Reactions of primary and secondary amines with substituted hydroquinones: Nuclear amination, side-chain amination, and indolequinone formation

Full text of DOI:10.1021/jo980541v

J . Org. Chem. 1998, 63, 7563-7567
7563
Sch em e 1
Rea ction s of P r im a r y a n d Secon d a r y
Am in es w ith Su bstitu ted Hyd r oqu in on es:
Nu clea r Am in a tion , Sid e-Ch a in Am in a tion ,
a n d In d olequ in on e F or m a tion
Manisha Chakraborty, David B. McConville,
Yanhui Niu, Claire A. Tessier, and Wiley J . Youngs*
Department of Chemistry, The University of Akron,
Akron, Ohio 44325-3601
Received March 24, 1998
In tr od u ction
Nitrogen addition and substitution chemistry1 of quinon-
oid systems is very rich, versatile, and important from
a synthetic point of view. Michael addition reactions
and substitution chemistry2,3 of quinones have been
studied since the 19th century.4,5 Nitrogen addition to
quinonoid compounds can occur in two ways, (1) nuclear
amination and (2) side-chain substitution. Nuclear
amination6 of a quinonoid ring occurs by the substitu-
tion of hydrogen, alkyl groups, or halides by an amine
moiety. Side-chain substitution or amination7,8 takes
place by the replacement of hydrogen from an alkyl
group on the quinonoid ring by an amine. Both pri-
mary and secondary amines are known to give nuclear
and side-chain amination. However, nuclear amina-
tion (Scheme 1) is more usual in the case of primary
amines while side-chain amination is more typical
with secondary amines having bulky alkyl groups. Re-
cently the nuclear amination reaction has been used to
form quinonamine polymers for coatings on metal
surfaces.9-11
tems.14 Indolequinone and isoindolequinones are present
in naturally occurring compounds.15 A novel high yield
synthesis of isoindolequinones has been reported in our
previous publication.16
The Heck reaction, which involves the palladium-
catalyzed coupling of vinyl or aryl halides with alkenes,
is well-known.17 It has been used to form polycyclic18 and
bicyclic nitrogen heterocycles from acyclic precursors.19
Hegedus and co-workers have extensively studied pal-
ladium-mediated intramolecular amination of olefins
with primary and secondary amines.20 This reaction
involves the formation of a new C-N bond by nucleophilic
addition of an amine to an alkene that is η2-bonded to a
Pd(II) center. Cationic heterocycles have been formed
using this synthetic strategy with polysubstituted alk-
enes and tertiary amines.21 Palladium-catalyzed cycliza-
tion reactions of various allyl-containing diaminobenzo-
quinones to form substituted indolequinone systems have
been reported.22 Palladium catalyzed aryl halide ami-
nation with primary and secondary amines has been
investigated by Hartwig23 and Buchwald.24
The study of the syntheses of N-heterocycles is of
interest because such systems are present in large
numbers of biologically important natural12,13 and un-
natural compounds. A broad spectrum of antimicrobials
contains heterocycles as structural units, and some of
them have the quinonoid nucleus present. There has
been significant interest in the study of antibacterial and
antimicrobial properties of quinone-hydroquinone sys-
(14) For example see: (a) Cooper, E. A.; Haines, R. B. Biochem J .
1928, 22, 317. (b) Cooper, E. A.; Haines, R. B. Biochem. J . 1929, 23, 4.
(c) J ohnson, M. G.; Kiyokawa, H.; Tani, S.; Koyama, J .; Morris-
Natschke, S. L.; Mauger, A.; Bowers-Daines, M. M.; Lange, B. C.; Lee,
K.-H. Bioorg. Med. Chem. 1997, 5, 1469.
(15) Thomson, R. H. Naturally Occurring Quinones III: recent
advances; Chapman and Hall: New York, 1987; pp 657-658.
(16) Chakraborty, M.; McConville, D. B.; Koser, G. F.; Tessier, C.
A.; Saito, T.; Rinaldi, P. L.; Youngs, W. J . J . Org. Chem. 1997, 62,
8193.
(17) (a) Heck, R. F. Acc. Chem. Res. 1979, 12, 146. (b) Heck, R. F.
Org. React. 1982, 27, 345.
(18) Zhang, Y.; Wu, G.-Z.; Angel, G.; Negishi, E. J . Am. Chem. Soc.
1990, 112, 8590.
(1) Finley, K. T. The Chemistry of the Quinonoid Compounds; Patai,
S., Ed.; J ohn Wiley & Sons: London, New York, Sydney, Toronto, 1974;
pp 900-1101.
(2) Yamaoka, T.; Nagakura, S. Bull. Chem. Soc. J pn. 1971, 44, 2971.
