Switchable palladium-catalyst reaction of bromomethyl sulfoxides, CO, and N-nucleophiles: Aminocarbonylation at Csp3 versus oxidative carbonylation of amines

Article abstract of DOI:10.1021/jo301778n

The palladium-catalyzed reaction of α-bromomethyl sulfoxides, carbon monoxide, and N-nucleophiles follows different reaction pathways according to the catalytic system and the reaction conditions. The Pd-xantphos catalyst affords high yields of α-sulfinyl amides by an aminocarbonylation process and is the first example of this type of transformation for a nonbenzylic sp³-hybridized carbon. On the other hand, the oxidative carbonylation of amines occurs with α-bromomethyl sulfoxides, carbon monoxide, and catalytic Pd(PPh₃)₄ under aerobic conditions, yielding ureas and oxalamides from either primary or secondary amines. The reaction with ambident nucleophiles such as amino alcohols was highly selective and took place exclusively at the amino group despite the presence of the alcohol functionality. In parallel to the reaction paths for simple amines, amino alcohols were converted into hydroxy sulfinyl amides when the reaction was catalyzed by Pd-xantphos, while Pd(PPh₃)₄ catalyst afforded cyclic carbamates. The alkoxycarbonylation reaction of bromomethyl sulfoxides with simple alcohols and CO leading to the corresponding sulfinyl esters is also described.

Full text of DOI:10.1021/jo301778n

Subscriber access provided by UniSA Library
Article
Switchable Palladium-Catalyst Reaction of Bromomethyl
Sulfoxides, CO and N-Nucleophiles: Aminocarbonylation
at Csp3 versus Oxidative Carbonylation of Amines
Cristian Mollar, Carmen Ramirez de Arellano, Mercedes Medio-Simon, and Gregorio Asensio
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 05 Oct 2012
Downloaded from http://pubs.acs.org on October 6, 2012
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 23
The Journal of Organic Chemistry
1
2
3
4
.
Switchable Palladium-Catalyst Reaction of
Bromomethyl Sulfoxides, CO and N-Nucleophiles:
5
6
7
8
Aminocarbonylation at Csp3 versus Oxidative Carbonylation of Amines
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Cristian Mollar, Carmen Ramirez de Arellano, Mercedes Medio-Simón* and Gregorio Asensio
Departamento de Química Orgánica Universidad de Valencia 46100ꢀBurjassotꢀValenciaꢀSpain
email:Mercedes.Medio@uv.es
Abstract: The palladium-catalyzed reaction of α-bromomethyl sulfoxides, carbon monoxide and
N-nucleophiles follows different reaction pathways according to the catalytic system and the
reaction conditions. The Pd-xantphos catalyst affords high yields of α-sulfinyl amides by an
aminocarbonylation process and is the first example of this type of transformation for a non
benzylic sp3 hybridized carbon. On the other hand, the oxidative carbonylation of amines occurs
with α-bromomethyl sulfoxides, carbon monoxide and catalytic Pd(PPh3)4 under aerobic
conditions, yielding ureas and oxalamides from either primary or secondary amines. The reaction
with ambident nucleophiles such as aminoalcohols was highly selective and took place
exclusively at the amino group despite the presence of the alcohol functionality. In parallel to the
reaction paths for simple amines, aminoalcohols were converted into hydroxy sulfinyl amides
when the reaction was catalyzed by Pd-xantphos, while Pd(PPh3)4 catalyst afforded cyclic
carbamates. The alkoxycarbonylation reaction of bromometyl sulfoxides with simple alcohols
and CO leading to the corresponding sulfinyl esters is also described.
Introduction
Palladium-catalyzed cross-coupling reactions are now a mainstay of fine chemical synthesis. The
good compatibility of palladium-catalyzed synthetic procedures with a wide range of subsidiary
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 23
1
2
3
4
5
6
7
8
9
functional groups on the reactive partners justifies the continuous efforts being made to extend
the scope of the organic transformations promoted by this metal.1 In this area, carbonylation
reactions2 occupy a prominent place since they provide direct, convenient access to the
omnipresent carbonyl building blocks. In general, the three-component reaction is carried out
with carbon, oxygen or nitrogen nucleophiles, carbon monoxide, and aryl or alkyl halides as
electrophiles. The alkoxycarbonylation reaction is perhaps the most robust among palladium-
catalyzed carbonylation processes since alternative side reactions are limited and poorly favored.3
The opposite can be said of the carbonylative reaction of aryl halides with aryl metal reagents4 or
amines.5 Nevertheless, the use of the carbonylation reaction has been progressively extended by
challenging contributions. In this way, the development of new and effective palladium ligands
allowed to overcome the drawbacks deriving from competing side reactions; moreover, the array
of suitable substrates has been extended to include reluctant electrophiles such as aryl chlorides
or aryl bromides in the case of carbonylative Sonogashira reactions or nucleophiles, like
ammonia, phenols or anilines.6 In general, alkyl halides prove to be worse substrates than aryl
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
7
halides, and only a few examples of the carbo- and alkoxycarbonylation8 of alkyl derivatives
have been described to date. In addition, the intermolecular aminocarbonylation reaction with
alkyl halides, benzyl halides9 or α-halomethyl ketones is a difficult transformation since direct
nucleophilic substitution is highly favored. In sharp contrast, α-bromomethyl sulfoxides do not
react with amines at the electrophilic α carbon 10 and, for this reason, they are singular substrates
for the aminocarbonylation at sp3-hybridized carbon atoms, as shown in this paper. This
transformation is also interesting from a synthetic point of view since α-sulfinyl carbonyl
derivatives are reliable synthetic intermediates11 and metal ligands.12 These compounds are
readily available in the homochiral pure form following the procedure reported herein.
2
ACS Paragon Plus Environment

Page 3 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Furthermore, interesting singular structural properties of these compounds, such as the S--O
interaction between sulfur and the carbonyl oxygen atom, have been described.13 This
intramolecular interaction seems to play a critical role in, for instance, the stereochemical control
of the Pummerer rearrangement. Previously, we showed that bromomethyl sulfoxides give
ketosulfoxides with moderate to good yields in carbonylative Suzuki reactions with boronic acids
and CO at atmospheric pressure at 60oC. The high chemoselectivity of the three-component
reaction versus direct coupling is observed under these conditions.14 The new carbon-carbon
bond formation, which occurs at the α position of a sulfinyl group from a halosulfoxide,
overcomes the limitation of uncatalyzed reactions where nucleophiles such as Grignard reagents
react at the sulfur atom with displacement of the halomethyl group.15 Alternatively, other
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
α−functionalizations of sulfoxides described to date usually occur through the corresponding
16
anions,11 and require strong bases that often favor secondary competing reactions.
This
scenario prompted us to further explore the palladium-catalyzed carbonylation of halosulfoxides
by testing their reaction with amines, alcohols and aminoalcohols.
Results and discussion
The palladium-catalyzed aminocarbonylation reaction in primary alkyl halides is a difficult
transformation because oxidative addition in this kind of substrates is slow,17 while the
competitive direct nucleophilic substitution with amines proves favorable. This trend is observed
even with benzyl halides,9 which are activated toward the palladium oxidative addition. In
contrast bromomethyl sulfoxides are good substrates in palladium-catalyzed cross-coupling
reactions,18 but are poor substrates in SN2 reactions with usual nucleophiles.10, 15 By bearing this
background in mind, we first explored the possibility of carrying out the aminocarbonylation of
the sp3-hybridized carbon of bromomethyl sulfoxides. The aminocarbonylation of sulfoxides 1a
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 23
1
2
3
4
5
6
7
8
9
or (S)ꢀ1b took place adequately with aliphatic 2a-f and aromatic amines 2g-i with CO at
atmospheric pressure and catalytic Pd2(dba)3-xantphos affording the corresponding racemic (3aa-
3ah) or chiral sulfinyl amides (3ba, 3be, and 3bi) with high yields (93-99%) (Table 1).
Palladium-catalyzed aminocarbonylation requires the presence of the base in stoichiometric
amount or an excess of base to neutralize the acid formed during the reaction. Common organic
trialkyl amines and inorganic salts (K3PO4, K2CO3, CsF) were testedto promote the reaction . CsF
was found to be the most effective, which is in agreement with previous results in several
carbonylative Suzuki reactions. 14
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 1. Palladium-Catalyzed Synthesis of Chiral and Racemic Sulfinyl Amides.
Sulfinyl amides prove to be attractive substrates as potential chiral ligands. The scarce references
available on the synthesis of this class of compounds involve the use of dicylohexylcarbodiimide
13
to activate the corresponding acid
or the use of amide anions previously generated under
4
ACS Paragon Plus Environment

