Aromatization reactions of 2-cyclohexenones and 1,3-cyclohexadien-1-amines with iodine/sodium alkoxide

Article abstract of DOI:10.1016/S0040-4020(00)01171-6

2-Cyclohexenones containing an electron withdrawing group in the 4-position and the corresponding N-alkyl-1,3-cyclohexadien-1-amines undergo regioselective iodination and aromatization to give 2-iodophenols and N-alkyl-2-iodoanilines, respectively, upon reaction with iodine and sodium alkoxide. By contrast, N,N-dialkyl-1,3-cyclohexadien-1-amine derivatives undergo non-iodinative aromatization to simple N,N-dialkylanilines under similar conditions.

Full text of DOI:10.1016/S0040-4020(00)01171-6

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 1689±1698
Aromatization reactions of 2-cyclohexenones and
1,3-cyclohexadien-1-amines with iodine/sodium alkoxide
²
Shridhar G. Hegde,p Amude M. Kassim and April I. Kennedy
Pharmacia Corporation, 800 North Lindbergh Blvd., St. Louis, MO 63167, USA
Received 17 October 2000; accepted 11 December 2000
AbstractÐ2-Cyclohexenones containing an electron withdrawing group in the 4-position and the corresponding N-alkyl-1,3-cyclohexa-
dien-1-amines undergo regioselective iodination and aromatization to give 2-iodophenols and N-alkyl-2-iodoanilines, respectively, upon
reaction with iodine and sodium alkoxide. By contrast, N,N-dialkyl-1,3-cyclohexadien-1-amine derivatives undergo non-iodinative aroma-
tization to simple N,N-dialkylanilines under similar conditions. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
systems have also found limited application in the regio-
selective ortho-iodination of steroidal phenols.
Aromatic iodo compounds are versatile reagents in organic
synthesis. In particular, bifunctional reagents such as
2-iodophenols and 2-iodoanilines are useful precursors for
the synthesis of a variety of benzoheterocyclic systems. For
example, palladium catalyzed annulations and carbonyl-
ative cyclizations of these materials with dienes and
acetylenes have been widely used in the synthesis of bio-
logically important heterocycles such as benzofurans,1
dihydrobenzofurans,2,3 benzopyrans,3 indolines,4 indoles,5
¯avones,6 chromones,6 quinolines7 and tetrahydroquino-
lines.3 Additional utilities of 2-iodophenols and 2-iodo-
anilines include transition metal catalyzed coupling
reactions with organoboron compounds to provide phenols
and anilines with alkyl,8 aryl9 and heteroaryl10 substituents
in the ortho position. A wide variety of methods are
available for the direct iodination of phenols and anilines.11
Although some simple 2-iodophenols and 2-iodoanilines are
readily accessible via this approach, only a limited number
of methods are suitable for the regioselective preparation of
more highly substituted analogues. For example, direct
iodination of substituted phenols with iodine/thallium(I)
acetate has been reported to yield 2-iodophenols regio-
selectively in a few instances.12 However, the yields of
desired products are generally low due to competing
diiodination. Iodinations of N-alkylanilines and N,N-dialkyl-
anilines under the same conditions are further complicated
by competing oxidative coupling processes.12 Iodine/
copper(II) acetate13 and iodine/mercury(II) acetate14
In a recent communication, we reported that the aromati-
zation of a variety of easily accessible 2-cyclohexenones
1a±h with iodine and sodium alkoxide gives 2-iodophenols
2a±h in good yields and high regioselectivity (Eq. (1)).15
Herein we provide full experimental details of this work and
further extension of the methodology to the aromatization of
the corresponding 1,3-cyclohexadien-1-amines to produce
aniline derivatives. In addition, we describe examples of
heterocyclic synthesis utilizing some of the 2-iodophenols
and 2-iodoanilines prepared in this study.
2. Results and discussion
2.1. Aromatization of 2-cyclohexenones
The 2-cyclohexenones 1a±h were readily prepared using
previously reported procedures.15±18 Treatment of
compounds 1a±h with 6 equiv. of sodium ethoxide in
ethanol followed by slow addition of 2 equiv. of iodine at
2788C gave 50±86% isolated yields of 2-iodophenols
2a±h as a single regioisomer19 in each case (Eq. (1),
Table 1).
ꢀ1†
Keywords: regioselective iodination; aromatization; 2-iodophenols;
2-iodoanilines.
p
Corresponding author. Tel.: 11-314-694-5062; fax: 11-314-694-1080;
e-mail: shridhar.g.hegde@monsanto.com
Current address: Array Biopharma Inc., 1885 33rd Street, Boulder, CO
80301, USA.
Crude products from these reactions generally contained
small amounts of 2,6-diiodophenols (3±5%) and non-iodi-
nated phenols (3±5%) as byproducts which were readily
²
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)01171-6

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S. G. Hegde et al. / Tetrahedron 57 (2001) 1689±1698
Table 1. Preparation of 2-iodophenols from 2-cyclohexenones
2-Cyclohexenone substrate
E
R1
R2
Iodophenol product
Yield (%)
1a
1b
1c
1d
1e
1f
CO2Me
CO2Et
CO2Et
CO2Et
CO2Me
CO2Et
CO2Et
CO2Et
H
H
H
H
Me
CF3
CO2Et
2-Thienyl
2-Furyl
H
2a
2b
2c
2d
2e
2f
66
86
77
61
50
78
65
64
H
Me
CF3
Ph
1g
1h
H
H
2g
2h
Scheme 1.
removed by preparative HPLC. Low reaction temperature
was critical in minimizing the formation of these by-
products. For example, iodination at room temperature
gave 40±50% of monoiodophenols, 20±25% of diiodo-
phenols and 20±25% of non-iodinated phenols. Carefully
controlled stoichiometry of iodine was also important in
ensuring high yield of the desired 2-iodophenols. Using
greater than 2 equiv. of iodine gave increasing amounts of
the diiodophenols whereas less than two equivalents
resulted in only partial conversion of the starting material.
The reaction appears to be limited to 2-cyclohexenones with
an electron withdrawing substituent in the 4-position. For
example, bicyclic dione 3 and bicyclic imide 5 gave the
expected iodophenols 4 and 6 in 56 and 84% isolated yields,
respectively (Eqs. (2) and (3)). However, simple cyclo-
hexenones such as 3-methyl-2-cyclohexenone, 3-phenyl-2-
cyclohexenone and 3,4-dimethyl-2-cyclohexenone gave
mostly unreacted starting material and small amounts of
unidenti®ed non-aromatic products.
ꢀ3†
The reaction most likely proceeds via anionic diiodination
of cyclohexenones 1a±h and subsequent dehydroiodination
and aromatization (Scheme 1). The preferential formation of
a thermodynamically more stable, linearly conjugated dieno-
late 7 accounts for the regioselectivity of iodination.
Although there are two possible diiodo intermediates 8a
(a,a) and 8b (a,g), both of these structures provide the
same iodophenol upon dehydroiodination and aromatization.
The diiodophenol and non-iodinated phenol byproducts
may result from competing mono- and triiodinations of
enolate 7 and subsequent dehydroiodination.
2.2. Aromatization of 1,3-cyclohexadien-1-amines
The results of extending the aromatization methodology to
the corresponding 1,3-cyclohexadien-1-amine derivatives
9a±e and 11a±f are illustrated in Eqs. (4) and (5).
