Tandem Reductive Alkylation-Cyclization for the Preparation of Unsymmetrieal 1,4-Disubstituted 2,3-Diketopiperazines

Full text of DOI:10.1021/jo9800309

J . Org. Chem. 1998, 63, 4131-4134
4131
Sch em e 1
Ta n d em Red u ctive Alk yla tion -Cycliza tion
for th e P r ep a r a tion of Un sym m etr ica l
1,4-Disu bstitu ted 2,3-Dik etop ip er a zin es
Christopher J . Dinsmore*,† and J effrey M. Bergman
Department of Medicinal Chemistry, Merck Research
Laboratories, West Point, Pennsylvania, 19486
Received J anuary 6, 1998
Derivatives of piperazine have found wide use in
medicinal chemistry as molecular scaffolds for the posi-
tioning of substituents in biologically active molecules.1
During the course of an ongoing drug discovery project,
we required a general method for the preparation of
unsymmetrical 1,4-disubstituted 2,3-diketopiperazines.
While the Riebsomer condensation of a 1,2-diamine with
dialkyl oxalate is frequently employed,2 it generally
requires elevated reaction temperature as well as prior
construction of the appropriate N,N′-disubstituted 1,2-
diamine. We felt that a more flexible approach, featuring
simultaneous amine derivatization and ring construction,
would enable the more efficient synthesis of 1,4-disub-
stituted analogues. Here, we describe a modified protocol
(Scheme 1) involving the conversion of protected N-(2-
aminoethyl)oxamates (e.g., 1) to stable amine salts (e.g.,
2), followed by tandem reductive amination and cycliza-
tion to provide 1,4-disubstituted 2,3-diketopiperazines 3.
This coupling reaction enables the rapid convergent
synthesis of a diverse array of adducts from readily
available monoalkylethylenediamine derivatives and al-
dehydes or ketones.
The performance of this reaction was first explored
using the protected amine 1, available in a single step
from 1-phenylethylenediamine.3 Reductive coupling of
the derived amine salt 2 with benzaldehyde using sodium
triacetoxyborohydride and molecular sieves cleanly pro-
vided product 3a within several hours in 72% isolated
yield (Table 1, entry 1). At the outset of these studies, it
seemed plausible that under the mildly acidic reaction
conditions the amine 2 could undergo either competitive
cyclization to give 4 or acyl transfer to produce 5.4,5
Gratifyingly, these side reactions were largely precluded
in the presence of most aldehydes and ketones.6 Sub-
stituted benzaldehydes (entries 2-5) were efficiently
converted to the corresponding N-benzyl-2,3-diketopip-
erazines (3b-e) regardless of their electronic nature (cf.
entries 1-3) or steric environment (entries 4 vs 5).
Additionally, 2,3-diketopiperazines were prepared from
cinnamaldehyde (3f) and aliphatic aldehydes (3g-i).
While the less hindered aldehydes also underwent bis-
alkylation to produce acyclic oxamate byproducts 6 as
minor components (entries 6 and 7), the branched alde-
hydes performed more smoothly (entries 8 and 9). Reac-
tions with ketones were more sensitive; although ace-
tophenone failed to react, enabling the predominant
formation of byproducts 4 and 5 (entry 10), the cyclic
N-Boc-4-piperidone led to 3k in high yield (entry 11).
Other N-(2-aminoethyl)oxamates were evaluated to
further probe the utility of the transformation. Modifica-
tion of the nitrogen substituent from phenyl in 1 to benzyl
in 7 was well tolerated, leading to 2,3-diketopiperazine
8 in good yield (eq 1). Thus, the amide cis-trans
conformational mobility has little influence on the course
of the reaction.7 Installation of a substituent on the
aminoethyl chain (e.g., 9) reduces the efficiency of the
reductive amination-cyclization sequence (eq 2). Al-
though the desired product was obtained (10, 26%), a
combination of premature cyclization (11) and acyl
migration (12) preceded reductive amination, possibly by
virtue of the Thorpe-Ingold effect.8
* To whom correspondence should be addressed.
† Tel.: (215) 652-8257. Fax: (215) 652-3971. E-mail: christopher_
dinsmore@merck.com.
(1) ) Giannis, A.; Kolter, T. Angew, Chem., Int. Ed. Engl. 1993, 32,
1244-1267.
(2) (a) Riebsomer, J . L. J . Org. Chem. 1950, 15, 68-73. (b) Hori, T.;
Yoshida, C.; Murakami, S.; Takeno, R.; Nakano, J .; Nitta, J .; Tsuda,
H.; Kishimoto, S.; Saikawa, I. Chem. Pharm. Bull. 1981, 29, 684-698.
(c) Mueller-Westerhoff, U.; Zhou, M. J . Org. Chem. 1994, 59, 4988-
4992.
(3) Substituted 1-arylethylenediamines are also readily prepared.
See: Poindexter, G. S.; Owens, D. A.; Dolan, P. L.; Woo, E. J . Org.
