H), 1.15 ppm (m, 6H); 13C NMR (100 MHz, C6D6):
d=162.87, 148.86, 148.82, 137.11, 116.33, 116.16, 115.11, 82.67, 82.65,
81.07, 23.79, 23.66 ppm; HRMS-ESI: m/z: calcd for C14H14NaO2:
237.0891; found: 237.0894 [M+Na+].
Typical NMR-scale catalytic reactions: In the glove box, the particular
homoleptic lanthanide amide [Ln{NACHTUNGRTNEUNG(SiMe3)2}3] (5 mmol) and the substrate
3,6-Dimethylene-1,8-dihydrofuroACTHNUTRGNEUNG
[3,4-e]isobenzofuran (20): 1H NMR
(400 MHz, C6D6): d=7.00 (s, 2H), 4.69 (s, 2H), 4.50 (s, 2H), 4.37 ppm (s,
4H); 13C NMR (100 MHz, C6D6): d=164.05, 137.37, 136.36, 122.89, 81.39,
74.00 ppm; HRMS-ESI: m/z: calcd for C12H11O2: 187.0759; found:
187.0747.
(0.1 mmol) were weighed into separate vials, and [D6]-benzene (300 mL)
or [D10]-o-xylene was added by syringe to each vial. The solutions were
then mixed to yield a homogeneous, clear solution which was then trans-
ferred to a J. Young NMR tube equipped with a Teflon valve. The tube
was closed and removed from the glove box. The NMR tube was next
sealed and frozen at ꢀ788C until the time for NMR analysis, then
brought to the desired temperature, and the ensuing hydroalkoxylation/
A
E
(30):
1H NMR (400 MHz, [D10]-o-xylene): d=7.41 (s, 2H), 7.39 (s, 2H), 7.27
(m, 4H), 7.16 (m, 4H), 6.42 (s, 2H), 4.67 ppm (s, 4H); 13C NMR
(100 MHz, [D10]-o-xylene): d=163.66, 149.88, 143.79, 141.47, 137.25,
123.00, 122.82, 109.04, 108.96, 79.51 ppm; HRMS-ESI: m/z: calcd for
C24H19O2, 339.1385; found: 339.1373 [M+H+].
1
cyclization reaction was monitored by H NMR spectroscopy.
Typical preparative-scale catalytic reactions: Scale-up catalytic reactions
were carried out using the following procedure. In a glove box, the par-
ticular homoleptic lanthanide amide [La{NACHTNUTGRNEG(UN SiMe3)2}3] (31 mg, 50 mmol)
ACHUTNGRENUN(G 3E,7E)-3,7-Dibenzylidene-5-methyl-1,5-dihydrofuroACHTUNGTRNE[NUGN 3,4-f]isobenzofuran
(34): 1H NMR (400 MHz, [D10]-o-xylene): d=7.38 (m, 2H), 7.22 (m,
6H), 7.17 (m, 4H), 6.42 (s, 2H), 5.10 (q, J=6.3 Hz, 1H), 4.70 (s, 2H),
1.28 (d, J=6.3 Hz, 3H); 13C NMR (100 MHz, [D10]-o-xylene): d=163.20,
162.13, 152.10, 147.68, 144.68, 144.36, 144.20, 143.68, 134.15, 119.98,
119.69, 105.22, 105.04, 89.26, 81.70, 29.01 ppm; HRMS-ESI: m/z: calcd
for C25H21O2: 353.1542; found: 353.1552 [M+H+].
and the substrate (1 mmol) were weighed into separate vials, and 400 mL
of [D6]benzene or [D10]-o-xylene was added by syringe to each vial. The
reagents were then mixed to yield a homogeneous, clear solution and
transferred to a solvent storage tube equipped with a Teflon valve and a
magnetic stir bar. The tube was next closed and removed from the glove
box. The mixture was then freeze–pump–thaw degassed and warmed to
room temperature. The resulting solution was stirred with heating at the
selected temperature for 12 h. After completion of the reaction, this reac-
tion mixture was filtered through a small plug of silica gel to remove the
catalyst. This crude product was then purified by flash column chroma-
tography or Kugelrohr distillation.
ACHUTNGRENUN(G 1E,5E)-1,5-Dibenzylidene-3,7-dimethyl-3,7-dihydrofuroACHTUTGNREN[NUGN 3,4-f]isobenzo-
furan (36): 1H NMR (400 MHz, [D10]-o-xylene): d=7.34 (m, 4H), 7.22
(m, 6H), 7.13 (m, 2H), 6.33 (s, 2H), 5.12 (m, 2H), 1.28 ppm (m, 6H);
13C NMR (100 MHz, [D10]-o-xylene): d=162.15, 152.33, 144.32, 141.50,
134.12, 123.03, 119.86, 108.88, 105.10, 89.30, 29.01 ppm; HRMS-ESI: m/z:
calcd for C26H22NaO2: 389.1517; found: 389.1518 [M+Na+].
3,8-Dimethylene-2,7-dioxaspiroACTHNUTRGNEUNG
[4.4]nonane (2): 1H NMR (400 MHz,
C6D6): d=4.42 (s, 2H), 3.76 (s, 2H), 3.37 (s, 4H), 1.91 ppm (s, 4H);
13C NMR (100 MHz, C6D6): d=161.53, 81.03, 76.43, 47.99, 38.25 ppm;
HRMS-ESI: m/z: calcd for C9H13O2: 153.0916; found: 153.0908 [M+H+].
G
U
(38):
1H NMR (400 MHz, [D10]-o-xylene): d=8.05 (m, 2H), 7.49 (m, 6H), 7.21
(m, 4H), 6.06 (s, 2H), 4.97 ppm (s, 4H); 13C NMR (100 MHz, [D10]-o-
xylene): d=162.98, 147.96, 143.97, 140.89, 139.19, 135.09, 121.32, 121.23,
108.83, 105.08, 81.64 ppm; HRMS-ESI: m/z: calcd for C48H36NaO4:
699.2511; found: 699.2506 [2M+Na+].
meso-1,9-Dimethyl-3,7-dimethylene-2,8-dioxaspiro
[4.4]nonane
(4):
ACHUTNGRENUN(G 1E,7E)-1,7-Dibenzylidene-3,5-dimethyl-3,5-dihydrofuroACHTUTGNREN[NUGN 3,4-f]isobenzo-
ESI: m/z: calcd for C11H16O2: 203.1048; found: 203.1040 [M+Na+].
furan (40): 1H NMR (400 MHz, [D10]-o-xylene): d=8.17 (s, 1H), 7.63 (s,
1H), 7.33 (m, 4H), 7.16 (m, 6H), 6.41 (s, 2H), 5.26 (m, 2H), 1.39 ppm
(m, 6H); 13C NMR (100 MHz, [D10]-o-xylene): d=162.15, 156.22, 152.85,
142.76, 137.30, 134.24, 121.20, 121.02, 109.34, 104.55, 86.20, 28.96 ppm;
HRMS-ESI: m/z: calcd for C26H22NaO2: 389.1517; found: 389.1528
[M+Na+].
