Synthesis of 1,2,3,4-Tetrahydroisoquinolines Containing Electron-Withdrawing Groups

Full text of DOI:10.1021/jo972184e

4116
J . Org. Chem. 1998, 63, 4116-4119
Syn th esis of
1,2,3,4-Tetr a h yd r oisoqu in olin es Con ta in in g
Electr on -With d r a w in g Gr ou p s
George J . Quallich,* Teresa W. Makowski,
Andrew F. Sanders, Frank J . Urban, and
Enrique Vazquez
Process Research and Development, Central Research
Division, Pfizer Inc., Groton, Connecticut 06340
catalytic copper(I) bromide and sodium hydride as base.8
These researchers evaluated sodium hydride, n-butyl-
lithium, sodium tert-butoxide, and lithium tert-butoxide,
lithium hydride and determined that only sodium hydride
was effective in the displacement.9 The sodium hydride
conditions were applied to commercially available 2-chloro-
4-nitrobenzoic acid to afford a 77% yield of 6a (R ) Et),
Scheme 1. Although only sodium hydride was reported
to be effective, alternatives were investigated prior to
scale-up because of the significant exotherm and hydro-
gen evolution, which results on addition of this base.
Sodium methoxide was found to be an acceptable base,
yielding 6a (R ) Me) in 70% yield with dimethyl malo-
nate as solvent.10 This was achieved by addition of
sodium methoxide to 2-chloro-4-nitrobenzoic acid in dim-
ethyl malonate followed by the addition of copper (I)
bromide.11 The reaction after 6 h at 70 °C had progressed
only 5-15% and required 18-24 h for completion. Thus,
an explanation for the initial slow rate was sought. No
delayed exotherm was observed with a temperature chart
recorder. Additives such as sodium bromide, sodium
chloride, palladium acetate, and nickel acetylacetonate
did not increase the reaction rate. The initial slow rate
of reaction was believed to result from low solubility of
the carboxylic acid sodium salt, which is predominately
out of solution, gradually being solubilized as the reaction
proceeds. Enhanced reaction rate (4 h) was obtained by
significant increase in agitation.12 2,5-Dibromobenzoic
acid and 2-chloro-5-(trifluoromethyl)benzoic acid simi-
larly provided the diesters 6b (R ) Me) and 6c (R ) Me)
in 77% and 83% yield, respectively, Scheme 1.
Received December 2, 1997
In tr od u ction
Synthesis of tetrahydroisoquinolines containing electron-
withdrawing groups in the aryl ring was required for the
preparation of novel pharmaceutical agents. Unfortu-
nately, many of the isoquinoline (Pomeranz-Fritsch)1,
dihydroisoquinoline (Bischler-Napieralski),2 and tet-
rahydroisoquinoline (Pictet-Spengler)3 routes rely on an
electron-neutral or preferably an electron-rich aromatic
nucleus for cyclization.4 Modification of the Bischler-
Napieralski reaction, using oxalyl chloride to generate a
superior acylating agent, still provided low yields of
product when a nitro group was contained in the aryl
ring.5 Thus, a method was sought to prepare tetrahy-
droisoquinolines containing electron-withdrawing groups.
Resu lts a n d Discu ssion
The tetrahydroisoquinoline approach evaluated the
formation of the heterocyclic ring via double displacement
with a nitrogen nucleophile on a substituted benzene
derivative. Access to appropriately substituted benzene
derivatives was envisioned by malonate displacement.6
To this end, reaction of methyl 2-chloro-4-nitrobenzoate
(1) with sodium hydride and dimethyl malonate in
dimethyl sulfoxide afforded 3, wherein the leaving group
was the p-nitro instead of the desired o-chloro group, eq
1. To achieve the desired regiochemistry, methyl 2,4-
dinitrobenzoate (2) was used generating triester 4 in 39%
yield.
The malonate moiety in 6a -c was hydrolyzed and
decarboxylated with aqueous methanolic sodium hydrox-
ide, affording the diacids 7a -c in g88% yield. Having
assembled all the carbon atoms necessary for the tet-
rahydroisoquinolines, borane reduction of diacids 7 into
diols 8 was performed. The yield of diol 8a obtained with
borane in THF on a 3 g scale (13 mmol) of 7a was 78%.
