Decarboxylative Mannich Reactions with Substituted Malonic Acid Half-Oxyesters

Article abstract of DOI:10.1021/acs.joc.0c02895

The decarboxylative Mannich reaction between imines and substituted malonic acids half-oxyesters (SMAHOs) has been developed using 1,4-diazabicyclo[2.2.2]octane (DABCO) as an organocatalyst. The reaction proceeds under simple reaction conditions and toler

Full text of DOI:10.1021/acs.joc.0c02895

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Article
Decarboxylative Mannich Reactions with Substituted Malonic Acid
Half-Oxyesters
Tania Xavier, Sylvie Condon,* Christophe Pichon, Erwan Le Gall, and Marc Presset*
Cite This: J. Org. Chem. 2021, 86, 5452−5462
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ABSTRACT: The decarboxylative Mannich reaction between
imines and substituted malonic acids half-oxyesters (SMAHOs)
has been developed using 1,4-diazabicyclo[2.2.2]octane (DABCO)
as an organocatalyst. The reaction proceeds under simple reaction
conditions and tolerates a broad range of substrates, affording
general access to β2,3-aminoesters, the syn diastereomer being the
major one. An alternative multicomponent protocol has also been
developed to increase the overall eco-compatibility of the process.
potential character of the Mannich reaction.25 In continuation
with our work on Mannich reactions26,27 and substituted
MAHOs,28 we disclose herein the development of organo-
catalyzed decarboxylative Mannich reactions involving SMA-
HOs (Scheme 1).
INTRODUCTION
■
Malonic acid half-oxyesters (MAHOs) and malonic acid half-
thioesters (MAHTs) constitute an attractive class of pro-
nucleophiles,1−3 with similar properties to β-ketoacids.4
Indeed, they provide efficient access to ester and thioester
enolates, respectively, through decarboxylation under mild
reaction conditions,5,6 avoiding the use of either strong bases
or Lewis acids and thus increasing the overall eco-compatibility
of a transformation.7 Inspired by the biosynthesis of
polyketides,8,9 different groups have developed the use of
unsubstituted MAHTs and MAHOs in olefination
(Galat)10−12 and addition (aldol or Mannich-type) reactions.13
In this latter case, a seminal report by Ricci in 2007 disclosed
the organocatalyzed enantioselective addition of unsubstituted
MAHTs to sulfonylated imines using a catalyst derived from
Cinchona alkaloids.14 Tan subsequently reported the use of
substituted MAHTs,15 whereas the groups of Shibata16 and
Nakamura17 focused on the addition to ketimines. In all of
these works, the relative anti configuration has been observed.
Less work has been done using MAHO starting materials, and
Rouden reported the first decarboxylative Mannich-type
reaction mediated by triethylamine in dimethylformamide
(DMF).18 Enantioselective versions were then developed by
Ma using either a thiourea catalyst for their addition to
trifluoromethyl ketimines or a chiral Cu(I) complex catalyst in
the case of cyclic aldimines.19,20 However, the use of
substituted MAHOs (SMAHOs) in decarboxylative Mannich
reactions remains elusive. The only examples required very
particular reagents such as 2-amido MAHOs.21,22 Such a
reaction would however constitute attractive access to β2,3
amino acid derivatives, which constitute valuable precursors for
the preparation of peptidomimetics or β-lactams.23,24 Although
the use of MAHOs led to β3 amino acid derivatives, no general
method has been reported for the preparation of the
disubstituted analogues. Moreover, none of the above-
mentioned contributions exploit the intrinsic multicomponent
Scheme 1. Decarboxylative Mannich Reactions
RESULTS AND DISCUSSION
■
We began our study by the optimization of the decarboxylative
Mannich reaction between tosyl imine 1a and SMAHO 2a
(Table 1). The use of the conditions previously developed for
Galat reactions led to the formation of the expected β2,3-
aminoester 3aa but in a low (12%) yield, the olefination
product being the major one (entry 1). As the present
transformation does not require the formation of an iminium,
we decided to change the catalyst for a tertiary amine, 1,4-
diazabicyclo[2.2.2]octane (DABCO). This slight modification
resulted in a notable improvement of the reaction as the yield
increased to 52% (entry 2). The relative syn configuration
Received: December 7, 2020
Published: April 6, 2021
https://doi.org/10.1021/acs.joc.0c02895
© 2021 American Chemical Society
J. Org. Chem. 2021, 86, 5452−5462
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a
Table 1. Optimization of the Reaction Conditions
Scheme 2. Scope of SMAHOs
a
entry
cat
solvent
toluene
toluene
DMF
ACN
1,4-dioxane
DME
THF
2-Me THF
THF
THF
THF
yield (%)
d.r.
1
2
3
4
5
6
7
8
morpholine
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DMAP
12
52
57:43
77:23
b
0
89
78
73
95
72
97
74
72
83
59:41
76:24
77:23
67:33
74:26
56:44
73:27
39:61
70:30
9
c
10
11
12
TEA
DIPEA
TMEDA
c
THF
a
b
c
Isolated yields. Decomposition. 1.0 equiv.
could be attributed to the major diastereomer by comparison
1
of the H NMR spectrum of 3aa with analogous compounds,
as we previously described the preparation of anti β2,3
aminoesters, whose configurations were unambiguously
determined by X-ray diffraction analysis.29 Although the use
of a lower amount of catalyst or a lower temperature led to
poor conversions, the screening of various solvents (entries 3−
8) revealed that the reaction was more productive with
moderately polar solvents, among which tetrahydrofuran
(THF) was found to be the best, but with a slightly lower
diastereoselectivity (95%, entry 7). Even if no chiral induction
was observed using quinine or cinchonidine, various tertiary
amines were evaluated (entries 9−12). Although 4-dimethy-
laminopyridine (DMAP) displayed quite high activity but with
a poor selectivity (entry 9), the use of more hindered catalysts
such as triethylamine (TEA) (entry 10) or N,N-diisopropyle-
thylamine (DIPEA) (entry 11) led to decreased yields and the
use of tetramethylethylenediamine (TMEDA) required the use
of a stoichiometric amount (entry 12). These results
demonstrated the importance of the pKa of the catalyst, the
less basic ones being the most active ones, thus leading to
higher yields (in dimethyl sulfoxide (DMSO), the pKa values
of the conjugated acids of DABCO, TEA, and DMAP are 8.9,
9.0, and 9.2, respectively).
It should be noted that such optimized conditions (20 mol
% of DABCO in 0.3 M THF under reflux) worked perfectly in
the case of 2a. When a more hindered SMAHO bearing a
benzyl substituent was used, the isolated yield dropped to 48%.
Nevertheless, further studies revealed that the concentration
needed to be increased to 1.0 M to ensure complete
conversion and have led to an improved yield of 59% (vide
infra), no further improvement being observed with a
concentration of 2.0 M.
b
Reaction performed on a 1 mmol scale. TPs = 2-thiophenesulfonyl.
Yields of isolated products; diastereomeric ratios (d.r.) determined
a
by gas chromatography (GC) analysis of the crude reaction mixture.
Reaction conditions: 1 (0.25 mmol), 2 (1.0 equiv), DABCO (20 mol
%), THF (C = 1.0 M), reflux, 14 h.
diastereoselectivity increased with the length of the substituent.
Similarly, different SMAHOs bearing a primary unsaturated
group such as benzyl, allyl, or propargyl 2d−f afforded the
expected β-aminoesters 3ad, 3be, and 3af in 59, 88, and 57%
yields, respectively, with similar diastereoselectivities. The use
of a more complex lateral chain is also possible, as illustrated
by compound 3bg (63%). On the other hand, the nature of the
ester group of 2 has only a limited influence on the reaction
issue and the benzyl derivatives (3bh, 94%) could be used with
a high efficiency.
Concerning the imine partner, the reaction offered
numerous possibilities (Scheme 3). It is first important to
note that different sulfonylated groups could be introduced on
the nitrogen atom. Therefore, the use of imines bearing a
mesyl or a potentially removable 2-thiophenesulfonyl30 group
showed similar activities to the tosylated ones (3ca: 89%, 3ba:
88%). The latter is particularly interesting as the deprotection
of 3bd could be achieved using Mg in MeOH without change
of the diasteromeric ratio.29 In the case of imines deriving from
benzaldehydes, substitution was possible at all positions of the
aromatic ring. The introduction of a simple methyl group
(substrates 1d−f) demonstrated the influence of steric
hindrance on the reaction issue, as a lower yield of 76% was
obtained in the case of the ortho position than in the meta and
para positions (91 and 88%, respectively), but without
influence on the diastereoselectivity. Moreover, imines bearing
classical functional groups showed expected reactivities, as the
presence of electron-withdrawing group (EWG) groups such
as 2-Cl (3ga, 91%) or 2-Br (3ha, 95%) as well as 4-CF3 (3ia,
97%) led to higher yields. Importantly, the present reaction
We next turned our attention to the scope of the reaction,
starting with SMAHOs as the nature of the substituent
appeared to be crucial during the optimization process
(Scheme 2). The introduction of alkyl chains in the malonic
position of the SMAHO is possible, and the n-butyl (3bb,
51%)- and n-octyl (3ac, 68%)-substituted products were
obtained in appropriate yields. It should be noted that the
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a
a
Scheme 3. Scope of Imines
Scheme 4. Three-Component Reactions
a
Yields of isolated products; d.r. determined by GC analysis of the
crude reaction mixture. Reaction conditions: 4 (0.25 mmol), 5 (1.0
equiv), 2 (1.0 equiv), DABCO (20 mol %), THF (C = 1.0 M), reflux,
14 h. TPs = 2-thiophenesulfonyl.
MAHTs15 or aldol reactions with acetamido-MAHOs
preferentially led to the relative anti configuration.31 On the
basis of previous studies,18,32 the mechanism of the present
transformation is probably initiated by a reversible addition of
the enol form A of deprotonated SMAHO 2 onto the imine 1.
This elementary step probably occurs through the 6-membered
transition state TS-1. Then, decarboxylation of intermediate B
leads to enolate C, which could be stabilized by an
intramolecular hydrogen bond. The cycle is completed by
protonation of C, affording the expected product 3 as well as
regenerating the catalyst (Scheme 5). A competing decarbox-
ylation/addition pathway is unlikely as it would presumably
result in the addition of an (E)-enolate on the imine, thus
leading to a reversed stereoselectivity.
a
Yields of isolated products; d.r. determined by GC analysis of the
crude reaction mixture. Reaction conditions: 1 (0.25 mmol), 2 (1.0
equiv), DABCO (20 mol %), THF (C = 1.0 M), reflux, 14 h. TPs = 2-
thiophenesulfonyl.
conditions were also compatible with the use of other types of
imines, such as the heterocyclic, vinylic, and aliphatic ones.
Therefore, an imine deriving from 2-thiophenecarboxaldehyde
afforded 3ja in 87% yield and the use of the cinnamaldehyde
derivative 2k led to the product 3ka in a good (83%) yield.
The aliphatic derivative 2l allowed us to obtain 3la in a 48%
yield, but with a reversed diastereoselectivity.
On the basis of this mechanism, the protonation step is
expected to be the stereo-determinating one, as the products
Scheme 5. Putative Mechanism of the Reaction
As previously noted, the development of decarboxylative
Mannich reactions involving MAHTs or MAHOs has been
limited to the use of preformed imines. Owing to the
importance of multicomponent reactions in the development
of eco-compatible chemistry, we explored the feasibility of this
modification in the present case. Thus, a 1:1:1 mixture of
benzaldehyde 4a, tosylamide 5a, and SMAHO 2a was
submitted to the optimized conditions, and we were pleased
to see that the expected 3aa was isolated in an only slightly
lower yield of 85% (95% with the preformed imine). The
multicomponent protocol was extended to other sulfonamides
(3ba: 57%; 3ca: 32%), SMAHOs (3ad: 46%; 3be: 40%), and
aldehyde (3ga: 62%). In all cases, yields are lower than those
observed in two-component reactions, probably because a
partial decarboxylation of 2 competes with the imine
formation. Even if the origin of the lower diastereoselectivity
observed in some cases remains unclear, it may be due to the
presence of water in the reaction media (Scheme 4).
