Synthesis of fused indoles by sequential palladium-catalyzed Heck reaction and N-heteroannulation

Article abstract of DOI:10.1016/j.tet.2005.02.033

A route to 3,4-fused indoles via two consecutive palladium-catalyzed reactions; an intramolecular Heck reaction followed by a reductive N-heteroannulation is described. Using this route, a number of indoles have been prepared having a variety of ring sizes anchored to the 3- and 4-position of the indole nucleus. Furthermore, a number of functional groups, both carbon and heteroatom substituents can be introduced in (and on) the additional ring without any detrimental effects on the two reactions.

Full text of DOI:10.1016/j.tet.2005.02.033

Tetrahedron 61 (2005) 3637–3649
Synthesis of fused indoles by sequential palladium-catalyzed Heck
reaction and N-heteroannulation
*
¨
Bjorn C. G. Soderberg, Jeremiah W. Hubbard, Stacey R. Rector and Shannon N. O’Neil
¨
C. Eugene Bennett Department of Chemistry, West Virginia University, Morgantown, WV 26506-6045, USA
Received 20 December 2004; revised 9 February 2005; accepted 11 February 2005
Abstract—A route to 3,4-fused indoles via two consecutive palladium-catalyzed reactions; an intramolecular Heck reaction followed by a
reductive N-heteroannulation is described. Using this route, a number of indoles have been prepared having a variety of ring sizes anchored to
the 3- and 4-position of the indole nucleus. Furthermore, a number of functional groups, both carbon and heteroatom substituents can be
introduced in (and on) the additional ring without any detrimental effects on the two reactions.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
ratio (Scheme 1). Reductive N-heteroannulation of 3 using
10 mol % palladium diacetate (Pd(OAc)2), 20 mol %
1,3-bis(diphenylphosphino)propane (dppp) in DMF at
120 8C and 4 atm of carbon monoxide gave an acceptable
63% yield of the fused indole 6 after 70 h.
The palladium-catalyzed reductive N-heteroannulation of
2-(1-alkenyl)nitrobenzenes have been utilized to prepare
indoles and carbazoles,1–7 2,20-biindoles,8 1H-indol-2-yl-
1H-quinolinones,9 b-carbolines,10 and 1,2-dihydro-4(3H)-
carbazolones.11,12 We have communicated a novel route to
3,4-fused indoles consisting of two consecutive palladium-
catalyzed reactions, an intramolecular Heck reaction
followed by a reductive N-heteroannulation.13 For example,
compound 2, prepared by O-alkylation of 2-bromo-3-
hydroxy-1-nitrobenzene (1) with 1-bromo-3-butene, was
reacted under standard Heck condition to give a mixture of
three isomeric 5-nitro-1-benzopyrans (3–5) in an 18:4:1
Based on the results shown in Scheme 1, a systematic
survey of this reaction sequence to fused indoles was
undertaken. The starting materials for the Heck reaction
were prepared by benzylic nucleophilic substitution using
2-bromo-3-nitrobenzylbromide (7) and a variety of unsatu-
rated alkoxides and phenoxides. Compounds 8–15, prepared
in this fashion were used directly in Heck reactions
(Table 1). The benzylic bromide 7 was also reacted with
allyl amine, allyl sulfide, and the anion of dimethyl
malonate to give 16–18, respectively (Scheme 2). Com-
pound 16 was reacted with acetic anhydride to give the
amide 20, the allyl sulfide 17 was oxidized to the sulfoxide
20 using sodium periodate and to the sulfone 21 using a
urea–hydrogen peroxide complex. Finally, the malonate
adduct 18 was deprotonated and alkylated with allyl
bromide to give 22.
The allylic amide 23 was prepared from 2-bromo-3-
nitrobenzoic acid (24) via the corresponding acid chloride
(Scheme 3). Transformation of 24 to the isocyanate 25 using
diphenylphosphoryl azide followed by reaction with sodium
methoxide furnished the expected methyl carbamate
(Scheme 3). Deprotonation and alkylation using 4-bromo-
1-butene gave 26 albeit in low overall yield.
Scheme 1.
Keywords: Palladium-catalyzed; Indoles; Reductive; Annulation.
*
With a number of precursors in hand, the intramolecular
Heck reaction was examined.14 Facile Heck reaction was
Corresponding author. Tel.: C1 3042933435; fax: C1 3042934904;
e-mail: bjorn.soderberg@mail.wvu.edu
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.02.033

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B. C. G. Soderberg et al. / Tetrahedron 61 (2005) 3637–3649
3638
observed in most cases using palladium diacetate, tris-
(o-tolyl)phosphine (TTP), in triethyl amine (TEA). In some
cases, the cyclization afforded products derived from exo to
endo double bond migration during the reaction (entries 1,
2, 9, 10, and 12, Table 1). The isomers were readily
separated on silica gel and the exocyclic product was always
the major isomer. Exclusive or highly selective formation
of the exo isomer has been reported in related systems.15,16
A vinyl-substituted cyclization product was exclusively
obtained in one case (entry 3). This result can be explained
mechanistically via insertion of the alkene into the oxidative
addition intermediate 44 to give a new s-palladium
complex 45 having a cis-relationship between the
palladium moiety and the newly formed carbon–carbon
bond. b-Hydride elimination requires a cis-geometry
between the metal and the proton. Due to the presence of
the sterically demanding nitro group, rotation of the metal is
slow compared to the competing b-hydride elimination
toward the methyl group forming 31 (Scheme 4). For
compounds with two potential directions for the b-hydride
elimination, the vinyl-substituted product is usually the
major or sole isomer formed.14 A single stereoisomer was
formed upon cyclization of 11 (entry 4). Although the
alkene geometry of the product 32 is unknown, the
depicted geometry is consistent with a syn alkene insertion,
s-bond rotation, and syn b-hydride elimination sequence.
