A new regio- and chemoselective approach to β-keto amides and β-enamino carboxamides via 1,3,2-dioxaborinanes

Article abstract of DOI:10.1055/s-2003-817787

Surprisingly, 5,6-disubstituted 2,2-difluoro-4-alkoxy-1,3,2-dioxaborinanes, which can be easily obtained from β-keto esters, reacted regio- and chemoselectively with amines under mild reaction conditions to form 2,2-difluoro-4-alkylamino-1,3,2-dioxaborina

Full text of DOI:10.1055/s-2003-817787

698
LETTER
A New Regio- and Chemoselective Approach to b-Keto Amides and b-Enamino
Carboxamides via 1,3,2-Dioxaborinanes
R
egio- andChe
m
o
oselective
A
g
pproachto
b
d
-KetoAmide
a
s
a
nd
b
-En
n
amino Carboxamid
Šes tefane,* Slovenko Polanc
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva 5, 1000 Ljubljana, Slovenia
Fax +386(1)2419220; E-mail: bogdan.stefane@uni-lj.si
Received 26 August 2003
Furthermore, we wish to describe the specific reactivity of
Abstract: Surprisingly, 5,6-disubstituted 2,2-difluoro-4-alkoxy-
1,3,2-dioxaborinanes, which can be easily obtained from b-keto
esters, reacted regio- and chemoselectively with amines under mild
reaction conditions to form 2,2-difluoro-4-alkylamino-1,3,2-di-
5,6-disubstituted 2,2-difluoro-4-alkoxy-1,3,2-dioxa-bori-
nanes (2a–e) towards a series of amino and hydrazino
compounds, which, despite the common use of difluoride
oxaborinanes in almost quantitative yields. The latter compounds complexes as intermediates in organic synthesis,11 have
can be easily deprotected, yielding b-keto amides, or directly trans-
formed into b-enamino carboxamides. This procedure was also ap-
plied to the reaction of 2,2-difluoro-4-alkoxy-1,3,2-dioxaborinanes
with arylhydrazines which selectively afforded b-hydrazono esters,
in some cases without further cyclization to pyrazolones.
never been studied before. To the best of our knowledge
these reactions represent the first examples of the direct
transformation of 2,2-difluoro-4-alkoxy-1,3,2-dioxabori-
nanes to 2,2-difluoro-4-alkyl-amino-1,3,2-dioxabori-
nanes.
Key words: keto amides, enamino carboxamines, dioxaborinanes,
chemoselectivity.
b-Keto amides and b-enamino carboxamides are impor-
tant intermediates in the synthesis of natural products,1
heterocycles,2 and g-aminols.3 Additionally, b-N-alke-
nylenamino carboxamides have been utilized in the asym-
metric synthesis of spirolactams4 and some of them are
also known to act as acyl-CoA: cholesterol acyltrans-
ferase inhibitors.5 For these reasons it is of interest to find
new, efficient, and simple procedures for the preparation
of these compounds.
Scheme 1
Table 1 Preparation of Dioxaborinanes 2
Entry
R
R1
H
R2
Et
Et
Et
Product Yield (%)a
Generally, b-keto esters react with primary amines at
room or elevated temperatures, to form b-enamino esters.
Only in a few cases selective preparation of the corre-
sponding b-keto amides starting from b-keto esters has
been achieved. For example, by using 4-dimethyl-ami-
nopyridine as a catalyst, it is possible to prepare b-keto
amides directly from b-keto esters if secondary amines are
used.6 An alternative approach to b-keto amides is the
room temperature aminolysis of b-ketothio ester deriva-
tives,7 but these compounds are not so readily available.8
1
2
3
4
5
Me
Ph
2a
90
88
99
99
99
H
2b12
2c
–(CH2)4–
Me
Me
MeO2CCH2 Me
–(CH2)2–
2d
2e
a Isolated yields after reaction in toluene at r.t. for 16 h.
In a previous communication,9 we described the regiose-
lective synthesis of b-enaminones and pyrazoles, starting
from 1,3-diketonatoboron difluorides. Here we report that
2,2-difluoro-4-alkoxy-1,3,2-dioxaborinanes, easily avail-
able from the corresponding b-keto esters and BF3·OEt2
(Scheme 1, Table 1),10 react with various amines to give
2,2-difluoro-4-alkylamino-1,3,2-dioxaborinanes.
