Diastereoselective cyclopentane construction

Full text of DOI:10.1021/jo991866u

J . Org. Chem. 2000, 65, 3861-3863
3861
Sch em e 1
Dia ster eoselective Cyclop en ta n e
Con str u ction
Douglass F. Taber,* Yanong Wang, and
Thomas F. Pahutski, J r.
Department of Chemistry and Biochemistry, University of
Delaware, Newark, Delaware 19716
Received December 6, 1999
In the course of other work,1 we have observed that
reduction of the tosylhydrazone of ketone 2 (Scheme 1)
with NaBH3CN gave efficient cyclization to the cyclo-
pentanes 3 and 4, with high selectivity for the cis-dialkyl
product 3.
Sch em e 2
We prepared ketone 2 by condensation of the nitrile 1
with the Grignard reagent prepared from 5-bromopen-
tene. Reduction was carried out by the method of Kim.2
We observed efficient cyclization (70%), with the domi-
nant cyclized product having a methyl doublet at δ 0.59,
and the minor cyclized product having a methyl doublet
at δ 0.92. In a closely related system,3 the cis diastere-
omer had a chemical shift of δ 0.69, and the trans
diastereomer had a methyl doublet at δ 0.93. We also
isolated a 29% yield of the reduced but not cyclized
product 5 from the reaction.
We had thought1 that these cyclizations were proceed-
ing by a free-radical mechanism. Thus (Scheme 2),
reduction of the tosylhydrazone would give the monoalkyl
diazene 6. Hydrogen atom abstraction would give 7,
which would lose nitrogen to give the alkyl radical 8. The
intermediate radical 8 could either accept a hydrogen
atom from 6 to give the uncyclized product 5, or cyclize
to a mixture of 9 and 10, which would accept hydrogen
atoms to become 3 and 4. This mechanism was supported
by parallel work that had been reported by Myers.4
This view of the mechanism suggested that a higher
concentration of reactants should favor the open chain
product 5, while a lower concentration of reactants should
favor the cyclized products 2 and 3. In a brief study (Table
1) we found this to be the case.
Ta ble 1. Effect of Con cen tr a tion on th e Cycliza tion of
Keton e 2
With these results in hand, we carried out the cycliza-
tion under more conventional free radical conditions. To
this end we prepared (Scheme 3) the alcohol 12. The
derived imidazole thiocarbamate 13 was contaminated
with 10% of the alkene 14, but was too unstable to purify,
so we immediately submitted it to reduction with Bu3-
SnH in refluxing benzene. This gave 3 and 4 as before,
but now in a 29:71 cis-to-trans ratio, and in 39% yield.
As before, the major side product was the reduced but
not cyclized alkene 5 (39% yield). This was accompanied
by a 10% yield of the elimination product 14, from
dehydration of 12 in the course of thiocarbamylation. An
additional minor component, observed at δ 42 in the 13C
NMR spectrum of the mixture of 3 and 4, was assigned
the structure 15.5 We did not observe 15 in the mixture
of 3 and 4 from the reduction of the tosylhydrazone of 2.
We hypothesize (Scheme 4) that with Bu3SnH, the
radical was at least partially equilibrating between the
(1) Taber, D. F.; Wang, Y.; Stachel, S. J . Tetrahedron Lett. 1993,
34, 6209.
(2) Kim, S.; Oh, C. H.; Ko, J . S.; Ahn, K. H.; Kim, Y. J . J . Org. Chem.
1985, 50, 1927.
(3) Taber, D. F.; Anthony, J . M. Tetrahedron Lett. 1980, 21, 2779.
(4) (a) Myers, A. G.; Movassaghi, M.; Zheng, B. J . Am. Chem. Soc.
1997, 119, 8572. (b) Myers, A. G.; Movassaghi, M.; Zheng, B. Tetra-
hedron Lett. 1997, 38, 6569.
(5) Walling reported that phenylcyclohexane is eventually produced
under conditions of slow H-atom transfer: Walling, C.; Cioffari, A. J .
