Palladium(0)-catalyzed coupling of organozinc iodide reagents with bromopyridines: Synthesis of selectively protected pyridine-containing azamacrocycles

Article abstract of DOI:10.1021/jo0109523

The synthesis of azamacrocycles in which the ring nitrogens are regioselectively functionalized is described. An organozinc palladium(0)-catalyzed coupling with an appropriately functionalized bromopyridine generated a key intermediate, which was transformed in two steps to a desired precursor and subjected to an intramolecular N-alkylation to effect a macrocyclization affording selectively protected azamacrocycles 1-3.

Full text of DOI:10.1021/jo0109523

J . Org. Chem. 2002, 67, 1407-1410
1407
P a lla d iu m (0)-Ca ta lyzed Cou p lin g of
Or ga n ozin c Iod id e Rea gen ts w ith
Br om op yr id in es: Syn th esis of Selectively
P r otected P yr id in e-Con ta in in g
Aza m a cr ocycles
F igu r e 1. Structures of selectively protected pyridine-
containing azamacrocycles.
Renato T. Skerlj,* Yuanxi Zhou, Trevor Wilson, and
Gary J . Bridger
Sch em e 1a
AnorMED, Inc., #200-20353 64th Avenue,
Langley, British Columbia, Canada V2Y 1N5
rskerlj@anormed.com
Received September 25, 2001
Abstr a ct: The synthesis of azamacrocycles in which the
ring nitrogens are regioselectively functionalized is de-
scribed. An organozinc palladium(0)-catalyzed coupling with
an appropriately functionalized bromopyridine generated a
key intermediate, which was transformed in two steps to a
desired precursor and subjected to an intramolecular N-
alkylation to effect a macrocyclization affording selectively
protected azamacrocycles 1-3.
Over the past few years, we have reported a novel
series of bicyclam structures that exhibit potent and
selective inhibition of HIV-1 replication by antagonism
of the chemokine receptor CXCR4.1,2 To identify the
pharmacophore necessary for potent anti-HIV activity,
a series of unsymmetrical pyridine-containing azamac-
rocycles were necessary to complete the SAR (Figure 1).
However, a review of the literature3 revealed that
methods to synthesize these azamacrocycles with the
ability to regioselectively functionalize the macrocyclic
ring nitrogens were lacking. This paper reports the first
synthesis of selectively protected azamacrocycles 1-3
utilizing an organozinc palladium(0)-catalyzed coupling
strategy to generate appropriately functionalized precur-
sors, which were then subjected to intramolecular N-
alkylation to effect the macrocyclization.
a
Reagents and conditions: (a) BH3‚THF, THF, 60 °C; (b)
2-NO2C6H4SO2Cl (NsCl), NEt3, CH2Cl2, room temperature; (c)
ZnI(CH2)4CN, (PPh3)2PdCl2, THF, 60 °C; (d) BH3‚Me2S, THF, 60
°C, 4 h; (e) BrCOCH2Br, Na2CO3, THF, -15 °C; (f) K2CO3, CH3CN,
60 °C; (g) BH3‚THF, THF, 50 °C; (h) ClP(O)(OEt)2, Et3N, CH2Cl2,
room temperature; (i) K2CO3, PhSH, DMF, room temperature, 4
h.
group was accomplished using 3 equiv of BH3‚THF in
THF at 60 °C to afford the corresponding amine in 72%
yield. At this stage, we explored the utility of different
protecting groups for the primary amine that could also
be used in the macrocyclization reaction. Two protecting
groups that we investigated were the diethylphosphora-
mide5 and the 2-nitrobenzenesulfonamide;6 however, on
the basis of preliminary experiments that were used to
probe the macrocyclization, it was found that the sul-
fonamide was far superior. As a consequence, to complete
the synthesis of compounds 1 and 2, we used the
2-nitrobenzenesulfonamide 5, which was prepared in 65%
yield.
Generation of the C-C bond at the pyridine C-6
position was explored using the palladium(0)-catalyzed
coupling of the bromopyridine 5 with 4-cyanobutylzinc
iodide based on the pioneering work by Negishi7 in the
palladium(0)-catalyzed cross-coupling reaction of orga-
nozinc iodides.8 Several different groups9 have subse-
quently extended the Negishi cross-coupling method to
bromopyridines using organozinc iodides, and several
methods9,10 have been reported in the literature for the
generation of organozinc iodides; however, in our hands
a modified method described by Walker9c proved to be
the most reliable. After some experimentation, it was
The sequence leading to compounds 1 (R ) Ns) and 2
(R ) Dep) is shown in Scheme 1. The starting material,
(6-bromopyridin-2-yl)acetonitrile 4, was readily available
in 91% yield from 2,6-dibromopyridine using a methodol-
ogy that we recently developed.4 Reduction of the cyano
* Corresponding author.
(1) For a review on azamacrocycles as anti-HIV agents, see: Bridger,
G. J ., Skerlj, R. T., DeClercq, E., Eds. Advances in Antiviral Drug
Design; J ai Press: Connecticut, 1999; Vol 3, pp 161-229.
(2) (a) Gerlach, L. O.; Skerlj, R. T.; Bridger, G. J .; Schwartz, T. W.
