Intermolecular addition of amines to an N-tosyloxy β-lactam

Full text of DOI:10.1021/jo961184w

J . Org. Chem. 1996, 61, 7959-7962
7959
In ter m olecu la r Ad d ition of Am in es to a n
Sch em e 1
N-Tosyloxy â-La cta m 1
J ohn R. Bellettini and Marvin J . Miller*
Department of Chemistry and Biochemistry,
University of Notre Dame, Notre Dame, Indiana 46556
Received J une 24, 1996
The proposed mechanism for the formation of amide 4b
1
2
is shown in Scheme 2 (R ) t-Bu, R ) H). First the
amine apparently attacked the â-lactam carbonyl opening
the ring to afford hydroxylamine 5. Elimination of a
molecule of p-toluenesulfonic acid from 5 afforded imine
The emergence of resistance by bacteria to many of the
currently used â-lactam antibiotics has led to the search
for new and improved antibiotics.2 One area of interest
in our research group is the development of new methods
to selectively functionalize the â-lactam ring. We have
recently reported the discovery of a remarkable reaction
for the addition of nucleophiles to the C-3 position of
N-tosyloxy â-lactams (Scheme 1).3 Treatment of a variety
of N-tosyloxy â-lactams with a tertiary amine base in the
presence of various nucleophiles including azide, chloride,
bromide, iodide, acetate, and others afforded products in
which the nucleophile had added to the C-3 position of
the â-lactam and the N-O bond had been cleaved. The
addition proceeded with predominately trans stereo-
chemistry relative to the substituent at C-4. Presumably,
this transformation occurred by a base-catalyzed eno-
6
which then hydrolyzed to give the observed product 4.
Interestingly, substitution of isopropylamine for diiso-
propylamine or tert-butylamine completely altered the
course of the reaction. Thus, treatment of â-lactam 1
1
with 2 equiv of isopropylamine followed by H NMR
analysis of the crude reaction mixture showed that no
addition of isopropylamine to the C-3 position had
occurred. Instead, after purification, amide 4c was
isolated in good yield (82-89%), indicating that isopro-
pylamine attacked â-lactam 1 only at the carbonyl carbon
1
2
as shown in Scheme 2 (R ) i-Pr, R ) H). The addition
of diethylamine also was tried since it is more hindered
than isopropylamine but less hindered than diisopropyl-
amine and tert-butylamine. Treatment of â-lactam 1
with 2 equiv of diethylamine afforded a 32% yield of
addition to C-3.
N
lization followed by an S 2′ displacement of the tosylate
during attack of the nucleophile on the enol intermediate.
Hoffman and co-workers have recently described a simi-
lar transformation on acyclic hydroxamate systems.4
One class of nucleophiles which we had not yet fully
explored was amine nucleophiles. The addition of amines
to the C-3 position of N-tosyloxy â-lactams would allow
for the facile introduction of the R-amino substituent on
the â-lactam ring and therefore provide a useful route
to important R-amino â-lactam derivatives. In some of
our previous work we showed that tertiary amines such
as triethylamine and diisopropylethylamine (H u¨ nig’s
base) added competitively with some of the nucleophiles
used in the nucleophilic addition reaction.3 By using
primary and secondary amines, we anticipated that the
amine would serve as both the catalyst and the nucleo-
phile to provide precursors to biologically interesting
R-amino â-lactams.
Nucleophilic addition of ammonia or an ammonia
equivalent at the C-3 position of various C-4-substituted
N-tosyloxy â-lactams would provide a direct route to
monobactam6 precursors (Scheme 3). Subsequent acy-
lation of the C-3 amine with physiologically appropriate
3
side chains and standard introduction of the ring N-SO H
linkage would allow production of a tremendous variety
of monobactams and analogs. Current variation of
substituents at the C-4 position of monobactams most
often requires access to the corresponding â-hydroxy
amino acid precursors 7. While some naturally-occuring
â-hydroxy amino acids, such as serine (7, R ) H) and
threonine (7, R ) Me), are readily available, others are
much less common or require total syntheses them-
selves.7 Alternatively, optically pure â-hydroxy acids 10
For this study we chose â-lactam 1 as our substrate.
