Borane-mediated aldol cycloreduction of monoenone monoketones: Diastereoselective formation of quaternary centers

Article abstract of DOI:10.1021/jo020629f

Exposure of monoenone monoketones to catecholborane in THF at ambient temperature results in tandem 1,4-reduction-aldol cyclization. For aromatic and heteroaromatic enones, six-membered cyclic aldol products are formed in excellent yield with high levels of syn diastereoselectivity. Five-membered ring formation proceeds less readily, but the yield of cyclized product is improved through introduction of Rh(I) salts.

Full text of DOI:10.1021/jo020629f

Bor a n e-Med ia ted Ald ol Cyclor ed u ction of Mon oen on e
Mon ok eton es: Dia ster eoselective F or m a tion of Qu a ter n a r y
Cen ter s
Ryan R. Huddleston, David F. Cauble, and Michael J . Krische*
Department of Chemistry and Biochemistry, University of Texas at Austin, Austin, Texas 78712
mkrische@mail.utexas.edu
Received October 1, 2002
Exposure of monoenone monoketones to catecholborane in THF at ambient temperature results in
tandem 1,4-reduction-aldol cyclization. For aromatic and heteroaromatic enones, six-membered
cyclic aldol products are formed in excellent yield with high levels of syn diastereoselectivity. Five-
membered ring formation proceeds less readily, but the yield of cyclized product is improved through
introduction of Rh(I) salts.
SCHEME 1. Ca tech olbor a n e-Med ia ted Ald ol
Cyclor ed u ction
In tr od u ction
The aldol reaction represents a fundamental method
of stereogenic C-C bond formation. Due to its broad
significance, considerable effort has been invested in the
development of catalytic processes that yield stereo-
chemically defined aldol products.1 Despite these efforts,
a paucity of methods exists for catalytic aldol cyclization.
Classically, aldol cyclization has been achieved through
the use of organic catalysts.2 Inspired by the recent
introduction of methods for the catalytic reductive con-
densation of enones and aldehydes,3,4 the first examples
of metal-catalyzed aldol cyclization were recently re-
ported from our lab, i.e., the diastereoselective Co-
catalyzed aldol cycloreduction of monoenone monoalde-
hydes.5
oylation,6 utilize silane as a terminal reductant. Stimu-
lated by the utility of boron enolates in the context of
aldol chemistry7 and accounts of sequential 1,4-enone
hydroboration-intermolecular aldol condensation,8 we
herewith report studies on the catecholborane-mediated
aldol cycloreduction of monoenone monoketones. Upon
exposure to catecholborane, aromatic and heteroaromatic
monoenone monoketones afford six-membered cyclic aldol
products in excellent yield with high levels of syn
diastereoselectivity (Scheme 1).
Prior studies pertaining to sequential 1,4-enone hy-
droboration-intermolecular aldol condensation empha-
size the sensitivity of the reaction with respect to the
borane reagent.8 Competitive carbonyl reduction for both
enone and aldehyde partners is problematic, necessitat-
ing use of borane reagents that are highly selective for
conjugate reduction. Moreover, in prior studies, the boron
Barring a single exception,3e all reported catalytic
reductive aldol processes, including mechanistically re-
lated catalytic enone hydroallylation and hydrocarbam-
(1) For selected reviews on catalytic enantioselective aldol reactions,
see: (a) Machajewski, T. D.; Wong, C.-H., Lerner, R. A. Angew. Chem.,
Int. Ed. 2000, 39, 1352. (b) Denmark, S. E.; Stavenger, R. A. Acc. Chem.
Res. 2000, 33, 432. (c) Nelson, S. G. Tetrahedron: Asymmetry 1998, 9,
357. (d) Carreira, E. M. In Comprehensive Asymmetric Catalysis;
J acobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999;
Vol. III, p 1. (e) Braun, M. In Stereoselective Synthesis, Methods of
Organic Chemistry (Houben-Weyl), ed. E21; Helmchen, G., Hoffman,
R., Mulzer, J ., Schaumann, E., Eds.; Thieme: Stuttgart, 1996; Vol. 3,
p 1730.