On a larger scale, only 40-50% yields of 8a were isolated
along with lactone 10 or hydroxy acid 11, eq 2.
A more efficient diethyl malonate displacement7 of
2-bromo-4-nitrobenzoic acid was known that employed
* To whom correspondence should be addressed. Tel.: (860) 441-
3675. Fax: (860) 441-5445.
(1) (a) Pomeranz, C. Montash 1893, 14, 116. (b) Gensler, W. J . Org.
Reac. 1951, 6, 191-206.
(2) (a) Bischler, A.; Napieralski, B. Ber. 1893, 26, 1903. (b) Whaley,
W. M.; Govindachari, T. R. Org. React. 1951, 6, 74-150.
(3) (a) Pictet, A.; Spengler, T. Ber. 1911, 44, 2030. (b) Whaley, W.
M.; Govindachari, T. R. Org. React. 1951 6, 151-190.
(4) (a) Grethe, G.; Bradsher, C. K.; Dyke, S. F.; Fukumoto, K.;
Kametani, T. K.; Kinsman, R. G.; McDonald, E. The Chemistry of
Heterocyclic Compounds Isoquinolines Part 1; Wiley: New York, 1981.
(b) Kathawala, F. G.; Coppola, G. M.; Schuster, H. F.; Bunting, J . W.;
Duarte, F. F.; Mathison, I. W.; Nair, M. D.; Popp, F. D.; Premila, M.
S.; Solomons, W. E. The Chemistry of Heterocyclic Compounds Iso-
quinolines Part 2; Wiley: New York, 1990.
(5) Larsen, R. D.; Reamer, R. A.; Corley, E. G.; Davis, P.; Grabowski,
E. J . J .; Reider, P. J .; Shinkai, I. J . Org. Chem. 1991, 56, 6034-8.
(6) Bunnett, J . F.; Zahler R. E. Chem. Rev. 1951, 49, 273.
(7) (a) For copper(I)-promoted malonate coupling reaction with aryl
halides, see: Setsune, J . Matsukawa, K.; Wakemoto, H.; Kitao, T.
Chem. Lett. 1981, 367-70. (b) Aryl halide displacements by malonate
without copper catalysis see: Quallich, G. J .; Morrissey, P. M. Synthesis
1993, 51-3 and references therein.
This incomplete reduction, attributed in the literature
to the formation of insoluble polymers halting the reac-
(8) (a) Bruggink, A.; McKillop, A. Angew. Chem., Int. Ed. Engl. 1974,
13, 340-1. (b) Bruggink, A.; McKillop, A. Tetrahedron 1975, 31, 2607-
19.
(9) Recovered starting material was obtained with these bases.
(10) Diethyl malonate also provided the desired product 6a (R )
Et) along with the corresponding methyl ester 6a (R ) Me) resulting
from transesterification with sodium methoxide. Methyl esters are
typically more crystalline than ethyl esters, as found here with melting
points of 153 °C vs 104 °C, respectively.
(11) Bromobenzene is converted to anisole in 95% yield with
copper(I) bromide catalysis in methanol with sodium methoxide.
Aalten, H. L.; Koten, G.; Grove, D. M.; Kuilman, T.; Piekstra, O. G.;
Hulshof, L. A.; Sheldon, R. A. Tetrahedron 1989, 45, 5565-78.
(12) Toluene or tetrahydrofuran as cosolvents prevented the reaction
from proceeding.
S0022-3263(97)02184-1 CCC: $15.00 © 1998 American Chemical Society
Published on Web 05/19/1998

Notes
J . Org. Chem., Vol. 63, No. 12, 1998 4117
Sch em e 1
tion,13 is a general problem when diacids are reduced with
borane. Use of more reactive sodium borohydride/boron
trifluoroetherate to form borane14 or prior treatment with
trimethyl borate15 to generate the acyloxyborane did not
enhance conversion of diacid 7a into 8a .16 Therefore, the
cyclic anhydride of 7a was made in situ and directly
reduced with borane to generate the desired diols in good
yield.17 Further investigation into direct diacid reduction
revealed that small quantities (5%) of triacid 6a (R ) H)
were responsible for halting the reaction. Triacid 6a (R
) H) is labile in NMR solvents such as dimethyl sulfox-
ide, but it could be detected in acetone where decarboxy-
lation to 7a occurred more slowly. HPLC was found to
be the best method for monitoring the hydrolysis/decar-
boxylation of 6a .18 Extraction of the crude 6a (R ) H)/
7a mixture into ethyl acetate and heating until the
decarboxylation to 7a was complete provided a reliable
process. This borane reduction of diacid 7a , without
triacid 6a (R ) H) present, provided clean diol 8a in 89%
yield.