(3) Crosby, A. H.; Lutz, R. E. J . Am. Chem. Soc. 1956, 78, 1233.
(4) Plimpton, R. T. J . Chem. Soc. 1880, 49, 633.
(5) Meyer, G.; Suida, H. J ustus Liebigs Ann. Chem. 1918, 416, 181.
(6) Cameron, D. W.; Giles, R. G. F.; Titman, R. B. J . Chem. Soc. C
1969, 1245.
(19) Harris, G. D., J r.; Herr, R. J .; Weinreb, S. M. J . Org. Chem.
1992, 57, 2528.
(7) Cameron, D. W.; Scott, P. M.; Todd, L. J . Chem. Soc. 1964, 42.
(8) Cameron, D. W.; Cromartie, R. I. T.; Hamied, Y. K.; Scott, P.
M.; Todd, L. J . Chem. Soc. 1964, 62.
(9) Kaleem, K.; Chertok, F.; Erhan, S. J . Polym. Sci., Part A: Polym.
Chem. 1989, 27, 865.
(10) (a) Nithianandam, V. S.; Erhan, S. J . Appl. Polym. Sci. 1991,
42, 2385. (b) Nithianandam, V. S.; Kaleem, K.; Chertok, F.; Erhan, S.
J . Appl. Polym. Sci. 1991, 42, 2893. (c) Nithianandam, V. S.; Chertok,
F.; Erhan, S. J . Appl. Polym. Sci. 1991, 42, 2899.
(11) Nithianandam, V. S.; Erhan, S. Polymer 1991, 32, 1146.
(12) Remers, W. A.; Spande, T. F. In Indoles Part Three; Houlihan,
W. J ., Ed.; The Chemistry of Heterocyclic Compounds Monograph; J ohn
Wiley & Sons: New York, 1979.
(20) Hegedus, L. S. Angew. Chem., Int. Ed. Engl. 1988, 27, 1113.
(21) van der Schaaf, P. A.; Sutter, J .-P.; Grellier, M.; van Mier, G.
P. M.; Spek, A. L.; van Koten, G.; Pfeffer, M. J . Am. Chem. Soc. 1994,
116, 5134.
(22) Weider, P. R.; Hegedus, L. S.; Asada, H.; D’Andreq, S. V. J .
Org. Chem. 1985, 50, 4276.
(23) (a) Louie, J .; Hartwig, J . F. Tetrahedron Lett. 1995, 36, 3609.
(b) Paul, F.; Patt, J .; Hartwig, J . F. J . Am. Chem. Soc. 1994, 116, 5969.
(c) Hartwig, J . F.; Richards, S.; Baran˜ano, D.; Paul F. J . Am. Chem.
Soc. 1996, 118, 3626. (d) Driver, M. S.; Hartwig, J . F. J . Am. Chem.
Soc. 1996, 118, 4206. (e) Driver, M. S.; Hartwig, J . F. J . Am. Chem.
Soc. 1996, 118, 7217. (f) Louie, J .; Paul, F.; Hartwig, J . F. Organome-
tallics 1996, 15, 2794.
(13) Gilchrist, T. L. Heterocyclic Chemistry; J ohn Wiley & Sons: New
York, 1985.
(24) Wolfe, J . P.; Wagaw, S.; Buchwald, S. L. J . Am. Chem. Soc.
1996, 118, 7215.
S0022-3263(98)00541-6 CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/01/1998

7564 J . Org. Chem., Vol. 63, No. 21, 1998
Notes
Ta ble 1. Yield s (%) of Mon oa m in a ted (5, 6) a n d Dia m in a ted (7) Com p ou n d s fr om Rea ction s of 1 a n d Bu NH2 u n d er
Differ en t Rea ction Con d ition s
1.2 equiv of amine,
rt, air, CH2Cl2, 15 h
excess amine,
air, rt, 15 h
excess amine,
air, reflux, 20 min
excess amine,
argon, reflux, 1 d
excess amine, Pd(II)a,
argon, reflux, 1 d
mono(I) 5
78
Pd(PhCN)2Cl2 and PPh3.
mono(II) 6
mono 6
di 7
27
mono 6
di 7
mono 6
di 7
mono 6
di 7
10
none
none
44
37
48
43
50
a
Here we present nuclear amination25 and side-chain
amination reactions26,27 which were observed in the
reaction of 2,3-diiodo-5,6-dimethylhydroquinone (1) or
2,3-dimethylhydroquinone (8) with primary and second-
ary amines and the first crystallographic characterization
of the amination products. We have studied nuclear
amination in regards to degree of amination, stages of
amination, and diheteroamination using two different
amines. Side-chain amination has been studied with
secondary amines such as diethylamine and diisopropy-
lamine. We also report a new palladium-catalyzed
synthesis of an indolequinone derivative (11) from the
reaction of 1 and i-Pr2NH. The diaminated product
(butyl derivative, 7), indolequinone (11), and the side-
chain aminated product (12) have been characterized
crystallographically.
