Indium-Triflate-Catalyzed Ritter Reaction in Liquid Sulfur Dioxide

Article abstract of DOI:10.1002/ejoc.201600013

The use of liquid sulfur dioxide as a reaction solvent facilitates the Ritter reaction between alcohols and nitriles. In(OTf)₃ was found to be a viable catalyst for this transformation. The newly developed catalytic conditions for the Ritter reaction were successfully applied to the synthesis of various amides, which were formed in good to excellent yields. The catalytic activation of secondary alcohols for Ritter reactions in liquid sulfur dioxide was also found to be effective.

Full text of DOI:10.1002/ejoc.201600013

DOI: 10.1002/ejoc.201600013
Full Paper
Ritter Reaction
Indium-Triflate-Catalyzed Ritter Reaction in Liquid Sulfur
Dioxide
Daniels Posevins,[a] Krista Suta,[a] and Māris Turks*[a]
Abstract: The use of liquid sulfur dioxide as a reaction solvent reaction were successfully applied to the synthesis of various
facilitates the Ritter reaction between alcohols and nitriles. amides, which were formed in good to excellent yields. The
In(OTf)3 was found to be a viable catalyst for this transforma- catalytic activation of secondary alcohols for Ritter reactions in
tion. The newly developed catalytic conditions for the Ritter liquid sulfur dioxide was also found to be effective.
Introduction
give N-tert-butylamides.[20] Later, Bi(OTf)3 catalysis was success-
fully used for the synthesis of 4-amidotetrahydropyrans involv-
ing Prince–Ritter[21] and Sakurai–Prince–Ritter[22] reaction se-
quences. Also, Cu(OTf)2 and TiF4 were found to catalyze the
Ritter-type transformation of secondary alcohols into the corre-
sponding amides in the presence of stoichiometric amounts of
thionyl chloride, which generated alcohol-derived chlorosulfites
as reactive intermediates in situ.[23] More recently, Yaragorla et
al. reported the microwave assisted solvent-free Ritter reaction
of tertiary and benzyl alcohols, using Ca(OTf)2 as a catalyst.[24]
The Ritter reaction is a one-pot process for amide formation in
which a nitrile reacts with a carbenium ion. The latter can be
generated from an alcohol or an alkene in a strongly ionizing
medium.[1] The classical Ritter reaction involves the use of at
least a stoichiometric amount of a corrosive Brønsted acid (i.e.,
concd. H2SO4), and as a result, it cannot usually be used with
compounds containing acid-labile functional groups.[2] Never-
theless, because of its atom economy and easy application, the
Ritter reaction has proved to be useful in the synthesis of differ-
ent biologically active molecules and pharmaceuticals.[3] The
Ritter reaction, as well as the Prince–Ritter[4] and Sakurai–
Prince–Ritter reaction sequences,[5] has found a wide applica-
tion in the synthesis of natural products and natural-product-
like molecules, e.g., the alkaloids (+)-8-ethylnorlobelol,[6] (+)-
aristotelone,[7] and ( )-2-isocyanoallopupukeanane.[8]
Over the past two decades, vast progress has been made in
the development of catalytic variations of the Ritter reaction.[9]
The first known example of a Lewis-acid-catalyzed Ritter reac-
tion using boron trifluoride etherate complex as a catalyst was
reported by Badparva et al. in 1994.[10] Since then, a variety of
catalysts have been tested for their ability to catalyze the Ritter
reaction. Successful examples include FeCl3·6H2O[11] and FeCl3/
AgSbF6,[12] as well as CoII[13] and CoIII[14] catalysts and others.
