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Albany Molecular Research, Inc.

Trip Report for "6th Annual Florida Heterocyclic Conference" Gainesville, Florida, February 27­March 2, 2005

Jeremy A. Cody, Ph.D.; Matthew Isherwood, Ph. D.; John W. Lippert, III, Ph.D.; John E. Mangette, Ph.D.; Scott V. Plummer, Ph.D.

April 19, 2005

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Albany Molecular Research, Inc.

Memorandum

TO: William G. Earley, Ph.D.; David J. Fairfax, Ph.D.; Michael A. Guaciaro, Ph.D.; Peter R. Guzzo, Ph.D.; Michael D. Ironside, Ph.D.; Richard King, Ph.D.; Douglas B. Kitchen, Ph.D.; Donald E. Kuhla, Ph.D.; David D. Manning, Ph.D.; Bruce F. Molino, Ph.D.; Bruce J. Sargent, Ph.D.; Eric Smart ; Michael P. Trova, Ph.D.; Paul F. Vogt, Ph.D.; Mark A. Wolf, Ph.D.; Jim Zhang, Ph.D. Jeremy A. Cody, Ph.D.; Matthew Isherwood, Ph. D.; John W. Lippert, III, Ph.D.; John E. Mangette, Ph.D.; Scott V. Plummer, Ph.D. April 7, 2004 "6th Annual Florida Heterocyclic Conference" Gainesville, Florida, February 27­March 2, 2005

FROM: DATE: RE:

Abstract: The Sixth Annual Florida Heterocyclic Course and Conference was held over a three-day period from February 28th to March 2 at the University of Florida in Gainesville and was organized by ARKAT-USA with sponsorship from IUPAC. The twopart short course in heterocyclic chemistry was held in the afternoons and was presented by Drs. Alan Katritzky and Gordon Gribble. The conference contained lectures from world renowned heterocyclic chemists from both academia and industry. There was also a poster session ongoing throughout the event. This report highlights selected chemistry topics presented in both the short course and the lectures. All of the information presented below is referenced back to the speaker in question unless otherwise noted.

I. Plenary Lectures "Transition Metal catalyzed Reactions for the Synthesis and Functionalization of Heterocycles" Professor Alois Fürstner, Max-Planck-Institute fur Kohlenforschung Professor Fürstner presented some of his group's recent research efforts directed toward the synthesis of heterocyclic natural products. The prodigiosins are a class of conjugated pyrroles which display immunosuppressive properties and synergistic action with cyclosporin and FK506. A total synthesis of the structurally interesting butylcycloheptylprodigiosin was presented, the main strategy to which is outlined in the retro synthetic analysis in Scheme 1. The approach was to start with the nine-membered ring already in place early in the synthesis and utilize a novel palladium catalyzed 2

cyclization of a ,-unsaturated O-pentafluorobenzoyloxime which was originally reported by Narasaka and coworkers. This reaction could be used to form the pyrrole ring which could then be appended sequentially with the other two pendant heterocycles. Scheme 1

NH N MeO Butylcycloheptylprodigiosin H N MeO O NH O

NH

Boc (HO)2B

N OR N

In the forward sense (Scheme 2), reduction of the cyclic ,-unsaturated ketone and subsequent acylation afforded the diallyl acetate in high yield. Palladium catalyzed addition of methyl acetoacetate to the diallyl acetate produced the expected -ketoester derivative in good yield. In situ hydrolysis and dicarboxylation of the -ketoester afforded a methyl ketone which was converted to the oxime. O-Acylation of the oxime with pentafluorobenzoyl chloride afforded the cyclization precursor. The cyclization which proceeds via Pd-insertion between the N-O bond went in decent yield giving rise to a cyclic imine intermediate. The imine was aromatized to the 2-methylpyrrole using the strong base potassium diaminopropylamine and protected as the Boc-derivative. Scheme 2

O 1. DIBAL-H, 97% 2. Ac2O, Et3N, 97% O OAc MeO NaH, Pd(0) cat., 74% O O MeO O 1. aq. DMSO, 2. H2NOH 3. F5C6CO2Cl 95%

N

O O

C6F6 Pd(OAc)2 cat. (o-tolyl)3P cat., Et3N 54% N H 1. KAPA, 65% 2. Boc2O, DMAP, 69% NBoc

The butyl side-chain was then incorporated in a series of four steps starting with regioselective hydroboration of the endo-cyclic alkene (Scheme 3). The alcohol obtained after

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oxidative hydrolysis was converted to the ketone with the Dess-Martin periodinane. A standard Wittig reaction afforded an alkene which was subjected to a directed hydrogenolysis using Crabtree's catalyst. Critical to appending the remaining two heterocyclic rings was finding a method to functionalize the pyrrole methyl group. This was done by a ceric ammonium nitrate oxidation to the corresponding aldehyde. Biphasic solvent conditions (CHCl3/H2O/DME) were adopted as this was found to improve yields by limiting over oxidation. The aldehyde was then condensed with 4-methoxy-3pyrrolin-2-one under basic conditions which also cleaved the Boc-protecting group. The resulting pyrrolin-2-one was converted to a pyrrole-2-triflate with a rearrangement of bonds in the neighboring ring. Finally, a Suzuki coupling was used to attach the terminal pyrrole and afford butylcycloheptylprodigiosin in good yield. Scheme 3

O 1. Ph3P=CHCH2CH2CH3 N Boc 2. H2, Crabtree N

NBoc

1. BH3, H2O2 2. Dess-Martin 65% 1. MeO N H

CAN Boc CHCl3 / H2O / DME 65%

O N NH MeO OTf

(HO)2B

Boc N Butylcycloheptylprodigiosin

N OHC

Boc

aq NaOH, DMSO 69% 2. Tf2O

Pd(0) cat., LiCl 70%

Professor Fürstner then moved on to discuss some new synthetic methodology developed in his group, namely platinum and gold catalyzed cycloisomerization reaction of alkenes. It has been shown by other groups that complexation of enynes to PtCl2 engenders a host of selective cycloisomerization reactions which likely involve platinum carbenes as reactive intermediates (Scheme 4). These species are best viewed as latent cyclopropyl methyl cations that can evolve along different pathways. The cycloisomerization reactions result in a significant increase in structural complexity forming functionalized bicyclic cyclopropanes. The Fürstner group set out to extend the utility of the process for the synthesis of the bicyclo[3.1.0]hexanone skeleton, a structural motif which is present in a number of terpenes.

