Reformatsky Reaction to Alkynyl N- tert-Butanesulfinyl Imines: Lewis Acid Controlled Stereodivergent Synthesis of β-Alkynyl-β-Amino Acids

Article abstract of DOI:10.1021/acs.joc.8b01918

A highly diastereoselective Refortmatsky reaction to N-tert-butanesulfinyl propargylaldimines and ketimines is presented. The reaction proceeded with excellent yields and diastereoselectivities provided by the sulfinyl group in the presence of Me₃Al. The use of TBSOTf as a Lewis acid promoter switched the sense of the stereoinduction. Thus, this methodology allowed the stereodivergent asymmetric synthesis of β-alkynyl β-amino acid derivatives, from the same sulfinyl configuration, by simply changing the Lewis acid promoter.

Full text of DOI:10.1021/acs.joc.8b01918

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Note
Reformatsky Reaction to Alkynyl N-tert-Butanesulfinyl Imines: Lewis
Acid Controlled Stereodivergent Synthesis of #-Alkynyl-#-Aminoacids
Luis Fernández-Sánchez, Jose A. Fernandez-Salas, M. Carmen Maestro, and Jose Luis Garcia Ruano
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01918 • Publication Date (Web): 14 Sep 2018
Downloaded from http://pubs.acs.org on September 17, 2018
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The Journal of Organic Chemistry
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Reformatsky Reaction to Alkynyl N-tert-Butanesulfinyl Imines: Lew-
is Acid Controlled Stereodivergent Synthesis of β-Alkynyl-β-
Aminoacids
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Luis Fernández-Sánchez, ‡ José A. Fernández-Salas, ‡* M. Carmen Maestro, ‡* Jose L. García
Ruano ‡
‡ Departamento de Química Orgánica (módulo-1), Universidad Autónoma de Madrid, Cantoblanco, 28049-Madrid,
Spain
KEYWORDS. Asymmetric synthesis, N-sulfinyl imines, β-aminoacids, Reformatsky reaction, stereodivergent
ABSTRACT: A highly diastereoselective Refortmatsky reaction to N-tert-butanesulfinyl propargylaldimines and ketimines
is presented. The reaction proceeded with excellent yields and diastereoselectivities provided by the sulfinyl group in the
presence of Me3Al. The use of TBSOTf as Lewis acid promoter switched the sense of the stereoinduction. Thus, this
methodology allowed the stereodivergent asymmetric synthesis of β-alkynyl β-amino acid derivatives, from the same
sulfinyl configuration by simply changing the Lewis acid promoter.
The development of efficient and practical strategies
for the stereoselective construction of privileged struc-
tures is an ongoing objective and still holds a preferred
position in organic chemistry research.1 β-Amino acids
constitute a fundamental class of building-blocks for the
synthesis of significant molecules with interesting phar-
macological applications, showing hypoglycemic and
antiketogenic properties as well as antibacterial and anti-
fungal activities.2 Besides their intrinsic relevance, β-
amino acids are precursors for β-lactams, which are im-
portant building blocks present in a large number of anti-
biotics.3 On the other hand, the corresponding β-peptides
display high tendency towards the formation of stable
secondary structures of notable biological transcendence.4
Moreover, β-amino acids have been widely used in mod-
ern organic chemistry as chiral templates for asymmetric
synthesis.2a Therefore, several groups have focused their
attention on the development of efficient methods for the
asymmetric synthesis of β-amino acids.2a,5 Addition to
imines,5 including N-sulfinyl imines,6 of ester enolates or
silyl ketene acetals4g,4i,4k,5f and Reformatsky-type reagents7
have been the approaches of choice to face this challenge.
Although significant efforts have been devoted to synthe-
sis of β-amino acids, a number of challenges in connec-
tion with its substrate generality still persist, being the
synthesis of challenging γ,δ–alkynyl-β-amino acid deriva-
tives one of them. Propargyl β-amino acids are a special
class of non-proteinogenic amino acids. In addition to
potentially changing biological properties , these amino
acids are key intermediates for interesting compounds
with pharmacological activity, such as Xemilofiban, which
has proven to be a platelet aggregation inhibitor that can
prevent ischemia, heart attacks and other major adverse
cardiac events.8 In this regard, asymmetric synthesis of
propargylamines have been well established,9 featuring
the alkynylation of imines as the preferred approach.
Despite remarkable progress, the enolizable moiety
makes the synthesis of related γ,δ-alkynyl-β-aminoacids10
inaccessible following this strategy. To circumvent this
limitation, the use of alkynyl imines or their precursors11
as substrates in Mannich-type stereoselective reactions
has emerged in the last decades.12 Snapper and Hoveyda
described an efficient silver-catalyzed asymmetric Man-
nich reaction with chiral ligands of silyl ketene acetal, to
N-ortho-methoxyphenyl alkynyl imine.12a However, the
ortho-methoxyphenyl directing group is difficult to re-
move, requiring an oxidative procedure incompatible
with many functional groups. The diastereoselective syn-
thesis of β-alkynyl β-amino acids has also been addressed
using
a chiral auxiliary in either the imine ((S)-
phenylglycinol)12c or the nucleophile (chiral phenol deriv-
ative).12d Both methods only disclosed the reactivity of one
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α,β-unsaturated imine and a multistep oxidative cleavage
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protocol for the amino acid deliverance is required. Re-
cently, Maruoka and coworkers have followed a similar
approach pursuing the synthesis of very challenging chiral
α-tertiary amines by using alkynyl sulfinyl ketimines as
platforms, though β-amino acids synthesis is not compat-
ible with this methodology (A, Scheme 1).13 Taking all
these precedents into consideration, the development of
an efficient and general method for the asymmetric syn-
thesis of β-alkynyl β-amino acid derivatives would be
highly desirable. The great progress in the field of asym-
metric synthesis over the past decades has allowed high
control over the selectivity of a given reaction. However,
access to the opposite diastereoisomer is not usually pos-
sible by using the same set of starting materials under
similar reaction conditions. Thus, development of new
methodologies that allow access to both stereoisomers by
using the same configuration of the starting materials are
highly desirable.5f,14 Herein, we describe a Reformatsky
reaction to readily accessible N-sulfinyl alkynyl imines as
chiral templates. Facile sulfinyl cleavage would lead to the
synthesis of enantiopure β-alkynyl β-amino acid deriva-
tives. This straightforward approach gives access to both
stereoisomers of the desired γ,δ-alkynyl β-amino acids
using the same configuration at the sulfur atom of the
sulfinyl group. This stereodivergent approach relies on
the use of different Lewis acids (B, Scheme 1), which effi-
ciently switches the reactivity of the imine.
Table 1. Reformatsky reaction with alkynyl sulfinyl
imines: Optimization.a
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2a
T
t
Conv.b,c
(%)
d.r.b
(3a:3a’)
Ent
L. Acids (eq.)
(eq.) (oC) (h)
1
ꢀ
2.5
2
rt 1.25 100 (75) 87:13
2d
3
ꢀ
0
0
15
4
ꢀ
ꢀ
ꢀ
ꢀ
2.5
3.5
3.5
4
90
4
ꢀ
0
20 100 (72) 90:10
5
ꢀ
ꢀ10
ꢀ10
5
5
20
ꢀ
6
ꢀ
100 (84)
91:9
7
ꢀ
4
ꢀ40 18
ꢀ
ꢀ
ꢀ
ꢀ
8
Cu(OTf)2 (1.1)
AlMe3 (1.1)
BF3·OEt3 (2.1)
TMSOTf (2.1)
TBSOTf (2.1)
4
rt
22
9
4
ꢀ78
rt
3
100 (88) >98:2
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11
12
4
22 100 (80) 86:14
4
ꢀ78
ꢀ78
6
65 (62)
14:86
4
6
100 (86)
7:93
a
Scheme 1. Previous works (A), present work (B).
All reactions were carried out with 1a (0.1 mmol) and Zn (0.4
b
1
c
mmol) in 0.25 mL of THF. Determined by H-NMR. Isolated
yield of the major diastereoisomer in brackets. d Reaction carried
out with 2 equiv. of Zn.
