Electrophilic aromatic addition reaction: Electrophilic attack at an aromatic H substituent position

Article abstract of DOI:10.1021/jo048297x

(Chemical Equation Presented) We report and propose a mechanism for an unusual electrophilic aromatic addition reaction (Ad_EAr). During our preparation of 5,7-dibromo-8-methoxyquinaldine as a key intermediate in the synthesis of 7-bromoquinaldine-5,8-dione, direct bromination in either acidic or neutral conditions led only to the formation of 5-bromo-8-methoxyquinaldine. Under basic methanolic conditions, however, we unexpectedly obtained the 5,7-dibromo-8,8-dimethoxy-7,8-dihydroquinaldine adduct 2a. This result not only allows for the functionalization of aromatic compounds via the addition adducts, but also introduces the possibility of an alternate mechanism for electrophilic substitution reactions.

Full text of DOI:10.1021/jo048297x

Electrophilic Aromatic Addition Reaction: Electrophilic Attack at
an Aromatic H Substituent Position
Han Young Choi, Ekaruth Srisook,† Kun Sam Jang, and Dae Yoon Chi*
Department of Chemistry, Inha University, 253 Yonghyundong Namgu, Inchon 402-751, Korea
dychi@inha.ac.kr
Received September 24, 2004
We report and propose a mechanism for an unusual electrophilic aromatic addition reaction (AdEAr).
During our preparation of 5,7-dibromo-8-methoxyquinaldine as a key intermediate in the synthesis
of 7-bromoquinaldine-5,8-dione, direct bromination in either acidic or neutral conditions led only
to the formation of 5-bromo-8-methoxyquinaldine. Under basic methanolic conditions, however,
we unexpectedly obtained the 5,7-dibromo-8,8-dimethoxy-7,8-dihydroquinaldine adduct 2a. This
result not only allows for the functionalization of aromatic compounds via the addition adducts,
but also introduces the possibility of an alternate mechanism for electrophilic substitution reactions.
Introduction
regarding intermediate identity based solely on struc-
tural information obtained from the products. In cases
where isolated adducts have been identified, the inter-
mediates sometimes imply significant mechanistic dif-
ferences when compared to the majority of known elec-
trophilic aromatic substitutions. One example of this is
the series of adducts identified in the nitration of furan,
whose mode of decomposition differs greatly from that
commonly seen in six-membered systems.3 Moreover,
when rearomatization by deprotonation is blocked, the
known ipso attack of the nitro group at the substituted
position also showed the possibility of electrophilic ad-
dition on benzenoid systems.4
Herein, we wish to report and propose a mechanism
for an unusual electrophilic aromatic addition reaction
(AdEAr). During our preparation of 5,7-dibromo-8-meth-
oxyquinaldine5 as a key intermediate in the synthesis of
7-bromoquinaldine-5,8-dione,6 direct bromination in ei-
ther acidic or neutral conditions led only to the formation
of 5-bromo-8-methoxyquinaldine. Under basic methanolic
conditions, however, we unexpectedly obtained the 5,7-
Although a wide variety of electrophilic species can
attack aromatic rings and effect substitution, a single
broad mechanism encompasses the large majority of
electrophilic aromatic substitution reactions through the
reversible formation of π and σ complexes.1 In electro-
philic substitution, the formation of the σ complex is
generally the rate-determining step, with the aromati-
zation occurring much faster than the addition of the
nucleophile to the σ complex carbocation, but there are
exceptions. Some authors indicate that nucleophile ad-
dition proceeds faster than deprotonation,2 but the in-
ability to isolate the intermediate adductssdue to their
rapid rearomatization or further reaction to multiaddi-
tion productssforces investigators to draw conclusions
* Author to whom correspondence should be addressed. Phone: +82-
32-860-7686. Fax: +82-32-867-5604.
† Present address: Department of Chemistry, Burapha University,
Chonburi, 20131, Thailand.
(1) (a) Carey, F. A.; Sundberg, R. J. Advanced Organic Chemistry
Part A, 4th ed.; Kluwer Academic/Pluneum Publisher: New York, 2000;
Chapter 10. (b) Olah, G. A. Acc. Chem. Res. 1971, 4, 240-248. (c) Ridd,
J. H. Acc. Chem. Res. 1971, 4, 248-253. (d) Lenoir, D. Angew. Chem.,
Int. Ed. 2003, 42, 854-857.