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Scheme 4

Cl2Pt PtCl2 R PtCl2 R R R R products PtCl2 Cl2Pt

Mechanism and proposal Cl2Pt R OH Cl2Pt R H OH O [1,2 H-shift] R

It was envisaged that incorporation of a hydroxyl group in the propargylic position might give access to an alternative transformation of synthetic utility. If the PtCl2 induced cyclization occurred as predicted the intermediate carbene might be expected to undergo a 1,2-hydrogen shift. The theory proved successful and the expected product was obtained in a model reaction using catalytic PtCl2 with toluene as solvent (Scheme 5). Four other examples also gave moderate to good yields. Evidence for the proposed 1,2hydrogen shift reaction mechanism was gained by using a deuterium labeling technique. A propargyl alcohol incorporating a deuterium in the methine position was subjected to reaction conditions. On examination of the product it was found that the deuterium had migrated to the neighboring C-atom adjacent to the newly formed carbonyl group. Scheme 5

HO PtCl2 (5 mol%) toluene, 60-80 oC 74% Ph or, (PPh3)AuCl / AgSbF6 (2 mol%) CH2Cl2, 20 oC 75% O O O Ph O

other examples:

O

Ph 81% 60% 66%

Ph 52%

5

It was also found that PtCl2 could be replaced by (PPh3)AuCl/AgSbF6 as catalyst. The resulting cationic gold complex was particularly reactive and induced the cyclization at ambient temperature in CH2Cl2. Extending the practicality of the reaction further it was found that the procedure could be reduced to a one-pot process from precursor propargylaldehydes. Treatment of an aldehyde with allyl chlorodimethylsilane in the presence of PtCl2 at 80 °C in CH3CN enabled both an initial carbon-carbon forming reaction and the subsequent cycloisomerization. The new methodology was used in the synthesis of the natural product trans-sabinol (Scheme 6). A Lewis acid catalyzed addition of allenyl silane produced a 1,3-butadienyl derivative which underwent the cycloisomerization under the standard reaction conditions without incident. The ketone was reduced to give a 1:1 mixture of cis- and trans- alcohols which were separated by preparative GC. Scheme 6

O

.

SiMe3

HO

O PtCl2 (5 mol%) toluene, 80 oC, 2 h 78% NaBH4, CeCl3 MeOH 65%

OH

BF3-Et2O CH2Cl2, -78 oC 50%

trans-sabinol

References: (1) Narasaka, K. Bull. Chem. Soc. Jpn. 2002, 75, 1451 (2) Fürstner et al. Angew. Chem. 2005, in press. (prodigiosin synthesis) (3) Mamane, V.; Gress, T.; Krause, H.; Fürstner, A. J. Am. Chem. Soc. 2004, 126, 8654 "Anion Based Strategies by Regiocontrolled Synthesis of Heterocycles" Mikael Begtrup, Department of Medicinal Chemistry, The Danish University of Pharmaceutical Sciences. Dr. Begtrup gave a synthetically powerful presentation for the formation of a wide range of heterocyclic rings. The presentation was applicable for a wide-range of heterocyclic systems. Schemes 7, 8, and 9 illustrate the regiocontrol one can have with a pyrazole system and two one pot synthetic schemes toward both phenanthridines and quinoxalines, respectively. For further schemes and references I would recommend viewing his notes in full.

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Scheme 7

Scheme 8

7

Scheme 9

"Organotrifluoroborates in Selective Organic Synthesis" Gary A. Molander, Department of Chemistry, University of Pennsylvania One methodology project currently ongoing in the Molander group is the use of organotrifluoroborates in Suzuki-type cross coupling reactions. The organotrifluoroborates provide an alternative to tin (Stille coupling) and other boron derivatives (Suzuki-Miyaura coupling). Organotrifluoroborates have the same environmental advantageous of other boron derivatives and are stable to air and moisture. The majority of the organotrifluoroborates are solids, easily accessed, atom efficient and compatible with many functional groups. Organotrifluoroborates are prepared from other boron derivatives upon treatment with KHF2 (Scheme 10).

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Scheme 10 General Methods of Organotrifluoroborate Synthesis

RMgX or + RLi B(OR)3 KHF2 acetone (aq.) RBF3K

2 BH

CH2O (aq) KHF2 acetone (aq.) KHF2 BF3K BF3K

BF3K

acetone (aq.) KHF2 acetone (aq.) O BH O

The Suzuki-Miyaura cross-coupling reactions of organotrifluoroborates provide good yields of coupled products with a wide range of tolerated functional groups. Some representative examples can be seen in Schemes 11-15. For further reading see Molander, G. A.; Bernardi, C. R. J. Org. Chem. 2002, 67, 8424-8429. Scheme 11 Alkyl/Aryl Cross-Coupling

Br CH3BF3K + NHAc OTf PhCH2BF3K+ NO2 OTf Cl BF3K + Ac cat. PdCl2(dppf) . CH2Cl2 Cs2CO3 THF, H2O heat 67% cat. PdCl2(dppf) . CH2Cl2 Cs2CO3 THF, H2O heat 89% cat. PdCl2(dppf) . CH2Cl2 Cs2CO3 THF, H2O heat 73% CH3

NHAc Bn

NO2 Cl

Ac

9

Scheme 12 Aryl/Aryl Cross-Coupling

1% Pd(OAc)2 K2CO3 H2O heat 82% 0.5 mol% PdCl2(dppf) . CH2Cl2 BF3K + F Br CN K2CO3 EtOH heat 70% 0.5% Pd(OAc)2, PPh3 K2CO3 MeOH heat 52% MeO F CN F

BF3K + Br

OH

OH

F

MeO

BF3K + Br

Scheme 13 Alkenyl/Alkenyl Cross-Coupling

Cl + BF3K Ph Br Pd(OAc)2/ 2 PPh3 Cs2CO3 THF, H2O heat 85% O Ph Cl

Ph

Ph O Br +

BF3K

Pd(OAc)2/ 2 PPh3 Cs2CO3 THF, H2O heat 95%

10

Scheme 14 Alkenyl/Heteroaryl Cross-Coupling

Ph BF3K Br + N S PdCl2(dppf) t-BuNH2 i-PrOH, H2O heat 83% H N PdCl2(dppf) t-BuNH2 i-PrOH, H2O heat 70% Ph Ph S N

Ph BF3K

+

Br

H N

Scheme 15 Heteroaryl/Heteroaryl Cross-Coupling

BF3K + S Br N S PdCl2(dppf) Et3N EtOH heat 83% PdCl2(dppf) N Et3N EtOH heat 67% N S N S S N

BF3K + S Br

N

To complete the talk and to validate the use of organotrifluoroborates in Suzuki-Miyaura cross-coupling reactions Gary Molander described work conducted in his lab for the formal total synthesis of Oximidine II (Scheme 16). Oximidine II is a salicylate enamide macrolide isolated from Pseudomonas sp. Q52002 with the observed biological activity to inhibit mammalian vacuolor-type H+ ATPase. The Suzuki-type cross-coupling using potassium organotrifluoroborates was employed for the macrocyclization to provide the core of Oximidine II. The complete work is described in the reference: Molander, G. A.; Dehmel, F. J. Am. Chem. Soc. 2004, 126, 10313-10318.

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Scheme 16 Molander's Formal Synthesis of Oximidine II

OBn 1. O O O TIPS HO OMOM OH O O OMOM OBn TBDMSOTf imidazole, DMAP DMF, RT 79%

NaHMDS, THF Br 2. TBAF, THF 98%

Br

OBn TBDMSO O O OMOM

1.

