Stereoselective animation, bisamination, and amination/esterification of bis(trimethylsilyl)-1,2-bisketene initiated by chiral amines

Full text of DOI:10.1021/jo000075l

J . Org. Chem. 2000, 65, 3877-3879
3877
3). The first efforts to achieve this goal2b were not
Ster eoselective Am in a tion , Bisa m in a tion ,
a n d Am in a tion /Ester ifica tion of
Bis(tr im eth ylsilyl)-1,2-bisk eten e In itia ted
by Ch ir a l Am in es
Wen-wei Huang, Patrick A. Moore, Adel Rafai Far, and
Thomas T. Tidwell*
successful,2b,c but in classic studies Pracejus et al.3
demonstrated the feasibility of this process in both ester
and amide formation. Further work in other laboratories
has expanded the scope of this process.4
Department of Chemistry, University of Toronto,
Toronto, Ontario M5S 3H6, Canada
Recently Dejmek and Selke4f,g have studied the reac-
tions of bisketene 1 with alcohols using copper(II) cata-
lysts such as 6 with chiral bidentate ligands. Lactones 7
were formed (eq 4), but with no observed enantioselec-
Received J anuary 19, 2000
Recent studies1 in our laboratory have demonstrated
that the 1,2-bisketene 1 with 1 equiv of n-BuNH2 or
PhCH2NH2 (eq 1) gives rapid conversion to ketenyl
amides 2 as the only observable products, while reaction
with 2 equiv of amine gave the succinamides 3, with little
selectivity in formation of meso and dl isomers. Kinetic
studies showed there are different rate laws for the first
and second steps, and for 0.020 M n-BuNH2 the observed
rate constant of the first step exceeded that of the second
by a factor of 3.8 × 104.
tivity, a result attributed to racemization of the initial
product.4f,g The reaction of 1 with alcohols catalyzed by
tertiary amines gives ketenyl esters (eq 5).5
Fu et al.4h used the chiral azaferrocene 9 to catalyze
the addition of CH3OH to arylalkylketenes 10 to give
â-aryl propionates with 75-80% ee (eq 6). Chiral amino
esters react with haloketenes forming amides with de up
to 95%.4i
In the reaction of 2a (R ) n-Bu) with CH3OH there
was >9/1 selectivity for the erythro ester amide 4 (eq 2).1
The product-determining step in this reaction is proton
transfer to Câ of an intermediate enol ester, and a model
5 was presented to explain the diastereoselectivity (eq
2).1 This structure involves assistance by the amide
carbonyl in proton transfer to Câ in a conformation which
minimizes the interaction between the bulky Me3Si
groups.
We have now examined the stereoselectivity in each
step of eqs 1 and 2, initiated with chiral amines. Reaction
of 1 with 1 equiv of R-(+)-1-phenylethylamine in acetone
at -78 °C followed by removal of the solvent gave the
The demonstrated selectivity in the reaction of eq 2
invites questions as to other selectivity which might
become manifest in such reactions. Thus the addition of
chiral alcohols or amines to unsymmetrical ketenes
RR1CdCdO forming esters or amides has been recog-
nized since 19192 to provide the opportunity for stereo-
selectivity in the generation of the new stereocenter (eq
(3) (a) Pracejus, H.; Tille, A. Chem. Ber. 1963, 96, 854-865. (b)
Winter, S.; Pracejus, H. Chem. Ber. 1966, 99, 151-159.
(4) (a) Tidwell, T. T. Ketenes; Wiley: New York, 1995; Section 5.9.
(b) Anders, E.; Ruch, E.; Ugi, I. Angew. Chem., Int. Ed. Engl. 1973,
12, 25-29. (c) Buschmann, H.; Scharf, H.-D.; Hoffmann, N.; Esser, P.
Angew. Chem., Int. Ed. Engl. 1991, 30, 477-515. (d) Miller, J . R.;
Pulley, S. R.; Hegedus, L. S.; DeLombaert, S. J . Am. Chem. Soc. 1992,
114, 5602-5607. (e) Fehr, C. Angew Chem., Int. Ed. Engl. 1996, 35,
2566-2587. (f) Dejmek, M. M.; Selke, R. Angew. Chem., Int. Ed. Engl.