Treatment of 2a–e with various amines led to the corre-
sponding 2,2-difluoro-4-alkylamino-1,3,2-dioxabori-
nanes (3, Scheme 2).
The reaction appeared to be highly solvent dependent.
The best conversions and yields of compounds 3 were ob-
tained in acetonitrile.13 Conversions were significantly
lower in other solvents (ethyl acetate, diethyl ether, THF,
dichloromethane, and nitromethane). In those solvents,
which might act as good nucleophiles (alcohols) the
reaction did not occur and b-keto esters were isolated as
the only products. We also varied the amount of amine,
i.e. 1–3 equivalents, and the temperature of the reaction.
The best results were obtained by treating 2,2-difluoro-4-
alkoxy-1,3,2-dioxaborinanes (2a–e) with 1.3 equivalents
of the corresponding amine in acetonitrile at 25 °C
SYNLETT 2004, No. 4, pp 0698–0702
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9.
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3.
2
0
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Advanced online publication: 17.02.2004
DOI: 10.1055/s-2003-817787; Art ID: D21503ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Regio- and Chemoselective Approach to b-Keto Amides and b-Enamino Carboxamides
699
The reaction has been applied to a series of amines. As
shown in Table 2, yields are generally good. The reaction
works well with primary amines (including t-butylamine)
and secondary amines. In order to extend the scope of this
methodology, we decided to study the chemo- and regi-
oselectivity of the reaction. For this reason the dimethyl 2-
acetylsuccinate analog, 2d (Table 1), was prepared. The
latter compound reacted with different types of amines by
addition only to the ester group at the b-position to the car-
bonyl group. In such a manner we were able to carry out
selective introduction of an amido group to a multi func-
tional system. Even more, in the case of cystine amine
(entry 13, Table 2) the amino group reacted exclusively,
leading to a single product. Subsequently, having demon-
strated that 2d can be selectively transformed, we briefly
investigated the reactivity of 2-acetylbutyrolactone boron
complex 2e with various amines. Thus, as outlined in
Table 2, the reaction of 2e with amines led, as expected,
to lactone opening and so deriving 5-(2-hydroxyethyl)
substituted products 3o and 3p. Identification of 3 was
confirmed by X-ray structure analysis and NMR spectros-
copy. One can observe in 13C NMR spectra 19F–13C cou-
pling of 2.5 Hz for =C–O–BF2 and 2 Hz for –C=O→BF2.
Scheme 2
(Table 2). Moreover, many attempts to form the 2,2-di-
fluoro-4-alkoxy-1,3,2-dioxaborinanes in situ, which
could then react with amines to derive the desired prod-
ucts, failed.
The reaction seems to be initiated by the attack of an ami-
no group to the ester carbonyl moiety yielding an a-
alkoxy-a-alkylamino-1,3,2-dioxaborinane intermediate
which in turn eliminates an a-alkoxy group, thus forming
a more stable amido product of type 3.
Different reactivities for alkyl and aryl hydrazines were
also found. Alkylhydrazines reacted with 2a similar to
amino compounds, deriving hydrazido analogs 3e and 3f,
whereas arylhydrazines led to hydrazono derivatives14
4a–e (Table 3). It is noteworthy that methylhydrazine
Table 2 Preparation of 2,2-Difluoro-4-alkylamino-1,3,2-dioxaborinanes
Entry
R
R1
H
H
H
H
H
H
R3
R4
Product 3
Time (h)
0.5
0.5
0.5
0.5
4
Yield (%)a
96
1
Ph
Ph
Ph
Ph
Ph
Ph
–(CH2)5–
a
b
c
d
e
f
2
t-Bu
H
71
3
CH2=CHCH2
H2NCH2CH2
(Me)2N
Me
H
89
4
H
89
5
H
81
6
NH2
H
0.5
0.5
0.5
0.5
0.5
0.5
0.5
1
80
7
–(CH2)4–
–(CH2)4–
i-Pr
g
h
i
99
8
PhCH2
i-Pr
H
78
9
Me
Me
Me
Me
Me
Me
Me
Me
H
H
92
10
H
3-PyCH2
H
H
j
95
11
MeO2CCH2
MeO2CCH2
MeO2CCH2
MeO2CCH2
HO(CH2)2
HO(CH2)2
H
k
l
99
12
–(CH2)4–
97
13
HSCH2CH2
CH2=CHCH2
i-Pr
H
H
H
H
m
n
o
p
71
14
0.5
0.5
0.5
90
15
45
16
(MeO)2CHCH2
53
a Isolated yields.