Trans substituted alkenes related to 11 have previously
been shown to give products with the same stereo-
chemistry.14,17,18
We initially studied the reductive N-heteroannulation of 3
using conditions previously employed for substituted
styrenes. Thus, reaction of 3 with 6 mol % Pd(OAc)2 and
24 mol % PPh3 in acetonitrile at 70 8C and 3 atm of carbon
monoxide for 19.5 h, gave the expected indole 6 in low
isolated yield (11%) together with recovered starting
material (51%). Reaction of 3 for 70 h at 100 8C, using
the same solvent and catalyst system, improved the yield of
product (6) to 37% but a significant amount of starting
material still remained (32%). After some optimization, a
catalyst system consisting of 10 mol % Pd(OAc)2, 12 mol %
of 1,3-bis(diphenylphosphino)propane in dimethylforma-
mide at 4 atm of CO and 120 8C gave 6 in 63% yield. The
last reaction proved to be very clean, and no other organic
1
products was observed by H NMR of the crude reaction
mixture. It is interesting to note that no detectable amount
(by 1H NMR at 270 MHz) of isomerization to the
endocyclic benzopyranes 4–5 was observed in the initial
reactions wherein the starting material 3 was not completely
consumed. We have recently shown that better yields are
obtained in some cases using bis(dibenzylidenacetone)pal-
ladium in combination with 1,10-phenanthroline. The
reason for the need for two ligands is not clear at this
point in time. Most of the reactions presented in Table 1
utilize the latter catalyst system. For the methylene and
benzylidene substituted substrates, N-heteroannulation to
form a 3,4-fused indole was observed in moderate to good
yields (33–83%) in all cases examined. Compound 31 did
not afford any cyclized product under any of the cyclization
conditions described above. Attempts to isomerize the
double bond of 31 using basic (potassium t-butoxide or
triethylamine) or acidic conditions (p-toluenesulfonic acids)
were fruitless.
Non-regioselective Heck reactions forming products
derived from insertion into the internal or terminal position
of the alkene was observed using a longer tether between
the bromide and the alkene (entries 7–8). Both 7-exo and
8-endo (entry 7)19 and 8-exo and 9-endo (entry 8)
cyclizations were observed. The isomers were in both
cases inseparable and were used in the next step as a
mixture. Compound 13 did not furnish either a 9- or 10-
membered cyclization product but gave a complex mixture
of unidentified products. Similar results have been reported
by Ma and Negishi using 9-membered ring precursors.20
The mixtures of tricyclic compounds 34:35 and 36:37 were
also subjected to the reductive N-heteroannulation reaction
(entries 7–8, respectively). In both cases, a moderate
amount of fused indoles was isolated derived from
cyclization of the exocyclic isomer. Curiously, reduction
of the nitro group to an amine was observed for the two
endocyclic compounds 35 and 37.27
In conclusion, a novel route to fused indoles has been
developed based on two palladium-catalyzed reactions.
This methodology has been used to prepare indoles having
a 6–8-membered rings anchored to the 3- and 4-postion of
the indole nucleus. Nitrogen- and oxygen-containing rings
as well as an example of a carbocyclic ring have been
prepared. Applications of this sequence in total synthesis are
currently underway in our laboratories.
Attempted Heck reaction of allylic amine 16 did not
produce the anticipated cyclization products but gave, in
addition to recovered starting material, a complex mixture
of unidentified products. Poor yields of products has
previously been reported using N-allyl N-(2-halo)benzyl-
amines in intramolecular Heck reactions.21,22 It is not
unlikely that the initial s-complex, formed by oxidative
addition of palladium(0) into the aryl-bromine bond in 16, is
coordinated to the pendant amine, forming a relatively
stable complex.23–26 This effectively removes palladium
from the catalytic cycle, and the reaction is quenched. The
amide 19, having a substantially lower ability to coordinate
to the metal, cyclized to form the expected products 38 and
39. Finally, unsuccessful cyclizations were observed using
sulfide 17, sulfoxide 20, and sulfone 21. Intramolecular
Heck reactions of allyl aryl sulfides have been reported. To
our knowledge, no examples of allyl benzyl sulfides,
sulfones, or sulfoxides have been reported in the literature.
2. Experimental
2.1. General procedures
All NMR spectra were determined in CDCl3 and the
chemical shifts are expressed in d values relative to Me4Si
1
(0.0 ppm, H and 13C) or CDCl3 (77.0 ppm, 13C) internal
standards. 1H–1H coupling constants are reported as
calculated from spectra; thus a slight difference between
Ja,b and Jb,a is usually obtained. Results of APT (attached
proton test)—13C NMR experiments are shown in
Palladium-catalyzed N-heteroannulation of the Heck pro-
ducts having an exocyclic double bond was examined next.