ꢀ2†

S. G. Hegde et al. / Tetrahedron 57 (2001) 1689±1698
Table 2. Preparation of N-alkyl-2-iodoanilines from N-alkyl-1,3-cyclohexadien-1-amines
1691
Compounds 9a±e and 11a±f were readily synthesized by
condensing the corresponding cyclohexenones with primary
and secondary amines, respectively. Treatment of the
secondary enamines 9a±e with 6 equiv. of sodium ethoxide
and 2 equiv. of iodine at 2788C afforded the iodoanilines
10a±e in 42±61% yield as a single regioisomer in each case
(Eq. (4), Table 2, entries 1±5). The bicyclic dienamine 9f
also gave the expected iodoaniline 10f in 47% yield (Table
2, entry 6). However, the tertiary enamines 11a±f gave only
the non-iodinated aromatic products 12a±f in 74±89% yield
under identical conditions (Eq. (5), Table 3). In this case,
complete conversion of the starting material to the product
was observed with 2 equiv. of sodium ethoxide and 1 equiv.
of iodine. Employing a large excess of iodine (3±4 equiv.)
and sodium ethoxide (9±12 equiv.) did not alter the course
of the reaction signi®cantly.
ꢀ4†
ꢀ5†

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S. G. Hegde et al. / Tetrahedron 57 (2001) 1689±1698
Table 3. N,N-Dialkylanilines from N,N-dialkyl-1,3-cyclohexadien-1-amines
A possible explanation for the divergence in the reactions of
secondary and tertiary enamines may lie in the mechanisms
and relative rates of iodination (Scheme 2). Secondary
enamines 9a±e have the ability to form the aza-enolate
species 13 via deprotonation. Therefore their iodination is
most likely assisted by an anion and the reactivity may
parallel the cyclohexenones. The aza-enolate species 13
may undergo a,a- or a,g diiodination to give 14 or 15.
Further dehydroiodination of 14 or 15 leads to the 2-iodo-
anilines 10. By contrast, the tertiary enamines 11a±f are
incapable of forming a similar aza-enolate species. In this
case the iodination is most likely not assisted by an anion
and, consequently, slower than the iodination of secondary
enamines. We propose that the iodinations of 11a±f are
suf®ciently slow to allow dehydroiodination of the initial
mono-iodo species 16 and 17 to successfully compete
with the diiodination step and result in non-iodinated
N,N-dialkylanilines. Consistent with this proposal,
compounds 11a±f may also be aromatized with iodine
using milder bases such as aliphatic tertiary amines. For
example, treatment of 11a with 1 equiv. of iodine and
2.5 equiv. of triethylamine or DBU at room temperature
gave 12a in 56 and 63% isolated yields, respectively.
2.3. Synthetic utility of 2-iodophenols and 2-iodoanilines
The 2-iodophenols and 2-iodoanilines described herein are
useful precursors for the regioselective synthesis of benzo-
heterocyclic systems containing multiple substituents. The
synthetic utility can be illustrated by the preparation of
2,3-dihydrobenzofurans 19a and 19b (Scheme 3) and the
indoline derivative 20 (Scheme 4). Thus, iodophenols 2a
and 2f were alkylated with allyl bromide and the resulting
allyl 2-iodophenyl ethers 18a and 18b were subjected to
tributyltin hydride mediated cyclization reaction20±23 using
catalytic 1,10-azobiscyclohexylnitrile (ACN) as the free

S. G. Hegde et al. / Tetrahedron 57 (2001) 1689±1698
1693
Scheme 2.
radical initiator to produce the regioisomeric 2,3-dihydro-
benzofurans 19a and 19b in high yield. The indoline
derivative 20 was obtained by the cyclization of iodoaniline
10a under similar conditions.
the regioselective synthesis of benzoheterocyclic systems
with multiple substituents on the benzene ring. In addition,
we have provided a useful preparative method for the
aromatization of N,N-dialkyl-1,3-cyclohexadien-1-amine
derivatives to the corresponding N,N-dialkylanilines.
In conclusion, we have developed an ef®cient methodology
for the regioselective synthesis of 2-iodophenols and
2-iodoanilines with an electron withdrawing group in the
4-position and a variety of alkyl and aryl substituents in 3-
or 5-positions. These materials are valuable precursors in
3. Experimental
Melting points were determined with a Mettler Toledo FP62
Scheme 3.
Scheme 4.

1694
S. G. Hegde et al. / Tetrahedron 57 (2001) 1689±1698
melting point apparatus and are uncorrected. All 1H, 13C and
19F NMR spectra were recorded on a Bruker AM 360 NMR
spectrometer at 360, 90 and 340 MHz, respectively. 1H and
13C chemical shifts (d) are given in ppm relative to tetra-
methylsilane as the internal standard. 19F chemical shifts (d)
are expressed in ppm relative to ¯uorotrichloromethane,
with up®eld shifts taken as negative. IR spectra were
recorded on a Nicolet NEXUS 470 FT-IR instrument.
Preparative HPLC was performed on a Waters Prep 500
system with a 25 mm steel column packed with Kieselgel
60 (230±400 mesh). Compound 1f was purchased from
Aldrich Chemical Company. Compounds 1a,16 1b±e,15
1g,17 1h,18 324 and 9f24 were prepared according to
previously published methods.
NaHSO3 solution and brine, dried (MgSO4) and evaporated.
The residue was puri®ed by preparative HPLC using 20%
ethyl acetate±hexane as the eluent.
3.2.1. Iodophenol 2a. 66% Yield from cyclohexenone 1a;
1
mp 172±1748C; H NMR (DMSO-d6) d 2.42 (s, 3H), 3.76
(s, 3H), 6.76 (s, 1H), 8.16 (s, 1H), 11.05 (s, 1H); 13C NMR
(DMSO-d6) d 21.4, 51.6, 80.7, 117.5, 121.6, 141.4, 142.2,
160.0, 165.4; IR (neat) 3278, 1739, 1672, 1592, 1396, 1267,
1107, 779 cm21. Anal. calcd for C9H9IO3: C, 37.01; H, 3.11;
I, 43.45. Found: C, 37.12; H, 3.15; I, 43.30.
3.2.2. Iodophenol 2b. 86% Yield from cyclohexenone 1b;
mp 136±1388C; 1H NMR (DMSO-d6) d 1.27 (t, Jˆ7.3 Hz,
3H), 4.26 (q, Jˆ7.1 Hz, 2H), 7.23 (s, 1H), 8.19 (s, 1H),
11.71 (s, 1H); 13C NMR (DMSO-d6) d 13.8, 61.4, 88.9,
3.1. 3a,7a-Dihydro-2-methyl-1H-isoindole-1,3,5(2H,4H)-
trione (5)
1
2
112.4, 121.9, 123.0 (q, JC±Fˆ273.4 Hz), 129.0 (q, JC±F
ˆ
31.9 Hz), 141.8, 160.1, 164.0; 19F NMR (DMSO-d6) d
255.95; IR (neat) 3358, 1700, 1595, 1398, 1257, 1136,
1063 cm21. Anal. calcd for C10H8F3IO3: C, 33.36; H, 2.24;
I, 35.24. Found: C, 33.32; H, 2.22; I, 35.17.
