Application of palladium (O)-catalyzed processes to the synthesis of oxazole-containing partial ergot alkaloids

Article abstract of DOI:10.1021/jo970374j

Syntheses of the potent 5-HT(1A) agonists 2 and 3 were accomplished in several steps from the 6-iodo partial ergoline alkaloid 8. Disparate tactics available for construction of differentially substituted oxazoles led to the development of new and general methodology critical to the efficient preparations of 2 and 3. A novel palladium(O)- and copper(I)-cocatalyzed cyanation reaction provided efficient access to the nitrile 10, a key intermediate in the synthesis of 2. A palladium(O)-catalyzed cross-coupling reaction of 16 with oxazole-2-lyzinc chloride formed the potent 5-HT(1A) agonist 3.

Full text of DOI:10.1021/jo970374j

8634
J . Org. Chem. 1997, 62, 8634-8639
Articles
Ap p lica tion of P a lla d iu m (0)-Ca ta lyzed P r ocesses to th e Syn th esis
of Oxa zole-Con ta in in g P a r tia l Er got Alk a loid s
Benjamin A. Anderson,* Lisa M. Becke, Richard N. Booher,‡ Michael E. Flaugh,‡
Nancy K. Harn, Thomas J . Kress, David L. Varie, and J ames P. Wepsiec
Lilly Research Laboratories, A Division of Eli Lilly and Company, Chemical Process Research and
Development Division and Neuroscience Discovery Research, Indianapolis, Indiana 46285-4813
Received February 27, 1997X
Syntheses of the potent 5-HT1A agonists 2 and 3 were accomplished in several steps from the 6-iodo
partial ergoline alkaloid 8. Disparate tactics available for construction of differentially substituted
oxazoles led to the development of new and general methodology critical to the efficient preparations
of 2 and 3. A novel palladium(0)- and copper(I)-cocatalyzed cyanation reaction provided efficient
access to the nitrile 10, a key intermediate in the synthesis of 2. A palladium(0)-catalyzed cross-
coupling reaction of 16 with oxazol-2-ylzinc chloride formed the potent 5-HT1A agonist 3.
When appropriately substituted at the 6-position, the
of efficient preparation of the two drug candidates, 2 and
3. Substituted tricyclic partial ergolines 1 have been
prepared from the Kornfeld-Woodward ketone 4 (eq
1).2a,4 Lilly workers have recently reported an enan-
partial ergolines 1 are potent serotonin agonists at the
5-HT1A receptor. Among the earliest examples of these
agents are the 6-methoxy compound 1a and the 6-car-
boxamido compound 1b.1 Later, 6-acyl derivatives such
as 1c were also found to have powerful serotonergic
activity. Extensive pharmacological studies on both 1b
and 1c have been conducted.2 More recently, derivatives
containing various heterocyclic functionalities at the
6-position were identified which exhibit strong seroton-
ergic activity.3 Connection of an oxazole either through
its 5 or 2 position to the partial ergot alkaloid framework
led to compounds 2 and 3, both of which exhibit particu-
larly interesting 5-HT1A agonist activity.
tiospecific synthesis of 5, a key indoline precursor to
optically pure 1b.4a,b With access to 5 thus provided, our
efforts focused on the selective functionalization of this
advanced intermediate. The development of new meth-
odology proved critical to the efficient preparations of 2
and 3. Most notably, we were challenged with adapting
key palladium(0)-catalyzed coupling processes to ensure
safe and reproducible production of the desired targets.
The strategies required to produce the structurally
similar candidates 2 and 3 were governed by the dispar-
ate methodologies available for construction of the two
oxazoles.5 5-Aryl oxazoles may be prepared by the
condensation of an aryl aldehyde with tosylmethyl iso-
cyanide (TosMIC) (eq 2).6 This reaction was expected to
The clinical potential of the oxazolyl ergoline deriva-
tives prompted our investigation into the development
‡ Neuroscience Discovery Research.
X Abstract published in Advance ACS Abstracts, November 1, 1997.
(1) (a) Flaugh, M. E.; Mullen, D. L.; Fuller, R. W.; Mason, N. R. J .
Med. Chem. 1988, 31, 1746. (b) Kruse, L. I.; Meyer, M. D. J . Org. Chem.
1984, 49, 4761.
(2) (a) Foreman, M. M.; Fuller, R. W.; Leander, J . D.; Wong, D. T.;
Nelson, D. L.; Calligaro, D. O.; Swanson, S. P.; Lucot, J . B.; Flaugh,
M. E. J . Pharmacol. Exp. Ther. 1993, 260, 51. (b) Foreman, M. M.;
Fuller, R. W.; Rasmussen, K.; Nelson, D. L.; Calligaro, D. O.; Zhang,
L.; Barrett, E.; Booher, R. N.; Paget, C. J ., J r.; Flaugh, M. E. J .
Pharmacol. Exp. Ther. 1994, 270, 1270.
(3) Booher, R. N.; Flaugh, M. E.; Lawhorn, D. E.; Martinelli, M. J .;
Paget, C. J ., J r.; Schaus, J . M. U.S. Patent 5 347 013, 1994.
(4) (a) Leanna, M. R.; Martinelli, M. J .; Varie, D. L.; Kress, T. J .
Tetrahedron Lett. 1989, 30, 3953. (b) Martinelli, M. J .; Leanna, M. R.;
Varie, D. L.; Peterson, B. C.; Kress, T. J .; Wepsiec, J . P.; Khau, V. V.
