One-pot synthesis of benzo[f]indole-4,9-diones from1,4-naphthoquinones and terminal acetylenes

Article abstract of DOI:10.1248/cpb.59.1289

In this paper, a concise one-pot method for the construction of benzo[f]indole-4,9-dione motifs is described. These transformations proceed via a sequential palladium- and copper-catalyzed coupling reaction of 1,4-naphthoquinones with terminal acetylenes,

Full text of DOI:10.1248/cpb.59.1289

October 2011
Regular Article
Chem. Pharm. Bull. 59(10) 1289—1293 (2011)
1289
One-Pot Synthesis of Benzo[ f ]indole-4,9-diones from1,4-Naphthoquinones
and Terminal Acetylenes
,a
b
b
d
,b,c
*
*
Mitsuaki YAMASHITA, Kazunori UEDA, Koichi SAKAGUCHI, Harukuni TOKUDA, and Akira IIDA
a Faculty of Pharmacy, Takasaki University of Health and Welfare; Nakaorui-machi, Takasaki 370–0033, Japan: b School
c
of Agriculture, Kinki University; Naka-machi, Nara 631–8505, Japan: Research and Development Center for Medicinal
Plants; Kadoma-machi, Kanazawa 920–1164, Japan: and d Department of Complementary and Alternative Medicine
R&D, Graduate School of Medical Science, Kanazawa University; Takara-machi, Kanazawa 920–8640, Japan.
Received July 11, 2011; accepted August 1, 2011; published online August 2, 2011
In this paper, a concise one-pot method for the construction of benzo[ f ]indole-4,9-dione motifs is described.
These transformations proceed via a sequential palladium- and copper-catalyzed coupling reaction of 1,4-naph-
thoquinones with terminal acetylenes, followed by a copper-catalyzed intramolecular cyclization reaction of the
resulting coupling product.
Key words indolequinone; Sonogashira coupling; cascade reaction; copper; palladium
Indolequinones are interesting and valuable compounds
because they are often found in antitumor agents such as
mitomycin C 11—3) and EO9 24,5) (Fig. 1). Despite their at-
tractive biological activities, there are a limited number of ef-
ficient methods for synthesizing indolequinones.6—15) Among
Fig. 1. Heterocycle-Fused Quinones
those reported, the following three strategies exceptionally
provide versatile entries to indolequinones: reactions of 1,4-
naphthoquinones with enamines;16—19) Mn(III)-initiated
oxidative free radical reactions of 2-amino-1,4-naphtho-
quinones with b-dicarbonyl compounds20—22); and cycliza-
tion of 3-acetylamino-2-alkynyl-1,4-naphthoquinones, which
are synthesized from 3-acetylamino-2-bromo-1,4-naphtho-
quinone and terminal acetylenes by the Sonogashira reac-
tion.23) However, these methods have some drawbacks such
Chart 1. Construction of Benzo[ f ]indole-4,9-dione Motifs
as a limited range of substituents on substrates and/or several human tumor cell lines.29,30) To develop a concise
unsatisfactory yields because of structural changes in the method to synthesize its related structural motifs such as 5-
substrates. In an earlier report, our group described the hydroxy-2-(1-hydroxyethyl)-1-methyl-1H-benzo[ f ]indole-
one-pot synthesis of indolequinones from 2-amino-3-bromo- 4,9-dione (4aa), 3-bromo-5-hydroxy-2-(methylamino)naph-
1,4-naphthoquinone derivatives and terminal acetylenes by thalene-1,4-dione (5a) and but-3-yn-2-ol (6a)31) were se-
the Sonogashira coupling/cyclization cascade reaction.24) Al- lected as substrates. To identify the most active catalyst sys-
though this method provided concise access to benzo tem, additive screening was conducted. According to the op-
[f]indole-4,9-dione motifs, a stoichiometric amount of timal reaction conditions reported by our group,24) all experi-
copper salt was required to obtain satisfactory yields. ments were performed with 2.0 eq of acetylene, 0.8 eq of an
According to the reported methods typically used for indole additive, 20 mol% of copper salt, and 200 eq of pyridine in
syntheses, we tested the reactions using a catalytic amount of N,Nꢀ-dimethylformamide (DMF) at 80 °C.32) However,
copper(I) salts with bidentate ligands such as bipyridine, bidentate ligands such as trans-N,Nꢀ-dimethylcyclohexane-
1,10-phenanthroline, and trans-N,Nꢀ-dimethylcyclohexane- 1,2-diamine, 2,2ꢀ-bipyridine, L-proline, and 1,10-phenanthro-
1,2-diamine.25—27) However, no coupling reactions were ob- line, which are typically used in copper-mediated coupling
served, and degradation of the starting naphthoquinone to a reactions,25,26) were ineffective in promoting the reaction
dehalogenated compound gradually occurred during the (Table 1, entries 3—6). In contrast, most inorganic bases
reaction.28) Thus, we attempted to develop more efficient proved applicable and furnished the cyclized product 4aa in
reaction conditions for preparing indolequinones. In this 13—63% yields with K2CO3 being suitable (Table 1, entries
paper, we describe the development of a cascade reaction for 7—10). Test reactions with 0.2 and 2.0 eq of K2CO3 (Table 1,
constructing benzo[ f ]indole-4,9-dione motifs involving the entries 11, 12) resulted in lower yields of 4aa, which sug-
Sonogashira reaction and intramolecular cyclization with gests that the optimum amount of K2CO3 is 0.8 eq
a catalytic amount of copper salts (Chart 1).