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B. C. G. Soderberg et al. / Tetrahedron 61 (2005) 3637–3649
3639
Table 1. Intramolecular Heck reaction and N-heteroannulation
Entry
Bromoalkenea,b
Coupling product(s)a,b
Indolea,b
1
8 (67%)
27 (76%)
29 (73%)
28 (20%)
46 (78%)
2
3
30 (25%)
9 (50%)
10 (72%)
11 (62%)
47 (80%)
Complex mixture of products
31 (78%)
4
32 (82%)c
48 (68%)
5
6
12 (67%)
33 (81%)
49 (83%)
Complex mixture of products
13 (46%)
7
34 (37%)d
50 (44%)e
35 (60%)d
51 (64%)e
14 (65%)
8
36 (18%)f
15 (91%)
37 (13%)f
39 (26%)
41 (14%)
53 (15%)g,h
52 (44%)g
9
19
38 (69%)
54 (41%)
10
22
40 (72%)
55 (65%)

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B. C. G. Soderberg et al. / Tetrahedron 61 (2005) 3637–3649
3640
Table 1 (continued)
Entry
Bromoalkenea,b
Coupling product(s)a,b
Indolea,b
11
23
26
42 (51%)
56 (61%)i
12
43 (47%)j
57 (33%)
a See Section 2 for details.
b Isolated yield of pure compound given in parenthesis.
c Only one alkene isomer was obtained, however, the stereochemistry is not known.
d Calculated yield from an inseparable 1:1.6 mixture of 34 and 35.
e Calculated yields starting from a mixture of 34 and 35.
f
Calculated yields from an inseparable 1.37:1 mixture of 36 and 37.
g Calculated yields from a mixture of 36 and 37.
h This product was tentatively assigned from a mixture of 52 and 53.
Minor amounts of impurity remained after extensive purification.
i
j
Minor amount of products tentatively assigned as endocyclic isomers were also isolated.
Scheme 3.
Scheme 2.
parentheses, where relative to CDCl3, (C) denotes CH3 or
CH and (K) denotes CH2 or C.
Scheme 4.
Tetrahydrofuran (THF) was distilled from sodium benzo-
High Resolution Mass Spectra (HRMS) were performed at
University of California Riverside Mass Spectrometry
Center.
phenone ketyl prior to use. Pyridine, hexanes, acetonitrile,
and ethyl acetate were distilled from calcium hydride.
Chemicals prepared according to literature procedures have
been footnoted first time used; all other reagents were
obtained from commercial sources and used as received. All
reactions were performed under an argon atmosphere in
oven-dried glassware unless otherwise stated. Solvents were
removed from reaction mixtures and products on a rotary
evaporator at water aspirator pressure. Elemental Analyses
were performed by Atlantic Microlab, Inc., Norcross, GA.
2.1.1. 2-Bromo-3-nitro-1-(3-butenyloxy)benzene (2). To
a solution of 2-bromo-3-nitrophenol28 (1) (1.09 g,
5.00 mmol) in DMSO (31 mL) was added KOH (3.00 g,
20.0 mmol). After 5 min of stirring, 4-bromo-1-butene
(2.00 mL, 20.0 mmol) was added to the resulting red
solution. After 43 h, water (150 mL) was added, and the

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3641
1
mixture was extracted with diethyl ether (4!150 mL). The
combined organic phases were dried (MgSO4), filtered, and
the solvents were removed. Purification by chromatography
(hexanes/EtOAc, 9:1) gave 2 (1.27 g, 4.67 mmol, 93%) as
a pale yellow oil that solidified upon storage in freezer
(K20 8C). Mp 27–28 8C; 1H NMR (270 MHz) d 7.37 (t, JZ
8.1 Hz, 1H), 7.30 (dd, JZ8.1, 1.6 Hz, 1H), 7.05 (dd, JZ8.1,
1.6 Hz, 1H), 5.94 (tdd, JZ17.0, 10.3, and 6.4 Hz, 1H), 5.21
(dd, JZ17.0, 1.4 Hz, 1H), 5.15 (br d, JZ10.3 Hz, 1H), 4.12
(t, JZ6.5 Hz, 2H), 2.62 (q, JZ6.7 Hz, 2H); 13C NMR
(67.5 MHz) d 156.3 (K), 151.4 (K), 133.4 (C), 128.5 (C),
117.4 (K), 116.1 (C), 115.4 (C), 104.3 (K), 69.0 (K),
33.0 (K); IR (neat) 3080, 2935, 1588, 1535, 1456, 1363,
1276, 1040 cmK1; Anal. Calcd for C10H10BrNO3: C, 44.14;
H, 3.70. Found: C, 44.43; H, 3.73.
(144 mg, 0.51 mmol, 50%) as a faint yellow oil. H NMR
(270 MHz) d 7.75 (dd, JZ7.7, 0.78 Hz, 1H), 7.61 (d, JZ
7.9 Hz, 1H), 7.45 (t, JZ7.9 Hz, 1H), 5.81 (ddd, JZ17.4,
10.3, 7.5 Hz, 1H), 5.27 (d, JZ18.0 Hz, 1H), 5.21 (d, JZ
11.1 Hz, 1H), 4.63 (d, JZ14.0 Hz, 1H), 4.51 (d, JZ
14.0 Hz, 1H), 4.01 (pent, JZ6.3 Hz, 1H), 1.35 (d, JZ
6.5 Hz, 3H); 13C NMR (67.5 MHz) d 150.7 (C), 141.5 (C),
139.4 (K), 131.4 (K), 127.8 (K), 123.4 (K), 116.6 (C),
113.1 (C), 77.4 (K), 69.2 (C), 21.2 (K); IR (neat) 1535,
1361, 1104, 912, 729 cmK1; HRMS (EI) calcd for
C11H12BrNO3 285.0001, found 284.9996.
