Palladium-mediated intramolecular aryl amination on furanose derivatives: An expedient approach to the synthesis of chiral benzoxazocine derivatives and tricyclic nucleosides

Article abstract of DOI:10.1021/jo052420i

Pd-catalyzed intramolecular arylamination on sugar derivatives has been accomplished by using bulky biaryl phosphine ligands. An application of this methodology on a variety of D-glucose-derived substrates, 2a-f, led to the synthesis of highly functionalized cis-fused tricyclic oxazocines, 3a-e. The products could subsequently be transformed to the optically active benzoxazocine derivative 4 and tricyclic nucleoside 6. This is the first example of the synthesis of eight-membered rings via intramolecular cycloamination of furanose derivatives, which provides a very useful method for the catalytic synthesis of medium-ring heterocycles.

Full text of DOI:10.1021/jo052420i

the presence of a Pd(0) catalyst,4 ring-closing metathesis,5 or
Pd(0)-induced ring cyclization.6 The above methodologies either
require a relatively lengthy sequence of reactions or furnish low
yields of the reaction products. As a part of our research program
related to the synthesis of benzannulated medium-ring ethers7
or amines,8 we planned to synthesize eight-membered rings
bearing both oxygen and nitrogen atoms because of their
expected useful biological activities.9 Interest in the use of the
easily accessible carbohydrates from the chiral pool for the
synthesis of optically active heterocycles has also been growing
rapidly.10 In a continuation of our interest in the carbohydrate-
based synthesis of medium-ring heterocycles, we felt that the
use of the chiron approach,11 along with the application of
Palladium-Mediated Intramolecular Aryl
Amination on Furanose Derivatives: An
Expedient Approach to the Synthesis of Chiral
Benzoxazocine Derivatives and Tricyclic
Nucleosides
Arpita Neogi, Tirtha Pada Majhi,
Ranjan Mukhopadhyay, and Partha Chattopadhyay*
DiVision of Medicinal Chemistry, Indian Institute of Chemical
Biology, 4 Raja S. C. Mullick Road, Kolkata- 700032, India
partha@iicb.res.in
ReceiVed NoVember 23, 2005
(3) For recent syntheses of medium-ring heterocycles, see: (a) Evans,
P. A.; Holmes, A. B.; Russel, K. Tetrahedron: Asymmetry 1990, 1, 589-
592. (b) Kitano, T.; Shirai, N.; Motoi, M.; Sato, Y. J. Chem. Soc., Perkin
Trans. 1 1992, 2851-2854. (c) Crombie, L.; Haigh, D.; Jones, R. C. F.;
Mat-zin, A. R. J. Chem. Soc., Perkin Trans. 1 1993, 2047-2054. (d) Coates,
W. J.; Dhanak, D. Heterocycles 1993, 36, 1631-1639. (e) Wright, D. L.;
Weekly, R. M.; Groff, R.; McMills, M. C. Tetrahedron Lett. 1996, 37,
2165-2168. (f) Bergmann, D. J.; Campi, E. M.; Jackson, W. R.; Patti, A.
F.; Saylik, D. Tetrahedron Lett. 1999, 40, 5597-5600. (g) Ouyang, X.;
Kiselyov, A. S. Tetrahedron 1999, 55, 8295-8302. (h) Zhang, J.; Jacobson,
A.; Rusche, J. R.; Herlihy, W. J. Org. Chem. 1999, 64, 1074-1076. (i)
Monovich, L. G.; Hue´rou, Y. L.; Ro¨nn, M.; Molander, G. A. J. Am. Chem.
Soc. 2000, 122, 52-57. (j) Ra¨cker, R.; Do¨ring, K.; Reiser, O. J. Org. Chem.
2000, 65, 6932-6939. (k) Meyers, A. I.; Downing, S. V.; Weiser, M. J. J.
Org. Chem. 2001, 66, 1413-1419. (l) Donohoe, T. J.; Raoof, A.; Linney,
I. D.; Helliwell, M. Org. Lett. 2001, 3, 861-864. (m) Iradier, F.; Arraya´s,
R. G.; Carretero, J. C. Org. Lett. 2001, 3, 2957-2960. (n) Tempest, P.;
Ma, V.; Kelly, M. G.; Jones, W.; Hulme, C. Tetrahedron Lett. 2001, 42,
4963-4968. (o) Kan, T.; Kobayashi, H.; Fukuyama, T. Synlett 2002, 697-
699. (p) Ma, D.; Tang, G.; Kozikowski, A. P. Org. Lett. 2002, 4, 2377-
2380. (q) Ikemoto, T.; Ito, T.; Nishiguchi, A.; Tomimatsu, K. Tetrahedron
Lett. 2004, 45, 9335-9339.