(2) Aldol cyclizations have been catalyzed by antibodies and chiral
amines: (a) List, B.; Lerner, R. A.; Barbas, C. F., III. Org. Lett. 1999,
1, 59. (b) Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed. Engl.
1971, 10, 496. (c) Hajos, Z. G.; Parrish, D. R. J . Org. Chem. 1974, 39,
1615. (d) Agami, C.; Platzer, N.; Sevestre, H. Bull. Soc. Chim. Fr. 1987,
2, 358. (e) Eder, U.; Weichert, R.; Sauer, G. German Patent DE
2014757, Oct. 7, 1971.
(3) For catalytic reductive aldol processes, see: (a) Revis, A.; Hilty,
T. K. Tetrahedron Lett. 1987, 28, 4809. (b) Matsuda, I.; Takahashi,
K.; Sato, S. Tetrahedron Lett. 1990, 31, 5331. (c) Isayama, S.;
Mukaiyama, T. Chem. Lett. 1989, 2005. (d) Kiyooka, S.; Shimizu, A.;
Torii, S. Tetrahedron Lett. 1998, 39, 5237. (e) Ooi, T.; Doda, K.; Sakai,
D.; Maruoka, K. Tetrahedron Lett. 1999, 40, 2133. (f) Taylor, S. J .;
Morken, J . P. J . Am. Chem. Soc. 1999, 121, 12202. (g) Taylor, S. J .;
Duffey, M. O.; Morken, J . P. J . Am. Chem. Soc. 2000, 122, 4528. (h)
Zhao, C.-X.; Duffey, M. O.; Taylor, S. J .; Morken, J . P. Org. Lett. 2001,
3, 1829.
(5) Baik, T.-G.; Luiz, A. L.; Wang, L.-C.; Krische, M. J . J . Am. Chem.
Soc. 2001, 123, 5112. A nonstereoselective catalytic aldol cycloreduction
was subsequently reported: Emiabata-Smith, D.; McKillop, A.; Mills,
C.; Motherwell, W. B.; Whitehead, A. J . Synlett 2001, 1302.
(6) (a) Muraoka, T.; Matsuda, I.; Itoh, K. J . Am. Chem. Soc. 2000,
122, 9552. (b) Muraoka, T.; Matsuda, I.; Itoh, K. Organometallics 2001,
20, 4676.
(7) For selected reviews on boron enolates, see: (a) Paterson, I.;
Doughty, V. A.; Florence, G.; Gerlach, K.; McLeod, M. D.; Scott, J . P.;
Trieselmann, T. ACS Symposium Series 783; American Chemical
Society: Washington, DC, 2001; p 195. (b) Cowden, C. J .; Paterson, I.
Org. React. 1997, 51, 1. (c) Gennari, C. Pure Appl. Chem. 1997, 69,
507. (d) Paterson, I. Chem. Ind. 1988, 12, 390. (e) Evans, D. A.; Nelson,
J . V.; Taber, T. R. Top. Stereochem. 1982, 13, 1.
(8) (a) Boldrini, G. P.; Mancini, F.; Tagliavini, E.; Tromboli, C.;
Umani-Ronchi, A. Chem. Commun. 1990, 1680. (b) Evans, D. A.; Fu,
G. C. J . Org. Chem. 1990, 55, 5678. (c) Matsumoto, Y.; Hayashi, T.
Synlett 1991, 349. (d) Boldrini, G. P.; Bortolotti, M.; Mancini, F.;
Tagliavini, E.; Trombini, C.; Umani-Ronchi, A. J . Org. Chem. 1991,
56, 5820.
(4) For a review, see: Huddleston, R. R.; Krische, M. J . Synlett 2002,
in press.
10.1021/jo020629f CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/20/2002
J . Org. Chem. 2003, 68, 11-14
11

Huddleston et al.