2.1.5. 2-Bromo-3-nitro-1-[(3-phenyl-2-propen1-1yloxy)-
methyl]benzene (11). To a slurry of hexane washed sodium
hydride (77 mg, 3.22 mmol) in THF (10 mL) was added
3-phenyl-2-propen-1-ol (347 mg, 2.59 mmol) via syringe.
The reaction mixture was stirred until no more gas was
evolved (1 h). The formed alkoxide was cooled to K 78 8C
and added via pipette to a solution of 7 (502 mg, 1.70 mmol)
and tetrabutylammonium iodide (64 mg, 0.17 mmol) in
THF (10 mL). The resulting mixture was stirred (44 h) in
the cold bath while warming to ambient temperature.
Workup as described for 8 and purification by chromato-
graphy (hexanes/EtOAc, 19:1) gave 11 (369 mg,
1.06 mmol, 62%) as a faint yellow oil. 1H NMR
(270 MHz) d 7.75 (d, JZ7.5 Hz, 1H), 7.68, (d, JZ8.1 Hz,
1H), 7.50 (t, JZ7.9 Hz, 1H), 7.42–7.21 (m, 5H), 6.72 (d,
JZ15.8 Hz, 1H), 6.38 (dt, JZ16.0, 6.1 Hz, 1H), 4.66 (s,
2H), 4.29 (dd, JZ5.9, 1.2 Hz, 2H); 13C NMR (67.5 MHz) d
150.5 (C), 140.9 (C), 136.2 (C), 132.6 (K), 131.1 (K),
128.3 (K), 127.7 (K), 127.6 (K), 126.3 (K), 125.0 (K),
123.3 (K), 112.9 (C), 71.3 (C), 70.9 (C); IR (neat) 1537,
1265, 739 cmK1; HRMS (EI) calcd for C16H14BrNO3
347.0157, found 347.0161.
2.1.2. 2-Bromo-3-nitro-1-[(2-propen-1-yloxy)methyl]-
benzene (8). In a conical vial was placed 2-propen-1-ol
(210 mL, 3.09 mmol) and small pieces of sodium (52 mg,
2.24 mmol). After 3 h, the resulting alkoxide was added via
pipette to a solution of 2-bromo-3-bromomethyl-1-nitro-
benzene (7)1 (300 mg, 1.02 mmol), tetrabutylammonium
iodide (39 mg, 0.11 mmol) in THF (10 mL). The conical
vial was rinsed with THF (9 mL total). The resulting
mixture was stirred at ambient temperature (27 h), diluted
with water (15 mL), and extracted with diethyl ether (3!
15 mL). The combined organic phases were dried (MgSO4),
and filtered, and the solvents were removed. Purification by
chromatography (hexanes/EtOAc, 4:1) gave 8 (186 mg,
0.68 mmol, 68%) as a faint yellow oil. 1H NMR (270 MHz)
d 7.75 (d, JZ7.7 Hz, 1H), 7.64, (d, JZ7.9 Hz, 1H), 7.47 (t,
JZ7.9 Hz, 1H), 5.99 (10 line pattern, JZ17.2, 10.3, 5.3 Hz,
1H), 5.37 (dd, JZ17.2, 1.6 Hz, 1H), 5.27 (dd, JZ10.3,
1.4 Hz, 1H), 4.16 (td, JZ5.5, 1.4 Hz, 2H), 4.63 (s, 2H); 13C
NMR (67.5 MHz) d 150.7 (C), 141.1 (C), 133.9 (K),
131.2 (K), 127.8 (K), 123.5 (K), 117.5 (C), 113.1 (C),
71.5 (C), 71.0 (C); IR (neat) 3081, 2858, 1532, 1353,
1102 cmK1; Anal. Calcd for C10H10BrNO3: C, 44.14; H,
3.70. Found: C, 44.14; H, 3.66.
2.1.6. 2-Bromo-3-nitro-1-[(3-buten-1-yloxy)methyl]ben-
zene (12). Reaction of sodium hydride (118 mg, 4.92 mmol)
and 3-butene-1-ol (0.30 mL, 3.49 mmol) in THF (10 mL,
2 h) followed by reaction of the formed alkoxide with 7
(590 mg, 2.00 mmol) in THF (10 mL, 42 h), as described
for 11, gave after workup and chromatography (hexanes
then hexanes/EtOAc, 49:1) 12 (345 mg, 1.35 mmol, 67%)
2.1.3. 2-Bromo-3-nitro-1-[(2-buten-1-yloxy)methyl]ben-
zene (9). Reaction of sodium (95 mg, 4.11 mmol) with
2-butene-1-ol (1.00 mL, 11.72 mmol) for (3.5 h) followed
by reaction of the formed alkoxide with 7 (294 mg,
1.00 mmol) and tetrabutylammonium iodide (40 mg,
0.11 mmol) in THF (total 20 mL) for 66 h, as described
for 8, gave after chromatography (hexanes/EtOAc, 4:1) 9
1
as a faint yellow oil. H NMR (270 MHz) d 7.73 (d, JZ
7.7 Hz, 1H), 7.63 (d, JZ7.9 Hz, 1H), 7.46 (t, JZ7.7 Hz,
1H), 5.88 (ddt, JZ17.0, 10.3, 6.7 Hz, 1H), 5.14 (d, JZ
17.8 Hz, 1H), 5.09 (d, JZ11.3 Hz, 1H), 4.62 (s, 2H), 3.66 (t,
JZ6.7 Hz, 2H), 2.44 (q, JZ6.5 Hz, 2H); 13C NMR
(67.5 MHz) d 150.7 (C), 141.2 (C), 134.8 (K), 131.2
(K), 127.8 (K), 123.5 (K), 116.7(C), 113.1 (C), 71.8
(C), 70.5 (C), 34.1 (C); IR (neat) 1534, 1352, 1119,
796 cmK1; HRMS (EI) calcd for C11H12BrNO3 285.0001,
found 284.9996.