Pd-catalyzed intramolecular arylamination on sugar deriva-
tives has been accomplished by using bulky biaryl phosphine
ligands. An application of this methodology on a variety of
D-glucose-derived substrates, 2a-f, led to the synthesis of
highly functionalized cis-fused tricyclic oxazocines, 3a-e.
The products could subsequently be transformed to the
optically active benzoxazocine derivative 4 and tricyclic
nucleoside 6. This is the first example of the synthesis of
eight-membered rings via intramolecular cycloamination of
furanose derivatives, which provides a very useful method
for the catalytic synthesis of medium-ring heterocycles.
(4) Ohno, H.; Hamaguchi, H.; Ohata, M.; Kosaka, S.; Tanaka, T. J. Am.
Chem. Soc. 2004, 126, 8744-8754.
(5) Van Otterlo, W. A. L.; Morgans, G. L.; Khanye, S. D.; Aderibigbe,
B. A. A.; Michael, J. P.; Billing, D. G. Tetrahedron Lett. 2004, 45, 9171-
9175.
(6) Davion, Y.; Guillaumet, G.; Le´ger, J.-M.; Jarry, C.; Lesur, B.; Me´rour,
J.-Y. Heterocycles 2003, 60, 1793-1804.
(7) (a) Nandi, A.; Mukhopadhyay, R.; Chattopadhyay, P. J. Chem. Soc.,
Perkin Trans. 1 2001, 3346-3351. (b) Nandi, A.; Chattopadhyay, P.
Tetrahedron Lett. 2002, 43, 5977-5980.
(8) Majhi, T. P.; Nandi, A.; Neogi, A.; Mukhopadhyay, R.; Chatto-
padhyay, P. Synthesis 2005, 2307-2314.
The abundance of medium rings incorporating oxygen or
nitrogen atoms in medicinally interesting compounds1 continues
to ensure that they are important synthetic targets for organic
chemists.2,3 For example, the benzoxazocine ring is often present
in pharmaceutical agents as a core structural motif. Synthetic
routes to medium-ring heterocycles involving direct ring closure
are often slow and hampered by unfavorable enthalpies and
entropies of the reaction. A few reported approaches for the
construction of the oxazocine ring are based on the cyclization
of bromoallenes bearing oxygen nucleophilic functionalities in
(9) (a) Stillings, M. R.; Freeman, S.; Myers, P. L.; Readhead, M. J.;
Welbourn, A. P.; Rance, M. J.; Atkinson, D. C. J. Med. Chem. 1985, 28,
225-233. (b) Nagarajan, K.; Goud, A. N.; Rao, V. R.; Shah, R. K.; Shenoy,
S. J. Proc. Indian Acad. Sci., Chem. Sci. 1992, 104, 549-568. (c) Mather,
G. G.; Labroo, R.; Guern, M.-E. L.; Lepage, F.; Gillardin, J.-M.; Levy, R.
H. Chirality 2000, 12, 153-159. (d) Seto, S. Tetrahedron Lett. 2004, 45,
8475-8478. (e) Seto, S.; Tanioka, A.; Ikeda, M.; Izawa, S. Bioorg. Med.
Chem. Lett. 2005, 15, 1479-1484. (f) Seto, S.; Tanioka, A.; Ikeda, M.;
Izawa, S. Bioorg. Med. Chem. Lett. 2005, 15, 1485-1488. (g) Novelli, A.;
Diaz-Trelles, R.; Groppetti, A.; Fernandez-Sanchez, M. T. Amino Acids
2005, 28, 183-191.
(10) For selected examples of heterocycles from carbohydrates, see: (a)
Clark, J. S.; Hamelin, O.; Hufton, R. Tetrahedron Lett. 1998, 39, 8321-
8324. (b) Wong, J. C. Y.; Lacombe, P.; Sturino, C. F. Tetrahedron Lett.
1999, 40, 8751-8754. (c) Leeuwenburgh, M. A.; Litjens, R. E. Z. N.; Codee,
J. D. C.; Overkleeft, H. S.; Vander Marel, G. A.; Van Boom, J. H. Org.
Lett. 2000, 2, 1275-1277. (d) Holt, D. J.; Barker, W. D.; Jenkins, P. R.;
Panda, J.; Ghosh, S. J. Org. Chem. 2000, 65, 482-493. (e) Oishi T.; Uehara,
H.; Nagumo, Y.; Shoji, M.; Brazidec, J.-Y. L.; Kosaka, M.; Hirama, M.
