Preparing functional bis(indole) pyrazine by stepwise cross-coupling reactions: An efficient method to construct the skeleton of dragmacidin D

Article abstract of DOI:10.1021/jo026450m

A direct approach for selective construction of properly substituted bis(indole) pyrazine, the skeleton of a marine alkaloid dragmacidin D, has been developed. The key steps involved the regioselective introduction of two indole units, using the palladium

Full text of DOI:10.1021/jo026450m

P r ep a r in g F u n ction a l Bis(in d ole) P yr a zin e by Step w ise
Cr oss-cou p lin g Rea ction s: An Efficien t Meth od to Con str u ct th e
Sk eleton of Dr a gm a cid in D
Cai-Guang Yang, Gang Liu, and Biao J iang*
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, P. R. China
jiangb@pub.sioc.ac.cn
Received September 16, 2002
A direct approach for selective construction of properly substituted bis(indole) pyrazine, the skeleton
of a marine alkaloid dragmacidin D, has been developed. The key steps involved the regioselective
introduction of two indole units, using the palladium(0)-catalyzed Suzuki and the Stille cross-
coupling reactions sequentially.
The structure uniqueness and biological importance of
certain bis(indole) secondary metabolites, containing
either an imidazole- or a pyrazine-derived spacer unit,
have driven the search for even more efficient synthetic
routes to these compounds.1 Dragmacidin D, a novel
secondary metabolite, was isolated from a deep-water
marine sponge of the genus Spongosorites by Wright in
19922 and Capon in 1995.3 Structurally, it varied from
the previously reported dragmacidins.4 To the best of our
knowledge, this was the first of the marine derived bis-
(indole) compound to have alkyl substitution on C-4 of
an indole ring, the first to incorporate the 2-aminoimi-
dazole functionality which has been reported previously
in the Agealasidae,5 Axinellidae,5 and Verongidae6 sponges,
and the first to have the 2(1H)-pyrazinone spacer. Drag-
macidin D exhibited a broad spectrum of biological
activity. It inhibited the growth of the feline leukemia
virus, the opportunistic fungal pathogens Cryptococcus
neoformans and Candida albicans, and the P388 and
A549 tumor cell lines. Further biological studies indicated
that dragmacidin D and its co-metabolite dragmacidin
E have been identified as potent inhibitors of serine-
threonine protein phosphatases, while dragmacidin D
was a selective inhibitor of PP1.7 In particular, dragma-
cidin D was found to selectively inhibit neural nitric oxide
synthase (bNOS) in the presence of inducible NOS
(iNOS).8 This ability may be useful in a variety of
therapeutic areas including the treatment of Alzheimer’s,
Parkinson’s, and Huntington’s diseases.9
Its unique structure and wide range of biological and
pharmacological activities have attracted much attention
and prompted many research groups to undertake the
synthetic study.10 The first successful construction of the
bis(indol-3-yl)-2(1H) pyrazinone ring system in dragma-
cidin D has been achieved via the condensation of two
indolyl glycine derived units, followed by the selective
reduction and intramolecular cyclization by our group,11
and then the intramolecular condensation of the oxo-
tryptamine with ketoamide under heating condition by
Horne.12 In prior work, we have reported the enantiose-
lective synthesis of the 2-aminoimidazole segment of
dragmacidin D.13 As a continuing study, we wish to report
an efficient synthesis of functional bis(indole) pyrazine
1, the skeleton of dragmacidin D, by the sequential
implementation of palladium(0)-catalyzed Suzuki and
Stille cross-coupling reactions that are exquisitely selec-
tive.
(1) For a review, see: Faulkner, D. J . Nat. Prod. Rep. 2001, 18, 1
and references therein.
(2) Wright, A. E.; Pomponi, S. A.; Cross, S. S.; McCarthy, P. J . Org.
Chem. 1992, 57, 4772.
(3) Murray, L. M.; Lim, T. K.; Hooper, J . N. A.; Capon, R. J . Aust.
J . Chem. 1995, 48, 2053.
(4) (a) Dragmacidin: Kohmoto, S.; Kashman, Y.; McConnell, O. J .;
Rinehart, K. L., J r.; Wright, A.; Koehn, F. J . Org. Chem. 1988, 53,
3116. (b) Dragmacidin A and Dragmacidin B: Morris, S. A.; Andersen,
R. J . Tetrahedron 1990, 46, 715. (c) Dragmacidin C: Fahy, E.; Potts,
B. C. M.; Faulkner, D. J .; Smith, K. J . Nat. Prod. 1991, 54, 564.
(5) Keifer, P. A.; Schwartz, R. E.; Koker, M. E. S.; Hughes, R. G.,
J r.; Rittschof, D.; Rinehart, K. L. J . Org. Chem. 1991, 56, 2965.
