A Publicationof Reliable Methods
for the Preparationof Organic Compounds

Working with Hazardous Chemicals
The procedures in Organic Syntheses are intended for use only by persons with proper
training in experimental organic chemistry. All hazardous materials should be handledusing the standard procedures for work with chemicals described in references such as"Prudent Practices in the Laboratory" (The National Academies Press, Washington, D.C.,
2011;
thefulltext
canbeaccessed
freeofchargeathttp://www.nap.edu/catalog.php?record_id=12654).
All chemical waste should be
disposed of in accordance with local regulations. For general guidelines for themanagement of chemical waste, see Chapter 8 of Prudent Practices.
In some articles in Organic Syntheses, chemical-specific hazards are highlighted in red“Caution Notes” within a procedure. It is important to recognize that the absence of acaution note does not imply that no significant hazards are associated with the chemicals
involved in that procedure. Prior to performing a reaction, a thorough risk assessment
should be carried out that includes a review of the potential hazards associated with eachchemical and experimental operation on the scale that is planned for the procedure.
Guidelines for carrying out a risk assessment and for analyzing the hazards associatedwith chemicals can be found in Chapter 4 of Prudent Practices.
The procedures described in Organic Syntheses are provided as published and areconducted at one's own risk. Organic Syntheses, Inc., its Editors, and its Board ofDirectors do not warrant or guarantee the safety of individuals using these procedures andhereby disclaim any liability for any injuries or damages claimed to have resulted from orrelated in any way to the procedures herein.

September 2014: The paragraphs above replace the section “Handling and Disposal of Hazardous
Chemicals” in the originally published version of this article. The statements above do not supersede any
specific hazard caution notes and safety instructions included in the procedure.

DOI:10.15227/orgsyn.070.0195

Organic Syntheses, Coll. Vol. 9, p.502 (1998); Vol. 70, p.195 (1992).

1,2-ADDITION OF A FUNCTIONALIZED ZINC-COPPER
ORGANOMETALLIC [RCu(CN)ZnI] TO AN α,β-UNSATURATEDALDEHYDE: (E)-2-(4-HYDROXY-6-PHENYL-5-HEXENYL)-1HISOINDOLE-1,3(2H)-DIONE[1H-Isoindole-1,3(2H)-dione, 2-(4-hydroxy-6-phenyl-5-hexenyl)-]

Submitted by Ming Chang P. Yeh, Huai Gu Chen, and Paul Knochel1.
Checked by Thomas Wagler, Brian E. Jones, Thomas C. Zebovitz, and David L. Coffen.

1. Procedure
A. 2-(3-Iodopropyl)-1H-isoindole-1,3(2H)-dione 2. A dry, one-necked, 500-mL, round-bottomed
flask equipped with a magnetic stirring bar and a reflux condenser with a gas inlet at the top, is charged
with 13.4 g (50 mmol) of 2-(3-bromopropyl)-1H-isoindole-1,3(2H)-dione 1 (Note 1), 17.95 g (120mmol) of sodium iodide (Note 2), and 100 mL of acetone. The reaction mixture is stirred at reflux undernitrogen for 21 hr (Note 3). The solvent is removed on a rotary evaporator and the resulting solid isdissolved in 300 mL of dichloromethane and 200 mL of water. The two layers are separated in aseparatory funnel and the aqueous layer is extracted with two 100-mL portions of dichloromethane. The
combined organic extracts are washed successively with 100 mL of an aqueous 10% solution of sodium
thiosulfate, three 100-mL portions of water and 150 mL of brine. The organic layer is dried overanhydrous magnesium sulfate. After filtration, the solvent is removed on a rotary evaporator. The crude
white solid is dried for several hours at room temperature under reduced pressure to remove traces ofsolvent [15.0–15.5 g (47.6–49.2 mmol) 95–98% yield]. This material can be used directly in the next
step (Note 4).
B. Formation of the copper-zinc organometallic 3 from 2-(3-iodopropyl)-1H-isoindole-1,3(2H)dione. A dry, 100-mL, three-necked, round-bottomed flask is equipped with a magnetic stirring bar, 50mL pressure-equalizing addition funnel bearing a rubber septum, three-way stopcock, and athermometer. The air in the flask is replaced by dry argon and the flask is charged with 4.71 g (72mmol) of cut zinc (ca. 1.5 × 1.5 mm; (Note 5)). The flask is again flushed three times with argon. 1,2Dibromoethane (Note 6), (0.2 mL, 2.3 mmol) and 3 mL of tetrahydrofuran (THF) (Note 7) aresuccessively injected into the flask which is then heated gently with a heat gun until ebullition of solvent