J . Biol. Chem. 2001, 276, 14153-14160. (b) Hendrix, C. W.; Flexner,
C.; MacFarland, R. T.; Giandomenico, C.; Fuchs, E. J .; Redpath, E.;
Bridger, G.; Henson, G. W. Antimicrob. Agents Chemother. 2000, 44,
1667-1673. (c) Bridger, G. J .; Skerlj, R. T.; Padmanabhan, S.;
Martellucci, S. A.; Henson, G. W.; Struyf, S.; Witvrouw, M.; Schols,
D.; De Clercq, E. J . Med. Chem. 1999, 42, 3971-3981. (d) Este, J . A.;
Cabrera, C.; De Clercq, E.; Struyf, S.; Van Damme, J .; Bridger, G. J .;
Skerlj, R. T.; Abrams, M. J .; Henson, G.; Gutierrez, A.; Clotet, B.;
Schols, D. Mol. Pharmacol. 1999, 55, 67-73. (e) Bridger, G. J .; Skerlj,
R. T.; Padmanabhan, S.; Martelluci, S. A.; Henson, G. W.; Abrams, M.
J .; J oao H. C.; Witvtouw, M.; De Vreese, K.; Pauwels, R.; De Clercq,
E. J . Med. Chem. 1996, 39, 109-119. (f) Bridger, G. J .; Skerlj, R. T.;
Thornton, D.; Padmanabhan, S.; Martelluci, S. A.; Henson, G. W.;
Abrams, M. J .; Yamamoto, N.; De Vreese, K.; Pauwels, R.; De Clercq,
E. J . Med. Chem. 1995, 38, 366-378.
(4) Skerlj, R. T.; Bogucki, D.; Bridger, G. J . Synlett 2000, 10, 1488-
1490.
(5) Qian, L.; Sun, Z.; Mertes, M. P.; Mertes, K. B. J . Org. Chem.
1991, 56, 4904-4907.
(6) Fukuyama, T.; J ow, C.-K.; Cheung, M. Tetrahedron Lett. 1995,
36, 6373-6374.
(3) (a) Moretto, A. F.; Zhang, H.-C.; Maryanoff, B. E. J . Am. Chem.
Soc. 2001, 123, 3157-3158. (b) An, H.; Cook, P. D. Tetrahedron Lett.
1996, 37, 7233-7236. (c) Costa, J .; Delgado, R. Inorg. Chem. 1993,
32, 5257-5265. (d) Rothermel, G. L.; Miao, L.; Hill, A. L.; J ackels, S.
C. Inorg. Chem. 1992, 31, 4854-4859.
10.1021/jo0109523 CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/17/2002

1408 J . Org. Chem., Vol. 67, No. 4, 2002
Notes
Sch em e 2a
Ta ble 1. P a lla d iu m (0)-Ca ta lyzed Cou p lin g of
Br om op yr id in es w ith Or ga n ozin c Iod id e Rea gen tsa
substrate
R
n
X(CH2)mZnI
product: yield (%)
a
Reagents and conditions: (a) BH3‚Me2S, THF, 60 °C; (b)
5
5a
5
5b
5c
Ns
Dep
Ns
Dep
Ns
2
2
2
1
1
CN(CH2)4ZnI
CN(CH2)4ZnI
BocNH(CH2)5ZnI
CN(CH2)5ZnI
CN(CH2)5ZnI
6: 72
BrCOCH2Br, Na2CO3, THF, -15 °C; (c) K2CO3, CH3CN, 60 °C;
(d) BH3‚THF, THF, 50 °C.
6a : 77
no reaction
6b: 95
6c: 66
amine with bromoacetyl bromide in THF in the presence
of Na2CO3 at -15 °C afforded the acetamide 7 in 56%
overall yield from 6 (Scheme 1).13
a
Reactions were carried out in THF at 60 °C using 4 equiv of
organozinc iodide reagent.
Our initial attempt at effecting the intramolecular
macrocyclization utilizing Cs2CO3 as a base14 in DMF
under high-dilution conditions15 at 50 °C resulted in the
isolation of the macrocycle 8 in 50% yield as well as a
side product in 18% yield, which after characterization
was identified as having lost SO2.16 By optimizing the
reaction conditions, we found that K2CO3 in CH3CN at
60 °C completely shut down the formation of the side
product, resulting in the isolation of compound 8 as the
sole product in 84% yield. Reduction of the amide function
with BH3‚THF complex in THF at 50 °C liberated the
secondary amine, affording the selectively protected
azamacrocycle 1 (R ) Ns) in a 70% yield (Scheme 1). To
protect the alternative secondary amine, compound 1 was
treated with diethylphosphoryl chloride, affording the
diethylphosphoramidate 9 in 77% yield (although any
protecting group could have been used). Selective depro-
tection of the 2-nitrobenzenesulfonamide group was then
accomplished using thiophenol in the presence of K2CO3
to give compound 2 (R ) Dep) in 50% yield. This reaction
sequence demonstrates that selective protection of either
secondary amine is possible. Both compounds 1 and 2
were subsequently further elaborated and their products
assessed for antiviral activity.17
The synthesis of macrocycle 3 (R ) Ns) was completed
starting from nitrile 6c using a methodology similar to
that described for the preparation of 1 (Scheme 2).
Reduction of the cyano group of compound 6c was
accomplished using 6 equiv of BH3‚Me2S in THF at 60
°C over 4 h to afford the corresponding amine (a short
reaction time was critical to avoid reduction of the nitro
group of the 2-nitrobenzenesulfonamide protecting group).
