Catalytic Mannich-type reaction of phosphorylimidates

Article abstract of DOI:10.1016/j.tet.2010.04.090

Phosphorylimidates reacted with N-Boc imines in the presence of a catalytic amount of potassium hexamethyldisilazide, to afford the corresponding Mannich-type adducts in high yields. It was shown that, like sulfonylimidates, phosphorylimidates can function as ester equivalents. In contrast to sulfonylimidates however, phosphorylimidates exhibited high anti-selectivity even in low polar solvents. An explanation for the anti-selectivity is given.

Full text of DOI:10.1016/j.tet.2010.04.090

Tetrahedron 66 (2010) 6457e6461
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Catalytic Mannich-type reaction of phosphorylimidates
*
ꢀ
Shu Kobayashi , Junya Nakano, Ryosuke Matsubara
Department of Chemistry, School of Science and Graduate School of Pharmaceutical Sciences, The University of Tokyo, The HFRE Division, ERATO, Japan Science Technology Agency
(JST), Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Phosphorylimidates reacted with N-Boc imines in the presence of a catalytic amount of potassium
hexamethyldisilazide, to afford the corresponding Mannich-type adducts in high yields. It was shown
that, like sulfonylimidates, phosphorylimidates can function as ester equivalents. In contrast to sulfo-
nylimidates however, phosphorylimidates exhibited high anti-selectivity even in low polar solvents. An
explanation for the anti-selectivity is given.
Received 26 December 2009
Received in revised form 30 March 2010
Accepted 22 April 2010
Available online 5 May 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Dedicated to Professor Steven V. Ley on the
occasion of his receipt of the Tetrahedron
Prize
1. Introduction
2. Results and discussion
Mannich-type reactions have been widely used over the past
two decades for the synthesis of nitrogen containing compounds.1
Most of these reactions utilize preformed enolates and their de-
rivatives as nucleophiles, while the development of direct-type
reactions, i.e., the in situ generation and use of carbonyl nucleo-
philes, has only recently become a focus area of research.2 Given the
synthetic versatility of aldehydes and esters, the development of
the use of these substrates as nucleophiles is especially important.
While the catalytic Mannich-type reaction in which aldehydes are
used as nucleophiles has been realized using enamine catalysis,
there are only a few examples of the use of ester nucleophiles
We set out to investigate the behavior of phosphorylimidates6
by exposing this type of substrate to Mannich-type reaction con-
ditions developed in our laboratory and varying the Brønsted base
catalysts. The results are summarized in Table 1. While a strong
organic base, such as DBU, did not catalyze the reaction (entry 1),
the use of 10 mol % potassium tert-butoxide (KOtBu) afforded the
desired adduct in 69% yield and with high diastereoselectivity in
favor of the anti product (entry 2). Alkali earth metal alkoxides and
amides generally afforded moderate yields (entries 3e9). The best
Table 1
Effect of bases
bearing no activating a-substituents, such as COR, Ar, CN or OH.
-proton.3 In order
-proton must be
O
EtO P
NH
This is because of the high pKa value of the ester
to solve this problem the pKa value of the
a
a
EtO
O
P
Boc
EtO
EtO
Me
N
Boc
base (10 mol%)
N
N
reduceddeither dynamically, by employing a Lewis acidic metal
catalyst to activate the carbonyl group, or statically, by designing
suitable esters or ester derivatives.4 We have recently reported on
the Mannich-type reaction of sulfonylimidates with N-Boc imines,
under either DBU- or alkali earth metal alkoxide/amide-catalyzed
conditions, to afford the corresponding adducts in good yields and
with high diastereoselectivity.5 The reaction can proceed to afford
either the syn or anti isomers, depending on the choice of solvent
and catalyst. As part of an ongoing investigation into imidate
chemistry, we now wish to report on the use of a phosphor-
ylimidate as a novel nucleophile in a catalytic Mannich-type re-
action of N-Boc imines.
+
Ph
i
THF, RT, 24 h
MS 4A
i
OPr
Ph
OPr
(1.5 equiv)
(1.0 equiv)
Me
Entry
Base
Yield (%)
anti/syna
1
2
3
4
5
6
7
8
DBU
0
69
0
62
47
43
69
9
d
KOtBu
87/13
d
Mg(OtBu)2
Ba(OtBu)2
Ca(OiPr)2
Sr(OiPr)2
67/33
80/20
71/29
67/33
85/15
76/24
86/14
85/15
Ba(OiPr)2
Ca(HMDS)2
1/2[Sr(HMDS)2]2
Na(HMDS)
K(HMDS)
9
10
11
72
84
89
* Corresponding author. E-mail address: shu_kobayashi@chem.s.u-tokyo.ac.jp
(S. Kobayashi).
a
Determined by 1H NMR spectroscopy of the crude products.
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.04.090

6458
S. Kobayashi et al. / Tetrahedron 66 (2010) 6457e6461
Table 3
yield and anti-selectivity was obtained by using potassium hex-
amethyldisilazide (KHMDS) as a catalyst (entry 11). Such anti-se-
lectivity is in contrast to what we observed with sulfonylimidates,
which always gave syn-selectivity in THF, irrespective of the metal
catalysts used.3i
Mannich-type reactions of phosphorylimidates
O
P
EtO
EtO
NH
O
P
EtO
Boc
KHMDS (10 mol%)
N
Boc
EtO
N
N
+
R2
R1
DMF, 0 oC
48 h, MS 4A
i
Further investigations were carried out (see Table 2). Since we
know from our sulfonylimidate chemistry that anti-selectivity is
favored when the metal enolate ion pair is dissociative,3j 18-crown-
6 was added to bind the potassium cation. This afforded the for-
mation of a naked aza-enolate (entry 2). As expected, higher anti-
selectivity was observed (anti/syn¼92/8). Decreasing the reaction
temperature further increased the selectivity (entries 3 and 4). As
a result of solvent screening, toluene was also found to be a good
solvent (entry 5); the desired product was obtained in 92% yield,
albeit with lower selectivity (anti/syn¼87/13). On the other hand,
use of dichloromethane (DCM) shut down the reaction (entry 6).
DMF is the best solvent to use for achieving high anti-selectivity in
sulfonylimidate chemistry, and it proved to be equally good with
the phosphoryimidates; use of DMF as solvent afforded high anti-
selectivity, even in the absence of 18-crown-6 (entries 7e10).