Synlett 2004, No. 4, 698–702 © Thieme Stuttgart · New York

700
B. Štefane, S. Polanc
LETTER
Table 3 Preparation of Hydrazono Derivatives
4
Ar
R
R1
H
H
H
R2
Et
Et
Et
Time (h)
Yield (%)a
a15
b
2,4-NO2C6H3
Ph
12
12
12
91
93
95
2-NO2,4-CNC6H3 Ph
Ph
c
d
2-NO2,4-CNC6H3 Me
2-NO2,4-CNC6H3 Me
H
Et
8
5
89
87
e
MeO2CCH2
Me
a Isolated yields.
reacted selectively with N–1, deriving a single product,
illustrating once again the high chemoselectivity of the
transformation.
Deprotection of 3 with sodium acetate (5 equiv) in a re-
fluxing mixture of solvents ethanol/water 1/1 v/v, afford-
ed b-keto amides 5 in good yields (Scheme 3, Table 4).
On the basis of these results, we then designed an experi-
mentally convenient one-pot synthesis of b-enamino car-
boxamides from dioxaborinanes.19 Reaction of 3 and
amine (5 equiv) in propanol at 130 °C in an Ace pressure
tube, gave high yields of b-enamino carboxamides 6. As
illustrated in Table 4, selective introduction of an amino
moiety can be applied either on the enamino or amido part
of the molecule (Table 4, entry 8–11) simply by changing
the sequence of the reactions. Despite the rather high
instability of the N-allylenamines 6c and 6e, they could be
stored in the refrigerator for a couple of days.
Scheme 3
Table 4 Preparation of b-Keto Amides and b-Enamino Carboxamides
Entry
1
Product
5a
R
R1
H
H
H
H
R3
R4
H
H
H
H
H
H
R5
–
Time (h)
Yielda (%)
Ph
Ph
Ph
Me
i-Pr
15
2
88
97
91
98
95
93
97
96
90
87
89
93
90
2
5b
3-PyCH2
CH2=CHCH2
i-Pr
–
3
5c16
5d17
5e6a
5f18
5g
–
3
4
–
10
16
16
2
5
–(CH2)4–
–(CH2)4–
i-Pr
–
6
PhCH2
–(CH2)4–
3-PyCH2
i-Pr
–
7
Me
Ph
Ph
Ph
Ph
Ph
MeO2CCH2
–
8
6a
H
H
H
H
H
H
H
H
H
i-Pr
5
9
6b
3-PyCH2
CH2CH=CH2
i-Pr
12
8
10
11
12
13
6c
3-PyCH2
CH2=CHCH2
–(CH2)5–
i-Pr
6d
5
6e
CH2CH=CH2
PhNH
5
6f
–(CH2)4–
H
5
a Isolated yields.
Synlett 2004, No. 4, 698–702 © Thieme Stuttgart · New York

LETTER
Regio- and Chemoselective Approach to b-Keto Amides and b-Enamino Carboxamides
701
off and washed with mixture of solvents petroleum ether/
EtOAc = 5/1 (5 mL), yielding pure product. In the case of
dimethyl 2-acetylsuccinate and 2-acetylbutyrolactone the
reaction mixture was evaporated to dryness yielding
yellowish oil, which was used in the next step without
further purification. Compound 2a: mp 28–31 °C (from
hexane). IR (NaCl-plates): n = 2980, 1590, 1540, 1380,
1330, 1185, 1040, 790 cm–1. 1H NMR (300 MHz, CDCl3):
d = 1.42 (t, 3 H, J = 7.2 Hz), 2.18 (s, 3 H), 4.51 (q, 2 H,
J = 7.2 Hz), 5.41 (s, 1 H). 13C NMR (75 MHz, CDCl3): d =
13.8, 23.1, 66.3, 87.1, 175.0 (t, J = 2.3 Hz), 186.4 (t, J = 1.4
Hz). MS (EI, 70 eV): m/z (%) = 178 (52) [M+], 135 (42), 84
(100), 69 (97). HRMS (EI): m/z calcd for C6H9BF2O3:
178.0613; found: 178.0618. Compound 2d: yellowish oil. IR
(NaCl-plates): n = 2963, 1719, 1609, 1509, 1337, 1053 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.22 (s, 3 H), 3.35 (s, 2 H),
3.77 (s, 3 H), 4.10 (s, 3 H). 13C NMR (75 MHz, CDCl3): d =
21.2, 29.6, 53.1, 56.6, 92.1, 172.7, 174.2, 185.4. MS (EI, 70
eV): m/z (%) = 236(16) [M+], 217(89), 177(68), 97(100),
55(75). HRMS (EI): m/z calcd for C8H11BF2O5: 236.0668;
found: 236.0674.