We began our studies investigating the Reformatsky
reaction of the α-bromo ester derivative 2a and the al-
kynyl N-sulfinyl imine bearing a phenyl ring 1a as model
substrate (Table 1). After optimizing the amount of
Reformatsky reagent (2a) and the temperature (entries 1-
6), the reaction showed a good efficiency when carried
With the aim of developing a new stereodivergent
procedure, which would allow us to synthesize both enan-
tiomers of the corresponding alkynyl β-amino acid deriva-
tive starting from the same configuration at the sulfinyl
group, we used a highly oxophilic Lewis acid which could
potentially modify the transition state through which the
reaction takes place. Consequently, when the reaction
o
out at -10 C in presence of 4 equivalents of the α-bromo
o
ester (entry 6). At -40 C the reaction did not take place
and the starting imine was recovered (entry 7). Gratify-
ingly, in the presence of AlMe3 at -78 oC,15 the desired γ,δ–
alkynyl-β-amino ester derivative 3a was obtained with
complete diastereoselectivity (>98:2) in 88% isolated yield
(entry 9).
was performed in the presence of BF3·OEt2, compound
with the S configuration (3a) was still obtained as major
diastereoisomer (entry 10). TMSOTf reverses the selectivi-
ty of the reaction, leading to R-configured isomer with a
reasonably high stereocontrol (entry 11). To our delight,
when a more sterically hindered silyl derivative was used,
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of such β-alkynyl β-tertiary amino acid derivatives has
the diastereoselectivity was improved up to 93:7, since the
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facial discrimination increased as well (entry 12).
never been described. The absolute configuration of the
asymmetric centers of 3g were unequivocally assigned as
(Rs, S) by X-ray crystallographic analysis.16
After optimizing the reaction conditions, we studied
the scope of the reaction regarding the synthesis of the S
isomer. The results were summarized in Scheme 1. Firstly,
different substitution in the aryl unit was considered.
Arenes bearing an electron-rich (OMe) and an electron-
deficient group (CO2Me) as well as a bromo group in
both ortho and para position were well tolerated and the
desired products were obtained with complete diastere-
oselectivity and from good to excellent yields (3b-3e).
Aliphatic alkynyl imine 1f led to the β-amino ester prod-
uct in high yield and only one diastereomer was observed
(3f). Similarly, imine 1g, bearing a TMS-substituted al-
kyne, underwent efficient Reformatsky reaction to give
versatile product 3g.
We then studied the Reformatsky reaction to alkynyl
N-sulfinyl imines mediated by TBSOTf in order to evalu-
ate the scope of reaction (Table 3). Regarding the al-
dimines, these new reaction conditions tolerated elec-
tron-rich (OMe) and electron-deficient groups (CO2Me)
as well as a bromo substituent in both ortho and para
position of the phenyl group, leading to the desired β-
amino ester products in good yields and diastereoselectiv-
ities (3a’-e’). Imines bearing alkyl and TMS substituted
alkynes underwent efficient Reformatsky reaction, to give
adducts 3f’ and 3g’ in good yields and very good diastere-
oselectivities. No reaction was observed with methyl
ketimine 1h.
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Table 2. Highly diastereoselective Reformastky reac-
tion to alkynyl N-sulfinyl imines: AlMe3.a
Table 3. Highly diastereoselective Reformastky reac-
tion to alkynyl N-sulfinyl imines: TBSOTf.a
a All reactions were carried out with 1 (0.1 mmol), 2a (0.4 mmol),
Zn (0.4 mmol) and TBSOTf (0.21 mmol) in 0.25 mL of THF. The
1
diastereomeric ratio was determined by H NMR. Isolated yields
of the major diastereoisomer.
a All reactions were carried out with 1 (0.1 mmol), 2a (0.4 mmol),
Zn (0.4 mmol) and AlMe3 (0.11 mmol) in 0.25 mL of THF. The
diastereomeric ratio was determined by 1H NMR. Isolated yields.
We propose that the Reformatsky reaction proceeded
via a chair-like transition state17 where both the bulky
tert-butyl ester group and the substituent in the sulfinyl
imine could occupy equatorial positions. The reaction
with aldimines (E isomer) and ketimines (Z isomer) takes
place through a common transition state, although the
E/Z isomeric distribution of the starting imine should be
considered. Me3Al would be simply acting as Lewis acid,
enhancing the reactivity of the imine.18 In this context,
Me3Al could also be involve in differentiating the two
Me3Al imine isomers reaction rates, which are in rapid
equilibrium.13a,17a,19 Highly oxophilic Lewis acid (R3SiOTf)
could potentially coordinate to the oxygen atom of the
sulfinyl group, disengaging the six-membered chair-like
In addition to sulfinyl aldimines, the corresponding
less reactive and challenging ketimines proved to be suit-
able substrates in the Me3Al-promoted Reformatsky reac-
tion. Thus, differently substituted aryl and alkyl terminus
acetylene ketimines led to the desired β-amino ester with
a α-tertiary amine moiety with complete diastereselectivi-
ty (3h-3k). It should be noted, that chiral α-tertiary
amines are fundamental and recurrent motifs in naturally
occurring and synthetic bioactive compounds and their
synthesis still stands as an important challenge in organic
chemistry.13a To the best of our knowledge, the synthesis
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Page 4 of 10
vacuum/nitrogen. For thin layer chromatography (TLC) silica
transition state. Thus, the reaction would take place un-
der non-chelation control. The tert-butyl group of the
sulfinyl group would direct the approach of the nucleo-
phile to the less hindered re-face of the imine, leading to
the opposite configuration (R) at the carbon atom that
bears the amino group (Scheme 2).
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gel plates with fluorescence indicator 254 nm were used and
compounds were visualized by irradiation with UV light
and/or by treatment with a solution of potassium permangaꢀ
nate in water followed by heating. Flash column chromatogꢀ
raphy was performed using silica gel (230−400 mesh) and
compressed air. Hexane, ethyl acetate, dichloromethane and
diethyl ether for flash chromatography were acquired from
commercial sources and were used without previous purificaꢀ
tion. Optical rotation was recorded in cells with 10 cm path
length; the specific solvents and concentrations (in g/100 mL)
are indicated. NMR spectra were acquired on a Bruker Avance
300 MHz spectrometer, running at 300, 75 and 282 MHz for
1H, 13C and 19F respectively. Chemical shifts (δ) are reported
in ppm relative to residual solvent signals (CDCl3, 7.26 ppm
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1
for H NMR and 77.2 ppm for 13C NMR respectively). 13C
NMR spectra were acquired on a broad band decoupled mode.
The following abbreviations are used to describe peak patterns
when appropriate: s (singlet), d (doublet), t (triplet), q (quarꢀ
tet), m (multiplet), bs (broad singlet). Mass spectra (MS) were
obtained by ESI ionization mode. High resolution mass specꢀ
tra (HRMS) were performed by ESI ionization mode using a
time ofꢀflight (TOF) mass analyzer, as indicated for each
compound. Zn, dust; <10µ (2.5g). Zinc was previously actiꢀ
vated by washing successively with HCl 5% (3 x 3ml), H2O (3
x 3ml), acetone (3 x 3 ml) and anhydrous Et2O (3 x 3 ml).
Then, it was carefully dried under high vacuum.
Scheme 2. Proposed transition states for AlMe3- and
R3SiOTf-mediated Reformatsky reactions
As mentioned above, apart from the high stereoinduc-
tion provided, the tert-butane sulfinyl group is an easily
removable auxiliary (Scheme 3). Treatment of sulfina-
mides 3a and 3f with HCl in methanol allows the efficient
deprotection to the amino ester (4a and 4f) in high yields
without erosion in the enantiomeric purity, whereas de-
liverance of the optically pure β-alkynyl β-amino acid (5a
and 5f) was efficiently accomplished in the presence of
H2O.
Nꢀsulfinyl imine synthesis.
General procedure A: Synthesis of N-sulfinyl aldimines
(1a-g): To a solution of (R)ꢀtertꢀbutane sulfinamide (2.5
mmol) in anhydrous THF (6.5 mL) under argon atmosphere, a
solution of the corresponding aldehyde (3 mmol) in anhydrous
THF (1 mL) was added. Subsequently, Ti(OEt)4 (10 mmol)
was added and the mixture was stirred at 40ꢀ45 ºC. After 16h,
MeOH (2.5 mL) and a solution of saturated NaHCO3 were
added until formation of a yellow precipitate was observed.