Formation of the heterocyclic ring by double displace-
ment with ammonia was investigated.19 Conversion of
the alcohols into leaving groups was accomplished by
mesylation.20 Attempts to cyclize the dimesylate 12
derived from 8a with ammonia at 1 atm employing a dry
ice coldfinger to maintain ammonia throughout the
reaction gave recovered starting material. Ammonia was
not sufficiently nucleophilic under these conditions.21 We
hypothesized that addition of trimethylsilyl chloride
would form (trimethylsilyl)amine in situ22 and cyclization
would proceed. Repeating the ammonia reaction condi-
tions with dimesylate 12 in methylene chloride solution
with 10 equiv of trimethylsilyl chloride generated 9a in
47% yield.
test the proposal, benzylic chloride 13 was isolated in 95%
yield by allowing the mesylation of 8a to warm to
ambient temperature overnight. Treatment of 13 with
ammonia at 1 atm without trimethylsilyl chloride as
previously described provided recovered benzylic chloride
13. Thus, trimethylsilyl chloride enhanced the nucleo-
philicity of ammonia in the cyclization at one atmosphere.
Higher yields of tetrahydroisoquinoline 9a were ob-
tained with ammonia and tetrahydrofuran as cosolvent
without trimethylsilyl chloride. The reaction was con-
ducted at 120 psi in a Parr apparatus at ambient
temperature, providing 9a in 75% yield. These preferred
cyclization conditions were employed for the dimesylates
derived from 8b and 8c, similarly generating the tet-
rahydroisoquinolines 9b and 9c.
In contrast to the ammonia cyclizations, the ring
formation reaction was more straightforward with sub-
stituted amines. Dimesylate 12 cyclized to N-allyl 14 in
95% yield using allylamine in methylene chloride at room
temperature for 16 h. The corresponding benzylic chlo-
ride 13 proceeded to 50% conversion under the same
conditions, but heating to 50 °C for 2 h completed the
conversion to 14 in 71% yield, Scheme 2. Thus, the
benzylic mesylate was again a better leaving group than
chloride under these conditions.
Reaction of excess aniline with dimesylate 13 in
tetrahydrofuran provided an 86% yield of 15 without
evidence of elimination to the styrene. Diol 8a was used
to prepare isochroman 16 in 61% yield by treatment
under Mitsunobu conditions.23
An alternative explanation was that trimethylsilyl
chloride’s function in the cyclization was to generate
ammonium chloride, which subsequently converted dime-
sylate 12 to the benzylic chloride 13, and chloride 13 was
more readily displaced than the benzylic mesylate 12. To
(13) (a) Lane, C. F. Chem. Rev. 1976, 76, 773-97. (b) Firestone, R.
A.; Harris, E. E.; Reuter, W. Tetrahedron 1967, 23, 943-55.
(14) Brown, H. C.; Rao, B. C. J . Am Chem. Soc. 1960, 82, 681.
(15) (a) Lane, C. F.; Myatt, H. L.; Daniels, J .; Hopps, H. B. J . Org.
Chem. 1974, 39, 3052. (b) Plesek, J .; Hermanek, S.; Petrina, A. Chem.
Abstr. 1973, 79, 146061y.
(16) Alane did not provide better conversion to the diol. Brown, H.
C.; Yoon, N. M. J . Am. Chem. Soc. 1966, 88, 1464-72.
(17) Direct reduction of diacid 7c with lithium aluminum hydride
afforded diol 8c; see the Experimental Section.
Con clu sion
In summary, a method to prepare tetrahydroisoquino-
lines and an isochroman containing electron-withdrawing
groups in the aromatic ring has been demonstrated.