Reaction of the crude amine with bromoacetyl bromide
in THF in the presence of Na2CO3 at -15 °C afforded
the acetamide 12 in 66% overall yield from 6c. Intramo-
lecular macrocyclization utilizing K2CO3 in CH3CN at 60
°C under high-dilution conditions15 resulted in the isola-
tion of compound 13 as the sole product in 91% yield.
found that an excess of 4-cyanobutylzinc iodide (4 equiv)
was required for complete reaction of the bromopyridine
using dichlorobis(triphenylphosphine)palladium(II) as
the catalyst. Initial attempts at the coupling reaction
using compound 5 resulted in variable yields (40 to 72%)
of the desired product 6 with a lower yield being more
pronounced on a larger scale. However, use of the
diethylphosphoramidate 5a resulted in a clean reaction
affording the desired product 6a in 77% yield (Table 1),
indicating that the outcome of the reaction was influ-
enced by the nitrogen protecting group. In fact, the
variable yield with compound 5 was due to the formation
of a side product, which was identified as compound 10,
where the nitro group of the sulfonamide was reduced
to the corresponding aniline (Scheme 1). We suspected
that excess zinc in the reaction medium was responsible
for the reduction of the nitro group. Indeed, it was found
that filtration of the 4-cyanobutylzinc iodide solution
through a 0.45 µm filter prior to being added to the
bromide 5 resulted in a consistent yield (65-72%) of the
coupled product 6 with no detection of the reduced
compound 10.
Since the ultimate goal was to install a pendant amine
function at C-6, the coupling reaction was also attempted
using N-tert-butyloxycarbamoyl-5-pentylaminezinc io-
dide;11 however, attempted coupling of this reagent with
compound 5 resulted in no reaction (Table 1). Two
additional examples that were studied in the palladium-
(0)-catalyzed coupling reaction were the sulfonamide 5c
and the phosphoramidate 5b, which were required for
the synthesis of 3. Coupling of compound 5b with
5-cyanopentylzinc iodide afforded the desired product 6b
in 95% yield, whereas coupling of compound 5c with the
same organozinc reagent afforded the product 6c in 66%
yield.
Reduction of the cyano group of compound 6 was
accomplished using 6 equiv of BH3‚Me2S in THF at 60
°C over 4 h to afford the corresponding amine.12 In this
case, it was important to stop the reaction after 4 h to
prevent the formation of byproduct 11 also arising from
reduction of the nitro group of the 2-nitrobenzenesulfona-
mide protecting group (Scheme 1). Reaction of the crude
(11) N-tert-Butyloxycarbamoyl-5-pentylamine iodide exhibited 1H
NMR (CDCl3) δ 1.28-1.43 (m, 13H), 1.74 (quintet, J ) 6.9 Hz, 2H),
2.98-3.09 (m, 2H), 3.09 (t, J ) 6.9 Hz, 2H), 4.72 (br s, 1H) and was
prepared from the corresponding alcohol using triphenylphosphine-
iodine: Verheyden, J . P. H.; Hershkowitz, R. L.; Rein, B. M.; Chung,
B. C. J . Am. Chem. Soc. 1964, 86, 964-965.
(12) Brown, H. C.; Choi, Y. M.; Narasimhan, S. J . Org. Chem. 1982,
47, 3153-3163.
(13) Bridger, G. J .; Abrams, M. J .; Padmanabhan, S.; Gaul, F.;
Larsen, S.; Henson, G. W.; Schwartz, D. A.; Longley, C. B.; Burton, C.
A.; Ultee, M. E. Bioconjugate Chem. 1996, 7, 255-264.
(14) Ostrowicki, A.; Koepp, E.; Vogtle, F. Top. Curr. Chem. 1992,
161, 37-67.
(7) (a) Negishi, E. Acc. Chem. Res. 1982, 15, 340-348 and references
therein. (b) Negishi, E.; King, A. O.; Okukado, N. J . Org. Chem. 1977,
42, 1821-1823.
(8) For a recent review on the use of functionalized organozinc
compounds, see: Boudier, A.; Bromm, L. O.; Lotz, M.; Knochel, P.
Angew. Chem., Int. Ed. 2000, 39, 4414-4435.
(9) (a) Schmidt, B.; Ehlert, D. K. Tetrahedron Lett. 1998, 39, 3999-
4002. (b) Billotte, S. Synlett 1998, 379-380. (c) Walker, M. A.; Kaplita,
K. P.; Chen, T.; King, H. D. Synlett 1997, 169-170. (d) Sakamoto, T.;
Nishimura, S.; Kondo, Y.; Yamanaka, H. Synthesis 1988, 485-486.
(10) (a) Knochel, P.; Singer, R. D. Chem. Rev. 1993, 93, 2117-2118.
(b) Rieke, R. D. Science 1989, 246, 1260-1264.
(15) Chavez, F.; Sherry, A. D. J . Org. Chem. 1989, 54, 2990-2992.
(16) Loss of SO2 has previously been observed with 2,4-dinitroben-
zenesulfonamide: Fukuyama, T.; Cheung, M.; Low, C.-K.; Hidai, Y.;
Kan, T. Tetrahedron Lett. 1997, 38, 5831-5834.
(17) Bridger, G. J .; Skerlj, R. T. Unpublished results.

