Fast ruthenium-catalysed allylation of thiols by using allyl alcohols as substrates

Article abstract of DOI:10.1002/chem.200900192

The allylation of aromatic and aliphatic thiols, by using allyl alcohols as substrates, requires only minutes at ambient temperature with either a Ru ^Iv catalyst, [Ru(Cp*)(n³CH₅)(CH ₃CN)₂](PF₆)₂ (2; Cp* = pentamethylcyclopentadienyl) or a combination of [Ru(Cp*)(CH ₃CN)₃](PF₆) and camphor sulfonic acid. Quantitative conversion is normal and the catalyst possesses high functional-group tolerance. The use of [Ru(Cp*)(CH₃CN) ₃](PF₆) alone affords poor results. A comparison is made to the results from catalytic runs based on the use of carbonates rather than alcohols, by using 2 as the catalyst, and it is shown that the products from the alcohols are formed faster, so there is no advantage in using a carbonate substrate. The observed branched-to-linear (b/1) ratios when using substituted alcohols decrease with time suggesting that the catalysts isomerise the products. A new methodology from which one can select the desired isomeric product is proposed. DFT calculations and NMR spectroscopic measurements, by using an arene sulfonic acid as co-catalyst, suggest that ⁶-complexes are not relevant for the catalytic system. Moreover, the DFT results indicate that l)any rf-complexes from the acids RC₆H₄SO ₃H result from deprotonation of the acid, 2) complexation of the thiol, via the deprotonated sulfur atom, is preferred over complexation of the O atom of the sulfonate, RC₆H₄SO₃and 3) a sulfonate O-atom complex will be difficult to detect.

Full text of DOI:10.1002/chem.200900192

DOI: 10.1002/chem.200900192
Fast Ruthenium-Catalysed Allylation of Thiols by Using Allyl Alcohols as
Substrates
Alexey B. Zaitsev,[a] Helen F. Caldwell,[a] Paul S. Pregosin,*[a] and Luis F. Veiros*[b]
Abstract: The allylation of aromatic
and aliphatic thiols, by using allyl alco-
hols as substrates, requires only mi-
nutes at ambient temperature with
use of carbonates rather than alcohols,
by using 2 as the catalyst, and it is
shown that the products from the alco-
hols are formed faster, so there is no
advantage in using a carbonate sub-
strate. The observed branched-to-linear
(b/l) ratios when using substituted alco-
hols decrease with time suggesting that
the catalysts isomerise the products. A
new methodology from which one can
select the desired isomeric product is
proposed. DFT calculations and NMR
spectroscopic meaACTHNUTRGENUGNsurements, by using
an arene sulfonic acid as co-catalyst,
suggest that h6-complexes are not rele-
vant for the catalytic system. More-
over, the DFT results indicate that
1) any h6-complexes from the acids
RC6H4SO3H result from deprotonation
of the acid, 2) complexation of the
thiol, via the deprotonated sulfur atom,
is preferred over complexation of the
either a RuIV catalyst, [Ru
C3H5)(CH3CN)2]
tamethylcyclopentadienyl) or a combi-
nation of [Ru(Cp*)(CH3CN)3](PF6)
G
(h3-
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
A
R
ACHTUNGTRENNUNG
and camphor sulfonic acid. Quantita-
tive conversion is normal and the cata-
lyst possesses high functional-group tol-
erance. The use of [Ru
ACHTUNGTRNE(NUNG Cp*)-
Keywords: alcohols
density functional calculations
·
allylation
·
·
ꢀ
A
U
O atom of the sulfonate, RC6H4SO3
sults. A comparison is made to the re-
sults from catalytic runs based on the
and 3) a sulfonate O-atom complex
will be difficult to detect.
NMR spectroscopy · ruthenium
Introduction
times can be markedly reduced by using a more labile,
smaller coordination sphere.[9] This latter point is pertinent
as, according to the literature, many of the allylation reac-
tions with ruthenium are fairly slow, requiring a number of
hours, and occasionally elevated temperatures.[5,6] Further,
our new RuIV catalysts are capable of inducing novel Frie-
del–Crafts-type coupling chemistry[10] and allow allyl alco-
hols, rather than allyl carbonates or halides or acetates etc.,
to be used as substrates in this allylation chemistry, thereby
avoiding unnecessary waste of the leaving group.[11]
Ruthenium catalysts are finding increasing applications in
organic synthesis.[1–4] Although allylation with various ruthe-
nium complexes is well-known,[5,6] there has been renewed
interest in applying [RuACTHUNRGTNE(NUG Cp*)]-based catalysts (Cp*=pen-
tamethylcyclopentadienyl) in allylation chemistry,[4e,6] as
these complexes are capable of preferentially producing
branched (rather than linear) allyl-organic products.
In a series of reports, we have recently suggested that the
regioselectivity of the [Ru
(Cp*)]-catalysed allylation reac-
With respect to the catalyst, oxidative addition reactions
of 1 readily afford RuIV allyl salts.[8,12–14] that can be easily
tions derives from orbital control[7,8] and that the reaction
[a] Dr. A. B. Zaitsev, Dr. H. F. Caldwell, Prof. Dr. P. S. Pregosin
Laboratory of Inorganic Chemistry, ETHZ
Hçnggerberg, 8093 Zꢀrich (Switzerland)
Fax : (+41)44-633-1071
E-mail: pregosin@inorg.chem.ethz.ch
[b] Prof. Dr. L. F. Veiros
Centro de Quꢁmica Estrutural, Complexo I
Instituto Superior Tꢂcnico, Av. Rovisco Pais 1
1049-001 Lisbon (Portugal)
Fax : (+351)21-846-44-55
E-mail: veiros@ist.utl.pt
(h3-C3H5)
transformed into [RuACHTUNGTNRE(NUNG Cp*)ACHTUNGTERNNUG ACHTUNGTRE(GNNUN CH3CN)2]ACHTUNGRTEN(NUGN PF6)2 (2).