The achievement of a major syn diastereomer was intriguing
as related reports on decarboxylative Mannich reactions with
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1
were recorded on a Bruker Avance II 400 MHz spectrometer. H
NMR chemical shifts were referenced to the residual solvent signal;
13C NMR chemical shifts were referenced to the deuterated solvent
signal. Multiplicity was defined by distortionless enhancement by
polarization transfer (DEPT) 135 analysis. 19F NMR chemical shifts
were referenced to external CFCl3 (0.0 ppm). Data are presented as
follows: chemical shift δ (ppm), multiplicity (s = singlet, d = doublet,
t = triplet, q = quartet, quint = quintet, hept = heptuplet, m =
multiplet, br = broad), coupling constant J (Hz), integration.
Diastereomeric ratios (d.r.) were determined by GC analysis of the
crude reaction mixture.
proved to be stereochemically stable under the reaction
conditions. This is consistent with the higher activities
observed in the cases of the more acidic protonated catalysts.
The preference for the syn configuration may arise from a
minimized 1,2-allylic strain (A1,2), consistent with decreased
selectivities observed with smaller R1 groups. This interaction
is yet balanced by a minimized allylic 1,3-allylic strain (A1,3),
which leads to the minor anti diastereomer. In both
conformations, the bulky R group of the imine directs the
proton approach on the less hindered face of the enolate
(Scheme 6). An interaction between the lone pair of the
Preparation of Imines. General Procedure 1 (GP1). A round-
bottom flask (RBF) equipped with a stir bar was charged with
sulfonamide (1.0 equiv), Dowex H-form (15% w/w), toluene (0.25
M), and aldehyde (1.2 equiv). The RBF was equipped with a Dean−
Stark apparatus, and the reaction was stirred under reflux using an oil
bath overnight. Then, the hot reaction mixture was filtered on a fritted
funnel, rinsed with toluene, and the filtrate was evaporated.
Purification by recrystallization (EA/PE) afforded the desired
product.
Scheme 6. Stereochemical Outcome of the Protonation Step
Compound 1a.34 Following GP1 performed with p-toluenesulfo-
namide (5.198 g, 30.0 mmol, 1.0 equiv), Dowex (0.780 g, 15% w/w),
and benzaldehyde (3.6 mL, 35.0 mmol, 1.2 equiv) in toluene (120
mL, 0.25 M), the desired product was obtained as a white powder
(6.615 g, 85%). mp: 112−114 °C (litt: 109−111 °C). Rf (PE/EA: 80/
1
20, UV + KMnO4): 0.60. GC (50 + 10/270 − 15): 19.6 min. H
NMR (400 MHz, CDCl3): δ 9.03 (s, 1H), 7.94−7.87 (m, 4H), 7.61
(t, J = 7.4 Hz, 1H), 7.48 (t, J = 7.6 Hz, 2H), 7.34 (d, J = 8.2 Hz, 2H),
2.43 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 170.2 (CH),
144.7 (C), 135.2 (C), 135.1 (CH), 132.5 (C), 131.4 (2 CH), 129.9
(2 CH), 129.2 (2 CH), 128.2 (2 CH), 21.8 (CH3).
Compound 1b.35 Following GP1 performed with 2-thiophene-
sulfonamide (5.030 g, 30.8 mmol, 1.0 equiv), Dowex (0.500 g, 10%
w/w), and benzaldehyde (3.5 mL, 34.4 mmol, 1.1 equiv) in toluene
(75 mL, 0.5 M), the desired product was obtained as brown needles
(6.730 g, quantitative). mp: 108−110 °C (litt: 108−109 °C). Rf (PE/
EA: 80/20, UV + KMnO4): 0.33. GC (50 + 10/270 − 15): 18.7 min.
1H NMR (400 MHz, CDCl3): δ 9.00 (s, 1H), 7.94 (d, J = 7.5 Hz,
2H), 7.81−7.77 (m, 1H), 7.71 (dt, J = 5.0, 1.4 Hz, 1H), 7.63 (t, J =
7.4 Hz, 1H), 7.50 (t, J = 7.4 Hz, 2H), 7.14 (ddd, J = 5.1, 3.7, 1.4 Hz,
1H). 13C{1H} NMR (100 MHz, CDCl3): δ 170.4 (CH), 138.6 (C),
135.3 (CH), 134.3 (CH), 134.2 (CH), 132.3 (C), 131.6 (2 CH),
129.3 (2 CH), 127.9 (CH).
nitrogen atom and the protonated catalyst leading to the same
issue could also be envisioned. Nevertheless, a proton transfer
by another species such as the solvent or the generated water
in the 3CR protocol cannot be ruled out and may explain the
reversed selectivity observed with bulky catalysts.
In conclusion, we have developed a new route for the
preparation of β2,3-aminoesters involving an organocatalyzed
decarboxylative Mannich reaction. The transformation could
be performed with a variety of SMAHOs and tolerates a broad
range of imines. The original preference for the syn products is
proposed to arise from a minimized 1,2-allylic strain during the
protonation step. A multicomponent protocol could be used to
increase the overall eco-compatibility of the process.
Compound 1c.36 Following GP1 performed with methanesulfo-
namide (2.850 g, 30.0 mmol, 1.0 equiv), Dowex (0.427 g, 15% w/w),
and benzaldehyde (3.6 mL, 35.0 mmol, 1.2 equiv) in toluene (120
mL, 0.25 M), the desired product was obtained as beige needles
(4.707 g, 85%). mp: 93−95 °C (litt: 90−92 °C). Rf (Cy/EA: 70/30,
1
UV + KMnO4): 0.28. GC (50 + 10/270 − 15): 12.6 min. H NMR
EXPERIMENTAL SECTION
(400 MHz, CDCl3): δ 9.03 (s, 1H), 7.96 (d, J = 7.5 Hz, 2H), 7.66 (t,
J = 7.5 Hz, 1H), 7.53 (t, J = 7.5 Hz, 2H), 3.14 (s, 3H). 13C{1H} NMR
(100 MHz, CDCl3): δ 171.8 (CH), 135.3 (CH), 132.2 (C), 131.4 (2
CH), 129.4 (2 CH), 40.4 (CH3).
■
General Information. All commercially available reagents were
used as received. Substituted malonates were prepared from the
adequate dialkyl malonate and alkyl halide with NaH in DMF. THF
was dried over activated 3 Å molecular sieves prior to use.33 Other
solvents (ethyl acetate = EA, petroleum ether = PE, cyclohexane = Cy,
diethyl ether, ethanol, and methanol) were used as received. Room
temperature (rt) means 18−25 °C. Melting points (mp) are
Compound 1d.30 Following GP1 performed with 2-thiophene-
sulfonamide (0.816 g, 5.0 mmol, 1.0 equiv), Dowex (0.122 g, 15% w/
w), and o-tolualdehyde (0.69 mL, 6.0 mmol, 1.2 equiv) in toluene (20
mL, 0.25 M), the desired product was obtained as a yellow solid
(1.019 g, 77%). mp: 90−92 °C (litt: 107−108 °C). Rf (Cy/EA: 70/
uncorrected and were measured on a Buchi B-545 apparatus.
̈
1
30, UV + KMnO4): 0.59. GC (50 + 10/270 − 15): 19.1 min. H
Analytical thin-layer chromatography (TLC) was performed on
TLC silica gel plates (0.25 mm) precoated with a fluorescent
indicator (Merck 60F254). Visualization was effected using ultraviolet
light (λ = 254 nm) and/or an aqueous solution of KMnO4. Flash
chromatography (FC) was performed on 40−63 μm silica gel with
mixtures of solvents. Gas chromatography (GC) was recorded on a
Shimadzu 2025 chromatograph (Tinj = Tdet = 250 °C) with a ZB-
5MSi capillary column (l = 5.5 m), using nitrogen as a carrier gas and
a flame ionization detector. Retention times are given in minutes
(min). High-resolution mass spectra (HRMS) were obtained at the
NMR (400 MHz, CDCl3): δ 9.33 (s, 1H), 8.06 (d, J = 7.8 Hz, 1H),
7.82 (d, J = 3.7 Hz, 1H), 7.73 (d, J = 4.6 Hz, 1H), 7.52 (t, J = 7.5 Hz,
1H), 7.36−7.27 (m, 2H), 7.17 (t, J = 4.6 Hz, 1H), 2.64 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3): δ 168.9 (CH), 142.6 (C), 138.8
(C), 135.0 (CH), 134.1 (CH), 134.0 (CH), 131.8 (CH), 130.9
(CH), 130.3 (C), 127.8 (CH), 126.8 (CH), 19.8 (CH3).
Compound 1e. Following GP1 performed with 2-thiophenesulfo-
namide (0.816 g, 5.0 mmol, 1.0 equiv), Dowex (0.122 g, 15% w/w),
and m-tolualdehyde (0.71 mL, 6.0 mmol, 1.2 equiv) in toluene (20
mL, 0.25 M), the desired product was obtained as off-white flakes
(0.791 g, 60%). mp: 62−64 °C. Rf (Cy/EA: 70/30, UV + KMnO4):
́
́
ICOA of the Universite of Orleans by electrospray ionization (ESI)
using a quadrupole time-of-flight (Q-TOF) analyzer. NMR spectra
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0.59. GC (50 + 10/270 − 15): 19.3 min. HRMS (ESI+): [M + Na]+
calcd for C12H11NNaO2S2: 288.0123. Found: 288.0125. 1H NMR
(400 MHz, CDCl3): δ 8.96 (s, 1H), 7.81−7.76 (m, 2H), 7.74−7.69
(m, 2H), 7.44 (d, J = 7.4 Hz, 1H), 7.38 (t, J = 7.5 Hz, 1H), 7.14 (ddd,
J = 5.0, 3.8, 1.4 Hz, 1H), 2.39 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3): δ 170.6 (CH), 139.3 (C), 138.7 (C), 136.2 (CH), 134.2
(CH), 134.1 (CH), 132.2 (CH), 131.6 (CH), 129.2 (CH), 129.2
(CH), 127.8 (CH), 21.2 (CH3).
Compound 1k.38 Following GP1 performed with p-toluenesulfo-
namide (2.568 g, 15 mmol, 1.0 equiv), Dowex (0.378 g, 15% w/w),
and trans-cinnamaldehyde (2.2 mL, 17.5 mmol, 1.2 equiv) in toluene
(60 mL, 0.25 M), the desired product was obtained as an off-white
powder (3.780 g, 88%). mp: 117−119 °C (litt: 120−122 °C). Rf (PE/
EA: 80/20, UV + KMnO4): 0.42. GC (50 + 10/270 − 15): 22.8 min.
1H NMR (400 MHz, CDCl3): δ 8.69 (d, J = 9.4 Hz, 1H), 7.77 (d, J =
7.9 Hz, 2H), 7.48−7.43 (m, 2H), 7.40 (d, J = 16.0 Hz, 1H), 7.36−
7.30 (m, 3H), 7.25 (d, J = 7.8 Hz, 2H), 6.89 (dd, J = 15.7, 9.5 Hz,
1H), 2.34 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 171.0 (CH),
154.0 (CH), 144.6 (C), 135.4 (C), 134.2 (C), 131.7 (CH), 129.9 (2
CH), 129.3 (2 CH), 128.7 (2 CH), 128.0 (2 CH), 124.7 (CH), 21.7
(CH3).