(3) (a) Michels, J. G.; Hayes, K. J. J. Am. Chem. Soc. 1958, 80, 1114-
1116. (b) Kolb, V. M.; Darling, S. D.; Koster, D. F.; Meyers, C. Y. J.
Org. Chem. 1984, 49, 1636-1639.
(4) (a) Fischer, A.; Ramsay, J. N. Can. J. Chem. 1974, 52, 3960-
3970. (b) Fisher, A.; Greig, C. C.; Roderer, R. Can. J. Chem. 1975, 53,
1570-1578. (c) Hahn, R. C.; Strack, D. L. J. Am. Chem. Soc. 1974, 96,
4335-4337
(2) (a) Hebel, D.; Rozen, S. J. Org. Chem. 1991, 56, 6298-6301. (b)
Strand, J. W.; Kovacic, P. J. Am. Chem. Soc. 1973, 95, 2977-2982. (c)
Kovacic, P.; Levisky, J. A. J. Am. Chem. Soc. 1966, 88, 1000-1005.
(d) DeRosa, M.; Brillembourg, I. J. Chem. Soc., Chem. Commun. 1986,
1585-1586. (e) DeRosa, M.; Nieto, G. C. Tetrahedron Lett. 1988, 29,
2405-2408.
10.1021/jo048297x CCC: $30.25 © 2005 American Chemical Society
Published on Web 01/21/2005
1222
J. Org. Chem. 2005, 70, 1222-1226

Electrophilic Aromatic Addition Reaction
TABLE 1. Bromomethoxylation of 8-Methoxyquinaldine
(1a) under Various Conditionsa
yield of product (%)b
brominating
agent
base
(equiv)
entry
2a
3ac
1
2
3
4
5
6
Br2
Br2
Br2
Br2
Br2
NBS
NaHCO3 (3.5)
NaHCO3 (2)
NaOMe (3)
NaOMe (1)
NaOH (1)
65
51
25
90
80
97
96
12
trace
NaHCO3 (3.5)
a All reactions were carried out on 2.0 mmol of 8-methoxy-
quinaldine 1a with 3 equiv of bromine for 10 min at room
temperature. b Isolated yield. c 5-Bromo-8-methoxyquinaldine.
FIGURE 1. The X-ray structure of tetrahedral adduct 2a.
SCHEME 2. The Addition Reaction of
1-Methoxynaphthalene (1b)
SCHEME 1. The Addition Reaction of
8-Methoxyquinaldine (1a)
dibromo-8,8-dimethoxy-7,8-dihydroquinaldine adduct 2a
as the major product. To the best of our knowledge, this
is the first reported isolation of an addition adduct at an
aromatic H substituent position during the electrophilic
aromatic substitution of a benzenoid compound. This
result not only allows for the functionalization of aromatic
compounds via the addition adducts, but also introduces
the possibility of an alternate mechanism for electrophilic
substitution reactions.
nonisolable intermediates or addition adducts which
differ from product. Because the pyridyl moiety structur-
ally differentiates quinoline from naphthalene, we pro-
posed that pyridine might play a role in sufficiently
stabilizing addition adducts for isolation. To investigate
the importance of the pyridine moiety, we added 1 equiv
of pyridine into the reaction mixture under the same
conditions. Surprisingly, we succeeded in obtaining the
addition product in nearly quantitative yield (Scheme 2).
This is the first isolation of the addition product at an
aromatic H substituent position of a nonheterocyclic
compound from the AdEAr reaction.
