2,5-Dialkyl Cyclohexenones by Fe(CO)5-Mediated Carbonylation of Alkenyl Cyclopropanes: Functional Group Compatibility

Article abstract of DOI:10.1021/jo0302760

The preparation of alkenyl cyclopropanes 1 with a variety of common organic functionalities is reported. These substrates were subjected to the Fe(CO)₅-mediated carbonylation process under a CO atmosphere, leading to the formation of 2,5-disubstituted cyclohexenones 2, important intermediates for target-directed synthesis.

Full text of DOI:10.1021/jo0302760

2,5-Dia lk yl Cycloh exen on es by F e(CO)5-Med ia ted Ca r bon yla tion
of Alk en yl Cyclop r op a n es: F u n ction a l Gr ou p Com p a tibility
Douglass F. Taber,* Pramod V. J oshi, and Kazuo Kanai
Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716
taberdf@udel.edu
Received August 29, 2003
The preparation of alkenyl cyclopropanes 1 with a variety of common organic functionalities is
reported. These substrates were subjected to the Fe(CO)5-mediated carbonylation process under a
CO atmosphere, leading to the formation of 2,5-disubstituted cyclohexenones 2, important
intermediates for target-directed synthesis.
SCHEME 1a
In tr od u ction
We recently reported1a a general method for the
construction of 5-alkyl cyclohexenones2 by UV irradiation
of alkenyl cyclopropanes 1 in the presence of Fe(CO)5
under a CO atmosphere.3 The ease of preparation of the
enantiomerically pure alkenyl cyclopropanes used in this
process enables the rapid construction of cyclohexane
derivatives. This reaction enables the rapid assembly of
2,5-disubstituted cyclohexenone derivatives, which are
suitable intermediates for target-directed synthesis.4 We
report here a preliminary investigation of the compat-
ibility of this procedure with common organic functional
groups.
a
Conditions: (a) Fe(CO)5, hν, benzene; DBU.
Resu lts a n d Discu ssion
Esta blish m en t of th e Rea ction . Fe-mediated car-
bonyl insertion across a vinyl cyclopropane system to
generate the corresponding cyclohexenone was first
reported by Sarel and co-workers.1b Their study aimed
at establishing whether vinyl cyclopropanes could provide
a ligand of four π electrons for metal coordination. This
early work did not address the regio- and stereochemical
issues arising from such a carbonyl insertion.
We initally1a focused on the vinyl cyclopropane 4
(Scheme 1). We observed three regioisomers from the
photochemically initiated Fe(CO)5 carbonylation. Thus,
UV irradiation (Scheme 1) with Fe(CO)5 in benzene
followed by treament with DBU converted cyclopropane
4 mainly to the 5-alkyl cyclohexenone 5, the desired
regioisomer. We also observed the regioisomer 6 and the
alkene-migrated enone 7. While the enone 7 was a minor
product from the Fe-mediated carbonylation of 4, the
corresponding enone 9 was the dominant product from
the Fe-mediated carbonylation of 8. We concluded that
7 was formed by “Fe-H” isomerization of 4, and we tried
several additives to suppress this unwanted alkene
migration. We eventually found that running the reaction
in 2-propanol minimized the formation of the isomerized
byproducts 7 and 9.
(1) (a) Taber, D. F.; Kanai, K.; J iang, Q.; Bui, G. J . Am. Chem. Soc.
2000, 122, 6807. (b) Sarel, S. Acc. Chem. Res. 1978, 11, 204. (c)
Khusnutdinov, R. I.; Dzhemilev, U. M. J . Organomet. Chem. 1994, 471,
1. (d) Schulze, M. M.; Gockel, U. Tetrahedron Lett. 1996, 37, 357. (e)
Schulze, M. M.; Gockel, U. J . Organomet. Chem. 1996, 525, 155.
(2) For alternate approaches to 5-alkyl cyclohexenones, see: (a)
Asaoka, M.; Shima, K.; Takei, H. Tetrahedron Lett. 1987, 28, 5669.
(b) Schwarz, J . B.; Devine, P. N.; Meyers, A. I. Tetrahedron 1997, 53,
8795. (c) Hareau, G. P.-J .; Koiwa, M.; Hikichi, S.; Sato, F. J . Am. Chem.
Soc. 1999, 121, 3640. (d) Sarakinos, G.; Corey, E. J . Org. Lett. 1999,
1, 811.
