A practical, Nenitzescu-based synthesis of LY311727, the first potent and selective s-PLA2 inhibitor

Full text of DOI:10.1021/jo9614452

J . Org. Chem. 1996, 61, 9055-9059
9055
itzescu reaction efficiency is highly dependent upon
substituent effects and reaction medium. The utility of
the Nenitzescu adducts has been somewhat limited,
however, by the highly reactive â-(hydroxymethyl)indole
nucleus. This report describes the Nenitzescu reaction
with specific substrates and the practical incorporation
of their products into LY311727.
A P r a ctica l, Nen itzescu -Ba sed Syn th esis of
LY311727, th e F ir st P oten t a n d Selective
s-P LA2 In h ibitor
J . M. Pawlak, V. V. Khau, D. R. Hutchison, and
M. J . Martinelli*
Chemical Process Research & Development, Lilly Research
Laboratories, A Division of Eli Lilly and Company,
Indianapolis, Indiana 46285-4813
Resu lts a n d Discu ssion
Received J uly 30, 1996
Nentizescu reaction precursors were prepared from
reaction of readily available methyl propionylacetate (3)
with benzylamine to afford the corresponding enamino
esters 4 (eq 1). Catalytic p-TsOH‚H2O ensured complete
In tr od u ction
Patients with acute pancreatitis, bacterial peritonitis,
adult respiratory distress syndrome (ARDS), septic shock,
and arthritis all display extraordinarily high blood levels
of secretory phospholipase A2 (s-PLA2).1 The in vivo
trigger for s-PLA2 release under such conditions is
mediated by a number of mechanisms, all of which have
been investigated as a primary site for drug discovery.
However, it is believed that potent and selective inhibi-
tors of s-PLA2 itself will provide important clinical
therapies. A significant study on the structure of human
nonpancreatic s-PLA2 revealed the native crystal form,2
as well as that complexed with a phosphonate transition
state analogue.3 The former structural information af-
forded an elegant example of a contemporary structure-
based search for selective s-PLA2 inhibitors, optimally
resulting in exciting clinical candidates. From that
study, LY311727 (1) emerged as the first potent and
selective inhibitor of human nonpancreatic s-PLA2.1 The
exciting in vitro activity of LY311727 signified that an
effective synthesis was warranted to support further in
vivo studies.
formation of the enamino esters 4 as a 13:1 Z:E mixture
under azeotropic conditions, whereas clean formation of
the amide 5 was the dominant pathway without acid
catalysis.9
For the reaction of enamino ester 4 with p-benzo-
quinone (6) to produce indole 2, a survey was conducted
using solvents of widely varying dielectric constants. The
results shown in Table 1 (Scheme 1) demonstrate that
the yields of 2 are highly variable and virtually indepen-
dent of dielectric constant. Optimal yields in CH3NO2
required 48 h reaction time at ambient temperature,
whereas reaction in 1,2-dichloroethane showed optimal
performance within 3-6 h. Other solvents provided
similarly moderate yields but involved more tedious
workups. The less efficient reaction in 1,2-dichloroethane
was preferred on a small scale due to the short reaction
time, especially since these inexpensive starting materi-
als were readily available. However, CH3NO2 was the
preferred solvent on a larger scale based upon the higher
chemical efficiency and ease of product isolation by simple
filtration directly from the crude reaction mixture. The
mother liquors were shown to contain an assortment of
the typical Nenitzescu reaction byproducts as the mass
balance.5
The Nenitzescu reaction is an interesting process
presumed to involve an internal oxidation-reduction
sequence.5,6 Since electron transfer characterized by deep
burgundy reaction mixtures may be an important mecha-
nistic aspect, the outcome should be sensitive to the
reaction medium. Patrick reported on the use of ni-
tromethane (CH3NO2) as an optimal Nenitzescu reaction
solvent with methyl enamino esters as substrates.8
Although empirically this solvent was the most efficient
medium, the rationale was more complex than dielectric
The Nenitzescu reaction is a highly regioselective
synthetic entry into 1,2,3-trisubstituted 5-oxyindoles,
affording the requisite 5-hydroxy moiety and 3-(meth-
oxycarbonyl) substitution pattern (cf. 2) for compounds
such as 1.4 Nenitzescu precursors are the readily avail-
able â-keto esters which after being transformed into the
enamino ester are reacted selectively with p-benzo-
quinone to afford this desired selectivity pattern.5 Al-
though the reaction has been reviewed, several new
advances have since been made,6 including new quinone
surrogates7 and solvent optimization studies.8 The Nen-
(1) Schevitz, R. W.; Bach, N. J .; Carlson, D. G.; Chirgadze, N. Y.;
Clawson, D. K.; Dillard, R. D.; Draheim, S. E.; Hartley, L. W.; J ones,
N. D.; Mihelich, E. D.; Olkowski, J . L.; Snyder, D. W.; Sommers, C.;
Wery, J .-P. Nature Stuct. Biol. 1995, 2, 458.