We next wanted to study the effect of base on the
reaction (Table 1). Treatment of 8-methoxyquinaldine 1a
with only 2 equiv of NaHCO3 allowed some intermediate
product, 5-bromo-8-methoxyquinaldine, 3a, to remain
(entry 2). Alternatively, treatment of 1a with strong bases
such as sodium methoxide or sodium hydroxide resulted
in little to no formation of the addition product 2a (entries
3-5). (It is likely that compound 2a could be obtained in
higher yield as a minor product by decreasing the amount
of strong base used). Surprisingly, NaOH treatment also
produced trace amounts of 5,7-dibromo-8-methoxyquinal-
dine. Last, in utilizing N-bromosuccinimide (NBS) as the
brominating reagent, only product 3a was observed,
possibly due to the lower electrophilic reactivity of NBS
toward aromatic systems. These results indicated that
the reactivity of the base as well as that of the bromine
reagent are very important in forming the addition
adduct. Using strong base decreased the reactivity of
bromine and resulted in elimination to form the substitu-
tion product. In addition, although some reports indicate
that NBS can be used in the AdE reaction of olefins, it
was insufficiently reactive in the case of aromatic sys-
tems.7
Results and Discussion
The conversion of 8-methoxyquinaldine 1a by the
treatment of bromine (3.0 equiv) in the presence of
NaHCO3 (3.5 equiv) occurred simply at room temperature
(Scheme 1) and led to the formation of an intermediate,
5-bromo-8-methoxyquinaldine, which was indicated from
TLC monitoring. After addition of water, the nearly pure
addition product 2a was precipitated as a racemic
mixture. The proton NMR spectrum shows the H7 peak
at 4.88 ppm (d, J ) 7.0 Hz) as well as two different
methoxy peaks, clearly proving the existence of the
tetrahedral product.
Structural characterization of 2a was further con-
firmed by elemental analysis, mass spectroscopy, and
single-crystal X-ray analysis. X-ray crystallographic data
for 2a (Figure 1) illustrate that the bromine at C7 is in
an axial-like orientation and is antiplanar with respect
to one methoxy group, thereby placing H7 in an equato-
rial-like orientation, rendering it resistant to rearoma-
tization by E2-elimination.
Upon first extension of this methodology to 1-methoxy-
naphthalene (1b), only the substitution products were
obtained (Scheme 2). Interestingly, the TLC analysis
used to monitor this reaction indicated the formation of
(5) (a) Choi, H. Y.; Lee, B. S.; Chi, D. Y.; Kim, D. J. Heterocycles
1998, 48, 2647-2652. (b) Yoon, E. Y.; Choi, H. Y.; Shin, K. J.; Yoo, K.
H.; Chi, D. Y.; Kim, D. J. Tetrahedron Lett. 2000, 41, 7475-7480. (c)
Yoo, K. H.; Yoon, E. Y.; Park, Y. Y.; Park, S. W.; Lee, C.-O.; Lee, W.
G.; Chi, D. Y.; Kim, D. J. Bull. Korean Chem. Soc. 2001, 22, 1067-
1068.
(6) Choi, H. Y.; Kim, D. W.; Chi, D. Y.; Yoon, E. Y.; Kim, D. J. J.
Org. Chem. 2002, 67, 5390-5393.
(7) Sasaki, M.; Yudin, A. K. J. Am. Chem. Soc. 2003, 125, 14242-
14243.
J. Org. Chem, Vol. 70, No. 4, 2005 1223

Choi et al.
TABLE 2. Bromoalkoxylation of Various Methoxy Bicyclic Aromatic Compounds under NaHCO3-Methanol
Conditionsa
a Unless otherwise noted, all reactions were carried out under the same conditions as in Table 1, entry 1. b Isolated yield. c Acetonitrile
was used as a solvent.
SCHEME 3. The Reactions of 8-Ethoxyquinaldine
and 8-Methoxyquinaldine
To check the generality of the reaction, we attempted
the bromoalkoxylation of various bicyclic aromatic com-
pounds under the same reaction conditions as Table 1,
entry 1 (Table 2). The AdEAr reaction of 5-methoxy-
quinaldine 1c (entry 1) proceeded well, giving the stable
addition product 2c in very high yield (90%). Alterna-
tively, we obtained a mixture of both addition and
substitution products when the â-methoxy compound,
1
6-methoxyquinaldine (1d), was used (entry 2). The H
NMR spectrum of 2d showed a long-range coupling
constant between H5 and H7 of 2.0 Hz, which is unusu-
ally large due to the planar W conformation of the four
σ bonds. This suggests that the bromomethoxylated
product exists in the same conformer as 2a. TLC analysis
indicates only 1.5 equiv of bromine are required to
complete the reaction. Like the quinoline, the reaction
of 7-methoxyisoquinoline 1e gave product 2e with similar
results (entry 3). To study the effects of nonalcoholic
solvents in the presence of additional nucleophiles, the
hydroxy ether derivative 1f was treated in acetonitrile
(entry 4). The bromoalkoxylated spiro compound 2f was
isolated in moderate yield along with the dibromo
byproduct, indicating the possibility of introducing vari-
ous nucleophiles in conjunction with nonnucleophilic
solvents for use in the AdEAr reaction.
