HBF4·DEE-catalyzed formation of sulfinyl imines: Synthesis and mechanistic studies

Article abstract of DOI:10.1016/j.tetlet.2018.02.051

A mild acid-catalysed method is reported for the formation of sulfinyl imines from tert-butanesulfinamide and aromatic or aliphatic aldehydes using tetrafluoroboric acid diethyletherate (10 mol%) in dichloromethane. Reactions were performed at room temper

Full text of DOI:10.1016/j.tetlet.2018.02.051

Accepted Manuscript
HBF4 •DEE-catalyzed formation of sulfinyl imines: synthesis and mechanistic
studies
Björn Blomkvist, Peter Dinér
PII:
S0040-4039(18)30239-9
https://doi.org/10.1016/j.tetlet.2018.02.051
TETL 49736
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
6 December 2017
13 February 2018
19 February 2018
Please cite this article as: Blomkvist, B., Dinér, P., HBF4 •DEE-catalyzed formation of sulfinyl imines: synthesis
and mechanistic studies, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.02.051
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Graphical Abstract
HBF4•DEE-catalyzed formation of sulfinyl imines:
synthesis and mechanistic studies
Leave this area blank for abstract info.
Björn Blomkvista and Peter Dinéra*
Department of Chemistry, KTH-Royal Institute of Technology, Teknikringen 30, 10044 Stockholm, Sweden
‡
1.004
O
S
O
S
1.643
HBF4•DEE (10 mol%)
1.289
+
R
O
1.729
H2N
R
N
2.138
MgSO4
CH2Cl2, RT, 2 h
up to 97% yield

1
Tetrahedron Letters
HBF4•DEE-catalyzed formation of sulfinyl imines: synthesis and mechanistic studies
Björn Blomkvist a and Peter Dinér a*
a Department of Chemistry, KTH–Royal Institute of Technology, Teknikringen 30, Sweden
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A mild acid-catalysed method is reported for the formation of sulfinyl imines from tert-
butanesulfinamide and aromatic or aliphatic aldehydes using tetrafluoroboric acid
diethyletherate (10 mol%) in dichloromethane. Reactions were performed at room temperature
and gave the corresponding sulfinyl imines in excellent yield after 2 hours. A DFT study was
performed and a mechanism for the reaction is postulated.
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
Sulfinyl imine
Brönsted acid catalysis
Tetrafluoroboric acid
Mechanistic study
DFT
1. Introduction
As a result, tert-butanesulfinyl imine based strategies have
recently been utilized in several total syntheses, providing high
levels of stereoselectivies.15-18
Chiral sulfinamides function as amine equivalents and have
been used as versatile chiral auxiliaries in asymmetric synthesis.1-
The sulfinamide reagent, usually tert-butanesulfinamide, reacts
3
The most common method to prepare sulfinyl imines from
aldehydes and ketones is to use an excess of titanium(IV)
alkoxide.19,10 Alternative methods applying weak protic or Lewis
acids, such as Amberlyst,20 pyridinium p-toluene sulfonate,21
Yb(OTf)3,22 and CuSO4,3 have been developed for the synthesis
of aldimines, however they usually require stoichiometric
amounts of reagent, extensive heating or a large excess of the
reacting aldehyde (Scheme 2).
with aldehydes and ketones to provide tert-butanesulfinyl imines
in high yields. These imines can then react with different classes
of nucleophiles where the tert-butanesulfinyl moiety acts as a
chiral directing group giving products with high stereoselectivity.
tert-Butanesulfinyl imines have been used in the asymmetric
synthesis of many versatile building blocks, including syn- and
anti- 1,2- or 1,3-amino alcohols,4-8 -branched and ,-
dibranched amines,9,10 and - or -amino acids and esters.11-14
O
OH
R1
H2N
R1
R
NH2 OH
H2N
R1
R1
R2
R2
O
R2
R
NH2 OH
S
N
R1
R1
R1
R2
H2N
1
NH2
O
NH2
R2
R1
OH
R1
OMe
NH2
R4 R3
R2
OH
R1
R2
Scheme 1. Overview of strategies utilising the tert-
butanesulfinyl moiety as a chiral auxillilary.4-14

