Rearrangement of N-tert-butanesulfinyl α-halo imines with alkoxides to N-tert-butanesulfinyl 2-amino acetals as precursors of N-protected and N-unprotected α-amino carbonyl compounds

Article abstract of DOI:10.1021/jo300752c

Reaction of N-tert-butanesulfinyl α-halo imines with alkoxides afforded new N-tert-butanesulfinyl 2-amino acetals in good to excellent yield. These N-tert-butanesulfinyl 2-amino acetals are convenient precursors for the TMSOTf-promoted synthesis of the co

Full text of DOI:10.1021/jo300752c

Article
pubs.acs.org/joc
Rearrangement of N-tert-Butanesulfinyl α-Halo Imines with Alkoxides
to N-tert-Butanesulfinyl 2-Amino Acetals as Precursors of N-
Protected and N-Unprotected α-Amino Carbonyl Compounds
Filip Colpaert,† Sven Mangelinckx,† Bram Denolf, and Norbert De Kimpe*
Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links
653, B-9000 Ghent, Belgium
S
* Supporting Information
ABSTRACT: Reaction of N-tert-butanesulfinyl α-halo imines
with alkoxides afforded new N-tert-butanesulfinyl 2-amino
acetals in good to excellent yield. These N-tert-butanesulfinyl
2-amino acetals are convenient precursors for the TMSOTf-
promoted synthesis of the corresponding N-protected α-amino
aldehydes and ketones, as well as for the HCl-promoted
synthesis of 2-amino acetal hydrochlorides and α-amino
ketone and α-amino aldehyde hydrochlorides in high yield.
Via this method, an asymmetric synthesis of (S)-cathinone
hydrochloride (er 94:6) was achieved.
ment, led to the synthesis of very specific N-unprotected α-
amino ketones.9 Very recently, a useful route toward specific
α,α-unsubstituted N-sulfonyl α-amino ketones from terminal
alkynes was developed via a rhodium(II)-catalyzed denitroge-
native hydration reaction of the corresponding N-sulfonyl-
1,2,3-triazoles.1b
The utility of α-amino carbonyl compounds is not without
shortcomings, as nitrogen- or carbon-protecting groups are
usually needed in order to prevent undesired inter- and
intramolecular self-condensation reactions.1a−h,10 2-Amino
acetals are protected α-amino carbonyl compounds and are
known as useful synthetic building blocks for nitrogen-
containing heterocycles.11
In our research group, the reaction of α-halo imines with
alkoxides has been studied in detail, giving rise to a variety of 2-
alkoxyaziridine intermediates, 2-amino acetals, cyclopropyl-
amines, α-alkoxy ketones, imidates, and amides, among other
compounds.12 C-Oxygen-substituted aziridines are usually
unstable compounds and appear primarily as intermediates en
route to the final products.13 A related reaction of interest is the
Duhamel ring contraction of halogenated heterocyclic
enamines with sodium methoxide leading to 2-(dimethoxy-
methyl)azaheterocycles via bicyclic C-methoxy-substituted
aziridinium intermediates.12g,14 However, in general, the
nitrogen deprotection of the N-alkyl or N-aryl compounds
after reaction of α-halo imines with alkoxides provides a
limitation in the reported applications.
INTRODUCTION
■
α-Amino carbonyl compounds are important and versatile
compounds that are indispensable in the synthesis of nitrogen-
containing natural products and are widely used in the
pharmaceutical industry.1 Their utility stems from the broad
scope of synthetic transformations that are possible with both
the amino and carbonyl functional groups. Several α-amino
carbonyl compounds are also known for their metabolic roles in
health and disease,2 like aminoacetone, which is putatively
overproduced in patients with diabetes mellitus and cri-du-chat
syndrome3 and is also known as the penultimate precursor to
the antitumor agent Azinomycin A.4
Numerous syntheses of α-amino carbonyl compounds have
been developed, and new ones continue to be devised to
provide access to these important chemical building blocks.1a−h
However, most of these methods have their disadvantages. A
common preparation of α-amino ketones proceeds via
amination of α-halo ketones,1c−e in which side reactions such
as dehalogenation followed by Michael addition,1e Favorskii
type rearrangement,5 and Voigt−Amadori rearrangement1e
compete when certain combinations of substrates and amines
are used. Amination of α-hydroxy ketones for the synthesis of
α-amino ketones may give the formation of undesired crossover
products and is limited by the various substitution patterns
allowed in the substrates.6 The ring-opening of alkoxy epoxides
with amines resulted only in very specific α,α-dialkylated α-
aminoaryl ketones,7 while ring-opening of phenylsulfinyl
epoxides with amines was limited to some α-aminoalkyl
ketones and α-amino aldehydes.8 The Neber-rearrangement
of oxime tosylates and dimethylhydrazone methiodides to the
corresponding azirine intermediates, followed by acid treat-
Received: April 11, 2012
Published: June 29, 2012
© 2012 American Chemical Society
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Scheme 1. Reactivity of N-tert-Butanesulfinyl α-Halo Imines 1 toward Alkoxides
Table 1. Reaction of N-tert-Butanesulfinyl α-Chloro Imines 1a and 1b with NaOMe in MeOH
a
b
entry
NaOMe (equiv)
R1
temp (°C)/time (h)
3/5
dr 3
yield 5 (%)
1
2
3
4
5
6
7
8
3
3
3
3
1
3
3
3
Me
Me
Me
Me
Me
−78/1
rt/2
100:0
0:100
100:0
30:70
75:25
100:0
0:100
100:0
100:0
100:0
0:100
77:23
5a (81)
−40/2
41:59
52:48
50:50
62:48
−78 to rt/1
c
d
rt/1
4-ClC6H4
4-ClC6H4
4-ClC6H4
−78/1
rt/2
5b (93)
−40/1
57:43
58:42
57:43
+ −30/1
+ −20/1
+ −10/1
a
b
c
Determined via 1H NMR analysis of the crude reaction mixture. Isolated yield after purification via flash chromatography. 1 equiv of 1 M NaOMe
in MeOH was added to a solution of imine 1a in THF. Incomplete conversion of 63% of imine 1a to compounds 3 and 5.
d
Recently, our and other research groups prepared a variety of
chiral aziridines 2 with very good stereoselectivity via various
nucleophilic addition reactions across α-chlorinated N-tert-
butanesulfinyl imines 1.15 Nevertheless, the reactivity of α-
halogenated N-tert-butanesulfinyl imines 1 toward alkoxides has
never been studied. It was envisioned that reaction of N-tert-
butanesulfinyl α-halo imines 1 with alkoxides would result in
the synthesis of sulfinamides 3, which cyclize to N-tert-
butanesulfinyl 2-alkoxyaziridines 4, as interesting intermediates
for the formation of new N-tert-butanesulfinyl 2-amino acetals 5
(Scheme 1).
Only two synthetic methods for the synthesis of specific N-
sulfinyl 2-aminoacetals have been reported, one via a
condensation reaction of the corresponding N-sulfinyl imine,
possessing a 2-methyl-1,3-dioxolanyl group, with an ester
enolate,16 and a second via reduction of N-[1-
(triethoxymethyl)ethylidene]sulfinamide.17 The 2-amino ace-
tals 5, together with the corresponding N-tert-butanesulfinyl α-
amino aldehydes and ketones 6, could be elaborated as new
stable precursors for the synthesis of a variety of α-amino
carbonyl compounds 7 (Scheme 1).
Cathinone is the main active compound isolated from the
leaves of Catha edulis (Khat) and exhibits cardiovascular
activity, next to an activity similar to amphetamines and
dopamine.19 Herein, the developed synthetic pathway will be
also explored toward the asymmetric synthesis of cathinone.
The expected easy removal of the N-tert-butanesulfinyl group
at nitrogen is important from a practical viewpoint, especially as
compared to the less convenient deprotection reactions in
literature protocols. While the N-tert-butanesulfinyl group is
primarily used as a chiral directing and electron-withdrawing
group in the reactions of imines 1 with nucleophiles, herein the
N-sulfinyl group is currently mainly used as a practical N-
protective and stabilizing group (except for the asymmetric
synthesis of cathinone), comparable in reactivity to a Boc
group, sensu strictu.20
RESULTS AND DISCUSSION
■
Initially, the reactivity of N-tert-butanesulfinyl α-halo imines 1
toward alkoxides was studied with nonaromatic N-tert-
butanesulfinyl α-chloro imine 1a and aromatic N-tert-
butanesulfinyl α-chloro imine 1b in reactions with NaOMe
(1 M in MeOH) (Table 1).
Recently, Davis and co-workers reported the synthesis of N-
sulfinyl α-amino ketones via the addition of 2-lithio-1,3-
dithianes to enantiopure sulfinimines in an effort to achieve
the asymmetric synthesis of (S)-cathinone (Scheme 1).18 (S)-
As recently described by our research group, the synthesis of
the aromatic N-tert-butanesulfinyl α-chloro ketimines 1b,c, as
single E-isomers in 88−89% yield, was performed by
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condensation of the appropriate phenacyl chlorides with (Rs)-
tert-butanesulfinamide in the presence of 2 equiv of Ti(OEt)4 in
THF.15a,g The aliphatic N-tert-butanesulfinyl α-chloro ketimine
1a was obtained via a similar procedure starting from α-chloro
acetone in 63% yield with an E/Z-ratio of 85:15.15i
corresponding N-tert-butanesulfinyl 2-amino acetal 5b was
isolated in 93% yield after purification via flash chromatography
(Table 1, entry 7). In an effort to determine the temperature at
which sulfinamides 3 were transformed to N-sulfinyl 2-amino
acetals 5, the reaction of N-sulfinyl imine 1b with NaOMe was
repeated starting at −40 °C with a gradual increase of
temperature (Table 1, entry 8). When 3 equiv of 1 M
NaOMe in MeOH were added to N-sulfinyl imine 1b at −40
°C for 1 h, followed by stirring at −30 °C for 1 h and
subsequently at −20 °C for 1 h, sulfinamide 3b was formed
with a diastereomeric ratio of 57:43. Subsequent stirring at −10
°C for 1 h afforded a full conversion to the corresponding N-
tert-butanesulfinyl 2-amino acetal 5b, which indicates that the
conversion from sulfinamide 3b to acetal 5b proceeds readily
between −20 and −10 °C (entry 8). Subsequently, the
optimized reaction conditions leading to the synthesis of N-tert-
butanesulfinyl 2-amino acetals 5a and 5b were also applied to
aromatic N-sulfinyl α-chloroketimines 1c and 1f (R1 = C6H5,
2,4-Cl2C6H3), aromatic N-sulfinyl α-bromoketimines 1d,e (R1
= 4-MeOC6H4, 4-NO2C6H4), nonaromatic N-sulfinyl α-
bromoketimine 1g (R1 = iPr), and N-sulfinyl α-chloro
aldimines 1h,i (R1 = H). Furthermore, in addition to
NaOMe, NaOEt (0.75 M in EtOH) was also used as a
nucleophile in the corresponding alcohol as solvent (Table 2).
The initial reaction conditions involved the addition of 3
equiv of a freshly prepared 1 M solution of NaOMe in MeOH
to N-sulfinyl imine 1a at −78 °C and subsequent stirring for 1 h
at −78 °C (Table 1, entry 1). After aqueous workup, the
formation of N-tert-butanesulfinyl 2-chloro-1-methoxy-1-meth-
ylethylamine 3a with a diastereomeric ratio of 77:23 (1H NMR
analysis) was observed. Unfortunately, sulfinamide 3a was
unstable at room temperature and was smoothly converted
back to the corresponding N-sulfinyl imine 1a upon standing a
short time in CDCl3. The moderate diastereomeric ratio
obtained and the easy reversal of adduct 3 to starting imine 1
indicate that the equilibrated addition reaction is thermody-
namically controlled.