(3) (a) Davies, H. M. L.; Bruzinski, P. R.; Lake, D. H.; Kong, N.;
Fall, M. J . J . Am. Chem. Soc. 1996, 118, 6897. (b) Zhou, S.-M.; Deng,
M.-Z.; Xia, L.-J . Angew. Chem., Int. Ed. 1998, 37, 2845. (c) Lo, M. M.-
C.; Fu, G. C. J . Am. Chem. Soc. 1998, 120, 10270. (d) Charette, A. B.;
J uteau, H.; Lebel, H.; Molinaro, C. J . Am. Chem. Soc. 1998, 120, 11943.
(e) Schwartz, J . B.; Meyers, A. I. J . Org. Chem. 1998, 63, 1619. (f)
Temme, O.; Taj, S.-A.; Andersson, P. G. J . Org. Chem. 1998, 63, 6007.
(g) Fox, M. E.; Li, C.; Marino, J . P., J r.; Overman, L. E. J . Am. Chem.
Soc. 1999, 121, 5467.
(4) For examples of the importance of 2,5-dialkyl cyclohexenones
in natural product synthesis, see: (a) Ohshima, T.; Xu, Y.; Takita, R.;
Shimizu, S.; Zhong, D.; Shibasaki, M. J . Am. Chem. Soc. 2002, 124,
14546. (b) Armstrong, A.; Davies, N. G. M.; Martin, N. G.; Rutherford,
A. P. Tetrahedron Lett. 2003, 44, 3915. (c) Corminboeuf, O.; Overman,
L. E.; Pennington, L. D. J . Am. Chem. Soc. 2003, 125, 6650.
Our preliminary exploration of the scope of this cyclo-
carbonylation is shown in Scheme 2. Disubstituted
10.1021/jo0302760 CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/28/2004
2268
J . Org. Chem. 2004, 69, 2268-2271

Fe(CO)5-Mediated Carbonylation of Alkenyl Cyclopropanes
SCHEME 2a
SCHEME 4a
a
Conditions: (a) Fe(CO)5, hν, benzene; DBU.
SCHEME 3a
a
Conditions: (a) KOtBu, Ph3P(CH2)3CO2Et; (b) LAH, THF, 0
°C; (c) TBDMSCl, TEA, DMAP, CH2Cl2; (d) (1) Ph3P, DIAD, THF,
(2) LAH, THF, (3) TsCl, TEA, DMAP, CH2Cl2; (e) NCS, Ph3P; (f)
(1) TsCl, TEA, DMAP, CH2Cl2, (2) NaSO2Ph, THF; (g) (1) BsCl,
TEA, DMAP, CH2Cl2, (2) KCN, DMF-H2O; (h) (1) Ph3P, DIAD,
THF, (2) LAH, THF, (3) Boc2O, TEA, DMAP, CH2Cl2.
a
Conditions: (a) Fe(CO)5, hν, 2-propanol; DBU.
alkenes participated efficiently, while the yield of the
cyclohexenones was lower with trisubstituted alkenes.
Since the starting alkenyl cyclopropanes were mixtures
of Z- and E-isomers, we subjected each of the isomers
separately to the Fe-mediated process and found that
each participated efficiently.
TABLE 1. Resu lts of P h otolysis of Alk en yl
Cyclop r op a n es
The issue of absolute stereocontrol was addressed by
preparing the enantiomerically pure cyclopropane 4 from
the commercially available enantiomerically pure epoxide
16. The product cyclohexenone 5 was shown to be >95%
ee by chiral HPLC anaylsis (Scheme 3). Thus, no race-
mization occurred during the Fe-mediated carbonylation
process. All other alkenyl cyclopropanes in the work
described here were racemic.
F u n ction a l Gr ou p Com p a tibility. Wittig homolo-
gation5 (Scheme 4) of the aldehyde 171a gave the ester
18. Reduction of ester 18 with lithium aluminum
hydride gave the key intermediate, alcohol 19. The
alcohol 19 was protected under standard conditions to
give 1a . Mitsunobu6a,b reaction of 19 gave the azide which
was converted to sulfonamide 1b and Boc-amine 1f.
Chlorination of alcohol 19 with NCS6c gave the chloro
cyclopropane 1c. Tosylation of 19 followed by sulfone
displacement6d gave 1d , and cyanide displacement6e of
the benzenesulfonate of 19 gave cyclopropane 1e.
