Direct carbon-carbon bond formation via soft enolization of thioesters: An operationally simple mannich addition reaction

Article abstract of DOI:10.1055/s-0028-1083278

Thioesters undergo soft enolization and direct Mannich addition to sulfonylimines on treatment with magnesium bromide ethyl etherate and N,N-diisopropylethylamine. The reactions proceed readily with a range of sulfonylimines and, in the case of 2,4,6- tri

Full text of DOI:10.1055/s-0028-1083278

56
SHORT PAPER
Direct Carbon–Carbon Bond Formation via Soft Enolization of Thioesters:
An Operationally Simple Mannich Addition Reaction
D
irec
t
Car
u
bon–Carbon
l
Bond F
i
ormati
a
on via Soft
n
Enolization
n
of Thioester
e
s
M. Yost, Michelle R. Garnsey, Mark C. Kohler, Don M. Coltart*
Department of Chemistry, Duke University, Durham, NC 27708, USA
Fax +1(919)6601605; E-mail: don.coltart@duke.edu
Received 21 October 2008
sulfonylimine 1 reacted cleanly and with acceptable yield.
Whereas imine 4 did produce the desired addition product
5, it did so to only a very small extent and produced sev-
eral unidentified byproducts. No Mannich addition (→7)
Abstract: Thioesters undergo soft enolization and direct Mannich
addition to sulfonylimines on treatment with magnesium bromide
ethyl etherate and N,N-diisopropylethylamine. The reactions pro-
ceed readily with a range of sulfonylimines and, in the case of 2,4,6-
triisopropylphenyl thiopropionate, give moderate to good syn dia- occurred in the reaction between 6 and 2. Instead, N-ben-
stereoselectivity.
zylamine, benzaldehyde and 2 were isolated following
workup.
Key words: enolates, imines, Mannich addition reactions, magne-
sium, thioesters
SO2Ph
MgBr2⋅OEt2
i-Pr2NEt
N
O
PhO2SHN
Ph
O
CH2Cl2, 15 min
+
+
Ph
Ph
SPh
SPh
SPh
The Mannich addition reaction provides a convenient ap-
proach to the synthesis of b-amino acid derivatives, which
are extremely important compounds in organic and me-
dicinal chemistry.1 Typically, Mannich reactions are car-
ried out using a preformed enolate species, along with one
of a variety of different imine derivatives (sulfonylimine,
alkyl imine,2 etc.). While effective, the step-wise proce-
dures required to generate the enolates are time-consum-
ing, particularly if trapping is involved, and require that
all manipulations be conducted under anhydrous condi-
tions and, when strong bases are used, at low temperature.
In contrast, soft enolization3,4 provides a mild and
straightforward approach to conducting enolate chemis-
try. Here, rather than forcing deprotonation with a strong
base such as lithium diisopropylamide (LDA), a relatively
weak basic amine is used in combination with a Lewis
acid to effect deprotonation. We have been investigating
this mode of enolization with thioesters in the context of
direct aldol additions and direct crossed Claisen coupling
reactions.5 Given the efficiency and operational simplicity
of these soft enolization-based transformations, we sought
to extend this approach to the synthesis of b-amino acid
derivatives. In this report, we describe the development of
a magnesium bromide ethyl etherate (MgBr2·OEt2) pro-
moted direct Mannich addition reaction between
thioesters and sulfonylimines using soft enolization.
63%
1
2
3
MgBr2⋅OEt2
i-Pr2NEt
CH2Cl2, 3 h
Boc
N
O
BocHN
O
Ph
SPh
21%
4
2
5
Bn
MgBr2⋅OEt2
i-Pr2NEt
N
O
BnHN
Ph
O
CH2Cl2
+
Ph
SPh
SPh
no reaction
6
2
7
Scheme 1 Model studies of the MgBr2·OEt2-promoted Mannich
addition employing soft enolization.
Having established the viability of the desired transforma-
tion, we investigated its scope with various sulfo-
nylimines (Table 1).8 The sulfonylimines used ranged
from electron-rich to electron-poor, and also included an
a,b-unsaturated system (11). In general, the reactions pro-
ceeded readily and gave yields ranging from 57–74%. In
addition, a small amount (up to ~10%) of the correspond-
ing b-lactam was obtained in each case.