1
d/l-1,9-Dimethyl-3,7-dimethylene-2,8-dioxaspiro
N
(400 MHz, [D10]-o-xylene): d=5.02 (s, 2H), 4.46 (s, 2H), 4.38 (q, J=
6.6 Hz, 2H), 2.65 (s, 4H), 1.68 ppm (d, J=6.3 Hz, 6H); 13C NMR
(100 MHz, [D10]-o-xylene): d=168.81, 87.32, 77.39, 51.33, 42.64,
27.72 ppm; HRMS-ESI: m/z: calcd for C11H16NaO2, 204.1048; found:
203.1038 [M+Na+].
(3E,6E)-3,6-Dibenzylidene-1,8-dihydrofuro
(42):
1H NMR
1H NMR (400 MHz, [D10]-o-xylene): d=7.98 (s, 2H), 7.48 (m, 3H), 7.38
(m, 3H), 7.29 (m, 2H), 7.20 (m, 2H), 6.03 (s, 2H), 4.70 ppm (s, 4H);
13C NMR (100 MHz, [D10]-o-xylene): d=163.17, 145.24, 144.15, 139.37,
137.06, 133.94, 128.28, 127.37, 107.92, 105.44, 80.14 ppm; HRMS-ESI: m/
z: calcd for C24H19O2: 339.1385; found: 339.1388 [M+H+].
3,7-Dimethylene-1,5-dihydrofuro
[3,4-f]isobenzofuran
(10):
(400 MHz, C6D6): d=6.52 (s, 2H), 4.70 (s, 4H), 4.68 (s, 2H), 4.44 ppm (s,
2H); 13C NMR (100 MHz, C6D6): d=161.64, 140.76, 135.14, 113.43, 78.77,
72.96 ppm; HRMS-ESI: m/z: calcd for C12H11O2: 187.0759; found:
187.0749 [M+H+].
3-Methyl-1,5-dimethylene-3,7-dihydrofuro
[3,4-f]isobenzofuran
(12):
Kinetic studies of hydroalkoxylation/cyclization: In a typical experiment,
an NMR sample was prepared as described above (see Typical NMR-
1H NMR (400 MHz, C6D6): d=6.73 (s, 1H), 6.54 (s, 1H), 5.19 (q, J=
Chem. Eur. J. 2010, 16, 5148 – 5162
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5151

T. J. Marks and S. Seo
Scale Catalytic Reactions) but maintained at ꢀ788C until kinetic meas-
urements were begun. The sample tube was inserted into the probe of
the INOVA-400 spectrometer which had been previously set to the de-
sired temperature (T ꢁ0.18C; checked with a methanol or ethylene
glycol temperature standard). A single acquisition (nt=1) with a 458
pulse was used during data acquisition to avoid saturation. The data were
processed with the SigmaPlot 2002 program.[43] The product concentra-
tion was measured from the area of the olefinic peak cis to oxygen, As,
standardized to Al, the methyl peak area of the free NHACTHNUGTRNEUNG(SiMe3)2 formed
as turnover commenced. The turnover frequency, Nt (hꢀ1), was calculated
from the least-squares determined slope (m) according to Equation (8),
where [catalyst]0 is the initial concentration of the precatalyst. As deter-
mined from the least-square analysis, the uncertainty in Nt values is on
the order of 2–8%.
Scheme 2. Synthesis of 1,3-propanediol derivatives. i) NaOEt, EtOH, RT,
12 h; ii) K2CO3, TBAHS, CH3CN, reflux, 12 h; iii) LiAlH4, Et2O, reflux,
3 h; iv) NaBH4, MeOH, RT, 1 h; v) NaH, THF, reflux, 12 h. TBAHS=
tert-butylammonium hydrogensulfate.
½productꢂ ¼ mt
ð8Þ
ð9Þ
60min
h
m
Ntðhꢀ1Þ ¼
ꢃ
½catalystꢂ0
of propargyl bromide or substituted propargyl bromides to
the commercially available dimethyl malonate, acetyl ace-
tone, or dimethyl propagylmalonate, followed by reduction
using LiAlH4 or NaBH4, affords each substrate in good
yield. A synthetic scheme for para-substituted alcohols 9,
11, 13, 27, 29, 33 and 35 is summarized in Scheme 3. Thus,
substrates 9, 13, 27, 29 and 35 were synthesized via Sonoga-
shira coupling and oxidation, followed by addition of the
Grignard reagent derived from compound 43, according to
published procedures.[45] Substrates 11 and 33 were obtained
by oxidation to the corresponding aldehydes, mono acetal
protection, reduction, Sonogashira coupling, deprotection of
the acetal, and then Grignard reaction. A synthetic scheme
for meta- and ortho-substituted dialcohols 15, 17, 19, 37, 39
and 41 is summarized in Scheme 4. Compounds 50 and 51
can be obtained from compounds 46[46] and 47[47] by benzylic
Results
The principal goal of this contribution is to explore the
scope and selectivity of the lanthanide-mediated intramolec-
ular tandem double hydroalkoxylation/cyclization of di-
alkynyl dialcohols, in search of general, highly stereoselec-
tive catalytic pathways for diheterocycle construction. This
section first presents synthetic routes to the various dialkyn-
yl dialcohol substrates. Second, the effects of varying sub-
strate substituents on the intramolecular tandem double hy-
droalkoxylation/cyclizations are explored, including the
rates and stereochemistry of transformations involving ter-
minal diACHTUNGTRENNUNGalkynyl diACHTUNGTRENNUNGalcohols versus internal dialkynyl dialco-
hols. Third, metal effects on the
course and rates of catalytic in-
tramolecular tandem double
hydroalkoxylation/cyclizations
of the various alkynyl alcohol
substrates are described. Final-
ly, the reaction kinetics and
plausible mechanistic pathways
are discussed, including rate
laws, activation parameters, ki-
netic isotope effects, and their
mechanistic implications.