Compound 5 was prepared by the reaction of 1-methoxy-3-
trimethylsilyloxy-1,3-butadiene (Danishefsky's diene) and
N-methylmaleimide using the general method of cyclo-
hexenone synthesis described in Ref. 16. A solution of
11.36 g (0.066 mol) of 1-methoxy-3-trimethylsilyloxy-1,3-
butadiene and 6.59 g (0.059 mol) of N-methylmaleimide in
25 mL of toluene was heated at re¯ux for 24 h. The reaction
mixture was then concentrated under reduced pressure to
afford a pale yellow oil. To a solution of the above oil in
20 mL of acetone and 130 mL of methylene chloride at
2788C under nitrogen atmosphere was added a mixture of
trimethylsilyl tri¯ate (41.7 mL of a 0.06 M solution in
methylene chloride, 0.0025 mol) and collidine (16.7 mL of
a 0.03 M solution in methylene chloride, 0.0005 mol),
resulting in a clear straw-colored solution. After 15 min,
the reaction was quenched with an additional 0.5 equiv. of
collidine in methylene chloride. The reaction mixture was
then diluted with water (100 mL) and extracted with
methylene chloride (3£100 mL). The combined extracts
were washed with 5% HCl solution, dried (MgSO4) and
evaporated. The residue was puri®ed by preparative HPLC
using 20% ethyl acetate±hexane as the eluent to give 7.18 g
(68%) of compound 5 as a pale yellow solid: mp 99±1008C;
1H NMR (CDCl3) d 2.59±2.66 (m, 1H), 2.91 (s, 3H), 2.92±
2.98 (m, 1H), 3.41±3.46 (m, 1H), 3.72±3.75 (m, 1H), 6.09
(dd, Jˆ2.42, 10.2 Hz, 1H), 6.8 (dd, Jˆ3.76, 10.2 Hz, 1H);
13C NMR (CDCl3) d 25.4, 33.3, 37.5, 41.7, 131.4, 141.9,
174.8, 177.3, 193.7; IR (neat) 1776, 1709, 1686, 1618, 1434,
1301, 1258 cm21. Anal. calcd for C9H9NO3: C, 60.33; H,
5.06; N, 7.82. Found: C, 60.24; H, 5.09; N, 7.76.
3.2.3. Iodophenol 2c. 77% Yield from cyclohexenone 1c;
1
mp 83±858C; H NMR (DMSO-d6) d 1.25 (t, Jˆ7.1 Hz,
6H), 4.23 (m, 4H), 7.02 (s, 1H), 8.08 (s, 1H), 11.48 (s,
1H); 13C NMR (DMSO-d6) d 13.8, 13.9, 61.1, 61.4, 87.0,
113.7, 122.2, 134.9, 140.1, 159.9, 164.7, 166.9; IR (neat)
3232, 1712, 1697, 1585, 1252, 1078 cm21. Anal. calcd for
C12H13IO5: C, 39.58; H, 3.60; I, 34.85. Found: C, 39.65; H,
3.58; I, 34.95.
3.2.4. Iodophenol 2d. 61% Yield from cyclohexenone 1d;
mp 105±1078C; 1H NMR (DMSO-d6) d 1.07 (t, Jˆ7.0 Hz,
3H), 4.08 (q, Jˆ7.2 Hz, 2H), 6.93 (s, 1H), 7.03±7.04 (m,
1H), 7.08±7.09 (m, 1H), 7.59±7.60 (m, 1H), 8.03 (s, 1H),
11.21 (s, 1H); 13C NMR (DMSO-d6) d 13.7, 60.7, 83.7,
116.6, 123.7, 126.6, 127.5, 135.6, 140.4, 140.7, 159.2,
166.0; IR (neat) 3140, 1654, 1573, 1370, 1305, 1274,
1252, 780 cm21. Anal. calcd for C13H11IO3S: C, 41.73; H,
2.96; I, 33.91. Found: C, 41.82; H, 2.96; I, 34.00.
3.2.5. Iodophenol 2e. 50% Yield from cyclohexenone 1e;
mp 107±1098C; 1H NMR (DMSO-d6) d 3.72 (s, 3H), 6.56±
6.57 (m, 1H), 6.66±6.67 (m, 1H), 7.09 (s, 1H), 7.74±7.75
(m, 1H), 7.98 (s, 1H), 11.17 (s, 1H); 13C NMR (DMSO-d6) d
52.1, 83.5, 108.9, 111.9, 113.4, 121.9, 131.2, 140.2, 143.6,
150.9, 159.3, 166.8; IR (neat) 3254, 1691, 1672, 1410, 1303,
1270, 751 cm21. Anal. calcd for C12H9IO4: C, 41.89; H,
2.64; I, 36.88. Found: C, 41.83; H, 2.67; I, 36.95.
3.2. General procedure for the preparation of iodo-
phenols 2a±h, 4 and 6
3.2.6. Iodophenol 2f. 59% Yield from cyclohexenone 1f;
mp 111±1138C; 1H NMR (CDCl3) d 1.37 (t, Jˆ7.3 Hz, 3H),
2.75 (s, 3H), 4.33 (q, Jˆ7.1 Hz, 2H), 6.01 (s, 1H), 6.86 (d,
Jˆ8.4 Hz, 1H), 7.77 (d, Jˆ8.4 Hz, 1H); 13C NMR (CDCl3)
d 14.4, 27.3, 61.1, 96.9, 111.9, 124.1, 132.4, 144.2, 157.6,
To a solution of 0.15 mol of sodium ethoxide (prepared by
dissolving 3.45 g of sodium in 80 mL of ethanol) at 2788C
was added 0.025 mol of the cyclohexenone substrate. After
stirring for 15 min, 12.7 g (0.05 mol) of iodine was added in
small portions. The reaction mixture was stirred for 3 h at
2788C and allowed to warm to room temperature. After
stirring at room temperature overnight, the reaction mixture
was neutralized with 5% HCl solution and then concentrated
by evaporation of ethanol under reduced pressure. The
resulting suspension was extracted with ethyl acetate. The
organic layer was washed successively with saturated
167.0; IR (neat) 3337, 1673, 1554, 1249, 1025, 771 cm21
.
Anal. calcd for C10H11IO3: C, 39.24; H, 3.62; I, 41.46.
Found: C, 39.37; H, 3.65; I, 41.29.
3.2.7. Iodophenol 2g. 65% Yield from cyclohexenone 1g;
1
mp 65±668C; H NMR (DMSO-d6) d 1.25 (t, Jˆ7.2 Hz,
3H), 4.25 (q, Jˆ7.2 Hz, 2H), 7.15 (d, Jˆ8.4 Hz, 1H), 7.43
(d, Jˆ8.4 Hz, 1H), 11.48 (s, 1H); 13C NMR (DMSO-d6) d

S. G. Hegde et al. / Tetrahedron 57 (2001) 1689±1698
1695
1
13.7, 61.6, 85.5, 117.1, 122.4 (q, JC±Fˆ275.4 Hz), 125.7,
1.19 (t, Jˆ7.1 Hz, 3H), 2.10 (t, Jˆ8.4 Hz, 2H), 2.12 (s,
3H), 2.46 (t, Jˆ8.8 Hz, 2H), 3.90 (br, 1H), 4.04 (d, Jˆ
4.9 Hz, 2H), 4.06 (q, Jˆ7.1 Hz, 2H), 4.65 (s, 1H), 5.86 (s,
2H), 6.68 (s, 2H), 6.71 (s, 1H); 13C NMR (CDCl3) d 13.9,
21.5, 23.6, 28.9, 46.7, 58.4, 96.0, 100.4, 107.6, 107.7, 108.2,
120.4, 131.0, 146.3, 147.3, 149.0, 150.1, 167.8; IR (neat)
3402, 1738, 1366, 1231, 1217, 1037 cm21. Anal. calcd for
C18H21NO4: C, 68.55; H, 6.71; N, 4.44. Found: C, 68.36; H,
6.72; N, 4.39.