Recently, tris(pentafluorophenyl)borane was found to be an ef-
fective catalyst for the Prince–Ritter reaction sequence to give
hexahydro-1H-furo[3,4-c]pyranyl amide derivatives.[15] It was
also discovered that immobilized Lewis acids such as ZnCl2–
SiO2,[16] polyvinylpyrrolidone-supported BF3,[17] montmorillon-
ite KSF,[18] and Fe3+-montmorillonite K10[19] can serve as reusa-
ble catalysts in the Ritter reaction. In 2006, Bi(OTf)3 was found
to catalyze the Ritter reaction of tBuOH with different nitriles to
The reactivity of nitrile component and the formation of the
intermediate carbenium ion during the reaction can be affected
by the reaction medium. Polar aprotic solvents solvate charged
species such as carbenium ions, and solubilize other polar com-
pounds (e.g., Lewis acidic salts) that can then act as homogene-
ous catalysts for the reaction. Interestingly, the unique charac-
teristics of liquid sulfur dioxide as a reaction medium for carb-
enium ion formation have previously been observed by P.
Walden[25] and G. A. Olah.[26,27] Sulfur dioxide is a colorless, non-
combustible gas that can easily be liquefied to give a colorless,
mobile liquid (b.p. –10 °C; triple point: –75.5 °C/1.65 × 10–3 atm)
with a relatively low vapour pressure (ca. 3 bar at 20 °C; ca.
10 bar at 60 °C; ca. 20 bar at 100 °C).[28] It is supplied commer-
cially at a reasonable cost (≤5 EUR/kg) for the high purity prod-
uct (99.98 %, H2O content ≤50 ppm). Thus, it is considerably
cheaper than traditional solvents (e.g., DMSO, DMF, MeCN, THF)
of equal quality. Moreover, a portion of this solvent can be re-
used many times by circulating it within a semi-closed circuit,
similarly to supercritical CO2 systems. Therefore it can be used
as a commercially acceptable solvent.
In 1994, Mayr et al. reported the efficient allylation of aro-
matic acetals with allylsilanes in liquid SO2 in the absence of a
Lewis acid catalyst.[29] The same group also conducted NMR
spectroscopic studies of iminium ions in liquid SO2.[30] Also
other reactions involving ionic intermediates, such as Friedel–
Crafts acylations,[31] silyl-group-controlled carbenium-ion rear-
rangements,[32] and Lewis-acid-mediated epoxyolefin cycliza-
tions[33] were found to proceed better in liquid SO2 than in
other ordinary solvents. These methods benefit from the phe-
[a] Institute of Technology of Organic Chemistry, Faculty of Materials Science
and Applied Chemistry, Riga Technical University,
P. Valdena 3/7, 1048 Riga, Latvia
E-mail: maris_turks@ktf.rtu.lv
http://www.ktf.rtu.lv/
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/ejoc.201600013.
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nomenon of ion solvation in liquid sulfur dioxide, which has an active intermediate that is capable of generating the carb-
been the subject of several recent papers.[34] Synthetic methods enium ion in the reaction medium; the carbenium ion is then
in which SO2 is used as a reagent to introduce different func- further converted into the desired Ritter reaction product.[12]
tionalities have been extensively studied, and still continue to We found that conventional Brønsted acids and inorganic tri-
be developed.[35] The latest results on the use of liquid SO2 as flates gave the best results. In(OTf)3 showed a clear advantage
either a solvent or a reagent in synthetic preparations have over the other catalysts in terms of conversion, and therefore it
been recently reviewed.[36]
was used for further investigations. Also at 80 °C it showed an
identical reactivity, and did not induce the degradation of the
reaction products. Additionally, Al(OTf)3, Bi(OTf)3, and Fe(OTf)3
showed reasonable catalytic activities in the initial tests
(Table 2, entries 8–10). However, the use of Al(OTf)3 at higher
temperatures (80 °C) resulted in substantial degradation, and
the desired product (i.e., 6) was formed in only 47 % yield.
Iron(III) and bismuth(III) triflates were briefly tested further us-
ing secondary alcohols as substrates (reactions similar to those
shown in Table 4), but the isolated yields of the desired amides
did not surpass those obtained by using In(OTf)3.