Substrate synthesis:[44] To ex-
plore the effects of the various
substrates on lanthanide com-
ꢀ
plex-mediated tandem C O
bond forming reactivity and se-
lectivity, a number of new di-
alkynyl dialcohols were synthe-
sized and characterized. Com-
pounds 1, 3, 5, 21, 22 and 23
were synthesized by adapting
published procedures, as out-
Scheme 3. Synthesis of para-substituted diol derivatives. i) [PdACHTUNGTRNEG(UN PPh3)4], CuI, TEA, 508C, 5 h; ii) (COCl)2,
DMSO, TEA, CH2Cl2, ꢀ788C to RT, 12 h; iii) MeMgBr, THF, reflux, 2 h; iv) TBAF, THF, RT, 2 h; v) PCC,
4 ꢂ molecular sieves, CH2Cl2, reflux, 5 h; vi) ethylene glycol, TsOH, toluene, reflux, 2 h; vii) NaBH4, MeOH,
lined in Scheme 2.[39] Addition RT, 2 h; viii) PPTS, acetone/H2O 2:1, reflux, 12 h.
5152
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Chem. Eur. J. 2010, 16, 5148 – 5162

Double Intramolecular Hydroalkoxylation/Cyclization
FULL PAPER
bromination using NBS and a radical initiator, followed by
hydrolysis according to published procedures. Sonogashira
coupling is then conducted to afford the substrates 15, 19, 37
and 41. Compounds 17 and 39 can be synthesized through
Swern oxidation to corresponding aldehydes, followed by
Grignard methylation. Unfortunately, the same reaction se-
quence applied to 19 and 41 does not yield the expected
products.
using the evolved HNACHTUNGTRENNUNG(SiMe3)2
signals as an internal standard
(e.g., Figure 1). Turnover fre-
quencies were determined in
[D10]-o-xylene or [D6]-benzene
solutions from the slope of the
kinetic plots of the [product]/
AHCTUNGTERG[NNUN catalyst] ratio versus time.
During the course of reactions,
the monocyclized intermediates
are generally observed in the
1H NMR spectra except in the
case of the very rapid conver-
sions (Table 1, entries 5, 6, and
7). The final spirofuran and iso-
benzofuran products can be
straightforwardly purified by
column chromatography or
vacuum transfer, and were char-
Scheme 4. Synthesis of meta- and ortho-substituted diol derivatives. i) NBS, cat. BPO, CCl4, reflux, 12 h;
ii) CaCO3, dioxane/H2O 2:1, reflux, 12 h; iii) [PdACTHNUGRTNEUNG(PPh3)4], CuI, TEA, 508C, 5 h; iv) TBAF, THF, RT, 2 h;
v) (COCl)2, DMSO, TEA, CH2Cl2, ꢀ788C to RT, 12 h; vi) MeMgBr, THF, reflux, 2 h. NBS=N-bromosuccini-
mide, BPO=benzoyl peroxide.
1
acterized by H, 13C NMR spec-
Scope of terminal dialkynyl dialcohol catalytic intramolecu-
lar hydroalkoxylation/cyclization: The homoleptic [Ln{N-
troscopy, and either high-resolution MS or elemental analy-
sis (see the Experimental Section for details).
A
It can be seen in Table 1 that the anaerobic cyclization of
the diverse series of dialkynyl dialcohols, mediated by the
homoleptic [La{NACTHNUTRGNEUNG(SiMe3)2}3] precatalyst, proceeds with
precatalysts for the clean and, in most cases, quantitative
tandem double intramolecular hydroalkoxylation/cyclization
of a variety of selected terminal dialkynyl dialcohols to yield
the corresponding spirofuran and isobenzofuran heterocy-
cles as summarized in Table 1, where Nt is the catalytic turn-
over frequency for final product formation at the tempera-
ture indicated. In general, the catalytic tandem double intra-
molecular hydroalkoxylation/cyclization reactions of the ter-
minal dialkynyl dialcohols examined proceed to completion
at 70–1208C under inert atmosphere, at 5 mol% catalyst
near-quantitative conversions and reasonably rapid turnover
frequencies at 70–1208C. The reaction scope was designed
to probe a variety of structural effects on this catalytic trans-
formation, including five-membered ring formation using a
variety of primary and secondary alcohols. It is found that
spirofurans (Table 1, entries 1–3) and isobenzofurans
(Table 1, entries 6–11) are cleanly formed via 5-exo cycliza-
tion and that there is no NMR spectroscopic evidence for
the alternative 6-endo cyclizations products [e.g., Eq. (11)].
As observed for the organolanthanide-mediated hydroalkox-
ylation/cyclization of simple alkynyl alcohols,[33b] arene-sub-
stituted alcohol cyclization rates are somewhat more rapid
than those for linear alkohols. Thus, the overall 15!16 and
19!20 transformations are significantly more rapid than
1!2 (Nt =5.8, 6.1 hꢀ1 at 708C vs. 3.9 hꢀ1 at 1208C). The sec-
ondary alkynyl alcohol cases raise interesting questions
about structural effects governing cyclization rates. For the
aromatic substrates, the presence of a secondary alkynyl al-
cohol enhances the cyclization rates; thus, 17!18 is more
loading in 1 to 12 h. In the present study, the homoleptic
lanthanide amides, [Ln{N
spectroscopy to undergo essentially instantaneous Ln N
bond protonolysis by the dialkynyl dialcohols at room tem-
perature to yield the corresponding alkoxides and free HN-
ACHTUNGTRENNUNG
(SiMe3)2. In regard to reaction sequence, in situ 1H NMR
spectroscopy indicates that at 1208C with 5 mol% [La{N-
ACHTUNGTRENNUNG(SiMe3)2}3] as the precatalyst, the dialkynyl alcohol sub-
strates first undergo conversion to monocyclized intermedi-
ates on essentially the same time scale as the intermediates
then undergo conversion to the final products [e.g., Eq. (10),
Figure 1]. At the conclusion of turnover, only the bicyclic
products are observed in this tandem double hydroalkoxyla-
tion/cyclization. Quantitative aspects of the reaction prog-
ress are conveniently monitored from intensity changes in
the product olefinic resonances by 1H NMR spectroscopy,
Chem. Eur. J. 2010, 16, 5148 – 5162
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5153

T. J. Marks and S. Seo
Table 1. Catalytic lanthanide-mediated tandem double intramolecular
hydroalkoxylation/cyclization of alkyne-terminal dialkynyl dialcohols.