In summary, we have explored the previously unknown
direct conversion of 5,6-disubstituted 2,2-difluoro-4-
alkoxy-1,3,2-dioxaborinanes to 2,2-difluoro-4-alkyl-ami-
no analogues with a variety of amines. As well, we have
demonstrated a preparatively useful method for the syn-
thesis of b-keto amides and b-enamino carboxamides in
two overall steps and good yields starting from easily
accessible starting materials. This chemo- and regioselec-
tive approach could be the method of choice for the prep-
aration of such systems.
Acknowledgment
The authors thank Dr. B. Kralj and Dr. D. Žigon (Mass Spectro-
metry Center, Jožef Stefan Institute, Ljubljana, Slovenia) for mass
measurements. The Ministry of Education, Science and Sport of
Slovenia (P0–0503–0103) and (P1-0230-103) is gratefully ack-
nowledged for financial support.
(11) Ishihara, K. In Lewis Acids in Organic Synthesis, Vol. 1;
Yamamoto, H., Ed.; Wiley-WHC: Weinheim, 2000, 89.
(12) Stahl, I. Chem. Ber. 1985, 118, 3159.
References
(1) (a) Schlessinger, R. H.; Bebernitz, G. R.; Lin, P. J. Am.
Chem. Soc. 1985, 107, 1777. (b) DeShong, P.; Ramesh, S.;
Elango, V.; Perez, J. J. J. Am. Chem. Soc. 1985, 107, 5219.
(c) Boeckman, R. K.; Starrett, J. E.; Nickell, D. G.; Sum,
P.-E. J. Am. Chem. Soc. 1986, 108, 5549. (d) Boeckman, R.
K.; Perni, R. B. J. Org. Chem. 1986, 51, 5489.
(13) General Procedure for the Reaction of 2,2-Difluoro-4-
alkoxy-1,3,2-dioxaborinanes (2a–e) with Amines. To a
solution of the corresponding amine (1.3 mmol) in MeCN (5
mL) 2,2-difluoro-4-alkoxy-1,3,2-dioxaborinane (1 mmol)
was added at r.t. The reaction mixture was stirred at r.t. for
the period of time noted in Table 2. In the case where
product precipitated from the reaction mixture, it was
filtered off and washed with cold MeCN (3 mL), otherwise
the reaction solvent was evaporated in vacuo and the residue
dissolved in CH2Cl2 or EtOAc (30 mL), washed with H2O
(2 × 10 mL), dried over MgSO4 and evaporated in vacuo. In
some cases products were purified by flash chromatography.
Selected spectroscopic data for compound of type 3.