TABLE 1. Ca tech olbor a n e-Med ia ted Ald ol
enolate was preformed in the absence of the aldehyde
partner. Given this precedent, the outcome of a related
intramolecular process was uncertain, as boron enolate
formation must take place in the presence of the appen-
dant electrophilic partner. Indeed, initial experiments
directed toward the aldol cycloreduction of monoenone
monoaldehyde substrates proved to be unsuccessful
across a range of boranes due to competitive aldehyde
reduction.
Cyclor ed u ction of Mon oen on e Mon ok eton es 1a -5a a
Resu lts a n d Discu ssion
To attenuate and perhaps circumvent competitive
reduction of the appendant electrophile, monoenone
monoketone substrates 1a -6a were examined.9,10 Initial
studies focused on the aldol cycloreduction of compound
1a . Monoenone monoketone 1a was screened against an
assortment of borane reagents (9-BBN, BH3-DMS, pina-
colborane, diisopinocampheylborane, and catecholbo-
rane). Eventually, it was found that exposure of 1a to a
slight excess of catecholborane in dry tetrahydrofuran at
ambient temperature provides the desired cycloreduction
product 1b in 89% isolated yield with a syn:anti ratio of
>99:1, as determined by HPLC analysis (Table 1). As 1,4-
enone hydroboration is known to result in the formation
(Z)-boron enolates,8c the observed syn diastereoselectivity
may be accounted for on the basis of a stereochemical
model involving the intermediacy of a Zimmerman-
Traxler-type transition state (Scheme 2).11 The structural
assignment of 1b was corroborated by single-crystal
X-ray diffraction analysis.12 These conditions proved to
be general for the cycloreduction of both aromatic and
heteroaromatic monoenone monoketones 1a -5a (Table
1). Aliphatic enones and enoates produce complex mix-
tures of reduction products under these conditions.
a
Standard Conditions: To a solution of monoenone monoketone
(1.0 mmol, 100 mol %) in anhydrous THF (2 mL, 0.5 M) was added
catecholborane (128 µL, 1.2 mmol, 120 mol %) dropwise over 2
min. The solution was stirred under an argon atmosphere for 3 h
and then quenched by dropwise addition of methanol (1 mL). The
reaction mixture was directly absorbed onto silica gel and purified
by column chromatography to afford the cyclized product.
Five-membered ring formation was next explored.
Exposure of phenyl-substituted monoenone monoketone
6a to the conditions specified in Table 1 produced only a
5% yield of the desired cycloreduction product 6b, along
with the product of simple conjugate reduction and
recovered starting material. In the course of previous
studies on the sequential 1,4-enone hydroboration-aldol
condensation, catalytic Rh(I) salts have been shown to
SCHEME 2. Ster eoch em ica l Mod el Accou n tin g for
th e Obser ved Syn Dia ster eoselectivity of th e
Ca tech olbor a n e-Med ia ted Ald ol Cyclor ed u ction
(9) Representative procedure for the preparation of substrates 1a -
5a is as follows. 1-Methylcyclopentene (30.4 mmol, 100 mol %) dissolved
in CHCl3 (200 mL, 0.15 M) was treated with ozone at -60 °C for 1.5
h. The solution was purged with N2, and triphenylphosphine (30.4
mmol, 100 mol %) was added; the reaction mixture was allowed to stir
for 2 h at 25 °C. At this point, the appropriate Wittig reagent (30.4
mmol, 100 mol %) was added in portions over 10 min and the solution
stirred for 18 h. The residue was evaporated onto silica and subjected
to column chromatography to afford monoenone monoketones 1a -5a .
