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DOI:10.15227/orgsyn.070.0101

Organic Syntheses, Coll. Vol. 9, p.516 (1998); Vol. 70, p.101 (1992).

IODOLACTAMIZATION: 8-exo-IODO-2-AZABICYCLO[3.3.0]
OCTAN-3-ONE[Cyclopenta[b]pyrrol-2(1H)-one, hexahydro-6-iodo-, (3aα,6α,6aα)-]Submitted by Spencer Knapp and Frank S. Gibson1.
Checked by Chris Melville and James D. White.

1. Procedure
CAUTION! The following operations produce lachrymatory and corrosive vapors and must be
carried out in a well-ventilated fume hood.
A. 2-Cyclopentene-1-acetamide. A dry, 250-mL, three-necked, round-bottomed flask is equippedwith a magnetic stirring bar, serum stopper, 25-mL pressure equalizing addition funnel, and an argon
atmosphere with provision for venting gaseous reaction products (Note 1). The vessel is charged with20 g (152 mmol) of 2-cyclopentene-1-acetic acid (Note 2) and 25 mL of dry toluene (Note 3). Oxalylchloride (17.3 mL, 1.3 equiv) is added slowly over a 30-min period by means of the addition funnel,
taking care to release any pressure buildup. (Caution: gaseous hydrogen chloride evolution!.) The dark
reaction mixture is stirred for an additional 20 min while the second reaction vessel is assembled, thenconcentrated to about 2/3 volume at the vacuum pump (Note 4).
A 250-mL, three-necked, round-bottomed flask equipped with magnetic stirring bar, serum stopper,
dry ice condenser, and argon atmosphere is cooled by means of a dry ice/acetone bath and charged withapproximately 150 mL of dry liquid ammonia. The 2-(2-cyclopentenyl)acetyl chloride reaction mixture
is added carefully but steadily (Note 5) to the cold and rapidly stirred ammonia by syringe. (Caution:vigorous exothermic reaction!). Residual acid chloride is transferred by rinsing the first vessel with 5
mL of toluene. After the addition the mixture is stirred for an additional 5 min, then 60 mL ofdichloromethane is added. The cold bath is removed and the excess ammonia is allowed to escape into
the fume hood by stirring the open vessel overnight.
The crude reaction mixture is filtered and the filtrate is reserved. The solids are triturated by stirring
vigorously with 100 mL of methanol for 20 min with gentle warming to about 40°C. The solids arefiltered and triturated again in the same way. The three organic filtrates are combined and concentrated
to near dryness. The resulting semi-solid is redissolved in 100 mL of dichloromethane, filtered toremove residual ammonium chloride, and concentrated to a light brown solid, 18.9 g. The crude productis dissolved in 60 mL of boiling tetrahydrofuran and allowed to crystallize in a −6°C freezer overnight.
The amide is collected by filtration, washed with 5 mL of cold ether, and dried under reduced pressure,giving 15.77 g of white flakes, mp 128–129°C. The filtrate is concentrated to about 8 mL, brought to thecloud point by the addition of a few drops of hexane, and cooled in the freezer. Filtration as before gives