Tetrahedron Lett. 1990, 31, 7579. (c) Carr, M. A.; Creviston, P. E.;
Hutchison, D. R.; Kennedy, J . H.; Khau, V. V.; Kress, T. J .; Leanna,
M. R.; Marshall, J . D.; Martinelli, M. J .; Peterson, B. C.; Varie, D. L.;
Wepsiec, J . P. J . Org. Chem. 1997, 62, 8640. (d) For a synthesis utili-
zing a synthon other than the Kornfeld-Woodward ketone, see ref 1b.
serve as a key step in the synthesis of 2; however, this
methodology does not accommodate the preparation of
2-substituted oxazoles such as 3. Preliminary experi-
ments indicated that related cyclodehydration strategies
would also be ineffective for the synthesis of 3 (eq 3).7
The convergent cross-coupling approach detailed herein
was therefore pursued (eq 4). Despite these strategic
differences, a parallel development of 2 and 3 demanded
(5) (a) Turchi, I. J . In Heterocyclic Compounds; Turchi, I. J ., Ed.;
Wiley & Sons: New York, 1986; Vol. 45, Chapter 1. (b) Turchi, I. J .;
Dewar, M. J . S. Chem. Rev. (Washington, D.C.) 1974, 75, 389-437.
S0022-3263(97)00374-5 CCC: $14.00 © 1997 American Chemical Society

Pd-Catalyzed Synthesis of Ergot Alkaloids
J . Org. Chem., Vol. 62, No. 25, 1997 8635
(0) have been reported.10 Oxygen sensitivity of the
catalyst was implicated as the source of reproducibility
problems in the present case. When conducted under a
nitrogen atmosphere but in solvents that were not
previously deoxygenated, cyanation of 9 proceeded at the
inconsistent rates described above. Less than 10%
conversion occurred when a deoxygenated solvent was
employed; however, brief introduction of a subsurface
purge of air into the reaction mixture initiated the
transformation. When conducted in solvent that had
been presaturated with oxygen, cyanation of 9 was
complete within 24 h.11 To our knowledge, this sensitiv-
ity of the Pd(PPh3)4-catalyzed cyanation reaction to
oxygen has not been previously reported.12 We postulate
that oxygen served to enhance the activity of the catalyst
and/or catalyst precursor by oxidatively depleting inhibi-
tory quantities of the triphenylphosphine ligand. Similar
initiating effects by oxygen have been reported for related
palladium(0)-catalyzed cross-coupling processes.13
the identification of an advanced intermediate that could
be employed in the preparation of both targets.
Resu lts a n d Discu ssion
Catalytic amounts of CuI are reported to enhance
reaction rates of the Stille reaction, in part by competing
with palladium for the phosphine ligands.14 We consid-
ered addition of CuI a more controlled method for catalyst
modification than introduction of oxygen. Iodide 9 was
converted to 10 in 3 h when the reaction was conducted
in deoxygenated solvent employing 5 mol % of Pd(PPh3)4
and 10 mol % of CuI in 67% yield after recrystallization
(Table 1).15 Small quantities of 11 (<2%) were sometimes
observed and represented the only detectable side prod-
uct generated in the reaction. Conversion to 10 was not
observed when the reaction was carried out in the
absence of the palladium catalyst (KCN, 10 mol % of CuI,
THF, reflux).16 The accelerating effect of copper salts on
palladium(0)-catalyzed cyanation appears to be general
and is currently being evaluated in greater detail.
Deprotection of 10 was typically conducted on unpu-
rified material by hydrolysis with sodium hydroxide in
ethanol to give 11 in 97% yield from 9. Analytically pure
indoline was separated from the contaminating species,
benzoate and triphenylphoshine, by extraction with 1 N
HCl. Manganese dioxide oxidized 11 to 12 in 70%
yield.4b,c,17 Treatment of 12 with DIBALH provided 13
in 90% yield. Reaction of 13 with TosMIC and 3 equiv
of sodium methoxide in refluxing methanol for 5 h
provided the desired oxazole 2 in 81% yield.
Syn th esis of th e 5-Oxa zole Der iva tive 2. As il-
lustrated above (eq 2), preparation of the 5-oxazole
derivative 2 employing a condensation reaction with
TosMIC required access to the corresponding carboxal-
dehyde 13. Preparation of 13 was accomplished in six
steps from the optically active intermediate 5 in 35%
overall yield (Scheme 1). Selective C-6 iodination of 5
was accomplished originally by use of N-iodosuccinimide
(NIS). The combination of I2 and H5IO6 in a water-acetic
acid-sulfuric acid solution proved more desirable for
application on multikilogram scale.8 N-Propyl iodide and
potassium carbonate readily effected double alkylation
of the primary amine 8. The alkylation reaction was
allowed to progress to the point at which slight quantities
of quaternized nitrogen were generated. Otherwise,
purification difficulties were encountered due to contami-
nation by small amounts of the monoalkylated product.
This protocol significantly simplified product purification
since the tetra-n-propylammonium species was easily
removed by aqueous washes.
The indoline 10 has been prepared by cyanation of the
6-bromo derivative analogous to 9 employing Rosen-
mund-von Braun conditions (CuCN, NMP, 200 °C,
76%).4b High reaction temperatures, copper waste, and
moderate yields led us to consider an alternate protocol.
We chose to evaluate a transition metal-catalyzed pro-
cess. Complete conversion of 9 to 10 was accomplished
employing the Sekiya-Ishikawa protocol (KCN, Pd-
(PPh3)4, THF, reflux),9 furnishing the desired product
under moderate conditions but with inconsistent reaction
rates (12-48 h).
(10) (a) Tschaen, D. M.; Desmond, R.; King, A. O.; Fortin, M. C.;
Pipik, B.; King, S.; Verhoeven, T. R. Synth. Commun. 1994, 24, 887.
(b) Takagi, K.; Sasaki, K.; Sakakibara, Y. Bull. Chem. Soc. J pn. 1991,
64, 1118. (c) Chatani, N.; Hanafusa, T. J . Org. Chem. 1986, 51, 4714.