(10) Procedure for the preparation of substrate 6a is as follows. To
a stirred suspension of PCC (15.65 g, 72.6 mmol, 200 mol %) at ambient
temperature in CH2Cl2 (100 mL, 0.36 M) was added dropwise 3-acetyl-
1-propanol (3.61 g, 36.3 mmol, 100 mol %). The dark solution was
stirred for 2 h at 25 °C and then filtered through a pad of silica. The
product was purified by Kugelrohr distillation to afford 4-oxo-pentanal
(2.71 g, 77% yield) as a clear colorless oil. A portion of the purified
monoketone monoaldehyde (1.82 g, 18.2 mmol, 100 mol %) was
dissolved in CH2Cl2 (200 mL, 0.091 M), and the acetophenone-derived
Wittig reagent (18.2 mmol, 100 mol %) was added in portions over 10
min; the solution was allowed to stir for 18 h. The residue was
evaporated onto silica and subjected to column chromatography to
afford the monoenone monoketone 6a (4.75 g, 86% yield) as a clear
colorless oil.
enable the condensation of R,â-unsaturated carbonyl
compounds that otherwise do not participate in this
transformation.8b Hence, catecholborane-mediated cyclo-
reduction was attempted in the presence of Wilkinson’s
catalyst [ClRh(PPh3)3] (10 mol %). Ultimately, this
system proved to be problematic due to background
reactions involving nonproductive substrate reduction
and decomposition. Hence, attention was turned to less
reactive boranes. As established in our initial screening,
substrates 1a -6a are unreactive toward pinacolborane
at ambient temperature over prolonged periods of expo-
sure. Therefore, Rh-catalysis of the pinacolborane-medi-
ated cycloreduction of 6a was explored.
Whereas catecholborane-mediated cycloreduction of 6a
provides only a 5% yield of cycloreduction product 6b,
exposure of 6a to pinacolborane and 10 mol % Wilkinson’s
catalyst affords a 22% yield of 6b. Exposure of 6a to
pinacolborane and 10 mol % [Rh(COD)Cl]2/BINAP im-
(11) Zimmerman, H. E.; Traxler, M. D. J . Am. Chem. Soc. 1957,
79, 1920.
(12) See Supporting Information for crystallographic data.
12 J . Org. Chem., Vol. 68, No. 1, 2003

Diastereoselective Formation of Quaternary Centers
TABLE 2. Rh -Ca ta lyzed Ald ol Cyclor ed u ction of 6a a n d
2a a
studies are aimed at developing catalyst systems of
enhanced substrate scope, enantioselective catalytic sys-
tems, and the discovery of related catalytic functional
group interconversions.
Exp er im en ta l Section
All reactions were run under an atmosphere of argon, unless
otherwise indicated. Anhydrous solvents were transferred by
an oven-dried syringe. Flasks were flame-dried and cooled
under a stream of nitrogen. Preparative column chromatog-
raphy employing silica gel was performed according to the
method of Still.13 Solvents for chromatography are listed as
volume/volume ratios. Melting points were determined in open
capillaries and are uncorrected. High-resolution mass spectra
(HRMS) are reported as m/e (relative intensity). Accurate
masses are reported for the molecular ion (M + 1) or a suitable
fragment ion. Proton nuclear magnetic resonance (1H NMR)
spectra were recorded at 300 or 400 MHz in CDCl3. Chemical
Shifts are reported in delta (δ) units, parts per million (ppm)
downfield from trimethylsilane. Coupling constants are re-
ported in hertz (Hz). Carbon-13 nuclear magnetic resonance
(13C NMR) spectra were recorded at 75 or 100 MHz in CDCl3.
Chemical shifts are reported in delta (δ ) units, parts per
million (ppm) relative to the center of the triplet at 77.00 ppm
for deuteriochloroform. 13C NMR spectra were routinely run
with broadband decoupling.
Representative procedures for the preparation of substrates
1a -5a and substrate 6a are provided in the text. Additionally,
representative procedures for the cycloreduction of substrates
1a -5a and substrate 6a are provided in Tables 1 and 2,
respectively.