1
(206 mg, 0.72 mmol, 72%) as a faint yellow oil. H NMR
(270 MHz) d 7.74 (d, JZ6.9 Hz, 1H), 7.63, (d, JZ7.9 Hz,
1H), 7.45 (t, JZ7.9 Hz, 1H), 5.81 (dq, JZ15.2, 6.3 Hz, 1H),
6.64 (dtq, JZ15.2, 5.9, 1.2 Hz, 1H), 4.60 (s, 2H), 4.08 (dd,
JZ6.1, 1.0 Hz, 2H), 1.75 (dd, JZ6.3, 1.2 Hz, 3H); 13C
NMR (67.5 MHz) d 150.8 (C), 141.3 (C), 131.4 (K),
130.4 (K), 127.8 (K), 126.8 (K), 123.5 (K), 113.2 (C),
2.1.7. 2-Bromo-3-nitro-1-[(5-hexen-1-yloxy)methyl]ben-
zene (13). t-Butyl lithium (1.7 M, 2.4 mL, 4.08 mmol) was
added to a solution of 5-hexene-1-ol (0.50 mL, 4.16 mmol)
in THF (20 mL) and the reaction mixture was stirred until
no more gas was evolved (2 h). The formed alkoxide was
added to a solution of 7 (598 mg, 2.03 mmol) and
tetrabutylammonium iodide (77 mg, 0.21 mmol) in THF
(10 mL) that had been stirred for 1 h. The resulting solution
was stirred (89.5 h) at ambient temperature. The mixture
was diluted with water (30 mL) and extracted with
71.8 (C), 70.8 (C), 17.8 (K); IR (neat) 1537, 1360 cmK1
.
2.1.4. 2-Bromo-3-nitro-1-[(3-buten-2-yloxy)methyl]ben-
zene (10). Reaction of sodium (95 mg, 4.12 mmol) with
3-butene-2-ol (0.52 mL, 6.00 mmol) in THF (1 mL) for 66 h
followed by addition of the formed alkoxide to a solution of
7 (298 mg, 1.01 mmol) and tetrabutylammonium iodide
(38 mg, 0.10 mmol) in THF (total 20 mL), as described for
8, gave after chromatography (hexanes/EtOAc, 7:3) 10

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3642
dichloromethane (4!20 mL). The combined organic
phases were dried (MgSO4), filtered, and the solvents
were removed on a rotary evaporator at water aspirator
pressure. Purification by chromatography (hexanes/EtOAc,
9:1) gave 13 (291 mg, 0.93 mmol, 46%) as a faint yellow
oil. 1H NMR (600 MHz) d 7.72 (d, JZ7.8 Hz, 1H), 7.63 (d,
JZ7.8 Hz, 1H), 7.46 (t, JZ7.8 Hz, 1H), 5.82 (ddt, JZ17.4,
10.2, 6.6 Hz, 1H), 5.02 (d, JZ16.8 Hz, 1H), 4.97 (d, JZ
10.2, 1H), 4.61 (s, 2H), 3.60 (t, JZ6.6 Hz, 2H), 2.10 (q, JZ
7.2 Hz, 2H), 1.70 (pentet, JZ6.6 Hz, 2H), 1.52 (pentet, JZ
7.2 Hz, 2H); 13C NMR (150 MHz) d 150.9 (C), 141.5 (C),
138.6 (K), 131.3 (K), 127.9 (K), 123.6 (K), 114.7 (C),
113.3 (C), 71.9 (C), 71.3 (C), 33.5 (C), 29.1 (C), 25.5
organic phases were dried (MgSO4) and filtered, and the
solvents were removed. Purification by chromatography
(hexanes/EtOAc, 9:1) gave 16 (853 mg, 3.15 mmol, 93%)
1
as an orange oil. H NMR (270 MHz) d 7.69 (dd, JZ7.5,
1.4 Hz, 1H), 7.58 (dd, JZ7.9, 1.6 Hz, 1H), 7.43 (t, JZ
7.9 Hz, 1H), 5.93 (ddt, JZ17.2, 10.3, 5.9 Hz, 1H), 5.22 (dd
with further fine splitting, JZ17.2, 1.6 Hz, 1H), 5.14 (dd,
JZ10.3, 1.4 Hz, 1H), 3.94 (s, 2H), 3.29 (d with further fine
splitting, JZ5.9 Hz, 2H), 1.62 (br s, 1H); 13C NMR
(67.5 MHz) d 151.0 (C), 142.5 (C), 136.1 (K), 132.4
(K), 127.7 (K), 123.1 (K), 116.2 (C), 114.5 (C), 52.7 (C),
51.2 (C); IR (neat) 3324, 1534, 1360 cmK1; Anal. Calcd for
C10H11BrN2O2: C, 44.30; H, 4.09. Found: C, 44.38; H,
4.07.