(6) Cimino, G.; De Rosa, S.; De Stefano, S.; Self, R.; Sodamo, G.
Tetrahedron Lett. 1983, 24, 3029.
(8) Longley, R. E.; Isbrucker, R. A.; Wright, A. E. U.S. Patent 6,-
087,363, J uly 7, 2000.
(9) (a) Thorns, V.; Hansen, L.; Masliah, E. Exp. Neurol. 1998, 150,
14. (b) Molina, J . A.; J imenez-J imenez, F. J .; Orti-Pareja, M.; Navarro,
J . A. Drug Aging 1998, 12, 251.
(10) A total synthesis of (()-dragmacidin D was reported (Garg, N.
K.; Sarpong, R.; Stoltz, B. M. J . Am. Chem. Soc. 2002, in press.) while
the manuscript was in progress.
(11) J iang, B.; Gu, X.-H. Heterocycles 2000, 53, 1559.
(12) Miyake, F. Y.; Yakushijin, K.; Horne, D. A. Org. Lett. 2002, 4,
941.
(7) Capon, R. J .; Rooney, F.; Murray, L. M.; Collins, E.; Sim, A. T.
R.; Rostas, J . A. P.; Butler, M. S.; Carroll, A. R. J . Nat. Prod. 1998,
61, 660.
(13) Yang, C.-G.; Wang, J .; J iang, B. Tetrahedron Lett. 2002, 43,
1063.
10.1021/jo026450m CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/23/2002
9392
J . Org. Chem. 2002, 67, 9392-9396

Preparation of Functional Bis(indole) Pyrazine
converted to the corresponding bromo analogue directly
to give the desired fragment 2,5-dibromo-3-methoxy-
lpyrazine 4 in moderate yield.17
To evaluate the reaction scope of dibromopyrazine 4,
both the reactivity and the regioselectivity of Suzuki
chemistry were first investigated. Thus, treatment of 4
with an excess of phenylboronic acid and 10 mol % of
tetrakis(triphenylphosphine)palladium in the presence of
aqueous sodium carbonate in refluxing benzene-metha-
nol under argon atmosphere for 4 h produced the corre-
sponding diphenylpyrazine 5 in 94% yield. As expected,
treatment of compound 4 with an equivalent amount of
phenylboronic acid under the above condition solely
yielded 6 in high yield. The regioselectivity of the Suzuki
cross-coupling reaction was determined by the following
procedure. The reaction of monobrominated pyrazine 3
and phenylboronic acid highly afforded compound 7,
which was subjected to the diazotization bromination
sequence to give brominated phenylpyrazine 8 in moder-
1
ate yield. The H NMR experiment indicated that com-
pounds 6 and 8 were not the same, which demonstrated
that the cross-coupling reaction of dibromopyrazine 4
could be steadily achieved by stepwise and in complete
selectivity under the standard Suzuki conditions.
F IGURE 1. Retrosynthetic approach.