is observed; the zinc suspension is stirred a few minutes and heated again. The process is repeatedthree times; 0.15 mL (1.2 mmol) of chlorotrimethylsilane2 3 4 is then injected into the addition funnel.
The cut zinc foil turns grey. After 15 min the reaction mixture is heated to 30°C with an oil bath and18.9 g (60 mmol) of iodide 2 dissolved in 30 mL of THF is added dropwise over 40 min. After addition,
the reaction mixture is stirred for 4 hr at 43°C to give a dark brown-yellow solution of the zinc reagent(Note 8). A second, dry, 250-mL, three-necked, round-bottomed flask is equipped with a magnetic
stirring bar, three-way stopcock connected to vacuum and an argon source, and two glass stoppers. The
flask is charged with 4.59 g (108 mmol) of lithium chloride (Note 9). The flask is heated with an oilbath at 130°C (oil bath temperature) under vacuum (0.1 mm) for 2 hr to dry the lithium chloride. The
reaction flask is then cooled to 25°C and flushed with argon. The two glass stoppers are replaced by alow temperature thermometer and a rubber septum and 4.84 g (54 mmol) of copper cyanide (Note 10) isadded. The flask is flushed three times with argon and 40 mL of freshly-distilled THF (Note 7) is added
to give, after 15 min, a clear yellow-green solution of the complex CuCN·2LiCl (Note 11). This solution
is cooled to ca. −40°C and the two flasks are connected via a stainless steel cannula. The solution of thezinc reagent is transferred to the THF solution of copper cyanide and lithium chloride (Note 12). The
resulting dark green solution is warmed to 0°C within 5 min and is ready to use in the next step after 5
min of stirring at this temperature.
C. (E)-2-(4-Hydroxy-6-phenyl-5-hexenyl)-1H-isoindole-1,3(2H)-dione 4. The THF solution of thecopper-zinc reagent is cooled to −78°C and 19.9 mL (162 mmol) of boron trifluoride etherate (Note 13)
is added dropwise. The reaction mixture is warmed to −30°C and stirred for 30 min, then cooled to −60°
C. (E)-Cinnamaldehyde (5.71 g, 43.2 mmol) is added slowly via a syringe. The reaction mixture isallowed to stir at −30°C for 14 hr (Note 14) and for 30 min at 0°C. After this time, conversion iscomplete as indicated by GLC analysis and the reaction mixture is poured into an Erlenmeyer flask
containing 500 mL of ethyl acetate, 100 mL of a saturated aqueous solution of ammonium chloride and5 mL of ammonium hydroxide. The mixture is filtered by suction through 10 g of Celite on a sinteredglass funnel, the contents of the funnel are washed twice with 50 mL of ethyl acetate and the filtrate isseparated into two layers. The organic layer is washed successively with 100 mL of aqueous 10%
sodium thiosulfate, and twice with 100 mL of a saturated aqueous solution of ammonium chloride. The
combined aqueous phases are extracted with 100 mL of ethyl acetate and the combined organic phases
are washed with 100 mL of a saturated aqueous sodium chloride solution, then dried over magnesium
sulfate. After filtration, the solvent is removed on a rotary evaporator (ca. 10 mm) to afford 19.85 g of acrude yellowish oil. Flash chromatography separation5 of the oil using silica gel (230-400 mesh, 570 g)
and ethyl acetate/hexane (1:2) gives 6.92 g (50% yield) of the 1,2-addition product 4 as a pale yellow
solid, mp 87–88°C, after removal of the solvents (Note 15).