Chem. Commun. 2001, 381-382. (f) Peczuh, M. W.; Snyder, N. L.
Tetrahedron Lett. 2003, 44, 4057-4061. (g) Tripathi, S.; Singha, K.; Achari,
B.; Mandal, S. B. Tetrahedron 2004, 60, 4959-4965.
* To whom correspondence should be addressed. Tel.: +91 33 2473 0492.
Fax: +91 33 2473 5197.
(1) For selected examples of eight-membered heterocycles, see: (a) Basil,
B.; Coffee, E. C. J.; Gell, D. L.; Maxwell, D. R.; Sheffield, D. J.;
Wooldridge, K. R. H. J. Med. Chem. 1970, 13, 403-406. (b) Klayman, D.
L.; Scovill, J. P.; Bartosevich, J. F.; Mason, C. J. J. Med. Chem. 1979, 22,
1367-1373. (c) Vedejs, E.; Galante, R. J.; Goekjian, P. G. J. Am. Chem.
Soc. 1998, 120, 3613-3622. (d) Ma, D.; Tang, G.; Kozikowski, A. P. Org.
Lett. 2002, 4, 2377-2380. (e) Staerk, D.; Witt, M.; Oketch-Rabah, H. A.;
Jaroszewski, J. W. Org. Lett. 2003, 5, 2793-2796.
(11) For our earlier efforts on the synthesis of eight-membered cyclic
ethers using regioselective radical cyclization, see: Chattopadhyay, P.;
Mukherjee, M.; Ghosh, S. Chem. Commun. 1997, 2139-2140.
(2) For recent reviews, see: (a) Evans, P. A.; Holmes, A. B. Tetrahedron
1991, 47, 9131-9166. (b) Yet, L. Chem. ReV. 2000, 100, 2963-3008.
10.1021/jo052420i CCC: $33.50 © 2006 American Chemical Society
Published on Web 03/21/2006
J. Org. Chem. 2006, 71, 3291-3294
3291

SCHEME 1. Construction of O-Bromo/Iodo Benzylated Sugar Amines 2a-fa
a Reagents and conditions: (i) 70% AcOH (v/v), rt, overnight; (ii) aq NaIO4, MeOH, rt, 45 min; (iii) RNH2 (1.2 equiv), anhydrous CH2Cl2, MS (4 Å),
rt, 12 h, N2; (iv) NaBH4, dry MeOH, rt, 3 h.
TABLE 1. Preparations of Sugar Amines 2a-f
intramolecular C-N ring closure between aromatic bromides
or iodides and an aliphatic amine, offers a better and more
convenient alternative to the synthesis of benzoxazocine deriva-
tives in optically pure form.
Over the past few years much effort has gone into developing
palladium-catalyzed aryl-amination chemistry.12 The initial work
by Hartwig and Louie13a and Buchwald and Wolfe13b focused
on the intermolecular amination of aryl bromides or iodides to
give substituted anilines. More recently, this aryl-amination
chemistry has undergone optimization, particularly with the
development of new ligand systems,14 and an intramolecular
version has been utilized for the synthesis of heterocyclic
compounds.15
In this paper, we describe a facile conversion of D-glucose
to tricyclic sugar-annulated benzoxazocine derivatives in chiral
recognition. Herein, we report the synthesis of a new tricyclic
form. Cleavage of the sugar ring of these tricyclic derivatives
nucleoside analogue in which the furanose ring is linearly cis
provides a convenient route for entry into chiral, functionalized
fused with a benzoxazocine moiety. The present communication
benzoxazocines.
deals with the scope of the aryl-amination reaction on sugar
The possibility of converting the intermediate furanose
derivatives for developing functionalized chiral benzoxazocine
derivatives to nucleoside analogues is an added attraction. It
derivatives and tricyclic nucleosides incorporating an eight-
should be mentioned that the design of conformationally
membered ring.
