Mixed phosphane η5-CpRuCl(PR3)2 complexes as ambifunctional catalysts for anti-markovnikov hydration of terminal alkynes

Article abstract of DOI:10.1021/ja2026823

The catalytic activity of [CpRu(L)₂(MeCN)]PF₆ (L = 2-diphenylphosphinopyridine with bulky groups at C-6) for anti-Markovnikov hydration of terminal alkynes to aldehydes is retained when one heterocyclic ligand L is replaced by L′ = PPh₃. Equal amounts of CpRuCl(PPh₃)₂ (1) and phosphane L in acetone solution equilibrate to a mixture of 1, CpRuCl(L)(PPh₃) (2), and CpRuCl(L)₂ (3), which acts as highly active in situ catalyst for preparative anti-Markovnikov hydration of alkynes in water-rich media (2 mol % [Ru], 60 °C, 3-18 h in 4:1 (v/v) acetone/water). Reactions were completed in <15 min at 160 °C.

Full text of DOI:10.1021/ja2026823

S 1
Supporting Information
Mixed Phosphane η5-CpRuCl(PR3)2 Complexes as Ambifunctional Catalysts for anti-
Markovnikov Hydration of Terminal Alkynes
Florian Boeck, Thomas Kribber, Li Xiao, and Lukas Hintermann*
Department Chemie, Technische Universität München, 85748 Garching, Germany
E-Mail: lukas.hintermann@tum.de
Content
1. GENERAL.......................................................................................................................2
2. SYNTHESIS OF CATALYST COMPLEXES ...................................................................4
General procedure for preparing complexes [CpRu(Lc)(Ln)(MeCN)]PF6 (GP1)................4
3. KINETICS OF THE CATALYTIC ANTI-MARKOVNIKOV HYDRATION .........................7
General procedure for recording hydration kinetics with HPLC quantification (GP2) .......7
4. NMR IN SITU LIGAND EXCHANGE EXPERIMENT.....................................................14
5. GENERAL PROCEDURES FOR PREPARATIVE ALKYNE HYDRATION...................16
General procedure for catalytic anti-Markovnikov hydration of terminal alkynes (GP3) .16
General procedure for catalytic anti-Markovnikov hydration of terminal alkynes at
elevated temperature, with microwave heating (GP4) ...................................................16
6. SUBSTRATES FOR CATALYTIC ANTI-MARKOVNIKOV HYDRATION .....................18
7. PRODUCTS OF ANTI-MARKOVNIKOV ALKYNE HYDRATION..................................20
8. NMR SPECTRA............................................................................................................26

S 2
1. General
Syntheses of and with air-sensitive materials were performed under argon, using freshly
distilled and degassed solvents. The catalyst is not particularly sensitive to oxygen, but
oxidation of the aldehyde product may be problematic when working in air.
TLC were performed on coated plates (Merck, Kieselgel 60, F254 indicator) and detected by
UV and molybdenum stain solution (10 g of (NH4)6[Mo7O24]·4 H2O + 0.1 g of Ce(SO4)2·4 H2O
+ 200 mL H2O +10 mL of H2SO4 conc.). Preparative chromatography (CC, column
chromatography) was performed using Acros silica gel 60 (0.040–0.063 mm) using
pressured air (0.1-0.3 bar) for flash elution.
Analytical data:
Analytical data were obtained from in-house services at the Institute of Organic Chemistry,
RWTH Aachen University and at the Department of Chemistry, TU München. MS: m/z
1
(% *relative abundance). H NMR: δ/ppm, J/Hz, referenced to tetramethylsilane as internal
standard. 13C NMR: δ/ppm, J/Hz, referenced to tetramethylsilane as internal standard. IR:
ν/cm-1, intensity: vs = very strong, s = strong, m = medium, w = weak, vw = very weak.
Melting points (MP) were measured in a metal block using a digital thermometer, therefore
represent "corrected" values.1
Materials:
Unless otherwise mentioned, chemicals were obtained from commercial suppliers and used
as received. Solvents: DMF, DCM and acetone were bought in 99% purity and used without
purification.
The following substances were prepared according to literature procedures:
ISIPHOS;2 4,4-Dimethyl-6-heptyn-2-one;3 3-(Methoxymethoxy)oct-1-yne;4 1-Phenylbut-3-yn-
1-yl acetate;5 10,11-Didehydrocinchonine.6
CpRuCl(PPh3)2 was obtained commercially, or synthesized according to the literature.7
1 G. V. D. Tiers, J. Chem. Educ. 1990, 67, 258.
2
L. Hintermann, T. T. Dang, A. Labonne, T. Kribber, L. Xiao, P. Naumov, Chem. – Eur. J. 2009, 15,
7167.
3 D. Felix, J. Schreiber, G. Ohloff, A. Eschenmoser, Helv. Chim. Acta 1971, 54, 2896.
4 L. Hintermann, T. Kribber, A. Labonne, E. Paciok, Synlett 2009, 2412.
5 T. Kribber, A. Labonne, L. Hintermann, Synthesis 2007, 2809.
6 K. M. Kacprzak, W. Lindner, N. M. Maier, Chirality 2008, 20, 441.
7 M. I. Bruce, C. Hameister, A. G. Swincer, R. C. Wallis, Inorg. Syntheses 1990, 28, 270.

S 3
AZARYPHOS ligands2 used in this study:
The AZARYPHOS ligands used were prepared according to the detailed procedures in ref.2
The ligands Lb and Ld are also commercially available from Aldrich.
i-Pr
Ph
Ph P
N
Ph P
N
2
2
Ph P
N
Ph P
N
2
2
i-Pr
i-Pr
Ph
Ph
a
b
c
d
L
L
L
L
t
t
2,4,6
2,4,6
BuPyPPh
AmPyPPh
i-Pr C H PyPPh
Ph C H PyPPh
3 6 2 2
2
2
3
6
2
2
BUPYPHOS
TAMPYPHOS
ISIPHOS
TRIPPYPHOS
Abbreviations:
AMH
aq
anti-Markovnikov hydration (of terminal alkynes)
aqueous solution
CC
column chromatography
CAr
carbon in an aryl group
η5-cyclopentadienyl
Cp
DCC
DCM
DMAP
DMF
ISIPHOS
N,N´-dicyclohexylcarbodiimide
dichloromethane
4-N,N-dimethylaminopyridine
N,N-dimethylformamide
N
PPh2
MP
melting point
NHS
rt
N-hydroxysuccinimide
room temperature
sat.
TBME
TLC
saturated
tert-butylmethylether, t-BuOMe
thin layer chromatography

S 4
2. Synthesis of catalyst complexes
–
–
PF6
PPh2
–
PF6
PF6
Ph2
P
+
Ru
+
Ru
Ru+
Ln
Ln
MeCN
Ph2P
N
R
MeCN
Ld (1 equ); MeCN
N
N
MeCN
acetone
A
tripp
B
tripp
(L = La)
(Le = PPh3)
(Lf = PBu3)
Cad
Cde
Cdf
Ln
(2 equ)
MeCN
–
PPh2
N
PF6
+
Ru
Ph2P
N
La R = t-Bu
Lb R = t-Am
Lc R = 2,4,6i-Pr3C6H2
Ld R = 2,4,6Ph3C6H2
N
Ph2P
N
R
R
R
Me
(R = t-Bu) dd (R = tripp)
Caa
Cbb
C
(R = t-Am)
For the synthesis of homoleptic complexes [CpRu(Ln)2(MeCN)]PF6, see refs.8,9
General procedure for preparing complexes [CpRu(Lc)(Ln)(MeCN)]PF6 (GP1)
In a Schlenk tube, a mixture of solid [CpRu(Lc)(MeCN)2]PF6 (B; 1 equiv) and ligand Ln (1
equivalent) was placed under argon. Degassed acetone (50 mL/mmol) was added by syringe
and the mixture was stirred for 3.5 h at r.t. The solvents were removed in vacuum, until a
resinous residue remained. To this was added degassed hexanes (= petroleum ether
fraction; 50 mL/mmol) and the vessel placed in a warm (ca 40 °C) water bath. The resinous
residue slowly transformed into a microcrystalline yellow solid, which was ground to a
powder by means of a spatula. The resulting yellow suspension was stirred magnetically for
10 min. The supernatant liquid was removed via steel cannula and/or a filter stick. The
remaining yellow powder (yield >90%) was washed twice with hexanes, dried in high vacuum
and stored under argon.
The homogeneity of the mixed phosphane complexes [CpRu(L1)(L2)(MeCN)]PF6 with respect
to complex impurities ([CpRu(L1)2(MeCN)]PF6 and [CpRu(L2)(MeCN)]PF6, and
[CpRu(L1)(MeCN)2]) was determined by 31P NMR and found to be ≥95%. In cases where the
homoleptic complex [CpRu(L2)2(MeCN)]PF6 was found in the product, the complex synthesis
was repeated with an adjusted (smaller) amount of L2.
8 L. Hintermann, L. Xiao, A. Labonne, U. Englert, Organometallics 2009, 28, 5739–5748.
9 A. Labonne, T. Kribber, L. Hintermann, Org. Lett. 2006, 8, 5853.