Compound 3f: mp 151–153 °C (from MeCN). IR (KBr):
n = 3445, 3350, 1677, 1605, 1503, 1407, 1355, 1230, 911,
778, 693 cm–1. 1H NMR (300 MHz, DMSO-d6): d = 3.32 (s,
3 H), 5.54 (br s, 2 H), 6.78 (s, 1 H), 7.50–7.62 (m, 3 H), 7.88–
7.91 (m, 2 H). 13C NMR (75 MHz, DMSO-d6): d = 40.0,
84.2, 127.5, 129.9, 133.2, 134.1, 169.0 (t, J = 2.6 Hz), 170.9
(t, J = 2.0 Hz). MS (EI, 70 eV): m/z (%) = 240 (41) [M+],
195(46), 105 (100), 94 (34), 77 (45). HRMS (EI): m/z calcd
for C10H11BF2N2O2: 240.0882; found: 240.0891. Compound
3h: mp 135–137 °C (from Et2O–EtOAc). IR (KBr): n =
3399, 2955, 1612, 1528, 1339, 1263, 1197, 1038, 978, 743,
698 cm–1. 1H NMR (300 MHz, DMSO-d6): d = 1.64–1.66
(m, 4 H), 2.19–2.26 (m, 4 H), 4.52 (s, 2 H), 7.27–7.40 (m, 5
H), 9.49 (br s, 1 H). 13C NMR (75 MHz, DMSO-d6): d =
21.8, 22.0, 22.3, 31.0, 44.6, 95.7, 128.3, 128.4, 129.5, 137.9,
168.0 (t, J = 2.6 Hz), 174.2 (t, J = 2.2 Hz). MS (EI, 70 eV):
m/z (%) = 279 (24) [M+], 91 (100). HRMS (EI): m/z calcd for
C14H16BF2NO2: 279.1242; found: 279.1249. Compound 3k:
mp 108–109 °C (from light petroleum ether–EtOAc). IR
(KBr): n = 3458, 3370, 3284, 2996, 2961, 1744, 1663, 1597,
1356, 1179, 954, 784, 578 cm–1. 1H NMR (300 MHz,
DMSO-d6): d = 2.00 (s, 3 H), 3.38 (s, 2 H), 3.59 (s, 3 H), 8.72
(br s, 1 H), 9.09 (bs, 1 H). 13C NMR (75 MHz, DMSO-d6):
d = 20.4, 29.8, 51.8, 91.6, 169.5 (t, J = 2.3 Hz), 170.7, 176.3
(t, J = 2.3 Hz). MS (EI, 70 eV): m/z (%) = 221 (27) [M+], 162
(100), 97 (94). HRMS (EI): m/z calcd for C7H10BF2NO4:
221.0671; found: 221.0677. Compound 3p: The colorless oil
obtained on work-up was subjected to flash chromatography
(1:10 MeOH–CHCl3 elution). IR (NaCl-plates): n = 3564,
3401, 2945, 1605, 1523, 1458, 1300, 1200, 1128, 1047 cm–1.
(e) Karadogan, B.; Parsons, P. J. Tetrahedron 2001, 57,
8699.
(2) (a) Zhang, C.; Moran, E. J.; Woiwode, T. F.; Short, K. M.;
Mjalli, A. M. M. Tetrahedron Lett. 1996, 37, 751.
(b) Beholz, L. G.; Benovsky, P.; Ward, D. L.; Barta, N. S.;
Stille, J. R. J. Org. Chem. 1997, 62, 1033. (c) Amaresh, R.
R.; Perumal, P. T. Tetrahedron 1999, 55, 8083.
(3) (a) Bartoli, G.; Bosco, M.; Dalpozzo, R.; Marcantoni, E.;
Massaccesi, M.; Rinaldi, S.; Sambri, L. Tetrahedron Lett.
2001, 42, 8811. (b) Filippini, M.-H.; Rodriguez, J. Synlett
1999, 1951. (c) Cossy, J.; Bouzide, A.; Leblanc, C. J. Org.
Chem. 2000, 65, 7257.
(4) (a) Cossy, J.; Bouzide, A.; Leblanc, C. Synlett 1993, 202.
(b) Cossy, J.; Bouzide, A.; Pfau, M. J. Org. Chem. 1997, 62,
7106. (c) Cossy, J.; Bouzide, A. Tetrahedron 1997, 53,
5775. (d) Charonnet, E.; Filippini, M.-H.; Rodriguez, J.
Synlett 1999, 1951. (e) Cossy, J.; Bouzide, A.; Leblanc, C. J.
Org. Chem. 2000, 65, 7257.
(5) Augelli-Szafran, C. E.; Blankley, C. J.; Roth, B. D.; Trivedi,
B. K.; Bousley, R. F.; Essenburg, A. D.; Hamelehle, K. L.;
Krause, B. R.; Stanfield, R. L. J. Med. Chem. 1993, 36, 2943.