SCHEME 1. Syn th esis of Br om id e P yr a zin e
With the desired reactivity and regioselectivity of
dibromopyrazine 4 in mind, we then focused our attention
on the study of the coupling of 4 with indol-3-ylboronic
acid (Scheme 2). Similarly, a high yield of coupling
product 10b was obtained by reaction of N-tosyl indol-
3-ylboronic acid 9b18 and 2,5-dibromo-3-methoxylpyra-
zine 4. However, all efforts toward the critical second
introduction of the tosyl protective indole unit to the
intermediate 10b failed. Neither treatment of dibro-
mopyrazine 4 with an excess of the electron-deficient
indolylboronic acid 9b directly nor treatment of com-
pound 10b with another equivalent amount of 9b gave
the desired bis(indole) pyrazine. No improvement was
obtained by employing a stronger base such as Ba(OH)2,19
or a higher reaction temperature, or a more active
palladium catalyst bearing the bidentate ligand (dppf),20
or the recent efficient method developed by Fu.21 On the
other hand, coupling of bromide indolylpyrazine 10b with
phenylboronic acid under the above Suzuki condition
afforded the desired product 11 in 80% yield. We then
considered the more active indolylboronic acid bearing
an electron-donating protective group, and decided to use
the tert-butyldimethylsilyl (TBDMS) moiety as the pro-
tective group. According to the literature reported, the
required N-(tert-butyldimethylsilyl)indol-3-ylboronic ac-
ids 14a -c were prepared from the corresponding 3-bro-
moindoles 13a -c by halogen-metal exchange with t-
BuLi at -78 °C, followed by transmetalation of the
The use of palladium complex chemistry has been
extensively explored for the synthesis and functionaliza-
tion of indoles.14 Retrosynthetically, the functional bis-
(indole) pyrazine 1 was envisioned to arise by a stepwise,
regioselective introduction of the indole fragments 14b
and 14d to the 2- and 5-positions of the pyrazine 4 by a
palladium(0)-catalyzed cross-coupling reaction. The syn-
thetic route we were looking for had to fulfill the
requirement of special regioselectivity. As illustrated in
Figure 1, one of the partners, dibromopyrazine 4, could
be easily prepared from the commercially available
2-aminopyrazine 2. The indole building blocks 14b and
14d could be readily obtained from the corresponding
indoles 12b and 12c according to a known procedure.15
4,7-Disubstituted indole 12c was easily available from
m-cresol according to our prior report.13
(17) (a) J ovanovic, M. V. Heterocycles 1983, 20, 2011. (b) Brachwitz,
H. J . Prak. Chem. 1969, 40, 311.
(18) (a) Alvarez, A.; Guzma´n, A.; Ruiz, A.; Velarde, E.; Muchowski,
J . M. J . Org. Chem. 1992, 57, 1653. (b) Zheng, Q.; Yang, Y.; Martin,
A. R. Heterocycles 1994, 37, 1761.
(19) (a) Watanabe, T.; Miyaura, N.; Suzuki, A. Synlett 1992, 207.
(b) Suzuki, A. Pure Appl. Chem. 1994, 66, 213. (c) Pascal, C.; Dubois,
J .; Gue´nard, D.; Tchertanov, L.; Thoret, S.; Gue´ritte, F. Tetrahedron
1998, 54, 14737.
As shown in Scheme 1, the synthesis was started with
2-amino-5-bromo-3-methoxylpyrazine 3 prepared from
commercially available 2-aminopyrazine 2 as described
in the literature.16 Then the diazotization of compound
3 afforded intermediate diazonium compound which was
(14) For a review, see: Hegedus, L. S. Angew. Chem., Int. Ed. Engl.
1988, 27, 1113.
(15) Amat, M.; Hadida, S.; Sathyanarayana, S.; Bosch, J . J . Org.
Chem. 1994, 59, 10.
(20) (a) Oh-e, T.; Miyaura, N.; Suzuki, A. J . Org. Chem. 1993, 58,
2201. (b) Mohri, S.; Stefinovic, M.; Snieckus, V. J . Org. Chem. 1997,
62, 7072.
(21) (a) Littke, A. F.; Dai, C.; Fu, G. C. J . Am. Chem. Soc. 2000,
122, 4020. (b) Netherton, M. R.; Fu, G. C. Org. Lett. 2001, 3, 4295.
(16) Camerino, B.; Palamidessi, G. Gazz. Chim. Ital. 1960, 90, 1807.
J . Org. Chem, Vol. 67, No. 26, 2002 9393

Yang et al.
SCHEME 2. Syn th esis of In d ole Rea gen ts 14 a n d Bis(in d ole) P yr a zin e 15
SCHEME 3. Syn th esis of Com p ou n d 1
resulting 3-lithioindole with B(OEt)3.15 It was noteworthy
that BuLi achieved highly selective lithiation of the
substituted 3-bromoindoles 13a -c to give the corre-
sponding 3-lithioindole as the single product instead of
t-BuLi. With the electron-rich indol-3-ylboronic acids
14a -c prepared by using the modified procedure in hand,
we then examined the coupling of bromide indolylpyra-
zine 10b with indolylboronic acid 14a under the above
Suzuki condition. Gratifyingly, the desired cross-coupling
product 15 was readily obtained in 80% yield. Moreover,
the electronic effect of the two indoles induced by protec-
tive groups would lead to the expected selectivity toward
the assembly of the 2-aminoimidazole segment on the
indole ring. This might provide a possible strategy to
accomplish the final total synthesis.