(d) Davison, J . B.; Peerce-Landers, P. J .; J asinski, R. J . J . Electrochem.
Soc. 1983, 130, 1862. (e) Prochazka, H.; Siroky, M. Collect. Czech.
Chem. Commun. 1983, 48, 1765.
(11) Triphenylphosphine oxide was observed in the reaction mix-
tures by HPLC only in cases where the cyanation reaction was
successful.
(12) Decreased yields have been reported for cyanation reactions
employing [11C]KCN and aged, dilute solutions of Pd(PPh3)4. Ander-
sson, Y.; La˚ngstro¨m, B. J . Chem. Soc., Perkin Trans. 1 1994, 1395.
(13) Farina, V.; Roth, G. P. Adv. Met.-Org. Chem. 1996, 5, 1-53.
(14) Farina, V.; Kapadia, S.; Krishnan, B.; Wang, C.; Liebeskind,
L. S. J . Org. Chem. 1994, 59, 5905.
A variety of modifications designed to improve the
limited scope and modest reliability of cyanation reac-
tions catalyzed by tetrakis(triphenylphosphine)palladium-
(15) The use of excess CuI in the presence of crown ethers has been
reported to be beneficial to the tetrakis(triphenylphosphine)palladium-
(0)-catalyzed cyanation reactions of bromopyrazines: Sato, N.; Suzuki,
M. J . Heterocycl. Chem. 1987, 24, 1371. This protocol does not
circumvent purification problems associated with liberation of the
product from the metal waste.
(16) Aryl halides have been converted to the corresponding aryl
nitriles using KCN and catalytic CuI but at high reaction temperatures
over extended time periods. Carr, R. M.; Cable, K. M.; Wells, G. N.;
Sutherland, D. R. J . Labeled Compd. Radiopharm. 1994, 34, 887.
(17) Preparation of 12 was also accomplished by dehydration of 1b
(POCl3, CH3CN, >95%).
(6) van Leusen, A. M.; Hoogenboom, B. E.; Siderius, H. Tetrahedron
Lett. 1972, 2369.
(7) None of the typical reagent combinations (e.g. PBr3, PI3, TM-
SOTf) effected cyclodehydration of the hemiacetal precursor 6 to the
oxazole product 7. This observation is consistent with literature
precedent that suggests such strategies are typically problematic for
the preparation of 4,5-unsubstituted oxazoles (ref 5). For an exception,
see: Moeller, H. German Patent 4 233 771, 1994.
(8) Suzuki, H.; Nakamura, K.; Goto, R. Bull. Chem. Soc. J pn. 1966,
39, 128.
(9) Sekiya, A.; Ishikawa, N. Chem. Lett. 1975, 277.

8636 J . Org. Chem., Vol. 62, No. 25, 1997
Anderson et al.
Sch em e 1a
a
Key: (a) I2, H5IO6, H2O, AcOH, H2SO4 (90%); (b) K2CO3, n-PrI, CH3CN (83%); (c) KCN, Pd(PPh3)4, CuI, THF; (d) NaOH, EtOH (97%);
(e) MnO2, AcOH4b (70%); (f) DIBALH, toluene (90%); (g) NaOMe, TosMIC, MeOH (81%).
Ta ble 1. Effect of Cu I on Cya n a tion Rea ction a
in one step.18 Employing similar conditions (t-BuOK/
H2O/THF), formation of 15 and 16 was observed by HPLC
although 16 was only a minor product (15%). The
debenzoylation and indoline oxidation were therefore
effected in two steps (Scheme 2). Deprotection of 9 was
accomplished by treatment with sodium hydroxide in
ethanol. Oxidation with manganese dioxide in dichlo-
romethane (23 °C, 24 h) provided a 92% yield of 16.
Alternatives to the MnO2 oxidation were explored since
eliminating the copious metal waste was desirable.
Several methods (e.g. DDQ, chloranil, DMSO/oxalyl
chloride) accomplished the transformation with variable
success. Swern conditions were considered most advan-
tageous owing to the efficiency of the reaction and the
water solubility of the byproducts. The low-temperature
DMOS/oxalyl chloride protocol provided the desired
oxidation product 16 in 63% yield but was complicated
by a competing electrophilic aromatic substitution reac-
tion which led to the production of 17 in 10% yield (eq
6).19
iodide
product
addend
time, h
% convnb
9
9
16
16
10
10
12
12
10 mol % of CuI
none
10 mol % of CuI
none
3
100
100
100
∼25
12-48
3
20
2 equiv of KCN, 5 mol % of Pd(PPh3)4, THF. b Calculated using
a
uncorrected HPLC values.
The optimal point for oxidation of the indoline to indole
was given careful consideration. The nature of the
substituent at the 6 position significantly influences the
efficiency of this oxidation. Preliminary experiments
evaluated the option of oxidizing the indoline 14 after
installation of the oxazole group. Oxidation of 14 was
accomplished by use of selenous acid in 50% yield (eq 5).
The reaction was only moderately successful, and the
selenous acid was considered unacceptable because of
contamination concerns. Other methods, such as MnO2
or Pd/C, were either ineffective or complicated by com-
peting reactions. Therefore, installation of the oxazole
group after oxidation as described above was preferred.
Although a reliable route to 2 was established, stra-
tegic issues prompted further refinement since maximal
overlap of synthetic steps common to production of 2 and
3 was not achieved. Conducting the cyanation reaction
prior to conversion to the desired indole was a costly
divergence since a related oxidation would also need to
be accomplished in the synthesis of 3. The sequence
described in Scheme 1 was modified to effect deprotection
and oxidation prior to cyanation (Scheme 2). This
transposition of steps represents two strategic advan-
tages. Most notably, 16 is the most desirable coupling
partner for the convergent cross-coupling approach to the
preparation of 3. The revision would also have the
beneficial effect of reducing the molecular weight of
material forward processed in the synthesis of 2 by early
stage cleavage of the N-benzoyl protecting group.
