Sulfinamides as highly effective amine protecting groups and their use in the conversion of Amino alcohols into morpholines

Article abstract of DOI:10.1002/ejoc.201100337

1,2-Amino alcohols have been converted into morpholines by using sulfinamides as temporary protecting/activating groups on the amine. We have developed a procedure for the selective synthesis of monoprotected N-sulfinyl amino alcohols through a double sul

Full text of DOI:10.1002/ejoc.201100337

FULL PAPER
DOI: 10.1002/ejoc.201100337
Sulfinamides as Highly Effective Amine Protecting Groups and Their Use in
the Conversion of Amino Alcohols into Morpholines
Sven P. Fritz,[a] Amara Mumtaz,[a][‡] Muhammad Yar,[a][‡‡] Eoghan M. McGarrigle,[a] and
Varinder K. Aggarwal*[a]
Keywords: Nitrogen heterocycles / Amino alcohols / Sulfinamides / Annulation / Protecting groups
1,2-Amino alcohols have been converted into morpholines by
using sulfinamides as temporary protecting/activating
groups on the amine. We have developed a procedure for the
selective synthesis of monoprotected N-sulfinyl amino
alcohols through a double sulfinylation/hydrolysis strategy.
Following the reaction of the sulfinamides with bromoethyl-
diphenylsulfonium triflate, protected morpholines were ob-
tained in high yields. Subsequent treatment with HCl liber-
ated the morpholine hydrochloride salts. The usefulness of
this high yielding and efficient methodology has been dem-
onstrated in the formal synthesis of the antidepressant drug
(S,S)-reboxetine.
these groups unsuitable. We have therefore considered alter-
native groups that are both easy to introduce and easy to
remove. However, standard amine protecting groups, for ex-
ample, Boc, Cbz and Ac, were not suitable in the annulation
process as their use led to alternative products.[4] We there-
fore considered the possibility of using sulfinamides. Al-
though the extensive practical and pioneering work of
Davis and Ellman has demonstrated their use in highly
stereoselective amine synthesis[5–7] and simple mild methods
for their deprotection have been developed,[8] sulfinamides
have not been commonly employed as direct amine protect-
ing groups.
Introduction
Efficient methods for the synthesis of saturated hetero-
cycles are especially important in medicinal chemistry
where such motifs are ubiquitous.[1] We have previously re-
ported the synthesis of pharmaceutically important build-
ing blocks such as morpholines and benzodiazepines from
readily available amino alcohols and bromoethylsulfonium
salt 1, which is now commercially available (Scheme 1).[2,3]
In this paper we describe the (nontrivial) synthesis of
sulfinamides[9] derived from amino alcohols, their success-
ful use in annulation and their straightforward deprotec-
tion. Furthermore, we illustrate the application of the meth-
odology in a formal synthesis of the antidepressant (S,S)-
reboxetine.
Scheme 1. Methodology for the preparation of heterocycles from
amino alcohols.[2c]
For cleavable groups on nitrogen, only sulfonyl groups in
the form of Ts, Ns, Bts or SES have been reported, but
occasionally issues relating to functional group compati-
bility and/or ease of removal (especially for Ts) can make
Results and Discussion
Our initial efforts focused on the preparation of sulfin-
amide 4a derived from the amino alcohol 3a. The use of
nBuLi with methyl p-tolylsulfinate ester 5[10] gave the de-
sired product, but the reaction was found to be somewhat
capricious in our case and partial reaction with the OH
could not be avoided. The use of p-tolylsulfinyl chloride (6),
which had to be freshly prepared due to its instability, or
the much more stable p-tolylsulfinyl p-tolyl sulfone (7)[11,12]
led to a mixture of starting material 3a, the desired sulfin-
amide 4a and the bis-protected adduct 8a under a variety of
conditions (Scheme 2). The difficulty in generating mono-
sulfinamides in high yields from amines could be one of the
reasons why this group has not been used extensively for
[a] School of Chemistry, University of Bristol,
Cantock’s Close, Bristol, BS8 1TS, U.K.
Fax: +44-117 9298611
E-mail: V.Aggarwal@Bristol.ac.uk
[‡] Current address: Department of Chemistry, Comsats Institute
of Information Technology,
University Road, Postal Code 22060, Abbottabad, KPK,
Pakistan
[‡‡]Current address: Chemistry Department, King Fahd University
of Petroleum & Minerals,
P. O. Box 1347, Dhahran 31261, Saudi Arabia
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100337.
3156
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3156–3164

Sulfinamides as Amine Protecting Groups and Their Uses
amine protection especially as it would share some of the Table 1. Synthesis of N-p-tolylsulfinyl-protected amino alcohols
4a–e and diamine 4f.
benefits of the ubiquitous tosyl group but with the added
benefit of a much simpler deprotection.
Scheme 2. Initial investigation of sulfinamide formation.
The mixture of products obtained (Scheme 2) indicated
to us that under the mildly basic conditions the desired
product 4a was easily deprotonated and that the resulting
anion had similar nucleophilicity to the neutral amine 3a,
thus leading to the bis-protected adduct 8a. We therefore
sought to exploit the reactivity of sulfinamide 4a in a
double protection/hydrolysis strategy. Thus, treatment of
amino alcohol 3a with 2.2 equiv. of p-tolylsulfinyl p-tolyl
sulfone (7) led to full conversion to 8a. Subsequent treat-
ment with NaOH in MeOH selectively cleaved one of the
[a] Isolated yield. Obtained as a mixture of isomers (epimeric at
sulfur). [b] With sulfinyl chloride as sulfinylating agent. [c] X =
NS(O)pTol.
sulfinyl groups to give the desired sulfinamide 4a in high
overall yield (Scheme 3). This protocol was general for a
series of amino alcohols furnishing the sulfinamides 4a–f in
high yields as mixtures of isomers (Table 1).
Table 2. Optimisation of the conditions for annulation.
Entry
Base
Yield [%]
Scheme 3. Optimised synthesis of mono-N-protected sulfinamide.
1
2
3
Et3N
DBU
NaH
no conversion observed
49
93
We then turned to the annulation reaction with the bro-
moethylsulfonium salt 1. A number of bases were tested in
this reaction (Table 2) and NaH in CH2Cl2 was found to be
optimum.[13]
and were isolated by simple filtration (Table 4). Salt 12e is
When applied to our sulfinamides 4a–f, the protected an especially notable morpholine that has been incorpo-
morpholines 9a–e and the piperazine 9f were all obtained rated into a number of potential drug molecules.[14]
in high yields (Table 3).
Finally, the methodology was applied to a formal synthe-
The annulation reaction is believed to proceed via the sis of (S,S)-reboxetine, an antidepressant drug marketed by
intermediate vinyl sulfonium salt 2 and involves conjugate Pfizer.[15–17] Starting from the amino diol 13, the reaction
addition, proton transfer and cyclisation (Scheme 4).
with excess p-tolylsulfinyl chloride (6) or p-tolylsulfinyl p-
To complete our synthetic strategy, we deprotected two tolyl sulfone (7) followed by partial hydrolysis gave the re-
representative substrates by facile treatment with HCl in quired sulfinamide 14. The primary alcohol was then pro-
Et2O. The amine hydrochloride salts 12a/12e precipitated tected as the trityl ether and the β-hydroxy sulfinamide 15
Eur. J. Org. Chem. 2011, 3156–3164
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3157

V. K. Aggarwal et al.
Table 4. Representative examples of deprotection.
FULL PAPER
Table 3. Synthesis of N-p-tolylsulfinyl-protected morpholines and
piperazines.
[a]
Entry
Substrate
Yield of 9 [%]
1
2
3
4
5
6
4a
4b
4c
4d
4e
4f
92
92
93
73
82
71[b]
[a] Isolated yield. Obtained as a mixture of isomers (epimeric at
sulfur). [b] X = NS(O)pTol.
[a] p-Tolylsulfinyl chloride was reisolated from Et2O as a yellow oil
in 87% yield.
was subjected to our standard annulation reaction, which
furnished 16 in 94% yield. Without protection of the pri-
mary alcohol we found that competing formation of a
seven-membered ring occurred, leading to a mixture of two
heterocycles. Finally, simultaneous deprotection of both the
trityl and sulfinamide groups was achieved with HCl in
Et2O, giving the morpholine hydrochloride 17 in 94% yield.
This material was converted into (S,S)-reboxetine,[16] thus
completing a formal synthesis of the drug (Scheme 5).
Conclusions
We have found that the p-tolylsulfinyl group is an ideal
amine protecting group in the synthesis of morpholines
from amino alcohols. Not only does it enable the annu-
Scheme 4. Proposed mechanism for the annulation reaction.
Scheme 5. Formal synthesis of (S,S)-reboxetine.
3158
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3156–3164

Sulfinamides as Amine Protecting Groups and Their Uses
troscopic data were consistent with those reported in the litera-
ture.[18,19]
lation reaction to proceed in high yield with the stable and
crystalline bromoethylsulfonium salt 1 but it is also very
easily deprotected to give the HCl salt of the morpholine.
Furthermore, we have developed a highly effective method
for installing the sulfinyl group onto primary amines. We
expect this will increase the use of the sulfinyl group as a
highly effective amine protecting group. Application of this
significantly improved annulation methodology has been
demonstrated in a formal synthesis of (S,S)-reboxetine.