ently, the introduction of the 6-bromoindole building
block with an electron-withdrawing protective group such
as Ts or Boc to the C-2 position of the dibromopyrazine
4 and then the 4,7-disubstituted indole unit with an
electron-donating protective group such as TBDMS to the
C-5 position of 4 sequentially finished the regioselective
synthesis of the target molecule 1. The coupling of
N-tosyl-6-bromoindol-3-ylboronic acid 9a 18 and dibro-
mopyrazine 4 gave a very low yield of 10a due to the less
reactive indolylboronic acid 9a (Scheme 2). Consequently,
as illustrated in Scheme 3, the coupling of the more active
boronic acid 14b with dibromopyrazine 4 produced the
expected 3-pyrazinylindole 16 in good yield. Considering
that the different electronic effect of the protective group
on the indole rings would be helpful for the final total
synthesis of natural product, we decided to change the
TBDMS protective group in 16 to an electron-withdraw-
ing group such as Boc. The removal of the silyl moiety
After successfully constructing the bis(indole) pyrazine,
we then started the synthetic study to the skeleton of
dragmacidin D with properly substituted groups. Appar-
9394 J . Org. Chem., Vol. 67, No. 26, 2002

Preparation of Functional Bis(indole) Pyrazine
from 16 was accomplished with tetrabutylammonium
fluoride in THF at room temperature to give 3-pyrazi-
nylindole 17 in over 95% yield.22 Then indole 17 was
readily protected by treatment with Boc2O in the pres-
ence of DMAP as a catalyst to provide compound 18 in
96% yield.23 Unfortunately, the introduction of the 4,7-
disubstituted indole building block to 18 was unsuccess-
ful under Suzuki conditions, because the 4,7-disubsti-
tuted indolylboronic acid 14c was very unstable and
easily converted to the corresponding indole 12c. For this
reason, it was necessary to study the tin-based pal-
ladium(0)-catalyzed coupling process as a route to the
introduction of the 4,7-disubstituted indole unit.24 There-
fore, the required 3-tributylstannylindole 14d was pre-
pared by reaction of the 3-lithioindole derivative with
tributyltin chloride. Stille coupling of the crude 3-tribu-
tylstannylindole 14d with 3-pyrazinylindole 18 in the
presence of a cocatalyst of tetrakis(triphenylphosphine)-
palladium and copper(I) iodide in heating DMF for 12 h
resulted in four partially deprotected products 19a -c
and 1 in 61% total yield along with unconverted start-
ing material 18.25 This indicated that both the Boc
and the TBDMS protective groups on the indole rings
were unstable under Stille conditions due to the basic
property.
Exp er im en ta l Section
Gen er a l P r oced u r e.27 The assignment of compound 1 was
supported by an X-ray crystallographic structure determina-
tion.
2,5-Dib r om o-3-m et h oxylp yr a zin e (4). A mixture of
2-amino-5-bromo-3-methoxylpyrazine 3 (1.02 g, 5 mmol) in 20
mL of 40% hydrobromic acid was stirred at room temperature
for 1 h. Under cooling in a brine-ice bath, to this mixture was
added 4 mL of water containing NaNO2 (1.04 g, 15 mmol). The
addition was completed within 20 min with continuous stir-
ring. The whole was slowly allowed to reach room temperature,
left standing for 1 h at 50 °C, and partially neutralized with
saturated sodium bicarbonate solution. The resulting solution
was extracted with CH2Cl2. The combined organic layer was
washed with water and brine successively, dried (Na2SO4), and
concentrated under vacuum. Purification by flash chromatog-
raphy (silica, hexane/AcOEt 20:1) gave compound 4 (648 mg,
54%) as a light yellow solid. Mp 122-123 °C (CH2Cl2/hexane);
1H NMR (CDCl3, 300 MHz) δ 4.08 (s, 3H), 8.05 (s, 1H); 13C
NMR (CDCl3, 75 MHz) δ 157.0, 138.0, 135.1, 127.7, 56.0; EIMS
m/z (%) 268 (M+, 100), 267/269 (38), 266/270 (55). Anal. Calcd
for C5H4Br2N2O: C, 22.39; H, 1.49; N, 10.45. Found: C, 22.64;
H, 1.58; N, 10.69.
Gen er a l P r oced u r e: P a lla d iu m (0)-Ca ta lyzed Su zu k i
Cou p lin g R ea ct ion of Br om op yr a zin e w it h In d ol-3-
ylbor on ic Acid . A mixture of indol-3-ylboronic acid, bromopy-
razine, aqueous sodium carbonate (2 M), and tetrakis-
(triphenylphosphine)palladium (10 mol %) in benzene and
methanol (v/v 4:1) was refluxed under an argon atmosphere.
The reaction was monitored with TLC. When the reaction was
completed, anhydrous sodium sulfate was added. The mixture
was filtered and the filtrate was evaporated under vacuum.
The residue was subjected to flash column chromatography
(eluted with ethyl acetate/hexane) to give cross-coupling
products.