The substrates 1a -f were subjected to the photo-
chemically initiated Fe(CO)5 carbonylation process under
one atmosphere of CO pressure in Pyrex tubes in a
Rayonet apparatus (350 nm) at ambient temperature. All
of the reactions were run in 2-propanol to minimize the
entry X
2/3
yield (%)
1
2
3
4
5
6
(a) OTBS
(b) NHTs
(c) Cl
(d) SO2Ph
(e) CN
5.9:1
5.2:1
6.3:1
4.7:1
4.2:1
3.4:1
80
75
68
68
66
72
(f) NHBoc
formation of the isomerized byproducts. At the end of the
irradiation, we found it convenient to add DBU1a to
convert the intermediate products to the more stable
conjugated isomers (Table 1).
Lim ita tion s of th e Ca r bon yla tion P r ocess. An
alkenyl cyclopropane bearing a free alcohol (X) OH, 19)
underwent several competing oxido-reductive processes
along with the desired cyclocarbonylation diminishing its
synthetic utility (yield of enone 2g ) 34%). The free thio
group (X ) SPh) similarly underwent competing oxida-
tion reactions, making it incompatible with this process
(yield of enone 2h ) 26%). Cyclopropane 1 with a ketone
(X ) COCH3) gave alkene migration to conjugate the
double bond with the ketone as a competing side reaction
(yield of enone 2i ) 24%). Ester 18 similarly gave the
desired cyclohexenone 2j along with the product of
migration to conjugate the alkene with the ester (yield
of enone 2j ) 27%).
(5) (a) Schimdt, U.; Leiberknecht, A.; Griesser, H.; Utz, R.; Beuttler,
T. F., Barknoviah, F. Synthesis 1986, 361. (b) Danheiser, R. L.;
Halgason, A. L. J . Am. Chem. Soc. 1994, 116, 9471.
(6) (a) Mitunobu, O. Synthesis 1981, 1. (b) Hughes, D. L. Org. Prep.
Proc. Int. 1996, 28, 127. (c) Sugimoto, O.; Mori, M.; Tanji, K.-i.
Tetrahedron Lett. 1999, 40, 7477. (d) Taber, D. F.; Yu, H. J . Org. Chem.
1997, 62, 1687. (e) Taber, D. F.; Song, Y. J . Org. Chem. Soc. 1997, 62,
6603.
Cyclopropane 1 with a bromo functionality (X ) Br)
seemed to participate efficiently in the carbonylation
J . Org. Chem, Vol. 69, No. 7, 2004 2269

Taber et al.
SCHEME 5a
sequentially, 0.5 M aqueous HCl and brine. The combined
organic extract was dried (Na2SO4) and concentrated. The
residue was chromatographed to give 1.11 g (91% yield) of
1
alcohol 19 as a clear oil. TLC: Rf ) 0.17 (25% MTBE/PE). H
NMR δ: 7.27-7.35 (5 H, m); 5.30 (1 H, m); 4.88 (1 H, ddd, J
) 1.2, 2.5, 10.8 Hz); 4.54 (2 H, s); 3.60 (2 H, m); 3.21 (1 H, dd,
J ) 2.2, 10.1 Hz); 2.41-2.43 (1 H, m); 2.20 (2 H, m); 1.72 (2 H,
m); 1.57 (2 H, m); 1.12 (1 H, m); 0.68 (1 H, dt, J ) 4.9, 8.4 Hz);
0.61 (1 H, dt, J ) 4.9, 8.4 Hz). 13C NMR δ d: 16.2, 20.2, 127.7,
127.9, 128.5, 130.6, 133.1, u: 12.3, 23.7, 32.1, 61.4, 72.6, 73.7,
138.2. IR: 3408, 1452, 1070 cm-1. MS (m/z): 246 (M+), 169,
139 (100), 129, 121. HRMS: calcd for C16H22O2 246.1619, found
246.1609.
a
Conditions: (a) CH(OEt)3, p-TsOH, (CH2OH)2.
process, but DBU treatment after the photolysis led to
partial elimination of the bromide (yield of enone 2k )
21%, yield of allyl enone ) 7%). Cyclopropane diene 1 (X
) CH2) was not a suitable substrate, as it gave a complex
mixture of alkenes, apparently resulting from double
bond migration under carbonylation conditions.