restricted nucleosides as monomers in oligonucleotide analogues
The starting material, 1,2:5,6-di-O-isopropylidene glucofura-
nose, was smoothly converted to the O-2-bromo/iodo benzylated
and as potent antiviral agents16 has attracted considerable
attention recently. Anticipating better biological activities,
sugar amines, 2a-f, through the intermediate O-(2-bromo-
nucleosides with bi- and tricyclic carbohydrate moieties17,18 have
benzyl) glucofuranosides, 1a-e,7a and O-(2-iodo-benzyl) glu-
been synthesized to restrict the conformational flexibility of the
nucleoside into conformers, which are ideal for nucleic acid
cofuranoside, 1f. Selective removal of the 5,6-O-isopropylidene
moiety from the benzylated products, 1a-f, was smoothly
effected with 70% aqueous HOAc at 25 °C, and the resulting
diol on NaIO4 oxidation, imine formation with aliphatic amines,
(12) For reviews of palladium-catalyzed aminations, see: (a) Wolfe, J.
P.; Wagaw. S.; Marcoux, J.-F.; Buchwald, S. L. Acc. Chem. Res. 1998, 31,
and subsequent NaBH4 reduction in MeOH afforded the desired
amines, 2a-f, in good yields (Scheme 1; Table 1). The spectral
data of 2a-f are in excellent agreement with the assigned
structures.
Our initial goal was to explore the synthesis of benzoxazo-
cine-annulated furanose derivatives 3a-e from 2a-f through
Pd-catalyzed intramolecular cycloamination reactions in the
presence of bases and ligands. After considering several
phosphine ligands, we chose to pursue the conditions reported
by Buchwald et al.19 Entry 1 of Table 2 clearly indicates that
the reaction under these conditions failed to provide the desired
compound, 3a. We next applied other conditions reported in
the literature20 (entry 2, Table 2) to effect intramolecular
805-818. (b) Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2046-2067.
(c) Yang, B. H.; Buchwald, S. L. J. Organomet. Chem. 1999, 576, 125-
146. (d) Muci, A. R.; Buchwald, S. L. Practical Palladium Catalysts for
C-N and C-O bond Formation. In Cross-Coupling Reaction: A Practical
Guide; Miyaura, N., Ed.; Topics in Current Chemistry Ser. 219; Springer-
Verlag: New York, 2002; pp 131-209. (e) Barluenga, J.; Valde´s, C. Chem.
Commun. 2005, 4891-4901.
(13) (a) Louie, J.; Hartwig, J. F. Tetrahedron Lett. 1995, 36, 3609-
3612. (b) Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 1996, 61, 1133-
1135.
(14) (a) Wolfe, J. P.; Wagaw, S.; Buchwald, S. L. J. Am. Chem. Soc.
1996, 118, 7215-7216. (b) Driver, M. S.; Hartwig, J. F. J. Am. Chem.
Soc. 1996, 118, 7217-7218. (c) Hamann, B. C.; Hartwig, J. F. J. Am Chem.
Soc. 1998, 120, 7369-7370. (d) Hartwig, J. F.; Kawatsura, M.; Hauck, S.
I.; Shaughnessy, K. H.; Alcazar-Roman, L. M. J. Org. Chem. 1999, 64,
5575-5580. (e) Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.; Buchwald,
S. L. J. Org. Chem. 2000, 65, 1158-1174. (f) Lee, S.; Hartwig, J. F. J.
Org. Chem. 2001, 66, 3402-3415. (g) Charles, M. D.; Schultz, P.;
Buchwald, S. L. Org. Lett. 2005, 7, 3965-3968.
(15) (a) Brain, C. T.; Brunton, S. A. Tetrahedron Lett. 2002, 43, 1893-
1895. (b) Yamada, K.; Kubo, T.; Tokuyama, H.; Fukuyama, T. Synlett 2002,
231-234. (c) Zhu, Y.-M.; Kiryu, Y.; Katayama, H. Tetrahedron Lett. 2002,
43, 3577-3580. (d) Evindar, G.; Batey, R. A. Org. Lett. 2003, 5, 133-
136. (e) Margolis, B. J.; Swidorski, J. J.; Rogers, B. N. J. Org. Chem. 2003,
68, 644-647. (f) Brain, C. T.; Steer, J. T. J. Org. Chem. 2003, 68, 6814-
6816.
(17) For the syntheses of bicyclic nucleosides, see: (a) Ravn, J.; Nielsen,
P. J. Chem. Soc., Perkin Trans. 1 2001, 985-993. (b) Thomasen, H.;
Meldgaard, M.; Freitag, M.; Wengel, J.; Petersen, M.; Nielsen, P. Chem.