We had to give up the protective group strategy and
turned to the construction of the skeleton of dragmacidin
D first. After the Stille coupling time was prolonged to
24 h, the properly substituted bis(indolyl) pyrazine 1 was
available as a single product in 92% yield from the
reaction of compound 17 with 14d . Next, we examined
the possibility of the introduction of the 2-aminoimidazole
segment at the C-4′′ position of the disubstituted indole
ring in compound 1. Total silylation of 1 by treatment
with TBDMS triflate in the presence of LHMDS yielded
the required 20 in high yield.26 To our delight, the
lithiation of 20 with BuLi occurred regioselectively to give
the expected compound 21 as a single product in 70%
isolated yield.
5-Br om o-3-m eth oxyl-2-(N-tosylin dol-3-yl)pyr azin e (10b).
Pyrazine 10b (390 mg, 85%) was obtained as a white solid from
4 (268 mg, 1.0 mmol), 9b (380 mg, 1.2 mmol), aqueous sodium
carbonate (1.0 mL, 2 M), and tetrakis(triphenylphosphine)-
palladium (116 mg, 0.1 mmol) by the general procedure with
1
chromatography. Mp 201-202 °C (CH2Cl2/hexane); H NMR
(CDCl3, 300 MHz) δ 2.33 (s, 3H), 4.20 (s, 3H), 7.23 (d, J ) 8.4
Hz, 2H), 7.35 (m, 2H), 7.82 (d, J ) 8.4 Hz, 2H), 8.01 (m, 1H),
8.35 (s, 1H), 8.50 (s, 1H), 8.64 (m, 1H); 13C NMR (CDCl3, 100
MHz) δ 156.2, 145.3, 137.2, 134.9, 134.8, 132.1, 130.0, 129.1,
129.0, 126.9, 125.3, 124.0, 123.6, 115.9, 113.2, 55.0, 21.6; EIMS
m/z (%) 457/459 (M+, 34), 302/304 (100); HRMS calcd for
In summary, the above reaction sequence provided at
least two places where we could plan to bring in the
2-aminoimidazole chain in order to accomplish a total
synthesis. One would be the coupling of intermediate 17
with a proper indole building block bearing an alkyl
substitution at the 4-position, the other would be at the
4′′-position in fragment 20. The strategy developed here
to build the skeleton of dragmacidin D by critically
selective introduction of two indole units, using Suzuki
and Stille cross-coupling reactions sequentially, combined
with the flexible route for the preparation of the 2-ami-
noimidazole segment may be applicable to the final
asymmetric total synthesis of bis(indole) marine alkaloid
dragmacidin D.
C
20H16BrN3O3S 457.0097, found 457.0099.
3-Meth oxyl-5-ph en yl-2-(N-tosylin dol-3-yl)pyr azin e (11).
11 (71 mg, 80%) was obtained as a yellow solid from 10b (92
mg, 0.2 mmol), phenylboronic acid (31 mg, 0.25 mmol), aqueous
sodium carbonate (0.3 mL, 2 M), and tetrakis(triphenylphos-
phine)palladium (25 mg, 0.025 mmol) by the general procedure
with chromatography. Mp 147-149 °C (CH2Cl2/hexane); 1H
NMR (CDCl3, 400 MHz) δ 2.29 (s, 3H), 4.25 (s, 3H), 7.19 (d, J
) 8.1 Hz, 2H), 7.32-7.50 (m, 5H), 7.82 (d, J ) 8.2 Hz, 2H),
8.03 (dd, J ) 7.2 and 1.5 Hz, 1H), 8.08 (d, J ) 7.2 Hz, 2H),
8.56 (s, 1H), 8.76 (s, 1H), 8.77 (dd, J ) 7.0 and 2.0 Hz, 1H);
13C NMR (CDCl3, 100 MHz) δ 156.5, 145.5, 145.2, 137.2, 136.3,
135.2, 135.0, 132.2, 130.0, 129.5, 129.4, 128.9, 128.8, 127.0,
126.6, 125.1, 124.0, 123.9, 117.0, 113.3, 53.8, 21.6; EIMS m/z
(%) 455 (M+, 84), 300 (100). Anal. Calcd for C26H21N3O3S: C,
68.57; H, 4.62; N, 9.23. Found: C, 68.26; H, 4.86; N, 8.97.
N -t er t -Bu t yld im e t h ylsilyl-3,4-d ib r om o-7-m e t h oxyl-
in d ole (13c). Under a dry ice-acetone bath, freshly recrystal-
lized NBS (660 mg, 3.7 mmol) was added to a solution of
4-bromo-7-methoxylindole 12c (1.2 g, 3.53 mmol) in anhydrous
THF (15 mL). The mixture was stirred for 6 h at this
temperature, allowed to warm to room temperature, and
(22) (a) Corey, E. J .; Snider, B. B. J . Am. Chem. Soc. 1972, 94,
2549. (b) Corey, E. J .; Venkateswarlu, A. J . Am. Chem. Soc. 1972, 94,
6190.
