An oxazoline-mediated synthesis of the pyrrolophenanthridine alkaloids and some novel derivatives

Article abstract of DOI:10.1021/jo951474x

An unsymmetrical biaryl coupling between the Grignard of N-benzyl-7-bromoindoline 25 and the appropriately substituted (o-methoxyaryl)oxazoline 15 leads to an intermediate biaryl which can be elaborated in one step to the 1H-pyrrolo[3,2,1-de]phenanthridine ring system. This simple two-step sequence provides general access to the pyrrolophenanthridine alkaloids 2-6.

Full text of DOI:10.1021/jo951474x

1004
J . Org. Chem. 1996, 61, 1004-1013
An Oxa zolin e-Med ia ted Syn th esis of th e P yr r olop h en a n th r id in e
Alk a loid s a n d Som e Novel Der iva tives
Richard H. Hutchings and A. I. Meyers*
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523
Received August 8, 1995X
An unsymmetrical biaryl coupling between the Grignard of N-benzyl-7-bromoindoline 25 and the
appropriately substituted (o-methoxyaryl)oxazoline 15 leads to an intermediate biaryl which can
be elaborated in one step to the 1H-pyrrolo[3,2,1-de]phenanthridine ring system. This simple two-
step sequence provides general access to the pyrrolophenanthridine alkaloids 2-6.
The construction of biaryl compounds, particularly un-
The 1H-pyrrolo[3,2,1-de]phenanthridine ring system 1
constitutes the core structural framework of the pyrrolo-
phenanthridine alkaloids. These compounds have been
isolated from various species of Amaryllidaceae,16 and
representative members of this class include the alkaloids
oxoassoanine (2) and pratosine (3). Moreover, since their
discovery several of these alkaloids have been shown to
possess significant levels of biological activity. The
alkaloid hippadine (4), for example, was found to revers-
ibly inhibit fertility in male rats with a remarkable
decrease in both testicular weight and in DNA content.17
Kalbretorine (5), was found to markedly inhibit the
growth and viability of S-180 tumor cells in mice,16c and
the betaine ungeremine (6) has generated a good deal of
interest due to its antitumor and antileukemic activity.18
symmetrical and axially chiral biaryls, continues to repre-
sent a challenging goal in organic synthesis.1 Indeed, the
biaryl axis constitutes an important structural feature
in numerous natural products of diverse biosynthetic
origin2 including a variety of lignans,3 tannins,4 and
alkaloids.5 Moreover, compounds which contain a biaryl
axis have proven to be an important source of therapeutic
agents,6 reagents,7 and auxiliaries for asymmetric syn-
thesis.8 Chiral 2-substituted-1,1′-binapthyls, for ex-
ample, have demonstrated significant utility as both
catalytic and stochiometeric auxiliaries in a variety of
asymmetric carbon-carbon bond-forming reactions.8a In
addition, synthetic biaryls have been used as crown
ethers,9 chiral host molecules,10 and molecular spacers.11
It is not suprising that a key step in most biaryl
syntheses involves the introduction of a new carbon-
carbon bond between two aromatic rings. While this is
a task familiar to organic chemists,12 many early methods
which were developed to effect aryl-aryl bond formation
are limited in utility. Thus, recent work in this area has
focused on the development of new biaryl coupling
strategies which specifically address the problems of
regio- and stereoselectivity in aryl-aryl bond formation.1
Accordingly, work in our laboratory has demonstrated
that aryloxazolines are useful precursors for the con-
struction of both constitutionally unsymmetrical and
axially chiral biaryls.13 In conjunction with these studies,
we now report the application of this methodology to a
general synthesis of the pyrrolophenanthridine class of
alkaloids.14,15
X Abstract published in Advance ACS Abstracts, J anuary 15, 1996.
(1) For a recent review on biaryl synthesis, see: Bringmann, G.;
Walter, R.; Weirich, R. Angew. Chem., Int. Ed. Engl. 1990, 29, 977-
91.
(2) (a) Thomson, R. H. In The Chemistry of Natural Products; Blackie
and Son: Glasgow, 1985. (b) Torssell, K. G. B. In Natural Product
Chemistry; Wiley: Chichester, 1983.
(3) Whiting, D. A. Nat. Prod. Rep. 1987, 499.
(12) Sainsbury, M. M. Tetrahedron 1980, 36, 3327. See also ref 1.
(13) (a) Meyers, A. I.; Nelson, T. D. Tetrahedron Lett. 1994, 35, 3259.
(b) Meyers, A. I.; Nelson, T. D. J . Org. Chem. 1994, 59, 2655. (c) Meyers,
A. I.; Nelson, T. D. Tetrahedron Lett. 1993, 34, 3061. (d) Moorlag, H.;
Meyers, A. I. Tetrahedron Lett. 1993, 34, 6989. (e) Meyers, A. I.; Meier,
A.; Rawson, D. J . Tetrahedron Lett. 1992, 33, 853. (f) Rawson, D. J .;
Meyers, A. I. J . Chem. Soc., Chem. Commun. 1992, 494. (g) Meyers,
A. I.; Himmelsbach, R. J . J . Am. Chem. Soc. 1985, 107, 682. (h) Meyers,
A. I.; Lutomski, K. A. J . Am. Chem. Soc. 1982, 104, 879. For
applications in natural product synthesis, see: (i) Warshawsky, A. M.;
Meyers, A. I. J . Am. Chem. Soc. 1990, 112, 8090. (j) Meyers, A. I.;
Flisak, J . R.; Aitken, R. A. J . Am. Chem. Soc. 1987, 109, 5446.
(14) For a general introduction to the amaryllidaceae alkaloids,
see: (a) Martin, S. In The Alkaloids; Brossi, A., Ed.; Academic Press:
New York, 1987; Vol. 30, Chapter 3, pp 252-369. (b) Cook, J . W.;
Loudon, J . D. In The Alkaloids; Brossi, A., Ed.; Academic Press: New
York, 1952; Vol. 2, Chapter 11, pp 331. (c) Lewis, J . R. Nat. Prod. Rep.
1995, 12, 339.
(4) Plant polyphenols: Synthesis, Properties, Significance; Heming-
way, R. W., Lakes, P. E., Eds.; Plenum: New York, 1992.
(5) Cordell, G. A. In Introduction to Alkaloids, A Biogenetic Ap-
proach; Wiley: New York, 1981.
(6) For leading references and examples, see: Meyers, A. I.; Nelson,
T. D. J . Org. Chem. 1994, 59, 2577.
(7) For example lithium 4,4′-di-tert-butylbiphenyl (LiDBB) is an
important electron transfer agent used to prepare alkyllithiums;
Freeman, P. K.; Hutchinson, L. L. Tetrahedron Lett. 1976, 1849.
(8) For recent review of the synthetic applications of C2-symmetric
biaryls, see: (a) Rosini, C.; Franzini, L.; Raffaelli, A.; Salvadori, P.
Synthesis 1992, 503. (b) Narasaka, K. Synthesis 1991, 1. Tomioka, K.
Synthesis 1990, 541.
(9) Cram, D. J . Angew. Chem., Int. Ed. Engl. 1988, 27, 1009.
(10) Webber, E. J . Mol. Graphics 1989, 7, 12.
(11) Brandmeier, V.; Feigel, M.; Bremer, M. Angew. Chem., Int. Ed.
Engl. 1989, 28, 486.
0022-3263/96/1961-1004$12.00/0 © 1996 American Chemical Society

Oxazoline-Mediated Synthesis of Pyrrolophenanthridine Alkaloids
J . Org. Chem., Vol. 61, No. 3, 1996 1005
Sch em e 1
Sch em e 2
Although a number of alternative synthetic routes are
available for construction of the pyrrolophenanthridine
ring system,19,20 many of these are characterized by low
yields and/or a lack of generality. Accordingly, we felt
that a mild aryloxazoline coupling to a 7-haloindole
derivative could provide an efficient and high-yielding
route to this class of compounds. On the basis of a simple
retrosynthetic analysis (Scheme 1), it was envisioned that
an oxazoline-mediated (unsymmetrical) biaryl coupling
could be employed to form the pivotal biaryl carbon-
carbon bond of the pyrrolophenanthridone system. It
was, therefore, envisioned that the oxazoline moiety not
only would function as a directing group for the pivotal
coupling step but would also contain the protected
carboxyl group which would ultimately become the C-7
lactam carbonyl of the pyrrolophenanthridone ring. In
view of the ready availability of a wide array of substi-
tuted aryloxazolines, this approach seemed well suited
to provide access to a wide variety of pyrrolophenanthri-
dine derivatives.
Following the above retrosynthetic sequence as a guide,
two possible routes to the core pyrrolophenanthridine
(15) For a preliminary communication on this work, see: Meyers,
A. I.; Hutchings, R. H. Tetrahedron Lett. 1993, 34, 6185.
(16) Hippadine: (a) Ghosal, S.; Rao, P. H.; J aiswal, D. K.; Kumar,
ring system were initially considered (Scheme 2). The
synthesis outlined as path A attracted us initially because
it would avoid additional protection of the bromoindole
7. Simple transformation of 7, to its magnesium or
potassium salt, followed by Grignard formation and aryl
coupling should provide a direct route to the biaryl 8.
Subsequent acid hydrolysis of the oxazoline moiety
should yield the intermediate amino ester 11, which was
expected to spontaneously cyclize to the pyrrolophenan-
thridin-7-one(s) 12. Previous studies by Rapoport and
co-workers, however, showed that 7-lithio-N-metalated
indoles were generally unreactive species due to their
poor solubility in ethereal solvents.21 It was, therefore,
decided to pursue an oxazoline-mediated biaryl coupling
via N-(methoxymethyl)-7-bromoindole (9) (path B). In
this instance, the methoxymethyl ether (MOM) protect-
ing group was selected not only for its stability to the
reaction conditions but also because its small size may
have a minimal steric impact on the biaryl coupling
reaction. Moreover, exposure of the biaryl intermediate
10 to mild acid might result in simultaneous N-depro-
tection and hydrolysis of the oxazoline moiety, providing
intermediate amino ester 11. We were also aware that
11 may undergo a spontaneous cyclization to the desired
pyrrolophenanthridin-7-one(s) 12.
Y.; Frahm, A. W. Phytochem. 1981, 20, 2003. (b) El Mehgazi, A. M.;
Ali, A. A.; Mesbah, M. K. Planta Med. 1975, 28, 336. Kalbretorine: (c)
Ghosal, S.; Lochan, R.; Ashutosh; Kumar, Y.; Srivastava, R. S.
Phytochemistry 1985, 24, 1825. Pratorinine, pratorimine, pratosine:
(d) Ghosal, S.; Saini, K. S.; Frahm, A. W. Phytochemistry 1983, 22,
2305. Oxoassoanine, assoanine: (e) Llabres, J . M.; Viladomat, F.;
Bastida, J .; Codina, C.; Rubiralta, M. Phytochemistry 1986, 25, 2637.