Compound 1f.37 Following GP1 performed with 2-thiophenesul-
fonamide (0.816 g, 5.0 mmol, 1.0 equiv), Dowex (0.122 g, 15% w/w),
and p-tolualdehyde (0.71 mL, 6.0 mmol, 1.2 equiv) in toluene (20
mL, 0.25 M), the desired product was obtained as a yellow solid
(0.943 g, 71%). mp: 137−139 °C. Rf (Cy/EA: 80/20, UV + KMnO4):
0.33. GC (50 + 10/270 − 15): 19.8 min. 1H NMR (400 MHz,
CDCl3): δ 8.95 (s, 1H), 7.83 (d, J = 7.3 Hz, 2H), 7.78 (d, J = 4.0 Hz,
1H), 7.69 (d, J = 4.0 Hz, 1H), 7.30 (d, J = 7.7 Hz, 2H), 7.13 (t, J = 4.0
Hz, 1H), 2.43 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 170.2
(CH), 146.9 (C), 138.9 (C), 134.1 (CH), 133.9 (CH), 131.7 (2
CH), 130.1 (2 CH), 129.7 (C), 127.8 (CH), 22.2 (CH3).
Compound 1g. Following GP1 performed with 2-thiophenesulfo-
namide (2.630 g, 16.1 mmol, 1.0 equiv), Dowex (0.400 g, 15% w/w),
and 2-chlorobenzaldehyde (2.0 mL, 17.7 mmol, 1.1 equiv) in toluene
(80 mL, 0.2 M), the desired product was obtained as a white solid
(3.858 g, 76%). mp: 121−123 °C. Rf (PE/EA: 70/30, UV + KMnO4):
0.48. GC (50 + 10/270 − 15): 19.7 min. HRMS (ESI+): [M + H]+
calcd for C11H9ClNO2S2: 285.9758. Found: 285.9760. 1H NMR (400
MHz, CDCl3): δ 9.44 (s, 1H), 8.17 (dt, J = 7.8, 1.5 Hz, 1H), 7.84−
7.78 (m, 1H), 7.74 (dt, J = 5.1, 1.5 Hz, 1H), 7.58−7.50 (m, 1H), 7.46
(d, J = 8.1 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.16 (ddd, J = 5.1, 3.8,
1.5 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 166.8 (CH),
139.1 (C), 137.9 (C), 136.0 (CH), 134.7 (CH), 134.6 (CH), 130.6
(CH), 130.3 (CH), 129.6 (C), 128.0 (CH), 127.6 (CH).
Compound 1l.39 A 125 mL separatory funnel was charged with
sulfinate 6 (0.735 g, 2 mmol, 1.0 equiv) and CH2Cl2 (20 mL, 0.1 M).
After addition of 14 mL of aq. sat. NaHCO3, the reaction was
manually shaken for 45 s. The layers were separated, and the aqueous
layer was extracted with 20 mL of CH2Cl2. The combined organic
layers were dried over Na2SO4 and evaporated to give the desired
product as a colorless oil (0.320 g, 71%). Rf (Cy/EA: 70/30, UV +
1
KMnO4): 0.38. H NMR (400 MHz, CDCl3): δ 8.59 (t, J = 4.5 Hz,
1H), 7.80 (d, J = 7.5 Hz, 2H), 7.33 (d, J = 7.5 Hz, 2H), 2.49 (m, 2H),
2.43 (s, 3H), 1.64 (h, J = 7.4 Hz, 2H), 0.94 (t, J = 7.4 Hz, 3H).
13C{1H} NMR (100 MHz, CDCl3): δ 178.5 (CH), 144.8 (C), 134.6
(C), 129.8 (2 CH), 128.1 (2 CH), 37.7 (CH2), 21.7 (CH3), 18.1
(CH2), 13.6 (CH3).
Preparation of SMAHOs. General Procedure 2 (GP2).40 An RBF
equipped with a stir bar was charged with the malonate derivative (1.0
equiv) and the solvent (0.5 M). A 5 M aqueous solution of KOH
(1.0−1.2 equiv) was added with a syringe, and the reaction was stirred
at rt overnight. Then, the mixture was concentrated, diluted with
water, and the resulting aqueous layer was washed with Et2O (three
times), acidified to pH = 1 with aqueous 1 M HCl, saturated with
NaCl, and extracted with EA (three times). The combined organic
layers were dried (Na2SO4) and evaporated to afford the expected
product.
Compound 1h. Following GP1 performed with 2-thiophenesulfo-
namide (1.270 g, 7.8 mmol, 1.0 equiv), Dowex (0.180 g, 15% w/w),
and 2-bromobenzaldehyde (1.0 mL, 8.6 mmol, 1.1 equiv) in toluene
(40 mL, 0.2 M), the desired product was obtained as a white solid
(2.216 g, 86%). mp: 126−128 °C. Rf (PE/EA: 80/20, UV + KMnO4):
0.23. GC (50 + 10/270 − 15): 20.7 min. HRMS (ESI+): [M + H]+
calcd for C11H9BrNO2S2: 329.9252. Found: 329.9253. 1H NMR (400
MHz, CDCl3): δ 9.38 (s, 1H), 8.17 (dd, J = 7.6, 1.9 Hz, 1H), 7.81
(dd, J = 3.7, 1.1 Hz, 1H), 7.74 (dd, J = 5.0, 1.1 Hz, 1H), 7.66 (dd, J =
7.9, 1.4 Hz, 1H), 7.45 (td, J = 7.7, 1.9 Hz, 1H), 7.44−7.36 (m, 1H),
7.17 (dd, J = 5.0, 3.8 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ
169.2 (CH), 137.9 (C), 136.1 (CH), 134.7 (CH), 134.6 (CH), 134.0
(CH), 131.1 (C), 130.8 (CH), 129.1 (C), 128.2 (CH), 128.0 (CH).
Compound 1i.35 Following GP1 performed with 2-thiophenesul-
fonamide (2.448 g, 15.0 mmol, 1.0 equiv), Dowex (0.367 g, 15% w/
w), and α,α,α-trifluoro-p-tolualdehyde (2.4 mL, 17.5 mmol, 1.2
equiv) in toluene (60 mL, 0.25 M), the desired product was obtained
as a beige solid (2.960 g, 62%). mp: 106−108 °C (litt: 125−127 °C).
Rf (PE/EA: 70/30, UV + KMnO4): 0.42. GC (50 + 10/270 − 15):
Compound 2a.41 Following GP2 performed with dimethyl 2-
methylmalonate (1.33 mL, 10.0 mmol, 1.0 equiv) and potassium
hydroxide (0.561 g, 10.0 mmol, 1.0 equiv) in MeOH (20 mL), the
1
desired product was obtained as a colorless oil (0.926 g, 70%). H
NMR (400 MHz, CDCl3): δ 11.15 (br s, 1H), 3.74 (s, 3H), 3.48 (q, J
= 7.3 Hz, 1H), 1.42 (d, J = 7.3 Hz, 3H). 13C{1H} NMR (100 MHz,
CDCl3): δ 176.1 (C), 170.4 (C), 52.8 (CH3), 45.9 (CH), 13.6
(CH3).
Compound 2b. Following GP2 performed with dimethyl 2-
butylmalonate (1.019 g, 6.4 mmol, 1.0 equiv) and potassium
hydroxide (0.434 g, 7.7 mmol, 1.2 equiv) in MeOH (11 mL), the
desired product was obtained as a colorless oil (0.871 g, 78%). HRMS
(ESI+): m/z [M + H]+ calcd for C8H15O4: 175.0965. Found:
1
175.0967. H NMR (400 MHz, CDCl3): δ 10.38 (br s, 1H), 3.75 (s,
3H), 3.38 (t, J = 6.9 Hz, 1H), 1.98−1.83 (m, 2H), 1.39−1.28 (m,
4H), 0.89 (t, J = 6.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ
175.5 (C), 170.0 (C), 52.8 (CH3), 51.7 (CH), 29.5 (CH2), 28.7
(CH2), 22.4 (CH2), 13.9 (CH3).
1
17.6 min. H NMR (400 MHz, CDCl3): δ 9.05 (s, 1H), 8.07 (d, J =
8.0 Hz, 2H), 7.82 (dt, J = 3.6, 1.5 Hz, 1H), 7.78−7.70 (m, 3H), 7.17
(ddd, J = 5.1, 3.6, 1.5 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ
Compound 2c.42 Following GP2 performed with diethyl 2-
octylmalonate (5.498 g, 20.2 mmol, 1.0 equiv) and potassium
hydroxide (1.133 g, 20.2 mmol, 1.0 equiv) in EtOH (40 mL), the
2
168.7 (CH), 137.8 (C), 136.1 (q, JC−F = 33.0 Hz, C), 135.2 (C),
134.9 (CH), 134.8 (CH), 131.6 (2 CH), 128.1 (CH), 126.3 (q, 3JC−F
1
= 3.7 Hz, 2 CH), 123.4 (q, JC−F = 272.8 Hz, CF3). 19F{1H} NMR
1
(377 MHz, CDCl3): δ −63.3 (s, 3 F).
desired product was obtained as a colorless oil (3.560 g, 72%). H
Compound 1j.35 Following GP1 performed with 2-thiophenesul-
fonamide (1.000 g, 6.1 mmol, 1.0 equiv), Dowex (0.150 g, 15% w/w),
and thiophene-2-carboxaldehyde (0.6 mL, 6.7 mmol, 1.1 equiv) in
toluene (30 mL, 0.2 M), the desired product was obtained as an off-
white solid (1.077 g, 68%). mp: 136−138 °C (litt: 145−147 °C). Rf
(PE/EA: 70/30, UV + KMnO4): 0.32. GC (50 + 10/270 − 15): 19.0
NMR (400 MHz, CDCl3): δ 11.31 (br s, 1H), 4.20 (q, J = 7.2 Hz,
2H), 3.35 (t, J = 7.4 Hz, 1H), 1.95−1.84 (m, 2H), 1.38−1.18 (m,
15H), 0.85 (t, J = 6.8 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ
175.7 (C), 165.5 (C), 61.8 (CH2), 51.9 (CH), 31.9 (CH2), 29.3
(CH2), 29.3 (2 CH2), 28.9 (CH2), 27.4 (CH2), 22.7 (CH2), 14.2
(CH3), 14.1 (CH3).
1
min. H NMR (400 MHz, CDCl3): δ 9.08 (s, 1H), 7.80 (m, 2H),
Compound 2d. Following GP2 performed with diethyl 2-
benzylmalonate (1.070 g, 4.3 mmol, 1.0 equiv) and potassium
hydroxide (0.239 g, 4.3 mmol, 1.0 equiv) in EtOH (10 mL), the
desired product was obtained as a colorless oil (0.657 g, 69%). HRMS
(ESI+): m/z [M + Na]+ calcd for C12H14NaO4: 245.0784. Found:
7.76 (dd, J = 3.8, 1.4 Hz, 1H), 7.68 (dd, J = 5.0, 1.4 Hz, 1H), 7.21
(dd, J = 5.0, 3.8 Hz, 1H), 7.12 (dd, J = 5.0, 3.8 Hz, 1H). 13C{1H}
NMR (100 MHz, CDCl3): δ 162.4 (CH), 139.5 (CH), 139.2 (C),
138.1 (C), 137.3 (CH), 134.0 (CH), 133.8 (CH), 129.1 (CH), 127.8
(CH).
1
245.0785. H NMR (400 MHz, CDCl3): δ 11.06 (br s, 1H), 7.35−
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7.29 (m, 2H), 7.26 (t, J = 7.9 Hz, 3H), 4.20 (q, J = 7.1 Hz, 2H), 3.75
(t, J = 7.7 Hz, 1H), 3.27 (d, J = 7.7 Hz, 2H), 1.24 (t, J = 7.1 Hz, 3H).
13C{1H} NMR (100 MHz, CDCl3): δ 174.7 (C), 168.7 (C), 137.5
(C), 128.9 (2 CH), 128.7 (2 CH), 127.0 (CH), 62.0 (CH2), 53.7
(CH), 34.7 (CH2), 14.0 (CH3).