Page 5 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
strongly basic conditions. Therefore, the aminocarbonylation described herein is a competitive
alternative for these compounds in simplicity and atom economy terms. The absolute
configuration of the starting chiral sulfoxides is retained in the formation of the corresponding
sulfinyl amides. The palladium-catalyzed cross-coupling reactions of chiral bromomethyl
sulfoxide (S)-1b and boronic acids, previously described by us,18 also takes place with retention
of the configuration. As expected, the chiral HPLC analysis of sulfinyl amides 3ba, 3be and 3bi
proved that chiral purity is preserved during transformation. The absolute configuration of
sulfinyl amides 3be and 3bi has been established by single-crystal X-ray diffraction (for ORTEP
diagrams, see Supporting Information).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The crystal structure of sulfinyl amide (R)-3bi is shown in Figure 1.
Figure 1. X-ray thermal ellipsoid plot of compound (R)-3bi (50% probability level).
The palladium-catalyzed reaction of amines, carbon monoxide and bromethyl sulfoxides depends
on the ligand, and also on the presence or absence of oxygen. Sulfinyl amides 3 were prepared in
high yields with Pd2(dba)3-xantphos as the catalyst under aerobic or anaerobic conditions.
Conversely, the preparation of compounds 3 using Pd(PPh3)4 requires the rigorous exclusion of
oxygen. Under aerobic conditions (see Experimental Section19) oxidative carbonylation of the
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 23
1
2
3
4
5
Table 2. Palladium-Catalyzed Oxidative Carbonylation of Amines mediated by α-Bromomethyl Sulfoxide 1a.
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Products
O
Conditions
O
O
NH(CH2)7CH3
[NH(CH2)7CH3]2
S
S
Ph
Ph
O
4a (95%)
4a (24%)
3aa
3aa
(5%)
A
B
-
(52%)
6 (18%)
(NHBn)2
O
NHBn
S
O
Ph
O
4b (93%)
4b
3ab (3%)
3ab (53%)
A
B
-
6
(20%)
(19%)
O
NH(CH2)4Ph
[NH(CH2)4Ph]2
S
Ph
O
O
4c(93%)
4c (20%)
3ac (5%)
3ac(51%)
A
B
-
6
(19%)
O
NBu2
S
NBu2
O
Ph
O
2
5a (60%)
5a (5%)
3ad
3ad
(9%)
(89%)
A
B
6
(9%)
6 (3%)
N
O
O
N
S
Ph
O
2
5b (48%)
5b (4%)
3ae (5%)
3ae (90%)
A
B
6 (8%)
6 (4%)
O
O
N
O
N
S
O
Ph
O
2
5c (55%)
5c (5%)
3af (5%)
3af (89%)
A
B
6 (8%)
6 (6%)
6
ACS Paragon Plus Environment

Page 7 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
amine20 occurs, while ureas 4 or oxalamides 5 were the main products from the primary or
secondary amines (Table 2). Ureas 4a-c, slightly contaminated by sulfinyl amides 3aa-ac, were
obtained with very high yields from amines 2a-c. Oxalamides 5, the common by-products in the
carbonylation of amines, were not detected from amines 2a-c under our reaction conditions. In
contrast, oxalamides 5a-c were the major products of secondary aliphatic amines 2d-2f, which
were contaminated only by sulfinyl amides 3ad-af, the three-component cross-coupling products
(Table 2). Primary amines gave symmetrical ureas 4, most probably through an isocyanate
intermediate (vide infra), which is an unfeasible reaction pathway in the case of secondary
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
amines. Detection of isocyanates in the oxidative carbonylation of amines has been previously
reported.20
The formation of ureas and oxalamides described herein occurred under very mild conditions if
compared with the precedents in this area. In this sense, it is noteworthy that: i) carbonylation
takes place with CO at an atmospheric pressure. Previous procedures require up to 50 atm of CO;
ii) ureas are the only product from primary amines that are free of contamination by oxalamides,
the usual by-products in these amine carbonylations.
Next, we turned our attention to explore selective aminocarbonylation reactions using
dinucleophiles, such as aminoalcohols, where amino- and/or alkoxycarbonylation could take
place alternatively. The alkoxycarbonylation of bromomethyl sulfoxides has not yet been
described; hence, the reaction of 1-bromomethyl sulfoxides, CO and simple alcohols was first
evaluated (Table 3). To optimize the reaction conditions, sulfoxide 1a, ethanol and Pd(PPh3)
were selected. The initial screening was conducted in alcohol with an excess or stoichiometric
hydroxylic base, which is usual in palladium-catalyzed alkoxycarbonylation reactions.2b
Reactions took place in aprotic-coordinating solvents, such as THF, containing two equivalents
of alcohol, but did not proceed in ethanol. A moderate base like CsF proved more effective than
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 23
1
2
3
4
5
6
other usual bases employed to promote the reaction. The yields obtained using Pd2(dba)3-
xantphos or Pd(PPh3)4 in the alkoxycarbonylation of bromomethylsulfoxide were similar.
7
8
9
Table 3. Palladium-Catalyzed Alkoxycarbonylation of α-Bromomethyl Sulfoxides 1.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
O(CH2)2OMe
O
OEt
O
O(CH2)2Cl
O
OBu
S
S
S
S
O
O
O
O
8aa (83%)
8ad (61%)
8ab (78%)
8ac (63%)
O
O
OBn
OEt
O
S
OCH2CO2Et
S
S
O
O
O
8ae (89%)
8af (25%)
(R)- 3ba(99%)
The carbonylation of bromomethyl sulfoxide with aliphatic low-boiling point primary alcohols
and catalytic Pd(PPh3)4 gave the corresponding sulfinyl esters with excellent yields (Table 3).
Reactions were conducted below the alcohol boiling temperature and did not require special
equipment. On the other hand, benzyl alcohol, which is easily oxidized under palladium catalysis,
gave only a moderate yield (Table 3). Substituted alcohols containing additional functional
coordinating groups also reacted efficiently in the three-component process (Table 3).
8b-d
Bromomethyl sulfoxide behaves better than halomethyl ketones
in the alkoxycarbonylation
reaction since the competitive dehalogenation reaction is more difficult in the former case.
A three-component reaction between bromomethyl sulfoxide 1, CO and aminoalcohols occurred
and exclusively gave aminoacarbonylation products 10 when Pd(dba)2-xantphos was used as the
catalyst. However, selectivity dramatically changed when Pd(PPh3)4 was used to catalyze the
reaction; cyclic carbamates 11 were obtained in the latter case (Scheme 1). The different
8
ACS Paragon Plus Environment