(1)
the diaminated compound 3,6-bis(n-butylamino)tolu-
quinone (7) in 48% yield. Reaction of BuNH2 in the
presence of palladium(II) gives 6 in 43% yield and 7 in
50% yield (eq 1). Table 1 shows the comparison of the
yields of the aminated products under different reaction
conditions. The monobutylaminated product 6 undergoes
complete conversion to the dibutylaminated compound
7 in refluxing BuNH2 in air (eq 2). The dibutylaminated
product 7 has been characterized by NMR, IR, elemental
analysis, mass spectrometry, and X-ray crystallography
(see Supporting Information).
Resu lts a n d Discu ssion
Nuclear amination of 1 appears to proceed in stages
starting with the replacement of an iodide by an amine.
This is followed by the replacement of the other iodide
by hydrogen and the substitution of a methyl group by a
second amine molecule. The second amine always bonds
to the position para to the first amine even at the cost of
methyl group replacement. Reaction of 1 with 1.2 equiv
of i-PrNH2 in CH2Cl2 for 15 h under air gives the
monoaminated compound 2,3-dimethyl-6-(isopropylamino)-
1,4-benzoquinone (3) and the diaminated compound 3,6-
bis(isopropylamino)toluquinone (4, Scheme 1). None of
the intermediate 2,3-dimethyl-5-iodo-6-(isopropylamino)-
1,4-benzoquinone (2) remains after 15 h, but it is isolated
when the reaction is run for 3.5 h. Butylamine gives two
types of monoaminated compounds under the same
conditions for 15 h: 2,3-dimethyl-5-iodo-6-(n-butylamino)-
1,4-benzoquinone (5), containing a single iodine atom,
and 2,3-dimethyl-6-(n-butylamino)-1,4-benzoquinone (6).
Only the initial stages of monoamination products (5, 6)
are observed for BuNH2, while i-PrNH2 gives the final
stage of amination forming the diaminated product 4 in
15 h. The low yields in case of i-PrNH2 are due to the
formation of uncharacterized black materials after the
reaction, but no starting material is recovered.
(2)
Compound 7 was previously synthesized26a in 32% yield
from the reaction of toluquinone and BuNH2. Formation
of 4 is also described in a brief report26b from the reaction
of toluquinone and i-PrNH2 in EtOH.
Diamination using two different amines has been
studied in the reactions of 2,3-dimethylhydroquinone (8)
with octadecylamine and BuNH2. Reaction of 8 with 5
equiv of octadecylamine in EtOH at room temperature
under air gives the monoaminated product 2-octadecy-
lamino-5,6-dimethylquinone (9) in 54% yield (Scheme 2).
Due to the comparatively slow reaction rate for octade-
cylamine only the monoaminated product is obtained at
room temperature. The yield of 9 decreases to 39% when
only 1 equiv of octadecylamine is used. Reaction of 9 with
excess BuNH2 under reflux in air for 1.5 h gives the
diheteroaminated product 2-octadecylamino-5-(n-buty-
lamino)-6-methylquinone (10) in 80% yield (Scheme 2).
Formation of the octadecylaminated product 9 shows that
the primary amines with long chain alkyl groups can
undergo nuclear amination. Successful formation of 10
offers the possibility of diheteroamination.
The yields of the aminated compounds have been
increased by running these reactions under argon using
amines as reactants as well as solvents. Use of the
catalyst {Pd(PhCN)2Cl2/PPh3}, however, did not increase
the yields significantly. Reaction of 1 with i-PrNH2 under
reflux and argon for 1 day (eq 1) gives only the diami-
nated product 4 in 69% yield. However, BuNH2 gives
both the monoaminated compound 6 in 37% yield and
The suggested mechanism for nuclear amination in air
has been reported28a to involve oxygen uptake and the
formation of formaldehyde. Generally the quinonoid
form is observed in the final products of nuclear amina-
tion. Alternatively, the reaction may be proceeding by a
radical mechanism.
(25) (a) Kumanotani, J .; Kagawa, F.; Hikosaka, A. Sugita, K. Bull.
Chem. Soc. J pn. 1968, 41, 2118. (b) Yoshihira, K.; Sakaki, S.; Ogawa,
H.; Natori, S. Chem. Pharm. Bull. 1968, 16, 2383.
(26) Hikosaka, A. Bull. Chem. Soc. J pn. 1970, 43, 3928.
(27) (a) Cameron, D. W.; Scott, P. M. J . Chem. Soc. 1964, 5569. (b)
Dean F. M.; Houghton, L. E.; Morton, R. B. J . Chem. Soc. C 1968,
2065.