1-P h en yl-oct-2-en e-1,7-d ion e (1a ). In accordance with the
procedure outlined in ref 9 of the text, the title compound was
obtained in 81% yield as a white crystalline solid. 1H NMR
(400 MHz, CDCl3): δ 1.82 (qt, J ) 7.2 Hz, 2H), 2.15 (s, 3H),
2.33 (m, 2H), 2.50 (t, J ) 7.2 Hz, 2H), 6.89 (m, 1H), 7.01 (m,
1H), 7.46 (m, 2H), 7.55 (m, 1H), 7.92 (m, 2H). 13C NMR (100
MHz, CDCl3): δ 22.4, 30.5, 32.3, 43.0, 126.6, 128.7, 128.7,
132.9, 138.0, 148.7, 190.7, 208.2. FTIR (NaCl): 2935, 2253,
1713, 1670, 1620, 1598, 1578, 1448, 1357, 1288, 1227, 1159,
907, 740, 650 cm-1. HRMS: calcd [M + 1] for C14H16O2
217.1229, found 217.1229. Mp: 61-62 °C.
a
Standard Conditions: Entry 1 was performed in accordance
with the procedure outlined in ref 9 of the text. Entries 2 and 3
were performed in accordance with the following procedure. To a
solution of Rh(I) catalyst (0.08 mmol, 8 mol %) and ligand (0.088
mmol, 8.8 mol %) in anhydrous THF (2 mL, 0.5 M) was added 6a
(202 mg, 1.0 mmol, 100 mol %). Pinacolborane (128 µL, 1.2 mmol,
120 mol %) was added dropwise over 2 min. The solution was
stirred under an argon atmosphere for 18 h and then quenched
by dropwise addition of methanol (1 mL). The reaction mixture
was directly absorbed onto silica gel and purified by column
chromatography to give 6b. Entry 4 was performed in accordance
with the procedure for entries 2 and 3 with the following adjust-
ments: Rh(I) catalyst (0.01 mmol, 2 mol %), ligand (0.025 mmol,
5.0 mol %), anhydrous DCE (5 mL, 0.1 M), 2a (132 mg, 0.5 mmol,
100 mol %), and pinacolborane (145 µL, 1.0 mmol, 200 mol %).
proved the isolated yield of 6b to 32%. Additional
screening of Rh(I) source and phosphine ligand did not
result in any further improvement in yield for the
cycloreduction of 6a . Indeed, this study suggests that
aldol cyclizations proceeding through the intermediacy
of (Z)-boron enolates are intrinsically more difficult for
five-membered ring formation than for six-membered
ring formation. In support of this contention, exposure
of 2a to pinacolborane and 10 mol % [Rh(COD)Cl]2/
BINAP proceeds smoothly to give the six-membered ring
aldol cycloreduction product 2b in 82% yield as a single
diastereomer. The acquisition of both 2b and 6b as nearly
racemic materials (3 and 6% enantiomeric excess, re-
spectively) supports the assertion that the aldol cyclore-
ductions catalyzed by Rh(I) proceed through the inter-
mediacy of the boron enolate, rather than the rhodium
enolate (Table 2).
1-Na p h th a len -2-yl-oct-2-en e-1,7-d ion e (2a ). In accor-
dance with the procedure outlined in ref 9 of the text, the title
compound was obtained in 83% yield as a white crystalline
solid. 1H NMR (400 MHz, CDCl3): δ 1.85 (qt, J ) 7.2 Hz, 2H),
2.16 (s, 3H), 2.38 (m, 2H), 2.52 (t, J ) 7.2 Hz, 2H), 7.07 (m,
2H), 7.56 (m, 2H), 7.95 (m, 4H), 8.43 (m, 1H). 13C NMR (100
MHz, CDCl3): δ 22.5, 30.5, 32.4, 43.1, 124.7, 126.5, 127.0,
128.0, 128.5, 128.7, 129.7, 130.2, 132.7, 135.3, 135.6, 148.6,
190.4, 208.2. FTIR (NaCl): 2942, 2253, 1713, 1666, 1630, 1617,
1468, 1356, 1294, 1220, 1188, 1126, 1095, 912, 741, 651 cm-1
.
HRMS: calcd [M + 1] for C18H18O2 267.1385, found 267.1392.
Mp: 69-70 °C.