S 5
[CpRu(2,4,6Ph3C6H2PyPPh2-κP)-
(MeCN)2]PF6 (B): This material was
synthesized as described earlier
from A and Ld in MeCN solution.8
PF6
NCMe
-
-
PF6
+
Ru
Ph
Ph P
+
Ru
+ MeCN
Ph
NCMe
Ph
Ph
Ph
NCMe
P
N
N
Ph
Me2CO
Ph
Ph
Ph
[CpRu(tBuPyPPh2)2(MeCN)]PF6 (IIa = Caa): Synthesized
from A and La in MeCN solution as described earlier.9 This
complex has earlier been synthesized by Grotjahn.10
PF6
-
Ph2
P
Ph2
+
Ru
P
N
N
N
N
N
Me
[CpRu(tAmPyPPh2)2(MeCN)]PF6 (Cbb): Synthesized from A
and La in MeCN solution as described earlier.9
PF6
-
Ph2
P
Ph2
P
+
Ru
N
N
Me
[CpRu(2,4,6Ph3C6H2PyPPh2)2(MeCN)]PF6 (Cdd): This complex
was synthesized as described earlier from A and Ld in MeCN
solution.8,9
-
PF6
Ph2
Ph2
P
+
Ru
P
N
N
Ph
Ph
Ph
Ph
Me
Ph
Ph
[η5-CpRu(2,4,6-Ph3C6H2PyPPh2)(PPh3)(MeCN)]PF6 (Cde): Synthesized
according to the GP1 from [η5-CpRu(2,4,6-Ph3C6H2PyPPh2)(MeCN)2]PF6
(100 mg, 0.104 mmol) and PPh3 (27.3 mg, 0.104 mmol).
-
PF6
+
Ru
Ph
Ph P
PPh3
NCMe
N
Ph
1H NMR (300 MHz, CDCl3): δ = 2.04 (t, J = 1.4 Hz, 3 H, MeCN), 4.17 (s,
Ph
5 H, Cp), 6.57–6.66 (m, 2 HArl), 6.86–6.94 (m, 6 HArl), 6.96–7.17 (m, 20
Ph
HArl), 7.19–7.35 (m, 8 HArl), 7.37–7.44 (m, 3 HArl), 7.46–7.52 (m, 2 HArl), 7.69–7.76 (m, 4 HArl).
1H NMR (300 MHz, acetone-d6): δ = 2.23 (t, JPH = 1.4 Hz, 3 H, MeCN), 4.29 (s, 5 H, Cp),
6.72–6.79 (m, 2 HArl), 6.99–7.07 (m, 6 HArl), 7.09–7.49 (m, 29 HArl), 7.51–7.57 (m, 4 HArl),
7.75–7.78 (m, 2 HArl), 7.87–7.90 (m, 2 HArl). 31P NMR (120 MHz, CDCl3): δ = –144.4 (sept, JPF
-
= 712 Hz, PF6 ), 40.1 (d, JPP = 35.3 Hz), 45.8 (d, JPP = 35.3 Hz). 31P NMR (120 MHz,
acetone-d6): δ = 44.6 (d, JPP = 35.8 Hz), 40.7 (d, JPP = 36.0 Hz), –144.4 (sept, JPF = 708 Hz,
-
PF6 ). MS (ESI, CHCl3): m/z = 1036.67 [M+], 996.27, 734.60.
10 D. B. Grotjahn, D. A. Lev, J. Am. Chem. Soc. 2004, 126, 12232–12233.

S 6
CpRu(2,4,6Ph3C6H2PyPPh2)(PBu3)(MeCN)]PF6 (Cdf): Synthe-
sized according to the GP1 from [η5-CpRu(2,4,6Ph3C6H2PyPPh2)-
(MeCN)2]PF6 (96.1 mg, 0.10 mmol) and tributylphosphane (25
µL, 0.10 mmol).
-
PF6
Ph2
P
+
Ru
P
N
N
Ph
Ph
Me
1H NMR (400 MHz, acetone-d6): δ = 0.80 (t, J = 7.2 Hz, 9 H, 3 ×
CH3), 1.13–1.40 (m, 15 H, CH2), 1.62–1.74 (m, 3 H, PCH2) 2.43
(t, JPH = 1.3 Hz, 3 H, MeCN), 4.53 (s, 5 H, Cp), 7.01–7.06 (m, 1
Ph
HArl), 7.13–7.59 (m, 25 HArl), 7.72 (d, J = 2.1 Hz, 1 HArl), 7.78 (d, J = 2.0 Hz, 1 HArl), 7.84–7.89
(m, 2 HArl) ppm. 31P NMR (162 MHz, acetone-d6): δ = 46.5 (d, J = 37.8 Hz), 22.6 (d, J = 37.8
Hz), –144.4 (sept, J = 708 Hz, PF6) ppm. MS (ESI, CHCl3): m/z = 935.96
[CpRu(2,4,6Ph3C6H2PyPPh2)(PBu3)]+, 734.23.
X-ray analysis: Crystals suitable for an X-ray analysis were obtained from a solution of the
complex in acetone by overlayering with hexanes and standing for 2 d in a fridge at 4 °C.
(κN-Acetonitrile)(η5-cyclopentadienyl)(κP-2-diphenylphosphanyl-6-(2,4,6-triphenylphenyl)py-
ridine)-(κP-tributylphosphane)ruthenium(II) hexafluorophosphate; C60H65F6N2P3Ru; unit cell
parameters: a 18.3756(11), b 14.6058(9), c 22.0886(13); β 111.7290(10); space group
P21/n. CCDC 813354 contains the supplementary crystallographic data.
[CpRu(PPh3)2(MeCN)]PF6 (Cee): In a dry Schlenk vessel under argon,
-
PF
6
[CpRu(η6-naphthalene)]PF6 (A; 87.9 mg, 0.20 mmol) and PPh3 (105 mg,
0.40 mmol) were dissolved in degassed MeCN (5 mL) and stirred for 43
h at 60 °C. The solvent was removed in vacuum. To the resinous
residue, hexanes (5 mL) were added and the vessel kept for 1 h at 50 °C.
+
Ru
Ph P
PPh
3
3
N
Me
The residue, which had converted to a microcrystalline yellow solid, was ground to a powder
by means of a spatula. After stirring the yellow suspension for another 30 min at 50 °C, the
supernatant was removed via cannula and/or a filter stick, the residual powder was washed
twice with hexanes and then dried in vacuum to give fine, bright-yellow powder.
1
C43H38F6NP3Ru (Mr 876.75). H NMR (400 MHz, acetone-d6): δ = 2.36 (t, JPH = 1.4 Hz, 3 H,
MeCN-Ru), 4.60 (s, 5 H), 7.18–7.23 (m, 12 HPh), 7.33–7.37 (m, 12 HPh), 7.43–7.48 (m, 6
HPh). 31P NMR (162 MHz, acetone-d6): δ = 41.9 (s), –144.4 (sept, J = 708 Hz, PF6). MS (ESI,
CHCl3): m/z = 731.3 (10) [M+], 691.1 (100).

