[3,3]-sigmatropic rearrangement/5-exo-dig cyclization reactions of benzyl alkynyl ethers: Synthesis of substituted 2-indanones and indenes

Article abstract of DOI:10.1021/jo200271s

Substituted benzyl alkynyl ethers, prepared from the corresponding α-alkoxy ketones in a two-step sequence involving enol triflate formation and KOtBu-induced E2 elimination, undergo [3,3]-sigmatropic rearrangement/ intramolecular 5-exo-dig cyclization at 60 °C to form substituted 2-indanones in good overall yields. 1,3-cis-Disubstituted-2-indanones are formed preferentially when the benzylic substituent R¹ is bulky. Substituted indenes may be prepared from 2-indanones in high yields by Horner-Wadsworth-Emmons reaction.

Full text of DOI:10.1021/jo200271s

NOTE
pubs.acs.org/joc
[3,3]-Sigmatropic Rearrangement/5-exo-dig Cyclization Reactions of
Benzyl Alkynyl Ethers: Synthesis of Substituted 2-Indanones and
Indenes
Armen A. Tudjarian and Thomas G. Minehan*
Department of Chemistry and Biochemistry, California State University, Northridge 18111 Nordhoff Street, Northridge,
California 91330, United States
S Supporting Information
b
ABSTRACT: Substituted benzyl alkynyl ethers, prepared from
the corresponding R-alkoxy ketones in a two-step sequence
involving enol triflate formation and KOtBu-induced E2 elimi-
nation, undergo [3,3]-sigmatropic rearrangement/intramole-
cular 5-exo-dig cyclization at 60 °C to form substituted 2-in-
danones in good overall yields. 1,3-cis-Disubstituted-2-
indanones are formed preferentially when the benzylic substituent R1 is bulky. Substituted indenes may be prepared from
2-indanones in high yields by HornerꢀWadsworthꢀEmmons reaction.
nol ethers are functional groups that possess significant
potential in organic chemistry for the formation of carbonꢀ
derived Weinreb amide11 10 with the appropriate organolithium
or Grignard reagent (path B, Scheme 2; Table 1, entries 3ꢀ4 and
6ꢀ10). Pathway B proved to be more general for the synthesis of
R-alkoxy ketones; indeed, attempted synthesis of electron-rich
substrates 3g and 3i by diazoketone-alcohol coupling led to
extensive decomposition and minimal yields of the desired
products.
Y
carbon bonds.1ꢀ3 Due to their linear geometry, alkynyl ethers are
relatively unhindered to approach by functional groups present
in the same or different molecules; furthermore, alkynyl ethers
can prospectively form up to three new bonds in a single
reaction.4
Treatment of R-alkoxy ketones 3 with LHMDS at ꢀ78 °C,
followed by addition of NPhTf2 in THF/DMPU, led to enol
triflates 11aꢀj, which were sensitive to trace amounts of acid and
heat. After rapid filtration of the crude reaction mixture through
silica gel, the enol triflates were immediately treated with potas-
sium tert-butoxide (1 M in THF) at ꢀ78 °C to effect elimination
of triflate ion, affording benzyl alkynyl ethers 12aꢀi. The crude
benzyl alkynyl ethers were also sensitive to heat and silica gel
chromatography, so they were directly warmed to 60 °C in
toluene to effect [3,3]-sigmatropic rearrangement/5-exo-dig
cyclization to provide the substituted indanones 13aꢀi in good
overall yields. This process was successfully employed for alkynyl
ether substrates derived from electron-rich (Table 1, entries 2
and 3) and electron-deficient (entry 4) benzylic alcohols and
electron-rich (entries 6 and 7) and electron-deficient (entry 8)
aryl ketones.
We have recently uncovered a straightforward methodology
for the preparation of alkynyl ethers (Scheme 1)2 involving the
coupling of alcohols 2 with diazoketones 1 in the presence of
indium triflate as a catalyst; the R-alkoxy ketone product 3 is
readily transformed into the enol triflate or phosphate at low
temperatures, which then undergoes base-induced elimination.3
Allyl-1-alkynyl ethers 7 are thermally unstable and undergo a
rapid [3,3]-sigmatropic rearrangement5 upon generation at
ꢀ78 °C to form allyl ketene intermediate 8, which is subse-
quently trapped by an alcohol or amine to form γ,δ-unsaturated
carboxylic acid derivatives 9 in high yields.4
Guided by the pioneering studies of Arens6 and Schmidt,7 we
have also shown that benzyl-1-alkynyl ether 12, which is stable at
ambient temperatures, undergoes sigmatropic rearrangement
and intramolecular cyclization at 60 °C to form 1-phenyl-2-
indanone 13 in 98% yield. Due to the efficiency of this process,
we decided to further explore its scope and utility, and in this
Note we report our findings on the diastereoselectivity of the
benzyl alkynyl ether sigmatropic rearrangement/intramolecular
cyclization reaction and its applicability to the preparation of
substituted 2-indanones and indenes.