Interception of the original synthetic route was ac-
complished by a palladium(0)-catalyzed cyanation reac-
tion of 16. The accelerating effect of cocatalytic CuI was
once again demonstrated as complete conversion to 12
was accomplished within 3 h (Table 1). A cyanation
reaction conducted under identical conditions without
CuI resulted in only ∼25% conversion after 20 h. Prepa-
ration of 2 from 5 via the intermediate 16 was achieved
in seven steps and in 48% overall yield.
Syn th esis of th e 2-Oxa zole Der iva tive 3. In our
parallel development of 2 and 3, we envisioned 16 as a
critical intermediate in the preparation of both targets.
While 16 effectively provided access to 2, the intermedi-
ate also proved advantageous in a convergent preparation
of 3 (Scheme 2). The oxazole substituent was introduced
(18) Rebek, J .; Tai, D. F.; Shue, Y.-K. J . Am. Chem. Soc. 1984, 106,
1813.
Literature precedent suggested the possibility of con-
verting the protected indoline 9 directly to the indole 16
(19) Keirs, D.; Overton, K. J . Chem. Soc., Chem. Commun. 1987,
1660.

Pd-Catalyzed Synthesis of Ergot Alkaloids
J . Org. Chem., Vol. 62, No. 25, 1997 8637
Sch em e 2a
a
Key: (a) NaOH, EtOH (78%); (b) MnO2, CH2Cl2 (92%); (c) KCN, 5 mol % of Pd(PPh3)4, 10 mol % of CuI, THF (89%).
directly onto the partial ergot framework by a cross-
coupling reaction of 16 with a suitably activated oxazole.
variety of aryl halides, as well as aryl and vinyl triflates.25
Oxazol-2-ylzinc derivatives have furthermore been dem-
onstrated as useful intermediates for the preparation of
2-acyloxazole derivatives.26
The iodoindoline 9 reacted with oxazol-2-ylzinc chloride
to give the oxazole product in 52% yield.25a Oxidation of
the indoline with MnO2 after debenzoylation afforded
only 37% of the indole, further prompting development
of the strategies summarized above.
Trialkyltin derivatives of substituted oxazoles can be
successfully coupled to aryl iodides in the presence of Pd-
(PPh3)4.20 A brief examination of this reaction (eq 4: ArX
) 16; M ) SnBu3) demonstrated the viability albeit a
clear need for optimization. Despite the modest yield of
the reaction (11%), the most serious concern was the
generation of stoichiometric quantities of trialkyltin
byproducts. The potential for toxic alkyltin contamina-
tion of the final product ultimately precluded its use.21
Con clu sion
The palladium(0)-catalyzed coupling of a zinc deriva-
tive was investigated as an alternative. Cross-coupling
reactions of organozinc reagents are well-known and have
been demonstrated to accommodate functionalities such
as acidic amides.22 Functional group compatibility was
an important consideration given the presence of the
unprotected indole nitrogen present in 16.
We have developed syntheses of the potent 5-HT1A
agonists 2 and 3 utilizing 16 as an advanced intermediate
common to both syntheses. Selective C-6 iodination of
the partial ergot alkaloid 5 was accomplished in high
yield, providing the precursor to 16. A novel palladium-
(0)- and copper(I)-cocatalyzed cyanation reaction, which
eliminated harsh reaction conditions and excessive cop-
per waste, was developed to provide efficient and repro-
ducible access to the key intermediate 12. The desired
5-substituted oxazole 2 was produced by a condensation
reaction employing tosylmethyl isocyanide.
In the event, oxazol-2-ylzinc chloride was prepared by
the addition of excess zinc chloride to a solution of oxazol-
2-yllithium.23 Indole 16 was added to the resulting
mixture along with the palladium(0) catalyst prepared
from Cl2Pd(PPh3)2/2 equiv of n-BuLi (eq 7).24 Conversion
In a generally valuable method for the C-2 elaboration
of oxazoles, an organozinc derivative of the unsubstituted
oxazole was coupled with 16 in the presence of a pal-
ladium(0) catalyst to provide the desired product 3. The
syntheses of both 2 and 3 were achieved by cross-coupling
methodology and provided new insights into these fun-
damental processes. Not only should the methods re-
ported here for the manipulation of partial ergot alkaloids
provide a general strategy for the preparation of related
pharmacologically active agents but the palladium(0)-
catalyzed methodologies should find general application.
to the desired product 3 was accomplished after 1 h (THF,
reflux) in 54% yield. No improvement in yield was
achieved when excess oxazol-2-ylzinc chloride was em-
ployed. Not only did this one-pot method eliminate the
potential of toxic alkyltin contamination of 3 but it
circumvented the inconvenient isolation typically re-
quired of 2-stannyloxazoles.
Exp er im en ta l Section
All starting materials were commercially available, except
for 5 which was prepared by the reported method.4b Oxazole
may be prepared by the method of Brederick and Bangert.27
Reactions were routinely performed under an inert atmosphere
(N2). Where noted, THF was deoxygenated by a subsurface
N2 purge for 1 h immediately prior to use. Evaporation of
solvents was accomplished by rotary evaporation at 10-20
Torr.
The cross-coupling reaction of the oxazol-2-ylzinc chlo-
ride reagent developed for this synthesis has been
investigated in detail by us and others, and the reagent
was shown to be an efficient coupling partner with a
(20) Dondoni, A.; Fantin, G.; Fogagnolo, M.; Medici, A.; Pedrini, P.