(K2CO3 : Cu2Oꢁ4 : 1). Without pyridine or Cu2O, the desired
product 4aa was obtained in low yields (Table 1, entries 13,
14). Furthermore, the coupling reaction did not initiate with-
Results and Discussion
We have previously reported that (S)-5-hydroxy-2-(1ꢀ-hy- out Pd(OAc)2 (Table 1, entry 15). A blank experiment con-
doxyethyl)naphtho[2,3-b]furan-4,9-dione (3), which is a firmed that in the absence of K2CO3, almost no 4aa was
secondary metabolite found in the inner bark of Tabebuia formed (Table 1, entry 2). The base pyridine is essential for
avellanedae, exhibits potent antiproliferative effects against this reaction, and the yield of 4aa significantly decreased
© 2011 Pharmaceutical Society of Japan
∗ To whom correspondence should be addressed. e-mail: yamashita@takasaki-u.ac.jp; iida@nara.kindai.ac.jp

1290
Vol. 59, No. 10
Table 1. Effect of Additives and Reagents on the Conversion of Naphthoquinone 5a to the Cyclized Product 4aaa)
Yield (%)b,c)
Entry
Time (h)
Additives
7aa
4aa
1d)
2
3
4
5
6
7
8
1
24
24
24
12
24
12
1
None
None
Trace
42
58
Trace
Trace
Trace
ꢂ6
Trace
34
trans-N,Nꢀ-Dimethylcyclohexane-1,2-diamine
17 (8)e)
5 (21)e)
22
2,2ꢀ-Bipyridine
L-Proline
1,10-Phenanthroline
K3PO4
17 (20)e)
16
51
Cs2CO3
13
9
4
Na2CO3
11
39
10
11f)
12g)
13h)
14i)
15j)
16k)
1
12
1
24
12
12
16
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
5
5
12
13
63
34
56
ꢂ4
ꢂ4
0
46
43 (13)e)
19 (27)e)
ꢂ7
a) Substrate 5a (0.5 mmol), Pd(OAc)2 (3 mol%), copper salt (0.1 mmol), acetylene 6a (1.0 mmol), pyridine (8.0 ml), and K2CO3 (0.4 mmol) were stirred in DMF at 80 °C. b)
Isolated yield. c) Recovery of 5a was less than 5%, unless otherwise noted. d) Cu2O (0.05 mmol) was used. e) The numbers in parentheses are the yields of recovered 5a.
f) Additive (0.1 mmol) was used. g) Additive (1.0 mmol) was used. h) Without pyridine. i) Without Cu2O. j) Without Pd(OAc)2. k) Et3N was used instead of pyridine.
Table 2. Effect of Copper Salts on the Conversion of Naphthoquinone 5a
when Et3N was used instead of pyridine (Table 1, entry 16).