Entry
Substrate
Product[a]
Nt [hꢀ1] ([8C])[b]
1
3.9 (120)[c]
2
3
6.8 (120)[c]
7.4 (120)[c]
4
5
decomposed[d]
>1000[e]
Figure 1. 1H NMR monitoring (500 MHz) of the cyclization 1!2 mediat-
ed by a [La{NACHTNUGTRNEN(UG SiMe3)2}3] precatalyst in C6D6 A) t=0.0 h at 258C, B) t=
6
7
>1000[e]
>1000[e]
1.0 h at 908C, C) t=40 min at 1208C, D) t=2.0 h at 1208C, E) t=4.0 h at
1208C, F) t=9.0 h at 1208C, and G) authentic methylenetetrahydrofuran
sample for reference.
Stereoselectivity issues for hydroalkoxylation/cyclization of
internal dialkynyl dialcohols: The intramolecular hydro-
AHCTUNGTRENNUNG
8
9
5.8 (70)
7.2 (70)
AHCTUNGTRENNUNG
nide amido precatalysts proceeds effectively and selectively
to yield the corresponding isobenzofurans, as shown in
Table 2, where Nt is the measured turnover frequency for
final product formation at the temperature indicated. In
general, the catalytic hydroalkoxylation/cyclization reactions
of the internal dialkynyl dialcohols examined proceed to
completion at 1208C, with 5 mol% catalyst loading in 6 to
12 h. Reaction progress is again conveniently monitored
from intensity changes in product olefinic resonances by
10
6.1 (70)
1
[a] Yields ꢄ95% by H NMR spectroscopy and GC/MS. [b] Turnover fre-
quencies measured in [D6]-benzene with 5 mol% [La{N(SiMe3)2}3] preca-
AHCTUNGTRENNUNG
1H NMR spectroscopy, using evolved HN
ACHTNUGTRENUNG(SiMe3)2 as the cali-
brant. Turnover frequencies were again calculated in [D10]-
o-xylene from the slopes of the kinetic plots of the [product]/
talyst. [c] Turnover frequencies measured in [D10]-o-xylene with 5 preca-
talyst mol%. [d] Decomposed at 1208C over the course 4 d. [e] Nt >
1000=too fast to determine the turnover frequency.
AHCTUNGTREG[NNNU catalyst] ratio versus time. During the course of the reac-
rapid than 15!16 (Nt =7.2 vs. 5.8 hꢀ1 at 708C). For linear
secondary dialkynyl dialcohols, the cyclization rate is also in-
creased; thus, the 3!4 and 5!6 transformations are signifi-
cantly more rapid than 1!2 (Nt =6.8, 7.4 hꢀ1 vs. 3.9 hꢀ1 at
1208C). However, this trend for linear alkynyl alcohols is
opposite that in single hydroalkoxylation/cyclizations. An-
other interesting observation concerning this transformation
is that the diastereomers 3 and 5 exhibit very similar cycliza-
tion rates. This result suggests that future diastereomeric
substrates can be used as mixtures of d/l and meso isomers.
The arene-substituted dialcohols can be categorized as
ortho, meta and para substrates according to the alcohol po-
sition. The alcohol positional dependence of cyclization
rates (Nt) for these substrates is pronounced: para>ortho>
meta (Nt =>1000, 6.1, 5.8 hꢀ1 at 708C, respectively).
tion, monocyclized intermediates are again first observed in
the 1H NMR spectra. The final products were purified by
column chromatography or vacuum transferred with other
volatiles and characterized by 1H, 13C NMR spectroscopy,
NOESY, and high-resolution MS or elemental analysis (see
the Experimental Section). According to the previous mech-
anistic results for internal monoalcohol hydroalkoxylation/
cyclization (Scheme 1), the stereochemistry of the principal
products is expected to be the E conformer. Indeed, the
actual stereochemistry in the present transformations is con-
firmed to be the E conformers in each case by NOESY ex-
periments.
The scope of the present organolanthanide-mediated hy-
droalkoxylation/cyclizations of alkyne-internal dialkynyl di-
AHCTUNGTREGaNNNU lcohols is summarized in Table 2. Under identical reaction
conditions, the cyclization rates of the alkyne-internal di-
alkynyl dialcohols (Table 2) are significantly slower than
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Chem. Eur. J. 2010, 16, 5148 – 5162

Double Intramolecular Hydroalkoxylation/Cyclization
FULL PAPER
Table 2. Lanthanide-mediated catalytic intramolecular hydroalkoxyla-
tion/cyclization of alkyne-internal dialkynyl dialcohols.
Entry Substrate
Product[a]
Nt [hꢀ1] ([8C])[b]
1
traces (120)[c]
hanced rates; thus, the 33!34 and 35!36 transformations
are significantly more rapid than 29!30 (Nt =4.4, 5.8 hꢀ1 vs.
1.8 hꢀ1 at 1208C), and the 39!40 transformation is signifi-
cantly more rapid than 37!38 (Nt =1.09 hꢀ1 vs. 0.31 hꢀ1 at
1208C). The arene-substituted substrates can be categorized
as ortho, meta and para according to the alcohol positions,
and the alcohol positional dependence of the cyclization
rates (Nt) for these substrates is significantly less than for
the terminal alkynyl substrates discussed above: para>
ortho>meta (Nt =1.8, 0.66, 0.31 hꢀ1 at 1208C, respectively).
product mixture
(120)[d]
2
3
4
5
1.8 (120)
2.2 (120)
4.4 (120)
Metal ion effects on catalytic dialkynyl dialcohol hydroal-
koxylation/cyclization: In the case of catalytic aminoalkene
hydroamination/cyclization, both increasing the Ln3+ ionic
radius and opening the lanthanocene coordination sphere by
ansa-fusion of the ancillary ligands[48] increases the observed
turnover frequencies (Nt), presumably reflecting the signifi-
cant steric demands in the olefinic insertive transition state.
In contrast, an approximately opposite ionic radius–Nt trend
is observed for less sterically demanding aminoalkyne hy-
6
7
8
9
5.8 (120)
0.31 (120)
1.09 (120)
0.66 (120)
droamination/cyclization where smaller Ln3+ ions permit
[19a,j]
ꢀ
closer N C bond-forming approach in the transition state.
These basic mechanistic scenarios are supported by DFT
level quantum chemical computation.[32a,b] Interestingly, our
previous non-lanthanocene catalytic intramolecular alkynyl
alcohol hydroalkoxylation/cyclization results (Scheme 1) ex-
hibit kinetic trends similar to those in the aforementioned
aminoalkene hydroamination/cyclization. Catalyst structural
effects qualitatively similar to those in aminoalkene hydro-
AHCTUNGTREGaNNUN mination/cyclization and alkynyl alcohol hydroalkoxyla-
tion/cyclization are also operative in the present bicycliza-
tion systems. Thus, for the representative cyclization 1!2,
Table 3 shows that the measured Nt values for 2 formation
increase substantially with increasing metal ionic radius.[49]
That is, these tandem double hydroalkoxylation/cyclizations
of dialkynyl dialcohols experiences similar appreciable ac-
celeration in rate when larger ionic radius Ln3+ catalysts are
introduced, and the kinetic and other data argue that the
1
[a] Yields ꢄ95% by H NMR spectroscopy and GC/MS. [b] Turnover fre-
quencies measured in [D10]-o-xylene with 5 mol% [La{N(SiMe3)2}3] pre-
AHCTUNGTRENNUNG
catalyst. [c] Traces= ꢆ5% completion after one week. [d] Product mix-
ture=products too numerous to accurately determine the turnover fre-
quency.