4-Methylphenyl (4-Methylphenyl)sulfinyl Sulfone[11,20] (7a) and (7b):
In an open flask, sodium p-toluenesulfinate (3.40 g, 19.2 mmol,
1 equiv.) was added to thionyl chloride (1.40 mL, 19.2 mmol,
1 equiv.) in PE containing 12 drops of DMF. After the vigorous
reaction had ceased a second portion of sodium p-toluenesulfinate
(3.40 g, 19.2 mmol, 1 equiv.) was added and the reaction mixture
was stirred for 24 h at room temp. under nitrogen. If necessary
some additional PE was added to replace the solvent, which had
evaporated. The reaction was poured into ice–water and the pre-
cipitated solid was collected by filtration, washed with PE and
dried in vacuo to afford the named product as a white powder
(4.51 g, 80%). To obtain analytically pure samples, the compound
was dissolved in CH2Cl2 and the resulting suspension filtered. The
pure product was crystallized from the filtrate by addition of n-
hexane; m.p. 86–87 °C (from CH2Cl2/n-hexane) [ref.[11] 83–85 °C
Experimental Section
Sulfinyl Protection. General Method A:
A mixture of Et3N
(3.0 equiv.) and β-amino alcohol (1.0 equiv.) or diamine (0.5 equiv.)
3a–f in CH2Cl2 (0.5 m) was added dropwise over 5 min to a stirred
mixture of sulfinylating agent (2.2 equiv.) 6 or 7 in CH2Cl2 (0.5 m)
at 0 °C. The mixture was stirred at 0 °C for 1 h and then the ice
bath was removed and the reaction stirred at room temp. for a
further 3–4 h (Completion was monitored by TLC, EtOAc/PE, 1:1,
for near-disappearance of the mono-protected substrate). The mix-
ture was quenched with sat. aq. NaHCO3 (5 mL) and extracted
with CH2Cl2 (3ϫ 30 mL). The combined organic phases were dried
with MgSO4 before in vacuo solvent removal. The residue was dis-
solved in MeOH (0.1 m) and the stirred solution cooled to 0 °C. A
1 m solution of NaOH in MeOH (1.05 equiv. of base) was added
dropwise over 5 min and the reaction stirred for a further 5 min
(completion was monitored by TLC, 1:1 EtOAc/PE, for disappear-
ance of the bis-protected substrate). After completion, the reaction
was quenched with sat. aq. NaHCO3 (5 mL) and extracted with
CH2Cl2 (3ϫ 30 mL). The combined organic phases were dried with
MgSO4 before in vacuo solvent removal. The residue was purified
by flash chromatography (1:1 EtOAc/PE) to afford the N-mono-
protected amino alcohol or diamine 4a–f.
(CH Cl /n-hexane)]. IR (neat): ν = 2922–1653 (br. w, C–H),
˜
max
2
2
1590, 1488, 1401, 1383, 1321, 1292 cm–1. In CDCl3, compound 7 is
1
a mixture of isomers in rapid equilibrium; both isomers: H NMR
(400 MHz, CDCl3): δ = 7.04–8.00 (m, 8 H, ArH), 2.49/2.44/2.40
(3ϫ s, 6 H, 3ϫ ArCH3) ppm. 13C NMR (100 MHz, CDCl3): δ =
146.6 (C), 144.6 (C), 142.0 (C), 140.2 (C), 136.4 (CH), 133.0 (C),
130.1 (CH), 129.9 (CH), 129.3 (CH), 128.5 (CH), 127.4 (CH), 124.4
(C), 21.7 (CH3), 21.6 (CH3), 21.4 (CH3) ppm. MS (EI+): m/z = 278
[M – O]+, 155 [pTolSO2]+, 139 [pTol S(O)]+.
The spectroscopic data (1H) are consistent with those reported in
the literature.[11c]
N-(1-Hydroxy-2-methylpropan-2-yl)-4-methyl-N-(p-tolylsulfinyl)-
benzenesulfinamide (8a): According to general method A, 8a (a yel-
low oil) was identified by 1H NMR prior to treatment with NaOH/
MeOH. It was obtained as a 1:1 mixture of diastereoisomers. Rf
1
(EtOAc/PE, 1:1): 0.5. H NMR (400 MHz, CDCl3): δ = 7.50–7.63
(m, 8 H, ArH), 7.22–7.35 (m, 8 H, ArH), 4.23 (br. s, 1 H, OH),
4.15 (br. s, 1 H, OH), 3.95 (d, J = 9.8 Hz, 1 H, CHH), 3.92 (d, J
= 9.8 Hz, 1 H, CHH), 3.51 (d, J = 9.8 Hz, 1 H, CHH), 3.42 (d, J
= 9.8 Hz, 1 H, CHH), 2.41 (s, 6 H, 2ϫ ArCH3), 2.39 (s, 6 H, 2ϫ
ArCH3), 1.41 (s, 3 H, CH3), 1.37 (s, 3 H, CH3), 1.35 (s, 3 H, CH3),
1.35 (s, 3 H, CH3) ppm.
Annulation. General Method B: NaH (3.5 equiv., 60% in mineral
oil) and then bromoethylsulfonium triflate (1, 1.2 equiv.) were
slowly added (Caution: hydrogen gas is released) to a stirred solu-
tion of the N-sulfinyl-protected β-amino alcohol or diamine 4a–f
(1 equiv.) in CH2Cl2 at 0 °C. The reaction was stirred at 0 °C for
2 h, then warmed to room temperature and stirred for an additional
14 h. The mixture was quenched with water (10 mL) and extracted
with CH2Cl2 (3ϫ 30 mL). The combined organic phases were dried
with MgSO4 and concentrated in vacuo. The residue was purified
by flash chromatography (1:1 EtOAc/PE) to give N-sulfinyl-pro-
tected morpholines or piperazine 9a–f.
N-(1-Hydroxy-2-methylpropan-2-yl)-4-methylbenzenesulfinamide
(4a): According to general method A, using either 4-methylphenyl
(4-methylphenyl)sulfinyl sulfone (7; 783 mg, 2.66 mmol) or 4-meth-
ylbenzene-1-sulfinyl chloride (6; 465 mg, 2.66 mmol), 2-amino-2-
methylpropan-1-ol (108 mg, 1.21 mmol) and Et3N (0.51 mL,
3.6 mmol) in a total volume of 5 mL of CH2Cl2. The residue was
dissolved in MeOH (12 mL) and a 1 m NaOH solution in MeOH
(1.27 mL) was added dropwise. This afforded the sulfinamide
[255 mg, 93% (from 7) or 261 mg, 95% (from 6)] as a yellow oil.
Deprotection. General Method C: N-Sulfinyl-protected morpholine
9a or 9e was treated with 10 equiv. of HCl in Et2O (2 m) and stirred
for 10 min, during which morpholine hydrochloride precipitated.
The now slightly yellow Et2O solution (containing sulfinyl chloride
6) was decanted by syringe. The precipitate was washed twice with
small amounts of Et2O and dried in vacuo to afford pure morph-
oline hydrochloride 12a or 12e.
R (EtOAc/PE, 1:1): 0.2. IR (neat): ν
= 3240–3380 (O–H and
˜
f
max
N–H), 3050 (ArC–H), 2890–2970 (C–H), 952–1086 (S=O) cm–1. 1H
NMR (400 MHz, CDCl3): δ = 7.57 (d, J = 8.2 Hz, 2 H, ArH), 7.29
(d, J = 8.2 Hz, 2 H, ArH), 4.16 (br. s, 1 H, NH), 3.77 (br. s, 1 H,
OH), 3.54–3.67 (dd, J = 11.8, 7.0 Hz, 1 H, CH), 3.42 (dd, J = 11.8,
5.9 Hz, 1 H, CH), 2.41 (s, 3 H, ArCH3), 1.42 (s, 3 H, CH3), 1.22
(s, 3 H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 141.9 (C),
141.4 (C), 129.5 (CH), 125.5 (CH), 70.9 (CH2), 58.2 (C), 26.5
(CH3), 23.3 (CH3), 21.3 (ArCH3) ppm. MS (ESI+): m/z = 250 [M
+ Na]+. HRMS (ESI+): calcd. for C11H17NO2SNa+ [M + Na]+
250.0872; found 250.0872.
Protection/Sulfinylating Reagents
4-Methylbenzene-1-sulfinyl Chloride[18,19] (6): Sulfuryl chloride
(1.98 mL, 24.4 mmol, 3 equiv.) was added dropwise over 30 min to
a vigorously stirred solution of p-tolyl disulfide (2.00 g, 8.1 mmol)
in acetic acid (0.93 mL, 16 mmol, 2 equiv.) at –40 °C. The mixture
was stirred for 3 h at –40 °C and then warmed to +35 °C for 1 h.