To determine the optimal copper salts, reactions with vari-
to the Cyclized Product 4aaa)
ous copper(I) (CuI, CuBr, and CuOTf) and copper(II) salts
(CuO, CuBr2, and CuCl2)33) were examined. The results are
shown in Table 2. Both copper(I) and copper(II) salts af-
forded the cyclized product 4aa in moderate yields (13—
55%, Table 2, entries 1—6), but required a prolonged reac-
tion time. Furthermore, decreasing the amount of Cu2O led
to a lower yield of 4aa (Table 2, entry 7). Thus, it was deter-
mined that Cu2O is the preferred catalyst and the optimal
amount of Cu2O is 0.2 eq (based on 4aa).
Yield (%)b,c)
Entry
Time (h)
Cu salts
7aa
4aa
To investigate the generality of this method, halonaphtho-
quinones 5b—d were reacted with terminal acetylenes 6.
The results are summarized in Table 3. No coupling reactions
occurred when naphthoquinone 5b was used with an unsub-
stituted NH2 group (Table 3, entry 1).34) The reaction of 5c,
which contains a more general naphthoquinone motif, with a
stoichiometric amount of Cu2O gave the cyclized product
4ca in 56% yield at rt (Table 3, entry 2). A comparable result
was attained when a catalytic amount of Cu2O was used,
demonstrating the utility of our catalytic cascade reaction
(Table 3, entry 4). A TLC analysis during the reaction shown
1
2
3
4
12
12
12
12
12
16
2
CuI
10
5
5
47
9
14
6
38
28
55
13
48
52
30
CuBr
CuOTf
CuO
CuBr2
CuCl2
Cu2O
5
6
7d)
a) Substrate 5a (0.5 mmol), Pd(OAc)2 (3 mol%), Cu2O (0.1 mmol), acetylene 6a
(1.0 mmol), pyridine (8.0 ml), and additives (0.4 mmol) were stirred in DMF at 80 °C.
b) Isolated yield. c) Recovery of 5a was less than 5%, unless otherwise noted. d)
Cu2O (0.5 mmol) was used.
in Table 3 entry 4 revealed that the coupling reaction com- 5d was used as the substrate. This was owing to the increased
pleted within 5 h at rt, although a small amount of a cyclized formation of the dehalogenated product 7aa (Table 3, entries
product was observed after 5 h.35) On the other hand, only a 5, 6). Alkynes bearing phenyl or 2-phenylethyl substituent
small amount of a coupling product was formed in the ab- reacted smoothly with 5a to give the desired product 4ab and
sence of K2CO3 (Table 3, entry 3).36) Thus, we assume that 4ac in moderate yields, suggesting the hydroxyethyl moiety
K2CO3 functions to regenerate the active copper acetylide/ on the acetylene is not essential for the developed method
pyridine complexes and promote the coupling reaction al- (Table 3, entries 7, 8).
though the exact role of K2CO3 is unclear. Contrary to our
We have already reported that the cuprous acetylide/pyri-
expectations, a lower yield was observed with catalytic dine complex, which forms during the reaction, plays a cru-
amounts than stoichiometric quantities of Cu2O when iodide cial role in the intramolecular cyclization step.24) To deter-

October 2011
1291
Table 3. Effect of Varying Substrates and Acetylenes on the Conversion of Naphthoquinones 5 to the Cyclized Product 4a)
Product, Yield (%)b,c)
Entry
1
Time (h)
12
Substrate
R3
7
4
CH(OH)CH3 (6a)
2e,f,g,h)
24
CH(OH)CH3 (6a)
CH(OH)CH3 (6a)
CH(OH)CH3 (6a)
CH(OH)CH3 (6a)
CH(OH)CH3 (6a)
Ph (6b)
3e,g,h)
4e,h)
5e,f,g)
6e)
6
24
0.5
0.5
1
7
8
1
CH2CH2Ph (6c)
a) Substrate 1 (0.5 mmol), Pd(OAc)2 (3 mol%), Cu2O (0.1 mmol), acetylene (1.0 mmol), pyridine (8.0 ml), and K2CO3 (0.4 mmol) were stirred in DMF at 80 °C. b) Isolated
yield. c) Recovery of 5 was less than 5%, unless otherwise noted. d) The numbers in parentheses are the yields of recovered 5. e) Pyridine (4.0 ml) was used. f ) Cu2O
(0.5 mmol) was used. g) Without K2CO3. h) At rt.
mine the role of K2CO3 in the final cyclization step, the reac-
tion of isolated 8ca with K2CO3 in pyridine and DMF at rt
was examined (Chart 2). After 24 h, the cyclized product 4ca
was obtained in 14% yield along with 46% recovery of unre-
acted 8ca, suggesting that K2CO3 itself partially contributes
to the cyclization process. Furthermore, the cuprous
acetylide/pyridine complex functions as the primary catalyst
for the intramolecular cyclization reaction.