2

OBn BH OH O O OMOM Pd(PPh3)4 CsCO3 THF, H2O (10:1) 42%

THF 2. CH2O (aq.) 3. KHF2, acetone, MeCN, H2O, RT 100% (crude) BnO

Br

BF3K

Br

BnO OH O O OMOM TBDMSOTf imidazole, DMAP DMF, RT 84% TBDMSO

O O

OMOM

DDQ CH2Cl2, buffer RT to reflux 86%

HO TBDMSO O O OMOM TBDMSO O O

H N O OMOM

N OMe

Oximidine II

"Quinazolines, Pyridines and Isoquinolines-The Chemical Development of UK338,003" Dr. Paul Hodgson, Pfizer, Ltd., Sandwich, UK Dr. Paul Hodgson presented the process development work involved in the preparation of the compound UK-338,003. This quinazoline compound has been nominated for the treatment of benign prostatic hyperplasia. BPH is characterized by the enlargement of the prostate resulting in urethral constriction. The disease affects >50% of males over 60 in the US, and the probability of a 50 year old man requiring surgery for BPH during his lifetime is 25-30 percent. Scheme 17 below illustrates the retrosynthetic analysis for three basic routes described in the presentation. The two principal steps are the

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formation of the aryl-aryl bond (pyridine-quinazoline), as well as the incorporation of the isoqinoline moiety via annulation. Scheme 17

NHSO2Me MeO MeO N N N NH2 UK-338,003 N MeO MeO Hal N N NH2 + HN LG NHSO2Me

SnR3 N ROUTE 1

MeO MeO NHSO2Me + R1 N MeO MeO N R2 R3

R2 R3 M/Hal M/Hal N

ROUTE 2 M = Zn ROUTE 3 M = B

The bond-forming chemistry of Route 1 is shown in Scheme 18. The Stille coupling of the chloroquinazoline with the aryl stannane proceeded in acceptable yield; however pebble-like inorganic aggregates were formed in the reaction. The corresponding Suzuki reaction with 2-pyridine boronic acid was less successful. This procedure suffered from significant proto-dehalogenation. The condensation of the tetrahydroisoquinoline with the chloroquinazoline in the subsequent step, however, was successful.

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Scheme 18

Bu3Sn N MeO MeO I N N NH2 Cl 1.5 eq. Pd(PPh3)4 LiCl (2 eq.) CuI (0.2 eq.) dioxane 75% MeO MeO N N N NH2 Cl HCl.HN Et3N 90% NHSO2Me MeO MeO N N N NH2 N NHSO2Me

As the route described above was not commercializable due to scale-up problems with the Stille reaction, a second pathway was explored as shown below in Scheme 19. This route contained an initial aryl-aryl coupling of a zincate with 2-bromopyridine. In the kilo-lab a significant problem was encountered in two of the five runs. An in-process test of these runs indicated that the zincate was not formed to an appreciable extent. The zinc had to be filtered off, and the aryl iodide solution was resubmitted to the reaction conditions. The biaryl product was subsequently coupled to a tetrahydroisoquinolineguanidine species in acceptable yields. Route 2 contained significant upgrades from Route 1. The waste generated from this process was estimated at 600 kg/kg, while that generated from Route 1 was 2720 kg/kg. The process was also quite convergent and displayed consistent performance upon scale-up.

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Scheme 19

NHSO2Me MeO MeO I F CN 1) Zn, TMSCl THF 2) Pd(OAc)2, PPh3 Br N 55% NHSO2Me MeO MeO N N N NH2 N MeO MeO N F CN H2N N NH CsCO3, DMSO 70%

The difficulties encountered during the zincate coupling led to the development of a third route (Scheme 20) in which a Suzuki coupling was performed instead. This Suzuki coupling was achieved via the stable N-phenyldiethanolamine pyridyl boronate (Hodgson, Salingue Tetrahedron Lett. 2004, 45, 685). Very low levels of deiodinated by-product were encountered, and a 61% yield was achieved in the pilot plant. The annulation of the biaryl product with a tetrahydroquinoline-cyanamide species provided UK-388,003 in 84% yield in the pilot plant. This third route to the API was convergent and contained high yielding steps. The amount of waste was also reduced further to only 240 kg/kg. Scheme 20

NHSO2Me MeO MeO I NH2 CN Pd(OAc)2 PPh3, CuI, K2CO3 THF, 100 C H N O B O N MeO MeO N NH2 CN sodium tert-pentoxide DMSO, 84% NHSO2Me MeO MeO N N N NH2 N N

NC

61%

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"Heterocyclic Receptor Selective Prostaglandin Ligands" Mitchell A. deLong, The Proctor & Gamble Co., Cincinnati, OH Early research into prostaglandin pharmacology revealed a possible role in bone growth acceleration in infants and in fracture healing. However, chemical instability, severe side effect profiles, and lack of reproducible activity across species slowed progress on active compounds. In the mid­1990's the prostaglandin receptors were cloned, allowing more accurate initial testing. This prompted Proctor & Gamble to reestablish a research program aimed at developing an anabolic agent for the treatment of osteoporosis. Initial efforts at evaluating many known prostaglandin receptor ligands identified BW­245 (see below for a structural comparison versus a natural prostaglandin, PGF2) as a potent agonist of the DP prostanoid receptor with a Ki of 0.3 nM in the hDP binding assay. Unfortunately,

CO2H O HN N O HO HO HO CO2Et OH

BW­245 (one diastereomer)

PGF2

chemists working with the compound suffered facial flushing, headache and nausea, similar to the severe side effects attributed to activity at the EP prostanoid receptors. Subsequent work focused on PGF2 which had good activity at the FP receptor (hFP IC50 of 5 nm). Preparation of tetrahydro analogs produced some highly active compounds. The benzothiophene analog, with an hFP IC50 of 2 nM and >10,000 nM at most other PG receptors, was chosen for development. Bone density studies and cross section analyses clearly demonstrated bone regeneration in rats and dogs comparable to that induced by parathyroid hormone (PTH) injections.

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R (CH2)4CH3 CH2OPh OH CO2H HO OH R CH2S CH2O(m-ClPh) CH2SPh S

hFP IC50 (nM) 450 10 2 2.5 5.5

CH2S(o-ClPh)

25 12

F S 2

Further testing, though, revealed cardiac necrosis in baboons at high dose levels. As a result, other lead compounds are being evaluated, while testing continues on the benzothiophene analog for glaucoma and skin care, indications with much lower dose levels. References: (1) Kiriyama, M.; Ushikubi, F.; Kobayashi, T.; Hirata, M.; Sugimoto, Y.; Narumiya, S. Br. J. Pharmacol. 1997, 122, 217. (2) deLong, M. A.; Wos, J. A.; De, B.; Ebetino, F. H. US 6,372,730. (3) deLong, M. A.; Soper, D. L.; Wos, J. A.; De, B. US 6,586,463. (5) Wos, J. A.; deLong, M. A.; Amburgey, Jr., J. S.; De, B.; Dai, H. G.; Wang, Y. US 5,977,173. "Heterocyclic Azadiene Diels-Alder Reactions: Scope and Applications" Dale Boger, Scripps Research Institute, La Jolla, CA, USA Dr. Boger initially presented an overview of heteroaromatic azadiene Diels-Alder reactions used to prepare a wide range of heterocycles such as those shown in Scheme 21. The triazines, diazines, and tetrazines shown react with a wide variety of dienophiles and heterodienophiles. Electron-rich dienophiles usually participate in an inverse electron demand Diels-Alder reaction at room temperature. Neutral and electron-

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deficient dienophiles require higher reaction temperatures. The heterocycles prepared via this process are valuable intermediates for the preparation of natural products. Scheme 21

R N EDG 1,3,5-triazines R R = H, CO2Et, SCH3 R N N EDG 1,2,4,5-tetrazines R R = OMe, CO2Et, SCH3 R1 N N 1,2-diazines O N R2 R O N R2 R R1 R N N R N N R N N R

R N N

The utility of this Azadiene Diels-Alder reaction was exemplified via the synthesis of the marine natural product Ningalin B. The reaction of the readily prepared electron-rich diphenylacetylene 1 with the electron-deficient tetrazine 2 proceeded to give the desired 1,2-diazine 3 in excellent yield (Scheme 22). Subsequent reductive ring contraction (Zn, HOAc, 62%) provided the core pyrrole found in the natural product. Extensive biological testing was undertaken on this material, as well as analogs prepared in a similar manner. Several analogs of Ningalin B were found to possess moderate cytotoxic activity (IC50 10-125 µm), and these materials were also found to be potent multi-drug resistance reversing agents.