(28) Diao, L.; Yang, C.; Wan, P. J . Am. Chem. Soc. 1995, 117, 5369.

Notes
J . Org. Chem., Vol. 63, No. 21, 1998 7565
Sch em e 2
Sch em e 3
F igu r e 1. Thermal ellipsoid plot of indolequinone 11.
During the investigation of the amination of 1 with
i-Pr2NH in the presence of a palladium catalyst we
encountered an unexpected reaction forming an indole-
quinone derivative and a side-chain aminated product.
The cascade reaction of 1 with i-Pr2NH in the presence
of a stoichiometric amount of bis(benzonitrile)palladium-
(II) dichloride [Pd(PhCN)2Cl2] and PPh3 under argon gave
1-isopropyl-2,5,6-trimethylindole-4,7-quinone (11) in 10%
yield and the side-chain aminated product 2,3-diiodo-5,6-
bis((diisopropylamino)methyl)hydroquinone (12) in 32%
yield (eq 3).
F igu r e 2. Thermal ellipsoid plot of side-chain aminated
product 12.
Compound 11 has been characterized by X-ray crystal-
lography (Figure 1) and spectroscopy.
The side-chain aminated product 12 was first observed
as one of the products from the Pd-assisted synthesis of
indolequinone. Later, it was synthesized in 37% yield
without Pd catalyst from the reaction of 1 with i-Pr2NH
in air at 50 °C. The structure of 12 has also been
confirmed by X-ray crystallography (Figure 2). Reaction
of 1 with diethylamine gives a side-chain aminated
product that has been characterized spectroscopically.
The mechanism of side-chain amination is not defined.6
However a tandem reaction involving formation of quino-
ne methides,28,29 Michael addition of i-Pr2NH to the CH2
groups, and proton transfers is proposed as the mecha-
nism for the formation of 12 from 1.
(3)
Formation of 11 was not observed when this reaction
was run at room temperature. This new Pd-catalyzed
formation of an indolequinone derivative 11 from the
diiodohydroquinone (1) and i-Pr2NH seems promising, as
it is a multistep, one-pot synthesis from readily available
precursors. The proposed mechanism for this multistep
reaction is shown in Scheme 3. The low overall yield
(10%) from the cascade reaction can be rationalized with
respect to the involvement of at least six steps (of average
68% yield) in the formation of 11: (1) oxidation of the
hydroquinone to quinone a ; (2) an addition elimination
reaction of an amine with a quinone to form b; (3)
coordination and insertion of palladium into the carbon-
halogen bond to form c; (4) activation of a C-H bond of
a methyl of isopropylamine to form the six-membered
cyclic intermediate d containing Pd in the ring; (5)
reductive elimination of Pd; (6) dehydrogenation to form
the five-membered pyrrole ring. It is conceivable that
the aforementioned steps may not occur in the sequence
shown and that other steps may also be involved.
Con clu sion s
Though nuclear amination and side-chain amination
reactions have been studied before, we have increased
the yields of the aminated compounds. We have also
confirmed the structures of these products by X-ray
crystallography. This is the first crystallographic proof
of the methyl group replacement in nuclear amination,
presumably by a series of steps culminating in a retro-
Mannich reaction and hydrogen replacement in side-
chain amination reactions. The effects of nucleophilicity,
basicity, and steric requirements determine whether
nuclear versus side-chain amination takes place in these
systems. Electronic factors have been shown to be
important in determining whether nuclear or side chain
(29) Skibo, E. B. J . Org. Chem. 1992, 57, 5874.

7566 J . Org. Chem., Vol. 63, No. 21, 1998
Notes
amination occurs in related systems.30 The presence of
bulky alkyl groups on amines generally promotes side-
chain amination. Therefore, side-chain amination is
observed in the case of i-Pr2NH due to its higher basicity
and larger steric requirement but not for reactions of
primary amines (i.e. i-PrNH2, BuNH2, octadecylamine)
with 1. The rate of nuclear amination is slower for
primary amines with larger R groups as evidenced by
the comparatively slower reaction rates of butylamine
and octadecylamine compared to that of isopropylamine.