(2) Wery, J .-P.; Schevitz, R. W.; Clawson, D. K.; Bobbitt, J . L.; Dow,
E. R.; Gamboa, G.; Goodson, T.; Hermann, R. B.; Kramer, R. M.;
McClure, D. B.; Mihelich, E. D.; Putnam, J . E.; Sharp, J . D.; Stark, D.
H.; Teater, C.; Warrick, M. W.; J ones, N. D. Nature 1991, 352, 79.
(3) Scott, D. L.; White, S. P.; Browning, J . L.; Rosa, J . J .; Gelb, M.
H.; Sigler, P. B. Science 1991, 254, 1007.
(6) (a) Allen, G. R.; Pidacks, C.; Weiss, M. J . J . Am. Chem. Soc. 1966,
88, 2536. (b) Poletto, J . F.; Allen, G. W.; Sloboda, A. E.; Weiss, M. J . J .
Med. Chem. 1973, 16, 757. (c) Kuckla¨nder, U. Tetrahedron 1973, 29,
921. (d) Kuckla¨nder, U. Tetrahedron Lett. 1971, 23, 2093. (e) Kuck-
la¨nder, U. Tetrahedron 1972, 28, 5251. (f) Coates, R. M.; MacManus,
P. A. J . Org. Chem. 1982, 47, 4822. g) Kuckla¨nder, U. Tetrahedron
1975, 31, 1631.
(7) Kita, Y.; Tohma, H.; Inagaki, M.; Hatanaka, K. Heterocycles
1992, 33, 503.
(8) Patrick, J . B.; Saunders, E. K. Tetrahedron Lett. 1979, 42, 4009.
(9) Haynes, L. W.; Cook, A. G. in Enamines: Synthesis, Structure,
and Reactions, 2nd ed.; Cook, A. G., Ed.; Marcel Dekker, Inc.: New
York, 1988; p 103.
(4) (a) Gribble, G. W. Contemp. Org. Synth. 1994, 11, 145. (b) Pindur,
U.; Adam, R. J . Heterocyc. Chem. 1988, 25, 1.
(5) Allen, G. R. Org. React. 1973, 20, 337.
S0022-3263(96)01445-4 CCC: $12.00 © 1996 American Chemical Society

9056 J . Org. Chem., Vol. 61, No. 25, 1996
Notes
Sch em e 1
Ta ble 1. Rea ction Med ia for 4 + 6 f 2
Ta ble 2. Red u ction of 7 To Affor d Meth ylin d ole
14:(Hyd r oxym eth yl)in d ole 8a
solvent
ꢀ
yield of 2 (%)
[H]
solvent
T (°C)
ambient
0
0
0 f ambient
reflux
reflux
reflux
22 f 70
0
14:8
PhMe
CHCl3
2.38
4.70
6.19
25
49
50
47
22
30
83
LAH‚bis-THF
LAH‚bis-THF
LAH
THF
CH2Cl2
THF
CH2Cl2
Tol/THF
MeOH
Et2O
Tol/THF
THF
CH2Cl2
CH2Cl2
THF
THF
THF
>4:1
>4:1
8:1
8:1
0
PhMe/HOAc 2/16g
ClCH2CH2Cl
Acetone
10.4
20.7
32.6
38.6
LAH
MeOH
CH3NO2
NaBH4
NaBH4
LiBH4
LiBH4
DIBAL
DIBAL
DIBAL
LAH (solid)
LAH (soln)
LiAl(O-t-Bu)3H
Red-Al
0
0
trace
3:1
3:1
1:0
0:1
1:0
trace
trace
constant considerations alone. Initial charge-transfer
complexation has been implicated, thereby warranting
the use of such polar media. With CH3NO2 as the
reaction medium, however, direct product crystallization
occurred as the reaction progressed.