(6) (a) Cossy, J.; Thellend, A. Synthesis 1989, 753. (b) Cossy,
J.; Belotti, D.; Bouzide, A.; Thellend, A. Bull. Soc. Chim. Fr.
1994, 131, 723.
(7) Ley, S. V.; Woodward, P. R. Tetrahedron Lett. 1987, 28,
3019.
(8) (a) Booth, P. M.; Fox, C. M. J.; Ley, S. V. Tetrahedron Lett.
1983, 24, 5143. (b) Ley, S. V.; Woodward, P. R.
Tetrahedron Lett. 1987, 28, 345.
(9) Štefane, B.; Polanc, S. New J. Chem. 2002, 26, 28.
(10) General Procedure for the Preparation of 2,2-Difluoro-
4-alkoxy-1,3,2-dioxaborinanes (2a–e). To a solution of the
corresponding 1,3-ketoester (1 mmol) in toluene (5 mL)
BF3·Et2O (3 equiv) was added at r.t. After being stirred at r.t.
for 16 h, the reaction mixture was concentrated to 1/3 of
volume (in the case of ethyl acetoacetate, ethyl
benzoylacetate, and ethyl cyclohexanone-2-carboxylate)
and than cooled to –10 °C. Precipitated material was filtered
Synlett 2004, No. 4, 698–702 © Thieme Stuttgart · New York

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B. Štefane, S. Polanc
LETTER
1H NMR (300 MHz, CDCl3): d = 2.07 (s, 3 H), 2.44 (t, 2 H,
J = 5.4 Hz), 3.16 (bs, 1 H), 3.37 (s, 6 H), 3.51 (t, 2 H, J = 5.4
Hz), 3.74 (dd, 2 H, J1 = 4.8 Hz, J2 = 5.4 Hz), 4.46 (t, 1 H,
J = 5.4 Hz), 8.22 (t, 1 H J = 4.8 Hz). 13C NMR (75 MHz,
CDCl3): d = 20.4, 28.3, 42.2, 54.3, 62.5, 96.7, 101.5, 169.3
(t, J = 2.5 Hz), 174.7 (t, J = 1.7 Hz). MS (EI, 70 eV): m/z
(%) = 281 (0.3) [M+], 111(81), 84(100).
7.67 (m, 1 H), 8.48 (dd, 1 H, J1 = 1.8 Hz, J2 = 4.6 Hz), 8.54
(d, 1 H, J = 2.1 Hz), 8.86 (br s, 1 H). 13C NMR (75 MHz,
CDCl3): d = 24.2, 40.3, 45.6, 87.8, 123.4, 127.7, 128.2,
128.8, 135.0, 135.3, 137.1, 148.5, 149.0, 162.1, 170.2. MS
(EI, 70 eV): m/z (%) = 295 (31) [M+], 252 (49), 188 (56), 160
(100), 146 (85), 104 (83), 92 (47). HRMS (EI): m/z calcd for
C18H21N3O: 295.1685; found: 295.1690. Compound 6b: The
colorless oil obtained on work-up was subjected to flash
chromatography (1:1 light petroleum ether–EtOAc elution).
Mp 114–116 °C (from Et2O). IR (KBr): n = 3227, 2961,
1620, 1545, 1324, 1215, 1017, 922, 791, 768, 733, 702 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.16 (d, 6 H, J = 6.8 Hz),
4.07–4.14 (m, 1 H), 4.19 (d, 2 H, J = 6.6 Hz), 4.50 (s, 1 H),
4.98 (br s, 1 H), 7.20 (ddd, 1 H, J1 = 0.8 Hz, J2 = 4.7 Hz,
J3 = 7.7 Hz), 7.27–7.37 (m, 5 H), 7.56 (ddd, 1 H,
(14) General Procedure for the Preparation of Hydrazones 4.
To a stirred solution of 2,2-difluoro-4-alkoxy-1,3,2-
dioxaborinane (1 mmol) in MeCN (5 mL) the corresponding
arylhydrazine (1.05 mmol) was added, which promptly
dissolved. The reaction mixture was stirred at r.t. for 5–12 h.