Chem. 1992, 57, 6257-6265.
(4) Base treatment of the amine‚HCl 2 (e.g., Et3N/CDCl3 or EtOAc/
aqueous NaHCO3) resulted in immediate (<3 min) cyclization to give
2,3-diketopiperazine 4.
(a) HCl, EtOAc, 0 °C; (b) 4-Br-C6H4CHO, Na(AcO)3BH, ClCH2-
CH2Cl, 4 Å molecular sieves, 0 °C to rt, ca. 10 h.
(5) For intramolecular cyclizations of oxamides: (a) N-Acylation:
Lewis, R. T.; Macleod, A. M.; Merchant, K. J .; Kelleher, F.; Sanderson,
I.; Herbert, R. H.; Cascieri, M. A.; Sadowski, S.; Ball, R. G.; Hoogsteen,
K. J . Med. Chem. 1995, 38, 923-933. (b) C-Acylation: Southwick, P.
L.; Fitzgerald, J . A.; Madhav, R.; Welsh, D. A. J . Org. Chem. 1969,
34, 3279-3285. (c) Harada, T.; Morimoto, M.; Nagasawa, M.; Inoue,
H.; Ohishi, T.; Takeda, M.; Takamura, N. Chem. Pharm. Bull. 1992,
40, 1986-1989.
In none of the examples herein was the accumulation
of an intermediate secondary amine observed. Further-
(6) In most cases, reactions in Table 1 also produced minor amounts
of 4 and 5 in up to 10% yields, as judged by HPLC and 1H NMR
analyses.
S0022-3263(98)00030-9 CCC: $15.00 © 1998 American Chemical Society
Published on Web 05/21/1998

4132 J . Org. Chem., Vol. 63, No. 12, 1998
Notes
Sch em e 2a
Ta ble 1. Red u ctive Am in a tion -cycliza tion of Am in e 2
w ith Ald eh yd es a n d Keton es to Give
2,3-d ik etop ip er a zin es 3a
a
(a) HCl, EtOAc, 0 °C; (b) RCHO, Na(AcO)3BH, ClCH2CH2Cl,
4 Å molecular sieves, 0 °C to rt, 1 h; nd ) not detected.
explore this further, an example of such an entity (14)
was prepared for study (Scheme 2).
Compound 13, available from the hydrolysis and re-
functionalization of 3a , was deprotected to provide the
corresponding stable HCl salt 14. An initial control
experiment demonstrated that when an equimolar mix-
ture of 2 and 14 was stirred with 4 Å powdered sieves,
cyclization and acyl transfer (2 f 4 + 5 and 14 f 3a )
occurred at similar rates over the course of several
hours.9a,b The same transformations were much more
rapid in the presence of Na(AcO)3BH, suggesting that Na-
(AcO)3BH contributes to accelerating the cyclizations of
2 and 14.9c Second, exposure of 14 to the reductive
amination conditions in the presence of benzaldehyde
provided 3a in less than 1 h as the sole product, which
was isolated in 87% yield (Scheme 2). None of 6c or 15
was detected, indicating rapid cyclization. Third, the
same experiment with butyraldehyde produced a mixture
of 3a and 6d , reflecting the enhanced susceptibility of
the secondary amine in 14 to a second reductive alkyla-
tion in cases of more reactive aldehydes (e.g., Table 1,
entries 6 and 7).
The tandem reductive coupling-cyclization provides
convenient access to a diverse array of 1,4-disubstituted
2,3-diketopiperazines in convergent fashion. The mild
reaction conditions employed and the wide availablity of
aldehydes and ketones are attractive features. Aromatic
aldehydes, branched aliphatic aldehydes, and cyclic
ketones were the most successful substrates for the
transformation. Application of this methodology to the
preparation of biologically active molecules will be de-
scribed elsewhere.
Exp er im en ta l Section
Meth yl N-[2-(ter t-Bu toxyca r bon yla m in o)eth yl]-N-(p h e-
n yl)oxa m a te (1). To a solution of 1-phenylethylenediamine
(10.0 mL, 70.5 mmol) in 120 mL of CH2Cl2 at 0 °C was added
di-tert-butyl dicarbonate (15.4 g, 70.5 mmol). After 4 h, triethyl-
a
See ref 6. All reactions were carried out on 1.5 mmol scale
using 2 equiv of Na(AcO)3BH, 1.1 equiv of aldehyde or ketone,
and 4 Å powdered sieves at 0 °Cfrt as described in the Experi-
(7) Analysis of the 1H NMR spectra of oxamates 1 and 6 (23 °C,
CDCl3) indicates conformational homogeneity for 1, but a 45:55 mixture
for 6. The cis-amide preference in amides of N-alkylanilines (cf. 1) is
well-known: Saito, S.; Toriumi, Y.; Tomioka, N.; Itai, A. J . Org. Chem.