The stereochemistry of the reaction was further inves-
tigated. Although it is well-known that many polar
addition reactions of halogen electrophiles to alkenes take
place with exclusive antistereochemistry, there are also
many examples of syn additions.8 The antiaddition can
result from bridged bromonium ion intermediates and
from very rapid capture of a carbocation intermediate by
nucleophilic solvent. On the other hand, if the principal
intermediate were an ion pair that collapsed faster than
translocation about the anion, the syn addition could
predominate. In the case of bromoalkoxylation, syn
addition could be possible only when the brominating
agent was hypobromite, which was reported to be formed
from bromine in methanol under basic condition.9 How-
ever, the mixture of both addition products could be
obtained if the cationic intermediate were very stable.
Therefore, the addition orientation can show the
interpretation of reaction stereochemistry and mecha-
nism. When methoxy compounds were treated in metha-
nol solvent, we were unable to distinguish where each
methoxy group came from. Therefore, the reactions of
8-ethoxyquinaldine (1h) in methanol and 8-methoxy-
quinaldine (1a) in ethanol were used in this study as
shown in Scheme 3. Both reactions yielded a mixture of
addition products, 5a and 6a, the major product being
the antiaddition one. The structures of both products
were confirmed by X-ray crystallography (Figure 2). The
result elucidated that the alkoxylquinaldine reacted with
bromine molecules to produce a stable cation intermedi-
ate and was finally attacked by a nucleophilic alkoxide,
preferentially at the opposite side of the bromine group.
We have proposed a mechanism for this addition
reaction (Scheme 4) in which the brominated reactant
probably forms a cationic intermediate (σ complex),
(9) (a) Dicks, P. F.; Glover, S. A.; Goosen, A.; McCleand C. W.
Tetrahedron 1987, 43, 923-934. (b) Gervat, S.; Leonel, E.; Barraud,
J.; Ratovelomanana, V. Tetrahedron Lett. 1993, 34, 2115-2118.
(8) Heasley, G. E.; Bower, T. R.; Dougharty, K. W.; Easdon, J. C. J.
Org. Chem. 1980, 45, 5150-5155.
1224 J. Org. Chem., Vol. 70, No. 4, 2005

Electrophilic Aromatic Addition Reaction
SCHEME 4. Mechanism of the AdEAr Reaction
stabilized by the methoxy group. The formation of the
stable complex possibly leads to either deprotonation-
aromatization or nucleophilic capture. The aromatization
from 2b requires that the proton should be either anti-
coplanar or syn-coplanar to methoxy. As the hydrogen
occupies a gauche position with respect to the adjacent
methoxy substituents in the A conformer, the change of
conformation from A to B conformer (Scheme 4) might
require much higher activation energy due to steric
hindrance. These bulky moieties may hinder the solvent
or other bases from assisting in proton removal, favoring
either (a) regeneration of the reactant from the σ complex
or (b) nucleophilic attack at the ipso position of the
methoxy group, giving the kinetic addition adduct 2 as a
racemic mixture. Although the formation of aromatic
products is usually considered as under thermodynamic
control, carbocation sequences often give products under
kinetic control.10 Moreover, the fused ring and the bulky
group also make changing conformation impossible. The
R-methoxy compounds 1a-c,f yielded only addition ad-
ducts 2a-c,f, whereas the â-methoxy compounds 1d-e
gave a mixture of both addition and substitution prod-
ucts, perhaps due to the acidity of the proton at the bromo
position. The benzylic protons of the σ complex interme-
diates for 1d-e should be easier to remove than the
nonbenzylic protons of 1a-c,f.