On the other hand, when 3 equiv of NaOMe (1 M in
MeOH) were added to N-sulfinyl imine 1a at room
temperature and the reaction mixture was stirred for 2 h, the
corresponding N-tert-butanesulfinyl 2-amino acetal 5a was
formed (Table 1, entry 2). After purification of the reaction
mixture via flash chromatography, N-tert-butanesulfinyl 2-
amino acetal 5a was isolated in 81% yield. The proposed
mechanism involves the formation of the corresponding N-
sulfinyl 2-methoxyaziridine 4a, which undergoes spontaneous
ring-opening, followed by attack of a second equivalent of
NaOMe.12g,h,l−n,13 Subsequently, in an effort to isolate or detect
the intermediate N-sulfinyl 2-methoxyaziridine 4a, some other
reaction conditions were tested. Repeating the reaction at −40
°C for 2 h afforded a full conversion to N-tert-butanesulfinyl 2-
chloro-1-methoxy-1-methylethylamine 3a with a reversed
diastereomeric ratio of 41:59 in comparison to the reaction
performed at −78 °C (Table 1, entry 3). Upon performing the
addition of NaOMe at −78 °C, after which the temperature was
allowed to warm up to room temperature for 1 h, a mixture of
sulfinamide 3a (dr 52:48) and N-tert-butanesulfinyl 2-amino
acetal 5a in a ratio of 30:70 was obtained (entry 4). Adding 1
equiv of NaOMe instead of 3 equiv to N-sulfinyl imine 1a at
room temperature in THF for 1 h resulted in an incomplete
conversion of 63% to a mixture of sulfinamide 3a (dr 50:50)
and 2-amino acetal 5a in a ratio of 75:25 (entry 5).
Unfortunately, no intermediate N-sulfinyl 2-methoxyaziridine
4a could be detected in any of these attempted reactions,
indicating the inherent instability of this highly activated
aziridine 4a.
Table 2. Synthesis of N-tert-Butanesulfinyl 2-Amino Acetals
5
time
(h)
yield 5
a
entry
X
imine 1
R1
R2
R3
(%)
1
Cl
Cl
Cl
Cl
Cl
Cl
Br
Br
Cl
Br
Cl
Cl
Cl
Cl
1a
1b
1a
1b
1c
1c
1d
1e
1f
Me
H
Me
Me
Et
2
2
5a (81)
5b (93)
5c (70)
5d (95)
5e (83)
5f (97)
5g (94)
5h (97)
5i (93)
5j (76)
2
4-ClC6H4
H
3
Me
H
2
4
4-ClC6H4
H
Et
2
5
C6H5
H
Me
Et
2
6
C6H5
H
2
7
4-MeOC6H4
H
Me
Me
Me
Me
Me
Et
2
8
4-NO2C6H4
H
2
9
2,4-Cl2C6H3
H
2
10
11
12
13
14
1g
1h
1h
1i
iPr
H
H
H
H
H
2
b
Me
Me
Et
Et
16
16
16
16
5k (96)
5l (77)
5m (57)
5n (28)
Me
Et
Furthermore, when the substrate was altered from non-
aromatic N-sulfinyl imine 1a to aromatic N-sulfinyl imine 1b
and 3 equiv of 1 M NaOMe was added at −78 °C for 1 h, the
corresponding N-tert-butanesulfinyl 2-chloro-1-methoxy-1-phe-
nylethylamine 3b was obtained after aqueous work up in a
diastereomeric ratio of 62:48 (Table 1, entry 6). Similarly,
sulfinamide 3b was unstable and reverted to the corresponding
N-sulfinyl imine 1b upon standing overnight at room
temperature in CDCl3. Direct treatment of sulfinamide 3b
with various bases, either 5 equiv of K2CO3 in acetonitrile at
room temperature for 1 h or 1.5 equiv of LiHMDS in THF at 0
°C for 1 h, did not afford the desired N-sulfinyl 2-
methoxyaziridine 4b, and instead N-sulfinyl imine 1b was
recovered as the major product.
1i
a
b
Isolated yield after purification via flash chromatography. Perform-
ing the same experiment starting with racemic N-sulfinyl aldimine 1h
led to the isolation of racemic acetal 5k in 97% yield.
N-tert-Butanesulfinyl α-chloro and α-bromo imines 1d−i were
synthesized in 77−92% yield via condensation of the
appropriate α-halo ketones and aldehydes with (Rs)-tert-
butanesulfinamide in the presence of 2 equiv of Ti(OEt)4 in
THF.15a,c,g Noteworthy, since the N-sulfinyl group is only used
as a N-protective and stabilizing group, the experiment for the
synthesis of N-tert-butanesulfinyl 2-amino acetal 5k (R1 = H; R2
= R3 = Me) was also repeated starting from racemic N-sulfinyl
aldimine 1h, leading to the same result as obtained via the
treatment of chiral aldimine (RS)-1h with NaOMe.
When 3 equiv of 1 M NaOMe in MeOH were added to N-
sulfinyl imine 1b at room temperature for 2 h, the
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A wide variety of N-tert-butanesulfinyl 2-amino acetals 5 were
obtained in good to excellent yields after purification via flash
chromatography, except for N-sulfinyl 2-amino acetal 5n, which
was isolated in only 28% yield because of the formation of the
corresponding N-sulfinyl α-amino aldehyde 6i upon column
chromatography (Table 2, entry 14 and Table 3).
TMSOTf in CH2Cl2 at −78 °C for 0.5 h afforded the
corresponding N-tert-butanesulfinyl α-amino ketones 6a−g in
71 to 99% yield (Table 3, entries 1−10).
N-tert-Butanesulfinyl α-amino aldehydes 6h,i were obtained
in quantitative yield from N-tert-butanesulfinyl 2-amino acetals
5k−n (R1 = H) via a similar procedure, but this time TMSOTf
had to be added at room temperature for 0.5 h to achieve full
conversion (Table 3, entries 11−14). Exceptionally, to obtain
full conversion of N-tert-butanesulfinyl 2-amino acetal 5k into
N-tert-butanesulfinyl α-amino aldehyde 6h, after addition of 3
equiv of TMSOTf at room temperature for 30 min, two
additional 3 equiv aliquots of TMSOTf were added
subsequently at room temperature for 30 min, which afforded
N-tert-butanesulfinyl α-amino aldehyde 6h in 95% yield (Table
3, entry 11). Increasing the amount of TMSOTf to 10 equiv at
room temperature for 30 min or increasing to reflux
temperature did not afford full conversion of acetal 5k into
aldehyde 6h.
Table 3. Synthesis of N-tert-Butanesulfinyl α-Amino Ketones
6a−g and α-Amino Aldehydes 6h,i
entry
R1
R2
R3
temp (°C)
yield 6 (%)
1
Me
Me
H
Me
Et
−78
−78
−78
−78
−78
−78
−78
−78
−78
−78
rt
6a (91)
6a (88)
6b (99)
6b (92)
6c (82)
6c (71)
6d (99)
6e (99)
6f (99)
6g (76)
2
H
3
4-ClC6H4
H
Me
Et
When N-sulfinyl 2-amino acetal 5e (R1 = Ph; R2 = H; R3 =
Me) was treated with aqueous 6 M HCl in a two-phase system
with CH2Cl2 at room temperature for 1 h, the corresponding
N-sulfinyl α-amino ketone 6c was also formed but was
contaminated with unidentified side products.
In a following step, N-tert-butanesulfinyl α-amino carbonyl
compounds 6 were treated with HCl to achieve N-deprotection
and formation of the corresponding hydrochlorides of α-amino
ketones and aldehydes 7 (Table 4 and Scheme 2). When N-tert-
4
4-ClC6H4
H
5
C6H5
H
Me
Et
6
C6H5
H
7
4-MeOC6H4
H
Me
Me
Me
Me
Me
Et
8
4-NO2C6H4
H
9
2,4-Cl2C6H3
H
10
11
12
13
14
iPr
H
H
H
H
H
a
Me
Me
Et
Et
6h (95)
rt
6h (99)
6i (99)
6i (99)
Me
Et
rt
rt
Table 4. HCl-Promoted N-Deprotection of N-tert-
Butanesulfinyl α-Amino Carbonyl Compounds 6
a
For obtaining full conversion of 5k into 6h, after addition of 3 equiv
of TMSOTf at room temperature for 30 min, additionally two times 3
equiv of TMSOTf were added subsequently at room temperature for
30 min.
The substitution pattern of aromatic N-sulfinyl α-haloketi-
mines 1b−f seemed not to have any peculiar effect on the
reaction with alkoxides to the corresponding N-tert-butane-
sulfinyl 2-amino acetals 5 (Table 2, entries 5−9). Even when
the more steric N-sulfinyl α-chloroketimine 1f (R1 = 2,4-
Cl2C6H3) was used as an aromatic substrate with an ortho
substitution, the desired N-tert-butanesulfinyl 2-amino acetal 5i
was obtained in 93% yield (Table 2, entry 9). The more bulky
isopropyl group of nonaromatic N-sulfinyl α-bromoketimine 1g
(R1 = iPr) had no detrimental effect and the corresponding N-
tert-butanesulfinyl 2-amino acetal 5j was isolated in 76% yield
(Table 2, entry 10). When N-tert-butanesulfinyl α-chloro
aldimines 1h,i were used as substrates, the reaction time had
to be increased to 16 h to obtain a full conversion (Table 2,
entries 11−14). The latter observation indicates that the
aziridines 4 without an additional substituent at the 2-position
(R1 = H) are more difficult to form and/or are less prone
toward ring-opening and further conversion to α-amino acetals
5. Noteworthy, when KOtBu was used as nucleophile instead of
NaOMe and NaOEt in reaction with N-tert-butanesulfinyl α-
chloro aldimines 1h,i, complex mixtures were obtained, which
contained the corresponding α,β-unsaturated imines and α,β-
unsaturated aldehydes in various ratios.
a
entry
R1
R2
yield 7 (%)
1
2
3
4
5
6
7
8
Me
H
H
H
H
H
H
H
7a (96)
7b (99)
7c (92)
7d (95)
7e (88)
7f (86)
7g (94)
4-ClC6H4
C6H5
4-MeOC6H4
4-NO2C6H4
2,4-Cl2C6H3
iPr
b
H
Et
b
7i + 8c
a
Isolated yield after precipitation in Et2O. An inseparable mixture of
α-amino aldehyde hydrochloride 7i and 2-amino acetal hydrochloride
8c in a ratio of 75:25 was obtained.
butanesulfinyl α-amino ketones 6a−g (R1 ≠ H) were treated
with 10 equiv of 3 M HCl in MeOH at room temperature for 1
h, the corresponding α-amino ketone hydrochlorides 7a−g
were obtained in excellent yields (86−99%) after precipitation
in dry Et2O (Table 4, entries 1−7).
Unfortunately, when N-tert-butanesulfinyl α-amino aldehyde
6i (R1 = H) was treated with 3 M HCl in MeOH under the
same conditions, an inseparable mixture of the desired α-amino
aldehyde hydrochloride 7i and the corresponding 2-amino
acetal hydrochloride 8c in a ratio of 75:25 was obtained.
Therefore, N-tert-butanesulfinyl α-amino aldehydes 6h,i (R1 =
H) were treated with 10 equiv of anhydrous 4 M HCl in
dioxane for 1 h at room temperature in Et2O (Scheme 2).
When N-tert-butanesulfinyl α-amino aldehyde 6h (R2 = Me)
was treated with HCl in dioxane, the formation of the desired
In a following step, the N-tert-butanesulfinyl 2-amino acetals
5 could be easily transformed to the corresponding N-tert-
butanesulfinyl α-amino ketones 6a−g and N-tert-butanesulfinyl
α-amino aldehydes 6h,i via a mild TMSOTf-promoted cleavage
of the acetal functionality (Table 3).21 Treatment of N-tert-
butanesulfinyl 2-amino acetals 5a−j (R1 ≠ H) with 3 equiv of
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Scheme 2. HCl-Promoted N-Deprotection of N-tert-Butanesulfinyl α-Amino Aldehydes 6h,i
α-amino aldehyde hydrochloride 7h was observed, but because
of its high hygroscopicity, aldehyde 7h was partially converted
to the corresponding hydrate 9a. The equilibrium of α-amino
aldehydes and the corresponding hydrates is known in the
literature.22 Furthermore, a partial cyclotrimerization of
aldehyde 7h to the corresponding 1,3,5-trioxane 10a was also
observed, in addition to some other unidentified side products.