2
Tetrahedron
Scheme 2. Lewis acid, aminocatalytic and Brönsted acid
Therefore, we were delighted to note that catalytic amounts of
tetrafluoroboric acid diethyletherate (HBF4•DEE, 10 mol%, 25 µl
from a 0.5 M stock solution in THF) in the presence of molecular
sieves (4 Å) promoted the reaction between benzaldehyde and
tert-butanesulfinamide to form 1a (66% conv.) at room
temperature in only 2 h (Table 1, entry 1). Weaker organic acids,
such as acetic acid or p-nitrobenzoic acid, did not promote the
reaction (Table 1, entries 2 and 4), while methane sulfonic acid
promoted the reaction with lower conversion (46%, Table 1,
entry 3). The molecular sieves could be replaced with magnesium
sulfate giving similar conversion (69%, Table 1, entry 5). With a
stock solution in CH2Cl2, the conversion was increased
significantly (80% conv., Table 1, entry 6) and changing the
solvent completely to CH2Cl2 led to a further increase of the
conversion (89%, Table 1, entry 8). The use of other solvents
(Et2O, EtOH, MeCN, Table 1, entries 9-11) led to a decrease in
conversion compared to toluene and CH2Cl2. Lower catalyst
loading (1, 2.5 and 5 mol%, Table 1, entries 12-14) led to a
significantly lower conversion after two hours. An increased
amount of MgSO4 was added in order to drive the reaction to
completion, but no noteworthy change in conversion was
observed (Table 1, entries 15-17). At higher concentration of the
reaction mixture (1.0 M compared to 0.25 M) an increase in
conversion to the sulfinyl imine was achieved (94%, Table 1,
entry 18). The formation of the sulfinyl imine from p-
toluenesulfinamide was less effective compared to the tert-
butanesulfinamide, giving the product in only 37% yield after
two hours and only 48% yield after extended reaction time (Table
1, entry 19). Unfortunately, the reaction between tert-
butanesulfinamide and ketones (e.g. acetophenone) did not yield
the corresponding sulfinyl imine.
promoted protocols for the formation of tert-butanesulfinyl
imines.
Recently, Cid and co-workers reported an aminocatalytic
method for the formation of sulfinyl imines from aldehydes.23
The use of catalytic pyrrolidine and equimolar amounts of the
sulfinamide and aldehyde at 60 °C, provided the corresponding
sulfinyl imine in excellent yield (Scheme 2).
In an effort to expand the applicability of the use of sulfinyl
imines in asymmetric synthesis, we aimed to develop a mild and
highly efficient acid-catalyzed protocol for the formation of
sulfinyl imines from sulfinamides and aldehydes which operates
with short reaction times and at room-temperature.
2. Results and Discussion
Since the N-S bond of the N-sulfinyl group is commonly
cleaved by treatment with strong acids such as hydrochloric acid
in the presence of water,3 most of the previous acid promoted
transformations have used weak acids, often in stoichiometric
amounts and under reflux conditions, in order to form sulfinyl
imines from aldehydes (Scheme 2).
Table 1.
Screening of different acids and additives for the formation of
the sulfinyl imine from benzaldehyde and tert-
butanesulfinamide.a
With the optimized reaction conditions in hand, we set out to
investigate the synthetic utility and substrate scope of the
reaction. The parent benzaldehyde was easily converted to
sulfinyl imine 1a (93%) in excellent isolated yield after two
hours at room temperature and a similar result was obtained for
the bulkier 1-naphthaldehyde (Table 2, entries 1 and 2).
Entry HX (mol %)
R
Desiccant
(equiv.)
Solvent
Conv.
(%)
1
2
HBF4 (10)
A
A
4Å MS
4Å MS
Tolueneb
Tolueneb
66
0
AcOH (10)
3
4
MeSO3H (10)
A
A
4Å MS
4Å MS
Tolueneb
Tolueneb
46
0
Table 2.
p-NO2-
Substrate scope for sulfinyl imine formation from aliphatic
PhCO2H (10)
and aromatic aldehydes and tert-butanesulfinamide.a
5
6
HBF4 (10)
HBF4 (10)
A
A
MgSO4 (1)
MgSO4 (1)
Tolueneb
Toluenec
69
80
7
MeSO3H (10)
HBF4 (10)
HBF4 (10)
HBF4 (10)
HBF4 (10)
HBF4 (5)
A
A
A
A
A
A
A
A
A
A
A
A
B
MgSO4 (1)
MgSO4 (1)
MgSO4 (1)
MgSO4 (1)
MgSO4 (1)
MgSO4 (1)
MgSO4 (1)
MgSO4 (1)
MgSO4 (3)
MgSO4 (3)
MgSO4 (5)
MgSO4 (1)
MgSO4 (1)
Toluenec
CH2Cl2
Et2Oc
61
Entry
R
rProduct
Isolated yield
(%)
8
89
9
68
1
2
3
4
5
6
7
8
Ph
1a
1b
1c
1d
1e
1f
93
88
94
97
91
92
93
97
10
11
12
13
14
15
16
17
18d
19e
EtOHc
17
1-naphthyl
4-nitrophenyl
3-nitrophenyl
4-cyanophenyl
3-methoxyphenyl
salicyl
MeCNc
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
38
71
HBF4 (2.5)
HBF4 (1)
50
21
HBF4 (5)
61
1g
1h
HBF4 (10)
HBF4 (5)
88
3-bromophenyl
68
HBF4 (10)
HBF4 (10)
94
9
2-furyl
1i
1j
82
94
37 (48)e
10
3-phenylpropionyl
a Reagents and conditions: benzaldehyde (0.25 mmol, 0.25 M), (R)-tert-
11
12
13
cyclohexyl
tert-butyl
1k
1l
91
92
94
butanesulfinamide (0.275 mmol), magnesium sulphate (0.25 mmol),
c
HBF4•DEE (10 mol%), 2 h, rt. b 5% THF as co-solvent. 5% CH2Cl2 as co-
solvent. d Benzaldehyde (1.0 M). e After 18 h.
1-cyclohexene
1m