(C); IR (neat)2937, 2863, 1639, 1535, 1117, 733, 643 cmK1
;
HRMS (DCI, CH4) calcd for C13H18BrNO3 (MHC)
314.0392, found 314.0389.
2.1.11. 2-Propen-1-yl 2-bromo-3-nitrobenzyl sulfide (17).
Reaction sodium hydride (60 mg, 2.50 mmol) and 2-pro-
penyl-1-thiol (140 mL mL, 1.81 mmol) in THF (10 mL, 1 h)
followed by reaction of the formed thiolate with 7 (587 mg,
1.99 mmol) in THF (10 mL, 25 h), as described for 11, gave
after work up (extracted with dichloromethane (4!15 mL))
and chromatography (hexanes then hexanes/EtOAc, 49:1) a
mixture of product (17) and starting material. The mixture
was dissolved in chloroform (20 mL) and triphenylphos-
phine (61 mg, 0.23 mmol) was added. The resulting
mixture was stirred (21.25 h) at 70 8C. The solvents were
removed at reduced pressure and the crude material was
purified by chromatography (hexanes/EtOAc, 9:1) to give
17 (425 mg, 1.86 mmol, 94%) as a faint yellow solid. Mp
2.1.8. 2-Bromo-3-nitro-1-[(2-ethenyl)phenoxy]methyl]-
benzene (14). Reaction of sodium hydride (26 mg,
1.08 mmol) and 2-ethenylphenol (102 mg, 0.76 mmol) in
THF (10 mL, 1.5 h) followed by reaction of the formed
alkoxide with 7 (128 mg, 0.44 mmol) in THF (10 mL, 44 h),
as described for 11, gave after work up and chromatography
(hexanes then hexanes/EtOAc, 9:1) 14 (95 mg, 0.28 mmol,
65%) as a faint yellow solid. Mp 68–71 8C; 1H NMR
(270 MHz) d 7.77 (d with further fine splitting, JZ7.7 Hz,
1H), 7.67 (dd, JZ7.9, 1.6 Hz, 1H), 7.53 (dd, JZ7.5, 1.6 Hz,
1H), 7.47 (t, JZ7.9 Hz, 1H), 7.23 (t, JZ6.4 Hz, 1H), 7.14
(q, JZ17.8, 11.1 Hz, 1H), 6.99 (t, JZ7.5 Hz, 1H), 6.86 (d,
JZ8.1 Hz, 1H), 5.77 (dd, JZ17.8, 1.4 Hz, 1H), 5.31 (dd,
JZ11.3, 1.4 Hz, 1H), 5.18 (s, 2H); 13C NMR (67.5 MHz) d
154.8 (C), 150.8 (C), 139.7 (C), 131.2 (K), 131.1 (K),
129.0 (K), 128.2 (K), 127.2 (C), 126.6 (K), 124.0 (K),
121.7 (K), 114.9 (C), 113.1 (C), 112.3 (K), 69.5 (C); IR
1
35–38 8C; H NMR (270 MHz) d 7.59 (dd, JZ3.6, 1.6 Hz,
1H), 7.56 (dd, JZ3.8, 1.6 Hz, 1H), 7.41 (t, JZ7.7 Hz, 1H),
5.83 (ddt, JZ16.4, 10.5, 7.1 Hz, 1H), 5.20–5.12 (m, 2H),
3.86 (s, 2H), 3.13 (dt, JZ7.1, 1.0 Hz, 2H); 13C NMR
(67.5 MHz) d 151.3 (C), 140.9 (C), 133.5 (K), 133.2 (K),
127.6 (K), 123.1 (K), 117.7 (C), 115.4 (C), 35.3 (C),
(neat) 1536, 1486, 1361, 1111, 907, 850, 733 cmK1
.
34.5 (C); IR (neat) 1535, 1426, 1360, 1225, 990, 649 cmK1
GCMS (EI) m/z 288.
;
2.1.9. 2-Bromo-3-nitro-1-[2-(2-propen-1-ylphenoxy)-
methyl]benzene (15). Reaction of sodium hydride
(158 mg, 6.56 mmol) with 2-(2-propen-1-yl)phenol in
THF (25 mL, 1H) followed by reaction of the formed
alkoxide with 7 (1.02 g, 3.44 mmol) and tetrabutylammo-
nium iodide (127 mg, 0.35 mmol) in THF (25 mL, 42.5 h),
as described for 11, gave after work up and chromatography
(hexanes/EtOAc, 49:1) 15 (1.09 g, 3.14 mmol, 91%) as a
faint yellow oil. 1H NMR (270 MHz) d 7.78 (d, JZ7.7 Hz,
1H), 7.64 (dd, JZ7.9, 1.2 Hz, 1H), 7.45 (t, JZ7.9 Hz, 1H),
7.20–7.15 (m, 2H), 6.94 (t, JZ7.5 Hz, 1H), 6.85 (d, JZ
8.3 Hz, 1H), 6.03 (ddq, JZ17.6, 9.5, 6.5 Hz, 1H), 5.14 (s,
2H), 5.11–5.04 (m, 2H), 3.49 (d, JZ6.5 Hz, 2H); 13C NMR
(67.5 MHz) d 155.4 (C), 150.7 (C), 139.8 (C), 136.6 (K),
131.0 (K), 130.1 (K), 128.7 (C), 128.1 (K), 127.4 (K),
123.9 (K), 121.5 (K), 115.6 (C), 112.9 (C), 111.5 (K),
69.1 (C), 34.4 (C); IR (neat) 3078, 1534, 1492, 1364,
1236 cmK1; HRMS (EI) calcd for C16H12BrNO3 347.0157,
found 347.0170.