In the literature it is known that the equilibrium between the
free aldehyde and its trimer is highly temperature-dependent.23
Treatment of N-tert-butanesulfinyl α-amino aldehyde 6i (R2 =
Et) with HCl in dioxane afforded the corresponding α-amino
aldehyde hydrochloride 7i. In contrast to the synthesis of α-
amino aldehyde hydrochloride 7h, in this case no cyclo-
trimerization was observed and aldehyde 7i was isolated in 77%
yield after precipitation in Et2O. Nevertheless, during 1H NMR
analysis, α-amino aldehyde hydrochloride 7i was partially
5k−m (R1 = H) were treated with 3 M HCl in MeOH under
the same conditions, the corresponding 2-amino acetal
hydrochlorides 8a−c were obtained in 75−95% yields (Table
5, entries 7−9).
Treatment of N-tert-butanesulfinyl 2-amino acetal 5n (R1 =
H) with HCl in MeOH under the same conditions afforded an
inseparable mixture of the corresponding α-amino aldehyde
hydrochloride 7i and 2-amino acetal hydrochloride 8d (Table
5, entry 10). In an effort to obtain α-amino aldehyde
hydrochloride 7h (R1 = H, R2 = Me), N-tert-butanesulfinyl 2-
amino acetal 5k was treated with a large excess (50 equiv) of
anhydrous 4 M HCl in dioxane for 16 h at room temperature in
Et2O, but only 2-amino acetal hydrochloride 8a was isolated in
95% yield after precipitation in dry Et2O.
Additionally, the reactivity of N-tert-butanesulfinyl α-chloro-
α-methylketimine 1j toward alkoxides was studied in the
synthesis of the corresponding N-tert-butanesulfinyl 2-amino
acetal 5o (Scheme 3). N-tert-Butanesulfinyl α-chloroketimine
1j was synthesized in 75% yield via condensation of α-chloro
propiophenone with (Rs)-tert-butanesulfinamide in the pres-
ence of 2 equiv of Ti(OEt)4 in THF.15a Subsequently, when N-
tert-butanesulfinyl α-chloro-α-methylketimine 1j, which was
obtained in a diastereomeric ratio of 78:22 after purification via
flash chromatography, was reacted with 3 equiv of NaOMe at
room temperature for 2 h, the corresponding N-tert-
butanesulfinyl 2-amino acetal 5o was formed in a diastereo-
meric ratio of 83:17 (Scheme 3). Unfortunately, N-sulfinyl 2-
amino acetal 5o seemed unstable on column and could not be
isolated via flash chromatography. Instead, the corresponding
N-sulfinyl α-amino ketone 6j was isolated in a disappointing
yield of 13% and a diastereomeric ratio of 82:18. Therefore, in a
next attempt, the crude N-sulfinyl 2-amino acetal 5o was
treated immediately with TMSOTf in CH2Cl2 at −78 °C for 30
min, leading to the synthesis of the corresponding N-sulfinyl α-
amino ketone 6j, which can be considered as N-tert-
butanesulfinyl cathinone. Unfortunately, during purification
via flash chromatography, the formed diastereomers of 6j could
not be completely separated. N-Sulfinyl α-amino ketone 6j was
isolated as two diastereomerically enriched fractions in 43%
yield (dr 75:25) and 17% yield (dr 94:6), respectively. In a last
step, when N-sulfinyl α-amino ketone 6j (dr 94:6) was treated
with 3 M HCl in MeOH, the corresponding α-amino ketone
hydrochloride 7j, i.e. (S)-cathinone hydrochloride 7j, was
isolated in 88% yield after precipitation in dry Et2O.
Noteworthy, Davis and co-workers recently reported the
synthesis of N-sulfinyl α-amino ketone 6j in 70% yield via
hydrolysis of the corresponding N-sulfinyl α-amino dithioace-
tal.18 Nevertheless, during this hydrolysis step complete
racemisation occurred, resulting from the removal of the α-
proton in the α-amino carbonyl compound forming the enol.18
Comparison of the optical rotations ([α]D (S)-7j −47.2 (c 0.2,
H2O, er 94:6) vs −48.0 (c 1.0, H2O, ee > 95%)) reported in the
literature24 confirmed the assigned absolute stereochemistry of
synthesized products 6j and 7j.
1
converted to the corresponding hydrate 9b. H NMR analysis
of 9b in DMSO-d6 showed an equilibrium ratio of 80:20
between aldehyde 7i and the corresponding hydrate 9b, while a
reversed ratio of aldehyde 7i and the deuterated form of
hydrate 9b of 13:87 was obtained via 1H NMR analysis in D2O.
In order to elaborate N-tert-butanesulfinyl 2-amino acetals 5
as new stable N- and C-protected precursors for a variety of α-
amino carbonyl compounds 7, these acetals 5 were also treated
with 3 M HCl in MeOH (Table 5). Treatment of N-tert-
butanesulfinyl 2-amino acetals 5a−f (R1 ≠ H) with 10 equiv of
3 M HCl in MeOH at room temperature for 1 h afforded the
corresponding α-amino ketone hydrochlorides 7a−c in
excellent yields (89−99%) after precipitation in Et2O (Table
5, entries 1−6). When N-tert-butanesulfinyl 2-amino acetals
Table 5. Synthesis of α-Amino Ketone and Aldehyde
Hydrochlorides 7 and 2-Amino Acetal Hydrochlorides 8
entry
R1
R2
R3
yield 7/8 (%)
1
2
Me
Me
H
Me
Et
7a (90)
7a (99)
7b (97)
7b (92)
7c (90)
7c (89)
H
3
4-ClC6H4
H
Me
Et
4
4-ClC6H4
H
5
C6H5
C6H5
H
H
Me
Et
6
H
a
7
Me
Me
Et
Et
Me
Et
8a (75)
8
H
8b (95)
8c (81)
9
H
Me
Et
b
10
H
7i + 8d
a
Treating 2-amino acetal 5k with 50 equiv HCl in dioxane for 16 h at
room temperature in dry Et2O afforded 2-amino acetal hydrochloride
b
8a in 95% yield. An inseparable mixture of α-amino aldehyde
hydrochloride 7i and 2-amino acetal hydrochloride 8d in a ratio of
56:44 was obtained.
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Article
Scheme 3. Reaction of N-tert-Butanesulfinyl α-Chloro-α-methylketimine 1j with NaOMe in MeOH, Synthesis of N-tert-
Butanesulfinyl α-Amino Ketone 6j, and Subsequent N-Deprotection to (S)-Cathinone Hydrochloride 7j
Synthesis of (RS)-N-tert-Butanesulfinyl 2-Amino Acetals 5.
The synthesis of (RS)-N-tert-butanesulfinyl 2,2-dimethoxypropylamine
In conclusion, it was demonstrated that new N-tert-
5a is representative. To (RS)-N-(2-chloro-1-methylethylidene)-tert-
CONCLUSIONS
■
butanesulfinyl 2-amino acetals are formed in good to excellent
butanesulfinamide 1a (1 equiv, 1.0 g, 5.12 mmol) was added 1 M
yield via reaction of N-tert-butanesulfinyl α-halo imines with
alkoxides. The proposed mechanism involves formation of the
corresponding N-sulfinyl 2-alkoxyaziridines as unstable inter-
mediates, which open spontaneously, followed by an attack of a
second equivalent of the alkoxide. These N-tert-butanesulfinyl
2-amino acetals were shown to act as convenient precursors for
the TMSOTf-promoted synthesis of the corresponding N-
protected α-amino aldehydes and ketones in high yield.
Furthermore, the HCl-promoted synthesis of α-amino ketone
and α-amino aldehyde hydrochlorides and 2-amino acetal
hydrochlorides from these N-protected α-amino ketones and
aldehydes, and the corresponding acetals, in high yield
demonstrates the utility. Finally, this method was used for
the asymmetric synthesis of (S)-cathinone (er 94:6).
NaOMe in MeOH (3 equiv, 15.35 mL, 15.35 mmol) at room
temperature. The reaction was stirred for 2 h at room temperature and
quenched with a saturated solution of NH4Cl (1 mL). Subsequently,
the reaction mixture was diluted with saturated aqueous NaHCO3 (25
mL), and the aqueous phase was extracted with EtOAc (3 × 25 mL).
The combined organic phases were dried (MgSO4), filtered, and
evaporated in vacuo. The crude product was purified via flash
chromatography to yield 0.92 g (4.14 mmol, 81%) of pure (RS)-N-tert-
butanesulfinyl 2,2-dimethoxypropylamine 5a. For the synthesis of
(RS)-N-tert-butanesulfinyl 2-amino acetals 5k−n, the reaction time was
increased to 16 h instead of 2 h. (RS)-N-tert-Butanesulfinyl 2-amino
acetals 5g and 5h were purified by recrystallization from dry Et2O.
(RS)-N-tert-Butanesulfinyl 2,2-Dimethoxypropylamine 5a. Rf
= 0.22 (EtOAc). Yellow oil, yield 81% (0.92 g): [α]D −49.6 (c 0.3,
CHCl3); IR (cm−1) νmax 1051, 2955, 3218; 1H NMR (300 MHz,
CDCl3) δ 1.23 (9H, s), 1.34 (3H, s), 3.04 (1H, d × d, J = 12.4, 8.3
Hz), 3.20 (3H, s), 3.22 (3H, s), 3.24−3.32 (1H, m), 3.37 (1H, d × d, J
= 12.4, 4.4 Hz); 13C NMR (75 MHz, CDCl3) δ 20.3, 22.7 (3C), 48.5,
48.9, 49.3, 56.0, 100.6; MS (ES, pos. mode) m/z (%) 192 (M + H+ −
CH3OH, 100), 246 (M + Na+, 10). Anal. Calcd for C9H21NO3S: C
48.40; H 9.48; N 6.27. Found: C 48.21; H 9.23; N 6.20.
EXPERIMENTAL SECTION
■
Synthesis of (RS)-N-tert-Butanesulfinyl 2-Chloro-1-methoxy-
ethylamines 3a−b. The synthesis of (RS)-N-tert-butanesulfinyl 2-
chloro-1-methoxy-1-methylethylamine 3a is representative. To (RS)-
N-(2-chloro-1-methylethylidene)-tert-butanesulfinamide 1a (1 equiv,
0.2 g, 1.02 mmol) at −78 °C was added 1 M NaOMe in MeOH (3
equiv, 3.06 mL, 3.06 mmol). The reaction was stirred for 1 h at −78
°C and quenched with a saturated solution of NH4Cl (1 mL).
Subsequently, the reaction mixture was diluted with saturated aqueous
NaHCO3 (5 mL), and the aqueous phase was extracted with EtOAc (3
× 5 mL). The combined organic phases were dried (MgSO4), filtered,
and evaporated in vacuo to yield 0.23 g (1.02 mmol, 99%) of (RS)-N-
tert-butanesulfinyl 2-chloro-1-methoxy-1-methylethylamine 3a in a
diastereomeric ratio of 77:23. Because sulfinamides 3a,b are unstable
at room temperature and are smoothly converted back to the
corresponding N-sulfinyl imines 1a,b upon standing a short time in
(RS)-N-tert-Butanesulfinyl 2-(4-Chlorophenyl)-2,2-dimeth-
oxyethylamine 5b. Rf = 0.31 (EtOAc). White crystals, yield 93%
(1.03 g): [α]D −18.1 (c 0.3, CHCl3); mp 124.5−124.7 °C; IR (cm−1)
1
νmax 1042, 2958, 3188; H NMR (300 MHz, CDCl3) δ 1.04 (9H, s),
2.92 (1H, d × d, J = 9.9, 4.4 Hz), 3.19 (3H, s), 3.20 (3H, s), 3.36 (1H,
d × d, J = 13.2, 9.9 Hz), 3.56 (1H, d × d, J = 13.2, 4.4 Hz), 7.31−7.45
(4H, m); 13C NMR (75 MHz, CDCl3) δ 22.4 (3C), 49.0 (2C), 49.6,
56.0, 101.9, 128.4 (2C), 128.7 (2C), 134.2, 137.7; MS (ES, neg.
mode) m/z (%) 318/320 (M − H+, 100). Anal. Calcd for
C14H22ClNO3S: C 52.57; H 6.93; N 4.38. Found: C 52.37; H 6.71;
N 4.23.