Synthesis 1987, 693.
(21) Barnes, J . M.; Stoner, H. B. Pharmacol. Rev. 1959, 11, 211.
(22) (a) Knochel, P.; Singer, R. D. Chem. Rev. (Washington, D.C.)
1993, 93, 2117. (b) Erdik, E. Tetrahedron 1992, 44, 9577.
(23) Efforts to prepare and cross-couple the 2-boronic acid derivative
of oxazole were unsuccessful.
(24) Negishi, E.; Takahashi, T.; Akiyoshi, K. J . Chem. Soc., Chem.
Commun. 1986, 1338.
(25) (a) Anderson, B. A.; Harn, N. K. Synthesis 1996, 583. (b) Crowe,
E.; Hossner, F.; Hughes, M. J . Tetrahedron 1995, 51, 8889.
(26) Harn, N. K.; Gramer, C. J .; Anderson, B. A. Tetrahedron Lett.
1995, 36, 9453.
(27) Bredereck, H.; Bangert, R. Angew. Chem., Int. Ed. Engl. 1962,
1, 662.

8638 J . Org. Chem., Vol. 62, No. 25, 1997
Anderson et al.
1-Ben zoyl-6-iodo-1,2,2a,3,4,5-h exah ydr oben z[cd]in dole-
4-a m in e (8). H2SO4 (4.4 g, 45 mmol) was added dropwise to
a solution of 5 (10 g, 36 mmol) in 1:1 acetic acid/water (50 mL).
Periodic acid (2.2 g, 9.6 mmol) and I2 (4.8 g, 18.9 mmol) were
added in rapid succession. The solution was heated at 60 °C
for 1 h. With vigorous agitation, a 20% NaHSO3 solution (10
mL) was added to the warm mixture. After the solution was
cooled with an ice bath, CH2Cl2 (50 mL) was added and the
pH adjusted to 12 with a 10 N NaOH solution (60 mL). The
two-phase mixture was warmed to rt, and CH2Cl2 (50 mL) was
added. The organic layer was isolated, and the aqueous layer
was extracted once with CH2Cl2. The extracts were combined
and dried over anhydrous Na2SO4. CH3CN (70 mL) was added,
and a solvent exchange to CH3CN was affected. A mixture
with a yellow precipitate resulted, and it was cooled at -15
°C overnight. The mixture was filtered cold, and the solid was
rinsed twice with cold CH3CN (30 mL). Then 13.1 g (90%
mL). The mixture was heated at reflux for 30 min. After the
solution was cooled to rt, the solvent was evaporated. The
resulting solid was dissolved in tert-butyl methyl ether (100
mL), and the solution was washed with water. The product
was extracted from the organic phase with 1 N HCl solution.
The acidic phase was neutralized with a 5 N NaOH solution
and then extracted with CH2Cl2. The combined organic
extracts were dried over anhydrous Na2SO4 and concentrated
to give 3.7 g of 11 as a pale orange solid (g97% yield): mp
115-116 °C; IR (KBr) 2210 cm-1; 1H NMR (500 MHz, CDCl3)
δ 7.29 (d, J ) 8.0 Hz, 1 H), 6.41 (d, J ) 8.1 Hz, 1 H), 4.17 (s,
1 H), 3.77 (t, J ) 7.4 Hz, 1 H), 3.22 (m, 3 H), 3.05 (dd, J ) 6.2,
17.8 Hz, 1 H), 2.66 (m, 1 H), 2.48 (m, 4 H), 2.22 (m, 1 H), 1.47
(m, 5 H), 0.91 (t, J ) 7.3 Hz, 6 H); 13C NMR (75 MHz, CDCl3)
δ 154.1, 137.4, 134.0, 130.8, 119.3, 105.8, 99.5, 57.4, 55.8, 52.8,
38.9, 29.6, 27.5, 22.6, 11.9; MS m/z 283 (M+). Anal. Calcd for
C18H25N3: C, 76.28; H, 8.89; N, 14.82. Found: C, 76.65; H,
9.11; N, 14.75.
yield) of 8 was obtained: mp 178-180 °C; IR (KBr) 1640 cm-1
;
1H NMR (300 MHz, CDCl3) δ 7.55 (m, 7 H), 4.27 (broad s, 1
H), 3.70 (t, J ) 15 Hz, 1 H), 3.30 (m, 2 H), 3.05 (dd, J ) 17 Hz,
J ) 6 Hz, 1 H), 2.18 (m, 2 H), 1.30 (q, J ) 12 Hz, 1H); 13C
NMR (75 MHz, CDCl3) δ 168.5, 141.8, 137.7, 136.8, 136.2,
136.2, 134.5, 130.8, 128.6, 127.4, 115.9, 92.4, 58.1, 49.2, 42.8,
38.1, 36.8; MS m/z 404 (M+). Anal. Calcd for C18H17IN2O2:
C, 53.48; H, 4.24; N, 6.93. Found: C, 53.20; H, 4.11; N, 6.64.