ꢅ
ꢀ
those of the corresponding alkyne-terminal dialkynyl dialco-
hols (Table 1). For linear alkyne-internal diACTHUNRTGNEUNGalkynyl dialco-
turnover-limiting step is C C insertion into the Ln O bond
(Scheme 1, step i) as will be discussed in more detail below.
hols (Table 2, entry 1), hydroalkoxylation/cyclizations are
extremely sluggish in comparison to the alkyne-terminal
substrates. The substrate having an SiMe3-terminated alkyn-
yl alcohol (Table 2, entry 2) is observed to yield multiple
Kinetic and mechanistic analysis of dialkynyl dialcohol hy-
droalkoxylation/cyclization: Quantitative kinetic studies of
representative cyclization 1!2 were carried out with 2.5–
20.0 mol% precatalyst in [D10]-o-xylene at 1208C by
1H NMR spectroscopic monitoring. The evolution of specific
olefinic resonances (shown in Figure 1; either that at dꢆ3.7
1
products as judged by H NMR spectroscopy and is reminis-
cent of our previous findings that hydroalkoxylation/cycliza-
tion of the SiMe3-terminated internal alkynyl alcohols re-
veals interesting product profiles which include the desired
exocyclic ether, a SiMe3-eliminated exocyclic ether, and the
Me3Si-O-functionalized substrate [Eq. (12)].[33b] Secondary
aromatic dialkynyl dialcohols undergo cyclizations at en-
1
or at 4.5 ppm) was monitored by H NMR spectroscopy and
integrated versus NH
ichiometrically generated
(Figure 1). Cyclizations were performed with a 10–90 fold
ACHTUNGTRENNUNG
Chem. Eur. J. 2010, 16, 5148 – 5162
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5155

T. J. Marks and S. Seo
Table 3. Effect of varying lanthanide ionic radius on turnover frequen-
cies in catalytic dialkynyl dialcohol intramolecular hydroalkoxylation/cyc-
lization.
versus initial substrate concentration because of possible
product participation influence on the reaction rate. Fig-
ure 3a shows that the half-life points increase linearly with
initial substrate concentration, clearly indicating zero-order
kinetics in [substrate] [Eqs. (13), (14)].
ꢀd½Sꢂ
n
ð13Þ
ð14Þ
ð15Þ
¼ k ½Sꢂ
Entry
Ln
Ionic radius [ꢂ]
Nt [hꢀ1] ([8C])[a]
dt
1
2
3
4
5
La
Nd
Sm
Y
1.160
1.109
1.079
1.019
0.977
3.9 (120)
3.7 (120)
2.3 (120)
0.63 (120)
1.9 (120)
½Sꢂ0
2k
n ¼ 0 : ½Sꢂt ¼ ½Sꢂ0ꢀkt t1=2
n ¼ 1 : ½Sꢂt ¼ ½Sꢂ0eꢀkt t1=2
¼
¼
ln2
k
Lu
[a] Turnover frequencies for product 2 formation measured in [D10]-o-
xylene with 5 mol% precatalyst.
ð2nꢀ1ꢀ1Þ
ð16Þ
ð17Þ
in general ðn ¼ 1Þ, t1=2
ð2nꢀ1ꢀ1Þ
¼
nꢀ1
k ðnꢀ1Þ ½Sꢂ0
molar excess of substrate over catalyst, and in all cases sub-
strate was completely consumed by the end of the reaction.
In the present study, the linear increase of bicyclized prod-
uct 2 with conversion time suggests zero-order dependence
while the decrease of substrate 1 with time shows deviations
from the zero-order linearity (depressed rates) after about
the first half-life (Figure 2). This deviation can be modeled
by competitive product or intermediate inhibition of the
conversion.[19d,l,n,50] Since this kinetic plot can be fit very
well over a broad range of conversions with an exponential
curve (Figure 2), it is not straightforward to distinguish be-
tween zero-order kinetics with substantial competitive prod-
uct or intermediate inhibition and real first-order kinetics by
the integrated rate law method alone. Therefore, the half-
life method in conjunction with the initial rate method[51]
was employed to estimate the reaction order in dialkynyl di-
alcohol substrate concentration for transformation 1!2
lnt1=2 ¼ ln
þ ð1ꢀnÞ ln½Sꢂ0
k ðnꢀ1Þ
Modified general Equation (17) shows that the slope of
the line equals 1ꢀn (n=reaction order). Figure 3b also indi-
cates zero-order kinetics in [substrate]. Therefore, the ob-
served deviation from linearity likely reflects product or in-
termediate participation. Further discussion of these mecha-
using 5 mol% [La{NACHTUNGTRNEG(UN SiMe3)2}3] as the precatalyst. Three re-
actions starting with different initial substrate concentrations
1
were analyzed by H NMR spectroscopy. Instead of actual
half-life points for each run, projected half-life points from
the first 20% conversion data were determined and plotted
Figure 3. a) Plot of half-life points projected from the initial 20% conver-
sion as a function of initial substrate concentration for the hydroalkoxyla-
tion/cyclization of 2,2-di(prop-2-ynyl)propane-1,3-diol (1) using the pre-
Figure 2. Concentration of substrate 2,2-di(prop-2-ynyl)propane-1,3-diol
catalyst [La{NACHTUNGTERNNU(G SiMe3)2}3] in [D10]-o-xylene at 1208C. The line is the least-
&
(1, ), intermediate (5-methylene-3-(prop-2-ynyl)-tetrahydrofuran-3-yl)-
squares fit to the data points with y intercept 0.0. b) Half-life method
~
methanol (1a, ), and product 3,8-dimethylene-2,7-dioxaspiro
G
plot for the hydroalkoxylation/cyclization of 2,2-di(prop-2-ynyl)propane-
*
(2, ) as a function of time for the hydroalkoxylation/cyclization of 1
1,3-diol (1) using the precatalyst [La{NACHTNGUTERNNU(G SiMe3)2}3] in [D10]-o-xylene at
using 5.0 mol% [La{N
G
1208C. The line is the least-squares fit to the data points. The b[0] and
1208C.
b[1] denote the intercept and slope of each plot, respectively.