1
(RS)-N-tert-Butanesulfinyl 2,2-Diethoxypropylamine 5c. Rf =
CDCl3, only H NMR and IR data could be reported.
0.21 (petroleum ether/EtOAc 1:1). Yellow oil, yield 70% (1.26 g):
(RS)-N-tert-Butanesulfinyl 2-Chloro-1-methoxy-1-methyl-
ethylamine 3a. Yellow oil, 99% (0.23 g): dr 77:23; IR (cm−1) νmax
752, 1043, 2959, 3228; 1H NMR (300 MHz, CDCl3) major
diastereomer δ 1.25 (9H, s), 1.57 (3H, s), 3.36 (3H, s), 3.57 (1H,
d, J = 11.0 Hz), 3.65 (1H, d, J = 11.0 Hz), 3.94 (1H, br s); minor
diastereomer δ 1.27 (9H, s), 1.58 (3H, s), 3.32 (3H, s, OCH3), 3.64
(1H, d, J = 11.6 Hz), 3.72 (1H, d, J = 11.6 Hz), 4.09 (1H, br s).
(RS)-N-tert-Butanesulfinyl 2-Chloro-1-methoxy-1-phenyl-
ethylamine 3b. Yellow oil, 99% (0.29 g): dr 62:48; IR (cm−1) νmax
749, 1070, 2980, 3196; 1H NMR (300 MHz, CDCl3) major
diastereomer δ 1.36 (9H, s), 3.28 (3H, s), 3.71 (1H, d, J = 11.6
Hz), 4.10 (1H, d, J = 11.6 Hz), 4.33 (1H, br s), 7.34−7.52 (4H, m);
minor diastereomer δ 1.27 (9H, s), 3.39 (3H, s), 3.93 (2H, s), 4.57
(1H, br s), 7.34−7.52 (4H, m).
1
[α]D −56.2 (c 0.4, CHCl3); IR (cm−1) νmax 1061, 2975, 3224; H
NMR (300 MHz, CDCl3) δ 1.17 (6H, t, J = 7.2 Hz), 1.23 (9H, s), 1.36
(3H, s), 2.99−3.10 (1H, m), 3.29−3.57 (6H, m); 13C NMR (75 MHz,
CDCl3) δ 15.4 (2C), 21.4, 22.6 (3C), 50.0, 55.9, 56.1, 100.3; MS (ES,
pos. mode) m/z (%) 203 (M + H+ − CH3CH2OH, 100), 274 (M +
Na+, 10). Anal. Calcd for C11H25NO3S: C 52.56; H 10.02; N 5.57.
Found: C 52.37; H 9.91; N 5.33.
(RS)-N-tert-Butanesulfinyl 2-(4-Chlorophenyl)-2,2-diethoxy-
ethylamine 5d. Rf = 0.23 (petroleum ether/EtOAc 1:1). Yellow
oil, yield 95% (1.02 g): [α]D −20.2 (c 0.4, CHCl3); IR (cm−1) νmax
1
1051, 2976, 3216; H NMR (300 MHz, CDCl3) δ 1.04 (9H, s), 1.20
(3H, t, J = 7.2 Hz), 1.21 (3H, t, J = 7.2 Hz), 2.94 (1H, d × d, J = 9.6,
4.1 Hz), 3.32−3.51 (5H, m), 3.56 (1H, d × d, J = 12.9, 4.1 Hz), 7.29−
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The Journal of Organic Chemistry
Article
7.36 (2H, m), 7.39−7.48 (2H, m); 13C NMR (75 MHz, CDCl3) δ
15.0, 15.2, 22.4 (3C), 50.3, 56.0, 56.7, 56.8, 101.4, 128.2 (2C), 128.6
(2C), 134.0, 138.6; MS (ES, neg. mode) m/z (%) 346/348 (M − H+,
100). HRMS Calcd for C16H26ClNO3S: 348.1395 [M + H]+. Found:
348.1386 [M + H]+.
(RS)-N-tert-Butanesulfinyl 2,2-Dimethoxy-2-phenylethyl-
amine 5e. Rf = 0.31 (EtOAc). Yellow crystals, yield 83% (1.22 g):
[α]D −25.7 (c 0.4, CHCl3); mp 106.2−106.6 °C; IR (cm−1) νmax 1034,
2958, 3187; 1H NMR (300 MHz, CDCl3) δ 1.03 (9H, s), 2.93 (1H, d
× d, J = 9.9, 4.4 Hz), 3.21 (3H, s), 3.22 (3H, s), 3.40 (1H, d × d, J =
13.2, 9.9 Hz), 3.56 (1H, d × d, J = 13.2, 4.4 Hz), 7.26−7.40 (3H, m),
7.44−7.49 (2H, m); 13C NMR (75 MHz, CDCl3) δ 22.4 (3C), 48.9,
49.0, 49.7, 56.0, 102.2, 127.2 (2C), 128.2 (2C), 128.3, 138.9; MS (ES,
pos. mode) m/z (%) 254 (M + H+ − CH3OH, 100), 308 (M + Na+,
25). Anal. Calcd for C14H23NO3S: C 58.92; H 8.12; N 4.91. Found: C
58.66; H 7.94; N 4.75.
(RS)-N-tert-Butanesulfinyl 2,2-Diethoxy-2-phenylethylamine
5f. Rf = 0.25 (petroleum ether/EtOAc 1:1). Yellow oil, yield 97%
(1.34 g): [α]D −25.3 (c 0.3, CHCl3); IR (cm−1) νmax 1052, 2975,
3219; 1H NMR (300 MHz, CDCl3) δ 1.03 (9H, s), 1.21 (3H, t, J = 7.2
Hz), 1.22 (3H, t, J = 7.2 Hz), 2.95 (1H, d × d, J = 9.9, 4.0 Hz), 3.34−
3.51 (5H, m), 3.56 (1H, d × d, J = 12.9, 4.0 Hz), 7.25−7.39 (3H, m),
7.47−7.53 (2H, m); 13C NMR (75 MHz, CDCl3) δ 15.1, 15.2, 22.4
(3C), 50.5, 55.9, 56.6, 56.7, 101.7, 127.0 (2C), 128.1 (3C), 139.9; MS
(ES, pos. mode) m/z (%) 268 (M + H+ − CH3CH2OH, 100), 336 (M
+ Na+, 25). Anal. Calcd for C16H27NO3S: C 61.31; H 8.68; N 4.47.
Found: C 61.57; H 8.79; N 4.63.
220 (M + H+ − CH3OH, 100). Anal. Calcd for C11H25NO3S: C 52.26;
H 10.02; N 5.57. Found: C 52.49; H 10.31; N 5.82.
(RS)-N-tert-Butanesulfinyl 2,2-Dimethoxy-1,1-dimethylethyl-
amine 5k. Rf = 0.35 (EtOAc). Yellow oil, yield 96% (0.96 g): [α]D
1
−91.1 (c 0.3, CHCl3); IR (cm−1) νmax 1067, 2954, 3304; H NMR
(300 MHz, CDCl3) δ 1.16 (3H, s), 1.20 (9H, s), 1.30 (3H, s), 3.54
(3H, s), 3.59 (3H, s), 3.63 (1H, br s), 4.14 (1H, s); 13C NMR (75
MHz, CDCl3) δ 22.6 (3C), 22.7, 22.9, 55.3, 58.5, 58.8, 58.9, 111.8; MS
(ES, pos. mode) m/z (%) 238 (M + H+, 100), 206 (M + H+
−
CH3OH, 40). HRMS Calcd for C10H23NO3S: 238.1471 [M + H]+.
Found: 238.1472 [M + H]+.
(RS)-N-tert-Butanesulfinyl 2,2-Diethoxy-1,1-dimethylethyl-
amine 5l. Rf = 0.33 (petroleum ether/EtOAc 1:1). Yellow oil, yield
77% (0.76 g): [α]D −86.8 (c 0.3, CHCl3); IR (cm−1) νmax 1059, 1113,
2975, 3306; 1H NMR (300 MHz, CDCl3) δ 1.18 (3H, s), 1.20 (9H, s),
1.23 (3H, t, J = 7.2 Hz), 1.24 (3H, t, J = 7.2 Hz), 1.32 (3H, s), 3.51−
3.71 (2H, m), 3.73 (1H, br s), 3.79−3.92 (2H, m), 4.28 (1H, s); 13C
NMR (75 MHz, CDCl3) δ 15.5 (2C), 22.6 (3C), 22.8 (2C), 55.3,
58.7, 66.3, 66.6, 109.1; MS (ES, pos. mode) m/z (%) 220 (M + H+ −
CH3CH2OH, 100). HRMS Calcd for C12H27NO3S: 266.1784 [M +
H]+. Found: 266.1787 [M + H]+.
(RS)-N-tert-Butanesulfinyl 1-Dimethoxymethyl-1-ethylpro-
pylamine 5m. Rf = 0.41 (EtOAc). Yellow oil, yield 57% (0.66 g):
[α]D −76.8 (c 0.3, CHCl3); IR (cm−1) νmax 1064, 1450, 2918, 3310;
1H NMR (300 MHz, CDCl3) δ 0.89 (3H, t, J = 7.2 Hz), 0.95 (3H, t, J
= 7.2 Hz), 1.23 (9H, s), 1.48−1.89 (4H, m), 3.53 (3H, s), 3.57 (1H, br
s), 3.59 (3H, s), 4.25 (1H, s); 13C NMR (75 MHz, CDCl3) δ 7.8, 8.0,
22.8 (3C), 25.3, 25.9, 56.0, 58.7, 59.0, 63.3, 111.9; MS (ES, pos.
mode) m/z (%) 266 (M + H+, 20), 234 (M + H+ − CH3OH, 100).
HRMS Calcd for C12H27NO3S: 266.1784 [M + H]+. Found: 266.1788
[M + H]+.
(RS)-N-tert-Butanesulfinyl 2,2-Dimethoxy-2-(4-methoxy-
phenyl)ethylamine 5g. Yellow crystals, yield 94% (2.68 g): [α]D
−22.2 (c 0.3, CHCl3); mp 134.5−134.8 °C; IR (cm−1) νmax 1036,
1
1242, 1510, 1608, 2954, 3172; H NMR (300 MHz, CDCl3) δ 1.06
(9H, s), 2.93 (1H, d × d, J = 9.9, 4.1 Hz), 3.18 (3H, s), 3.20 (3H, s),
3.39 (1H, d × d, J = 13.1, 9.9 Hz), 3.53 (1H, d × d, J = 13.1, 4.1 Hz),
3.82 (3H, s), 6.86−6.92 (2H, m), 7.35−7.41 (2H, m); 13C NMR (75
MHz, CDCl3) δ 22.5 (3C), 48.8, 48.9, 49.7, 52.3, 56.0, 102.1, 113.5
(2C), 128.5 (2C), 131.0, 159.5; MS (ES, pos. mode) m/z (%) 338 (M
+ Na+, 10), 284 (M − CH3OH, 20), 178 (M − 137, 100). Anal. Calcd
for C15H25NO4S: C 57.12; H 7.99; N 4.44. Found: C 57.34; H 7.91; N
4.65.