Results and Discussion
Bearing in mind the aforementioned unique properties of liquid
SO2, we became interested in its possible use as a solvent for
the Ritter reaction. To the best of our knowledge, the sole ex-
ample of a Ritter reaction in liquid SO2 comes from the work
of Bakke and Knudsen,[37] who studied the rearrangement of
dicyclopentadiene-derived carbenium ions during the Ritter re-
action, and concluded that in liquid SO2 the reaction can be
carried out at lower temperatures to give nitrile adducts with
well-defined configurations.
Table 2. Catalyst screening for the Ritter reaction of benzyl alcohol in liquid
SO2.[a]
We began our experiments with benzhydryl alcohol (1). This
compound was heated in liquid sulfur dioxide as a solvent in
the absence of Lewis or Brønsted acidic additives in order to
investigate the ability of liquid SO2 to promote the formation
of carbenium ions (Table 1). The formation of dibenzyl ether (3)
from alcohol 1 in liquid SO2 in the absence of a nitrile proved
the feasibility of such an approach. Gratifyingly, in the presence
of 5 equiv. of acetonitrile at 150 °C, full conversion to the Ritter
product was observed, and amide 2 was isolated in 97 % yield
(Table 1, entry 3).
Entry
Catalyst
TfOH
Time
[h]
Conversion (GC–MS) [%][b]
6
7
1
2
3
4
5
6
7
8
9
30
26
24
16
28
23
23
23
22
21
47
48
26
31
36
25
27
16
20
31
21
18
21
22
23
[c]
H2SO4
MeCN·BF3
FeCl3·6H2O[d,e]
Cu(OTf)2
In(OTf)3
Sc(OTf)3
Al(OTf)3
68 (57[f]
23
57
52
)
Table 1. The Ritter reaction of benzhydryl alcohol in liquid SO2 in the absence
of catalyst.[a]
Bi(OTf)3
Fe(OTf)3
10
55
[a] The reactions were carried out in a pressure reactor at 60 °C unless other-
wise stated. [b] External calibration of the GC–MS was carried out using each
of the components. [c] 0.5 equiv. [d] The reaction was carried out at 90 °C.
[e] Benzyl chloride was verified as a side-product of the reaction. [f] Isolated
yield.
Entry
Time
[h]
Temp.
[°C]
MeCN
additive [equiv.]
Conversion
(GC–MS) [%][b]
2
3
To demonstrate the superiority of combination of liquid SO2
with selected Lewis and Brønsted acids, the Lewis and Brønsted
acids were also tested with AcOH and MeCN as solvents
(Table 3). The results verified our expectations, and proved that
better conversions can be achieved when liquid SO2 is used as
a solvent compared to the results obtained under more conven-
tional conditions for the Ritter reaction.
1
2
3
29
24
24
+150
+120
+150
–
5
5
0
15
89
66
0
>99 (97[c]
)
[a] The reactions were carried out in a pressure reactor. [b] External calibra-
tion of the GC–MS was carried out using each of the components. [c] Isolated
yield.
We went on to investigate the reactivity of various secondary
To evaluate the capability of various Brønsted and Lewis and tertiary alcohols under our newly developed catalytic con-
acids to catalyze the Ritter reaction in liquid SO2 solution, ditions for the Ritter reaction [i.e., In(OTf)3 and liquid SO2]. In
benzyl alcohol (4) was treated with a variety of potential cata- order to achieve full conversion to the desired amides, all the
lysts in the presence of acetonitrile (5 equiv.) at 60 °C. The prod- reactions were carried out at +100 °C. The results are summa-
uct composition was determined by GC–MS (Table 2). The for- rized in Table 4. No more than 20 mol-% of the catalyst was
mation of dibenzyl ether (7) was also observed during the necessary to give the desired N-alkyl amides in yields up to
course of these reactions. This compound is considered to be 97 %. The reactions of benzhydryl alcohol with MeCN and PhCN
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Table 3. Screening of various conditions for the Ritter reaction of benzyl alco-
hol with acetonitrile.
for the catalytic Ritter reaction. We found that the excess of the
nitrile has to be decreased to 3 equiv., and the catalyst loading
must be increased to 20 mol-% in order to achieve full conver-
sion. 2-Adamantanol proved to be the most viable substrate of
the secondary alcohols tested, and amides 11l and 11m were
isolated in almost quantitative yields (Table 4, entries 13 and
14).