Am. Chem. 1972, 94, 6064.
10.1021/jo991866u CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/19/2000

3862 J . Org. Chem., Vol. 65, No. 12, 2000
Notes
Sch em e 3
a reliable approach to the family of thermodynamically
less stable cis 1,2-dialkylcyclopentane derivatives.
Exp er im en ta l Section
Gen er a l. 1H NMR (at 300 MHz) and 13C NMR (at 75 MHz)
spectra were obtained as solutions in deuteriochloroform (CDCl3).
The infrared (IR) spectra were determined as solutions in CCl4
in a 1 cm KBr solution cell using a FTIR. Rf values indicated
refer to thin-layer chromatography (TLC) on 5.0 × 10 cm, 250
µm analytical plates coated with silica gel 60 F254, developed in
the solvent system indicated. Elemental analysis was carried
out by Quantitative Technologies Inc., P.O. Box 470, Salem
Industrial Park, Bldg 5, Whitehouse, NJ 08888. Column chro-
matography was carried out following the procedure described
by Taber10 using silica gel 60 particle size 0.040-0.063 µm. The
solvent mixtures used are volume/volume mixtures. All glass-
ware was dried in a vacuum oven and all reactions were carried
out under a flow of dry nitrogen. Tetrahydrofuran (THF) and
diethyl ether were from Aldrich Sure/Seal bottles, kept under
dry nitrogen. All reaction mixtures were stirred magnetically,
unless otherwise noted.
1-(3-Meth oxyp h en yl)-5-h exen on e (2). To a 1-L three-neck
round-bottom flask, 5-bromo-1-pentene (25.0 g, 0.17 mol) in
anhydrous ether (50 mL) was added dropwise to magnesium
turnings (5.2 g, 0.21 mol) in anhydrous ether (125 mL), over 15
min at gentle reflux. After 1 h, the reaction was allowed to cool
to room temperature, and 3-methoxybenzonitrile (20.3 g, 0.153
mol) in anhydrous ether (100 mL) was added over 15 min. After
13 h at reflux, the reaction mixture was cooled to 0 °C and then
partitioned between Et2O and sequentially, 1 N aqueous HCl
and saturated aqueous NaCl. The combined organic extracts
were dried (MgSO4) and concentrated to leave 2 as a clear oil
(20.6 g, 66% yield). 1H NMR δ 7.54-7.51 (d, J ) 8.1 Hz, 1H),
7.48 (s, 1H), 7.36 (t, J ) 8.1 Hz, 1H), 7.11-7.08 (d, J ) 8.1 Hz,
1H), 5.83 (ddt, J ) 17.1, 9.9, 6.9 Hz, 1H), 5.02 (d, J ) 17.1 Hz,
Sch em e 4
(8) It was formally possible that the cyclization of the monoalkyl
diazene might be proceeding via sequential sigmatropic rearrange-
ments (6 f i f 3). To assess this alternative, we prepared and reduced
the deuterated ketone ii. The cyclized product iv showed ∼15%
incorporation of H (1H NMR) at one ortho position. There was not
enough of the reduced but not cyclized product to analyze, so we also
prepared and reduced the ketone v. The product vii also showed ∼15%
incorporation of H at one ortho position, so the cyclization is apparently
not proceeding by a mechanism that would lead to significant aryl H-D
exchange. It would be unusual if the kinetic isotope effects for the
conversion of iii to iv and for the conversion of vi to vii were each
∼3.3.
