Benzoylation of dianions: Preparation of monobenzoylated derivatives of symmetrical secondary diamines

Full text of DOI:10.1021/jo9908501

J . Org. Chem. 1999, 64, 7661-7662
7661
Ch a r t 1
Ben zoyla tion of Dia n ion s: P r ep a r a tion of
Mon oben zoyla ted Der iva tives of
Sym m etr ica l Secon d a r y Dia m in es
Tao Wang,* Zhongxing Zhang, and
Nicholas A. Meanwell
Bristol-Myers Squibb Pharmaceutical Research Institute,
5 Research Parkway, P.O. Box 5100,
Wallingford, Connecticut 06492
Received May 25, 1999
Monoacylated symmetrical secondary diamines are
building blocks1 or intermediates2 widely used in the drug
discovery process that are present in several investiga-
tional and established drugs.3 Examples include the
cardiotonic agent vesnarinone and the antihypertensive
agent prazosin (Chart 1). Direct monoacylation of sym-
metrical diamines is frequently fraught with the com-
plication associated with the tendency for bis-acylation
to occur. To date, there are a number of indirect, multi-
step preparations of monoacylated symmetric secondary
diamines from diamines4,5 with the most common path-
way involving the selective monoprotection of one nitro-
gen atom, followed by acylation of the remaining nitrogen
and finally deprotection, to afford the desired product.5
There have been few reports of the direct transforma-
tion of diamines to mono benzoyl diamines,6-9 the main
difficulty with this simple transformation being the
formation of dibenzoyl diamines.6 Under normal basic
conditions using, for example, pyridine as the base and
solvent, the dibenzoylated compound 4a was the domi-
nant product, even through a large excess (10 equiv) of
piperazine 1a was used (Scheme 1). A possible explana-
tion of the uncontrollable dibenzoylation of symmetrical
secondary diamines under these conditions is that the
monobenzoylated intermediate 3a is more soluble in the
solvent than piperazine 1a and reacts preferentially with
the benzoyl chloride to provide predominantly the ob-
served dibenzoylated product 4a .
Sch em e 1
This problem has been resolved to some degree by
application of a rather laborious procedure involving the
multistep addition of starting materials with very cau-
tious control of the pH (range 3.8-5.4) of the reaction
mixture.5,6 Similarly, Watthey and co-workers described
the direct monoaroylation of piperazine and homopip-
erazine in moderate yields (46-60%) using AcOH as the
solvent.7 In this case, the authors took advantage of the
fact that piperazine was mostly present as a monoacetate
salt and the product remained in that form after the
benzoylation. Alternative procedures have utilized ben-
zoic acid8 and benzoic esters9 as coupling partners.
After encountering several of these problems in the
preparation of monobenzoylated piperazine derivatives,
we sought a more reliable and predictable procedure that
would be of general applicability. The criteria established
for this new methodology were: (a) simple and readily
available starting materials; (b) mild, preferably room
temperature conditions; (c) the formation of the product
cleanly in high yield.
It was rationalized that the reactivity of the diamine
could be altered by making the mono or disalt 5 of
diamine 1, which should be more reactive toward an aroyl
chloride than diamine 1 itself, thus affording the mono-
acylated product 3a under kinetical control (Scheme 2).
In developing this strategy, several experimental proto-
cols were explored: 1 (a) 1 equiv of BuLi, (b) 1 equiv of
BzCl;10 2 (a) 1 equiv of BuLi, (b) 1 equiv of TMSCl, (c) 1
equiv of BzCl;11 3 (a) 2 equiv of BuLi, (b) 1 equiv of BzCl;12
4 (a) 2 equiv of BuLi, (b) 1 equiv of TMSCl, (c) 1 equiv of
BzCl;13 5 (a) 1 equiv of BuLi, (b) 1 equiv of TMSCl, (c) 1
equiv of BuLi, (d) 1 equiv of BzCl.14
(1) (a) Fukushi, H.; Mabuchi, H.; Terashita, Z.-I.; Nishikawa, K.;
Sugihara, H. Chem. Pharm. Bull. 1994, 42, 551. (b) Ross, D. D.;
Lednicer, D. J . Heterocycl. Chem. 1982, 91, 975. (c) Walsh, D. A.; Green,
J . B.; Franzyshen, S. K.; Nolan, J . C.; Yanni, J . M. J . Med. Chem. 1990,
33, 2028. (d) Kurokama, M.; Sato, F.; Fujiwara, I.; Hatano, N.; Honda,
Y.; Yoshida, T.; Naruto, S.; Mastumoto, J .-I.; Uno, H. J . Med. Chem.
1991, 34, 927. (e) Dillard, R. D.; Yen, T. T.; Stark, P.; Pavey, D. E. J .