The synthesis of â-lactam 1 from the corresponding
commercially available â-hydroxy ester by our hydrox-
8
are readily available by asymmetric enzymatic and
9
chemical reductions. Their conversion to 4-substituted-
5
N-hydroxy â-lactams 11 by standard protocol followed
5
amate-mediated approach was straightforward and has
by tosylation and subsequent reaction with an ammonia
equivalent (12 f 9) may provide an effective route to an
increased variety of monobactams 8.
been reported.3b To avoid competitive attack of the
nucleophilic amines at the â-lactam carbonyl, we first
studied reactions with sterically hindered amines. Thus,
treatment of â-lactam 1 with 2 equiv of diisopropylamine
afforded addition to the C-3 position of â-lactam 1 in
excellent overall yield (Table 1). The addition of another
relatively hindered amine, tert-butylamine, also afforded
mostly the anticipated C-3 addition products 2b (major)
and 3b (minor) as well as small amounts of amide 4b.
We previously demonstrated that azide is very effective
in the C-3 nucleophile transfer reaction.3b While azides
are readily reduced to amines, we also thought that it
would be interesting to determine the compatibility of
the C-3 nucleophile transfer process with other ammonia
equivalents to avoid the generation and use of intermedi-
ate azides. One of our first considerations was that
removal of the tert-butyl group from 2b should afford the
(
1) Results presented, in part, at the 29th Great Lakes Meeting of
the American Chemical Society, Normal, IL, May 1996, Program and
Abstracts, 131, and at the 210th National Meeting of the American
Chemical Society, Chicago, IL, August 1995, Program and Abstracts,
(6) Slusarchyk, W. A.; Dejneka, T.; Gordon, E. M.; Weaver, E. R.;
Koster, W. H. Heterocycles 1984, 21, 191.
(7) For an enzyme-mediated synthesis of novel â-hydroxy amino
acids, see: Lotz, B. T.; Gasparski, C. M.; Peterson, K.; Miller, M. J . J .
Chem. Soc., Chem. Commun. 1990, 1107.
3
58.
(2) Davies, J . Science 1994, 264, 375.
3) (a) Guzzo, P. R.; Teng, M.; Miller, M. J . Tetrahedron 1994, 50,
(
8
275. (b) Teng, M.; Miller, M. J . J . Am. Chem. Soc. 1993, 115, 548.
4) (a) Hoffman, R. V.; Nayyar, N. K. J . Org. Chem. 1995, 60, 7043
and references therein. (b) Hoffman, R. V.; Nayyar, N. K. J . Org. Chem.
995, 60, 5992 and references therein.
5) Miller, M. J . Acc. Chem. Res. 1986, 19, 49.
(8) (a) Christen, M; Crout, D. H. G.; Holt, R. A.; Morris, J . G.; Simon,
H. J . Chem. Soc., Perkin Trans. 1 1992, 491. (b) Servi, S. Synthesis
1990, 1. (c) Sih, C. J .; Chen, C.-S. Angew. Chem., Int. Ed. Engl. 1984,
23, 570.
(
1
(
(9) Guzzo, P. R.; Miller, M. J . J . Org. Chem. 1994, 59, 4862.
S0022-3263(96)01184-X CCC: $12.00 © 1996 American Chemical Society

7
960 J . Org. Chem., Vol. 61, No. 22, 1996
Ta ble 1. Rea ction s of 1 w ith Am in e Nu cleop h iles
Notes
entry
R1
i-Pr
t-Bu
i-Pr
R2
2 (%)a
3 (%)a
4 (%)a
4a (0)
4b (3-10)
4c (82-89)
4d (0)
4e (0)
4f (0)
4g (0)
pKa
i-Pr2NEtd
1
2
3
4
5
6
7
i-Pr
H
H
Et
H
H
2a (86-88)
2b (80-89)
2c (0)
2d (29-32)
2e (21-22)
2f (37-44)
2g (45-49)
3a (5)
3b (6-7)
3c (0)
3d (0)
3e (0)
3f (0)
3g (0)
11.1b
10.5b
10.6b
no
no
no
no
yes
yes
yes
b
Et
11.0
Ph3C
Ph2CH
allyl
6.1c
7.2c
b
allyl
9.3
a
Isolated yields after purification. b See ref 13. c Determined in methylcellosolve/water, see ref 11. d In some cases, i-Pr2NEt was added
to catalyze the enolization.