(RS)-N-tert-Butanesulfinyl 2,2-Dimethoxy-2-(4-nitrophenyl)-
ethylamine 5h. Yellow crystals, yield 97% (1.52 g): [α]D −4.6 (c
0.5, CHCl3); mp 121.7−122.0 °C; IR (cm−1) νmax 1042, 1347, 1520,
2958, 3188; 1H NMR (300 MHz, CDCl3) δ 1.02 (9H, s), 2.98 (1H, d
× d, J = 9.6, 4.7 Hz), 3.21 (3H, s), 3.25 (3H, s), 3.39 (1H, d × d, J =
13.5, 9.6 Hz), 3.64 (1H, d × d, J = 13.5, 4.7 Hz), 7.63−7.72 (2H, m),
8.19−8.29 (2H, m); 13C NMR (75 MHz, CDCl3) δ 22.4 (3C), 49.2,
49.3, 49.5, 56.1, 101.9, 123.3 (2C), 128.5 (2C), 146.5, 147.9; MS (ES,
neg. mode) m/z (%) 329 (M − H+, 100). Anal. Calcd for
C14H22N2O5S: C 50.89; H 6.71; N 8.48. Found: C 50.64; H 6.49;
N 8.22.
(RS)-N-tert-Butanesulfinyl 2-(2,4-Dichlorophenyl)-2,2-dime-
thoxyethylamine 5i. Rf = 0.30 (petroleum ether/EtOAc 1:1).
Yellow oil, yield 93% (1.48 g): [α]D +4.7 (c 0.5, CHCl3); IR (cm−1)
νmax 751, 1053, 1467, 2956, 3205; 1H NMR (300 MHz, CDCl3) δ 0.99
(9H, s), 2.97 (1H, d × d, J = 9.4, 5.0 Hz), 3.17 (3H, s), 3.24 (3H, s),
3.70 (1H, d × d, J = 13.8, 9.4 Hz), 3.79 (1H, d × d, J = 13.8, 5.0 Hz),
7.25 (1H, d × d, J = 8.3, 2.2 Hz), 7.40 (1H, d, J = 2.2 Hz), 7.72 (1H, d,
J = 8.3 Hz); 13C NMR (75 MHz, CDCl3) δ 22.3 (3C), 45.9, 48.6, 49.0,
55.9, 101.6, 126.6, 130.8, 132.4, 132.7, 134.2, 134.9; MS (ES, pos.
mode) m/z (%) 322/324/326 (M + H+ − CH3OH, 100). Anal. Calcd
for C14H21Cl2NO3S: C 47.46; H 5.97; N 3.95. Found: C 47.67; H
6.05; N 4.07.
(RS)-N-tert-Butanesulfinyl 2,2-Dimethoxy-3-methylbutyl-
amine 5j. Rf = 0.27 (petroleum ether/EtOAc 1:1). Yellow oil, yield
76% (0.54 g): [α]D −41.6 (c 0.2, CHCl3); IR (cm−1) νmax 753, 1048,
1122, 1471, 2960, 3225; 1H NMR (300 MHz, CDCl3) δ 0.97 (3H, d, J
= 6.9 Hz), 0.98 (3H, d, J = 6.9 Hz), 1.22 (9H, s), 2.10 (1H, sept, J =
6.9 Hz), 3.11 (1H, d × d, J = 13.2, 10.5 Hz), 3.21 (3H, s), 3.25 (3H,
s), 3.30−3.41 (2H, m); 13C NMR (75 MHz, CDCl3) δ 17.3, 17.4, 22.7
(3C), 32.6, 44.9, 48.5, 49.3, 55.7, 102.3; MS (ES, pos. mode) m/z (%)
(RS)-N-tert-Butanesulfinyl 1-Diethoxymethyl-1-ethylpropyl-
amine 5n. Rf = 0.28 (petroleum ether/EtOAc 1:1). Yellow oil,
yield 28% (0.42 g): [α]D −67.3 (c 0.2, CHCl3); IR (cm−1) νmax 1058,
1113, 2973, 3304; 1H NMR (300 MHz, CDCl3) δ 0.89 (3H, t, J = 7.2
Hz), 0.98 (3H, t, J = 7.2 Hz), 1.19−1.27 (6H, m), 1.23 (9H, s), 1.50−
1.87 (4H, m), 3.49−3.59 (1H, m), 3.64−3.74 (1H, m), 3.69 (1H, br
s), 3.79−3.89 (2H, m), 4.41 (1H, s); 13C NMR (75 MHz, CDCl3) δ
7.9, 8.1, 15.5, 15.6, 22.8 (3C), 25.0, 26.0, 55.9, 63.1, 66.4, 66.7, 109.2;
MS (ES, pos. mode) m/z (%) 248 (M + H+ − CH3CH2OH, 100).
HRMS Calcd for C14H31NO3S: 294.2097 [M + H]+. Found: 294.2095
[M + H]+.
Synthesis of (RS)-N-tert-Butanesulfinyl α-Amino Ketones
6a−g and 6j and (RS)-N-tert-Butanesulfinyl α-Amino Aldehydes
6h,i. The synthesis of (RS)-N-tert-butanesulfinyl 2-oxopropylamine 6a
is representative. To a solution of (RS)-N-tert-butanesulfinyl 2,2-
dimethoxypropylamine 5a (1 equiv, 0.5 g, 2.24 mmol) in CH2Cl2 (5
mL) was added dropwise TMSOTf (3 equiv, 1.22 mL, 6.73 mmol) at
−78 °C. The reaction was stirred for 30 min at −78 °C, and
subsequently, the reaction mixture was diluted with saturated aqueous
NaHCO3 (10 mL), and the aqueous phase was extracted with CH2Cl2
(3 × 10 mL). The combined organic phases were dried (MgSO4),
filtered, and evaporated in vacuo. The crude product was purified via
flash chromatography to yield 0.36 g (2.04 mmol, 91%) of pure (RS)-
N-tert-butanesulfinyl 2-oxopropylamine 6a. (RS)-N-tert-Butanesulfinyl
2-oxopropylamine 6a was also obtained starting from (RS)-N-tert-
butanesulfinyl 2,2-diethoxypropylamine 5c in 88% yield. For the
synthesis of (RS)-N-tert-butanesulfinyl α-amino aldehydes 6h,i, the
reaction temperature was increased to room temperature instead of
−78 °C. To obtain full conversion of N-tert-butanesulfinyl 2-amino
acetal 5k into N-tert-butanesulfinyl α-amino aldehyde 6h, after
addition of 3 equiv of TMSOTf at room temperature for 30 min,
two additional 3 equiv aliquots of TMSOTf were added subsequently
at room temperature for 30 min. (RS)-N-tert-Butanesulfinyl 2-(4-
nitrophenyl)-2-oxoethylamine 6e was purified by recrystallization from
dry Et2O.
(RS)-N-tert-Butanesulfinyl 2-Oxopropylamine 6a. Rf = 0.07
(Et2O). Yellow oil, yield 88−91% (0.36 g): [α]D −97.0 (c 0.4,
CHCl3); IR (cm−1) νmax 1046, 1362, 1723, 2961, 3247; 1H NMR (300
MHz, CDCl3) δ 1.24 (9H, s), 2.21 (3H, s), 3.90 (1H, d × d, J = 18.7,
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4.4 Hz), 4.07 (1H, d × d, J = 18.7, 6.1 Hz), 4.36 (1H, m); 13C NMR
(75 MHz, CDCl3) δ 22.7 (3C), 27.3, 51.8, 56.5, 203.4; MS (ES, pos.
mode) m/z (%) 178 (M + H+, 100). HRMS Calcd for C7H15NO2S:
178.0896 [M + H]+. Found: 178.0897 [M + H]+.
80), 149 (M − 42, 100). HRMS Calcd for C8H17NO2S: 192.1053 [M
+ H]+. Found: 192.1051 [M + H]+.
(RS)-N-tert-Butanesulfinyl-2-amino-2-ethylbutanal 6i. Rf
=
0.21 (Et2O). Colorless oil, yield 99% (0.37 g): [α]D −55.0 (c 0.2,
CHCl3); IR (cm−1) νmax 1055, 1458, 1730, 2966, 3221; 1H NMR (300
MHz, CDCl3) δ 0.85 (3H, t, J = 7.2 Hz), 0.89 (3H, t, J = 7.2 Hz), 1.28
(9H, s), 1.77−2.03 (4H, m), 4.11 (1H, br s), 9.35 (1H, s); 13C NMR
(75 MHz, CDCl3) δ 7.5, 7.7, 22.8 (3C), 27.4, 28.5, 56.5, 68.9, 201.2;
MS (ES, pos. mode) m/z (%) 220 (M + H+, 100). HRMS Calcd for
C10H21NO2S: 220.1366 [M + H]+. Found: 220.1362 [M + H]+.
(RS)-N-tert-Butanesulfinyl 1-Methyl-2-oxo-2-phenylethyl-
amine 6j. Rf = 0.22 (Et2O). Colorless oil, yield 60% (43%, dr
75:25, 0.40 g + 17%, dr 94:6, 0.16 g): [α]D −54.8 (c 0.4, CHCl3, dr
92:8); IR (cm−1) νmax 700, 752, 970, 1061, 1220, 1450, 1686, 2979,
(RS)-N-tert-Butanesulfinyl 2-(4-Chlorophenyl)-2-oxoethyl-
amine 6b. Rf = 0.20 (Et2O). White crystals, yield 92−99% (0.42
g): [α]D −126.9 (c 0.5, CHCl3); mp 114.0−114.3 °C; IR (cm−1) νmax
1
1063, 1232, 1587, 1678, 2953, 3296; H NMR (300 MHz, CDCl3) δ
1.28 (9H, s), 4.40−4.44 and 4.48−4.52 (1H, m), 4.57−4.65 and 4.68−
4.71 (1H, m), 4.63 (1H, br s), 7.43−7.49 (2H, m), 7.84−7.91 (2H,
m); 13C NMR (75 MHz, CDCl3) δ 22.8 (3C), 48.2, 56.6, 129.2 (4C),
132.8, 140.5, 193.8; MS (ES, pos. mode) m/z (%) 274/276 (M + H+,
100). Anal. Calcd for C12H16ClNO2S: C 52.64; H 5.89; N 5.12.
Found: C 52.37; H 5.72; N 5.01.
(RS)-N-tert-Butanesulfinyl 2-Oxo-2-phenylethylamine 6c. Rf =
0.37 (EtOAc). Yellow oil, yield 71−82% (0.38 g): [α]D −111.2 (c 0.5,
CHCl3); IR (cm−1) νmax 1066, 1227, 1689, 2957, 3268; 1H NMR (300
MHz, CDCl3) δ 1.29 (9H, s), 4.51 (1H, d × d, J = 17.6, 3.3 Hz),
4.57−4.65 (1H, m), 4.70 (1H, d × d, J = 17.6, 6.1 Hz), 7.46−7.54
(2H, m), 7.59−7.65 (1H, m), 7.92−7.97 (2H, m); 13C NMR (75
MHz, CDCl3) δ 22.8 (3C), 48.3, 56.5, 127.8 (2C), 128.9 (2C), 134.0,
134.5, 194.8; MS (ES, pos. mode) m/z (%) 240 (M + H+, 100).
HRMS Calcd for C12H17NO2S: 240.1053 [M + H]+. Found: 240.1053
[M + H]+.
(RS)-N-tert-Butanesulfinyl 2-(4-Methoxyphenyl)-2-oxoethyl-
amine 6d. Rf = 0.16 (Et2O). Yellow oil, yield 99% (0.63 g): [α]D
−100.7 (c 0.4, CHCl3); IR (cm−1) νmax 749, 981, 1064, 1172, 1238,
1599, 1679, 2934, 3274; 1H NMR (300 MHz, CDCl3) δ 1.29 (9H, s),
3.88 (3H, s), 4.44 (1H, d × d, J = 19.8, 5.5 Hz), 4.62 (1H, d × d, J =
19.8, 6.1 Hz), 4.64 (1H, br s), 6.93−6.98 (2H, m), 7.89−7.94 (2H,
m); 13C NMR (75 MHz, CDCl3) δ 22.8 (3C), 47.8, 55.5, 56.5, 114.1
(2C), 127.5, 130.1 (2C), 164.1, 193.2; MS (ES, pos. mode) m/z (%)
270 (M + H+, 100). HRMS Calcd for C13H19NO3S: 270.1158 [M +
H]+. Found: 270.1161 [M + H]+.