Commun. 2002, 1888-1889. (c) Freitag, M.; Thomasen, H.; Christensen,
N. K.; Petersen, M.; Nielsen, P. Tetrahedron 2004, 60, 3775-3786.
(18) For the syntheses of tricyclic nucleosides, see: (a) Nielsen, P.;
Petersen, M.; Jacobsen, J. P. J. Chem. Soc., Perkin Trans. 1 2000, 3706-
3713. (b) Ravn, J.; Thorup, N.; Nielsen, P. J. Chem. Soc., Perkin Trans. 1
2001, 1855-1861.
(16) For reviews, see: (a) Kool, E. T. Chem. ReV. 1997, 97, 1473-
1488. (b) Herdewijn, P. Biochim. Biophys. Acta 1999, 1489, 167-179. (c)
Leumann, C. J. Bioorg. Med. Chem. 2002, 10, 841-854.
(19) Wolfe, J. P.; Rennels, R. A.; Buchwald, S. L. Tetrahedron 1996,
52, 7525-7546.
3292 J. Org. Chem., Vol. 71, No. 8, 2006

TABLE 2. Optimization of the Intramolecular Palladium Catalyzed Cycloamination Reaction
entry
substrate
base
catalyst
ligand
solvent
product
yield (%)
1
2
3
4
5
6
7
8
9
2a
2a
2a
2a
2a
2a
2b
2c
2d
2d
2e
2f
K2CO3 + KO-tBu
KO-tBu
Pd(PPh3)4
Pd(OAc)2
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
no ligand
(BINAP
(BINAP
(BINAP
(BINAP
Ph3P
(BINAP
(BINAP
(BINAP
(BINAP
(BINAP
(BINAP
toluene
toluene
DMF
3a
3a
3a
3a
3a
3a
3b
3c
3d
3d
3e
3a
nra
30b
20c
75d
50e
5f
K2CO3 + KO-tBu
K2CO3 + KO-tBu
K2CO3 + KO-tBu
K2CO3 + KO-tBu
K2CO3 + KO-tBu
K2CO3 + KO-tBu
Cs2CO3
K2CO3 + KO-tBu
K2CO3 + KO-tBu
Cs2CO3
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
74d
68d
65g
77d
70d
55g
10
11
12
a Reaction conditions: 10 mol % Pd(PPh3)4, no ligand, 2.0 equiv K2CO3, 2.0 equiv KO-tBu, toluene (10 mL/mmol substrate), 90 °C, 24 h, nr ) no
reaction. b Reaction conditions: 2 mol % Pd(OAc)2, 4 mol % (BINAP, 2.0 equiv KO-tBu, toluene (10 mL/mmol substrate), 90 °C, 24 h. c Reaction conditions:
10 mol % Pd2(dba)3, 7 mol % (BINAP, 2.0 equiv K2CO3, 2.0 equiv KO-tBu, DMF (10 mL/mmol substrate), 105 °C, 16 h. d Reaction conditions: 10 mol
% Pd2(dba)3, 7 mol % (BINAP, 2.0 equiv K2CO3, 2.0 equiv KO-tBu, toluene (10 mL/mmol substrate), 90 °C, 16 h. e Reaction conditions: 10 mol %
Pd2(dba)3, 10 mol % (BINAP, 2.0 equiv K2CO3, 2.0 equiv KO-tBu, toluene (10 mL/mmol substrate), 90 °C, 18 h. f Reaction conditions: 10 mol %
Pd2(dba)3, 10 mol % Ph3P, 2.0 equiv K2CO3, 2.0 equiv KO-tBu, toluene (10 mL/mmol substrate), 90 °C, 24 h. g Reaction conditions: 10 mol % Pd2(dba)3,
7 mol % (BINAP, 5.0 equiv Cs2CO3, toluene (10 mL/mmol substrate), 90 °C, 16 h.
worked best as the base component. The use of a weak base21
SCHEME 2. Synthesis of cis-Fused Furobenzoxazocines
like Cs2CO3 (5 equiv) gave a slight lowering of the yield (entry
9, Table 2). However, this worked better when the iodo substrate
2f was used (entry 12, Table 2).