Sch em e 2
Sch em e 4
Treatment of â-lactam 1 with 2 equiv of tritylamine along
with the addition of 2 equiv of diisopropylethylamine, to
catalyze the apparently required enolization, led to
addition of tritylamine to the C-3 position in 21-22%
yield. Treatment of â-lactam 1 with 2 equiv of amino-
Sch em e 3
diphenylmethane (pK
) 7.2)11 also afforded no addition
a
to C-3; however, when diisopropylethylamine was added
to the reaction the C-3 addition product 2f was obtained
in 37-44% yield.
The addition of diallylamine was attempted since rho-
dium-catalyzed isomerization of the allyl groups to imines
followed by hydrolysis of the imines should afford the free
amine.12 Interestingly, treatment of â-lactam 1 with 2
equiv of diallylamine afforded urea 13 in 24% yield. Only
a small amount (<10%) of the desired C-3-substituted
â-lactam 2g was isolated. The presumed pathway for the
formation of urea 13 is shown in Scheme 4. Apparently
attack of diallylamine in an S
of â-lactam 1 opened the ring to form hydroxamate anion
4 which then initiated a facile Lossen rearrangement
to isocyanate 15. Isocyanate 15 was then trapped by
another molecule of diallylamine to give the observed
N
2 fashion at the C-4 carbon
free amine. However, our attempts to remove the tert-
butyl group from 2b have so far been unsuccessful. Since
1
the trityl group can be deprotected under relatively mild
conditions,10 we attempted to add tritylamine to the C-3
product 13. Diallylamine may not be basic enough (pK
)
a
position of â-lactam 1. Treatment of â-lactam 1 with 2
9.3)13 to sufficiently catalyze the proposed enolization,
equiv of tritylamine afforded only recovery of starting
) 6.1)11 is not
thus allowing for other chemistry, such as the observed
attack at C-4, to take place. When the reaction was
repeated using 3 equiv of diisopropylethylamine and 1.6
equiv of diallylamine, the C-3 addition product 2g was
obtained in 45-49% yield along with 13-15% of 13.
material. Apparently, tritylamine (pK
basic enough to catalyze the proposed enolization. It
appears as though the pK of the amine needs to be
approximately 11 to efficiently catalyze the enolization.
a
a
(
10) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 2nd ed.; J ohn Wiley & Sons: New York, 1991; pp 366-367.
11) Dahn, H.; Farine, J .-C; Nguy eˆ n, T. T. T. Helv. Chim. Acta 1980,
3, 780.
(12) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 2nd, ed.; J ohn Wiley & Sons: New York, 1991; p 362.
(13) Hall, H. K., J r. J . Am. Chem. Soc. 1957, 79, 5441.
(
6

Notes
J . Org. Chem., Vol. 61, No. 22, 1996 7961
Compound 2g after deprotection represents a formal
synthesis of the monobactams.
After the solution was stirred for 44 h at rt, the solvent was
evaporated to afford a white solid. The solid was chromato-
graphed on silica gel eluting with 30% EtOAc in hexanes to
afford 19 mg (86%) of 2a as a white solid and 1 mg (5%) of 3a as
a colorless oil. An analytical sample of 2a was obtained by
Hydroxylamines are effective nucleophiles despite their
reduced basicity relative to ammonia or alkylamines.
N-O-reduction also affords amines from hydroxylamines.
Thus, the addition of an O-protected hydroxylamine to
the C-3 position of N-tosyloxy â-lactams was anticipated
to give the desired monobactam precursors after N-O-
reduction; also, retention of the N-O bond would provide
access to novel structural types and complement our
interest in hydroxamate-substituted â-lactam antibiot-
ics.14 Treatment of â-lactam 1 with 2 equiv of O-
benzylhydroxylamine resulted in no observed addition to
C-3. Most of the starting material was recovered.