0
-78 f ambient
ambient
reflux
reflux
reflux
Protection of the 5-hydroxyl moiety of indole 2 was
accomplished in reasonable yield by reaction with MeI
and K2CO3 in acetone or MEK at reflux. Reaction times
were typically long (3 days), with incomplete conversion
even when an enormous excess of reagents was employed.
Alkylation could also be accomplished in H2O under
phase transfer conditions (aqueous NaOH, MeI, n-Bu4N+-
Br-, reflux) in good yield (78%). The alkylation of 5-hy-
droxyindoles is known to be problematic, and C-alkyla-
tion can be the dominant by-product; however, this was
not observed.10 Alternatively, appendage of the requisite
â-propyl phosphonate moiety could be accomplished,
although this strategy was abandoned due to its limited
compatibility with subsequent elaborations, specifically
reduction of the C-3 ester (vide infra).
toluene
a
Ratios determined by NMR analysis.
without N-substitution.12 Most conditions afforded the
3-methylindole when the reducing agent was added to
the substrate. However, addition of ester 7 to LAH in
THF at ambient temperature afforded very clean reduc-
tion to the desired alcohol 8 as determined by chromato-
graphic analysis. Quench to precipitate the aluminum
salts,13 filtration, and concentration afforded the alcohol
8 in nearly quantitative yield. Crystallization was ac-
complished from a mixture of EtOAc/hexanes, and the
crystalline product was stored indefinitely at refrigerator
temperatures.
NMR analysis of the product, however, revealed a
second component containing vinylic protons. Chromato-
graphic analysis of the NMR sample still in CDCl3
showed the appearance of a new material at slightly
higher Rf that was not present prior to initial sampling.
Spectroscopic analysis of the crude product in CDCl3
freshly eluted over basic alumina showed only the alcohol
8. Over the next 24 h, however, the solution became
reddish in color concomitant with the appearance of the
new product proposed to have the structure 16. The acid-
Having established an access to quantities of 7, atten-
tion was next turned to the reduction of indole-3-
carboxylic esters.11 It became readily apparent that
overreduction of ester 7 to irreversibly afford the 3-meth-
yl product 14 was a predominant pathway under a
variety of conditions (eq 2, Table 2). In fact, the literature
(10) Suehiro, T. Chem. Ber. 1967, 100, 905, 915.
(11) (a) Leete, E. J . Am. Chem. Soc. 1959, 81, 6023. (b) Dolby, L. J .;
Booth, D. L. J . Org. Chem. 1965, 30, 1550. (c) Chatterjee, A.; Biswas,
K. M. J . Org. Chem. 1975, 40, 1257.
(12) (a) Leete, E.; Marion, L. Can. J . Chem. 1953, 31, 775. (b)
Rossiter, E. D.; Saxton, J . E. J . Chem. Soc. 1953, 3654. (c) Biswas, K.
M.; J ackson, A. H. Tetrahedron 1968, 24, 1145.
(13) Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis; J ohn
Wiley & Sons: New York, 1967; pp 581-595.
suggested that overreduction might not be controllable,
although the problem appears to be more significant

Notes
J . Org. Chem., Vol. 61, No. 25, 1996 9057
Sch em e 2
catalyzed equilibrium shown in eq 3 could explain these
results; however, attempts to isolate and fully character-
ize 16 have thus far been unsuccessful.
TsCl/NaCN; BF3‚Et2O/NaCN; ZnCl2/NaCN; Et3Al/TMS-
CN. However, addition of the alcohol 8 to a solution of
BF3‚Et2O/TMSCN in CH2Cl2 provided the best yield of
nitrile 9 (83%). Optimization for formation of the 3,3′-
methylbis(indole) 18 was found to occur by reaction of 8
with Et3Al in CH2Cl2 without added cyanide nucleophile.
Formation of 3,3′-methylbis(indole)s from 3-unsubsti-
tuted indoles is also known to occur in acidic medium in
the presence of CH2O.14
Nitrile hydrolysis to afford the amide 10 was most
efficiently accomplished with powdered KOH in t-BuOH
at reflux (Scheme 1).15 The amide 10 was crystallized
from i-PrOH in excellent yield (95%) with this protocol.