P r ep a r a tion of a n Aza bicyclic Cor e. When cyclo-
hexenone 2b (X ) NHTs) was treated7with ethylene
glycol, triethyl orthoformate, and p-toluenesulfonic acid
to protect the ketone as the ketal, we received instead
the cis-fused decahydroquinoline 20 as a 1:1 mixture of
diastereomers. These interesting cis-fused ring structures
represent the core of several alkaloids such as pumil-
iotoxin C8 and the lepadins (Scheme 5).9
Con clu sion . The Fe(CO)5-mediated carbonylation of
alkenyl cyclopropanes described here appears to be a
general method for the construction of 5-alkyl cyclohex-
enone derivatives. The process is tolerant of a variety of
common functional groups, which enhances the complex-
ity of the cyclohexenones generated by this method. The
product 2,5-disubstituted cyclohexenones are key build-
ing blocks for target directed synthesis.4
TBS Eth er 1a . To alcohol 19 (502 mg, 2.0 mmol) in 7 mL
of CH2Cl2 at 0 °C were added sequentially imidazole (417 mg,
6.1 mmol), DMAP (37.4 mg, 0.31 mmol), and TBSCl (615 mg,
4.1 mmol). The reaction mixture was stirred from 0 °C to room
temperature over 12 h. The mixture was partitioned between
MTBE and, sequentially, aqueous saturated NaHCO3 and
brine. The combined organic extract was dried (Na2SO4) and
concentrated. The residue was chromatographed to give 630
mg (86% yield) of the TBS ether 1a as an oil. TLC: Rf ) 0.87
1
(5% MTBE/PE). H NMR δ: 7.31 (5 H, m); 5.33 (1 H, dt, J )
7.5, 10.6 Hz); 4.83 (1 H, t, J ) 10.6 Hz); 4.51 (2 H, d, J ) 3.2
Hz); 3.62 (2 H, t, J ) 6.7 Hz); 3.30 (1 H, dd, J ) 3.1, 10.6 Hz);
2.19 (2 H, m); 1.67 (2 H, m); 1.48 (1 H, m); 1.1 (1 H, m); 0.91
(9 H, s); 0.71 (1 H, dt, J ) 5.0, 8.4 Hz); 0.67 (1 H, m); 0.05 (6
H, s). 13C NMR δ d: 5.1, 15.9, 18.5, 26.1, 127.7, 127.8, 128.5,
128.7, 132.7, u: 12.6, 18.5, 24, 33.1, 62.8, 72.6, 73.6, 138.7.
IR: 2852, 1255, 1100 cm-1. MS (m/z): 360 (M+),195, 141,
91(100). HRMS: (M+ H) calcd for C22H37O2Si 361.2563, found
361.2556.
Su lfon a m id e 1b. To DPPA6a (1.5 g, 5.5 mmol) in 7 mL of
THF at 0 °C was added DEAD (951 mg, 5.5 mmol) over 2 min.
The reaction mixture was stirred for 10 min, and then a
premixed 10 mL THF solution of alcohol 19 (1.12 g, 4.6 mmol)
and Ph3P (1.31 g, 5.0 mmol) was added over 5 min. The
reaction mixture was stirred from 0 °C to room temperature
over 2 h. The mixture was partitioned between MTBE and,
sequentially, aqueous saturated NH4Cl and brine. The com-
bined organic extract was dried (Na2SO4) and concentrated.
The residue was chromatographed to give 780 mg of the azide.
TLC: Rf ) 0.58 (7% MTBE/PE).
Exp er im en ta l Section 10
Ester 18. To potassium tert-butoxide (2.5 g, 0.022 mol) in
40 mL of THF was added phosphonium salt (10.2 g, 0.022 mol)
in three portions over 5 min. The reaction mixture was stirred
at 0 °C for 2 h and at room temperature for 15 min. The
reaction mixture was cooled back to 0 °C, and then aldehyde
17 (3.26 g, 0.017 mol) in 30 mL of THF was added dropwise
and the reaction mixture was stirred from 0 to 10 °C over 2 h.