Med. Chem. 1980, 23, 717. (f) Sturzebecher, J .; Prasa, D.; Hauptmann,
J .; Vieweg, H.; Wirkstrom, P. J . Med. Chem. 1997, 40, 3091. (g)
Leonardi, A.; Motta, G.; Boi, C.; Testa, R.; Poggesi, E.; Benedetti, P.
G. D.; Menziani, M. C. J . Med. Chem. 1999, 42, 427.
(2) (a) Williams, L.; Booth, S. E.; Undheim, K. Tetrahedron 1994,
50, 13697. (b) Li, R.-T.; Ding, P.-Y.; Han, M.; Cai, M.-S. Synth.
Commun. 1998, 28, 295.
(3) (a) Ohnishi, A.; Ishizaki, J . Clin. Pharmacol. 1988, 28, 719. (b)
Ravina, E.; Teran, C.; Santana, L.; Garcia, N.; Estevez, I. Heterocycles
1990, 31, 1967. (c) Scriabine, A.; Constantine, J . W.; Hess, H.-J .;
McShane, W. K. Experientia 1980, 24, 1150.
(4) (a) Manoury, P. M.; Binet, J . L.; Dumas, A. P.; Lefevre-Borg, F.;
Cavero, I. J . Med. Chem. 1986, 29, 19. (b) Dhawan, B.; Southwich, P.
L. Org. Prep. Proced. Int. 1975, 7, 85. (c) Southwich, P. L.; Dhawan,
B. Org. Prep. Proced. Int. 1976, 8, 205. (d) Lyle, R. E.; Coppola, B. P.;
Saavedra, J . E.; Lyle, G. G. Org. Prep. Proced. Int. 1978, 10, 304.
(5) Dorokhova, M. I.; Alekseeva, E. N.; Kuznetsova, I. A.; Portnov,
M. A.; Rozanova, Y. M.; Tikhnova, O. Y.; Mikhalev, V. A. Pharm. Chem.
J . 1974, 737, and references herein.
(6) (a) J acobi, K. Ber. Chem. 1933, 66, 113. (b) Cymerman-Craig,
J .; Rogers, W. P.; Tate, M. E. Austr. J . Chem. 1956, 9, 397.
(7) Desai, M.; Watthey, J . W. H.; Zuckerman, M. Org. Prep. Proced.
Int. 1976, 8, 85.
When piperazine 1a was treated with 2 equiv of
(10) At -78 °C, 3a /4a ) 1:3.2; At 0 °C, 3a /4a ) 1:2.2.
(11) At room temperature, 3a /4a ) 1:6.5.
(8) Masaguer, C. F.; Ravina, E. Tetrahedron Lett. 1996, 37, 5171.
(9) Um, I.-H.; Kwon, H.-J .; Kwon, D.-S. J . Chem. Res., Miniprint
1995, 1801.
(12) At 0 °C, 3a /4a ) 1.4:1; At room temperature, 3a /4a ) 35:1.
(13) At room temperature, 3a /4a ) 1:2.7.
(14) At room temperature, 3a /4a ) 1:1.
10.1021/jo9908501 CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/08/1999

7662 J . Org. Chem., Vol. 64, No. 20, 1999
Ta ble 1. Mon oa r oyla tion of Sym m etr ica l Secon d a r y Dia m in es
Notes
entry no.
diamine
piperazine
homopiperazine
2,5-dimethylpiperazine
CH3NHCH2CH2NHCH3
CH3NHCH2CH2CH2NHCH3
1,4,7-triazacyclononane
piperazine
acyl chloride
ratio of mono (3) to di (4) benzoylated producta
yield (%)b
1
2
3
4
5
6
7
8
C6H5COCl
C6H5COCl
C6H5COCl
C6H5COCl
C6H5COCl
C6H5COCl
2-MeOC6H4COCl
3-MeC6H4COCl
35:1
27:1
18:1
84
91
78
80
83
85c
90
89
5.6:1
>100:1
20:1
>100:1
>100:1
piperazine
a
b
Ratios were determined by LC-MS. Isolated yields. c Product was soluble in the aqueous layer.
Sch em e 2
Exp er im en ta l Section
Gen er a l. Benzoyl chlorides, piperazines, N,N′-dimethyl di-
amines, THF, and n-butyllithium are commercially available
from Aldrich and were used as received. 1H and 13C NMR spectra
were obtained at 300 MHz with samples dissolved in CD3OD or
CDCl3. The ratios of products were measured by LC-MS spectra,
using quenched samples from the reaction mixtures prior to
workup.
Typ ica l P r oced u r e for Mon oben zoyla tion : P r ep a r a tion
of N-(Ben zoyl)p ip er a zin e 3a . To a stirred solution of pipera-
zine (1.0 g, 11.6 mmol) in dry THF (50 mL) under argon was
added 2.5 M n-BuLi in THF (10.23 mL, 25.5 mmol) at room
temperature. After stirring for 1 h at room temperature, benzoyl
chloride (1.27 mL, 11.0 mmol) was added to the solution of
dianion, and the reaction mixture was stirred for an additional
10 min. The reaction mixture was quenched with MeOH, and
the solvents were evaporated. The residue was partitioned
between EtOAc (50 mL) and sat. NaHCO3. The aqueous layer
was saturated with NaCl and extracted with EtOAc (2 × 30 mL).