Sodium methoxide was employed in the copper catalyzed
displacement of o-halobenzoic acids instead of sodium
hydride. Small quantities of a tricarboxylic acid inter-
mediate were found to halt the borane reduction of a
diacid. A benzylic mesylate was demonstrated to be
better than chloride as a leaving group in cyclizations
(18) Puresil C18, 20% acetonitrile/80% 50 mM aqueous KH2PO4, flow
rate 1 mL/min, 280 nm.
(19) Cyclization of o-chloroethyl benzyl chloride with alkylamines
was a precedented route to tetrahydroisoquinolines. Lusinchi, X.;
Durand, S.; Delaby, R. Compt. Rend. 1959, 248, 426-8.
(20) Crossland, R. K.; Servis, K. L. J . Org. Chem. 1970, 35,
3195-6.
(21) Pilzey, J . S. Synthetic Reagents; Wiley: New York, 1983; Vol.
5, p 26.
(22) (Trimethylsilyl)amine is known to disproportionate at ambient
temperature into hexamethyldisilizane and ammonia. Wiberg, N.;
Uhlenbrock, W. Ber. 1971, 104, 2643-45.
(23) See the Experimental Section.

4118 J . Org. Chem., Vol. 63, No. 12, 1998
Notes
Sch em e 2
contents were acidified with concentrated HCl (22.4 mL) at
ambient temperature. The resulting white aqueous suspension
was extracted twice with ethyl acetate (150 and 75 mL), the
combined organic phases were dried with magnesium sulfate,
and the volume of extracts was reduced to 55 mL. The resulting
ethyl acetate slurry was heated to 65 °C for 6 h, effecting
complete decarboxylation of 6a (R ) H),18 and diacid 7a was
filtered off at ambient temperature and dried to afford 10 g of a
white solid: (88%; mp 180-82 °C; IR 3080, 3055, 2983, 1707,
with nitrogen nucleophiles. Nucleophilicity of ammonia
was enhanced by in situ formation of trimethylsilylamine.
Exp er im en ta l Section
Melting points were determined with
a Thomas-Hoover
capillary melting point apparatus and are uncorrected. Unless
otherwise stated, CDCl3 was used for NMR spectra, and KBr
for IR spectra. Microanalyses were performed by Schwarzkopf
Microanalytical Laboratory. All reagents and solvents were
obtained commercially from Aldrich and used without additional
purification.
1611, 1585, 1516, 1491, 1424, 1358, 1298, 1237 cm-1 1H NMR
.
(CD3)2SO δ 12.87 (bs, 2H), 8.25 (d, J ) 2 Hz, 1H), 8.18 (dd, J )
2, 8 Hz, 1H), 8.07 (d, J ) 8 Hz, 1H), 4.07 (s, 2H); 13C NMR (CD3)2-
SO δ 172.3, 167.5, 149.2, 138.8, 137.3, 132.1, 127,2, 122.4, 39.8.
Anal. Calcd for C9H17NO6: C, 48.01; H, 3.13; N, 6.22. Found:
C, 47.67; H, 3.19; N, 6.31.
2-(Ca r boxy-5-n itr op h en yl)m a lon ic Acid Dim eth yl Ester
(6a , R ) Me). A solution of 2-chloro-4-nitrobenzoic acid (75 g,
372 mmol) in dimethyl malonate (900 mL, 20 equiv) was
degassed with nitrogen for 15 min. Copper(I) bromide (5.4 g,
37 mmol) was added in one portion. Sodium methoxide (48.3 g,
894 mmol) was added in one portion with stirring. This caused
the reaction mixture to warm to 48 °C. After being stirred for
15 min, the reaction mixture was heated to 70 °C for 24 h.