2.1.12. Dimethyl 2-(2-bromo-3-nitrophenyl)-1,1-ethane-
dicarboxylate (18). To slurry of NaH (80% in mineral oil,
0.33 g, 11.0 mmol) in THF (25 mL) was added dimethyl-
malonate (1.14 mL, 10.0 mmol) via syringe. The reaction
mixture was stirred (2H) until no more gas was evolved and
a clear red solution was formed. A solution of 7 (2.95 g,
10.0 mmol) in THF (15 mL) was added to the formed anion.
The solution slowly turned milky and a yellowish
precipitate was formed. The resulting mixture was stirred
at ambient temperature (2 h), diluted with H2O (40 mL) and
extracted with diethyl ether (3!50 mL). The combined
organic phases were dried (MgSO4) and filtered, and the
solvents were removed. Purification by chromatography
(hexanesEtOAc, 4:1) gave 18 (2.55 g, 7.37 mmol, 74%) as
1
pale yellow crystals. Mp 68–70 8C; H NMR (270 MHz) d
7.59 (dd, JZ7.9, 1.8 Hz, 1H), 7.50 (dd, JZ7.7, 1.8 Hz, 1H),
7.37 (t, JZ7.9 Hz, 1H), 3.88 (t, JZ7.7 Hz, 1H), 3.73 (s,
3H), 3.46 (d, JZ7.7 Hz, 2H); 13C NMR (67.5 MHz) d 168.5
(C), 151.5 (C), 140.2 (C), 134.4 (K), 127.9 (K), 123.6
(K), 115.6 (C), 52.8 (K), 50.7 (K), 35.4 (C); IR (neat)
2.1.10. 2-Bromo-3-nitro-N-(2-propenyl)benzenemeth-
anamine (16). To a solution of 7 (1.00 g, 3.39 mmol)
dissolved in THF (15 mL) was added 2-propen-1-ylamine
(509 mL, 6.78 mmol) and triethylamine (950 mL,
6.78 mmol) via syringe. The resulting mixture was stirred
at ambient temperature (36 h), diluted with water (15 mL),
and extracted with diethyl ether (3!25 mL). The combined
1749, 1721, 1528, 1231 cmK1
; Anal. Calcd for
C12H12BrNO6: C, 41.64; H, 3.49. Found: C, 41.75; H, 3.45.
2.1.13. N-2-propen-1-yl-N-(2-bromo-3-nitrophenyl)-
methyl ethanamide (19). To a solution of 16 (0.78 g,

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3643
2.88 mmol) in pyridine (1.18 mL, 14.6 mmol) was added
acetic anhydride (1.66 mL, 17.4 mmol) via syringe.
The yellow mixture was stirred at ambient temperature
(overnight) then heated to 100 8C (oil-bath temperature,
1.5 h). The solvent was removed and the crude product was
purified by chromatography (hexanes/EtOAc, 9:1) affording
19 (0.89 g, 2.85 mmol, 99%) as a pale yellow solid.
Analytical data from a ca 3:1 mixture of rotamers. Mp
solvents were removed under reduced pressure. Purification
by chromatography (hexanes/EtOAc, 6:4) gave 21 (337 mg,
1.30 mmol, 80%) as a faint yellow solid. Mp 139–143 8C;
1H NMR (270 MHz) d 7.79 (dd, JZ7.7, 1.6 Hz, 1H), 7.73
(dd, JZ8.1, 1.8 Hz, 1H), 7.53 (t, JZ7.9 Hz, 1H), 5.93 (ddt,
JZ16.8, 10.3, 7.3 Hz, 1H), 5.54 (dd with further fine
splitting, JZ10.3, 0.8 Hz, 1H), 5.51 (dd with further fine
splitting, JZ16.8, 1.2 Hz, 1H), 4.63 (s, 2H), 3.80 (d, JZ
7.3 Hz, 2H); 13C NMR (67.5 MHz) d 151.6 (C), 135.7 (K),
130.8 (C), 128.4 (K), 125.4 (K), 125.4 (C), 123.8 (K),
116.9 (C), 58.1 (C), 57.2 (C); IR (neat) 1737, 1537, 1362,
1122, 942, 737 cmK1; GCMS (EI) m/z 214 (MCK NO2);
HRMS (DEI) calcd for C10H11BrNO4S 319.9592, found
319.9603.
1
53–55 8C; H NMR (270 MHz) d 7.71–7.34 (m, 3H), 5.82
(br m), 5.3–5.1 (m), 4.73 (s, major), 4.63 (s, minor), 4.05 (d,
JZ5.7 Hz, minor), 3.97 (br s, major), 2.23 (s, major), 2.09
(s, minor); 13C NMR (major) d 171.1 (C), 150.9 (C), 139.4
(C), 131.6 (K), 130.9 (K), 123.2 (K), 117.0 (C), 113.9
(C), 50.8 (C), 48.8 (C), 20.9 (K); 13C NMR (67.5 MHz)
(minor) d 170.6 (C), 151.0 (C), 138.8 (C), 132.0 (K),
129.3 (K), 123.7 (K), 117.9 (C), 113.4 (C), 51.6 (C),
48.0 (C), 21.1 (K); IR (neat) 1650, 1536 cmK1; Anal.