S 7
3. Kinetics of the catalytic anti-Markovnikov hydration
General procedure for recording hydration kinetics with HPLC quantification (GP2)
H
[Ru]-catalyst (2 mol-%)
O
N
Ph
Ph
0.5 mmol
H O (45 mg, 5 equiv)
2
O
acetone (2 mL)
50 °C
(int. standard; 74 mg)
• quantified by HPLC-analysis
(! = 213 nm)
Setup: Into a 10 mL Schlenk-tube with rubber septum, the internal standard N-pivaloylaniline
(74 mg, 0.42 mmol) and the ruthenium(II)-complex catalyst (2 mol%) were placed under an
atmosphere of argon. The solvent mixture, consisting of acetone and water (2 mL [→ c =
0.25 mol·L–1] containing 45 mg H2O, 2.5 mmol, 5 equivalents), was added by syringe from a
degassed (argon) stock-solution. After addition of 4-phenyl-1-butyne (70 µL, 0.5 mmol;
micro-syringe), the Schlenk tube was placed in a metal block heated to 50 °C.
Sampling: Using a micro syringe, 20 µL were removed from the reaction mixture and diluted
with HPLC mobile phase (5 mL; t-BuOMe/hexanes 1:5). The diluted sample was analyzed by
HPLC with UV-detection (stationary phase: Kromasil® 100 Si-5µ; mobile phase: t-BuOMe/-
hexanes = 1:5, flow = 1 mL/min, T = 20 °C; UV-detection λ = 213 nm).
Analysis: Integration of the peak areas for 4-phenylbutanal (tR = 5.0 min) and internal
standard (N-pivaloylaniline; tR = 7.5 min) and multiplication of the relative peak area
(∫product/∫int. standard) with a response factor and the mass of int. standard (74 mg) gave the time-
dependent product yield (in mg). The response factor was determined as follows: 10 mg
each of product and internal standard was dissolved in 10 mL of mobile phase and analyzed
by HPLC. The relative peak areas were: ∫int. standard /∫product = 0.62 (λ = 213 nm).
Figure S1. Example for an HPLC-trace of a catalytic AMH reaction.

S 8
A) Effect of AZARYPHOS ligand structure on catalytic activity
Experiments were performed according to the GP2.
Figure S2. Effect of the ligand structure on the kinetics of catalytic AMH

S 9
B) Effect of the ligand structure and combination in mixed ligand catalyst complexes
on kinetics of catalytic anti-Markovnikov hydration of alkynes
Kinetic curves were recorded according to the GP2. Mixed phosphane complexes have been
prepared according to the GP1.
The results with mixed phosphane complexes [CpRu(TRIPPYPHOS)(PAr3)(MeCN)]PF6
incorporating substituted triphenylphosphane ligands (PAr3; Ar = 4-fluorophenyl, 4-
chlorophenyl, 4-methylphenyl, 4-trifluoromethyl) are also shown in the graph. The results with
those mixed species were not substantially different (within the limits of accuracy of the
analytical method) from those with the mixed complex with PPh3.
Aside the triarylphosphane and the tributylphosphane (Cdf) containing complexes, only the
mixed complex incorporating triethyl phosphite (and, to a lesser degree, triphenylphosphite;
not shown) displayed some activity. Other mixed complexes incorporating tri-
cyclohexylphosphane,
tris-ortho-tolylphosphane,
tris-1-naphthylphosphane,
tris-2,6-
dimethoxyphenylphosphane or 4-tert-butylpyridine displayed no activity; some of the
sterically more hindered phosphane ligands failed to form stable mixed complexes.
Figure S3. Performance of mixed phosphane catalyst complexes in catalytic AMH.

S 10
C) Effect of the water concentration on the kinetics of anti-Markovnikov alkyne
hydration
Reactions were performed according to GP2 with complex Cdd, but using a reaction medium
prepared from acetone (2.0 mL) and variable amounts of water:
• 10 equivalents = 5 mmol = 0.1 mL H2O for 2 mL acetone (20:1)
• 20 equivalents = 10 mmol = 0.18 mL H2O for 2 mL acetone (10:1)
• 36.65 equivalents = 18.325 mmol = 0.33 mL H2O for 2 mL acetone (6:1)
• 55.5 equivalents = 27.75 mmol = 0.50 mL H2O for 2 mL acetone = (4:1).
In the reaction with „0 equivalents“, reagent grade acetone was used straight from the bottle.
According to the label, it may have contained water in excess of 1000 ppm (>0.1%).
Figure S4. Effect of the water concentration on the catalytic AMH.

S 11
D) Inhibitory effect of acetonitrile on the kinetics of anti-Markovnikov alkyne hydration
Experiments were performed according to the GP2, with complex Cdd and additional MeCN
([mol-%] relative to substrate). Since the catalyst complex incorporates coordinated MeCN,
an additional 2 mol-% of MeCN is present in all runs.
Figure S5. Inhibitory effect of added MeCN on the catalytic AMH.

S 12
E) Effect of various additives on the kinetics of anti-Markovnikov alkyne hydration
[CpRu(Ld)2(MeCN)]PF6
(Cdd; 2 mol-%)
H2O (45 mg, 5 equiv)
additive (20 mol-%)
O
Ph
0.5 mmol
Ph
acetone (2 mL), 50°C
int. standard (74 mg)
The standard hydration reaction (GP2) with complex Cdd was performed in the presence of a
range of additives at the 20 mol-% level. None of the additives increased the rate of the
catalytic reaction, however, several additives, including benzoic and anthranilic acid, were
compatible with the hydration reaction.
On the other hand, coordinating counter-ions like chloride and acetate reduced catalytic
activity considerably. The reaction does not proceed in the presence of bases (tert-amine).
Figure S6. Effect of various additives on the kinetics of the AMH.

S 13
F) Effect of catalyst loading on hydration kinetics
[Ru]-cat (x mol-%)
H O (5 equiv)
2
O
Ph
Ph
0.5 mmol
acetone (2 mL), 50°C
int. standard (74 mg)
Experiments performed according to the GP2, with [CpRu(TRIPPYPHOS)2(MeCN)]PF6 (Cdd).
The reactions with 2 mol-% of catalyst loading are, as expected, faster than reactions with 1
mol-% of catalyst loading. However, further increasing the catalyst loading to 3 or 4 mol-%
has only a small effect on the reaction kinetics. This is presumably due to the equilibrium:
Ru(MeCN)+ = Ru+(active) + MeCN
The precursor Ru(MeCN)+ dissociates to give the catalytically active Ru+-species and the
inhibitor MeCN reversibly. Therefore, a linear increase of the concentration of Ru(MeCN)+
does not lead to a linear increase of the active species Ru+.
Catalyst loadings below 1 mol-% do not give reliable results, because catalyst deactivation
(due to generation of inactive ruthenium carbonyl complexes) becomes notable. Catalysis
may stop before the substrate is consumed.
Figure S7. Effect of the catalyst loading on catalytic AMH.

S 14
4. NMR in situ ligand exchange experiment
BUPYPHOS (t-BuPyPPh2) (15.9 mg, 0.05 mmol, 1.0 eq) and CpRuCl(PPh3)2 (28.6 mg, 0.05
mmol, 1.0 eq) were dissolved in 1.5 mL of degassed acetone-d6 containing two drops of D2O.
The mixture was heated to 50 °C for 3 hours and cooled to rt (the ligand exchange is actually
much faster and appears to be completed within 30 min at 50 °C). A sample of 0.5 mL was
removed for NMR-analysis. At higher D2O-contents, spectra became more complex with
additional and broadened lines due to chemical exchange with aquo-complexes.
R
R
N
PPh2
N
Ph
Ph P
Ru
Cl
2 mol %
PPh3
Ph
Ph P
Ru
Cl
Ru
Cl
+
P
Ph3P
PPh3
Ph
Me2CO
N
Ph
N
60–70°C, 0.5–1 h
R
2 mol %
R
1H NMR (360 MHz, acetone-d6, r.t.); η5-Cp signal region.
Figure S8. 31P NMR (145.8 MHz, acetone-d6, r.t.); excerpt, coordinated phosphane signals.