Acetyl chloride was carefully removed in vacuo to afford the pure
product (1.40 g, 99%) as a bright-yellow oil. Stored at –20 °C under
argon, the compound was stable for approximately 48 h. The spec-
N-[(S)-1-Hydroxy-3-phenylpropan-2-yl]-4-methylbenzenesulfinamide
(4b): According to general method A, using 4-methylphenyl (4-
methylphenyl)sulfinyl sulfone (7; 556 mg, 1.89 mmol), (S)-2-amino-
Eur. J. Org. Chem. 2011, 3156–3164
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3159

V. K. Aggarwal et al.
3-phenylpropan-1-ol (130 mg, 0.86 mmol) and Et3N (0.36 mL, 3.63 (m, 2 H, mix.), 3.29–3.42 (m, 1 H, CHHO), 3.14–3.27 (m, 1
FULL PAPER
2.6 mmol) in a total volume of 3.5 mL of CH2Cl2. The residue was
dissolved in MeOH (9 mL) and a 1 m NaOH solution in MeOH
(0.9 mL) was added dropwise. This afforded the sulfinamide
(199 mg, 80%) as a pale-yellow gum after work-up as a 1:1 mixture
H, NCH), 2.76 (dddd, J = 9.7, 8.3, 5.6, 2.4 Hz, 1 H, NCH), 2.40
(s, 6 H, ArCH3, mix.), 1.77–1.96 (dqq, J = 5.6, 6.8, 6.8 Hz, 1 H,
CHMe2), 1.55–1.74 (dqq, J = 5.6, 6.8, 6.8 Hz, 1 H, CHMe2), 1.01
(d, J = 6.8 Hz, 3 H, CH3, min.), 0.95 (d, J = 6.8 Hz, 3 H, CH3,
min.), 0.79 (d, J = 6.8 Hz, 3 H, CH3, maj.), 0.72 (d, J = 6.8 Hz, 3
H, CH3, maj.) ppm. 13C NMR (101 MHz, CDCl3): 141.9 (C), 141.6
(C), 141.5 (C), 138.3 (C), 129.6 (CH), 129.4 (CH), 126.3 (CH),
125.5 (CH), 65.7 (CH), 64.6 (CH2), 64.3 (CH2), 61.8 (CH), 30.6
(CH), 30.2 (CH), 21.29 (CH3), 21.28 (CH3), 19.8 (CH3), 19.6
of diastereoisomers. R (EtOAc/PE, 1:1): 0.3. IR (neat): ν
=
˜
f
max
3200–3300 (O–H and N–H), 3020 (ArC–H), 2855–2921 (C–H),
941–1080 (S=O) cm–1. Both diastereoisomers: 1H NMR (400 MHz,
CDCl3): δ = 7.09–7.41 (m, 16 H, ArH, mix), 6.91 (dd, J = 6.6,
2.9 Hz, 2 H, ArH, mix), 5.16 (d, J = 9.3 Hz, 1 H), 4.69 (d, J =
9.3 Hz, 1 H), 3.48–3.84 (m, 4 H), 3.40 (dd, J = 11.6, 7.6 Hz, 1 H), (CH3), 18.3 (CH3), 18.0 (CH3) ppm. MS (CI+): m/z = 242 [M +
3.15–3.28 (m, 1 H), 2.82–3.00 (m, 2 H, CH2Ph), 2.55–2.77 (m, 2
H, CH2Ph), 2.39 (s, 3 H, ArCH3), 2.37 (s, 3 H, ArCH3) ppm. 13C
NMR (100 MHz, CDCl3): δ = 141.5 (C), 141.2 (C), 141.0 (C), 138.1
(C), 138.0 (C), 137.4 (C), 129.40 (CH), 129.37 (CH), 129.31 (CH),
129.29 (CH), 128.3 (CH), 128.2 (CH), 126.34 (CH), 126.30 (CH),
126.1 (CH), 125.6 (CH), 65.14 (CH2OH), 65.12 (CH2OH), 60.4
(CH), 57.9 (CH), 38.9 (CH2Ph), 38.4 (CH2Ph), 21.2 (CH3), 21.1
(CH3) ppm. MS (ESI+): m/z = 290 [M + H]+, 242, 150, 139
[pTolS(O)]+. HRMS (ESI+): calcd. for C16H20NO2S+ [M + H]+
290.1215; found 290.1213.
H]+, 225, 139 [pTolS(O)]+, 102, 86. HRMS (CI+): calcd. for
C12H20NO2S [M + H]+ 242.1215; found 242.1214.
N-[(S)-1-Hydroxypropan-2-yl]-4-methylbenzenesulfinamide (4e): Ac-
cording to general method A, using 4-methylphenyl (4-meth-
ylphenyl)sulfinyl sulfone (7; 1.29 g, 4.4 mmol), (S)-2-aminopropan-
1-ol (150 mg, 2.0 mmol) and Et3N (0.84 mL, 6.0 mmol) in a total
volume of 8 mL of CH2Cl2. The residue was dissolved in MeOH
(18 mL) and a 1 m NaOH solution in MeOH (2.0 mL) was added
dropwise. After work-up, this afforded the sulfinamide (388 mg,
91 %) as a clear oil as a 1.2:1 mixture of diastereoisomers. Rf
(EtOAc/PE, 1:1): 0.2. IR (neat): ν
= 3200–3390 (O–H and N–
˜
max
N-[(1R,2S)-1-Hydroxy-1-phenylpropan-2-yl]-4-methylbenzenesulfin-
amide (4c): According to general method A using 4-methylphenyl
(4-methylphenyl)sulfinyl sulfone (7; 783 mg, 2.66 mmol), (1R,2S)-
2-amino-1-phenylpropan-1-ol (183 mg, 1.21 mmol) and Et3N
(0.51 mL, 3.6 mmol) in a total volume of 5 mL of CH2Cl2. The
residue was dissolved in MeOH (12 mL) and a 1 m NaOH solution
in MeOH (1.27 mL) was added dropwise. This afforded the sulfina-
mide (315 mg, 81%) as a clear oil after work-up as a 1.3:1 mixture
H), 2870–2958 (C–H), 1015–1085 (S=O) cm–1 1 H NMR
.
(400 MHz, CDCl3): δ = 7.48–7.60 (4 H, m, ArH, mix.), 7.19–7.34
(m, 4 H, ArH, mix.), 4.97 (d, J = 9.0 Hz, 1 H, NH), 4.57 (br. s, 2
H, NH and OH), 3.89 (br. s, 1 H, OH), 3.37–3.67 (4 H, CH2, mix.),
3.23–3.32 (m, 1 H, CH), 3.08–3.22 (m, 1 H, CH), 2.40 (s, 3 H,
ArCH3, maj.) 2.38 (s, 3 H, ArCH3, min.), 1.24 (d, J = 6.6 Hz, 3 H,
CH3, min.), 1.03 (d, J = 6.8 Hz, 3 H, CH3, maj.) ppm. 13C NMR
(101 MHz, CDCl3): δ = 141.5 (C), 141.33 (C), 141.27 (C), 139.0
(C), 129.6 (CH), 129.5 (CH), 126.2 (CH), 125.6 (CH), 67.2 (CH2),
66.7 (CH2), 53.8 (CH), 52.4 (CH), 21.2 (ArCH3), 18.5 (CH3), 18.2
(CH3) ppm. MS (CI+): m/z = 214 [M + H]+, 197, 166, 139
[pTolS(O)]+. HRMS (CI+): calcd. for C10H16NO2S [M + H]+
214.0902; found 214.0901.
of diastereoisomers. R (EtOAc/PE, 4:6): 0.35. IR (neat): ν
=
˜
f
max
3240–3370 (O–H and N–H), 3050 (ArC–H), 2850–2924 (C–H),
969–1085 (S=O) cm–1. Both diastereoisomers: 1H NMR (400 MHz,
CDCl3): δ = 7.47–7.67 (m, 4 H, ArH, mix.), 7.11–7.42 (m, 14 H,
ArH, mix.), 5.29 (d, J = 7.9 Hz, 1 H, NH, min.), 4.78 (br. s, 1 H,
NH, maj.), 4.62 (d, J = 9.2 Hz, 2 H, PhCH and br. s, OH, mix.),
4.49 (d, J = 9.7 Hz, 1 H, PhCH, min.), 4.39 (br. s, 1 H, OH, min.),
3.70 (m, 1 H, NCH, maj.), 3.29–3.49 (m, 1 H, NCH, min.), 2.39
(s, 3 H, ArCH3, min.), 2.38 (s, 3 H, ArCH3, maj.), 1.06 (d, J =
6.8 Hz, 3 H, CH3, maj.), 0.90 (d, J = 7.0 Hz, 3 H, CH3, min.) ppm.
13C NMR (100 MHz, CDCl3): δ = 141.4 (C), 141.32 (C), 141.26
(C), 140.5 (C), 140.1 (C), 139.0 (C), 129.5 (CH), 129.4 (CH), 127.9
(CH), 127.3 (CH), 127.1 (CH), 126.9 (CH), 126.3 (CH), 126.2
(CH), 125.6 (CH), 76.2 (PhCH), 75.0 (PhCH), 56.9 (CH), 55.2
(CH), 21.2 (ArCH3), 17.8 (CH3), 16.4 (CH3) ppm. MS (CI+): m/z
= 290 [M + H]+, 272, 209, 139 [pTolS(O)]+. HRMS (CI+): calcd.
for C16H19NO2SH+ [M + H]+ 290.1215; found 290.1224.