(Vigorous stirring shortens this time.) The reaction was moni-
tored by NMR on an aliquot. Water (900 mL) was added to the
cooled reaction followed by hexanes (900 mL). The aqueous layer
was separated. Toluene (900 mL) was added to the aqueous
layer, and the biphasic mixture was filtered through Celite to
remove insolubles. The aqueous layer containing the carboxy-
late salt of 6a (R ) Me) was separated. (Hexane and toluene
extractions served to remove the excess dimethyl malonate and
thereby allow precipitation of product in the subsequent acidi-
fication.) Fresh toluene (1800 mL)24 was added to this aqueous
layer and the biphasic mixture acidified with 6 N aqueous HCl
(90 mL). A white precipitate formed, and the contents were
stirred for 18 h. Product 6a (R ) Me) was collected by filtration
and dried to give a white solid: 78.1 g (70%, mp 153 °C); IR
5-Br om o-2-(ca r boxym eth yl)ben zoic a cid (7b) was pre-
pared as for 13: 96% yield; mp 210-11 °C; IR 2922, 2852, 1694,
1459, 1377, 1293 cm-1; 1H NMR (CD3)2SO δ 12.75 (bs 2H), 7.96
(d, J ) 2 Hz, 1H), 7.69 (dd, J ) 2, 8 Hz, 1H), 7.29 (d, J ) 8 Hz,
1H), 3.89 (s, 2H). Anal. Calcd for C9H7BrO4: C, 41.73; H, 2.72.
Found: C, 41.97; H, 2.65.
2-(Ca r boxym eth yl)-5-(tr iflu or om eth yl)ben zoic a cid (7c)
was prepared as for 7a : 95% yield: mp 173-74 °C; IR 2922,
1705, 695, 1460, 1333, 1128 cm-1 1H NMR (CD3)2SO δ 12.82
;
(bs, 2H), 8.11 (s, 1H), 7.86 (d, J ) 8 Hz, 1H), 7.58 (d, J ) 8 Hz,
1H), 4.03 (s, 2H).
2-[2-(Hyd r oxym eth yl)-5-n itr op h en yl]eth a n ol (8a ). To a
THF (220 mL) solution of 2-(carboxymethyl)-4-nitrobenzoic acid,
7a (10.0 g, 44.4 mmol), was added sodium borohydride (5.06 g,
133 mmol) in portions. The contents were cooled to 0 °C, and
boron trifluoride diethyl etherate (21.3 mL, 133 mmol) was
added dropwise over 1 h. The contents were allowed to warm
to 25 °C and stirred for 16 h. The reaction was cooled to 0 °C
and cautiously quenched with aqueous sodium hydroxide (1 N,
178 mL). The contents were stirred for 3 h, THF was removed
under vacuum, the resulting aqueous suspension was cooled to
0 °C, and the product was filtered off. After drying, the product
was obtained as a white solid: 7.78 g (89%); mp 79-81 °C); IR
3277, 3192, 2964, 2932, 1614, 1525, 1507, 1170, 1134, 1089, 1067
2923, 2853, 1750, 1728, 1705, 1458, 1376, 1352, 1305, 1261 cm-1
;
1H NMR (CD3)2SO δ 8.37 (d, J ) 2 Hz, 1H), 8.30 (d, J ) 1 Hz,
2H), 5.82 (s, 1H), 3.83 (s, 6H); 13C NMR (CD3)2SO δ 168.0, 167.3,
149.4, 137.1, 135.8, 132.5, 125.4, 123.7, 54.5, 53.4. Anal. Calcd
for C11H10NO8: C, 48.49; H, 3.73; N, 4.71. Found: C, 48.27; H,
3.72; N, 4.76.
1
cm-1; H NMR (CD3)2SO δ 8.05 (d, J ) 9 Hz, 1H), 8.04 (s, 1H),
2-(4-Br om o-2-ca r boxyp h en yl)m a lon ic a cid d im eth yl es-
ter (6b) was prepared as 6a except the acidification was
performed without toluene present: 77% yield; mp 135-6 °C;
7.66 (d, J ) 9 Hz, 1H), 5.42 (t, J ) 5 Hz, 1H), 4.74 (t, J ) 5 Hz,
1H), 4.64 (d, J ) 5 Hz, 2H), 3.63 (m, 2H), 2.80 (t, J ) 6 Hz, 2H);
13C NMR (CD3)2SO δ 149.1, 146.6, 139.2, 127.8, 124.3, 121.3,
61.2, 60.6, 34.9. Anal. Calcd for C9H11NO4: C, 54.82; H, 5.62;
N, 7.10. Found: C, 54.54; H, 5.49; N, 7.07.