Anhydrolycorin-7-one: (f) Ghosal, S.; Rao, P. H.; J aiswal, D. K.; Kumar,
Y.; Frahm, A. W. Phytochemistry 1981, 20, 2003. Ungeremine, crias-
betaine, zefbetaine, zeflabetaine: (g) Ghosal, S.; Singh, S. K.; Srivas-
tava, R. S. Phytochemistry 1986, 25, 1975. Vasconine: (h) Bastida, J .;
Codina, C.; Viladomat, F. J . Nat. Prod. 1992, 55, 122.
(17) Chattopadhyay, S. C.; Chattopadhyay, U.; Mathur, P. P.; Saini,
K. S.; Ghosal, S. Planta Med. 1983, 49, 252.
(18) Cheng, R. K. Y.; Yan, S. J .; Cheng, C. C. J . Med. Chem. 1978,
21, 199.
(19) (a) Fales, H. M.; Guiffrida, L. D.; Wildman, W. C. J . Am.
Chem. Soc. 1956, 78, 4145. (b) Humber, L. C.; Kondo, H.; Kotera, K.;
Takagi, S.; Takeda, K.; Talyor, W. I.; Thomas, B. R.; Tsuda, Y.;
Tsukamoto, K.; Uyeo, H.; Yajima, H.; Yanaihara, N. J . J . Chem. Soc.
1954, 4622. (c) Cook, J . W.; Loudon, J . D.; McCloskey, P. J . J . Chem.
Soc. 1954, 4176. (d) Bennington, F.; Morin, R. D. J . Org. Chem. 1962,
27, 142. (e) Olson, D. R.; Wheeler, W. J .; Wells, J . N. J . Med. Chem.
1974, 17, 167. (f) Ghosal, S.; Saini, K. S.; Frahm, A. W. Phytochemistry
1983, 22, 2305. (g) Carruthers, W.; Evans, N. J . Chem. Soc. 1974, 1523.
(h) Onaka, T.; Kanda, Y.; Natsume, M. Tetrahedron Lett. 1974, 1179.
(i) Black, D. St. C.; Keller, P. A.; Kumar, N. Tetrahedron 1993, 49,
151. (j) Black, D. St. C.; Keller, P. A.; Kumar, N. Tetrahedron Lett.
1989, 30, 5807. (k) Snieckus, V.; Siddiqui, M. A. Tetrahedron Lett. 1990,
31, 1523. (l) Grigg, R.; Teasdale, A.; Sridharan, V. Tetrahedron Lett.
1991, 32, 3859. (m) Sakamoto, T.; Yasuhara, A.; Kondo, Y.; Yamanaka,
H. Heterocycles 1993, 36, 2597. (n) Castedo, L.; Guitian, E.; Perez, D.
Tetrahedron Lett. 1992, 33, 2407. (o) Castedo, L.; Guitian, E.; Meiras,
D. P. Tetrahedron Lett. 1990, 31, 2331. (p) Kanematsu, K.; Yasukouchi,
T.; Hayakawa, K. Tetrahedron Lett. 1987, 28, 5895. (q) Prabhakar, S.;
Lobo, A. M.; Marques, M. M. J . Chem. Res. 1987, 167.
A series of the potential precursors (2-aryl-4,4-di-
methyl-2-oxazolines) 15 were prepared from the corre-
(20) Several syntheses appeared in the literature durring the course
of this work: (a) Parnes, J . S.; Carter, D. S.; Kurz, L. J .; Flippin, L. A.
J . Org. Chem. 1994, 59, 3497. (b) Iwao, M.; Takehara, H.; Obata, S.;
Watanabe, M. Heterocycles 1994, 38, 1717.
(21) Rapoport, H.; Shiurba, J . F.; Moyer, M. P. J . Org. Chem. 1986,
51, 5106.

1006 J . Org. Chem., Vol. 61, No. 3, 1996
Hutchings and Meyers
Sch em e 3
and magnesium shot provided the desired Grignard 19
(>90% as determined by protolytic quench and GC
analysis). The Grignard reagent, thus generated, was
allowed to react with either the simple aryloxazoline 15a
or the (trimethoxyaryl)oxazoline 15c (Scheme 4). After
heating, the biaryl compounds 20 and 21 were clearly
indicated by thin layer chromatography. Workup and
silica gel chromatography subsequently provided the
corresponding biaryls in good yield (60-70%).
According to the original synthetic route (Scheme 2),
it was anticipated that acid hydrolysis of the the inter-
mediate indole biaryls (20 or 21) would result in ring
opening and cyclization to the corresponding pyrrolo-
phenanthridones. This procedure of oxazoline removal
is well precedented30 and has previously been applied to
a wide variety of aryl and alkyl systems.31 Unfortu-
nately, treatment of the biaryl 21 with aqueous 3 N HCl
or trifluoroacetic acid resulted in complete decomposition
of the starting material. Moreover, attempts to reduc-
tively cleave the oxazoline ring (methyl triflate, NaBH4,
oxalic acid) also led to decomposition of the biaryl 21.
It was also observed that treatment of 21 with sodium
hypochlorite (aqueous phosphate buffer), under phase
transfer conditions,32 provided a new compound whose
1H NMR indicated that both the oxazoline and N-
methoxymethyl groups were still intact. Moreover, the
sponding benzoic acids via the “one-pot” three-step
procedure employed previously.13,46
We next proceeded toward a synthesis of the requisite
MOM-protected 7-haloindole 9. Initially, the Fischer,22a
Batcho-Leimgruber,22b and Sugasawa22c indole syntheses
were identified as potential methods for the construction
of 7-substituted indoles from benzenoid precursors. A
review of the literature, however, revealed that these
classical methods had met with little success when
applied to a synthesis of the 7-haloindoles.23 An alterna-
tive approach to 9 involved the directed thallation-
halogenation of N-acetyl-2,3-dihydroindole recently re-
ported by Somei and co-workers (Scheme 3).24 Thus,
treatment of the protected indoline 16 with 1.6 equiv of
thallium trifluoroacetate (TTFA) in trifluoroacetic acid
(TFA) provided the crude organothallium compound 17
as a crystalline residue. Reaction of the (crude) indoline
17 with cupric bromide in DMF followed by basic hy-
drolysis of the N-acetyl group subsequently provided the
7-bromoindoline 18 (30-40%). Air oxidation of 18 and
protection as the MOM ether ultimately afforded 7-bro-
moindole 9 in moderate overall yield.25,26
It was found, however, that the bromoindole 9 was
unreactive toward magnesium metal, even after sonica-
tion for several hours. It has been previously observed27
that organohalides which contain ether, hydroxy, amino,
and other functional groups can form an insoluble coating
on the magnesium surface during their Grignard prepa-
ration. Thus, such compounds may appear inert toward
Grignard formation under standard conditions. In these
instances, the method of entrainment or continuous
activation has proven to be a highly effective method for
the preparation of “inert” organomagnesium halides.28,29
It was found that addition of 1,2-dibromotetrafluoro-
ethane, over a period of 60 min, to a mixture of 9 (THF)
1
only significant change that was observed by H NMR
was the disappearance of the indolyl methine protons at
C-1 and C-2. Further spectroscopic analysis (13C NMR,
infrared, and mass spectroscopy) indicated that the
oxindole 22 was the sole product from this reaction
(Scheme 5). The propensity of indoles to undergo oxida-
tions are well documented in the literature,33 and a
reasonable mechanism for this transformation is pre-
sented.
On the basis of the latter result, it was clear that some
modification of the indole fragment would be required
in order to achieve the final deprotection-cyclization
step. It was decided to pursue a biaryl coupling between
an aryloxazoline and the Grignard derived from N-ben-
zyl-7-bromoindoline (25). The resulting biaryls from this
process should exhibit greater stability under the acidic
conditions required for hydrolysis of the oxazoline moiety.
Furthermore, 2,3-dihydroindoles (indolines) more closely
resemble N-alkylanilines than indoles in their reactiv-
ity.34
The recent report by Iwao and Kuraishi35 on 7-substi-
tuted-2,3-dihydroindoles seemed to contain the ideal
solution to our indole precursors. This work was based
on a selective C-7 lithiation of 1-(tert-butoxycarbonyl)-
indoline (23) and offered some significant advantages
(higher yields and avoiding the use of highly toxic
thallium reagent) over the method of Somei previously
employed. Lithiation (sec-BuLi, TMEDA, THF) and
bromination of 23 with 1,2-dibromotetrafluoroethane
indeed provided the 7-bromoindoline (24) in ∼68% yield.
Subsequent removal of the Boc group (TFA, THF, 0 °C)
(22) (a) Fischer, E. Chem. Ber. 1886, 19, 1567. (b) Sundberg, R. J .
In The Chemistry of Indoles; Academic: New York, 1970. (c) Sugasawa,
T.; Adachi, M.; Sasakura, K.; Kitagawa, A. J . Org. Chem. 1979, 44,
578.
(23) (a) Stevens, F. J .; Higginbotham, D. H. J . Am. Chem. Soc. 1954,
76, 2206. (b) Clark, R. D.; Repke, D. B. Heterocycles 1984, 22, 195. (c)
Glennon, R. A.; Schubert, E.; J acyno, J . M. J . Med. Chem. 1980, 23,
1222.
(24) Somei, M.; Saida, Y.; Funamoto, T.; Ohta, T. Chem. Pharm.
Bull. 1987, 35, 3146.
(25) While this work was in progress, a report appeared (Dobson,
D. R.; Gilmore, J .; Long, D. Synlett 1992, 79) which described the
synthesis of 1 using the Bartoli procedure.26
(30) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 2nd ed.; J ohn Wiley & Sons: New York, 1991; pp 265-266.
(31) For example, see: Meyers, A. I.; Temple, D. L.; Haidukewych,
D.; Mihelich, E. D. J . Org. Chem. 1974, 39, 2787.
(26) Bartoli, G.; Palmieri, G.; Bosco, M.; Dalpozzo, R. Tetrahedron
Lett. 1989, 30, 2129.
(27) Lai, Y.-H. Synthesis 1981, 585.
(28) Kharasch, M. S.; Reinmuth, O. In Grignard Reactions of
nonmetallic Substances; Prentice-Hall: New York, 1954; Chapter 2, p
38.
(32) Weinreb, S. M.; Levin, J . I. Tetrahedron Lett. 1982, 23, 2347.
(33) The Acid Catalyzed Polymerization of Pyrroles and Indoles;
Smith, G. F. In Advances in Heterocyclic Chemistry; Katritzky, A. R.,
Ed.; Academic Press: New York, 1963; Vol. 2; p 287.