129.62, 130.4 (q, JC±Fˆ29.8 Hz), 159.4, 167.0; 19F NMR
2
(DMSO-d6) d 252.47; IR (neat) 3304, 1701, 1318, 1292,
1141 cm21. Anal. calcd for C10H8F3IO3: C, 33.36; H, 2.24; I,
35.24. Found: C, 33.48; H, 2.28; I, 35.09.
3.2.8. Iodophenol 2h. 64% Yield from cyclohexenone 1h;
mp 135±1378C; 1H NMR (DMSO-d6) d 0.79 (t, Jˆ7.0 Hz,
3H), 3.83 (q, Jˆ7.0 Hz, 2H), 6.98 (d, Jˆ8.4 Hz, 1H), 7.04
(d, Jˆ6.4 Hz, 2H), 7.33±7.39 (m, 3H), 7.69 (d, Jˆ8.4 Hz,
1H), 11.19 (s, 1H); 13C NMR (DMSO-d6) d 13.4, 60.0, 93.3,
113.2, 123.0, 127.1, 127.6, 128.7, 131.1, 144.3, 148.2,
159.8, 166.2; IR (neat) 3295, 1739, 1669, 1372, 1306,
1230, 699 cm21. Anal. calcd for C15H13IO3: C, 48.94; H,
3.56; I, 34.47. Found: C, 49.00; H, 3.58; I, 34.58.
3.3.3. Dienamine 9d. 58% Yield from cyclohexenone 1f
and 2-(aminomethyl)thiophene; mp 66±678C; 1H NMR
(CDCl3) d 1.19 (t, Jˆ7.2 Hz, 3H), 2.10 (t, Jˆ8.4 Hz, 2H),
2.14 (s, 3H), 2.46 (t, Jˆ8.8 Hz, 2H), 3.98 (br, 1H), 4.07 (q,
Jˆ7.2 Hz, 2H), 4.32 (d, Jˆ4.9 Hz, 2H), 4.72 (s, 1H), 6.87±
6.92 (m, 2H), 7.12±7.16 (m, 1H); 13C NMR (CDCl3) d 13.9,
21.5, 23.5, 28.8, 41.6, 58.5, 96.5, 108.6, 124.4, 125.3, 126.2,
140.0, 148.7, 149.6, 167.8; IR (neat) 3390, 1736, 1366,
1230, 1217, 703 cm21. Anal. calcd for C15H19NO2S: C,
64.95; H, 6.90; N, 5.05. Found: C, 64.80; H, 6.89; N, 5.00.
3.2.9. Iodophenol 4. 56% Yield from compound 3; mp
202±2038C; H NMR (DMSO-d6) d 1.00 (s, 3H), 2.39 (s,
1
2H), 2.79 (s, 2H), 6.87 (d, Jˆ8.6 Hz, 1H), 7.77 (d, Jˆ
8.6 Hz, 1H), 11.29 (s, 1H); 13C NMR (DMSO-d6) d 27.9,
33.1, 49.3, 50.3, 91.7, 113.0, 125.1, 128.2, 147.1, 161.6,
195.7; IR (neat) 3225, 1657, 1632, 1585, 1414, 1301,
1268, 1127, 833 cm21. Anal. calcd for C12H13IO2: C,
45.59; H, 4.14; I, 40.14. Found: C, 45.86; H, 4.10; I, 40.25.
3.3.4. Dienamine 9e. 61% Yield from cyclohexenone 1f
and furfurylamine; mp 64±658C; H NMR (CDCl3) d 1.18
1
(t, Jˆ7.1 Hz, 3H), 2.09 (t, Jˆ8.3 Hz, 2H), 2.13 (s, 3H), 2.44
(t, Jˆ8.9 Hz, 2H), 4.01 (br, 1H), 4.05 (q, Jˆ7.2 Hz, 2H),
4.13 (d, Jˆ4.9 Hz, 2H), 4.68 (s, 1H), 6.15 (d, Jˆ2.9 Hz,
1H), 6.24 (d, Jˆ1.8 Hz, 1H), 7.28 (s, 1H); 13C NMR
(CDCl3) d 13.9, 21.5, 23.5, 28.7, 39.7, 58.4, 96.2, 106.9,
108.5, 109.7, 141.5, 148.8, 149.8, 150.4, 167.8; IR (neat)
3384, 1725, 1509, 1259, 1203, 737 cm21. Anal. calcd for
C15H19NO3: C, 68.94; H, 7.33; N, 5.36. Found: C, 68.88; H,
7.30; N, 5.37.
3.2.10. Iodophenol 6. 84% Yield from compound 5; mp
236±2378C; H NMR (DMSO-d6) d 2.93 (s, 3H), 7.11 (s,
1
1H), 8.03 (s, 1H), 11.77 (br, 1H); 13C NMR (DMSO-d6) d
24.2, 91.6, 108.8, 123.8, 134.2, 134.7, 162.6, 167.2, 168.0;
IR (neat) 3238, 1760, 1682, 1620, 1598, 1108, 823 cm21
.
Anal. calcd for C9H6INO3: C, 35.67; H, 2.00; N, 4.62; I,
41.87. Found: C, 35.82; H, 2.03; N, 4.51; I, 41.96.
3.3. General procedure for the preparation of
dienamines 9a±e
3.4. General procedure for the preparation of
iodoanilines 10a±f
A solution of 4.9 g (0.027 mol) of the cyclohexenone 1f,
0.041 mol of a primary amine and 0.1 g of p-toluenesulfonic
acid in 70 mL of toluene was heated at re¯ux for 1 h in a
Dean±Stark apparatus with azeotropic removal of water.
The reaction mixture was then evaporated and the residue
was partitioned between ether and water. The organic layer
was washed successively with saturated NaHCO3 solution
and brine, dried (MgSO4) and evaporated. The residue was
puri®ed by preparative HPLC using 20% ethyl acetate±
hexane as the eluent. Attempted puri®cation of compound
9a led to decomposition. Therefore, in this particular case,
the crude product was directly used in the aromatization
reaction.
To a solution of 0.042 mol of sodium ethoxide (prepared by
dissolving 1.01 g of sodium in 30 mL of ethanol) at 2788C
was added 0.007 mol of the dienamine substrate. After stir-
ring for 15 min, 3.67 g (0.015 mol) of iodine was added in
small portions. The reaction mixture was stirred for 3 h at
2788C and allowed to warm to room temperature. After
stirring at room temperature overnight, the reaction mixture
was neutralized with 5% HCl solution and ethanol was
removed by evaporation under reduced pressure. The
resulting suspension was extracted with ethyl acetate. The
organic layer was washed successively with saturated
NaHSO3 solution and brine, then dried (MgSO4) and evapo-
rated. The residue was puri®ed by preparative HPLC using
10% ethyl acetate±hexane as the eluent.
3.3.1. Dienamine 9b. 69% Yield from cyclohexenone 1f
and benzylamine; mp 74±758C; H NMR (CDCl3) d 1.20
1
1
3.4.1. Iodoaniline 10a. 47% Yield from dienamine 9a; H
(t, Jˆ7.1 Hz, 3H), 2.11±2.15 (m, 5H), 2.47 (t, Jˆ8.8 Hz,
2H), 4.05 (br, 1H), 4.07 (q, Jˆ7.1 Hz, 2H), 4.15 (d, Jˆ
5.0 Hz, 2H), 4.69 (s, 1H), 7.22±7.29 (m, 5H); 13C NMR
(CDCl3) d 13.9, 21.5, 23.6, 28.9, 46.9, 58.4, 96.0, 108.1,
126.9, 127.1, 128.1, 137.2, 149.1, 150.4, 167.9; IR (neat)
3398, 1736, 1366, 1230, 1217, 773 cm21. Anal. calcd for
C17H21NO2: C, 75.25; H, 7.80; N, 5.16. Found: C, 75.11; H,
7.82; N, 5.16.
NMR (CDCl3) d 1.28 (t, Jˆ7.1 Hz, 3H), 2.71 (s, 3H), 3.79±
3.81 (m, 2H), 4.22 (q, Jˆ7.1 Hz, 2H), 4.94 (br, 1H), 5.12±
5.15 (m, 1H), 5.17±5.22 (m, 1H), 5.81±5.91 (m, 1H), 6.29
(d, Jˆ8.8 Hz, 1H), 7.71 (d, Jˆ8.8 Hz, 1H); 13C NMR
(CDCl3) d 13.7, 27.3, 45.7, 59.8, 95.0, 106.5, 116.0,
119.1, 131.4, 133.1, 143.5, 149.0, 166.5; IR (neat) 3388,
1704, 1589, 1365, 1249, 1171, 1080, 772 cm21. Anal.
calcd for C13H16INO2: C, 45.24; H, 4.67; N, 4.06; I, 36.76.