The R-alkoxy ketones 3 (Scheme 2 and Table 1) necessary for
the synthesis of benzyl alkynyl ethers 12 were prepared either by
coupling of the appropriate diazoketones 18 with benzyl alcohol
2 in the presence of 10 mol % In(OTf)3 (path A, Scheme 2;
Table 1, entries 1, 2, and 5)9 or by reaction of aryloxyacetic acid10
Alkynyl ethers derived from R,β-unsaturated ketones (entry 5)
and heteroaryl ketones (entry 9) also smoothly underwent the
rearrangement/cyclization process, furnishing indanones 13e
and 13i in 95% and 62% yields, respectively. However, attempted
elimination and thermolysis of alkyne-substituted enol triflate
11j (entry 10) led to a complex mixture of products, likely arising
Received: February 7, 2011
Published: March 15, 2011
r
2011 American Chemical Society
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|

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NOTE
Scheme 1. 1-Alkynyl Ether Synthesis and [3,3]-Sigmatropy
Scheme 2. Two Methods for the Synthesis of Ketones 3
from the intermediacy of various allenic species3 under the basic
conditions employed for elimination.
ethers are employed. Ketones 14aꢀe were prepared by protocol
A (Scheme 2) and subjected to enol triflate formation, tert-
butoxide induced triflate elimination, and thermal rearrange-
ment/cyclization to furnish 1,3-disubstituted-2-indanones 15
(Table 3). Only in the case of the phenyl-substituted ketone
14e did the reaction sequence fail to afford the desired indanone
product; enol triflate formation from 14e led to complicated
mixtures due to the heightened acidity of the benzylic proton and
the basic conditions involved.
Low to moderate diastereoselectivity was observed for methyl-,
butyl-, and isopropyl-substituted indanones 15aꢀc; however,
excellent diastereoselectivity (>95:5) was obtained for 1-tert-
butyl-3-phenyl-indanone 15d. The presence of crosspeaks be-
tween the C.1 and C.3 protons (Hb and Ha, respectively)
observed in the NOESY spectrum of 15d (as well as correlations
between Ha and Hc, Hc and Hd, and Hd and Hb) confirmed the cis
stereochemistry (Scheme 3). Mechanistically, we propose that
the large tert-butyl substituent prefers to be oriented trans to the
ketene in the nonaromatic intermediate 16a;15 5-exo-dig cycliza-
tion, followed by a syn-1,2-proton migration to the enolate
carbon atom, would give rise to the product with the observed
stereochemistry.
Finally, we sought to transform our 2-indanone products 13
into synthetically useful substituted indenes. Indenes are building
blocks in the synthesis of biologically active pharmaceutical
agents16 and are often used as ligands in olefin polymerization
catalysts.17 Addition of indanone 13b to a solution of diethyl-
(cyanomethyl)phosphonoacetate and NaH in THF and stirring
for 4 h at room temperature resulted in clean transformation to
indene 18b (91% isolated yield), arising from carbonyl olefina-
tion and base-mediated isomerization (Scheme 4). Reduction of
the nitrile functional group and in situ primary amine protection
as a tert-butyl carbamate was accomplished in a single step by
Monitoring the rates of rearrangement/cyclization12 for alky-
nyl ether substrates 12aꢀd by 1H NMR spectroscopy revealed
interesting trends (Table 2). Whereas unsubstituted parent
compound 12a underwent first-order decay to 13a at 57 °C in
CDCl3 with a half-life of 4.8 min, alkynyl ether 12b under the
same conditions displayed a half-life of only 0.8 min, and
methoxy-substituted substrate 12c could not be isolated at room
temperature, having completely rearranged to indanone 13c
upon warming the KOtBu elimination reaction of 11c from
ꢀ78 °C to ambient. In contrast, CF3-substituted alkynyl ether
12d displayed a half-life of 13.3 min at 57 °C. Assuming that the
rate-determining step of the transformation 12f13 is the [3,3]-
sigmatropic rearrangement, the rate acceleration observed for
substrates bearing electron-donating substituents (Y) on the
benzyl moiety suggests the development of charge deficiency
(either a radical or cationic intermediate)13 at the benzylic carbon
atom during the transition state for sigmatropic rearrangement.
A similar analysis of the rates of rearrangement of 12fꢀh
compared to 12a revealed again that electron-donating substit-
uents accelerated the rearrangement/cyclization process: whereas
12f displayed a half-life of 3.6 min at 57 °C, substrate 12g had
completely rearranged to 13g upon reaching room temperature
after generation at ꢀ78 °C. Intriguingly, however, it was found
that CF3-substituted alkynyl ether 12h underwent first-order
decay slightly faster than 12a, displaying a half-life of 4.6 min at
57 °C. These observations are consistent with a change in
mechanism14 upon proceeding from electron-donating to electron-
withdrawing substituents on the aromatic moiety X, with a radical
mechanism (pathway A, Figure 1) likely operative for the former
and a polar mechanism (pathway B, Figure 1) for the latter.
Next, we sought to examine the stereoselectivity of the
rearrangement/cyclization reaction when R-substituted benzyl
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NOTE
Table 1. Scope of Benzyl Alkynyl Ether [3,3]-Sigmatropy/
5-exo-dig Cyclization
Figure 1. Possible TS charge development for benzyl alkynyl ether
sigmatropy.
Table 3. Rearrangement/Cyclization of r-Substituted Benzyl
Alkynyl Ethersa
a Ketones 14 prepared by method A (Scheme 2). b Isolated yields.
