Efficient Synthesis of 4,5,9,10-Tetrahydropyrene: A Useful Synthetic Intermediate for the Synthesis of 2,7-Disubstituted Pyrenes

Full text of DOI:10.1021/jo990257j

6
888
J . Org. Chem. 1999, 64, 6888-6890
tive ring fusion of substituted m-cyclophanes,14 photo-
Efficien t Syn th esis of
1
2
chemical ring closure of 2,2′-divinylbiphenyls, and
4
,5,9,10-Tetr a h yd r op yr en e: A Usefu l
substitution of 4,5,9,10-tetrahydropyrene, 2, followed by
Syn th etic In ter m ed ia te for th e Syn th esis of
,7-Disu bstitu ted P yr en es
aromatization.9
,10,11,15
Previous syntheses of 2 have been
2
limited in scale or hampered by side reactions. Methods
1
6
for preparation of 2 include oxidation of m-cyclophanes,
†
†
,†
Daniel M. Connor, Scott D. Allen, David M. Collard,*
17
ring closure of biphenyl-2,2′-bis(acetic acid), photo-
†
‡
Charles L. Liotta, and David A. Schiraldi
18
chemical ring closure of 2,2′-divinylbiphenyl, and elec-
trochemical19 and photochemical reduction of pyrene.
8
School of Chemistry and Biochemistry, Molecular
Design Institute, and Polymer Education and Research
Center, Georgia Institute of Technology,
Atlanta, Georgia 30332-0400, KoSa Inc., P.O. Box 5750,
Spartanburg, South Carolina 29304-5750
Reported procedures4
,20,21
for the catalytic hydrogenation
of pyrene to 2 lead to mixtures of products that are
difficult to separate.2 A commonly practiced alternative
to hydrogenation is the cumbersome procedure of metal-
ammonia reduction24 of pyrene to afford the unstable 1,9-
dihydropyrene, acid isomerization to the more stable 4,5-
2,23
Received February 11, 1999
2
5,26
dihydropyrene,
and subsequent reduction by catalytic
or metal-ammonia reduction to af-
9
,20,28
hydrogenation
In tr od u ction
ford 2.2
7,28
Here we report an efficient procedure for the
Although the chemistry of pyrene, 1, is well-known,1,2
direct hydrogenation of pyrene to prepare 2 on a multi-
gram scale. Electrophilic aromatic substitution of 2 takes
place selectively at the 2- and 7-positions to give disub-
stituted analogues. The only previously reported dicar-
boxyl-functionalized 2,7-pyrenes were made by an eight-
step synthesis via cleavage of diphthaloylpyrenes and
by a long route via oxidative coupling of substituted
m-cyclophanes.29 We report a simple conversion of 2 to
there is considerable interest in the synthesis of new
derivatives for investigation of the carcinogenesis of
3
polycylic aromatic hydrocarbons (PAHs), as solvents in
4
5
coal liquification, and as fluorogens. Direct electrophilic
aromatic substitution on the pyrene ring occurs almost
1
3
6
exclusively at the electron rich 1-position, leading to 1-,
1
,3-, 1,6-, 1,8-, 1,3,6-, and 1,3,6,8-substituted products.
2
,7-diacetyl-4,5,9,10-tetrahydropyrene, 4, followed by
Only tert-butylation is directed to the 2- (and 7-) posi-
oxidation, methylation, and aromatization to give di-
methyl 2,7-pyrenedicarboxylate, 8, on a preparative scale.
The synthesis of significant quantities of 2, 4, and 8 could
7
tion(s). Pyrenes substituted in the 2- (and 7-) position(s)
have been sought as intermediates for the synthesis of
higher PAHs8
,910,11
and as monomers for the synthesis of
electroluminescent polymers.12 Synthesis of 2,7-substi-
tuted pyrenes requires indirect routes such as the base-
promoted decomposition of diphthaloylpyrenes,13 oxida-
(
14) Yamato, T.; Ide, S.; Tokuhisa, K.; Tashiro, M. J . Org. Chem.