Typically, nitrile hydrolysis is reported to occur with basic
peroxide,16 but many of these conditions also produced
the corresponding acid 21 as an unwanted byproduct.
With many of the reductions shown in Table 2, a
variable product profile resulted depending upon the
workup conditions. The rate of quench and the resulting
temperature (upon quench) were critical to control un-
desired reaction pathways. In some instances, rapid
quench afforded a new reducing agent concomitant with
an exotherm to provide overreduction of alcohol 8,
furnishing byproduct 14. Formation of unidentified
products also occurred in some instances (vide infra).
On the basis of the ease of overreduction and the
hypothesized acid-catalyzed alcohol rearrangement (eq
3), we were encouraged that it would be possible to
generate and trap the proposed immonium species 15.
Addition of Et2AlCN to the alcohol 8 in toluene at 0 °C
rapidly afforded two products that were characterized as
the desired nitrile 9 and the 3,3′-methylbis(indole) 18
(Scheme 2). The formation of the 3,3′-methylbis(indole)
18 was envisioned by a mechanism involving reaction of
8 with the Lewis acid (LA) to afford 15, which underwent
subsequent attack by another molecule of 8 followed by
eventual loss of CH2O.14 Inverse addition of the reaction
mixture to Et2AlCN resulted in an improved yield of
nitrile 9, but concomitant formation of 18 also occurred.
These results suggested the use of a better, more soluble,
and nucleophilic source of cyanide. A number of cyanide-
containing reagents were examined that provided nitrile
9 in moderate yield: ZnI2/TMSCN; Et2AlCN/TMSCN;
Cleavage of the methoxy protecting group at C-5 with
BBr3 in CH2Cl2 afforded 11, which was purified over silica
gel.17 Alkylation with 1218 under phase-transfer condi-
tions provided the penultimate phosphonate ester 13.
Once again, incomplete alkylation and a more complex
impurity profile were observed with NaH or t-BuOK/
DMF, even with excess reagents. Finally, ester cleavage
was effected with excess TMSI in CH2Cl2 at ambient
temperature for 2 h to yield the trimethylsilyl phosphonic
acid 22, which upon alcoholytic workup afforded 1.
The versatility of the approach summarized in Scheme
1 was further demonstrated through the preparation of
LY311727 and analogues.19 The regiochemical outcome
of the Nenitzescu reaction is well documented5 and allows
for the selective incorporation of a variety of substituents
in the indole ring. Controlled reduction of the ester
moiety afforded a reactive intermediate alcohol, also
providing insight for hydroxide displacement. The Lewis
acid-mediated cyanide reaction provided smooth conver-
sion of the alcohol to the nitrile. The Nenitzescu reaction
and the subsequent functional group modification has
(15) Hall, J . H.; Gisler, M. J . Org. Chem. 1976, 41, 3769.
(16) Kabalka, G. W.; Deshpande, S. M.; Wadgaonkar, P. P.; Chatla,
N. Synth. Commun. 1990, 20, 1445.
(17) Greene, T. W. Protective Groups in Organic Synthesis; J ohn
Wiley and Sons, Inc.: New York, 1981; p 87.
(18) Ornstein, P. A. Org. Prep. Proc. Int. 1988, 20, 371.
(19) A detailed study of these analogues will be disclosed in a future
report.
(14) (a) Thesing, J . Chem. Ber. 1954, 87, 692. (b) Noland, W. E.;
Robinson, D. N. Tetrahedron 1958, 3, 68. (c) Noland, W. E.; Ven-
kiteswaran J . Org. Chem. 1961, 26, 4263. (d) Bennett, R.; Shah, T.;
Maggiolo, A. J . Heterocycl. Chem. 1982, 19, 1251. (e) Sheu, J .-H.; Chen,
Y.-K.; Hong, Y.-L. J . Org. Chem. 1993, 58, 5784. (f) Mattocks, A. R. J .
Chem. Soc., Perkin Trans. 1 1978, 896. (g) Harrison, C.-A.; Leineweber,
R.; Moody, C. J .; Williams, J . M. J . Tetrahedron Lett. 1993, 34, 8527.