The mixture was partitioned between MTBE and, sequentially,
0.5 M aqueous HCl and brine. The combined organic extract
was dried (Na2SO4) and concentrated. The residue was chro-
matographed to give 4.02 g (81% yield) of the ester 18 as a
To the azide (909 mg, 3.4 mmol) in 11 mL of THF at 0 °C
was added LiAlH46b (190 mg, 5.0 mmol). The reaction mixture
was stirred over 2 h after which time 2 mL of methanol was
added over 15 min. The resulting solid was filtered through a
pad of Celite, and the solvent was removed. The residue was
dissolved in 9 mL of CH2Cl2 and treated with triethylamine
(441 mg, 4.4 mmol), DMAP (123 mg, 1 mmol), and p-
toluenesulfonyl chloride (767 mg, 4 mmol) at room temperature
for 12 h. The mixture was partitioned between CH2Cl2 and,
sequentially, 1 M aqueous NaOH and brine. The combined
organic extract was dried (Na2SO4) and concentrated. The
residue was chromatographed to give 1.02 g (35% yield from
19) of sulfonamide 1b as an light yellow oil. TLC: Rf ) 0.43,
0.35 (30% MTBE/PE). 1H NMR δ: 7.7 (2 H, d, J ) 8.3 Hz);
7.26-7.34 (5 H, m); 5.21 (1 H, dt, J ) 7.6, 10.6 Hz); 4.86 (2 H,
m); 4.54 (2 H, d, J ) 5.2 Hz); 3.45 (1 H, dd, J ) 3.9, 10.2 Hz);
3.27 (1 H, dd, J ) 2.8, 10.2 Hz); 2.92 (2 H, m); 2.41 (3 H, s);
2.22 (1 H, m); 2.14 (1 H, m); 1.60 (2 H, m); 1.45 (2 H, m); 0.67
1
clear oil. TLC: Rf ) 0.37 (10% MTBE/PE). H NMR δ: 7.26-
7.35 (5 H, m); 5.29 (1 H, dt, J ) 7.1, 9.9 Hz); 4.85 (1 H, t, J )
9.9 Hz); 4.55 (2 H, s); 4.13 (2 H, q, J ) 7.1 Hz); 3.34 (1 H, dd,
J ) 3.4, 6.8 Hz); 3.33 (1 H, dd, J ) 3.4, 6.8 Hz); 2.48 (2 H, m);
2.39 (2 H, m); 1.47 (1 H, m); 1.13 (1 H, m); 1.25 (3 H, t, J ) 7.1
13
Hz); 0.71 (1 H, m); 0.61 (1 H, m). C NMR δ d: 14.3, 15.2,
20.4, 126.4, 127.6, 127.7, 128.4, 133.7, u: 12.4, 23.2, 34.4, 60.3,
72.6, 73.4, 138.5, 173.2. IR: 1730, 1449, 1176 cm-1. MS (m/z):
288 (M+), 214, 181 (100), 121. HRMS: calcd for C18H24O3
288.1725, found 288.1717. Anal. Calcd for C18H24O3: C, 74.95;
H, 8.39. Found: C, 74.80; H, 8.55.
13
(1 H, dt, J ) 4.9, 8.4 Hz); 0.57 (1 H, m). C NMR δ d: 16.2,
20.5, 21.7, 127.2, 127.4, 127.8, 127.9, 128.6, 129.8, 133.7, u:
12.4, 24.6, 29.4, 42.6, 72.7, 73.7, 137.2, 138.5, 143.4. IR: 3280,-
1326, 1091 cm-1. MS (m/z): 399 (M+), 281, 261, 207, 139, 106
(100), 91. HRMS: calcd for C23H30O3NS (M + H) 400.1960,
found 400.1946.
Alcoh ol 19. To ester 18 (1.43 g, 4.9 mmol) in 16 mL of THF
at 0 °C was added LAH (376 mg, 9.9 mmol) in three portions.
The reaction mixture was stirred at 0 °C for 40 min (TLC
control). The mixture was partitioned between MTBE and,
Ch lor id e 1c. To alcohol 19 (497 mg, 2.0 mmol) in 6.7 mL
of CH2Cl2 at 0 °C was added triphenylphosphine (809 mg, 3.1
mmol), followed by N-chlorosuccinimide6c (404 mg, 3.0 mmol).
The reaction mixture was stirred from 0 °C to room temper-
ature over 1.5 h. The solvent was removed, and the residue
was chromatographed to give 428 mg (74% yield) of the
chloride 1c. TLC: Rf ) 0.28 (5% MTBE/PE). 1H NMR δ: 7.27-
(7) Back, T. G.; Nakajima, K. J . Org. Chem. 1998, 63, 6566.
(8) Ozawa, T.; Aoyagi, S.; Kibayashi, C. J . Org. Chem. 2001, 66,
3338.
(9) (a) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.
(b) Taber, D. F. J . Org. Chem. 1982, 47, 1351.
(10) For general experimental procedures, see the Supporting
Information.