2. Notes
1. The N-(3-bromopropyl)phthalimide 1 was purchased from Aldrich Chemical Company, Inc. or fromLancaster Synthesis Ltd.
2. Sodium iodide (Analytical Reagent) was purchased from Mallinckrodt, Inc.
3. A GLC analysis (Megabore Column (DB5)) shows a conversion of 95%. The remaining bromide 1 isconverted to the iodide 2 during the formation of the zinc organometallic (next reaction step).
4. The iodide 2 can be recrystallized from hexane/dichloromethane to give white needles; mp 87–88°C.6
The spectra are as follows: IR (CH2Cl2) cm−1: 3054.6 (m), 2892.5 (w), 1773.8 (m), 1716.1 (s), 1435.8(s), 1396.3 (m), 1265.6 (s); 1H NMR (360 MHz, CDCl3) δ: 2.25 (m, 2 H), 3.16 (t, 2 H, J = 7.2), 3.78 (t,2 H, J = 3.6), 7.34 (dd, 2 H, J = 6.0 and 3.1); 7.86 (dd, 2 H, J = 6.0 and 3.1); 13C NMR (90.5 MHz,CDCl3) δ: 2.1, 32.6, 38.2, 132.7, 134.8, 168.4.
5. This procedure uses cut zinc foil purchased from Alfa Products, Morton/Thiokol Inc. (foil, 0.25 mm
thick, 30 cm wide, 99.9% purity). However, zinc dust can also be used. The reaction time using zincdust is shorter and a lower reaction temperature may be possible. After formation of the zincorganometallic, the zinc dust is allowed to settle and the THF solution of the zinc organometallic istransferred via a syringe to the THF-solution of the complex CuCN·2LiCl. The checkers obtained a 51–56% yield of product, melting at 80–90°C.
6. 1,2-Dibromoethane and the chlorotrimethylsilane are purchased from Aldrich Chemical Company,Inc.
7. All the tetrahydrofuran used in this procedure was freshly distilled over sodium/benzophenone before

use.
8. A GLC analysis of hydrolyzed aliquots allows one to check the completion of the reaction. Less than
7% of the starting iodide 2 and more than 93% of N-propylphthalimide can be detected. A yield of 90%of the zinc reagent is assumed. The zinc reagent has also been formed at a reaction temperature of 33°C.
A reaction time of 16 hr is then required.
9. Anhydrous lithium chloride is purchased from Aldrich Chemical Company, Inc.
10. Copper cyanide, purchased from Aldrich Chemical Company, Inc., is not a hygroscopic salt anddoes not need to be dried before use.
11. A very small amount of undissolved lithium chloride may still be present and will dissolve after theaddition of the zinc reagent.
12. To effect the transfer, the argon pressure in the flask containing the copper salt is reduced byinserting a needle through the septum and by shutting off the argon gas entry. Washing the remaining
zinc foil with 5 mL of dry THF allows one to transfer the zinc reagent almost quantitatively.
13. Boron trifluoride etherate is purchased from Aldrich Chemical Company, Inc., and is manipulated
under argon.
14. An immersion cooler (Cryocool/Neslab) is used to maintain the temperature at −30°C.
15. A portion of this product is crystallized from 1:1 ethyl acetate:hexane to yield analytically pureproduct, mp 92–93°C (Anal. Calcd for C20H19NO3: C, 74.75; H, 5.96; N, 4.36. Found: C, 74.52; H, 6.03;
N, 4.29 ). The spectra are as follows: 1H NMR (300 MHz, CDCl3) δ: 1.67–1.81 (m, 4 H), 3.75 (t, 2 H, J= 6.9), 4.34 (m, 1 H), 6.19 (dd, 1 H, J = 15.9 and 6.8), 6.56 (d, 1 H, J = 15.9), 7.22–7.36 (m, 5 H), 7.70(m, 2 H), 7.82 (m, 2 H); 13C NMR (75.5 MHz, CDCl3) δ: 24.6, 34.1, 37.7, 72.4, 123.1, 126.4, 127.6,128.4, 128.5, 130.5, 131.9, 132.0, 133.8, 168.3; IR (CH2Cl2) cm−1: 3489.5 (br), 3058.2 (m), 3024.8 (m),2942.8 (m), 1771.3 (s), 1709.9 (s), 1467.6 (m), 1438.8 (s), 1398.8 (s), 1337.1 (s), 1266.2 (s), 1069.3(m), 969.0 (m). MS (EI) m/e 321 (M+, 45), 304 (5), 263 (2), 216 (24), 189 (20), 174 (87), 160 (89), 156(25), 148 (33), 133 (100), 115 (30), 105 (41), 91 (44), 77 (45); High resolution MS. Anal. Calcd for
C20H19NO3: 321.1365. Found: 321.1369.