(RS)-N-tert-Butanesulfinyl 2-(4-Nitrophenyl)-2-oxoethyl-
amine 6e. Yellow crystals, yield 99% (0.47 g): [α]D −118.6 (c 0.4,
CHCl3); mp 127.2−127.6 °C; IR (cm−1) νmax 850, 980, 1064, 1340,
1520, 1694, 2964, 3314; 1H NMR (300 MHz, CDCl3) δ 1.30 (9H, s),
4.53−4.58 (1H, m), 4.54 (1H, d × d, J = 19.5, 3.9 Hz), 4.74 (1H, d ×
d, J = 19.5, 7.2 Hz), 8.08−8.15 (2H, m), 8.33−8.39 (2H, m); 13C
NMR (75 MHz, CDCl3) δ 22.8 (3C), 48.9, 56.8, 124.1 (2C), 129.0
(2C), 138.9, 150.8, 193.8; MS (ES, pos. mode) m/z (%) 285 (M + H+,
100). Anal. Calcd for C12H16N2O4S: C 50.69; H 5.67; N 9.85. Found:
C 50.54; H 5.49; N 9.64.
1
3266; H NMR (300 MHz, CDCl3) δ major (RS,S)-6j 1.23 (9H, s),
1.56 (3H, d, J = 7.2), 4.22 (1H, d, J = 9.4 Hz), 4.96−5.09 (1H, m),
7.46−7.54 (2H, m), 7.57−7.64 (1H, m), 7.92−7.99 (2H, m); δ minor
(RS,R)-6j 1.29 (9H, s), 1.44 (3H, d, J = 7.2 Hz), 4.80 (1H, d, J = 5.0
Hz), 4.96−5.09 (1H, m), 7.46−7.54 (2H, m), 7.57−7.64 (1H, m),
7.92−7.99 (2H, m); 13C NMR (75 MHz, CDCl3) δ major (RS,S)-6j
21.5, 22.6 (3C), 54.8, 56.6, 128.6 (2C), 128.9 (2C), 133.8, 134.1,
199.1; δ minor (RS,R)-6j 21.6, 22.7 (3C), 54.7, 55.7, 128.6 (2C), 128.9
(2C), 133.8, 134.0, 199.7; MS (ES, pos. mode) m/z (%) 254 (M + H+,
100). HRMS Calcd for C13H19NO2S: 254.1209 [M + H]+. Found:
254.1207 [M + H]+.
Synthesis of α-Amino Ketone Hydrochlorides 7a−g and 7j
and 2-Amino Acetal Hydrochlorides 8. The synthesis of 1-
aminopropan-2-one hydrochloride 7a is representative. To a solution
of (RS)-N-tert-butanesulfinyl 2-oxopropylamine 6a (0.20 g, 1.13
mmol) in MeOH (3 mL) was added a 3 M solution of HCl (10
equiv, 3.77 mL, 11.30 mmol) in MeOH at room temperature. The
mixture was stirred for 1 h at room temperature. Subsequently, the
reaction mixture was concentrated in vacuo. Precipitation in dry Et2O
afforded 0.12 g (1.09 mmol, 96%) of pure 1-aminopropan-2-one
hydrochloride 7a. 1-Aminopropan-2-one hydrochloride 7a was also
obtained starting from (RS)-N-tert-butanesulfinyl 2,2-dimethoxypropyl-
amine 5a and (RS)-N-tert-butanesulfinyl 2,2-diethoxypropylamine 5c
in 90 and 99% yield, respectively, via the same procedure. Treatment
of (RS)-N-tert-butanesulfinyl 2,2-dimethoxy-1,1-dimethylethylamine
5k, (RS)-N-tert-butanesulfinyl 2,2-diethoxy-1,1-dimethylethylamine 5l,
and (RS)-N-tert-butanesulfinyl 1-dimethoxymethyl-1-ethylpropylamine
5m with HCl in MeOH under similar conditions afforded the
synthesis of 2-amino acetal hydrochlorides 8a−c. Treating (RS)-N-tert-
butanesulfinyl 2,2-dimethoxy-1,1-dimethylethylamine 5k with 50 equiv
of HCl in dioxane at room temperature for 16 h afforded 2-amino
acetal hydrochloride 8a in 95% yield
(RS)-N-tert-Butanesulfinyl 2-(2,4-Dichlorophenyl)-2oxoethyl-
amine 6f. Rf = 0.21 (Et2O). Yellow oil, yield 99% (0.60 g): [α]D
−73.2 (c 0.2, CHCl3); IR (cm−1) νmax 751, 816, 981, 1059, 1583, 1702,
2961, 3218; 1H NMR (300 MHz, CDCl3) δ 1.26 (9H, s), 4.44 (1H, d
× d, J = 17.9, 3.7 Hz), 4.53 (1H, d × d, J = 6.1, 3.7 Hz), 4.61 (1H, d ×
d, J = 17.9, 6.1 Hz), 7.36 (1H, d × d, J = 8.3, 2.2 Hz), 7.48 (1H, d, J =
2.2 Hz), 7.64 (1H, d, J = 8.3 Hz); 13C NMR (75 MHz, CDCl3) δ 22.7
(3C), 52.0, 56.6, 127.6, 130.8, 131.2, 132.9, 134.1, 138.8, 196.3; MS
(ES, pos. mode) m/z (%) 308/310/312 (M + H+, 100). HRMS Calcd
for C12H25Cl2NO2S: 308.0273 [M + H]+. Found: 308.0285 [M + H]+.
(RS)-N-tert-Butanesulfinyl 3-Methyl-2-oxobutylamine 6g. Rf
= 0.20 (Et2O). Colorless oil, yield 76% (0.31 g): [α]D −94.3 (c 0.3,
CHCl3); IR (cm−1) νmax 1057, 1363, 1468, 1715, 2972, 3218; 1H
NMR (300 MHz, CDCl3) δ 1.16 (6H, d, J = 7.2 Hz), 1.24 (9H, s),
2.66 (1H, sept, J = 7.2 Hz), 3.95 (1H, d × d, J = 18.7, 3.3 Hz), 4.11
(1H, d × d, J = 18.7, 6.1 Hz), 4.28−4.34 (1H, m); 13C NMR (75
MHz, CDCl3) δ 18.2, 18.3, 22.7 (3C), 39.0, 49.2, 56.4, 209.6; MS (ES,
pos. mode) m/z (%) 206 (M + H+, 100). HRMS Calcd for
C9H19NO2S: 206.1209 [M + H]+. Found: 206.1205 [M + H]+.
(RS)-N-tert-Butanesulfinyl-2-amino-2-methylpropanal 6h. Rf
= 0.09 (Et2O). Colorless oil, yield 95−99% (0.27 g): [α]D −77.1 (c
1-Aminopropan-2-one Hydrochloride 7a. Yellow crystals, yield
90−99% (0.12 g): mp 70.8−71.1 °C vs 70.0−74.0 °C in lit.;25 IR
(cm−1) νmax 1721, 2928; 1H NMR (300 MHz, D2O, int. ref CH3CN δ
2.00) δ 2.23 (3H, s), 4.03 (2H, s); 13C NMR (75 MHz, D2O, int. ref
CH3CN δ 1.0) δ 26.6, 47.8, 204.1; MS (ES, pos. mode) m/z (%) 96
(M − HCl + Na+, 100). Anal. Calcd for C3H8ClNO: C 32.89; H 7.36;
N 12.79. Found: C 32.67; H 7.42; N 12.93. All spectroscopic data
were in good agreement with reported data.25a,b
2-Amino-1-(4-chlorophenyl)ethanone Hydrochloride 7b.
White crystals, yield 92−99% (0.15 g): mp 298.5−298.8 °C vs
270.0−290.0 °C in lit.;25b,26 IR (cm−1) νmax 1250, 1467, 1588, 1681,
1
2979; H NMR (300 MHz, CD3OD, int. ref CH3CN δ 2.00) δ 4.57
(2H, s), 7.52−7.61 (2H, m), 7.96−8.04 (2H, m); 13C NMR (75 MHz,
CD3OD, int. ref CH3CN δ 0.0) δ 45.4, 129.6 (2C), 130.1 (2C), 132.8,
141.2, 191.5; MS (ES, pos. mode) m/z (%) 170/172 (M + H+ − HCl,
100). Anal. Calcd for C8H9Cl2NO: C 46.63; H 4.40; N 6.80. Found: C
46.84; H 4.07; N 6.57. All spectroscopic data were in good agreement
with reported data.25b
2-Amino-1-phenylethanone Hydrochloride 7c. Yellow crys-
tals, yield 89−92% (0.19 g): mp 198.3−198.6 °C vs 182.0−206 °C in
lit.;.25b,d,27 IR (cm−1) νmax 759, 1241, 1504, 1696, 2866; 1H NMR (300
MHz, CD3OD, int. ref CH3CN δ 2.00) δ 4.58 (2H, s), 7.51−7.59 (2H,
m), 7.63−7.71 (1H, m), 7.98−8.04 (2H, m); 13C NMR (75 MHz,
CD3OD, int. ref CH3CN δ 0.0) δ 45.4, 128.5 (2C), 129.4 (2C), 134.3,
1
0.1, CHCl3); IR (cm−1) νmax 1054, 1461, 1732, 2919, 3236; H NMR
(300 MHz, CDCl3) δ 1.24 (9H, s), 1.42 (3H, s), 1.44 (3H, s), 3.90
(1H, s), 9.48 (1H, s); 13C NMR (75 MHz, CDCl3) δ 22.5 (3C), 23.6,
23.7, 56.1, 62.0, 200.5; MS (ES, neg. mode) m/z (%) 190 (M − H+,
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135.0, 192.5; MS (ES, pos. mode) m/z (%) 136 (M + H+ − HCl,
100). Anal. Calcd for C8H10ClNO: C 55.99; H 5.87; N 8.16. Found: C
56.08; H 6.11; N 8.26. All spectroscopic data were in good agreement
with reported data.25b,27a
C8H20ClNO2: C 48.60; H 10.20; N 7.08. Found: C 48.89; H 10.37; N
7.21.
1-Dimethoxymethyl-1-ethylpropylamine Hydrochloride 8c.
White crystals, yield 81% (96 mg): mp 137.3−137.6 °C; IR (cm−1)
νmax 1072, 1112, 1507, 2910, 3363; 1H NMR (300 MHz, CD3OD, int.
ref CH3CN δ 2.00) δ 0.91 (3H, t, J = 7.7 Hz), 0.92 (3H, t, J = 7.7 Hz),
1.69 (2H, q, J = 7.7 Hz), 1.70 (2H, q, J = 7.7 Hz), 3.57 (6H, s), 4.35
(1H, s); 13C NMR (75 MHz, CD3OD, int. ref CH3CN δ 0.0) δ 6.5
(2C), 24.2 (2C), 58.3 (2C), 63.2, 106.4; MS (ES, pos. mode) m/z (%)
162 (M + H+ − HCl, 100). Anal. Calcd for C8H20ClNO2: C 48.60; H
10.20; N 7.08. Found: C 48.24; H 10.03; N 6.96.
Synthesis of 2-Amino-2-ethylbutyraldehyde Hydrochloride
7i. To a solution of (RS)-N-tert-butanesulfinyl-2-amino-2-ethylbutanal
6i (0.10 g, 0.45 mmol) in dry Et2O (3 mL) was added a 4 M solution
of HCl (10 equiv, 1.14 mL, 4.54 mmol) in dioxane at room
temperature. The mixture was stirred for 1 h at room temperature.
Subsequently, the reaction mixture was concentrated in vacuo.