1-Be n zoyl-1,2,2a ,3,4,5-h e xa h yd r o-6-iod o-N ,N -d ip r o-
p ylben z[cd ]in d ole-4-a m in e (9). The primary amine 8 (100
g, 0.25 mol), potassium carbonate (137 g, 1.0 mol), and
1-iodopropane (97 mL, 1.0 mol) were slurried together in CH3-
CN (1 L). The heterogeneous reaction mixture was warmed
to approximately 75 °C and stirred for 17 h. The mixture was
cooled to room temperature, and water (500 mL) and tert-butyl
methyl ether (500 mL) were added. The organic layer was
separated and washed with water. CH3CN (500 mL) was
added to the organic layer, and the volume was reduced in
half by evaporation. A small amount of precipitated black
solids was removed by hot gravity filtration. The filtrate was
cooled to rt, and orange crystals formed. The mixture was
filtered cold, and the solid was rinsed twice with cold CH3CN
(75 mL). 9 (100 g, 83% yield) was obtained: mp 109-110 °C;
1,2,2a ,3,4,5-Hexa h yd r o-6-iod o-N,N-d ip r op ylben z[cd ]in -
d ole-4-a m in e (15). To a slurry of the indoline 9 (10 g, 20.5
mmol) in EtOH (100 mL) was added a 5 N NaOH solution (41
mL, 205 mmol). The mixture was refluxed for 2 h, and the
resulting solution was allowed to cool to rt overnight. The
EtOH was evaporated, and EtOAc (150 mL) was added. The
solution was washed with water, dried over anhydrous Na2-
SO4, and evaporated to give a brown gum (7.5 g). Chroma-
tography on silica gel (EtOAc) yielded 6.2 g (78%) of 15 as a
brown oil: 1H NMR (500 MHz, CDCl3) δ 7.38 (d, J ) 8.0 Hz,
1 H), 6.27 (d, J ) 8.0 Hz, 1 H), 3.66 (m, 2 H), 3.14 (m, 3 H),
2.76 (m, 2 H), 2.43 (m, 4 H), 2.15 (m, 2 H), 1.48 (m, 4 H), 0.91
(t, J ) 7.0 Hz, 6 H); 13C NMR (75 MHz, CDCl3) δ 169.0, 150.5,
137.1, 132.6, 108.9, 85.8, 60.6, 58.5, 56.0, 52.9, 39.9, 34.6, 29.3,
22.6; MS m/z 384 (M+). Anal. Calcd for C17H25IN: C, 53.13;
H, 6.56; N, 7.29; I, 33.02. Found: C, 53.34; H, 6.47; N, 7.35;
I, 33.00.
6-Iod o-N,N-d ip r op ylben z[cd ]in d ole-4-a m in e (16).
A
solution of the indoline 15 (78.0 g, 0.2 mol) in CH2Cl2 (1 L)
was stirred with MnO2 (100 g, 1.15 mol) for 24 h. The mixture
was vacuum filtered through Celite. Chromatography on a
Prep 500 column using toluene, then 3% EtOAc in toluene,
and ending with 5% EtOAc in toluene yielded 71.9 g (92%) of
16 as an orange oil.
Alter n a te Syn th esis. To a solution of oxalyl chloride (0.28
g, 2.2 mmol) in CH2Cl2 (2 mL) at -60 °C was added via syringe
DMSO (0.34 g, 4.4 mmol) in CH2Cl2 (0.6 mL). After 5 min,
indoline 15 (0.76 g, 2.0 mmol) in CH2Cl2 (1 mL) was added
via syringe. After 10 min, triethylamine (1.0 g, 9.9 mmol) was
added. The cold bath was removed and the mixture allowed
to warm to rt. Water (4 mL) was added, the organic layer was
separated, and the aqueous was extracted with CH2Cl2. The
combined extracts were washed with brine, dried over anhy-
drous MgSO4, and evaporated to give a brown oil (0.70 g).
Chromatography on silica gel (4:1 hexane/EtOAc) yielded 0.48
g (64%) of 16 and 0.09 g (10%) of 17.
1
IR (KBr) 1638 cm-1; H NMR (300 MHz, CDCl3) δ 7.50 (m, 7
H), 4.28 (broad s, 1 H), 3.66 (t, J ) 11.0 Hz, 1 H), 3.34 (m, 1
H), 3.20 (m, 1 H), 2.81 (dd, J ) 6 Hz, J ) 18 Hz, 1 H), 2.47 (m,
5 H), 2.16 (m, 1 H), 1.38 (m, 5 H), 0.91 (t, J ) 7 Hz, 6 H); 13C
NMR (75 MHz, CDCl3) δ 168.6, 141.7, 137.9, 137.6, 137.6,
136.3, 130.7, 128.6, 127.4, 106.8, 93.3, 58.0, 52.9, 38.5, 35.1,
29.1, 22.6, 11.9; MS m/z 488 (M+). Anal. Calcd for C24H29
-
IN2O: C, 59.02; H, 5.99; N, 5.74. Found: C, 59.03; H, 5.87;
N, 5.64.
1-Ben zoyl-6-cya n o-1,2,2a ,3,4,5-h exa h yd r o-N,N-d ip r o-
p ylben z[cd ]in d ole-4-a m in e (10). The iodide 9 (0.63 g, 1.29
mmol), pulverized anhydrous KCN (0.092 g, 1.42 mmol), Pd-
(PPh3)4 (0.075 g, 0.065 mmol), and CuI (0.024 g, 0.126 mmol)
were placed in a flask which was maintained under vacuum
for 1 h. After the solution was flushed with N2, deoxygenated
THF (6.5 mL) was added via syringe. The resulting mixture
was refluxed under N2 for 3 h. After the solution was cooled
to rt, EtOAc (30 mL) was added and the mixture was filtered
through Celite. The filtrate was washed with water and brine,
dried over anhydrous MgSO4, and evaporated to an oil (0.57
g, 114% recovery). Compound 10 was typically used directly
in the next step without purification. An analytically pure
sample was prepared by recrystallization from isopropyl
alcohol to yield a gray solid (67% yield): mp 110-111 °C; IR
(KBr) 2212, 1624 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.52 (m,
7 H), 4.34 (m, 1 H), 3.72 (t, J ) 11.1 Hz, 1 H), 3.33 (m, 1 H),
3.25 (m, 1 H), 3.13 (m, 1 H), 2.74 (dd, J ) 10 Hz, J ) 18 Hz,
1 H), 2.47 (m, 4 H), 2.28 (m, 1 H), 1.47 (m, 5 H), 0.90 (t, J )
7 Hz, 6 H); 13C NMR (125 MHz, CDCl3) δ 169.5, 145.4, 138.7,
136.1, 134.6, 133.7, 131.6, 129.1, 127.8, 118.1, 114.3, 106.7,
58.9, 57.2, 53.1, 38.1, 29.7, 28.1, 22.9, 12.2; MS m/z 283 (M+).