The feasibility of synthesizing benzoxazocines and tricyclic
nucleoside analogues from the annulated sugar derivatives could
be realized using 3a (Scheme 3). Thus, 3a was converted to
the functionalized benzoxazocine 4 through a sequence of
reactions involving the removal of the 1,2-O-isopropylidene
group with 4% H2SO4 (v/v) in CH3CN/H2O (3:1), NaIO4
cleavage of the diol, NaBH4 reduction of the carbonyl group,
and acetylation. The formation of 4 was deduced from the
cyclization, but this effected the transformation in only 30%
appearance of four methylene carbon signals at δ 59.2, 59.8,
yield. However, application of the more recently disclosed
63.8, and 77.3 in its 13C NMR spectrum. As an application of
reagents [Pd2(dba)3/(BINAP/KO-tBu + K2CO3]15e gave the
our methodology, a nucleobase could be successfully installed
on 3a by cleavage of the acetonide group, acetylation to form
the anomeric mixture of diacetates 5, and reaction with 2,4-
bis(trimethylsilyloxy)uracil in the presence of TMS-OTf in
CH3CN at room temperature. The presence in each case of two
desired cyclic products 3a-e in 68-77% yield (Scheme 2).
The assigned structures of the products 3a-e were based on
spectroscopic data. The stereochemistries of H-3a (δ 4.30-4.45,
d, J ) 3.0 Hz) and other protons were derived by a comparison
of the J values with those of similar products prepared by us.7a
doublets at δ 5.65, 7.44 (J ) 8.1 Hz) and a broad singlet at
Because we did not encounter any example of an intra-
molecular cycloamination to prepare oxazocine rings and the
reported condition for benzazepine analogues did not efficiently
1
8.89 (olefin and NH protons of uracil, respectively) in the H
NMR of 6 confirmed the presence of nucleobase in the product.
The assignment of the structure 6 was further supported by 1H-
provide access to the desired ring systems, we sought to explore
1H COSY results. Anchimeric assistance by the neighboring
further the scope of this reaction (Table 2).
acetoxy group directs the incoming nucleobase to the â face,22
Evaluations of ligands and palladium sources showed that
the best conditions for the reaction were Pd2(dba)3 as the
palladium source, (BINAP as the ligand, KO-tBu with K2CO3
as the base, and toluene as the solvent. A stoichiometric ratio
of catalyst/ligand [10 mol % Pd2(dba)3/7 mol % (BINAP]
should be used in all cases. The use of excess ligand furnished
a low yield of the desired product, 3a (entry 5, Table 2).
Loadings of catalyst less than 10 mol % were also less effective.
A combination of K2CO3 (2.0 equiv) and KO-tBu (2.0 equiv)
forming the nucleoside derivative 6.
In conclusion, it has been demonstrated that a Pd-catalyzed
intramolecular arylamination reaction can be applied to carbo-
hydrate-derived substrates to synthesize tricyclic furobenzox-
azocines. The key step in this synthesis exploits recent
advancements in the area of palladium catalysts on sugar
(21) Meyers, C.; Maes, B. U. W.; Loones, K. T. J.; Bal, G.; Lemie`re, G.
L. F.; Dommisse, R. A. J. Org. Chem. 2004, 69, 6010-6017.
(22) (a) Niedballa, U.; Vorbru¨ggen, H. J. Org. Chem. 1974, 39, 3654-
3660. (b) Vorbru¨ggen, H.; Krolikewiez, K.; Bennua, B. Chem. Ber. 1981,
114, 1234-1255. (c) Vorbru¨ggen, H.; Ho¨fle, G. Chem. Ber. 1981, 114,
1256-1268.
(20) Beccalli, E. M.; Broggini, G.; Paladino, G.; Zoni, C. Tetrahedron
2005, 61, 61-68.
J. Org. Chem, Vol. 71, No. 8, 2006 3293

SCHEME 3. Conversion of 3a to Benzoxazocine Derivatives and a Modified Nucleosidea
a Reagents and conditions: (i) 4% H2SO4 (v/v), acetonitrile/water (3:1), rt, 12 h; (ii) aq NaIO4, MeOH, rt, 45 min; (iii) NaBH4, anhydrous MeOH, rt, 3
h; (iv) Ac2O, pyridine, rt, 12 h, overall yield, 60%; (v) Ac2O, pyridine, rt, 12 h, 90%; (vi) 2,4-bis-(trimethylsilyloxy)uracil, TMS-OTf, anhydrous acetonitrile,
rt, 5 h, N2, 60%.