IR 2922, 2853, 1765, 1734, 1688, 1459, 1313, 1227, 1148 cm-1
;
1H NMR δ 8.28 (d, J ) 2 Hz, 1H), 7.73 (dd, J ) 2 Hz, 1H), J )
8 Hz, 1H), 7.36 (d, J ) 8 Hz, 1H), 5.78 (s, 1H), 3.79 (s, 6H); 13C
NMR δ 170.7, 168.4, 136.5, 134.7, 133.9, 132.1, 129.8, 122.4, 54.1,
53.0. Anal. Calcd for C12H11O6: C, 43.53; H, 3.35. Found: C,
43.50; H, 3.07.
2-[4-Br om o-2-(h yd r oxym eth yl)p h en yl]eth a n ol (8b) was
prepared as for 8a in 76% yield: mp 94-5 °C; IR 3182, 2922,
1
2853, 1460, 1376 cm-1; H NMR (CD3)2SO δ 7.50 (d, J ) 2 Hz,
1H), 7.32, (dd, J ) 2 Hz, J ) 8 Hz, 1H), 7.11 (d, J ) 8 Hz, 1H),
5.21 (t, J ) 5 Hz, 1H), 4.67 (t, J ) 5 Hz, 1H), 4.50 (d, J ) 5 Hz,
2H), 3.53 (m, 2H), 2.66 (t, J ) 7 Hz, 2H); 13C NMR (CD3)2SO δ
143.2, 136.1, 131.7, 129.4, 129.2, 119.0, 61.3, 60.1, 34.6. Anal.
Calcd for C9H11BrO2: C, 46.78; H, 4.80. Found: C, 46.80; H,
4.65.
2-[2-Ca r b oxy-4-(t r iflu or om et h yl)p h en yl]m a lon ic a cid
d im eth yl ester (6c) was prepared as for 6a except the
acidification was performed without toluene present: 83%
yield: mp 140-41 °C; IR 2922, 2852, 1744, 1718, 1459, 1376,
1337, 1120 cm-1; 1H NMR δ 8.41 (s, 1H), 7.86 (d, J ) 8 Hz, 1H),
7.65 (d, J ) 8 Hz, 1H), 5.89 (s, 1H), 3.81 (s, 6H). Anal. Calcd
for C13H11F3O6: C, 48.76; H, 3.46. Found: C, 48.80; H, 3.45.
2-(Ca r boxym eth yl)-4-n itr oben zoic Acid (7a ). Sodium
hydroxide (10.10 g, 253 mmol) in water (120 mL) was added over
85 min to a solution of 2-(carboxy-5-nitrophenyl)malonic acid
dimethyl ester, 6a (R ) Me) (15.0 g, 51 mmol), in methanol (120
mL) at ambient temperature. After 3 h, the reaction was
complete, the methanol was removed under vacuum, and the
2-[2-(H yd r oxym et h yl)-4-(t r iflu or om et h yl)p h en yl]et h a -
n ol (8c). A THF (30 mL) solution of diacid 7c (3 g, 12 mmol)
was added to a suspension of lithium aluminum hydride (1.4 g,
37 mmol) in THF (30 mL) at a rate to maintain gentle reflux.
The contents were stirred for 16 h and quenched with water
(1.4 mL), aqueous sodium hydroxide (15%, 1.4 mL), and water
(4 mL). The solids were filtered off, and solvent was removed
under vacuum to yield 1.34 g of the diol as an oil; IR 3294, 3197,
3054, 2924, 1620, 1483, 1456, 1375 cm-1; 1H NMR δ 7.60 (s, 1H),
7.54 (d, J ) 8 Hz, 1H), 7.34 (d, J ) 8 Hz, 1H), 4.67 (s, 2H), 3.89
(t, J ) 6 Hz, 2H), 3.54 (bs, 1H), 2.97 (t, J ) 6 Hz, 2H), 2.64 (bs,
(24) Toluene prevented gumming of 6a (R ) Me) but was not
essential for the corresponding bromo 6b or trifluoromethyl 6c
derivatives.

Notes
J . Org. Chem., Vol. 63, No. 12, 1998 4119
1H). Anal. Calcd for C10H11F3: C, 54.55; H, 5.04. Found: C,
54.78; H, 5.13.
Allylamine (2.3 mL, 30.6 mmol) was added to a solution of
dimesylate (2.15 g, 6 mmol) in methylene chloride (30 mL), and
the contents were stirred at ambient temperature for 16 h.