In summary, we have demonstrated a novel reaction
and mechanismselectrophilic aromatic addition reaction
(AdEAr) at an aromatic H substituent positionsfor fused
bicyclic aromatic compounds, as well as the first isolation
of the corresponding addition adducts. These stable
adducts should provide new tools for the functionalization
of aromatic rings. The methoxy bicyclic aromatic system
is a good example of the addition reaction of bromine and
methoxide. Further studies regarding mechanism as well
as applications of the addition products are currently
underway in our laboratory.
Experimental Section
Typical Procedure for the Electrophilic Aromatic
Addition Reaction. To the suspension of methoxy compound
(2 mmol) and NaHCO3 (3.5 or 1.75 equiv) in MeOH (6 mL)
was added a solution of Br2 (3.0 or 1.5 equiv) in MeOH (1.5
mL) with stirring at room temperature. After 5 min, water (3
mL) was added and the reaction was stirred for another 5 min.
Then, water (30 mL) and Na2SO3 (0.32 g) were added. The
mixture was extracted with CH2Cl2 (2 × 20 mL) and the
combined organic layers were washed with brine and dried
(Na2SO4). The residue was purified by flash column chroma-
tography.
5,7-Dibromo-8,8-dimethoxy-7,8-dihydroquinaldine (2a).
Yellowish crystalline solid, mp 142-143 °C; 1H NMR (200
MHz, CDCl3) δ 2.69 (s, 3H), 3.00 (s, 3H), 3.54 (s, 3H), 4.87 (d,
J ) 7.0 Hz, 1H), 6.68 (d, J ) 7.0 Hz, 1H), 7.24 (d, J ) 8.0 Hz,
1H), 7.85 (d, J ) 8.2 Hz, 1H); 13C NMR (50 MHz, CDCl3) δ
25.1, 47.1, 48.9, 52.0, 98.4, 123.2, 124.0, 125.1, 129.2, 135.9,
150.4, 158.8; MS (EI) 365 (M+), 363 (M+), 361 (M+), 330, 254,
252 (100), 250, 237, 222, 203, 188, 174, 157, 142, 128, 115,
102, 86. Anal. Calcd for C12H13Br2NO2: C, 39.70; H, 3.61; N,
3.86. Found: C, 39.74; H, 3.66; N, 3.61.
FIGURE 2. The X-ray structure of products 5a and 6a.
(10) de la Mare, P. B. Acc. Chem. Res. 1974, 7, 361-368.
J. Org. Chem, Vol. 70, No. 4, 2005 1225

Choi et al.
2,4-Dibromo-1,1-dimethoxy-1,2-dihydronaphthalene
dried (Na2SO4). After removal of solvent in vacuo, the residue
was purified by flash column chromatography (60% EtOAc-
hexane), giving 1f (1.82 g, 84%) as white foam: mp 106 °C;
1H NMR (200 MHz, CDCl3) δ 2.15 (m, 2H), 2.74 (s, 3H), 3.99
(t, J ) 5.4 Hz, 2H), 3.99 (t, J ) 6.0 Hz, 2H), 5.01 (br s, 1H),
7.12 (dd, J ) 5.8, 3.2 Hz, 1H), 7.27 (d, J ) 8.4 Hz, 1H), 7.32-
7.39 (m, 2H), 8.00 (d, J ) 8.4 Hz, 1H); 13C NMR (50 MHz,
CDCl3) δ 25.4, 32.2, 61.6, 70.9, 112.8, 120.9, 122.9, 126.0, 128.0,
1
(2b). Colorless liquid; H NMR (200 MHz, CDCl3) δ 2.88 (s,
3H), 3.44 (s, 3H), 4.82 (d, J ) 7.0 Hz, 1H), 6.65 (d, J ) 7.0 Hz,
1H), 7.40-7.66 (m, 2H), 7.67-7.79 (m, 2H); 13C NMR (50 MHz,
CDCl3) δ 47.4, 48.5, 51.3, 98.6, 125.3, 127.3, 128.2, 129.0, 129.3,
129.6, 131.0, 132.5; MS (CI) 350 (M+), 348 (M+), 346 (M+), 332,
330, 328, 318, 316, 314, 303, 301, 299, 275, 273, 271, 238, 236,
223, 221, 195, 193. Anal. Calcd for C12H12Br2O2: C, 41.41; H,
3.48. Found: C, 41.46; H, 3.85.
136.5, 140.5, 154.6, 158.7; MS (CI) 246 (M+ + 29), 218 (M+
+
6,8-Dibromo-5,5-dimethoxy-5,6-dihydroquinaldine (2c).