Anal. Calcd for C18H25N3: C, 77.48; H, 7.54; N, 10.84.
Found: C, 77.55; H, 7.49; N, 10.74.
16: 1H NMR (500 MHz, CDCl3) δ 7.88 (broad s, 1 H), 7.46
(d, J ) 8.4 Hz, 1 H), 6.94 (d, J ) 8.4 Hz, 1 H), 6.82 (s, 1 H),
3.26 (m, 1 H), 2.91 (m, 4 H), 2.59 (m, 4 H), 1.51 (m, 4 H), 0.92
(t, J ) 7.3 Hz, 6 H); 13C NMR (125 MHz, CDCl3) δ 135.4, 133.2,
131.7, 128.6, 118.1, 113.8, 110.5, 85.5, 58.9, 53.1, 34.6, 24.5,
22.5, 11.9; MS m/z 382 (M+). Anal. Calcd for C17H23IN2: C,
53.41; H, 6.06; N, 7.33. Found: C, 53.37; H, 5.96; N, 7.19.
17: 1H NMR (500 MHz, CDCl3) δ 7.23 (s, 1 H), 4.28 (broad
s, 1 H), 3.72 (s, 1 H), 3.55 (q, J ) 13.5, 46.6 Hz, 2 H), 3.16 (m,
3 H), 2.73 (m, 2 H), 2.42 (m, 4 H), 2.16 (m, 2 H), 1.98 (s, 3 H),
1.49 (m, 4 H), 0.91 (t, J ) 7.0 Hz, 6 H); 13C NMR (125 MHz,
CDCl3) δ 149.3, 137.5, 135.8, 132.8, 118.2, 85.3, 58.6, 55.9, 52.9,
39.9, 34.4, 29.3, 22.5, 14.8, 11.8; MS m/z 444 (M+).
6-Cya n o-N,N-d ip r op ylben z[cd ]in d ole-4-a m in e (12). Io-
dide 16 (0.40 g, 1.04 mmol), pulverized anhydrous KCN (0.13
g, 2.0 mmol), Pd(PPh3)4 (0.057 g, 0.049 mmol), and CuI (0.019
g, 0.099 mmol) were placed in a flask which was maintained
under vacuum for 1 h. After the solution was flushed with
N2, deoxygenated THF (5 mL) was added via syringe. The
resulting mixture was heated at 60 °C under N2 for 3 h. After
the solution was cooled to rt, EtOAc (25 mL) was added. The
solution was washed with water, and the product was ex-
6-Cya n o-1,2,2a ,3,4,5-h exa h yd r o-N,N-d ip r op ylben z[cd ]-
in d ole-4-a m in e (11). A 5 N NaOH solution (5 mL, 25 mmol)
was added to a solution of unpurified 10 (5 g) in EtOH (50

Pd-Catalyzed Synthesis of Ergot Alkaloids
J . Org. Chem., Vol. 62, No. 25, 1997 8639
tracted from the organic phase with a 1 N HCl solution. The
acidic phase was basified at 0 °C with a 5 N NaOH solution
and then extracted with EtOAc. The combined organic
extracts were washed with brine, dried over anhydrous Na2-
SO4, and concentrated to give 0.29 g of a light brown oil.
Chromatography on silica gel (3:1 to 1:1 hexane/EtOAc) yielded
0.26 g (89%) of 12 as a yellow oil which crystallized upon
standing: mp 109-110 °C; IR (KBr) 2219 cm-1; 1H NMR (500
MHz, CDCl3) δ 8.51 (s, 1 H), 7.34 (d, J ) 8.5 Hz, 1H), 7.20 (d,
J ) 8.4 Hz, 1 H), 6.97 (s, 1 H), 3.30 (m, 2 H), 3.02 (m, 2 H),
2.83 (m, 1 H), 2.59 (t, J ) 7.3 Hz, 4 H), 1.51 (m, 4 H), 0.94 (t,
J ) 7.3 Hz, 6 H); 13C NMR (75 MHz, CDCl3) δ 138.2, 135.1,
126.9, 125.8, 119.5, 114.7, 109.3, 99.2, 58.4, 52.9, 28.4, 24.5,
22.5, 11.8; MS m/z 281 (M+). Anal. Calcd for C18H23N3: C,
76.83; H, 8.24; N, 14.93. Found: C, 76.78; H, 8.35; N, 14.94.
6-F or m yl-N,N-d ip r op ylben z[cd ]in d ole-4-a m in e (13). A
solution of the nitrile 12 (10 g, 35.6 mmol) in toluene (100 mL)
was cooled to -58 °C, and DIBALH as a 1 M solution in
toluene (71 mL, 71 mmol) was added dropwise over 2 h. Thirty
minutes after addition was complete, cooling was removed and
glacial acetic acid (20 mL) was added slowly to control foaming.