Chart 2. Conversion of the Coupling Product 8ca to the Cyclized Product
4ca

1292
Vol. 59, No. 10
2-(1-Hydroxyethyl)-1-methyl-1H-benzo[ f ]indole-4,9-dione (4ca)
Starting from 5c and 6a, this compound was prepared according to the gen-
eral procedure. Pyridine (4.0 ml) was used. The reaction was performed at rt
for 24 h. The column chromatography (hexane/EtOAcꢁ2/1) gave 7ca37)
(trace) and 4ca (67 mg, 53% yield) as pale yellow needles with mp 200—
Finally, (S)-4aa, which was synthesized from 5a and com-
mercially available (S)-6a according to the developed
method, was evaluated for its ability to suppress the growth
of human tumor cell lines including A549 (lung) and MCF-7
(breast). Compared with 3, compound (S)-4aa exhibited less 201 °C. 4ca: rf (hexane/EtOAcꢁ1/1)ꢁ0.2. 1H-NMR d: 1.69 (3H, d,
Jꢁ6.5 Hz), 2.00 (1H, d, Jꢁ7.0 Hz), 4.12 (3H, s), 4.94 (1H, dq, Jꢁ6.5,
potent antiproliferative effects against both cell lines (IC50 of
7.0 Hz), 6.69 (1H, s), 7.65—7.69 (2H, m), 8.11—8.14 (2H, m). 13C-NMR d:
(S)-4aa: 41.5 and 56.1 mM, respectively; IC50 of 3: 0.92 and
22.1, 33.7, 60.1, 104.6, 125.8, 126.0, 126.7, 130.2, 132.8, 133.2, 133.4,
0.48 mM, respectively).29,30) Further structure–activity rela-
133.7, 147.6, 175.1, 179.9. IR (KBr): 3433, 1647, 1586, 1474, 1443, 1358,
1246, 963, 714. HR-MS (ESI) m/z: [MꢄH]ꢄ Calcd for [C15H14NO3]ꢄ,
256.0974; Found, 256.0985.
tionship (SAR) studies on 4aa derivatives are underway in
our laboratory and will be reported in due course.
5-Hydroxy-1-methyl-2-phenyl-1H-benzo[ f ]indole-4,9-dione (4ab)
Starting from 5a and 6b, this compound was prepared according to the gen-
eral procedure. The column chromatography (hexane/EtOAcꢁ5/1) gave 7aa
(6 mg, 6% yield) and 4ab (104 mg, 69% yield) as orange needles with mp
208—209 °C. 4ab: rf (hexane/EtOAcꢁ2/1)ꢁ0.60. 1H-NMR d: 4.05 (3H, s),
6.79 (1H, s), 7.20 (1H, dd, Jꢁ1.5, 8.5 Hz), 7.44—7.58 (6H, m), 7.71 (1H,
dd, Jꢁ1.5, 7.5 Hz), 12.65 (1H, s). 13C-NMR d: 34.7, 108.0, 115.6, 119.1,
124.0, 127.6, 128.9, 129.2, 129.3, 130.1, 131.6, 134.5, 135.4, 144.1, 162.1,
175.5, 187.0. IR (KBr): 3109, 1630, 1458, 1439, 1323, 1265, 1234, 826,
758, 698. HR-MS (ESI) m/z: [MꢄH]ꢄ Calcd for [C19H14NO3]ꢄ, 304.0974;
Found, 304.0973.
Conclusion
We have demonstrated a concise method for constructing
substituted indolequinones using a Sonogashira coupling/cy-
clization cascade reaction with K2CO3 and a catalytic amount
of Cu2O. The experimental simplicity of the proposed cat-
alytic system is expected to have a variety of applications in
synthetic and medicinal chemistry.