3
14
(S)-N-Boc-2-phenethyl
1o
83
proton is significantly shifted towards the oxygen on the diethyl
a Reagents and conditions: benzaldehyde (0.25 mmol, 1.0 M), (R)-tert-butane-
sulfinamide (0.275 mmol), magnesium sulphate (0.25 mmol), HBF4•DEE (10
mol%), CH2Cl2 (0.25 mL), 2 h, rt.
ether, which indicates that the initial acid in dichloromethane is
the protonated diethyl ether with tetrafluoroborate as the
counterion (Fig. 1A). In order to determine the initial state of the
different components of the reaction mixture, we optimized and
compared the stability (∆∆G) of HBF4•DEE-protonated
benzaldehyde (Fig. 2B) and protonated tert-butanesulfinamide
(Fig. 1C and D). The result show that protonation of the
benzaldehyde by HBF4•DEE is an unfavored process (+4.67 kcal
mol-1, Fig. 1B), while protonation on the sulfinamide nitrogen is
only slightly favored (-1.38 kcal mol-1, Fig. 1C). The most stable
species on the Gibbs free energy surface, and presumably in the
reaction mixture, was the O-protonated sulfinamide (Fig. 1D),
which was stabilized with -10.5 kcal mol-1 compared to the
HBF4•DEE. This suggests that O-protonated sulfinamide is the
initial state in the reaction mixture.
Aromatic aldehydes with electron withdrawing substituents,
such as nitro and cyano groups, in the para- and meta-position,
and electron donating substituents, such as 3-methoxy and 2-
hydroxy, were also converted to the corresponding imine
products in excellent yields (Table 2, entries 3-7). The bromo-
substituted substrate gave sulfinyl imine 1h in excellent yield,
while a slightly lower yield was observed for the more electron-
rich, heteroaromatic furfural (82%, Table 2, entries 8 and 9). On
the other hand, the aliphatic 3-phenylpropionaldehyde gave an
excellent yield (Table 2, entry 10), showing that the potential
side-reaction of enolization is not interfering in formation of the
product. Aliphatic secondary, tertiary and ,-unsaturated
aldehydes gave the corresponding sulfinyl imines in excellent
yields (Table 2, entries 11-13), which contrasts with the amino
catalytic method by Cid and co-workers23 for aliphatic aldehydes
that requires extended reaction times and excess aldehydes.
Finally, the sulfinyl imine from N-Boc-L-phenylalaninal (Table
2, entry 14) was successfully isolated in 83% yield without
epimerization of the stereocenter in the -position (see ESI). In
addition, it has previously been reported that acids in the
presence of the tetrafluoroborate counterion can cause
epimerization on the stereogenic sulfur.24 However, no
epimerization was observed during the reaction as confirmed via
chiral column HPLC (see ESI).
1.1. Computational studies of the mechanism of the HBF4•DEE-
catalyzed formation of sulfinyl imines.
In order to understand the mechanism of the HBF4•DEE-
Figure 1. Gibb’s free energies of the different protonated species; A)
HBF4•DEE; B) protonated aldehyde, C) N-protonated sulfinamide; D) O-
protonated sulfinamide in dichloromethane at the M062X/6-311+G(d,p)–
CPCM (CH2Cl2, UFF) level of theory.
catalyzed formation of sulfinyl imines, we performed
a
computational study using DFT. To begin with, we investigated
the initial state of HBF4•DEE in order to understand the
activation mode of the acid. The optimization of HBF4•DEE at
the M062X/6-311+(d,p) level of theory, with the inclusion of
solvent effects (CPCM, UFF, dichloromethane), show that the