Found: C, 45.28; H, 4.68; N, 4.03; I, 36.85.
3.3.2. Dienamine 9c. 71% Yield from cyclohexenone 1f
and piperonylamine; mp 72±738C; H NMR (CDCl3) d
1
1
3.4.2. Iodoaniline 10b. 56% Yield from dienamine 9b; H

1696
S. G. Hegde et al. / Tetrahedron 57 (2001) 1689±1698
NMR (CDCl3) d 1.35 (t, Jˆ7.1 Hz, 3H), 2.79 (s, 3H), 4.29
(q, Jˆ7.1 Hz, 2H), 4.61 (d, Jˆ5.5 Hz, 2H), 5.32 (br, 1H),
6.37 (d, Jˆ8.8 Hz, 1H), 7.25±7.39 (m, 5H), 7.75 (d, Jˆ
8.8 Hz, 1H); 13C NMR (CDCl3) d 14.5, 28.1, 48.3, 60.6,
95.7, 107.4, 120.1, 127.2, 127.6, 128.9, 132.2, 138.0,
144.3, 149.8, 167.3; IR (neat) 3387, 1702, 1590, 1507,
1249, 1170, 1078, 771 cm21. Anal. calcd for C17H18INO2:
C, 51.66; H, 4.59; N, 3.54; I, 32.11. Found: C, 51.72; H,
4.63; N, 3.48; I, 32.04.
organic layer was washed successively with saturated
NaHCO3 solution and brine, then dried (MgSO4) and evapo-
rated. The residue was puri®ed by preparative HPLC using
20% ethyl acetate±hexane.
3.5.1. Dienamine 11a. 75% Yield from cyclohexenone 1f
and morpholine; mp 82±848C; 1H NMR (CDCl3) d 1.24 (t,
Jˆ7.1 Hz, 3H), 2.15 (s, 3H), 2.18 (t, Jˆ9.3 Hz, 2H), 2.50 (t,
Jˆ9.0 Hz, 2H), 3.03 (t, Jˆ4.9 Hz, 4H), 3.69 (t, Jˆ4.9 Hz,
4H), 4.11 (q, Jˆ7.1 Hz, 2H), 4.82 (s, 1H); 13C NMR
(CDCl3) d 14.6, 21.8, 24.4, 25.4, 46.5, 59.3, 66.4, 102.7,
110.5, 147.8, 153.7, 168.3; IR (neat) 1705, 1603, 1269,
1232, 1113 cm21. Anal. calcd for C14H21NO3: C, 66.91;
H, 8.42; N, 5.57. Found: C, 66.87; H, 8.37; N, 5.54.
3.4.3. Iodoaniline 10c. 61% Yield from dienamine 9c; mp
84±868C; 1H NMR (CDCl3) d 1.27 (t, Jˆ7.2 Hz, 3H), 2.71
(s, 3H), 4.22 (q, Jˆ7.2 Hz, 2H), 4.27 (d, Jˆ5.5 Hz, 2H),
5.17 (br, 1H), 5.87 (s, 2H), 6.28 (d, Jˆ8.6 Hz, 1H), 6.70
(s, 2H), 6.74 (s, 1H), 7.67 (d, Jˆ8.6 Hz, 1H); 13C NMR
(CDCl3) d 13.7, 27.3, 47.4, 59.8, 95.0, 100.4, 106.6,
106.9, 107.8, 119.3, 119.7, 131.1, 131.4, 143.5, 146.3,
147.4, 148.9, 166.5; IR (neat) 3398, 1698, 1592, 1488,
1236, 1171, 1037, 770 cm21. Anal. calcd for C18H18INO4:
C, 49.22; H, 4.13; N, 3.19; I, 28.89. Found: C, 49.42; H,
4.17; N, 3.15; I, 28.71.
3.5.2. Dienamine 11b. 85% Yield from cyclohexenone 1f
and thiomorpholine; 1H NMR (CDCl3) d 1.27 (t, Jˆ7.2 Hz,
3H), 2.18 (s, 3H), 2.19 (t, Jˆ9.7 Hz, 2H), 2.53 (t, Jˆ8.9 Hz,
2H), 2.59±2.61 (m, 4H), 3.51±3.54 (m, 4H), 4.15 (q,
Jˆ7.1 Hz, 2H), 4.83 (s, 1H); 13C NMR (CDCl3) d 14.6,
22.0, 24.6, 25.8, 26.0, 48.8, 59.3, 102.4, 109.3, 148.2,
152.4, 168.3; IR (neat) 1710, 1366, 1263, 1217, 1050,
1005 cm21. HRMS (EI) m/z calcd for C14H21NO2S:
267.1293. Found: 267.1292.
1
3.4.4. Iodoaniline 10d. 42% Yield from dienamine 9d; H
NMR (CDCl3) d 1.35 (t, Jˆ7.2 Hz, 3H), 2.79 (s, 3H), 4.29
(q, Jˆ7.2 Hz, 2H), 4.61 (d, Jˆ5.8 Hz, 2H), 5.30 (br, 1H),
6.46 (d, Jˆ8.7 Hz, 1H), 6.96±7.02 (m, 2H), 7.22±7.23 (m,
1H), 7.78 (d, Jˆ8.6 Hz, 1H); 13C NMR (CDCl3) d 14.5,
28.1, 43.6, 60.6, 95.9, 107.4, 120.5, 125.0, 125.4, 127.1,
132.2, 141.4, 144.3, 149.4, 167.2; IR (neat) 3379, 1703,
1588, 1365, 1242, 1172, 1079, 771 cm21. Anal. calcd for
C15H16INO2S: C, 44.90; H, 4.02; N, 3.49; I, 31.63. Found:
C, 45.14; H, 4.05; N, 3.46; I, 31.42.
3.5.3. Dienamine 11c. 75% Yield from cyclohexenone 1f
and piperidine; 1H NMR (CDCl3) d 1.24 (t, Jˆ7.2 Hz, 3H),
1.55 (br, 6H), 2.17 (s, 3H), 2.19 (t, Jˆ9.2 Hz, 2H), 2.51 (t,
Jˆ8.9 Hz, 2H), 3.08 (br, 4H), 4.11 (q, Jˆ7.1 Hz, 2H), 4.81
(s, 1H); 13C NMR (CDCl3) d 14.6, 22.1, 24.5, 24.6, 25.3,
26.0, 47.1, 59.1, 101.4, 108.2, 149.1, 154.4, 168.4; IR (neat)
1737, 1716, 1602, 1447, 1365, 1265, 1231, 1217,
1051 cm21. Anal. calcd for C15H23NO2: C, 72.25; H, 9.30;
N, 5.62. Found: C, 72.17; H, 9.31; N, 5.53.
1
3.4.5. Iodoaniline 10e. 55% Yield from dienamine 9e; H
NMR (CDCl3) d 1.28 (t, Jˆ7.2 Hz, 3H), 2.71 (s, 3H), 4.23
(q, Jˆ7.2 Hz, 2H), 4.34 (d, Jˆ5.5 Hz, 2H), 5.17 (br, 1H),
6.17 (d, Jˆ2.9 Hz, 1H), 6.24±6.26 (m, 1H), 6.39 (d, Jˆ
8.6 Hz, 1H), 7.30 (s, 1H), 7.72 (d, Jˆ8.6 Hz, 1H); 13C
NMR (CDCl3) d 13.7, 27.3, 40.8, 59.8, 95.1, 106.5, 106.7,
109.8, 119.7, 131.4, 141.6, 143.5, 148.7, 150.7, 166.5; IR
(neat) 3388, 1702, 1589, 1245, 1172, 1078, 770 cm21. Anal.
calcd for C15H16INO3: C, 46.77; H, 4.19; N, 3.64; I, 32.94.