Page 9 of 23
The Journal of Organic Chemistry
1
2
3
4
coordination possibilities of compounds 10 confer them interesting features for the facultative use
5
6
as ligands.
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 1. Palladium-catalyzed carbonylation of α-bromomethyl sulfoxides 1 and aminoalcohols 9.
Mechanisms
The most frequently postulated catalytic cycle2a,2b to account for amino- and alkoxycarbonylation
involves the following steps: oxidative addition of the electrophile to Pd(0) (step 1), migratory
insertion of carbon monoxide (step 2) and attack of the nucleophile (alcohol or amine) to the acyl
complex (step 3). Nevertheless, based on our previous findings in the palladium-catalyzed
carbonylative Suzuki reaction with these compounds,14 the above proposal hardly explains the
results obtained in the case of bromomethyl sulfoxides. In fact, the experimental data from this
work suggest an atypical sequence in the catalytic cycle, with the insertion of carbon monoxide
taking place after the transmetallation step instead of the usual CO insertion into the oxidative
addition complex. Moreover, we proved the reluctance of the oxidative addition complex I to
insert CO by monitoring this process by NMR.
Therefore, the amino and alkoxycarbonylation of bromomethyl sulfoxides could be explained
better as follows21: first, oxidative addition of sulfoxide 1 to palladium (0), followed by the attack
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 23
1
2
3
4
5
6
7
8
9
of the nucleophile (amine or alcohol) to the coordinated CO leading to complexes II or III, and
then, the reductive elimination step (Scheme 2). Formation of intermediate ArS(O)CH2PdOR via
metathesis from the oxidative addition complex, followed by insertion of carbon monoxide into
the Pd-OR bond and, finally, reductive elimination, cannot be ruled out to explain the
alkoxycarbonylation reaction. In fact, this alternative involving Pd-OR species could account for
the competitive oxidation of alcohols observed in some cases. A similar catalytic cycle based on
kinetic studies to account for the alkoxycarbonylation of aryl iodides in the presence of sodium
alkoxides has been previously postulated; however, this sequence is less likely in absence of
strong bases.22
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The Pd2(dba)3-xantphos catalyzed aminocarbonylation reaction of α-bromomethyl sulfoxides 1
occurs in the absence of competitive side reactions (Scheme 2). Conversely, dehalogenation of
the sulfoxide and oxidative carbonylations of the amine20 leading to ureas or oxalamides resulted
in detectable side pathways with Pd(PPh3)4 under anaerobic conditions. In this case,
bromomethyl sulfoxide behaves as an oxidant23 (Scheme 3). An schematic catalytic cycle 2
(Scheme 3) to account for the oxidative carbonylation of amines is proposed to involve a
complex Ia formed in the oxidative addition of bromomethyl sulfoxide to Pd(0). Accordingly, Ia
would react with CO and amine to give IIa, a carbamoyl dioorganopalladium complex. In the
case of primary amines, the subsequent hydrogen transfer to the metal leads to palladium hydride
complex IV and an isocyanate (via a). Ureas 4 are formed by the reaction of the isocyanate with a
second equivalent of amine, while methyl phenyl sulfoxide 6 results by reductive elimination
from complex IV. Alternatively, oxalamides 5 and methyl phenyl sulfoxide 6 would be produced
from the reaction of complex IIa and a second equivalent of the corresponding secondary amine
and carbon monoxide (via b).
10
ACS Paragon Plus Environment

Page 11 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Conversely under aerobic conditions, the oxidative carbonylation of amines became the main
process in the reaction of bromomethyl sulfoxide 1a with amines and Pd(PPh3)4. Ureas 4 or
oxalamides 5 were formed by a catalytic cycle in which molecular oxygen acted as the oxidant
(Scheme 4). Oxidative carbonylation could be explained by an alternative catalytic cycle
involving a peroxo complex24 of palladium without the participation of bromomethyl sulfoxide.
However, the catalyst displays longer activity and proves highly efficient in the presence of 1,
which is not consumed during the process, but is recovered (about 80%) after completing the
reaction. Thus, a catalytic cycle 3 is proposed to account for the oxidative carbonylation of
amines (Scheme 4). Intermediate complex IV participates in cycles 2 and 3 (Schemes 3 and 4),
but its evolution differs in the presence or absence of O2. Insertion of molecular oxygen into the
palladium-hydrogen bond in complex IV and loss of hydrogen peroxide by ligand exchange with
CO and amine under aerobic conditions close the catalytic cycle, with the regeneration of
complex IIa. The generated hydrogen peroxide could play the role of a further oxidant, but
palladium has been reported to accelerate its decomposition in O2 and water.25 Hydrogen
peroxide is a stronger oxidant than molecular oxygen. Nevertheless, the data from other
palladium-catalyzed oxidation reactions suggest that it is not a kinetically competent oxidant.25
The formation of cyclic carbamates 11 from aminoalcohols 9 is explained by following an
equivalent reaction pathway.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Formation of oxalamides 5 from secondary amines cannot be explained in the same way as ureas
4 given the lack of a β-hydrogen to be transferred from the corresponding carbamoyl
intermediate IIa. The oxidative carbonylation of secondary amines could be explained by an
alternative catalytic cycle, where molecular oxygen (via a peroxo complex of palladium)24 acts as
the oxidant, In addition, the formation of dehalogenated sulfoxide 6 under aerobic conditions
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 23
1
2
3
4
5
6
7
8
9
suggests that bromomethyl sulfoxide acts concomitantly with O2 as oxidant. In contast for
primary amines, bromomethyl sulfoxide seems to act as an oxidant, but only under anaerobic
conditions since dehalogenated sulfoxide is only detected in this way.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The ligand effect encountered in the palladium-catalyzed carbonylation reaction of sulfoxides 1
with amines could be attributed to differences in the ligand-dependent transꢀcis isomerization in
complex II, the common intermediate in both cycles. The trans-cis isomerization process in
complex II with monophosphine ligands opens temporary coordination sites in palladium, which
allows either the transfer of hydrogen in the case of a primary amine or the coordination of CO
followed by amine attack in the case of secondary amines, thus favoring the occurrence of the
oxidative carbonylation of amines instead of the aminocarbonylation reaction. These events may
be minimized in the case of the diphosphine xantphos which promotes a faster isomerization.26
Besides, the wide bite angle of xantphos favors the reductive elimination process and,
consequently, the formation of α-sulfinyl amides results in the prevailing pathway. The slower
reductive elimination promoted by monophosphines enhances the competitive oxidative
carbonylation of amines as an alternative reaction pathway.
12
ACS Paragon Plus Environment

Page 13 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 2. Cycle 1. Proposed catalytic cycle for the palladium-catalyzed alkoxy and aminocarbonylation of
sulfoxides 1.
Scheme 3. Cycle 2. Proposed catalytic cycles for the palladium-catalyzed oxidative carbonylation of amines with
sulfoxide 1a as oxidant.
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 23
1
2
3
4
5
6
7
8
[C(O)NR1R2]2
C(O)(NR1R2)2
5
CO,
R2R1NH
+ H2O2
4
R2R1NH
Pd
(0)/
Ln
R2NCO
PhS(O)CH2PdH(Ln)
9
IV
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
elimination
O2
CO,
PhS(O)CH2PdC(O)NR1R2(Ln)
R2R1NH
II
O
O
Pd(Ln)
PhS(O)CH2PdBr(Ln)
I
PhS(O)CH2PdOOH(Ln)
HOOPdC(O)NR1R2
Pd(0)/Ln
V
H2O2
CO, R2R1NH
via a
PhS(O)CH2Br
via b
(R1= H)
1a
/
(R1=H)
Consumed in the reaction
Not consumed in the reaction
Scheme 4. Cycle 3. Proposed catalytic cycles for the palladium-catalyzed oxidative carbonylation of amines with O2
as oxidant.
Conclusion
In conclusion, we describe palladium-catalyzed carbonylation involving a sp3-hybridized carbon
and N- and N,O-nucleophiles for the first time. The reaction takes advantage of the reluctance of
the electrophilic partner, that is, α-bromomethyl sulfoxides, to participate in nucleophilic
substitution reactions. Consequently the aminocarbonylation reaction can be carried out with high
selectivity for a wide range of amines and aminoalcohols. The developed method requires neither
overpressure of carbon monoxide nor sophisticated palladium ligands. The mild reaction
conditions allow us to obtain chiral and racemic α-sulfinyl amides with very high efficiency. The
effect of the ligand and reaction conditions driving the outcome of the process to the
aminocarbonylation reaction or the oxidative carbonylation of amines in almost a completely
14
ACS Paragon Plus Environment