Salt 2 is an excellent catalyst for the allylation of indole
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200900192.
derivatives, by using allyl alcohol substrates.[11b] Catalyst 2 is
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Chem. Eur. J. 2009, 15, 6468 – 6477

FULL PAPER
able to free one proton during the catalytic cycle thereby
making water the leaving group in the oxidative addition re-
action.[11a–c] Interestingly, a catalyst composed of HBF4 and 1
does not improve either the reaction rate or the regioselec-
We know of several reports[16–18] on catalytic S-allylation;
however, these literature procedures are either not atom ef-
ficient, in that they waste the leaving group,[17] or have a
narrow substrate scope. For example, palladium-catalysed
allylation of aromatic thiols by allyl alcohols in water/
hexane biphasic media[18] is applicable only to aromatic
thiols. We show here that our Ru catalysts rapidly allylate
various RSH compounds at room temperature in a few min-
ACHTUNGTRENNUNGtivACHTUNGTRENNUNG
ity;[11b] however, the use of either p-toluene sulfonic acid
(3) or camphor sulfonic acid (4) together with 1 markedly
AHCTUNGTREGuNNNU tes, in high yields by using allyl alcohols as substrates.
Results and Discussion
Catalyst [RuACTHUGNRTEN(NNGU Cp*)ACHTNUTREGGN(NNU CH3CN)3]ACHTUNGTREN(NUNG PF6) (1): Equation (1) shows
improves both the reaction kinetics and the product distri-
bution.[11a,b] These results suggest coordination of the sulfo-
nate anion and, subsequently, we have isolated and charac-
terized the neutral RuIV–allyl, bis-sulfonate complex, 5. De-
the general reaction, and it is convenient to begin by noting
a few results arising from the use of 1 as a catalyst.
Reaction of thiophenol with allyl alcohol, by using 5% of
catalyst 1, alone, gives 100% conversion to product,
PhSCH2CH=CH2, in approximately 70 min; however, with
R=p-AcC6H4, the reaction requires approximately 22 h to
approach 90% conversion. Further, with R=PhCH2, the re-
action is even slower, approximately 22 h for 30% conver-
sion. Clearly the reaction proceeds, but not always rapidly.
Catalyst salt 2: Table 1 gives results from a selection of thiol
allylation reactions by using several RSH nucleophiles with
alcohols as the substrates, all catalysed by salt 2. A compari-
son of these results with those from experiments with 1 is in-
formative. The reaction of PhSH with allyl alcohol
(entry 10) is finished in 30 min and the reaction with p-
AcC6H4SH (entry 15) is also complete within 30 min. Fur-
ther, the reaction of PhCH2SH with allyl alcohol (entry 1)
now requires only approximately 11 min for 100% conver-
sion! Clearly, catalyst 2 is considerably faster than 1. It is
worth noting that 2 reveals a high functional-group toler-
ance (see entries 10–15).
Apart from this comparison, Table 1 shows that allyl alco-
hol (entries 1–15) can react rapidly with a variety of aromat-
ic and aliphatic thiols to afford high yields of products fre-
quently in <1 h. Entries 6–9 are especially noteworthy. 1,2-
Ethane dithiol (entry 7) affords only a very modest amount
of allylation product after several hours. This suggests that a
potentially chelating five-membered ring
ꢀ
spite this, we believe that 6 or 7,[11a] as PF6 salts, are the
active precursors. Herein, we extend our studies to the Ru-
catalysed synthesis of allyl thioethers. In addition to their
recognized preparative utility,[15] allyl thioethers have been
called “privileged substrates” in cross-metathesis chemis-
try.[15a] Moreover, they are useful precursors in enantioselec-
tive syntheses,[15b,c] see Scheme 1, which shows the [Cu-
ACHTUNGTRENNUNG(PHOX)]-catalysed reaction (PHOX=phosphinooxazoline
ligands)[15b] of an allyl thioether with a carbene precursor to
afford a fully substituted new stereogenic centre (in 52–
78% ee; ee = enantiomeric excess) and the synthesis of an
allyl arylsulfonamide,[15c] by using a [Ru
(salen)] catalyst that
eventually affords the chiral amine with 78–86% ee. Further,
thio–allyl compounds are known to possess some useful an-
ticancer properties.[15f,1g]
complex, such as 8, formed when two S
atoms coordinate,[19a] might not be very
active. This would be in keeping with the lit-
erature, which reports fairly slow reactions
in which chelating lig
In agreement with this idea we note that the
use of HS(CH2)3SH as a substrate (entry 8),
ands are involved.[5,6]
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
Scheme 1. Synthetic applications of allyl thioethers.
which might form a six-membered chelate
Chem. Eur. J. 2009, 15, 6468 – 6477
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6469

P. S. Pregosin, L. F. Veiros et al.
Table 1. Allylation of thiols by using 2 as the catalyst.[a]
Carbonate chemistry: It is useful to compare these results,
those which utilise allyl alcohols, with the rates for the 2-cat-
alysed allylation reactions of PhSH ([Eq. (3)], X=H) by
using carbonates, under the same conditions. For the linear
carbonate Boc-OCH2CH=CH2 (Boc=tert-butoxycarbonyl),
after 90 min we find 84% conversion[19b] (vs. 30 min for
100% conversion with catalyst 2), and for the branched car-
Run
Thiol
Allyl substrate
t
Conv.