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Scheme 22

N N OMe MeO MeO MOMO 1 OMe MeO2C N N 2 CO2Me MeO MeO OMe OMe

mesitylene, 140 °C, 92%

MeO2C

N N 3

OMOM CO2Me

HO

OH HO

OH

Zn, HOAc 62%

MeO MeO OMe OMe O N O MeO2C OH OH Ningalin B N H 4 5 steps OMOM CO2Me

The method also plays a crucial role in the synthesis of Prodigiosin. This heterocyclic natural product displays potent antitumor, antibiotic, and antifungal activity. The reaction of tetrazine 2 with 1,1-dimethoxyethylene provided the inverse electron demand Diels-Alder product 5 (Scheme 23). Notably, this reaction proceeded at 25 °C. Reductive ring contraction of this electron-deficient diazine provided dimethyl 3methoxypyrrole-2,5-dicarboxylate in an acceptable yield. This short 2-step procedure provided the B ring of Prodigiosin.

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Scheme 23

MeO N MeO2C N N 2 N CO2Me OMe dioxane, 25 °C 94% MeO2C OMe 5 N N CO2Me

H3CO N NH NH

C5H11 Me MeO2C MeO

Zn, HOAc 68%

H N

CO2Me

Prodigiosin

6

Lastly, the synthesis of Roseophilin was described (Scheme 24). This pentacyclic natural product, isolated from Stryptomyces griseoviridis, has demonstrated significant cytotoxic activity against several human epidermoid and leukemia cell lines. The heterocyclic azadiene inverse electron demand Diels-Alder was once again used for the construction of the pyrrole ring present in the azafulvene core of this natural product. The reaction of tetrazine 2 with the optically active electron-rich enol ether 7 at room temperature provided the 1,2-diazine 8. Reductive ring contraction by treatment with Zn-TFA gave the pyrrole 9. Unlike the previously described zinc reductions, this reduction was less effective when using acetic acid. The pyrrole 9 was converted to triol 10 in 14 steps. Ring closing metathesis of 10 with Grubb' catalyst gave 11 as a 1:1 mixture of E and Z olefin isomers in high yield. With the completion of the ansa-bridged macrocycle, the intermediate 10 was converted to Roseophilin. The optical rotation of the prepared product was identical, but of opposite sign to the natural product. This indicates that the enantiomer of the naturally occurring Roseophilin was synthesized.

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Scheme 24

N N MeO2C OBn N N 2 CO2Me OBn

MeO 7 Zn, TFA 25 °C, 52%

25 °C, 60 h, 91%

MeO2C

N N 8

CO2Me

OBn

MeO2C

N H 9

CO2Me

CO2Me N SEM 10

PCy3 Cl Ph Ru Cl PCy3 DCM, 40 °C 88% CO2Me N SEM 11

N O HN

OMe

Cl

ent-Roseophilin

References: Review: Boger, D.L. Chem. Rev. 1986, 86, 781. Ningalin B: Boger, D.L.; Soenen, D.R.; Boyce, C.W.; Hendrick, M.P.; Jin, Q. J. Org. Chem. 2000, 65, 2479. Prodigiosin: Boger, D.L.; Patel, M. J. Org. Chem. 1988, 53, 1405. Ent-(-)-Roseophilin: Boger, D.L.; Hong, J. J. Am. Chem. Soc. 2001, 123, 8515.

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"Synthesis of Heterocycles via Iodine- and Palladium- Promoted Cyclization and Annulation" Richard C. Larock, Department of Chemistry, Iowa State University. Professor Larock broke his talk down into three parts: (1) the synthesis of various heterocyclic ring systems containing an iodine, (2) the application of these iodo heterocyclic compounds in cross-coupling reactions, and (3) cyclization and annulation chemistry associated with heterocyclic systems. The schemes outlined below represent only a small fraction of the heterocyclic chemistry presented. In part one, he discussed the synthesis of 3-iodobenzofurans, benzothiophenes, 3iodobenzo[b]selenophenes, 3-iodoindoles, isoxazoles, furans, isochromenes, naphthalenes, isocoumarins, pyrones, isoindolin-1-ones, quinolines, spirodienones, naphthalenes, and napthols. An example is shown in Scheme 25. [unpublished results] Scheme 25 ISOXAZOLES

N R1 R2 OMe E+ CH2Cl2 R1 N O E R2

N O Ph E E ICl Br2 PhSeBr ICl PhSeBr

R2 Ph

N O I

R2 R1

N O E

R2

R2

% 86 75 91 78 88 MeO MeO2C

R2 S

% 82

R2

%

89 80 n-Bu t-Bu TIPS 72 80 78

N Me

55

68 N i-Pr t-Bu 84 100

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Professor Larock then discussed the application of organopalladium chemistry on the above iodo substrates. Most notably he discussed the reaction of the iodo compounds with an alkyne of choice in order to synthesize a desired heterocycle or conjugated ring system. An example is illustrated in Scheme 26. [JACS, 1991, 113, 6689; JOC, 1998, 63, 7652].

Scheme 26 INDOLES

NHR1 + I R2C CR3 5% Pd(OAc)2 1 LiCl or n-Bu4NCl 5 base (5% PPh3) 100 °C, 12-48 h H N R1 N R2 R3

R N CH3

H N

CH3 Si CH3 CH3

Ac N

CH3 CH3 R H CH3 Ac Ts % Yield 80 71 91 86 57% H N

HO 60% H N

CH3 75% Ts N

CH3 Si CH3 CH3

CH3 CH3 OH

CH3 98%

H3C 70% 60%

Finally, Scheme 27 illustrates the last topic discussed regarding annulation. One example was presented which afforded pyridine systems [JOC, 2001, 66, 8042].

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Scheme 27 PYRIDINES

H3C Ph I N t-Bu + 2 PhC CCH2OH 5% Pd(OAc)2 10% PPh3 Na2CO3 100 °C, 2 h H3C Ph N Ph OH 95% t-Bu + 2 PhC CMe 3h N Ph CH3 96% t-Bu + 2 PhC CPh 16 h Ph 72% N Ph

N Br

N Br

N Br

t-Bu

+

2 PhC CEt

3h Et Ph 94%

N

II. Short Talks "Synthesis and Reactivity of 4-Functionalized Oxazolidin-2-ones" Dr. Thomas Kurz, Institute of Pharmacy, University of Hamburg, Germany An operationally simple method for the efficient synthesis of -hydroxycarboxylic acid derivatives was presented (see Scheme 28). Readily available cyanohydrins can be easily converted to 4-functionalized oxazolidin-2-ones in a three step one-pot process. Reaction of the cyanohydrins with carbonyldiimidazole gives an activated intermediate which can undergo addition and cyclization with a variety of primary amines. The resulting Nsubstituted 4-imino oxazolidin-2-ones are then hydrolyzed to the corresponding oxazolidin-2,4-diones. On treatment with a catalytic amount of sodium methoxide the oxazolidin-2,4-diones undergo ring opening to furnished -hydroxyamides. The reaction was extended to incorporated O-alkyl hydroxylamines and dialkylhydrazines as the amine components.