Page 15 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
selective manner shows the high potential of the three-component reactions presented herein,
which allows access to a wide range of products with minimal changes in simple and easily
available starting materials and catalyst systems.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Experimental Section
General methods. Solvents were degassed by the Freeze-Pump-Thaw method (five cycles) to
ensure the absolute strict absence of oxygen. Proton magnetic resonance and carbon magnetic
resonance were recorded at 300 MHz and 75 Hz, respectively. Chemical shifts are reported in δ
ppm in relation to the CHCl3 peak at 7.20 ppm (1H) or 77.0 ppm (13C). Multiplicities are reported
as follows: s= singlet, d= doublet, t= triplet, q= quartet, m= multiplet. The ee values of the
products were determined by HPLC (Chiralcel IA). Optical rotation measurements were
determined at room temperature. All the melting points were uncorrected. Reactions were
monitored by analytical thin layer chromatography using commercial aluminium sheets pre-
coated (0.2-mm layer thickness) with silica gel 60 F254. Product purification was performed by
flash chromatography with silica gel (230-400 mesh).
Starting materials
27
Bromomethyl phenyl sulfoxide (1a);
(1b),18a and trans-[Pd(CH2SOPh)Br(PPh3)2]18a were prepared according to the previously
(S)-1-(bromomethylsulfinyl)-4-methylbenzene
described procedures.
General procedure for the carbonylation of amines, aminoalcohols and alcohols
Aerobic conditions. A mixture of α-bromomethyl sulfoxide 1 (0.3 mmol), N- or O-nucleophile
(0.6 mmol), CsF (1.2 mmol) and the appropriate catalyst (0.03 mmol) was added to a flask fitted
with a reflux condenser and a septum inlet. The flask was fluxed with carbon monoxide and then
charged with THF (10 mL). The mixture was stirred at 65oC under an atmospheric pressure of
carbon monoxide (balloon).19 After the appropriate time, the mixture was cooled at room
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 23
1
2
3
4
5
6
7
8
temperature, quenched with water (10mL) and extracted with diethyl ether (2x 15mL) and
dichloromethane (3 x15 mL). The combined organic extracts were dried with Na2SO4 and
evaporated under reduced pressure.
Anaerobic conditions. A mixture of α-bromomethyl sulfoxide 1 (0.3 mmol), N-nucleophile (0.6
mmol), CsF (1.2 mmol) and Pd(PPh3)4 (0.03 mmol) was added to a flask fitted with a reflux
condenser and a septum inlet. The flask was fluxed several times with carbon monoxide and then
charged with degassed THF (10 mL). The mixture was stirred at 65oC under an atmospheric
pressure of carbon monoxide (the balloon was immediately inflated before starting the reaction to
minimize air diffusion).19 After the appropriate time, the mixture was cooled at room
temperature, quenched with water (10mL) and extracted with diethyl ether (2x 15mL) and
dichloromethane (3 x15 mL). The combined organic extracts were dried with Na2SO4 and
evaporated under reduced pressure
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N-Octyl-2-(phenylsulfinyl)acetamide (3aa). Chromatographic purification in a silica gel column with
n-hexane–ethyl acetate (1 : 1 to 1 : 2). White solid: 84 mg, 95% yield; mp 40–44 ºC; 1H NMR (CDCl3)
δ 7.70-7.67 (m, 2H), 7.46-7.44 (m, 3H), 3.62 (d, J= 14.1 Hz, 1H), 3.41 (d, J= 14.1 Hz, 1H), 3.18-3.05
(m, 2H), 1.19 (m, 12H), 0.81 (t, J= 6.6 Hz, 3H); 13CNMR (CDCl3) δ 163.7, 143.8, 131.3, 129.1, 124.4,
58.8, 39.7, 31.7, 29.3, 29.2, 29.1, 26.8, 22.6, 14.0; HRMS (EI) m/z (M+) calcd for C16H25NO2S
295.1606, found 295.1600.
N-Benzyl-2-(phenylsulfinyl)acetamide (3ab).28 Chromatographic purification on a silica gel
1
column with n-hexane–ethyl acetate (1 : 1 to 1 : 2). Pale yellow liquid: 79 mg, 96% yield; H-
NMR (CDCl3) δ 7.49-7.40 (m, 5H), 7.25-7.13 (m, 5H), 4.35 (dd, J=14.7 and 6 Hz, 1H), 4.27 (dd,
13
J=14.7 and 6 Hz, 1H), 3.69 (d, J= 14.4 Hz, 1H), 3.42 (d, J= 14.4 Hz, 1H); C-NMR (CDCl3) δ
163.5, 141.3, 137.5, 129.4, 128.7, 131.5, 127.9, 127.5, 123.9, 58.3, 43.6; HRMS (E.I.) m/z (M+)
calcd. for C15H15NO2S 273.0823, found 273.0811.
N-(4-phenylbutyl)-2-(phenylsulfinyl)acetamide (3ac). Chromatographic purification in a silica
gel column with n-hexane–ethyl acetate (1 : 1 to 1 : 2). White solid: 88 mg, 93% yield; mp 55–59
1
ºC; H-NMR (CDCl3) δ 7.53-7.50 (m, 2H), 7.44-7.42 (m, 3H), 7.14-7.08 (m, 5H), 6.90-6.80 (m,
1H), 3.61 ( d, J= 14.3 Hz, 1H), 3.38 ( d, J= 14.3 Hz, 1H), 3.24-3.06 (m, 2H), 2.54 (t, J= 7.2 Hz,
2H), 1.59-1.36 (m, 4H); 13C-NMR (CDCl3) δ 163.9, 142.4, 141.9, 132.0, 129.8, 128.8, 128.7,
126.2, 124.3, 59.0, 39.9, 35.8, 29.4, 29.0; HRMS (E.I.) m/z (M+) calcd. for C18H21NO2S
315.1293, found 315.1283.
16
ACS Paragon Plus Environment