S 15
Table S1. NMR data and population analysis:
δ(31P)
δ(1H)Cp
∫
31P
∫ (1H)Cp
CpRuCl(PPh3)2
39.9 ppm (s)
28%
55%
4.09 (s)
28%
CpRuCl(PPh3)(t-BuPyPPh2)
39.3 (d, J = 41.4 Hz)
43.5 (d, J = 41.4 Hz)
43.3 (s)
(27.4%)
(27.4%)
4.17 (s)
4.21 (s)
56%
CpRuCl(t-BuPyPPh2)2
Σ (mol-%)
17%
16%
100%
100%

S 16
5. General procedures for preparative alkyne hydration
General procedure for catalytic anti-Markovnikov hydration of terminal alkynes (GP3)
Reactions were performed on a scale of 0.25–4.0 mmol: Freshly degassed solvent
(acetone/water = 4:1 (v/v); 2.5 mL/mmol) was added to a Schlenk-tube (not dried) equipped
with a magnetic stirring bar under argon, containing CpRuCl(PPh3)2 (2–10 mol-%; typically 2
mol-%) and AZARYPHOS ligand (2–10 mol-%, 1–1.2 equiv. relative to Ru; typically 2 mol-
%). The mixture was heated to 65 °C for 30 min.* The substrate was added at once and the
reaction mixture heated to 70 °C with stirring.** Reaction progress was checked by TLC- or
GC/MS-analysis. After completion of the reaction (2–16 h), acetone was removed under
reduced pressure (e.g., rotatory evaporator). The aqueous/organic mixture was extracted
with t-BuOMe (3 x 5 mL). The combined organic phase was washed with brine (5 mL) and
dried over MgSO4. Filtration and evaporation afforded the crude product, which was purified
by Kugelrohr distillation or column chromatography (CC).
Notes: * This ligand exchange phase may be omitted (compare also GP4), but it appeared
that slightly better results were obtained with it, particularly at lower catalyst loadings. ** The
mixture may be cooled to r.t., prior to addition of the substrate, in order to prevent evapo-
ration losses of the solvent (if the substrate is added in a counter-stream of argon).
General procedure for catalytic anti-Markovnikov hydration of terminal alkynes at
elevated temperature, with microwave heating (GP4)
Reactions were typically performed on a 0.5 mmol scale: In a 20 mL microwave vessel under
argon, CpRuCl(PPh3)2 (2 mol-%), AZARYPHOS ligand (2 mol-%) and substrate (1 equiv.)
were combined with a freshly degassed solvent mixture (acetone/water = 4:1 (v/v);1.25
mL/mmol) and heated to 160 °C for 2–15 min (focused microwave irradiation with external
IR-temperature sensor; the heating power is variable and regulated by the microwave unit so
as to keep the temperature constant at 160 °C; see next page for a representative
experiment protocol). After cooling to r.t., acetone was removed under reduced pressure and
the aqueous/organic mixture extracted with t-BuOMe (3 x 5 mL). The combined organic
phase was washed with brine (5 mL) and dried over MgSO4. Filtration and evaporation
afforded the crude product, which was purified by Kugelrohr distillation or column
chromatography (CC).

S 17
Microwave heating protocol for a representative catalytic hydration
Reaction: (Table 1, entry 3b)
CpRuCl(PPh ) (0.02)
3 2
ISIPHOS (0.02)
O
HO
HO
acetone/H O (4:1)
2
96%
160 °C, 15 min

S 18
6. Substrates for catalytic anti-Markovnikov hydration
Cholesteryl 5-hexynoate. To a solution of cholesterol
(10 mmol, 3.87 g) and 5-hexynoic acid (12 mmol, 1.35 g)
in DCM (20 mL) at 0 °C, DCC (15 mmol, 15 mL of a 1 M
H
H
solution in DCM) and DMAP (5 mmol, 611 mg) was
added successively. The mixture was warmed to r.t.
H
H
O
O
(23 °C) and stirred for 20 h. The suspension was filtered and the solid washed with TBME.
The combined filtrate was evaporated and the residue purified by CC (TBME/n-pentane
1:100–1:30) to give 4.74 g (99%) of a white solid.
1
CAS-Nr.: 949584-05-8, MP: 75–76 °C. H NMR (400 MHz, CDCl3): δ = 0.67 (s, 3H), 0.85 (d,
J = 1.8 Hz, 3H), 0.87 (d, J = 1.8 Hz, 3H), 0.91 (d, J = 6.5 Hz, 3H), 1.02 (s, 6H), 1.07-1.21 (m,
7H), 1.25-1.39 (m, 4H), 1.42-1.64 (m, 7H), 1.77-1.89 (m, 5H), 1.92-2.06 (m, 3H), 2.26 (dt,
J = 2.6, 7.0 Hz, 2H), 2.31 (d, J = 7.6 Hz, 2H), 2.42 (t, J = 7.4 Hz, 2H), 4.55-4.64 (m, 1H), 5.37
(d, J = 4.6 Hz, 1H) ppm. 13C NMR (101 MHz, CDCl3): δ = 12.1 (CH3), 18.1 (CH2), 19.0 (CH3),
19.6 (CH3), 21.3 (CH2), 22.8 (CH3), 23.1 (CH3), 24.0 (CH2), 24.1 (CH2), 24.5 (CH2), 28.0
(CH2), 28.3 (CH), 28.5 (CH2), 32.1 (CH), 32.1 (CH2), 33.5 (CH2), 36.0 (CH), 36.4 (CH2), 36.8
(C), 37.2 (CH2), 38.4 (CH2), 39.7 (CH2), 39.9 (CH2), 42.5 (C), 50.2 (CH), 56.3 (CH), 56.9
(CH), 69.2 (C≡CH), 74.1 (CHOR), 83.5 (C≡C), 122.7 (C=CH), 139.7 (C=C), 172.5 COOR)
~
ppm. IR (ATR)
!
= 3262 (m), 2940 (vs), 2968 (s), 1718 (vs), 1462 (s), 1375 (s), 1323 (s),
1263 (vs), 1240 (s), 1196 (m), 1152 (m), 1062 (w), 959 (vw), 923 (w), 839 (w), 801 (m), 732
(w), 689 (vs) cm-1. MS (EI, 70 eV): m/z (%) = 480 (3), 369 (55), 368 (100), 353 (24), 260 (18),
255 (14), 247 (15), 147 (25), 145 (19), 107 (11), 105 (12), 95 (15), 81(14), 67 (11), 57 (10),
55 (14). Elemental analysis: calc. (%) for C33H52O2: C 82.44, H 10.90; found: C 82.63, H
10.98.
OH
N-(N’-Hex-5-ynoyl-L-α-aspartyl)-L-phenylalanine 1-methyl
ester (N’-Hex-5-ynoyl-aspartame). DCC (3.35 mmol,
691 mg) and N-hydroxysuccinimide (3.35 mmol, 385 mg)
were added to a solution of 5-hexynoic acid (3.04 mmol,
341 mg) in DCM (5 mL). The mixture was stirred at 40 °C for
O
O
H
N
HN
OMe
O
O
3 h, cooled to rt, and filtered. The solid material was rinsed thoroughly with DCM. The com-
bined filtrate was evaporated under reduced pressure and the resulting crude material dissol-
ved in DMF (3 mL). N-(L-α-Aspartyl)-L-phenylalanine 1-methyl ester (aspartame) (1.52 mmol,
0.448 mg) was added and the solution heated to 60 °C for 16 h. After cooling to rt, the
mixture was diluted with DCM (10 mL) and washed with HCl (aq) (2 M, 10 mL). The organic
layer was dried over MgSO4, filtered and evaporated under reduced pressure. Purification of