(100 MHz, CDCl3): (two diastereomers) δ 175.0 (C), 173.9 (C),
143.1 (C), 142.9 (C), 138.8 (C), 138.2 (C), 137.9 (C), 137.5 (C),
129.3 (2 CH), 129.2 (2 CH), 128.4 (2 CH), 128.3 (2 CH), 127.6
(CH), 127.5 (CH), 127.1 (2 CH), 127.0 (2 CH), 127.0 (2 CH),
126.7 (2 CH), 60.4 (CH), 60.0 (CH), 52.0 (CH3), 51.9 (CH3), 46.2
(CH), 46.1 (CH), 21.5 (CH3), 21.5 (CH3), 15.4 (CH3), 13.6 (CH3).
Following a similar procedure, the reactions performed using 2a
(33 mg, 0.25 mmol, 1.0 equiv), imine 1a (65 mg, 0.25 mmol, 1.0
equiv), and cinchonidine (15 mg, 0.05 mmol, 0.2 equiv) or quinine
(16 mg, 0.05 mmol, 0.2 equiv) in dry THF (0.25 mL, 1 M) led to 3aa
(72 mg, 82%, d.r. = 65:35 and 80 mg, 91%, d.r. = 45:55, respectively).
Chiral high-performance liquid chromatography (HPLC) analysis
using a ChiralPak IC column (CH3CN/MeOH, 35:65, 1.0 mL/min)
displayed no significant difference with racemic 3aa.
General Procedure 3 (GP3). A 10 mL microwave tube equipped
with a stir bar was charged with the SMAHO (0.25 mmol, 1.0 equiv),
DABCO (6 mg, 0.05 mmol, 0.2 equiv), imine (0.25 mmol, 1.0 equiv),
and dry THF (0.25 mL, 1 M). The vial was then sealed with a septum
open to air with a needle, and the reaction was stirred at reflux for 14
h. The reaction mixture was then evaporated, and purification by FC
of the crude material afforded the expected product.
Compound 3bb. Following GP3 performed with SMAHO 2b (44
mg, 0.25 mmol, 1.0 equiv) and imine 3b (63 mg, 0.25 mmol, 1.0
equiv), the desired product was obtained after purification by FC
[V(SiO2) = 50 mL, Cy/EA: 90/10 (250 mL), 80/20 (250 mL)] as a
white solid (49 mg, 51%, d.r. = 69:31). mp: 113−115 and 120−124
°C. Rf (Cy/EA: 70/30, UV + KMnO4): 0.40. GC (50 + 10/270 −
15): 21.4 and 21.7 min. HRMS (ESI+): [M + H]+ calcd for
C18H24NO4S2: 382.1141. Found: 382.1140. 1H NMR (400 MHz,
CDCl3): (two diastereomers) δ 7.41 (dt, J = 5.0, 1.6 Hz, 1H), 7.38
(dt, J = 5.0, 1.5 Hz, 1H), 7.34 (dd, J = 3.6, 1.7 Hz, 1H), 7.32−7.26
(m, 1H), 7.20−7.13 (m, 6H), 7.09−7.00 (m, 4H), 6.86 (ddd, J = 5.0,
3.6, 1.5 Hz, 1H), 6.82 (ddd, J = 5.1, 3.7, 1.4 Hz, 1H), 6.34 (d, J = 9.3
Hz, 1H), 5.80 (d, J = 8.8 Hz, 1H), 4.66 (dd, J = 8.8, 5.8 Hz, 1H), 4.59
(t, J = 8.3 Hz, 1H), 3.57 (s, 3H), 3.45 (s, 3H), 2.79−2.67 (m, 2H),
1.74−1.64 (m, 4H), 1.52−1.44 (m, 1H), 1.33−1.17 (m, 7H), 0.86 (t,
J = 6.4 Hz, 6H). 13C{1H} NMR (100 MHz, CDCl3): (two
diastereomers) δ 175.0 (C), 173.4 (C), 142.1 (C), 141.5 (C),
139.0 (C), 138.2 (C), 132.5 (CH), 132.1 (CH), 131.9 (CH), 131.5
(CH), 128.6 (2 CH), 128.4 (2 CH), 127.9 (CH), 127.7 (CH), 127.2
(CH), 127.0 (CH), 126.9 (2 CH), 126.3 (2 CH), 59.7 (CH), 59.1
(CH), 52.4 (CH), 52.2 (CH), 52.0 (CH3), 51.8 (CH3), 30.1 (CH2),
29.6 (CH2), 29.5 (CH2), 28.5 (CH2), 22.6 (CH2), 22.5 (CH2), 14.0
(CH3), 13.9 (CH3).
Compound 3ac. Following GP3 performed with SMAHO 2c (61
mg, 0.25 mmol, 1.0 equiv) and imine 1a (65 mg, 0.25 mmol, 1.0
equiv), the desired product was obtained after purification by FC
[V(SiO2) = 50 mL, Cy/EA: 90/10 (250 mL), 80/20 (250 mL)] as a
white solid (78 mg, 68%, d.r. = 74:26). mp: 92−94 and 97−100 °C.
Rf (Cy/EA: 70/30, UV + KMnO4): 0.51. GC (50 + 10/270 − 15):
27.5 and 27.9 min. HRMS (ESI+): [M + H]+ calcd for C26H38NO4S:
460.2516. Found: 460.2514. 1H NMR (400 MHz, CDCl3): (two
diastereomers) δ 7.49 (t, J = 7.5 Hz, 4H), 7.12−7.01 (m, 10H), 7.03−
6.92 (m, 4H), 6.22 (d, J = 9.3 Hz, 1H), 5.86 (d, J = 9.0 Hz, 1H), 4.56
(dd, J = 9.1, 6.4 Hz, 1H), 4.41 (t, J = 8.8 Hz, 1H), 4.00 (q, J = 7.1 Hz,
2H), 3.80 (m, 2H), 2.69−2.59 (m, 2H), 2.30 (s, 3H), 2.29 (s, 3H),
1.73−1.51 (m, 4H), 1.29−1.12 (m, 24H), 1.09 (t, J = 7.1 Hz, 3H),
0.91 (t, J = 7.1 Hz, 3H), 0.86 (t, J = 6.8 Hz, 6H). 13C{1H} NMR (100
MHz, CDCl3): (two diastereomers) δ 174.5 (C), 173.0 (C), 143.0
(C), 142.8 (C), 139.2 (C), 138.7 (C), 138.1 (C), 137.5 (C), 129.3 (2
CH), 129.1 (2 CH), 128.3 (2 CH), 128.2 (2 CH), 127.5 (CH), 127.3
(CH), 127.2 (2 CH), 127.1 (2 CH), 127.0 (2 CH), 126.5 (2 CH),
60.9 (CH2), 60.5 (CH2), 59.7 (CH), 59.0 (CH), 52.6 (CH), 52.3
(CH), 31.9 (CH2), 31.9 (CH2), 30.3 (CH2), 29.5 (CH2), 29.4
(CH2), 29.3 (CH2), 29.3 (CH2), 29.3 (CH2), 29.3 (CH2), 29.0
(CH2), 27.4 (CH2), 27.2 (CH2), 22.7 (CH2), 22.7 (CH2), 21.5
(CH3), 21.4 (CH3), 14.2 (2 CH3), 14.1 (CH3), 13.9 (CH3).
Compound 3ad.22 Following GP3 performed with SMAHO 2d
(56 mg, 0.25 mmol, 1.0 equiv) and imine 1a (65 mg, 0.25 mmol, 1.0
equiv), the desired product was obtained after purification by FC
Compound 2e. Following GP2 performed with diethyl 2-
allylmalonate (0.985 g, 4.9 mmol, 1.0 equiv) and potassium hydroxide
(0.275 g, 4.9 mmol, 1.0 equiv) in EtOH (10 mL), the desired product
was obtained as a colorless oil (0.603 g, 71%). HRMS (ESI+): m/z [M
+ H]+ calcd for C8H13O4: 173.0808. Found: 173.0806. 1H NMR (400
MHz, CDCl3): δ 10.83 (br s, 1H), 5.77 (ddt, J = 17.0, 10.1, 6.8 Hz,
1H), 5.13 (d, J = 17.0 Hz, 1H), 5.07 (d, J = 10.1 Hz, 1H), 4.21 (q, J =
7.1 Hz, 2H), 3.47 (t, J = 7.5 Hz, 1H), 2.68−2.62 (m, 2H), 1.27 (t, J =
7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 174.8 (C), 168.8
(C), 133.7 (CH), 118.1 (CH2), 62.0 (CH2), 51.5 (CH), 32.9 (CH2),
14.1 (CH3).
Compound 2f.43 Following GP2 performed with diethyl 2-
propargylmalonate (1.702 g, 8.6 mmol, 1.0 equiv) and potassium
hydroxide (0.482 g, 8.6 mmol, 1.0 equiv) in EtOH (18 mL), the
1
desired product was obtained as a colorless oil (0.963 g, 65%). H
NMR (400 MHz, CDCl3): δ 11.10 (br s, 1H), 4.23 (q, J = 7.1 Hz,
2H), 3.61 (t, J = 7.5 Hz, 1H), 2.78 (d, J = 7.5 Hz, 2H), 2.03 (s, 1H),
1.27 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 173.6
(C), 167.7 (C), 79.6 (C), 70.9 (CH), 62.4 (CH2), 51.0 (CH), 18.4
(CH2), 14.0 (CH3).
Compound 2g. Following GP2 performed with diethyl 2-(2-((4-
methylbenzoyl)oxy)ethyl) malonate (1.400 g, 4.4 mmol, 1.0 equiv)
and potassium hydroxide (0.297 g, 5.3 mmol, 1.2 equiv) in EtOH (9
mL), the desired product was obtained as a colorless oil (0.825 g,
63%). HRMS (ESI+): m/z [M + H]+ calcd for C15H19O6: 295.1176.
1
Found: 295.1175. H NMR (400 MHz, CDCl3): δ 10.85 (br s, 1H),
7.91 (d, J = 7.5 Hz, 2H), 7.23 (d, J = 7.5 Hz, 2H), 4.41 (m, 2H),
4.27−4.16 (m, 2H), 3.63 (t, J = 7.1 Hz, 1H), 2.50−2.35 (m, 5H),
1.26 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 174.3
(C), 168.7 (C), 166.6 (C), 144.0 (C), 129.7 (2 CH), 129.2 (2 CH),
127.1 (C), 62.3 (CH2), 62.1 (CH2), 49.0 (CH), 28.0 (CH2), 21.7
(CH3), 14.0 (CH3).
Compound 2h. A 25 mL RBF equipped with a stir bar was charged
with 7 (0.316 g, 2.0 mmol, 1.0 equiv), benzyl alcohol (0.21 mL, 2.0
mmol, 1.0 equiv), and toluene (8 mL, 0.25 M). The reaction was
stirred at reflux for 8 h. Then, the mixture was diluted with Et2O (20
mL), and the resulting organic layer was extracted with saturated
aqueous NaHCO3 (two times). The combined aqueous layers were
cooled down to 0 °C (ice/water bath) and acidified to pH = 1 with
aqueous 1 M HCl, saturated with NaCl, and extracted with Et2O
(three times). The combined organic layers were dried (Na2SO4) and
evaporated to afford the expected product as a pale yellow oil (0.357
g, 85%). HRMS (ESI+): m/z [M + H]+ calcd for C11H13O4: 209.0808.
1
Found: 209.0810. H NMR (400 MHz, CDCl3): δ 9.55 (br s, 1H),
7.50−7.23 (m, 5H), 5.23 (s, 2H), 3.58 (q, J = 7.2 Hz, 1H), 1.51 (d, J
= 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 175.8 (C),
169.8 (C), 135.3 (C), 128.7 (2 CH), 128.5 (CH), 128.2 (2 CH), 67.5
(CH2), 46.1 (CH), 13.7 (CH3).