5-Hydroxy-1-methyl-2-phenethyl-1H-benzo[ f ]indole-4,9-dione (4ac)
Starting from 5a and 6c, this compound was prepared according to the gen-
eral procedure. The column chromatography (hexane/EtOAcꢁ5/1) gave 7aa
(10 mg, 10% yield) and 4ac (106 mg, 64% yield) as pale yellow prisms with
mp 163—164 °C. 4ac: rf (hexane/EtOAcꢁ2/1)ꢁ0.60. 1H-NMR d: 2.93 (2H,
t, Jꢁ7.5 Hz), 3.02 (2H, t, Jꢁ7.5 Hz), 3.88 (3H, s), 6.56 (1H, s), 7.15—7.33
(6H, m), 7.52 (1H, dd, Jꢁ7.0, 7.0 Hz), 7.65 (1H, d, Jꢁ7.0 Hz), 12.64 (1H,
s). 13C-NMR d: 28.1, 32.6, 34.4, 106.2, 115.5, 119.0, 123.9, 126.7, 127.5,
128.3, 128.7, 130.8, 134.6, 135.3, 140.1, 143.7, 162.0, 175.1, 187.0. IR
(KBr): 3109, 1626, 1465, 1450, 1438, 1362, 1346, 1263, 1217, 1150, 1017,
826, 785, 746, 702. HR-MS (ESI) m/z: [MꢄH]ꢄ Calcd for [C21H18NO3]ꢄ,
332.1287; Found, 332.1291.
Experimental
1
General All melting points are uncorrected. H- and 13C-NMR spectra
(500 MHz for 1H and 125 MHz for 13C) were obtained in CDC13, unless
otherwise noted. The chemical shift values are expressed in ppm relative
to internal tetramethylsilane. Abbreviations are as follows: s, singlet; d,
doublet; t, triplet; m, multiplet; br, broad. IR is expressed in cmꢃ1. Purifica-
tion was performed using silica gel column chromatography. All reagents
were purchased from chemical companies and used as received. All reac-
tions were conducted under an argon atmosphere, unless otherwise stated.
Product 7ba37) is a known compound.
Synthesis of Starting Materials Compounds 5a,24) 5c,38) and 5d24) were
prepared by the reported methods.
2-(3-Hydroxybut-1-yn-1-yl)-3-(methylamino)naphthalene-1,4-dione
(8ca) Starting from 5c and 6a with a stoichiometric amount of Cu2O, this
compound was prepared according to the general procedure. The reaction
was quenched after 4 h. The column chromatography (hexane/EtOAcꢁ2/1)
gave 4ca (47 mg, 37% yield) and 8ca (39 mg, 31% yield). 8ca: red needles
2-Amino-3-bromo-5-hydroxynaphthalene-1,4-dione (5b) To a solu-
tion of 2-bromo-8-hydroxynaphthalene-1,4-dione38) (253 mg, 1.0 mmol) in
EtOH (8.0 ml), 28% aqueous NH3 (0.7 ml, 10 mmol) was added, and then,
the mixture was stirred for 24 h at rt. After evaporation to remove the sol-
vent, the crude product was dissolved in DMF (2.0 ml). NBS (178 mg,
1.0 mmol) was added to the solution, and the mixture was stirred for 1 h at
rt. The mixture was extracted with EtOAc. The organic extracts were washed
with brine and dried over Na2SO4. The column chromatography (hexane/
EtOAcꢁ2/1) gave 5b (130 mg, 49% yield) as orange needles with mp 222—
223 °C. 5b: rf (hexane/EtOAcꢁ2/1)ꢁ0.40. 1H-NMR d: 5.37 (1H, br s), 6.21
(1H, br s), 7.28 (1H, d, Jꢁ9.0 Hz), 7.52 (1H, dd, Jꢁ7.5, 9.0 Hz), 7.64 (1H, d,
Jꢁ7.5 Hz), 12.48 (1H, s). 13C-NMR (DMSO-d6) d: 99.4, 114.4, 119.7,125.7,
130.4, 135.1, 150.6, 160.6, 178.5, 181.8. IR (KBr): 3439, 3333, 1638, 1616,
1572, 1458, 1383, 1267, 1240, 1059, 766, 683. High resolution (HR)-MS
(electrospray ionization (ESI)) m/z: [MꢄNa]ꢄ Calcd for [C10H6BrNNaO3]ꢄ,
289.9429; Found, 289.9420.