(34) Albert, A. In Heterocyclic Chemistry; an Introduction; 2nd ed.;
Oxford University Press: New York, 1968; p 321.
(29) Grignard, V. Compt. Rend. 1934, 198, 625.
(35) Iwao, M.; Kuraishi, T. Heterocycles 1992, 34, 1032.

Oxazoline-Mediated Synthesis of Pyrrolophenanthridine Alkaloids
J . Org. Chem., Vol. 61, No. 3, 1996 1007
Sch em e 4
Sch em e 5
Sch em e 6
it was found that nearly complete Grignard formation
(85-95%, determined by protolytic quench and GC) could
be achieved by initiating Grignard formation with a
single addition of 1,2-dibromotetrafluoroethane.
and treatment of the corresponding free amine with
butyllithium and benzyl bromide furnished N-benzyl-7-
bromoindoline (25) in good yield over three steps (60%).
A reaction between the Grignard of 25 (generated by
a single addition of dibromotetrafluoroethane) and the
oxazoline 15c subsequently provided the coupled product
26 in a 73% yield (Scheme 6). Moreover, treatment of
the biaryl 26 with 10% ethanolic H2SO4 resulted only in
hydrolysis of the oxazoline to the amino ester 27, which
could be subsequently trans esterified to the methyl ester
28 using methanolic sodium methoxide. In order to effect
the final ring closure to 2, the N-benzylindoline 28 was
subjected to hydrogenation. The intermediate amine
smoothly underwent spontaneous acylation by the adja-
cent carbomethoxyl group affording oxoassoanine (2)
(56%). It was also found that a “one-pot” cyclization of
the biaryl 26 would directly furnish 2 in excellent overall
yield (50% from 25). The latter alkaloid was readily
transformed to pratosine (3) by oxidation with DDQ
(55%).16f
When the Grignard of 25 was coupled with the aryl-
oxazoline 15c, the desired biaryl 26 was obtained, but
with much lower yields than expected (30-40%). More-
over, it appeared that the low yields in this reaction were
due to incomplete Grignard formation as indicated by the
presence of the bromoindoline 25 in the crude reaction
mixture (GC). In a separate study of the Grignard for-
mation step, we found that the entrainer (1,2-dibromotet-
rafluoroethane) was reacting with the intermediate or-
ganomagnesium compound and regenerating the starting
material.36 To overcome this undesirable side reaction,
With suitable conditions to effect the aryl coupling and
cyclization sequence in hand, a series of simple pyrrol-
(36) 1,2-Dibromotetrafluoroethane is a well-recognized source of
electrophilic bromine.

1008 J . Org. Chem., Vol. 61, No. 3, 1996
Ta ble 1. Syn th esis of th e P yr r olop h en a n th r id on e An a logs 30
Hutchings and Meyers
Sch em e 7
vided the pyrrolophenanthridone alkaloid anhydroly-
corin-7-one (36), which was readily transformed to hip-
padine (4) in 73% yield by oxidation with DDQ.
ophenanthridine analogs were synthesized in good yield
from the corresponding aryloxazolines (Table 1).
In order to assess the versatility of this approach, a
synthesis of the alkaloids hippadine (4) and kalbretorine
(5) was next investigated. These presented an additional
challenge since the requisite oxazoline precursors were
not readily available from a commercial source. Fur-
thermore, a synthesis of these compounds was of interest
since they are also known to exhibit some biological
activity (vide supra).
The aryloxazoline 34, which could serve to reach both
4 and 5, was prepared from piperonal by a series of steps
described in Scheme 7. Bromination37 and sodium chlo-
rite oxidation38 of piperonal furnished the acid 31, which
was transformed to the methoxy derivative 32 by copper-
catalyzed methoxide ion displacement of bromine.39
Conversion of the latter to the amide 33 and cyclization
gave the oxazoline 34.
To further utilize this sequence to reach the pyrrol-
ophenanthridone alkaloid kalbretorine (5), it was neces-
sary to incorporate an additional oxygen substituent into
the aryloxazoline 34. This task represented some con-
cern since it is not trivial to effect aromatic hydroxyla-
tions in a direct and regiospecific manner.40 One prom-
ising solution to this problem involved the regioselective
lithiation and hydroxylation of the aryloxazoline 3441,42
using bis(trimethylsilyl) peroxide as the electrophilic
hydroxyl.43 In a simple model study we found that the
fluorooxazoline 15e could be lithiated and hydroxylated
with this reagent, affording the intermediate phenol
which was transformed (KOH, CH3I) to the o-(meth-
oxyaryl)oxazoline 37 (Scheme 8). This compound was
(40) For a review of this subject, see: Wedemeyer, K.-F. In Methoden
der Organischen Chemie. Phenole; Muller, E., Ed.; Georg Thieme
Verlag: Stuttgart, 1976; Vol. IV/1C.
Coupling of the aryloxazoline with the magnesio de-
rivative of 25 yielded the intermediate biaryl 35 in 68%
yield. Subsequent hydrolysis and cyclization of 35 pro-
(41) (a) For a recent examples of aromatic hydroxylations, see:
Parker, K. A.; Koziski, K. A. J . Org. Chem. 1987, 52, 674. (b) Davis, F.
A.; Sheppard, A. C. Tetrahedron 1989, 45, 5703. (c) For a procedure
involving lithiation-boration-oxidation, see: Beak, P.; Brown, R. A.
J . Org. Chem. 1982, 47, 34. (d) For hydroxylation of aryl Grignards
using oxodiperoxymolybdenum-pyridine-hexamethylphosphoric tria-
mide (MoOPH), see: Lewis, N. J .; Gabhe, S. Y.; DeLaMater, M. R. J .
Org. Chem. 1977, 42, 1479.
(37) Becker, D.; Hughes, L. R.; Raphael, R. A. J . Chem. Soc., Perkin
Trans. 1 1977, 1674.
(38) Pinnick, H. W.; Childers, W. E.; Bal, B. S. Tetrahedron 1981,
37, 2091.
(39) Mayer, W.; Fikentschen, R. Chem. Ber. 1958, 91, 1536.

Oxazoline-Mediated Synthesis of Pyrrolophenanthridine Alkaloids
J . Org. Chem., Vol. 61, No. 3, 1996 1009
Sch em e 8
Sch em e 9
Sch em e 10
subsequently transformed to the novel fluorine-contain-
ing pyrrolophenanthridone 39 via the biaryl 38 (68% over
two steps).
The successful implementation of the latter sequence
was next applied to the preparation of the aryloxazo-
lines 41 and 42. Thus, metalation and hydroxylation of
34 yielded the intermediate phenol 40 in 20-35% iso-
lated yield (50-70% based on recovered starting mate-
rial)44 which was readily converted to the benzyl or silyl
ether (41 and 42, respectively) under usual conditions
(Scheme 9).
Interestingly, the coupling between the Grignard of 25
and the benzyl ether 41 resulted in regioselective dis-
placement of only the benzyloxy group, thus providing
the undesired methoxy biaryl 43 (Scheme 10). This may
be the result of enhanced chelation between the benzyl-
oxy group and the adjacent methylenedioxy substituent
in 41, thus making benzyloxy displacement more facile.
It has been noted earlier45a that o-methoxy groups
flanked by m-methoxy substituents are more readily
displaced in the aryloxazolines. Thus, replacing the
benzyloxy substituent with a bulkier triisopropylsilyl
substituent (TIPS) appeared to have reduced45b the
chelation of magnesio ion by the oxygens, thus allowing
the o-methoxy substituent to be readily displaced, provid-
ing the correct biaryl, 44. Desilylation and cyclization
of 44 subsequently yielded the pyrrolophenanthridone 45
(14%),45 which is a known precursor to the alkaloid
kalbretorine (5).20b
Exp er im en ta l Section
Gen er a l. All NMR spectra (1H, 13C) were taken at 300 MHz
in CDCl3, CCl4, or C6D6. Elemental analyses were performed
by Atlantic Microlab, Norcross, GA.
Ch r om a togr a p h y. TLC was performed on kieselgel 60,
F254 aluminum plates (0.20 nm). Visualization was ac-
complished with ultraviolet (254 nm) or Dragendorff’s reagent
(on the oxazolines). Flash chromatography was performed
using Amicon (200-400 mesh) silica gel or 135x catalyst
support grade silica-alumina (Davidson). HPLC was carried
out with a UV detector (254 nm). Solvents, ratios, flow rates
are given in the individual procedures.
Rea gen ts a n d Ma ter ia ls. Unless otherwise stated, all
reagents were obtained from commercial suppliers and used
without further purification. Solvents were dried according
to established protocols by distillation under argon from an
appropriate drying agent. THF and benzene were distilled
from sodium benzophenone. Dichloromethane was distilled
(42) (a) Lithiation and hydroxylation of 4,4-dimethyl-2-(3-chloro-
phenyl)-2-oxazoline with molecular oxygen was previously attempted
in this group, but in poor yield (20%): Meyers, A. I.; Gabel, R. A.,
unpublished results. (b) Lithiation and hydroxylation of 4,4-dimethyl-
2-phenyl-2-oxazoline with MoOPh was reported by Avila (54%): Avila,
W. B. Ph.D. Dissertation, Colorado State University, 1981.
(43) Ricci, A.; Taddei, M. Synthesis 1986, 633.
(44) The undesired phenol resulting from lithiation at the 3-position
was obtained in 15-20% yield.
(45) (a) Meyers, A. I.; Reuman, M. Tetrahedron Rep. 1985, 41, 837.
(b) Frye, S. V.; Eliel, E. L. Tetrahedron Lett. 1986, 3223. We thank
the referee for pointing out this reference and suggestions for the
regiochemistry observed.

1010 J . Org. Chem., Vol. 61, No. 3, 1996
Hutchings and Meyers
from CaH2. All air- or moisture-sensitive reactions were
performed under argon; the glassware was dried (130 °C) and
evacuated and then purged 3× with argon.
(t), 67.6,(s) 55.7(q), 55.5(q), 55.4(q), 28.1(q); IR (thin film) 2965,
2933, 1752, 1658 cm-1; low-resolution mass spectrum (GC-
MS) m/ z (rel abundance) 479 (1, M+), 442 (21), 328 (8), 72
(33), 45 (100).
N-(Meth oxym eth yl)-7-br om oin d ole (9). To an ice-cold
suspension of oil free KH (1.2 g, 10.0 mmol) in THF (20 mL)
was added 7-bromoindole26 (1.10 g, 5.58 mmol) in THF (10 mL).