1998, 37, 1540-1542. (g) Dejmek, M. M.; Selke, R. Synlett 2000, 13-
21. (h) Hodous, B.; Ruble, J . C.; Fu, G. C. J . Am. Chem. Soc. 1999,
121, 2637-2638. (i) Roger, F.; Le Pironnec, M.-G.; Guerro, M.; Gougeon,
P.; Gall, P.; le Grel, P.; Baudy-Floc’h, M. Synthesis 1999, 1341-1344.
(5) (a) Egle, I.; Lai, W.-Y.; Moore, P. A.; Renton, P.; Tidwell, T. T.;
Zhao, D.-c. J . Org. Chem. 1997, 62, 18-25. (b) Rafai Far, A.; Tidwell,
T. T. J . Org. Chem. 1998, 63, 8636-8637.
(1) Allen, A. D.; Moore, P. A.; Missiha, S.; Tidwell, T. T. J . Org.
Chem. 1999, 64, 4690-4696.
(2) (a) For a recent thematic collection on diastereoselection, see:
Chem. Revs. 1999, 99, 1067-1480. (b) Weiss, R. Monatsch. Chem. 1919,
40, 391-402. (c) McKenzie, A.; Christie, E. W. J . Chem. Soc. 1934,
1070-1075.
10.1021/jo000075l CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/20/2000

3878 J . Org. Chem., Vol. 65, No. 12, 2000
Notes
Ta ble 2. Solven t a n d Tem p er a tu r e Effects on th e
Dia ster eoselectivity in th e Mon oa m in a tion of Bisk eten e
1 w ith R-P h CH(NH2)CO2CH3 a n d S-t-Bu CH(NH2)CO2CH3
Ta ble 1. Solven t a n d Tem p er a tu r e Effects on th e
Dia ster eoselectivity in th e Mon oa m in a tion of Bisk eten e
1 w ith R-1-P h en yleth yla m in e
solvent temp (°C) 2b (R/ S) solvent temp (°C) 2b (R/ S)
amine
solvent temp (°C) diastereomer ratio
a
pentane
toluene
CH2Cl2
CH2Cl2
CH3CN
Et3Na
-78
-78
25
-78
-40
-78
57/43
64/36
57/43
73/27
66/34
58/42
CS2
-78
-78
-78
-78
-78
63/37
33/67
42/58
37/63
33/67
R-PhCH(NH2)CO2CH3 CH2Cl2
40
25
0
68/32
67/33
70/30
66/34
55/45
57/43
55/45
THF
Et2O
EtOAc
acetone
CH2Cl2
CH2Cl2
acetone
S-t-BuCH(NH2)CO2CH3 CH2Cl2
CH2Cl2
0
40
25
0
CH2Cl2
a
Neat amine was added directly into 2 mL of reaction solvent.
coincidental, as the selectivity in the first step is governed
by the configuration of the chiral amine, while in the
second step the existing chiral center in the substrate is
responsible.
In the addition of alcohols to bisketene 1 in pentane
at 22 °C catalyzed by lithium alkoxides the dl/meso ratios
of the product succinates were 18/82 (MeOH), 55/45
(EtOH), 57/43 (i-PrOH), and 92/8 (t-BuOH).5a The prefer-
ence for the dl product with the larger t-BuOH parallels
the preference for dl product in formation of 3b and may
reflect the same conformational preference previously
suggested for the proton delivery step.5a
To compare the selectivities of other chiral amines the
methyl esters of R-phenylglycine and S-tert-butylglycine
were reacted with 1 giving the ketenylamides 2c,d ,
respectively. Qualitatively these amines are less reactive
than is R-1-phenylethylamine, in accord with the previ-
ously observed7 dependence of amination reactivity on
amine pKa. The reactions are inordinately slow below 0
°C, and reliable results could not be obtained below this
temperature. After evaporation of the solvent the prod-
ucts were analyzed directly by spectral means, and the
presence of the two diastereomeric products was observed
by 1H NMR, although the R/ S configurations of the new
chiral center at C2 were not established. The selectivities
of the reactions are reported in Table 2, but the highest
de obtained of 39% and 13%, respectively, were not as
high as those with R-1-phenethylamine (Table 1). Inter-
estingly no improvement in selectivity was noticed at
lower temperature, and the reversal in selectivity be-
tween CH2Cl2 and acetone found for R-1-phenylethy-
lamine was not observed for 2c.