The precipitated material was filtered off and washed with
cold MeCN (3 mL) and then recrystallized. Compound 4c:
mp 100–102 °C (from EtOH). IR (KBr): n = 3215, 1724,
1605, 1443, 1301, 764 cm–1. 1H NMR (300 MHz, CDCl3):
d = 1.29 (t, 3 H, J = 7.2 Hz), 2.52 (s, 3 H), 3.91 (s, 2 H), 4.13
(s, 3 H), 4.28 (q, 2 H, J = 7.2 Hz), 7.43–7.46 (m, 3 H), 7.77–
7.81 (m, 2 H), 10.76 (br s, 1 H). 13C NMR (75 MHz, CDCl3):
d = 14.0 (2 C), 33.6, 40.0, 61.5, 117.4, 126.2, 128.8, 129.8,
136.4, 142.6, 143.7, 147.5, 167.7. MS (EI, 70 eV): m/z
(%) = 345 (100) [M+], 225 (35), 103 (91), 77 (68). HRMS
(EI): m/z calcd for C16H19N5O4: 345.1437; found: 345.1449.
Compound 4e: mp 102–103 °C (from light petroleum ether–
EtOAc). IR (KBr): n = 3318, 2954, 2226, 1734, 1624, 1567,
1524, 1283, 1157, 998, 918, 762 cm–1. 1H NMR (300 MHz,
DMSO-d6): d = 2.11 (s, 3 H), 2.93 (d, 2 H, J = 6.9 Hz), 3.62
(s, 3 H), 3.69 (s, 3 H), 3.94 (t, 1 H, J = 6.9 Hz), 7.72 (d, 1 H,
J = 9.0 Hz), 7.97 (dd, 1 H, J1 = 1.8 Hz, J2 = 9.0 Hz), 8.57 (d,
1 H, J = 1.8 Hz), 10.63 (bs, 1 H). 13C NMR (75 MHz,
DMSO-d6): d = 15.4, 33.0, 49.4, 51.6, 52.3, 99.8, 116.1,
117.8, 130.6, 131.3, 138.1, 143.3, 152.6, 170.7, 171.4. MS
(EI, 70 eV): m/z (%) = 348 (30) [M+], 317 (30), 256 (100),
210(23). HRMS (EI): m/z calcd for C15H16N4O6: 348.1070;
found: 348.1081.
(15) Wilde, H.; Hauptmann, S.; Ostermann, G.; Mann, G. J.
Prakt. Chem. 1984, 326, 829.
(16) Garcia, M. J.; Rebolledo, F.; Gotor, V. Tetrahedron 1994,
50, 6935.
(17) Stumm, G.; Niclas, H. J. J. Prakt. Chem. 1989, 331, 736.
(18) Sato, M.; Ogasawara, H.; Komatsu, S. Chem. Phar. Bull.
1984, 32, 3848.
(19) General Procedure for the Preparation of b-
Carboxamido Enamines 6. In a typical experiment the
solution of 2,2-difluoro-4-alkylamino-1,3,2-dioxaborinane
(1 mmol) and corresponding amine (5 equiv) in PrOH (5
mL) was heated with stirring in an Ace pressure tube at 130–
140 °C. After heating for 5–12 h, the reaction mixture was
evaporated under reduced pressure and the residue purified
by flash chromatography. Spectroscopic data for compound
of type 6. Compound 6a: The colorless oil obtained on work-
up was subjected to flash chromatography (5:3 light
petroleum ether–EtOAc elution). Mp 117–120 °C (from
Et2O). IR (KBr): n = 3213, 2963, 1624, 1593, 1428, 1303,
1212, 1171, 1124, 1035, 768, 708 cm–1. 1H NMR (300 MHz,
CDCl3): d = 1.09 (d, 6 H, J = 6.9 Hz), 3.36–3.48 (m, 1 H),
4.41 (s, 1 H), 4.48 (d, 2 H, J = 6.0 Hz), 5.45 (br s, 1 H), 7.23
(dd, 1 H, J1 = 4.6 Hz, J2 = 7.8 Hz), 7.34–7.39 (m, 5 H), 7.64–