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Scheme 28

OH R1 O H N R3

O

OH R1 CN

O 1. CDI 2. R2-NH2 Et3N 3. HCl/THF O R1

2 N R

NaOMe (0.2 eq) MeOH R1

OH O

H N

O

R2

1. CDI 2. R2ONH2 R1 O O O R1 N O R2 NH NaOMe (0.2 eq) MeOH R1 OH N NH2 O R2 OH H N N R5 R4

Additionally, by leaving out the hydrolysis step the intermediate N-substituted 4-imino oxazolidin-2-ones could be used for a variety of transformations. For example, in a case where an O-alkyl-hydroxylamine was used as the primary amine component, cleavage of the ring with catalytic sodium methoxide gave a straightforward access to O-substituted -hydroxyamidoximes. References: (1) Kurz, T.; Widyan, K. Org. Biomol. Chem. 2004, 2, 2023. (2) Kurz, T.; Widyan, K. Org. Lett. 2004, 6, 4403. "Straightforward Ring Expansion of Pyroglutamates to Perhydro-1,3-diazepine-2,4diones" Christian Stevens, Nicolai Dieltiens and Diederica Claeys, Research group SynBioC, Department of Organic Chemistry, Ghent University While trying to prepare 1-carbamoyl-2-pyrrolidinones, the authors discovered a new and convenient method for preparation perhydro-1,3-diazepine-2,4-diones. In initial experiments, treatment of a pyroglutamate with an isocyanate produced a complex mixture of products resulting from reaction at both the N-atom and the C2-atom. Performing the reaction with NaH as a base in Et2O improved the selectivity and the sodium salt of the expected urea was precipitated cleanly. However, when the reaction

25

was performed in THF, the now soluble intermediate sodium salt unexpectedly underwent an anionic rearrangement as proposed in Scheme 29. Scheme 29

R2 O O N N R1O O

O

N H R NCO

2

OR1 O

NaH (1.1 eq) THF RT, 16 h

O N R2

N O O

OR1

O R2 N O N

O OR1

O R2 N O NH

O OR1

O R2 N O NH

O OR1 42-93%

R1 = methyl, ethyl, benzyl R2 = pheny, benzyl, allyl 2-chloroethyl

Cyclization onto the adjacent carbonyl group affords a strained intermediate which ring opens to the seven-membered cyclic product. Despite utilizing optically active pyroglutamates as starting materials, the final products obtained after rearrangement were racemic. This can be rationalized by equilibration between conjugated anions. Moderate to high yields of the corresponding 1,3-diazepine-2,4-diones were obtained after purification by chromatography or recrystallization. Reference: (1) Stevens, C. V.; Dieltiens, N.; Claeys, D. D.; Org. Lett. 2005, 7, 1117. "Design and Novel Synthesis of Substituted Quinazolin­ and Pyrimidin­4­ones as New Calcilytic Templates" Irina Shcherbakova, NPS Pharmaceuticals, Inc., Salt Lake City, UT. As an alternative approach for treating osteoporosis, scientists at NPS have been searching for a way to indirectly and transiently increase levels of PTH, a natural bone growth promoter, through antagonism of the calcium receptor (CaR), a known PTH regulator. Following the identification of quinazolinone NPS 53574 as a lead compound via high­ throughput screening, analog preparation was carried out using the synthesis shown in Scheme 30.

26

O N N O

NPS 53574 (IC50 = 3.5 µM)

Scheme 30

COCl

O O R1 N R2

R3

NH2

O N R3

CO2H R1 NH2

R2

pyridine

200 °C, 2-3 h or 240 °C, microwave, 10 min, for R1 = F

R1

N R2

In vitro testing on more than twenty compounds indicated a clear preference for R2 = o­OH (attributed to increased permeability associated with intramolecular hydrogen bonding) and an optimized structure with R1 = 6­F and R3 = 3­F.

F O N N Ph N OH

IC50 (µM): 14 2.8 0.3 0.19

O N Ph

O N N HO Ph F

O N N HO

In vivo testing of analogs with IC50 values less than 0.5 µM showed rapid, dose­related increases in plasma PTH levels in rats, but also a quick return (within 10 minutes) to the preinjection status. The duration of the effect was not long enough to alter the plasma calcium ion levels. More recent work has shown that the pyrimidinone compounds, prepared as in Scheme 31, were more potent and had improved pharmacological properties. Compound 12 was the best reported in the series with an IC50 = 80 nM for the calcium receptor.

27

Scheme 31

O R2 R1 O R4 R2 R1 NH O NHR3 KOH R1 R2 CO2Et 1.

HO OH

H+ 2. KOH

O R2

O R1

1. (COCl)2 CO2H 2. R3NH2 3. H+ R2

O R1

O NHR3

1. NH3 2. R4COCl

O N R3 R4 H3C

CH3 O N F

H3C 12 HO

References: (1) Shcherbakova, I.; Balandrin, M. F.; Fox, J.; Ghatak, A.; Heaton, W. L.; Conklin, R. L. Bioorg. Med. Chem. Lett. 2005, 15, 1557. (2) Shcherbakova, I.; Balandrin, M. F.; Huang, G.; Geoffroy, O.; Fox, J.; Nair, S. K. WO 2004/092121 A2. "Synthesis of Biologically Active Heterocycles: Exploring the Effects of NF­B Regulation" Jetze J. Tepe, Michigan State University, East Lansing, MI. In an effort to improve the efficacy of chemotherapeutic agents, the Tepe group has focused on developing and evaluating imidazolines as inhibitors of NF­B mediated gene transcription. Activation of NF­B by TNF­ is suspected to protect cancer cells by preventing programmed cell death. This same activation is also thought to be initiated by some chemotherapy drugs. Standard chemotherapy in conjunction with a second agent to block NF­B activation is proposed to inhibit cancer cell protection, and thus sensitize the cells to standard drugs. To generate the imidazolines, a route was developed that allowed for differentiation at four sites on the heterocyclic ring with essentially complete stereochemical control. Treatment of azalactones 13 (prepared by EDCI dehydration of N­acyl amino acids), with trimethylsilylchloride and a preformed imine generated a 1,3­dipolar cycloaddition product through the proposed N­silylated intermediate 14 (see Scheme 32). Loss of the carboxylate giving the free acid and hydrolysis of the trimethylsilyl group produced the final imidazoline 16. Acetyl chloride was the only other reagent to promote the reaction; ten other Lewis acids failed. Yields of 16 ranged from 60­90%, and in almost all cases, only the trans diastereoisomer was obtained (NOE experiments and X-ray crystallography). The selectivity was rationalized by steric repulsion between R3 of the imine and the trimethylsilyl group on the ring nitrogen.