Precipitation in dry Et2O afforded 0.053 g (0.35 mmol, 77%) of 2-
amino-2-ethylbutanal hydrochloride 7i. 1H NMR analysis in DMSO-d6
showed an equilibrium between aldehyde 7i and the corresponding 2-
amino-2-ethylbutane-1,1-diol hydrochloride 9b in a ratio of 80:20,
while a reversed ratio of 7i/9b 13:87 was obtained via 1H NMR
analysis in D2O.
2-Amino-1-(4-methoxyphenyl)ethanone Hydrochloride 7d.
White crystals, yield 94% (0.18 g): mp 210.2−210.5 °C vs 195.0−
205.0 °C in lit.;25b,26b,27d IR (cm−1) νmax 829, 1176, 1250, 1504, 1602,
1
1682, 2884, 2986; H NMR (300 MHz, CD3OD, int. ref CH3CN δ
2.00) δ 3.86 (3H, s), 4.51 (2H, s), 7.00−7.08 (2H, m), 7.94−8.04 (2H,
m); 13C NMR (75 MHz, CD3OD, int. ref CH3CN δ 0.0) δ 44.9, 55.4,
114.6 (2C), 127.1, 130.9 (2C), 165.6, 190.7; MS (ES, pos. mode) m/z
(%) 166 (M + H+ − HCl, 100). Anal. Calcd for C9H12ClNO2: C
53.61; H 6.00; N 6.95. Found: C 53.87; H 6.27; N 7.04. All
spectroscopic data were in good agreement with reported data.25b
2-Amino-1-(4-nitrophenyl)ethanone Hydrochloride 7e.
White crystals, yield 88% (0.12 g): mp 218.2−218.5 °C vs 226.0−
250.0 °C in lit.;27d,28 IR (cm−1) νmax 855, 1240, 1345, 1494, 1527,
1
1687, 2941, 3082; H NMR (300 MHz, CD3OD, int. ref CH3CN δ
2.00) δ 4.67 (2H, s), 8.20−8.27 (2H, m), 8.34−8.41 (2H, m); 13C
NMR (75 MHz, CD3OD, int. ref CH3CN δ 0.0) δ 45.4, 123.8 (2C),
129.4 (2C), 138.1, 151.3, 191.2; MS (ES, pos. mode) m/z (%) 181 (M
+ H+ − HCl, 100). Anal. Calcd for C8H9ClN2O3: C 44.36; H 4.19; N
12.93. Found: C 44.58; H 4.33; N 13.05.
2-Amino-2-ethylbutanal Hydrochloride 7i. The 1H and 13C
NMR spectral data of 7i in DMSO-d6 were obtained from a mixture of
7i and the corresponding hydrate 9b in a ratio of 80:20. White solid,
yield 77% (53 mg): mp 199.2−199.5 °C (carbonization); IR (cm−1)
νmax 1513, 1730, 2883; 1H NMR (300 MHz, DMSO-d6) δ 0.88 (6H, t,
J = 7.2 Hz), 1.86 (4H, q, J = 7.2 Hz), 8.50 (3H, br s), 9.53 (1H, s); 13C
NMR (75 MHz, DMSO-d6) δ 7.8 (2C), 25.4 (2C), 66.8, 201.3; MS
(ES, pos. mode) m/z (%) 116 (M + H+, 100).
2-Amino-1-(2,4-dichlorophenyl)ethanone Hydrochloride 7f.
White crystals, yield 86% (0.17 g): mp 231.5−231.9 °C; IR (cm−1)
1
νmax 815, 969, 1121, 1231, 1416, 1471, 1583, 1703, 2875, 2972; H
NMR (300 MHz, CD3OD, int. ref CH3CN δ 2.00) δ 4.53 (2H, s),
7.51 (1H, d × d, J = 8.3, 1.9 Hz), 7.65 (1H, d, J = 1.9 Hz), 7.87 (1H, d,
J = 8.3 Hz); 13C NMR (75 MHz, DMSO-d6, int. ref CH3CN δ 0.0) δ
45.7, 126.6, 129.6, 131.0, 131.3, 136.8, 191.7; MS (ES, pos. mode) m/z
(%) 204/206/208 (M + H+ − HCl, 100). Anal. Calcd for
C8H8Cl3NO: C 39.95; H 3.35; N 5.82. Found: C 40.17; H 3.52; N
6.00.
2-Amino-2-ethylbutane-1,1-diol Hydrochloride 9b. The 1H
and 13C NMR spectral data of 9b in D2O were obtained from a
mixture of 9b and the corresponding aldehyde 7i in a ratio of 87:13.
Data: 1H NMR (300 MHz, D2O, int. ref CH3CN δ 2.00) δ 0.88 (6H, t,
J = 7.2 Hz), 1.69 (4H, q, J = 7.2 Hz), 5.09 (1H, s); 13C NMR (75
MHz, D2O, int. ref CH3CN δ 0.0) δ 5.3 (2C), 22.5 (2C), 62.1, 88.3;
MS (ES, pos. mode) m/z (%) 134 (M + H+, 100).
1-Amino-3-methylbutan-2-one Hydrochloride 7g. White
crystals, yield 94% (0.11 g): mp 169.2−169.4 °C vs 147.0−164.0 °C
in lit.;29 IR (cm−1) νmax 995, 1140, 1420, 1472, 1720, 2876, 2971; H
1
NMR (300 MHz, CD3OD, int. ref CH3CN δ 2.00) δ 1.12 (6H, d, J =
7.2 Hz), 2.72 (1H, sept, J = 7.2 Hz), 4.01 (2H, s); 13C NMR (75 MHz,
CD3OD, int. ref CH3CN δ 0.0) δ 17.2 (2C), 38.8, 45.8, 207.1; MS
(ES, pos. mode) m/z (%) 101 (M + H+ − HCl, 100). Anal. Calcd for
C5H12ClNO: C 43.64; H 8.79; N 10.18. Found: C 43.84; H 8.98; N
10.37.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
General experimental conditions and copies of H NMR and
13C NMR spectra for (RS)-N-tert-butanesulfinyl 2-chloro-1-
methoxyethylamines 3a−b, (RS)-N-tert-butanesulfinyl 2-amino
acetals 5, (RS)-N-tert-butanesulfinyl α-amino ketones 6a−g and
6j and (RS)-N-tert-butanesulfinyl α-amino aldehydes 6h,i, α-
amino ketone hydrochlorides 7a−g, (S)-cathinone hydro-
chloride 7j, 2-amino acetal hydrochlorides 8, 2-amino-2-
ethylbutanal hydrochloride 7i, and 2-amino-2-ethylbutane-1,1-
diol hydrochloride 9b. This material is available free of charge
via the Internet at http://pubs.acs.org.
S-2-Amino-1-phenyl-1-propanone Hydrochloride 7j. White
crystals, yield 88% (er 94:6, 54 mg): mp 185.3−185.9 °C vs 179.0−
182.0 °C in lit.;19a,24[α]D −47.2 (c 0.2, H2O, er 94:6) vs [α]D −48.0 (c
1.0, H2O, ee >95%) in lit.;19a,24 IR (cm−1) νmax 700, 1243, 1504, 1688,
1
2883; H NMR (300 MHz, CD3OD, int. ref CH3CN δ 2.00) δ 1.53
(3H, d, J = 6.9 Hz), 5.10 (1H, q, J = 6.9 Hz), 7.51−7.61 (2H, m),
7.65−7.73 (1H, m), 7.99−8.05 (2H, m); 13C NMR (75 MHz,
CD3OD, int. ref CH3CN δ 0.0) δ 16.4, 51.4, 128.6 (2C), 129.1 (2C),
132.9, 134.5, 195.0; MS (ES, pos. mode) m/z (%) 150 (M + H+ −
HCl, 100). Anal. Calcd for C9H12ClNO: C 58.23; H 6.52; N 7.54.
Found: C 58.31; H 6.69; N 7.68. All spectroscopic data were in good
agreement with reported data.19a,24
AUTHOR INFORMATION
■
2,2-Dimethoxy-1,1-dimethylethylamine Hydrochloride 8a.
White crystals, yield 75−95% (78 mg): mp 135.8−136.1 °C; IR
Corresponding Author
1
(cm−1) νmax 1073, 1186, 2936, 3388; H NMR (300 MHz, CD3OD,
*Tel: +32 (0)9 264 59 51. Fax: +32 (0)9 264 62 21. E-mail:
norbert.dekimpe@UGent.be.
int. ref CH3CN δ 2.00) δ 1.25 (6H, s), 3.55 (6H, s), 4.25 (1H, s); 13
C
NMR (75 MHz, CD3OD, int. ref CH3CN δ 0.0) δ 20.6, 57.4, 58.2,
108.0; MS (ES, pos. mode) m/z (%) 134 (M + H+ − HCl, 100). Anal.
Calcd for C6H16ClNO2: C 42.48; H 9.51; N 8.26. Found: C 42.61; H
9.88; N 8.07.
Notes
The authors declare no competing financial interest.
†Postdoctoral Fellow of the Research Foundation − Vlaanderen
(FWO)
2,2-Diethoxy-1,1-dimethylethylamine Hydrochloride 8b.
White crystals, yield 95% (68 mg): mp 130.8−131.2 °C; IR (cm−1)
1
νmax 1057, 1505, 2884, 2977; H NMR (300 MHz, CD3OD, int. ref
ACKNOWLEDGMENTS
■
CH3CN δ 2.00) δ 1.22 (6H, t, J = 7.2 Hz), 1.23−1.32 (6H, m), 3.58−
3.71 (2H, m), 3.78−3.91 (2H, m), 4.37 (1H, s); 13C NMR (75 MHz,
CD3OD, int. ref CH3CN δ 0.0) δ 14.8, 21.1, 57.4, 66.7, 105.3; MS (ES,
pos. mode) m/z (%) 162 (M + H+ − HCl, 100). Anal. Calcd for
The authors are indebted to the Research Foundation −
Flanders (FWO − Vlaanderen) and Ghent University (BOF)
for financial support.
6031
dx.doi.org/10.1021/jo300752c | J. Org. Chem. 2012, 77, 6023−6032

The Journal of Organic Chemistry
Article
L.; Sulmon, P.; Schamp, N. Tetrahedron Lett. 1983, 24, 2885. (m) De
Kimpe, N.; Verhe, R.; De Buyck, L.; Hasma, H.; Schamp, N.
Tetrahedron 1976, 32, 2457. (n) De Kimpe, N.; Verhe, R.; De Buyck,
L.; Moens, L.; Sulmon, P.; Schamp, N. Synthesis 1982, 765. (o) De
Kimpe, N.; Stanoeva, E. Synthesis 1994, 695. (p) De Kimpe, N.;
Boeykens, M.; Boelens, M.; De Buck, K.; Cornelis, J. Org. Prep. Proced.
Int. 1992, 24, 679. (q) De Kimpe, N.; Stevens, C.; Virag, M.
Tetrahedron 1996, 52, 3303. (r) De Kimpe, N.; Aelterman, W.; De
Geyter, K. J. Org. Chem. 1997, 62, 5138. (s) Aelterman, W.; Giubellina,
N.; Stanoeva, E.; De Geyter, K.; De Kimpe, N. Tetrahedron Lett. 2004,
45, 441.
REFERENCES
■
(1) (a) Baktharaman, S.; Hili, R.; Yudin, A. K. Aldrichim. Acta 2008,
41, 109 and references therein. (b) Miura, T.; Biyajima, T.; Fujii, T.;
Murakami, M. J. Am. Chem. Soc. 2012, 134, 194 and references therein.
(c) Fisher, L. E.; Muchowski, J. M. Org. Prep. Proced. Int. 1990, 22,
403. (d) Katritzky, A. R.; Cheng, D.; Musgrave, R. P. Heterocycles
1996, 42, 273. (e) Mayer, D. In Houben-Weyl, Methoden der
Organischen Chemie, 4th ed.; Muller, E. G., Ed.; Thieme: Stuttgart,
̈
1977; Vol. 7/2c, pp 2251−2307. (f) Gryko, D.; Chalko, J.; Jurczak, J.