Decarboxylative Mannich Reactions. Compound 3aa.44 A 10
mL microwave tube equipped with a stir bar was charged with 2a
(132 mg, 1.0 mmol, 1.0 equiv), DABCO (22 mg, 0.2 mmol, 0.2
equiv), imine 1a (259 mg, 1.0 mmol, 1.0 equiv), and dry THF (1.0
mL, 1 M). The vial was then sealed with a septum open to air with a
needle, and the reaction was stirred at reflux using a dry block heater
for 14 h. The reaction mixture was then evaporated, and the desired
product was obtained after purification by FC [V(SiO2) = 50 mL, Cy/
EA: 80/20 (500 mL)] as a white solid (288 mg, 83%, d.r. = 65:35).
mp: 81−83 and 96−100 °C (litt: 103−104 °C). Rf (Cy/EA: 70/30,
UV + KMnO4): 0.39. GC (50 + 10/270 − 15): 20.7 and 20.9 min. 1H
NMR (400 MHz, CDCl3): (two diastereomers) δ 7.51 (d, J = 8.1 Hz,
2H), 7.48 (d, J = 8.5 Hz, 2H), 7.14−7.06 (m, 6H), 7.06 (d, J = 8.2
Hz, 2H), 7.03 (d, J = 8.4 Hz, 2H), 7.02−6.93 (m, 4H), 6.11 (d, J =
9.1 Hz, 1H), 5.92 (d, J = 8.9 Hz, 1H), 4.58−4.46 (m, 2H), 3.56 (s,
3H), 3.45 (s, 3H), 2.91−2.74 (m, 2H), 2.31 (s, 3H), 2.30 (s, 3H),
1.15 (d, J = 7.0 Hz, 3H), 1.10 (d, J = 7.0 Hz, 3H). 13C{1H} NMR
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[V(SiO2) = 50 mL, Cy/EA: 90/10 (350 mL), 80/20 (350 mL)] as a
white solid (65 mg, 59%, d.r. = 75:25). mp: 119−121 and 130−133
°C (litt: 114−115 and 129−130 °C). Rf (Cy/EA: 70/30, UV +
524.1169. H NMR (400 MHz, CDCl3): (two diastereomers) δ 7.91
(d, J = 7.8 Hz, 2H), 7.87 (d, J = 7.7 Hz, 2H), 7.39−7.28 (m, 4H),
7.28−7.19 (m, 4H), 7.19−7.13 (m, 6H), 7.11−7.05 (m, 4H), 6.85−
6.76 (m, 2H), 6.47 (d, J = 9.5 Hz, 1H), 6.16 (d, J = 9.3 Hz, 1H), 4.79
(dd, J = 9.3, 6.3 Hz, 1H), 4.64 (t, J = 8.9 Hz, 1H), 4.41−4.27 (m,
4H), 4.06−3.90 (m, 2H), 3.90−3.70 (m, 2H), 2.95 (m, 2H), 2.42 (m,
3H), 2.41 (m, 3H), 2.34−2.18 (m, 2H), 2.02−1.93 (m, 2H), 1.04 (t, J
= 7.1 Hz, 3H), 0.88 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz,
CDCl3): (two diastereomers) δ 173.7 (C), 172.3 (C), 166.6 (C),
166.5 (C), 143.9 (C), 143.8 (C) 141.8 (C), 141.3 (C), 138.2 (C),
137.8 (C), 132.5 (CH), 132.2 (CH), 132.0 (CH), 131.6 (CH), 129.7
(2 CH), 129.7 (2 CH), 129.2 (2 CH), 129.1 (2 CH), 128.5 (2 CH),
128.4 (2 CH), 128.0 (CH), 127.8 (CH), 127.2 (C), 127.2 (C), 127.1
(CH), 127.1 (CH), 127.0 (2 CH), 126.4 (2 CH), 63.0 (CH2), 62.3
(CH2), 61.3 (CH2), 61.0 (CH2), 60.0 (CH), 59.1 (CH), 49.8 (CH),
49.3 (CH), 29.5 (CH2), 28.3 (CH2), 21.7 (2 CH3), 14.0 (CH3), 13.8
(CH3).
Compound 3bh. Following GP3 performed with SMAHO 2h (52
mg, 0.25 mmol, 1.0 equiv) and imine 1b (63 mg, 0.25 mmol, 1.0
equiv), the desired product was obtained after purification by FC
[V(SiO2) = 50 mL, Cy/EA: 80/20 (500 mL)] as an pale yellow solid
(97 mg, 94%, d.r. = 65:35). mp: 121−126 °C. Rf (Cy/EA: 70/30, UV
+ KMnO4): 0.34. GC (50 + 10/270 − 15): 26.3 and 26.7 min. HRMS
(ESI+): [M + Na]+ calcd for C21H21NNaO4S2: 438.0804. Found:
438.0802. 1H NMR (400 MHz, CDCl3): (two diastereomers) δ
7.37−7.33 (m, 2H), 7.32−7.26 (m, 8H), 7.23−7.06 (m, 10H), 7.06−
6.99 (m, 4H), 6.83−6.75 (m, 2H), 6.39 (d, J = 9.2 Hz, 1H), 6.14 (d, J
= 9.2 Hz, 1H), 5.06 (d, J = 12.5 Hz, 1H), 5.02 (d, J = 12.5 Hz, 1H),
4.95 (d, J = 11.5 Hz, 1H), 4.91 (d, J = 11.5 Hz, 1H), 4.64 (t, J = 8.2
Hz, 2H), 3.02−2.87 (m, 2H), 1.25 (d, J = 6.9 Hz, 3H), 1.18 (d, J =
7.0 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): (two
diastereomers) δ 174.5 (C), 173.3 (C), 141.8 (C), 141.5 (C),
138.4 (C), 137.9 (C), 135.4 (2 C), 132.3 (CH), 132.1 (CH), 131.8
(CH), 131.6 (CH), 128.6 (2 CH), 128.6 (2 CH), 128.5 (2 CH),
128.4 (2 CH), 128.4 (CH), 128.3 (CH), 128.3 (2 CH), 128.2 (2
CH), 127.8 (CH), 127.7 (CH), 127.1 (CH), 127.0 (CH), 127.0 (2
CH), 126.5 (2 CH), 66.8 (CH2), 66.7 (CH2), 60.5 (CH), 60.4 (CH),
46.2 (CH), 46.2 (CH), 15.3 (CH3), 14.0 (CH3).
1
KMnO4): 0.34. GC (50 + 10/270 − 15): 27.5 and 28.2 min. H
NMR (400 MHz, CDCl3): (two diastereomers) δ 7.46 (d, J = 8.0 Hz,
2H), 7.41 (d, J = 8.0 Hz, 2H), 7.20−7.06 (m, 6H), 7.04−6.94 (m,
14H), 6.93−6.87 (m, 4H), 6.29 (d, J = 9.4 Hz, 1H), 6.02 (d, J = 9.1
Hz, 1H), 4.56 (dd, J = 9.3, 5.0 Hz, 1H), 4.44 (t, J = 8.7 Hz, 1H),
3.85−3.74 (m, 2H), 3.59 (q, J = 7.1 Hz, 2H), 3.04 (dd, J = 13.3, 3.7
Hz, 1H), 2.96−2.79 (m, 4H), 2.75−2.66 (m, 1H), 2.23 (s, 3H), 2.21
(s, 3H), 0.85 (t, J = 7.1 Hz, 3H), 0.69 (t, J = 7.1 Hz, 3H). 13C{1H}
NMR (100 MHz, CDCl3): (two diastereomers) δ 173.7 (C), 172.3
(C), 143.2 (C), 142.9 (C), 138.9 (C), 138.6 (C), 138.2 (C), 138.1
(C), 138.0 (C), 137.4 (C), 129.4 (2 CH), 129.2 (2 CH), 129.0 (2
CH), 128.9 (2 CH), 128.6 (2 CH), 128.4 (4 CH), 128.3 (2 CH),
127.7 (CH), 127.5 (CH), 127.2 (2 CH), 127.1 (2 CH), 127.0 (2
CH), 126.8 (CH), 126.5 (2 CH), 126.5 (CH), 60.9 (CH2), 60.6
(CH2), 59.6 (CH), 58.7 (CH), 54.4 (CH), 54.3 (CH), 36.4 (CH2),
35.3 (CH2), 21.5 (CH3), 21.5 (CH3), 13.9 (CH3), 13.7 (CH3).
Compound 3be. Following GP3 performed with SMAHO 2e (43
mg, 0.25 mmol, 1.0 equiv) and imine 1b (63 mg, 0.25 mmol, 1.0
equiv), the desired product was obtained after purification by FC
[V(SiO2) = 50 mL, Cy/EA: 90/10 (250 mL), 80/20 (250 mL)] as an
off-white solid (80 mg, 88%, d.r. = 77:23). mp: 83−90 °C. Rf (Cy/EA:
80/20, UV + KMnO4): 0.30. GC (50 + 10/270 − 15): 21.1 and 21.4
min. HRMS (ESI+): [M + H]+ calcd for C18H22NO4S2: 380.0984.
Found: 380.0985. 1H NMR (400 MHz, CDCl3): (two diastereomers)
δ 7.38 (d, J = 5.0 Hz, 1H), 7.33 (d, J = 4.9 Hz, 1H), 7.32−7.27 (m,
1H), 7.26−7.21 (m, 1H), 7.16−7.11 (m, 6H), 7.06−6.98 (m, 4H),
6.83 (t, J = 4.3 Hz, 1H), 6.77 (t, J = 4.3 Hz, 1H), 6.37 (d, J = 9.3 Hz,
1H), 5.88 (d, J = 9.0 Hz, 1H), 5.77−5.63 (m, 2H), 5.13−4.99 (m,
4H), 4.68 (dd, J = 8.9, 5.7 Hz, 1H), 4.58 (t, J = 8.6 Hz, 1H), 4.02 (q, J
= 7.1 Hz, 2H), 3.88 (q, J = 7.1 Hz, 2H), 2.86−2.73 (m, 2H), 2.46 (m,
2H), 2.27 (m, 2H), 1.09 (t, J = 7.1 Hz, 3H), 0.98 (t, J = 7.1 Hz, 3H).
13C{1H} NMR (100 MHz, CDCl3): (two diastereomers) δ 173.8 (C),
172.2 (C), 142.1 (C), 141.4 (C), 138.6 (C), 137.8 (C), 134.7 (CH),
134.0 (CH), 132.5 (CH), 132.1 (CH), 131.9 (CH), 131.5 (CH),
128.5 (2 CH), 128.4 (2 CH), 128.0 (CH), 127.7 (CH), 127.2 (CH),
127.0 (2 CH), 127.0 (CH), 126.4 (2 CH), 118.2 (CH2), 117.7
(CH2), 61.1 (CH2), 60.8 (CH2), 59.4 (CH), 58.7 (CH), 52.0 (CH),
51.9 (CH), 34.5 (CH2), 33.3 (CH2), 14.2 (CH3), 14.0 (CH3).