1995, 60, 4715-4720 and references therein.
b
c
mental Section. Purified yield based on 1f3. The byproduct
6a (R ) cinnamyl) was also islolated in 35% yield. d The byproduct
e
6b (R ) n-Bu) was also islolated in 16% yield. HPLC analysis
indicated complete conversion of 2 to approximately equal amounts
of 4 and 5. Although 4 was lost in the aqueous workup, 5 was
isolated in 37% yield.
(8) Detar, D. F.; Luthra, N. P. J . Am. Chem. Soc. 1980, 102, 4505-
4512.
(9) (a) The use of molecular sieves as a neutral acid scavenger for
the absorption of HCl has been documented: Weinstock, L. M.; Karady,
S.; Roberts, F. E.; Hoinowski, A. M.; Brenner, G. S.; Lee, T. B. K.;
Lumma, W. C.; Sletzinger, M. Tetrahedron Lett. 1975, 3979-3982. (b)
Compounds 2 and 14 were stirred with 4 Å molecular sieves in ClCH2-
CH2Cl (0 °C to rt) and assayed by RP-HPLC (2 and 3 are stable to the
chromatography conditions). After 16 h, both had undergone ca. 70%
conversion. (c) In the presence of Na(AcO)3BH, complete conversion
occurred within 1 h.
more, products derived from acyl transfer from such an
intermediate were not detected, and only unhindered
aldehydes produced tertiary amine byproducts 6 emanat-
ing from a second reductive amination. This suggests
that intramolecular cyclization of the putative secondary
amine is fast relative to competing transformations. To

Notes
J . Org. Chem., Vol. 63, No. 12, 1998 4133
amine was added (14.7 mL, 106 mmol), followed by dropwise
addition of methyl oxalyl chloride (6.81 mL, 74.0 mmol). After
45 min, the solution was poured into EtOAc, washed with water,
a 10% HCl solution, a saturated NaHCO3 solution, and brine,
dried over Na2SO4, filtered, and concentrated. The product was
crystallized from a stirred 5% EtOAc/hexane solution to afford
1 (15.39 g, 68%) as a white powder: Rf 0.36 (50% EtOAc/hexane);
1H NMR (400 MHz, CDCl3) δ 7.35-7.42 (m, 3H), 7.25 (bd, J )
8 Hz, 2H), 4.87 (bs, 1H), 3.91 (t, J ) 6.0 Hz, 2H), 3.53 (s, 3H),
3.37 (dt, J ) 5.8 and 6 Hz, 2H), 1.41 (s, 9H); ES HRMS exact
mass calcd for C16H23N2O5 (M + H+) 323.1601, found 323.1603.
Anal. Calcd for C16H22N2O5: C, 59.62; H, 6.88; N, 8.69.
Found: C, 59.23; H, 6.65; N, 8.57.
crude reaction mixture from EtOAc provided 3f (20%) as a white
solid. Flash chromatography of the mother liquor (25 × 80 mm
silica, 50-100% EtOAc/hexane) provided 6a (35%) as a colorless
oil. For 3f: Rf 0.41 (5% MeOH/CHCl3); 1H NMR (400 MHz,
CDCl3) δ 7.26-7.43 (m, 10H), 6.63 (d, J ) 15.9 Hz, 2H), 6.21
(dt, J ) 15.9 and 6.9 Hz, 2H), 4.33 (d, J ) 6.9 Hz, 4H), 3.95 (m,
2H), 3.68 (m, 2H); ES HRMS exact mass calcd for C19H19N2O2
(M + H+) 307.1441, found 307.1433. For 6a : Rf 0.25 (25%
EtOAc/hexane); 1H NMR (400 MHz, CDCl3) δ 7.20-7.35 (m,
15H), 6.46 (d, J ) 15.9 Hz, 2H), 6.18 (dt, J ) 15.9 and 6.6 Hz,
2H), 3.95 (t, J ) 6.6 Hz, 2H), 3.52 (s, 3H), 3.31 (d, J ) 6.6 Hz,
4H), 2.75 (t, J ) 6.6 Hz, 2H); ES HRMS exact mass calcd for
C29H31N2O3 (M + H+) 455.2329, found 455.2310.