The crude of reaction was filtered over celite, dried with
MgSO4 and the solvent was evaporated under reduced presꢀ
sure. The residue was purified by flashꢀcolumn chromatogꢀ
raphy.
General procedure B. Synthesis of N-sulfinyl ketimines
(1h-1k): To a solution of (R)ꢀtert-butane sulfinamide (0.43
mmol) in anhydrous CH2Cl2 (5.6 mL) under argon atmosphere,
a solution of the corresponding ketone (0.52 mmol) in anhyꢀ
drous CH2Cl2 (1mL) was added. Subsequently, Ti(OEt)4 (1.7
mmol) was added and the mixture was heated at reflux. After
4 hours Ti(OEt)4 (1.72 mmol) was added. After 16h, MeOH
(2.5 mL) and a solution of saturated NaHCO3 were added until
a formation of yellow precipitate was observed. The crude of
reaction was filtered through celite, dried with MgSO4 and the
solvent was evaporated under reduced pressure. The residue
was purified by flashꢀcolumn chromatography.
Scheme 3. Sulfinyl group cleavage. Synthesis of β-alkynyl β-
amino esters and β-amino acids
In conclusion, we have described a highly diastereose-
lective Reformatsky reaction to enantiopure alkynyl N-
sulfinylimines. The methodology tolerates a reasonably
high range of aldimines and ketimines bearing differently
substituted alkynyl groups. In addition, by simply chang-
ing the Lewis acid promoter, the reactivity switched, and
allowed to prepare selectively both epimers from N-
sulfinylimines with the same configuration at the sulfur
atom. Finally, the sulfinyl group can be easily removed,
leading to the desired enantiomerically pure β-alkynyl β-
amino acids.
(RS,E)-2-Methyl-N-(3-phenylprop-2-ynylidene)propane-2-
sulfinamide (1a)
Following the general procedure A, 3ꢀphenylpropiolaldehyde
(3 mmol), gave 1a (636 mg, 2.73 mmol, 91% yield). Eluent: nꢀ
1
hexane/AcOEt (8/1). [α]20 ꢀ242.0 (c 1.00, CHCl3). H NMR
EXPERIMENTAL SECTION
D
(CDCl3): δ 8.03 (s, 1H), 7.60ꢀ7.57 (m, 2H), 7.46ꢀ7.35 (m, 3H),
1.26 (s, 9H). 13C NMR (CDCl3): δ 147.8, 132.6, 130.4, 128.6,
120.9, 100.1, 85.6, 58.4, 22.6. IR (NaCl): 2961, 2868, 2204,
1727, 1563, 1364, 1179, 1090 cmꢀ1. MS (ESI+) m/z (%): 489
General considerations: All solvents were dried using acꢀ
tivated 4Å molecular sieves and stored under nitrogen. 4Å
molecular sieves, 1.6ꢀ2.5 mm of particle size, were activated
by microwave (700W) (3 x 60 sec) and subsequent cycles of
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+
(2M+Na) (61), 256 (M+Na)+ (87), 234 (M+H)+ (37), 178
(100), 115 (35). HRMS (ESI): m/z calcd for C13H16NOS
[M+H]+: 234.0947, found: 234.0949.
(6/1). The spectroscopic data are in accordance with the
literature.20
(RS,E)ꢀ2ꢀMethylꢀNꢀ[3ꢀ(trimethylsilyl)propꢀ2ꢀ
ynylidene]propaneꢀ2ꢀsulfinamide (1g)
1
2
3
(RS,E)-N-[3-(4-Methoxyphenyl)prop-2-ynylidene]-2-
methylpropane-2-sulfinamide (1b)
Following
the
general
procedure
A,
3ꢀ
4
5
6
7
8
9
Following
the
general
procedure
A,
3ꢀ(4ꢀ
(trimethylsilyl)propiolaldehyde (3 mmol), gave 1g (543 mg,
2.37 mmol, 79% yield). Eluent: nꢀhexane/AcOEt (from 7/1 to
methoxyphenyl)propiolaldehyde (3 mmol), gave 1b (731 mg,
2.76 mmol, 92% yield). Eluent: nꢀhexane/AcOEt (6/1). [α]20
3/1). [α]20 ꢀ268.9 (c 0.85, CHCl3); H NMR (CDCl3): δ 7.78
1
D
D
1
ꢀ168.5 (c 0.82, CHCl3). H NMR (CDCl3): δ 8.01 (s, 1H),
(s, 1H), 1.22 (s, 9H), 0.25 (s, 9H). 13C NMR (CDCl3): δ 148.4,
108.4, 100.3, 59.0, 23.2, 0.0. IR (NaCl): 2962, 2928, 2902,
2869, 2202, 1563, 1365, 1250, 1098, 1070 cmꢀ1. MS (ESI+)
m/z (%): 545 (68), 481 (2M++Na) (16), 284 (26), 252
(M+Na)+ (22), 230 (M +1)+ (46), 174 (100), 156 (15). HRMS:
m/z calcd for C10H20NOSSi [M+H]+: 230.1029, found:
230.1021.
7.54ꢀ7.51 (m, 2H), 6.90ꢀ6.87 (m, 2H), 3.83 (s, 3H), 1.25 (s,
9H). 13C NMR (CDCl3): δ 161.4, 147.9, 134.6, 114.4, 113.2,
101.2, 85.3, 58.3, 55.4, 22.6. IR (NaCl): 2983, 2961, 2868,
2846, 2197, 1603, 1560, 1509, 1459, 1296, 1174, 1085, 1033
cmꢀ1. MS (ESI+) m/z (%): 549 (2M+Na)+ (60), 286 (M+Na)+
(8), 264 (M+1)+ (52), 208 (100), 180 (18), 139 (36). HRMS:
m/z calcd for C14H18NO2S [M+H]+: 264.1052, found:
264.1060.
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(RS,Z)-2-methyl-N-(4-phenylbut-3-yn-2-ylidene)propane-2-
sulfinamide (1h)13a
(RS,E)-Ethyl
ynyl]benzoate (1c)
Following the general procedure A, ethyl 4ꢀ(3ꢀoxopropꢀ1ꢀynꢀ
4-[3-(tert-butylsulfinylimino)prop-1-
Following the general procedure B, 4ꢀphenylbutꢀ3ꢀynꢀ2ꢀone
(0.43 mmol), gave 1h (80 mg, 0.3225 mmol, 75% yield) as a
mixture of isomers Z:E (93:7). Eluent: nꢀhexane/AcOEt (5/1).
1
1ꢀyl)benzoate (3 mmol), gave 1c (631 mg, 2.07 mmol, 69%
[α]20 ꢀ208.3 (c 0.70, CHCl3). H NMR (CDCl3): δ 7.57ꢀ7.54
D
yield). Eluent: nꢀhexane/AcOEt (6/1). [α]20 ꢀ154.1 (c 0.85,
(m, 2H), 7.46ꢀ7.35 (m, 3H), 2.46 (s, 3H), 1.27 (s, 9H); 13C
NMR (CDCl3): δ 162.1, 132.5, 130.5, 128.6, 120.7, 102.2,
84.2, 56.9, 29.4, 22.2. IR (NaCl): 2982, 2926, 2865, 2209,
2158, 1563, 1365, 1178, 1081 cmꢀ1. MS (ESI+) m/z (%): 517
(2M++Na) (90), 270 (M+Na)+ (17), 248 (M+1)+ (23), 192
(100). HRMS: m/z calcd for C14H18NOS [M+H]+: 248.1103,
found: 248.1108.
D
1
CHCl3); H NMR (CDCl3): δ 8.04 (s, 1H), 8.06ꢀ8.04 (m, 2H),
7.65ꢀ7.62 (m, 2H), 4.39 (c, J= 7.1 Hz, 2H), 1.39 ( t, J= 7.1 Hz,
3H), 1.26 (s, 9H). 13C NMR (CDCl3): δ 165.6, 147.5, 132.4,
132.4, 131.8, 129.6, 125.2, 98.5, 87.4, 61.4, 58.6, 22.6, 14.3.
IR (NaCl): 2981, 2929, 2870, 2206, 1721, 1564, 1274, 1176,
1092 cmꢀ1. MS (ESI+) m/z (%): 633 (2M+Na)+ (55), 306
(M+1)+ (69), 250 (100), 187 (9). HRMS: m/z calcd for
C16H20NO3S [M+H]+: 306.1158, found: 306.1165.