Entry Catalyst
Time
[h]
Solvent
Conversion
(GC–MS) [%][a]
7
Next, we turned our attention to enantiomerically pure sub-
strates. The Ritter reaction of L-(–)-borneol proceeded cleanly,
6
8
AcOH[b]
MeCN[c]
AcOH[b]
MeCN[c]
AcOH[b]
MeCN[c]
0
9
0
19
0
2
0
3
0
10
0
0
>99
–
>99
–
<99
–
albeit with racemization; the products obtained showed no op-
tical activity (Scheme 1). This can be explained by a 6,2-hydride
shift of the intermediate carbenium ion.[40] The relative configu-
ration of the borneol-derived Ritter products was determined
by 13C and 1H NMR spectroscopic analysis and comparison with
literature data.[3b] Additionally, the molecular structures of
amides ( )-13a and ( )-13b were unambiguously established
1
2
3
4
5
6
H2SO4
H2SO4
Al(OTf)3
Al(OTf)3
In(OTf)3
In(OTf)3
28
27
24
23
24
24
[a] External calibration of the GC–MS was carried out using each of the com-
ponents. [b] BnOH (4; 0.2
and acetonitrile (excess).
M) and acetonitrile (5 equiv.). [c] BnOH (4; 0.2 M)
by X-ray analysis.[41] When
L-(–)-borneol was subjected to similar
reaction conditions in the absence of a nitrile additive, com-
plete degradation of the starting material was observed. Addi-
tionally, more conventional conditions for the Ritter reaction of
required only 5 mol-% of In(OTf)3, and the corresponding am-
ides (i.e., 2 and 11a) were isolated in 85 and 82 % yields, respec-
tively (Table 4, entries 1 and 2).
L-(–)-borneol with acetonitrile [H2SO4 (10 equiv.) and AcOH or
TFA (trifluoroacetic acid) as solvent] resulted in a complex reac-
tion mixture from which the desired amide [i.e., ( )-13a] was
isolated in 55 % yield.[41] Additionally, an experiment in which
the MeCN·BF3 complex was used as a “two-in-one” combination
of catalyst and reagent did not provide the expected product
(i.e., 13a). To the best of our knowledge, the direct synthesis of
Table 4. In(OTf)3-catalyzed Ritter reaction in liquid SO2.[a]
amides ( )-13a–( )-13d by the Ritter reaction of L-(–)-borneol
has not been reported previously.
[a] The reactions were carried out in a pressure reactor. [b] Entries 1–7:
5.0 equiv. of nitrile was used; entries 8–14: 3.0 equiv. of nitrile was used.
Also 1-adamantanol showed good reactivity. Thus, N-ada-
mant-1-yl amides 11b–11f (Table 4, entries 3–7) were obtained
in excellent yields using only 10 mol-% of In(OTf)3. It should
be noted that the electrophilic chloroacetonitrile/chloroacetyl
moiety, and the π-system of the acrylonitrile/acryloyl moiety
are compatible with the developed reaction conditions. The
synthesis of amides 11b and 11d[38] can be viewed as particu-
larly useful, since these molecules are considered to be precur-
sors of the antiviral and anti-Parkinson drug Amantadine.[39]
It is important to note that less activated secondary alcohols
also provided the Ritter products in good to excellent yields
Scheme 1. In(OTf)3-catalyzed Ritter reaction of
in liquid sulfur dioxide.