992, 57, 271-275. (b) Umemoto, T.; Satani, S.; Sakata, Y.; Misumi,
S. Tetrahedron Lett. 1975, 36, 3159-3162.
1
(
15) Bolton, R. J . Chem. Soc. 1964, 4637-4640. (b) Minabe, M.;
Mochizuki, H.; Yoshida, M.; Toda, T. Bull. Chem. Soc. J pn. 1989, 62,
68-72. (c) Harvey, R. G.; Schmolka, S.; Cortez, C.; Lee, H. Synth.
Commun. 1988, 18, 2207-2210.
*
Corresponding author.
Georgia Institute of Technology.
KoSa Inc.
†
‡
(16) Baker, W.; McOmie, J . F. W.; Norman, J . M. J . Chem. Soc. 1951,
1114-1121. (b) Boekelheide, V.; Anderson, P. H.; Hylton, T. A. J . Am.
Chem. Soc. 1974, 96, 1558-1563.
(1) Harvey, R. G. Polycyclic Aromatic Compounds; Wiley-VCH: New
York, 1997. (b) Clar, E. Polycyclic Hydrocarbons; Academic Press:
London, 1964.
(17) Chatterjee, N. N.; Bose, A.; Roy, H. B. J . Indian Chem. Soc.
1947, 24, 169-172.
(
2) Vollmann, H.; Becker, H.; Corell, M.; Streek, H. Liebigs Ann.
Chem. 1937, 531, 1-125.
3) El-Baykoumy, K. Chem. Res. Toxicol. 1992, 5, 585-590. (b) Rice,
J . E.; Rivenson, A.; Braley, J .; LaVoie, E. J . J . Toxicol. Environ. Health
(18) Padwa, A.; Doubleday: C.; Mazzu, A. J . Org. Chem. 1977, 42,
3271-3279.
(
(19) Hanson, P. E.; Blaabjerg, O.; Berg, A. Acta Chem. Scand. B
1978, 32, 720-726.
1
1
1
3
2
987, 21, 525-532.
4) Minabe, M.; Nakada, K. Bull. Chem. Soc. J pn. 1985, 58, 1962-
967.
(
(20) Fu, P. P.; Lee, H. M.; Harvey, R. G. J . Org. Chem. 1980, 45,
2797-2803.
(5) Brocklehurst, P. J .; Hemingway, E. U.S. Patent 3,657,139, April
(21) Friedman, S.; Metlin, S.; Svedi, A.; Wender, I. J . Am. Chem.
Soc. 1959, 24, 1287-1289. (c) Korre, S. C.; Klein, M. T.; Quann, R. J .
Ind. Eng. Chem. Res. 1995, 34, 101-117. (d) Yalpani, M. Chem. Ber.
1990, 123, 983-987. (e) Berg, A.; Lam, J .; Hansen, P. E. Acta Chem.
Scand. B 1986, 40, 665-667. (f) Chirico, R. D.; Knipmeyer, S. E.;
Nguyen, A.; Smith, N. K.; Steele, W. V. J . Chem. Thermodyn. 1993,
25, 729-761. (g) Yalpani, M.; K o¨ ster, R. Chem. Ber. 1990, 123, 719-
724. (h) Cameron, J . M. L.; Cook, J . W.; Graham, W. J . Chem. Soc.
1945, 286-288.
8, 1972.
(6) Dewar, M. J . S.; Dennington, R. D. J . Am. Chem. Soc. 1989, 111,
804-3808.
(7) Yamato, T.; Miyazawa, A.; Tashiro, M. Chem. Ber. 1993, 126,
505-2512. (b) Rodenburg, L.; Brandsma, R.; Tintel, C.; Thuijl, J . van;
Lugtenburg, J .; Cornelisse, J . Recl. Trav. Chim. Pays-Bas 1986, 105,
56-161. (c) Yozo, M.; Yamano, E.; Miyazawa, A.; Tashiro, M. J . Chem.
Soc., Perkin Trans. 2 1996, 3, 359-364.
8) Van der Braken-van Leersum, A. M.; Tintel, C.; Van’t Zelfde,
M.; Cornelisse, J .; Lugtenburg, J . Recl. Trav. Chim. Pays-Bas 1987,
1
(
(22) Eisenbraun, E. J .; Webb, T. E.; Burnham, J . W.; Harris, L. E.