Colorless crystalline solid, mp 151-152 °C; 1H NMR (200 MHz,
CDCl3) δ 2.64 (s, 3H), 2.89 (s, 3H), 3.45 (s, 3H), 4.80 (d, J )
7.0 Hz, 1H), 6.94 (d, J ) 7.0 Hz, 1H), 7.19 (d, J ) 7.8 Hz, 1H),
7.93 (d, J ) 8.0 Hz, 1H); 13C NMR (50 MHz, CDCl3) δ 24.8,
46.6, 48.7, 51.4, 99.0, 123.2, 126.0, 127.0, 132.6, 135.6, 147.2,
159.4; MS (CI) 366 (M+ + 1), 364 (M+ + 1), 362 (M+ + 1), 332,
282, 254, 252 (100). Anal. Calcd for C12H13Br2NO2: C, 39.70;
H, 3.61; N, 3.86. Found: C, 39.92; H, 4.01; N, 3.69.
1), 200, 172, 144. Anal. Calcd for C13H15NO2: C, 71.87; H, 6.96;
N, 6.45. Found: C, 71.92; H, 7.26; N, 6.09.
(S,R)- and (R,S)-5,7-Dibromo-8-ethoxy-8-methoxy-7,8-
dihydroquinaldine (5a). Colorless crystalline solid, mp 141
°C; 1H NMR (400 MHz, CDCl3) δ 1.42 (t, J ) 7.2 Hz, 3H), 2.64
(s, 3H), 2.97 (s, 3H), 3.76 (q, J ) 7.1 Hz, 2H), 4.86 (d, J ) 6.8
Hz, 1H), 6.64 (d, J ) 6.8 Hz, 1H), 7.19 (d, J ) 8.0 Hz, 1H),
7.80 (d, J ) 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 14.9,
24.6, 47.6, 51.6, 56.5, 98.0, 122.9, 123.5, 124.6, 128.9, 135.5,
150.1, 158.6; MS (EI) 379 (M+, 11), 377 (M+, 24), 375 (M+, 12),
332, 316, 290, 268, 252 (100), 239, 223, 210, 188. Anal. Calcd
for C13H15Br2NO2: C, 41.41; H, 4.01; N, 3.78. Found: C, 41.56;
H, 4.38; N, 3.58.
(S,S)- and (R,R)-5,7-Dibromo-8-ethoxy-8-methoxy-7,8-
dihydroquinaldine (6a). Colorless crystalline solid, mp 123-
124 °C; 1H NMR (400 MHz, CDCl3) δ 0.91 (t, J ) 7.0 Hz, 3H),
2.67 (s, 3H), 2.84-2.88 (m, 1H), 3.52 (s, 3H), 3.58-3.62 (m,
1H), 4.86 (d, J ) 7.2 Hz, 1H), 6.67 (d, J ) 6.8 Hz, 1H), 7.22 (d,
J ) 7.6 Hz, 1H), 7.84 (d, J ) 8.0 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 15.0, 24.7, 47.1, 48.6, 59.8, 97.8, 122.6, 123.8, 124.9,
129.2, 135.6, 150.6, 158.5; MS (EI) 379 (M+, 5), 377 (M+, 10),
375 (M+, 5), 330, 316, 290, 268, 252 (100), 237, 223, 210, 202,
188. Anal. Calcd for C13H15Br2NO2: C, 41.41; H, 4.01; N, 3.78.
Found: C, 41.46; H, 4.37; N, 3.59.