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
Organometallic compounds are among the most versatile intermediates for the formation of carboncarbon bonds, but their high reactivity allows preparation of only relatively unfunctionalized reagents.
In contrast, organozinc halides with a less reactive carbon-metal bond, display a high functional grouptolerance, and can include a variety of functional groups such as esters,7 8 9,10 11 12 13 enoates,8,14
ketones,7,15,16 nitriles,17 18 19 20 halides,21 22 amino groups,14,23 24 phosphonates,25 thioethers,26 sulfoxides,26and sulfones.26 A transmetallation of these zinc organometallics to the corresponding copper
compounds, carried out using the THF-soluble copper salt CuCN·2LiCl, affords highly reactive copper
reagents [RCu(CN)ZnX]. In this procedure, we describe the synthesis of an alkylzinc iodide with aphthalimido group at the γ-position, its conversion to the corresponding copper derivative, and its
regiospecific 1,2-addition to cinnamaldehyde in the presence of boron trifluoride etherate. Copper
reagent 3 reacts with several other electrophiles in excellent yields (see Scheme). This preparation
illustrates the convenient synthesis of highly functionalized organozinc halides in THF27 and their highsynthetic potential.

References and Notes
1. The Willard H. Dow Laboratories, Department of Chemistry, The University of Michigan, AnnArbor, MI 48109.
2. For various activations of zinc metal Erdik, E. Tetrahedron 1987, 43, 2203; for zinc activation
with chlorotrimethylsilane, see: (a) Gawronski, J. K. Tetrahedron Lett. 1984, 25, 2605;
3. Picotin, G.; Miginiac, P. J. Org. Chem. 1987, 52, 4796;
4. Picotin, G.; Miginiac, P. Tetrahedron Lett. 1987, 28, 4551.
5. Still, W. C.; Kahn, M.; Mitra, M. J. Org. Chem. 1978, 43, 2923.
6. Martinkus, K. J.; Tann, C.-H.; Gould, S. J. Tetrahedron 1983, 39, 3493.
7. Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J. J. Org. Chem. 1988, 53, 2390;
8. Yeh, M. C. P.; Knochel, P.; Butler, W. M.; Berk, S. C. Tetrahedron Lett. 1988, 29, 6693;
9. Majid, T. N.; Knochel, P. Tetrahedron Lett. 1990, 31, 4413.
10. Tamaru, Y.; Ochiai, H.; Nakamura, T.; Tsubaki, K.; Yoshida, Z.-i. Tetrahedron Lett. 1985, 26,5559;
11. Tamaru, Y.; Ochiai, H.; Nakamura, T.; Yoshida, Z.-i. Tetrahedron Lett. 1986, 27, 955;
12. Nakamura, E.; Sekiya, K.; Kuwajima, I. Tetrahedron Lett. 1987, 28, 337;