Org. Prep. Proced. Int. 1971, 3, 249-254.
1
06, 120-128.
(23) Harvey, R. G.; Halonen, M. J . Chromatogr. 1966, 25, 294-302.
(24) Harvey, R. G. Synthesis 1970, 4, 161-172.
(9) Harvey, R. G., Konieczny, M.; Pataki, J . J . Org. Chem. 1983,
4
8, 2930-2932.
(25) Harvey, R. G.; Rabideau, P. W. Tetrahedron. Lett. 1970, 42,
3695-3698. (b) Schnieders, C.; M u¨ llen, K.; Huber, W. Tetrahedron
1984, 40, 1701-1711.
(
(
10) Lee, H.; Harvey, R. G. J . Org. Chem. 1986, 51, 2847-2848.
11) Klassen, S. E.; Daub, G. H.; VanderJ agt, D. L. J . Org. Chem.
1
983, 48, 4861-4366. (b) Miller, D. W.; Herreno-Saenz, D.; Huang, K.
(26) Harvey, R. G.; Arzadon, L.; Grant, J .; Urberg, K. J . Am. Chem.
Soc. 1969, 91, 4535-4541.
H.; Heinze, T. M.; Fu, P. P. J . Org. Chem. 1992, 57, 3746-3748.
(12) Kreyenschmidt, M.; Baumgarten, M.; Tyutyulkov, N.; M u¨ llen,
(27) Rodenburg, L.; Floor, M.; Lefeber, A.; Cornelisse, J .; Lugten-
burg, J . Recl. Trav. Chim. Pays-Bas 1988, 107, 1-8.
(28) Musa, A.; Sridharan, B.; Lee, H.; Mattern, D. L. J . Org. Chem.
1996, 61, 5481-5484.
K. Angew. Chem., Int. Ed. Engl. 1994, 33, 1957-1959. (b) Kreyen-
schmidt, M.; Uckert, F.; M u¨ llen, K. Macromolecules 1995, 28, 4577-
4
4
582.
(13) Flammang, R.; Martin, R. H. Bull Soc. Chim. Belg. 1971, 80,
(29) Staab, H. A.; Kirrstetter, R. G. H. Liebigs Ann. Chem. 1979,
886-898.
33-438.
1
0.1021/jo990257j CCC: $18.00 © 1999 American Chemical Society
Published on Web 08/10/1999

Notes
J . Org. Chem., Vol. 64, No. 18, 1999 6889
Sch em e 1a
Sch em e 2a
facilitate the synthesis of new larger fused aromatics for
cancer research and provide new difunctional monomers.
methylation of aromatic diacids which are insoluble in
3
3
acidic methanol at reflux. Aromatization of 7 (DDQ in
benzene)9 afforded quantitative conversion to 8, but
separation from the reduced DDQ proved difficult and
Resu lts a n d Discu ssion
led to low isolated yields. However, treatment of 7 with
Catalytic hydrogenation of commercially available
10
bromine in CS
2
gave 8 in high yield with a simple
2
0
pyrene (Aldrich) with 10% Pd on carbon in dry EtOAc
procedure for workup and purification.
gave no reaction, similar to the results reported elswhere.28
However, the hydrogenation proceeded smoothly if the
pyrene was first desulfurized by treatment with Raney
nickel in EtOAc. This simple desulfurization procedure
proved easier than the careful recrystallization and
column chromatography reported by others.26,28 A com-
monly cited procedure for hydrogenation (10% Pd/C,
EtOAc, 50 psi for 65 h) is reported to yield a 45/45/10
mixture of tetrahydropyrene (2), dihydropyrene, and
pyrene (1).20 By optimizing the conditions of this proce-
dure (10% Pd/C, desulfurized pyrene, wet EtOAc, 40 psi
for 64-72 h), we obtained a 85/15 mixture of tetrahy-
dropyene (2) and overreduced product hexahydropyene
The method described above provides an improved
synthesis of 4,5,9,10-tetrahydropyrene, 2, for use as an
intermediate in the synthesis of various 2,7-disubstituted
pyrenes. Electrophilic aromatic substitution (illustrated
here by Friedel-Crafts acylation, followed by oxidation
of the methyl ketone to the corresponding carboxylic acid)
and subsequent aromatization provides 2,7-disubstituted
pyrenes. The synthesis of dimethyl 2,7-pyrenedicarboxy-
late shown here has been scaled-up to prepare tens of
grams of product in 5 steps (33% overall yield, not
optimized) with minimal purification throughout.