(RS,Z)-N-[4-(2-Methoxyphenyl)but-3-yn-2-ylidene]-2-
methylpropane-2-sulfinamide (1i)
(RS,E)-N-[3-(4-Bromophenyl)prop-2-ynylidene]-2-
methylpropane-2-sulfinamide (1d)
Following the general procedure B, 4ꢀ(2ꢀmethoxyphenyl)butꢀ
3ꢀynꢀ2ꢀone (0.43 mmol), gave 1h (103 mg, 0.37 mmol, 86%
Following the general procedure A, ethyl 3ꢀ(4ꢀ
bromophenyl)propiolaldehyde (3 mmol), gave 1d (758 mg,
2.43 mmol, 81% yield). Eluent: nꢀhexane/AcOEt (5/1). [α]20D ꢀ
130.6 (c 0.96, CHCl3). 1H NMR (CDCl3): δ 8.00 (s, 1H), 7.54ꢀ
7.50 (m, 2H), 7.45ꢀ7.41 (m, 2H), 1.25 (s, 9H). 13C NMR
(CDCl3): δ 147, 133.9, 132.0, 125.1, 119.8, 98.7, 86.4, 58.5,
22.6. IR (NaCl): 2961, 2926, 2868, 2205, 1562, 1486, 1179,
1090, 1011 cmꢀ1. MS (ESI+) m/z (%) 647 (2M+Na)+ (28), 314
(M +3)+ (66), 312 (M+1)+ (64), 258 (100), 256 (100). HRMS:
m/z calcd for C13H14BrNOS [M+H]+: 312.0052, found:
312.0036.
yield). Eluent: nꢀhexane/AcOEt (from 4/1 to 3/1). [α]20
ꢀ
D
1
212.9 (c 0.70, CHCl3); H NMR (CDCl3): δ 7.49 (d, J = 7.5
Hz, 1H), 7.39 (t, J = 7.9 Hz, 1H), 6.96ꢀ6.88 (m, 2H), 3.88 (s,
3H), 2.46 (s, 3H), 1.26 (s, 9H). 13C NMR (CDCl3): δ 162.4,
161.1, 134.6, 132.4, 120.6, 110.9, 109.8, 99.4, 88.3, 57.0,
55.8, 29.2, 22.2.; IR (NaCl): 2961, 2210, 2118, 1568, 1491,
1463, 1280, 1249, 1087cmꢀ1. MS (FAB+) m/z (%): 555
(2M+1)+ (18), 278 (M+1)+ (100), 222 (58), 57 (21). HRMS:
m/z calcd for C15H20NO2S [M+H]+: 278.1215, found:
278.1219.
(RS,Z)-N-[4-(4-Bromophenyl)but-3-yn-2-ylidene]-2-
methylpropane-2-sulfinamide (1j)
(RS,E)-N-[3-(2-Bromophenyl)prop-2-ynylidene]-2-
methylpropane-2-sulfinamide (1e)
Following
Following the general procedure B, 4ꢀ(2ꢀmethoxyphenyl)butꢀ
3ꢀynꢀ2ꢀone (0.43 mmol), gave 1j (129 mg, 0.4 mmol, 92%
yield) as a mixture of isomers Z:E (92:8). Eluent: nꢀ
hexane/AcOEt (from 8/1 to 2/1). [α]20D ꢀ311.9 (c 0.61, CHCl3).
1H NMR (CDCl3): δ 7.53ꢀ7.40 (AA´BB´ system, 4H), 2.45 (s,
3H), 1.26 (s, 9H). 13C NMR (CDCl3): δ 161.4, 133.91, 132.0,
125.3, 119.5, 100.9, 85.2, 57.1, 29.3, 22.2. IR (NaCl): 2968,
2924, 2865, 2211, 1558, 1471, 1081 cmꢀ1. MS (FAB+) m/z
(%): 651 (2M+1)+ (9), 326 (M+1)+ (96), 272 (56), 270 (59), 57
(86). HRMS: m/z calcd for C14H17NOSBr [M+H]+: 326.0214,
found: 326.0218.
the
general
procedure
A,
3ꢀ(2ꢀ
bromophenyl)propiolaldehyde (3 mmol), gave 1e (727 mg,
2.34 mmol, 78% yield). Eluent: nꢀhexane/AcOEt (5/1); [α]20D ꢀ
1
171.1 (c 1.03, CHCl3). H NMR (CDCl3): δ 8.08 (s, 1H),
7.64ꢀ7.58 (m, 2H), 7.34ꢀ7.24 (m, 2H), 1.26 (s, 9H). 13C NMR
(CDCl3): δ 147.6, 134.4, 132.8, 131.4, 127.2, 126.4, 123.3,
97.8, 89.1, 58.6, 22.6. IR (NaCl): 2961, 2926, 2867, 2206,
1561, 1470, 1179, 1090 cmꢀ1. MS (ESI+) m/z (%): 647
(2M+Na)+ (16), 312 (M +1)+ (53), 258 (100), 256 (100);
HRMS: m/z calcd for C13H14BrNOS [M+H]+: 312.0052,
found: 312.0045.
(RS,Z)-N-(Hex-3-yn-2-ylidene)-2-methylpropane-2-
sulfinamide (1k)
Following the general procedure B, hexꢀ3ꢀynꢀ2ꢀone (0.43
(RS,E)-2-Methyl-N-(oct-2-ynylidene)propane-2-
sulfinamide (1f)
Following the general procedure A, octꢀ2ꢀynal (3mmol), gave
1f (361 mg, 1.59 mmol, 53% yield). Eluent: nꢀhexane/AcOEt
mmol), gave 1k (63 mg, 0.32 mmol, 73% yield). Eluent: nꢀ
1
hexane/AcOEt (4/1). [α]20 ꢀ242.6 (c 0.67, CHCl3). H NMR
D
(CDCl3): δ 2.42 (q, J = 7.4 Hz, 2H), 2.31 (s, 3H), 1.22ꢀ1.17
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(m, 3H), 1.20 (s, 9H). 13C NMR (CDCl3): δ 163.4, 106.9, 76.3,
Page 6 of 10
Following the general procedure C, imine 1c (0.43 mmol)
1
2
3
4
5
6
7
8
56.5, 29.5, 22.0, 13.3, 12.8. IR (NaCl): 2980, 2215, 1578,
1364, 1252, 1088 cmꢀ1. MS (FAB+) m/z (%): 399 (2M+1)+
(10), 200 (M+1)+ (100), 144 (53), 57 (34). HRMS: m/z calcd
for C10H18NOS [M+H]+: 200.1109, found: 200.1107.
after 16h, gave 3c as major diastereoisomer (156 mg, 0.37
mmol, 86% yield). Eluent: nꢀhexane/AcOEt, (3/1 to 2/1).
[α]20D ꢀ48.6 (c 1.48, in CHCl3); 1H NMR (CDCl3): δ 8.00ꢀ7.88
(m, 2H), 7.51ꢀ7.39 (m, 2H), 4.70ꢀ4.64 (m, 1H), 4.42 (d, J= 6.8
Hz, 1H), 4.36 (c, J= 7.2 Hz, 2H), 2.89 (dd, J= 16.0, 5.1 Hz,
1H), 2.79 (dd, J= 15.9, 7.0 Hz, 1H), 1.47 (s, 9H), 1.38 (t, J=
7.2 Hz, 3H), 1.25 (s, 9H). 13C NMR (CDCl3): δ 169.6, 166.0,
131.6, 130.2, 129.4, 127.0, 90.1, 84.4, 81.9, 61.2, 56.1, 45.4,
42.6, 28.1, 22.6, 14.3. IR (NaCl): 2979, 2927, 2205, 1720,
1606, 1458, 1367, 1273, 1163 cmꢀ1. MS (ESI+): m/z (%): 865
(2M+Na)+ (15), 843 (2M+1)+ (100), 444 (M+Na)+ (4), 422
(M+1)+ (8), 366 (22). HRMS: m/z calcd for C22H32NO5S
[M+H]+: 422.1995, found: 422.1970.
Diastereoselective Reformatsky reaction to imines.