5-Bromo-6,6-dimethoxy-5,6-dihydroquinaldine (2d). Off-
1
white solid, mp 67-68 °C; H NMR (200 MHz, CDCl3) δ 2.54
(s, 3H), 3.23 (s, 3H), 3.42 (s, 3H), 5.17 (d, J ) 2.2 Hz, 1H),
6.16 (dd, J ) 10.2, 2.2 Hz, 1H), 6.83 (d, J ) 10.6 Hz, 1H), 7.00
(d, J ) 7.8 Hz, 1H), 7.49 (d, J ) 7.6 Hz, 1H); 13C NMR (50
MHz, CDCl3) δ 24.5, 48.4, 49.4, 51.4, 98.9, 122.6, 128.9, 132.0,
132.9, 136.3, 150.0, 158.7; MS (EI) 285 (M+), 283 (M+), 253,
251, 204, 173, 158, 130, 103, 77, 63, 51; HRMS (EI) calcd for
C12H14BrNO2 (M+) 283.0208, found 283.0206.
8-Bromo-7,7-dimethoxy-7,8-dihydroisoquinoline (2e).
1
Yellowish liquid; H NMR (200 MHz, CDCl3) δ 3.20 (s, 3H),
3.44 (s, 3H), 5.24 (d, J ) 1.4 Hz, 1H), 6.14 (dd, J ) 10.0, 1.4
Hz, 1H), 6.67 (d, J ) 10.0 Hz, 1H), 7.09 (d, J ) 5.2 Hz, 1H),
8.52 (d, J ) 4.8 Hz, 1H), 8.57 (s, 1H); 13C NMR (50 MHz,
CDCl3) δ 46.6, 48.3, 51.3, 98.8, 121.4, 128.1, 130.9, 133.7, 137.7,
149.3, 150.8; MS (EI) 271 (M+), 269 (M+), 240, 238, 225, 223,
190, 175, 159, 144, 116, 89, 63; HRMS (EI) calcd for C11H12-
BrNO2 (M+) 269.0051, found 269.0051.
Acknowledgment. This work was supported by the
Real Time Molecular Imaging Project of KISTEP (2004-
02156) in Korea and we thank Professor Peter Beak and
Ms. Lynne Miller-Deist for helpful discussions. High
resolution mass spectra were carried out at the Korea
Basic Science Institute (Daegu, Korea). This work is
dedicated to Professor John A. Katzenellenbogen of the
University of Illinois at Urbana-Champaign on the
occasion of his 60th birthday (May 10, 2004).
5′,7′-Dibromo-7′H-spiro[1,3-dioxane-2,8′-quinaldine] (2f).
Colorless crystalline solid, mp 138-139 °C; 1H NMR (200 MHz,
CDCl3) δ 1.71-2.00 (m, 2H), 2.66 (s, 3H), 3.70-3.91 (m, 2H),
4.11-4.19 (m, 1H), 5.02 (d, J ) 6.6 Hz, 1H), 5.10-5.22 (m,
1H), 6.61 (d, J ) 7.0 Hz, 1H), 7.22 (d, J ) 8.0 Hz, 1H), 7.81 (d,
J ) 8.2 Hz, 1H); 13C NMR (50 MHz, CDCl3) δ 24.8, 25.1, 48.9,
63.0, 95.3, 123.6, 123.9, 125.1, 128.6, 135.9, 152.7, 158.5; MS
(CI) 378, 376, 374, 298, 296, 294, 240, 238. Anal. Calcd for
C13H13Br2NO2: C, 41.63; H, 3.49; N, 3.73. Found: C, 41.97;
H, 3.88; N, 3.62.
8-(3-Hydroxypropanoxy)quinaldine (1f). To solution of
8-hydroxyquinaldine (1.59 g, 10 mmol) and K2CO3 (2.76 g, 20
mmol) in acetone (30 mL) was added 4-bromopropanol and the
reaction was refluxed for 24 h. The solution was poured into
water (50 mL), then extracted with CH2Cl2 (2 × 50 mL). The
combined organic layer was washed with water and brine and
Supporting Information Available: Experimental pro-
cedure of starting materials and characterization data of the
rest of the compounds and crystallographic data collection
parameters for 2a. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO048297X
1226 J. Org. Chem., Vol. 70, No. 4, 2005