(23) (a) Grehn, L.; Ragnarsson, U. Angew. Chem., Int. Ed. Engl.
1984, 23, 296. (b) Flynn, D. L.; Zelle, R. E.; Grieco, P. A. J . Org. Chem.
1983, 48, 2424.
(24) For a review, see: Stille, J . K. Angew. Chem., Int. Ed. Engl.
1986, 25, 508.
(25) Liebeskind, L. S.; Fengl, R. W. J . Org. Chem. 1990, 55, 5359.
(26) Soll, R. M.; Humber, L. G.; Deininger, D.; Asselin, A. A.; Chau,
T. T.; Weichman, B. M. J . Med. Chem. 1986, 29, 1457.
(27) For detailed information, see: J iang, B.; Yang, C.-G.; Wang, J .
J . Org. Chem. 2001, 66, 4865.
J . Org. Chem, Vol. 67, No. 26, 2002 9395

Yang et al.
diluted with ether. The organic phase was washed with water
and brine, dried over sodium sulfate, and concentrated under
vacuum. Purification by flash chromatography (silica, hexane)
afforded compound 13c (980 mg, 66%). Mp 123-125 °C
(hexane); 1H NMR (CDCl3, 300 MHz) δ 7.26 (s, 1H), 7.24 (d, J
) 8.5 Hz, 1H), 6.49 (d, J ) 8.5 Hz, 1H), 3.87 (s, 3H), 0.87 (s,
9H), 0.60 (s, 6H); 13C NMR (CDCl3, 75 MHz) δ 146.7, 133.5,
131.5, 127.3, 125.7, 104.2, 103.5, 92.6, 54.3, 26.7, 19.6, -1.3;
EIMS m/z (%) 419 (M+, 55), 417/421 (M+, 28), 347 (100); HRMS
calcd for C15H21Br2NOSi 416.9761, found 416.9760.
1 (386 mg, 92%) as a yellow solid. Mp 230-232 °C (AcOEt/
1
hexane); H NMR (DMSO-d6, 300 MHz) δ 4.01 (s, 3H), 4.18
(s, 3H), 6.75 (d, J ) 8.4 Hz, 1H), 7.25 (d, J ) 8.5 Hz, 1H), 7.34
(dd, J ) 8.5 and 1.7 Hz, 1H), 7.70 (d, J ) 2.6 Hz, 1H), 7.73 (d,
J ) 1.7 Hz, 1H), 8.37 (d, J ) 2.6 Hz, 1H), 8.47 (s, 1H), 8.70 (d,
J ) 8.4 Hz, 1H), 11.79 (br s, 1H), 12.06 (br s, 1H); 13C NMR
(DMSO-d6, 100 MHz) δ 154.4, 146.1, 140.9, 137.3, 137.2, 136.0,
129.8, 127.8, 127.6, 125.1, 124.3, 123.0, 114.8, 114.4, 114.3,
110.4, 103.9, 103.5, 55.6, 53.6; EIMS m/z (%) 529 (M+, 100);
HRMS calcd for C22H16Br2N4O2 525.9643, found 525.9646.