Found: C, 46.98; H, 4.28; N, 3.57; I, 32.77.
3.5.4. Dienamine 11d. 80% Yield from cyclohexenone 1f
and N-methylbenzylamine; H NMR (CDCl3) d 1.27 (t,
1
Jˆ7.2 Hz, 3H), 2.24 (s, 3H), 2.34 (t, Jˆ9.6 Hz, 2H), 2.56
(t, Jˆ9.3 Hz, 2H), 2.86 (s, 3H), 4.15 (q, Jˆ7.1 Hz, 2H), 4.41
(s, 2H), 4.78 (s, 1H), 7.12 (d, Jˆ7.1 Hz, 2H), 7.24 (t,
Jˆ7.3 Hz, 1H), 7.32 (t, Jˆ7.7 Hz, 2H); 13C NMR (CDCl3)
d 14.7, 22.3, 24.7, 25.9, 37.9, 54.5, 59.1, 99.3, 107.4, 126.6,
127.3, 128.8, 138.0, 149.9, 154.0, 168.5; IR (neat) 1709,
1603, 1453, 1366, 1262, 1216, 1051, 747 cm21. HRMS
(EI) m/z calcd for C18H23NO2: 285.1729. Found: 285.1703.
3.4.6. Iodoaniline 10f. 47% Yield from dienamine 9f; mp
102±1038C; H NMR (CDCl3) d 1.06 (s, 6H), 1.29 (d,
1
Jˆ6.4 Hz, 2H), 2.38 (s, 2H), 2.77 (s, 2H), 3.71±3.79 (m,
1H), 4.84 (d, Jˆ6.9 Hz, 1H), 6.48 (d, Jˆ8.8 Hz, 1H), 7.93
(d, Jˆ8.8 Hz, 1H); 13C NMR (CDCl3) d 22.9, 28.6, 33.4,
44.9, 51.0, 51.2, 91.4, 108.6, 123.2, 129.0, 146.8, 150.6,
196.4; IR (DMSO) 3436, 1661, 1025, 953 cm21. Anal.
calcd for C15H20INO: C, 50.43; H, 5.64; N, 3.92; I, 35.52.
Found: C, 50.66; H, 5.67; N, 3.79; I, 35.31.
3.5.5. Dienamine 11e. 39% Yield from cyclohexenone 1h
and N-methylallylamine; 1H NMR (CDCl3) d 0.85 (t,
Jˆ7.2 Hz, 3H), 2.43 (t, Jˆ9.5 Hz, 2H), 2.70 (t, Jˆ9.3 Hz,
2H), 2.84 (s, 3H), 3.81±3.83 (m, 2H), 4.37 (q, Jˆ7.2 Hz,
2H), 4.75 (s, 1H), 5.09±5.19 (m, 2H), 5.71±5.79 (m, 1H),
7.17±7.32 (m, 5H); 13C NMR (CDCl3) d 13.8, 25.2, 25.3,
37.7, 53.7, 59.1, 97.9, 108.0, 116.5, 126.6, 127.5, 127.6,
133.1, 144.4, 151.5, 153.5, 168.7; IR (neat) 1728, 1671,
1259, 1178, 1091, 1017, 797 cm21. HRMS (EI) m/z calcd
for C19H23NO2: 297.1729. Found: 297.1715.
3.5. General procedure for the preparation of
dienamines 11a±f
3.5.6. Dienamine 11f. 75% Yield from cyclohexenone 1f
and 1-(4-¯uorophenyl)piperazine; mp 102±1038C; 1H NMR
(CDCl3) d 1.27 (t, Jˆ7.3 Hz, 3H), 2.21 (s, 3H), 2.25 (t,
Jˆ9.2 Hz, 2H), 2.56 (t, Jˆ8.8 Hz, 2H), 3.11 (t, Jˆ5.4 Hz,
4H), 3.24 (t, Jˆ5.4 Hz, 4H), 4.15 (q, Jˆ7.1 Hz, 2H), 4.90 (s,
1H), 6.85±6.89 (m, 2H), 6.93±6.97 (m, 2H); 13C NMR
A solution of 0.027 mol of the cyclohexenone substrate,
0.041 mol of a secondary amine and 0.1 g of p-toluene-
sulfonic acid in 70 mL of toluene was heated at re¯ux for
24 h in a Dean±Stark apparatus with azeotropic removal of
water. The reaction mixture was evaporated and the residue
was partitioned between ethyl acetate and water. The

S. G. Hegde et al. / Tetrahedron 57 (2001) 1689±1698
1697
(CDCl3) d 14.6, 22.0, 24.6, 25.8, 46.2, 50.0, 59.3, 102.9,
Anal. calcd for C18H21NO2: C, 76.30; H, 7.47; N, 4.94.
Found: C, 76.18; H, 7.48; N, 4.91.
2
3
110.2, 115.7 (d, JC±Fˆ22.1 Hz), 118.3 (d, JC±Fˆ7.6 Hz),
1
147.8, 148.0, 153.4, 157.5 (d, JC±Fˆ239.4 Hz), 168.4; 19F
1
3.6.5. Aniline 12e. 89% Yield from dienamine 11e; H
NMR (CDCl3) d 2125.62; IR (neat) 1682, 1524, 1509,
1229, 1195, 828 cm21. Anal. calcd for C20H25FN2O2: C,
69.74; H, 7.32; N, 8.13. Found: C, 69.63; H, 7.35; N, 8.18.
NMR (CDCl3) d 1.00 (t, Jˆ7.2 Hz, 3H), 3.03 (s, 3H),
3.99±4.01 (m, 2H), 4.05 (q, Jˆ7.2 Hz, 2H), 5.13±5.20
(m, 2H), 5.78±5.88 (m, 1H), 6.56 (d, Jˆ2.7 Hz, 1H), 6.68
(dd, Jˆ2.7, 6.1 Hz, 1H), 7.31±7.41 (m, 5H), 7.90 (d, Jˆ
8.8 Hz, 1H); 13C NMR (CDCl3) d 13.9, 38.1, 54.7, 60.0,
110.1, 113.9, 116.5, 117.4, 126.8, 127.7, 128.5, 132.6,
132.7, 143.4, 145.4, 151.3, 168.0; IR (neat) 1698, 1597,
1279, 1147, 1097, 700 cm21. Anal. calcd for C19H21NO2:
C, 77.26; H, 7.17; N, 4.74. Found: C, 77.13; H, 7.20; N,
4.70.
3.6. General procedure for the preparation of
N,N-dialkylanilines 12a±f
To a solution of 0.008 mol of sodium ethoxide (prepared by
dissolving 0.18 g of sodium in 20 mL of ethanol) at 2788C
was added 0.004 mol of the dienamine substrate. After
stirring for 15 min, 1.01 g (0.004 mol) of iodine was
added in small portions. The reaction mixture was stirred
for 3 h at 2788C and allowed to warm to room temperature.
After stirring at room temperature overnight, the reaction
mixture was neutralized with 5% HCl solution and ethanol
was removed by evaporation under reduced pressure. The
resulting suspension was extracted with ethyl acetate. The
organic layer was washed successively with saturated
NaHSO3 solution and brine, then dried (MgSO4) and evapo-
rated. The residue was puri®ed by preparative HPLC using
10% ethyl acetate±hexane as the eluent.