Compound 3af. Following GP3 performed with SMAHO 2f (43
mg, 0.25 mmol, 1.0 equiv) and imine 1a (65 mg, 0.25 mmol, 1.0
equiv), the desired product was obtained after purification by FC
[V(SiO2) = 50 mL, Cy/EA: 90/10 (250 mL), 80/20 (500 mL)] as a
pale yellow glue (55 mg, 57%, d.r. = 76:24). Rf (Cy/EA: 80/20, UV +
KMnO4): 0.17. GC (50 + 10/270 − 15): 22.2 and 22.3 min. HRMS
(ESI+): [M + H]+ calcd for C21H24NO4S: 386.1420. Found:
386.1417. 1H NMR (400 MHz, CDCl3): (two diastereomers) δ
7.51 (t, J = 7.8 Hz, 4H), 7.16−7.03 (m, 10H), 7.06−6.96 (m, 4H),
6.10 (d, J = 8.9 Hz, 1H), 5.97 (d, J = 9.5 Hz, 1H), 4.76 (dd, J = 9.7,
4.8 Hz, 1H), 4.68 (t, J = 8.1 Hz, 1H), 4.09−3.99 (m, 2H), 4.00−3.91
(m, 2H), 2.91 (q, J = 6.8 Hz, 2H), 2.59−2.49 (m, 2H), 2.49−2.35 (m,
2H), 2.32 (s, 3H), 2.31 (s, 3H), 2.07 (q, J = 2.4 Hz, 1H), 2.03 (q, J =
2.5 Hz, 1H), 1.11 (t, J = 7.1 Hz, 3H), 1.03 (t, J = 7.5 Hz, 3H).
13C{1H} NMR (100 MHz, CDCl3): (two diastereomers) δ 172.6 (C),
171.3 (C), 143.2 (C), 143.0 (C), 138.4 (C), 138.0 (C), 137.6 (C),
137.9 (C), 129.4 (2 CH), 129.3 (2 CH), 128.5 (2 CH), 128.4 (2
CH), 128.0 (CH), 127.7 (CH), 127.2 (2 CH), 127.1 (2 CH), 127.1
(2 CH), 126.6 (2 CH), 80.9 (C), 80.3 (C), 71.2 (CH), 71.1 (CH),
61.4 (CH2), 61.3 (CH2), 58.3 (CH), 58.2 (CH), 51.1 (CH), 50.7
(CH), 21.5 (2 CH), 19.8 (CH2), 18.7 (CH2), 14.1 (CH3), 14.0
(CH3).
Compound 3ca. Following GP3 performed with SMAHO 2a (33
mg, 0.25 mmol, 1.0 equiv) and imine 1c (46 mg, 0.25 mmol, 1.0
equiv), the desired product was obtained after purification by FC
[V(SiO2) = 50 mL, Cy/EA: 50/50 (500 mL)] as a pale yellow glue
(60 mg, 89%, d.r. = 65:35). Rf (Cy/EA: 50/50, UV + KMnO4): 0.36.
1
GC (50 + 10/270 − 15): 15.5 and 15.8 min. H NMR (400 MHz,
CDCl3): (two diastereomers) δ 7.34−7.24 (m, 4H), 7.27−7.18 (m,
6H), 6.05 (d, J = 9.3 Hz, 1H), 5.91 (d, J = 9.5 Hz, 1H), 4.65 (dd, J =
9.5, 6.8 Hz, 1H), 4.52 (t, J = 8.4 Hz, 1H), 3.60 (s, 3H), 3.51 (s, 3H),
2.89 (quint, J = 7.0 Hz, 1H), 2.82 (quint, J = 7.6 Hz, 1H), 2.53 (s,
6H), 1.16 (d, J = 7.1 Hz, 3H), 1.12 (d, J = 7.1 Hz, 3H). 13C{1H}
NMR (100 MHz, CDCl3): (two diastereomers) δ 175.2 (C), 173.9
(C), 139.5 (C), 138.9 (C), 129.1 (2 CH), 128.9 (2 CH), 128.3 (2
CH), 127.2 (2 CH), 126.9 (2 CH), 60.4 (CH), 59.9 (CH), 52.2
(CH3), 52.0 (CH3), 46.2 (CH), 46.1 (CH), 41.9 (CH3), 41.8 (CH3),
15.6 (CH3), 13.6 (CH3).
Compound 3ba.44 Following GP3 performed with SMAHO 2a
(33 mg, 0.25 mmol, 1.0 equiv) and imine 2b (63 mg, 0.25 mmol, 1.0
equiv), the desired product was obtained after purification by FC
[V(SiO2) = 50 mL, Cy/EA: 90/10 (250 mL), 80/20 (500 mL)] as an
off-white solid (74 mg, 88%, d.r. = 65:35). mp: 106−107 °C. Rf (Cy/
EA: 70/30, UV + KMnO4): 0.29. GC (50 + 10/270 − 15): 19.9 and
1
20.1 min. H NMR (400 MHz, CDCl3): (two diastereomers) δ 7.31
(dt, J = 5.0, 1.3 Hz, 1H), 7.28 (dt, J = 4.9, 1.3 Hz, 1H), 7.24 (dt, J =
3.8, 1.3 Hz, 1H), 7.24−7.17 (m, 1H), 7.11−7.06 (m, 6H), 7.01−6.96
(m, 4H), 6.77−6.69 (m, 2H), 6.26 (d, J = 9.2 Hz, 1H), 6.04 (d, J =
9.2 Hz, 1H), 4.56 (dd, J = 8.8, 7.2 Hz, 1H), 4.51 (dd, J = 9.0, 6.7 Hz,
1H), 3.53 (s, 3H), 3.43 (s, 3H), 2.88−2.74 (m, 2H), 1.12 (d, J = 7.1
Hz, 3H), 1.09 (d, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz,
CDCl3): (two diastereomers) δ 175.0 (C), 173.8 (C), 141.8 (C),
141.5 (C), 138.6 (C), 137.9 (C), 132.4 (CH), 132.1 (CH), 131.8
(CH), 131.6 (CH), 128.5 (2 CH), 128.4 (2 CH), 127.8 (CH), 127.7
Compound 3bg. Following GP3 performed with SMAHO 2g (74
mg, 0.25 mmol, 1.0 equiv) and imine 1b (63 mg, 0.25 mmol, 1.0
equiv), the desired product was obtained after purification by FC
[V(SiO2) = 50 mL, Cy/EA: 90/10 (250 mL), 80/20 (500 mL)] as a
pale yellow paste (79 mg, 63%, d.r. = 67:33). Rf (Cy/EA: 70/30, UV
+ KMnO4): 0.29. GC (50 + 10/270 − 15): 21.9 and 22.0 min. HRMS
(ESI+): [M + Na]+ calcd for C25H27NNaO6S2: 524.1172. Found:
5458
https://doi.org/10.1021/acs.joc.0c02895
J. Org. Chem. 2021, 86, 5452−5462

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(CH), 127.2 (CH), 127.1 (CH), 126.9 (2 CH), 126.5 (2 CH), 60.6
(CH), 60.3 (CH), 52.1 (CH3), 52.0 (CH3), 46.2 (CH), 46.1 (CH),
15.4 (CH3), 13.7 (CH3).
equiv), the desired product was obtained after purification by FC
[V(SiO2) = 50 mL, Cy/EA: 70/30 (500 mL)] as a white solid (78
mg, 88%, d.r. = 64:36). mp: 124−126 and 138−142 °C. Rf (Cy/EA:
80/20, UV + KMnO4): 0.20. GC (50 + 10/270 − 15): 20.5 and 20.7
min. HRMS (ESI+): [M + Na]+ calcd for C16H19NNaO4S2: 376.0648.
Found: 376.0648. 1H NMR (400 MHz, CDCl3): (two diastereomers)
δ 7.42−7.36 (m, 1H), 7.40−7.34 (m, 1H), 7.31 (dt, J = 3.8, 1.2 Hz,
1H), 7.28 (dt, J = 3.8, 1.2 Hz, 1H), 7.00−6.88 (m, 8H), 6.87−6.78
(m, 2H), 6.24 (d, J = 9.0 Hz, 1H), 6.01 (d, J = 8.6 Hz, 1H), 4.58 (dd,
J = 9.2, 6.9 Hz, 1H), 4.53 (dd, J = 8.8, 6.9 Hz, 1H), 3.59 (s, 3H), 3.50
(s, 3H), 2.86 (m, 2H), 2.25 (s, 3H), 2.24 (s, 3H), 1.17 (d, J = 7.1 Hz,
3H), 1.14 (d, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3):
(two diastereomers) δ 175.1 (C), 173.9 (C), 141.9 (C), 141.6 (C),
137.5 (C), 137.4 (C), 135.7 (C), 135.0 (C), 132.3 (CH), 132.1
(CH), 131.7 (CH), 131.5 (CH), 129.2 (2 CH), 129.1 (2 CH), 127.1
(CH), 127.0 (CH), 126.8 (2 CH), 126.4 (2 CH), 60.3 (CH), 60.1
(CH), 52.1 (CH3), 52.0 (CH3), 46.2 (CH), 46.0 (CH), 21.1 (2
CH3), 15.3 (CH3), 13.7 (CH3).
Compound 3ga. Following GP3 performed with SMAHO 2a (33
mg, 0.25 mmol, 1.0 equiv) and imine 1g (71 mg, 0.25 mmol, 1.0
equiv), the desired product was obtained after purification by FC
[V(SiO2) = 50 mL, Cy/EA: 90/10 (250 mL), 80/20 (500 mL)] as a
white solid (85 mg, 91%, d.r. = 81:19). mp: 119−126 °C. Rf (Cy/EA:
70/30, UV + KMnO4): 0.32. GC (50 + 10/270 − 15): 20.7 and 21.1
min. HRMS (ESI+): [M + H]+ calcd for C15H17ClNO4S2: 374.0282.
Found: 374.0282. 1H NMR (400 MHz, CD3COCD3): (two
diastereomers) δ 7.62 (dt, J = 5.0, 1.3 Hz, 1H), 7.59 (dd, J = 5.0,
1.2 Hz, 1H), 7.51−7.39 (m, 4H), 7.35−7.25 (m, 4H), 7.21−7.14 (m,
4H), 6.91 (ddd, J = 5.0, 3.9, 1.3 Hz, 1H), 6.87 (ddd, J = 5.0, 3.9, 1.4
Hz, 1H), 5.37 (dd, J = 9.8, 6.5 Hz, 1H), 5.21 (t, J = 9.3 Hz, 1H), 3.60
(s, 3H), 3.50 (s, 3H), 3.01 (quint, J = 6.5 Hz, 1H), 2.91−2.83 (m,
1H), 1.13 (d, J = 7.8 Hz, 3H), 1.01 (d, J = 6.5 Hz, 3H). 13C{1H}
NMR (100 MHz, CD3COCD3): (two diastereomers) δ 174.4 (C),
173.4 (C), 143.1 (C), 143.0 (C), 137.6 (C), 137.6 (C), 133.7 (C),
133.1 (C), 132.8 (CH), 132.7 (CH), 134.5 (2 CH), 130.2 (CH),
130.0 (CH), 129.8 (CH), 129.7 (CH), 129.7 (CH), 129.1 (CH),
128.2 (CH), 127.9 (CH), 127.8 (CH), 127.7 (CH), 57.3 (CH), 57.2
(CH), 52.1 (CH3), 52.0 (CH3), 46.5 (CH), 45.0 (CH), 14.7 (CH3),
12.3 (CH3).
Compound 3bd.22 Following GP3 performed with SMAHO 2d
(56 mg, 0.25 mmol, 1.0 equiv) and imine 1b (63 mg, 0.25 mmol, 1.0
equiv), the desired product was obtained after purification by FC
[V(SiO2) = 50 mL, Cy/EA: 90/10 (250 mL), 80/20 (350 mL)] as a
white solid (71 mg, 66%, d.r. = 78:22). mp: 108−110 and 115−117
°C (litt: 106−107 °C). Rf (Cy/EA: 70/30, UV + KMnO4): 0.38. GC
(50 + 10/270 − 15): 26.0 and 26.5 min. 1H NMR (400 MHz,
CDCl3): (two diastereomers) δ 7.36 (dt, J = 5.0, 1.4 Hz, 1H), 7.31
(dt, J = 3.8, 1.3 Hz, 2H), 7.25−7.21 (m, 4H), 7.19 (d, J = 7.4 Hz,
2H), 7.15−7.10 (m, 9H), 7.09−6.99 (m, 6H), 6.81 (ddd, J = 5.1, 3.7,
1.2 Hz, 1H), 6.74 (ddd, J = 4.9, 3.7, 1.1 Hz, 1H), 6.54 (d, J = 9.3 Hz,
1H), 6.14 (d, J = 9.1 Hz, 1H), 4.69 (dd, J = 9.3, 4.5 Hz, 1H), 4.61 (t, J
= 8.7 Hz, 1H), 3.88 (q, J = 7.0, 2H), 3.69 (q, J = 7.1 Hz, 2H), 3.12
(dd, J = 13.3, 3.9 Hz, 1H), 3.08−2.88 (m, 4H), 2.86−2.77 (m, 1H),
0.92 (t, J = 7.1 Hz, 3H), 0.78 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100
MHz, CDCl3): (two diastereomers) δ 173.7 (C), 172.2 (C), 142.0
(C), 141.3 (C), 138.6 (C), 138.5 (C), 137.9 (2 C), 132.6 (CH),
132.1 (CH), 132.0 (CH), 131.6 (CH), 129.0 (2 CH), 128.9 (2 CH),
128.6 (2 CH), 128.5 (2 CH), 128.5 (2 CH), 128.4 (2 CH), 128.0
(CH), 127.7 (CH), 127.2 (CH), 127.1 (2 CH), 127.0 (CH), 126.8
(CH), 126.5 (CH), 126.3 (2 CH), 61.0 (CH2), 60.7 (CH2), 59.9
(CH), 58.9 (CH), 54.4 (CH), 54.2 (CH), 36.4 (CH2), 35.3 (CH2),
13.9 (CH3), 13.8 (CH3).