3-Met h oxyl-2-(N-t osylin d ol-3-yl)-5-(N-ter t-b u t yld im e-
th ylsilylin d ol-3-yl)p yr a zin e (15). 15 (98 mg, 80%) was
obtained as a yellow solid from 10b (92 mg, 0.2 mmol), 14a
(70 mg, 0.25 mmol), aqueous sodium carbonate (0.3 mL, 2 M),
and tetrakis(triphenylphosphine)palladium (25 mg, 0.025
mmol) by the general procedure with chromatography. Mp
220-222 °C (CH2Cl2/hexane); 1H NMR (CDCl3, 400 MHz) δ
0.67 (s, 6H), 0.98 (s, 9H), 2.30 (s, 3H), 4.32 (s, 3H), 7.20 (d, J
) 8.2 Hz, 2H), 7.24-7.38 (m, 4H), 7.56 (m, 1H), 7.81 (d, J )
8.2 Hz, 2H), 7.82 (s, 1H), 8.04 (d, J ) 7.5 Hz, 1H), 8.50 (m,
1H), 8.52 (s, 1H), 8.72 (s, 1H), 8.79 (m, 1H); 13C NMR (CDCl3,
100 MHz) δ 156.5, 145.0, 144.6, 142.2, 135.2, 135.0, 134.2,
132.0, 131.3, 129.9, 129.7, 128.7, 127.9, 126.9, 124.9, 123.8,
123.7, 122.4, 121.5, 121.1, 117.4, 116.2, 114.3, 113.2, 53.9, 26.3,
21.5, 19.3, -3.4; EIMS m/z (%) 608 (M+, 30). Anal. Calcd for
3-Meth oxyl-2-(N-ter t-bu tyld im eth ylsilyl-6-br om oin d ol-
3-yl)-5-(N-ter t-bu tyld im eth ylsilyl-4-br om o-7-m eth oxylin -
d ol-3-yl)p yr a zin e (20). To a solution of compound 1 (280 mg,
0.53 mmol) was added dropwise LHMDS (1 M, 1.8 mL, 1.8
mmol) under cooling in a dry ice-acetone bath. After this
mixture was stirred for 10 min at this temperature, TBDMS
triflate (0.47 mL, 2.5 mmol) was added to the reaction, and
then the reaction system was allowed to reach room temper-
ature. Two hours later, a buffer solution (pH 7) was added to
the mixture and the mixture was extracted with ether. The
organic layer was successively washed with 1 N aqueous
hydrochloric acid, saturated sodium bicarbonate, and brine,
and then dried over sodium sulfate and concentrated under
vacuum. Purification by flash chromatography (silica, hexane)
afforded 20 (350 mg, 88%) as a spumy solid. Mp 204-205 °C
1
C
34H36N4O3SSi: C, 67.10; H, 5.92; N, 9.21. Found: C, 67.11;
(CH2Cl2/hexane); H NMR (CDCl3, 300 MHz) δ 0.59 (s, 6H),
H, 6.11; N, 8.97.
0.70 (s, 6H), 0.96 (s, 9H), 1.00 (s, 9H), 3.93 (s, 3H), 4.20 (s,
3H), 6.58 (d, J ) 8.4 Hz, 1H), 7.29 (d, J ) 8.4 Hz, 1H), 7.37
(dd, J ) 8.5 and 1.5 Hz, 1H), 7.46 (s, 1H), 7.68 (d, J ) 1.5 Hz,
1H), 8.20 (s, 1H), 8.44 (s, 1H), 8.72 (d, J ) 8.5 Hz, 1H); 13C
NMR (CDCl3, 100 MHz) δ 155.3, 146.8, 142.3, 141.5, 137.7,
136.7, 135.3, 134.3, 132.5, 129.5, 128.8, 125.5, 124.2, 124.0,
117.6, 116.5, 115.7, 114.1, 104.9, 103.4, 54.3, 53.7, 26.8, 26.3,
19.6, 19.3, -1.3, -3.9; EIMS m/z (%) 756 (M+, 22); HRMS calcd
for C34H44Br2N4O2Si2 754.1353, found 754.1336.
3-Meth oxyl-2-(N-ter t-bu tyld im eth ylsilyl-6-br om oin d ol-
3-yl)-5-(N-ter t-bu tyld im eth ylsilyl-7-m eth oxylin d ol-3-yl)-
p yr a zin e (21). To a solution of compound 20 (113 mg, 0.15
mmol) in dry THF (1 mL) was added dropwise BuLi (2 M, 80
µL, 0.16 mmol) at -78 °C. After continuous stirring for 30 min
at this temperature, saturated ammonium chloride was added
to quench the reaction. The mixture was diluted with ether,
and the organic phase was washed with water and brine, dried
over sodium sulfate, and concentrated under vacuum. Purifi-
cation by flash chromatography (silica, hexane) gave compound
21 (70 mg, 70%) as a white solid. Mp 228-229 °C (CH2Cl2/
hexane); 1H NMR (CDCl3, 300 MHz) δ 0.64 (s, 6H), 0.69 (s,
6H), 0.95 (s, 9H), 0.99 (s, 9H), 3.94 (s, 3H), 4.26 (s, 3H), 6.73
(d, J ) 8.5 Hz, 1H), 7.21 (m, 1H), 7.35 (dd, J ) 8.6 and 1.7 Hz,
1H), 7.66 (d, J ) 1.4 Hz, 1H), 7.85 (s, 1H), 8.11 (d, J ) 8.1 Hz,
1H), 8.13 (s, 1H), 8.68 (d, J ) 8.4 Hz, 1H), 8.69 (s, 1H); 13C
NMR (CDCl3, 100 MHz) δ 155.9, 147.2, 142.9, 142.3, 136.1,
134.6, 132.0, 130.8, 128.8, 124.2, 123.9, 121.7, 116.5, 116.3,
115.7, 114.3, 113.9, 102.7, 54.0, 53.6, 26.8, 26.3, 19.5, 19.3,
-1.4, -3.9; EIMS m/z (%) 676 (M+, 16), 531 (14); HRMS calcd
for C34H45BrN4O2Si2 676.2288, found 676.2311.