Analogous to the addition of tritylamine, aminodiphe-
nylmethane, and diallylamine, O-benzylhydroxylamine
recrystallization from hexanes: mp 104-106 °C; R
f
0.24 (2:3
-1 1
EtOAc:hexanes); IR (CHCl ) 3435, 1745 (CO) cm ; H NMR (300
3
MHz, CDCl
H), 1.33 (d, J ) 6.0 Hz, 3H), 3.11 (heptet, J ) 6.6 Hz, 2H), 3.57
qd, J ) 6.1, 2.2 Hz, 1H,), 3.77 (d, J ) 2.2 Hz, 1H), 6.04 (br s,
3
) δ 1.03 (d, J ) 6.7 Hz, 6H), 1.11 (d, J ) 6.6 Hz,
6
(
1
5
1
H); 13C NMR (75 MHz, CDCl
2.57, 72.57, 172.56; HRMS (FAB) calcd for C10 O (MH )
20 2
85.1654, found 185.1652. Anal. Calcd for C10H N O: C, 65.18;
3
) δ 18.88, 22.29, 23.25, 46.10,
+
H
21
N
2
H, 10.94; N, 15.20. Found: C, 65.40; H, 10.70; N, 15.29.
Compound 3a : R 0.34 (2:3 EtOAc:hexanes); IR (CHCl ) 3420,
) δ 1.03 (d, J ) 6.5
Hz, 6H), 1.15 (d, J ) 6.5 Hz, 6H), 1.23 (d, J ) 6.5 Hz, 3H), 3.13
f
3
-
1 1
1
745 (CO) cm ; H NMR (500 MHz, CDCl
3
(
1
2
heptet, J ) 6.5 Hz, 2H), 3.62-3.69 (m, 1H), 4.42 (dd, J ) 5.0,
13
.5 Hz, 1H), 5.80 (br s, 1H); C NMR (125 MHz, CDCl
3
) δ 16.68,
(
pK
the proposed enolization. Treatment of â-lactam 1 with
.6 equiv of O-benzylhydroxylamine and 3 equiv of
a
) 4.3)15 apparently is not basic enough to catalyze
1.85, 23.45, 47.76, 52.69, 67.80, 172.32; HRMS (FAB) calcd for
+
C10H21N O (MH ) 185.1654, found 185.1651.
2
1
(()-tr a n s-3-(N-(1,1-Dim et h ylet h yl)a m in o)-4-m et h yl-2-
a zetid in on e (2b), (()-cis-3-(N-(1,1-d im eth yleth yl)a m in o)-
diisopropylethylamine led to addition at C-3. However,
the product appeared to decompose over time. To help
prevent this decomposition, the hydroxylamine was acy-
4
-m eth yl-2-a zetid in on e (3b), a n d N-(1,1-Dim eth yleth yl)-3-
oxobu ta n a m id e (4b). To a stirred solution of 58 mg (0.23
mmol) of â-lactam 1 in 2.0 mL of anhydrous MeCN at rt under
N was added 50 µL (0.48 mmoL) of tert-butylamine. After the
2
solution was stirred for 47 h at rt, the white precipitate which
had formed was filtered off and the filtrate was concentrated to
afford a yellow solid. The yellow solid was chromatographed
on silica gel eluting with EtOAc to afford 31 mg (89%) of 2b as
a white solid, 2 mg (6%) of 3b as a light yellow oil, and 1 mg
lated (Ac
2
O, pyridine) and â-lactam 16 was isolated in
1
0% yield (eq 1).