Exp er im en ta l Section
(3). The use of Raney nickel as an aqueous slurry for the
desulfurization of pyrene introduces water (ca. 0.5%) to
the reaction mixture. We found that drying the pyrene/
4
,5,9,10-Tetr a h yd r op yr en e, 2. Raney nickel (ca. 10 g as a
thick water slurry) was added to a solution of pyrene (21.0 g,
04 mmol) in EtOAc (250 mL), and the mixture was stirred
EtOAc solution over MgSO
4
increases the extent of
1
overreduction (i.e., formation of 3). This is the most
selective hydrogenation of pyrene to tetrahydropyrene to
our knowledge and avoids the difficulties involved in
separating the product from unreacted starting material
and underreduced products (i.e., dihydropyrene). Rather
than separate 2 from the overreduced byproduct 3 by
charge-transfer chromatography,22 we chose to convert
the crude mixture to the diacetyl compounds 4 and 5,
Scheme 1.
vigorously for 2 d. The mixture was vacuum filtered (caution
was exercised not to let the Raney nickel become dry). The
filtrate was hydrogenated at 40-45 psi in the presence of
palladium on carbon (5.0 g of 10% Pd/C) for 64-72 h. The
mixture was filtered through a fine fritted glass filter, and the
solvent was removed under reduced pressure to give crude
product (quantitative) containing 4,5,9,10-tetrahydropyrene, 2,
and ca. 15% of 4,5,9,10-hexahydropyrene, 3. The crude product
was used without further purification. 1H NMR (500 MHz,
1
3
3
CDCl ): δ 2.89 (s, 8H, benzylic), 7.1 (m, 6H, Ar H). C NMR
(
(
1
125 MHz, CDCl
3
): δ 28.3, 125.9, 127.0, 130.6, 135.4. IR
Functionalization of 2 in the 2- and 7-positions was
performed by diacylating according to a published pro-
-
1
CHCl
3
): 3065, 3048, 2941, 2833, 1605, 1451, 914, 730 cm
.
1
,2,3,6,7,8-Hexahydropyrene (present in the mixture): H NMR
9
cedure. Trituration of the crude product once with 10%
(
500 MHz, CDCl
) 6.1 Hz, H1,3,6,8), 7.10 (s, 4H, Ar H).
,7-Dia cetyl-4,5,9,10-tetr a h yd r op yr en e, 4, a n d 4,10-Di-
a cetyl-1,2,3,6,7,8-h exa h yd r op yr en e, 5. A solution of crude
3
) δ 2.03 (t, 4H, J ) 6.1 Hz, H2,7), 3.05 (t, 8H, J
2
(v/v) Et O in benzene provided pure 4 in good yield. It
was through purification and identification of the byprod-
uct of this procedure, 5 (from the soluble fraction of the
crude mixture), that we were able to identify the byprod-
uct of the hydrogenation mixture as 1,2,3,6,7,8-hexahy-
dropyrene, 3. This simple purification, coupled with the
efficient direct hydrogenation of pyrene, is a significant
advancement in the synthetic availability of 2,7-disub-
stituted pyrenes. Oxidation of 4 to the diacid was
2
4
3
,5,9,10-tetrahydropyrene (40.0 g, 0.194 mol) containing ca. 15%
in freshly distilled CH Cl (1 L) was added dropwise under N
(64.6 g, 0.485 mol) and acetyl chloride (345
2
2
2
to a mixture of AlCl
3
mL, 4.85 mol) at 0 °C. The mixture was stirred at 0 °C for an
additional 30 min and at room temperature 2 h. The dark brown
solution was poured onto ice (ca. 1.5 L) and stirred overnight.