[%]
1
2
PhCH2SH
ꢁ11 min
30 min
18 h
100
>90%
100
HSCH2CO2Me
3
4
5
6
Boc-Cys-OH
CySH
40 min
9 min
100
100
100
100
bonate, PhCHACHTNUGRTENUNG(OBoc)CH=CH2, after 60 min we obtain 95%
conversion (vs. 20 min for 100% conversion with 2).
tBuSH
30 min
8 min
10 min
5.5 h
11
16
7[b]
8[b]
20 h
93
9[b]
10 min
100
10
11
12
13
14
15
PhSH
30 min
19 min
22 min
40 min
12 min
30 min
100
100
100
100
100
100
These results indicate that there is no advantage to be
gained by using the carbonate as a leaving group. Table 2
p-MeOC6H4SH
p-MeC6H4SH
p-ClC6H4SH
p-NCC6H4SH
p-AcC6H4SH
Table 2. Allylation of p-RC4H4SH by using allyl carbonates with 2 as the
catalyst.[a]
Run
R
Allyl substrate
t
Conv.
[%]
16[c]
17[d]
18
PhSH
PhSH
PhSH
20 min
7 min
100
100
100
1
2
H
30 min
100
30 min
72 h
30 min
72 h
50
91
26
71
Me
ꢁ6 min
3
Cl
4
5
6
MeO
CN
17 min
55 min
45 min
100
100
100
19[e]
PhSH
15 min
100
Ac
1.5 h
17 h
ꢂ80
20[f]
21[g]
PhCH2SH
100
7[b]
H
50 min
95 min
240 min
45 min
25 min
30 min
100
100
95
Boc-Cys-OH
6 min
100
8[c]
Me
[a] CD3CN (0.5 mL), allyl alcohol (0.07 mm),
(0.07 mm) (unless otherwise stated). [b] CD3CN (0.5 mL), allyl alcohol
(0.14 mm), 2 (0.0070 mm), thiol (0.07 mm). [c] branched-to-linear (b/l)
ratios 3.1:1. [d] The product is PhCH=CHCH=CHCHACTHNURTGNEU(GN SPh)Ph and con-
tains some impurities. [e] b/l 3:1. [f] b/l 0.6:1. [g] The observed ratio of
diastereomers is approximately 2:1.
2 (0.0035 mm), thiol
9[d]
Cl
10[e]
11[f]
12[g]
MeO
CN
100
100
100
COMe
ring, also results in a very slow, but somewhat faster, dially-
lation reaction. However, by using the larger dithiol, HS-
[a] CD3CN (0.5 mL), allyl carbonate (0.07 mm),
2 (0.0021 mm), thiol
ACHTUNGTRENNUNG(CH2)4SH (entry 9, [Eq. (2)]), for which the chelate ring will
(0.21 mm). [b] b/l 2.3:1. [c] b/l 1.4:1. [d] b/l 1.7:1. [e] b/l 1.4:1. [f] b/l 3.0:1.
[g] b/l 1.3:1.
not be so stable, the diallylation reaction is quite rapid and
finished in approximately 10 min. Table 1, entries 16–19
show that a number of different allyl alcohols can serve as
substrates in the reaction with PhSH.
gives results for the allylation of several thiophenols, by
using allyl carbonates, under different conditions (3 instead
of 5 mol% catalyst, and a three-fold excess of the thiophe-
nol, instead of 1:1). Again, several of the thiophenols react
much slower when carbonates are used as substrates.
Table 3 shows the effect of adding either a base or a sul-
fonic acid on the rate of allylation of p-MeC6H4SH with the
carbonate PhCH
[Eq. (4)].
ACHTUNGRTENN(UNG OBoc)CH=CH2 in the presence of 2
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Fast Ruthenium-Catalysed Allylation of Thiols
FULL PAPER
Table 3. Effect of added acid or base on the allylation of p-MeC6H4SH
Table 4. Allylation of thiols by using 1+4 the as catalyst.[a]
by PhCHACHTUNGTRENNUNG
(OBoc)CH=CH2 with 2 as the catalyst (see Equation (3)).[a]
Run Thiol
Allyl substrate
t
Conv.
[%]
l/b
ratio
Acid/base
t [min]
Conv.
[%]
b/l
ratio
1
PhCH2SH
50 min
15 min
55 min
35 min
100
100
100
100
none
95
140
85
5
25
100
100
100
100
100
1.4:1
6.8:1
5:1
1:1
1:1.4
2
Boc-Cys-OH
CySH
diisopropylethylamine
tributylamine
p-toluene sulfonic acid (3)
camphor sulfonic acid (4)
3
4
tBuSH
5
PhSH
ꢁ10 min 100
[a] CD3CN (0.5 mL), allyl carbonate (0.07 mm),
(0.21 mm), acid or base (0.21 mm).
2 (0.0021 mm), thiol
6
p-MeOC6H4SH
p-MeC6H4SH
p-ClC6H4SH
p-NCC6H4SH
p-AcC6H4SH
10 min
10 min
6 min
100
100
100
100
100
7
8
9
7 min
10
ꢁ5 min
11
12
13
PhSH
16 min
2.5 h
3 h
100
1:0.54
PhSH
90–95% only b
p-ClC6H4SH
100%
100
only b
16 min
41 h
8 d
1:13
1:0.2
1:0
14
PhSH
Addition of base is not very advantageous, whereas the sul-
fonic acid significantly accelerates this transformation. We
note that addition of acid 3 markedly increases the reaction
rate. Apart from the possible positive effect of the sulfonate
anion as a ligand (see below), these results suggest that the
thiophenol need not lose a proton to be effective in this
chemistry. If proton loss were to be important, one might
expect that base rather than acid would accelerate the reac-
tion.