S 19
the crude product by CC (DCM/MeOH = 20:1+1% AcOH) gave 385 mg (65%) of a white
solid.
1
MP: 119–120 °C. H NMR (250 MHz, CDCl3): δ = 1.80 (quint., J = 6.9 Hz, 2H), 1.98 (t,
J = 2.6 Hz, 1H), 2.22 (dt, J = 2.6, 6.8 Hz, 2H), 2.32 (dd, J = 6.5, 7.8 Hz, 2H), 2.68 (dd,
J = 6.5, 17.2 Hz, 1H), 2.91 (dd, J = 4.6, 16.1 Hz, 1H), 3.03 (dd, J = 6.9, 13.9 Hz, 1H), 3.15
(dd, J = 5.7, 13.9 Hz, 7H), 3.70 (s, 3H), 4.72-4.90 (m, 2H), 6.88 (d, J = 8.0 Hz, 1H), 2.31 (d,
J = 7.6 Hz, 2H), 2.42 (t, J = 7.4 Hz, 2H), 4.55-4.64 (m, 1H), 5.37 (d, J = 4.6 Hz, 1H), 7.08-
7.16 (m, 2H), 7.18-7.32 (m, 3H), 7.25 (br s, 1H) ppm. 13C NMR (63 MHz, CDCl3): δ = 17.9
(CH2), 24.0 (CH2), 34.9 (CH2), 35.9 (CH2), 37.8 (CH2), 49.2 (CH3), 52.6 (CH), 53.8 (CH), 69.7
(C≡CH), 83.3 (C≡C), 127.3 (CArH), 128.7 (CArH), 129.4 (CArH), 135.9 (CAr), 170.5 (CONR),
~
171.7 (COOMe), 173.1 (COOH), 174.6 (CONR) ppm. IR (ATR)
!
= 2916 (m), 2844 (w),
1707 (s), 1686 (vs), 1468 (m), 1437 (w), 1408 (w), 1387 (vw), 1345 (w), 1314 (vw), 1284 (m),
1254 (w), 1224 (m), 1194 (vw), 1109 (vw), 1038 (vw), 919 (m), 751 (vw), 724 (w), 690 (w),
667 (vw), 657 (vw) cm-1. MS (EI, 70 eV): m/z (%) = 370 (4), 310 (4), 293 (4), 225 (24), 224
(94), 181 (6), 167 (10), 166 (12), 149 (17), 143 (89), 120 (23), 111 (16), 100 (30), 99 (95), 98
(79), 83 (48), 70 (67), 61 (81), 56 (100), 55 (76), 43 (64); MALDI-TOF: m/z = 410.863
[M+Na]+ Elemental analysis: calc. (%) for C20H24N2O6: C 61.84, H 6.23, N 7.21; found: C
61.77, H 6.47, N 7.32.

S 20
7. Products of anti-Markovnikov alkyne hydration
Decanal. a) (Table 1, entry 1a) Synthesis according to GP3 with 1-
O
decyne (2 mmol, 277 mg), CpRuCl(PPh3)2 (30 mg, 2.0 mol-%) and
ISIPHOS (24 mg, 2.5 mol-%) at 60 °C for 18 h. Purification by CC (TBME/n-pentane = 1:50)
gave 310 mg (99%) of a colorless liquid.
b) (Table 1, entry 1b) Synthesis according to GP4 with 1-decyne (1 mmol, 138 mg),
CpRuCl(PPh3)2 (14.5 mg, 2.0 mol-%) and ISIPHOS (9.3 mg, 2.0 mol-%) at 160 °C for 15 min.
Purification by CC (TBME/n-pentane = 1:50) gave 145 mg (93%) of a colorless liquid.
1
Known compound: CAS-Nr.: 112-31-2, H NMR (300 MHz, CDCl3): δ = 0.88 (t, J = 7.1 Hz,
3H), 1.22-1.37 (m, 12H), 1.63 (quint, J = 7.3 Hz, 2H), 2.42 (dt, J = 1.9, 7.3 Hz, 2H), 9.76 (t,
J = 1.9 Hz, 1H) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.0 (CH3), 22.1 (CH2), 22.6 (CH2), 29.1
(CH2), 29.2 (CH2), 29.3 (CH2), 29.4 (CH2), 31.8 (CH2), 43.9 (CH2), 202.8 (CHO) ppm.
Analytical data agree with those reported in literature.11
O
(4-n-Propylphenyl)acetaldehyde. (Table 1, entry 2) Synthesis ac-
cording to GP3 with (4-n-propylphenyl)acetylene (5 mmol, 720 mg),
CpRuCl(PPh3)2 (73 mg, 2 mol-%) and ISIPHOS (58 mg, 2.5 mol-%)
at 60 °C for 17 h. Kugelrohr distillation at 120 °C gave 709 mg (87%) colorless liquid.
1H NMR (400 MHz, CDCl3): δ = 0.95 (t, J = 7.3 Hz, 3H), 1.63 (s, J = 7.4 Hz, 2H), 2.59 (t,
J = 7.7 Hz, 2H), 3.65 (d, J = 2.4 Hz, 2H), 7.13 (d, J = 8.1 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H),
9.73 (t, J = 2.4 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.0 (CH3), 24.7 (CH2), 37.8
(CH2), 50.4 (CH2), 129.0 (CAr), 129.1 (2 x CArH), 129.5 (2 x CArH), 141.9 (CAr), 199.6 (CHO)
~
ppm. IR (CHCl3)
!
= 3432 (w), 3091 (w), 3051 (w), 3022 (m), 3259 (vs), 2929 (vs), 2870 (s),
2723 (w) 1725 (vs), 1514 (s), 1461 (m), 1420 (m), 1382 (w), 1118 (vw), 1039 (w), 1022 (w),
995 (vw), 935 (vw), 802 (m), 536 (w), 513 (w) cm-1. MS (EI, 70 eV): m/z (%) = 162 (29), 133
(100), 105 (22), 91 (35), 77 (11). Elemental analysis: calc. (%) for C11H14O: C = 81.44, H =
8.70; found: C = 81.17, H = 8.74.
HO
11-Hydroxyundecanal. a) (Table 1, entry 3a) Synthesis
according to GP3 with 10-undecyn-1-ol (1 mmol, 168 mg),
O
CpRuCl(PPh3)2 (15 mg, 2 mol-%) and ISIPHOS (12 mg, 2.5 mol-%) at 60 °C for 3 h.
Purification by CC (TBME/n-pentane = 1:1) gave 175 mg (94%) of white solid.
b) (Table 1, entry 3b) Synthesis according to GP4 with 10-undecyn-1-ol (1 mmol, 168 mg),
CpRuCl(PPh3)2 (14.5 mg, 2.0 mol-%) and ISIPHOS (9.3 mg, 2.0 mol-%) at 160 °C for 15 min.
Purification by CC (TBME/n-pentane = 1:1) gave 179 mg (96%) of colorless liquid.
11
X. -Q. Li, C. Zhang, Synthesis 2009, 1163.