When amination occurs with excess amine, the first
monoaminated product with iodine ortho to the amine
is not isolable. Usually monoaminated products are
reactive and convert to diaminated products. Degree of
amination depends on the reaction time, amount of
amine, and reaction temperature. The new multistep
one-pot synthesis of the indolequinone seems promising
for the synthesis of related derivatives with other second-
ary amines. Synthesis of indolequinones and amination
reactions are under further investigation. These nuclear
aminated and side-chain aminated compounds can be
used as novel redox active ligands.
mmol), and PPh3 (32.2 mg, 0.12 mmol), degassed i-PrNH2 (15
mL) was added and the violet solution was refluxed for 1 d under
argon. Excess amine was removed under vacuum. Flash
column chromatography of the crude solid with 7% ethyl acetate
in petroleum ether gave violet solid 4 in 69% yield (166 mg):
mp 126.5 °C; 1H NMR (CDCl3) δ 1.24 (d, 6 H, 2 CH3), 1.26 (d, 6
H, 2 CH3), 2.05 (s, 3 H, CH3), 3.59 (h, 1 H on isopropyl), 4.24 (h,
1 H on isopropyl), 5.25 (s, 1 vinyl H), 6.52 (br d, N-H), 6.65 (br
d, N-H); 13C NMR (CDCl3) δ 10.4, 21.9, 24.3, 44.2, 45.5, 92.2,
101.8, 147.1, 149.9, 179.4, 179.6; IR (CCl4) ν 3277 (w, N-H),
3338 (w, N-H), 1641 (w, CdC), 1611 (s, CdO), 1578 (s, CdO),
1497 (vs, amido type), 2932 (w, CH3) cm-1; UV-vis (CH3CN)
λmax (log ꢀ) 220 (4.48), 334 (4.53) nm; FDMS found for C13H20O2N2
m/e 236 (M+). Anal. Calcd for C13H20O2N2: C, 66.10; H, 8.47;
N, 11.86. Found: C, 66.01; H, 8.62; N, 11.65.
2,3-Dim et h yl-5-iod o-6-(n -b u t yla m in o)-1,4-b en zoq u in o-
n e (5). To 1 (400 mg, 1.02 mmol) in CH2Cl2 (8 mL), was added
n-BuNH2 (0.1 mL, 1.2 mmol) at room temperature, and the
yellow solution was stirred in air. The solution gradually turned
violet after 0.5 h and was stirred for 15 h. The volatiles were
removed under vacuum. Flash column chromatography of the
crude solid with 7% ethyl acetate in petroleum ether gave
1
orange-violet solid 5 in 78% yield (264 mg): mp 77-78 °C; H
NMR (CDCl3) δ 0.96 (t, 3 H, J ) 7.1 Hz, CH3), 1.48 (m, 2 H,
CH2), 1.68 (m, 2 H, CH2), 2.00 (q, 3 H, J ) 1.3 Hz, CH3), 2.12 (q,
3 H, J ) 1.1 Hz, CH3), 3.80 (td, 2 H, J ) 6.86, 7.1 Hz, CH2), 5.85
(br s, 1 H, N-H); 13C NMR (CDCl3) δ 12.3, 13.9, 14.6, 19.9, 32.8,
45.2, 136.1, 143.5, 149.2, 179.9, 182.0; IR (CCl4) ν 3342 (m, N-H)
1661 (s, CdC), 1583 (vs, CdO), 1514 (m, amido type), 2942 (m,
CH3) cm-1; UV-vis (CH3CN) λmax (log ꢀ) 212 (4.25), 285 (4.03),
502 (3.34) nm; FDMS found for C12H16NO2I, m/e 333 (M+). Anal.
Calcd for C12H16NO2I: C, 43.24; H, 4.80; N, 4.20. Found: C,
43.85; H, 4.93; N 4.09.
Exp er im en ta l Section
Ma ter ia ls. All chemicals were reagent grade materials. The
compounds 2,3-diiodo-5,6-dimethylhydroquinone (1)31 and bis-
(benzonitrile)palladium dichloride32 were prepared by literature
procedures. The compounds 2,3-dimethylhydroquinone (8), bu-
tylamine, octadecylamine (Aldrich), isopropylamine, diisopro-
pylamine (Lancaster), triphenylphosphine (J anssen Chimica),
carbon tetrachloride, acetonitrile (Fisher), and deuterated chlo-
roform (Cambridge Isotope Laboratory) were used as received.
Diisopropylamine was distilled from KOH.
Gen er al Tech n iqu es. Field desorption mass spectra (FDMS)
were obtained on a Finnigan MAT95Q mass spectrometer by
Dr. Robert Lattimer at B F Goodrich. Some of the reactions
were carried out in air and some under argon using standard
Schlenk techniques33 as mentioned. Reaction temperatures were
monitored externally. Melting points were recorded under air.
All reactions were monitored by thin-layer chromatography
carried out on E. Merck silica gel plates (60F-254) using UV
light. Flash column chromatography34 was carried out using
silica gel (Baker 40 µm). Elemental analyses were done by
Midwest Microlab in Indianapolis, IN, and Schwarzkopf Mi-
croanalytical Laboratory in Woodside, NY.