8 min
15 min
6 d
1:13
1:8
1:0
15
PhSH
PhSH
100
100
15 min
16.5 h
1:10
1:11
16[b]
ꢁ12 min 100
230 min 100
1:2.9
1:0.2
17
18
19
20
21
22
PhSH
ꢁ11 min 100
1:2.8
1:0.6
HSCH2CO2Me
HSCH2CO2H
Boc-Cys-OH
PhCH2SH
tBuSH
15 h
100
Catalyst system [RuACHTGNURTEN(NNGU Cp*)AHCTNURTEGG(NNNU CH3CN)3]ACTHGUNTREN(UNGN PF6)/camphorsulfonic
acid: Table 4 shows a set of similar reactions except that the
catalyst is now formed from salt 1 plus acid 4 and presum-
12 min
ꢂ100
1:3.2
20 min
48 h
1:4.2
1:0.8
ACHTUNGTRENNUNG
ably involves a Ru–O(sulfonate) bond.[11a] The reaction of
100
PhSH with allyl alcohol (entry 5) now requires ꢁ10 min for
full conversion at room temperature and thus is faster than
with either 1 (70 min) or 2 (30 min). The reaction of thio-
phenol with the substituted allyl alcohol, PhCH(OH)CH=
CH2 (entry 17) requires ꢁ12 min, whereas with 2 full con-
version requires approximately 20 min. This mixture clearly
constitutes our fastest catalyst. Further, it also affords the
best branched-to-linear (b/l) ratios. For example, for the re-
30 min
5 d
100
100
1:2.5
1:0
80 min
15 h
80–90
100
1:0.8
1:0.8
[a] CD3CN (0.5 mL), allyl alcohol (0.07 mm),
(0.0035 mm), thiol (0.07 mm). [b] The reaction mixture was quenched
after 4 min by addition of 25% aq. NH3 (0.02 mL).
1
(0.0035 mm),
4
action of CH2=CHCH(OH)ACTHNUTRGNE(NUG o-tolyl) with PhSH (entry 15,
Table 4, [Eq. (5)] we find 100% conversion after 8 min with
out on a 0.28 mmol preparative scale in acetonitrile solution
(0.14m concentration of substrates), and the products isolat-
ed (see Equations (6–8) and the Experimental Section).
Evaporation of the reaction mixture, preparation of a solu-
tion in dichloromethane (for N-Boc-Cys-OH, ethyl acetate
was used as the solvent) and filtration affords the allyl thiol
ethers in high yield and purity after removal of the solvent.
This simple isolation procedure makes this chemistry very
attractive.
a b/l ratio of approximately 13:1 (rather than 3:1 with 2).
The catalytic reaction does not proceed by using the acid
alone.
To demonstrate the synthetic value of the new catalytic
system derived from 1 and 4 several reactions were carried
Although not indicated in Table 4, doubling the amount
of acid 4 (5 mol% 1, 10 mol% 4) for reaction 7, does not ac-
celerate the chemistry. After 10 min we find 100% conver-
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6471

P. S. Pregosin, L. F. Veiros et al.
With the 1-naphthyl analogue, the isomerisation requires
hours before the linear isomer dominates. For the carbonate
chemistry, both the reaction and the isomerisation are fairly
slow (ca. 95% converted after 4 h, and the branched isomer
still dominates after 5 h). Assuming that the regioselectivity
is orbital controlled,[8] and that the branched kinetic product
is formed first, these new results indicate that literature-ob-
served branched-to-linear ratios measured after many hours
must be interpreted with caution. In any case, it is useful to
know that, in some cases, if one waits long enough, the
linear product can be obtained in an essentially pure form.
These observations on product isomerisation prompted us
to consider how one might “preserve” the high b/l ratios ob-
served with short reaction times. To this end, we have
chosen to quench the reaction shown in Equation (5) with
25% aqueous NH3 after only 3 min, thereby inhibiting the
isomerisation by blocking several coordination positions.
Analysis of the mixture of the above products, after column
chromatography on silica gel, reveals a b/l ratio of 11:1 with
100% conversion (see Scheme 2 for comparison data). We
have also quenched the reaction of (1-naphthyl)-
CH(OH)CH=CH2 with PhSH and find 98% conversion
after 5 min with a b/l ratio of approximately 7:1. This ratio
is unchanged after 24 h. The same reaction when quenched
after 2 min afforded only 85% conversion, but a much
larger, approximately 16:1, b/l ratio, which did not change
after 3 h. Since the b/l ratios found for much longer catalyst
sion with a b/l ratio of 7.7:1. Doubling the amount of 1
(10 mol% 1, 5 mol% 4) also has little or no affect (after
10 min, 100% conversion with a b/l ratio of 6.0:1). As we
will show, these rather different b/l ratios are due to isomeri-
sation. We have suggested[11] a mechanism for this allylic al-
cohol-based allylation chemistry for indoles[11a,b] and pre-
sume that the thiol reactions proceed in a related fashion.
Isomerisation reactions: The observed branched-to-linear
ratios for the allylation products are good, but not excellent.
This prompted us to study the
time dependence of the isomer
distribution by means of
1H NMR
spectroscopy.
Scheme 2 shows the results of
these measurements for four
catalysed reactions: Scheme 2a
and b report on thiophenol
with the bulky secondary alco-
hols (1-naphthyl)CH(OH)CH=
CH2
and
(o-tolyl)-
c) thio-
CH(OH)CH=CH2
phenol with the more routine
alcohol PhCH(OH)CH=CH2,
(all three reactions catalysed
by 1+4) and d) results from
the reaction of p-Cl-thiophenol
with the carbonate, PhCH
ACHTUNGTNER(NUNG OC-
ACHTUNGTRENNUNG(O)O-tBu)CH=CH2, catalysed
by 2. These results show that
the metal complex is capable
of inducing isomerisation of
the branched isomer to the
linear isomer, in all four exam-
ples, albeit at different rates.[20]
For the reaction involving
PhCH(OH)CH=CH2, catalysed
by 1+4, the linear product is
now the major component
after approximately 45 min.
Scheme 2. Isomerisation from branched to linear isomers as a function of time.
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Chem. Eur. J. 2009, 15, 6468 – 6477

Fast Ruthenium-Catalysed Allylation of Thiols
FULL PAPER
contact times indicate mostly or exclusively linear products,
as indicated in the scheme, this quenching provides us with
an experimental methodology from which we can select the
desired isomeric product. Of course, the quenching is suc-
cessful because our catalyst is so fast. The subject of product
isomerisation in connection with catalytic allylation has not
been discussed in the literature and our approach represents
the first proposed solution to this problem.