Rep r esen ta tive P r oced u r e for th e P r ep a r a tion of 2,3-
Dik etop ip er a zin es fr om Oxa m a tes: 4-Ben zyl-1-p h en yl-2,3-
d ik etop ip er a zin e (3a ). Through a solution of 1 (500 mg, 1.55
mmol) in 10 mL of EtOAc at 0 °C was bubbled anhydrous HCl
gas for 3 min. After being stirred for an additional 20 min, the
solution was concentrated to provide 2 as a white foam (400 mg,
100%): 1H NMR (400 MHz, CD3OD) δ 7.42-7.51 (m, 3H), 7.37
(bd, J ) 8 Hz, 2H), 4.11 (t, J ) 6.4 Hz, 2H), 3.52 (s, 3H), 3.15 (t,
J ) 6.4 Hz, 2H); ES HRMS exact mass calcd for C11H15N2O3 (M
+ H+) 223.1077, found 223.1068. Anal. Calcd for C11H14N2O3‚
1.0HCl‚0.1H2O: C, 50.72; H, 5.88; N, 10.75. Found: C, 50.82;
H, 5.85; N, 10.75. To a 0 °C solution of 2 in 3.0 mL of
1,2-dichloroethane were added 0.50 g of 4 Å powdered molecular
sieves, benzaldehyde (174 µL, 1.70 mmol), and sodium triac-
etoxyborohydride (439 mg, 2.33 mmol). After 30 min, the ice
bath was removed, and the reaction was stirred for 4 h. The
solution was poured into EtOAc, washed with a saturated
NaHCO3 solution and brine, dried over Na2SO4, filtered, and
concentrated. Flash chromatography (25 × 80 mm silica, 75%
EtOAc/hexanes) provided 3a (313 mg, 72%) as a white solid: Rf
0.48 (5% MeOH/CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.31-
7.43 (m, 9H), 7.27 (tt, J ) 8.4 and 1.1 Hz, 1H), 4.75 (s, 2H),
3.87-3.90 (m, 2H), 3.55-3.58 (m, 2H); ES HRMS exact mass
calcd for C17H17N2O2 (M + H+) 281.1283, found 281.1284. Anal.
Calcd for C17H16N2O2: C, 72.84; H, 5.75; N, 9.99. Found: C,
72.99; H, 5.92; N, 10.15.
4-(n -Bu tyl)-1-ph en yl-2,3-diketopiper azin e (3g) an d Meth -
yl N-[2-(Di-n -Bu tyla m in o)eth yl]-N-(p h en yl)oxa m a te (6b).
Flash chromatography (40 × 70 mm silica, 2-4% MeOH/CH2-
Cl2) provided an inseparable mixture of 3g (43%) and 6b (16%)
as a colorless oil. For 3g: Rf 0.30 (5% MeOH/CH2Cl2); 1H NMR
(400 MHz, CDCl3) δ 7.24-7.42 (m, 5H), 3.95 (m, 2H), 3.66 (m,
2H), 3.54 (t, J ) 7.5 Hz, 2H), 1.62 (m, 2H), 1.39 (m, 2H), 0.96 (t,
J ) 7.3 Hz, 3H); ES HRMS exact mass calcd for C14H19N2O2 (M
+ H+) 247.1441, found 247.1449. For 6b: Rf 0.30 (5% MeOH/
1
CH2Cl2); H NMR (400 MHz, CDCl3) δ 7.24-7.42 (m, 5H), 3.83
(t, J ) 6.8 Hz, 2H), 3.52 (s, 3H), 2.62 (t, J ) 6.8 Hz, 2H), 2.38 (t,
J ) 7.2 Hz, 4H), 1.62 (m, 4H), 1.45 (m, 4H), 0.87 (t, J ) 7.2 Hz,
6H); ES HRMS exact mass calcd for C19H31N2O3 (M + H+)
335.2329, found 335.2329.
4-(2-Meth yl-1-pr opyl)-1-ph en yl-2,3-diketopiper azin e (3h ).
Crystallization of the crude reaction mixture from EtOAc
provided 3h (78%) as white flakes: Rf 0.17 (5% MeOH/CH2Cl2);
1H NMR (400 MHz, CDCl3) δ 7.41 (bt, J ) 8 Hz, 2H), 7.35 (bd,
J ) 8 Hz, 2H), 7.28 (bt, J ) 8 Hz, 1H), 3.95-3.98 (m, 2H), 3.66-
3.68 (m, 2H), 3.37 (d, J ) 7.5 Hz, 2H), 2.06 (m, 1H), 0.98 (d, J
) 6.6 Hz, 6H); ES HRMS exact mass calcd for C14H19N2O2 (M +
H+) 247.1434, found 247.1441. Anal. Calcd for C14H18N2O2: C,
68.27; H, 7.37; N, 11.37. Found: C, 67.94; H, 7.48; N, 11.44.
(S)-4-[(2-ter t-Bu toxyca r bon yla m in o-3-p h en yl)p r op yl]-1-
p h en yl-2,3-d ik etop ip er a zin e (3i). Flash chromatography (40
× 70 mm silica, 1.5-3% MeOH/CH2Cl2) provided 3i (60%) as a
white solid: Rf 0.13 (5% MeOH/CH2Cl2); [R]20D ) -106.4° (c 0.10,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.40 (bt, J ) 8.4 Hz, 2H),
7.22-7.34 (m, 8H), 4.79 (bd, J ) 9 Hz, 1H), 4.19 (m, 1H), 3.94-
4.06 (m, 2H), 3.80 (m, 1H), 3.71 (m, 1H), 3.57 (m, 1H), 3.11 (dd,
J ) 13.9 and 4 Hz, 1H), 2.98 (dd, J ) 13.8 and 6.4 Hz, 1H), 2.78
(dd, J ) 13.8 and 7.7 Hz, 1H), 1.40 (s, 9H); ES HRMS exact
mass calcd for C24H30N3O4 (M + H+) 424.2231, found 424.2234.