(3%) of 4b as a white solid. An analytical sample of 2b was
obtained by recrystallization from hexanes: mp 117-119 °C; R
f
-
1
1
0
.15 (EtOAc); IR (KBr) 3270, 1750 (CO) cm
;
H NMR (300
MHz, CDCl
3
) δ 1.12 (s, 9H), 1.37 (d, J ) 6.1 Hz, 3H), 1.78 (br s,
1
3
1
H), 3.43 (qd, J ) 6.1, 1.7 Hz), 3.71 (s, 1H), 6.09 (br s, 1H);
NMR (75 MHz, CDCl
HRMS (FAB) calcd for
57.1339. Anal. Calcd for C
C
3
) δ 19.04, 29.61, 50.51, 56.65, 68.70, 170.06;
In summary, we have shown that N-tosyloxy â-lactams
+
C
8
H
17
N
2
O (MH ) 157.1341, found
O: C, 61.51; H, 10.32; N,
are highly reactive molecules. Nucleophilic attack by
amines on the â-lactam ring can occur at all three carbon
atoms of the â-lactam ring. The position where the amine
attacks the â-lactam ring appears to depend largely on
the basicity and steric hinderance of the amine nucleo-
1
8
H
16
N
2
17.93. Found: C, 61.38; H, 10.15; N, 17.97. Compound 3b: R
f
-
1 1
0
.32 (EtOAc); IR (CHCl
MHz, CDCl ) δ 1.11 (s, 9H), 1.21 (d, J ) 6.3 Hz, 3H), 1.55 (br s,
H), 3.73-3.85 (m, 1H), 4.25 (dd, J ) 4.9, 0.7 Hz), 5.90 (br s,
H); 13C NMR (75 MHz, CDCl
) δ 16.39, 29.78, 50.39, 51.36,
3.46, 172.16; HRMS (FAB) calcd for C
3
) 3420, 1755 (CO), cm ; H NMR (300
3
1
1
6
3
phile. Apparently, the pK
needs to be approximately 11 to efficiently promote attack
at C-3. If the pK of the amine is not basic enough, other
a
of the amine nucleophile
+
8
H
17
N
2
O (MH ) 157.1341,
found 157.1304. Compound 4b: mp 40-43 °C; R 0.50 (EtOAc);
f
IR (CHCl
(
(
3
) 3440, 3350, 1710 (CO), 1670 (CO) cm-
300 MHz, CDCl ) δ 1.36 (s, 9H), 2.26 (s, 3H), 3.33 (s, 2H), 6.69
br s, 1H); 13C NMR (75 MHz, CDCl
) δ 28.64, 31.02, 50.87, 51.34,
64.40, 205.07; HRMS (FAB) calcd for C
found 157.1124.
1
; H NMR
1
a
more basic non-nucleophilic amines need to be added to
the reaction to apparently promote prior enolization.
Control of nucleophile transfer to the C-3 position of
â-lactams promises to considerably enhance the chem-
istry of this very important class of compounds. The
alternate reactivity demonstrated in these reactions also
may lead to new considerations in the design of thera-
peutic agents. For example, we have recently demon-
strated use of N-(arylsulfonyl)oxy â-lactams as electro-
philic “bombs” as novel and potent â-lactamase inhibitors.16
3
3
+
•
1
8 2
H15NO (M ) 157.1103,
N-(1-Meth yleth yl)-3-oxobu ta n a m id e (4c). To a stirred
solution of 34 mg (0.13 mmol) of â-lactam 1 in 1.0 mL of
anhydrous MeCN at rt under N2 was added 25 µL (0.29 mmol)
of isopropylamine. After the solution was stirred at rt for 14 h,
the solvent was evaporated to afford a yellow oil. The oil was
chromatographed on silica gel eluting with 80% EtOAc in
hexanes to afford 17 mg (89%) of 4c as a white solid. An
analytical sample was obtained by recrystallization from hex-
anes: mp 51-53 °C; R
3420, 3330, 1715 (CO), 1670 (CO) cm
CDCl ) δ 1.17 (d, J ) 6.5 Hz, 6H), 2.27 (s, 3H), 3.38 (s, 2H),
.02-4.14 (m, 1H), 6.74 (br s, 1H); C NMR (125 MHz, CDCl
δ 22.56, 31.07, 41.46, 49.78, 164.40, 204.83; HRMS (FAB) calcd
f 3
0.28 (4:1 EtOAc:hexanes); IR (CHCl )
-
1
1
Exp er im en ta l Section
; H NMR (500 MHz,
3
Gen er a l Meth od s. Instruments and general methods used
13
4
3
)
3
b
have been described previously.