Notes
J . Org. Chem., Vol. 67, No. 4, 2002 1409
5b (180 mg, 85%) as a white foam after purification (EtOAc-
CH2Cl2, 30:70): 1H NMR (CDCl3) δ 1.29 (dt, J ) 6.9, 0.6 Hz,
6H), 3.55-3.60 (m, 1H), 3.97-4.15 (m, 4H), 4.20 (dd, J ) 10.4,
6.8 Hz, 2H), 7.30 (d, J ) 7.5 Hz, 1H), 7.38 (d, J ) 7.5 Hz, 1H),
7.50-7.56 (m, 1H); 13C NMR (CDCl3) δ 16.52 (3J PC ) 7.0 Hz),
46.35, 62.90 (2J PC ) 5.1 Hz), 120.57, 127.02, 139.40, 142.01,
160.22; exact mass m/z calcd for C10H1681BrN2O3P 324.13, found
[M + Na]+ 347.00.
Reduction of amide 13 to the corresponding secondary
amine with BH3‚THF complex in THF at 50 °C afforded
the selectively protected azamacrocycle 3 (R ) Ns) in 77%
yield (Scheme 2). Compound 3 was also further elabo-
rated and the product assessed for antiviral activity.17
In conclusion, the palladium(0)-catalyzed coupling of
an organozinc iodide reagent and a bromopyridine fol-
lowed by intramolecular macrocyclization represents an
efficient strategy for the synthesis of selectively func-
tionalized pyridine-containing azamacrocyles.
Gen er a l P r oced u r e for th e P d (0)-Ca ta lyzed Cou p lin g of
Br om op yr id in es w ith Or ga n ozin c Iod id e Rea gen ts. To a
round-bottom flask containing Zn dust (1.30 g, 20.0 mmol) was
added dibromoethane (305.2 mg, 1.62 mmol), and the resulting
mixture was warmed to 60 °C and then allowed to cool for 1
min. This heating-cooling process was repeated three more
times, and then the flask was allowed to cool for an additional
3 min. Trimethylsilyl chloride (26.5 mg, 0.24 mmol) in THF (20
mL) was added; the resulting mixture was warmed to 60 °C,
and a solution of alkyl iodide (6.5 mmol) in THF (1 mL) was
added. The mixture was stirred at 60 °C until all the alkyl iodide
had been consumed (ca. 4 h, TLC control). The resulting solution
of alkylzinc iodide was transferred by a syringe fitted with a
0.45 µm filter to a second flask charged with the bromopyridine
5-5c (1.3 mmol) and (Ph3P)2PdCl2 (45 mg, 0.06 mmol). The
resulting mixture was stirred for 18 h at 60 °C under N2, cooled
to room temperature, and quenched with saturated aqueous
NH4Cl solution (5 mL). The resulting mixture was stirred for
20 min at room temperature and diluted with ethyl acetate (200
mL), and the organic phase was washed with saturated aqueous
NH4Cl (50 mL) and brine (50 mL) and dried over Na2SO4. The
organic phase was concentrated, and the crude material was
purified by flash column chromatography on silica gel using ethyl
acetate-CH2Cl2 or MeOH-CH2Cl2 as the eluant.
{2-[6-(4-Cya n obu tyl)p yr id in -2-yl]eth yl}-2-n itr oben zen e-
su lfon a m id e (6). Bromide 5 (503 mg, 1.3 mmol) gave 6 (363
mg, 72%) as a light yellow oil after purification (EtOAc-CH2-
Cl2, 5:95): 1H NMR (CDCl3) δ 1.69-1.78 (m, 2H), 1.83-1.93 (m,
2H), 2.41 (t, J ) 7.1 Hz, 2H), 2.83 (t, J ) 7.5 Hz, 2H), 3.00 (t, J
) 5.9 Hz, 2H), 3.54 (dt, J ) 5.7, 5.7 Hz, 2H), 6.86 (d, J ) 12.3
Hz, 1H), 7.00 (d, J ) 8.1 Hz, 1H), 7.08 (br s, 1H), 7.50 (dd, J )
7.5, 7.5 Hz, 1H), 7.71-7.76 (m, 2H), 7.83-7.86 (m, 1H), 8.14-
8.18 (m, 1H); 13C NMR (CDCl3) δ 17.40, 25.42, 29.07, 36.43,
37.53, 42.98, 120.20, 121.18, 121.21, 125.66, 131.34, 133.10,
133.71, 134.66, 137.47, 148.39, 158.61, 161.27; exact mass m/z
calcd for C18H20N4O4S 388.12, found [M + H]+ 389.01.
{2-[6-(5-Cya n op en t yl)p yr id in -2-yl]m et h yl}-2-n it r ob en -
zen esu lfon a m id e (6c). Bromide 5c (594 mg, 1.60 mmol) gave
6c (407 mg, 66%) as a yellow oil after purification (EtOAc-CH2-
Cl2, 5:95): 1H NMR (CDCl3) δ 1.43-1.53 (m, 2H), 1.65-1.78 (m,
4H), 2.36 (t, J ) 7.1 Hz, 2H), 2.68 (t, J ) 7.7 Hz, 2H), 4.39 (d, J
) 6.0 Hz, 2H), 6.85 (s, 1H), 6.99 (d, J ) 12.6 Hz, 1H), 7.02 (d, J
) 12.9 Hz, 1H), 7.50 (dd, J ) 7.7, 7.7 Hz, 1H), 7.65-7.72 (m,
2H), 7.86-7.89 (m, 1H), 8.08-8.13 (m, 1H); 13C NMR (CDCl3) δ
17.38, 25.51, 28.53, 28.63, 37.83, 48.32, 119.40, 120.12, 122.12,
125.77, 131.43, 133.02, 133.77, 134.18, 137.46, 148.35, 153.88,
161.67; exact mass m/z calcd for C18H20N4O4S 388.12, found [M
+ H]+ 388.99.