L-(–)-borneol and (–)-menthol
On the other hand, optically active (–)-menthol [(–)-14] pro-
(Table 4, entries 8 and 10–14) when subjected to the In(OTf)3/ duced enantiomerically pure amides (–)-15a and (–)-15b in
liquid SO2 catalytic system. For cyclohexanol and cyclopentanol, 30 % yield when In(OTf)3 (20 mol-%) in liquid sulfur dioxide was
our protocol provided the best isolated yields reported to date used. Amide (–)-15b was isolated in 48 % yield when the
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amount of In(OTf)3 was increased to 1 equiv. However, for benz-
amide (–)-15a, increasing the catalyst loading did not result in
further improvements of the yield. The only detectable side-
products were various menthol-derived alkenes; these possibly
result from the loss of a proton from the intermediate carb-
enium ion. The isolated yields of products (–)-15a and (–)-15b
remained at the same level also when water (0.5 to 1.5 equiv.)
was added to quench the intermediate nitrilium ion. It should
be noted that enantiomerically pure menthol derivatives are
well-recognized in organic synthesis as chiral auxiliaries and li-
gands. The approach reported here is one of the most direct
ways to obtain valuable menthylamine precursors[42] after re-
moval of the chloroacetyl group.[38] Moreover, the relatively
cheap supply of both (–)-menthol and (+)-menthol ensures easy
access to both (–)-menthylamine and (+)-menthylamine.
Finally, we tested substrates that are known to undergo
structural changes under SN1 reaction conditions. In separate
experiments, we submitted cyclopropylmethanol (16) and
cyclobutanol (17) to our Ritter conditions (Scheme 2). Both sub-
strates 16 and 17 showed good reactivity, and both gave a
mixture of constitutional isomers 18–20 with total isolated
yields of 61 and 54 %, respectively. In the two cases, the prod-
uct distribution was identical within the limits of experimental
error, with a slight predominance of N-cyclobutyl acetamide
(19). These observations are consistent with previous reports on
Scheme 2. Ritter reactions of cyclopropylmethanol (16), cyclobutanol (17),
and 3-methylbutan-2-ol (21) in liquid SO2.
+
the nature of C4H7 species.[43] This suggests that the transient
intermediate cations have relatively long lifetimes (at least
10–10 s)[43e] to undergo rearrangement before being trapped by
Regarding the reaction mechanism, we hypothesize that two
the nitrile. On the other hand, product 25 was observed as the pathways can operate in parallel. Firstly, the classical In(OTf)3-
major component of the crude reaction mixture when 3- catalyzed mechanism of the Ritter reaction can be discussed
methyl-butan-2-ol (21) was submitted to the indium-triflate- (left cycle, Scheme 3). In this case, alcohol 26 directly complexes
catalyzed Ritter reaction. This result clearly indicates the forma- to the indium center and gives carbenium ion 27, which exists
tion of carbenium ion 22+, which, under the given experimental in equilibrium with nonionized species. Further reaction with
conditions, undergoes a 1,2-hydride shift to give carbenium ion nitrile 28 gives rise to nitrilium ion intermediate 29, which is
23+. This then reacts further to give the major isolable com- then hydrolyzed to give amide 30 either during work-up or by
pound (i.e., 25).
In(OH)(OTf)2 species formally present in the medium. The use
Scheme 3. Proposed mechanisms of In(OTf)3-catalyzed Ritter reactions in liquid sulfur dioxide.
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temperature, and the SO2 was distilled back into the storage cylin-
der. The reactor was opened, and the resulting mixture was parti-
tioned between CH2Cl2 (30 mL) and water (15 mL). The aqueous
phase was extracted with CH2Cl2 (3 × 20 mL). The combined or-
ganic layers were dried (Na2SO4), filtered, and evaporated under
reduced pressure. The residue was purified by silica gel chromatog-
raphy (EtOAc/hexanes) to give product 2 (680 mg, 97 %) as a color-
less solid.