open 8 and the two cyclized diastereomers 9 and 10. The
concentrations of each of these, and the relative rates of
H-atom transfer to each, then determined the final
product ratio.6 With the tosylhydrazone reduction, on the
other hand, the hydrogen atom donor was the much
faster monoalkyl diazene.7 In this case, the competition
was between direct H-atom transfer to the benzylic
radical 8, and cyclization. The cyclized radical then
accepted an H-atom before appreciable retrocyclization
and equilibration could occur.8,9
We expect that the high diastereoselectivity that we
have observed for the cyclization of 2 will be generally
true for the cyclization of aryl ketones, thus establishing
(6) (a) This analysis is complicated by the many competing rate
constants involved. It is relevant that Newcomb reported the H-atom
transfer to a benzylic radical from Bu3SnH is about 2 orders of
magnitude slower than H-atom transfer to a terminal alkyl radical:
Newcomb, M. Tetrahedron 1993, 49, 1151. (b) The reversibility of
benzylic radical cyclization might help to rationalize the contrasting
diastereoselectivity observed by Rawal: Chambournier, G.; Krishna-
murthy, V. Rawal, V. H. Tetrahedron Lett. 1997, 38, 6313.
(7) Myers (ref 4b) concluded that H-atom transfer from a monoalkyl
diazene is about 1 order of magnitude faster than H-atom transfer
from Bu3SnH.
(9) For each cyclization, the ratio of 3 to 4 was established by
integration of the secondary methyl signals in the 1H NMR spectrum
of the mixture of the two.
(10) Taber, D. F. J . Org. Chem. 1982, 47, 1351.

Notes
J . Org. Chem., Vol. 65, No. 12, 2000 3863
1 H), 5.00 (d, J ) 9.9 Hz., 1H), 3.85 (s, 3H), 2.96 (t, J ) 7.2 Hz,
2H), 2.15 (q, J ) 7.2 Hz, 2H), 1.85 (m, 2H); 13C NMR δ CH3:
54.2 CH2: 114.4, 36.5, 31.8, 21.9 CH: 137.3, 128.7, 119.8, 118.4,
111.4 C: 199.6, 159.2, 137.7; IR 2938, 1688, 1641, 1597, 1549,
1464 cm-1; Anal. Calcd for C13H16O2: C, 76.24; H, 7.89. Found:
C, 75.85; H, 7.87.
the reaction mixture was cooled to room temperature and
partitioned between ether and saturated aqueous NH4Cl. The
combined organic extracts were dried (MgSO4) and concentrated
to a crude oil which was chromatographed, to give 12 as a
colorless oil (21.4 g, 68% yield). TLC Rf (1:4 EtOAc:hexanes) )
0.40. 1H NMR δ 7.25 (t, J ) 8.1 Hz, 1 H), 6.89-6.91 (m, 2H),
6.81 (d, J ) 8.1 Hz, 1H), 5.77 (ddt, J ) 6.0, 17.1, 9.9 Hz, 1H),
4.98 (d, J ) 17.1 Hz, 1H), 4.94 (d, J ) 9.9 Hz, 1H), 4.63 (m, 1H),
3.80 (s, 3H), 2.07 (q, J ) 6.0 Hz, 2H), 1.66-1.81 (m, 2H), 1.47-
1.57 (m, 1H), 1.35-1.45 (m, 1H); 13C NMR δ CH3: 53.9 CH2:
113.7, 37.1, 32.3, 23.7 CH: 137.9, 128.5, 117.4, 111.8, 110.5, 73.0
C: 159.0, 146.1; IR 3615, 2937, 1586 cm-1. Anal. Calcd for
1-Met h yl-2-(3-m et h oxyp h en yl)cyclop en t a n e
3 a n d 4,
P r ed om in a n tly 3. The ketone 2 (2.07 g, 10.1 mmol) was added
to p-toluenesulfonyl hydrazide (2.08 g, 11.2 mmol) in anhydrous
THF (20 mL) at reflux. After 16 h, the mixture was cooled to
room temperature and then partitioned between water and
EtOAc. The combined organic extracts were dried (MgSO4) and
concentrated to give 3.73 g of a solid. Recrystallization of the
solid from 1:1 hexanes/1-chlorobutane (30 mL) gave the tosyl-
C
13H18O2: C, 75.39; H, 8.80. Found: C, 74.98; H, 8.80.