1
ketenyl amide 2b as a solid which by H NMR consisted
of two diastereomers in a 67/33 ratio (eq 1). One recrys-
tallization from ether at -20 °C gave the major isomer
as a white crystalline solid in a 97.7/2.3 diastereomer
1
ratio by H NMR, and dissolving this in CH3OH for 10
min followed by evaporation of the solvent gave the ester
amides 4b which by 1H NMR have a 97.6/2.4 erythro/
threo selectivity for the configuration of the succinyl
framework (eq 2).6 The stereochemistry of erythro-4b was
established by X-ray analysis as the 2S,3R arrangement
shown, and this establishes the S configuration as shown
for 2b. Models predicting the stereochemistry of ketenyl
amide 2b analogous to those originally suggested by
Pracejus3 may be considered (see Supporting Informa-
tion).
The effects of solvent and temperature on the selectiv-
ity of the formation 2b are summarized in Table 1. It is
striking that the configuration favored is reversed for the
oxygen-containing solvents as compared to the others
studied.
Reaction with R-(+)-1-phenylethylamine of recrystal-
lized ketenyl amide 2b with 97.7% S-configuration at -78
°C in CH2Cl2 gave two succinamides as identified by H
1
NMR, namely meso-3b (2S,3R) and only one of the d,l-
3b isomers, assigned as the 2S, 3S isomer,6a in relative
yields of 27 and 73%, respectively. Thus there is a 73/27
preference for protonation of the enol amide to form
succinamide in CH2Cl2 at -78 °C in both the first (Table
1) and second amination steps. The 2S,3S isomer 3b was
separated from the meso isomer by recrystallization from
ether and fully characterized.
In summary the first amination step of the reaction of
bisketene 1 with R-(+)-1-phenylethylamine in CH2Cl2 at
-78 °C proceeds with a 73/27 selectivity for proton
transfer in the intermediate enol amides to form the R
ketenyl amide 4b. By contrast in oxygen-containing
solvents the S configuration is favored. Further amina-
tion of ketenyl amide 2b (either R or S) proceeds with a
73/27 preference for formation of dl bisamide 3b. The
major stereoisomeric ketenyl amide intermediate from
the first amination may be purified by recrystallization
and undergoes esterification with CH3OH to form the
erythro ester amide 2b with 95% de.
Reaction of bisketene 1 with 2 equiv of R-(+)-1-
phenylethylamine in CH2Cl2 at -78 °C and analysis by
1H NMR revealed the presence of meso-3b (2S,3R), and
the d,l (2S,3S and 2R,3R) isomers of 3b in relative yields
of 25, 20, and 55%, respectively. The 2R,3R isomer of 3b
was separated from this mixture by recrystallization, and
its individual spectral properties were confirmed. The
preference for the R,R product indicates that just as in
the experiment with S ketenyl amide 2b (vide supra) that
the initial chiral center creates a preference for the same
configuration in the second step, and the occurrence in
the second step of the same 73/27 selectivity found above
for the first addition starting with S-2b predicts the
relative yields of the three stereoisomers to be 27, 20,
and 53%, respectively, in good agreement with the
observed results. That the selectivities are the same is
Exp er im en ta l Section
R-(+)-1-Phenylethylamine (Norse Laboratory, 95% ee), R-
phenylglycine methyl ester hydrochloride (Aldrich, 99%), and
S-tert-butylglycine methyl ester, also known as L-tert-leucine
methyl ester (Aldrich, 99%), were used as received.
N-(R)-(1′-P h en yleth yl)-(S)-2,3-bis(tr im eth ylsilyl)-4-oxobu t-
3-en a m id e (S-2b). To bisketene 1 (1.14 g, 5.04 mmol) in 50 mL
of acetone stirred at -78 °C was added R-(+)-1-phenylethy-
(6) (a) The designations of meso- and d,l for 3b and erythro for 4a ,b
refer to the succinyl moiety. (b) δ 1.95 and 1.97 and J ) 0 for d,l-3b;
δ 2.22 and 2.27 and J ) 11 Hz for meso-3b. The 1H NMR signals
assigned to erythro-4b were confirmed by reacting 1 first with CH3-
OH to form the ketenyl ester and then with R-1-phenylethylamine to
form all four stereoisomers of 4b (2S,3R;2R,3S;2S,3S; 2R,3R) for which
all the 1H NMR signals of the succinyl moiety could be assigned.