J1 = J2 = 2.0 Hz, J3 = 7.7 Hz), 8.32 (d, 1 H, J = 2.0 Hz), 8.45
(dd, 1 H, J1 = 1.5 Hz, J2 = 4.7 Hz), 9.40 (bs, 1 H). 13C NMR
(75 MHz, CDCl3): d = 23.1, 40.6, 45.7, 90.8, 123.4, 127.8,
128.4, 129.0, 134.7, 135.3, 136.3, 148.4, 148.7, 161.4,
169.4. MS (EI, 70 eV): m/z (%) = 295 (64) [M+] 237 (69),
209 (100), 92 (98). HRMS (EI): m/z calcd for C18H21N3O:
295.1685; found: 295.1694. Compound 6d: The colorless oil
obtained on work-up was subjected to flash chromatography
(1:10 MeOH–CHCl3 elution). Colorless oil. IR (NaCl-
plates): n = 3300, 2969, 1614, 1540, 1496, 1299, 1213, 1168,
770, 702 cm–1. 1H NMR (300 MHz, CDCl3): d = 1.07 (d, 6
H, J = 6.6 Hz), 3.33–3.43 (m, 1 H), 3.88–3.92 (m, 2 H), 4.41
(s, 1 H), 5.07–5.22 (m, 2 H), 5.17 (br s, 1 H), 5.83–5.92 (m,
1 H), 7.33–7.38 (m, 5 H), 8.81 (bs, 1 H). 13C NMR (75 MHz,
CDCl3): d = 24.1, 41.2, 45.4, 88.4, 115.5, 127.6, 128.1,
128.6, 135.3, 137.3, 161.5, 170.1. MS (EI, 70 eV): m/z
(%) = 244 (53) [M+], 188 (100), 160 (71), 146 (84), 104 (95).
HRMS (EI): m/z calcd for C15H20N2O: 244.1576; found:
244.1580. Compound 6e: The colorless oil obtained on
work-up was subjected to flash chromatography (10:1 light
petroleum ether–EtOAc elution). Colorless oil. IR (NaCl-
plates): n = 2933, 1853, 1609, 1596, 1573, 1481, 1408, 1219,
1123, 1022, 775, 702 cm–1. 1H NMR (300 MHz, CDCl3):
d = 1.50–1.63 (m, 6 H), 3.33–3.48 (m, 4 H), 3.58–3.62 (m, 2
H), 4.77 (s, 1 H), 5.03–5.21 (m, 2 H), 5.72–5.81 (m, 1 H),
7.33–7.39 (m, 5 H), 9.52 (br s, 1 H). 13C NMR (75 MHz,
CDCl3): d = 24.7, 25.9, 46.6, 85.1, 115.3, 127.7, 128.0,
128.5, 128.6, 135.7, 137.2, 162.7, 169.1. MS (EI, 70 eV):
m/z (%) = 270 (42) [M+], 186 (100), 159 (65), 84 (66).
HRMS (EI): m/z calcd for C17H22N2O: 270.1732; found:
270.1739. Compound 6f: The colorless oil obtained on
work-up was subjected to flash chromatography (5:1 light
petroleum ether–EtOAc elution). Mp 114–117 °C. IR (KBr):
n = 3296, 2968, 2937, 1646, 1599, 1531, 1456, 1167, 752
cm–1. 1H NMR (300 MHz, CDCl3): d = 1.14 (d, 3 H, J = 6.6
Hz), 1.18 (d, 3 H, J = 6.6 Hz), 1.61–1.70 (m, 2 H), 1.70–1.92
(m, 3 H), 2.12–2.45 (m, 3 H), 3.21 (t, 1 H, J = 4.9 Hz), 4.05–
4.16 (m, 1 H), 6.31 (br s, 1 H), 6.85–6.90 (m, 1 H), 7.04–7.07
(m, 2 H), 7.24–7.30 (m, 3 H). 13C NMR (75 MHz, CDCl3):
d = 22.7, 22.8, 23.3, 24.3, 25.0, 29.0, 41.3, 49.9, 112.9,
119.2, 145.4, 148.2, 170.6. MS (EI, 70 eV): m/z (%) = 273
(25) [M+], 214 (100), 93 (32). Anal. Calcd for C16H23N3O: C,
70.30; H, 8.48; N, 15.37. Found: C, 70.01; H, 8.32; N, 15.63.
Synlett 2004, No. 4, 698–702 © Thieme Stuttgart · New York