Scheme 3. Mechanistic Proposal for the Formation of
Indanone 15d
a R-Alkoxy ketone 3 prepared by method A (Scheme 2). b R-Alkoxy
c
ketone 3 prepared by method B (Scheme 2). A complex mixture of
products was formed. d Yield (from 3) based on weight obtained after
rapid filtration of the crude triflation reaction mixture through silica gel
(see text). e Isolated yield (from 11) after silica gel chromatography.
Table 2. Kinetic Data for the First-Order Decay of 12 to 13 at
57 °C in CDCl3
substrate
t1/2(min)
k (minꢀ1
)
12a
12b
12d
12f
4.8
0.8
0.145
0.905
0.052
0.191
0.149
benzyl alkynyl ethers are employed as substrates. The 2-inda-
nones obtained by this method may be easily transformed into
useful substituted indene products.
13.3
3.6
12h
4.6
’ EXPERIMENTAL SECTION
Representative Procedure for the Synthesis of Ketones
3a, 3b, 3e, and 14aꢀe. 2-(Benzyloxy)-1-phenylethanone 3a.
A mixture of the diazoacetophenone (136 mg, 1 mmol) and benzyl
alcohol (162 mg, 1.5 mmol) was dissolved in dry toluene (4 mL)
under argon and stirred at room temperature for 2 min. Indium(III)
trifluoromethanesulfonate (56.2 mg, 0.1 mmol, 10 mol %) was added,
and a rapid evolution of nitrogen gas was observed. The reaction was
monitored by TLC, and when complete consumption of the starting
material was observed, saturated NaHCO3 (10 mL) was added, and the
reaction mixture was diluted with ether (20 mL). The phases were
employing Caddick’s protocol18 (cat. NiCl2 H2O, NaBH4,
Boc2O, MeOH) to afford indene 19b in 60% yield.
3
In conclusion, we have shown that the [3,3]-sigmatropic
rearrangement of benzyl alkynyl ethers may be successfully
employed for a variety of substrates bearing electron- deficient
and electron-rich aromatic and heteroaromatic ring systems, and
the rates of rearrangement vary depending upon the electronic
nature of the aromatic substituents. Furthermore, 1,3-cis-disub-
stituted-2-indanones are formed in excess when R-substituted
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NOTE
Scheme 4. Transformation of 2-Indanones into Substituted
Indenes
14e (71%): 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 7.6 Hz, 2H),
7.55 (t, J = 7.4 Hz, 1H), 7.46ꢀ7.41 (m, 6H), 7.35 (t, J = 7.6 Hz, 4H), 7.28
(t, J = 7.8 Hz, 2H), 5.64 (s, 1H), 4.77 (s, 2H); 13C NMR (100 MHz,
CDCl3) δ 196.3, 141.3, 135.1, 133.5, 128.7, 128.5, 128.0, 127.8, 127.4,
83.8, 77.4, 77.1, 76.8, 71.4; HRMS (ESI) calculated for C21H18NaO2
325.1204, found 325.1541 (M þ Na)þ.
Representative Procedure for the Synthesis of Ketones
3c, 3d, and 3fꢀj. To a solution of the aryloxy acetic acid10 (1 g,
6 mmol) in 11 mL dichloromethane at 0 °C was added 1,10-carbonyl
diimidazole (1.26 g, 7.82 mmol) at 0 °C. The solution bubbled, and
upon completion it was warmed to room temperature for 30 min. The
solution was cooled to 0 °C, and triethylamine (1.1 mL, 8.4 mmol) was
added, followed by the Weinreb amine hydrochloride salt (0.82 g, 8.4
mmol). The solution was allowed to warm to room temperature and was
stirred overnight. The mixture was diluted with 1 M HCl (10 mL) and
EtOAc (20 mL). The phases were separated, and the aqueous phase was
back-extracted with EtOAc (1 ꢁ 20 mL). The combined organic extracts
were then dried over Na2SO4, filtered, and concentrated in vacuo. Crude
amide 10 was taken directly to the next step without further purification.
To a solution of Weinreb amide 10 (5 mmol) in THF (5 mL) at
ꢀ78 °C under argon was added a solution of aryllithium reagent
(generated from the corresponding aryl bromide 1 M in THF by the
addition of 0.95 equiv n-BuLi) dropwise. Upon completion of the
addition, TLC indicated complete conversion to the aryl ketone. The
mixture was allowed to warm to ꢀ20 °C and was quenched with
saturated NH4Cl solution (10 mL). The mixture was diluted with ether
(3 mL) and was allowed to stir at room temperature for one hour. The
phases were separated, and the aqueous phase was back-extracted with
EtOAc (1 ꢁ 20 mL). The combined organic extracts were then dried
over Na2SO4, filtered, and concentrated in vacuo. Purification of the
residue by flash chromatography (SiO2) afforded R-alkoxyketones 3.
3c (71%): 1H NMR (400 MHz, CDCl3) δ 7.83 (dd, J = 8.4, 1.2 Hz,
2H), 7.45ꢀ7.25 (m, 5H), 6.83 (d, J = 8.8 Hz, 2H), 4.62 (s, 2H), 4.54
(s, 2H), 3.67 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 196.3, 159.4, 134.9,
133.4, 129.7, 129.4, 128.6, 128.3, 127.8, 113.8, 72.9, 72.2, 55.1; HRMS (ESI)
calculated for C16H16NaO3 279.0997, found 279.1098 (M þ Na)þ.