General procedure C. Table 2. AlMe3: To a solution of the
corresponding imine (0.086 mmol) in anhydrous THF (0.2
o
mL) under argon atmosphere at ꢀ78 C, AlMe3 (0.0946 mmol)
was added, and the mixture stirred for 5 min. Then, orꢀ
o
ganozinc reagent21 was dropwise added at ꢀ78 C. After the
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
time indicated at the table 2, NH4Cl (sat. solution, 1.5 mL) was
added. The organic phase was separated, and the aqueous
layer was extracted with Et2O (2 x 10mL) and CH2Cl2 (10
mL), dried over MgSO4, filtered and the solvent evaporated
under reduced pressure. The residue was purified by flashꢀ
column chromatography.
tert-Butyl
(S)-5-(4-bromophenyl)-3-[(RS)-1,1-
dimethylethylsulfinamido]pent-4-ynoate (3d)
Following the general procedure C, imine 1d (0.43 mmol)
after 2h, gave 3d as major diastereoisomer (158 mg, 0.37
mmol, 86% yield). Eluent: nꢀhexane/AcOEt, (3/1 to 2/1).
[α]20D ꢀ47.6 (c 0.70, in CHCl3). 1H NMR (CDCl3): δ 7.37ꢀ7.34
(m, 2H), 7.21ꢀ7.18 (m, 2H), 4.67ꢀ4.60 (m, 1H), 4.39 (d, J= 6.7
Hz, 1H), 2.80 (dd, J = 15.9, 5.2 Hz, 1H), 2.71 (dd, J = 16.0,
7.0 Hz, 1H), 1.48 (s, 9H), 1.24 (s, 9H). 13C NMR (CDCl3): δ
169.6, 133.1, 131.5, 122.8, 121.4, 88.3, 84.1, 81.8, 56.0, 45.3,
42.6, 28.1, 22.6. IR (NaCl): 2978, 2923, 2208, 1729, 1486,
1367, 1153, 1070 cmꢀ1. MS (ESI+): m/z (%): 879 (2M++Na)
(27), 857 (2M+1)+ (100), 430 (M +3)+ (27), 428 (M+1)+ (24).
HRMS: m/z calcd for C19H26NO3SBr [M+H]+: 428.0889,
found: 428.0871.
General procedure D. Table 3. TBSOTf: To a solution of
the corresponding imine (0.086 mmol) in anhydrous THF (0.2
mL) under argon atmosphere at ꢀ78 oC, TBSOTf (0.181 mmol)
was added. The mixture was stirred 5 min. To the resulting
o
mixture organozinc reagent4 was added dropwise at ꢀ78 C.
After the time indicated in the table 3, NH4Cl (sat. solution,
1.5 mL) was added. The organic phase was separated and the
aqueous layer was extracted with Et2O (2 x 10mL) and CH2Cl2
(10 mL), dried over MgSO4, filtered and the solvent was
evaporated under reduced pressure. The residue was purified
by flashꢀcolumn chromatography.
tertꢀButyl
(S)ꢀ3ꢀ[(RS)ꢀ1,1ꢀdimethylethylsulfinamido]ꢀ5ꢀ
phenylpentꢀ4ꢀynoate (3a)
tert-Butyl
(S)-5-(2-bromophenyl)-3-[(RS)-1,1-
Following the general procedure C, imine 1a (0.43 mmol)
after 3h, gave 3a as major diastereoisomer (132 mg, 0.38
mmol, 88% yield). Eluent: nꢀhexane/AcOEt, (2/1). [α]20D ꢀ59.4
(c 0.63, CHCl3). 1H NMR (CDCl3): δ 7.43ꢀ7.40 (m, 2H), 7.31ꢀ
7.27 (2m, 3H), 4.70ꢀ4.64 (m, 1H), 4.41 (d, J= 6.7 Hz, 1H),
2.88 (dd, J= 15.9, 5.2 Hz, 1H), 2.78 (dd, J= 15.9, 7.0 Hz, 1H),
1.48 (s, 9H), 1.26 (s, 9H); 13C NMR (CDCl3): δ 169.7, 131.7,
128.5, 128.3, 122.5, 87.1, 85.1, 81.8, 56.0, 45.4, 42.8, 28.1,
22.6. IR (NaCl): 2979, 2928, 2203, 1731, 1367, 1154, 1069
cmꢀ1; MS (ESI+): m/z (%): 721 (2M+Na)+ (100), 699 (2M+1)+
(48), 350 (M+1)+ (16), 294 (40). HRMS: m/z calcd for
C19H28NO3S [M+H]+: 350.1784; found: 350.1787.
dimethylethylsulfinamido]pent-4-ynoate (3e)
Following the general procedure C, imine 1e (0.43 mmol)
after 10 h, gave 3e as major diastereoisomer (180 mg, 0.42
mmol, 98% yield). Eluent: nꢀhexane/AcOEt, (3/1 to 2/1).
[α]20D ꢀ56.9 (c 0.50, in CHCl3); 1H NMR (CDCl3): δ 7.56ꢀ7.54
(m, 1H), 7.45ꢀ7.42 (m, 1H), 7.26ꢀ7.21(m, 1H), 7.18ꢀ7.12 (m,
1H), 4.74ꢀ4.68 (m, 1H), 4.46 (d, J= 6.8 Hz, 1H), 2.86 (dd, J =
16.1, 5.1 Hz, 1H), 2.76 (dd, J = 16.1, 6.8 Hz, 1H), 1.47 (s,
9H), 1.25 (s, 9H). 13C NMR (CDCl3): δ 169.6, 133.5, 132.4,
129.6, 127.0, 125.6, 124.6, 91.8, 83.6, 81.8, 56.1, 45.5, 42.6,
28.1, 22.6. IR (NaCl): 2979, 2928, 2870, 2206, 1729, 1471,
1367, 1154, 1062 cmꢀ1. MS (ESI+): m/z (%): 879 (2M++Na)
(40), 857 (2M+1)+ (100), 428 (M+1)+ (27). HRMS: m/z calcd
for C19H26NO3SBr [M+H]+: 428.0889, found: 428.0867.
tert-Butyl (S)-3-[(RS)-1,1-dimethylethylsulfinamido]dec-4-
ynoate (3f)
tertꢀButyl
(S)ꢀ3ꢀ{[(RS)ꢀtertꢀbutylsulfinyl]amino}ꢀ5ꢀ(4ꢀ
methoxyphenyl)pentꢀ4ꢀynoate (3b)
Following the general procedure C, imine 1b (0.43 mmol)
after 3h, gave 3a as major diastereoisomer (137 mg, 0.36
mmol, 84% yield). Eluent: nꢀhexane/AcOEt, (2/1). 97 % e.d.
(Chiralcel OD, 1.0 mL/min, hexane/iPrOH (95:5), λ=254nm,
Following the general procedure C, imine 1f (0.43 mmol) after
5 h, gave 3f as major diastereoisomer (136 mg, 0.40 mmol,
tRR = 12.0 min, tRS = 19.6 min, . [α]20 ꢀ41.9 (c 1.08, CHCl3).
92% yield). Eluent: nꢀhexane/AcOEt, (3/1 to 1/1). [α]20 ꢀ57.6
D
D
1H NMR (CDCl3): δ 7.39ꢀ7.32 (m, 2H), 6.84ꢀ6.79 (m, 2H),
4.67ꢀ4.61 (m, 1H), 4.38 (d, J= 6.7 Hz, 1H), 3.80 (s, 3H), 2.87
(dd, J= 15.8, 5.2 Hz, 1H), 2.77 (dd, J= 15.8, 7.0 Hz, 1H), 1.47
(s, 9H), 1.25 (s, 9H). 13C NMR (CDCl3): δ 169.8, 159.8, 133.2,
114.6, 113.9, 85.7, 85.1, 81.7, 56.0, 55.3, 45.5, 43.0, 28.1,
22.6. IR (NaCl): 2980, 2924, 2198, 1731, 1366, 1249, 1153
cmꢀ1. MS (ESI+): m/z (%): 781 (2M+Na)+ (26), 759 (2M+1)+
(100), 380 (M+1)+ (4). HRMS: m/z calcd for C20H30NO4S
[M+H]+: 380.1890, found: 380.1890.