R1
O Pr
i
O Pr
(1.5 equiv)
R2
(1.0 equiv)
Entry
R1
R2
Yield (%)
anti/syna
1
Ph
Ph
Ph
Me
Et
H
88
94
59
88
86
71
80
92
91
93
70
77
38
31
87
96/4
96/4
d
2
3b
4
p-MeO-C6H4
p-F-C6H4
p-Cl-C6H4
p-Me-C6H4
m-Me-C6H4
o-Me-C6H4
1-Naphthyl
2-Furyl
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
94/6
93/7
96/4
95/5
95/5
94/6
95/5
79/21
90/10
86/14
88/12
98/2
5
6
7
8
9
10
11c
12
13
14d
15d
2-Thienyl
3-Pyridyl
iBu
tBu
Table 2
Optimization of reaction conditions
a
Determined by 1H NMR spectroscopy of the crude products.
O
P
NH
b
EtO
EtO
O
P
Phosphorylimidate (5.0 equiv) and imine (1.0 equiv) were used. Reaction time
was 10 min.
EtO
EtO
Me
KHMDS (10 mol%)
solvent, temp.,
Boc
Boc
c
KOtBu (10 mol %) was used.
Imine (2.0 equiv) was used.
N
N
N
+
d
i
i
Ph
(1.5 equiv)
OPr
Ph
OPr
time, MS 4A
Me
(1.0 equiv)
O
P
NH
EtO
EtO
O
Entry
Solvent
Temp
Time (h)
Yield (%)
anti/syna
H2SO4 (7.0 equiv)
100 oC, 3 h
P(OEt)2
Boc
Ph
H2N HN
Ph
N
1
THF
THF
THF
THF
Toluene
DCM
DMF
DMF
DMF
DMF
rt
rt
24
24
24
48
48
48
24
24
48
72
89
74
73
80
92
Trace
72
79
88
85/15
92/8
96/4
94/6
87/13
d
2b
3b
4b
5
i
O
OPr
0 ꢀ
0 ꢀ
C
C
i
PrOH-H2O (95/5)
Me
Me
ꢀC
ꢀC
88%
0
0
rt
0
0
0
6
7
8
9
Scheme 1. Conversion to N-phosphorylamide.
93/7
95/5
96/4
95/5
ꢀC
ꢀC
ꢀC
10
88
anti-selectivity observed could be explained by a transition state
model wherein metal coordination with the aza-enolate nitrogen
and N-Boc imine oxygen is not involved; otherwise, when metal
coordination is possible, syn-selectivity resulted.7 Applying this
explanation to phosphorylimidate chemistry, it is therefore ap-
propriate to reason that the addition reactions of phosphor-
ylimidates proceeded via a noncoordinating transition state, even
in less polar solvents such as toluene and THF. Although this is still
speculative, we believe that the Lewis basic P]O oxygen atom
may have a high tendency to coordinate to the metal cation, either
in a uni- or multi-molecular fashion. As a result, coordination
between the metal cation and the N-Boc imine oxygen is less fa-
vored in the transition state for both steric and electronic reasons.
The assumed transition state model for the Mannich-type reaction
of phosphorylimidates is given in Figure 1.
a
Determined by 1H NMR spectroscopy of the crude products.
18-Crown-6 (10 mol %) was added.
b
Having determined the optimized reaction conditions in hand
(Table 2, entry 9), the substrate generality was examined next
(Table 3). Besides propionimidate (entry 1), butyrimidate can also
be used (entry 2). The use of acetimidate led to a mixture of mono-
and double-addition products (entry 3). This phenomenon was
previously observed with sulfonylimidates,3g but it was possible to
suppress it by using an excess amount of phosphorylacetimidate
(5 equiv). Various aromatic aldehyde-derived Boc imines, including
heteroaromatics, provide the corresponding adducts in good to
high yields and with high selectivity (entries 4e13). Enolizable
isovaleraldehyde-derived Boc imine could also be used, as shown in
entry 14. Moreover, it was noted that the sterically demanding
pivaldehyde-derived Boc imine was tolerated and afforded the
desired product in high yield and with high selectivity (entry 15).
The Mannich-type adducts were readily converted to amides
under acidic conditions; the adduct was treated with sulfuric acid
at 100 ꢀC for 3 h to afford the corresponding N-phosphorylamide in
88% yield. No epimerization was observed during this trans-
formation (Scheme 1).
O t
Bu
KLn
N
O
Me
R
O
P(O)(OEt)2
N
i
In contrast to the metal-catalyzed addition reactions of sulfo-
nylimidates, phosphorylimidates afforded the corresponding ad-
ducts with anti-selectivity in all the reactions investigated in this
study. In our sulfonylimidate studies, a combination of experi-
mental results and X-ray diffraction analyses suggested that the
Pr
(L = DMF, 18-crown-6 or phosphorylimidate)
Figure 1. Assumed transition state model for the Mannich-type reaction of
phosphorylimidates.

S. Kobayashi et al. / Tetrahedron 66 (2010) 6457e6461
6459
3. Conclusion
a solution of KHMDS (10 mol %) in DMF (0.2 mL) was added to the
mixture. The mixture was stirred for 48 h at this temperature and
then quenched with satd NH4Cl (aq) and diluted by the addition of
Et2O and H2O. The mixture that was obtained was washed with
water (three times) and then dried over anhydrous Na2SO4. Filtra-
tion and removal of solvents afforded the crude product. The di-
astereomer ratio was determined by 1H NMR analysis of the crude
product. Purification of the crude product was conducted by
chromatography on SiO2, to afford the desired product.
In summary, in an ongoing study of the development of novel
nucleophiles, phosphorylimidates have been successfully used in
the catalytic, direct Mannich-type reactions. In contrast to sulfo-
nylimidates, phosphorylimidates afford high anti-selectivity, even
in less polar solvents. An explanation for the anti-selectivity is
given. Further application of this methodology as well as de-
velopment of its asymmetric variant is ongoing in our laboratory.