3.6.6. Aniline 12f. 75% Yield from dienamine 11f; mp 88±
1
908C; H NMR (CDCl3) d 1.37 (t, Jˆ7.2 Hz, 3H), 2.63 (s,
3H), 3.22 (t, Jˆ5.2 Hz, 4H), 3.44 (t, Jˆ5.3 Hz, 4H), 4.32 (q,
Jˆ7.0 Hz, 2H), 6.74±6.77 (m, 2H), 6.89±6.93 (m, 2H),
6.97±7.02 (m, 2H), 7.93 (d, Jˆ8.5 Hz, 1H); 13C NMR
(CDCl3) d 14.5, 22.9, 47.9, 50.3, 60.2, 111.8, 115.7 (d,
3
2JC±Fˆ22.2 Hz), 117.4, 118.29 (d, JC±Fˆ7.6 Hz), 119.8,
1
132.7, 142.9, 147.8, 153.2, 157.5 (d, JC±Fˆ239.5 Hz),
167.3; 19F NMR (CDCl3) d 2125.79; IR (neat) 1681,
1600, 1508, 1292, 1227, 1154, 827, 777 cm21. Anal. calcd
for C20H23FN2O2: C, 70.16; H, 6.77; N, 8.18. Found: C,
70.16; H, 6.80; N, 8.21.
3.6.1. Aniline 12a. 85% Yield from dienamine 11a; mp
1
56±588C; H NMR (CDCl3) d 1.35 (t, Jˆ7.2 Hz, 3H),
2.58 (s, 3H), 3.23 (t, Jˆ4.9 Hz, 4H), 3.82 (t, Jˆ4.9 Hz,
4H), 4.29 (q, Jˆ7.2 Hz, 2H), 6.66±6.69 (m, 2H), 7.89 (d,
Jˆ8.6 Hz, 1H); 13C NMR (CDCl3) d 14.5, 22.8, 47.9, 60.2,
66.7, 111.4, 116.9, 120.0, 132.7, 142.4, 153.4, 167.3; IR
(neat) 1700, 1605, 1234, 1123, 771 cm21. Anal. calcd for
C14H19NO3: C, 67.45; H, 7.68; N, 5.62. Found: C, 67.48; H,
7.70; N, 5.61.
3.6.7. Methyl 5-iodo-2-methyl-4-(2-propenyloxy)benzo-
ate (18a). To a solution of 4.0 g (0.014 mol) of iodophenol
2a and 2.42 g (0.02 mol) of allyl bromide in 50 mL of
acetone was added 2.84 g (0.02 mol) of potassium carbonate
and the resulting slurry was heated at re¯ux for 1 h. After
cooling to room temperature, the mixture was ®ltered and
the ®ltrate was evaporated under reduced pressure. The
residue was diluted with water (100 mL) and extracted
with ethyl acetate (3£100 mL). The combined organic
layers were washed with water, dried (MgSO4) and evapo-
rated. Puri®cation of the residue by preparative HPLC using
2% ethyl acetate±hexane as the eluent gave 4.10 g (90%) of
1
3.6.2. Aniline 12b. 88% Yield from dienamine 11b; H
NMR (CDCl3) d 1.35 (t, Jˆ7.2 Hz, 3H), 2.57 (s, 3H),
2.65±2.68 (m, 4H), 3.68±3.71 (m, 4H), 4.29 (q, Jˆ
7.1 Hz, 2H), 6.61±6.65 (m, 2H), 7.88 (d, Jˆ8.5 Hz, 1H);
13C NMR (CDCl3) d 14.5, 22.9, 26.0, 50.6, 60.1, 111.8,
117.4, 119.0, 132.9, 142.7, 152.3, 167.2; IR (neat) 1702,
1602, 1261, 1224, 1156, 1080, 773 cm21. Anal. calcd for
C14H19NO2S: C, 63.37; H, 7.22; N, 5.28. Found: C, 63.44;
H, 7.27; N, 5.33.
1
compound 18a as a pale yellow solid: mp 110±1118C; H
NMR (CDCl3) d 2.48 (s, 3H), 3.77(s, 3H), 4.53±4.55 (m,
2H), 5.23±5.26 (m, 1H), 5.41±5.46 (m, 1H), 5.91±5.99 (m,
1H), 6.52 (s, 1H), 8.28 (s, 1H); 13C NMR (CDCl3) d 21.6,
51.1, 68.9, 81.4, 114.0, 117.3, 122.8, 131.2, 141.3, 142.7,
158.9, 165.4; IR (neat) 1702, 1368, 1248, 1096, 981,
776 cm21. Anal. calcd for C12H13IO3: C, 43.40; H, 3.95; I,
38.21. Found: C, 43.39; H, 3.96; I, 38.18.
1
3.6.3. Aniline 12c. 74% Yield from dienamine 11c; H
NMR (CDCl3) d 1.36 (t, Jˆ7.2 Hz, 3H), 1.61±1.67 (m,
6H), 2.59 (s, 3H), 3.28 (t, Jˆ5.7 Hz, 4H), 4.29 (q, Jˆ
7.1 Hz, 2H), 6.67±6.69 (m, 2H), 7.88 (d, Jˆ8.6 Hz, 1H);
13C NMR (CDCl3) d 14.5, 22.9, 22.5, 25.5, 48.9, 59.6,
111.5, 117.1, 118.3, 132.7, 142.4, 153.8, 167.4; IR (neat)
1703, 1602, 1233, 1126, 774 cm21. Anal. calcd for
C15H21NO2: C, 72.84; H, 8.56; N, 5.66. Found: C, 72.60;
H, 8.60; N, 5.60.
3.6.8. Ethyl 3-iodo-2-methyl-4-(2-propenyloxy)benzoate
(18b). Treatment of 4.0 g (0.014 mol) of iodophenol 2f
with 2.42 g (0.02 mol) of allyl bromide and 2.84 g
(0.02 mol) of potassium carbonate as above gave 4.28 g
(95%) of compound 18b as a pale yellow solid: mp 46±
1
488C; H NMR (CDCl3) d 1.29 (t, Jˆ7.2 Hz, 3H), 2.69 (s,
1
3.6.4. Aniline 12d. 84% Yield from dienamine 11d; H
3H), 4.25 (q, Jˆ7.2 Hz, 2H), 4.55±4.56 (m, 2H), 5.23±5.26
(m, 1H), 5.44±5.49 (m, 1H), 5.92±6.02 (m, 1H), 6.55 (d,
Jˆ8.6 Hz, 1H), 7.72 (d, Jˆ8.6 Hz, 1H); 13C NMR (CDCl3)
d 13.6, 26.5, 60.2, 69.1, 96.4, 107.9, 117.2, 123.9, 131.1,
131.4, 144.0, 158.7, 166.4; IR (neat) 1701, 1276, 1247,
1211, 1183, 1090, 1061, 771 cm21. Anal. calcd for
C13H15IO3: C, 45.11; H, 4.37; I, 36.66. Found: C, 44.98;
H, 4.35; I, 36.53.
NMR (CDCl3) d 1.38 (t, Jˆ7.4 Hz, 3H), 2.62 (s, 3H),
3.09 (s, 3H), 4.32 (q, Jˆ7.4 Hz, 2H), 4.61 (s, 2H), 6.56±
6.58 (m, 2H), 7.20 (d, Jˆ7.2 Hz, 2H), 7.27 (t, Jˆ7.1 Hz,
1H), 7.34 (t, Jˆ7.7 Hz, 2H), 7.92 (d, Jˆ8.4 Hz, 1H); 13C
NMR (CDCl3) d 14.6, 23.1, 38.5, 55.9, 59.9, 108.9, 114.2,
117.0, 126.6, 127.2, 128.8, 133.0, 138.1, 142.8, 152.1,
167.5; IR (neat) 1699, 1602, 1253, 1158, 1076, 772 cm21
.