The solution was stirred (15 min), TMEDA (0.926 mL, 6.13
mmol) was introduced, and stirring was continued for an
additional 30 min. Chloromethyl methyl ether (465 µL, 6.13
mmol) was added, and the mixture was stirred (1 h), quenched
with water, and warmed to rt. Extraction with ethyl acetate,
drying (Na2SO4), and removal of the solvent in vacuo provided
the crude amine which was purified by silica gel chromatog-
raphy (hexanes/ethyl acetate/Et3N 16:3:1) to give 1.14g (82%)
of 9 as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 7.56 (dd,
J ) 1.2, 7.8 Hz, 1H), 7.41 (dd, J ) 1.2, 7.8 Hz, 1H), 7.18 (d, J
) 3.3 Hz, 1H), 6.98 (t, J ) 7.8 Hz, 1H), 6.53 (d, J ) 3.3 Hz,
1H), 5.80 (s, 2H), 3.28 (s, 3H); 13C NMR (75.5 MHz, CDCl3) δ
133.0, 131.2, 127.6, 121.6, 120.6, 104.5, 102.8, 77.8, 54.8, 28.2.
Gen er a l P r oced u r e for Gr ign a r d F or m a tion a n d Ox-
a zolin e-Bia r yl Cou p lin g (En tr a in m en t Meth od ). Syn -
th esis of th e Bia r yl 20. To a suspension of the bromoindole
9 (478 mg, 2.00 mmol) and granular magnesium (96 mg, 4.00
mmol, 200 mesh) in THF (10 mL) was added 1,2-dibromotet-
rafluoroethane (120 µL, 1.00 mmol) in portions over the period
of 1 h. The resulting Grignard reagent was added, via syringe,
to a solution of the oxazoline 15a 46 in THF (10 mL), and the
reaction mixture was heated to reflux until TLC (hexanes/ethyl
acetate/Et3N, Dragendorff’s stain) indicated the absence of
starting material (3-12 h). The reaction was quenched with
water, extracted with ethyl acetate (3 × 20 mL), dried (Na2-
SO4), and concentrated in vacuo to give the crude biaryl which
was purified by silica gel chromatography (hexanes/ethyl
acetate/Et3N 10:9:1) to give 438 mg (65%) of 20 as a light
yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.67 (d, J ) 7.2 Hz,
1H), 7.58 (dd, J ) 1.2, 7.8 Hz, 1H), 7.41-7.51 (m, 3H), 7.10-
7.15 (m, 2H), 6.99 (dd, J ) 1.2, 7.2 Hz, 1H), 6.56 (d, J ) 3.0
Hz, 1H), 4.85 (s, 2H), 3.49 (d, J ) 8.0 Hz, 1H), 3.30 (d, J ) 8.0
Hz, 1H), 2.78 (s, 3H), 1.05 (s, 3H), 0.99 (s, 3H); IR (thin film)
N-Ben zyl-7-br om oin d olin e (25). A solution of 7-bromoin-
doline35 (1.8 g, 9.1 mmol) in THF (40 mL) was cooled to -78
°C and treated with n-BuLi (4.02 mL, 10.05 mmol, 2.5 M in
hexanes). After 15 min benzyl bromide (1.19 mL, 10.1 mmol)
was added and the mixture was allowed to warm to rt. After
several hours the mixture was quenched with water and
extracted with ethyl acetate. The organic layers were com-
bined, dried (Na2SO4), and concentrated to give a crude oil.
Chromatography (hexanes/ethyl acetate/Et3N 90:5:5) and Kugel-
rohr distillation (ot 250 °C, 0.5 mm) provided 2.6 g (99%) of
25 as a light yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.2-7.4
(m, 6H), 7.00-7.06 (m, 1H), 6.60 (dd, J ) 7.2, 8.0 Hz, 1H),
4.82 (s, 2H), 3.41 (t, J ) 8.8 Hz, 2H), 2.98 (t, J ) 8.8 Hz, 2H);
13C NMR (75.5 MHz, CDCl3) δ 148.7(s), 138.9(s), 133.9(s),
132.7(d), 128.3(d), 127.8(d), 126.9(d), 123.6(d), 120.0(d), 103.4-
(s), 54.6(t), 53.4(t), 28.5(t); low-resolution mass spectrum (GC-
MS) m/ z (rel abundance) 289:287 (M+, 27:28), 206 (25), 117
(36), 91 (100). Anal. Calcd for C15H14NBr: C, 62.51; H, 4.89.
Found: C, 62.60; H, 4.84.
Gen er a l P r oced u r e for Gr ign a r d F or m a tion a n d Ox-
azolin e-Biar yl Cou plin g (Sin gle Addition Meth od). Syn -
th esis of th e Bia r yl 26. A 50 mL round bottomed flask
containing granular magnesium (96 mg, 4.00 mmol) was
heated (110 °C) for ca. 1 h and then cooled to rt under an
atmosphere of argon. N-Benzyl-7-bromoindoline (636 mg, 2.40
mmol) in 5 mL of THF and 1,2-dibromotetrafluoroethane (119
µL, 1.00 mmol) were introduced sequentially, and the resulting
mixture was allowed to stir for 1 h (gas evolution). The
Grignard reagent prepared in this manner was then trans-
ferred, via syringe, to a 50 mL two-necked round bottomed
flask (equipped with a stir bar and reflux condensor) which
contained a predried (NaH) solution of 15c46 (574 mg, 2.0
mmol) in THF (8 mL). The mixture was heated (50-60 °C)
for 4-6 h during which time biaryl formation was followed by
thin layer chromatography (Rf ) 0.17; hexanes/ethyl acetate/
Et3N 80:15:5). When the absence of starting material was
indicated by TLC, the mixture was cooled to rt, quenched with
water (50 mL), and diluted with ethyl acetate (50 mL). The
organic layer was separated, washed with brine, dried (Na2-
SO4), and concentrated to give the crude biaryl which was
purified by silica gel chromatography to give 673 mg (74%) of
26 as a light yellow glass: 1H NMR (300 MHz, C6D6) δ 7.62
(s, 1H), 6.90-7.20 (m, 7H), 6.85 (s, 1H), 6.83 (t, J ) 7.4 Hz,
1H), 4.08 (ABq, J AB ) 14 Hz, ∆δAB ) 50.2 Hz, 2H), 3.64 (brd,
J ) 7 Hz, 2H), 3.32 (s, 3H), 3.23 (s, 3H), 3.15-3.25 (brm, 1H),
2966, 2928, 1654 cm-1
.
Bia r yl 21. Following the procedure for 20, the indole 9 (956
mg, 4.00 mmol) was converted to its Grignard reagent and
allowed to react with the aryloxazoline 15c46 to give 1.18 g
(71%) of the biaryl 21 as a viscous yellow oil, which was
purified by silica gel chromatography (hexanes/ethyl acetate/
Et3N 10:9:1): 1H NMR (300 MHz, CDCl3) δ 7.55 (dd, J ) 0.9,
7.8 Hz, 1H), 7.31 (s, 1H), 6.95-7.15 (m, 4H), 6.54 (d, J ) 3.3
Hz, 1H), 4.87 (ABq, J ) 10.2 Hz, ∆δAB ) 16.8 Hz, 2H), 3.96 (s,
3H), 3.84 (s, 3H), 3.46 (d, J ) 8.1 Hz, 1H), 3.31 (d, J ) 8.1 Hz,
1H), 2.85 (s, 3H), 1.08 (s, 3H), 1.03 (s, 3); 13C NMR (75.5 MHz,
CDCl3) δ 163.2(s), 149.8(s), 147.9(s), 133.7(s), 132.6(s), 129.8-
(s), 129.3(d), 125.4(s), 124.3(d), 121.3(s), 119.9(d), 119.5(d),
113.7(d), 111.6(d), 102.8(d), 79.0(t), 77.9(t), 66.5(s), 56.0(q),
55.8(q), 55.1(q), 27.8 (q). Further characterization was not
attempted although this material was carried forward to
pratosine, 5.
Hyp och lor ite Oxid a tion of 21 to th e Oxin d ole 22.
According to the method of Weinreb,32 the biaryl-oxazoline
21 (394 mg, 1.00 mmol) in ethyl acetate (10 mL) was treated
with tetrabutylammonium bisulfate (34 mg, 0.1 mmol) and
sodium hypochlorite (17 mL, 5.25%). The biphasic mixture
was stirred at rt (6 h) at which time TLC (ethyl acetate)
indicated the absence of 21 and the presence of a new less
polar compound. The organic layer was separated, dried (Na2-
SO4), and concentrated to a crude oil which was characterized
without further purification: 1H NMR (300 MHz, C6D6) δ 7.55
(s, 1H), 7.50 (dd, J ) 0.6, 6.9 Hz, 1H), 6.98 (dd, J ) 1.9, 6.9
Hz, 1H), 6.85 (t, J ) 7.8 Hz, 1H), 6.68 (s, 1H), 4.83 (d, J )
10.5 Hz, 1H), 4.56 (d, J ) 10.5, 1H), 3.52 (d, J ) 3.6 Hz, 2H),
3.42 (s, 3H), 3.38 (s, 3H), 2.85 (s, 3H), 1.03 (s, 3H), 0.93 (s,
3H); 13C NMR (75.5 MHz, C6D6) δ 170.3(s), 160.9(s), 150.9(s),
149.3(s), 138.0(s), 134.6(d), 130.7(s), 129.3,(s) 128.5(s), 127.1-
(s), 123.9,(d) 123.5(d), 121.2(s), 114.5(d), 112.1(d), 78.6(t), 72.2-
2.85-2.95 (brm, 1H), 2.74 (t, J ) 8.4 Hz, 2H), 1.19 (s, 6H); 13
C
NMR (75.5 MHz, CDCl3) δ 163.4(s), 149.8(s), 149.0(s), 147.3-
(s), 138.9(s), 133.3(s), 130.5(s), 129.5(d), 127.8(d), 127.6(d),
126.4(d), 123.3(s), 123.2(d), 120.4(s), 117.7(d), 112.8(d), 112.0-
(d), 79.2(t), 66.7(s), 55.8(q), 55.5(q), 55.1(t), 53.7(t), 28.4(t), 27.9-
(q); IR (thin film) 1646 cm-1; low-resolution mass spectrum
(GC-MS) m/ z (rel abundance) 442 (M+, 7), 342 (18), 266 (12),
207 (7), 178 (6), 91 (100).