2-Br om o-N-(5-{6-[2-(2-n itr oben zen esu lfon yla m in o)eth -
yl]p yr id in -2-yl}p en tyl) Aceta m id e (7). To a solution of 6 (410
mg, 1.05 mmol) in anhydrous THF (15 mL) at room temperature
was added neat BH3‚Me2S (0.6 mL, 6.0 mmol) over a period of
2 min. The reaction mixture was warmed to 60 °C, and stirring
was continued for another 4 h. After the reaction mixture was
cooled to room temperature, 6 N HCl (3.3 mL) was carefully
added dropwise, resulting in the evolution of H2 (g). The mixture
was heated to 70 °C for 2 h, resulting in a clear solution. Water
(10 mL) was added, and the aqueous solution was washed with
diethyl ether (3 × 25 mL) and cooled to 0 °C. To the solution
was added 10 N NaOH (2.3 mL), and the aqueous phase was
saturated with solid K2CO3. The liberated amine was extracted
with chloroform (6 × 20 mL), and the combined organic extracts
were dried over a 1:1 mixture of K2CO3 and Na2SO4. Evaporation
of the solvent gave the crude amine (320 mg, 77%), which was
used directly in the next step: 1H NMR (CDCl3) δ 1.38-1.50
(m, 4H), 1.68-1.73 (m, 2H), 2.68-2.80 (m, 4H), 2.97 (t, J ) 5.9
Hz, 2H), 3.54 (t, J ) 5.9 Hz, 2H), 4.95 (s, 1H), 6.83 (d, J ) 7.5
Hz, 1H), 6.96 (d, J ) 7.5 Hz, 1H), 7.46 (dd, J ) 7.8, 7.8 Hz, 1H),
7.69-7.72 (m, 2H), 7.80-7.81 (m, 1H), 8.13-8.16 (m, 1H). To a
Exp er im en ta l Section
1H NMR and 13C NMR spectra were recorded, respectively,
at 300 and 75 MHz on a Bruker Avance 300 spectrometer. Mass
spectra were obtained on
a Bruker Esquire LC Ion Trap
spectrometer. Thin-layer chromatography (TLC) was performed
on precoated SiO2 60 F-254 plates (230-400 mesh). THF was
dried over sodium and freshly distilled before use. All reactions
were performed in oven-dried glassware under a positive pres-
sure of nitrogen. Reaction mixtures were stirred magnetically.
[2-(6-Br om op yr id in -2-yl)eth yl]-2-n itr oben zen esu lfon a -
m id e (5). To 6-bromo pyridyl-2-acetonitrile4 (7.0 g, 35 mmol) in
anhydrous THF (15 mL) at room temperature was added a 1.0
M solution of BH3‚THF (104 mL, 104 mmol) in THF over a period
of 20 min. The reaction mixture was warmed to 60 °C and stirred
for 18 h. After the reaction mixture was cooled to room
temperature, 6 N HCl (30 mL) was added dropwise and the
mixture was heated at 70 °C for 2 h and then cooled to room
temperature. The resulting clear solution was washed with
diethyl ether (3 × 25 mL) and cooled to 0 °C. To the solution
was added 10 N NaOH (20 mL), and the aqueous phase was
saturated with K2CO3. The liberated amine was extracted with
chloroform (6 × 20 mL), and the combined organic extracts were
dried over a 1:1 mixture of K2CO3 and Na2SO4. Evaporation of
the solvent gave crude 2-(6-bromopyridin-2-yl)ethylamine (5.1
g, 72%): 1H NMR (CDCl3) δ 2.90 (t, J ) 6 Hz, 2H), 3.12 (t, J )
6 Hz, 2H), 7.12 (d, J ) 9 Hz, 1H), 7.31 (d, J ) 9 Hz, 1H), 7.46
(dd, J ) 9, 9 Hz, 1H). Using the procedure of Fukuyama,6 crude
2-(6-bromopyridin-2-yl)ethylamine (5.1 g, 25.36 mmol) gave 5
(6.3 g, 64%) as a white solid after purification (CH2Cl2): 1H NMR
(CDCl3) δ 3.02 (t, J ) 6.3 Hz, 2H), 3.55 (dt, J ) 6.3, 6.3 Hz, 2H),
5.93 (br t, 1H), 7.08 (d, J ) 7.5 Hz, 1H), 7.26-7.32 (m, 1H), 7.44
(dd, J ) 7.5, 7.5 Hz, 1H), 7.74 (m, 2H), 7.84-7.87 (m, 1H), 8.12-
8.15 (m, 1H); 13C NMR (CDCl3) δ 37.14, 42.91, 122.92, 125.91,
126.73, 131.34, 133.24, 133.95, 134.08, 134.14, 139.33, 142.24,
159.85; exact mass m/z calcd for C13H1281BrN3O4S 386.99, found
[M + H]+ 387.90.
N-(6-Br om op yr id in -2-ylm eth yl)-2-n itr oben zen esu lfon a -
m id e (5c). Using the procedure of Fukuyama,6 6-bromopyridin-
2-ylmethylamine18 (3.16 g, 16.90 mmol) gave 5c (4.6 g, 78%) as
a yellow solid after purification (EtOAc-CH2Cl2, 30:70): 1H
NMR (CDCl3) δ 4.45 (d, J ) 6 Hz, 2H), 6.41 (t, J ) 6 Hz, 1H),
7.28-7.30 (m, 2H), 7.47 (dd, J ) 7.7, 7.7 Hz, 1H), 7.59-7.72 (m,
2H), 7.91 (dd, J ) 7.8, 1.5 Hz, 1H), 7.98 (dd, J ) 7.8 Hz, 1.5,
1H); 13C NMR (CDCl3) δ 48.52, 121.07, 126.03, 127.54, 130.91,
133.15, 133.95, 134.35, 139.49, 141.96, 148.10, 156.91; exact
mass m/z calcd for C12H1081BrN3O4S 372.98, found [M + H]+
373.86.