28

Scheme 32

R4

N

R4 R1 TMS

+

R1 N

O R2 13 R4 N N

O

_

O

R3

O R1 TMS R2

NH O N

R3 O R2

TMSCl CH2Cl2 reflux

N 14

15

R1

H R3

R2 CO2H

16 (SP-4-84, R1=R2=R3=Ph, R4=Bn)

In testing for biological activity, the imidazolines, alone, were found to be inactive against leukemia T cells. However, they significantly improved the sensitivity of the cancer cells to chemotherapeutic agents. Imidazoline SP-4-84 gave the best results with an efficacy enhancement of 75­fold for camptothecin and 6­fold for cisplatin. More detailed evaluation showed that the imidazoline acted by preventing nuclear translocation of NF­B. References: (1) Wang, C.-Y.; Mayo, M. W.; Baldwin Jr., A. S. Science 1996, 274, 784. (2) Peddibhotla, S.; Jayakumar, S.; Tepe, J. J. Org. Lett. 2002, 4, 3533. (3) Peddibhotla, S.; Tepe, J. J. Synthesis 2003, 1433. (4) Peddibhotla, S.; Tepe, J. J. J. Am. Chem. Soc. 2004, 126, 12776. (5) Sharma, V.; Lansdell, T. A.; Peddibhotla, S.; Tepe, J. J. Chem. Biol. 2004, 11, 1689. "Unexpected Reactions of ,­Dihalo Carbonyl Compounds with Potassium Thiocyanate and Arylhydrazines" Joachim G. Schantl, University of Innsbruck, Innsbruck, Austria. As a follow­up to previously reported work on the reaction of ­halo ketones with potassium thiocyanate and phenylhydrazine in acetic acid to generate interesting [3 + 2] cycloaddition products (see Scheme 33), the speaker described the reaction of ,­dihalo ketones under the same conditions.

29

Scheme 33

O R1 R1 PhHN N S (R2 or R3 = H) R2 NH or S

1 R R3 HR N NH N N Ph S 2

R2

R3

KSCN PhNHNH2 HOAc

X X = Cl, Br

(R2 = H, R3 = H)

Aldehyde 17 produced 18, identified by X-ray crystallography, which is a 2:1:2 adduct of aldehyde:KSCN:hydrazine.

O H CH2R Br Br 17 KSCN ArNHNH2 HOAc RH2C N N S 18 R

Ar

N NHPh

The proposed reaction path involves hydrazone formation and displacement of one or both bromine atoms by thiocyanate (see Scheme 34). Elimination of HBr or HSCN would give diazodiene 20, a Michael acceptor, and its tautomer 21, a nucleophilic species.

30

Scheme 34

O H

CH2R Br Br 17

KSCN ArNHNH2 HOAc

ArHN H

N X

CH2R SCN

_

ArN HX H

N

ArHN CH2R H SCN

N

H R SCN

19 (X = Br or SCN)

20

21

RH2C N N

+S

R _ CN 24 _ HCN N NHPh ArN

R N

R N S CN 23 NHAr

ArHN _ HNCS

N

R SCN N NAr

Ar

H NCS CH2 R 22

RH2C N N S 18

R

Ar

N NHPh

Dimerization to give 22 is followed by loss of thiocyanic acid and tautomerization to 23. [1,5] Electrocyclic ring closure, loss of hydrogen cyanide and tautomerization gives 18. When ,­dichloroacetophenones were used as the starting material, thiadiazolium thiocyanate salts 25, resulting from electrocyclic ring closure, were isolated (see Scheme 35). As reported in the literature, they react with nitrogen and oxygen nucleophiles at the 5­position to form 2,5­dihydro[1,2,3]thiadiazoles. Unexpectedly, though, aliphatic ketones reacted with 25, presumably through the enol tautomer, to open the ring by attack at sulfur (see Scheme 36). The product 26 could then be rationalized with a [3 + 2] cycloaddition with thiocyanate followed by tautomerization and protonation.

31

Scheme 35

O Ar1 Cl Cl Ar2HN Ar1 X (X = Cl or SCN) Ar1 _ CN Ar1 Ar2

+

Ar1 N SCN _ HX N Ar2 N S CN

KSCN Ar2NHNH2 HOAc

Ar2

N N

_

Ar1 Nu _ Ar2 N N Nu

HCN

+S

N N

S

NCS

S

25

Scheme 36

_

NCS

N + Ar2 N

Ar1 OH S R1 R2 Ar2 N N

Ar1 S R1

O R2

Ar2 _ N

Ar1 N

+

O S R1 R2

25

S C N _

R2 Ar1 Ar2HN N S 26 O S NH R1

Reference: (1) Schantl, J. G.; Nadenik, P. Synlett 1998, 786.

32

III. Short Course, Part 1 ­ "Benzotriazole Synthetic Methodology" Alan R. Katritzky, University of Florida, Gainesville, FL . The Katritzky section of the short course covered the powerful applications of benzotriazole (Bt) in synthetic methodology. The course outline from day one, part one, included Bt-mediated synthetic methodology, Bt-mediated acylation, imidoylation, thioacylation and sulfonation. Bt (1) is intrinsically unreactive, stable, and inexpensive (Figure 1). Bt is easily inserted and can behave as a leaving group and as a proton activator. An attached Bt group is also an ambient anion-directing group; it can stabilize cations, and it can act as a radical or carbanion precursor. Figure 1

N N N

A. Bt-Mediated Acylation The use of N-acylazoles as acylating agents is not new. Most particularly the work of H. A. Staab in the 1960's showed the advantages of the use of acylimidazoles and other acylazoles as acylating agents. N-Acylbenzotriazoles can be prepared classically from the acid chloride or directly from the carboxylic acid. [JOC, 2000, 8210; Tetrahedron, 1992, 7817; Synthesis, 2003, 2795.] Peptide chain extension can be carried out on unprotected amino acids with minimal racemization (<5%) via stepwise or fragment coupling (Scheme 37). [Unpublished Results]

33

Scheme 37

Stepwise Coupling:

R1 O OH Et3N CH3CN/H2O R.T. 0.5 hr O

R1 Cbz NH

O Bt

R2 + H2N

R2 O

Cbz NH HN HO R1 O

85~98%

R1 Cbz NH

R2 O Bt + H2N

O HN

R2 O 85~98% R3

R3 O

Et3N

Cbz NH HN HN HO O

HO

CH3CN/H2O R.T. 0.5~1.0 hr

Fragment Coupling:

R1 O R1 BtH, SOCl2 O HO R1 R2 0 °C O R3 R2 O Bt = CH2Ph, = Me, 85% R1 = Me, R2 = CH2Ph, 90% Ph Ph O + O Bt H2N O HN O Bt Et3N CH3CN/H2O R.T. 2.0 hr O HO O HO O H2N R1 O OH Cbz NH HN HN O 92~95% R3 O R2

R2

Cbz NH HN

Cbz NH HN

Cbz NH HN O HN HN O 86%

Cbz NH HN

B. C-Acylation of Heterocycles C-Acylation of N-acylbenzotriazoles with furan, thiophene, pyrrole, and indole under Friedel-Crafts type conditions usually provides high yields (Scheme 38). CAcylation reactions of furan and thiophene were carried out in the presence of TiCl4 (at R.T.) and/or ZnBr2 (at 110 °C), and these conditions gave comparable yields of the 2-acylated products. C-Acylation of pyrroles and indoles produced regiospecific products in the presence of TiCl4. [JOC, 2003, 5720.]