Next, we turned our attention to the issue of diastereose-
lectivity in the case of the propionate thioester Mannich
addition. To this end, sulfonylimine 1 and S-phenyl
thiopropionate9 (16) were combined under the soft eno-
lization conditions described above. Unfortunately, while
the reaction proceeded rapidly and with very good conver-
sion, it showed no appreciable diastereoselectivity
(Table 2, entry 1). In an effort to improve the selectivity
of the transformation, a variety of propionate thioesters
were examined, each of which differed in the steric bulk
of the thiol component used to prepare them. While the S-
ethyl thioester 17 also failed to react diastereoselectively,
the more bulky S-tert-butyl species 18 gave a 2.2:1
We began our studies by establishing whether soft eno-
lization could indeed be used to facilitate a direct Mannich
reaction. This was done by combining commercially
available S-phenyl thioacetate (2) and various imines (1,
46 and 6)7 in dichloromethane, in the presence of magne-
sium bromide ethyl etherate and N,N-diisopropylethyl-
amine (DIPEA; Scheme 1). Of the imines tested, only the
SYNTHESIS 2009, No. 1, pp 0056–0058
0
2
.
0
1
.2
0
0
9
Advanced online publication: 12.12.2008
DOI: 10.1055/s-0028-1083278; Art ID: C04908SS
© Georg Thieme Verlag Stuttgart · New York

SHORT PAPER
Direct Carbon–Carbon Bond Formation via Soft Enolization of Thioesters
57
In conclusion, we have developed a simple, direct Man-
nich addition reaction based on MgBr2·OEt2-promoted
soft enolization of thioesters. The reaction proceeds readi-
ly with a range of sulfonylimines and, in the case of 2,4,6-
triisopropylphenyl thiopropionate, gives moderate to
good diastereoselectivity in favor of the syn isomer.
Table 1 Scope of the MgBr2·OEt2-Promoted Thioester Mannich
Addition Reaction Using Thioester 2
MgBr2⋅OEt2
i-Pr2NEt
CH2Cl2
O
PhSO2HN
R
O
SO2Ph
N
+
SPh
SPh
R
2
Entry Sulfonylimine (R)
Time (min) Product
Yield (%)
Unless stated to the contrary, where applicable, the following con-
ditions apply: Reactions were carried out using dried solvents (see
below) under a slight static pressure of Ar (pre-purified quality),
which had been passed through a column (5 × 20 cm) of Drierite.
Glassware was dried in an oven at 120 °C for at least 12 h prior to
use and then either cooled in a desiccator cabinet over Drierite or as-
sembled quickly while hot, sealed with rubber septa, and allowed to
cool under a stream of Ar. Reactions were stirred magnetically us-
ing Teflon-coated magnetic stirring bars. Teflon-coated magnetic
stirring bars and syringe needles were dried in an oven at 120 °C for
at least 12 h prior to use then cooled in a desiccator cabinet over
Drierite. Hamilton microsyringes were dried in an oven at 60 °C for
at least 24 h prior to use and cooled in the same manner. Commer-
cially available Norm-Ject disposable syringes were used. Anhy-
drous benzene, toluene, Et2O, CH2Cl2, THF, MeCN and DME were
obtained using an Innovative Technologies solvent purification sys-
tem. All other anhydrous solvents were of anhydrous quality pur-
chased from Sigma–Aldrich. Commercial grade solvents were used
for routine purposes without further purification. Et3N, pyridine,
DIPEA, 2,6-lutidine, i-Pr2NH, and TMEDA were distilled from
CaH2 under a N2 atmosphere prior to use. Flash column chromatog-
raphy was performed on silica gel 60 (32–63 mm). 1H and 13C NMR
spectra were recorded on a Varian spectrometer (400 MHz and 100
MHz, respectively) at ambient temperature. All 1H chemical shifts
are reported in ppm (d) relative to TMS (d = 0.00 ppm); 13C shifts
are reported in ppm (d) relative to CDCl3 (d = 77.16 ppm). Diaste-
1
2
3
4
5
1 (Ph)
15
30
3
12
13
14
15
63
67
74
73
57
8 (4-ClC6H4)
9 (4-MeOC6H4)
10 (2-MeC6H4)
11 [(E)-CHCHPh]
60
120
30
Table 2 Effect of Thioester on Diastereoselectivity
MgBr2⋅OEt2
i-Pr2NEt
CH2Cl2
O
PhSO2HN
Ph
O
SO2Ph
N
+
SR
SR
Ph
1
Entry Thioester (R)
Time Product syn/anti Conversion
(h)
(%)
92
70
74
78
62
1
2
3
4
5
16 (Ph)
17 (Et)
2
21
22
23
24
25
1.1:1
1.1:1
2.2:1
3.1:1
5.2:1
3
18 (t-Bu)
3
19 [2,6-(Me)2C6H3]
6
1
reomeric ratios and percent conversions were determined by H
20 [2,4,6-(i-Pr)3C6H2]
6
NMR analysis of the crude materials.