(c 1.76, in CHCl3). H NMR (CDCl3): δ 4.43ꢀ4.37 (m, 1H),
1
4.25 (d, J= 6.2 Hz, 1H), 2.74 (dd, J = 15.9, 5.2 Hz, 1H), 2.65
(dd, J = 15.9, 7.0 Hz, 1H), 2.16 (dt, J= 2.0, 7.0 Hz, 2H), 1.45
(s, 9H), 1.40ꢀ1.27 (m, 5H), 1.22 (s, 9H), 0.88 (t, J= 6.9 Hz,
3H). 13C NMR (CDCl3): δ 169.9, 86.0, 81.5, 78.0, 55.8, 44.9,
43.2, 31.0, 28.2, 28.1, 22.6, 22.2, 18.6, 14.0. IR (NaCl): 2959,
2932, 2862, 2204, 1732, 1367, 1156, 1061 cmꢀ1. MS (ESI+):
m/z (%): 709 (2M+Na)+ (100), 687 (2M+1)+ (34), 344 (M+1)+
(29), 288 (76), 214 (13). HRMS: m/z calcd for C18H34NO3S
[M+H]+: 344.2253; found: 344.2259.
Ethyl
4-((S)-5-(tert-butoxy)-3-[(RS)-1,1-
dimethylethylsulfinamido]-5-oxopent-1-yn-1-yl)benzoate (3c)
tert-Butyl
(S)-3-[(RS)-1,1-dimethylethylsulfinamido]-5-
(trimethylsilyl)pent-4-ynoate (3g)
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The Journal of Organic Chemistry
(d, J = 15.1 Hz, 1H), 2.52 (d, J = 15.1 Hz, 1H), 2.18 (c, J = 7.5
Following the general procedure C, imine 1g (0.43 mmol)
1
2
3
4
5
6
7
8
after 16 h, gave 3g as major diastereoisomer (138 mg, 0.4
Hz, 2H), 1.51 (s, 3H), 1.45 (s, 9H), 1.19 (s, 9H), 1.10 (t, J =
7.5 Hz, 3H). 13C NMR (CDCl3): δ 170.0, 87.1, 81.6, 80.6,
55.6, 51.1, 48.6, 29.5, 28.1, 22.6, 13.7, 12.4. IR (NaCl): 2979,
1719, 1458, 1236, 1158, 1068 cmꢀ1. MS (ESI+): m/z (%): 631
(2M+1)+ (19), 316 (M+1)+ (100), 260 (94), 186 (35), 57 (63).
HRMS: m/z calcd for C16H30NO3S [M+H]+: 316.1946; found:
316.1945.
mmol, 93% yield). Eluent: nꢀhexane/AcOEt, (2/1). [α]20D ꢀ56.9
1
(c 0.70, in CHCl3). H NMR (CDCl3): δ 4.43ꢀ4.37 (m, 1H),
4.31 (d, J= 7.4 Hz, 1H), 2.64 (dd, J = 15.9, 5.2 Hz, 1H), 2.53
(dd, J = 15.9, 6.6 Hz, 1H), 1.45 (s, 9H), 1.21 (s, 9H), 0.13 (s,
9H). 13C NMR (CDCl3): δ 169.9, 103.7, 89.9, 81.9, 56.2, 45.8,
43.0, 28.3, 22.8, 0.0. IR (NaCl): 2955, 2929, 2207, 2867,
1737, 1315, 1153, 1055 cmꢀ1. MS (ESI+): m/z (%): 713
(2M+Na)+ (100), 691 (2M+1)+ (30), 346 (M++1) (34), 290
(90). HRMS: m/z calcd for C16H32NO3SSi [M+H]+: 346.1866;
found: 346.1882.
tert-Butyl
(R)-3-[(RS)-1,1-dimethylethylsulfinamido]-5-
phenylpent-4-ynoate (3a’)
9
Following the general procedure D, imine 1a (0.086 mmol)
after 5 h, gave 3a’ as major diastereoisomer (26 mg, 0.074
mmol, 86% yield). Eluent: nꢀhexane/AcOEt, (3/1 to 2/1).
[α]20D ꢀ 26.7 (c 0.66, in CHCl3). 1H NMR (CDCl3): δ 7.43ꢀ7.40
(m, 2H), 7.30ꢀ7.27 (m, 3H), 4.67ꢀ4.60 (m, 1H), 3.98 (d, J= 6.7
Hz, 1H), 2.84 (dd, J = 15.9, 7.8 Hz, 1H), 2.73 (dd, J = 15.9,
5.5 Hz, 1H), 1.46 (s, 9H), 1.23 (s, 9H). 13C NMR (CDCl3): δ
169.5, 131.8, 128.5, 128.2, 122.4, 87.4, 85.3, 81.6, 56.3, 45.4,
43.2, 28.1, 22.6.
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11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
tert-Butyl
(R)-3-[(RS)-1,1-dimethylethylsulfinamido]-3-
methyl-5-phenylpent-4-ynoate (3h)
Following the general procedure C, imine 1h (0.43 mmol)
after 16 h, gave 3h as major diastereoisomer (116 mg, 0.32
mmol, 74% yield). Eluent: nꢀhexane/AcOEt, (4/1 to 2/1).
[α]20D ꢀ87.9 (c 0.72, in CHCl3). 1H NMR (CDCl3): δ 7.43ꢀ7.40
(m, 2H), 7.26ꢀ7.24 (m, 3H), 4.90 (s, 1H), 2.83 (d, J = 15.1 Hz,
1H), 2.59 (d, J = 15.1 Hz, 1H), 1.63 (s, 3H), 1.44 (s, 9H), 1.21
(s, 9H). 13C NMR (CDCl3): δ 169.8, 131.8, 128.3, 128.2,
122.6, 90.4, 85.1, 81.9, 55.8, 51.6, 48.3, 29.3, 28.2, 22.6. IR
(NaCl): 2980, 2926, 2210, 1720, 1369, 1159, 1070 cmꢀ1. MS
(ESI+): m/z (%): 749 (2M+Na)+ (100), 727 (2M+1)+ (28), 364
(M+1)+ (51), 308 (66), 187 (74), 122 (45). HRMS: m/z calcd
for C20H30NO3S [M+H]+: 364.1940; found: 364.1954.
tert-Butyl (R)-3-[(RS)-1,1-dimethylethylsulfinamido]-5-(4-
methoxyphenyl)pent-4-ynoate (3b’)
Following the general procedure D, imine 1b (23 mg, 0.06
mmol, 0.086 mmol) after 4 h, gave 3b’ as major diastereoisoꢀ
mer (69% yield). Eluent: nꢀhexane/AcOEt, (3/1). [α]20 ꢀ24.7
D
1
(c 1.05, in CHCl3). H NMR (CDCl3): δ 7.35 (d, J = 8.7 Hz,
2H), 6.81 (d, J = 8.7 Hz, 2H), 4.66ꢀ4.59 (m, 1H), 3.92 (d, J=
6.6 Hz, 1H), 3.79 (s, 3H), 2.83 (dd, J = 15.9, 7.8 Hz, 1H), 2.71
(dd, J = 15.8, 5.5 Hz, 1H), 1.46 (s, 9H), 1.22 (s, 9H). 13C NMR
(CDCl3): δ 169.5, 159.8, 133.2, 114.6, 113.9, 86.0, 85.2, 81.5,
56.2, 55.3, 45.5, 43.4, 28.1, 22.6.
tert-Butyl (R)-3-[(RS)-1,1-dimethylethylsulfinamido]-5-(2-
methoxyphenyl)-3-methylpent-4-ynoate (3i)
Following the general procedure C, imine 1i (0.43 mmol) after
16 h, gave 3i as major diastereoisomer (159 mg, 0.4 mmol,
94% yield). Eluent: nꢀhexane/AcOEt, (2/1). [α]20 ꢀ90.1 (c
Ethyl
4-{(R)-5-(tert-butoxy)-3-[(RS)-1,1-
D
0.80, in CHCl3). 1H NMR (CDCl3): δ 7.44ꢀ7.41 (m, 1H), 7.27ꢀ
7.21 (m, 1H), 7.88ꢀ7.81 (m, 2H), 4.86 (s, 1H), 3.83 (s, 3H),
2.97 (d, J = 10.6, 1H), 2.69 (d, J = 10.6, 1H), 1.65 (s, 3H),
1.46 (s, 9H), 1.23 (s, 9H). 13C NMR (CDCl3): δ 169.9, 160.1,
134.0, 129.7, 120.4, 112.0, 110.9, 94.2, 81.7, 55.8, 55.7, 52.0,
48.1, 29.3, 28.1, 22.6, 22.2. IR (NaCl): 2979, 2932, 2210,
17319, 1575, 1494, 1369, 1247, 1161 cmꢀ1. MS (ESI+): m/z
(%): 416 (M+Na)+ (36), 394 (M+1)+ (72), 217 (100). HRMS:
m/z calcd for C21H32NO4S [M+H]+: 394.2046; found:
394.2064.