[2-(6-Br om op yr id in -2-yl)eth yl]p h osp h or a m id ic Acid Di-
eth yl Ester (5a ). Using the procedure of Bridger et al.,2f 2-(6-
bromopyridin-2-yl)ethylamine (705 mg, 3.51 mmol) gave 5a (1.08
g, 92%) as a white foam after purification (MeOH-CH2Cl2,
5:95): 1H NMR (CDCl3) δ 1.32 (t, J ) 7.1 Hz, 6H), 2.80-2.92
(m, 1H), 2.95 (t, J ) 6.6 Hz, 2H), 3.29-3.39 (m, 2H), 3.94-4.12
(m, 4H), 7.14 (d, J ) 8.9 Hz, 1H), 7.35 (d, J ) 9.1 Hz, 1H), 7.47
(dd, J ) 9.1, 9.1 Hz, 1H); 13C NMR (CDCl3) δ 16.62 (3J PC ) 6.9
Hz), 39.53 (2J PC ) 5.2 Hz), 40.91, 62.70 (2J PC ) 5.1 Hz), 122.92,
81
126.33, 139.43, 142.15, 161.10; exact mass m/z calcd for C11H18
-
BrN2O3P 338.10, found [M + Na]+ 361.10.
N-(6-Br om opyr idin -2-ylm eth yl)ph osph or am idic Acid Di-
eth yl Ester (5b). Using the procedure of Bridger et al.,2f
6-bromopyridine-2-ylmethylamine18 (123 mg, 0.66 mmol) gave
(18) Chuang, C.-L.; Dos Santos, O.; Xu, X.; Canary, J . W. Inorg.
Chem. 1997, 36, 1967-1972.

1410 J . Org. Chem., Vol. 67, No. 4, 2002
Notes
stirred solution of crude N-{2-[6-(5-aminopentyl)pyridin-2-yl]-
ethyl}-2-nitrobenzenesulfonamide (320 mg, 0.82 mmol) and
anhydrous Na2CO3 (460 mg, 4.34 mmol) in anhydrous THF (15
mL) at -15 °C was added dropwise a solution of bromoacetyl
bromide (247 mg, 1.23 mmol) in THF (1 mL). The reaction
mixture was stirred at -15 °C for an additional 2 h, diluted with
ethyl acetate (200 mL), and warmed to room temperature. The
resulting organic solution was washed with saturated aqueous
NaHCO3 (60 mL) and brine (60 mL), dried over Na2SO4, and
concentrated. Purification of the crude material by flash column
chromatography on silica gel (2 × 20 cm) using ethyl acetate-
CH2Cl2 (40:60) gave 7 (311 mg, 73%) as a white foam: 1H NMR
(CDCl3) δ 1.36-1.43 (m, 2H), 1.56-1.66 (m, 2H), 1.69-1.79 (m,
2H), 2.80 (t, J ) 7.5 Hz, 2H), 2.98 (t, J ) 5.7 Hz, 2H), 3.30 (td,
J ) 6.9, 6.9 Hz, 2H), 3.54 (td, J ) 5.4, 5.4 Hz, 2H), 3.86 (s, 2H),
6.56 (br s, 1H), 6.87 (d, J ) 7.5 Hz, 1H), 6.99 (d, J ) 7.8 Hz,
1H), 7.26 (br s, overlapped with CHCl3, 1H), 7.47 (d, J ) 7.7
Hz, 1H), 7.68-7.76 (m, 2H), 7.83-7.86 (m, 1H), 8.15-8.18 (m,
1H); 13C NMR (CDCl3) δ 26.31, 28.99, 29.32, 29.40, 35.96, 37.86,
40.09, 42.66, 120.53, 120.80, 125.22, 130.96, 132.64, 133.27,
134.37, 136.98, 148.20, 158.03, 161.90, 165.48; exact mass m/z
calcd for C20H2581BrN4SO5 514.09, found [M + H]+ 515.02.
4-(2-Nitr oben zen esu lfon yl)-4,7,17-tr ia za bicyclo[11.3.1]-
h ep ta d eca -1(17),13,15-tr ien -6-on e (8). A solution of 7 (439 mg,
0.86 mmol) and K2CO3 (604 mg, 4.3 mmol) in anhydrous CH3-
CN (1000 mL) was stirred for 18 h at 60 °C. The reaction mixture
was then cooled to room temperature and concentrated. The
residue was diluted with ethyl acetate (400 mL), and the organic
solution was washed with saturated aqueous NaHCO3 (100 mL)
and brine (100 mL) and dried over Na2SO4. Concentration of
the organic fractions and purification of the crude material by
flash column chromatography on silica gel (2 × 20 cm) using
ethyl acetate-CH2Cl2 (50:50) gave 8 (310 mg, 84%) as a white
solid: 1H NMR (CDCl3) δ 1.53 (q, J ) 6.9 Hz, 2H), 1.62-1.70
(m, 2H), 1.82-1.90 (m, 2H), 2.89-2.93 (m, 2H), 3.02-3.05 (m,
2H), 3.47 (dt, J ) 5.4, 5.4 Hz, 2H), 3.77-3.81 (m, 2H), 3.83 (s,
2H), 7.06 (dd, J ) 7.8, 7.8 Hz, 2H), 7.56-7.63 (m, 2H), 7.68-
7.73 (m, 2H), 8.02-8.05 (m, 1H), 8.59 (br s, 1H); 13C NMR
(CDCl3) δ 24.09, 26.02, 26.77, 35.51, 37.14, 39.22, 53.10, 53.43,
121.29, 122.33, 124.69, 131.90, 132.09 (2C), 134.23, 137.66,
148.67, 157.93, 161.53, 168.38; exact mass m/z calcd for
C20H24N4O5S 432.15, found [M + H]+ 433.07.