1-Th iop h en -2-yl-oct-2-en e-1,7-d ion e (3a ). In accordance
with the procedure outlined in ref 9 of the text, the title
compound was obtained in 78% yield as a white crystalline
solid. 1H NMR (400 MHz, CDCl3): δ 1.79 (qt, J ) 9.6 Hz, 2H),
2.11 (s, 3H), 2.31 (m, 2H), 2.45 (t, J ) 9.6 Hz, 2H), 6.77 (m,
1H), 7.06 (m, 2H), 7.67 (m, 2H). 13C NMR (100 MHz, CDCl3):
δ 22.2, 30.3, 32.0, 42.8, 126.1, 128.5, 132.2, 134.1, 145.3, 148.0,
182.3, 208.4. FTIR (NaCl): 3054, 2987, 2358, 1714, 1657, 1610,
1515, 1415, 1354, 1265, 1083, 913, 744 cm-1. HRMS: calcd for
[M + 1] for C12H14O2S 223.0793, found 223.0795. Mp: 48-50
°C.
Con clu sion
Exposure of monoenone monoketones to catecholborane
in THF at ambient temperature results in tandem 1,4-
reduction-aldol cyclization. For aromatic and heteroaro-
matic enones, six-membered cyclic aldol products are
formed in excellent yield with exceptionally high levels
of syn diastereoselectivity. Five-membered ring formation
precedes less readily, but the yield of cyclized product is
improved through introduction of Rh(I) salts. Future
1-F u r a n -2-yl-oct-2-en e-1,7-d ion e (4a ). In accordance with
the procedure outlined in ref 9 of the text, the title compound
was obtained in 79% yield as a white crystalline solid. 1H NMR
(400 MHz, CDCl3): δ 1.82 (qt, J ) 7.2 Hz, 2H), 2.15 (s, 3H),
(13) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.
J . Org. Chem, Vol. 68, No. 1, 2003 13

Huddleston et al.
2.32 (m, 2H), 2.50 (t, J ) 7.2 Hz, 2H), 6.55 (m, 1H), 6.81 (m,
1H), 7.10 (m, 1H), 7.24 (m, 1H), 7.61 (m, 1H). 13C NMR (100
MHz, CDCl3): δ 22.3, 30.5, 32.2, 43.0, 112.6, 117.9, 125.6,
146.7, 147.9, 153.4, 178.0, 208.2. FTIR (NaCl): 2900, 253,
1794, 1713, 1666, 1620, 1568, 1467, 1395, 1298, 1165, 1090,
1014, 912, 742, 650 cm-1. HRMS: calcd for [M + 1] for
(m, 1H), 7.76 (m, 1H). 13C NMR (100 MHz, CDCl3): δ 21.6,
25.9, 27.7, 30.2, 39.2, 53.9, 70.4, 128.6, 132.8, 135.2, 144.2,
199.5. FTIR (NaCl): 2936, 2862, 2253, 1793, 1636, 1563, 1518,
1460, 1443, 1414, 1386, 1288, 1263, 1235, 1212, 908, 726, 650
cm-1. HRMS: calcd for [M + 1] for C12H16O2S 225.0949, found
225.0955.
C
12H14O3 207.1021, found 207.1015. Mp: 58-60 °C.