(؎)-N,NЈ-(Cyclohexane-1,2-diyl)bis(4-methylbenzenesulfinamide)
(4f): According to general method A, using 4-methylphenyl (4-
methylphenyl)sulfinyl sulfone (7; 783 mg, 2.66 mmol), (Ϯ)-trans-cy-
clohexane-1,2-diamine (69 mg, 0.61 mmol) and Et3N (0.51 mL,
3.6 mmol) in a total volume of 5 mL of CH2Cl2. The residue was
dissolved in MeOH (12 mL) and a 1 m NaOH solution in MeOH
(1.27 mL) was added dropwise. After work-up, this afforded the
sulfinamide (197 mg, 84%) as a yellow oil as an approximate
1:6:6:1 mixture of diastereoisomers. Rf (EtOAc/PE, 1:1): 0.17. IR
(neat): ν
= 3170 (N–H), 3050 (ArC–H), 2858–2928 (C–H),
˜
max
1016–1087 (S=O) cm–1. Two major diastereoisomers: 1H NMR
(400 MHz, CDCl3): δ = 7.34–7.71 (m, 8 H, ArCH, mix.), 7.08–7.26
(m, 8 H, ArCH, mix.), 5.60 (d, J = 4.8 Hz, 2 H, NH), 5.08 (d, J =
7.9 Hz, 2 H, NH), 2.93 (m, 2 H, 2ϫ NCH), 2.65–2.80 (m, 2 H, 2ϫ
NCH), 2.41 (s, 6 H, CH3, maj.), 2.39 (s, 6 H, CH3, maj.), 2.16 (dd,
J = 11.9, 2.7 Hz, 2 H, CH2), 1.59–1.73 (m, 2 H, CH2), 1.46–1.57
(m, 4 H, CH2), 1.10–1.32 (m, 6 H, CH2), 0.79–1.28 (m, 2 H,
CH2) ppm. 13C NMR (100 MHz, CDCl3): δ = 141.9 (C), 141.3 (C),
141.1 (C), 140.5 (C), 129.5 (CH), 129.3 (CH), 126.1 (CH), 125.2
(CH), 57.8 (NCH), 54.6 (NCH), 35.0 (CH2), 34.8 (CH2), 24.9
(CH2), 24.4 (CH2), 21.4 (CH3), 21.3 (CH3) ppm. Distinguishable
The spectroscopic data are comparable to those reported in the
literature (1R,2R and 1S,2S diastereomers).[10]
N-(؎)-(1-Hydroxy-3-methylbutan-2-yl)-4-methylbenzenesulfinamide
(4d): According to general method A, using 4-methylphenyl (4-
methylphenyl)sulfinyl sulfone (7; 783 mg, 2.66 mmol), (Ϯ)-2-
amino-3-methylbutan-1-ol (125 mg, 1.21 mmol) and Et3N
(0.51 mL, 3.6 mmol) in a total volume of 5 mL of CH2Cl2. The
residue was dissolved in MeOH (12 mL) and a 1 m NaOH solution
in MeOH (1.27 mL) was added dropwise. After work-up, this af-
forded the sulfinamide (272 mg, 93%) as a clear oil as a 1.2:1 mix-
1
peaks of minor diastereoisomers: H NMR (400 MHz, CDCl3): δ
= 2.44 (s, 3 H, CH3, min.), 2.31 (s, 3 H, CH3, min.) ppm. 13C NMR
(100 MHz, CDCl3): δ = 129.6 (CH), 129.5 (CH), 127.1 (CH), 125.6
(CH) ppm. MS (ESI+): m/z = 391 [M + H]+. HRMS (ESI+): calcd.
for C20H27N2O2S2 [M + H]+ 391.1523; found 391.1508.
ture of diastereoisomers. R (EtOAc/PE, 1:1): 0.4. IR (neat): ν
˜
f
max
= 3200–3390 (O–H and N–H), 3050 (ArC–H), 2870–2958 (C–H),
1
1015–1100 (S=O) cm–1. H NMR (400 MHz, CDCl3): δ = 7.61 (d,
J = 8.3 Hz, 2 H, ArH), 7.54 (d, J = 8.3 Hz, 2 H, ArH), 7.21–7.34
(m, 4 H, ArH, mix.), 4.64–4.84 (m, 2 H, NH, mix.), 4.13 (d, J =
10.1 Hz, 1 H, OH), 3.67–3.92 (m, 2 H, CHHOH and OH), 3.44–
3,3-Dimethyl-4-(p-tolylsulfinyl)morpholine (9a): According to gene-
ral method B, using N-(1-hydroxy-2-methylpropan-2-yl)-4-methyl-
3160
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3156–3164

Sulfinamides as Amine Protecting Groups and Their Uses
benzenesulfinamide (4a; 50 mg, 0.22 mmol, 1 equiv.), bromoethyl-
sulfonium triflate (1; 1.2 equiv.) and NaH (3.5 equiv.) afforded N-
sulfinyl-protected morpholine 9a (51 mg, 92%) as a brown oil. Rf
(؎)-3-Isopropyl-4-(p-tolylsulfinyl)morpholine (9d): According to ge-
neral method B, using N-(1-hydroxy-3-methylbutan-2-yl)-4-methyl-
benzenesulfinamide (4d; 50 mg, 0.20 mmol, 1 equiv., dr 1.2:1), bro-
(EtOAc/PE, 1:1): 0.43. IR (neat): νmax = 3020 (ArC–H), 2852–2970 moethylsulfonium triflate (1; 1.2 equiv.) and NaH (3.5 equiv.) af-
˜
(C–H), 984–1118 (S=O) cm–1. 1H NMR (400 MHz, CDCl3): δ = forded N-sulfinyl-protected morpholine 9d (40.4 mg, 73%) as a
7.47 (d, J = 8.3 Hz, 2 H, ArH), 7.23 (d, J = 8.3 Hz, 2 H, ArH),
3.76 (dddd, J = 11.1, 3.4, 2.7, 0.6 Hz, 1 H, OCHH), 3.41 (dd, J =
brown oil as a 1.4:1 mixture of diastereoisomers. Rf (EtOAc/PE,
1:1): 0.7. IR (neat): νmax = 3025 (ArC–H), 2772–2972 (C–H), 1007–
˜
1
11.1, 0.6 Hz, 1 H, OCHH), 3.27–3.37 (m, 2 H, OCHH and 1207 (S=O) cm–1. H NMR (400 MHz, CDCl3): δ = 7.50–7.60 (m,
OCHH), 3.16 (ddd, J = 12.6, 11.1, 3.4 Hz, 1 H, NCHH), 2.43 (dt,
J = 12.6, 2.7 Hz, 1 H, NCHH), 2.37 (s, 3 H, ArCH3), 1.54 (s, 3 H,
4 H, ArH, mix.), 7.27–7.34 (m, 4 H, ArH, mix.), 3.80–3.95 (m, 4
H, mix.), 3.69–3.79 (m, 2 H, mix.), 3.63 (ddd, J = 10.9, 3.2, 3.2 Hz,
CH3), 1.43 (s, 3 H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 1 H, NCH, maj.), 3.57 (ddd, J = 11.2, 3.8, 3.8 Hz, 1 H, NCH,
140.9 (C), 140.4 (C), 129.5 (CH), 126.4 (CH), 77.8 (OCH2), 67.6 min.), 3.43 (ddd, J = 14.1, 10.6, 3.7 Hz, 1 H, NCHH, maj.), 3.10–
(OCH2), 56.7 (NC), 36.9 (NCH2), 25.5 (CH3), 22.1 (CH3), 21.3 3.19 (m, 2 H, mix.), 2.98 (dt, J = 13.7, 3.8 Hz, 1 H, NCHH, min.),
(CH3) ppm. MS (ESI+): m/z = 276 [M + Na]+. HRMS (ESI+):
2.75–2.86 (m, 2 H, mix.), 2.47–2.59 (m, 1 H, isoprop-CH, min.),
2.42 (s, 6 H, 2ϫ ArCH3, mix.), 2.30 (m, 1 H, isoprop-CH, maj.),
1.08 (d, J = 6.8 Hz, 3 H, CH3, min.), 1.05 (d, J = 6.8 Hz, 3 H,
CH3, min.), 0.87 (d, J = 6.6 Hz, 3 H, CH3, maj.), 0.76 (d, J =
6.8 Hz, 3 H, CH3, maj.) ppm. 13C NMR (100 MHz, CDCl3): δ =
141.3 (C), 141.2 (C), 140.6 (C), 140.5 (C), 129.6 (CH), 129.3 (CH),
126.27 (CH), 126.25 (CH), 69.0 (CH2), 68.0 (CH2), 67.7 (CH2),
67.3 (CH2), 64.9 (CH), 61.3 (CH), 44.8 (CH2), 40.6 (CH2), 26.3
(CH), 25.4 (CH), 21.35 (CH3), 21.32 (CH3), 20.31 (CH3), 20.28
(CH3), 19.8 (CH3), 18.8 (CH3) ppm. MS (CI+): m/z = 268
[M + H]+, 224, 195, 139 [pTolS(O)]+, 128. HRMS (CI+): calcd. for
C14H22NO2S+ [M + H]+ 268.1371; found 268.1368.
calcd. for C13H19NO2SNa+ [M + Na]+ 276.1038; found 276.1028.