Acid Hyd r olysis of 26 to 27. The biaryl 26 (260 mg, 0.558
mmol) was dissolved in 10 mL of 10% H2SO4/ethanol (v/v) and
heated to reflux overnight. After cooling to rt, the mixture
was made basic with a 10% sodium hydroxide solution and
extracted (2 × 20 mL) with dichloromethane. The organic
layers were combined, dried (Na2SO4), and concentrated to the
crude product which was purified by silica gel chromatography
(hexanes/ethyl acetate/Et3N 4:10:1) to give 152 mg (56%) of
27 as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 7.48, (s,
1H), 7.0-7.25 (m, 6H), 6.60-6.68 (m, 3H), 4.02 (d, J ) 15 Hz,
1H), 3.87 (d, J ) 15 Hz, 1H, partially obscured) 3.65 (s, 3H),
3.35-3.40 (m, 1H), 3.15 (apparent q , J ) 8.7 Hz, 1H), 2.95-
3.05 (m, 2H) 1.29 (br s, 1H), 0.94 (s, 3H), 0.88 (s, 3H); 13C NMR
(75.5 MHz, CDCl3) δ 167.9(s), 150.9(s), 148.5(s), 147.6(s), 138.8-
(s), 134.8(s), 130.9(s), 129.7(d), 128.1(d), 127.3(d), 126.7(d) ,
123.8(d), 123.7(s), 122.2(s), 117.9(d), 113.8(d), 75.2(t), 55.9(q),
55.7(q), 54.9(t), 53.9(t), 48.7(s), 28.3(t), 26.5 (q); IR (thin film)
3361, 2964, 2935, 2847, 1700, 1600 cm-1; low-resolution mass
(46) Meyers, A. I.; Mihelich, E. D.; Gabel, R. J . Org. Chem. 1978,
43, 1372.

Oxazoline-Mediated Synthesis of Pyrrolophenanthridine Alkaloids
J . Org. Chem., Vol. 61, No. 3, 1996 1011
spectrum (GC-MS) m/ z (rel abundance) 460 (M+, 52), 280
(100), 91 (99), 72 (47).
abundance) 382 (M+, 23), 282 (38), 219 (26), 206 (32), 91 (100),
65 (32). Anal. Calcd for C26H26N2O: C, 81.64; H, 6.85; N, 7.32.
Found: C, 81.46; H, 6.89; N, 7.28.
Tr a n sester ifica tion of 27 to 28. The biaryl 27 (50 mg,
0.108 mmol) was dissolved in 5 mL of methanol containing
excess sodium methoxide and heated to reflux overnight. After
cooling to rt, the mixture was quenched with water and
extracted (2 × 20 mL) with dichloromethane. The organic
layers were combined, dried (Na2SO4), and concentrated to the
crude methyl ester which was purified by silica gel chroma-
tography (hexanes/ethyl acetate/Et3N 4:10:1) to give 24 mg
(56%) of 28 as a colorless oil: 1H NMR (300 MHz, C6D6) δ 7.58
(s, 1H), 6.95-7.2 (m, 7H), 6.85 (t, J ) 7.8 Hz, 1H), 6.80 (s,
1H), 4.05 (ABq, J ) 14.1 Hz, ∆δ ) 31 Hz, 2H), 3.43 (s, 3H),
3.32 (s, 1H), 3.21 (s, 3H), 2.9-3.2 (m, 2H), 2.79 (t, J ) 8.0 Hz,
2H); 13C NMR (75.5 MHz, C6D6) δ 167.7, 152.1, 149.7, 148.6,
139.7, 135.9, 130.9, 130.3, 128.5, 128.4, 126.9, 124.7, 123.7,
123.1, 118.7, 114.4, 113.6, 55.8, 55.3, 55.1, 54.4, 51.3, 28.8; IR
Bia r yl 29b. Following the general procedure for 26, the
oxazoline 15b46 (376 mg, 1.6 mmol) was coupled with the
Grignard of N-benzyl-7-bromoindoline (500 mg, 1.74 mmol);
workup and silica gel chromatography (hexanes/ethyl acetate/
Et3N 80:15:5) provided 490 mg (74%) of 29b as a light yellow
glass: 1H NMR (300 MHz, C6D6) δ 7.99 (d, J ) 8.6 Hz, 1H),
7.00-7.20 (m, 8H), 6.79 (t, J ) 7.4 Hz, 1H), 6.61 (dd, J ) 2.7,
8.6 Hz, 1H), 4.01 (ABq, J ) 11.5 Hz, ∆δAB ) 27 Hz, 2H), 3.61
(brs, 2H), 3.12 (s, 3H), 3.00-3.20 (m, 1H, partially obscured
by s at 3.12), 2.80-3.00 (m, 1H), 2.70 (t, J ) 8.4 Hz, 2H), 1.16
(s, 6H); 13C NMR (75.5 MHz, C6D6) δ 162.7(s), 161.1(s), 149.9-
(s), 142.9(s), 139.7(s), 132.0(d), 130.9(s), 130.2(d), 128.4(d),
128.3(d), 126.9(d), 124.7(s), 123.8(d), 121.7(s), 118.6(d), 115.8-
(d), 113.4(d), 79.0(t), 67.6(s), 56.4(t), 54.6(q), 54.1(t), 28.8(t),
28.2(q); IR (thin film) 1650 cm-1; low-resolution mass spectrum
(GC-MS) m/ z (rel abundance) 412 (M+, 7), 312 (17), 236 (12),
206 (14), 91 (100), 65 (20).
Bia r yl 29c. Following the general procedure for 26, the
oxazoline 15d 46 (350 mg, 1.58 mmol) was coupled with the
Grignard of N-benzyl-7-bromoindoline (500 mg, 1.74 mmol);
workup and silica gel chromatography (hexanes/ethyl acetate/
Et3N 18:1:1) provided 530 mg (83%) of 29c as a light yellow
glass: 1H NMR (300 MHz, C6D6) δ 7.73 (dd, J ) 2.0, 7.1 Hz,
1H), 6.90-7.20 (m, 9H), 6.75 (t, J ) 7.4 Hz, 1H), 3.98 (ABq,
J AB ) 14.1 Hz, 2H), ∆δAB ) 45.3 Hz), 3.55 (ABq, J AB ) 7.9 Hz,
∆δAB ) 1.5 Hz, 2H), 3.13 (dt, J ) 7.4, 9.0 Hz, 1H), 2.86 (dt, J
) 9.0, 10.3 Hz, 1H), 2.66 (t, J ) 9.0 Hz, 2H), 2.22 (s, 3H), 1.14
(s, 3H), 1.05 (s, 3H); 13C NMR (75.5 MHz, C6D6) δ 163.0(s),
149.9(s), 140.3(s), 139.8(s), 138.0(s), 131.6(d), 130.6(s), 130.3-
(s), 130.0(s), 128.6(d), 128.3(d), 127.5(d), 127.3(d), 126.9(d),
123.8(d), 122.6(s), 118.4(d), 79.0(t), 67.7(s), 56.0(t), 54.3(t), 28.7-
(t), 28.1(q), 28.0(q), 20.6(q); IR (thin film) 1657 cm-1; low-
resolution mass spectrum (GC-MS) m/ z (rel abundance) 396
(M+, 7), 296 (13), 233 (18), 218 (12), 178 (9), 91 (100), 65 (21).
Bia r yl 29d . Following the general procedure for 26,
1-methoxy-2-naphthyloxazoline13h (306 mg, 1.20 mmol) was
coupled with the Grignard of N-benzyl-7-bromoindoline (300
mg, 1.04 mmol); workup and silica gel chromatography (hex-
anes/ethyl acetate/Et3N 85:10:5) provided 360 mg (78%) of 29d
as a light yellow solid: mp 115 °C; 1H NMR (300 MHz, C6D6)
δ 7.80-7.87 (m, 4H), 7.45-7.55 (m, 2H), 7.17 (dd, J ) 0.7, 7.2
Hz, 1H), 7.0-7.10 (m, 3H), 6.94 (dd, J ) 0.7, 7.5 Hz, 1H), 6.75-
6.82 (m, 3H), 3.82 (ABq, J AB ) 7.9 Hz, ∆δAB ) 2.7 Hz, 2H),
3.54 (ABq, J AB ) 13.7 Hz, ∆δAB ) 5.1 Hz, 2H), 3.15-3.25 (m,
1H), 2.95-3.15 (m, 3H), 1.32 (s, 3H), 1.30 (s, 3H); 13C NMR
(75.5 MHz, C6D6) δ 163.8(s), 149.9(s), 138.7(s), 138.4(s), 134.0-
(s), 132.0(s), 130.4(d), 128.2(d), 127.9(d), 127.8(d), 127.7(d),
127.4(d), 126.8(d), 126.4(d), 126.2(s), 126.1(d), 123.7(d), 120.0-
(s), 117.6(d), 79.3(t), 67.2(s), 55.2(t), 53.6(t), 28.4(t), 28.0(q);
IR (thin film) 1657 cm-1; low-resolution mass spectrum (GC-
MS) m/ z (rel abundance) 432 (M+, 12), 332 (19), 256 (21), 241
(12), 228 (10), 91 (100), 65 (21).
(thin film) 1725 cm-1
.
Cycliza tion of 28 to Oxoa ssoa n in e (2). A solution of the
methyl ester 28 (24 mg, 0.06 mmol) in methanol (5 mL)
containing a catalytic amount of acetic acid (0.1 mL) was
hydrogenated (1 atm) in the presence of 10 mg of 10% Pd/C.
After 2 h the absence of starting material was indicated by
TLC (CH2Cl2/methanol 99:1) and the mixture was diluted with
CH2Cl2 and filtered through Celite. The filtrate was washed
with 3 N NaOH, dried (Na2SO4), and concentrated in vacuo
to give 11 mg (66%) of the alkaloid 2 as a tan powder: mp
266-269 °C (lit.16e mp 260-270 °C); 1H NMR (300 MHz,
CDCl3) δ 7.89 (s, 1H), 7.77 (d, J ) 8 Hz, 1H), 7.49 (s, 1H), 7.27
(d, J ) 8 Hz, 1H), 7.17 (t, J ) 8 Hz, 1H), 4.45 (apparent t, J
) 8 Hz, 2H), 4.05 (s, 3H), 4.01 (s, 3H), 3.40 (apparent t, 2H, J
) 8 Hz); 13C NMR (75.5 MHz, CDCl3) δ 159.62, 152.8, 149.5,
139.3, 130.8, 128.4, 123.5, 123.1, 121.3, 119.1, 116.6, 108.7,
102.9, 56.2, 56.0, 46.4, 27.3; IR (CCl4) 1643, 1606 cm-1
.
Gen er a l P r oced u r e for th e “On e-P ot” Hyd r olysis-
Cycliza tion . P r ep a r a tion of Oxoa ssoa n in e (2) fr om 26.
The biaryl 26 (477 mg, 1.07 mmol) was dissolved in 10 mL of
10% H2SO4/ethanol (v/v) and heated to reflux overnight. After
cooling to rt, the mixture was hydrogenated (1 atm) in the
presence of 25 mg of 10% Pd/C (4 h) during which time the
product precipitated. When the absence of starting material
was indicated by TLC (CH2Cl2/methanol 99:1), the mixture was
diluted with sufficient hot ethanol to redissolve the product
then filtered through Celite. The filtrate was concentrated to
one-quarter of its original volume, diluted with water (15 mL),
neutralized with saturated NaHCO3, and extracted with CH2-
Cl2. The organic layers were combined, dried (Na2SO4), and
concentrated in vacuo to give 210 mg (70%) of the alkaloid 2
as a tan powder: mp, 268-269 °C (from EtOH). Spectral data
were identical to those reported above.