Chirality 2003, 15, 514. (g) Eckardt, M. In Science of Synthesis; Georg
Thieme Verlag: Stuttgart, 2006; Vol. 25, p 492. (h) Suffert, J. In Science
of Synthesis; Georg Thieme Verlag: Stuttgart, 2004; Vol. 26, p 953.
(13) Singh, G. S.; D’hooghe, M.; De Kimpe, N. Chem. Rev. 2007,
107, 2080.
̂
(i) Besse, P.; Veschambre, H.; Dickman, M.; Chenevert, R. J. Org.
(14) (a) Dejaegher, Y.; Mangelinckx, S.; De Kimpe, N. J. Org. Chem.
2002, 67, 2075. (b) Li, J.-Y.; Zhao, B.-X.; Zhang, W.; Huang, X.-J.;
Wang, Y.; Sun, P.-H.; Ye, W.-C.; Chen, W.-M. Tetrahedron 2012, 68,
3972. (c) Plaquevent, J.-C.; Giard, T.; Trancard, D.; Cahard, D. Res.
Adv. Org. Chem. 1 2000, 61. (d) Duhamel, L.; Poirier, J. M.
Tetrahedron Lett. 1976, 2437.
Chem. 1994, 59, 8288. (j) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem.
Rev. 1996, 96, 835. (k) Moiseev, I. K.; Makarova, N. V.; Zemtsova, M.
N. Chem. Heterocycl. Compd. 1999, 35, 637.
(2) Kudrin, A. N.; Vorob’ev, V. G. Amino Ketones; Meditsina:
Moscow, 1970; p 346.
(3) Bechara, E. J. H.; Dutra, F.; Cardoso, V. E. S.; Sartori, A.;
(15) (a) Denolf, B.; Leemans, E.; De Kimpe, N. J. Org. Chem. 2007,
72, 3211. (b) Denolf, B.; Leemans, E.; De Kimpe, N. J. Org. Chem.
Olympio, K. P. K.; Penatti, C. A. A.; Adhikari, A.; Assunca̧ o, N. A.
Comp. Biochem. Physiol., Part C: Pharmacol., Toxicol. Endocrinol. 2007,
146, 88.
(4) Sharma, V.; Kelly, G. T.; Foulke-Abel, J.; Watanabe, C. M. H.
Org. Lett. 2009, 11, 4006.
(5) (a) Stevens, C. L.; Ash, A. B.; Thuillier, A.; Amin, J. H.; Balys, A.;
Dennis, W. E.; Dickerson, J. P.; Glinski, R. P.; Hanson, H. T.; Pillai, M.
D.; Stoddard, J. W. J. Org. Chem. 1966, 31, 2593. (b) Stevens, C. L.;
Blumbergs, P.; Monk, M. J. Org. Chem. 1963, 28, 331.
̃
2008, 73, 5662. (c) Denolf, B.; Mangelinckx, S.; Tornroos, K. W.; De
̈
Kimpe, N. Org. Lett. 2006, 8, 3129. (d) Denolf, B.; Mangelinckx, S.;
Tornroos, K. W.; De Kimpe, N. Org. Lett. 2007, 9, 187. (e) Hodgson,
̈
D. M.; Kloesges, J.; Evans, B. Org. Lett. 2008, 10, 2781. (f) Chen, Q.;
Li, J.; Yuan, C. Synthesis 2008, 2986. (g) Leemans, E.; Mangelinckx, S.;
De Kimpe, N. Synlett 2009, 1265. (h) Hodgson, D. M.; Kloesges, J.;
Evans, B. Synthesis 2009, 1923. (i) Colpaert, F.; Mangelinckx, S.;
Leemans, E.; Denolf, B.; De Kimpe, N. Org. Biomol. Chem. 2010, 8,
3251. (j) Leemans, E.; Colpaert, F.; Mangelinckx, S.; De Brabandere,
S.; Denolf, B.; De Kimpe, N. Synlett 2011, 674.
(6) Kirrmann, A.; Nouri-Bimorghi, R.; Elkik, E. Bull. Soc. Chim. Fr.
1969, 2385.
(7) Stevens, C. L.; Chang, C. H. J. Org. Chem. 1962, 27, 4392.
(8) (a) Satoh, T.; Kaneko, Y.; Sakata, K.; Yamakawa, K. Chem. Lett.
1985, 585. (b) Satoh, T.; Kaneko, Y.; Sakata, K.; Yamakawa, K. Bull.
Chem. Soc. Jpn. 1986, 59, 457. (c) Satoh, T.; Oohara, T.; Ueda, Y.;
Yamakawa, K. J. Org. Chem. 1989, 54, 3130.
(16) Fujisawa, T.; Kooriyama, Y.; Shimizu, M. Tetrahedron Lett. 1996,
37, 3881.
(17) Hua, D. H.; Lagneau, N.; Wang, H.; Chen, J. Tetrahedron:
Asymmetry 1995, 6, 349.
(18) Davis, F. A.; Jing, C. ARKIVOC 2008, ii, 190.
(9) (a) Parcell, R. F. Chem. Ind. 1963, 1396. (b) Parcell, R. F.;
Sanchez, J. P. J. Org. Chem. 1981, 46, 5229. (c) Lantos, I.; Gombatz,
K.; McGuire, M.; Pridgen, L.; Remich, J.; Shilcrat, S. J. Org. Chem.
1988, 53, 4223. (d) Ueda, S.; Naruto, S.; Yoshida, T.; Sawayama, T.;
Uno, H. Chem. Commun. 1985, 218. (e) Zawalski, R. C.; Lisiak, M.;
Kovacic, P.; Luedtke, A.; Timberlake, J. W. Tetrahedron Lett. 1980, 21,
428. (f) Morrow, D. F.; Butler, M. E.; Huang, E. C. Y. J. Org. Chem.
1965, 30, 579. (g) Ooi, T.; Takahashi, M.; Doda, K.; Maruoka, K. J.
Am. Chem. Soc. 2002, 124, 7640.
(10) (a) Jurczak, J.; Golebiowski, A. Chem. Rev. 1989, 89, 149.
(b) Reetz, M. T. Chem. Rev. 1999, 99, 1121. (c) Hili, R.; Yudin, A. K. J.
Am. Chem. Soc. 2006, 128, 14772. (d) Hili, R.; Yudin, A. K. J. Am.
Chem. Soc. 2009, 131, 16404.
(11) (a) Enders, D.; Funk, R.; Klatt, M.; Raabe, G.; Hovestreydt, E.
R. Angew. Chem., Int. Ed. Engl. 1993, 32, 418. (b) Yamazaki, S.;
Takebayashi, M. J. Org. Chem. 2011, 76, 6432. (c) Anan, H.; Tanaka,
A.; Tsuzuki, R.; Yokota, M.; Yatsu, T.; Fujikura, T. Chem. Pharm. Bull.
1996, 44, 1865. (d) de la Fuente, M. C.; Pullan, S. E.; Biesmans, I.;
Domínguez, D. J. Org. Chem. 2006, 71, 3963.
(12) (a) De Kimpe, N.; Verhe, R. In The Chemistry of α-Halo Ketones,
α-Halo Aldehydes, and α-Halo Imines; Wiley: Chichester, U.K., 1988; p
496. (b) De Kimpe, N.; Schamp, N. Org. Prep. Proced. Int. 1979, 11,
̂
(19) (a) Besse, P.; Veschambre, H.; Dickman, M.; Chenevert, R. J.
Org. Chem. 1994, 59, 8288. (b) Kohli, J. D.; Goldberg, L. I. J. Pharm.
Pharmacol. 1982, 34, 338. (c) Kalix, P. Life Sci. 1983, 32, 801.
(20) (a) Robak, M. T.; Herbage, M. A.; Ellman, J. A. Chem. Rev.
2010, 110, 3600. (b) Ferreira, F.; Botuha, C.; Chemla, F.; Perez-Luna,
A. Chem. Soc. Rev. 2009, 38, 1162.
(21) Graham, M. A.; Wadsworth, A. H.; Zahid, A.; Rayner, C. M. Org.
Biomol. Chem. 2003, 1, 834.
(22) (a) Fischer, E. Chem. Ber. 1908, 41, 1019. (b) Myers, A. G.;
Kung, D. W.; Zhong, B. J. Am. Chem. Soc. 2000, 122, 3236.
́
(23) Auge, J.; Gil, R. Tetrahedron Lett. 2002, 43, 7919.
(24) (a) Kim, D. J.; Cho, B. T. Bull. Korean Chem. Soc. 2003, 24,
1641. (b) Hwang, G. I.; Chung, J.-H.; Lee, W. K. Tetrahedron 1996,
52, 12111.
(25) (a) Kazachkov, M.; Yu, P. H. J. Chromatogr., B 2005, 824, 116.
(b) Han, Y.; Hu, H. Synthesis 1990, 615. (c) Albert, A.; Matsuura, S. J.
Chem. Soc. 1961, 5131. (d) Baumgarten, H. E.; Bower, F. A. J. Am.
Chem. Soc. 1954, 76, 4561.
(26) (a) Norris, T. O.; Mckee, R. L. J. Am. Chem. Soc. 1955, 77, 1056.
(b) Hagedorn, I.; Eholzer, U.; Etling, H. Chem. Ber. 1965, 98, 193.
(c) Cheng, S. S.; Jonsson, S.; Semeniuk, F. T. J. Pharm. Sci. 1962, 51,
108.
(27) (a) Abdalla, G. M.; Sowell, J. W. J. Heterocycl. Chem. 1987, 24,
297. (b) Castro, A. J.; Brain, D. K.; Fisher, H. D.; Fuller, R. K. J. Org.
Chem. 1954, 19, 1444. (c) Smith, P. A. S.; Most, E. E. J. Org. Chem.
1957, 22, 358. (d) Baumgarten, H. E.; Petersen, J. M. J. Am. Chem. Soc.
1960, 82, 459. (e) Dhane, D. L.; Noras, K. A.; Mushrif, A. U. Indian J.
Chem. 1975, 13, 858.
(28) Long, L. M.; Troutman, H. D. J. Am. Chem. Soc. 1949, 71, 247.
(29) (a) Bader, H.; Downer, J. D. J. Chem. Soc. 1953, 1636.
(b) Jackman, M.; Klenk, M.; Fishburn, B.; Tullar, B. F.; Archer, S. J.
Am. Chem. Soc. 1948, 70, 2884.
115. (c) De Kimpe, N.; Verhe,
Proced. Int. 1980, 12, 49. (d) De Kimpe, N.; Stanoeva, E.; Verhe,
Schamp, N. Synthesis 1988, 587. (e) De Kimpe, N.; Sulmon, P.;
́
R.; De Buyck, L.; Schamp, N. Org. Prep.
́
R.;
Moens, L.; Schamp, N.; Declerq, J.-P.; Van Meerssche, M. J. Org.
̈
Chem. 1986, 51, 3839. (f) De Kimpe, N.; Schamp, N. Bull. Soc. Chim.
Belg. 1974, 83, 507. (g) De Kimpe, N.; Verhe,
́
R.; De Buyck, L.;
Moens, L.; Schamp, N. Tetrahedron Lett. 1981, 22, 1837. (h) De
̈
Kimpe, N.; De Cock, W.; Stevens, C. Tetrahedron 1992, 48, 2739.
(i) De Kimpe, N.; Schamp, N. J. Org. Chem. 1975, 40, 3749. (j) De
Kimpe, N.; Verhe, R.; De Buyck, L.; Schamp, N. Bull. Soc. Chim. Belg.
1977, 86, 663. (k) De Kimpe, N.; Verhe, R.; De Buyck, L.; Schamp, N.
J. Org. Chem. 1977, 42, 3704. (l) De Kimpe, N.; Verhe, R.; De Buyck,
6032
dx.doi.org/10.1021/jo300752c | J. Org. Chem. 2012, 77, 6023−6032