5156
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Chem. Eur. J. 2010, 16, 5148 – 5162

Double Intramolecular Hydroalkoxylation/Cyclization
FULL PAPER
nistic implications is deferred to the Discussion Section.
When the initial concentration of dialkynyl dialcohol is held
constant, and the concentration of precatalyst is varied over
10-fold range, a plot of the reaction rate of 2 formation
from 1a versus precatalyst concentration (Figure 4a) and a
ure 5c) kinetic analyses[52] yield activation parameters
DH° =17.5
18.2ACTHUNGTRNENUG
(1.4) kcalmolꢀ1.[53] Furthermore, an -OH versus -OD iso-
A
ACHTUNGTREN(NUNG 3.5) e.u., and Ea =
topic labeling study (Table 2, entry 4), assayed by 1H and
2H NMR spectroscopy of product formation, yields a kinetic
plot of ln
G
G
isotope effect (KIE) of kH/kD =0.82ACTHNGUTERNN(UG 0.02).
reaction order, Figure 4b) indicate the rate law to be the
first-order in [catalyst]. Overall, the empirical rate law can
be expressed as in Equation (18) and is identical to that de-
termined for organolanthanide-catalyzed aminoalkene
Discussion
hydro
A
Scope of catalytic intramolecular dialkynyl dialcohol hydro-
alkoxylation/cyclization: A central goal of this research was
hydroalkoxylation/cyclization.[33]
0
1
ð18Þ
rate ¼ k½substrateꢂ ½catalystꢂ
Figure 4. a) Determination of the reaction order in lanthanide concentra-
tion for the hydroalkoxylation/cyclization of 2,2-di(prop-2-ynyl)propane-
1,3-diol (1) to 3,8-dimethylene-2,7-dioxaspiro
[La{N(SiMe3)2}3] precatalyst in [D10]-o-xylene at 1208C. b) van ꢁt Hoff
plot of the hydroalkoxylation/cyclization of 2,2-di(prop-2-ynyl)propane-
1,3-diol (1) using [La{N(SiMe3)2}3] as the precatalyst in [D10]-o-xylene at
ACHTUNGERTN[NUNG 4.4]nonane (2) using the
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
1208C. The lines are least-squares fits to the data points. The b[0] and
b[1] denote the intercept and slope of each plot, respectively.
Figure 5. a) Concentration of product 2 (3,8-dimethylene-2,7-dioxaspiro-
AHCTUNGTRENNUNG
Variable-temperature kinetic studies were conducted by
in situ 1H NMR spectroscopy for the rate of 2 formation
mediated by [La{N
normalized to the free NH
of 2 formation mediated by [La{NAHCNUTGTRENNUNG
of substrate concentration over a 308C temperature range
(100–1308C), suggesting zero-order dependence on substrate
concentration, in accord with the kinetic results discussed
above. Standard Eyring (Figure 5b) and Arrhenius (Fig-
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
G
ACHTUNGTRENNUNG
lyst in [D10]-o-xylene. The line represents the least-squares fit to the data
points. c) Arrhenius plot for the intramolecular hydroalkoxylation/cycli-
zation of 1 using [La{NACTHNUTRGNEUNG(SiMe3)2}3] as the precatalyst in [D10]-o-xylene.
The line represents the least-squares fit to the data points. The b[0] and
b[1] denote the intercept and slope of each plot, respectively.
Chem. Eur. J. 2010, 16, 5148 – 5162
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5157

T. J. Marks and S. Seo
to explore the scope of homoleptic [Ln{N
nide amido precatalyst-mediated tandem double intramolec-
ular hydroalkoxylation/cyclizations of dialkynyl dialcohols.
(SiMe3)2}3] lantha-
yl dialcohols proceed with excellent stereoselectivity, and
are completely E-selective. This high E selectivity can be ra-
tionalized in terms of a transition state in which the R sub-
stituents occupy the less sterically hindered positions in a
chair-like cyclic transition state, similar to those proposed
and identified computationally for analogous hydroamina-
tion/cyclizations,[19,32] and monofunctional hydroalkoxyla-
tion/cyclizations[33b] (Scheme 1; B versus C). Some explana-
The results in Tables 1 and 2 indicate that [Ln{NACHTNUTRGNEG(UN SiMe3)2}3]
complexes are competent precatalysts for the formation of
diverse five-membered ring fused diheterocycles having a
variety of alkyl and aryl substituents. In the tandem double
hydroalkoxylation/cyclization of both primary and secon-
dary dialkynyl dialcohols, there is a marked difference in
cyclization rates between alkyl and aromatic dialkynyl di-
ACHTUNGTRENNUNGalcohols. In general, the cyclization rates for the arene-func-
tionalized alkynyl alcohols are more rapid than those of
linear alkynyl alcohols. This may reflect configurations in
which the arene-functionalized
alkynyl alcohols have more ac-
cessible, pre-organized struc-
tures than the linear alkynyl al-
cohols, involving interaction of
the electrophilic lanthanide
tion of the R substituent effects on the cyclization reaction
kinetics is also possible. Among the principal factors, the in-
terplay of non-bonded repulsions and electronic contribu-
tions doubtless governs the hydroalkoxylation/cyclization ki-
netics. The fact that the cyclization rates of the alkyne-ter-
minal alkynyl alcohols are invariably greater than those of
the internal alkynyl alcohols under identical reaction condi-
tions, and that rates increase with increasing Ln+3 ionic
radius, argues that non-bonded repulsions dominate the first
stages of the cyclization process. However, the correspond-
ing linear alkyne-internal dialkynyl dialcohol proceeds to
only ꢆ5% completion at 1208C over seven days (Table 2,
entry 1). This rate depression appears to reflect the interplay
of R substituent steric and electronic factors. For the arene-
substituted alkyne-internal substrate systems, the primary
and secondary dialkynyl dialcohol cyclization rates indicate
that among the several factors including sterics, electronics,
and metal binding, electronic factors govern the cyclization
rate. Thus, the cyclization rates of the arene-functionalized
secondary dialkynyl dialcohols are substantially greater than
those of arene-functionalized primary dialkynyl dialcohols
similar to the case of monofunctional hydroalkoxylation/cy-
clization.[33b]
center with the electron-rich
arene p system (e.g., A).[54]
Comparison of the differences in primary and secondary
dialkynyl dialcohol cyclization rates raises interesting ques-
tions. Specifically, the cyclization rates of the linear and
arene-functionalized secondary dialkynyl dialcohols are
greater than those of linear and arene-functionalized pri-
mary dialkynyl dialcohols. This suggests that among the sev-
eral possible factors influencing rates, including sterics, elec-
tronics, and metal binding strength, the cyclization rates are
not dominantly controlled by steric factors above all other
factors. Rather, electronic factors and metal complexation
effects play an important role in the cyclization rates. Note
that one secondary diACTHNUGRTENUNGalkynyl dialcohol does not proceed
cleanly and gives only a decomposed mixture at 1208C over
four days (Table 1, entry 4).