3d (68%): 1H NMR (400 MHz, CDCl3) δ 7.91 (dd, J = 9.6 Hz, 2H),
7.61ꢀ7.42 (m, 7H), 4.81 (s, 2H), 4.72 (s, 2H); 13C NMR (100 MHz,
CDCl3) δ 196.0, 141.6, 134.7, 133.7, 129.5, 128.8, 127.9, 127.8, 125.4,
125.3, 115.4, 72.8, 72.5; HRMS (ESI) calculated for C16H13 F3NaO2
317.0765, found 317.0852 (M þ Na)þ.
separated, and the aqueous phase was back-extracted with ether (1 ꢁ
20 mL). The combined organic extracts were then dried over Na2SO4,
filtered, and concentrated in vacuo. Purification of the residue by flash
chromatography (SiO2) afforded R-alkoxyketone 3a.
3a3 (87%): 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 7.6 Hz, 2H),
7.57 (t, J = 7.6 Hz, 1H), 7.46 (t, J = 8.0 Hz, 2H), 7.40- 7.27 (m, 5H), 4.82
(s, 2H), 4.70 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 197.2, 136.9,
134.6, 133.9, 129.4, 128.8, 128.6, 128.2, 127.9, 127.1, 123.6, 73.4,
72.4; HRMS (ESI) calculated for C15H14NaO2 249.0892, found
249.0854 (M þ Na)þ.
3b (82%): 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 7.6 Hz, 2H),
7.51 (t, J = 7.6 Hz, 1H), 7.46ꢀ7.27 (m, 6H), 4.72 (s, 2H), 4.65 (s, 2H),
2.34 (s, 3H); 13C NMR: (100 MHz, CDCl3) δ 196.3, 137.6, 135.0,
134.4, 133.5, 129.2, 128.7, 128.2, 128.0, 73.2, 72.5, 21.2; HRMS (ESI)
calculated for C16H16NaO2 263.1048, found 263.1107 (M þ Na)þ.
3e (61%): 1H NMR (400 MHz, CDCl3) δ 7.83 (dd, J = 8.4, 1.2 Hz,
2H), 7.45ꢀ7.25 (m, 5H), 6.83 (d, J = 8.8 Hz, 2H), 4.62 (s, 2H), 4.54
(s, 2H), 3.67 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 196.3, 159.4,
134.9, 133.4, 129.7, 129.4, 128.6, 128.3, 127.8, 113.8, 72.9, 72.2, 55.1;
HRMS (ESI) calculated for C16H16NaO3 279.0997, found 279.1098
(M þ Na)þ.
14a (75%):1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 7.6 Hz, 2H),
7.46 (t, J = 7.6 Hz, 1H), 7.36ꢀ7.25 (m, 7H), 4.65 (d, J = 16.8 Hz, 1H),
4.54 (q, J = 6.4 Hz, 1H), 4.52 (d, J = 16.8 Hz, 1H), 1.54 (d, J = 6.4 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 195.9, 142.9, 135.0, 131.1, 128.6,
128.5, 128.2, 127.8, 127.7, 126.3, 78.3, 77.9, 71.2, 24.0, 23.9;
HRMS (ESI) calculated for C16H16NaO2 263.1048 found 263.1632
(M þ Na)þ.
3f (69%): 1H NMR (400 MHz, CDCl3) δ 7.83ꢀ7.80 (d, J = 8.4 Hz,
2H), 7.41ꢀ7.23 (m, 7H), 4.73 (s, 2H), 4.68 (s, 2H), 2.39 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 195.9, 144.4, 137.4, 132.4, 129.3, 128.5,
128.1, 128.0, 73.3, 72.5, 21.7; HRMS (ESI) calculated for C16H16NaO2
263.1048, found 263.1055 (M þ Na)þ.
14b (78%): 1H NMR: (400 MHz, CDCl3) δ 7.84 (d, J = 8.4 Hz, 2H),
7.50 (t, J = 7.6 Hz, 1H), 7.40ꢀ7.25 (m, 7H), 4.63 (d, J = 16.8 Hz, 1H),
4.49 (d, J = 16.8 Hz, 1H), 4.40 (t, J = 6.8 Hz, 1H), 1.97 (m, 1H), 1.72 (m,
1H), 1.43 (m, 1H), 1.30 (m, 1H), 0.86 (t, J = 7.6 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 196.4, 141.7, 135.1, 133.3, 128.6, 128.5, 128.3,
127.9, 127.0, 83.1, 71.3, 37.9, 28.0, 22.6, 14.0; HRMS (ESI) calculated
for C19H22NaO2 305.1517, found 305.1343 (M þ Na)þ.
3g (82%): 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 8.8 Hz, 2H),
7.40ꢀ7.32 (m, 5H), 6.88 (d, J = 8.8 Hz, 2H), 4.69 (s, 2H), 4.66 (s, 2H),
3.81 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 194.9, 163.8, 150.6, 137.5,
130.3, 128.5, 128.0, 127.9, 116.2, 114.7, 113.9, 73.3, 72.5, 55.4; HRMS (ESI)
calculated for C16H16NaO3 279.0997, found 279.0780 (M þ Na)þ.