4. Experimental
4.2.1. iso-Propyl anti-3-(tert-butoxycarbonylamino)-N-(diethoxyphos-
phoryl)-2-methyl-3-phenylpropionimidate. Colorless oil. 1H NMR
4.1. Preparation of phosphorylimidates
(C6D6)
d
¼7.62 (1H, d, J¼8.9 Hz), 7.54 (2H, d, J¼7.6 Hz), 7.09 (2H, t,
J¼7.6 Hz), 7.00 (1H, t, J¼7.6 Hz), 5.20 (1H, quint, J¼6.2 Hz), 5.03 (1H,
dd, J¼10.3, 10.3 Hz), 4.20e4.15 (2H, m), 4.02e3.92 (3H, m), 1.34 (9H,
s),1.29e1.25 (6H, m),1.09 (3H, d, J¼6.2 Hz),1.05 (3H, t, J¼7.2 Hz), 0.96
HCl gas was bubbled into a mixture of a nitrile (400 mmol) and
2-propanol (400 mmol) for 10e20 min (exothermic). The mixture
was then left for 3e10 h under an Ar atmosphere. Removal of all the
volatiles by evaporation afforded an almost pure imidate HCl salt in
40e80% yield. This product could be used in the next reaction
without further purification but, if required, further purification
could be carried out by washing the solid with dry Et2O. The imi-
date HCl salts were hygroscopic, but could be stored under an inert
gas atmosphere in the refrigerator.
To a solution of iso-propylpropionimidate HCl salt (5.39 g,
35.57 mmol) in DCM (82.5 mL) was added Et3N (15.0 mL,
106.72 mmol) dropwise at room temperature (rt). To the resultant
suspension were added (EtO)2(O)PCl (4.75 mL, 35.57 mmol) and
DMAP (367.5 mg, 3.557 mmol). The mixture was stirred until
(EtO)2(O)PCl was consumed (ca. 24 h). The mixture was poured into
water and extracted with DCM. The organic fraction was dried over
anhydrous Na2SO4. Filtration and evaporation of the solvents
afforded the crude product, which was purified by column chro-
matography on SiO2 to give iso-propyl N-diethoxyphosphor-
ylpropionimidate (7.087 g, 86% yield).
(3H, d, J¼6.2 Hz); 13C NMR (C6D6)
¼177.40 (d, J¼15.9 Hz), 155.10,
d
142.36,128.82,127.86,127.64, 78.16, 70.33, 62.60 (d, J¼5.8 Hz), 58.90,
46.70 (d, J¼4.3 Hz), 28.44, 21.15, 20.95, 16.43 (d, J¼5.8 Hz), 16.30 (d,
J¼5.8 Hz), 15.01; 31P NMR (C6D6)
¼6.51; IR (neat) 3289, 2979, 2935,
d
2363, 1715, 1640, 1520, 1455, 1365, 1289, 1246, 1171, 1106, 1034, 970,
916, 879, 852, 765, 703, 637, 614, 573, 517 cmꢁ1; HRMS (DART); exact
mass calcd for C22H38N2O6P [MþH]þ, 457.2468. Found 457.2445.
4.2.2. iso-Propyl syn-3-(tert-butoxycarbonylamino)-N-(diethoxyphos-
phoryl)-2-methyl-3-phenylpropionimidate. White solid. 1H NMR
(C6D6)
d
¼7.71 (2H, d, J¼7.6 Hz), 7.15 (2H, d, J¼7.6 Hz), 7.01 (1H, t,
J¼7.2 Hz), 6.13 (1H, d, J¼8.9 Hz), 5.36 (1H, t, J¼10 Hz), 4.83 (1H, quint,
J¼6.2 Hz), 4.53e4.49 (1H, m), 4.06e43.99 (2H, m), 3.87e3.83 (2H,
m), 1.56 (3H, d, J¼6.9 Hz), 1.42 (9H, s), 1.12e1.07 (6H, m), 0.90 (3H, d,
J¼6.2 Hz), 0.70 (3H, d, J¼6.2 Hz); 13C NMR (C6D6)
d¼176.02 (d,
J¼17.3 Hz), 155.86, 142.60, 128.46 (d, J¼2.9 Hz), 127.87, 127.36, 78.39,
69.46, 62.34 (d, J¼7.2 Hz), 62.19 (d, J¼5.8 Hz), 57.59, 44.61 (d,
J¼4.3 Hz), 28.55, 20.96, 20.54, 16.45, 16.37 (t, J¼7.9 Hz); 31P NMR
(C6D6)
d¼2.99; IR (neat) 3734, 3269, 2979, 2360, 1709, 1650, 1525,
4.1.1. iso-Propyl
N-diethoxyphosphoryl-propionimidate. Colorless
1455, 1366, 1240, 1172, 1107, 1038, 969, 770, 701, 624, 501 cmꢁ1
;
oil. 1H NMR (C6D6)
d¼5.06 (1H, quint, J¼6.2 Hz), 4.10e4.00 (4H, m),
HRMS (DART); exact mass calcd for C22H38N2O6P [MþH]þ, 457.2468.
Found 457.2454. Mp 115e116 ꢀC.
2.79 (2H, q, J¼7.8 Hz), 1.14e1.11 (9H, m), 1.00 (6H, d, J¼6.2 Hz); 13C
NMR (C6D6)
d
¼176.24 (d, J¼17.3 Hz), 69.25, 62.14 (d, J¼5.8 Hz),
28.94 (d, J¼2.9 Hz), 21.23, 16.45 (d, J¼7.2 Hz), 11.07; 31P NMR (C6D6)
4.2.3. iso-Propyl anti-3-(tert-butoxycarbonylamino)-N-(diethoxyphos-
d
¼4.34; IR (neat) 3550, 2982, 2360, 1648, 1466, 1375, 1297, 1230,
phoryl)-2-ethyl-3-phenylpropionimidate. Colorless oil. 1H NMR (C6D6)
1110, 1034, 968, 763, 606, 506 cmꢁ1; HRMS (DART); exact mass
calcd for C10H23NO4P [MþH]þ, 252.1365. Found 252.1372.
d
¼7.69 (1H, d, J¼8.9 Hz), 7.56 (2H, d, J¼7.6 Hz), 7.09 (2H, t, J¼7.6 Hz),
7.00 (1H, t, J¼7.2 Hz), 5.22 (1H, quint, J¼6.2 Hz), 5.06 (1H, dd, J¼10.3,
10.3 Hz), 4.22e4.15 (2H, m), 4.06e4.02 (1H, m), 3.97e3.90 (1H, m),
3.82 (1H, t, J¼11.3 Hz), 1.74e1.63 (1H, m), 1.34 (9H, s), 1.31e1.25 (6H,
m),1.22e1.14 (1H, m),1.09 (3H, d, J¼6.2 Hz),1.07 (3H, t, J¼7.2 Hz), 0.75
4.1.2. iso-Propyl N-diethoxyphosphoryl-butyrimidate. Colorless oil.