1
with mp 154—156 °C. rf (hexane/EtOAcꢁ1/1)ꢁ0.1. H-NMR d: 1.56 (3H,
d, Jꢁ7.0 Hz), 1.67 (1H, br s), 3.52 (3H, d, Jꢁ5.5 Hz), 4.83 (1H, q,
Jꢁ7.0 Hz), 6.45 (1H, br s), 7.61 (1H, dd, Jꢁ1.0, 7.5 Hz), 7.73 (1H, dd,
Jꢁ1.0, 7.5 Hz), 8.02 (1H, dd, Jꢁ1.0, 7.5 Hz), 8.12 (1H, dd, Jꢁ1.0, 7.5 Hz).
13C-NMR d: 23.7, 31.7, 59.0, 77.2, 97.0, 101.3, 126.5, 126.6, 130.0, 132.3,
133.4, 135.0, 148.4, 181.0, 181.5. IR (KBr): 3318, 1674, 1597, 1566, 1516,
1331, 1292, 721. HR-MS (ESI) m/z: [MꢄH]ꢄ Calcd for [C15H14NO3]ꢄ,
256.0974; Found, 256.0987.
Antiproliferative Effect Assay The antiproliferative effects of indole-
quinone (S)-4aa was examined in cancer cell lines. These cells were main-
tained in usual 10% fetal serum Dulbecco’s minimum essential medium
(DMEM) through experiments and exposed to four dose concentrations of
(S)-4aa in a humidified atmosphere (37 °C, 5% CO2) for 72 h. After the re-
action, cells were further incubated with 0.25% trypan blue dye for 20 min
and counted for viable cells under light microscopic apparatus. IC50 values
were calculated from separate experiments performed in triplicate.
General Procedure for Synthesis of Benzo[ f ]indole-4,9-diones Under
Ar atmosphere, a mixture of Cu2O (14 mg, 0.10 mmol), acetylene 6
(1.0 mmol), K2CO3 (55 mg, 0.40 mmol), and pyridine (8.0 ml, 100 mmol)
was stirred for 2 h at rt. A solution of compound 5 (0.50 mmol) and
Pd(OAc)2 (3.4 mg, 0.015 mmol) in DMF (5.0 ml) was added to this suspen-
sion, and the reaction mixture was stirred at 80 °C for 1 h. The mixture was
quenched with H2O at 0 °C and extracted with CHCl3. The organic extracts
were washed with H2O and brine, dried over Na2SO4, and then concentrated.
5-Hydroxy-2-(1-hydroxyethyl)-1-methyl-1H-benzo[ f ]indole-4,9-dione
(4aa) Starting from 5a and 6a, this compound was prepared according to
the general procedure. The column chromatography (hexane/EtOAcꢁ2/1)
gave 7aa39) (5 mg, 5% yield) and 4aa (86 mg, 63% yield) as yellow needles
with mp 219—220 °C. 4aa: rf (hexane/EtOAcꢁ1/1)ꢁ0.33. 1H-NMR d: 1.68
(3H, d, Jꢁ6.5 Hz), 1.98 (1H, d, Jꢁ7.5 Hz), 4.11 (3H, s), 4.93 (1H, dq,
Jꢁ6.5, 7.5 Hz), 6.65 (1H, s), 7.17 (1H, dd, Jꢁ1.0, 8.5 Hz), 7.53 (1H, dd,
Jꢁ7.5, 8.5 Hz), 7.63 (1H, dd, Jꢁ1.0, 7.5 Hz), 12.6 (1H, s). 13C-NMR d:
22.1, 33.4, 62.0, 105.1, 115.4, 119.2, 124.1, 126.8, 131.8, 134.3, 135.4,
145.4, 162.0, 175.7, 186.7. IR (KBr): 3530, 1630, 1458, 1374, 1352, 1219,
1080. HR-MS (ESI) m/z: [MꢃH]ꢃ Calcd for [C15H13NO4]ꢃ, 270.0766;
Found, 270.0757.
Acknowledgements The authors are grateful to Taheebo Japan Co.,
Ltd. and Sanshin Metal Working Co., Ltd. for the generous financial support
for this project.
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October 2011
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30 mol% of bidentate ligand: using bipyridine, no desired product and
50% yield of dehalogenated product 7ca were obtained; using 1,10-
phenanthroline, no desired product and 50% yield of dehalogenated
product 7ca were obtained; using trans-N,Nꢀ-dimethylcyclohexane-
1,2-diamine, no desired product and 62% yield of dehalogenated prod-
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(2004).
and 8% yields, respectively when the reaction was quenched after 5 h.
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