2,3-Dim eth yl-6-(n -bu tyla m in o)-1,4-ben zoqu in on e (6). To
a degassed mixture of 1 (400 mg, 1.02 mmol), Pd(PhCN)2Cl2 (19.6
mg, 0.04 mmol), and PPh3 (32.2 mg, 0.12 mmol) was added
degassed n-BuNH2 (15 mL), and the violet solution was refluxed
for 1 d under argon. Excess amine was removed under vacuum.
Flash column chromatography of the crude solid with 7% ethyl
acetate in petroleum ether gave orange-violet solid 6 in 43% yield
(90 mg): mp 80 °C; 1H NMR (CDCl3) δ 0.94 (t, 3 H, J ) 7.1 Hz,
CH3 on butyl group), 1.40 (m, 2 H, CH2 on butyl), 1.61 (m, 2 H,
CH2 on butyl), 1.98 (vwq, 3 H, J ) 1.1 Hz, CH3 on quinone ring),
2.04 (vwq, 3 H, J ) 1.1 Hz, CH3 on quinone ring), 3.07 (td, 2 H,
J ) 7.1, 5.7 Hz, N-CH2 on butyl), 5.42 (s, 1 H, vinyl H), 5.64
(br s, N-H); 13C NMR (CDCl3) δ 12.0, 13.0, 13.8, 20.3, 30.4, 42.3,
97.8, 136.4, 144.8, 146.7, 184.3, 185.9; IR (CCl4) ν 3396 (m, N-H)
1642 (s, CdC), 1604 (vs, CdO), 1508 (s, amido type), 2932 (m,
CH3) cm-1; UV-vis (CH3CN) λmax (log ꢀ) 212 (4.01), 288 (3.73),
478 (3.01) nm; FDMS found for C12H17NO2, m/e 207 (M+). Anal.
Calcd for C12H17NO2: C, 69.56; H, 8.21; N, 6.76. Found: C,
69.26; H, 8.37; N 6.60.
2,3-Dim eth yl-6-(isop r op yla m in o)-1,4-ben zoqu in on e (3).
To 1 (400 mg, 1.02 mmol) in CH2Cl2 (8 mL) was added i-PrNH2
(0.1 mL, 1.2 mmol) at room temperature, and the yellow solution
was stirred in air. The solution gradually turned violet after
0.5 h and was stirred for 15 h. The volatiles were removed under
vacuum. Flash column chromatography of the crude solid with
7% ethyl acetate in petroleum ether gave orange-violet solid 3
3,6-Bis(n -bu tyla m in o)tolu qu in on e (7). To a degassed
mixture of 1 (400 mg, 1.02 mmol), Pd(PhCN)2Cl2 (19.6 mg, 0.04
mmol), and PPh3 (32.2 mg, 0.12 mmol), was added degassed
n-BuNH2 (15 mL), and the violet solution was refluxed for 1 d
under argon. Excess amine was removed under vacuum. Flash
column chromatography of the crude solid with 7% ethyl acetate
in petroleum ether gave violet solid 7 in 50% yield (134 mg):
1
in 8% yield (15 mg): mp 89-90 °C; H NMR (CDCl3) δ 1.24 (d,
6 H, J ) 6.5 Hz, 2 CH3 on isopropyl), 1.98 (vw q, 3 H, J ) 1.1
Hz, CH3 on quinone), 2.04 (vw q, 3 H, J ) 1.1 Hz, CH3 on
quinone), 3.50 (dh, 1H, J ) 6.3, 7.1 Hz, H on isopropyl), 5.43 (s,
H, vinyl H), 5.43 (br s, 1 H, N-H); 13C NMR (CDCl3) δ 12.0,
13.0, 21.9, 44.0, 98.0, 136.5, 144.7, 145.5, 184.5, 185.9; IR (CCl4)
ν 3383 (m, N-H) 1642 (s, CdC), 1602 (vs, CdO), 1507 (s, amido
type), 2927 (m, CH3) cm-1; UV-vis (CH3CN) λmax (log ꢀ) 212
1
mp 108 °C; H NMR (CDCl3) δ 0.92 (t, 3 H, CH3), 0.96 (t, 3 H,
CH3), 1.41 (m, 4 H, 2 CH2), 1.62 (m, 4 H, 2 CH2), 2.08 (s, 3 H,
CH3), 3.14 (dt, 2 H, N-CH2), 3.58 (dt, 2 H, N-CH2), 5.24 (s, 1
H, vinyl H), 6.62 (s, 1 H, N-H), 6.72 (s, 1 H, N-H); 13C NMR
(CDCl3) δ 10.5, 13.9, 13.9, 20.1, 20.4, 30.5, 33.0, 42.4, 44.9, 91.9,
102.0, 148.2, 151.0, 179.2, 179.3; IR (CCl4) ν 3295 (m, N-H),
3351 (m, N-H), 1643 (m, CdC), 1609 (s, CdO), 1497 (s, amido
type), 2930 (s, CH3) cm-1; UV-vis (CH3CN) λmax (log ꢀ) 216
(3.35), 240 (1.30, sh), 342 (3.45) nm; FDMS found for C15H24O2N2,
m/e 264 (M+). Anal. Calcd for C15H24O2N2: C, 68.18; H, 9.09;
N, 10.60. Found: C, 68.55; H, 9.34; N, 10.61.