a second crop of white flakes, 1.46 g, mp 128–129°C (total yield 17.23 g, 90.6%) (Note 6).
B. 8-exo-Iodo-2-azabicyclo[3.3.0]octan-3-one. A dry, 500-mL, three-necked, round-bottomed flask
equipped with magnetic stirring bar, serum stopper, 50-mL pressure-equalizing addition funnel, cold
water bath, and argon atmosphere is charged with 12.5 g (100 mmol) of 2-cyclopentene-1-acetamide,
29.2 mL (210 mmol) of triethylamine (Note 7), and 80 mL of dry pentane (Note 8). By means of theaddition funnel, 41 mL (210 mmol) of trimethylsilyl trifluoromethanesulfonate (Note 9) is slowly added
to the cooled and rapidly stirred amide suspension over a 50-min period. After the addition is complete,
the reaction mixture is stirred for an additional 20 min at room temperature, then the stirring is stopped,
and the two layers are allowed to separate.
A second, dry, 500-mL, three-necked, round-bottomed flask is equipped with magnetic stirring bar,
serum stopper, vacuum pump connection, and argon atmosphere. The (top) pentane layer from the firstflask, which contains the bis(trimethylsilyl)imidate, is carefully transferred to the second flask bycannula, maintaining the argon atmosphere, and leaving the oily triethylammonium
trifluoromethanesulfonate layer behind. This remaining salt is triturated with 30 mL of a dry 2:1
pentane/ether mixture by stirring for 15 min, allowing the layers to separate, then transferring the extract
to the second flask as before. The trituration is repeated with a 30-mL portion of anhydrous ether, andthe combined extracts in the second flask are concentrated with stirring to about 1/3 volume using thevacuum pump (Note 10).
A third, dry, 500-mL, three-necked, round-bottomed flask equipped with an addition funnel,
magnetic stirring bar, serum stopper, cold water bath, and argon atmosphere is charged with 53.3 g (210mmol) of molecular iodine and 140 mL of anhydrous ether. The mixture is allowed to stir for 10 min todissolve most of the iodine. The concentrated organic extract in the second flask is now added to theiodine solution with stirring and cooling over 15 min. The reaction mixture warms slightly during theaddition, but should not reach reflux. An additional 10 mL of anhydrous ether is used to complete thetransfer of the bis(trimethylsilyl)imidate. Near the end of the addition, the oily black layer (whichcontains the cyclized iminium salt) solidifies, leaving a clear light brown ether supernatant. The serum
stopper is carefully removed and the solid residue gently broken up using a spatula. The stopper isreplaced and the reaction mixture is allowed to stand for an additional 45 min with occasional swirlingby hand. The reaction is quenched by removing the addition funnel and stopper and slowly adding 20
mL of saturated aqueous sodium carbonate. (Caution: vigorous gas evolution!). At this point stirring
can be resumed. A 20-mL portion of saturated aqueous sodium sulfite is added slowly (more gasevolution), and the process is repeated until 100 mL each of saturated aqueous sodium carbonate andsulfite have been added. The reaction mixture is filtered, the crude solid iodolactam is reserved, and theorganic layer is separated and reserved. The aqueous layer is saturated with sodium chloride andextracted with four, 100-mL portions of dichloromethane. The five organic extracts are combined, driedover anhydrous sodium sulfate, and concentrated to a light brown solid. This residue is dissolved in 20
mL of tetrahydrofuran and hexane is added to the cloud point. Cooling in the freezer gives colorlessneedles, which are collected and dried under reduced pressure to afford 1.60 g of iodolactam, mp 138–139°C.
The reserved solid from filtration is dried under reduced pressure, dissolved in 65 mL of hot
tetrahydrofuran and filtered. The solution is allowed to cool, first at room temperature, then in thefreezer. The product (16.77 g, mp 138–139°C) is collected as before. The mother liquor is concentrated
to about 10 mL, brought to the cloud point by the addition of hexane, and cooled in the freezer, resulting
in an additional crop of 1.70 g, mp 138–139°C. The total amount of iodolactam is 19.80 g, representing
a 79% yield from the amide (Note 11).