It is interesting to compare the isomerisation rate for
Trostꢄs catalyst, 1, with that for the RuIV-complex 2. An iso-
lated sample (via the quench) consisting of an 11:1 mixture
C6H5SO3H)]
A
G
ACHTUNGTRENNUNG
G
G
ACHTUNGTRENNUNG
with one equivalent of the corresponding arene sulfonic acid
of (o-tolyl)CH
(SPh)CH=CH2 and its linear isomer was
in acetone solution at room temperature. There are many
1
treated with 1 (5 mol%) in CD3CN for 3 h. The b/l ratio of
the mixture changed from 11:1 to 0.33:1.0, and after 16 h,
only the linear isomer could be observed [Eq. (9)].
known [Ru
(Cp*)
U
the isolated[22a] crude yellow solids (see the Experimental
Section) reveals signals at around d=6 ppm which might[22a]
correspond to the protons of h6-arene products, plus minor
but significant resonances between d=7 and 8 ppm that can
be assigned to the protons of the free arene sulfonic acid
(Figure 1). The amount of uncomplexed arene increases
In a second experiment, treatment of the same isomeric
mixture with complex 2 gave a b/l ratio of 1:0.9 after 19 h.
Both catalysts isomerise the mixture, but [Ru
(CH3CN)3](PF6) seems faster.
ACHTUNGTRNE(NUNG Cp*)-
N
ACHTUNGTRENNUNG
Co-catalyst p-toluene sulfonic acid (3) and h6-arene com-
plexes: The assumption that a sulfonate anion complexes
the ruthenium provides an explanation for the more favour-
able kinetics and b/l ratios observed when using a catalyst
made up of 1 together with 4.[11a] However, a monosubstitut-
ed sulfonate complex has not yet been isolated. We have
carried out some experiments by using 3, an acid that is
known[11a] to be capable of complexing Ru through the sul-
fonate oxygen. This alternative sulfonic acid is relevant as a
model as it forms an excellent catalyst together with 1 in the
allylation of indole[11a] and is quite effective in our thiol
chemistry. The reaction of (o-tolyl)CH(OH)CH=CH2 with
PhSH (catalysed by a 1:1 mixture of 1 and 3) at ambient
temperature is complete in only 5 min with a b/l ratio of ap-
proximately 10:1 (see also Table 3). After 30 min the b/l
ratio has been reduced to 3.5:1. The analogous reaction of
(1-naphthyl)CH(OH)CH=CH2 with PhSH by using 1 plus 3
is complete in 4 min with a b/l ratio of approximately 5:1.
After 10 min, the b/l ratio has been reduced to 3.6:1.
Figure 1. 1H NMR spectra in the high-frequency region for the three
zwitterionic [RuACTHNUTRGNEUNG
(Cp*)(h6-sulfonic acid anion)] complexes that were even-
tually shown to be 13–15. The ratios free arene/complexed arene are
shown (400 MHz, [D6]acetone).
with the electron-withdrawing ability of the para substituent.
The observed ratios of h6-arene complex/free acid are 12:1,
10:1 and 2:1, respectively. At least in acetone solution, one
can form an h6-arene-type complex, even if these are not
completely pure. We find no evidence for O complexation.
Unfortunately, we found no evidence, by means of
1H NMR spectroscopy, for a complex of 3 in acetonitrile so-
lution. However, there is still the possibility that a transient
O–sulfonate or an h6-arene complex of the type [Ru-
DFT calculations: If the arene of these phenyl sulfonic acids
is not completely complexed in a weakly coordinating sol-
vent such as acetone, it seems unlikely that they will be ef-
fective ligands in acetonitrile solution. Undoubtedly one
could shift the equilibrium by addition of more sulfonic
acid;[22b] however, in the catalytic reactions, the ratio of Ru
to acid is 1:1. To pursue this point further we have calculat-
ed the relative stabilities of several h6 complexes based on
the chemistry of Equation (10) in acetone solution:
ACHTUNGTRENNUNG CAHTUNTGERN(NUGN PF6) might be formed during
(Cp*)(h6-p-CH3C6H4SO3H)]
the reaction. Alternatively, the aromatic moiety of any of
the various p-RC6H4SH nucleophiles might well serve as a
source of an arene donor. Of course, the S atom, either as
RSH or as the thiolate, is certainly a possible ligand for
ruthenium. To investigate the relative stability of such p spe-
cies, an attempt was made to generate the complexes
[RuACHTUNGTRENNUNG ACHTUNRTGEN(GNNU PF6) (9), [RuACTHNUGTRENNGUN
(Cp*)(h6-p-CH3C6H4SO3H)] (Cp*)(h6-
Chem. Eur. J. 2009, 15, 6468 – 6477
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www.chemeurj.org
6473

P. S. Pregosin, L. F. Veiros et al.
þ
*
½RuðCp ÞðCH3CNÞ3ꢃ þ RC6H4X !
2) the DG value for the anionic chloro-arene is practically
zero, at the accuracy level of the method employed (see
Computational Details), so that this result agrees reasonably
with the 2:1 ratio observed by NMR spectroscopy. Again,
these DG values follow the trend of the electron-donating
capability of the ligand. The stronger electron arene donors
will have in total less negative charge corresponding to
more stable h6 complexes. The charges calculated for the
arene ligands in 12--15 are: ꢀ0.39 for PhSꢀ, ꢀ0.53 for R=
ð10Þ
6
þ
*
½RuðCp Þðh -RC6H4XÞꢃ þ 3 CH3CN
in which R=H and X=SH for the thiol and R=Me, H or
Cl for X=SO3H.