P r a tosin e (3). According to the method of Black,19k
a
solution of oxoassoanine (2) (31 mg, 0.11 mmol) and 2,3-
dichloro-5,6-dicyano-1,4-benzoquinone (100 mg, 0.44 mmol) in
benzene (50 mL) was heated to reflux for 12 h. Subsequent
workup and silica gel chromatography (CH2Cl2) provided 17
mg (55%) of 3 as a tan powder: mp 234-235 °C (lit.19k mp
4,5-Dih ydr opyr r olo[3,2,1-de]ph en an th r idin -7-on e (30a).
Following the general procedure for 2, cyclization of the biaryl
29a (156 mg, 0.408 mmol) and purification by silica gel
chromatography (ether/dichloromethane/Et3N 10:5:1) provided
62 mg (69%) of the pyrrolophenanthridone 30a as a tan solid:
mp 89-90 °C; 1H NMR (300 MHz, CDCl3) δ 8.49 (dd, J ) 1.2,
8.1 Hz, 1H), 8.10 (d, J ) 7.8 Hz, 1H), 7.80 (d, J ) 7.8 Hz, 1H),
7.69 (dt, J ) 1.6, 7.2 Hz, 1H), 7.53 (dt, J ) 1.2, 8.1 Hz, 1H),
7.24 (dd, J ) 1.2, 7.5 Hz, 1H), 7.13 (t, J ) 7.5 Hz, 1H), 4.37-
4.42 (m, 2H), 3.34 (apparent t, J ) 8 Hz, 2H); 13C NMR (75.5
MHz, CDCl3) δ 159.8(s), 139.6(s), 133.6(s), 131.8(d), 130.6(s),
128.2(d), 127.6(d), 127.2(s), 124.3(d), 123.1(d), 121.9(d), 119.6-
1
232-233 °C); H NMR (300 MHz, CDCl3) δ 8.01 (d, J ) 3.6
Hz, 1H), 7.93 (s, 1H), 7.91 (d, J ) 7.8 Hz, 1H), 7.70 (dd, J )
0.6, 7.5 Hz, 1H), 7.58 (s, 1H), 7.44 (t, J ) 7.5 Hz, 1H), 6.86 (d,
J ) 3.6 Hz, 1H), 4.10 (s, 3H), 4.03 (s, 3H); 13C NMR (75.5 MHz,
CDCl3) δ 158.3, 153.5, 149.5, 131.0, 129.4, 128.4, 123.8, 123.4,
122.3, 120.7, 117.9, 116.6, 110.6, 110.0, 103.6, 56.24, 56.20.
Bia r yl 29a . Following the general procedure for 26, the
oxazoline 15a 46 (450 mg, 2.19 mmol) was coupled with the
Grignard of N-benzyl-7-bromoindoline (540 mg, 1.87 mmol);
workup and silica gel chromatography (hexanes/ethyl acetate/
Et3N 85:10:5) provided 463 mg (65%) of the biaryl as a light
(d), 116.6(s), 46.3(t), 27.1(t); IR (thin film) 1644, 1626 cm-1
;
1
yellow solid: mp 92-94 °C; H NMR (300 MHz, C6D6) δ 7.95
low-resolution mass spectrum (GC-MS) m/ z (rel abundance)
221 (M+, 82), 220 (100), 191 (22), 165 (15), 96 (25). Anal. Calcd
for C15H11NO: C, 81.43; H, 5.01; N, 6.33. Found: C, 81.38;
H, 5.04; N, 6.23.
10-Meth oxy-4,5-dih ydr opyr r olo[3,2,1-de]ph en an th r idin -
7-on e (30b). Following the general procedure for 2, cyclization
of the biaryl 29b (350 mg, 0.850 mmol) and purification by
silica gel chromatography (CH2Cl2/MeOH 95:5) provided 150
(dd, J ) 1.5, 7.8Hz, 1H), 7.42 (dd, J ) 1.5, 7.5 Hz, 1H), 6.80-
7.20 (m, 9H), 6.78 (t, J ) 7.5 Hz, 1H), 3.7-4.1 (m, 2H), 3.59
(s, 2H), 2.75-3.15 (m, 2H), 2.67 (t, J ) 8.4 Hz, 2H), 1.13 (s,
6H); 13C NMR (75.5 MHz, C6D6) δ 162.8(s), 150.0(s), 141.0(s),
139.5(s), 131.1(s), 130.9(d), 130.3(d), 130.0(d), 129.2(s), 128.5-
(d), 128.3(d), 127.0(d), 126.9(d), 124.6(s), 123.8(d), 118.7(d),
79.2(t), 67.7(s), 56.4(t), 53.9(t), 28.8(t), 28.1(q); IR (thin film)
1650 cm-1; low-resolution mass spectrum (GC-MS) m/ z (rel

1012 J . Org. Chem., Vol. 61, No. 3, 1996
Hutchings and Meyers
mg (70%) of the pyrrolophenanthridone 30b as a tan solid: mp
217-218 °C; H NMR (300 MHz, CD2Cl2) δ 8.63 (d, J ) 8.9
MS) m/ z (rel abundance) 249 (M+, 71), 234 (61), 206 (55), 177
(79), 165 (100).
1
Hz, 1H), 7.82 (dd, J ) 0.8, 8.0 Hz, 1H), 7.55(d, J ) 2.5 Hz,
1H), 7.31 (m, 1H), 7.18 (d, J ) 8.0 Hz, 1H), 7.13 (t, J ) 2.5
Hz, 1H), 7.10 (d, J ) 2.5 Hz, 1H), 4.37 (m, 2H), 3.96 (s, 3H),
3.38 (m, 2H); 13C NMR (75.5 MHz, CD2Cl2) δ 163.0(s), 159.8-
(s), 140.8(s), 136.1(s), 131.4(s), 130.3(d), 124.9(d), 123.1(d),
121.4(d), 120.0(d), 116.6(s), 115.8(d), 105.1(d), 55.9(q), 46.5(t),
27.6(t); IR (CH2Cl2) 1645, 1604 cm-1; low-resolution mass
spectrum (GC-MS) m/ z (rel abundance) 251 (M+, 87), 250
Bia r yl 35. Following the general procedure for 26, the
oxazoline 34 (550 mg, 2.20 mmol) was coupled with the
Grignard of N-benzyl-7-bromoindoline (540 mg, 1.87 mmol);
workup and silica gel chromatography (hexanes/ethyl acetate/
Et3N 85:10:5) gave 540 mg (68%) of 35 as a white solid: mp
125 °C; 1H NMR (300 MHz, CDCl3) δ 7.15-7.25 (m, 6H),
7.04 (dd, J ) 1.1, 7.2 Hz, 1H), 6.86 (dd, J ) 1.1, 7.2 Hz, 1H),
6.80 (s, 1H), 6.70 (t, J ) 7.4 Hz, 1H), 5.92 (brs, 2H), 3.70-
4.00 (m, 4H), 3.05-3.30 (m, 2H), 2.91 (t, J ) 8.5 Hz, 2H), 1.25
(s, 6H); 13C NMR (75.5 MHz, CDCl3) δ 163.2(s), 149.5(s),
149.1(s), 146.5(s), 139.1(s), 135.0(s), 130.9(s), 129.6(d), 128.2-
(d), 128.0(d), 126.6(d), 123.6(s), 123.4(d), 121.8(s), 118.1(d),
110.4(d), 109.6(d), 101.5(t), 79.4(t), 66.9(s), 55.8(t), 53.6(t),
28.5(t), 28.0(q); IR (thin film) 1648 cm-1; low-resolution
mass spectrum (GC-MS) m/ z (rel abundance) 426 (M+, 11),
326 (23), 250 (29), 206 (9), 178 (13), 91 (100), 65 (24). Anal.
Calcd for C27H26N2O3: C, 76.03 H, 6.14. Found: C, 76.00; H,
6.21.
(100), 207 (39), 178 (34), 152 (30). Anal. Calcd for C16H13
NO2: C, 76.48; H, 5.21. Found: C, 76.27; H, 5.29.
-
11-Meth yl-4,5-d ih yd r op yr r olo[3,2,1-d e]p h en a n th r id in -
7-on e (30c). Following the general procedure for 2, cyclization
of the biaryl 29c (300 mg, 0.757 mmol) and purification by
silica gel chromatography (CH2Cl2/MeOH 97:3) provided 147
mg (82%) of the pyrrolophenanthridone 30c as a tan solid: mp
187 °C (from MeOH); 1H NMR (300 MHz, CD2Cl2) δ 8.45 (dd,
J ) 1.3, 7.9 Hz, 1H), 8.19 (d, J ) 8.3 Hz, 1H), 7.57 (dd, J )
0.8, 7.3 Hz, 1H), 7.47 (t, J ) 7.7 Hz, 1H), 7.33 (dd, J ) 0.8, 7.3
Hz, 1H), 7.47 (t, J ) 7.7 Hz, 1H), 7.33 (dd, J ) 0.8, 7.3 Hz,
1H), 7.19 (t, J ) 8.0 Hz, 1H), 4.35-4.41 (m, 2H), 3.39 (apparent
t, J ) 8.4 Hz, 2H), 2.92 (s, 3H); 13C NMR (75.5 MHz, CD2Cl2)
δ 160.1(s), 148.6(s), 140.5(s), 136.2(d), 133.1(s), 131.3(s), 129.1-
(s), 127.4(d), 126.8(d), 124.9(d), 124.3(d), 122.9(d), 118.4(s),
46.3(t), 27.4(t), 25.7 (q); IR (thin film) 1643, 1591 cm-1; low-
resolution mass spectrum (GC-MS) m/ z (rel abundance) 235
(M+, 94), 234 (100), 219 (15), 204 (13), 191 (14), 178 (9), 102
(18), 89 (16). Anal. Calcd for C16H13NO: C, 81.68; H, 5.57.
Found: C, 81.44; H, 5.63.