(3S)-3-Benzyl-4-(p-tolylsulfinyl)morpholine (9b): According to gene-
ral method B, using N-[(S)-1-hydroxy-3-phenylpropan-2-yl]-4-
methylbenzenesulfinamide (4b; 64.0 mg, 0.22 mmol, 1 equiv., dr
1:1), bromoethylsulfonium triflate (1; 1.2 equiv.) and NaH
(3.5 equiv.) afforded N-sulfinyl-protected morpholine 9b (64 mg,
92%) as a clear oil as a 1:1 mixture of diastereoisomers. Rf (EtOAc/
PE, 1:1): 0.4. IR (neat): ν
= 3025 (ArC–H), 2860–2952 (C–H),
˜
max
982–1104 (S=O) cm–1. Both diastereoisomers: 1H NMR (500 MHz,
CDCl3): δ = 7.38 (d, J = 8.2 Hz, 2 H, ArH), 7.25 (d, J = 7.6 Hz, 2
H, ArH), 7.09–7.22 (m, 10 H, ArH), 7.04–7.08 (m, 2 H, ArH), 6.94
(d, J = 6.9 Hz, 2 H, ArH), 3.50–3.95 (m, 11 H, mix.), 3.36 (dd, J
= 13.8, 7.7 Hz, 1 H, CH), 3.14 (dd, J = 13.4, 10.0 Hz, 1 H, CH),
2.86–3.00 (m, 5 H, mix.), 2.34 (s, 3 H, ArCH3), 2.30 (s, 3 H,
ArCH3) ppm. 13C NMR (125 MHz, CDCl3): δ = 141.19 (C), 141.18
(C), 140.1 (C), 140.0 (C), 138.2 (C), 138.0 (C), 129.5 (CH), 129.4
(CH), 129.3 (CH), 129.2 (CH), 128.6 (CH), 128.5 (CH), 126.5
(CH), 126.4 (CH), 126.3 (CH), 126.2 (CH), 70.0 (CH2O), 68.9
(3S)-3-Methyl-4-(p-tolylsulfinyl)morpholine (9e): According to ge-
neral method B, using N-[(S)-1-hydroxypropan-2-yl]-4-methylben-
zenesulfinamide (4e; 100 mg, 0.47 mmol, 1 equiv., dr 1:1), bromo-
ethylsulfonium triflate (1; 1.2 equiv.) and NaH (3.5 equiv.) afforded
N-sulfinyl-protected morpholine 9e (92 mg, 82%) as a clear oil as
a 1:1 mixture of diastereoisomers. Rf (EtOAc/PE, 1:1): 0.4. IR
(neat): ν
= 3077 (ArC–H), 2856–2969 (C–H), 1062–1114
˜
max
(CH2O), 68.1 (CH2O), 67.4 (CH2O), 59.2 (CH), 57.6 (CH), 42.4 (S=O) cm–1. H NMR (400 MHz, CDCl3): δ = 7.48–7.58 (m, 4 H,
(CH2Ph), 40.5 (CH2Ph), 36.2 (NCH2), 35.8 (NCH2), 21.3 (CH3), ArH, mix.), 7.28–7.35 (m, 4 H, ArH, mix.), 3.69–3.86 (m, 4 H,
21.2 (CH3) ppm. MS (ESI+): m/z = 316 [M + H]+, 224, 176, 139 mix.), 3.35–3.62 (m, 6 H, mix.), 3.30 (dd, J = 11.2, 8.6 Hz, 1 H,
1
[pTolS(O)]+. HRMS (ESI+): calcd. for C18H22NO2S+ [M + H]+
316.1371; found 316.1384.
CHH), 3.01 (ddd, J = 12.7, 9.7, 3.3 Hz, 1 H, CHH), 2.63–2.75 (m,
2 H, mix.), 2.41 (s, 6 H, 2ϫ ArCH3), 1.41 (d, J = 6.8 Hz, 3 H,
CH3), 1.40 (d, J = 6.4 Hz, 3 H, CH3) ppm. 13C NMR (100 MHz,
CDCl3): δ = 141.22 (C), 141.18 (C), 140.0 (C), 139.5 (C), 129.6
(CH), 129.5 (CH), 126.3 (CH), 126.1 (CH), 73.1 (CH2), 72.6 (CH2),
67.3 (CH2), 67.0 (CH2), 52.9 (CH), 52.8 (CH), 41.1 (CH2), 40.7
(CH2), 21.30 (CH3), 21.29 (CH3), 15.8 (CH3), 15.7 (CH3) ppm. MS
(CI+): m/z = 240 [M + H]+, 153, 139 [pTolS(O)]+, 125, 102. HRMS
(CI+): calcd. for C12H18NO2S+ [M + H]+ 240.1058; found 240.1062.
(2R,3S)-3-Methyl-2-phenyl-4-(p-tolylsulfinyl)morpholine (9c): Ac-
cording to general method B, using N-[(1R,2S)-1-hydroxy-1-phen-
ylpropan-2-yl]-4-methylbenzenesulfinamide
(4c;
71.0 mg,
0.25 mmol, 1 equiv., dr 1.3:1), bromoethylsulfonium triflate (1;
1.2 equiv.) and NaH (3.5 equiv.) afforded N-sulfinyl-protected
morpholine 9c (74 mg, 93%) as a brown oil. Isolated as a 1.3:1
mixture of diastereoisomers. Rf (EtOAc/PE, 1:1): 0.5. IR (neat):
ν
˜
max = 3020 (ArC–H), 2861–2940 (C–H), 912–1122 (S=O) cm–1. 1H (؎)-1,4-Bis(p-tolylsulfinyl)decahydroquinoxaline (9f): According to
NMR (500 MHz, CDCl3): δ = 7.56–7.64 (m, 4 H, ArH, mix.), 7.20–
7.37 (m, 14 H, ArH, mix.), 4.81 (d, J = 2.9 Hz, 1 H, OCHPh, min.),
general method B, using N,NЈ-(cyclohexane-1,2-diyl)bis(4-methyl-
benzenesulfinamide) (4f; 50 mg, 0.13 mmol, 1 equiv., dr 1:6:6:1),
4.75 (d, J = 2.9 Hz, 1 H, OCHPh, maj.), 4.05 (m, 2 H, mix.), 3.90 bromoethylsulfonium triflate (1; 1.2 equiv.) and NaH (3.5 equiv.)
(m, 1 H, OCHH, mix.), 3.78–3.81 (m, 2 H, mix.), 3.72 (ddd, J = to afford N-sulfinyl-protected piperazine 9f (38 mg, 71%) as a
12.4, 11.4, 3.1 Hz, 1 H, NCHH, min.), 3.50 (ddd, J = 13.3, 12.4, brown oil as an approximate 1:6:6:1 mixture of diastereoisomers.
3.7 Hz, 1 H, NCHH, min.), 3.34 (ddd, J = 13.6, 12.3, 3.8 Hz, 1 H, R (EtOAc/PE, 1:1): 0.4. IR (neat): ν
= 3050 (ArC–H), 2858–
˜
f
max
NCHH, maj.), 3.11 (dd, J = 13.6, 3.2 Hz, 1 H, NCHH, maj.), 2.88
(dd, J = 13.3, 3.1 Hz, 1 H, NCHH, min.), 2.45 (s, 3 H, ArCH3,
2928 (C–H), 1016–1087 (S=O) cm–1. Two major diastereoisomers:
1H NMR (400 MHz, CDCl3): δ = 7.40–7.51 (m, 8 H, ArH, mix.),
maj.), 2.43 (s, 3 H, ArCH3, min.), 1.08 (d, J = 6.8 Hz, 3 H, CH3, 7.23–7.29 (m, 8 H, ArH, mix.), 3.33 (td, J = 9.8, 3.7 Hz, 2 H),
maj.), 1.03 (d, J = 6.8 Hz, 3 H, CH3, min.) ppm. 13C NMR 3.21–3.28 (m, 2 H), 3.05–3.19 (m, 2 H), 2.96 (ddd, J = 12.1, 9.2,
(125 MHz, CDCl3): δ = 141.30 (C), 141.25 (C), 140.28 (C), 140.25 3.5 Hz, 2 H), 2.76–2.87 (m, 2 H), 2.62–2.74 (m, 2 H), 2.40 (s, 2ϫ
(C), 139.2 (C), 139.1 (C), 129.7 (CH), 129.6 (CH), 128.2 (CH), 3 H, ArCH3, maj.), 2.38 (s, 2ϫ 3 H, ArCH3, maj.), 2.24–2.34 (m,
128.1 (CH), 127.3 (CH), 127.2 (CH), 126.30 (CH), 126.26 (CH),
125.4 (CH), 125.3 (CH), 81.3 (CHPh), 80.8 (CHPh), 68.9 (OCH2),
4 H), 1.89–2.05 (m, 8 H), 1.37–1.60 (m, 4 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 141.03 (C), 140.96 (C), 140.4 (C), 140.0
67.7 (OCH2), 57.3 (NCHMe), 56.8 (NCHMe), 40.1 (NCH2), 38.9 (C), 129.54 (CH), 129.49 (CH), 126.35 (CH), 125.9 (CH), 64.9
(NCH2), 21.33 (ArCH3), 21.30 (ArCH3), 12.0 (CH3), 11.3
(CH3) ppm. MS (ESI+): m/z = 338 [M + Na]+. HRMS (ESI+):
calcd. for C18H21NO2SNa+ [M + Na]+ 338.1180; found 338.1185.