S 21
Known compound: CAS-Nr.: 22054-16-6, MP: 76–77 °C 1H NMR (400 MHz, CDCl3):
δ = 1.27-1.36 (m, 12H), 1.40-1.51 (m, OH), 1.56 (quint, J = 7.0 Hz, 2H), 1.63 (quint, J = 7.1
Hz, 2H), 2.42 (ddt, J = 1.0, 1.9, 7.3 Hz, 2H), 3.64 (dt, J = 1.0, 6.6 Hz, 2H), 9.77 (dt, J = 0.9,
1.9 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ = 22.3 (CH2), 25.9 (CH2), 29.4 (CH2), 29.5
(2 x CH2), 29.6 (CH2), 29.7 (CH2), 33.0 (CH2), 44.1 (CH2), 63.2 (CH2), 202.9 (CHO) ppm.
Analytical data agree with those reported in literature.12
HO
11-Oxo-undecanoic acid. (Table 1, entry 4) Synthesis ac-
cording to GP3 with 10-undecynoic acid (2 mmol, 365 mg),
O
O
CpRuCl(PPh3)2 (30 mg, 2 mol-%) and ISIPHOS (24 mg, 2.5 mol-%) at 60 °C for 3 h.
Purification by CC (TBME/n-pentane = 1:5 + 2% AcOH) gave 388 mg (97%) off-white solid.
1
MP: 46–47 °C H NMR (400 MHz, CDCl3): δ = 1.25-1.37 (m, 10H), 1.56 (quint, J = 7.0 Hz,
2H), 1.63 (quint, J = 7.4 Hz, 2H), 2.35 (t, J = 7.5 Hz, 2H), 2.42 (dt, J = 1.9, 7.4 Hz, 2H), 9.76
(t, J = 1.9 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ = 22.3 (CH2), 24.9 (CH2), 29.2 (CH2),
29.3 (CH2), 29.4 (CH2), 29.5 (CH2), 34.2 (CH2), 44.1 (CH2), 180.0 (COOH), 203.0 (CHO)
~
ppm. IR (ATR):
!
= 3432 (w), 3091 (w), 3051 (w), 3022 (m), 3259 (vs), 2929 (vs), 2870 (s),
2723 (w) 1725 (vs), 1514 (s), 1461 (m), 1420 (m), 1382 (w), 1118 (vw), 1039 (w), 1022 (w),
995 (vw), 935 (vw), 802 (m), 536 (w), 513 (w) cm-1.
O
4,4-dimethyl-6-oxoheptanal. (Table 1, entry 5) Synthesis according to
GP3 with 4,4-dimethyl-6-heptyn-2-one (0.5 mmol, 69 mg), CpRuCl(PPh3)2
(14.5 mg, 4 mol-%) and ISIPHOS (9.3 mg, 4 mol-%) at 65 °C for 4 h.
Purification by CC (Et2O/n-pentane = 1:4) gave 75 mg (96%) colorless liquid.
1
O
Known compound: CAS-Nr.: 919091-25-1, H NMR (360 MHz, CDCl3): δ = 1.01 (s, 6H),
1.66-1.73 (m, 2H), 2.14 (s, 3H), 2.34 (s, 2H), 2.38-2.45 (m, 2H), 9.77 (t, J = 1.8 Hz, 1H) ppm.
13C NMR (90 MHz, CDCl3): δ = 27.1 (CH3), 32.5 (CH3), 33.0 (C), 33.4 (CH2), 39.4 (CH2), 53.5
(CH2), 202.5 (CHO), 208.3 (CO) ppm. Analytical data agree with those reported in literature.9
3-(Methoxymethyloxy)-octanal. (Table 1, entry 6) Synthesis according
MOMO
O
to GP3 from 3-(methoxymethyloxy)-1-octyne (1 mmol, 170 mg),
CpRuCl(PPh3)2 (36.3 mg, 5 mol-%) and ISIPHOS (29.3 mg, 6.5 mol-%) at 60 °C for 20 h.
Purification CC (TBME/n-pentane = 1:10) gave 103 mg (55%) as colorless liquid.
Known compound: CAS-Nr.: 108383-17-1, 1H NMR (400 MHz, CDCl3): δ = 0.89 (t,
J = 7.1 Hz, 3H), 1.24-1.39 (m, 6H), 1.47-1.58 (m, 1H), 1.59-1.69 (m, 1H), 2.56 (ddd, J = 1.8,
4.8, 16.3 Hz, 1H), 2.64 (ddd, J = 2.8, 7.0, 16.3 Hz, 1H), 3.35 (s, 3H), 4.08 (quin, J = 6.0 Hz,
1H), 4.66 (d, J = 7.0 Hz, 1H), 4.69 (d, J = 7.0 Hz, 1H), 9.81 (dd, J = 1.9, 2.8 Hz, 1H) ppm.
13C NMR (100 MHz, CDCl3): δ = 14.1 (CH3), 22.6 (CH2), 25.0 (CH2), 31.8 (CH2), 35.0 (CH2),
12
M. Marchetti, C. Botteghi, S. Paganelli, M. Taddei, Adv. Synth. Catal. 2003, 345, 1229.

S 22
48.8 (CH2), 55.7 (OCH3), 73.2 (CHOR), 95.8 (CH2O2), 201.3 (CHO) ppm. Analytical data
agree with those reported in literature.4
OAc
4-Acetoxy-4-phenylbutanal. a) (Table 1, entry 7a) Synthesis according to
GP3 with 1-phenylbut-3-yn-1-yl acetate (1 mmol, 188 mg), CpRuCl(PPh3)2
(15 mg, 2 mol-%) and ISIPHOS (9.3 mg, 2 mol-%) at 65 °C for 4 h.
Purification CC (Et2O/n-pentane = 1:4) gave 188 mg (92%) colorless liquid.
O
b) (Table 1, entry 7b) Synthesis according to GP4 with 1-phenyl-3-butyn-1-yl acetate
(1 mmol, 188 mg), CpRuCl(PPh3)2 (14.5 mg, 2.0 mol-%) and ISIPHOS (9.3 mg, 2.0 mol-%) at
160 °C for 2 min. Purification by CC (Et2O/n-pentane = 1:4) gave 203 mg (99%) colorless
liquid.
1
Known compound: CAS-Nr.: 76698-68-5, H NMR (400 MHz, CDCl3): δ = 2.00 (s, 3H), 2.04-
2.21 (m, 2H), 2:39 (t, 1H J = 7.1 Hz, 2H), 5.70 (dd, J = 6.0, 7.5 Hz, 1H), 7.15-7.38 (m, 5H),
9.65 (s, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ = 21.3 (CH3), 28.8 (CH2), 40.0 (CH2), 75.1
(CH), 126.4 (CArH), 128.3 (CArH), 128.7 (CArH), 139.7 (CAr), 170.3 (COOR), 201.1 (CHO)
ppm. Analytical data agree with those reported in literature.5
10-Acetoxy-4,7-bis(tert-butyldimethylsilyloxy)-10-phe-
OAc
OTBS
nyldecanal. a) (Table 1, entry 8a) Synthesis according to
GP3 from 10-Acetoxy-4,7-bis((tert-butyldimethylsilyl)oxy)-
10-phenyl-1-decyne (0.25 mmol, 133 mg), CpRuCl(PPh3)2
OTBS
O
(7.3 mg, 4 mol-%) and ISIPHOS (4.7 mg, 4 mol-%) at 65 °C in acetone/water = 8:1 (v/v) (2.5
mL) for 16 h. Purification by CC (Et2O/n-pentane = 1:4) gave 98 mg (71%) colorless oil.
b) (Table 1, entry 8b) Synthesis according to GP4 from 10-acetoxy-4,7-bis((tert-
butyldimethylsilyl)oxy)-10-phenyl-1-decyne (0.5 mmol, 266 mg), CpRuCl(PPh3)2 (14.5 mg,
4.0 mol-%) and ISIPHOS (9.3 mg, 4.0 mol-%) at 160 °C in acetone/water = 8:1 (v/v) (2.5 mL)
for 2 min. Purification by CC (Et2O/n-pentane = 1:4) gave 253 mg (92%) colorless oil.
1H NMR (360 MHz, CDCl3): δ = -0.04–0.05 (m, 12 H), 0.84-0.89 (m, 18H), 1.23-1.98 (m,
12H), 2.06 (s, 3H), 2.46 (t, J = 7.4 Hz, 2H,), 3.57-3.73 (m, 2H), 5.70 (t, J = 6.9 Hz, 1H), 7.24-
7.39 (m, 5H), 9.77 (t, J = 1.3 Hz, 1H) ppm. 13C-NMR (90 MHz, CDCl3): (interpreted as 1
compound, multiple shift values and ranges given for diastereomeric signals) δ = -4.45 – -
4.27 (4 x SiCH3), 18.05/18.08 (2 C), 21.3 (CH3), 26.0 (2 CH3), 28.8–28.9 (CH2),
31.42/31.59/31.61/31.75 (CH2), 32.11/32.18/32.29/32.40 (CH2), 32.48–32.80 (2 CH2),
39.69/39.70/39.76/39.77 (CH2), 71.17/71.18/71.25/71.27 (CH), 71.53/71.63/71.65/71.75
(CH), 76.10/76.12/76.16 (CH), 126.6 (CH), 127.9 (CH), 128.5 (CH), 140.7 (C), 170.3 (C),
202.5 (CH) ppm. MS (ESI, 70 eV, MeCN/H2O): m/z (%) = 573.4 (100, [M + Na]+). IR (ATR)
!
~
= 2952 (s), 2929 (s), 2857 (m), 1731 (s), 1472 (w), 1462 (vw), 1372 (w), 1236 (vs) 1023 (m),
1005 (m), 834 (vs), 773 (vs), 700 (w), 666 (vw) cm-1. Elemental analysis: To prevent