4-[(4-ter t-Bu toxyca r bon yl)-1-p ip er id in yl]-1-p h en yl-2,3-
d ik etop ip er a zin e (3k ). Flash chromatography (40 × 70 mm
silica, 2-4% MeOH/CH2Cl2) provided 3k (90%) as a white
4-(4-Nit r ob en zyl)-1-p h en yl-2,3-d ik et op ip er a zin e (3b ).
Crystallization of the crude reaction mixture from EtOAc
provided 3b (72%) as a white solid: Rf 0.19 (5% MeOH/CH2-
Cl2); 1H NMR (400 MHz, CDCl3) δ 8.24 (d, J ) 8.8 Hz, 2H), 7.54
(d, J ) 8.8 Hz, 2H), 7.42 (bt, J ) 7.5 Hz, 2H), 7.27-7.34 (m,
3H), 4.84 (s, 2H), 3.94-3.96 (m, 2H), 3.62-3.65 (m, 2H); ES
HRMS exact mass calcd for C17H16N3O4 (M + H+) 326.1135.,
found 326.1118. Anal. Calcd for C17H15N3O4: C, 62.76; H, 4.65;
N, 12.92. Found: C, 62.36; H, 4.52; N, 12.77.
4-(4-Meth oxyben zyl)-1-p h en yl-2,3-d ik etop ip er a zin e (3c).
Flash chromatography (25 × 80 mm silica, 75-100% EtOAc/
hexane) provided 3c (61%) as a white solid: Rf 0.43 (5% MeOH/
1
solid: Rf 0.11 (5% MeOH/CH2Cl2); H NMR (400 MHz, CDCl3)
δ 7.41 (bt, J ) 8 Hz, 2H), 7.35 (bt, J ) 8 Hz, 2H), 7.28 (bt, J )
8 Hz, 1H), 4.67 (tt, J ) 12.3 and 4.0 Hz, 1H), 4.24 (m, 1H), 3.92-
3.94 (m, 2H), 3.85 (m, 1H), 3.56-3.58 (m, 2H), 3.03 (dt, J ) 3.2
and 9.7 Hz, 1H), 2.84 (bt, J ) 12 Hz, 1H), 1.85 (m, 1H), 1.76
(bd, J ) 10 Hz, 1H), 1.55-1.68 (m, 2H), 1.46 (s, 9H); ES HRMS
exact mass calcd for C20H28N3O4 (M + H+) 374.2074, found
374.2069.
1
CHCl3); H NMR (400 MHz, CDCl3) δ 7.40 (bt, J ) 8 Hz, 2H),
7.32 (bd, J ) 8 Hz, 2H), 7.28 (d, J ) 8.7 Hz, 2H), 7.26 (m, 1H),
6.89 (d, J ) 8.7 Hz, 2H), 4.68 (s, 2H), 3.85-3.88 (m, 2H), 3.82
(s, 3H), 3.53-3.56 (m, 2H); ES HRMS exact mass calcd for
C18H19N2O3 (M + H+) 311.1390, found 311.1394.
4-(4-Br om oben zyl)-1-p h en yl-2,3-d ik etop ip er a zin e (3d ).
Crystallization of the crude reaction mixture from EtOAc
provided 3d (72%) as a white solid: Rf 0.44 (5% MeOH/CHCl3);
1H NMR (400 MHz, CDCl3) δ 7.50 (bt, J ) 8.4 Hz, 2H), 7.41 (bt,
J ) 8 Hz, 2H), 7.28-7.33 (m, 3H), 7.23 (d, J ) 8.6 Hz, 2H), 4.70
(s, 2H), 3.88-3.91 (m, 2H), 3.55-3.58 (m, 2H); ES HRMS exact
mass calcd for C17H16BrN2O2 (M + H+) 359.0390, found 359.0404.
Anal. Calcd for C17H15BrN2O2: C, 56.84; H, 4.21; N, 7.80.
Found: C, 57.05; H, 4.31; N, 7.69.
4-(2-Br om oben zyl)-1-p h en yl-2,3-d ik etop ip er a zin e (3e).
Crystallization of the crude reaction mixture from EtOAc
provided 3e (62%) as a white solid: Rf 0.49 (5% MeOH/CHCl3);
1H NMR (400 MHz, CDCl3) δ 7.60 (bd, J ) 8 Hz, 1H), 7.47 (bt,
J ) 8 Hz, 2H), 7.32-7.43 (m, 4H), 7.28 (m, 1H), 7.21 (bt, J ) 8
Hz, 1H), 4.91 (s, 2H), 3.94 (m, 2H), 3.65 (m, 2H); ES HRMS exact
mass calcd for C17H16BrN2O2 (M + H+) 359.0390, found 359.0371.