(
()-tr a n s-3-(N,N-Bis(1-m eth yleth yl)a m in o)-4-m eth yl-2-
+
for C
7
H
14NO
2
(MH ) 144.1025, found 144.1023. Anal. Calcd for
2
: C, 58.72; H, 9.15; N, 9.78. Found: C, 58.46; H, 8.91;
a zetid in on e (2a ) a n d (()-cis-3-(N,N-Bis(1-m eth yleth yl)-
C
7
H
13NO
a m in o)-4-m eth yl-2-a zetid n on e (3a ). To a stirred solution of
N, 9.67.
()-t r a n s-3-(N ,N -Die t h yla m in o)-4-m e t h yl-2-a ze t id i-
n on e (2d ). To a stirred solution of 41 mg (0.16 mmol) of
â-lactam 1 in 1.1 mL of anhydrous MeCN at rt under N was
3
0 mg (0.12 mmol) of â-lactam 1 in 1.0 mL of anhydrous MeCN
at rt under N was added 35 µL (0.25 mmol) of diisopropylamine.
(
2
2
(
14) (a) Miller, M. J .; Malouin, F. Acc. Chem. Res. 1993, 26, 241. (b)
Miller, M. J . Chem. Rev. 1989, 89, 1563.
15) Deles, J .; Kolaczkowska, E.; Superson, A. Pol. J . Chem. 1979,
3, 1025.
16) (a) Bulychev, A.; O’Brien, M. E.; Massova, I.; Teng, M.; Gibson,
T. A.; Miller, M. J .; Mobashery, S. J . Am. Chem. Soc. 1995, 117, 5938.
b) Teng, M.; Miller, M. J .; Nicas, T. I.; Grissom-Arnold, J .; Cooper, R.
D. G. Bioorg. Med. Chem. 1993, 1, 151.
added 40 µL (0.39 mmol) of diethylamine. After the solution
was stirred at rt for 40 h, the solvent was evaporated to afford
a brown solid. The solid was chromatographed on silica gel
eluting with 80% EtOAc in hexanes to afford 8 mg (32%) of 2d
(
5
(
as a colorless oil: R
f
0.36 (9:1 EtOAc:hexanes); IR (neat) 3280,
1750 (CO) cm ; H NMR (300 MHz, CDCl ) δ 1.07 (t, J ) 6.9
Hz, 6H), 1.36 (d, J ) 6.3 Hz, 3H), 2.62-2.84 (m, 4H) 3.66-3.78
-
1 1
(
3

7
962 J . Org. Chem., Vol. 61, No. 22, 1996
Notes
IR (neat) 3080, 1640 (CO) cm-1; H NMR (300 MHz, CDCl
) δ
3
m, 2H), 6.44 (br s, 1H); 13C NMR (75 MHz, CDCl
) δ 12.21,
9.64, 44.08, 49.50, 77.75, 169.32; HRMS (FAB) calcd for
1
(
3
1
1.07 (d, J ) 6.3 Hz, 3H), 2.21 (dd, J ) 15.6, 6.3 Hz, 1H), 2.30 (br
s, 1H), 2.61 (dd, J ) 15.6, 6.3 Hz, 1H), 3.14-3.40 (m, 5H), 3.76-
+
C
8
H
17
N
2
O (MH ) 157.1341, found 157.1306.
()-tr a n s-4-Meth yl-3-[(tr ip h en ylm eth yl)a m in o]-2-a zeti-
d in on e (2e). To a stirred solution of 50 mg (0.20 mmol) of
â-lactam 1 in 1.5 mL of anhydrous MeCN at rt under N were
added 110 mg (0.42 mmol) of tritylamine and 70 µL (0.40 mmol)
of diisopropylethylamine. After 48 h of stirring under N , the
1
3
(
4.14 (m, 4H), 5.06-5.26 (m, 8H), 5.67-5.98 (m, 4H); C NMR
(75 MHz, CDCl
116.67, 117.14, 117.98, 132.84, 133.36, 134.67, 171.93; HRMS
(FAB) calcd for C16
3
) δ 19.58, 38.88, 47.68, 49.13, 49.69, 59.13,
2
+
28 3
H N O (MH ) 278.2232, found 278.2252.