1H NMR (C6D6)
d
¼5.09 (1H, quint, J¼6.2 Hz), 4.10e4.02 (4H, m),
2.81 (2H, t, J¼7.6 Hz), 1.69 (2H, td, J¼14.4, 7.1 Hz), 1.14 (6H, t,
(3H, t, J¼7.2 Hz); 13C NMR (C6D6)
¼176.75 (d, J¼15.9 Hz), 155.06,
d
J¼6.9 Hz), 1.02 (6H, d, J¼6.2 Hz), 0.88 (3H, t, J¼7.6 Hz); 13C NMR
142.79, 128.81, 127.84, 127.60, 78.05, 70.23, 62.59 (q, J¼6.7 Hz), 58.10,
54.79 (d, J¼4.3 Hz), 28.43, 23.32, 21.13, 21.04,16.43(d, J¼5.8 Hz),16.30
(C6D6)
d
¼175.20 (d, J¼17.3 Hz), 69.15, 62.07 (d, J¼5.8 Hz), 36.98 (d,
J¼4.3 Hz), 21.26, 20.42, 16.43 (d, J¼5.8 Hz), 13.76; 31P NMR (C6D6)
(d, J¼7.2 Hz), 12.00; 31P NMR (C6D6)
¼6.75; IR (neat) 3293, 2978,
d
d
¼4.21; IR (neat) 2980, 2366, 1650, 1467, 1372, 1290, 1255, 1110,
1035, 965, 775, 608, 512 cmꢁ1; HRMS (DART); exact mass calcd for
2935, 2364, 1715, 1639, 1520, 1455, 1389, 1365, 1303, 1247, 1171, 1106,
1034, 970, 866, 799, 760, 703, 635, 610, 574, 522 cmꢁ1; HRMS (DART);
exact mass calcd for C23H40N2O6P [MþH]þ, 471.2624. Found 471.2632.
C11H25NO4P [MþH]þ, 266.1521. Found 266.1515.
4.1.3. iso-Propyl N-diethoxyphosphorylacetimidate. Colorless oil. 1H
4.2.4. iso-Propyl
3-(tert-butoxycarbonylamino)-N-(diethoxyphos-
NMR (C6D6)
d
¼5.06 (1H, quint, J¼6.5 Hz), 4.08e4.01 (4H, m), 2.28
phoryl)-3-phenylpropionimidate. Colorless oil. 1H NMR (C6D6)
(3H, s), 1.16 (6H, t, J¼7.2 Hz), 1.03 (6H, d, J¼6.2 Hz); 13C NMR (C6D6)
d
¼7.51 (1H, d, J¼8.9 Hz), 7.43 (2H, d, J¼7.6 Hz), 7.07 (2H, t, J¼7.6 Hz),
d
¼172.45 (d, J¼15.9 Hz), 69.43, 21.29 (t, J¼4.3 Hz),16.39 (d, J¼7.2 Hz);
31P NMR (C6D6)
d¼4.56; IR (neat) 3542, 2982, 2361, 1654, 1375, 1282,
6.98 (1H, t, J¼7.2 Hz), 5.51e5.47 (1H, m), 5.12 (1H, quint, J¼6.2 Hz),
4.21e4.14 (2H, m), 3.96e3.89 (2H, m), 3.58 (1H, t, J¼12.4 Hz), 2.72
(1H, dd, J¼13.1, 4.8 Hz), 1.39 (9H, s), 1.24 (3H, t, J¼6.9 Hz), 1.20 (3H,
1110, 1056, 965, 909, 837, 767, 618, 505 cmꢁ1; HRMS (DART); exact
mass calcd for C9H21NO4P [MþH]þ, 238.1208. Found 238.1205.
d, J¼6.2 Hz), 1.05e1.03 (6H, m); 13C NMR (C6D6)
d
¼173.42 (d,
4.2. General procedure for the addition reactions of
phosphorylimidates to imines
J¼15.9 Hz), 155.38, 143.50, 128.81, 127.85, 127.40, 78.26, 70.37, 62.54
(d, J¼5.8 Hz), 53.37, 42.90 (d, J¼4.3 Hz), 28.46, 21.24, 20.95,16.44 (d,
J¼7.2 Hz), 16.25 (d, J¼5.8 Hz); 31P NMR (C6D6)
¼6.35; IR (neat)
d
A mixture of imine (0.45 mmol), phosphorylimidate (0.3ꢀmmol),
3882, 3850, 3734, 3646, 3280, 2980, 2361, 1714, 1649, 1519, 1455,
ꢁ
and MS 4 A (50 mg) in DMF (0.4 mL) was cooled to 0 C, and
1365, 1298, 1246, 1173, 1108, 1033, 969, 774, 700, 626, 516 cmꢁ1
;

6460
S. Kobayashi et al. / Tetrahedron 66 (2010) 6457e6461
HRMS (DART); exact mass calcd for C21H36N2O6P [MþH]þ,
1H NMR (C6D6)
d
¼7.61 (1H, d, J¼9.6 Hz), 7.40 (1H, d, J¼8.2 Hz), 7.37
443.2311. Found 443.2304.
(1H, s), 7.05 (1H, t, J¼7.6 Hz), 6.85 (1H, d, J¼7.6 Hz), 5.20 (1H, quint,
J¼6.2 Hz), 5.04 (1H, dd, J¼10.3, 10.3 Hz), 4.22e4.15 (2H, m),
4.02e3.92 (3H, m), 2.03 (3H, s), 1.35 (9H, s), 1.30 (3H, d, J¼6.2 Hz),
1.26 (3H, t, J¼7.2 Hz),1.09 (3H, d, J¼6.9 Hz), 1.04 (3H, t, J¼7.2 Hz),1.00
4.2.5. iso-Propyl anti-3-(tert-butoxycarbonylamino)-N-(diethoxyphos-
phoryl)-3-(p-methoxyphenyl)-2-methylpropionimidate. Colorless oil.