(NCH), 63.0 (NCH), 44.4 (CH2), 43.3 (CH2), 30.1 (CH2), 29.7
(CH2), 25.3 (CH2), 24.4 (CH2), 21.29 (CH3), 21.25 (CH3) ppm. Dis-
tinguishable peaks of minor diastereoisomers: 1H NMR (400 MHz,
Eur. J. Org. Chem. 2011, 3156–3164
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3161

V. K. Aggarwal et al.
FULL PAPER
CDCl3): δ = 2.40 (s, 2ϫ 3 H, ArCH3, min.), 2.39 (s, 2ϫ 3 H,
and NH), 2890–2922 (C–H), 909–1085 (S=O) cm–1. Both diastereo-
ArCH3, min.) ppm. 13C NMR (100 MHz, CDCl3): δ = 129.63 (CH, isomers: 1H NMR (400 MHz, CDCl3): δ = 7.54 (d, J = 8.2 Hz, 2ϫ
min.), 129.59 (CH, min.) 126.30 (CH, min.), 126.0 (CH, min.) ppm. 2 H, ArH, mix.), 7.29 (d, J = 8.2 Hz, 2ϫ 2 H, ArH, mix.), 5.45 (d,
MS (ESI+): m/z = 417 [M + H]+, 139 [pTolS(O)]+. HRMS (ESI+):
J = 7.5 Hz, 1 H, 5.0 Hz, NH), 5.35 (t, J = 6.1 Hz, 1 H, NH), 3.67–
3.76 (m, 2 H, 2ϫ CHOH, mix.), 3.54–3.63 (m, 3 H, 3ϫ CHHOH,
mix.) 3.43–3.51 (m, 1 H, CHHOH, mix.), 2.87–3.14 (m, 4 H, 4ϫ
+
calcd. for C22H29N2O2S2 [M + H]+ 417.1677; found 417.1665.
3,3-Dimethylmorpholin-4-ium Chloride (12a): According to general
method C, using 3,3-dimethyl-4-(p-tolylsulfinyl)morpholine (9a;
33.8 mg, 0.13 mmol) and HCl in Et2O (2 m, 0.66 mL, 1.3 mmol,
10 equiv.) afforded pure morpholine hydrochloride 12a (18.6 mg,
NCHH, mix.), 2.40 (2ϫ
3
H, s, ArCH3) ppm. 13C NMR
(100 MHz, CDCl3): δ = 141.53 (C), 141.52 (C), 139.3 (C), 139.2
(C), 129.73 (CH), 129.71 (CH), 126.24 (CH), 126.22 (CH), 70.8
(CH), 70.1 (CH), 64.4 (CH2OH), 64.1 (CH2OH), 45.3 (NCH2), 45.0
(NCH2), 21.29 (ArCH3), 21.27 (ArCH3) ppm. MS (CI+): m/z = 230
[M + H]+. HRMS (CI+): calcd. for C10H16NO3S+ [M + H]+
230.0851; found 230.0841.
93%) as a white salt; m.p. 194–195 °C (directly from synthesis) (ref.
[6]
196–197 °C). IR (neat): ν
= 3356 (N–H), 2511 (NH2+), 1639
˜
max
(N+–H), 1384–1463 (C–H) cm–1. 1H NMR (400 MHz, [D4]meth-
anol): δ = 3.87 (m, 2 H, OCH2), 3.61 (s, 2 H, CCH2O), 3.27 (t, J
= 5.4 Hz, 2 H, NCH2), 1.41 (s, 6 H, 2ϫ CH3) ppm. 13C NMR
(100 MHz, [D4]methanol): δ = 74.4 (CH2O), 64.9 (CH2O), 55.2 (C),
40.5 (NCH2), 21.9 (CH3) ppm. MS (CI+): m/z = 116 [M – Cl]+,
93.0, 65.0, 57.0. HRMS (CI+): calcd. for C6H14NO+ [M – Cl]+
116.1075; found 116.1076.
N-[(2S)-2-Hydroxy-3-(trityloxy)propyl]-4-methylbenzenesulfinamide
(15): A stirred mixture of N-[(2S)-2,3-dihydroxypropyl]-4-methyl-
benzenesulfinamide (14; 100 mg, 0.44 mmol, 1 equiv.), Et3N
(0.09 mL, 0.7 mmol, 1.5 equiv.) and DMAP (2.2 mg, 0.02 mmol,
0.04 equiv.) in DMF (0.5 m, 0.8 mL) was treated with Ph3CCl
(134 mg, 0.48 mmol, 1.1 equiv.). After 24 h, the reaction was
quenched with ice–water (1 mL) and extracted with CH2Cl2 (3ϫ
30 mL). The combined organic phases were washed with brine
(10 mL), dried with MgSO4 and concentrated in vacuo. Flash
chromatography, eluting with 6:4 EtOAc/PE, afforded the product
(166 mg, 80%) as a clear oil as a 1:1 mixture of diastereoisomers.
The 1H NMR spectroscopic data are comparable to those reported
in the literature (δH recorded in [D6]DMSO).[21]
(S)-3-Methylmorpholin-4-ium Chloride (12e): According to general
method C, using (3S)-3-methyl-4-(p-tolylsulfinyl)morpholine (9e;
38 mg, 0.16 mmol) and HCl in Et2O (2 m, 0.8 mL, 1.6 mmol,
10 equiv.) afforded pure morpholine hydrochloride 12e (20 mg,
93%) as a white salt; m.p. Ͼ200 °C (directly from synthesis). [α]2D0
R (EtOAc/PE, 6:4): 0.3. IR (neat): ν
= 3296 (OH and NH),
˜
f
max
2872–3057 (C–H, aromatic and aliphatic), 1960 (C–H aromatic
overtones), 1665 and 1596 (C–C aromatic), 1448 (C–O–H) 1016–
= +3.0 (c = 1.0, MeOH). IR (neat): ν
= 3372 (br., N–H), 2988
˜
max
(C–H), 2508 (br., NH2+), 1639 (N+–H), 1306–1452 (C–H) cm–1. 1H 1085 (S=O and C–O) cm–1. Both diastereoisomers: 1H NMR
NMR (400 MHz, [D4]methanol): δ = 3.91–4.02 (m, 2 H, 2ϫ
OCHH), 3.74 (ddd, J = 12.9, 11.3, 2.7 Hz, 1 H, OCHH), 3.44–3.52
(400 MHz, CDCl3): δ = 6.98–7.54 (m, 38 H, ArH, mix.), 4.38–4.68
(m, 2 H), 3.77–4.11 (m, 2 H), 3.67 (m, 2 H, 2ϫ CH, mix.), 3.20
(m, 1 H), 3.34–3.44 (m, 1 H), 3.29 (dt, J = 13.1, 2.4 Hz, 1 H, (dd, J = 10.1, 4.7 Hz, 1 H, TrOCHH), 2.84–3.10 (m, 7 H, mix.),
NCHH), 3.20 (ddd, J = 12.9, 11.4, 3.9 Hz, 1 H, NCHH), 1.26 (d, 2.31 (s, 3 H, ArCH3), 2.30 (s, 3 H, ArCH3) ppm. 13C NMR
J = 6.6 Hz, 3 H, CH3) ppm. 13C NMR (100 MHz, [D4]methanol):
(100 MHz, CDCl3): δ = 143.6 (C), 143.5 (C), 141.30 (C), 141.28
= 70.5 (CH2), 64.5 (CH2), 52.3 (CH), 44.5 (CH2), 14.6 (C), 139.9 (C), 139.1 (C), 129.54 (CH), 129.51 (CH), 128.4 (CH),
δ
(CH3) ppm. MS (CI+): m/z = 102 [M – Cl]+, 86, 72. HRMS (CI+): 127.9 (CH), 127.7 (CH), 127.1 (CH), 126.9 (CH), 126.2 (CH), 126.0
calcd. for C5H12NO+ [M – Cl]+ 102.0919; found 102.0920.
(CH), 86.7 (C), 86.6 (C), 69.5 (CH), 67.9 (CH), 65.1 (CH2), 64.5
(CH2), 46.6 (CH2), 46.1 (CH2), 21.3 (CH3), 21.2 (CH3) ppm. MS
(ESI+): m/z = 494 [M + Na]+, 243. HRMS (ESI+): calcd. for
C29H29NO3SNa+ [M + Na]+ 494.1764; found 494.1760.