2270 J . Org. Chem., Vol. 69, No. 7, 2004

Fe(CO)5-Mediated Carbonylation of Alkenyl Cyclopropanes
7.36 (5 H, m); 5.4 (1 H, m); 5.11 (1 H, t, J ) 10.1 Hz); 3.57 (2
H, t, J ) 6.6 Hz); 3.41 (1 H, m); 2.33 (2 H, m); 1.82 (2 H, m);
1.74 (1 H, m); 1.39 (1 H, m); 1.05 (1 H, ddd, J ) 4.7, 8.3, 13.0
Hz); 0.62 (1 H, m); 0.35 (1 H, t, J ) 5.4 Hz). 13C NMR δ d:
14.2, 18.1, 128.5, 127.7, 127.9, 130.1, 133.8, u: 12.4, 24.8, 32.5,
44.7, 70.5, 72.7, 138.6. IR: 2931, 1450, 1095 cm-1. MS (m/z):
264 (M+), 233, 183 (100), 173. HRMS: calcd for C16H21OCl
264.1281, found 264.1280.
Su lfon e 1d . To alcohol 19 (665 mg, 2.7 mmol) in 9 mL of
CH2Cl2 at 0 °C were added triethylamine (602 mg, 5.9 mmol),
DMAP (66 mg, 0.5 mmol), and p-toluenesulfonyl chloride (618
mg, 3.2 mmol). The reaction mixture was stirred from 0 °C to
room temperature over 12 h. The mixture was partitioned
between CH2Cl2 and, sequentially, 1 M aqueous NaOH and
brine. The combined organic extract was dried (Na2SO4) and
concentrated. The residue was chromatographed to give 863
mg of tosylate. TLC: Rf ) 0.42 (25% MTBE/PE).
To the tosylate (645 mg, 1.6 mmol) in 5 mL of THF were
added Bu4NI (2.99 g, 8.1 mmol), Cu powder (16 mg, catalytic),
and PhSO2Na6d (826 mg, 5 mmol). The reaction mixture was
refluxed for 12 h, cooled to room temperature, and diluted with
5 mL of H2O. The mixture was partitioned between CH2Cl2
and brine. The combined organic extract was dried (Na2SO4)
and concentrated. The residue was chromatographed to give
650 mg (65% yield from 19) of sulfone 1d as an oil. TLC: Rf )
0.43, 0.38 (40% MTBE/PE). 1H NMR δ: 7.9 (2 H, d, J ) 7.8
Hz); 7.65 (1 H, m); 7.56 (2 H, t, J ) 7.1 Hz); 7.26-7.37 (5 H,
m); 5.18 (1 H, dt, J ) 7.4, 10.7 Hz); 4.87 (1 H, t, J ) 9.7 Hz);
4.52 (2 H, m); 3.4(2 H, m); 3.11 (2 H, m); 2.26 (2 H, m); 1.81 (2
H, m); 1.6 (1 H, m); 1.11 (1 H, m); 0.71 (1 H, dt, J ) 4.9, 8.4
Hz); 0.59 (1 H, m). 13C NMR δ d: 15.5, 20.2, 127.2, 127.3, 127.7,
128, 129, 133.4, 134.1, u: 12.1, 22.4, 25.6, 55.2, 72.1, 72.4,
138.3, 138.9. IR: 1447, 1309,1087 cm-1. MS (m/z): 370 (M+),
279, 169, 120 (100). HRMS: calcd for C22H26O3S 370.1603,
found 370.1602.
Nitr ile 1e. To alcohol 19 (620 mg, 2.5 mmol) in 8 mL of
CH2Cl2 were added pyridine (332 mg, 3.3 mmol) and DMAP
(62 mg, 0.5 mmol), followed by benzenesulfonyl chloride (534
mg, 3 mmol). The reaction mixture was stirred for 12 h at room
temperature. The mixture was partitioned between CH2Cl2
and, sequentially, 1 M aqueous NaOH and brine. The com-
bined organic extract was dried (Na2SO4) and concentrated.