9058 J . Org. Chem., Vol. 61, No. 25, 1996
Notes
1158; UV (EtOH) 280 (8600), 215 (29 500); 1H NMR (300 MHz,
DMSO-d6) δ 1.02 (t, 3H, J ) 7.5 Hz), 2.71 (q, 2H, J ) 7.5 Hz),
3.72 (s, 3H), 4.40 (s, 3H), 5.32 (s, 2H), 6.62-7.24 (m, 8H); 13C
NMR (75 MHz, DMSO-d6) δ 15.7, 17.9, 46.3, 54.4, 55.9, 101.2,
110.8, 112.0, 126.5, 127.5, 128.5, 128.8, 129.0, 131.7, 139.3, 141.2,
154.0; MS m/z (M+) 295. Anal. Calcd for C19H21NO2: C, 77.26;
H, 7.17; N, 4.74. Found: C, 77.56; H, 7.20; N, 4.88.
afforded a powerful means to synthesize potent and
selective s-PLA2 inhibitors. Some of these agents are
currently being investigated clinically.
Exp er im en ta l Section
Melting points were determined on a hot stage microscope
and are uncorrected. All experiments were conducted under an
inert atmosphere of nitrogen unless otherwise noted and moni-
tored by thin-layer chromatography using Merck F254 silica gel
plates. All solvents and reagents were used as obtained. 1H,
13C NMR, and HETCOR spectra were obtained on either a GE
QE-300 or a Bruker ACP-300 spectrometer. Microanalyses were
conducted by the Physical Chemistry Department of Lilly
Research Laboratories.
3-(Cya n om et h yl)-2-et h yl-1-(p h en ylm et h yl)-1H -5-m et h -
oxyin d ole (9). BF3‚Et2O (57.8 g, 0.407 mol) and TMSCN (54.0
g, 0.544 mol) were added to CH2Cl2 (800 mL) at 0 °C under N2.
A solution of the (hydroxymethyl)indole 8 (40.0 g, 0.136 mol) in
CH2Cl2 (200 mL) was then added dropwise at a rate to maintain
the temperature e7 °C, forming a deep red reaction mixture.
After the solution was stirred for 1 h at 0 °C, saturated aqueous
NaHCO3 solution (300 mL) was added with continued stirring
for 40 min. The layers were separated, and the organic phase
was washed successively with 1 N HCl (300 mL), saturated
NaHCO3 (300 mL), and brine (300 mL) and dried (Na2SO4). The
resulting brown oil (46.5 g) was filtered over SiO2, eluting with
CH2Cl2, to afford 34.3 g (83%) as a light amber semisolid: TLC
(hexane/EtOAc (3:1)) Rf 0.46; IR (CHCl3, cm-1) 2251, 1486, 1454,
1157; UV (EtOH) 279 (7600); 1H NMR (300 MHz, CDCl3) δ 1.16
(t, 3H, J ) 7.6 Hz), 2.75 (q, 2H, J ) 7.6 Hz), 3.79 (s, 2H), 3.88
(s, 3H), 5.31 (s, 2H), 6.79-7.27 (m, 8H); 13C NMR (75 MHz,
DMSO-d6) δ 12.6, 14.7, 17.8, 46.4, 55.9, 100.2, 100.5, 111.3,
111.4, 120.1, 126.4, 127.5, 127.6, 129.0, 131.6, 139.0, 141.2, 154.4;
MS m/z (M+) 304. Anal. Calcd for C20H20N2O: C, 78.92; H, 6.62;
N, 9.20. Found: C, 78.77; H, 6.86; N, 8.91.
3-(Ca r b om et h oxy)-2-et h yl-1-(p h en ylm et h yl)-1H -5-h y-
d r oxyin d ole (2). Methyl propionylacetate (131.0 g, 1.0 mol)
and benzylamine (112.0 g, 1.05 mol) were dissolved in toluene
(500 mL), to which was added p-TsOH‚H2O (9.5 g, 0.05 mol).