Aqueous hydrochloric acid (1 N, 50 mL) was added, and the
layers were separated. The aqueous acidic phase was treated
with aqueous sodium hydroxide (5 N) until the pH was 10.
Extraction of the basic aqueous phase with chloroform (150 mL),
drying with magnesium sulfate, and removal of the solvent
under vacuum afforded 1.26 g (95%) of the tetrahydroisoquino-
6-Nitr o-1,2,3,4-tetr a h yd r oisoqu in olin e (9a ). Methane-
sulfonyl chloride (0.9 mL, 11.63 mmol) was added dropwise over
10 min to a solution of 2-[2-(hydroxymethyl)-5-nitrophenyl]e-
thanol (8a ) (1.0 g, 5.07 mmol) and triethylamine (1.8 mL, 12.91
mmol) in methylene chloride (20 mL) at <0 °C. TLC shows
complete reaction after 30 min; 1H NMR δ 8.17-11 (m, 2H), 7.65
(d, J ) 9 Hz, 1H), 5.36 (s, 2H), 4.49 (t, J ) 6 Hz, 2H), 3.25 (t, J
) 6 Hz, 2H), 3.08 (s, 3H), 2.98 (s, 3H). The reaction mixture
was washed with 10% aqueous HCl, saturated aqueous sodium
bicarbonate, and brine. The organic layer was dried with
magnesium sulfate, and methylene chloride was removed under
vacuum. The oil was dissolved in THF (100 mL) and evaporated
in vacuo (3×). The dimesylate 12 (1.9 g) was employed directly
in the next reaction without further purification. Ammonia (50
mL) was added to the dimesylate (1.9 g) in THF (30 mL) at -78
°C in a Parr apparatus. The contents were warmed to 24 °C for
60 h (120 psi). Ammonia was distilled off and solvent removed
under vacuum to give the crude product (786 mg, 82%). Toluene
was added, the solution filtered through magnesium sulfate, and
solvent removed under vacuum to yield 721 mg (75%) of an oil:
IR 2928, 2831, 1672, 1514, 1345, 1123 cm-1; 1H NMR δ 7.97 (s,
1H), 7.95 (d, J ) 9 Hz, 1H), 7.15 (d, J ) 9 Hz, 1H), 4.07 (s, 2H),
3.15 (t, J ) 6 Hz, 2H), 2.89 (t, J ) 6 Hz, 2H), 1.98 (bs, 1H).
Anal. Calcd for C9H10N2O2: C, 60.66; H, 5.66; N, 15.72.
Found: C, 60.48; H, 5.30; N.15.32.
1
line as an oil: IR 2921, 2852, 1528, 1462, 1344, 1259 cm-1; H
NMR δ 7.97 (s, 1H), 7.94 (d, J ) 8 Hz, 1H), 7.15 (d, J ) 8 Hz,
1H), 5.92 (m, 1H), 5.25 (m, 2H), 3.68 (s, 2H), 3.19 (m, 2H), 2.98
(t, J ) 6 Hz, 2H), 2.76 (t, J ) 6 Hz, 2H). Anal. Calcd for
C
12H14N2O2: C, 66.04; H, 6.47; N, 12.84. Found: C, 66.23; H,
6.57; N, 12.56.
6-Nit r o-2-p h en yl-1,2,3,4-t et r a h yd r oisoq u in olin e (15).