Page 17 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
N,N-Dibutyl-2-(phenylsulfinyl)acetamide (3ad).12a Chromatographic purification in a silica gel
column with n-hexane–ethyl acetate (1 : 1 to 1 : 2). White solid: 83 mg, 94% yield; mp 41–45 ºC;
1H-NMR (CDCl3) δ 7.76-7.73 (m, 2H), 7.52-7.50 (m, 3H), 3.98 (d, J= 13.9 Hz, 1H), 3.64 (d, J=
13.9 Hz, 1H), 3.29-3.00 (m, 4H), 1.46-1.15 (m, 8H), 0.87 (t, J= 7.2 Hz, 6H); 13C-NMR (CDCl3):
δ= 163.7, 143.8, 131.3, 129.1, 124.5, 62.2, 48.2, 46.0, 31.0, 29.6, 20.0, 19.8, 13.7, 13.6; HRMS
(E.I.) m/z (M+) calcd. for C16H25NO2S 295.1606, found 295.1593.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-(Phenylsulfinyl)-1-(pyrrolidin-1-yl)ethanone (3ae). Chromatographic purification in a silica
gel column with n-hexane–ethyl acetate (1 : 1 to 1 : 2). White solid: 69 mg, 97% yield; mp 104–
108 ºC; 1H-NMR (CDCl3) δ 7.69-7.66 (m, 2H), 7.47-7.41 (m, 3H), 3.93 (d, J= 13.2 Hz, 1H), 3.60
(d, J= 13.2 Hz, 1H), 3.45-3.32 (m, 3H), 3.09-3.01 (m, 1H), 1.86-1.63 (m, 4H); 13C-NMR (CDCl3)
δ 162.3, 143.7, 129.2, 131.4, 124.2, 63.2, 47.3, 46.0, 25.9, 24.3; HRMS (E.I.) m/z (M+) calcd. for
C12H15NO2S 237.0823, found 237.0814.
1-Morpholino-2-(phenylsulfinyl)ethanone (3af). Chromatographic purification on a silica gel
column with n-hexane–ethyl acetate (1 : 1 to 1 : 2). White solid: 74 mg, 98% yield; mp 146–150
ºC; 1H-NMR (CDCl3) δ 7.67-7.64 (m, 2H), 7.49-7.47 (m, 3H), 3.92 (d, J= 13.2 Hz, 1H), 3.66 (d,
J= 13.2 Hz, 1H), 3.41-3.63 (m, 8H); 13C-NMR (CDCl3) δ 162.7, 143.3, 131.6, 129.3, 124.1, 66.6,
66.5, 60.9, 46.8, 42.3; HRMS (E.I.) m/z (M+) calcd. for C12H15NO3S 253.0773, found 253.0761
N-(4-Methoxyphenyl)-2-(phenylsulfinyl)acetamide (3ag). Chromatographic purification in a
silica gel column with n-hexane–ethyl acetate (1 : 1 to 1 : 2). White solid: 86 mg, 99% yield; mp
1
124–126 ºC; H-NMR (CDCl3) δ 7.58-7.54 (m, 2H), 7.46-7.44 (m, 3H), 7.28 (d, J= 9.0Hz, 2H),
13
6.75 (d, J= 9.0 Hz, 2H), 3.84 (d, J= 14.4 Hz, 1H), 3.49 (d, J= 14.4 Hz, 1H), 3.71 (s, 3H); C-
NMR (CDCl3) δ 161.4, 156.6, 140.8, 131.8, 130.4, 129.5, 123.9, 122.0, 114.1, 58.5, 55.4; HRMS
(E.I.) m/z (M+) calcd. for C15H15NO3S 289.0773, found 289.0779.
N-(4-chlorophenyl)-2-(phenylsulfinyl)acetamide (3ah). Chromatographic purification in a
silica gel column with n-hexane–ethyl acetate (1 : 1 to 1 : 2). White solid: 84 mg, 95% yield; mp
1
162–166 ºC; H-NMR (CDCl3) δ 7.56-7.52 (m, 2H), 7.46-7.44 (m, 3H), 7.34 (d, J= 9.0Hz, 2H),
13
7.17 (d, J= 9.0Hz, 2H), 3.86 (d, J= 14.1 Hz, 1H), 3.52 (d, J= 14.1 Hz, 1H); C-NMR (CDCl3)
δ 161.6, 140.6, 135.9, 131.9, 129.6, 129.0, 123.8, 121.4, 58.5; HRMS (E.I.) m/z (M+): calcd. for
C14H12ClNO2S 293.0277, found 293.0269
(R)-2-(p-tolylsulfinyl)-N-octylacetamide (3ba). Chromatographic purification in a silica gel
column with n-hexane–ethyl acetate (1 : 1 to 1 : 2). White solid: 92 mg, 99% yield; mp 170–174
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 23
1
2
ºC; 1H-NMR (CDCl3) δ 7.26 (d, J= 8.1Hz, 2H), 7.22 (d, J= 8.1Hz, 2H), 3.60 (d, J= 14.1 Hz, 1H),
3.35 (d, J= 14.1 Hz, 1H), 3.24-3.03 (m, 2H), 2.34 (s, 3H), 1.20 (m, 12H), 0.81 (t, J= 6.9 Hz, 3H);
13C-NMR (CDCl3) δ 163.6, 142.1, 138.2, 130.1, 123.9, 58.5, 39.7, 31.8, 29.2, 29.1, 26.9, 22.6,
3
4
5
6
7
8
9
25
21.4, 14.1; HRMS (EI) m/z (M+) calcd. for C17H27NO2S 309.1762, found 309.1755; [α]D
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
+208.3 (c:1, acetone), ee > 99% (Chiralcel IA, Hexane:2-Propanol 95:5, flow 1 mL/min).
(R)-2-(p-tolylsulfinyl)-1-(pyrrolidin-1-yl)ethanone (3be). Chromatographic purification in a
silica gel column with n-hexane–ethyl acetate (1 : 1 to 1 : 2).White solid: 70 mg, 93% yield; mp
1
121–125 ºC; H-NMR (CDCl3) δ 7.55 (d, J= 8.1Hz, 2H), 7.26 (d, J= 8.1 Hz, 2H), 3.91 (d, J=
12.9 Hz, 1H), 3.57 (d, J= 12.9 Hz, 1H), 3.49-3.05 (m, 4H), 2.35 (s, 3H), 1.86-1.68 (m, 4H); 13C-
NMR (CDCl3) δ 162.4, 141.9, 140.4, 129.9, 124.2, 63.2, 47.3, 46.0, 25.9, 24.3, 21.4; HRMS
(E.I.) m/z (M+) calcd. for C13H17NO2S 251.0980, found 251.0970; [α]D25+140.2 (c: 1, acetone),
ee > 99% (Chiralcel IA, Hexane: 2-Propanol 96:4, flow 4 mL/min).
(R)-2-(p-tolylsulfinyl)-N-p-tolylacetamide (3bi). Chromatographic purification in a silica gel
column with n-hexane–ethyl acetate (1 : 1 to 1 : 2).White solid: 82 mg, 96% yield; mp 170–172
ºC. 1H-NMR (CDCl3) δ 7.43 (d, J= 8.1 Hz, 2H), 7.27 (d, J= 8.1 Hz, 2H), 7.22 (d, J= 8.1 Hz, 2H),
7.00 (d, J= 8.1 Hz, 2H), 3.80 (d, J= 14.1 Hz, 1H), 3.49 (d, J= 14.1 Hz, 1H), 2.35 (s, 3H), 2.33 (s,
3H); 13C-NMR (CDCl3) δ 161.6, 142.3, 137.6, 134.8, 134.2, 130.2, 129.4, 120.3, 60.3, 21.4, 21.0;
HRMS (E.I.) m/z (M+) calcd. for C16H17NO2S 287.0980, found 287.0985; [α]D25+211.4 (c:1,
acetone), ee > 99% (Chiralcel IA, Hexane: 2-Propanol 85:15, flow 3 mLl/min).
1,3-dioctylurea (4a).29 Chromatographic purification on a silica gel column with n-hexane–ethyl
acetate (1 : 1). White solid: 81 mg, 95% yield; mp 89–90 ºC; 1H-NMR (CDCl3) δ 5.00-5.01 (bb, 2H),
3.03-3.09 (m, 4H), 1.42-1.37 (m, 4H), 1,30-1,10 (m, 20H), 0.80 (t, J= 6.0 Hz, 6H); 13C-NMR (CDCl3)
δ 158.9, 40.2, 31.8, 30.4, 29.4, 29.3, 27.0, 22.6, 14.0; HRMS (E.I.) m/z (M+) calcd. for C17H36N2O
284.2827, found 284.2812.
1,3-Dibenzylurea (4b).30 Chromatographic purification in a silica gel column with n-hexane–ethyl
o
1
acetate (1 : 1). White solid: 67 mg, 93% yield; mp 170–171 C; H-NMR (CDCl3) δ 7.25-7.15 (m,
10H), 4.80 (bs, 2H), 4.26 (s, 2H), 4.24 (s, 2H); 13C-NMR (CDCl3) δ 158.0, 139.1, 128.6, 127.4, 127.3,
44.5; HRMS (E.I.) m/z (M+) calcd. for C15H16N2O 240.1263, found 240.1255.
1,3-Bis(4-phenylbutyl)urea (4c). Chromatographic purification in a silica gel column with n-hexane–
ethyl acetate (1 : 1). White solid: 90 mg, 93% yield; mp 76–80 oC; 1H-NMR (CDCl3) δ 7.22 -7.12 (m,
18
ACS Paragon Plus Environment