The resulting solution was stirred under reflux for 4 h using a
Dean-Stark trap to remove H2O (18.9 mL, 1.05 mol). The
reaction mixture was cooled to 10 °C, filtered to remove insoluble
materials, and concentrated to a crude oil (220 g) that was used
directly in the subsequent transformation. 1,4-Benzoquinone
(149.0 g, 1.38 mol) was dissolved in nitromethane (500 mL) and
cooled to 20 °C under N2. The freshly prepared crude enamino
ester (220 g) was dissolved in nitromethane (250 mL) and added
dropwise to the benzoquinone solution over 30 min. An ad-
ditional rinse of nitromethane (100 mL) was employed to ensure
complete transfer. A slight endotherm caused the internal
temperature to drop to 17 °C initially. The initial dark green
solution became dark brown red, and a precipitate was formed
within several hours. After 48 h at ambient temperature, the
reaction mixture was cooled in an ice bath, filtered, and washed
with fresh, cold nitromethane to afford a slightly reddish solid
(214 g, 69%) after drying. The material thus obtained could be
used without further purification. However, the crude solid
suspended in 1,2-dichloroethane (400 mL) was stirred at reflux
for 30 min and then filtered hot to provide 159 g (52%) as a light
yellow solid: mp 194-5 °C; TLC (hexane/EtOAc (1:1)) Rf 0.64;
IR (CHCl3, cm-1) 3019, 1689, 1464, 1454, 1145; UV (EtOH) 291
(11 900), 246 (17 800), 216 (33 300); 1H NMR (300 MHz, DMSO-
d6) δ 1.01 (t, 3H, J ) 7.4 Hz), 3.04 (q, 2H, J ) 7.4 Hz), 3.77 (s,
3H), 5.40 (s, 2H), 6.60-7.40 (m, 8H), 8.98 (s, 1H); 13C NMR (75
MHz, DMSO-d6) δ 14.3, 19.2, 46.3, 51.0, 102.3, 106.0, 106.1,
111.7, 112.4, 126.5, 127.7, 129.2, 130.8, 138.1, 151.1, 153.5, 165.7;
MS m/z (M+) 309. Anal. Calcd for C19H19NO3: C, 73.77; H, 6.19;
N, 4.53. Found: C, 73.57; H, 6.08; N, 4.57.
3-(Am id om et h yl)-2-et h yl-1-(p h en ylm et h yl)-1H -5-m et h -
oxyin d ole (10). The (cyanomethyl)indole 9 (14.0 g, 0.046 mol)
and powdered KOH (15.0 g, 0.23 mol) were added to t-BuOH
(180 mL) and stirred at reflux under N2 for 1 h. After cooling,
the reaction mixture was partitioned between saturated brine
solution (400 mL) and EtOAc (400 mL). The organic phase was
washed with brine, dried (Na2SO4), and concentrated. Purifica-
tion was accomplished by chromatography over SiO2 with CH2-
Cl2/EtOAc (1:1) to afford 12.6 g (85%) of a colorless solid: mp
169-170 °C; TLC (CH2Cl2/EtOAc (1:1)) Rf 0.26; IR (CHCl3, cm-1
)
3008, 1673, 1573, 1485, 1454, 1154; UV (EtOH) 283 (8600), 224
(26000); 1H NMR (300 MHz, DMSO-d6) δ 1.01 (t, 3H, J ) 7.5
Hz), 2.68 (q, 2H, J ) 7.5 Hz), 3.43 (br s, 2H), 3.40 (s, 2H), 3.70
(s, 3H), 5.32 (s, 2H), 6.61 (dd, 1H, J ) 2.3, 8.7 Hz), 6.89-7.25
(m, 7H); 13C NMR (75 MHz, DMSO-d6) δ 15.1, 18.0, 32.0, 46.4,
56.0, 101.5, 105.9, 110.5, 110.7, 126.5, 127.4, 128.8, 129.0, 131.7,
139.4, 141.0, 154.0, 173.4; MS m/z (M+) 322. Anal. Calcd for
C
20H22N2O2: C, 74.51; H, 6.88; N, 8.69. Found: C, 74.47; H,
7.01; N, 8.55.
3-(Am id om e t h yl)-2-e t h yl-1-(p h e n ylm e t h yl)-1H -5-h y-
d r oxyin d ole (11). The amide 10 (50.0 g, 0.16 mol) was
3-(Ca r bom eth oxy)-2-eth yl-1-(p h en ylm eth yl)-1H-5-m eth -
oxyin d ole (7). Indole 2 (106 g, 0.35 mol) and (n-Bu)4NBr (11.3
g, 0.035 mol) were placed in H2O (1 L) to which was then added
50% aqueous NaOH (333 mL) followed by MeI (148 g, 1.04 mol).