Anal. Calcd for C17H15BrN2O2: C, 56.84; H, 4.21; N, 7.80.
Found: C, 57.23; H, 4.27; N, 7.71.
Meth yl N-Ben zyl-N-[2-(ter t-bu toxyca r bon yla m in o)eth -
yl]oxa m a te (7). To a solution of Boc-glycine (5.71 g, 32.6 mmol)
in 50 mL of DMF at 0 °C were added benzylamine (4.27 mL,
39.1 mmol), HOBt‚H2O (5.72 g, 42.4 mmol), and EDC‚HCl (8.71,
45.6 mmol). After stirring overnight, allowing the reaction to
warm to room temperature, the solution was poured into EtOAc
and washed with water, a 10% HCl solution, a saturated
NaHCO3 solution, and brine. The solution was dried over Na2-
SO4, filtered, and concentrated to provide a pale yellow waxy
solid (8.27 g, 96%): 1H NMR (400 MHz, CDCl3) δ 7.24-7.33 (m,
5H), 6.62 (bs, 1H), 5.28 (bs, 1H), 4.44 (d, J ) 5.9 Hz, 2H), 3.81
(d, J ) 5.5 Hz, 2H), 1.42 (s, 9H). The product (7.30 g, 27.6 mmol)
was taken up in 50 mL of THF and then added dropwise to a 0
°C suspension of LiAlH4 (8.37 g, 226 mmol) in 40 mL of THF.
After the solution was overnight, allowing the reaction to warm
to room temperature, it was quenched by dropwise addition of
a saturated NH4Cl solution [CAUTION]. The solution was
poured into EtOAc, washed with a saturated NaHCO3 solution
and brine, dried over Na2SO4, filtered, and concentrated to
provide a yellow oil (4.22 g, 61%): 1H NMR (400 MHz, CDCl3)
4-(3-P h en yl-2-p r op en -1-yl)-1-p h en yl-2,3-d ik et op ip er a -
zin e (3f) a n d Meth yl N-[2-(Bis(3-p h en yl-2-p r op en yl)a m i-
n o)eth yl]-N-(p h en yl)oxa m a te (6a ). Crystallization of the

4134 J . Org. Chem., Vol. 63, No. 12, 1998
Notes
δ 7.23-7.34 (m, 5H), 4.96 (bs, 1H), 3.79 (d, J ) 6 Hz, 2H), 3.23
(m, 2H), 2.74 (m, 2H), 1.57 (bs, 1H), 1.44 (s, 9H). The product
(4.22 g, 16.9 mmol) was taken up in 50 mL of EtOAc and 50 mL
of saturated NaHCO3 solution and cooled to 0 °C. Methyl oxalyl
chloride (2.83 mL, 30.8 mmol) was added dropwise. After 10
min, the layers were separated, and the organic phase was
washed with a saturated NH4Cl solution, a saturated NaHCO3
solution, and brine, dried over Na2SO4, filtered, and concen-
trated. Purification by flash chromatography (60 × 80 mm silica,
30-40% EtOAc/hexanes) provided 7 (53%) as a colorless oil: Rf
J ) 13.0 and 3.7 Hz, 1H), 3.81 (d, J ) 14.8 Hz, 1H), 3.58 (m,
1H), 3.49 (dd, J ) 13.0 and 1.8 Hz, 1H), 3.13 (dd, J ) 13.7 and
5.7 Hz, 1H), 3.05 (dd, J ) 13.7 and 9.2 Hz, 1H); ES HRMS exact
mass calcd for C24H22BrN2O2 (M + H+) 449.0859, found 449.0859.
For 11: Rf 0.07 (5% MeOH/CH2Cl2); 1H NMR (400 MHz, CDCl3)
δ 7.39-7.42 (m, 3H), 7.23-7.32 (m, 6H), 7.16 (bd, J ) 7 Hz,
2H), 4.08 (m, 1H), 3.91 (dd, J ) 12.7 and 3.9 Hz, 1H), 3.84 (dd,
J ) 12.7 and 7.7 Hz, 1H), 3.01 (dd, J ) 14.1 and 5 Hz, 1H), 2.99
(dd, J ) 14.1 and 5.7 Hz, 1H); ES HRMS exact mass calcd for
C17H16N2O2 (M + H+) 281.1284, found 281.1289. Anal. Calcd
for C17H16N2O2: C, 72.84; H, 5.75; N, 9.99. Found: C, 72.58;
H, 5.85; N, 10.15. For 12: Rf 0.31 (50% EtOAc/hexane); 1H NMR
(400 MHz, CDCl3) δ 7.32 (bt, J ) 7.5 Hz, 2H), 7.12-7.27 (m,
5H), 6.72 (bt, J ) 7.3 Hz, 1H), 6.59 (bd, J ) 7.5 Hz, 2H), 4.43
(m, 1H), 3.97 (bs, 2H), 3.86 (s, 3H), 3.31 (dd, J ) 13.0 and 5.1
Hz, 1H), 3.24 (dd, J ) 13.0 and 7.3 Hz, 1H), 2.98 (dd, J ) 14.2
and 6.6 Hz, 1H), 2.96 (dd, J ) 14.2 and 7.0 Hz, 1H); ES HRMS
exact mass calcd for C18H21N2O3 (M + H+) 313.1558, found
313.1547.