1H NMR (C6D6)
d
¼7.54 (1H, d, J¼9.6 Hz), 7.46 (2H, d, J¼8.2 Hz), 6.68
(3H, d, J¼6.9 Hz); 13C NMR (C6D6)
¼177.51 (d, J¼17.3 Hz), 155.09,
d
(2H, d, J¼8.9 Hz), 5.21 (1H, quint, J¼6.2 Hz), 5.01 (1H, dd, J¼10.3,
10.3 Hz), 4.22e4.15 (2H, m), 4.04e3.93 (3H, m), 3.26 (3H, s), 1.36 (9H,
s), 1.30 (3H, d, J¼6.2 Hz), 1.26 (3H, t, J¼6.9 Hz), 1.10 (3H, d, J¼6.2 Hz),
142.30,138.28,128.81,124.93, 78.13, 70.29, 62.58 (d, J¼5.8 Hz), 58.89,
46.71 (d, J¼4.3 Hz), 28.44, 21.26, 21.15, 20.95, 16.43 (d, J¼5.8 Hz),
16.26 (d, J¼5.8 Hz), 15.04; 31P NMR (C6D6)
¼6.54; IR (neat) 3855,
d
1.07 (3H, t, J¼7.2 Hz),1.01 (3H, d, J¼6.9 Hz); 13C NMR (C6D6)
d¼177.63
3734, 3672, 3293, 2979, 2935, 2361, 1714, 1639, 1519, 1455, 1365,
(d, J¼17.3 Hz), 159.50, 155.14, 134.42, 128.92, 114.33, 78.14, 70.32,
62.63 (d, J¼5.8 Hz), 58.38, 54.70, 46.84 (d, J¼4.3 Hz), 28.49, 21.19,
20.99, 16.46 (d, J¼5.8 Hz), 16.33 (d, J¼5.8 Hz), 15.12; 31P NMR (C6D6)
1288, 1241, 1169, 1106, 1035, 970, 847, 764, 704, 621, 582, 445 cmꢁ1
;
HRMS (DART); exact mass calcd for C23H40N2O6P [MþH]þ, 471.2624.
Found 471.2623.
d
¼6.48; IR (neat) 3888, 3872, 3855, 3840, 3824, 3804, 3747, 3678,
3652, 3295, 2979, 2361,1713,1642,1514,1456,1366,1293,1247, 1173,
1105, 1035, 970, 832, 766, 620 cmꢁ1; HRMS (DART); exact mass calcd
for C23H40N2O7P [MþH]þ, 487.2573. Found 487.2559.
4.2.10. iso-Propyl anti-3-(tert-butoxycarbonylamino)-N-(diethoxy-
phosphoryl)-3-(o-methylphenyl)-2-methylpropionimidate. Colorless
oil. 1H NMR (C6D6)
d¼7.85 (1H, d, J¼7.6 Hz), 7.60 (1H, d, J¼9.6 Hz),
7.07 (1H, t, J¼7.2 Hz), 6.97e6.93 (2H, m), 5.42 (1H, dd, J¼10.0,
10.0 Hz), 5.20 (1H, quint, J¼6.2 Hz), 4.22e4.14 (2H, m), 4.05e3.93
(3H, m), 2.57 (3H, s), 1.33 (9H, s), 1.29e1.24 (6H, m), 1.08e1.05 (6H,
4.2.6. iso-Propyl anti-3-(tert-butoxycarbonylamino)-N-(diethoxyphos-
phoryl)-3-(p-fluorophenyl)-2-methylpropionimidate. Colorless oil. 1H
NMR (C6D6)
d
¼7.60 (1H, d, J¼8.9 Hz), 7.34 (2H, dd, J¼8.2, 5.5 Hz), 6.71
m), 0.97 (3H, d, J¼6.9 Hz); 13C NMR (C6D6)
¼177.45 (d, J¼15.9 Hz),
d
(2H, t, J¼8.6 Hz), 5.18 (1H, quint, J¼6.2 Hz), 4.95 (1H, dd, J¼10.3,
10.3 Hz), 4.21e4.13 (2H, m), 4.02e3.85 (3H, m),1.36 (9H, s),1.29e1.23
(6H, m), 1.08 (3H, d, J¼6.2 Hz), 1.05 (3H, t, J¼7.2 Hz), 0.91 (3H, d,
155.28, 141.33, 136.41, 130.36, 128.16, 78.12, 70.30, 62.59 (d,
J¼5.8 Hz), 53.89, 47.42, 28.42, 21.12, 20.92, 20.03, 16.43 (d,
J¼5.8 Hz), 16.31 (d, J¼7.2 Hz), 14.08; 31P NMR (C6D6)
¼6.59; IR
d
J¼6.9 Hz); 13C NMR (C6D6)
d¼177.21 (d, J¼15.9 Hz), 155.07, 138.10 (d,
(neat) 3855, 3734, 293, 2979, 2935, 2360, 1713, 1648, 1519, 1456,
1365, 1291, 1247, 1174, 1107, 1035, 970, 878, 762, 733, 633, 615, 579,
520, 458 cmꢁ1; HRMS (DART); exact mass calcd for C23H40N2O6P
[MþH]þ, 471.2624. Found 471.2616.
J¼2.9 Hz), 129.51 (d, J¼7.2 Hz), 127.84, 115.53 (d, J¼21.7 Hz), 78.32,
70.39, 62.65 (d, J¼5.8 Hz), 58.14, 46.63 (d, J¼4.3 Hz), 28.41, 21.11,
20.91, 16.39 (d, J¼7.2 Hz), 16.26 (d, J¼5.8 Hz), 14.91; 31P NMR (C6D6)
d
¼6.46; IR (neat) 3855, 3734, 3672, 3275, 2980, 2936, 2365, 1714,
1639, 1509, 1456, 1390, 1366, 1290, 1225, 1173, 1107, 1035, 970, 880,
838, 767, 620, 567, 528 cmꢁ1; HRMS (DART); exact mass calcd for
C22H37FN2O6P [MþH]þ, 475.2373. Found 475.2364.