34

Scheme 38

Regiospecific C-Acylation of Furan, Thiophene, and Indole

H3C

+ O R

O Bt O R O R Bt Bt

TiCl4 or ZnBr2

H3C

O O S O R

R

5 examples 54-98% (Avg 79%)

+ S

5 examples 58-97% (Avg 80%)

+ N X X = H, Me + N (i-Pr)3Si R

TiCl4 N X O

R

7 examples for X = H 21-91% (Avg 56%) 7 examples for X = Me 51-94% (Avg 70%) R

O O Bt TiCl4 N (i-Pr)3Si O O R Bt TiCl4 N X R 7 examples for X = H 15-92% (Avg 65%) 7 examples for X = Me 27-92% (Avg 69%) 6 examples 54-92% (Avg 79%)

N X X = H, Me

+

C. Thioacylation and Sulfonylation Thioamides have been made classically by three major routes in which are formed a C-C bond, and C=S double bond, or a C-N bond. The crystalline odorless thioacylbenzotriazoles and the easily prepared bis-benzotriazolylmethanethione, which are stable to storage, have many advantages for the preparation of thioamides (Scheme 39).

35

Scheme 39

Synthesis of Thioamides from Thioacylbenzotriazoles

S Bt H3C PhCH2NH2 Et3N H3C S N H 99%

· Aryl substituted thioacylbenzotriazoles have been prepared. · Use of hazardous and unstable thioacyl chlorides are avoided. · Thioacylbenzotriazoles react fast and readily with primary and secondary amines

Synthesis of Thiocarbonyl Compounds Using Thiocarbonyl-bisbenzotriazole

R3MgX or R3Li N N N SiMe3 CSCl2 Bt S Bt R1R2NH S R1 N R2 Bt R4R5NH, Et3N R1 S R1 N R2 R3

(35-95%) S N R2 N R4 R5

(57-99%)

D. Aminoalkylation In the second part of the benzotriazole short course, Professor Katritzky outlined the heteroalkylation methodology which had been extensively studied in his laboratories. The first method described involved the aminoalkylation of benzotriazole intermediates. The condensation of benzotriazole, a complex amine, and an aldehyde provided a Mannich-like product as shown in Scheme 40. Professor Katritzky emphasized that the classical Mannich reaction is limited mostly to the use of formaldehyde, while the benzotriazole mediated reaction is quite versatile in the identity of the aldehyde. The benzotriazole moiety can then be displaced with a variety of nucleophiles to provide a wide range of substrates.

36

Scheme 40

BtH + R1R2NH + R3CHO

OM R4 R3 R4 NO2 NR1R2 R4ZnBr R4 R

3 4R CNO 2 2

O R4 R3 NR1R2

Bt R3 NR1R2

R4

R4ONa R4SR4O

NR R

1 2

R4S R3 NR1R2

R3

NR1R2

Aromatic amines can be selectively monoalkylated conveniently using benzotriazole methodology as shown in Scheme 41. The benzotriazole moiety (Bt) can be smoothly reduced to amines by sodium borohydride or the Bt moiety can be replaced by an alkyl group using Grignard reagents. This method is particularly advantageous with respect to the N-alkylation of heteroaromatic amines. Scheme 41

Bt R1 Ar N H R2MgX or NaBH4 R2 R1 Ar N H

Ar = 4-ClPh, 2-pyridyl, etc.; R1 = H, Pr, etc.; R2 = Me, allyl, Bn, H, etc. X Bt N N H R1 R2MgX or NaBH4 N N H X

R2 R1

X = H, Me, Cl, Br, NO2; R1 = H, Pr, tBu; R2 = Me, allyl, Bn, H

The conversion of primary aliphatic amines into unsymmetrical secondary amines can also be achieved by Grignard reactions of 1-[(alkylamino)methyl]-benzotriazoles as shown in Scheme 42. The preparation of symmetrical secondary amines, as well as unsymmetrical tertiary amines, can also be undertaken in this manner.

37

Scheme 42

R1NH2 BtH/CH2O Bt N H R1 R2MgX R2 N H R1

NH3

2BtH/2CH2O

Bt Bt R1

N

H

R2MgX

R2 R2 R4

N

H

R2R3NH

BtH/R1CHO

Bt

N R3

R2

R4MgX

R1

N R3

R2

A wide variety of -amino ketones have been prepared in good yields by the reaction of enolates of ketones with the readily available adducts from an aldehyde, an amine and benzotriazole as shown in Scheme 43. Similarly, aminoalkylation of nitro compounds can also be achieved via the reaction of benzotriazole adducts with alkylnitronate anions. Scheme 43

OLi N R3 R2 R4 R5 O R4 R1 R5 N R3 R2

R1 R2R3NH BtH/R1CHO Bt

R1 = H, Me, Ph, Pr; R2 = H; R3 = Ph; R2R3 = -(CH2)5-, -(CH2)2O(CH2)2-; R4R5 = -(CH2)4-

NO2 R2R3NH BtH/R1CHO Bt R1 N R3 R2 Na

O2N R1 N R3 R2

R1 = H, Me, 2-pyridyl; R2 = H; R3 = Ph, c-C6H11; R2R3 = -(CH2)5,-(CH2)4-, -(CH2)2O(CH2)2-

1-(-Aminoalkyl)benzotriazoles in solution undergo partial ionization to the corresponding imminium cation as shown in scheme 44. This moiety can be trapped by enamines and vinyl ethers to give the corresponding N-(1-dialkylamino-3aminoalkyl)benzotriazoles and N-(1-alkoxy-3-aminoalkyl)benzotriazoles. These species

38

can further react with Grignard reagents or LAH to give 1,3-diamines and 1,3aminoethers. Scheme 44

R1 RHC N Bt R2 Vinyl ethers R3O R5 CHR4 R2"N R

'

CHR"'

Enamines

R3O Bt R4 R5 R NR1R2 R6MgX or LAH

R2"N Bt R"' R' R NR1R2

R3O R6 R4 R5 R NR1R2

E. Amidoalkylation The amidoalkylating reagent derived from the condensation of a primary (or secondary) amide with benzotriazole and an aldehyde as shown in Scheme 45 has been extensively studied by the Katritzky group. Scheme 45

O R1 H N H (or R3) BtH/R2CHO Dean Stark/toluene R1 O R2 N Bt H (or R3)

quantitative yields

A summary of amidoalkylation reactions is shown below in Scheme 46.

39

Scheme 46

O R

1

R2 N H H

O R1 N H

R2 CO2Et R3 R1 O N H R2 Ar

R3CH(CO2Et)2 NaBH4 ArH/AlCl3 O R1 N H CN_ O R2 Bt R3SNa R3ONa

O R1 N H

R2 NR3R4

HNR3R4

O R1 N H

R2 SR3

R3MgX

R2 N H OR3

O R1 N H

R2 R3 R1 O N H R

2

R1 CN

Several related processes were also discussed. Both thioamidoalkylation and sulfonamidoalkylation can be undertaken using this methodology. An example of each process is shown below in Scheme 47. Once again the benzotriazole moiety can be displaced with either a Grignard reagent or sodium borohydride. Scheme 47

N N N R1 OH H2N S R

1

R2

N N S N N H R2

R3MgX or NaBH4 R1

R3

S

N R2 H 60-99%

R1 = H, Pr, C5H11, C7H15, C11H23; R2 = Ph, NH2; R3 = PhCH2, Bu, Ph H N N N N N N OO S 2 R N R1 H R3 R1 OO S 2 R N H

R1

CHO

R3MgX or NaBH4

R2SO2NH2

71-97%

R1 = H, iPr-2-pyridyl, Ph; R2 = Ph; R3 = H, Ph

40

Lastly, acyloxyalkylation and thioalkylation reactions are also feasible using the benzotriazole method as shown in Scheme 48. Acyloxyalkylation is best achieved utilizing organozinc reagents, and various alkyl or aryl groups can be introduced at the alkoxy part of the ester. Scheme 48

N N O N R1 O R2 R3 R1 O O R2

R3ZnBr/THF reflux, 0.5-20 h

38-98% R1 = H, Pr, Ph; R2 = Me, Ph, C5H11; R3 = Bu, Ph, PhCH2, PhCH2CH2, etc.