4
Tetrahedron
Figure 2. Gibbs free energy diagram for HBF4•DEE-catalyzed formation of the sulfinyl imine at the M062X/6-311+G(d,p)–CPCM (CH2Cl2, UFF) level of
theory.
Figure 3. Geometries of minima and transitions states (A-F) on the M062X/6-311+G(d,p) –CPCM (CH2Cl2,UFF) level of theory.
Next, we investigated the potential energy surface for the
formation tert-butanesulfinyl imine from benzaldehyde and the
O-protonated sulfinamide (Fig. 2). Starting from the protonated
sulfinamide, we were able to locate the transition state (C) for the
formation of the hemiaminal intermediate (E) that is 20.9 kcal
mol-1 higher in Gibbs free energy than the free reactants (Fig. 2,
A and C). In the six-membered chair-like transition state (C), the
proton from the O-protonated sulfinamide is completely
transferred to the aldehyde oxygen, while the C-N bond still is
not formed (2.138 Å). Following the intrinsic reaction coordinate
(IRC) to the reactant side leads to an unstable complex B (+5.4
benzaldehyde. On the product side of the transition state, the N-
protonated hemiaminal intermediate (D) is formed in an
endothermic reaction (+12.6 kcal mol-1). Proton transfer from the
nitrogen to the more electronegative oxygen of the sulfinamide
moiety leads to a large stabilization (from +12.6 to +3.2 kcal mol-
1), which is due to the three hydrogen bonds that are formed
–
between the polar hydrogens and the BF4 –counterion (E). From
complex E, dehydration occurs in a concerted transition state that
suggests that the water molecule is leaving without the formation
of an intermediate when the proton is transferred from the
sulfinamide oxygen. In the transition state, the proton is
completely transferred to the leaving water molecule as the C–O-
–
kcal mol-1) between the protonated sulfinamide, BF4 , and

5
22.
23.
24.
Jiang, Z. Y.; Chan, W. H.; Lee, A. W. J. Org. Chem.
2005, 70, 1081-3.
bond is breaking (1.898 Å) leading to the protonated sulfinyl
imine and water (G, +12.5 kcal mol-1). The last step in the
catalytic cycle involves proton transfer from the protonated
sulfinyl imine to the oxygen of another sulfinamide yielding the
product in an overall exothermic process (-2.0 kcal mol-1).
Morales, S.; Guijarro, F. G.; Garcia Ruano, J. L.; Cid, M.
B. J. Amer. Chem. Soc. 2014, 136, 1082-9.
Aggarwal, V. K.; Barbero, N.; McGarrigle, E. M.; Mickle,
G.; Navas, R.; Suárez, J. R.; Unthank, M. G.; Yar, M.
Tetrahedron Letters 2009, 50, 3482-3484.
3. Conclusion
A rapid and convenient method was developed for the synthesis
of tert-butanesulfinyl imines from aldehydes and tert-
butanesulfinamide, catalyzed by HBF4•DEE (10 mol%) in
CH2Cl2 at room temperature in 2 h. Sulfinyl imines obtained from
both aliphatic, differently substituted aromatic and ,-
unsaturated aldehydes were obtained in high isolated yields. A
DFT-investigation suggests that the sulfinamide is protonated by
HBF4•DEE and the addition of sulfinamide occurs via a six-
membered chair-like transition state. The Gibbs free energy of
activation for this process is 20.5 kcal mol-1 and the overall
reaction is exothermic with 2.0 kcal mol-1.
Acknowledgments
B. B. and P.D. thanks KTH – Royal Institute of Technology
for financial support and the National Supercomputer Center
(NSC) in Linköping for computational resources.
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6
Tetrahedron
Research highlights
• A mild, efficient and catalytic method for the
formation of sulfinyl imines is reported.
• A computational investigation gave insight
into the mechanism of the reaction.
• Sulfinamide addition to aldehyde occurs via a
six-membered transition state.