4.2.11. iso-Propyl anti-3-(tert-butoxycarbonylamino)-N-(diethoxy-
phosphoryl)-2-methyl-3-(naphthalen-1-yl)propionimidate. Colorless
oil.1H NMR (C6D6)
d¼8.84(1H, brs), 8.00 (1H, brs), 7.79 (1H, brs), 7.58
(1H, d, J¼8.2 Hz), 7.50 (1H, d, J¼8.2 Hz), 7.37 (1H, br s), 7.20 (1H, q,
J¼8.2 Hz), 6.06 (1H, br s), 5.25 (1H, quint, J¼6.2 Hz), 4.32 (2H, br s),
4.26e4.18 (2H, m), 4.05e3.94 (2H, m),1.37 (3H, d, J¼6.2 Hz),1.31 (9H,
s), 1.28 (3H, t, J¼7.2 Hz), 1.10 (3H, d, J¼6.2 Hz), 1.05 (3H, t, J¼6.9 Hz),
4.2.7. iso-Propyl anti-3-(tert-butoxycarbonylamino)-3-(p-chloroph-
enyl)-N-(diethoxyphosphoryl)-2-methylpropionimidate. White solid.
1H NMR (C6D6)
d
¼7.64 (1H, d, J¼8.9 Hz), 7.26 (2H, d, J¼8.9 Hz), 6.99
(2H, d, J¼8.2 Hz), 5.18 (1H, quint, J¼6.2 Hz), 4.90 (1H, dd, J¼10.7,
9.3 Hz), 4.21e4.13 (2H, m), 4.02e3.97 (1H, m), 3.94e3.90 (1H, m),
3.86e3.82 (1H, m), 1.36 (9H, s), 1.29e1.23 (6H, m), 1.07 (3H, d,
J¼6.2 Hz), 1.05 (3H, t, J¼7.2 Hz), 0.88 (3H, d, J¼6.9 Hz); 13C NMR
0.92(3H, d,J¼6.9 Hz); 13CNMR (C6D6)
¼177.45 (d, J¼15.9 Hz),155.27,
d
129.00, 128.29, 127.84, 126.49, 126.04, 125.77, 78.20, 70.45, 62.60 (d,
J¼5.8 Hz), 28.40, 21.17, 21.03, 16.46 (d, J¼5.8 Hz), 16.31 (d, J¼7.2 Hz),
14.86; 31P NMR (C6D6)
d¼6.33; IR (neat)3855, 3839, 3734, 3672, 3646,
(C6D6)
d
¼177.05 (d, J¼15.9 Hz), 155.03,140.84,133.38, 129.26,128.91,
3630, 3295, 2979, 2935, 2361,1714,1649,1556,1509,1455,1390,1365,
1289, 1237, 1170, 1033, 970, 780, 637, 607, 577, 521 cmꢁ1; HRMS
(DART); exact mass calcd for C26H40N2O6P [MþH]þ, 507.2624. Found
507.2601.
78.34, 70.37, 62.64 (d, J¼2.9 Hz), 62.60 (d, J¼2.9 Hz), 58.24, 46.46 (d,
J¼4.3 Hz), 28.41, 21.12, 20.90, 16.41 (d, J¼7.2 Hz), 16.28 (d, J¼5.8 Hz),
14.82; 31P NMR (C6D6)
d¼6.56; IR (neat) 3850, 3734, 3289, 2979,
2935, 2361,1714,1648,1519, 1492, 1456, 1389, 1365, 1288, 1246, 1169,
1089, 1035, 970, 878, 825, 767, 617, 519 cmꢁ1; HRMS (DART); exact
mass calcd for C22H37ClN2O6P [MþH]þ, 491.2078. Found 491.2056.
Mp 67 ꢀC.
4.2.12. iso-Propyl anti-3-(tert-butoxycarbonylamino)-N-(diethoxyphos-
phoryl)-3-(2-furyl)-2-methylpropionimidate. Orange oil. 1H NMR
(C6D6)
d
¼7.15 (1H, s), 7.00 (1H, s), 6.22 (1H, d, J¼3.4 Hz), 5.96 (1H, s),
5.26 (1H, dd, J¼10.0 , 10.0 Hz), 5.15 (1H, quint, J¼6.5 Hz), 4.22e4.11
4.2.8. iso-Propyl anti-3-(tert-butoxycarbonylamino)-N-(diethoxyphos-
(3H, m), 4.05e3.94 (2H, m), 1.36 (9H, s), 1.26e1.21 (6H, m), 1.09e1.03
phoryl)-3-(p-methylphenyl)-2-methylpropionimidate. White solid. 1H
(9H, m); 13C NMR (C6D6)
d¼176.53 (d, J¼17.3 Hz), 155.11, 154.01,
NMR (C6D6)
d
¼7.58 (1H, d, J¼9.6 Hz), 7.45 (2H, d, J¼8.2 Hz), 6.91 (2H,
142.19, 110.38, 107.94, 78.50, 70.39, 62.68 (d, J¼5.8 Hz), 52.30, 44.33
(d, J¼4.3 Hz), 28.41, 21.09, 20.92, 16.41 (d, J¼7.2 Hz), 16.31 (d,
d, J¼8.2 Hz), 5.20 (1H, quint, J¼6.2 Hz), 5.02 (1H, dd, J¼10.3,10.3 Hz),
4.22e4.15 (2H, m), 4.03e3.92 (3H, m), 2.03 (3H, s), 1.35 (9H, s), 1.29
(3H, d, J¼6.2 Hz), 1.26 (3H, t, J¼6.9 Hz), 1.09 (3H, d, J¼6.2 Hz), 1.06
J¼5.8 Hz), 14.94; 31P NMR (C6D6)
¼5.51; IR (neat) 3855, 3839, 3734,
d
3672, 3646, 3630, 3295, 2979, 2935, 2361, 1714, 1649, 1556, 1509,
1455, 1390, 1365, 1289, 1237, 1170, 1033, 970, 780, 637, 607, 577,
521 cmꢁ1; HRMS (DART); exact mass calcd for C20H36N2O7P [MþH]þ,
447.2260. Found 447.2239.
(3H, t, J¼6.9 Hz), 1.00 (3H, d, J¼6.9 Hz); 13C NMR (C6D6)
¼177.55 (d,
d
J¼17.3 Hz), 155.11, 139.47, 136.99, 129.53, 128.19, 78.11, 70.29, 62.59
(d, J¼5.8 Hz), 58.67, 46.71 (d, J¼4.3 Hz), 28.48, 21.17, 20.98 (d,
J¼2.9 Hz), 16.46 (d, J¼7.2 Hz), 16.32 (d, J¼7.2 Hz), 15.08; 31P NMR
(C6D6)
d
¼6.51; IR (neat) 3855, 3840, 3735, 3672, 3647, 3293, 2979,
4.2.13. iso-Propyl anti-3-(tert-butoxycarbonylamino)-N-(diethoxyphos-
2361, 1715, 1644, 1518, 1455, 1365, 1289, 1246, 1172, 1106, 1034, 970,
818, 765, 620, 520þcmꢁ1; HRMS (DART); exact mass calcd for
C23H40N2O6P [MþH] , 471.2624. Found 471.2608. Mp 59e60 ꢀC.