Page 19 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
4H), 7.10-7.07 (m, 6H), 4.33-4.30 (bb, 2H), 3.11-3.04 (m, 4H), 2.57-2.51 (m, 4H), 1.61-1.54 (m, 4H),
1.51-1.37 (m, 4H); 13C-NMR (CDCl3) δ 158.2, 142.2, 128.4, 128.3, 125.8, 40.3, 35.5, 29.8, 28.6;
HRMS (E.I.) m/z (M+) calcd. for C21H28N2O 324.2216, found 324.2217.
N1,N1,N2,N2-tetrabutyloxalamide (5a).31 Chromatographic purification in a silica gel column
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
with n-hexane–ethyl acetate (1 : 1). Colorless oil: 56 mg, 60% yield; H-NMR (CDCl3) δ 3.38-
13
3.13 (m, 8H), 1.63-1.50 (m, 8H), 1.39-1.21 (m, 8H), 0.95-0.88 (m, 12H); C-NMR (CDCl3): δ=
165.0, 47.7, 43.5, 30.5, 29.2, 20.1, 20.0, 13.7, 13.6; HRMS (E.I.) m/z (M+) calcd. for C18H36N2O2
312.2777, found 312.2766.
1,2-Di(pyrrolidin-1-yl)ethane-1,2-dione (5b).32 Chromatographic purification in a silica gel
1
column with n-hexane–ethyl acetate (1 : 1). White solid: 28 mg, 48% yield; mp 73–75 ºC; H-
13
NMR (CDCl3) δ 3.49-3.42- (m, 8H), 1.90-1.83 (m, 8H); C-NMR (CDCl3) δ 163.1, 46.8, 45.0,
25.8, 24.1; HRMS (E.I.) m/z (M+) calcd. for C10H16N2O2 196.1212, found 196.1199.
1,2-Dimorpholinoethane-1,2-dione (5c).33 Chromatographic purification in a silica gel column
1
with n-hexane–ethyl acetate (1 : 1). White solid: 38 mg, 55% yield; mp 181–185 ºC; H-NMR
13
(CDCl3) δ 3.68-3.57 (m, 12H), 3.40-3.37 (m, 4H); C-NMR (CDCl3): δ= 162.7, 66.7, 66.4, 46.4,
41.4; HRMS (E.I.) m/z (M+) calcd. for C10H16N2O4 228.1110, found 228.1103.
Ethyl 2-(phenylsulfinyl)acetate (8aa).34 Chromatographic purification in a silica gel column
with n-hexane– ethyl acetate (5 : 1). Colorless oil: 53 mg, 83% yield; 1H NMR (CDCl3) δ 7.63-
7.61 (m, 2H ), 7.48-7.46 (m, 3H), 4.08 (q, J= 6.9 Hz, 2H), 3.78 (d, J= 13.5 Hz, 1H), 3.60 (d, J=
13.5 Hz, 1H), 1.14 (t, J= 7.2 Hz, 3H); 13C NMR (CDCl3) δ 164.0, 143.0, 131.7, 129.3, 124.1,
61.9, 61.6, 13.9; HRMS (EI) m/z (M+) calcd for C10H12O3S 212.0507, found 212.0500.
Butyl 2-(phenylsulfinyl)acetate (8ab). Chromatographic purification in a silica gel column with
1
n-hexane– ethyl acetate (5 : 1). Colorless oil: 56 mg, 78% yield; H NMR (CDCl3) δ 7.64-7.62
(m, 2H ), 7.48-7.46 (m, 3H), 4.03 (t, J= 6.6 Hz, 2H), 3.76 (d, J=13.5 Hz, 1H), 3.60 (d, J=13.5 Hz,
13
1H), 1.28-1.18 (m, 4H), 0.83 (t, J= 7.2 Hz, 3H); CNMR (CDCl3) δ 164.7, 143.1, 131.7, 129.3,
124.1, 65.8, 61.7, 30.3, 18.9, 13.6; HRMS (EI) m/z (M+) calcd for C12H16O3S 240.08202, found
240.0806.
2-Chloroethyl 2-(phenylsulfinyl)acetate (8ac). Chromatographic purification in a silica gel
column with n-hexane– ethyl acetate (5 : 1). Colorless oil: 46 mg, 63% yield; 1H NMR (CDCl3) δ
7.65-7.62 (m, 2H), 7.50-7.47 (m, 3H), 4.27 (t, J= 5.7 Hz, 2H), 3.82 (d, J= 13.8 Hz, 1H), 3.67 (d,
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 23
1
2
J= 13.8 Hz, 1H), 3.54 (t, J= 5.7 Hz, 2H); 13C NMR (CDCl3) δ 164.3, 142.8, 131.9, 129.4, 124.1,
65.2, 61.3, 40.9; HRMS (EI) m/z (M+) calcd for C10H11ClO3S 246.0117, found 246.0110.
2-Methoxyethyl 2-(phenylsulfinyl)acetate (8ad). Chromatographic purification in a silica gel
3
4
5
6
7
8
9
1
column with n-hexane– ethyl acetate (5 : 1).Colorless oil: 44 mg, 61% yield; H NMR (CDCl3)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
δ 7.63-7.61 (m, 2H), 7.48-7.46 (m, 3H), 4.18 (t, J= 4.8 Hz, 2H), 3.83 (d, J= 13.8 Hz, 1H), 3.65
(d, J= 13.8 Hz, 1H), 3.47 (t, J= 4.8 Hz, 2H), 3.29 (s, 3H); 13C NMR (CDCl3) δ 164.7, 143.0,
131.8, 129.4, 124.2, 69.9, 64.8, 61.5, 58.9; HRMS (EI) m/z (M+) calcd for C11H14O4S 242.0613,
found .242.0612.
Phenylsulfinyl-2-ethoxy-2-oxoethyl ester (8ae). Chromatographic purification in a silica gel
1
column with n-hexane– ethyl acetate (5 : 1 ). Colorless oil: 48 mg, 59% yield; H NMR (CDCl3)
δ 7.63-7.61 (m, 2H ), 7.48-7.47 (m, 3H), 4.57 (s, 2H), 4.17 (q, J= 7.2 Hz, 2H), 3.84 (d, J= 13.8
13
Hz, 1H),3.72 (d, J= 13.8 Hz, 1H), 1.22 (t, J= 7.2 Hz, 3H); C NMR (CDCl3) δ 167.0, 164.2,
142.9, 133.1, 129.4, 124.1, 61.7, 61.6, 61.5, 14.0; HRMS (EI) m/z (M+) calcd for C12H14O5S
270.0562, found 270.0554.
Benzyl 2-(phenylsulfinyl)acetate (8af). Chromatographic purification in a silica gel column
with n-hexane–AcOEt (5 : 1). Colorless oil: 21 mg, 25% yield; 1H NMR (CDCl3) δ 7.59-7.56 (m,
3H), 7.30-7.20 (m, 5H), 7.44-7.42 (m, 2H), 5.05 (s, 2H), 3.84 (d, J= 13.5 Hz, 1H), 3.64 (d, J=
13.5 Hz, 1H); 13C NMR (CDCl3) δ 164.5, 143.0, 134.7, 131.8, 129.4, 128.7, 128.6, 128.5, 124.2,
67.7, 61.6; HRMS (EI) m/z (M+) calcd for C15H14O3S 274.0664, found 274.0657.
(R)-Ethyl 2-(p-tolylsulfinyl)acetate (8ba).13 Chromatographic purification in a silica gel column
with n-hexane–ethyl acetate (5 : 1). Colorless oil: 55 mg, 81% yield; 1H NMR (CDCl3) δ 7.51 (d,
J= 8.1, Hz, 2H ), 7.27 (d, J= 8.1 Hz, 2H), 4.09 (q, J= 6.9 Hz, 2H), 3.80 (d, J= 13.5 Hz, 1H), 3.57
(d, J= 13.5 Hz, 1H), 2.36 (s, 3H), 1.15 (t, J= 7.2 Hz, 3H); 13C-NMR (CDCl3): δ= 14.0, 21.5, 61.7,
62.0, 124.2, 130.0, 139.8, 142.4, 164.8; HRMS (EI) m/z (M+) calcd for C11H14O3S 226.0664,
25
found 226.0660; ee> 99%, [α]D +155.3 (c: 1, acetone). (Chiralcel OD-H, Hexane: 2-Propanol
99:1, flow 2 mL/min).
N-(2-Hydroxyethyl)-2-(phenylsulfinyl)acetamide (10aa). Chromatographic purification in a
silica gel column with n-hexane–ethyl acetate (1 : 1 to 1 : 2). White solid: 65 mg, 96% yield; mp
101–104 ºC; 1H-NMR (CDCl3) δ 7.59-7.55 (m, 2H), 7.49-7.47 (m, 3H), 3.67 (d, J= 13.8 Hz, 1H),
13
3.60 (q, J= 4.8Hz, 2H), 3.50 (d, J= 13.8 Hz, 1H), 3.33 (q, J= 5.4Hz, 2H); C-NMR (CDCl3) δ
20
ACS Paragon Plus Environment