We find that DG is positive in all cases, so that replace-
ment of the three CH3CN ligands of [Ru
by one h6-arene ligand is always thermodynamically unfa-
vourable. The DG value, 1.9 kcalmolꢀ1, is smaller for PhSH,
(CH3CN)3]+
ACHUTGTNRENNUG(Cp*)ACHTUTGNRENNUGN
ꢀ
ꢀ
G
CH3 and X=SO3 , ꢀ0.55 for R=H and X=SO3 and
ꢀ
than for any of the three presumed sulfonic acid salts, 9–11:
4.8, 6.0 and 10.3 kcalmolꢀ1, respectively, suggesting that, if
at all, the thiol would most likely form the p complex.
Clearly, these values do not correspond to the experimental
results. Nevertheless, we note that the DG values calculated
for the three acids correlate with the electron-donating char-
acteristics of the h6-arene ligand, that is, a better electron-
donating group favours a more stable h6-arene complex. The
electron-donating ability of the arene ligands is associated
with the charge calculated (by means of a Natural Popula-
tion Analysis, NPA) for the h6 ligands in the various com-
plexes. Stronger arene donors are associated with larger pos-
itive charges on the arene ligands, so that in 9–11 one finds
+0.32 for R=CH3, +0.30 for R=H and +0.28 for R=Cl.
ꢀ0.57 for R=Cl and X=SO3 .
It is worth noting (at the top of Scheme 3) that the calcu-
lations predict that the thiolate, anion, PhSꢀ, should complex
via the S atom affording, 16, a relatively stable complex
with a DG value of ꢀ7.9 kcalmolꢀ1.[22c] If this were correct,
then each thiol reagent shown in the catalysis tables would
indeed afford a slightly different catalyst, thereby explaining
some of the varying observations with respect to the reac-
tion times and product distributions. Continuing, the com-
plexes 17–19, formed by complexation of an O atom from
the sulfonic acid, are predicted to be not very stable; this is
consistent with our observations that the sulfonic acids 3
and 4 do not readily complex via the O atom to any major
extent (in CH3CN solution).
The corresponding value for [RuACHTUNGTRNEUNG
(Cp*)(h6-C6H5SH)]+ is
+0.38.
We next considered the possibility that the anions,[21i,22a]
rather than the neutral acid species, were p-bonded and
have calculated the DG values for the reaction shown in the
bottom section of Scheme 3. Here, we are assuming that the
arene substrate can lose one proton to afford 12–15, and
that HPF6 will be the side product.[22c] The corresponding
DG values calculated for the formation of the neutral h6
zwitterionic species 12–15 are now ꢀ9.7, ꢀ5.5, ꢀ3.8 and
0.2 kcalmolꢀ1, respectively, and thus predict more stable h6
complexes.[22a] Note that 1) these values are in much better
agreement with the NMR spectroscopic observations and
Conclusions
The catalytic allylation of both aromatic and aliphatic thiols
by using a variety of allyl alcohols as substrates proceeds
rapidly to completion within minutes at ambient tempera-
ture, with catalyst 2, or
a combination of [RuACHTUNGTRENNUNG(Cp*)-
G
ACHTUNGTRENNUNG
cases, 100% conversion is attained in 15 min or less. Many
other catalysts require either many hours and/or elevated
temperatures.[5,6] Both catalysts work well and tolerate a
wide variety of substituents on the S atom; however, the cat-
alyst from 1 and 4 (or 3) is the
fastest. A comparison with the
results from catalytic runs
based on the use of carbonates
rather than alcohols clearly
shows that there is no advan-
AHCTUNGTERGtNNUN age in using an allyl precursor
with a carbonate (or acetate
etc.) leaving group. The
branched-to-linear ratios for
the products from experiments
that use substituted alcohols
decrease with time; however,
we have shown that one can
select the desired isomeric
product by either rapidly
quenching with NH3 (to afford
the branched product) or by
simply waiting (which gives
mostly linear product). The
Scheme 3. Results from the DFT calculations (for acetone solutions).
6474
www.chemeurj.org
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 6468 – 6477

Fast Ruthenium-Catalysed Allylation of Thiols
FULL PAPER
DFT results indicate that 1) the stable h6 complexes derived
from the acids RC6H4SO3H result from deprotonation of the
acid rather than simple h6-arene coordination, 2) complexa-
tion of the thiol, via the deprotonated sulfur atom, is pre-
1H, J1 =17.4, J2 =10.5 Hz), 4.96 (d, 1H, J=10.5 Hz), 4.75 (d, 1H, J=
17.4 Hz), 1.38 ppm (s, 6H); 13C NMR (75 MHz, CD2Cl2): d=144.7, 138.5,
135.1, 131.4, 128.6, 111.8, 50.4, 27.3 ppm.
The following three complexes, originally thought to be salts 9–11, are as-
signed the structures 13–15.
ꢀ
ferred over the O atom of the sulfonate, RC6H4SO3 and
[Ru
ACHTUNGTRENNUNG
3) a sulfonate O-atom complex will be difficult to detect, es-
pecially in acetonitrile solution. Presumably, for the catalyst
consisting of 1 plus 4 (or 3), we are generating a very small
amount of a quite active catalyst.
0.118 mmol) was added to
a
N
G
ACHTUNGTRENNUNG
(59.6 mg, 0.118 mmol) in acetone (3 mL). The cloudy yellow reaction
mixture was stirred for 2 h at room temperature and the solvent removed
under vacuum. The resulting yellow solid was washed three times with di-
ethyl ether and dried under high vacuum (HV). The product was found
to be a 1:10 mixture of benzene sulfonic acid and 13. Yield: 60.1 mg;
1H NMR (400 MHz, [D6]acetone): d=1.94 (s, 15H; C5Me5), 5.96 (m,
3H), 6.22 (d, 2H, J=5.6 Hz), 7.53 (m, 3H, benzene sulfonic acid),
8.82 ppm (d, 2H, J=7.6 Hz, benzene sulfonic acid).