phoryl)-2-methyl-3-(2-thienyl)propionimidate. Colorless oil. 1H NMR
(C6D6)
d
¼7.43 (1H, d, J¼9.6 Hz), 7.07 (1H, d, J¼3.4 Hz), 6.77 (1H, d,
J¼5.5 Hz), 6.64 (1H, t, J¼4.5 Hz), 5.37 (1H, dd, J¼10.3, 10.3 Hz), 5.15
(1H, quint, J¼6.2 Hz), 4.18e4.11 (2H, m), 4.06e3.93 (3H, m), 1.35 (9H,
4.2.9. iso-Propyl anti-3-(tert-butoxycarbonylamino)-N-(diethoxyphos-
phoryl)-3-(m-methylphenyl)-2-methylpropionimidate. Colorless oil.
s), 1.24e1.22 (6H, m), 1.10e1.03 (9H, m); 13C NMR (C6D6)
d¼176.73 (d,
J¼15.9 Hz), 155.06, 145.78, 126.97, 125.67, 124.60, 78.47, 70.36, 62.63

S. Kobayashi et al. / Tetrahedron 66 (2010) 6457e6461
6461
(q, J¼3.4 Hz), 54.21, 46.96 (d, J¼4.3 Hz), 28.43, 21.10, 20.91, 16.42 (d,
After cooling to room temperature, the mixture was diluted with
CH2Cl2 and neutralized by a satd aq solution of NaHCO3. All volatiles
were evaporated and the residue was diluted with CH2Cl2 and fil-
tered. After evaporation, the crude product was purified by column
chromatography (silica gel).
J¼5.8 Hz), 16.34 (d, J¼7.2 Hz), 15.29; 31P NMR (C6D6)
¼6.10; IR (neat)
d
3855, 3839, 3734, 3672, 3647, 2979, 2935, 2360,1714,1649,1519,1455,
1366, 1287, 1238, 1169, 1105, 1035, 968, 764, 700, 630, 586, 516 cmꢁ1
;
HRMS (DART); exact mass calcd for C20H36N2O6PS [MþH]þ, 463.2032.
Found 463.2030.
4.3.1. anti-3-Amino-N-(diethoxyphosphoryl)-2-methyl-3-phenyl-
4.2.14. iso-Propyl anti-3-(tert-butoxycarbonylamino)-N-(diethoxy-
propionamide. Orange oil. 1H NMR (C6D6)
d¼7.48 (2H, d, J¼7.4 Hz),
phosphoryl)-2-methyl-3-(3-pyridyl)propionimidate. Colorless oil. 1H
7.04 (1H, t, J¼7.2 Hz), 6.23 (2H, s), 4.20e4.15 (4H, m), 3.31 (1H, s),
NMR (C6D6)
d
¼8.93 (1H, s), 8.40 (1H, d, J¼3.4 Hz), 7.72 (2H, t,
1.35 (1H, d, J¼6.2 Hz), 1.14e1.11 (6H, m), 1.04 (3H, d, J¼6.2 Hz); 13C
J¼8.2 Hz), 6.68 (1H, q, J¼4.1 Hz), 5.16 (1H, quint, J¼6.2 Hz), 5.00
(1H, dd, J¼10.0, 10.0 Hz), 4.12e4.11 (2H, m), 3.97e3.87 (3H, m), 1.34
(9H, s), 1.26e1.21 (6H, m), 1.05 (3H, d, J¼6.2 Hz), 1.03 (3H, t,
NMR (C6D6)
d
¼128.80, 128.29, 64.34 (dd, J¼32.5, 5.1 Hz), 59.41,
47.83 (d, J¼11.6 Hz), 23.34,16.17 (d, J¼7.2 Hz),15.88; 31P NMR (C6D6)
d
¼ꢁ1.15; IR (neat) 3865, 3854, 3839, 3734, 3672, 3646, 3630, 2981,
J¼7.2 Hz), 0.85 (3H, d, J¼6.9 Hz); 13C NMR (C6D6)
d
¼176.84 (d,
2361, 1698, 1649, 1557, 1541, 1455, 1396, 1242, 1032, 969, 866, 766,
J¼15.9 Hz), 155.09, 149.97, 149.41, 137.44, 134.36, 123.73, 78.50,
70.4, 62.68 (d, J¼5.8 Hz), 56.62, 46.29 (d, J¼4.3 Hz), 28.37, 21.06,
20.88, 16.38 (d, J¼5.8 Hz), 16.25 (d, J¼7.2 Hz), 14.79; 31P NMR (C6D6)
702, 548, 418 cmꢁ1
; HRMS (DART); exact mass calcd for
C14H24N2O4P [MþH]þ, 315.1474. Found 315.1486.
d
¼6.40; IR (neat) 3902, 3888, 3882, 3866, 3855, 3840, 3824, 3803,
Acknowledgements
3747, 3734, 3672, 3647, 3631, 2980, 2361, 1714, 1649, 1519, 1455,
1365, 1236, 1170, 1034, 766, 623 cmꢁ1; HRMS (DART); exact mass
calcd for C21H37N3O6P [MþH]þ, 458.2420. Found 458.2405.
This work was partially supported by a Grant-in-Aid for Science
Research from the Japan Society for the Promotion of Science
(JSPS) and Global COE Program (Chemistry Innovation through
Cooperation of Science and Engineering), The University of Tokyo,
MEXT, Japan.