(7) Allen, A. D.; Tidwell, T. T. J . Org. Chem. 1999, 64, 266-271.

Notes
J . Org. Chem., Vol. 65, No. 12, 2000 3879
lamine (0.610 g, 5.04 mmol) in 10 mL of acetone. The solution
was stirred 1 h at -78 °C, and the solvent was evaporated giving
a solid which was washed with dry ether and recrystallized once
from ether at -20 °C to give S-2b (0.263 g, 15%) as a white
crystalline solid in 97.7% diastereomeric purity: mp 128-130
and with no significant impurities. Radial chromatography (2%
MeOH/CH2Cl2) separated the meso isomer (97% pure by NMR)
and the mixed d and l isomers, which were recrystallized from
EtOH/H2O. meso-3b (49 mg, 0.105 mmol, 13%): mp 140-142
1
°C, H NMR (CDCl3) δ -0.21 (s, 9), 0.16 (s, 9), 1.48 (m, 6), 2.22
°C; [R]25 ) +49.5 (c ) 0.030 in CH2Cl2); 1H NMR (CDCl3) δ
(d, 1, J ) 11 Hz), 2.27 (d, 1, J ) 11 Hz), 5.01 (m, 2), 5.57 (m),
7.3 (m, 10); 13C NMR (CDCl3) δ -1.5, -1.1, 21.7, 21.8, 37.4, 49.1,
49.2, 126.5, 126.6, 127.3, 127.4, 128.5, 128.6, 143.1, 172.6, 172.9;
IR (CDCl3) 3443, 1646, 1493 cm-1; EIMS m/z 468 (11), 453 (9),
363 (26), 235 (48), 105 (100), 73 (68); HRMS m/z calcd for
C26H40N2O2Si2 468.2628, found 468.2635. d-3b and l-3b (15 mg,
D
0.127 (s, 9), 0.169 (s, 9), 1.49 (d, 3, J ) 7.0 Hz), 1.87 (s, 1), 5.15
(m, 1), 5.98 (d, 1, J ) 7.8 Hz), 7.27-7.37 (m, 5); 13C NMR (CDCl3)
δ -2.0, -1.0, 10.6, 21.6, 32.1, 48.8, 126.1, 127.3, 128.6, 143.2,
172.3, 179.7; IR (CDCl3) 3415, 2081, 1646 cm-1; EIMS m/z 347
(M+, 18), 304 (12), 242 (100), 200 (14), 142 (22), 105 (38), 73 (78);
HRMS m/z calcd for C18H29NO2Si2 347.1737, found 347.1738.
1
0.032 mmol, 4%): mp 152-155 °C; H NMR (CDCl3) δ -0.033
1
The H NMR of the crude reaction mixture displayed signals of
(s, 18), 0.036 (s, 18), 1.51 (d, 6, J ) 7 Hz), 1.53 (d, 6, J ) 7 Hz),
1.95 (s, 2), 1.97 (s, 2), 5.1 (m, 4), 7.3 (m, 20), 7.6 (m, 4); 13C NMR
(CDCl3) δ -1.3, -1.2, 21.8, 22.0, 38.6, 38.7, 49.1, 49.15, 126.5,
126.7, 127.1, 127.2, 128.45, 128.5, 143.1, 143.8, 173.3, 173.5; IR
(CDCl3) δ 3455, 1650, 1627, 1493 cm-1; EIMS m/z 468 (14), 453
(7), 259 (50), 105 (100), 73 (60); HRMS m/z calcd for C26H40N2O2-
Si2 468.2628, found 468.2629.
R-2b: δ (CDCl3) 0.08 (s, 9), 0.13 (s, 9), 1.496 (d, 3, J ) 6.8 Hz),
1.85 (s, 1), 5.15 (m, l), 6.00 (bd, l, J ) 8.0 Hz), 7.27-7.37 (m, 5).