F u r a n -2-yl-(2-h yd r oxy-2-m et h yl-cycloh exyl)-m et h a -
n on e (4b). In accordance with the procedure outlined in Table
1 of the text, the title compound was obtained in 86% yield as
a clear colorless oil. 1H NMR (400 MHz, CDCl3): δ 1.20 (s,
3H), 1.31 (m, 2H), 1.53 (m, 1H), 1.82 (m, 5H), 3.12 (dd, J )
3.6, 12.2 Hz, 1H), 4.16 (br, 1H), 6.58 (m, 1H), 7.27 (m, 1H),
7.64 (m, 1H). 13C NMR (100 MHz, CDCl3): δ 21.5, 25.8, 27.0,
30.0, 39.2, 52.5, 70.4, 112.8, 118.7, 147.4, 152.4, 195.1. FTIR
(NaCl): 3054, 2986, 2938, 2859, 2685, 2305, 1652, 1567, 1464,
1-(1-Meth yl-1H-p yr r ol-2-yl)-oct-2-en e-1,7-d ion e (5a ). In
accordance with the procedure outlined in ref 9 of the text,
the title compound was obtained in 78% yield as a clear
1
colorless oil. H NMR (400 MHz, CDCl3): δ 1.79 (qt, J ) 9.6
Hz, 2H), 2.13 (s, 3H), 2.29 (m, 2H), 2.48 (t, J ) 9.6 Hz, 2H),
3.98 (s, 3H), 6.15 (m, 1H), 6.74-6.99 (m, 4H). 13C NMR (100
MHz, CDCl3): δ 22.7, 30.4, 32.0, 38.2, 43.1, 108.4, 119.5, 127.6,
131.6, 131.7, 144.7, 180.0, 208.4. FTIR (NaCl): 2949, 2253,
1712, 1656, 1605, 1527, 1460, 1407, 1308, 1237, 1095, 1068,
1443, 1422, 1396, 1265, 1166, 956, 909, 741, 705 cm-1
.
984, 912, 742, 650 cm-1. HRMS: calcd for [M + 1] for C13H17
NO2 220.1338, found 220.1338.
-
HRMS: calcd for [M + 1] for C12H16O3 209.1178, found
209.1175.
1-P h en yl-h ep t-2-en e-1,6-d ion e (6a ). In accordance with
the procedure outlined in ref 10 of the text, the title compound
was obtained in 66% yield as a clear colorless oil. 1H NMR
(400 MHz, CDCl3): δ 2.15 (s, 3H), 2.63 (m, 4H), 6.93 (m, 2H),
7.48 (m, 3H), 7.88 (m, 2H). 13C NMR (100 MHz, CDCl3): δ
26.5, 30.0, 41.5, 126.5, 128.4, 132.6, 137.6, 147.4, 190.5, 206.7.
FTIR (NaCl): 3055, 2987, 2685, 2411, 2306, 1716, 1671, 1651,
1622, 1599, 1579, 1447, 1422, 1366, 1265, 1180, 979, 896, 737,
704 cm-1. HRMS: calcd for [M + 1] for C13H14O2 203.1072,
found 203.1064.
(2-Hyd r oxy-2-m eth yl-cycloh exyl)-(1-m eth yl-1H-p yr r ol-
2-yl)-m eth a n on e (5b). In accordance with the procedure
outlined in Table 1 of the text, the title compound was obtained
in 80% yield as a clear colorless oil. 1H NMR (400 MHz,
CDCl3): δ 1.18 (s, 3H), 1.28 (m, 2H), 1.51 (m, 1H), 1.78 (m,
5H), 2.98 (dd, J ) 3.6, 12.2 Hz, 1H), 3.93 (s, 3H), 4.73 (br,
1H), 6.14 (m, 1H), 6.86 (m, 1H), 6.99 (m, 1H). 13C NMR (100
MHz, CDCl3): δ 21.7, 26.0, 28.0, 30.3, 38.4, 39.3, 52.7, 70.6,
108.6, 120.6, 130.7, 132.6, 197.1. FTIR (NaCl): 3442, 3054,
2986, 2937, 2305, 1623, 1422, 1408, 1392, 1265, 1096, 1068,
945, 901, 896, 738, 705 cm-1. HRMS: calcd for [M + 1] for
(2-H yd r oxy-2-m et h yl-cycloh exyl)-p h en yl-m et h a n on e
(1b). In accordance with the procedure outlined in Table 1 of
the text, the title compound was obtained in 89% yield as a
C
13H19NO2 222.1494, found 222.1486.