syn/anti ratio. A greater proportion of the syn diastere-
omer was produced when the even bulkier thioesters 19
and 20 were used, with the latter giving a syn/anti ratio of
5.2:1 (see experimental section for syn and anti assign-
ments).
Assignment of syn and anti Configuration
A crystal structure was obtained for the major diastereomer of 25,
which was determined to have the syn-configuration. Assignment of
the syn and anti diastereomers of 26–28 was done by comparison of
their 1H NMR spectra to that of 25. In each case, the major (syn) iso-
mer showed an apparent Hb triplet, whereas the minor (anti) isomer
showed a Hb doublet of doublets (Table 4).
Using thioester 20, the scope of the reaction was tested
with each of the sulfonylimines used previously (Table 3).
Once again, good to very good conversions were ob-
tained, with syn/anti ratios ranging from 2.1:1 to 5.3:1.
Synthesis of 25; Typical Procedure
MgBr2·OEt2 (0.181 g, 0.70 mmol) was added to a stirred solution of
thioester 20 (0.175 g, 0.60 mmol) and N-benzylidenebenzene-
sulfonamide (1; 0.123 g, 0.50 mmol) in CH2Cl2 (2.5 mL), followed
Table 3 Scope of the MgBr2·OEt2-Promoted Thioester Mannich
Addition Reaction Using Thioester 20
Table 4 Selected 1H NMR Shifts and Coupling Constants for Com-
pounds 25–28
MgBr2⋅OEt2
O
PhSO2HN
R
O
SO2Ph
i-Pr2NEt
CH2Cl2
N
+
O
SAr
SAr
O
PhSO2HN Hβ
PhSO2HN Hβ
Ar = 2,4,6-(i-Pr)3C6H2
R
Ph
SAr
Ph
SAr
20
Hα
Hα
syn
anti
Entry Sulfonylimine
(R)
Time Product syn/anti Conversion
Ar = 2,4,6-(i-Pr)3C6H2
(h)
12
12
12
12
12
(%)
73
80
66
80
61
Compd
25
syn Hb (d)
anti Hb (d)
1
2
3
4
5
1 (Ph)
25
26
27
28
29
5.3:1
2.6:1
4.6:1
2.4:1
2.1:1
4.46 (app t, J = 9.2 Hz)
4.44 (app t, J = 9.2 Hz)
4.40 (app t, J = 9.4 Hz)
4.77 (app t, J = 9.8 Hz)
4.67 (dd, J = 4.4, 9.6 Hz)
4.65 (dd, J = 4.4, 8.8 Hz)
4.62 (dd, J = 4.8, 9.2 Hz)
4.86 (dd, J = 4.4, 9.2 Hz)
8 (4-ClC6H4)
26
9 (4-MeOC6H4)
10 (2-MeC6H4)
27
28
11 [(E)-CHCHPh]
Synthesis 2009, No. 1, 56–58 © Thieme Stuttgart · New York

58
J. M. Yost et al.
SHORT PAPER
by DIPEA (0.17 mL, 1.0 mmol). Stirring was continued for 12 h,
then EtOAc (2.5 mL) and aq. HCl (10% v/v, 2.5 mL) were added.
Stirring was continued for 5 min then the mixture was diluted in
EtOAc (50 mL). The aqueous phase was extracted with EtOAc
(3 × 10 mL) and the combined organic extracts were washed with
brine (1 × 5 mL), dried (MgSO4), and evaporated to give a light-yel-
low oil. Flash chromatography over silica gel (EtOAc–hexanes,
10:90→15:85) gave 25 syn and anti as pure, colorless solids.
ESI-MS: m/z [M + Na]+ calcd for C33H41NNaO3S2: 586.2; found:
586.4.
3
1H NMR (CDCl3): d = 7.73–7.64 (m, 2 H), 7.51–7.02 (m, 13 H),
5.75 (d, J = 7.6 Hz, 1 H), 4.82 (q, J = 6.8 Hz, 1 H), 3.16 and 3.06 (d
AB q, JAB = 40.7 Hz, J = 6.4, 15.6 Hz, 2 H).