13. Tamaru, Y.; Ochiai, H.; Nakamura, T.; Yoshida, Z.-i. Org. Synth., Coll. Vol. VIII 1993, 274.
14. Yeh, M. C. P.; Knochel, P.; Santa, L. E. Tetrahedron Lett. 1988, 29, 3887.
15. Berk, S. C.; Knochel, P.; Yeh, M. C. P. J. Org Chem. 1988, 53, 5789.
16. Tamaru, Y.; Ochiai, H.; Nakamura, T.; Yoshida, Z.-i. Angew. Chem. 1987, 99, 1193; Angew.
Chem., Intern. Ed. Engl. 1987, 26, 1157.
17. Yeh, M. C. P.; Knochel, P. Tetrahedron Lett. 1988, 29, 2395;
18. Yeh, M. C. P.; Knochel, P. Tetrahedron Lett. 1989, 30, 4799;
19. Tamaru, Y.; Tanigawa, H.; Yamamoto, T.; Yoshida, Z.-i. Angew. Chem. 1989, 101, 358; Angew.
Chem., Intern. Ed. Engl. 1989, 28, 351;
20. Majid, T. N.; Yeh, M. C. P.; Knochel, P. Tetrahedron Lett. 1989, 30, 5069.
21. Comins, D. L.; O'Connor, S. Tetrahedron Lett. 1987, 28, 1843;
22. Comins, D. L.; Foley, M. A. Tetrahedron Lett. 1988, 29, 6711.
23. Chen. H. G.; Hoechstetter, C.; Knochel, P. Tetrahedron Lett. 1989, 30, 4795;
24. Jackson, R. F. W.; James, K.; Wythes, M. J.; Wood, A. J. Chem. Soc., Chem. Commun. 1989,644.
25. Retherford, C.; Chou, T.-S.; Schelkun, R. M.; Knochel, P. Tetrahedron Lett. 1990, 31, 1833.
26. Achyutha Rao, S.; Tucker, C. E.; Knochel, P. Tetrahedron Lett. 1990, 31, 7575.
27. Gaudemar, M. Bull. Soc. Chim. France 1962, 974.

Appendix
Chemical Abstracts Nomenclature (Collective Index Number);(Registry Number)silica gel
brine
ethyl acetate (141-78-6)
ammonium chloride (12125-02-9)
sodium chloride (7647-14-5)
sodium thiosulfate (7772-98-7)
nitrogen (7727-37-9)
copper (7440-50-8)acetone (67-64-1)
Benzophenone (119-61-9)
zinc (7440-66-6)
sodium (13966-32-0)
1,2-dibromoethane (106-93-4)
ammonium hydroxide (1336-21-6)
sodium iodide (7681-82-5)cinnamaldehyde
dichloromethane (75-09-2)
copper cyanide (544-92-3)
magnesium sulfate (7487-88-9)
iodide (20461-54-5)
Tetrahydrofuran (109-99-9)
hexane (110-54-3)
Lithium chloride (7447-41-8)
argon (7440-37-1)
boron trifluoride etherate (109-63-7)
CHLOROTRIMETHYLSILANE (75-77-4)

phthalimido(E)-2-(4-Hydroxy-6-phenyl-5-hexenyl)-1H-isoindole-1,3(2H)-dione
1H-Isoindole-1,3(2H)-dione, 2-(4-hydroxy-6-phenyl-5-hexenyl)- (121883-31-6)
2-(3-Iodopropyl)-1H-isoindole-1,3(2H)-dione (5457-29-4)2-(3-bromopropyl)-1H-isoindole-1,3(2H)-dione,
N-(3-bromopropyl)phthalimide (5460-29-7)
N-propylphthalimide (5323-50-2)(E)-Cinnamaldehyde (104-55-2)
Copyright © 1921-2005, Organic Syntheses, Inc. All Rights Reserved