The resulting heterogeneous mixture was brought to reflux,
whereupon a dark brown solution was obtained. After 30 min
at reflux, the reaction was cooled to ambient temperature and
extracted with EtOAc (3 × 900 mL). The combined organic
phase was washed with brine and dried (MgSO4) to yield
methoxyindole 7 as a crude tan solid (115.4 g). Recrystallization
from i-PrOH afforded a colorless crystalline solid (90.5 g, 80%):
mp 102-3 °C; TLC (hexane/EtOAc (3:1)) Rf 0.58; IR (CHCl3,
cm-1) 3013, 1690, 1479, 1462, 1169; UV (EtOH) 289 (12 000),
244 (19 600), 216 (34 100); 1H NMR (300 MHz, DMSO-d6) δ 1.07
(t, 3H, J ) 7.4 Hz), 3.12 (q, 2H, J ) 7.4 Hz), 3.80 (s, 3H), 3.86
(s, 3H), 5.52 (s, 2H), 6.80-7.56 (m, 8H); 13C NMR (75 MHz,
DMSO-d6) δ 14.3, 19.3, 46.4, 51.1, 55.8, 102.7, 103.7, 103.9,
111.9, 126.5, 127.4, 127.8, 129.2, 131.5, 138.0, 151.4, 155.8, 165.9;
MS m/z (M+) 323. Anal. Calcd for C20H21NO3: C, 74.28; H, 6.55;
N, 4.33. Found: C, 74.61; H, 6.73; N, 4.51.
3-(Hydr oxym eth yl)-2-eth yl-1-(ph en ylm eth yl)-1H-5-m eth -
oxyin d ole (8). The indole ester 7 (130 g, 0.40 mol) was
dissolved in THF (300 mL) and added dropwise to a slurry of
LAH (46 g, 1.2 mol) in THF (900 mL) at 0 °C under N2. After
the mixture was stirred for 4 h at 0 °C, water (46 mL) was added
slowly with efficient stirring, followed by 15% NaOH (46 mL)
and then water (138 mL). After filtration of the aluminum salts,
the filtrate was dried and concentrated to yield (hydroxymethyl)-
indole 8 as a colorless solid (93 g, 78%): mp 69-70 °C; TLC
(hexane/EtOAc (3:1)) Rf 0.20; IR (CHCl3, cm-1) 3010, 1485, 1454,
dissolved in CH2Cl2 (500 mL) and treated dropwise with 1.0 M
BBr3 in CH2Cl2 (470 mL, 0.47 mol) at 0 °C under N2. After being
stirred for 2 h, the mixture was diluted with CH2Cl2, washed
successively with water, saturated aqueous NH4Cl solution, and
brine, and dried (Na2SO4). After removal of the volatiles, 39.3
g of a light tan semisolid was obtained in 80.2% yield: TLC
(EtOAc) R
f 0.41; IR (CHCl3, cm-1) 3010, 2973, 1668, 1574, 1481,
1
1376; UV (EtOH) 283 (8200); H NMR (300 MHz, DMSO-d6) δ
1.05 (t, 3H, J ) 7.5 Hz), 2.72 (q, 2H, J ) 7.5 Hz), 3.43 (s, 2H),
5.32 (s, 2H), 6.54-7.29 (m, 10H), 8.66 (s, 1H); 13C NMR (75 MHz,
DMSO-d
6) δ 15.3, 18.0, 32.1, 46.4, 103.4, 105.3, 110.4, 111.0,
126.6, 127.4, 127.6, 129.2, 131.1, 139.5, 140.7, 151.3, 173.6; MS
m/z (M+) 308; HRMS calcd for C19H20N2O2 309.1603, found:
309.1610. Anal. Calcd for C19H20N2O2‚H2O: C, 69.92; H, 6.79;
N, 8.58. Found: C, 69.94; H, 7.02; N, 8.18.