13C NMR (CDCl3): d = 195.7, 140.3, 138.8, 134.5, 132.6, 129.8,
129.4, 129.0, 128.7, 128.1, 127.2, 126.9, 126.6, 55.2, 49.6.
ESI-MS: m/z [M + Na]+ calcd for C21H19NNaO3S2: 420.1; found:
420.1.
25 (syn)
Yield: 0.130 g (48.3%); colorless solid.
1H NMR (CDCl3): d = 7.61–7.56 (m, 2 H), 7.41–6.90 (m, 10 H),
5.67 (d, J = 9.2 Hz, 1 H), 4.46 (t, J = 9.2 Hz, 1 H), 3.32–3.14 [m,
2 H, including a qd at d = 3.27 (J = 6.8, 9.2 Hz)], 2.83 (sept, J = 6.8
Hz, 1 H), 2.43–2.27 (m, 1 H), 1.47 (d, J = 6.8 Hz, 3 H), 1.20 (d,
J = 6.8 Hz, 6 H), 1.13–1.03 (m, 6 H), 0.88–0.75 (m, 6 H).
13C NMR (CDCl3): d = 199.6, 152.6, 152.1, 151.2, 140.5, 138.4,
132.4, 128.8, 128.5, 127.8, 127.4, 127.2, 122.0 (2 overlapping
peaks), 120.9, 60.6, 54.0, 34.4, 31.8, 31.5, 24.5, 24.2, 23.94, 23.91,
23.6, 23.2, 16.4.
15
1H NMR (CDCl3): d = 7.86–7.81 (m, 2 H), 7.51–7.11 (m, 13 H),
6.33 (d, J = 16.0 Hz, 1 H), 5.92 (dd, J = 7.2, 16.0 Hz, 1 H), 5.42 (d,
J = 8.4 Hz, 1 H), 4.44–4.34 (m, 1 H), 3.02 (d, J = 5.2 Hz, 2 H).
13C NMR (CDCl3): d = 195.9, 140.8, 135.8, 134.5, 132.6, 129.8,
129.4, 129.1, 128.6, 128.1, 127.2, 126.8, 126.6, 126.5 (2 overlap-
ping peaks), 53.5, 48.4.
ESI-MS: m/z [M + Na]+ calcd for C23H21NNaO3S2: 446.1; found:
446.2.
ESI-MS: m/z [M + Na]+ calcd for C31H39NNaO3S2: 560.2; found:
560.3.
25 (anti)
Acknowledgment
Yield: 0.025 g (9.3%); colorless solid.
We thank Marina G. Dickens of the Duke University Chemistry
Department for obtaining the X-ray crystal structure of syn-25.
1H NMR (CDCl3): d = 7.61–7.56 (m, 2 H), 7.40–6.97 (m, 10 H),
6.23 (d, J = 9.2 Hz, 1 H), 4.67 (dd, J = 4.4, 9.6 Hz, 1 H), 3.36–3.22
[m, 2 H, including a dq at d = 3.30 (J = 4.4, 6.8 Hz)], 2.87 (sept,
J = 6.8 Hz, 1 H), 2.69–2.57 (m, 1 H), 1.40 (d, J = 7.2 Hz, 3 H), 1.23
(d, J = 6.8 Hz, 6 H), 1.18–1.09 (m, 6 H), 1.02–0.85 (m, 6 H).
References
(1) (a) Benaglia, M.; Cinquini, M.; Cozzi, F. Eur. J. Org. Chem.
2000, 563. (b) Hart, D. J.; Ha, D.-C. Chem. Rev. 1989, 89,
1447.
13C NMR (CDCl3): d = 202.6, 152.7, 152.1, 151.6, 141.2, 138.9,
132.2, 128.7, 128.4, 127.4, 126.8, 126.4, 122.2 (2 overlapping
peaks), 120.7, 60.6, 53.1, 34.5, 32.0, 31.6, 24.6, 24.2, 24.0, 23.9,
23.7, 23.4, 17.2.
ESI-MS: m/z [M + Na]+ calcd for C31H39NNaO3S2: 560.2; found:
560.3.
(2) For a recent example of an enolate addition to N-alkyl-
imines, see: Tanaka, S.-y.; Tagashira, N.; Chiba, K.; Yasuda,
M.; Baba, A. Angew. Chem. Int. Ed. 2008, 47, 6620.