The organic layer was dried over MgSO4 and concentrated to
afford the crude product 3a , which was generally of sufficient
purity to be used directly without further purification. Chro-
matography on a silica gel column (EtOAc/MeOH/Et3N, 7:3:1)15
Sch em e 3
n-butyllithium and 1 equiv of benzoyl chloride 2a at room
temperature, the monobenzoylated compound 3a was
found to be the predominant product (Scheme 2 and
Table 1). The ratio of mono and dibenzoylpiperazine
(3a :3b) 30 min after the addition of benzoyl chloride to
the solution of dianion was determined to be 35:1 by LC-
MS, and the crude product was of sufficient purity for
the further use. Employing Chou’s purification proce-
dure,15 the monobenzoyl piperazine was isolated in 84%
yield. In the other examples compiled in Table 1, using
acyclic diamines (entries 4 and 5),4a substituted pipera-
zines (entry 3),4-9 homopiperazine (entry 2),7 and 1,4,7-
triazacyclononane (entry 6), the monobenzoylated de-
rivatives 3a -f were always the predominant product. In
addition, the dianion of piperazine reacted with substi-
tuted benzoyl chlorides (entries 7 and 8) to provide only
the monobenzoylated piperazines 3g,h .
To probe further the application of this methodology,
the sequential functionalization of piperazine and ho-
mopiperazine with two different aroyl chlorides was
examined, as depicted in Scheme 3. The yield of the
product in each case was quantitative, providing a
reaction of sufficient reliability to be of utility in the
preparation of a solution phase combinatorial library.
In summary, a very convenient, efficient, and practical
methodology has been developed for monoaroylation of
symmetrical secondary diamines. Further applications
of this procedure which extend its scope and applicability
are under active investigation.
1
gave 1.76 g (84% yield). H NMR (300 MHz, CD3OD) δ 7.37 (m,
5H), 3.73 (br s, 2H), 3.42 (br s, 2H), 2,85 (br s, 4H); 13C NMR
(75 MHz, CD3OD) δ 170.9, 135.0, 129.6, 128.2, 126.5, 44.5;
HRMS m/ z: (M + H)+ calcd for C11H15N2O 191.1184, found
191.1181.
Typ ica l P r oced u r e for Diben zoyla tion : P r ep a r a tion of
N-(2-Meth oxyben zoyl)-N′-(ben zoyl)piper azin e 7. To a stirred
solution of piperazine (0.5 g, 5.81 mmol) in dry THF (50 mL)
under argon was added 2.5 M n-BuLi in THF (5.2 mL, 13.0
mmol) at room temperature. After stirring for 1 h at room
temperature, benzoyl chloride (0.64 mL, 5.51 mmol) was added
to the solution of dianion, and the reaction mixture was stirred
for an additional 10 min before 2-methoxybenzoyl chloride (0.99
g, 5.81 mmol) was added. Another 10 min later, the reaction
mixture was quenched with MeOH, and the solvents were
evaporated. The residue was partitioned between EtOAc (50 mL)
and sat. NaHCO3. The aqueous layer was saturated with NaCl
and extracted with EtOAc (2 × 30 mL). The organic layer was
dried over MgSO4 and concentrated to afford product 7 (1.29 g,
1
100% yield). H NMR (300 MHz, CD3OD) δ 7.50-6.80 (m, 9H),
3.90-3.20 (m, 11H); 13C NMR (75 MHz, CD3OD) δ 171.1, 168.7,
155.2, 134.8, 131.0, 129.9, 128.3, 127.7, 126.8, 126.5, 124.3, 120.6,
110.9, 104.2, 67.4, 54.8, 25.0; HRMS m/ z: (M + H)+ calcd for
C19H21N2O3 325.1552, found 325.1537.
Ack n ow led gm en t. The authors are very grateful to
Professor Gilbert Stork and Drs. Keith Combrink and
Owen Wallace for valuable advice. Also the authors
thank Dr. Chaoran Huang for assistance in obtaining
exact MS spectra.
Su p p or tin g In for m a tion Ava ila ble: 1H and 13C spectra
and HRMS data of compounds 3a -h , 7, and 8. This material
is available free of charge via the Internet at http://pubs.acs.org.
J O9908501
(15) (a) Chou, W.-C.; Tan, C.-W.; Chen, S.-F.; Ku, H. J . Org. Chem.
1998, 63, 10015. (b) Chou, W.-C.; Chou, M.-C.; Lu, Y.-Y.; Chen, S.-F.
Tetrahedron Lett. 1999, 40, 3419.