Another instructive observation in this investigation is
that these homoleptic [Ln{NACHTUNGRTNEUNG(SiMe3)2}3] lanthanide amido
precatalysts exhibit pronounced selectivity between ortho-,
meta-, and para-substituted arene dialkynyl dialcohols
(Table 1, entries 5, 8, and 10). The alcohol positional de-
pendence of the cyclization rates for these substrates is
para>ortho>meta. In this trend, the rapid tandem double
cyclization rate of the para-substituted arene dialkynyl di-
The selectivity between ortho-, meta-, and para-substitut-
ed arene internal dialkynyl dialcohols also exhibits trends
similar to those of the terminal arene-substituted substrates
(Table 2, entries 3, 7, and 9). The alcohol positional depend-
ence of the cyclization rates for these substrates is para>
ortho>meta. This trend can be explained on the basis of in-
terplay of the multiple factors as discussed above.
ACHTUNGTRENNUNGalcohol can be explained by the lack of inhibitory coordina-
tion by a second proximate, chelating substrate alcohol
ligand (A). If the selectivity derives only from the metal
complexation with a second alcohol ligand of substrate, the
rate of meta-substituted substrates should be more rapid
than that of ortho-substituted substrates. However, the ob-
served trend is opposite. Therefore, electronic effects also
doubtless play a significant role in the transition state, sug-
gesting a complex interplay of steric, electronic, and metal
complexation energetic factors.
Dialkynyl dialcohol hydroalkoxylation/cyclization—kinetics
and mechanism: The kinetic analysis for the 1!2 transfor-
mation catalyzed by [La{NACHTUNGTRNENUG(SiMe3)2}3] indicates essentially
zero-order rate dependence on substrate concentration (Fig-
ures 2 and 3) and first-order dependence on catalyst concen-
tration (Figure 4), similar to the scenario for lanthanocene-
mediated intramolecular aminoalkene, aminoalkyne, and
aminoallene hydroamination/cyclization and hydrophosphi-
nation,[19,20,32] and monofunctional hydroalkoxylation/cycliza-
Stereoselectivity in alkyne-internal dialkynyl dialcohol hy-
droalkoxylation/cyclization: The present lanthanide-mediat-
ed hydroalkoxylation/cyclizations of alkyne-internal dialkyn-
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Chem. Eur. J. 2010, 16, 5148 – 5162

Double Intramolecular Hydroalkoxylation/Cyclization
FULL PAPER
tions.[33b] In this tandem double hydroalkoxylation/cycliza-
tion, despite the apparent kinetic similarities, a plot of sub-
strate concentration versus time departs significantly from
the typical linearity (zero-order kinetics) after about one
half-life, resulting in depressed rates (seemingly first-order-
like kinetic behavior, Figure 2).[19d,l,n,50] Further investiga-
tions of this apparent first-order kinetic behavior using the
half-life method in conjunction with the initial rate method
reveal that the initial rate is still zero-order in substrate
(Figure 3), and a kinetic plot for product formation shows
the rate to be zero-order in substrate, suggesting the ob-
served rate depression is due primarily to competitive inhib-
ition by product and/or the reaction intermediate. It was
previously observed in lanthanocene-mediated hydroamina-
tion/cyclization and hydrophosphination/cyclization that var-
iable numbers of amine/phosphine substrate molecules are
coordinated to the metal center and that these significantly
modulate the diastereoselectivity of hydroelementation/cyc-
lization as well as influence rates, mainly via competition
with substrate or product molecules for the reaction cen-
ters.[19n]
troduce another substrate molecule 1 or intermediate 1a in
the Ln+3 coordination sphere. The first-order dependence of
the kinetic results on [Ln(OR)3] also argues that the active
catalyst is not in rapid pre-equilibrium with a more associat-
ed [{Ln(OR)3}n][55] species. An -OH versus -OD labeling
study (Table 2, entry 4) assayed by H and H NMR spec-
troscopy of product formation yields a kinetic isotope effect
(KIE) of kH/kD =0.82ACTHNUTRGNEUNG(0.02), suggesting a non-primary kinet-
1
2
ic isotopic effect, but rather a small inverse secondary kinet-
ic isotope effect,[56] and consistent with the alkyne insertion
being the turnover-limiting step in the catalytic cycle.
The present activation parameters for transformation 1!
2 can be compared to the corresponding parameters for the
hydroamination/cyclization of aminoalkenes, aminoalkynes,
and aminoallenes, the hydrophosphination/cyclization of a
phosphinoalkene, and the single monohydroalkoxylation/-
cyclization of alkynyl alcohol (Table 4). In the present study,
tandem double hydroalkoxylation/cyclization of an alkynyl
alcohol proceeds with a modest DH° and the largest nega-
tive magnitude of DS° for this series of transformations
(Table 4). That the tandem double alkynyl alcohol cycliza-
tion exhibits a modest enthalpic barrier and the largest mag-
nitude of DS° (more negative) implies a highly organized,
polar transition state characteristic of many d0, fn-centered
In the present tandem double hydroalkoxylation/cycliza-
tions, the catalytic sequence as shown in Scheme 5 can be
proposed. This scenario consists of two coupled cycles, I and
II, which generate the mono-
cyclized intermediate 1a and
transform it to bicyclized prod-
uct 2. These two cycles raise an
interesting question about the
turnover-limiting step. This
present results argue that two
turnover-limiting steps (steps i
and iii) are possible in the pres-
ent case, as shown in Scheme 5.
Comparison of the two plots
(1a and 2 evolution) in Figure 2
and the olefinic peak in
1H NMR spectrum of inter-
mediate 1a in Figure 1 indicate
that the cycle I is in most cases
slightly more rapid than the
cycle II. For the conversion 1!