The layers were separated, and the aqueous phase was washed
with CH Cl (1 × 300 mL). The combined organic layers were
3
0
31
performed using iodine in pyridine or by NaOBr.
2
2
, DMF)32 gave the dimethyl
washed with 5% NaOH (2 × 300 mL) and dried over MgSO
4
,
Methylation (CH I, Li CO
3
3
2
and the solvent was removed under reduced pressure. The
residue was triturated with ca. 100 mL of 10% Et O in benzene
ester 7 in moderate yield (not optimized), Scheme 2. This
method has proved particularly useful to us for the
2
to give 2,7-diacetyl-4,5,9,10-tetrahydropyrene, 4, as an off-white
9
solid (30 g, 53% from pyrene). Mp: 226-228 °C (lit. mp 225-
(
(
30) Paioni, R.; J enny, W. Helv. Chim. Acta 1970, 53, 141-155.
31) J ohnson, W. S.; Gutsche, C. D.; Offenhauer, R. D. J . Org. Chem.
1
946, 68, 1648-1650.
(33) J ones, J . R.; Liotta, C. L.; Collard, D. M.; Schiraldi, D. S.
Macromolecules, in press.
(
32) Staab, H. A.; Sauer, M. Liebigs Ann. Chem. 1984, 742-760.

6
890 J . Org. Chem., Vol. 64, No. 18, 1999
Notes
1
2
(
27 °C). H NMR (500 MHz, CDCl
3
): δ 2.60 (s, 6H, methyl), 2.95
to 1 M HCl (1.2 L), and the yellow precipitate was collected by
vacuum filtration and dried under reduced pressure to give
dimethyl 4,5,9,10-tetrahydropyrene-2,7-dicarboxylate, 7 (14.03
-
1
s, 8H, benzylic), 7.68 (s, 4H, Ar H). IR (KBr) 2881, 1683 cm
The solvent was removed from the filtrate of the trituration,
and the residue was recrystallized from CH Cl and then toluene
.
1
2
2
g, 61%), as a pale yellow solid. Mp: 209-212 °C. H NMR (500
to give 4,10-diacetyl-1,2,3,6,7,8-hexahydropyrene, 5, as a color-
less crystalline solid (333 mg, 20% yield based on 1,2,3,6,7,8-
hexahydropyrene present in the crude mixture). Mp: 181.0-
3 2
MHz, CDCl ) δ 2.93 (s, 4H, CH ), 3.91 (s, 6H, methyl), 7.76 (s,
-
1
4H, Ar H). IR (KBr): 2956, 1720, 1429, 1290, 1206, 768 cm
Dim eth yl 2,7-P yr en edicar boxylate, 8. (a) (Br /CS Rou te).
A solution of Br (6.28 mL) in CS (1.25 L) was added dropwise
to a solution of dimethyl 4,5,9,10-tetrahydropyene-2,7-dicar-
boxylate, 7 (16.4 g, 50.9 mmol), in CS (1.25 L) at 0 °C over 1 h.
The solution was stirred overnight at room temperature. A
solution of 5% Na (250 mL) followed by H O (250 mL) was
added with vigorous stirring, the layers were separated, and the
organic phase was dried over MgSO . The solvent was removed
under reduced pressure to give dimethyl 2,7-pyrenedicarboxy-
.
2
2
2
1
1
2
4
(
)
1
83.5 °C (lit. mp 182 °C). H NMR (500 MHz, CDCl
3
) δ 7.39 (s,
2
2
H, Ar H), 3.21 (t, 4H, J ) 6.2 Hz, benzylic-H1,3 or 6,8), 3.09 (t,
H, J ) 6.2 Hz, benzylic H1,3 or 6,8), 2.62 (s, 6H, methyl), 2.05
2
quintet, 2H, J ) 6.2 Hz, methylene H2 or 7), 1.94 (quintet, 2H, J
6.2 Hz, methylene H2 or
7
). IR (KBr): 2987, 2861, 1690, 1591,
2
S
2
O
3
2
-
1
256, 1131, 887 cm
,5,9,10-Tetr a h yd r op yen e-2,7-d ica r boxylic a cid , 6. (a ) I
P yr id in e Rou te. A mixture of 2,7-diacetyl-4,5,9,10-tetrahydro-
pyrene, 4 (20 g, 68 mmol), and I (37.9 g, 0.150 mol) in 300 mL
of freshly distilled pyridine was heated at reflux under N for
5 min. More I (17.2 g, 68 mmol) was added, and the mixture
was heated at reflux for an additional 1 h and then stirred for
1 h at room temperature. The volume was reduced to ca. 50
.