2
(()-tr a n s-3-(N-(Met h ylca r b on yl)-N-(p h en ylm et h oxy)-
a m in o)-4-m eth yl-2-a zetid in on e (16). To a stirred solution of
215 mg (0.842 mmol) of â-lactam 1 in 10 mL of anhydrous MeCN
solvent was evaporated and the residue was chromatographed
on silica gel eluting with 30% EtOAc in hexanes to afford 14
mg (21%) of 2e as a white solid. An analytical sample was
obtained by recrystallization from EtOAc-hexanes: mp 183-
at rt under N
ethylamine and 162 mg (1.32 mmol) of O-benzylhydroxylamine.
After the solution was stirred at rt under N for 46 h, 240 µL
2
were added 440 µL (2.53 mmol) of diisopropyl-
1
85 °C; R
f
0.30 (2:3 EtOAc:hexanes); IR (KBr) 3220, 1755 (CO)
cm ; H NMR (300 MHz, CDCl ) δ 0.38 (d, J ) 6.0 Hz, 3H),
.76 (br s, 1H), 3.02 (qd, J ) 6.0, 1.5 Hz, 1H), 3.63 (br s, 1H),
2
-
1
1
3
(2.54 mmol) of acetic anhydride was added followed by 210 µL
(2.60 mmol) of anhydrous pyridine. After 16 h of stirring at rt,
the solvent was evaporated, the residue was dissolved in EtOAc,
2
5
1
3
3
.96 (br s, 1H,), 7.16-7.54 (m, 15H); C NMR (75 MHz, CDCl )
δ 18.48, 57.98, 70.00, 70.51, 126.64, 128.06, 128.77, 145.98,
washed with 1.0 M HCl, saturated NaHCO
3
, and brine, dried
+•
1
3
70.43; HRMS (FAB) calcd for C23
42.1743. Anal. Calcd for C23
H
22
N
2
O (M ) 342.1732, found
(Na SO ), and filtered, and the solvent was evaporated to afford
2
4
H
22
N
2
O: C, 80.67; H, 6.48; N, 8.18.
a colorless oil. The oil was chromatographed using a Chroma-
totron (2-mm silica gel plate eluting with 40% EtOAc in hexanes)
to afford a mixture of 16 and N-acetyl-O-benzylhydroxylamine
as a colorless oil. The oil was dissoved in EtOAc, washed with
Found: C, 80.77; H, 6.70; N, 8.13.
()-tr a n s-4-Meth yl-3-[(d ip h en ylm eth yl)a m in o]-2-a zeti-
d in on e (2f). To a stirred solution of 200 mg (0.783 mmol) of
â-lactam 1 in 6.0 mL of anhydrous MeCN at rt under N were
added 410 µL (2.35 mmol) of diisopropylethylamine and 210
µL (1.22 mmol) of aminodiphenylmethane. After 62 h of stirring
2
at rt under N , the solvent was evaporated and the residue
(
2
5% Na
2
CO
3
(with a small amount of a 1.0 M NaOH solution
SO ), and filtered, and the solvent
added) and brine, dried (Na
2
4
was evaporated to afford a colorless oil. The oil was chromato-
graphed using a Chromatotron (1-mm silica gel plate eluting
with 50% EtOAc in hexanes) to afford 20 mg (10%) of 16 as a
was chromatographed on silica gel eluting with 40% EtOAc
in hexanes to afford 92 mg (44%) of 2f as a white solid. An
analytical sample was obtained by recrystallization from EtOAc-
colorless oil: R
(CO), 1675 (CO) cm ; H NMR (300 MHz, CDCl
f
0.21 (1:1 EtOAc:hexanes); IR (CHCl
3
) 3430, 1770
-
1 1
3
) δ 1.40 (d, J
hexanes: mp 138-139 °C; R
f