S 23
oxidation in air, a sample was reduced by NaBH4 to the primary alcohol: calc. (%) for
C30H56O5Si2: C 65.17, H 10.21; found: C 65.21, H 10.00.
Cholesteryl 6-oxohexanoate. (Table 1, entry 9) Synthe-
O
sis according to the GP3 from cholesteryl 5-hexynoate
(0.5 mmol, 240 mg), CpRuCl(PPh3)2 (36.3 mg, 5 mol-%)
and ISIPHOS (29.3 mg, 6.5 mol-%) in acetone/water
(4:1) (20 mL) with added DCM (1.5 mL) to increase
H
H
H
H
O
O
solubility, at 60 °C for 18 h. Purification by CC (TBME/n-pentane = 1:20–1:5) afforded
217 mg (88%) white crystalline solid.
MP: 81–82 °C, 1H NMR (400 MHz, CDCl3): δ = 0.68 (s, 3H), 0.86 (d, J = 1.8 Hz, 3H), 0.87 (d,
J = 1.8 Hz, 3H), 0.91 (d, J = 6.5 Hz, 3H), 1.02 (s, 6H), 1.05-1.23 (m, 7H), 1.24-1.40 (m, 4H),
1.42-1.63 (m, 8H), 1.65-1.72 (m, 4H), 1.78-1.89 (m, 2H), 1.92-2.06 (m, 2H), 2.27-2.33 (m,
4H), 2.44-2.49 (m, 2H), 4.57-4.66 (m, 1H), 5.38 (d, J = 3.8 Hz, 1H), 9.77 (t, J = 1.6 Hz, 1H)
ppm. 13C NMR (101 MHz, CDCl3): δ = 12.0 (CH3), 18.8 (CH3), 19.4 (CH3), 21.1 (CH2), 21.6
(CH2), 22.7 (CH3), 22.9 (CH3), 23.9 (CH2), 24.4 (CH2), 24.6 (CH2), 27.9 (CH2), 28.1 (CH),
28.3 (CH2), 31.9 (CH), 32.0 (CH2), 34.4 (CH2), 35.9 (CH), 36.3 (CH2), 36.7 (CH2), 37.1 (CH2),
38.2 (C), 39.6 (CH2), 39.8 (CH2), 42.4 (C), 43.6 (CH2), 50.1 (CH), 56.2 (CH), 56.7 (CH), 74.0
~
(CHOR), 122.6 (C=CH), 139.5 (C=C), 172.5 (COOR), 201.9 (CHO) ppm. IR (ATR)
!
= 2937
(vs), 2885 (s), 2718 (w), 1728 (vs), 1464 (s), 1368 (s), 1320 (vw), 1242 (w), 1172 (vs), 1087
(m), 1026 (m), 997 (s), 957 (w), 921 (vw), 882 (vw), 841 (w), 801 (m), 736 (w) cm-1. MS (EI,
70 eV): m/z (%) = 499 (3), 369 (100), 368 (98), 353 (45), 260 (31), 247 (27), 213 (16), 159
(14), 147 (39), 133 (16), 105 (19), 95 (20), 81 (26), 67 (21), 57 (25). Elemental analysis:
calc. (%) for C33H54O3: C 79.46, H 10.91; found: C 79.24, H 10.71.
O
2-((1S,4S,6R)-6-((S)-Hydroxy(quinolin-3-yl)methyl)quinuclidin-3-yl)
acetaldehyde. (Table 1, entry 10) Synthesized according to the GP3
from 10,11-didehydrocinchonine (0.5 mmol, 146 mg), p-toluenesulfonic
acid (0.5 mmol, 95 mg; this additive is necessary to neutralize the
tertiary amine functionality), CpRuCl(PPh3)2 (36.3 mg, 10 mol-%) and
OH
N
N
ISIPHOS (23.3 mg, 6.5 mol-%) in acetone/water (4:1) (2.5 mL) at 65 °C for 16 h. Heating
was stopped and the reaction mixture was treated with sat. aq. Na2CO3 (5 mL). The mixture
was extracted with EtOAc (3 x 5 mL). The combined organic solvents were dried over MgSO4
and filtered. Evaporation afforded a crude product, which was purified by CC (EtOAc/MeOH/-
NEt3 = 50:1:1–5:1:1) to give 95 mg (61%) off-white crystalline solid.
MP: 223–225 °C (dec.),1H NMR (360 MHz, CDCl3): δ = 1.10-1.16 (m, 1H), 1.22-1.38 (m, 1H),
1.47-1.65 (m, 2H), 1.67-1.73 (m, 1H), 1.95-2.06 (m, 1H), 2.12-2.24 (m, 1H), 2.65 (ddd,
J = 1.3, 6.3, 17.4 Hz, 1H), 2.75 (dd, J = 8.1, 17.1 Hz, 1H), 2.82-2.91 (m, 1H), 2.93-3.03 (m,