of liquid sulfur dioxide as a solvent might lower the activation
barrier by solvating the ionic intermediates. On the other hand,
it is reasonable to think that SO2 can be more than just a sol-
vent in this transformation. An equilibrium between alcohol 26,
sulfur dioxide, and the corresponding hydrogen sulfite species
(i.e., 31)[44] might have a positive impact on the formation of
carbenium ions under the aforementioned catalytic conditions
(right cycle, Scheme 3). The fact that benzhydryl alcohol (1)
provides the Ritter product in liquid SO2 in the absence of any
catalyst justifies the possible presence of species 32. In this
context, the complexation of In(OTf)3 to hydrogensulfite species
31 can provide intermediate 33, which collapses into carb-
enium ion 27. In addition to the classical Ritter pathway, it is
worth discussing the participation of inorganic hydrogen sulfite
General Procedure for In(OTf)3-Catalyzed Ritter Reaction in Liq-
uid Sulfur Dioxide: In(OTf)3 catalyst (0.15 mmol, 0.05 equiv.; or
0.3 mmol, 0.1 equiv.; or 0.6 mmol, 0.2 equiv.; according to Table 4)
and a nitrile (15.0 mmol, 5.0 equiv.; or 9.0 mmol, 3.0 equiv.; accord-
ing to Table 4 and Scheme 1) were placed into an oven-dried pres-
sure reactor (nominal volume: 150 mL) equipped with a glass tube
and a magnetic stirrer bar, and containing the alcohol (3.0 mmol,
1.0 equiv.; according to Table 4 and Scheme 1) under a nitrogen
atmosphere. The reactor was sealed, carefully degassed by applying
vacuum, and cooled to –50 °C. Sulfur dioxide (ca. 25 g) was added
from a storage cylinder by distillation. The reactor was sealed, and
its contents were allowed to reach room temperature. The resulting
mixture was heated to +100 °C [+80 °C for substrate (–)-14] in an
oil bath, and stirred at that temperature for 24 h. Then the reaction
mixture was slowly cooled to room temperature, and the SO2 was
distilled back into the storage cylinder. The reactor was opened,
and the resulting mixture was partitioned between CH2Cl2 (30 mL)
and water (15 mL). The aqueous phase was extracted with CH2Cl2
(3 × 20 mL). The combined organic layers were dried (Na2SO4), fil-
tered, and evaporated under reduced pressure. The residue was
purified by silica gel chromatography using hexanes and ethyl acet-
ate in an appropriate combination based on the Rf of the desired
product. The physicochemical characterization data of all products
were consistent with previously reported literature data.
–
species [free as HSO3 , or indium-bound as in In(HSO3)(OTf)2]
in the hydrolysis of nitrilium ion intermediate 29 via adduct 34.
Conclusions
In conclusion, we have discovered that liquid sulfur dioxide is
an excellent solvent for the Ritter reaction of alcohols. The best
proof of this is the fact that it is possible to achieve full conver-
sion to the expected amide in the reaction of benzhydrol with
acetonitrile in liquid sulfur dioxide in the absence of any addi-
tives. Indium(III) triflate was found to be the best catalyst
among the tested catalytic additives. Relatively activated benz-
hydryl, benzyl, and tertiary alcohols, and also secondary alco-
hols, which generate relatively less stable carbenium ions, can
all be subjected to the catalytic Ritter reaction in liquid sulfur
dioxide to give the corresponding amides in good to excellent
yields. To the best of our knowledge, the catalytic conditions
reported here provide the highest known isolated yields of the
corresponding amides for unactivated secondary alcohols like
cyclohexanol. The use of liquid sulfur dioxide as a reaction me-
dium plays a crucial role in facilitating the Ritter reaction, and
shows an apparent advantage over conventional solvents in
terms of the catalytic activity of different Lewis and Brønsted
acidic additives. This work complements previous research con-
cerning the generation and reactivity of carbenium ions in liq-
uid SO2. The investigation of other synthetic processes that
could benefit from the use of liquid SO2 as the reaction medium
is underway in our laboratory, and the results will be reported
elsewhere.
Acknowledgments
This work was financed by the Latvian Council of Science (grant
number 12.0291). The authors thank Dr. D. Stepanovs for X-ray
analysis of compounds ( )-13a and ( )-13b. D. P. and K. S. thank
JSC “Olainfarm” for a scholarship. K. S. thanks the K. Morbergs
foundation for a scholarship. JSC “Grindeks” is acknowledged
for the donation of organic solvents.
Keywords: Synthetic methods · Sulfur dioxide · Solvent
effects · Carbocations · Amides · Cyanides
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Published Online: February 12, 2016
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