dimethylethylsulfinamido]-5-oxopent-1-yn-1-yl}benzoate (3c’)
Following the general procedure D, imine 1c (31 mg, 0.073
mmol, 0.086 mmol) after 4 h, gave 3c’ as major diastereoisoꢀ
mer (84% yield). Eluent: nꢀhexane/AcOEt, (3/1 to 2/1). [α]20
ꢀ18.1 (c 1.20, in CHCl3). H NMR (CDCl3): δ 7.91ꢀ7.82 (m,
D
1
2H), 7.42ꢀ7.34 (m, 2H), 4.67ꢀ4.61 (m, 1H), 4.37ꢀ4.24 (m, 2H),
3.93ꢀ3.85 (m, 1H), 2.85ꢀ2.64 (m, 2H), 1.46 (s, 9H), 1.38 (t, J=
6.9 Hz, 3H), 1.22 (s, 9H). 13C NMR (CDCl3): δ 169.3, 166.0,
131.7, 130.2, 129.4, 127.0, 90.3, 84.5, 81.7, 61.1, 56.4, 45.4,
43.0, 28.1, 22.5, 14.3.
tert-butyl (R)-5-(4-bromophenyl)-3-[( RS)-1,1-
tert-Butyl
(R)-5-(4-bromophenyl)-3-[(RS)-1,1-
dimethylethylsulfinamido]-3-methylpent-4-ynoate (3j)
Following the general procedure C, imine 1j (0.43 mmol) after
16 h, gave 3j as major diastereoisomer (132 mg, 0.3 mmol,
dimethylethylsulfinamido}pent-4-ynoate (3d’)
Following the general procedure D, imine 1d (0.086 mmol)
after 5 h, gave 3d’ as major diastereoisomer (31 mg, 0.072
mmol, 83% yield). Eluent: nꢀhexane/AcOEt, (3/1 to 2/1).
70% yield). Eluent: nꢀhexane/AcOEt, (4/1). [α]20 ꢀ70.3 (c
D
0.52, in CHCl3). 1H NMR (CDCl3): δ 7.42ꢀ7.39 (m, 2H), 7.31ꢀ
7.26 (m, 2H), 4.94 (s, 1H), 2.85 (d, J = 15.0, 1H), 2.63 (d, J =
15.0, 1H), 1.63 (s, 3H), 1.46 (s, 9H), 1.23 (s, 9H). 13C NMR
(CDCl3): δ 169.7, 133.2, 131.4, 122.6, 121.6, 91.6, 84.0, 82.0,
55.9, 51.4, 48.2, 29.1, 28.1, 22.6. IR (NaCl): 3194, 2973,
2953 , 1739, 1488, 1352, 1217, 1156, 1131, 1052 cmꢀ1. MS
(ESI+): m/z (%):442 (M+1)+ (22), 267 (32), 265 (31), 122
(54), 57 (100). HRMS: m/z calcd for C20H29NO3SBr [M+H]+:
442.1052; found: 442.1038.
[α]20 ꢀ 4.8 (c 0.54, in CHCl3). 1H NMR (CDCl3): δ 7.35 (d, J
D
= 8.4 Hz, 2H), 7.21 (d, J = 8.4 Hz, 2H), 4.57ꢀ4.51 (m, 1H),
3.90 (d, J= 7.2 Hz, 1H), 2.76 (dd, J = 15.9, 7.7 Hz, 1H), 2.65
(dd, J = 15.9, 5.5 Hz, 1H), 1.39 (s, 9H), 1.16 (s, 9H). 13C NMR
(CDCl3): δ 169.4, 133.2, 131.5, 122.8, 121.4, 88.6, 84.2, 81.6,
56.3, 45.4, 43.0, 28.1, 22.5.
tert-Butyl
(R)-5-(2-bromophenyl)-3-[(RS)-1,1-
dimethylethylsulfinamido]pent-4-ynoate (3e’)
Following the general procedure D, imine 1e (0.086 mmol)
after 6 h, gave 3e’ as major diastereoisomer (29 mg, 0.068
tert-Butyl (R)-3-[(RS)-1,1-dimethylethylsulfinamido]-3-
methylhept-4-ynoate (3k)
mmol, 78% yield). Eluent: nꢀhexane/AcOEt, (3/1 to 2/1).
1
Following the general procedure C, imine 1k (0.43 mmol)
after 16 h, gave 3k as major diastereoisomer (121 mg, 0.39
[α]20 ꢀ 8.8 (c 0.60, in CHCl3). H NMR (CDCl3): 7.56ꢀ7.53
D
(m, 1H), 7.48ꢀ7.45 (m, 1H), 7.26ꢀ7.20 (m, 1H), 7.18ꢀ7.12 (m,
1H), 4.73ꢀ4.66 (m, 1H), 4.01 (d, J= 6.7 Hz, 1H), 2.89 (dd, J =
16.2, 7.9 Hz, 1H), 2.79 (dd, J = 16.2, 5.4 Hz, 1H), 1.47 (s,
mmol, 89% yield). Eluent: nꢀhexane/AcOEt, (4/1). [α]20
ꢀ
D
89.6 (c 0.51, in CHCl3). 1H NMR (CDCl3): δ 4.79 (s, 1H), 2.75
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
9H), 1.23 (s, 9H). 13C NMR (CDCl3): δ 169.4, 133.7, 132.3,
129.6, 127.0, 125.6, 124.6, 92.1, 83.8, 81.6, 56.3, 45.3, 43.0,
28.1, 22.6.
Page 8 of 10
General procedure F. The sulfinamide (0.0815 mmol) was
treated with HCl/H2O (6N). The mixture was stirred at 40oC.
After 15 h the solvent was evaporated in vacuo.
1
2
3
4
5
6
7
8
tert-Butyl (R)-3-[(RS)-1,1-dimethylethylsulfinamido]dec-4-
ynoate (3f’)
(S)-3-Amino-5-phenylpent-4-ynoic acid hydrochloride (5a)
Following the general procedure F, sulfinamide 3a (0.086
Following the general procedure D, imine 1f (0.086 mmol)
after 5 h, gave 3f’ as major diastereoisomer (22 mg, 0.062
mmol) after 1.5 h, gave 5a (15 mg, 0.08 mmol, 91%). [α]20
ꢀ
D
1
3.7 (c 0.66, in MeOH). H NMR (CD3OD): δ 6.15ꢀ6.13 (m,
2H), 6.08ꢀ6.03 (m, 3H), 3.36ꢀ3.32(m, 1H), 1.97 (s, 2H), 1.72ꢀ
1.63 (m, 2H). 13C NMR (CD3OD): δ 170.8, 131.4, 129.1,
128.2, 120.9, 86.7, 82.0, 39.8, 37.0. IR (NaCl): 3590, 3421,
2918, 2850, 2243, 1717, 1595, 1490, 1400, 1187 cmꢀ1. MS
(FAB+): m/z (%): 212 (M++ Na) (7), 190 (M+1)+ (16), 173
(27), 131 (100). HRMS: m/z calcd for C11H12NO2 [M+H]+:
190.0862; found: 190.0871.
mmol, 72% yield). Eluent: nꢀhexane/AcOEt, (2/1). [α]20
ꢀ
D
1
31.8 (c 0.45, in CHCl3). H NMR (CDCl3): δ 4.41ꢀ4.35 (m,
1H), 3.79 (d, J= 6.3 Hz, 1H), 2.71 (dd, J = 15.8, 7.8 Hz, 1H),
2.58 (dd, J= 15.9, 5.5 Hz, 1H), 2.16 (dt, J= 2.0, 6.9 Hz, 2H),
1.44 (s, 9H), 1.38ꢀ1.27 (m, 6H), 1.19 (s, 9H), 0.88 (t, J= 6.9
Hz, 3H). 13C NMR (CDCl3): δ 169.7, 86.1, 81.3, 78.3, 56.0,
45.0, 43.6, 31.0, 28.2, 28.1, 22.5, 22.1, 18.7, 13.9.