2. Notes
1. All reaction glassware was oven dried at 120°C and assembled hot. The submitters used threeevacuate/fill cycles from an argon-filled balloon fitted on a three-way stopcock to provide the inert
atmosphere.
2. 2-Cyclopentene-1-acetic acid (96%) was purchased from Aldrich Chemical Company, Inc., and used
as received.
3. Toluene was dried by distillation from −40 mesh calcium hydride. Unless otherwise specified,reagents in this procedure were obtained commercially and used as received.
4. In series with the usual (500 mL) dry ice/acetone trap, a trap filled with solid sodium hydroxide wasused to protect the pump from acidic vapors.
5. Continuous addition of the carboxylic acid chloride solution is required to prevent clogging thesyringe needle.
6. The spectral properties are as follows: FT-IR (KBr) cm−1: 3360, 3355, 1663, 1634; 1H NMR (400MHz, CDCl3) δ: 1.42–1.49 (m, 1 H), 2.07–2.35 (m, 5 H), 3.06–3.09 (m, 1 H), 5.66 (br s, 1 H), 5.75 (appdd, 1 H, J = 2, 5), 5.76 (app dd, 1 H, J = 2.5, 4.5), 5.94 (br s, 1 H); 13C NMR δ: 29.6, 31.8, 42.0, 42.3,131.7, 133.7, 175.0.
7. Triethylamine was dried by distillation from −40 mesh calcium hydride.
8. Pentane was dried by distillation from −40 mesh calcium hydride.
9. Trimethylsilyl trifluoromethanesulfonate (99%) was purchased from Aldrich Chemical Company,Inc., and used as received.
10. Any adventitious water introduced during these operations results in a decreased yield of iodo
lactam and the formation of iodo lactone as an undesired side product.
11. The spectral properties are as follows: FT-IR (KBr) cm−1: 3189, 3078, 3034, 1680; 1H NMR (400MHz, CDCl3) δ: 1.55–1.60 (m, 1 H), 1.99–2.06 (m, 1 H), 2.10–2.20 (m, 2 H), 2.33–2.45 (m, 1 H), 2.70
(dd, 1 H, J = 18, 10), 3.05–3.13 (m, 1 H), 4.16 (br s, 1 H), 4.40 (d, 1 H, J = 7.2), 5.75–5.85 (br s, 1 H);
13C NMR δ: 32.3, 32.9, 35.0, 35.5, 38.2, 69.8, 178.6.

Waste Disposal Information
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory";
National Academy Press; Washington, DC, 1995.

3. Discussion
This "iodolactamization" procedure has been optimized for the present example. Related reaction
conditions have been used to generate a series of iodo lactams from the corresponding unsaturated
amides (Table).2,3 For these (smaller scale) examples, the cyclization was carried out in tetrahydrofuran
solution, and isolation was by column chromatography. The lactams in entries 3, 4, and 8 have also been
prepared by the submitters in 81%, 82%, and 78% yields, respectively, using the procedure describedherein. Cyclization in ether solution rather than in tetrahydrofuran avoids the formation of iodobutanol,3
which must then be separated from product.
Iodo lactams are a useful, new class of difunctional compounds.2 Conversions of iodo lactams to Nacylaziridines,3,4 unsaturated lactams,3,5 azido lactams,3,4 amino lactams,3,4 hydroxy lactams,3 seleneno
lactams,6 7 annulated lactams,3,6,7,8 and other derivatives2 have been described. Syntheses of
ezoaminuroic acid5 and slaframine6,7 have used halo lactamizations for key steps. Halo lactams havealso been prepared from aspartic acid8 and glutamic acid,9 from N-substituted unsaturated amides10,11 12
13,14 and imidates,15,16,17 and from unsaturated amides whose competing O-cyclization reaction is lessfavored.18,19 20

TABLE
PREPARATION OF IODO LACTAMS
Entry

Unsaturated Amide

Iodo Lactam(s)% Yield (cis/trans)

135a

235b386488

584 (3:1)

688 (2:1)

786 (1:1)880c

10–20% of starting amide was also recovered. b54% of crotonamide was also
isolated. cOverall yield after separate desilylation.