Met h yl N-(2-Am in oet h yl)-N-(p h en yl)oxa m a t e H yd r o-
ch lor id e (14). A solution of 2,3-diketopiperazine 3a (350 mg,
1.25 mmol) was refluxed in 4 mL of 4 N HCl for 5 h. The solution
was partitioned between CH2Cl2 and saturated NaHCO3 solu-
tion, and the aqueous layer was extracted four times with CH2-
Cl2. The combined organics were dried over Na2SO4, filtered,
and concentrated to provide a pale red oil (228.3 mg, 81%): 1H
NMR (400 MHz, CDCl3) δ 7.32-7.33 (m, 4H), 7.26 (m, 1H), 7.17
(bt, J ) 8 Hz, 2H), 6.70, (bt, J ) 7.3 Hz, 1H), 6.63, (bd, J ) 8
Hz, 2H), 4.11 (bs, 1H), 3.81 (s, 2H), 3.22 (t, J ) 5.7 Hz, 2H),
2.91 (t, J ) 5.7 Hz, 2H), 1.44 (bs, 1H). The diamine product
was converted to oxamate 13 using the procedure described for
the synthesis of 1. Flash chromatography (40 × 60 mm silica,
20% EtOAc/hexane) provided 13 (84%) as a colorless oil: 1H
NMR (400 MHz, CDCl3) δ 7.20-7.39 (m, 9H), 7.14 (m, 1H), 4.48
and 4.43 (2bs, 2H, conformers), 3.93 and 3.78 (2m, 2H, conform-
ers), 3.53 (s, 3H), 3.48 and 3.39 (2m, 2H, conformers), 1.40 (bs,
9H). Through a solution of 13 (54 mg, 0.13 mmol) in 3 mL of
EtOAc at 0 °C was bubbled anhydrous HCl gas for 30 min. The
solution was concentrated to provide 14 as a white foam (46 mg,
100%): 1H NMR (400 MHz, CD3OD) δ 7.40-7.50 (m, 9H), 7.36
(m, 1H), 4.88 (bs, 2H), 4.27 (bs, 2H), 3.51 (s, 3H), 3.32 (m, 2H);
ES HRMS exact mass calcd for C18H21N2O3 (M + H+) 313.1547,
found 313.1546.
1
0.36 (50% EtOAc/hexane); H NMR (400 MHz, CDCl3) δ 7.27-
7.37 (m, 5H), 4.80 (bs, 1H), 4.67 (s, 45% of 2H), 4.52 (s, 55% of
2H), 3.90 (s, 45% of 3H), 3.85 (s, 55% of 3H), 3.43 (t, J ) 5.8 Hz,
55% of 2H), 3.27-3.32 (m, 2H and 45% of 2H), 1.44 (s, 9H); ES
HRMS exact mass calcd for C17H25N2O5 (M + H+) 337.1758,
found 337.1761.
4-Ben zyl-1-(4-br om oben zyl)-2,3-d ik etop ip er a zin e (8) was
prepared from 7 and 4-bromobenzaldehyde using the represen-
tative procedure. Recrystallization from hot 80% EtOAc/hexane
provided 8 (84%) as a white solid: Rf 0.17 (5% MeOH/CH2Cl2);
1H NMR (400 MHz, CDCl3) δ 7.45 (d, J ) 8.2 Hz, 2H), 7.26-
7.34 (m, 5H), 7.16 (d, J ) 8.2 Hz, 2H), 4.67 (s, 2H), 4.62 (s, 2H),
3.34 (m, 4H); ES HRMS exact mass calcd for C18H18BrN2O2 (M
+ H+) 373.0533, found 373.0546. Anal. Calcd for C18H17
-
BrN2O2: C, 57.92; H, 4.59; N, 7.51. Found: C, 57.84; H, 4.69;
N, 7.07.