The 1H NMR spectroscopic data are comparable to those reported
in the literature (other enantiomer reported).[22]
Formal Synthesis of (S,S)-Reboxetine
(2S)-4-(p-Tolylsulfinyl)-2-[(trityloxy)methyl]morpholine (16): Bromo-
N-[(2S)-2,3-Dihydroxypropyl]-4-methylbenzenesulfinamide (14): 4- ethylsulfonium triflate (1; 176 mg, 0.40 mmol, 1.25 equiv.) was
Methylphenyl (4-methylphenyl)sulfinyl sulfone (712 mg, slowly (H2 is set free) added to a stirred solution of N-[(S)-2-hy-
droxy-3-(trityloxy)propyl]-4-methylbenzenesulfinamide (15;
2.42 mmol, 7) or 4-methylbenzenesulfinyl chloride (422 mg,
2.42 mmol, 6) was added portion/dropwise over 5 min to a stirred
mixture of (S)-3-aminopropane-1,2-diol (13; 100 mg, 1.1 mmol)
150 mg, 0.32 mmol, 1 equiv.) and NaH (45 mg, 1.1 mmol,
3.5 equiv.) in CH2Cl2 (1.3 mL, 0.25 m) at 0 °C. The reaction was
and Et3N (0.46 mL, 3.3 mmol) in DMF (0.25 m, 4.4 mL) at 0 °C. stirred at 0 °C for 2 h and then being allowed to warm up to room
The reaction was stirred at 0 °C for 1 h before being allowed to
warm up and stirred for another 24 h (with 7) or 3 h (with 6). The
mixture was injected on to the top of a long silica plug and eluted
with PE (400 mL) to remove impurities and most of the DMF. The
eluting solvent was changed to 95:5 EtOAc/MeOH and the col-
lected fraction was concentrated in vacuo to afford a mixture of
the bis-protected amino diol in a small amount of DMF. DMF was
carefully removed under high vacuum, assisted by an oil bath,
heated to 80 °C, using a trap setup with a room-temperature (water
bath) trap. The resulting yellow residue was dissolved in water
(10 mL) and 1 m aq. NaOH (1.1 mL) was added (monitored by
temperature and stirred for an additional 14 h. The mixture was
quenched with water (5 mL) and extracted with CH2Cl2 (3ϫ
30 mL). The combined organic phases were dried with MgSO4 and
concentrated in vacuo. The residue was purified by flash
chromatography, eluting with 1:3 EtOAc/PE, to give the product
(150 mg, 94%) as a clear oil in a 1:1 mixture of diastereoisomers.
R (EtOAc/PE, 1:3): 0.33. IR (neat): ν
= 2862–3057 (C–H, ar.
˜
f
max
and aliph.), 1960 (C–H Ar.), 1596 (C–C Ar.), 1068–1090 (S=O and
1
C–O) cm–1. H NMR (400 MHz, CDCl3): δ = 7.48 (d, J = 7.6 Hz,
4 H, ArH, mix.), 7.31–7.39 (m, 6 H, ArH, mix.), 7.06–7.30 (m, 28
H, ArH, mix.), 3.55–3.92 (m, 4 H, CH, OCH2), 3.19–3.55 (m, 3 H,
TLC, 95:5 EtOAc/MeOH). The mixture was stirred for 15 min and OCH2, NCH2, mix.), 2.80–3.19 (m, 9 H, OCH2, NCH2, NCH2,
then concentrated in vacuo. The resulting residue was purified by
flash chromatography, eluting with 95:5 EtOAc/MeOH, to give the
monoprotected product [209 mg, 83% (with 7) and 231 mg, 92%
(with 6)] as a clear oil as a 1:1 mixture of diastereoisomers. Rf
mix.), 2.64 (dd, J = 12.2, 10.5 Hz, 2 H, NCH2) 2.36 (s, 3 H,
ArCH3), 2.34 (s, 3 H, ArCH3) ppm. 13C NMR (100 MHz, CDCl3):
δ = 143.7 (C), 143.6 (C), 141.49 (C), 141.46 (C), 139.3 (C), 139.2
(C), 129.6 (CH), 128.65 (CH), 128.55 (CH), 127.85 (CH), 127.76
(CH), 127.1 (CH), 127.0 (CH), 126.18 (CH), 126.15 (CH), 86.7
(EtOAc/MeOH, 92.5:7.5): 0.3. IR (neat): ν
= 3200–3300 (OH
˜
max
3162
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3156–3164

Sulfinamides as Amine Protecting Groups and Their Uses
McGarrigle, V. K. Aggarwal, Org. Lett. 2009, 11, 257–260; d)
J. Bornholdt, J. Felding, J. L. Kristensen, J. Org. Chem. 2010,
75, 7454–7457; e) J. An, N. J. Chang, L. D. Song, Y. Q. Jin, Y.
Ma, J. R. Chen, W. J. Xiao, Chem. Commun. 2011, 47, 1869–
1871; for the generation of morpholines via vinyl selenones,
see: f) L. Bagnoli, C. Scarponi, M. G. Rossi, L. Testaferri, M.
Tiecco, Chem. Eur. J. 2011, 17, 993–999.
(Trityl-C), 86.5 (Trityl-C), 75.5 (CH), 74.9 (CH), 66.9 (CH2), 66.3
(CH2), 64.5 (CH2), 64.3 (CH2), 51.1 (CH2), 47.8 (CH2), 46.0 (CH2),
42.7 (CH2), 21.44 (CH3), 21.38 (CH3) ppm. MS (ESI+): m/z = 520
[M + Na]+, 498 [M + H]+, 243. HRMS (ESI+): calcd. for
C31H31NO3SNa+ [M + Na]+ 520.1927; found 520.1916.
(2S)-Morpholin-2-ylmethanol: A solution of (2S)-4-(p-tolylsulfinyl)-
2-[(trityloxy)methyl]morpholine (16; 120 mg, 0.241 mmol, 1 equiv.)
in CH2Cl2 (0.48 mL, 0.5 m) was treated with 2 m HCl in Et2O
(1.2 mL, 2.4 mmol, 10 equiv.) at room temp. under nitrogen. After
1 h, a drop of methanol was added to the vigorously stirred reac-
tion and stirring was continued for 0.5 h. During this time the col-
our of the solution turned slightly yellow due to the formation of
p-tolylsulfinyl chloride (6). Furthermore, precipitation of the hy-
drochloride salt 17 as a coating inside the flask was observed. The
solvent was removed by syringe and in the same manner the mix-
ture was washed with Et2O (2ϫ 2 mL). Drying in vacuo afforded
(S)-2-(hydroxymethyl)morpholine hydrochloride (17) as a white so-
lid (36.3 mg, 94%). The product was deprotonated by addition of
NaOH (9.1 mg, 1 equiv.) to a solution of the hydrochloride salt in
CD3OD. Following solvent removal in vacuo, the resulting mixture
of the reported product and NaCl was subjected to NMR analysis
for comparison with previously reported data.
[3]
For related work on the application of vinyl sulfonium salts in
synthesis, see: a) K. H. Kim, L. S. Jimenez, Tetrahedron: Asym-
metry 2001, 12, 999–1005; b) H. Yamanaka, J. Matsuo, A. Ka-
wana, T. Mukaiyama, Chem. Lett. 2003, 32, 626–627; c) J. Mat-
suo, H. Yamanaka, A. Kawana, T. Mukaiyama, Chem. Lett.
2003, 32, 392–393; d) H. Yamanaka, J. Matsuo, A. Kawana, T.
Mukaiyama, ARKIVOC 2004, 42–65; e) M. G. Unthank, N.
Hussain, V. K. Aggarwal, Angew. Chem. 2006, 118, 7224–7227;
Angew. Chem. Int. Ed. 2006, 45, 7066–7069; f) C. G. Kokotos,
E. M. McGarrigle, V. K. Aggarwal, Synlett 2008, 2191–2195;
g) M. G. Unthank, B. Tavassoli, V. K. Aggarwal, Org. Lett.
2008, 10, 1501–1504; h) C. S. Xie, D. Y. Han, J. H. Liu, T. Xie,
Synlett 2009, 3155–3158; i) S. Catalan-Munoz, C. A. Muller,
S. V. Ley, Eur. J. Org. Chem. 2010, 183–190; j) R. Maeda, K.
Ooyama, R. Anno, M. Shiosaki, T. Azema, T. Hanamoto, Org.
Lett. 2010, 12, 2548–2550; k) C. S. Xie, D. Y. Han, Y. Hu, J. H.
Liu, T. A. Xie, Tetrahedron Lett. 2010, 51, 5238–5241; l) M.
Yar, M. G. Unthank, E. M. McGarrigle, V. K. Aggarwal,
Chem. Asian J. 2011, 6, 372–375.
M. Yar, S. P. Fritz, P. J. Gates, E. M. McGarrigle, V. K. Aggar-
wal, unpublished results.
For the use of p-toluenesulfinimines, see: a) P. Zhou, B. C.
Chen, F. A. Davis, Tetrahedron 2004, 60, 8003–8030; for an ex-
cellent autobiographical outline of this chemistry, see: b) F. A.
Davis, J. Org. Chem. 2006, 71, 8993–9003.
For the use of tert-butylsulfinimines, see: a) J. A. Ellman, T. D.
Owens, T. P. Tang, Acc. Chem. Res. 2002, 35, 984–995; b) J. A.
Ellman, Pure Appl. Chem. 2003, 75, 39–46; c) M. T. Robak,
M. A. Herbage, J. A. Ellman, Chem. Rev. 2010, 110, 3600–
3740.
For the general uses of sulfinimines, see: a) C. H. Senanayake,
D. Krishnamurthy, Z. H. Lu, Z. X. Han, I. Gallou, Aldrichim-
ica Acta 2005, 38, 93–104; b) D. Morton, R. A. Stockman,
Tetrahedron 2006, 62, 8869–8905.
a) V. K. Aggarwal, N. Barbero, E. M. McGarrigle, G. Mickle,
R. Navas, J. R. Suarez, M. G. Unthank, M. Yar, Tetrahedron
Lett. 2009, 50, 3482–3484; b) M. Wakayama, J. A. Ellman, J.