S 24
1H), 3.06-3.17 (m, 2H), 3.22-3.31 (m, 1H), 5.87 (s, 1H), 7.45 (t, J = 7.7 Hz, 1H), 7.62-7.69
(m, 2H), 7.94 (d, J = 8.3 Hz, 1H), 8.11 (d, J = 8.3 Hz, 1H), 8.90 (d, J = 4.5 Hz, 1H), 9.80 (s,
1H) ppm. 13C NMR (90 MHz, CDCl3): δ = 19.6 (CH2), 26.2 (CH2), 26.5 (CH), 29.2 (CH), 47.2
(CH2), 49.9 (CH2), 50.4 (CH2), 59.8 (CH2), 70.9 (CH), 77.2 (CH), 118.1 (CArH), 122.6 (CArH),
125.2 (CAr), 126.8 (CArH), 129.1 (CArH), 130.3 (CArH), 148.1 (CAr), 148.3 (CAr), 150.1 (CArH),
~
201.7 (CHO) ppm. IR (ATR)
!
= 3065 (w), 2931 (m), 2877 (m), 2715 (w), 2113 (vw), 1941
(vw), 1909 (vw), 1716 (vs) 1591 (m), 1569 (m), 1508 (m), 1459 (m), 1387 (w), 1333 (m),
1235 (w), 1209 (w), 1169 (w), 1114 (vs), 1059 (s), 1030 (s), 994 (s), 952 (m), 885 (s), 834
(m), 761 (vs), 687 (m) cm-1. MS (EI, 70 eV): m/z (%) = 311 (20), 310 (100), 282 (14), 281
(44), 172 (14), 159 (31), 158 (11), 153 (13), 152 (68), 143 (23), 142 (10), 140 (22), 130 (21),
125 (13), 124 (54), 82 (13), 56 (13), 55 (19). Elemental analysis: calc. (%) for C19H22N2O2 +
0.8 H2O: C 70.26, H 7.32, N 8.62; found: C 70.23, H 7.66, N 8.26. HRMS (ESI): calc. for
+
C19H23N2O2 : 311.17540; found: 311.17556.
Note: In CDCl3, the compound exists almost entirely in the hydroxyaldehyde form; in MeOH-
d4 solution, the hemiacetal form is favored (acetal/hydroxyaldehyde = 94:6). The silyl ether of
a related quinidine-derived hemiacetal has been described in the literature.13
1H NMR (360 MHz, MeOH-d4): δ = 1.08–1.19 (m, 1 H), 1.51–1.62 (m, 2
HO
H), 1.69–1.75 (m, 1 H), 1.79–1.92 (m, 2 H), 2.11–2.22 (m, 1 H), 2.74–
O
3.00 (m, 3 H), 3.05–3.14 (m, 1 H), 3.36–3.46 (m, 1 H), 4.53–4.60 (m, 1
N
H), 5.71 (br s, 1 H), 7.63–7.70 (m, 1 HAr), 7.72–7.82 (m, 2 HAr), 8.06 (d,
N
J = 8.5 Hz, 1 HAr), 8.19 (d, J = 8.3 Hz, 1 HAr), 8.83 (d, J = 4.6 Hz, 1 HAr)
ppm. Selected signal for the aldehyde form: 9.75–9.77 (br s, 1 H, CHO)
OH
6-Oxohexanoyl-aspartame: (Table 1, entry 11) Synthesis
according to GP3 from N´-5-hexynoyl-aspartame (0.5 mmol,
194 mg), CpRuCl(PPh3)2 (7.3 mg, 2 mol-%) and ISIPHOS
(4.7 mg, 2.0 mol-%) at 70 °C for 7 h. NMR of the crude
compound indicated complete and selective conversion to
O
O
H
N
HN
OMe
O
O
O
product, with a high degree of purity, aside of catalyst components still present (>96% crude
yield; see NMR spectra of crude product further below), but the compound was not readily
purified by the standard chromatographic methods at our disposal (i.e., SiO2, normal phase).
Therefore, a 2,4-dinitrophenylhydrazone was prepared for analysis (see below).
1H NMR (360 MHz, CDCl3): δ = 1.53-1.62 (m, 4H), 1.63 (s, J = 7.4 Hz, 2H), 2.26-2.23 (m,
2H), 2.37-2.44 (m, 2H), 2.70 (dd, J = 6.0, 16.9 Hz, 1H), 2.85 (dd, J = 5.6, 17.0 Hz, 1H), 3.02
(dd, J = 6.7, 13.9 Hz, 1H), 3.11 (dd, J = 5.6, 13.9 Hz, 1H), 3.65 (s, 3H), 4.76 (dd, J = 6.6,
13.4 Hz, 1H), 4.86 (dd, J = 5.9, 13.7 Hz, 1H), 7.10 (d, J = 6.7 Hz, 2H), 7.16-7.29 (m, 2H),
13 W. Braje, J. Frackenpohl, P. Langer, H. M. R. Hoffmann, Tetrahedron 1998, 54, 3495.

S 25
7.37 (d, J = 7.7 Hz, 1H), 9.68 (s, 1H), 10.50 (br, 1H) ppm. 13C NMR (90 MHz, CDCl3):
δ = 21.4 (CH2), 24.8 (CH2), 35.7 (CH2), 35.8 (CH2), 35.8 (CH2), 43.4 (CH2), 49.3 (CH), 52.4
(CH), 53.7 (CH), 127.0 (CArH), 128.5 (2 x CArH), 129.3 (2 x CArH), 135.8 (CAr), 170.5 (CONR),
171.6 (COOMe), 173.6 (COOH), 174.0 (CONR), 202.9 (CHO) ppm.
2,4-Dinitrophenylhydrazone of 6-oxohexanoyl-
OH
aspartame: (Table 1, entry 11) A sample of 6-oxo-
O
O
H
N
hexanoyl-aspartame was prepared as described
above. The organic solvent was removed under
reduced pressure. To the aqueous slurry was
added DCM (3 mL), p-toluenesulfonic acid (5 mg,
5 mol-%) and (2,4-dinitrophenyl)hydrazine (99 mg,
HN
OMe
O
O
N
HN
0.5 mmol, 1.0 eq). The mixture was heated for O N
2
10 min under reflux (40–50 °C), cooled to r.t.,
diluted with more DCM, washed with aqueous
NO
2
NH4Cl(sat.) and dried over MgSO4. Filtration and evaporation gave a crude product, which was
purified by CC (DCM/MeOH = 10:1) to give 277 mg (94%) of a yellow crystalline solid.
1H NMR (360 MHz, DMSO-d6): δ = 1.47-1.61 (m, 4H), 1.63 (s, J = 7.4 Hz, 2H), 2.08-2.17 (m,
2H), 2.34 (dd, J = 6.4, 11.9 Hz, 1H), 2.41 (dd, J = 8.5, 16.4 Hz, 1H), 2.62 (dd, J = 4.4,
15.5 Hz, 1H), 2.93 (dd, J = 8.3, 13.8 Hz, 1H), 3.00 (dd, J = 5.9, 13.8 Hz, 1H), 3.58 (s, 3H),
4.44 (dd, J = 7.8, 13.7 Hz, 1H), 4.62 (td, J = 5.6, 8.2 Hz, 1H), 7.15-7.29 (m, 5H), 7.87 (d,
J = 9.7 Hz, 1H), 8.01 (t, J = 5.3 Hz, 1H), 8.09 (d, J = 8.0 Hz, 1H), 8.16 (d, J = 7.5 Hz, 1H),
8.32 (dd, J = 2.7, 9.7 Hz, 1H), 8.84 (1H, J = 2.7 Hz, 1H), 11.36 (br, 1H), 12.24 (br, 1H) ppm.
13C NMR (90 MHz, DMSO-d6): δ = 25.1 (CH2), 25.7 (CH2), 32.3 (CH2), 35.3 (CH2), 36.7
(CH2), 37.0 (CH2), 49.5 (CH), 52.3 (CH), 54.1 (CH), 116.8 (CArH), 123.5 (CArH), 127.0 (CArH),
128.5 (CArH), 129.1 (CAr), 129.5 (CArH), 130.2 (CArH), 136.9 (CAr), 137.4 (CAr), 145.2 (CAr),
~
155.4 (C=NR), 171.4 (CONR), 172.1 (COOMe + COOH), 172.5 (CONR) ppm. IR (ATR)
!
=
3302 (vw), 2938 (vw), 2436 (vw), 2164 (w), 2023 (w), 1733 (w), 1616 (s), 1518 (s) 1427 (w),
1328 (vs), 1218 (m), 1139 (m), 1078 (w), 918 (vw), 834 (vw), 761 (vw), 744 (m), 705 (w), 697
(w), 675 (vw), 666 (w), 657 (vw) cm-1. MS (ESI, 70 eV, MeCN/H2O): m/z (%) = 1781 [3 x
M+Na]+ (6), 1211 [2 x M+K]+ (16), 1195 [2 x M+Na]+ (44), 1273 [2 x M+H]+ (8), 625 [M + K]+
(17), 609 [M+Na]+ (100), 587 [M+H]+ (30), 411 (12), 389 (10), 255 (10), 180 (22). HRMS
(ESI): calc. for C26H31N6O10+: 587.20962; found: 587.20870.

S 26
8. NMR Spectra
1H-NMR (400 MHz, CDCl3)
(Table 1, entry 9, starting material)
H
H
H
H
O
O
13C-NMR (100 MHz, CDCl3)
(Table 1, entry 9, starting material)
H
H
H
H
O
O

S 27
1H-NMR (360 MHz, CDCl3)
(Table 1, entry 11, starting material)
OH
O
O
H
N
HN
OMe
O
O
13C-NMR (90 MHz, CDCl3)
(Table 1, entry 11, starting material)
OH
O
O
H
N
HN
OMe
O
O

S 28
1H-NMR (300 MHz, CDCl3)
(Table 1, entry 1)
O
13C-NMR (76 MHz, CDCl3)
(Table 1, entry 1)
O

S 29
1H-NMR (400 MHz, CDCl3)
(Table 1, entry 2)
O
13C-NMR (100 MHz, CDCl3)
(Table 1, entry 2)
O

S 30
1H-NMR (400 MHz, CDCl3)
(Table 1, entry 3)
O
HO
13C-NMR (100 MHz, CDCl3)
(Table 1, entry 3)
O
HO