3h (73%): 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 8.0 Hz, 2H),
7.74 (d, J = 8.4 Hz, 2H), 7.39ꢀ7.33 (m, 5H), 4.76 (s, 2H), 4.70 (s, 2H);
13C NMR (100 MHz, CDCl3) δ 195.6, 137.5, 136.9, 134.8, 128.6, 128.4,
128.2, 128.1, 125.7, 73.5, 72.8; HRMS (ESI) calculated for
C16H13F3NaO2 317.0765, found 317.0923 (M þ Na)þ.
14c (73%): 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 8.0 Hz, 2H),
7.43 (t, J = 7.8 Hz, 1H), 7.33ꢀ7.21 (m, 7H), 4.52 (d, J = 16.0 Hz, 1H);
4.35 (d, J = 16.0 Hz, 1H); 3.97 (d, J = 8.0 Hz, 1H); 1.96 (m, J = 8.0 Hz,
1H); 0.98 (d, J = 8.0 Hz, 3H); 0.65 (d, J = 8.0 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 196.6, 140.3, 135.2, 133.3, 128.6, 128.5, 128.2, 128.0,
127.8, 127.7, 88.6, 71.6, 34.8, 19.2, 19.0; HRMS (ESI) calculated for
C18H20NaO2 291.1361, found 291.1440 (M þ Na)þ.
3i (85%): 1H NMR (400 MHz, CDCl3) δ 7.53 (s, 1H), 7.52ꢀ7.24
(m, 6H), 6.47 (m, 1H), 4.63 (s, 2H), 4.54 (s, 2H); 13C NMR (100 MHz,
CDCl3) δ 185.5, 150.9, 146.7, 137.3, 128.5, 128.3, 128.0, 127.9, 118.2,
112.3, 73.4, 72.2; HRMS (ESI) calculated for C13H12NaO3 239.0684,
found 239.0717 (M þ Na)þ.
1
14d (66%): H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 8.0 Hz,
2H), 7.49 (t, J = 7.8 Hz, 1H); 7.37 (t, J = 7.8 Hz, 2H). 7.32ꢀ7.25
(m, 5H), 4.62 (d, J = 16.0 Hz, 1H), 4.41 (d, J = 16.0 Hz, 1H), 4.15
(s, 1H), 0.96 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 196.5, 138.8,
135.3, 133.3, 128.6, 128.5, 128.0, 127.7, 127.6, 90.6, 71.9, 35.8; 26.4;
HRMS (ESI) calculated for C19H22NaO2 305.1517, found 305.1962
(M þ Na)þ.
3j (92%): 1H NMR (400 MHz, CDCl3) δ 7.36ꢀ7.25 (m, 5H), 4.62
(s, 2H), 4.19 (s, 2H), 2.37 (t, J = 6.8 Hz, 2H), 1.56 (m, J = 7.2 Hz, 2H),
1.38ꢀ1.26 (m, 5H), 0.89 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz,
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NOTE
CDCl3) δ 185.0, 137.1, 128.4, 127.9, 97.5, 82.7, 75.8, 73.3, 31.2, 28.5,
27.5, 22.5, 22.4, 19.0, 14.0; HRMS (ESI) calculated for C17H22NaO2
281.1517, found 281.1582 (M þ Na)þ.
(s, 1H), 3.65 (s, 2H), 2.34 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 214.2, 141.5, 137.2, 137.0, 135.2, 129.5, 128.5, 128.3, 127.9, 127.8,
126.0, 124.8, 59.4, 42.9, 21.1; HRMS (ESI) calculated for C16H14NaO
245.0942, found 245.0921 (M þ Na)þ.
Representative Procedure for Enol Triflate (11aꢀi) For-
mation. Hexamethyldisilazane (0.29 mL, 2.5 mmol) dissolved in dry
THF (1 mL) under argon was cooled to 0 °C in an ice bath, and n-BuLi
(0.75 mL), 2 M in cyclohexane, 1.5 mmol) was added dropwise. After
10 min, the mixture was cooled to ꢀ78 °C and a solution ofR-alkoxyketone
(1 mmol) in THF (1 mL) was added dropwise. The reaction mixture
was stirred for 1 h at ꢀ78 °C, and then a solution of N-phenyl triflimide
(1.5 mmol) in 1:1 THF/DMPU (1 mL) was added rapidly (1 s). The
mixture was allowed to warm to room temperature and then was stirred
for 1 h, at which time TLC indicated >90% consumption of starting
material. The phases were separated, and the aqueous phase was back-
extracted with ether (1 ꢁ 20 mL). The combined organic extracts were
then dried over Na2SO4, filtered, and concentrated in vacuo. The crude
enol triflate was filtered over silica gel employing 1% Et3N in the eluant
(95:5 hexanes/ether), and the material obtained was used directly in the
next reaction.
13g (88%): 1H NMR (400 MHz, CDCl3) δ 7.38ꢀ7.20 (m, 5H), 7.05
(d, J = 6.4 Hz, 2H), 6.87 (d, J = 6.4 Hz, 2H), 4.63 (s, 1H), 3.78 (s, 3H),
3.66 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 214.4, 158.9, 141.6, 137.2,
130.3, 129.5, 128.3, 127.9, 127.8, 126.0, 124.8, 114.2, 58.9, 55.2,
42.8; HRMS (ESI) calculated for C16H14NaO2 261.0891, found
261.0664 (M þ Na)þ.