Compound 3da. Following GP3 performed with SMAHO 2a (33
mg, 0.25 mmol, 1.0 equiv) and imine 1d (66 mg, 0.25 mmol, 1.0
equiv), the desired product was obtained after purification by FC
[V(SiO2) = 50 mL, Cy/EA: 80/20 (500 mL)] as a pale yellow glue
(67 mg, 76%, d.r. = 66:34). Rf (Cy/EA: 70/30, UV + KMnO4): 0.51.
GC (50 + 10/270 − 15): 20.2 and 20.5 min. HRMS (ESI+): [M +
1
H]+ calcd for C16H20NO4S2: 354.0828. Found: 354.0827. H NMR
(400 MHz, CD3COCD3): (two diastereomers) δ 7.60 (dt, J = 5.1, 1.4
Hz, 1H), 7.55 (dt, J = 5.0, 1.5 Hz, 1H), 7.37−7.29 (m, 4H), 7.23 (dd,
J = 3.4, 1.7 Hz, 1H), 7.17 (dd, J = 3.5, 1.7 Hz, 1H), 7.08−6.98 (m,
6H), 6.88 (ddd, J = 5.1, 3.8, 1.4 Hz, 1H), 6.83 (ddd, J = 5.1, 3.8, 1.5
Hz, 1H), 5.06−4.92 (m, 2H), 3.61 (s, 3H), 3.39 (s, 3H), 2.99−2.89
(m, 1H), 2.88−2.79 (m, 1H), 2.37 (s, 3H), 2.34 (s, 3H), 1.22 (d, J =
6.9 Hz, 3H), 0.92 (d, J = 7.0 Hz, 3H). 13C{1H} NMR (100 MHz,
CD3COCD3): (two diastereomers) δ 175.0 (C), 174.1 (C), 143.7
(C), 143.6 (C), 138.9 (C), 138.3 (C), 136.4 (C), 136.0 (C), 132.3
(CH), 132.2 (CH), 132.0 (CH), 132.0 (CH), 130.9 (CH), 130.9
(CH), 128.1 (CH), 128.0 (CH), 127.7 (CH), 127.7 (CH), 127.4
(CH), 127.2 (CH), 126.9 (CH), 126.7 (CH), 56.8 (CH), 56.7 (CH),
52.0 (CH3), 51.8 (CH3), 47.2 (CH), 46.5 (CH), 19.7 (CH3), 19.3
(CH3), 14.7 (CH3), 14.1 (CH3).
Compound 3ha. Following GP3 performed with SMAHO 2a (33
mg, 0.25 mmol, 1.0 equiv) and imine 1h (83 mg, 0.25 mmol, 1.0
equiv), the desired product was obtained after purification by FC
[V(SiO2) = 50 mL, Cy/EA: 70/30 (250 mL), 60/40 (250 mL)] as a
white solid (99 mg, 95%, d.r. = 82:18). mp: 132−134 and 138−141
°C. Rf (Cy/EA: 60/40, UV + KMnO4): 0.47. GC (50 + 10/270 −
15): 21.4 and 21.7 min. HRMS (ESI+): [M + H]+ calcd for
1
C15H17BrNO4S2: 417.9776. Found: 417.9774. H NMR (400 MHz,
Compound 3ea. Following GP3 performed with SMAHO 2a (33
mg, 0.25 mmol, 1.0 equiv) and imine 1e (66 mg, 0.25 mmol, 1.0
equiv), the desired product was obtained after purification by FC
[V(SiO2) = 50 mL, Cy/EA: 80/20 (500 mL)] as a white solid (80
mg, 91%, d.r. = 63:37). mp: 90−92 and 95−97 °C. Rf (Cy/EA: 70/
30, UV + KMnO4): 0.42. GC (50 + 10/270 − 15): 20.3 and 20.6 min.
HRMS (ESI+): [M + Na]+ calcd for C16H19NNaO4S2: 376.0648.
Found: 376.0650. 1H NMR (400 MHz, CDCl3): (two diastereomers)
δ 7.32 (dt, J = 5.0, 1.4 Hz, 1H), 7.29 (dt, J = 5.0, 1.4 Hz, 1H), 7.24
(dd, J = 3.3, 1.6 Hz, 1H), 7.22−7.17 (m, 1H), 7.02−6.93 (m, 2H),
6.89 (s, 1H), 6.87 (s, 1H), 6.82−6.71 (m, 6H), 6.18 (d, J = 9.1 Hz,
1H), 5.94 (d, J = 9.1 Hz, 1H), 4.52 (t, J = 8.1 Hz, 1H), 4.46 (t, J = 7.8
Hz, 1H), 3.53 (s, 3H), 3.44 (s, 3H), 2.90−2.72 (m, 2H), 2.13 (s, 6H),
1.11 (d, J = 7.1 Hz, 3H), 1.08 (d, J = 7.1 Hz, 3H). 13C{1H} NMR
(100 MHz, CDCl3): (two diastereomers) δ 175.1 (C), 173.9 (C),
141.9 (C), 141.5 (C), 138.4 (C), 138.1 (C), 138.0 (C), 137.8 (C),
132.4 (CH), 132.1 (CH), 131.7 (CH), 131.5 (CH), 128.6 (CH),
128.5 (CH), 128.4 (CH), 128.3 (CH), 127.7 (CH), 127.2 (CH),
127.1 (CH), 126.9 (CH), 124.0 (CH), 123.6 (CH), 60.6 (CH), 60.2
(CH), 52.1 (CH3), 52.0 (CH3), 46.1 (CH), 45.9 (CH), 21.4 (2
CH3), 15.4 (CH3), 13.6 (CH3).
CD3COCD3): δ 7.62 (dt, J = 5.0, 1.5 Hz, 1H), 7.59 (dt, J = 5.1, 1.5
Hz, 1H), 7.51−7.38 (m, 6H), 7.34 (dd, J = 3.4, 1.7 Hz, 2H), 7.22 (t, J
= 7.5 Hz, 2H), 7.10 (t, J = 7.6 Hz, 2H), 6.90 (ddd, J = 5.1, 3.7, 1.4 Hz,
1H), 6.87 (ddd, J = 5.1, 3.7, 1.4 Hz, 1H), 5.38 (dd, J = 9.6, 7.1 Hz,
1H), 5.18 (t, J = 8.5 Hz, 1H), 3.59 (s, 3H), 3.51 (s, 3H), 3.00 (quint,
J = 7.1 Hz, 1H), 2.91−2.82 (m, 1H), 1.11 (d, J = 7.1 Hz, 3H), 1.04
(d, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CD3COCD3): δ 174.4
(C), 173.3 (C), 143.0 (C), 143.0 (C), 139.3 (C), 139.2 (C), 133.6
(CH), 133.3 (CH), 132.8 (CH), 132.7 (CH), 132.6 (CH), 132.5
(CH), 130.1 (CH), 130.0 (CH), 129.8 (CH), 129.1 (CH), 128.7
(CH), 128.2 (CH), 127.9 (CH), 127.8 (CH), 124.4 (C), 123.5 (C),
59.6 (CH), 59.4 (CH), 52.1 (CH3), 52.0 (CH3), 46.6 (CH), 44.9
(CH), 14.8 (CH3), 11.9 (CH3).
Compound 3ia. Following GP3 performed with SMAHO 2a (33
mg, 0.25 mmol, 1.0 equiv) and imine 1i (80 mg, 0.25 mmol, 1.0
equiv), the desired product was obtained after purification by FC
[V(SiO2) = 50 mL, Cy/EA: 80/20 (250 mL), 70/30 (250 mL)] as an
off-white solid (98 mg, 97%, d.r. = 59:41). mp: 109−111 and 114−
117 °C. Rf (Cy/EA: 70/30, UV + KMnO4): 0.26. GC (50 + 10/270
− 15): 19.1 and 19.4 min. HRMS (ESI+): [M + Na]+ calcd for
C16H16F3NNaO4S2: 430.0365. Found: 430.0363. 1H NMR (400
MHz, CDCl3): (two diastereomers) δ 7.48−7.38 (m, 6H), 7.32−7.28
(m, 2H), 7.25−7.16 (m, 4H), 6.87−6.76 (m, 2H), 6.48 (d, J = 9.0 Hz,
Compound 3fa. Following GP3 performed with SMAHO 2a (33
mg, 0.25 mmol, 1.0 equiv) and imine 1f (66 mg, 0.25 mmol, 1.0
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1H), 6.24 (d, J = 8.9 Hz, 1H), 4.70 (t, J = 7.8 Hz, 1H), 4.64 (dd, J =
9.1, 6.1 Hz, 1H), 3.59 (s, 3H), 3.52 (s, 3H), 2.96−2.80 (m, 2H), 1.19
(d, J = 8.1 Hz, 3H), 1.17 (d, J = 7.2 Hz, 3H). 13C{1H} NMR (100
MHz, CDCl3): (two diastereomers) δ 174.8 (C), 173.5 (C), 142.9
(C), 142.0 (C), 141.6 (C), 141.2 (C), 132.6 (CH), 132.3 (CH),
Multicomponent Mannich Reactions. General Procedure 4
(GP4). A 10 mL microwave tube equipped with a stir bar was charged
with SMAHO 2 (0.25 mmol, 1.0 equiv), DABCO (6 mg, 0.05 mmol,
0.2 equiv), sulfonamide 5 (0.25 mmol, 1.0 equiv), aldehyde 4 (0.25
mmol, 1.0 equiv), and dry THF (0.25 mL, 1 M). The vial was sealed
with a septum open to air with a needle, and the reaction was stirred
at reflux using a dry block heater for 14 h. The resulting mixture was
then evaporated, and purification by FC of the crude material afforded
the expected product.
Compound 3aa. Following GP4 performed with SMAHO 2a (33
mg, 0.25 mmol, 1.0 equiv), tosylamide 5a (43 mg, 0.25 mmol, 1.0
equiv), and benzaldehyde 4a (25 μL, 0.25 mmol, 1.0 equiv), the
desired product was obtained after purification by FC [V(SiO2) = 50
mL, Cy/EA: 80/20 (500 mL), 70/30 (50 mL)] as a white solid (74
mg, 85%, d.r. = 53:47).
Compound 3ba. Following GP4 performed with SMAHO 2a (33
mg, 0.25 mmol, 1.0 equiv), 2-thiophenesulfonamide 5b (41 mg, 0.25
mmol, 1.0 equiv), and benzaldehyde 4a (25 μL, 0.25 mmol, 1.0
equiv), the desired product was obtained after purification by FC
[V(SiO2) = 50 mL, Cy/EA: 80/20 (250 mL), 70/30 (250 mL)] as an
off-white solid (48 mg, 57%, d.r. = 56:44).