Rea ction of Keten yla m id e 2b w ith Meth a n ol. Methanol
(10 mL) was added to solid S-2b (63.4 mg) at room temperature,
and after 10 min the resulting solution was evaporated to give
a gum which by 1H NMR consisted of 97.4% erythro-4b with
2.6% threo-4b. Recrystallization from pentane gave erythro-4b:
Solven t a n d Tem p er a tu r e Effects on th e Rea ction
betw een Bisk eten e 1 a n d R-1-P h en yleth yla m in e. To a
solution of bisketene 1 (ca. 70-100 mg) in 5 mL of solvent was
added ca. 0.9 equiv of amine in 2 mL of the same solvent. The
solvent was removed, and the diastereoselectivity of the reac-
tions was measured by 1H NMR.
mp 65-66 °C, [R]25 ) +41.5 (c ) 0.014 in CH2Cl2); 1H NMR
D
(CDCl3) δ -0.13 (s, 9), 0.03 (s, 9), 1.42 (d, 3, J ) 6.9 Hz, CH3),
2.18 (d, 1, J ) 11.6 Hz), 2.57 (d, 1, J ) 11.7 Hz), 3.52 (s, 3), 4.98
(m, 1), 5.42 (d, 1, J ) 7.4 Hz), 7.20-7.40 (m, 5); 13C NMR (CDCl3)
δ -1.8, -1.5, 21.6, 35.2, 37.2, 49.1, 50.9, 126.5, 127.4, 128.6,
143.1, 172.0, 175.6; IR (CDCl3) 3439, 1706, 1654 cm-1; EIMS
m/z 379 (M+, 19), 364 (52), 260 (47), 170 (35), 105 (100), 73 (74);
HRMS m/z calcd for C19H33NO3Si2 379.1999, found 379.2004.
Rea ction of Keten yla m id e 2b w ith 1 equ iv of R-1-
P h en yleth yla m in e. To a solution of recrystallized 97.7% S
ketenyl amide 2b (21.8 mg, 0.063 mmol) in 5 mL of CH2Cl2 was
added the amine (8.0 µL, 7.5 mg, 0.062 mmol) in 2 mL of CH2-
Cl2 in one portion at -78 °C. The reaction mixture was stirred
1 h at -78 °C, and evaporation of the solvent gave a white solid
which by 1H NMR consisted of meso-3b and the 2S,3S d,l isomer
of 3b in a 27/73 ratio. Recrystallization from ether gave 3b
N-(R)-(1′-P h en ylcar bom eth oxym eth yl)-(R,S)-bis(tr im eth -
ylsilyl)-4-oxobu t-3-en a m id es (2c). By an analogous procedure
as for the solvent and temperature effects study of the prepara-
tion of 2b, R-phenylglycine methyl ester (prepared from the
hydrochloride by treatment with Amerlite IRA-900 HCO3- form
ion-exchange resin) and 1 were reacted to give after evaporation
of the reaction solvent 2c: 1H NMR (CDCl3) δ (major isomer)
0.12 (s, 9), 0.17 (s, 9), 1.92 (s, 1), 3.72 (s, 3), 5.56 (d, 1, J ) 7.0
Hz), 6.75 (bd, 1, J ) 7.0 Hz), 7.34 (m, 5), (minor isomer) 0.10 (s,
9), 0.12 (s, 9), 1.89 (s, 1), 3.73 (s, 3), 5.58 (d, 1, J ) 6.6 Hz), 6.61
(bd, 1, J ) 6.8 Hz), 7.34 (m, 5); 13C NMR (CDCl3) δ (major isomer
only) -2.1, -1.0, 10.5, 32.0, 52.7, 56.6, 127.2, 128.5, 128.9, 136.7,
(2S,3S): mp 163-165 °C; [R]25 ) +70.8 (c ) 0.010 in CH2Cl2);
D
1H NMR (CDCl3) δ 0.04 (s, 18), 1.52 (d, 6, J ) 6.9 Hz), 1.94 (s,
2), 5.10 (m, 2), 7.20-7.38 (m, 10), 7.63 (bd, 2, J ) 6.7 Hz); 13C
NMR (CDCl3) δ -1.3, 21.8, 38.5, 49.1, 126.4, 127.1, 128.5, 143.7,
173.3; IR (CDCl3) 3435, 1648, 1626 cm-1; EIMS m/z 468 (M+,
32), 453 (10), 363 (60), 259 (66), 235 (28), 105 (100), 73 (58);
HRMS m/z calcd for C26H40N2O2Si2 468.2628, found 468.2632.