2, the half-life of 1 is about
100 min and that of 2 is about
200 min. Therefore, these half-
lives also confirm this approxi-
mate rate difference. The turn-
over-limiting step in the present
case then involves intramolecu-
ꢅ
ꢀ
lar C C insertion into the Ln
O bond of monocyclized prod-
uct 1a (Scheme 5, step iii), fol-
lowed by rapid protonolysis of
ꢀ
the resulting Ln C bond
(Scheme 5, step iv). This cycle
would be followed by substitu-
Scheme 5. Simplified proposed catalytic cycle for lanthanide-mediated tandem double intramolecular hydroal-
tion via transalcoholysis to in- koxylation/cyclization of dialkynyl dialcohols.
Chem. Eur. J. 2010, 16, 5148 – 5162
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5159

T. J. Marks and S. Seo
Table 4. Activation parameter comparison for intramolecular hydroamination/cyclization and hydroalkoxyla-
tion/cyclization processes.
Acknowledgements
Financial support by the NSF (Grant
CHE-0809589) is gratefully acknowl-
edged.
Entry
Substrate
Product
DH° [kcalmolꢀ1
]
DS° [e.u.]
Ea [kcalmolꢀ1
]
1[a]
17.7
N
ꢀ24.7(5)
18.5
17.6
ACHTUNGTNER(NUNG 2.0)
[1] a) R. H. Bates, M. Chen, W. R.
2[b]
16.9
12.7
N
ꢀ16.5(4)
ACHTUNGTNER(NUNG 1.4)
Roush, Curr. Opin. Drug Discov.
Devel.
2008,
11,
778–792;
b) K. S. M. Salih, M. T. Ayoub,
H. A. Saadeh, N. A. Al-Masoudi,
3[c]
4[d]
5[e]
6[f]
ꢀ27.0(5)
ꢀ27.4(6)
13.4
11.3
13.0
20.9
ACHTUNGTNER(NUNG 1.5)
M. S. Mubarak,
Heterocycles
2007, 71, 1577–1587; c) Y. Kash-
man, A. Rudi, D. Pappo, Pure
Appl. Chem. 2007, 79, 491–505;
d) M. C. Elliott, E. Williams, J.
Chem. Soc. Perkin Trans. 1 2001,
2303–2340; e) A. Mitchenson, A.
Nadin, J. Chem. Soc. Perkin
10.7(8)
ACHTUNGTNER(NUNG 2.0)
12.3
20.2
U
ꢀ25.9
ꢀ11.8(0.3)
ꢀ29.9(3.5)
A
ACHTUNGTRENNUNG
N
ACHTUNGTRENNUNG
Trans.
1
2000, 2862–2892;
7[g]
17.5
N
A
18.2ACTHNGUTRENNU(G 1.4)
f) M. C. Elliott, J. Chem. Soc.
Perkin Trans. 1 2002, 2301–2323;
g) A. J. Sargent, T. M. Cresp in
Comprehensive Organic Chemis-
try, Vol. 4 (Ed.: P. G. Sammes),
[a] Determined using [Sm{CH
using [La{CH(SiMe3)2}
(Cp’2)] as the precatalyst in [D8]toluene.[19g] [c] Determined using [La{CH
(Cp’2)] as the precatalyst in [D8]toluene.[19n] [d] Determined using [Sm{CH
(SiMe3)2}(Cp’2)] as the precatalyst in
[D8]toluene.[19j] [e] Determined using [Sm{CH (Cp’2)] as the precatalyst in [D6]benzene.[20d] [f] Deter-
(SiMe3)2}
mined using [La{N (SiMe3)2}3] as
(SiMe3)2}3] as the precatalyst in [D6]benzene.[33b] [g] Determined using [La{N
ACHTUNGTRENNUNG
A
R
ACHTUNGTRENNUNG
G
R
ACHTUNGTRENNUNG
Pergamon,
Oxford,
1979,
N
ACHTUNGTRENNUNG
pp. 693–744; h) A. R. Katritzky,
A. F. Pozharskii, Handbook of
Heterocyclic Chemistry, 2nd ed.,
Pergamon, Oxford, 2000.
C
ACHTUNGTRENNUNG
the precatalyst in [D10]-o-xylene.
[2] a) Z. Zhang, C. Liu, R. E.
Kinder, X. Han, H. Qian, R. A.
hydroelementations,[19] and together with the large Ea° value
Widenhoefer, J. Am. Chem. Soc. 2006, 128, 9066–9073; b) E. D.
Cox, J. M. Cook, Chem. Rev. 1995, 95, 1797–1842; c) R. C. Larcock,
W. W. Leong in Comprehensive Organic Synthesis, Vol. 4 (Eds.:
B. M. Trost, I. Fleming), Pergamon, New York, 1991; d) C. W. Bird,
G. W. H. Cheeseman in Comprehensive Heterocyclic Chemistry,
Vol. 4 (Eds.: A. R. Katrinsky, C. W. Rees), Pergamon, Oxford, 1984,
pp. 89–154.
ꢀ
doubtless reflects the very large Ln O bond enthalpies.
Overall, the present results obtained from the kinetic studies
(rate law, activation parameters) and from structural factors
affecting cyclization rates and reaction scope (metal ion size,
product ring size, substrate substituent effects) support the
hydroalkoxylation/cylization
mechanistic
scenario
of
[3] a) B. M. Trost, A. C. Gutierrez, R. C. Livingston, Org. Lett. 2009, 11,
2539–2542; b) F. E. McDonald, K. S. Reddy, Y. Dꢃaz, J. Am. Chem.
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5, 3103–3106; d) B. M. Trost, Y. H. Rhee, J. Am. Chem. Soc. 1999,
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Scheme 5,[33] roughly analogous to, but more elaborate than,
those established for hydroamination/cyclization[19] and hy-
drophosphination/-cyclization,[20] and having certain distinc-
tive differences.
[4] a) T.-L. Ho, Tandem Organic Reactions, Wiley, New York, 1992;
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Conclusion
Tandem double intramolecular hydroalkoxylation/cycliza-
tion processes for dialkynyl dialcohol substrates mediated
by homoleptic [Ln{NACHTUNRGTNE(UNG SiMe3)2}3] lanthanide amido precata-
lysts exhibit a broad reaction scope in substrate type, includ-
ing both alkyl and aryl primary and secondary terminal di-
alkynyl dialcohols and internal dialkynyl dialcohols. The
present process proceeds cleanly at 70–1208C and provides
exocyclic enol ethers such as spirofurans and isobenzofurans
in excellent conversion, high turnover frequencies, and re-
gioselectivities. Mechanistic data implicate turnover-limiting
ꢀ
ꢀ
insertion of C C unsaturation into Ln O bonds (involving a
highly organized transition state) with subsequent, rapid
ꢀ
Ln C protonolysis.
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Double Intramolecular Hydroalkoxylation/Cyclization
FULL PAPER
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