Experimental Section
[Ru
(22.6 mg, 0.119 mmol) was added to a solution of [Ru
(PF6) (60.0 mg, 0.119 mmol) in acetone (3 mL). The cloudy yellow reac-
ACHTUNGTRENNUNG
General information: All air-sensitive manipulations were carried out
under a nitrogen atmosphere. All solvents were dried over an appropri-
ate drying agent and then distilled under nitrogen. CD3CN was dried
over molecular sieves and stored under nitrogen. [D6]Acetone was dis-
tilled over CaSO4 and stored under nitrogen. All commercially available
starting materials were purchased from commercial sources and used as
G
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
tion mixture was stirred for 2 h at room temperature after which time the
solvent was removed under vacuum. The resulting yellow solid was
washed three times with diethyl ether and dried under HV. The product
was found to be a 1:12 mixture of p-toluene sulfonic acid and 14. Yield:
1
received. H, 13C and 2D NMR spectra were recorded with Bruker DPX-
1
54.5 mg; H NMR (400 MHz, [D6]acetone): d=1.90 (s, 15H; C5Me5), 2.19
250, 300, 400 and 500 MHz spectrometers at room temperature. Chemical
shifts are given in ppm and referenced to TMS for 1H NMR spectra.
Mass spectra were obtained from the analytical service of the ETHZ.
The allyl alcohols used in the allylation reactions were synthesised ac-
cording to a modified literature procedure.[11a]
(s, 3H), 2.34 (s, 3H; p-toluene sulfonic acid), 5.82 (d, 2H, J=5.6 Hz),
7.12 (d, 2H, J=5.6 Hz), 7.32 (d, 2H, J=7.6 Hz; p-toluene sulfonic acid),
7.69 ppm (d, 2H, J=7.6 Hz; p-toluene sulfonic acid).
[Ru
0.120 mmol) was added to an acetone (3 mL) solution of [Ru
(CH3CN)3](PF6) (60.4 mg, 0.120 mmol). The cloudy yellow reaction mix-
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
NMR spectroscopic procedure for monitoring the allylation of thiols by
using 1 and 4 as the catalyst: The thiol (0.07 mmol) was added to a solu-
tion of CD3CN (0.5 mL) containing the allylic alcohol (0.07 mmol), [Ru-
ACHTUNGTRENNUNG(Cp*)ACHTUNGTRENNUNG(MeCN)3]ACHTUNGTRENNUNG(PF6) (0.0018 g, 0.0035 mmol) and (1S)-(+)-10-camphor-
sulfonic acid (0.008 g, 0.0035 mm), in an oven-dried NMR tube, and the
A
ACHTUNGTRENNUNG
ture was stirred for 2 h at room temperature after which time the solvent
was removed under vacuum. The resulting yellow solid was washed three
times with diethyl ether and dried under HV. The product was found to
be
a 1:2 mixture of p-chloro sulfonic acid and 15. Yield: 64.6 mg.
mixture was monitored at ambient temperature.
1H NMR (400 MHz, [D6]acetone): d=2.02 (s, 15H; C5Me5), 6.35 (m,
4H), 7.73 (d, 2H, J=8.4 Hz; p-chloro sulfonic acid), 7.32 ppm (d, 2H,
J=8.4 Hz; p-chloro sulfonic acid).
Examples of preparative syntheses of allylthiols
(S)-Allyl-p-chlorothiophenol: 4-Chlorothiophenol (0.041 g, 0.28 mmol)
was added to a solution of allyl alcohol (20 mL, 0.29 mmol), [Ru
ACHTUNGTRNE(NUNG Cp*)-
Attempt to prepare a Ru–thiolate complex: p-Me-Thiophenol (9.8 mg,
G
ACHTUNGTRENNUNG
0.079 mmol) was added to
a solution of [RuACHTNUGRTNEG(NU Cp*)AHCTUTGNENRN(UG CH3CN)3]ACHTUNGTRENNUNG(PF6)
fonic acid (0.0033 g, 0.014 mm) in MeCN (2 mL). The reaction mixture
was stirred at room temperature for 1 h and then evaporated in vacuo at
408C. The resulting residue was dissolved in CH2Cl2 and filtered through
a plug of silica gel. Evaporation of the resulting solution afforded the
pure product as a transparent liquid (0.048 g, 93%). 1H NMR (250 MHz,
CDCl3): d=7.28 (s, 4H), 5.96–5.80 (m, 1H), 5.15 (d, 1H, J=13.3 Hz),
5.10 (d, 1H, J=5.5 Hz), 3.55 ppm (d, 2H, J=6.8 Hz); 13C NMR
(63 MHz, CDCl3): d=134.7, 133.6, 132.6, 131.7, 129.3, 118.3, 37.8 ppm;
HRMS-EI: m/z: calcd for C9H9ClS: 184.0108 [M]+; found: 184.0107.
(40.0 mg, 0.079 mmol) in MeCN (2 mL). Diisopropylethylamine
(0.07 mL, 0.396 mmol) was added and the pale-yellow solution turned
deep purple, which suggested the presence of a new Ru species. The reac-
tion mixture was stirred for 30 min at room temperature after which time
the solvent was reduced under vacuum. Diethyl ether was added to pre-
cipitate 13.1 mg of a brown solid which was found by 1H NMR spectros-
copy to be mainly p-Me-thiophenol. This brown solid was removed by fil-
tration and on further addition of diethyl ether to the filtrate, 27.2 mg of
a red crystalline solid precipitated. This was collected, washed three
times with diethyl ether and dried under vacuum. NMR spectroscopic
(S)-Allyl-N-Boc-cysteine: By using N-Boc-cysteine (0.062 g, 0.28 mmol)
instead of 4-chlorothiophenol, a 20 min reaction time, and ethyl acetate
as the eluent, (S)-allyl-N-Boc-cysteine was obtained as an oil (0.068 g,
93%). 1H NMR (300 MHz, CDCl3): d=8.72 (brs, 1H), 5.85–5.71 (m,
1H), 5.38 (brs, 1H), 5.16 (d, 1H, J=15.0 Hz), 5.16 (d, 1H, J=11.0 Hz),
4.55 (brs, 1H), 3.18 (d, 2H, J=7.1 Hz), 3.02–2.88 (m, 2H), 1.47 ppm (s,
9H); 13C NMR (75 MHz, CDCl3): d=175.9, 155.8, 134.0, 118.4, 80.9, 53.4,
35.6, 32.9, 28.6 ppm; HRMS-ESI: m/z: calcd for C11H19NNaO4S:
284.0927; found: 284.0925 [M+Na]+.