30d . Following the general procedure for 2, cyclization of
the biaryl 29d (200 mg, 0.46 mmol) and purification by silica
gel chromatography (benzene/ethyl acetate 1:9) provided 72
mg (57%) of the pyrrolophenanthridone 30d as a tan solid: mp
191-192 °C; 1H NMR (300 MHz, CDCl3) δ 8.90-9.00 (m, 1H),
8.51 (d, J ) 8.7 Hz, 1H), 8.42 (d, J ) 8.1 Hz, 1H), 7.90-8.00
(m, 1H), 7.90 (d, J ) 8.7 Hz, 1H), 7.63 (m, 2H), 7.31 (dd, J )
1.0, 7.1 Hz, 1H), 7.22 (t, J ) 8.1 Hz, 1H), 4.47 (m, 2H), 3.47
(apparent t, J ) 8.0 Hz, 2H); 13C NMR (75.5 MHz, CDCl3) δ
160.1(s), 140.5(s), 135.7(s), 132.1(s), 131.0(s), 129.5(s), 128.9-
(d), 128.4(d), 127.6(d), 126.9(d), 126.7(d), 126.0(s), 124.5(d),
124.1(d), 123.8(d), 123.1(d), 117.0(s), 46.2(t), 27.2(t); IR (thin
film) 1642, 1610 cm-1; low-resolution mass spectrum (GC-
MS) m/ z (rel abundance) 271 (M+, 100), 270 (75), 241 (32),
214 (11), 189 (13), 120 (12). Anal. Calcd for C19H13NO: C,
84.11; H, 4.82; N, 5.16. Found: C, 83.91; H, 4.88; N, 5.10.
An h yd r olycor in -7-on e (36). Following the general pro-
cedure for 2, cyclization of the biaryl 35 (380 mg, 0.89 mmol)
and purification by silica gel chromatography (CH2Cl2/MeOH
97:3) gave 156 mg (66%) of the pyrrolophenanthridone 36 as
a tan solid: mp 262-264 °C (lit.16f mp 260-270 °C); 1H NMR
(300 MHz, CDCl3) δ 7.89 (s, 1H), 7.72 (d, J ) 7.8 Hz, 1H),
7.52 (s, 1H), 7.27 (dd, J ) 0.9, 7.2 Hz, 1H), 7.17 (t, J ) 7.2 Hz,
1H), 6.11 (s, 2H), 4.45 (apparent t, J ) 8.1 Hz, 2H), 3.40
(apparent t, J ) 8.1 Hz, 2H); 13C NMR (75.5 MHz, CDCl3) δ
159.1(s), 151.5(s), 148.1(s), 139.1(s), 130.6(s), 130.3(s), 123.5-
(d), 122.9(d), 122.8(s), 119.1(d), 116.4(s), 106.5(d), 101.9(t),
100.6(d), 46.3(t), 27.2(t).
Hip p a d in e (4). According to the method of Ghosal,16a
a
solution of anhydrolycorin-7-one (36) (49 mg, 0.184 mmol) and
DDQ (125 mg, 0.550 mmol) in benzene (50 mL) was heated at
reflux for 12 h. Subsequent workup and silica gel chroma-
tography (CH2Cl2/ MeOH 97:3) provided 36 mg (73%) of 4 as
colorless crystals: mp 217-218 °C (lit.16a mp 217-218 °C); 1H
NMR (300 MHz, CDCl3) δ 8.01 (d, J ) 3.6 Hz, 1H), 7.95 (s,
1H), 7.88 (d, J ) 7.8 Hz, 1H), 7.72 (d, J ) 7.8 Hz, 1H), 7.62 (s,
1H), 7.44 (t, J ) 7.8 Hz, 1H), 6.87 (d, J ) 3.6 Hz, 1H), 6.14 (s,
2H); 13C NMR (75.5 MHz, CDCl3) δ 158.1, 152.5, 148.5, 131.6,
128.3, 123.9, 123.5, 122.5, 122.4, 121.3, 118.3, 116.6, 110.7,
108.0, 102.2, 101.6.
4,4-Dim et h yl-2-(3-flu or o-2-m et h oxyp h en yl)-2-oxa zo-
lin e (37). A solution of (m-fluorophenyl)oxazoline 15e (1.0 g,
5.18 mmol) in THF (50 mL) was cooled to -78 °C and treated
with n-BuLi (2.36 mL, 5.4 mmol, 2.3 M in hexanes). The
resulting yellow solution was maintained at -78 °C for 30 min,
at which time neat bis(trimethylsilyl) peroxide43 (1.15 g, 6.48
mmol) was added. The temperature bath was removed, and
the mixture was allowed to warm to rt with stirring overnight.
The deep purple solution was quenched with saturated NH4-
Cl, the volatiles were removed in vacuo, and the crude material
was dissolved in 5% HCl/MeOH (20 mL) and allowed to stir
at rt (30 min). The mixture was then diluted with water (150
mL) and extracted (3 × 20 mL) with dichloromethane. The
organic layers were combined, dried (Na2SO4), and concen-
trated to give the crude phenol which was directly dissolved
in DMSO (10 mL) and treated with powdered KOH (1.6 g, 40
mmol) and methyl iodide (618 µL, 10 mmol). After several
hours the mixture was diluted with water (300 mL) and
extracted (3 × 20 mL) with dichloromethane. The organic
layers were combined, washed with brine, dried (Na2SO4), and
concentrated to give the crude methoxyoxazoline. Silica gel
chromatography (hexanes/ethyl acetate 9:1) provided 520 mg
(45%) of the 37 as a clear oil: 1H NMR (300 MHz, CDCl3) δ
7.47 (apparent dt, J ) 8.0, 1.3 Hz, 1H), 7.14 (ddd, J ) 1.8,
8.0, 12 Hz, 1H), 7.00 (apparent td, J ) 4.8, 8.0 Hz, 1H), 4.08
(s, 2H), 3.9 (d, J ) 1.2 Hz, 3H), 1.35 (s, 6H); 13C NMR (75.5
MHz, CDCl3) δ 160.3(s), 155.9 (d, J CF ) 247 Hz), 147.1 (d, J CF
) 13 Hz), 126.1 (d, J CF ) 3 Hz), 124.0 (s), 123.5 (d, J CF ) 8
Hz), 119.1 (d, J CF ) 19 Hz), 79.1 (t), 67.5 (s), 62.0 (d, J CF ) 4
Hz), 28.2 (q); IR (thin film) 1649 cm-1; low-resolution mass
spectrum (GC-MS) m/ z (rel abundance) 223 (M+, 45), 208
(43), 180 (44), 151 (100), 137 (87), 109 (69).
2-Meth oxy-4,5-(m eth ylen ed ioxy)ben zoic Acid (32). To
a stirred solution of 5.08 g (221 mmol) of Na metal dissolved
in 400 mL of anhydrous methanol was added 2-bromopipero-
nylic acid (31)47 (18.0 g, 73.7 mmol). Once the acid had
dissolved, Cu powder (2.32 g, 36.5 mmol) was added and the
mixture was heated at reflux for 18 h. The mixture was cooled,
filtered through Celite, and concentrated to a white paste
which was dissolved in 400 mL of water and acidified to pH 3
with concentrated HCl. The free acid was extracted with ethyl
acetate, dried (Na2SO4), and concentrated to a white powder.
Recrystallization (EtOH/water) provided 11.0 g (76%) of the
pure acid 32 as a colorless solid: mp 152 °C (lit.48 mp 148-
1
149 °C); H NMR (300 MHz, CDCl3) δ 10.7 (brs, 1H), 7.49 (s,
1H), 6.57 (s, 1H), 5.99 (s, 2H), 3.98 (s, 3H); 13C NMR (75.5
MHz, CDCl3) δ 165.0, 155.3, 153.1, 142.5, 111.2, 110.1, 102.4,
94.2, 57.5; IR (thin film) 2500-3400 br, 1681 cm-1
.
4,4-D im e t h y l-2-(2-m e t h o x y -4,5-(m e t h y le n e d io x y )-
p h en yl)-2-oxa zolin e (34). Following the procedure for 15a ,46
the acid 32 (4.95 g, 25.2 mmol) provided 4.6 g (73%) of the
oxazoline 34 as a colorless solid, which was recrystallized from
hexanes: mp 74-75 °C; 1H NMR (300 MHz, CDCl3) δ 7.19 (s,
1H), 6.51 (s, 1H), 5.92 (s, 2H), 4.02 (s, 2H), 3.79 (s, 3H), 1.33
(s, 6H); 13C NMR (75.5 MHz, CDCl3) δ 160.8(s), 155.0(s), 150.5-
(s), 141.0(s), 110.2(d), 109.8(s), 101.6(t), 95.3(d), 78.7(t), 67.1-
(s), 57.2(q), 28.3(q); IR (thin film) 2966, 2888, 1638, 1505, 1485,
1430, 1263, 1194, 1032; low-resolution mass spectrum (GC-
(47) Dallacker, F. Ann. 1960, 14, 633.
(48) Arnold, R. T.; Bortnick, N. J . Am. Chem. Soc. 1945, 67, 1798.

Oxazoline-Mediated Synthesis of Pyrrolophenanthridine Alkaloids
J . Org. Chem., Vol. 61, No. 3, 1996 1013
Bia r yl (38). Following the general procedure for 26, the
oxazoline 37 (400 mg, 1.80 mmol) was coupled with the
Grignard of N-benzyl-7-bromoindoline (574 mg, 2 mmol);
workup and silica gel chromatography (hexanes/ethyl acetate/
Et3N 90:8:2) provided 580 mg (80%) of 38 as a light yellow oil:
1H NMR (300 MHz, C6D6) δ 7.59-7.68 (m, 1H), 7.25 (brd, J )
7.2 Hz, 2H), 7.00-7.15 (m, 5H), 6.70-6.80 (m, 3H), 4.03 (ABq,
J ) 14.1 Hz, ∆δAB ) 23.6 Hz, 2H), 3.58 (ABq, J ) 7.8 Hz, ∆δAB
) 0.3 Hz, 2H), 3.05-3.17 (m, 1H), 2.91 (apparent q, J ) 9.0
Hz, 1H), 2.66 (apparent t, J ) 9.0 Hz, 2H), 1.11 (s, 3H), 1.07
(s, 3H); 13C NMR (75.5 MHz, C6D6) δ 161.7 (d, J CF ) 3 Hz),
160.4 (d, J CF ) 245 Hz), 150.6, 139.4, 131.9 (d, J CF ) 3 Hz),
131.0, 130.6, 128.9 (d, J CF ) 18 Hz), 128.8 (d, J CF ) 8 Hz),
128.5, 128.3, 127.0, 125.7 (d, J CF ) 3 Hz), 124.4, 118.2, 117.3
(d, J CF ) 23 Hz), 116.3, 79.2 67.8, 55.7, 53.9, 28.6, 28.1, 28.0;
IR (thin film) 1653 cm-1; low-resolution mass spectrum (GC-
MS) m/ z (rel abundance) 400 (M+, 7), 300 (15), 237 (19), 224
(20), 183 (10), 91 (100), 65 (23).
solvent was removed in vacuo and the crude material was
purified by silica gel chromatography (hexanes/ethyl acetate/
benzene 10:1:1) to give 42 as a colorless solid: mp 119 °C; 1H
NMR (300 MHz, C6D6) δ 5.98 (s, 1H), 5.20 (s, 2H), 3.85 (s, 2H),
1.45 (m, 3H), 1.35 (s, 6H), 1.22 (d, J ) 7.3 Hz, 18H); 13C NMR
(75.5 MHz, CDCl3) δ 158.1(s), 155.3(s), 149.8(s), 139.1(s), 130.8-
(s), 107.4(s), 100.6(t), 89.0(d), 78.3(t), 68.2(s), 56.5(q), 28.6(q),
18.2(q), 13.9(d); IR (thin film) 1669 cm-1
.