were washed successively with cold aqueous HCl (1% v/v, 2 × 30
derivatives to form benzofused oxazocines. Overall, the best
conditions for this reaction are Pd2(dba)3 as the catalyst,
(BINAP as the ligand, KO-tBu with K2CO3 as the base, and
toluene as the solvent. The reaction worked on a variety of
D-glucose-derived substrates, as shown in Table 2, and can be
explored to synthesize tricyclic nucleoside analogues incorporat-
ing the oxazocine core. This simple protocol is capable of being
extended to many other carbohydrate-derived precursors, leading
mL) and water (3 × 50 mL) and then dried. The solvent was
evaporated under vacuum. The crude mass was purified by silica
gel flash chromatography to afford the diacetate 4 as colorless oil:
overall yield, 60% (eluent, light petroleum/ethyl acetate); [R]D
25
1
+68.43 (c 1.1, CHCl3). H NMR (CDCl3, 300 MHz): δ 1.87 (s,
3H), 2.04 (s, 3H), 3.04 (dd, 1H, J ) 13.7, 9.0 Hz), 3.20 (dd, 1H,
J ) 13.9, 5.2 Hz), 3.89-3.94 (m, 1H), 4.17 (d-like, 2H), 4.38 (d-
like, 3H), 4.65 (d, 1H, J ) 13.0 Hz), 4.95 (d, 1H, J ) 13.0 Hz),
7.00-7.41 (m, 9H). 13C NMR (CDCl3, 150 MHz) δ 20.7, 20.9,
59.2, 59.8, 63.8, 72.0, 77.3, 81.0, 120.1, 123.7, 127.6, 2 × 128.6,
2 × 129.1, 129.2, 130.6, 134.7, 138.8, 154.5, 170.1, 170.8. IR νmax
(liquid film): 1741, 1493, 1450, 1371, 1233, 1044 cm-1. ESIMS:
m/z 384 (MH+), 406 (MNa+). Anal. Calcd for C22H25NO5: C,
68.91; H, 6.57; N, 3.65. Found: C, 68.70; H, 6.40; N, 3.45.
(2R,3R,3aS,11aR)-3-Acetoxy-10-benzyl-2-(2,4-dioxo-3,4-dihy-
dro-2H-pyrimidin-1-yl)-3,3a,5,10,11,11a-hexahydro-2H-1,4-di-
oxa-10-aza-benzo[a]cyclopenta[e]cycloocten (6). 2,4-Bis-(trime-
thylsilyloxy)uracil was prepared by refluxing a mixture of uracil
(336 mg, 3.0 mmol) and trimethyl silyl chloride (2 drops) dissolved
in hexamethyl disilazane (5 mL) under N2 for 10 h. The residue,
obtained after evaporation of the solvent in vacuum, was dissolved
in dry CH3CN (5 mL) and added to a solution of diacetate
compound 5 (411 mg 1.0 mmol) in dry CH3CN (5 mL) and TMS-
OTf (0.5 mL). The mixture was stirred at room temperature under
N2 for 5 h. TLC showed the completion of the reaction. The solution
was neutralized with solid NaHCO3 and water (3 drops), and the
solvent was evaporated under vacuum. The gummy material was
extracted with CHCl3 (3 × 25 mL), and the organic part was washed
with brine solution (3 × 25 mL), dried, and concentrated under
vacuum. The crude product was purified by flash chromatography
over neutral alumina to afford 6 as a sticky liquid (247 mg): yield,
to a unity of structural types.
Experimental Section
General Procedure for the Cycloamination Reaction of 2a
and 2f. To a solution of amine 2a (1 mmol) in dry toluene (10
mL/mmol substrate) were added bases KO-tBu (224 mg, 2 equiv)
and K2CO3 [276 mg, 2 equiv; or Cs2CO3 (5 equiv) for 2f (1 mmol)],
Pd-catalyst (10 mol %), and (BINAP (7 mol %), and the reaction
mixture was heated at 90 °C for 16 h under an argon atmosphere.
After the disappearance of the starting amine (TLC), the crude
reaction mixture was passed through a silica bed and then extracted
with CH2Cl2 (4 × 25 mL). The organic layer was washed with
water (4 × 25 mL) and dried, and the solvent was evaporated under
reduced pressure. The crude mass was purified by flash chroma-
tography over silica gel to furnish the cyclized product 3a.