1698
S. G. Hegde et al. / Tetrahedron 57 (2001) 1689±1698
Tetrahedron Lett. 1998, 39, 9605±9608. (b) Wang, Y.;
Huang, T. Tetrahedron Lett. 1998, 39, 9605±9608.
5. (a) Sakamoto, T.; Kondo, Y.; Yamanaka, H. Heterocycles
1986, 24, 31±32. (b) Larock, R. C.; Yum, E. K. J. Am.
Chem. Soc. 1991, 113, 6689±6690. (c) Larock, R. C.; Yum,
E. K.; Refvik, M. D. J. Org. Chem. 1998, 63, 7652±7662.
6. Torii, S.; Okumoto, H.; Xu, L.-H.; Sadakane, M.;
Shostakovsky, M. V.; Ponomaryov, A. B.; Kalinin, V. N.
Tetrahedron 1993, 49, 6773±6784.
3.6.9. Methyl 3,6-dimethyl-2,3-dihydrobenzofuran-5-
carboxylate (19a). A solution of 2.0 g (0.004 mol) of 18a,
3.5 g (0.012 mol) of tributyltin hydride and 50 mg of
1,10-azobis(cyclohexanecarbonitrile) in 250 mL of toluene
was heated at re¯ux for 1 h. After cooling to room tempera-
ture, the mixture was evaporated under reduced pressure
and the residue was puri®ed by preparative HPLC using
2% ethyl acetate±hexane as the eluent to give 1.22 g
1
(98%) of 19a as a pale yellow oil: H NMR (CDCl3) d
7. (a) Torii, S.; Okumoto, H.; Xu, L.-H. Tetrahedron Lett. 1990,
31, 7175±7178. (b) Torii, S.; Xu, L.-H.; Sadakane, M.;
Okumoto, H. Synlett 1992, 513±514.
1.25 (d, Jˆ6.9 Hz, 3H), 2.49 (s, 3H), 3.39±3.48 (m, 1H),
3.77 (s, 3H), 4.02±4.06 (m, 1H), 4.64 (t, Jˆ8.9 Hz, 2H),
6.55 (s, 1H), 7.69 (s, 1H); 13C NMR (CDCl3) d 18.8, 21.8,
35.1, 50.8, 78.8, 111.7, 120.9, 126.1, 129.3, 142.0, 162.3,
8. Oh-e, T.; Miyaura, N.; Suzuki, A. J. Org. Chem. 1993, 58,
2201±2208 (and references cited therein).
167.0; IR (neat) 1715, 1255, 1134, 1116, 962, 783 cm21
.
9. Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981, 11,
513±519 (and references cited therein).
Anal. calcd for C12H14O3: C, 69.89; H, 6.84. Found: C,
69.89; H, 6.86.
10. Watanabe, T.; Miyaura, N.; Suzuki, A. Synlett 1992, 207±210
(and references cited therein).
3.6.10. Ethyl 3,4-dimethyl-2,3-dihydrobenzofuran-5-
carboxylate (19b). Treatment of 2.0 g (0.006 mol) of 18b
with 3.5 g (0.012 mol) of tributyltin hydride and 50 mg of
1,10-azobis(cyclohexanecarbonitrile) as above gave 1.25 g
(98%) of 19b as a pale yellow oil: 1H NMR (CDCl3) d 1.19
(d, Jˆ6.9 Hz, 3H), 1.28 (t, Jˆ7.1 Hz, 3H), 2.46 (s, 3H),
3.36±3.44 (m, 1H), 4.17±4.25 (m, 3H), 4.52 (t, Jˆ8.5 Hz,
2H), 6.56 (d, Jˆ8.4 Hz, 1H), 7.75 (d, Jˆ8.4 Hz, 1H); 13C
NMR (CDCl3) d 13.7, 16.8, 19.3, 35.1, 59.6, 78.5, 106.1,
121.8, 131.8, 131.9, 137.0, 161.4, 166.7; IR (neat) 1708,
1252, 1160, 1123, 1050, 780 cm21. Anal. calcd for
C13H16O3: C, 70.89; H, 7.32. Found: C, 70.83; H, 7.32.
11. For a review, see: (a) Merkushev, E. B. Synthesis 1988, 923±
937. For a comprehensive list of reagents for direct iodination
of aromatic compounds, see: (b) Larock, R. C. Comprehensive
Organic Transformations, VCH: New York, 1989 (pp 315±
318). (c) Bachki, A.; Foubelo, F.; Yus, M. Tetrahedron 1994,
50, 5139±5146 (and references cited therein). (d) Yang, S. G.;
Kim, Y. H. Tetrahedron Lett. 1999, 40, 6051±6054 (and refer-
ences cited therein). (e) Sy, W. Synth. Commun. 1992, 22,
3215±3219. (f) Boothe, R.; Dial, C.; Conaway, R.; Pagni,
R. M.; Kabalka, G. W. Tetrahedron Lett. 1986, 27, 2207±
2210 (and references cited therein).
12. Cambie, R. C.; Rutledge, P. S.; Smith-Palmer, T.; Woodgate,
P. D. J. Chem. Soc., Perkin Trans. 1 1976, 1161±1164.
13. Horiuchi, C. A.; Satoh, J. Y. J. Chem. Soc., Chem. Commun.
1982, 671±672.
3.6.11. Ethyl 3,4-dimethyl-2,3-dihydroindole-5-carboxyl-
ate (20). Treatment of 2.0 g (0.006 mol) of 10a with 3.5 g
(0.012 mol) of tributyltin hydride and 50 mg of
1,10-azobis(cyclohexanecarbonitrile) as above gave 0.8 g
(63%) of 20 as a white solid: mp 90±928C; 1H NMR
(CDCl3) d 1.13 (d, Jˆ6.9 Hz, 3H), 1.27 (t, Jˆ7.1 Hz, 3H),
2.44 (s, 3H), 3.15±3.18 (m, 1H), 3.25±3.33 (m, 1H), 3.63 (t,
Jˆ8.5 Hz, 1H), 4.01 (br, 1H), 4.18±4.23 (m, 2H) 6.32 (d,
Jˆ8.3 Hz, 1H), 7.68 (d, Jˆ8.3 Hz, 1H); 13C NMR (CDCl3)
d 13.8, 16.6, 18.9, 34.5, 54.1, 59.2, 104.7, 118.6, 131.7, 132.9,
136.3, 153.1, 167.1; IR (neat) 3359, 1686, 1598, 1587, 1255,
1241, 1143, 1050 cm21. Anal. calcd for C13H17NO2: C,
71.21; H, 7.81; N, 6.39. Found: C, 71.06; H, 7.77; N, 6.38.
14. Hillmann-Elias, A.; Hillman, G.; Schiedt, U. Z. Naturforsch B
1953, 8, 436±440.
15. Hegde, S. G.; Kassim, A. M.; Ingrum, A. I. Tetrahedron Lett.
1995, 36, 8395±8398.
16. Vorndam, P. E. J. Org. Chem. 1990, 55, 3693±3695.
17. Begue, J.-P.; Bonnet-Delpon, D.; Dogbeavou, A. Synth.
Commun. 1992, 22, 573±579.
18. Walker, G. N. J. Am. Chem. Soc. 1955, 77, 3664±3667.
19. Regiochemistry of iodophenols 2a±h was readily determined
1
by the coupling of aromatic proton resonances in H NMR
spectra. Compounds 2a±e exhibited singlets for the two
phenyl protons. By contrast, the phenyl protons in compounds
2f±h showed two doublets with coupling constants of
7.0±8.4 Hz consistent with ortho coupling.
References
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