Dim eth yl [3-[[3-(Am idom eth yl)-2-eth yl-1-(ph en ylm eth yl)-
1H-in d ol-5-yl]oxy]p r op yl]p h osp h on a te (13). The 5-hydroxy-
indole 11 (7.5 g, 0.023 mol), powdered KOH (4.0 g, 0.070 mol),
(n-Bu)4NBr (0.45 g, 0.0014 mol), and K2CO3 (2.5 g, 0.019 mol)
were combined in DMF (60 mL) at ambient temperature under
N2 for 15 min. A solution of dimethyl (3-bromopropyl)phospho-
nate18 (7.3 g, 0.028 mol) in DMF (25 mL) was added dropwise
and the resulting mixture stirred at ambient temperature for
16 h. The reaction mixture was diluted with CH2Cl2, washed
successively with H2O and brine, and dried (Na2SO4) to afford
10.4 g as a light tan solid (89.2%): mp 118-120 °C; TLC (CH2-
Cl2/i-PrOH (9:1)) Rf 0.29; IR (CHCl3, cm-1) 3007, 1673, 1485,
1040; 1H NMR (300 MHz, DMSO-d6) δ 1.21 (t, 3H, J ) 7.8 Hz),
1.90 (m, 4H), 2.72 (q, 2H, J ) 7.8 Hz), 3.44 (s, 2H), 3.62 (s, 3H),
3.66 (s, 3H), 3.98 (m, 2H), 5.34 (s, 2H), 6.62-7.31 (m, 10H); MS

Notes
J . Org. Chem., Vol. 61, No. 25, 1996 9059
m/z (M+) 458. Anal. Calcd for C24H31N2O5P: C, 62.87; H, 6.82;
N, 6.11. Found: C, 62.72; H, 6.97; N, 6.29.
1 M in hexane) at 0 °C under N2. After 1 h, the reaction was
carefully quenched with 1N HCl (10 mL) and extracted with
EtOAc (2 × 10 mL). The combined organic phase was washed
with 1 N HCl and brine, dried (Na2SO4), and concentrated.
Purification by chromatography over SiO2 (5:1 hexanes:EtOAc)
afforded 263 mg (87%) of the desired symmetrical dimer as a
foam: TLC (hexane/EtOAc (3:1)) Rf 0.50; IR (KBr, cm-1) 3007,
2936, 1618, 1484, 1453; UV (EtOH) 288 (12 600), 228 (36 500);
1H NMR (300 MHz, CDCl3) δ 1.05 (t, 3H, J ) 7.4 Hz), 2.77 (q,
2H, J ) 7.4 Hz), 3.62 (s, 3H), 4.21 (s, 1H), 5.31 (s, 2H), 6.67-
7.26 (m, 8H); 13C NMR (75 MHz, CDCl3) δ 14.6, 18.2, 20.1, 46.6,
55.7, 101.1, 110.0, 110.3, 110.7, 125.9, 127.2, 128.8, 128.9, 131.8,
138.6, 139.2, 153.8; MS m/z (M+) 542; HRMS calcd for C37H38N2O2
542.7276, found: 542.7271.
[3-[[3-(Am idom eth yl)-2-eth yl-1-(ph en ylm eth yl)-1H-in dol-
5-yl]oxy]p r op yl]p h osp h on ic Acid (1). The phosphonate ester
13 (8.75 g, 17.6 mmol) was dissolved in CH2Cl2 (200 mL) and
treated dropwise with TMSI (7.5 mL, 52.7 mmol) at ambient
temperature. After 1.5 h, the volatiles were removed and the
residue was digested in MeOH. After removal of the volatiles,
7.2 g (92.3%) of an off-white solid was obtained. The residue
could be recrystallized from a mixture of EtOAc/CH3CN/HOAc/
H2O (21/7/7/9) to afford 7.0 g as a colorless solid: mp 194-6 °C;
IR (KBr, cm-1) 2962, 1658, 1487, 1226, 1154; 1H NMR (300 MHz,
DMSO-d6) δ 1.04 (t, 3H, J ) 7.8 Hz), 1.75 (m, 2H), 2.00 (m, 2H),
2.81 (q, 2H, J ) 7.8 Hz), 3.42 (br s, 2H), 3.98 (m, 2H), 5.33 (s,
2H), 6.57-7.41 (m, 10H); MS m/z (M+) 430. Anal. Calcd for
C
22H27N2O5P: C, 61.39; H, 6.32; N, 6.51. Found: C, 61.35; H,
Ack n ow led gm en t. The authors would like to thank
Professor Leo Paquette, Professor Ted Taylor, Dr. Ed
Mihelich, and Mr. Nick Bach for helpful discussions.
6.38; N, 6.35.
3,3′-Meth ylbis-[2-eth yl-1-(p h en ylm eth yl)-1H-5-m eth oxy-
in d ole] (18). The alcohol 8 (0.30 g, 1 mmol) was dissolved in
CH2Cl2 (5 mL) and treated dropwise with Et3Al (1 mL, 1 mmol,
J O9614452