N N N R SPh

ArH/ZnBr2/Et2O reflux, 10h

Ar R 9-56% SPh

R = Ph; Ar= 4-MeOC6H4, 3,4-(OMe)2C6H3, 4-OHC6H4, etc.

Comprehensive Review: Katritzky et. al. Chem. Rev. 1998, 409. IV. Short Course, Part 2 ­ "Applications of Lithium and Palladium in Heterocycle Synthesis" Gordon W. Gribble, Department of Chemistry, Dartmouth College. Course Outline 1. Lithium 1.1 Generation of Heteroaryllithiums 1.2 Applications in Synthesis 1.3 Heterocyclic Ring Synthesis Using Lithium 2. Palladium 2.1 Palladium-Catalyzed Cross Coupling 2.2 Oxidative Coupling/Cyclization 2.3 Applications in Synthesis 2.4 Ring Construction

41

1. Lithium 1.1 Generation of Heteroaryllithiums Heteroaryllithiums can be synthesized by halogen-lithium exchange, direct deprotonation, and directed-lithiation (Scheme 49). Scheme 49 Generation of Heteroaryllithiums

Halogen-Lithium Exchage RLi Het-X X = I > Br >> Cl >> F Direct Deprotonation LDA or RLi X X = O, NR, S Directed-Lithiation R Z RLi X X Z = amides, carbamates, alkoxy, amines, halogens, etc. X H Li Z Li Z X Li

Het-Li + RX n-BuLi (1 equiv) t-BuLi (2 equiv)

1.2 Applications in Synthesis As one can imagine the use heteroaryllithiums in synthesis is extensive. Two examples presented by Gribble were his synthesis of ellipticine and isoellipticine (Scheme 50). This example stood out among the others because of the selective addition into the anhydride.

42

Scheme 50 Applications of Lithiated Indoles in Synthesis

O O Li N SO2Ph O O N SO2Ph O Li O O N SO2Ph N SO2Ph N HOOC O Me N N Me COOH Me N H ellipticine N

N

N

Me N H isoellipticine

1.3 Heterocyclic Ring Synthesis Using Lithium The majority of the syntheses of heterocyclic ring systems discussed were indole forming reactions. A comparison of two lithiation methods to synthesize indoles can be seen in Scheme 51. Scheme 51 Indole Ring Synthesis via Lithiation

Li R' NHBOC RLi -78 oC R R' Li N Boc 1. R''CN R' 2. HCl 40-68% Bn F N N Bn N LDA (2.5 equiv) reflux N Li 97% N H N H Bn N R'' DMF 34-84% R' N Boc (H) R R

R = Bu, t-Bu, s-Bu R' = H, 5-F, 5-OMe, 5-Me, 4-OMe, 5,7-diF R'' = Ph, t-Bu, Ac, 2-thienyl

43

2

Palladium

2.1 Palladium Catalyzed Cross-Coupling Gribble provided us with a complete list of the popular palladium cross-coupling reactions and examples of each. The complete list and generic reaction schemes can be seen in Scheme 52. Scheme 52 Common Palladium Catalyzed Cross-Coupling Reactions

Kumada Couplng R-MgX + R'-X Pd (0) R-R' + MgX2

Negishi Couplng R-ZnX + R'-X Pd (0) R-R' + ZnX2

Suzuki Couplng R-B(OH)2 + R'-X Pd (0) R-R'

Stille Couplng R-SnR''3 + R'-X Pd (0) R-R' + R''3SnX

Hiyama Couplng R-SiR''3 + R'-X Pd (0) R-R'

Heck Reaction Olefin + R'-X Pd (0) R-R'

Sonogashira Coupling Alkyne-H + R'-X Pd (0) Alkyne-R'

Buchwald-Hartwig Amination RNH2 + R'-X Pd (0) RNH-R'

Some miscellaneous palladium coupling reactions discussed were phosphination, cyanation, thiolation, methylation, and reduction. Another coupling described was the carbonylation reactions in which carbon monoxide is inserted into the activated bond and then the acylpalladium species is trapped by a nucleophile.

44

2.2 Oxidative Coupling/Cyclization The oxidative coupling/cyclization reactions begin with an insertion into a C-H bond to form the organopalladium species. An example of this chemistry can be seen in Scheme 53. Scheme 53 Oxidative Coupling/Cyclization

OAc Pd N H

Pd(OAc)2 N H HOAc palladation

insertion

AcOPd H N H

-HOAc hydride elimination N H

+

Pd(0)

2.3 Applications in Synthesis The applications of palladium cross-coupling chemistry in synthesis of natural products is extensive as the literature abounds with examples. 2.4 Ring Construction Gribble starts the discussion of heterocyclic ring synthesis by providing a list of recent reviews. Some of the general literature reviews are: a. J. J. Li and G. W. Gribble, "Palladium in Heterocyclic Chemistry", Pergamon, NY, 2000. b. B. Gabriele et al., "PdI2-Catalyzed Synthesis of Heterocycles", Synlett, 2004, 2468. c. R. C. Larock et al., "Synthesis of Heterocycles via Palladium pi-Olefin and piAlkyne Chemistry", Chem. Rev. 2004, 104, 2285. d. G. Kirsch et al., "Synthesis of Five- and Six-Membered Heterocycles Through Palladium-Catalyzed Reactions", Curr. Org. Syn. 2004, 1, 47. e. D.J. Hiasta et al., "Current Methods for the Synthesis of 2-Substituted Azoles", Tetrahedron 2004, 60, 8991. f. Y. Yamamoto et al., "Transition-Metal-Catalyzed Reactions in Heterocyclic Synthesis", Chem. Rev. 2004, 104, 2127. The majority of the examples of heterocyclic ring synthesis provided by Gribble were published recently (2004). Pyrroles, furans, and thiophenes can be assembled from vinylogous propargyl equivalents (Scheme 54).

45

Scheme 54

R3 R2 X R1 R5 R4 PdI2 KI, DMA RT to 100 oC 48-90% R2 X R1 R5 R3 R4 X = S, O, N-Alkyl

As one can imagine, fused ring systems can also be assembled using the same chemistry in Scheme 15 and several examples are discussed. Gribble closed his short course with descriptions of novel palladium catalysts and phosphine ligands presented in the literature in the last three years. The most intriguing palladium catalysts are the ones linked to beads (Scheme 55). The bead-bound palladium catalyst could relieve the pharmaceutical chemist of the inherent problem of removing palladium in the final steps of a drug production. Scheme 55

Me N N Pd O O Me O

P. Styring et al., Tetrahedron Lett. 2004, 45, 7915.

O RS Cl Pd S R M. Bradley et al., Tetrahedron Lett. 2004, 45, 8239. O N Bu N Cl Pd N N N H O H N O N H

Bu N

P. G. Steel et al., Tetrahedron Lett. 2004, 45, 8977.

46

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