The residue was chromatographed to give 930 mg (96%) of the
benzenesulfonate. TLC: Rf ) 0.27 (15% MTBE/PE).
u: 12.8, 25.2, 30.2, 40.5, 42.4, 72.9, 73.9, 138.9, 156.4. IR:1713,
1513, 1365 cm-1. MS (m/z): 346 (M+), 246, 169. HRMS: calcd
for C21H32O3N 346.2381, found 346.2382
Rep r esen ta tive P r oced u r e for F e(CO)5 Ca r bon yla tion
P r ocess. To alkenyl cyclopropane 1a (320 mg, 0.89 mmol) in
14 mL of 2-propanol (0.06 M) was added Fe(CO)5 (359 mg, 1.8
mmol). The reaction vessel was purged with CO, a CO balloon
was attached, and the mixture was photolyzed for 12 h at room
temperature in a Rayonet apparatus (350 nm). At the end of
irradiation, DBU (271 mg, 1.8 mmol) was added, and the
mixture was stirred at room temperature for 1 h under
nitrogen. The mixture was then partitioned between CH2Cl2
and, sequentially, 1 M aqueous HCl and brine. The combined
organic extract was dried (Na2SO4) and concentrated. The
residue was chromatographed to give 64.2 mg of unreacted
1a , 190 mg of 2a , and 31.8 mg of 3a . TLC (8% MTBE/PE): 1a
Rf ) 0.75, 2a Rf ) 0.37, and 3a Rf ) 0.49.
1
Cycloh exen on e 2a . H NMR δ: 7.27-7.38 (5 H, m); 6.71
(1 H, d, J ) 2.9 Hz); 4.52 (2 H, s); 3.59 (2 H, t, J ) 6.5 Hz);
3.42 (2 H, dd, J ) 2.0, 5.6 Hz); 2.46-2.57 (2 H, m); 2.41 (1 H,
m); 2.2-2.31 (2 H, m); 1.57-1.64 (2 H, m); 0.89 (9 H, s); 0.048
(6 H, s). 13 C NMR δ d: -5.1, 26.1, 36, 127.7, 127.8, 128.6, 144.3,
u 18.5, 25.9, 29.4, 31.7, 41.7, 62.8, 73.3, 73.5, 138.4, 139.4,
199.2. IR:1674, 1249, 1095 cm-1. MS (m/z): 331, 225, 191, 91
(100). HRMS: calcd for C19H27O3Si (M - C4H9) 331.1728, found
331.1729.
1
Cycloh exen on e 3a . H NMR δ: 7.27-7.35 (5 H, m); 6.71
(1 H, s); 4.54 (2 H, s); 3.87 (1 H, dd, J ) 4.3, 9.5 Hz); 3.6 (3 H,
m); 2.61 (1 H, m); 2.39 (2 H, m); 1.62 (2 H, m); 0.89 (9 H, s);
0.05 (6 H, s). 13 C NMR δ d: 5.1, 26.6, 47.5, 127.7, 127.8, 128.6,
145.2, u: 18.5, 25.4, 26.1, 26.2, 31.7, 62.9, 69.6, 73.4, 138.6,
139.3, 199.6. IR: 1667, 1251, 835 cm-1. MS (m/z): 389 (M +
H+), 331, 223,105, 91 (100). HRMS: calcd for C23H37O3Si (M
+ H) 389.2495, found 389.2512.
Deca h yd r oqu in olin e 20. To sulfonamide 2b (100 mg, 0.23
mmol) in 1.2 mL of diethyl ether was added ethylene glycol
(74 mg, 1.2 mmol) followed by p-toluenesulfonic acid (5.7 mg,
0.03 mmol) and triethyl orthoformate (100 mg, 0.68 mmol).
The reaction mixture was stirred at room temperature for 2
h. The solvent was removed, and the residue was chromato-
graphed to give 67.9 mg (62%) of ketals 20a and 20b (1H NMR
ratio ∼1:1). TLC: Rf ) 0.27 (30% MTBE/PE). The solid 20 was
recrystallized from a CH2Cl2-PE mixture to give crystals
suitable for X-ray structure determination, still in a 1:1 ratio.
1
Mp: 97-98 °C. H NMR δ: 7.72 (2 H, d, J ) 8.3 Hz); 7.67 (2
To 756 mg (1.9 mmol) of the benzenesulfonate in 7.8 mL of
3:1 DMF/H2O mixture was added KCN (1.2 g, 9.8 mmol). The
reaction mixture was maintained at reflux for 12 h, cooled to
room temperature, and diluted with 5 mL of H2O. The mixture
was partitioned between MTBE and brine. The combined
organic extract was dried (Na2SO4) and concentrated. The
residue was chromatographed to give 285 mg (57% yield from
19) of nitrile 1e as an oil. TLC: Rf ) 0.85 (36% MTBE/PE).