13h (91%): 1H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 8.0 Hz, 1H),
7.75 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 8.0 Hz, 2H), 7.45ꢀ7.18 (m, 5H),
4.71 (s, 1H), 3.73 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 212.9,
140.2, 136.7, 129.8, 129.4, 128.9, 128.5, 128.2, 126.9, 125.9, 125.7, 125.6,
125.4, 59.4, 42.8; HRMS (ESI) calculated for C16H11F3NaO 299.0659,
found 299.0721 (M þ Na)þ.
13i (62%): 1H NMR (400 MHz, CDCl3) δ 7.39ꢀ7.27 (m, 5H), 6.35
(m, 1H), 6.16 (m, 1H), 4.82 (s, 1H), 3.72 (d, J = 8.0 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ 211.4, 150.5, 142.7, 136.9, 128.3, 127.8, 125.6,
124.9, 110.4, 107.8, 53.3, 42.9; HRMS (ESI) calculated for C13H10NaO2
221.0578, found 221.0842 (M þ Na)þ.
Representative Procedure for Alkynyl Ether (12aꢀi) For-
mation and Sigmatropic Rearrangement/Cyclization to In-
danones 13aꢀi and 15aꢀd. The enol triflate obtained from the
above procedure (∼1 mmol) was dissolved in THF (1 mL) under argon
and cooled to ꢀ78 °C. A solution of potassium tert-butoxide (1 M in
THF, 3.0 mL, 3.0 mmol) was added dropwise, and the reaction mixture
darkened in color. After 20 min, a solution of saturated NaHCO3
(10 mL) was added, and the mixture was allowed to warm to room
temperature with stirring. Ether (10 mL) was added, and the phases
were separated. The aqueous later was back-extracted with ether (1 ꢁ
20 mL), and the combined organic extracts were then dried over
Na2SO4, filtered, and concentrated in vacuo. The crude alkynyl ether
was then dissolved in toluene (2 mL) and heated on an oil bath under
argon for 1 h, at which time TLC indicated complete conversion to the
indanone product. Concentration in vacuo and purification of the
residue by flash chromatography (SiO2) afforded indanones 13aꢀi
and 15aꢀd.
1
15a (61%; dr = 1:1): H NMR (400 MHz, CDCl3) δ 7.41ꢀ7.26
(m, 6H); 7.18ꢀ7.10 (m, 3H); 4.70 (s, 1H); 3.61 (q, J = 4.2 Hz, 1H); 1.48
(d, J = 5.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 216.4, 143.2, 140.1,
138.3, 128.9, 128.6, 128.0, 127.6, 126.0, 124.2, 59.0, 46.7, 15.8;
HRMS (ESI) calculated for C16H14NaO 245.0942, found 245.4017
(M þ Na)þ.
1
15b (53%; dr = 4:1): H NMR (400 MHz, CDCl3) δ 7.33ꢀ7.21
(m, 9H), 4.42 (s, 1H), 3.34 (t, J = 5.4 Hz, 1H), 1.86 (m, 2H), 1.41ꢀ1.19
(m, 4H), 0.80 (t, J = 6.0, 3H); 13C NMR (100 MHz, CDCl3) δ 214.2,
142.3, 141.0, 128.9, 128.5, 128.0, 127.7, 127.5, 58.9, 52.0, 31.2, 28.8, 22.7,
19.6; HRMS (ESI) calculated for C19H20NaO 287.1412, found
287.1361 (M þ Na)þ.
1
15c (48%; dr = 2:1): H NMR (400 MHz, CDCl3) δ 7.24ꢀ7.01
(m, 9H), 4.38 (s, 1H), 3.25 (d, J = 3.6 Hz, 1H), 2.29 (m, J = 4.0 Hz, 1H),
1.01 (d, J = 6.4 Hz, 3H), 0.89 (d, J = 6.4 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 213.8, 141.3, 140.9, 138.0, 128.9, 128.4, 128.0, 127.7, 127.5,
126.9, 126.1, 124.7, 58.9, 58.0, 31.2, 19.9, 19.6; HRMS (ESI) calculated
for C18H18NaO 273.1255, found 273.1271 (M þ Na)þ.
1
13a3 (98%): H NMR (400 MHz, CDCl3) δ 7.43ꢀ7.22 (m, 7H),
7.17 (d, J = 7.6 Hz, 2H), 4.71 (s, 1H), 3.68 (s, 2H); 13C NMR (100 MHz,
C6D6) δ 213.8, 141.4, 138.2, 137.3, 128.8, 128.5, 128.0, 127.9, 127.3,
126.0, 124.9, 59.8, 43.0; HRMS (ESI) calculated for C15H12NaO
231.0786, found 231.0777 (M þ Na)þ.
15d (69%): 1H NMR (400 MHz, CDCl3) δ 7.42 (d, J = 10.0 Hz, 2H);
7.31 (m, 1H); 7.20ꢀ7.09 (m, 6H); 4.40 (s, 1H), 3.09 (s, 1H), 0.99
(s, 9H); 13C NMR (100 MHz, CDCl3) δ 213.3, 141.3, 140.7, 138.6, 128.5,
128.0, 127.9, 127.6, 127.3, 126.6, 62.3, 58.6, 35.0; 30.5, 28.6; HRMS (ESI)
calculated for C19H20NaO 287.1412, found 287.1438 (M þ Na)þ.