5-Br om o-3-m eth oxyl-2-(N-ter t-bu tyldim eth ylsilyl-6-br o-
m oin d ol-3-yl)p yr a zin e (16). Pyrazine 16 (466 mg, 52%) was
obtained as a white solid from 4 (536 mg, 2.0 mmol), crude
14b (890 mg, 2.5 mmol), aqueous sodium carbonate (2.0 mL,
2 M), and tetrakis(triphenylphosphine)palladium (232 mg, 0.2
mmol) by the general procedure with chromatography. Mp
207-208 °C (CH2Cl2/hexane); 1H NMR (CDCl3, 300 MHz) δ
0.67 (s, 6H), 0.98 (s, 9H), 4.14 (s, 3H), 7.35 (dd, J ) 8.6 and
1.2 Hz, 1H), 7.66 (d, J ) 1.8 Hz, 1H), 8.11 (s, 1H), 8.32 (s,
1H), 8.56 (d, J ) 8.6 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ
155.8, 142.3, 139.0, 137.2, 135.8, 130.0, 128.4, 124.5, 124.1,
116.7, 113.1, 54.7, 26.3, 19.4, -3.8; EIMS m/z (%) 497 (M+,
100), 495/499 (53). Anal. Calcd for C19H23Br2N3OSi: C, 45.88;
H, 4.63; N, 8.45. Found: C, 46.21; H, 4.68; N, 8.27.
5-Br om o-3-m eth oxyl-2-(6-br om oin dol-3-yl)pyr azin e (17).
To a solution of compound 16 (398 mg, 0.8 mmol) in THF (15
mL) was added tetrabutylammonium fluoride (1 M in THF,
2.0 mL, 2.0 mmol). After the mixture was stirred for 1 h at
ambient temperature, water was added to quench the reaction
and the resulting mixture was extracted with ether. The
organic phase was dried over sodium sulfate and concentrated
under vacuum. Purification by flash chromatography (silica,
hexane/AcOEt 2:1) afforded compound 17 (292 mg, 95%). Mp
1
219-220 °C (AcOEt/hexane); H NMR (DMSO-d6, 400 MHz)
δ 4.09 (s, 3H), 7.29 (dd, J ) 8.6 and 1.6 Hz, 1H), 7.69 (d, J )
1.7 Hz, 1H), 8.30 (d, J ) 2.0 Hz, 1H), 8.40 (s, 1H), 8.50 (d, J
) 8.6 Hz, 1H), 11.83 (br s, 1H); 13C NMR (CDCl3, 100 MHz) δ
155.0, 139.2, 137.3, 136.5, 130.7, 128.7, 124.8, 124.0, 123.3,
115.0, 114.4, 109.3, 54.6; EIMS m/z (%) 383 (M+, 100), 381/
385 (M+, 51). Anal. Calcd for C13H9Br2N3O: C, 40.73; H, 2.35;
N, 10.97. Found: C, 41.01; H, 2.38; N, 10.93.
Ack n ow led gm en t. We thank the Shanghai Munici-
pal Committee of Science and Technology for financial
support to this research.
3-Met h oxyl-2-(6-b r om oin d ol-3-yl)-5-(4-b r om o-7-m et h -
oxylin d ol-3-yl)p yr a zin e (1). A mixture of compound 17 (308
mg, 0.80 mmol), crude 3-tributylstannylindole 14d (480 mg,
0.95 mmol), tetrakis(triphenylphosphine)palladium (116 mg,
0.1 mmol), and copper(I) iodide (30 mg) in DMF (5 mL) was
heated (80-90 °C of the bath) and stirred for 24 h. After the
mixture was cooled to room temperature, the system was
diluted with the addition of AcOEt and washed with saturated
aqueous potassium fluoride. The organic phase was washed
with water and brine, dried over sodium sulfate, and concen-
trated under vacuum. Purification by flash chromatography
(silica, eluted with ethyl acetate/hexane) afforded compound
Su p p or tin g In for m a tion Ava ila ble: X-ray analyst of
compound 1; experimental procedure and characterization
data for compounds 5-8, 10a , 13a -b, 14a -d , 18, 19b; copies
of 1H and 13C NMR spectra for compounds 4, 10b, 11, 15-17,
1, 20, and 21. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O026450M
9396 J . Org. Chem., Vol. 67, No. 26, 2002