(2-H y d r o x y -2-m e t h y l-c y c lo p e n t y l)-p h e n y l-m e t h a -
n on e (6b). In accordance with the procedures cited in Table
1
white crystalline solid. H NMR (400 MHz, CDCl3): δ 1.20 (s,
3H), 1.33 (m, 2H), 1.56 (m, 1H), 1.79 (m, 5H), 3.31 (dd, J )
3.6, 12.0 Hz, 1H), 4.45 (br, 1H), 7.49 (m, 2H), 7.60 (m, 1H),
7.95 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 21.5, 25.8, 27.3,
29.9, 39.2, 51.7, 70.4, 128.5, 129.1, 133.9, 138.2, 207.4. FTIR
(NaCl): 3481, 3081, 2991, 2954, 2912, 2815,1671, 1598, 1575,
1485, 1425, 1416, 1363, 1251, 1203, 987 cm-1. HRMS: calcd
for [M + 1] for C14H18O2 219.1385, found 219.1390. Mp: 59-
60 °C.
2 of the text, the title compound was obtained in 22 and 32%
1
yields as a clear colorless oil. H NMR (400 MHz, CDCl3): δ
1.38 (s, 3H), 1.93 (m, 6H), 3.47 (dd, J ) 9.0, 10.6 Hz, 1H), 4.51
(br, 1H), 7.48 (m, 2H), 7.58 (m, 1H), 7.94 (m, 2H). 13C NMR
(100 MHz, CDCl3): δ 22.5, 27.0, 30.7, 41.1, 54.3, 81.2, 128.5,
128.9, 133.8, 137.4, 205.6. FTIR (NaCl): 3470, 3156, 2972,
2876, 2253, 1662, 1598, 1461, 1449, 1377, 1229, 912, 734, 650
cm-1. HRMS: calcd for [M + 1] for C13H16O2 205.1229, found
205.1225.
(2-Hydr oxy-2-m eth yl-cycloh exyl)-n aph th alen -2-yl-m eth -
a n on e (2b). In accordance with the procedure outlined in
Table 1 of the text, the title compound was obtained in 91%
Ack n ow led gm en t. Acknowledgment is made to the
Robert A. Welch Foundation (F-1466), the NSF-CA-
REER program (CHE-0090441), the Herman Frasch
Foundation (535-HF02), the NIH (RO1 GM65149-01),
donors of the Petroleum Research Fund administered
by the American Chemical Society (34974-G1), the Eli
Lilly Faculty Grantee program, and the Research
Corporation Cottrell Scholar Award (CS0927) for partial
support of this research.
1
yield as a white crystalline solid. H NMR (300 MHz, CDCl3):
δ 1.25 (s, 3H), 1.38 (m, 2H), 1.60 (m, 1H), 1.90 (m, 5H), 3.31
(dd, J ) 3.0, 12.2 Hz, 1H), 4.60 (br, 1H), 7.61 (m, 2H), 7.94
(m, 4H), 8.48 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 21.6, 25.8,
27.5, 30.1, 39.3, 51.7, 70.5, 124.0, 127.2, 128.0, 129.0, 129.1,
130.0, 130.4, 132.7, 134.2, 136.1, 207.3. FTIR (NaCl): 3961,
3699, 3613, 3421, 3023, 2996, 2925, 2888, 2802, 2654, 2301,
1651, 1642, 1461, 1256, 906 cm-1. HRMS: calculated for [M
+ 1] for C18H20O2 269.1541, found 269.1539. Mp: 66-68 °C.
(2-Hyd r oxy-2-m eth yl-cycloh exyl)-th iop h en -2-yl-m eth -
a n on e (3b). In accordance with the procedure outlined in
Table 1 of the text, the title compound was obtained in 83%
yield as a clear colorless oil. 1H NMR (400 MHz, CDCl3): δ
1.21 (s, 3H), 1.31 (m, 2H), 1.54 (m, 1H), 1.82 (m, 5H), 3.11
(dd, J ) 3.6, 12.4 Hz, 1H), 4.27 (br, 1H), 7.16 (m, 1H), 7.69
Su p p or tin g In for m a tion Ava ila ble: Spectral data for all
new compounds (1H NMR, 13C NMR, IR, HRMS), and crystal-
lographic data for compound 1b. This material is available free
of charge via the Internet at http://pubs.acs.org.
J O020629F
14 J . Org. Chem., Vol. 68, No. 1, 2003