(4,7,17-Tr ia za bicyclo[11.3.1]h ep ta d eca -1(17),13,15-tr ien -
7-yl)p h osp h or a m id ic Acid Dieth yl Ester (2). To a stirred
solution of 9 (67 mg, 0.12 mmol) and anhydrous K2CO3 (134 mg,
0.97 mmol) in anhydrous DMF (1.5 mL) was added dropwise
neat thiophenol (75 mg, 0.68 mmol). The reaction mixture was
stirred at room temperature for 4 h and then concentrated. The
residue was diluted with ethyl acetate (100 mL), and the
resulting solid was filtered by being passed though a short Celite
column. Evaporation of the solvent and purification of the crude
material by radial chromatography (silica gel, 1 mm plate) using
MeOH-NH4OH-CH2Cl2 (3:3:94) as the eluant gave 2 (22.6 mg,
50%) as a light yellow oil: 1H NMR (CDCl3) δ 1.15 (t, J ) 7.1
Hz, 6H), 1.20-1.28 (m, 2H), 1.43-1.97 (m, 5H), 2.70-2.74 (m,
2H), 2.78-2.81 (m, 2H), 2.84-3.25 (m, 8H), 3.62-3.87 (m, 4H),
6.96 (m, 2H), 7.48 (dd, J ) 12, 12 Hz, 1H); 13C NMR (CDCl3) δ
16.47 (3J PC ) 7.1 Hz), 25.38, 28.33, 30.82, 36.76, 37.57, 48.48,
49.85 (2J PC ) 3.4 Hz), 50.01 (2J PC ) 3.4 Hz), 50.13, 62.19 (2J PC
) 5.7 Hz), 121.21, 121.25, 136.80, 159.30, 161.80; exact mass
m/z calcd for C18H32N3O3P 369.22, found [M + H]+ 370.10.
2-Br om o-N-(5-{6-[2-(2-n it r ob en zen esu lfon yla m in o)m e-
th yl]p yr id in -2-yl}h exyl) Aceta m id e (12). Following the pro-
cedure for the synthesis of compound 7, nitrile 6c (273 mg, 0.70
mmol), after purification of the crude material by flash column
chromatography on silica gel (2 × 20 cm) using ethyl acetate-
CH2Cl2 (20:80) gave 12 (243 mg, 67%) as a white foam: 1H NMR
(CDCl3) δ 1.34-1.37 (m, 4H), 1.59 (m, 2H), 1.62-1.69 (m, 2H),
2.63 (t, J ) 7.7 Hz, 2H), 3.25 (dt, J ) 6.6, 6.6 Hz, 2H), 5.89 (s,
2H), 4.38 (d, J ) 5.1 Hz, 2H), 6.51 (b, 1H), 6.90 (b, 1H), 6.96 (d,
J ) 12.0 Hz, 1H), 6.98 (d, J ) 12.3 Hz, 1H), 7.48 (dd, J ) 7.7,
7.7 Hz, 1H), 7.64-7.71 (m, 2H), 7.86-7.89 (m, 1H), 8.09-8.11
(m, 1H); 13C NMR (CDCl3) δ 26.88, 29.10, 29.44, 29.73, 38.12,
40.58, 48.36, 119.27, 122.11, 125.77, 131.40, 133.05, 133.81,
134.15, 137.40, 148.33, 153.73, 162.27, 165.84; exact mass m/z
calcd for C20H2581BrN4O5S 514.09, found [M + H]+ 515.03.
3-(2-Nitr oben zen esu lfon yl)-3,6,17-tr ia za bicyclo[11.3.1]-
h ep ta d eca -1(17),13,15-tr ien -5-on e (13). Following the proce-
dure for the synthesis of compound 8, acetamide 12 (243 mg,
0.47 mmol), after purification of the crude material by flash
column chromatography on silica gel (1.5 × 20 cm) using ethyl
acetate-CH2Cl2 (40:60), gave 13 (186 mg, 91%) as a white
foam: 1H NMR (CDCl3) δ 1.17-1.24 (m, 2H), 1.36-1.44 (m, 2H),
1.47-1.52 (m, 2H), 1.70-1.78 (m, 2H), 2.55-2.60 (m, 2H), 3.23
(dt, J ) 5.4, 5.5 Hz, 2H), 4.11 (s, 2H), 4.59 (s, 2H), 7.03 (d, J )
7.8 Hz, 1H), 7.11 (J ) 7.3 Hz, 1H), 7.48-7.51 (m, 1H), 7.57-
7.73 (m, 5H); 13C NMR (CDCl3) δ 23.33, 24.53, 27.17, 28.01,
35.73, 37.22, 53.71, 56.29, 121.10, 123.17, 124.70, 131.88, 131.93,
133.17, 134.12, 137.77, 148.45, 154.10, 162.94, 167.71; exact
mass m/z calcd for C20H24N4O5S 432.15, found [M + H]+ 433.05.