1-Met h yl-2-(3-m et h oxyp h en yl)cyclop en t a n e
3
a n d 4,
1
hydrazone as a white solid (3.69 g, 99% yield, mp ) 97 °C). H
P r ed om in a n tly 4. 1-(3-Methoxyphenyl)-5-hexenol 12 (5.0 g,
0.024 mol) was added to CH2Cl2 (100 mL), followed by addition
of 1,1′-thiocarbonyldiimidazole (4.8 g, 0.027 mol) and imidazole
(3.7 g, 0.027 mol). The reaction mixture was then heated to
reflux. After 1.5 h, the reaction mixture was partitioned between
CH2Cl2, and, sequentially, cold 1 N aqueous HCl, saturated
aqueous NaHCO3, and water. The combined organic extracts
were dried (MgSO4) and concentrated. The crude product was
taken up in benzene (1500 mL) and a catalytic amount of AIBN
(0.150 g) was added. The reaction mixture was heated to reflux,
and HSnBu3 (7.8 g, 0.027 mol) in benzene (100 mL) was added
over 1 h. After 24 h, the reaction mixture was cooled to room
temperature, and the benzene was removed under reduced
pressure to leave a crude oil, that was purified by column
chromatography to give 3 and 4 as a colorless oil (1.8 g, 39%
yield). TLC Rf (hexanes) ) 0.45. This oil was a 71:27 trans:cis
isomeric ratio. 1H NMR δ 7.18-7.25 (m, 1H), 6.70-6.81 (m, 3H),
3.79 (s, 3H), 3.10 (q, J ) 7.7 Hz, 0.3H), 2.21-2.43 (m, 1.7H),
1.63-2.09 (m, 4H), 1.23-1.42 (m, 2H), 0.91 (d, J ) 6.9 Hz, 2.1H),
0.59 (d, J ) 6.9 Hz, 0.7H); 13C NMR δ (major) CH3: 53.9, 17.2
CH2: 34.0, 33.4, 22.5 CH: 128.3, 119.1, 112.6, 109.9, 53.4, 41.6
C: 158.9, 146.5; IR 2954, 2869, 1600, 1583, 1549, 1491, 1452,
1263, 1157, 1053 cm-1. Anal. Calcd for C13H18O: C, 82.06; H 9.53.
Found: C, 82.14; H, 9.83. This was followed by a 4:1 mixture of
5 and 14 (2.3 g, 49% yield). TLC Rf (hexanes) ) 0.43. For 14:
1H NMR δ 7.21 (t, J ) 7.9 Hz, 1H), 6.93 (d, J ) 7.9 Hz, 1H),
6.87 (s, 1H), 6.75 (d, J ) 7.9 Hz, 1H), 6.38 (d, J ) 15.8 Hz, 1H),
6.23 (dt, J ) 15.8, 6.6 Hz, 1H), 5.85 (ddt, J ) 18.8, 10.1, 6.5 Hz,
1H), 5.05 (d, J ) 18.8 Hz, 1H), 4.99 (d, J ) 10.1 Hz, 1H), 3.81
(s, 3H), 2.22-2.33 (m, 4H); 13C NMR δ CH3: 53.7 CH2: 113.4,
32.0, 30.9 CH: 136.5, 129.0, 128.5, 127.9, 117.1, 110.9, 109.8 C:
NMR δ 7.91 (d, J ) 8.7 Hz, 2H), 7.88 (bs, 1H), 7.32 (d, J ) 8.7
Hz, 2H), 7.17-7.28 (m, 3H), 6.89 (d, J ) 7.0 Hz, 1H), 5.69-5.81
(ddt, J ) 6.7, 16.7, 9.2 Hz, 1H), 5.03 (d, J ) 9.2 Hz, 1H), 5.01 (d,
J ) 16.7 Hz, 1H), 3.82 (s, 3H), 2.53 (t, J ) 7.9 Hz, 2H), 2.42 (s,
3H), 2.05 (q, J ) 6.7 Hz, 2H), 1.56 (m, 2H); 13C NMR δ CH3:
54.0, 20.2, CH2: 115.5, 31.8, 24.4, 23.4, CH: 134.6, 128.7, 128.5,
127.3, 118.0, 114.4, 110.9, C: 158.9, 154.8, 143.4, 136.9, 136.5;
IR 3215, 1549, 1387 cm-1. Anal. Calcd for C20H24N2O3S: C,
64.31; H, 6.49; N, 7.52. Found: C, 63.94; H, 6.47; N, 7.57.