Compound 3ac. Following GP4 performed with SMAHO 2a (33
mg, 0.25 mmol, 1.0 equiv), mesylamide 5c (24 mg, 0.25 mmol, 1.0
equiv), and benzaldehyde 4a (25 μL, 0.25 mmol, 1.0 equiv), the
desired product was obtained after purification by FC [V(SiO2) = 50
mL, Cy/EA: 50/50 (500 mL)] as a white solid (22 mg, 32%, d.r. =
58:42).
Compound 3ad. Following GP4 performed with SMAHO 2d (56
mg, 0.25 mmol, 1.0 equiv), tosylamide 5a (43 mg, 0.25 mmol, 1.0
equiv), and benzaldehyde 4a (25 μL, 0.25 mmol, 1.0 equiv), the
desired product was obtained after purification by FC [V(SiO2) = 50
mL, Cy/EA: 90/10 (250 mL), 80/20 (250 mL)] as a white solid (50
mg, 46%, d.r. = 80:20).
Compound 3be. Following GP4 performed with SMAHO 2e (43
mg, 0.25 mmol, 1.0 equiv), 2-thiophenesulfonamide 5b (41 mg, 0.25
mmol, 1.0 equiv), and benzaldehyde 4a (25 μL, 0.25 mmol, 1.0
equiv), the desired product was obtained after purification by FC
[V(SiO2) = 50 mL, Cy/EA: 80/20 (500 mL)] as an off-white solid
(38 mg, 40%, d.r. = 73:23).
Compound 3ga. Following GP4 performed with SMAHO 2a (33
mg, 0.25 mmol, 1.0 equiv), 2-thiophenesulfonamide 5b (41 mg, 0.25
mmol, 1.0 equiv), and 2-chlorobenzaldehyde 4b (28 μL, 0.25 mmol,
1.0 equiv), the desired product was obtained after purification by FC
[V(SiO2) = 50 mL, Cy/EA: 90/10 (250 mL), 80/20 (250 mL)] as a
white solid (63 mg, 62%, d.r. = 75:25).
2
132.2 (CH), 131.9 (CH), 130.1 (q, JC−F = 32.5 Hz, C), 130.0 (q,
2JC−F = 32.5 Hz, C), 127.6 (2 CH), 127.3 (CH), 127.2 (CH), 127.1
(2 CH), 125.5 (q, 3JC−F = 3.8 Hz, 2 CH), 125.3 (q, 3JC−F = 3.5 Hz, 2
CH), 124.0 (q, 1JC−F = 273.1 Hz, 2 CF3), 60.1 (CH), 59.8 (CH), 52.3
(CH3), 52.2 (CH3), 45.8 (CH), 45.6 (CH), 15.6 (CH3), 13.6 (CH3).
19F{1H} NMR (377 MHz, CDCl3): (two diastereomers) δ −62.7 (s, 3
F), −62.7 (s, 3 F).
Compound 3ja. Following GP3 performed with SMAHO 2a (33
mg, 0.25 mmol, 1.0 equiv) and imine 1j (64 mg, 0.25 mmol, 1.0
equiv), the desired product was obtained after purification by FC
[V(SiO2) = 50 mL, Cy/EA: 80/20 (250 mL), 70/30 (250 mL)] as a
pale yellow glue (75 mg, 87%, d.r. = 60:40). Rf (Cy/EA: 70/30, UV +
KMnO4): 0.29. GC (50 + 10/270 − 15): 19.9 and 20.1 min. HRMS
(ESI+): [M + Na]+ calcd for C13H15NNaO4S3: 368.0055. Found:
1
368.0054. H NMR (400 MHz, CDCl3): (two diastereomers) δ 7.43
(td, J = 4.7, 2.3 Hz, 2H), 7.41−7.35 (m, 2H), 7.08 (d, J = 5.0 Hz,
2H), 6.93−6.84 (m, 2H), 6.80−6.72 (m, 2H), 6.72 (t, J = 3.2 Hz,
2H), 6.22 (d, J = 9.4 Hz, 1H), 6.03 (d, J = 9.6 Hz, 1H), 4.91 (dd, J =
9.4, 6.0 Hz, 1H), 4.87 (dd, J = 9.5, 5.5 Hz, 1H), 3.63 (s, 3H), 3.61 (s,
3H), 3.02−2.91 (m, 2H), 1.24 (d, J = 7.1 Hz, 3H), 1.20 (d, J = 7.2
Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): (two diastereomers) δ
174.8 (C), 173.8 (C), 142.5 (C), 141.9 (C), 141.6 (C), 140.8 (C),
132.4 (CH), 132.2 (CH), 132.0 (CH), 131.8 (CH), 127.2 (CH),
127.1 (CH), 126.7 (CH), 126.5 (CH), 126.4 (CH), 125.6 (CH),
125.5 (CH), 125.1 (CH), 56.3 (CH), 56.1 (CH), 52.2 (CH3), 52.2
(CH3), 46.3 (CH), 46.1 (CH), 15.2 (CH3), 14.1 (CH3).
Compound 3ka.45 Following GP3 performed with SMAHO 2a
(33 mg, 0.25 mmol, 1.0 equiv) and imine 1k (71 mg, 0.25 mmol, 1.0
equiv), the desired product was obtained after purification by FC
[V(SiO2) = 50 mL, Cy/EA: 80/20 (250 mL), 70/30 (250 mL)] as a
white solid (78 mg, 83%, d.r. = 64:36). mp: 109−113 °C (litt: 120
°C). Rf (Cy/EA: 80/20, UV + KMnO4): 0.25. GC (50 + 10/270 −
15): 23.0 and 23.2 min. 1H NMR (400 MHz, CDCl3): (two
diastereomers) δ 7.73 (d, J = 7.9 Hz, 4H), 7.31−7.20 (m, 6H), 7.18
(d, J = 7.9 Hz, 4H), 7.08 (t, J = 7.8 Hz, 4H), 6.19 (d, J = 15.9 Hz,
1H), 6.18 (d, J = 16.0 Hz, 1H), 5.85−5.71 (m, 2H), 5.58 (d, J = 9.2
Hz, 1H), 5.48 (d, J = 9.3 Hz, 1H), 4.16−4.01 (m, 2H), 3.68 (s, 6H),
2.90−2.81 (m, 1H), 2.79−2.71 (m, 1H), 2.27 (s, 6H), 1.29 (d, J = 7.2
Hz, 3H), 1.19 (d, J = 7.3 Hz, 3H). 13C{1H} NMR (100 MHz,
CDCl3): (two diastereomers) δ 175.1 (C), 174.3 (C), 143.5 (C),
143.4 (C), 138.4 (C), 138.1 (C), 136.1 (2 C), 133.9 (CH), 132.7
(CH), 129.7 (2 CH), 129.6 (2 CH), 128.5 (3 CH), 128.0 (CH),
128.0 (CH), 127.4 (2 CH), 127.3 (2 CH), 126.6 (CH), 126.6 (2
CH), 126.5 (2 CH), 124.6 (2 CH), 58.7 (CH), 58.5 (CH), 52.1 (2
CH3), 44.5 (CH), 44.4 (CH), 21.5 (2 CH3), 14.9 (CH3), 14.0
(CH3).
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02895.
■
sı
NMR spectra for all compounds (PDF)
Compound 3la. Following GP3 performed with SMAHO 2a (33
mg, 0.25 mmol, 1.0 equiv) and imine 1l (56 mg, 0.25 mmol, 1.0
equiv), the desired product was obtained after purification by FC
[V(SiO2) = 50 mL, Cy/EA: 80/20 (250 mL), 70/30 (250 mL)] as
colorless glue (38 mg, 48%, d.r. = 45:55). Rf (Cy/EA: 70/30, UV +
KMnO4): 0.38. GC (50 + 10/270 − 15): 18.1 and 18.1 min. HRMS
(ESI+): [M + H]+ calcd for C15H24NO4S: 314.1420. Found:
AUTHOR INFORMATION
Corresponding Authors
■
Sylvie Condon − ICMPE, Université Paris Est Créteil, CNRS,
ICMPE, UMR7182, F-94320 Thiais, France;
Email: condon@icmpe.cnrs.fr
1
314.1418. H NMR (400 MHz, CD3COCD3): (two diastereomers)
δ 7.80−7.70 (m, 4H), 7.39 (d, J = 7.5 Hz, 4H), 6.44−6.21 (m, 2H),
3.59 (s, 3H), 3.58 (s, 3H), 3.63−3.38 (m, 2H), 2.76−2.67 (m, 1H),
2.54 (m, 1H), 2.41 (s, 6H), 1.63−1.43 (m, 1H), 1.40−1.14 (m, 7H),
1.05 (d, J = 7.1 Hz, 3H), 1.03 (d, J = 7.1, 3H), 0.70 (t, J = 7.9 Hz,
3H), 0.68 (t, J = 6.8 Hz, 3H). 13C{1H} NMR (100 MHz,
CD3COCD3): (two diastereomers) δ 174.9 (C), 174.8 (C), 143.7
(C), 143.6 (C), 140.6 (C), 140.3 (C), 130.3 (2 CH), 130.3 (2 CH),
127.7 (2 CH), 127.7 (2 CH), 56.6 (CH), 55.9 (CH), 51.8 (CH3),
51.8 (CH3), 44.5 (CH), 44.2 (CH), 35.6 (CH2), 34.1 (CH2), 21.4 (2
CH3), 19.5 (CH2), 19.4 (CH2), 13.9 (CH3), 13.8 (CH3), 13.3 (CH3),
11.7 (CH3).
Marc Presset − ICMPE, Université Paris Est Créteil, CNRS,
ICMPE, UMR7182, F-94320 Thiais, France; orcid.org/
0000-0003-0994-5572; Email: marc.presset@u-pec.fr
Authors
Tania Xavier − ICMPE, Université Paris Est Créteil, CNRS,
ICMPE, UMR7182, F-94320 Thiais, France; orcid.org/
0000-0003-4306-8040
Christophe Pichon − ICMPE, Université Paris Est Créteil,
CNRS, ICMPE, UMR7182, F-94320 Thiais, France
5460
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Article
heteroarenesulfonyl Cinchona alkaloid amides. Chem. − Eur. J. 2015,
21, 3929−3932.
Erwan Le Gall − ICMPE, Université Paris Est Créteil, CNRS,
ICMPE, UMR7182, F-94320 Thiais, France; orcid.org/
0000-0002-8972-3971
(18) Baudoux, J.; Lefebvre, P.; Legay, R.; Lasne, M.-C.; Rouden, J.
Environmentally benign metal-free decarboxylative aldol and Mannich
reactions. Green Chem. 2010, 12, 252−259.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02895
(19) Yuan, H.-N.; Li, S.; Nie, J.; Zheng, Y.; Ma, J.-A. Highly
enantioselective decarboxylative Mannich reaction of malonic acid
half oxyesters with cyclic trifluoromethyl ketimines: Synthesis of β-
amino esters and anti-HIV Drug DPC 083. Chem. − Eur. J. 2013, 19,
15856−15860.
Notes
The authors declare no competing financial interest.
(20) Jia, C.-H.; Zhang, H.-X.; Nie, J.; Ma, J.-A. Catalytic asymmetric
decarboxylative Mannich reaction of malonic acid half esters with
cyclic aldimines: Access to chiral β-amino esters and chroman-4-
amines. J. Org. Chem. 2016, 81, 8561−8569.
(21) Singjunla, Y.; Baudoux, J.; Rouden, J. Straightforward and
stereoselective synthesis of α,β-diamino acid derivatives by means of
an organocatalyzed decarboxylative Mannich reaction. Eur. J. Org.
Chem. 2017, 3240−3243.
ACKNOWLEDGMENTS
■
The financial support of this work by the CNRS, the University
Paris-Est Créteil, and the University Paris-Est (Ph.D. grant to
T.X.) is gratefully acknowledged.
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