4.2.15. iso-Propyl anti-3-(tert-butoxycarbonylamino)-N-(diethoxy-
phosphoryl)-2,5-dimethylhexanimidate. Colorless oil. 1H NMR
(C6D6)
d
¼6.44 (1H, d, J¼9.6 Hz), 5.12 (1H, quint, J¼6.2 Hz),
4.18e4.08 (3H, m), 4.03e3.92 (2H, m), 3.56e3.53 (1H, m), 1.92e1.86
(1H, m), 1.45 (9H, s), 1.30e1.21 (8H, m), 1.12 (3H, d, J¼6.9 Hz),
1.09e1.06 (6H, m), 1.04 (3H, d, J¼6.2 Hz), 0.84 (3H, d, J¼6.9 Hz); 13C
References and notes
1. (a) Kobayashi, S.; Ishitani, H. Chem. Rev. 1999, 99, 1069; (b) Arend, M.; West-
ermann, B.; Risch, N. Angew. Chem., Int. Ed. 1998, 37, 1044; (c) Friestad, G. K.;
Mathies, A. K. Tetrahedron 2007, 63, 2541; (d) Kobayashi, S.; Ueno, M. In Com-
prehensive Asymmetric Catalysis, Supplement 1; Jacobsen, E. N., Pfaltz, A., Yama-
moto, H., Eds.; Springer: Berlin, 2004; Chapter 29.5, p 143.
2. For reviews on direct Mannich or Mannich-type reactions, see: (a) Verkade, J. M.
M.; van Hemert, L. J. C.; Quaedflieg, P. J. L. M.; Rutjes, F. P. J. T. Chem. Soc. Rev.
2008, 37, 29; (b) Ting, A.; Schaus, S. E. Eur. J. Org. Chem. 2007, 5797; (c) Marques,
M. M. B. Angew. Chem., Int. Ed. 2006, 45, 348.
NMR (C6D6)
d¼177.64 (d, J¼17.3 Hz), 155.73, 77.79, 70.17, 62.40 (d,
J¼7.2 Hz), 52.43, 46.26 (d, J¼5.8 Hz), 44.12, 28.56, 24.93, 24.19,
22.02, 21.18, 21.09, 16.47 (d, J¼7.2 Hz), 16.37 (d, J¼7.2 Hz), 15.23; 31P
NMR (C6D6)
d¼5.86; IR (neat) 3855, 3839, 3734, 3672, 3646, 3289,
2978, 2361, 1714, 1649, 1524, 1455, 1389, 1365, 1288, 1241, 1176,
1103, 1036, 1004, 968, 766, 619, 516 cmꢁ1; HRMS (DART); exact
mass calcd for C20H42N2O6P [MþH]þ, 437.2781. Found 437.2778.
3. For examples of catalytic direct-type Mannich-type reactions using substrates
bearing no activating groups at a-position, see acetonitrile as a nucleophile: (a)
4.2.16. iso-Propyl anti-3-(tert-butoxycarbonylamino)-N-(diethoxy-
Kumagai, N.; Matsunaga, S.; Shibasaki, M. Tetrahedron 2007, 63, 8598; (b) Ku-
magai, N.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2004, 126, 13632; Tri-
chloromethylketone as a nucleophile: (c) Morimoto, H.; Wiedemann, S. H.;
Yamaguchi, A.; Harada, S.; Chem, Z.; Matsunaga, S.; Shibasaki, M. Angew. Chem.,
Int. Ed. 2006, 45, 3146; (d) Morimoto, H.; Lu, G.; Aoyama, N.; Matsunaga, S.;
Shibasaki, M. J. Am. Chem. Soc. 2007, 129, 9588; (e) Morimoto, H.; Yoshino, T.;
Yukawa, T.; Lu, G.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2008, 47, 9125;
(N-Boc)acylanilide as a nucleophile: (f) Saito, S.; Tsubogo, T.; Kobayashi, S. Chem.
Commun. 2007, 1236; Sulfonylimidate as a nucleophile: (g) Matsubara, R.; Ber-
thiol, F.; Kobayashi, S. J. Am. Chem. Soc. 2008, 130, 1804; (h) Matsubara, R.; Ko-
bayashi, S. Synthesis 2008, 3009; (i) Nguyen, H. V.; Matsubara, R.; Kobayashi, S.
Angew. Chem., Int. Ed. 2009, 48, 5790; (j) Matsubara, R.; Berthiol, F.; Nguyen, H.
V.; Kobayashi, S. Bull. Chem. Soc. Jpn. 2009, 82, 1083.
phosphoryl)-2,4,4-trimethylpentanimidate. Colorless oil. 1H NMR
(C6D6)
d
¼6.29 (1H, d, J¼10.3 Hz), 5.03 (1H, quint, J¼6.2 Hz),
4.10e4.05 (2H, m), 4.03e3.91 (3H, m), 3.85 (1H, dd, J¼10.3, 7.6 Hz),
1.46 (9H, s), 1.31 (3H, d, J¼6.9 Hz), 1.18 (6H, m), 1.09 (3H, t, J¼7.2 Hz),
1.06e1.02 (12H, m); 13C NMR (C6D6)
d¼177.71 (d, J¼15.9 Hz),
156.04, 77.92, 70.19, 62.36 (d, J¼2.9 Hz), 61.63, 41.59 (d, J¼2.9 Hz),
36.31, 28.54, 27.50, 21.12, 21.01, 17.96, 16.36 (d, J¼5.8 Hz); 31P NMR
(C6D6)
d
¼4.32; IR (neat) 3855, 3839, 3734, 3672, 3647, 3464, 3293,
2977, 2361, 1719, 1649, 1504, 1390, 1366, 1247, 1174, 1035, 1000, 954,
764, 608, 522 cmꢁ1
; HRMS (DART); exact mass calcd for
4. Matsubara, R.; Kobayashi, S. Chem.dEur. J. 2009, 15, 10694.
C20H42N2O6P [MþH]þ, 437.2781. Found 437.2795.
5. After the publications on the use of sulfonylimidate as a nucleophile by our
group (Refs. 3gej), the catalytic asymmetric Michael reaction of sulfonylimi-
dates was reported. Maasa, A.; Utsumi, N.; Barbas, C. F., III. Tetrahedron Lett.
2009, 50, 145.
6. Phosphorylimidates were prepared according to a procedure similar to that used
for the sulfonylimidates. For details, see Experimental.
4.3. Conversion to N-phosphorylamide (Scheme 1)
A mixture of phosphorylimidate, 2-propanol and H2O (95/5),
and concentrated H2SO4 (ca. 7.0 equiv) was stirred at 100 ꢀC for 3 h.
7. For a detailed explanation of the stereoselectivities in sulfonylimidate reactions,
see Ref. 3j.