(2R,3R,3aS,11aR)-10-Benzyl-2,3-isopropylidenedioxy-3,3a,5,-
10,11,11a-hexahydro-2H-furo[3,2-c][1,5]benzoxazocine (3a). Pale
yellow solid; mp 116 °C; yield 75% (eluent, light petroleum/ethyl
acetate, 7:1); [R]25D +108.7 (c 2.0, CHCl3). 1H NMR (CDCl3, 300
MHz): δ 1.26 (s, 3H), 1.29 (s, 3H), 3.14 (dd-like, 1H), 3.26 (dd,
J ) 14.5, 5.2 Hz, 1H), 3.78-3.84 (m, 1H), 4.23 (d, 1H, J ) 13.1
Hz), 4.37 (d, 1H, J ) 3.0 Hz), 4.44 (d, 1H, J ) 13.2 Hz), 4.58
(d-like, 2H), 4.90 (d, 1H, J ) 12.9 Hz), 5.78 (d, 1H, J ) 3.6 Hz),
6.93-7.38 (m, 9H). 13C NMR (CDCl3, 75 MHz): δ 26.5, 26.8,
58.7, 59.3, 77.8, 79.8, 85.2, 89.4, 105.0, 111.3, 119.1, 122.6, 127.3,
2 × 128.4, 2 × 128.8, 129.1, 130.7, 133.1, 139.2, 154.8. IR νmax
(KBr): 2922, 1749, 1492, 1240, 1078, 1010 cm-1. EIMS: m/z 367
(M+, 70%). Anal. Calcd for C22H25NO4: C, 71.91; H, 6.86; N,
3.81. Found: C, 71.73; H, 6.98; N, 3.65.
(3R,4R)-3-Acetoxy-4-acetoxymethyl-1-benzyl-1,3,4,6-tetrahy-
dro-2H-benzo[c][1,5]oxazocine (4). Compound 3a (1 mmol) was
dissolved in CH3CN-H2O (3:1) containing 4% H2SO4, and the
mixture was stirred at room temperature for 12 h. The acidic
solution was neutralized with solid NaHCO3 at 0 °C and filtered,
and the filtrate was evaporated in a vacuum. The residue was
extracted with ethyl acetate (6 × 25 mL), and the combined organic
layers were dried and concentrated under vacuum. The colorless
residue was dissolved in a minimum volume of methanol and treated
with aqueous NaIO4 (256 mg, 1.2 mmol, dissolved in 3 mL of
water) at 0 °C with stirring for 45 min at room temperature. The
usual workup followed using a NaBH4 reduction of the crude in
dry methanol (20 mL), which afforded the diol. This was dissolved
in dry pyridine (5 mL), treated with Ac2O (0.5 mL), and stirred at
room temperature for 12 h. Pyridine was evaporated from the
reaction mixture under reduced pressure, and the product was
extracted with CHCl3 (6 × 25 mL). The combined organic layers
60% (eluent, light petroleum/ethyl acetate, 1:1); [R]D +98.69 (c
25
1
3.0, CHCl3). H NMR (CDCl3, 300 MHz): δ 2.12 (s, 3H), 3.31-
3.35 (m, 2H), 3.65-3.69 (m, 1H), 4.27 (d, 1H, J ) 13.2 Hz), 4.36
(d, 1H, J ) 3.5 Hz), 4.48 (d, 1H, J ) 13.2 Hz), 4.63 (d, 1H, J )
12.9 Hz), 5.01 (d-like, 2H), 5.65 (d, 1H, J ) 8.1 Hz), 5.90 (d, 1H,
J ) 2.2 Hz), 7.03-7.37 (m, 9H), 7.44 (d, 1H, J ) 8.1 Hz), 8.89 (s,
1H). 13C NMR (CDCl3, 75 MHz): δ 20.6, 53.4, 58.8, 77.6, 81.1,
82.0, 87.7, 87.9, 102.8, 119.5, 123.0, 127.5, 2 × 128.5, 2 × 128.7,
129.4, 130.9, 132.9, 138.9, 140.2, 150.2, 154.3, 163.1, 169.4. IR
ν
max (liquid film): 3206, 1749, 1692, 1601, 1455, 1377, 1227 cm-1
.
ESIMS: m/z 464 (MH+), 486(MNa+). Anal. Calcd for C25H25-
N3O6: C, 64.79; H, 5.44; N, 9.07. Found: C, 64.52; H, 5.23; N,
8.98.
Acknowledgment. We are grateful to Dr. B. Achari of our
department for helpful suggestions and CSIR for the award of
Senior Research Fellowships (A.N and T.M).
Supporting Information Available: Experimental procedures
1
for 1f, 2a-f, 3b-e, and 5; H and 13C NMR data for 1f, 2a-f,
3b-e, and 5; and NMR spectra files for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO052420I
3294 J. Org. Chem., Vol. 71, No. 8, 2006