Methanesulfonyl chloride (0.9 mL, mmol) was added dropwise
to a solution of diol 8a (1.0 g, 5 mmol) in methylene chloride (20
mL) at 0 °C. Fifteen minutes later, the reaction was complete
and the organic phase successively washed with 10% aqueous
HCl (20 mL), saturated aqueous sodium bicarbonate (20 mL),
and brine (20 mL). The organic layer was dried with magnesium
sulfate and solvent removed under vacuum. The resulting
dimesylate was dissolved in THF (20 mL), aniline (2.31 mL, 25
mmol) was added, and the contents were stirred at ambient
temperature for 18 h and heated to 60 °C for 18 h. The solvent
was removed under vacuum and methylene chloride (50 mL)
added. The organic phase was washed with water (50 mL),
saturated aqueous sodium bicarbonate (50 mL), and pH 4 buffer
(50 mL). The organic phase was dried with magnesium sulfate
and solvent removed under vacuum to afford 3.06 g of the crude
product. Chromatography on silica eluting with 20% ethyl
acetate/hexanes gave the product as a yellow solid: 1.11 g (86%);
7-Br om o-1,2,3,4-tetr a h yd r oisoqu in olin e (9b)25 was pre-
pared as for 9a : IR 3184, 3027, 2952, 2923, 1487, 1461, 1429,
1
1376, 1343, 1312 cm-1; H NMR δ 7.28 (d, J ) 8 Hz, 1H), 7.19
(s, 1H), 6.97 (d, J ) 8 Hz, 1H), 4.05 (s, 2H), 3.19 (t, J ) 6 Hz,
2H), 2.82 (t, J ) 6 Hz, 2H), 2.32 (bs, 1H); 13C NMR (CD3)2SO δ
136.3, 133.6, 131.5, 129.6, 129.4, 119.0, 45.8, 42.1, 26.8; EIMS,
M+ 212.0058 (calcd. 212.0074).
1
mp 137-8 °C); IR 2922, 2853, 1460, 1376, 1260 cm-1; H NMR
δ 8.06-8.03 (m, 2H), 7.34-7.26 (m, 3H), 7.00 (d, J ) 8 Hz, 2H),
6.89 (t, J ) 7 Hz, 1H), 4.48 (s, 2H), 3.60 (t, J ) 6 Hz, 2H), 3.09
(t, J ) 6 Hz, 2H). Anal. Calcd for C15H14N2O2: C, 70.85; H,
5.55; N, 11.02. Found: C, 70.49; H, 5.69; N, 11.19.
7-(Tr iflu or om eth yl)-1,2,3,4-tetr a h yd r oisoqu in olin e (9c)
was prepared as for 9a : IR 2929, 1622, 1587, 1465, 1432, 1383,
1373, 1332 cm-1; 1H NMR δ 7.38 (d, J ) 8 Hz, 1H), 7.27 (s, 1H),
7.20 (d, J ) 8 Hz, 1H), 4.08 (s, 2H), 3.18 (t, J ) 6 Hz, 2H), 2.87
(t, J ) 6 Hz, 2H), 2.05 (bs, 1H); EIMS, M+ 202.0861 (calcd
202.0844).
6-Nitr oisoch r om a n (16). To a solution of diol 8a (200 mg,
1 mmol), succinimide (100 mg, 1 mmol), and triphenylphosphine
(293 mg, 1.12 mmol) in THF (4 mL) at 0 °C was added diethyl
azodicarboxylate (180 ul, 1.14 mmol) in THF (2 mL). The
contents were stirred for 3.5 h, and solvent was removed under
vacuum. Chromatography provided the product as a white
solid: 111 mg (61%); mp 84 °C; IR 3037, 1683, 1613, 1564, 1401
Meth a n esu lfon ic a cid 2-[2-(ch lor om eth yl)-5-n itr op h e-
n yl]eth yl ester (13): IR 2922, 2853, 1460, 1347, 1259 cm-1
;
1H NMR δ 8.15 (s, 1H), 8.10 (d, J ) 7 Hz, 1H), 7.48 (d, J ) 7 Hz,
1H), 4.68 (s, 2H), 4.52 (t, J ) 8 Hz, 2H), 3.30 (t, J ) 8 Hz, 2H),
2.98 (s, 3H); 13C NMR δ 145.6, 142.9, 137.5, 131.6, 125.1, 122.6,
68.3, 42.4, 37.5, 31.9.
1
cm-1; H NMR δ 8.02 (d, J ) 9 Hz, 1H), 8.01 (s, 1H), 7.14 (d, J
) 9 Hz, 1H), 4.83, 4.00 (t, J ) 6 Hz, 2H), 2.96 (t, J ) 6 Hz, 2H).
Anal. Calcd for C9H9NO3: C, 60.33; H, 506; N, 7.82. Found:
C, 60.69; H, 5.28; N, 7.78.
2-Allyl-6-n itr o-1,2,3,4-tetr a h yd r oisoqu in olin e (14). The
dimesylate 12 was prepared as detailed in the synthesis of 9a .
(25) US patent no. 3,314,963, 1967; Chem. Abstr. 1967, 108567n.
J O972184E