Org. Chem. 2009, 74, 2646–2650; c) F. A. Davis, T. Ramachan-
dar, Y. F. Zhang, J. Chai, H. Qiu, J. H. Deng, V. Velvadapu,
Tetrahedron Lett. 2010, 51, 4042–4044.
For previous examples of the synthesis of sulfinamides, see: a)
C. W. Schroeck, C. R. Johnson, J. Am. Chem. Soc. 1971, 93,
5305; b) M. Furukawa, T. Okawara, Synthesis 1976, 339–340;
c) M. Uchino, M. Sekiya, Chem. Pharm. Bull. 1980, 28, 126–
133; d) P. Sun, S. M. Weinreb, M. Y. Shang, J. Org. Chem. 1997,
62, 8604–8608; e) D. A. Cogan, G. C. Liu, K. J. Kim, B. J.
Backes, J. A. Ellman, J. Am. Chem. Soc. 1998, 120, 8011–8019;
f) S. Gaillard, C. Papamicael, G. Dupas, F. Marsais, V. Lev-
acher, Tetrahedron 2005, 61, 8138–8147; g) J. Coulomb, V. Cer-
tal, L. Fensterbank, E. Lacote, M. Malacria, Angew. Chem.
2006, 118, 649–653; Angew. Chem. Int. Ed. 2006, 45, 633–637;
h) M. Harmata, P. G. Zheng, C. F. Huang, M. G. Gomes, W. J.
Ying, K. O. Ranyanil, G. Balan, N. L. Calkins, J. Org. Chem.
2007, 72, 683–685; i) M. Harmata, P. Zheng, Org. Lett. 2007,
9, 5251–5253, and references cited therein.
The spectroscopic data are consistent with those reported in the
literature.[16]
[4]
[5]
(S)-tert-Butyl 2-(Hydroxymethyl)morpholine-4-carboxylate: To ver-
ify its stereochemistry, 17 (19.9 mg, 0.13 mmol) was converted into
the Boc-protected morpholine according to a known procedure
(Boc2O, NEt3, CH2Cl2).[23] After purification by flash chromatog-
raphy, eluting with 1:1 EtOAc/hexane, this procedure afforded 19
(20.3 mg, 72%). Rf (EtOAc/hexane, 1:1): 0.2; [α]1D9 = +18.8 (c = 1.0,
CHCl3) [ref.[16] +20.7 (c = 1.01, CHCl3)].
[6]
The spectroscopic data are consistent with those reported in the
literature.[16,23]
[7]
[8]
Supporting Information (see footnote on the first page of this arti-
cle): General directions, experimental procedures, spectroscopic
and analytical data for all compounds.
Acknowledgments
M. Y. thanks the Higher Education Commission (HEC) of Paki-
stan and the University of Bristol for support of a studentship.
A. M. thanks the HEC of Pakistan for a 6 month travel grant.
We thank Dr. Jonathan Fray (Nottingham University) for useful
discussions. V. K. A. thanks the Royal Society of Chemistry (RSC)
for a Wolfson Research Merit Award and the Engineering and
Physical Sciences Research Council (EPSRC) for a Senior Research
Fellowship.
[9]
[1] For a review, see: R. Wijtmans, M. K. S. Vink, H. E. Schoe-
maker, F. L. van Delft, R. H. Blaauw, F. P. J. T. Rutjes, Synthe-
sis 2004, 641–662; for a recent example, see: a) B. A. Lanman,
A. G. Myers, Org. Lett. 2004, 6, 1045–1047; b) M. C. Wilkin-
son, Tetrahedron Lett. 2005, 46, 4773–4775; c) M. DЈhooghe, T.
Vanlangendonck, K. W. Tornroos, N. De Kimpe, J. Org. Chem.
2006, 71, 4678–4681; d) R. Pedrosa, C. Andres, P. Mendiguchi,
J. Nieto, J. Org. Chem. 2006, 71, 8854–8863; e) M. Breuning,
M. Winnacker, M. Steiner, Eur. J. Org. Chem. 2007, 2100–2106.
[2] For the generation of morpholines via the vinyl sulfonium salt,
see: a) M. Yar, E. M. McGarrigle, V. K. Aggarwal, Angew.
Chem. 2008, 120, 3844–3846; Angew. Chem. Int. Ed. 2008, 47,
3784–3786; b) M. Hansch, O. Illa, E. M. McGarrigle, V. K.
Aggarwal, Chem. Asian J. 2008, 3, 1657–1663; c) M. Yar, E. M.
[10]
[11]
J. L. G. Ruano, A. Parra, F. Yuste, V. M. Mastranzo, Synthesis
2008, 311–319, and references cited therein.
For the reactions of this reagent with enolates, see: a) H. Bred-
ereck, A. Wagner, H. Beck, R. J. Klein, Chem. Ber. 1960, 93,
2736–2742; b) R. B. Boar, A. C. Patel, Synthesis 1982, 584–586;
c) R. Caputo, C. Ferreri, L. Longobardo, G. Palumbo, S. Ped-
atella, Synth. Commun. 1993, 23, 1515–1522; d) H. W. Pinnick,
Eur. J. Org. Chem. 2011, 3156–3164
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3163

V. K. Aggarwal et al.
FULL PAPER
M. A. Reynolds, R. T. Mcdonald, W. D. Brewster, J. Org.
Chem. 1980, 45, 930–932.
[17] For the previous synthesis of (S,S)-reboxetine, see: a) P. Mel-
loni, A. Dellatorre, E. Lazzari, G. Mazzini, M. Meroni, Tetra-
hedron 1985, 41, 1393–1399; b) M. Cebula, K. E. Henegar,
US2005/187388, 2005; Chem. Abstr. 2005, 143, 229866; c) S. A.
Siddiqui, U. C. Narkhede, R. J. Lahoti, K. V. Srinivasan, Syn-
lett 2006, 1771–1773; d) G D. Tamagnan, D. Alagille, Molecu-
lar Neuroimaging, WO2007/5935, 2007; Chem. Abstr. 2007,
146, 121754; e) T. X. Metro, D. G. Pardo, J. Cossy, J. Org.
Chem. 2008, 73, 707–710; f) R. S. Reddy, P. V. Chouthaiwale,
G. Suryavanshi, V. B. Chavan, A. Sudalai, Chem. Commun.
2010, 46, 5012–5014.
[12] 1H and 13C NMR indicates the existence of this compound as
a (inconsequential) mixture of two isomers in CDCl3. For a
previous discussion, see: J. L. Kice, N. E. Pawlowski, J. Am.
Chem. Soc. 1964, 86, 4898, and references cited therein.
[13] We also prepared the iPr and tBu sulfinamides, but they were
not effective in the annulation reaction with bromoethylsulfon-
ium triflate 1.
[18] J. H. Youn, R. Herrmann, Tetrahedron Lett. 1986, 27, 1493–
1494.
[19] J. H. Youn, R. Herrmann, Synthesis 1987, 72–73.
[20] C. Roussel, C. Popescu, L. Fabre, Carbohydr. Res. 1996, 282,
307–313.
[14] a) K. M. Foote, J. W. M. Nissink, AstraZeneca, WO2010/
73034, 2010; Chem. Abstr. 2010 ,153, 145523; b) L. H. Pettus,
S. Xu, G.-Q. Cao, P. P. Chakrabarti, R. M. Rzasa, K. Sham,
R. P. Wurz, D. Zhang, S. Middleton, B. Henkle, M. H. Plant,
C. J. M. Saris, L. Sherman, L. M. Wong, D. A. Powers, Y.
Tudor, V. Yu, M. R. Lee, R. Syed, F. Hsieh, A. Tasker, J. Med.
Chem. 2008, 51, 6280–6292; c) P. I. Arvidsson, E. Arzel, J. Bur-
rows, M. Claesson, C. Ray, T. Rein, D. Rotticci, P. Soederman,
AstraZeneca, WO2007/40438, 2007; Chem. Abstr. 2007, 146,
401974.
[15] For the biological activity of reboxetine, see: J. C. Fleishaker,
Clin. Pharmacokinet. 2000, 39, 413–427.
[16] E. Brenner, R. M. Baldwin, G. Tamagnan, Org. Lett. 2005, 7,
937–939.
[21] H. Miyake, K. Take, S. Shigenaga, H. Azami, H. Sasaki, Y.
Eikyu, K. Nakai, J. Ishida, T. Manabe, N. Konishi, T. Tera-
saka, US2003/114668, 2003; Chem. Abstr. 1999, 130, 81525.
[22] J. M. Axten, C. W. Blackledge, G. P. Brady, Y. G. Feng, S. W.
Grant, J. R. Medina, W. H. Miller, S. P. Romeril, Glaxosmithk-
line, WO2010/59658, 2010; Chem. Abstr. 2010, 153, 11671.
[23] I. Collins, J. C. Reader, T. P. Matthews, K. M. Cheung, N. Pro-
isy, D. H. Williams, S. S. Klair, J. E. Scanlon, N. Piton, G. J.
Addison, M. Cherry, Cancer Research Techology Ltd,
WO2009/44162, 2009; Chem. Abstr. 2009, 150, 398578.
Received: March 9, 2011
Published Online: May 10, 2011
3164
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3156–3164