Synthesis of 2-(5-Methyl-3-phenyl-1H-inden-2-yl)ethane-
nitrile 18b. To a solution of diethyl(cyanomethyl)phosphonate
(531 mg, 3.0 mmol) in THF (1 mL) was added NaH (100 mg, 2.5
mmol) at 0 °C, and the solution was allowed to stir for 30 min. Then a
solution of 2-indanone 13b (100 mg, 0.45 mmol) in THF (1 mL) was
added, and the mixture was allowed to stir for 4 h at room
temperature. The mixture was diluted with saturated NaHCO3
(10 mL). Ether (20 mL) was added, and the phases were separated.
The aqueous later was back-extracted with ether (1 ꢁ 20 mL), and the
combined organic extracts were then dried over Na2SO4, filtered, and
concentrated in vacuo. Purification of the residue by flash chroma-
tography (SiO21) afforded indene 18b.
1
13b (93%): H NMR (400 MHz, CDCl3) δ 7.36ꢀ7.24 (m, 3H),
7.17ꢀ7.10 (m, 3H), 7.01 (s, 1H), 4.63 (s, 1H), 3.62 (s, 2H), 2.33 (m,
3H); 13C NMR (100 MHz, CDCl3) δ 216.8, 143.3, 140.0, 137.7, 128.8,
128.5, 128.0, 127.9, 126.7, 124.3, 123.1, 60.2, 47.1, 23.5; HRMS (ESI)
calculated for C16H14NaO 245.0942, found 245.1399 (M þ Na)þ.
13c (65%): 1H NMR (400 MHz, CDCl3) δ 7.36ꢀ7.27 (m, 4H), 7.15
(d, J = 7.6 Hz, 2H), 6.93 (m, 1H), 6.74 (m, 1H), 4.66 (s, 1H), 3.78
(s, 3H), 3.62 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 214.2, 159.5,
142.4, 138.0, 129.1, 128.8, 128.4, 127.3, 125.7, 114.7, 110.7, 60.2, 55.4,
42.3; HRMS (ESI) calculated for C16H14NaO2 261.0891, found
261.0922 (M þ Na)þ.
13d (72%): 1H NMR (400 MHz, CDCl3) δ 7.63ꢀ7.26 (m, 7H), 7.11
(dd, J = 9.2 Hz, 1H), 4.75 (m, 1H), 3.72 (s, 2H); 13C NMR (100 MHz,
CDCl3) δ 212.3, 142.2, 137.2, 130.5, 130.2, 129.0, 128.4, 128.1, 127.2,
126.4, 125.0, 123.0, 122.9, 122.7, 59.6, 42.8; HRMS (ESI) calculated for
C16H11F3NaO 299.0660, found 299.0598 (M þ Na)þ.
18b (91%): H NMR (400 MHz, CDCl3) δ 7.53ꢀ7.35 (m, 6H),
7.09ꢀ7.05 (m, 2H), 3.63 (s, 2H), 3.55 (s, 2H), 2.35 (s, 3H); 13C NMR:
(100 MHz, CDCl3) δ 144.8, 139.1, 136.4, 133.6, 130.5, 128.9, 128.8,
128.1, 126.5, 123.6, 121.2, 40.2, 21.5, 17.9; HRMS (ESI) calculated for
C18H15NNa 268.1102, found 268.1099 (M þ Na)þ.
1
13e (95%): H NMR (400 MHz, CDCl3) δ 7.30ꢀ7.24 (m, 4H),
5.54 (s, 1H), 3.98 (s, 1H), 3.53 (s, 2H), 1.67ꢀ1.49 (m, 8H); 13C NMR
(100 MHz, CDCl3) δ 215.8; 141.3; 137.3; 134.7; 127.6; 127.5; 127.0;
125.3; 124.7; 62.3; 43.4; 26.1; 25.4; 22.7; 22.1; HRMS (ESI) calculated
for C15H16NaO 235.1099, found 235.1174 (M þ Na)þ.
Synthesis of tert-Butyl 2-(5-methyl-3-phenyl-1H-inden-2-
yl)ethylcarbamate 19b. To a solution of nitrile 18b (35.0 mg, 0.142
mmol) in methanol (1.2 mL) at 0 °C were added Boc2O (69.0 mg, 0.32
13f (90%): 1H NMR (400 MHz, CDCl3) δ 7.38ꢀ7.30 (m, 3H), 7.21
(d, J = 7.2 Hz, 1H), 7.14 (d, J = 7.6 Hz, 2H), 7.02 (d, J = 8.0 Hz, 2H), 4.63
3580
dx.doi.org/10.1021/jo200271s |J. Org. Chem. 2011, 76, 3576–3581

The Journal of Organic Chemistry
NOTE
mmol) and NiCl2 6H2O (3.8 mg, 0.016 mmol). Then NaBH4 (42.4 mg,
(9) The protocol of Muthusamy et al. was followed for diazoketone-
alcohol coupling: Muthusamy, S.; Babu, S. A.; Gunanathan, C. Tetra-
hedron Lett. 2002, 43, 3133.
(10) Synthesis of aryloxyacetic acids: (a) Yu, H.; Ballard, C. E.;
Boyle, P. D.; Wang, B. Tetrahedron 2002, 58, 7663. (b) Solladie, G.;
Adamy, M.; Colobert, F. J. Org. Chem. 1996, 61, 4369.