The tosylhydrazone (1.00 g, 2.70 mmol) was dissolved in
anhydrous THF (10 mL). Zinc(II) chloride (446 mg, 3.7 mmol)
was added followed by NaBH3CN (212 mg, 3.7 mmol). The
reaction mixture was heated to reflux. After 18 h, the reaction
mixture was cooled to room temperature and partitioned be-
tween EtOAc and sequentially, saturated aqueous NaHCO3, 1
N aqueous HCl, and water. The organic extracts were dried
(MgSO4) and concentrated to a crude oil, which was purified by
column chromatography, to give 3 and 4 as a colorless oil (257
mg, 70% yield). TLC Rf (hexanes) ) 0.45. This oil was a 3:97
1
trans:cis isomeric mixture. H NMR δ 7.18 (t, J ) 8.1 Hz, 1H),
6.70-6.78 (m, 3H), 3.78 (s, 3H), 3.10 (q, J ) 7.7 Hz, 1H), 2.23-
2.34 (m, 1H), 1.81-1.99 (m, 4H), 1.61-1.76 (m, 1H), 1.32-1.43
(m, 1H), 0.91 (d, J ) 6.9 Hz, 0.09H), 0.59 (d, J ) 6.9 Hz, 2.91H);
13C NMR δ (major) CH3: 53.9, 14.8 CH2: 32.1, 27.6, 21.9 CH:
127.9, 120.1, 113.7, 109.5, 48.0, 36.9 C: 158.7, 144.6; IR 2955,
2872, 1582, 1548 cm-1. Anal. Calcd for C13H18O: C, 82.06; H,
9.53. Found: C, 81.83; H, 9.30. This was followed by 5 (106 mg,
29% yield). TLC Rf (hexanes) ) 0.42; 1H NMR δ 7.19 (t, J ) 7.5
Hz, 1H), 6.71-6.78 (m, 3H), 5.79 (ddt, J ) 17.0, 10.3, 7.1 Hz,
1H), 4.99 (d, J ) 17.0 Hz, 1H), 4.93 (d, J ) 10.3 Hz, 1H), 3.79
(s, 3H), 2.59 (t, J ) 7.5, 2H), 2.07 (q, J ) 7.1, 2H), 1.63 (q, J )
6.8 Hz, 2H), 1.43 (q, J ) 7.1, 2H); 13C NMR δ CH3: 53.6 CH2:
112.9, 34.3, 32.1, 29.3, 27.0 CH: 137.3, 127.7, 119.3, 112.7, 109.3
C: 158.1, 142.8; IR 2934, 1584 cm -1; Anal. Calcd for C13H18O:
C, 82.06; H, 9.53. Found: C, 81.69; H, 9.28. This was followed
by recovered ketone 2 (161 mg, 0.79 mmol).
1-(3-Meth oxyp h en yl)-5-h exen ol (12). In a 1-L three-neck
round-bottom flask, 5-bromo-1-pentene (25.0 g, 0.17 mol) in
anhydrous ether (50 mL) was added dropwise to magnesium
turnings (5.2 g, 0.21 mol) in anhydrous ether (300 mL), over 15
min at gentle reflux. After 1 h, 3-methoxybenzaldehyde 11 (20.8
g, 0.153 mol) in anhydrous ether (50 mL) was added dropwise
to the reaction mixture over 15 min. After 2 h at gentle reflux,
158.2, 137.7; IR 2929, 1548 cm-1
.
Ack n ow led gm en t. We thank DuPont Agricultural
Products for financial support. We also thank Dr. King
Mo Sun and Dr. J ames A. Kerschen for many helpful
comments and suggestions.
Su p p or tin g In for m a tion Ava ila ble: Spectroscopic data
for all new compounds (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
J O991866U