(4.51), 288 (4.26), 480 (3.52) nm; HRMS (EI) calcd for C11H15
-
NO2 m/e 193.1103, found m/e 193.1101 (error -1.1 ppm).
3,6-Bis(isop r op yla m in o)tolu qu in on e (4). To a degassed
mixture of 1 (400 mg, 1.02 mmol), Pd(PhCN)2Cl2 (19.6 mg, 0.04
(30) Skibo, E. B.; Islam, I.; Schulz, W. G.; Zhou, R.; Bess, L.; Boruah,
R. Synlett 1996, 297.
(31) Nicolaou, K. C.; Liu, A.; Zeng, Z.; McComb, S. J . Am. Chem.
Soc. 1992, 114, 9279.
(32) Hartley F. R. Organomet. Chem. Rev. A 1970, 6, 119.
(33) Shriver, D. F.; Drezdzon, M. A. The Manipulation of Air-
Sensitive Compounds, 2nd ed.; J ohn Wiley and Sons: New York, 1986.
(34) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.
P r oced u r e for th e Con ver sion of 6 to 7. Orange com-
pound 6 was refluxed in butylamine for 1.5 h in air, and the
volatiles were removed under vacuum. TLC and NMR showed
complete conversion to 7. The solid residue did not require
column chromatography.
5,6-Dim eth yl-2-(octa d ecyla m in o)-1,4-ben zoqu in on e (9).
To 1 (138 mg, 1 mmol) in EtOH (100 mL) was added octadecy-

Notes
J . Org. Chem., Vol. 63, No. 21, 1998 7567
lamine (1.347 g, 5 mmol) under air. The solution gradually
turned red and was stirred for 17 h at room temperature. The
volatiles were removed under vacuum. Flash column chroma-
tography of the crude solid with 5% ethyl acetate in petroleum
ether gave red solid 9 in 54% yield (218 mg): mp 77-77.5 °C;
1H NMR (CDCl3) δ 0.88 (t, 3 H, J ) 6.5 Hz, CH3), 1.25 (m, 30 H,
15 CH2), 1.62 (t, 2 H, J ) 7.1 Hz, CH2), 1.99 (vwq, 3 H, J ) 1.1
Hz, CH3), 2.05 (vwq, 3 H, J ) 1.1 Hz, CH3), 3.08 (q, 2 H, J ) 6.7
Hz, N-CH2), 5.42 (s, 1 H, vinyl H), 5.61 (s, 1 H, N-H); 13C NMR
(CDCl3) δ 11.8, 12.8, 14.2, 22.8, 27.1, 28.2, 29.3, 29.5, 29.6, 29.7,
32.0, 42.4, 97.6, 136.1, 144.4, 146.3, 183.9, 185.4; IR (CCl4) ν
3397 (m, N-H), 2927 (vs, CH3), 2855 (s, CH3), 1642 (s, CdC),
1604 (vs, CdO), 1506 (m, amido type) cm-1; UV-vis (CH2Cl2)
λmax (log ꢀ) 226 (4.33), 289 (4.36), 479 (3.53) nm; HRMS (FAB)
calcd for (MH+) m/e C26H46NO2 404.3529, found m/e 404.3514
(error -3.6 ppm).
Characterization data for 11 are as follows: mp 102-103 °C;
1H NMR (CDCl3) δ 1.54 (d, 6 H, 2 CH3 of isopropyl group), 2.01
(q, 3 H, CH3 on quinone ring), 2.03 (q, 3 H, CH3 on quinone ring),
2.35 (s, 3 H, CH3 on N), 6.31 (s, 1 H, vinyl H); 13C NMR (CDCl3)
δ 12.2, 12.7, 14.4, 20.9, 49.0, 108.2, 129.1, 138.2, 139.3, 141.6,
177.2, 184.1; IR (CCl4) ν 2928 (m, CH3), 2972 (m, CH3), 1637
(vs, CdO) cm-1; UV-vis (CH3CN) λmax (log ꢀ) 196 (4.40), 228
(4.33), 272 (4.27), 280 (4.25), 336 (3.61, br), 434 (3.28, sh) nm;
FDMS found for C14H17O2N, m/e 231 (M+). Anal. Calcd for
C14H17O2N: C, 72.72; H, 7.35; N, 6.06. Found: C, 73.01; H, 7.71;
N 5.93.