Bia r yl 43. Following the general procedure for 26, the
oxazoline 41 (200 mg, 0.56 mmol) was coupled with the
Grignard of N-benzyl-7-bromoindoline (287 mg, 1.00 mmol);
workup and silica gel chromatography (hexanes/ethyl acetate/
Et3N/benzene 10:3:1:1) provided 142 mg (47%) of 43 as a
colorless foam: 1H NMR (300 MHz, CDCl3) δ 7.15-7.23 (m,
5H), 7.01(d, J ) 7.2 Hz, 1H), 6.89 (d, J )7.2 Hz, 1H), 6.61 (t,
J ) 7.2 Hz, 1H), 6.40 (s, 1H), 5.81 (d, J ) 0.6 Hz, 1H), 5.46 (d,
J ) 0.6 Hz, 1H), 4.35 (d, J ) 15.3 Hz, 1H), 3.68-3.79 (m, 6H),
3.44 (apparent q, J ) 7.5 Hz, 1H), 3.09 (apparent q, J ) 8.7
Hz, 1H), 2.95 (apparent t, J ) 7.5 Hz, 1H), 1.15 (s, 3H), 1.07
(s, 3H).
Bia r yl 44. Following the general procedure for 26, the
oxazoline 42 (421 mg, 1.00 mmol) was coupled with the
Grignard of N-benzyl-7-bromoindoline (430 mg, 1.50 mmol);
workup and silica gel chromatography (hexanes/Et3N 19:1)
provided 465 mg (78%) of 44 as a colorless foam: 1H NMR
(300 MHz, C6D6) δ 6.9-7.3 (m, 7H), 6.70 (t, J ) 7.2 Hz, 1H),
6.59 (s, 1H), 5.07 (s, 2H), 4.43 (d, J ) 15.0 Hz, 1H), 3.92 (d, J
) 15.0 Hz, 1H), 3.70 (s, 2H), 3.15 (m, 1H), 2.83 (m, 1H), 2.64
(m, 2H), 1.41 (septet, J ) 7.2 Hz, 3H), 1.19 (s, 3H, partially
obscured), 1.18 (d, J ) 7.2 Hz, 18H), 0.93 (s, 3H); 13C NMR
(75.5 MHz, C6D6) δ 159.8(s), 150.2(s), 149.2(s), 140.2 (s), 138.6-
(s), 136.7(s), 135.7(s), 131.0(s), 130.7(d), 128.7(d), 128.5(d),
128.2(d), 126.7(d), 123.8(d), 122.5(s), 118.2(s), 117.7(d), 104.6-
(d), 100.7(t), 78.4(t), 68.0(s), 55.9(t), 54.1(t), 28.7(t), 28.0(q),
18.2(q), 13.9(s); IR (thin film) 1666 cm-1; low-resolution mass
spectrum (EI-DIP) m/ z (rel abundance) 598 (M+, 90), 555 (43),
499 (100), 422 (88).
8-Hyd r oxy-9,10-(m eth ylen ed ioxy)-4,5-d ih yd r op yr r olo-
[3,2,1-d e]p h en a n th r id in -7-on e (45). The biaryl 44 (380 mg,
0.635 mmol) was dissolved in 10 mL of 10% H2SO4/ethanol
(v/v) and heated at reflux overnight. After cooling to rt, the
reaction mixture was hydrogenated (1 atm) in the presence of
20 mg of 10% Pd/C (4 h). The debenzylated material was again
heated to reflux, and the formation of 45 was followed by TLC
(CHCl3/MeOH 99:1). The reaction mixture was diluted with
hot ethanol and filtered through Celite. The filtrate was
concentrated to one-quarter of its original volume, diluted with
water (15 mL), neutralized (pH ) 7) with saturated NaHCO3,
and extracted with CH2Cl2 (3 × 10 mL). The organic layers
were combined, dried (Na2SO4), and concentrated in vacuo to
give a crude solid which was purified by silica gel chromatog-
raphy (CHCl3/MeOH 99.5:0.5) to give 24 mg (14%) of the
pyrrolophenanthridone 45 as a tan solid: mp 294-295 °C
(lit.20b mp 295 °C); 1H NMR (300 MHz, CDCl3) δ 13.21 (s, 1H),
7.72 (dd, J ) 8.1 Hz, 1H), 7.2-7.3 (m, 2H), 7.14 (s, 1H), 6.12
(s, 2H), 4.43 (apparent t, J ) 8.4 Hz, 2H), 3.43 (apparent t, J
) 8.4 Hz, 2H); low-resolution mass spectrum (GC-MS) m/ z
(rel abundance) 281 (M+, 100), 252 (11), 195 (23), 167 (25).
11-F lu or o-4,5-d ih yd r op yr r olo[3,2,1-d e]p h en a n th r id in -
7-on e (39). Following the general procedure for 2, cyclization
of the biaryl 38 (388 mg, 0.97 mmol) and purification by silica
gel chromatography provided 200 mg (86%) of 39 as a tan
1
powder: mp 167-169 °C; H NMR (300 MHz, CD2Cl2) δ 8.29
(dd, J ) 1.5, 7.8 Hz, 1H), 8.20 (d, J ) 8.1 Hz, 1H), 7.40-7.60
(m, 2H), 7.34 (dd, J ) 0.9, 7.5 Hz, 1H), 7.19 (t, 1H, J ) 7.8
Hz), 4.36-4.41 (m, 2H), 3.39 (apparent t, J ) 8.1 Hz, 2H); 13
C
NMR (75.5 MHz, CDCl3) δ 160.6 (d, J CF ) 249 Hz), 158.9,
139.5, 130.4, 129.6 (d, J CF ) 5 Hz), 128.1 (d, J CF ) 9 Hz), 124.9,
124.6, 123.9 (d, J CF ) 32 Hz), 123.7 (d, J CF ) 1 Hz), 122.7 (d,
J CF ) 11 Hz), 119.1 (d, J CF ) 22 Hz), 114.2 (d, J CF ) 3 Hz),
46.4, 27.2; IR (thin film) 1652 cm-1; low-resolution mass
spectrum (GC-MS) m/ z (rel abundance) 239 (M+, 91), 238-
(100), 209(14), 183(7), 105(3). Anal. Calcd for C15H10NOF: C,
75.30; H, 4.21. Found: C, 75.29; H, 4.24.
4,4-Dim eth yl-2-(1-h yd r oxy-2-m eth oxy-4,5-(m eth ylen e-
d ioxy)p h en yl)-2-oxa zolin e (40). Following the procedure
for 37, the oxazoline 34 (2.49 g, 10.00 mmol) in THF was
treated with n-BuLi (4.58 mL, 11.00 mmol, 2.4 M in hexanes)
and bis(trimethylsilyl) peroxide43 (2.67 mL, 15 mmol) to give,
after workup and silica gel chromatography (hexanes/ethyl
acetate/ benzene 70:25:5), 600 mg (23%) of 40 as light yellow
needles: mp 149 °C (benzene); 1H NMR (300 MHz, C6D6) δ
14.49 (s, 1H), 5.90 (s, 1H), 5.37 (s, 2H), 3.54 (s, 2H), 3.68 (s,
6H), 0.98 (s, 6H); 13C NMR (75.5 MHz, CDCl3) δ 165.5 (s),
157.0(s), 152.0(s), 147.0(s), 129.3(s), 101.5(t), 96.7(s), 85.9(d),
78.0(t), 64.2(s), 55.9(q), 27.8(q); IR (thin film) 2000-3500 (br),
1637 cm-1; low-resolution mass spectrum (GC-MS) m/ z (rel
abundance) 265 (M+, 37), 193 (100), 178 (16), 150 (6).
4,4-Dim eth yl-2-(1-(ben zyloxy)-2-m eth oxy-4,5-(m eth yl-
en ed ioxy)p h en yl)-2-oxa zolin e (41). The phenol 40 (332 mg,
1.25 mmol) was combined with powdered KOH (200 mg, 5.00
mmol) and benzyl bromide (297 µL, 2.5 mmol) in DMSO (6
mL) and allowed to stir (8 h) at rt until TLC (hexanes/ethyl
acetate/benzene) indicated the absence of starting material.
The reaction mixture was diluted with water (150 mL) and
extracted with CH2Cl2 (3 × 20 mL). The extracts were
combined, washed with brine, dried (Na2SO4), and concen-
trated to give the crude material which was purified by silica
gel chromatography to give 410 mg (92%) of 41 as a colorless
oil: 1H NMR (300 MHz, C6D6) δ 7.50 (dd, J ) 0.6, 8.0 Hz, 2H),
7.00-7.25 (m, 3H), 6.02 (s, 1H), 5.27 (s, 2H), 5.23 (s, 2H), 3.80
(s, 2H), 3.22 (s, 3H), 1.28 (s, 6H); 13C NMR (75.5 MHz, CDCl3)
δ 158.0(s), 154.8(s), 150.7(s), 141.8(s), 137.9(s), 131.1(s), 128.5-
(d), 128.4(d), 128.0(d), 106.6(s), 101.1(t), 89.9(d), 78.6(t), 74.2-
(t), 68.1(s), 56.4(q), 28.5(q); IR (thin film) 1666 cm-1; low-
resolution mass spectrum (GC-MS) m/ z (rel abundance) 355
(M+, 6), 194 (45), 91 (100), 65 (36).
Ack n ow led gm en t. The authors are grateful to the
National Institutes of Health for financial support of
this work.
1
Su p p or tin g In for m a tion Ava ila ble: 300 MHz H NMR
spectra of all products (32 pages). This material is contained
in libraries on microfiche, immediately follows this article in
the microfilm version of the journal, and can be ordered from
the ACS; see any current masthead page for ordering
information.
4,4-Dim et h yl-2-(1-((t r iisop r op ylsilyl)oxy)-2-m et h oxy-
4,5-(m eth ylen ed ioxy)p h en yl)-2-oxa zolin e (42). The phe-
nol 40 (270 mg, 1.02 mmol) was combined with 2,6-lutidine
(128 µL, 1.1 mmol) and triisopropylsilyl triflate (295 µL, 1.10
mmol) in CH2Cl2 (5 mL). After stirring at rt (10 min), the
J O951474X