(3) For pioneering applications of soft enolization in direct
carbon–carbon bond formation, see: (a) Rathke, M. W.;
Cowan, P. J. J. Org. Chem. 1985, 50, 2622. (b) Rathke, M.
W.; Nowak, M. J. Org. Chem. 1985, 50, 2624. (c) Tirpak,
R. E.; Olsen, R. S.; Rathke, M. W. J. Org. Chem. 1985, 50,
4877.
29 (syn)
1H NMR (CDCl3): d = 7.84–7.78 (m, 2 H), 7.45–7.00 (m, 10 H),
6.17 (d, J = 16.0 Hz, 1 H), 5.82 (dd, J = 8.4, 16.0 Hz, 1 H), 5.35 (d,
J = 8.8 Hz, 1 H), 4.08 (app q, J = 7.6 Hz, 1 H), 3.34–3.05 [m, 3 H,
including an app pent at d = 3.10 (J = 6.8 Hz)], 2.88 (sept, J = 7.2
Hz, 1 H), 1.40 (d, J = 7.2 Hz, 3 H), 1.24 (d, J = 7.2 Hz, 6 H), 1.16–
0.96 (m, 12 H).
(4) Lim, D.; Zhou, G.; Livanos, A. E.; Fang, F.; Coltart, D. M.
Synthesis 2008, 2148.
(5) (a) Yost, J. M.; Zhou, G.; Coltart, D. M. Org. Lett. 2006, 8,
1503. (b) Zhou, G.; Yost, J. M.; Coltart, D. M. Synthesis
2007, 478. (c) Zhou, G.; Lim, D.; Coltart, D. M. Org. Lett.
2008, 10, 3809.
13C NMR (CDCl3): d = 201.1, 152.6, 152.2, 151.5, 141.0, 135.9,
134.2, 132.6, 129.0, 128.5, 128.2, 127.4, 126.6, 124.7, 122.2 (2
overlapping peaks), 120.8, 59.4, 52.6, 34.4, 32.0, 24.4, 24.2, 23.9,
23.6, 23.5, 15.6.
ESI-MS: m/z [M + Na]+ calcd for C33H41NNaO3S2: 586.2; found:
586.4.
(6) (a) Gizecki, P.; Youcef, R. A.; Poulard, C.; Dhal, R.;
Dujardin, G. Tetrahedron Lett. 2004, 45, 9589. (b) Wenzel,
A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 12964.
(7) 1 and 6 are commercially available (Aldrich).
(8) All sulfonylimines used here, with the exception of
commercially available 1 (Aldrich), were prepared by
condensation of the corresponding aldehyde and
benzenesulfonamide according to: Jin, T.-S.; Yu, M.-J.; Liu,
L.-B.; Zhao, Y.; Li, T.-S. Synth. Commun. 2006, 36, 2339.
(9) Thioester 17 is commercially available (Aldrich). 16, 18 and
19 were prepared from the corresponding commercially
available (Aldrich) thiols under typical conditions.5a The
thiol used in the synthesis of 20 was prepared according to:
Garrattz, D. G.; Beaulieu, P. L. Can. J. Chem. 1980, 58,
2737.
29 (anti)
1H NMR (CDCl3): d = 7.83–7.77 (m, 2 H), 7.46–6.98 (m, 10 H),
6.26 (d, J = 16.0 Hz, 1 H), 5.85 (dd, J = 6.6, 16.0 Hz, 1 H), 5.75 (d,
J = 9.2 Hz, 1 H), 4.28–4.19 (m, 1 H), 3.40–3.02 [m, 3 H, including
a dq at d = 3.19 (J = 4.0, 7.0 Hz)], 2.88 (sept, J = 6.8 Hz, 1 H), 1.39
(d, J = 7.0 Hz, 3 H), 1.30–0.84 [m, 18 H, including a d at d = 1.24
(J = 6.8 Hz)].
13C NMR (CDCl3): d = 202.7, 152.6, 152.2, 151.6, 141.7, 135.9,
132.4 (2 overlapping peaks), 129.0, 128.5, 128.1, 127.1, 126.7,
126.5, 122.2 (2 overlapping peaks), 120.7, 58.8, 51.5, 34.5, 32.0,
24.3, 24.2, 24.0, 23.9, 23.7, 23.4, 16.2.
Synthesis 2009, No. 1, 56–58 © Thieme Stuttgart · New York