5,6-Bis((diisopr opylam in o)m eth yl)-2,3-diiodoh ydr oqu in o-
n e (12). A suspension of 1 (100 mg, 0.25 mmol) in i-Pr2NH (15
mL) was heated under air. Within 0.5 h the mixture turned
into a solution and was heated at 50 °C for 1 d. It was filtered
to remove insoluble materials. The solid was washed with ethyl
acetate, and the combined filtrate was concentrated under
vacuum. Flash column chromatography of the solid residue with
20% ethyl acetate in petroleum ether gave a pale yellow solid
12 in 37% yield (55.7 mg): mp, starts getting black at 180 °C
6-Meth yl-5-(n -bu tyla m in o)-2-(octa d ecyla m in o)-1,4-ben -
zoqu in on e (10). To 9 (45 mg, 0.1 mmol) was added n-BuNH2
(0.5 mL, 5 mmol) under air. The solution was refluxed for 1.5
h, and it gradually turned violet. The volatiles were removed
under vacuum. Flash column chromatography of the crude solid
with 5% ethyl acetate in petroleum ether gave violet solid 10 in
1
and does not melt until 263 °C; H NMR (CDCl3) δ 1.15 (d, 24
H, 8 CH3), 3.13 (h, 4 H, 4 C-H), 3.74 (s, 4 H, 2 CH2); 13C NMR
(CDCl3) δ 19.9, 44.7, 48.7, 98.6, 120.2, 152.1; IR (CCl4) ν 2930
(m, CH3), 2971 (s, CH3), 2702 (w, br due to strongly H-bonded
OH) cm-1; UV-vis (CH3CN) λmax (log ꢀ) 214 (4.51), 318 (3.88)
nm; FDMS found for C20H34O2N2I2, m/e 588 (M+). Anal. Calcd
for C20H34O2N2I2: C, 40.81; H, 5.78; N, 4.76. Found: C, 41.03;
H, 6.00; N, 4.78.
1
80% yield (36 mg): mp 90-90.5 °C; H NMR (CDCl3) δ 0.90 (t,
3 H, J ) 6.5 Hz, CH3), 0.95 (t, 3 H, J ) 7.2 Hz, CH3), 1.26 (m,
32 H, 16 CH2), 1.63 (m, 4 H, 2 CH2), 2.08 (s, 3 H, CH3), 3.13 (q,
2 H, J ) 6.6 Hz, N-CH2), 3.58 (q, 2 H, J ) 6.6 Hz, N-CH2),
5.24 (s, 1 H, vinyl H), 6.63 (s, 1 H, N-H), 6.71 (s, 1 H, N-H);
13C NMR (CDCl3) δ 10.5, 13.9, 14.3, 20.1, 22.9, 27.2, 19.9, 32.8,
45.2, 136.1, 143.5, 149.2, 179.8, 182.0; IR (CCl4) ν 3295 (m,
N-H), 3353 (m, N-H), 1643 (m, CdC), 1612 (s, CdO), 1580 (s,
Ack n ow led gm en t. We thank the National Institute
of General Medicine, National Institutes of Health
(Grant No. 1R15GM54294-01) for financial support. We
also thank Dr. Robert Lattimer of B F Goodrich for
providing FDMS data.
CdO), 1500 (vs, amido type), 2928 (s, CH3), 2855(s, CH3) cm-1
;
UV-vis (CH3CN) λmax (log ꢀ) 226 (4.22), 344 (4.62) nm; MS (FAB)
found for C29H52O2N2, m/e 460. Anal. Calcd for C29H52O2N2:
C, 75.65; H, 11.30; N, 6.08. Found: C, 75.88; H, 11.27; N, 6.06.
1-Isop r op yl-2,5,6-tr im eth ylin d ole-4,7-qu in on e (11).
A
mixture of 1 (400 mg, 1.02 mmol), Pd(PhCN)2Cl2 (19.6 mg, 0.04
mmol), and PPh3 (32.2 mg, 0.12 mmol) was placed in a Schlenk
flask, and it was degassed thoroughly by three pump-fill cycles.
Degassed i-Pr2NH (20 mL) was added, and the solution was
refluxed for 1 d under argon. Excess amine was removed under
vacuum. Flash column chromatography of the crude solid with
4% ethyl acetate in petroleum ether gave orange solid 11 in 10%
yield (23.8 mg) along with yellow solid 12 in 32% yield (192 mg).
Su p p or tin g In for m a tion Ava ila ble: Tables of X-ray data
for compound 7 (6 pages). This material is contained in
libraries on microfiche, immediately follows this article in the
microfilm version of the journal, and can be ordered from the
ACS; see any current masthead page for ordering information.
J O980541V