Water (100 mL) was then slowly added, and the reaction
mixture was stirred for 2 h. The aqueous layer was separated
and treated with saturated Rochelle salt solution (50 mL) and
EtOAc (100 mL). The pH was adjusted to 10 with a 5 N NaOH
solution. The organic layer was separated, and the aqueous
was extracted with EtOAc. The combined extracts were
washed with brine, dried over anhydrous Na2SO4, and evapo-
rated to near dryness. Trituration with hexane gave 13 as a
The solid was washed with cold 50% MeOH in water to afford
18.4 g (81%) of 2 as a tan solid. An analytically pure sample
of 2 could be acquired by passing the material through a silica
plug with EtOAc: mp 165-166 °C; 1H NMR (500 MHz, CDCl3)
δ 7.94 (s, 2 H), 7.48 (d, J ) 8.4 Hz, 1 H), 7.22 (d, J ) 8.4 Hz,
1 H), 7.19 (s, 1 H), 6.90 (s, 1 H), 3.25 (m, 2 H), 3.01 (m, 2 H),
2.82 (m, 1 H), 2.59 (m, 4 H), 1.49 (q, J ) 7.2, 14.6 Hz, 4 H),
0.92 (t, J ) 7.3 Hz, 6 H); 13C NMR (75 MHz, CDCl3) δ 151.8,
149.7, 133.6, 129.5, 127.1, 122.1, 121.8, 118.5, 115.9, 114.6,
108.8, 58.5, 53.1, 29.4, 23.8, 22.6, 11.9; MS m/z 323 (M+). Anal.
Calcd for C20H25N3O: C, 74.27; H, 7.79; N, 12.99. Found: C,
74.33; H, 7.90; N, 13.19.
6-(2-Oxa zoyl)-N,N-d ip r op ylben z[cd ]in d ole-4-a m in e (3).
To a solution of oxazole (0.10 mL, 1.45 mmol) in deoxygenated
THF (10 mL) at -70 °C was added 1.6 M n-butyllithium in
hexane (1.0 mL, 1.6 mmol). After 30 min, 1 M zinc chloride
in ether (4.35 mL, 4.35 mmol) was added. The reaction
mixture was warmed to 0 °C for 1 h after which a solution of
the iodide 16 (0.55 g, 1.45 mmol) in deoxygenated THF (7 mL)
was added. The palladium catalyst (prepared by the treatment
of a suspension of (Ph3P)2PdCl2 (51 mg, 0.073 mmol) in
deoxygenated THF (5 mL) with 1.6 M n-butyllithium in hexane
(0.09 mL, 0.145 mmol)) was added, and the resulting mixture
was refluxed for 1 h. The final reaction mixture was diluted
with EtOAc (20 mL) and was washed with brine and water.
The organic solution was dried over anhydrous Na2SO4 and
concentrated. Chromatography on silica gel (4:4:1 CHCl3/
hexane/MeOH) gave 0.25 g (54%) of 3 as a yellow oil: IR (film)
1
1611, 1560 cm-1; H NMR (300 MHz, CDCl3) δ 9.12 (s, 1 H),
tan solid, 9.07 g (90% yield): IR (KBr) 1667 cm-1 1H NMR
;
7.85 (d, J ) 8.5 Hz), 7.71 (s, 1 H), 7.25 (d, J ) 6.8 Hz, 1 H),
7.14 (d, J ) 8.5 Hz, 1 H), 6.86 (s, 1 H), 3.83 (dd, J ) 2.7, 16.4
Hz, 1 H), 3.30 (m, 1 H), 3.17 (m, 1 H), 3.03 (m, 1 H), 2.84 (m,
1 H), 2.60 (m, 4 H), 1.52 (q, J ) 7.3, 14.8 Hz, 1 H), 0.91 (t, J
) 7.3 Hz, 6 H); 13C NMR (75 MHz, CDCl3) δ 163.4, 137.6, 134.4,
132.2, 127.8, 127.1, 123.4, 118.4, 115.6, 116.2, 108.5, 58.7, 53.1,
29.3, 24.3, 22.6, 11.9; HRMS (M+) calcd for C20H26N3O 324.2076,
found 324.2074. Anal. Calcd for C20H25N3O: C, 74.27; H, 7.79;
N, 12.99. Found: C, 73.97; H, 7.84; N, 12.90.
(300 MHz, CDCl3) δ 10.29 (s, 1 H), 9.44 (s, 1 H), 7.63 (d, J )
8.5 Hz, 1 H), 7.19 (d, J ) 8.5 Hz, 1 H), 6.93 (s, 1 H), 3.83 (m,
1 H), 3.30 (m, 1 H), 3.06 (m, 2 H), 2.80 (t, J ) 13.3 Hz, 1 H),
2.58 (m, 4 H), 1.51 (m, 4 H), 0.92 (t, J ) 7.3 Hz, 6 H); 13C
NMR (75 MHz, CDCl3) δ 192.0, 137.8, 137.0, 127.2, 125.7,
124.4, 119.7, 115.7, 109.1, 58.8, 53.2, 27.5, 24.2, 22.7, 12.0; MS
m/z 284 (M+). Anal. Calcd for C18H24NO: C, 76.02; H, 8.51;
N, 9.85. Found: C, 76.25; H, 8.71; N, 9.71.
6-(5-Oxa zoyl)-N,N-d ip r op ylben z[cd ]in d ole-4-a m in e (2).
To a solution of the aldehyde 13 (20.0 g, 70.4 mmol) in MeOH
(200 mL) was added NaOMe (12.8 g, 237 mmol) as a solid
portionwise. After the solution was stirred for 5 min, tosyl-
methyl isocyanide (16.5 g, 84.5 mmol) was added as a solid
portionwise. The resulting solution was refluxed for 5 h, after
which water (100 mL) was added to the hot reaction mixture.
After cooling to rt, the mixture was cooled at 0 °C and filtered.
Ack n ow led gm en t. David Marks is gratefully ac-
knowledged for providing analytical support. We are
also indebted to Bret Astleford and Robert Waggoner
for valuable experimental contributions.
J O970374J