1H NMR δ: 7.26-7.38 (5 H, m); 5.25 (1 H, dt, J ) 7.5, 10.5
Hz); 4.94 (1 H, t, J ) 10.5 Hz); 4.53 (2 H, s); 3.4(2 H, d, J )
6.8 Hz); 2.34 (4 H, m); 1.76 (2 H, m); 1.46 (1 H, m); 1.15 (1 H,
m); 0.71 (1 H, m); 0.63 (1 H, dt, J ) 4.7, 8,4 Hz). 13C NMR δ
d: 15.9, 20.6, 125.7, 127.7, 127.8, 128.5, 134.8, u: 12.5, 16.4,
H, d, J ) 8.3 Hz); 7.35-7.38 (4 H, m); 7.24-7.33 (9 H, m);
7.13 (2 H, d, J ) 8.3 Hz); 4.56 (2 H, q, J ) 11.7 Hz); 4.46 (2 H,
m); 4.31-4.39 (1 H, m); 4.26-4.3 (1 H, m); 3.82-3.94 (7 H,
m); 3.82-3.84 92 H, m); 3.56-3.75 (2 H, m); 3.28 (2 H, d, J )
5.8 Hz); 2.92 (2 H, q, J ) 13.6 Hz); 2.38 (6 H, d, J ) 19.9 Hz);
2.15(1 H, m); 2.01 (1 H, m); 1.72-1.8 (3 H, m); 1.64-1.69 (4
13
H, m); 1.5-1.59 (5 H, m); 1.34-1.49 (6 H, m). C NMR δ d:
21.6, 21.7, 32.5, 33.4, 43.4, 43.9, 49.7, 52.7, 127.1, 127.5, 127.6,
127.6, 127.8, 128.4, 128.5, 129.7, u: 20.3, 20.6, 22.2, 24.6, 24.9,
26.2, 30.7, 33.3, 40.1, 40.5, 64.1, 64.4, 64.5, 64.6, 72.4, 72.9,
73.3, 74.5, 110.2, 110.3, 138.5, 138.6, 138.7, 138.9, 142.9, 143.0.
IR (KBr): 1337, 1151, 1093 cm-1. MS (m/z,): 266, 222 (100),
197. HRMS: calcd for C21H34O3N (M + H) 472.2178, found
472.2158.
25.5, 26.4, 72.6, 73.4, 119.9, 138.5. IR: 2244, 1447, 1068 cm-1
.
MS (m/z): 255 (M+), 164, 134, 120 (100). HRMS: calcd for
C
17H21ON 255.1623, found 255.1617.
Boc-a m in e 1f. The amine (prepared as in 1b) was dissolved
Ack n ow led gm en t. We thank the NIH (GM 60287)
for support of this work. We thank Drs. Q. J iang and
B. Chen and undergraduates G. Bui and S. Patel for
their contributions to the Fe-mediated carbonylation
project. We thank J ohn Dykins for acquiring MS data.
in in 3.5 mL of CH2Cl2 and treated with triethylamine (117
mg, 1.2 mmol), DMAP (34 mg, 0.23 mmol), and di-tert-butyl
dicarbonate (218 mg, 1.0 mmol) at room temperature for 12
h. The mixture was partitioned between CH2Cl2 and, sequen-
tially, 1 M aqueous NaOH and brine. The combined organic
extract was dried (Na2SO4) and concentrated. The residue was
chromatographed to give 209 mg (50% yield from 19) of Boc-
Su p p or tin g In for m a tion Ava ila ble: Spectral data for
cyclohexenones 2b-f, and 3b-f; characterization data (1H
1
13
amine 1f as an oil. TLC: Rf ) 0.76, 0.72 (30% MTBE/PE). H
NMR and C NMR spectra) for alkenyl cyclopropanes 1a -f
NMR δ: 7.27-7.39 (5 H, m); 5.31 (1 H, dt, J ) 7.5, 10.6 Hz);
4.86 (1 H, t, J ) 10.6 Hz); 4.72 (1 H, d, J ) 5.9 Hz); 4.54 (2 H,
d, J ) 4.3 Hz); 3.40 (2 H, m); 3.13 (2 H, m); 2.21 (2 H, m); 1.57
(3 H, m); 1.44 (9 H, s); 1.12 (1 H, m); 0.7 (1 H, m); 0.6 (1 H, m).
13C NMR δ d: 14.5, 20.7, 28.9, 127.9, 128.1, 128.2, 128.8, 133.4,
and cyclohexenones 2a -f, 3a -f, and 20a + 20b; and X-ray
structure of 20a + 20b. This material is available free of
charge via the Internet at http://pubs.acs.org.
J O0302760
J . Org. Chem, Vol. 69, No. 7, 2004 2271