(S)-Meth yl N-[2-(ter t-Bu toxyca r bon yla m in o)-4-p h en yl-
1-bu tyl]-N-(p h en yl)oxa m a te (9). To a 0 °C solution of (S)-2-
(tert-butoxycarbonylamino)-3-phenyl-1-propionaldehyde10 (12.18
g, 48.9 mmol) in 200 mL of 1,2-dichloroethane were added 12 g
of 4 Å powdered molecular sieves, aniline (4.55 mL, 49.8 mmol),
and sodium triacetoxyborohydride (15.5 g, 73.3 mmol). After
20 min, the ice bath was removed, and the reaction was stirred
for 2 h. The solution was poured into EtOAc, washed with a
saturated NaHCO3 solution and brine, dried over Na2SO4,
filtered, and concentrated to provide a white solid (14.4 g,
90%): 1H NMR (400 MHz, CDCl3) δ 7.31 (t, J ) 7.5 Hz, 2H),
7.13-7.25 (m, 5H), 6.69 (t, J ) 7.3 Hz, 1H), 6.56 (d, J ) 8.6 Hz,
2H), 4.55 (bs, 1H), 3.8 (bs, 1H), 3.24 (dd, J ) 13.0 and 4.6 Hz,
1H), 3.05 (dd, J ) 13.0 and 6.9 Hz, 1H), 2.83-2.88 (m, 2H), 1.42
(s, 9H). The product (4.06 g, 12.5 mmol) was taken up in 80
mL of EtOAc and 40 mL of a saturated NaHCO3 solution and
cooled to 0 °C. Methyl oxalyl chloride (1.26 mL, 13.7 mmol) was
added dropwise. After 30 min, the layers were separated, and
the organic phase was washed with brine, dried over Na2SO4,
filtered, and concentrated to provide 9 (99%) as an oil: Rf 0.15
Meth yl N-[2-(1-ben zyl-1-n -bu tyl)a m in o)eth yl]-N-(p h en -
yl)oxa m a te (6d ) was prepared from 14 and n-butyraldehyde
using the representative procedure. Flash chromatography (40
× 70 mm silica, 1-3% MeOH/CH2Cl2) provided 6d (75%) as a
colorless oil: Rf pending; 1H NMR (400 MHz, CDCl3) δ 7.30-
7.38 (m, 3H), 7.20-7.30 (m, 5H), 7.14 (bd, J ) 8 Hz, 2H), 3.85
(t, J ) 6.9 Hz, 2H), 3.56 (s, 2H), 3.52 (s, 3H), 2.66 (t, J ) 6.9 Hz,
2H), 2.42 (t, J ) 7.3 Hz, 2H), 1.40 (m, 2H), 1.25 (m, 2H), 0.84 (t,
J ) 7.3 Hz, 3H); ES HRMS exact mass calcd for C22H29N2O3 (M
+ H+) 369.2173, found 369.2166.
1
(20% EtOAc/hexanes); H NMR (400 MHz, CDCl3) δ 7.34-7.38
(m, 3H), 7.18-7.26 (m, 5H), 7.11 (bd, J ) 7 Hz, 2H), 7.31 (t, J
) 7.5 Hz, 2H), 4.74 (d, J ) 8.6 Hz, 1H), 4.19 (dd, J ) 13.8 and
10.4 Hz, 1H), 4.07 (m, 1H), 3.50, (s, 3H), 3.45 (dd, J ) 13.8 and
3.7 Hz, 1H), 2.83 (dd, J ) 14.1 and 6.8 Hz, 1H), 2.79 (dd, J )
14.1 and 6.6 Hz, 1H), 1.39 (s, 9H); ES HRMS exact mass calcd
for C23H29N2O5 (M + H+): 413.2071. found 413.2069.
(S)-5-Ben zyl-4-(4-br om oben zyl)-1-p h en yl-2,3-d ik etop ip -
er a zin e (10), (S)-5-ben zyl-1-p h en yl-2,3-d ik etop ip er a zin e
(11), a n d (S)-m eth yl N-[3-p h en yl-1-(p h en yla m in o)-2-p r o-
p yl]oxa m a te (12) were prepared from 9 and 4-bromobenzal-
dehyde using the representative procedure. Flash chromatog-
raphy (40 × 70 mm silica, 30-55% EtOAc/hexanes, then 5%
MeOH/ CH2Cl2) provided 10 (26%) as a white solid, along with
11 (47%) as a white solid and 12 (10%) as a colorless oil. For
Ack n ow led gm en t. The authors thank K. D. Ander-
son, P. A. Ciecko, and M. M. Zrada for combustion
analyses, C. W. Ross and H. G. Ramjit for mass spectra,
W. C. Lumma for discussion, and J . M. Hartzell for help
in manuscript preparation.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra for
compounds 3c,f,i,k , 3g/6b, 6a ,d , 7, 9, 10, 12, and 14 (12 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.
10: Rf 0.13 (50% EtOAc/hexane); [R]20 ) -555.2° (c 0.050,
D
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.50 (bd, J ) 8.3 Hz, 2H),
7.41 (bt, J ) 8 Hz, 2H), 7.23-7.34 (m, 6H), 7.20 (d, J ) 8.2 Hz,
2H), 7.02 (bd, J ) 8 Hz, 2H), 5.29 (d, J ) 14.8 Hz, 1H), 4.00 (dd,
(10) Zlatoidsky, P. Helv. Chim. Acta 1994, 77, 575-578.
J O9800309