Page 21 of 23
The Journal of Organic Chemistry
1
2
3
4
5
164.2, 141.4, 131.7, 129.5, 124.0, 61.4, 59.9, 42.6; HRMS (E.I.) m/z (M+) calcd. for C10H13NO3S
227.0616, found 227.0626.
6
N,N-Bis(2-hydroxyethyl)-2-(phenylsulfinyl)acetamide (10ab).Chromatographic purification in
a silica gel column with n-hexane–ethyl acetate (1 : 1 to 1 : 2). White solid: 77 mg, 95% yield;
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
mp 101–104 ºC; H-NMR (CDCl3) δ 7.65-7.63 (m, 2H), 7.47-7.45 (m, 3H), 4.20 (d, J= 14.1 Hz,
1H), 3.81 (d, J= 14.1 Hz, 1H), 3.71-3.47 (m, 10H); 13C-NMR (CDCl3) δ 166.1, 142.4, 131.6,
129.4, 124.4, 72.2, 61.6, 60.0, 52.6, 50.4; HRMS (E.I.) m/z (M+) calcd. for C12H17NO4S
271.0878, found 271.0885.
(R)-2-(p-tolylsulfinyl)-N-(2-hydroxyethyl)acetamide (10ba). Chromatographic purification in a
silica gel column with n-hexane–ethyl acetate (1 : 1 to 1 : 2). White solid: 73 mg, 99% yield; mp
1
123–125 ºC; H-NMR (CDCl3) δ 7.44 (d, J=8.1Hz, 2H), 7.24 (d, J=8.1Hz, 2H), 3.65-3.27 (m,
13
7H), 2.33 (s, 3H); C-NMR (CDCl3) δ 164.3, 142.3, 138.3, 130.1, 124.1, 61.1, 60.8, 42.5, 21.4;
HRMS (E.I.) m/z (M+): calcd. for C11H15NO3S 241.0773, found 241.0771; [α]D +198.1 (c: 1,
25
acetone), ee > 99% (Chiralcel IA, Hexane: 2-Propanol 90:10, flow 2 mL/min).
Oxazolidin-2-one (11aa). Obtained under aerobic conditions. Chromatographic purification in a
silica gel column with n-hexane–ethyl acetate (1 : 1). White solid: 41 mg, 78% yield; mp 86–91
ºC; 1H-NMR (CDCl3) δ 6.40-6.10 (br s, 1H), 4.37 (t, J= 7.9 Hz, 2H), 3.55 (t, J= 7.9 Hz, 2H); 13C-
NMR (CDCl3) δ 160.7, 64.9, 40.6; HRMS (E.I.) m/z (M+) calcd. for C3H5NO2 87.0320, found
87.0299
3-(2-Hydroxyethyl)oxazolidin-2-one
(11ab).
Obtained
under
aerobic
conditions.
Chromatographic purification in a silica gel column with n-hexane–ethyl acetate (1 : 1). Colorless
1
oil: 61 mg, 77% yield; H-NMR (CDCl3) δ= 4.32 (t, J= 7.9 Hz, 2H), 3.75-3.65 (m, 4H), 3.60-
3.50 (brs, 1H), 3.36 (t, J= 5.6 Hz, 2H); 13C-NMR (CDCl3) δ 159.3, 62.1, 59.9, 46.6, 45.4; HRMS
(E.I.) m/z (M+) calcd. for C5H9NO3 131.0582, found 131.0611.
Acknowledgment This work was supported by the Spanish Miniterio de Ciencia e Innovación
and European Community Founds (FEDER) Grants (CTQ 2010-19999) and Consolider-
Ingenio2010 (CSD2007-00006). We acknowledge the SCSIE (Universidad de Valencia) for
access to the instrumental facilities
.
21
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 23
1
2
3
4
Supporting information
5
6
7
8
Copies of 1H and 13C NMR spectra for all compounds and HPLC chromatograms for chiral
compounds. The crystallographic information file (CIF) contains the supplementary
crystallographic data for this paper. This material is available free of charge over the Internet at
http://pubs.acs.org.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
References
1 Transition Metals for Organic Synthesis M. Beller, C. Bolm, Eds.; Wiley-VCH: Weinheim, 2004; vol. 2, 437.
2
Reviews: (a) Grigg; R.; Mutton, S. P. Tetrahedron 2010, 66, 5515. (b) Brennführer, A.; Neumann, H.; Beller; M.
Angew. Chem., Int. Ed. 2009, 48, 4114; (c) Brennführer, A.; Neumann, H.; Beller, M. ChemCatChem. 2009, 1, 28.
(d) Banard, C.F.J. Organometallics 2008, 27, 5402.
3 (a) Cho, C_H.; Larock, R. C. Tetrahedron Lett. 2010, 51, 3417. (b) Rami, S.; Bassam, E. A. Tetrahedron Lett.
2010, 51, 3211. (c) Schareina, T.; Zapf, A.; Cotte, A.; Gotta, M.; Beller, M. Adv. Synt & Cat. 2010, 352, 1205. (d)
Gabriele, B.; Veltri, L.; Mancuso, R.; Plastina, P.; Salerno, G.; Costa, M. Tetrahedron Lett. 2010, 51, 1663. (e)
Salvadori, J.; Balducci, E.; Zaza, S.; Petricci, E.; Taddei, M. J. Org. Chem. 2010, 75, 1841. (f) Yamamoto, Y. Adv
Synt & Cat. 2010, 352, 478. (g) Munday, R. H.; Martinelli, J. R.; Buchwald, S. L. J. Am. Chem. Soc.2008, 130,
2754
.
4
(a) Wakita,Y.; Yasunaga, T.; Akita, M.; Kojima, M. J. Organomet. Chem. 1986, 301, C17. (b) Kondo, T.; Tsuji,
Y.; Watanabe, Y. J. Organomet. Chem. 1988, 345, 397. (c) Suzuki, A. Pure Appl.Chem. 1994, 66, 213, (d) Ishikura,
M.; Terashima, M. J. Org. Chem. 1994, 59, 2634. (e) Ishiyama, T.; Kizaki, H.; Hayashi, T.; Suzuki, A.; Miyaura, N.
J. Org. Chem. 1998, 63, 4726. (f) Andrus, M. B.; Ma, Y.; Zang,Y.; Song, C. Tetrahedron Lett. 2002, 43, 9137. (g)
Mingji, D.; Liang, B.; Wang, C.; You, Z.; Xiang, J.; Dong, G.; Chen, J.; Yang, Z. Adv. Synth. Catal. 2004, 346,
1669. (h) Petz, A.; Péczely, G.; Pintér, Z.; Kollár; L. J. Mol. Catal. A: Chem. 2006, 255, 97. (i) Larini, P.; Guarna,
A.; Occhiato, E. G. Org. Lett. 2006, 8, 781. (j) Maerten, E.; Sauthier, M.; Mortreux, A.; Castanet, Y. Tetrahedron
2007, 63, 682. (k) Maerten, E.; Hassouna, F.; Couve-Bonnaire, S.; Montreux, A.; Carpentier, J.-F.; Castanet, Y.
Synlett 2003, 1874
.
5 (a) Ozawa, F.; Soyama, H.; Yanagihara, H.; Aoyama, I.; Takino, H.; Izawa, K.; Yamamoto, T.; Yamamoto, A. J.
Am. Chem. Soc. 1985, 107, 3235. (b) Yamamoto, A. Bull. Soc. Chem. Jpn. 1985, 68, 433.
6
(
a) Wu, X.-F.; Neumann, H.; Beller, M. Chem. Eur. J. 2012, 18, 419. (b) Wu, X.-F.; Neumann, H.; Beller, M.
Chem. Eur. J. 2010, 16, 12104. (c) Wu, X.-F.; Neumann, H.; Beller, M. ChemCatChem. 2010, 2, 509. (d).Wu, X.-F.;
Schranck J.; Neumann, H.; Beller, M. Tetrahedron Lett. 2011, 52, 3702. (e) Martinelli, J. R.; Clark, T. P.; Watson,
,
D. A.; Munday, R. H.; Buchwald, S. L. Angew. Chem., Int. Ed. 2007, 46, 8460.
7 Ishiyama, T.; Miyaura, N.; Suzuki, A. Tetrahedron Lett. 1991, 47, 6923
8
(a) Lindsell, W. E.; Palmer, D. D. D.; Preston, P. N.; Rosair, G. M.; Jones, R.V. H.; Whitton, A. J. Organometallics
2005, 24, 1119. (b) Lapidus, A. L.; Eliseev. O. L.; Bondarenko, T. N.; Sizan, O. E.; Ostapenko, E. G.; Beletskaya I.
P. Kinet. Catal. 2004, 45, 234. (c) Cavinato, G.; Pasqualetto, M.; Ronchin, L.; Tonilo, L. J. Mol. Catal. A: Chem.
1997, 125, 15. (d) Cavinato, G.; Tonilo, L. J. Mol. Catal. A: Chem. 1996, 104, 221.
9 (a) Troisi, L.; Granito, C.; Rosato, F.; Videtta; V. Tetrahedron Lett 2010, 51, 371. (b) For intramolecular versions
see: Wu, X.-F; Schranck, J.; Neumann, H.; Beller, M. ChemCatChem 2012, 4, 69. (c) Marosvölgyi-Hask, D.; Attila
Takács, A.; Riedl,S.; Kollar; L. Tetrahedron 2011, 67, 1036.
10
(a) Cinquini, M.; Landini, D.; Maia, A. J. Chem. Soc. Chem. Commun.1972, 734. (b) Numata, T.; Oae, S. Bull.
Soc. Chem. Jpn. 1972, 45, 2794.
11 (a) García-Ruano, J. L.; Alvarado, C.; Díaz-Tendero, S.; Alemán, J. Chem.ꢀ Eur. J. 2011, 17, 4030. (b) Obringer,
M.; Barbarotto, M.; Choppin, M. S.; Colobert, F. Org. Lett. 2009, 11, 3542. (c) Colobert, F.; Choppin, S.; Ferreiro-
Mederos, L.; Obringer, M.; Luengo-Arratta, S.; Urbano, A.; Carreño, M. C. Org. Lett. 2007, 9, 4451. (d)
22
ACS Paragon Plus Environment