4
2
/
4
1
2
late, 8, as a yellow solid (15.86 g, 98%). Mp: 287-289 °C.
NMR (500 MHz, CDCl ) δ 4.08 (s, 6H, methyl), 8.16 (s, 4H, Ar
4,5,9,10), 8.85 (s, 4H, Ar H1,3,6,8). IR (KBr): 2953, 1723, 1302,
H
2
3
4
2
H
-
1
1235 cm . Anal. Calcd for C20
C, 75.63; H, 4.44.
14 4
H O : C, 75.47; H, 4.43. Found:
2
mL under reduced pressure. Saturated NaOH (50 mL) and 20%
ethanol/water (700 mL) were added, and the solution was heated
at reflux for 2 h. The dark brown solution was cooled to room
temperature and vacuum filtered. The filtrate was acidified with
concentrated HCl, and the brown precipitate was collected by
vacuum filtration to give 4,5,9,10-tetrahydropyrene-2,7-dicar-
(b) DDQ Rou te. A solution of dimethyl 4,5,9,10-tetrahydro-
pyrene-2,7-dicarboxylate, 7 (6.09 g, 20.7 mmol), and 2,3-dichloro-
5,6-dicyano-1,4-benzoquinone (17.0 g, 74.9 mmol) in benzene
(250 mL) was heated to reflux for 3 d. The mixture was filtered
through a fine fritted glass filter, and the solid was triturated
with 5% NaOH (500 mL) and refiltered. The filtrate was
1
boxylic acid (19.4 g, 97%). Mp: >300 °C dec. H NMR (300 MHz,
extracted with CH Cl2 (1 × 300 mL, 1 × 100 mL), and the
2
DMSO-d
374, 1683, 1604, 1308 cm-1
b) Na OBr Rou te. A solution of Br
NaOH (93.8 g, 2.34 mol) in H O (635 mL) was added over 30
6
): δ 7.71 (s, 4H, Ar H), 2.90 (s, 8H, CH
2
). IR (KBr):
combined extracts were washed with 5% NaOH (300 mL) and
H O (300 mL). After drying of the sample over MgSO , the
3
.
2
4
(
2
(43 mL, 0.84 mol) and
solvent was removed under reduced pressure to give dimethyl
2,7-pyrenedicarboxylate, 8 (1.41 g, 26%), as a pale yellow solid.
2
min to a solution of 4 (26.01 g, 89.59 mmol) in 1,4-dioxane (1.2
L) at room temperature and the mixture was stirred for 4 h at
Ack n ow led gm en t. We gratefully acknowledge sup-
port of this project by KoSa Inc. (formerly Hoechst-
Trevira) and the Office of Naval Research-Georgia Tech
Molecular Design Institute. S.D.A. visited from Virginia
Commonwealth University as a participant in the NSF-
REU program. We thank Professor E. J . Eisenbraun for
supplying us with an authentic sample of tetrahydro-
pyrene, 2.
6
2 2 4
0 °C. A solution of 5% Na S O (100 mL) was added, the
mixture was vacuum filtered, and the filtrate was acidified with
concentrated HCl. The resulting white precipitate was collected
by vacuum filtration and dried in a vacuum oven to give 6 (28.24
g, 100%) as a white solid.
Dim eth yl 4,5,9,10-Tetr a h yd r op yen e-2,7-d ica r boxyla te, 7.
A mixture of 4,5,9,10-tetrahydropyrene-2,7-dicarboxylic acid, 6
2 3
(20.86 g, 70.95 mmol), Li CO (31.46 g, 425.7 mmol), and methyl
iodide (88 mL, 1.4 mol) in N,N-dimethylformamide (1 L) was
stirred at room temperature for 24 h. The mixture was added
J O990257J