0.37 (1:1 EtOAc:hexanes); IR
) 3420, 1760 (CO) cm 1; 1H NMR (300 MHz, CDCl
) δ
.00 (d, J ) 6.0 Hz, 3H), 2.13 (br s, 1H), 3.43 (qd, J ) 6.0, 1.8
) 6.2 Hz, 3H), 2.19 (s, 3H), 3.94 (qd, J ) 6.2 Hz, 2.4 Hz, 1H),
4.93 (d, J ) 9.8 Hz, 1H), 5.11 (d, J ) 1.6 Hz, 1H), 5.16 (d, J )
9.8 Hz, 1H), 6.15 (br s, 1H), 7.39 (s, 5H); 13C NMR (75 MHz,
-
(CHCl
3
3
1
Hz, 1H), 3.59 (t, J ) 1.8 Hz, 1H), 5.04 (s, 1H), 5.97 (br s, 1H),
3
CDCl ) δ 19.33, 20.47, 50.67, 70.35, 78.63, 128.69, 129.04, 129.46,
1
3
+
7
.17-7.35 (m, 6H), 7.38-7.48 (m, 4H); C NMR (75 MHz,
CDCl ) δ 19.17, 54.89, 66.38, 72.18, 127.08, 127.32, 127.41,
27.57, 128.54, 128.55, 143.14, 143.27, 169.36; HRMS (FAB)
134.21, 165.29, 173.59; HRMS (FAB) calcd for C13
249.1239, found 249.1264.
17 2 3
H N O (MH )
3
1
+
calcd for C17
Calcd for C17
6.80; H, 6.56; N, 10.61.
()-tr a n s-4-Met h yl-3-(N,N-d i(2-p r op en yl)a m in o)-2-a ze-
H
19
N
2
O (MH ) 267.1497, found 267.1490. Anal.
Ack n ow led gm en t. We appreciate the use of the
NMR facilities of the Lizzadro Magnetic Resonance
Research Center at Notre Dame. J .R.B. thanks the
Upjohn Co. for the Upjohn Fellowship Award for the
spring semester of 1995 and the Rohm and Haas Co.
for the Rohm and Haas Graduate Fellowship in Chem-
istry for the fall 1995 and spring 1996 semesters. We
also gratefully acknowledge Eli Lilly and Co. and the
NIH for providing partial financial support of this
research.
H
18
2
N O: C, 76.66; H, 6.81; N, 10.52. Found: C,
7
(
tid in on e (2g), a n d (()-2-((N,N-d i(2-p r op en yl)a m in o)ca r -
bon yl)-N,N-d i(2-p r op en yl)-1-m eth yleth a n a m in e (13). To a
stirred solution of 200 mg (0.783 mmol) of â-lactam 1 in 6.0 mL
2
of anhydrous MeCN at rt under N was added 410 µL (2.35
mmol) of diisopropylethylamine followed by 150 µL (1.22 mmol)
of diallylamine. After 67 h of stirring at rt, the solvent was
evaporated and the residue was chromatographed on silica gel
eluting with 30% EtOAc in hexanes to afford 69 mg (49%) of 2g
as a colorless oil and 29 mg (13%) of 13 as a light brown oil.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
Compound 2g: R
f
0.24 (2:3 EtOAc:hexanes); IR (neat) 3270, 1755
CO) cm ; H NMR (300 MHz, CDCl ) δ 1.33 (d, J ) 6.0 Hz,
H), 3.19-3.36 (m, 4H), 3.75 (qd, J ) 6.0, 2.1 Hz, 1H), 3.76 (s,
H), 5.13-5.26 (m, 4H), 5.76-5.95 (m, 2H), 6.58 (br s, 1H); 13
) δ 19.48, 49.19, 53.93, 76.88, 117.95,
spectra for compounds 2d , 2g, 3a /b, 4b, 13, and 16 (14 pages).
This material is contained in libraries on microfiche, im-
mediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
-
1
1
(
3
1
3
C
NMR (75 MHz, CDCl
35.08, 169.29; HRMS (FAB) calcd for C10
found 181.1319. Compound 13: R 0.63 (2:3 EtOAc:hexanes);
3
+
1
17 2
H N O (MH ) 181.1341,
f
J O961184W