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tert-Butyl
(R)-3-[(RS)-1,1-dimethylethylsulfinamido]-5-
(S)-3-Aminodec-4-ynoic acid hydrochloride (5f)
(trimethylsilyl)pent-4-ynoate (3g’)
Following the general procedure F, sulfinamide 3f (0.086
Following the general procedure D, imine 1g (0.086 mmol)
after 5 h, gave 3g’ as major diastereoisomer (23 mg, 0.067
mmol, 77% yield). Eluent: nꢀhexane/AcOEt, (4/1 to 2/1).
[α]20D ꢀ27.1 (c 0.78, in CHCl3). 1H NMR (CDCl3): δ 4.45ꢀ4.38
(m, 1H), 3.83 (d, J= 6.4 Hz, 1H), 2.74 (dd, J = 16.0, 7.8 Hz,
1H), 2.61 (dd, J = 15.9, 5.6 Hz, 1H), 1.44 (s, 9H), 1.19 (s, 9H),
0.14 (s, 9H). 13C NMR (CDCl3): δ 169.6, 103.8, 90.2, 81.7,
56.4, 45.4, 43.4, 28.3, 22.7, 0.0.
mmol) after 1.5 h, gave 5f (15 mg, 0.08 mmol, 93%). [α]20
=
D
1
ꢀ10,8 (c 0.83, in MeOH). H NMR (CD3OD): δ 2.89ꢀ2.83 (m,
2H), 2.32ꢀ2.25 (m, 2H), 1.59ꢀ1.51 (s, 2H), 1.46ꢀ1.34 (m, 6H),
0.94 (t, J = 6.8 Hz, 3H). 13C NMR (CD3OD): δ 131.4, 89.7,
75.1, 41.1, 32.0, 30.0, 29.0, 23.2, 19.1, 14.2. MS (FAB+): m/z
(%): 206 (M+ Na)+ (33), 201 (M+ NH4)+ (38), 184 (M+1)+
(100), 167 (7), 157 (8), 121 (5). HRMS: m/z calcd for
C10H18NO2 [M+H]+: 184.1332; found: 184.1362.
Supporting Information Available. The Supporting Infor-
Sulfinamide deprotection:
General procedure E. The corresponding sulfinamide
(0.0815 mmol) was treated with HCl in MeOH (0.163 mmol,
1.15 M). The mixture stirred at room temperature for 90 min.
Then, the reaction mixture was concentrated in vacuo, and
H2O (5mL) and HCl (1 M) were added (to acid pH). The
aqueous layer was washed with AcOEt (2 x 10mL), being the
organic layers discarded. The aqueous layer neutralized and
extracted with AcOEt (3 x 10mL). The organic phases dried
over MgSO4, filtered and the solvent was evaporated under
reduced pressure.
mation is available free of charge on the ACS Publication
1
website at DOI: 10.1021/acs.joc.7b01211. Copies of H and 13C
spectra for all new compounds and X-ray data for compound
3g are included. This material is free of charge via the Inter-
net at http://pubs.acs.org.
Corresponding Authors
*E-MAIL: (JAFS) j.fernandez@uam.es; (MCM)
carmen.maestro@uam.es
tert-Butyl (S)-3-amino-5-phenylpent-4-ynoate (4a)
Following the general procedure E, sulfinamide 3a (0.086
ACKNOWLEDGMENTS
mmol) after 16 h, gave 4a (21 mg, 0.086 mmol, 100%). [α]20
D
1
We are grateful to the Spanish Government (CTQ2015-
64561-R) and the European Research Council (ERC-CG-
UNBICAT, contract number: 647550). J. A. F.-S. thanks the
Spanish Goverment for a Juan de la Cierva Contract.
ꢀ 8.3 (c 0.41, in CHCl3). H NMR (CDCl3): δ 7.40ꢀ7.37 (m,
2H), 7.29ꢀ7.26 (m, 3H), 4.22ꢀ4.18 (m, 1H), 2.68 (dd, J = 15.6,
5.6 Hz, 1H), 2.61 (dd, J = 15.6, 7.5 Hz, 1H), 1.82 (s, 1H), 1.47
(s, 9H). 13C NMR (CDCl3): δ 170.2, 131.6, 128.2, 128.1,
123.0, 82.7, 81.0 (2C), 44.0, 41.0, 28.1. IR (NaCl): 2977,
2926, 2854, 1729, 1600, 1368, 1259, 1149 cmꢀ1. MS (FAB+):
m/z (%): 246 (M+1)+ (30), 190 (39), 173 (45), 131 (29), 73
(30), 57 (100). HRMS: m/z calcd for C15H20NO2 [M+H]+:
246.1494; found: 246.1495.
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The Journal of Organic Chemistry
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bis(trimethylsilyl)ketene
acetals
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The Journal of Organic Chemistry
Catalyzed Asymmetric Hydroalkynylation of Enamides: Difluoromethyl
Page 10 of 10
N-tert-Butylsulfinyl
Amines
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(11) In situ generation of alkynyl imines: (a) Kano, T.;
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ters: Mannich-Type Reactions of In Situ Generated C-
Alkynyl Imines with β-Keto Esters. Angew. Chem. Int. Ed.
2013, 52, 11509-11512. (b) Yurino, T.; Aota, Y.; Asakawa, D.;
Kano, T.; Maruoka, K. N-Boc-aminals as easily accessible
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(c) Hayashi, Y.; Yamazaki, T.; Kawauchi, G.; Sato, I. Pro-
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(12) (a) Josephsohn, N. S.; Carswell, E. L.; Snapper M. L.;
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Asymmetric Mannich Reactions of Silylketene Acetals and
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ble Reaction Condition Controlled Stereoselectivity Rever-
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(15) When the reaction was carried out at lower temper-
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14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
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46
47
48
49
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51
52
53
54
55
56
57
58
59
60
o
o
ature (-40 C or -10 C), lower conversion to the desired
products (specially with imines bearing functional groups
such as esters (1c), which demonstrated lower tolerance at
higher temperatures) were obtained.
(16) See the Supporting Information for X-ray structure.
CCDC 1850070 (3g) contain the supplementary crystallo-
graphic data for this paper. This data can be obtained free
of charge from The Cambridge Crystallographic Data Cen-
tre.
(17) (a) Cogan, D. A.; Liu, G.; Ellman, J. Asymmetric Syn-
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(18) Plobeck, N.; Powell, D. Asymmetric synthesis of dia-
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ometallic reagents to chiral N-tert-butanesulfinimines:
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(19) (a) Davis, F. A.; Friedman, A. J.; Kluger, E. W. Chem-
istry of the Sulfur-Nitrogen Bond. VIII. N-
Alkylidensulfinamides. J. Am. Chem. Soc. 1974, 96, 5000-
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(20) Ferreira, F.; Audouin, M.; Chemla, F. Influence of
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Enantiopure
N-tert-
Butanesulfinimines: Stereoselective Access to Enantiopure
cis-Ethynylaziridines. Chem. Eur. J. 2005, 11, 5269-5278.
(21) To a solution of zinc (0.0344 mmol) in THF anhydrous
(0.4 mL) under argon atmosphere, tert-butyl 2-bromoacetate
(0.344 mmol) was added. The mixture was stirred for 30 min
at reflux (it gets a greenish color). After the complete disso-
lution of the metal, the reaction was cooled until the corre-
sponding temperature.
(13) (a) Kano, T.; Aota, Y.; Maruoka, K. Asymmetric Syn-
thesis of Less Accessible α-Tertiary Amines from Alkynyl
Z-Ketimines. Angew. Chem. Int. Ed. 2017, 56, 16293-16296.
For other examples of the addition of lithium acetylides to
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2280. (c) Patterson, A. W.; Ellman, J. A. Asymmetric Syn-
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Additions to N-tert-Butanesulfinyl Ketimines. J. Org.
Chem. 2006, 71, 7110-7112. For the synthesis of α-tertiary
phenyl difluoromethyl propargylamines see: (d) Liu, J.;
Hu, J. Highly Diastereoselective Synthesis of α-
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