aReferences and Notes
1. Department of Chemistry, Rutgers The State University of New Jersey. New Brunswick, NJ
08903.
2. For a review covering all aspects of "iodolactamization", Knapp, S In "Advances in Heterocyclic
Natural Product Synthesis"; Pearson, W. H., Ed.; Jai Press: Greenwich, CN, 1996; pp. 57–98.
3. Knapp, S.; Levorse, A. T. J. Org. Chem. 1988, 53, 4006, and references therein. Preliminary
communication: Knapp, S.; Rodriques, K. E.; Levorse, A. T.; Ornaf, R. M. Tetrahedron Lett.
1985, 26, 1803.
4. Knapp, S.; Levorse, A. T. Tetrahedron Lett. 1987, 28, 3213.
5. Knapp, S.; Levorse, A. T.; Potenza, A. J. J. Org. Chem. 1988, 53, 4773.
6. Knapp, S.; Gibson, F. S.; Choe, Y. H. Tetrahedron Lett. 1990, 31, 5397;

7. Knapp, S.; Gibson, F. S. J. Org. Chem. 1992, 57, 4802.
8. Salzmann, T. N.; Ratcliffe, R. W.; Christensen, B. G.; Bouffard, F. A. J. Am. Chem. Soc. 1980,102, 6161.
9. Hardegger, E.; Ott, H. Helv. Chim. Acta 1955, 38, 312.
10. Biloski, A. J.; Wood, R. D.; Ganem, B. J. Am. Chem. Soc. 1982, 104, 3233.
11. Rajendra, G.; Miller, M. J. Tetrahedron Lett. 1985, 26, 5385;
12. Rajendra, G.; Miller, M. J. J. Org. Chem. 1987, 52, 4471;
13. Rajendra, G.; Miller, M. J. Tetrahedron Lett. 1987, 28, 6257.
14. Balko, T. W.; Brinkmeyer, R. S.; Terando, N. H. Tetrahedron Lett. 1989, 30, 2045.
15. Kano, S.; Yokomatsu, T.; Iwasawa, H.; Shibuya, S. Heterocycles 1987, 26, 359.
16. Takahata, H.; Takamatsu, T.; Mozumi, M.; Chen. Y.-S.; Yamazaki, T.; Aoe, K. J. Chem. Soc.,
Chem. Commun. 1987, 1627.
17. Kurth, M. J.; Bloom, S. H. J. Org. Chem. 1989, 54, 411.
18. Aida, T.; Legault, R.; Dugat, D.; Durst, T. Tetrahedron Lett. 1979, 4993.
19. Tamaru, Y.; Kawamura, S.; Tanaka, K.; Yoshida, Z. Tetrahedron Lett. 1984, 25, 1063;
20. Tamaru, Y.; Kawamura, S.-i. Bando, T.; Tanaka, K.; Hojo, M.; Yoshida, Z.-i. J. Org. Chem.
1988, 53, 5491.

Appendix
Chemical Abstracts Nomenclature (Collective Index Number);(Registry Number)sodium carbonate and sulfite
ezoaminuroic acidhydrogen chloride (7647-01-0)
ammonia (7664-41-7)
methanol (67-56-1)
ether (60-29-7)
ammonium chloride (12125-02-9)
sodium sulfite (7757-83-7)
sodium hydroxide (1310-73-2)
sodium chloride (7647-14-5)
sodium carbonate (497-19-8)
sodium sulfate (7757-82-6)
iodine (7553-56-2)
toluene (108-88-3)

Glutamic Acid (56-86-0)
Pentane (109-66-0)
dichloromethane (75-09-2)
Tetrahydrofuran (109-99-9)
oxalyl chloride (79-37-8)
hexane (110-54-3)
aspartic acid (56-84-8)
triethylamine (121-44-8)
argon (7440-37-1)
calcium hydride (7789-78-8)
iodoTrimethylsilyl trifluoromethanesulfonate (27607-77-8)
8-exo-Iodo-2-azabicyclo[3.3.0]octan-3-one (100556-58-9)
2-Cyclopentene-1-acetamide (72845-09-1)
2-cyclopentene-1-acetic acid2-(2-Cyclopentenyl)acetyl chloride
iodobutanol
crotonamide (23350-58-5)
Cyclopenta[b]pyrrol-2(1H)-one, hexahydro-6-iodo-, (3aα,6α,6aα)Copyright © 1921-2005, Organic Syntheses, Inc. All Rights Reserved