(11) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
(12) For seminal papers on substitutent effects on the aliphatic
Claisen rearrangment, see: (a) Burrows, C. J.; Carpenter, B. K. J. Am.
Chem. Soc. 1981, 103, 6983. (b) Burrows, C. J.; Carpenter, B. K. J. Am.
Chem. Soc. 1981, 103, 6984.
(13) A Hammett plot of ln(k/k0) vs σ for the data for substrates
12a,b, and d shows a break in slope at the data point for 12a, with a
strongly negative slope (F = ꢀ10.5) to 12b and a moderately negative
slope (F = ꢀ1.9) to 12d. The break in slope is suggestive of a change
in mechanism upon proceeding from substrates bearing electron-
donating substituents (12b) to substrates bearing electron-with-
drawing subsituents (12d). SeeRitchie, C. D.; Sager, W. F. Prog.
Phys. Org. Chem. 1964, 2, 323. See Supporting Information for data
graphs.
3
1.12 mmol) was added in small portions over 30 min. After warming to
room temperature and stirring for 2 h, the mixture was diluted with
saturated NaHCO3 (10 mL) and concentrated in vacuo to remove
methanol. Ethyl acetate (10 mL) was added and the phases were
separated. The aqueous later was back-extracted with ethyl acetate
(1 ꢁ 10 mL), and the combined organic extracts were then dried over
Na2SO4, filtered, and concentrated in vacuo. Purification of the residue
by flash chromatography (SiO2) afforded indene 19b.
19b (60%): 1H NMR (400 MHz, CDCl3) δ 7.49ꢀ7.35 (m, 6H), 7.00
(m, 2H), 3.47 (s, 2H), 3.35 (m, 2H), 2.71 (t, J = 6.8 Hz, 2H) 2.34 (s,
3H), 1.41 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 155.7, 146.3, 141.1,
138.0, 135.2, 129.1, 128.5, 128.3, 127.3, 125.3, 123.3, 120.4, 100.0, 79.2,
40.2, 40.0, 29.4, 28.3, 21.5; HRMS (ESI) calculated for C23H27NNaO2
372.1939, found 372.1763 (M þ Na)þ.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental details, charac-
(14) A Hammett plot of ln(k/k0) vs σ for the data for substrates 12a,
f, and h shows a break in slope at the data point for 12a, with a negative
slope (F = ꢀ1.62) to 12f and a slightly positive slope (F = þ0.05) to 12h.
Again, the break in slope is suggestive of a change in mechanism upon
proceeding from substrates bearing electron-donating substituents
(12f) to substrates bearing electron-withdrawing subsituents (12h).
See Supporting Information for data graphs.
b
terization data, H, 13C spectra of all products, and H NMR
kinetic data at 330 K. This material is available free of charge via
the Internet at http://pubs.acs.org.
1
1
’ AUTHOR INFORMATION
(15) (a) We thank a reviewer for mentioning the allylic strain
apparent in the anti disposition of the tert-butyl group in structure
16a. We believe that steric interactions between the tert-butyl group and
the phenyl-substituted ketene in the corresponding syn form (16s, see
Supporting Information) hinder alignment of the ketene carbonyl
carbon with the benzylic carbon atom (which is necessary for 5-exo-
dig cyclization to occur) by favoring rotamers in which the ketene is
directed away from the benzylic carbon atom. Thus, despite the allylic
strain present in 16a, it appears that the reaction proceeds preferentially
through 16a to 15d. (b) To assess if the product ratios obtained for
15aꢀc represent an equilibrium mixture arising from a reversible
process, we have attempted to obtain pure major or minor isomer from
these reactions and resubject them individually to the reaction condi-
tions. Chromatographic separation of the cis and trans indanone
products has proven quite difficult since the diastereomers co-elute in
most solvent systems. Thus, a mixture enriched in the major isomer of
indanone 15c (dr = >2:1) was heated to 57°C in an NMR tube (CDCl3
as solvent) for 30 minutes, and essentially no change in the isomer ratio
was observed. This suggests that the 5-exo-dig cyclization is irreversible
under these reaction conditions and that the isomer distributions are
under kinetic control.
(16) (a) Guillon, J.; Dallemagne, P.; Leger, J.-M.; Sopkova, J.;
Bovy, P. R.; Jarry, C.; Rault, S. Bioorg. Med. Chem. 2002, 10, 1043. (b)
Kolanos, R.; Siripurapu, U.; Pullagurla, M.; Riaz, M.; Setola, V.; Roth,
B. L.; Dukat, M.; Glennon, R. A. Bioorg. Med. Chem. Lett. 2005,
15, 1987. (c) Watanabe, N.; Nakagava, H.; Ikeno, A.; Minato, H.;
Kohayakawa, C.; Tsuji, J. Bioorg. Med. Chem. Lett. 2003, 13, 4317. (d)
Karaguni, I.-M.; Glusenkamp, K.-H.; Langerak, A.; Geisen, C.;
Ullrich, V.; Winde, G.; Moroy, T.; Muller, O. Bioorg. Med. Chem.
Lett. 2002, 12, 709.
Corresponding Author
*E-mail: thomas.minehan@csun.edu.
’ ACKNOWLEDGMENT
We thank the National Institutes of Health (SC2 GM081064-01)
and the Henry Dreyfus Teacher-Scholar Award for their gener-
ous support of our research program.
’ REFERENCES
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