3-(2-Nitr oben zen esu lfon yl)-3,6,17-tr ia za bicyclo[11.3.1]-
h ep ta d eca -1(17),13,15-tr ien e (3). Following the procedure for
the synthesis of compound 1, amide 13 (265 mg, 0.61 mmol),
after purification of the crude material by radial chromatography
(silica gel, 2 mm plate) using MeOH-NH4OH-CH2Cl2 (3:3:94)
as the eluant, gave 3 (198 mg, 77%) as a light yellow oil: 1H
NMR (CDCl3) δ 1.11-1.20 (m, 2H), 1.30-1.34 (m, 2H), 1.39-
1.48 (m, 2H), 1.82-1.91 (m, 2H), 2.31 (t, J ) 6.2 Hz, 2H), 2.58
(t, J ) 6.2 Hz, 2H), 2.83-2.87 (m, 2H), 3.38 (t, J ) 6.2 Hz, 2H),
4.63 (s, 2H), 7.08 (d, J ) 7.5 Hz, 1H), 7.26 (overlapped with
CHCl3, 1H), 7.58-7.66 (m, 2H), 7.67-7.73 (m, 2H), 8.14-8.17
(m, 1H); 13C NMR (CDCl3) δ 23.78, 24.81, 27.53, 27.57, 36.37,
47.12, 48.00, 49.53, 54.91, 120.60, 122.85, 124.50, 131.61, 131.93,
133.43, 133.89, 137.53, 148.69, 156.12, 162.24; exact mass m/z
calcd for C20H26N4O4S 418.17, found [M + H]+ 419.09.
4-(2-Nitr oben zen esu lfon yl)-4,7,17-tr ia za bicyclo[11.3.1]-
h ep ta d eca -1(17),13,15-tr ien e (1). Following the general pro-
cedure for the synthesis of compound 5, 8 (127 mg, 0.29 mmol)
gave after purification of the crude material by column chro-
matography over silica gel (1.0 × 20 cm) using MeOH-NH4-
OH-CH2Cl2 (3:3:94) 1 (90 mg, 70%) as a light yellow oil as well
as some recovered 8 (21 mg, 7.9%): 1H NMR (CDCl3) δ 1.32-
1.39 (m, 2H), 1.47-1.54 (m, 2H), 1.56 (1H, overlap with H2O),
1.85-1.91 (m, 2H), 2.66-2.73 (m, 4H), 2.87 (t, J ) 6.0 Hz, 2H),
3.07 (t, J ) 6.3 Hz, 2H), 3.18 (t, J ) 6.5 Hz, 2H), 3.88 (t, J ) 6.0
Hz, 2H), 7.01 (d, J ) 7.5 Hz, 2H), 7.50 (dd, J ) 7.8, 7.8 Hz, 1H),
7.60-7.69 (m, 3H), 7.97-8.01 (m, 1H); 13C NMR (CDCl3) δ 23.70,
26.32, 27.40, 36.03, 38.20, 47.72, 47.76, 49.29, 49.47, 121.43,
121.86, 124.47, 131.16, 131.96, 133.36, 133.87, 137.13, 148.65,
157.91, 161.66; exact mass m/z calcd for C20H26N4O4S 418.14,
found [M + H]+ 419.12.
[4-(2-Nitr oben zen esu lfon yl)-4,7,17-tr ia za bicyclo[11.3.1]-
h ep ta d eca -1(17),13,15-tr ien -7-yl]p h osp h or a m id ic Acid Di-
eth yl Ester (9). Using the procedure of Bridger et al.,2f amine
1 (151 g, 0.36 mmol) gave 9 (148 mg, 77%) as a white foam after
purification (EtOAc-CH2Cl2, 30:70): 1H NMR (CDCl3) δ 1.19
(t, J ) 7.1 Hz, 8H), 1.19-1.21 (m, 2H), 1.35-1.42 (m, 2H), 1.82-
1.91 (m, 2H), 2.32-2.42 (m, 2H), 2.79-2.90 (m, 6H), 3.01-3.05
(m, 2H), 3.74-3.92 (m, 6H), 7.02 (dd, J ) 12.3, 7.8 Hz, 2H), 7.51
(dd, J ) 7.5, 7.5 Hz, 1H), 7.58-7.62 (m, 1H), 7.68 (dd, J ) 7.1,
7.1 Hz, 2H), 8.03-8.06 (m, 1H); 13C NMR (CDCl3) δ 16.47 (3J PC
) 7.2 Hz), 24.44, 27.68, 28.16 (3J PC ) 2.9 Hz), 37.20, 39.77, 45.18
(2J PC ) 3.7 Hz), 47.83 (3J PC ) 4.3 Hz), 49.16, 49.49, 62.47 (2J PC
) 5.7 Hz), 121.84, 122.68, 124.34, 131.63, 132.04, 133.62, 133.86,
137.30, 148.51, 158.46, 162.48; exact mass m/z calcd for
Ack n ow led gm en t. We thank the Analytical Chem-
istry group at AnorMED for support.
Su p p or t in g In for m a t ion Ava ila b le: 1H NMR and 13C
NMR spectra of compounds 1-9 and 12-13. This material is
available free of charge via the Internet at http://pubs.acs.org.
C
24H35N4O7PS 554.20, found [M + H]+ 555.21.
J O0109523