studies are consistent with the formulation: [HN
ACHTUTGNRENGU(N CH2CH3)ACHTUNGTRENNUNG(CHMe2)2]
[Ru(Cp*)(p-MeC6H4S)2A(CH3CN)] for approximately 80% of the red
A
CHTUNGTRENNUNG
crystalline solid. 1H NMR (500 MHz, CD3CN): 1.35 (m, 15H; 5 methyl
groups from the ammonium ion), 1.46 (s, 15H; Cp*), 2.37 (s, 6H; methyl
groups of p-Me-thiophenol), 3.19 (d of q, 2H, J=7.5, 4.5 Hz; ethyl CH2),
3.71 (m, 2H; isopropyl CHMe2), 6.22 (1H, JNH =52.5 Hz; R3N+H), 7.21
(d, 2H, J=7.5 Hz; p-Me-thiophenol), 7.34 ppm (d, 2H, J=7.5 Hz; p-Me-
thiophenol); 13C NMR (125 MHz, CD3CN): d=10.3 (Cp* CCH3), 16.8
(CH2CH3), 18.1 (CH
ACTHGNURTEN(NUNG CH3)2), 20.7 (p-CH3-thiophenol), 43.5 (CH2CH3),
(S)-(a,a-Dimethylallyl)-p-chlorothiophenol: 4-Chlorothiophenol (0.041 g,
0.28 mmol) was added under nitrogen to a solution of 2-methyl-3-buten-
55.5 (CH(CH3)2), 97.1 (Cp* CCH3), 129.7 (meta thiophenol carbon
AHCTUNGTRENNUNG
atoms), 132.1 (ortho thiophenol carbon atoms), 136.5 (ipso thiophenol
carbon atom), 140.3 ppm (para thiophenol carbon atom); MS: m/z: 843
(2Cp*, 2Ru, 3p-Me-thiophenol), 719 (2Cp*, 2Ru, 2p-Me-thiophenol),
629 (2Cp*, 2Ru, 1p-Me-thiophenol 1S).
2-ol (30 mL, 0.28 mmol), [RuCAHTUNGTREN(NNUG Cp*)AHCTNURGTEG(NNUN MeCN)3]ACHTNGURTEN(UNNG PF6) (0.0071 g, 0.014 mmol)
and (1S)-(+)-10-camphorsulfonic acid (0.0033 g, 0.014 mm) in MeCN
(2 mL). The reaction mixture was stirred at room temperature for 3 h
and then quenched with 25% aqueous ammonia (0.08 mL). The resulting
mixture was evaporated in vacuo at 408C. The obtained residue was dis-
solved in CH2Cl2 and filtered through a plug of silica gel. Evaporation of
the resulting solution afforded 0.055 g (92% yield) of the product (b/l
24:1) as a transparent liquid. The branched isomer slowly isomerises to
the linear one when stored as a solution in CDCl3. 1H NMR (300 MHz,
CD2Cl2): d=7.43 (d, 2H, J=8.4 Hz), 7.32 (d, 2H, J=8.4 Hz), 5.98 (dd,
Computational details: The calculations were performed by using the
GAUSSIAN 03 software package[23] and the PBE1PBE functional, with-
out symmetry constraints. That functional uses a hybrid generalized gra-
dient approximation (GGA), including 25% mixture of Hartree–Fock[24a]
exchange with DFT[24b] exchange correlation, given by Perdew, Burke
and Ernzerhof functional (PBE).[25] The optimised geometries were ob-
Chem. Eur. J. 2009, 15, 6468 – 6477
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6475

P. S. Pregosin, L. F. Veiros et al.
tained with the LanL2DZ basis set[26] augmented with a f-polarization
function[27] for Ru and a standard 6–31G(d,p)[28] for the remaining ele-
ments (basis b1). Frequency calculations were performed, yielding no
imaginary frequency modes, and confirming the nature of the stationary
points as minima. Atomic charges were obtained by using a Natural Pop-
ulation Analysis (NPA).[29]
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[8] R. Hermatschweiler, I. Fernandez, P. S. Pregosin, E. J. Watson, A.
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AHCTUNGTRENNUNG
The reaction energy values reported were obtained from single-point
energy calculations by using a VTZP basis set (basis b2) and the geome-
tries optimised at the PBE1PBE/b1 level. Basis b2 consisted of a stan-
dard 3–21G[30] with an added f-polarization function[27] for Ru and a stan-
dard 6–311++GACHTUNGTRENNUNG
(d,p)[31] for the remaining elements. Solvent (acetone)
effects were considered in the PBE1PBE/b2//PBE1PBE/b1 energy calcu-
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Acknowledgement
P.S.P. thanks the Swiss National Science Foundation, the ETH Zurich,
and COST D40 for support, as well as the Johnson Matthey company for
the loan of ruthenium salts.
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Chem. Eur. J. 2009, 15, 6468 – 6477

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ꢀ
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Received: January 22, 2009
Published online: May 22, 2009
Chem. Eur. J. 2009, 15, 6468 – 6477
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6477