Page 23 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Ishigami,K.; Katsuta, R.; Watanabe, H. Tetrahedron 2006, 62, 2224. (e) Carreño, M. C.; Hernández-Torres, G.;
Urbano, A.; Colobert, F. Org. Lett. 2005, 7, 5517. (f) Lanners, S.; Khiri, N.; Solladié, G.; Hanquet, G. Tetrahedron
Lett. 2005, 46, 619. (g) García-Ruano, J. L.; Rodríguez-Fernández, M. M.; Maestro, M. C. Tetrahedron 2004, 60,
5701. (h) Silveira, C. C.; Braga, A. L.; Kaufman, T. S.; Lenardao, E. J. Tetrahedron 2004, 60, 8295. (i) Carreño, M.
C.; Des Mazery, R.; Urbano, A.; Colobert, F.; Solladié, G. J. Org. Chem. 2003, 68, 7779. (j) Nakamura, S.;
Nakayama, J.; Toru, T. J. Org. Chem. 2003, 68, 5766. (k) Ghosh, A. K.; Lei, H. Tetrahedron: Asymmetry 2003, 14,
629. (l) Colobert, F.; Des Mazery, R.; Solladié, G.; Carreño, M. C. Org. Lett. 2002, 4, 1723. (m) Nokami, J.;
Kataoka, K.; Shiraishi, K.; Osafune, M.; Hussain, I.; Sumida, S. J. Org. Chem. 2001, 66, 1228. (n) Toró, A.;
L’Heureux, A.; Deslongchamps, P. Org. Lett. 2000, 2, 2737. (o) García-Ruano, J. L. Top. Curr. Chem. 1999, 204, 1.
(p) Carreño, M. C. Chem Rev. 1995, 95, 1717.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
12 (a) Kankan, S.; Fun, H.K. J. Chem. Res. 2007, 668. (b) García-Ruano, J. L.; Gonzalez; A. M.; Lopez-Solera, I.;
Masaguer, J. R.; Navarro-Ranninger, C.; Raithby, P. R.; Rodríguez, J. H. Angew. Chem., Int. Ed. 1995, 34, 1351. For
further examples of complexes with sulfoxide ligands: (c) Chen, M. S.; Prabagaran, N.; Labenz, N. A.; White, M. C.
J. Am. Chem. Soc. 2005, 127, 6970. (d) Pettinari, C.; Pellei, M.; Cavicchio, G.; Crucianelli, M.; Panzeri, W.;
Colapietro, M.; Cassetta, A. Organometallics 1999, 18, 555. (e) Ogura, K.; Aizawa, T.; Uguiyama, K.; Iida, H. Bull.
Soc. Chem. Jpn. 1983, 56, 953. (f) Price, J. H.; Williamson, A. N.; Schramm, R. F.; Wayland, B. B. Inorg. Chem.
1972, 11, 1280.
13 Nagao, Y.; Miyamoto,S.; Miyamoto, M.; Takeshige, H.; Hayashi, K.; Sano, S.; Shiro, M.; Yamaguchi, K.; Sei, Y:
J. Am. Chem. Soc. 2006, 128, 9722.
14 Medio-Simon. M.; Mollar, C.; Rodriguez, N.; Asensio, G. Org. Lett. 2005, 7, 4669.
15 (a) Hojo, M.; Masuda, R.; Saeki, T.; Fujimori, K.; Tsutsumi, S. Synthesis 1977, 789 (b) Cardellicchio, C.;
Fiandanese,V.; Naso, F.; Scilimati, A. Tetrahedron. Lett. 1992, 33, 5121.
16 Corey, E. J.; Chavkovsky, M. J. Am. Chem. Soc. 1965, 87, 1345.
17
(a) Kirchhoff, J. H.; Netherton, M. R.; Hill, I. D.; Fu, G. C. J. Am. Chem. Soc. 2002, 124, 13662. (b) Hill, I. D.;
Netherton, M. R.; Fu, G. C. Angew. Chem., Int. Ed. 2003, 42, 5749. (c) Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2003,
125, 12527. (d) Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 14726. (e) Netherton, M. R.; Fu, G. C. Angew.
Chem., Int. Ed. 2002, 41, 3910. (f) Kirchhoff, J. H.; Dai, C.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 1945. (g)
Netherton, M. R.; Dai, C.; Neuschütz, K.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 10099. (h) Frisch, A. C.; Beller,
M. Angew. Chem., Int. Ed. 2005, 44, 674
.
18
(a) Rodríguez, N.; Cuenca, A.; Ramírez de Arellano, C.; Medio-Simón, M.; Peine, D.; Asensio, G. J. Org. Chem.
2004, 69, 8070.(b) Rodríguez, N.; Cuenca, A.; Ramírez de Arellano, C.; Medio-Simón, M.; Asensio, G. Org. Lett.
2003, 5, 1705. (c) Rodríguez, N.; Ramírez de Arellano, C.; Asensio, G.; Medio-Simón, M. Chem. Eur. J. 2007,
4223.(d) Gourlaouen, C.; Ujaque,G.; Lledós, A.; Medio-Simón, M.; Asensio, G.; Maseras, F. J. Org. Chem. 2009,
74, 4049.
19 For demonstration of diffusion of air into the balloon see Lee, J-Y.; Yoo, H-S.; Park, J. S.; Hwang, K-J.; Kim, J. S. J.
Chem. Educ. 2005, 82, 288.
20 (a) Ragaini, F. Dalton Trans. 2009, 6251 (b) Gabriele, B.; Salerno, G.; Mancuso, R.; Costa, M. J. Org. Chem.
2004, 69, 4741. (c) Gabriele, B.; Salerno, G.; Mancuso, R.; Costa, M. Chem. Commun. 2003, 486.
21 Cowell, A.; Stille, J. F. J. Am. Chem. Soc. 1980, 102, 4193.
22
Hu, Y.; Liu, J.; Lu, Z.; Luo, X.; Zhang, H.; Lan, Y.; Lei, A. J. Am. Chem. Soc 2010, 132, 3153
23 Rodriguez, N.; Medio-Simón, M.; Asensio, G. Adv. Synth. Cat. 2007, 349, 987.
24 Steinhoff, B. A.; Fix; S. R.; Stahl, S.S. J. Am. Chem. Soc. 2002, 124, 766.
.
25 (a) Roussel, M.; Mimoun, H. J. Org. Chem. 1980, 45, 5387. (b) Nashimura, T.; Onoue; T.; Ohe, K.; Uemura, S. J.
Org. Chem. 1999, 64, 6750. (c) Remias, J. E.; Sen, A. J. Mol. Catal. A: Chem 2002, 189, 33.
26 For examples of trans-chelating xantphos-Pd(II) complexes:(a)Yin, J.; Buchwald, S. L. J. Am. Chem. Soc. 2002,
124, 6043. (b) Grushin, V. V.; Marshall, W. J. J. Am. Chem. Soc. 2006, 128, 12644.
27 Cinquini, M.; Colonna, S. J. Chem. Soc. Perkin 1 1972, 1883.
28 Huang, C.G.; Chang, B.R.; Chang, N.C. Tetrahedron Lett. 2002, 43, 2721.
29 Bigi, F.; Frullanti, B.; Maggi, R.; Sartori, G.; Zambonin, E. J. Org. Chem. 1999, 64, 1004.
30 Pasha, M. A.; Jayashankara, V. P. Synth. Comm. 2006, 36, 1787.
31 Tsuda, T.; Isegawa, Y.; Saegusa, T. J. Org. Chem. 1972, 37, 2670.
32 Crumrine, D.S.; Dieschbourg, T.A.; O'Toole, J.G.; Tassone, B.A.: Vandeburg, S.C. J. Org. Chem. 1987, 52, 3699.
33 Lemoucheux, L.; Seitz, T.; Rouden, J.; Lasne, M. C. Org. Lett. 2004, 6, 3703.
34 Zhang, Q.; Wu, Y. Tetrahedron, 2007, 63, 10189.
23
ACS Paragon Plus Environment