Rea ction of Bisk eten e 1 w ith 2 equ iv of R-1-P h en yl-
eth yla m in e. To a solution of bisketene 1 (83.9 mg, 0.37 mmol)
in 5 mL of CH2Cl2 was added the amine (0.0954 g, 0.79 mmol)
in 2 mL of CH2Cl2 in one portion at -78 °C. The reaction mixture
was stirred 1 h at -78 °C, and the solvent was evaporated to
give a white solid which by 1H NMR consisted of meso-3b,2S,3S-
3b, and 2R,3R-3b in a ratio of 25/20/55. A 3-fold recrystallization
from ether gave 2R,3R-3b: mp 167-168 °C; 1H NMR (CDCl3) δ
-0.04 (s, 18), 1.53 (d, 6, J ) 6.9 Hz), 1.96 (s, 2), 5.14 (m, 2),
7.28-7.34 (m, 10), 7.57 (bd, 2, J ) 6.7 Hz); 13C NMR (CDCl3) δ
-1.2, 22.0, 38.6, 49.0, 126.7, 127.2, 128.5, 143.1, 173.5; IR
(CDCl3) 3436, 1648, 1625 cm-1; EIMS m/z 468 (34), 453 (11),
363 (68), 259 (69), 235 (27), 105 (100), 73 (54); HRMS m/z calcd
for C26H40N2O2Si2 468.2628, found 468.2631.
171.3, 172.7, 179.6; IR (CDCl3) 3422, 2082, 1740, 1662 cm-1
;
EIMS m/z 391 (M+, 9), 290 (191), 242 (31), 73 (100). HREIMS
m/z calcd for C19H29NO4Si2 391.1635, found 391.1638.
N-(S)-(1′-ter t-Bu t ylca r b om et h oxym et h yl)-(R,S)-b is(t r i-
m eth ylsilyl)-4-oxo-3-en a m id es (2d ). By an analogous proce-
dure as for the preparation of 2c S-tert-butylglycine methyl ester
and 1 gave 2d : 1H NMR (CDCl3) δ (major isomer) 0.164 (s, 9),
0.172 (s, 9), 0.98 (s, 9), 1.89 (s, 1), 3.70 (s, 3), 4.37 (d, 1, J ) 9.2
Hz) 6.43 (bd, 1, J ) 9.0 Hz), (minor isomer) 0.162 (s, 9), 0.174
(s, 9), 0.98 (s, 9), 1.88 (s, 1), 3.71 (s, 3), 4.38 (d, J ) 9.0 Hz), 6.28
(bd, J ) 8.8 Hz); 13C NMR (CDCl3) δ (major isomer) -1.9, -1.0,
10.6, 26.6, 31.1, 34.5, 51.6, 60.3, 172.0 (only one peak), 173.1,
(minor isomer) -2.0, -1.1, 10.7, 26.6., 32.2, 34.4, 51.7, 60.7,
173.2; IR (CDCl3) 3428, 2078, 1732, 1652 cm-1; EIMS m/z 371
(36), 328 (19), 270 (68), 214 (30), 155 (31), 73 (100). HREIMS
m/z calcd for C17H33NO4Si2 371.1948, found 371.1940.
Ack n ow led gm en t. Financial support by the Natu-
ral Sciences and Engineering Research Council of
Canada is gratefully acknowledged.
In a similar experiment to a stirred solution of R-(+)-1-
phenylethylamine (210 µL, 1.63 mmol) in 3 mL of CH2Cl2 at 25
°C was added in one portion bisketene 1 (184 mg, 0.814 mmol)
in 3 mL of CH2Cl2. A momentary pink color was observed but
disappeared within seconds. After 2 min of stirring the solvent
Su p p or tin g In for m a tion Ava ila ble: Further discussion,
spectra, and an X-ray crystallographic file on erythro-4b in
CIF format. This material is available free of charge via the
Internet at http://pubs.acs.org.
1
was evaporated and the resulting white solid was shown by H
NMR to consist of equal amounts of the meso and d,l diastere-
omers of 3b, with a 66/34 preference for one of the d,l-isomers
J O000075L