Calcd for C12H13BrN2O3: C, 46.02; H, 4.18. Found: C,
45.98; H, 4.21.
2.1.16. Dimethyl 1-(2-bromo-3-nitrophenyl)-2,2-pent-4-
ene-dicarboxylate (22). Sodium hydride (80% in mineral
oil, 0.21 g, 7.0 mmol) was added, at ambient temperature, to
a solution of 18 (2.20 g, 6.36 mmol) in THF (20 mL). The
reaction mixture was stirred (1 h) until no more gas was
evolved and a clear orange solution was formed. To the
solution was added 3-bromo-propene (606 mL, 7.00 mmol),
via syringe. The solution slowly turned milky and a
yellowish precipitate was formed. The resulting mixture
was stirred at ambient temperature (16 h), diluted with H2O
(40 mL) and extracted with diethyl ether (3!50 mL). The
combined organic phases were dried (MgSO4) and filtered,
and the solvents were removed. Purification by chromato-
graphy (hexanes/EtOAc, 9:1 followed by hexanes/EtOAc,
4:1) gave 22 (2.20 g, 5.71 mmol, 90%) as faint yellow
2.1.14. 2-Propen-1-yl 2-bromo-3-nitrobenzyl sulfoxide
(20). To a solution of 1:1 water/ethanol solution (4 mL) was
added sodium metaperiodate (289 mg, 1.35 mmol) and
cooled to 0 8C. Compound 17 (250 mg, 1.10 mmol)
dissolved in water/ethanol (1:1, 2 mL) was added to the
cooled solution via pipette. The resulting solution was
stirred at 0 8C (25 h). The mixture was then extracted with
dichloromethane (4!15 mL) and the combined organic
phases were dried (MgSO4), filtered, and the solvents were
removed at reduced pressure. Crude H1 NMR showed some
remaining starting material. Sodium metaperiodate
(265 mg, 1.24 mmol) was added to a solution of water/
ethanol (1:1, 6 mL) and the crude product at 0 8C. The
resulting solution was stirred (69.75 h) while warming from
0 8C to ambient temperature. The mixture was then
extracted with dichloromethane (4!15 mL) and the
combined organic phases were dried (MgSO4), filtered,
and the solvents were removed at reduced pressure.
Purification by chromatography (in sequence: hexanes/
EtOAc, 1:1, hexanes/EtOAc, 3:7, and hexanes/EtOAc, 1:9)
gave 20 (117 mg, 0.38 mmol, 35%) as a faint yellow solid.
Mp 79–80 8C; 1H NMR (270 MHz) d 7.71 (dd, JZ7.9,
1.8 Hz, 1H), 7.62 (dd, JZ7.7, 1.6 Hz, 1H), 7.48 (t, JZ
7.7 Hz, 1H), 6.00 (ddt, JZ17.0, 10.1, 7.5 Hz, 1H), 5.53 (d,
JZ9.1 Hz, 1H), 5.49 (dd, JZ17.0, 1.2 Hz, 1H), 4.42 (d, JZ
12.9 Hz, 1H), 4.07 (d, JZ12.9 Hz, 1H), 3.67 (dd, JZ12.9,
7.3 Hz, 1H), 3.52 (dd, JZ13.0, 7.5 Hz, 1H); 13C NMR
(67.5 MHz) d 151.4 (C), 135.3 (K), 134.0 (C), 128.2 (K),
125.2 (K), 124.7 (K), 124.2 (C), 116.0 (C), 57.6 (C),
1
crystals. Mp 57–60 8C; H NMR (270 MHz) d 7.59–7.48
(m, 2H), 7.35 (t, JZ7.9 Hz, 1H), 5.93 (ddt, JZ17.0, 9.9,
7.1 Hz, 1H), 5.2–5.1 (m, 2H), 3.69 (s, 3H), 3.57 (s, 2H), 2.70
(d, JZ7.1 Hz, 2H); 13C NMR (67.5 MHz) d 170.6 (C),
151.8 (C), 139.9 (C), 134.2 (K), 132.2 (K), 127.6 (K),
123.1 (K), 119.6 (C), 116.8 (C), 58.7 (C), 52.6 (K), 38.8
(C), 38.2 (C); IR (neat) 1732, 1536, 1215 cmK1; Anal.
Calcd for C15H16BrNO6: C, 46.65; H, 4.18. Found: C,
46.74; H, 4.19.
2.1.17. 2-Bromo-3-nitro-1-(N-(2-propen-1-yl)benzen-
amide (23). To a solution of 2-bromo-3-nitrobenzoic acid
(24) (1.00 g, 4.07 mmol) in dichloromethane (20 mL) was
added oxallyl chloride (1.00 mL, 11.46 mmol) via syringe.
The resulting mixture was heated at reflux (3 h) where after
the remaining solvent and excess reagent was removed. The
crude product was dissolved in dichloromethane (20 mL),
pyridine (1.0 mL, 12.36 mmol) was added via pipette, and
the resulting mixture was stirred (18 min) at ambient
temperature. The solution was cooled (K20 8C) and
2-propen-1-ylamine (440 mL, 5.86 mmol) was added via
syringe. The resulting mixture was stirred while warming to
ambient temperature (20 h). The solvents were removed on
under reduced pressure to give, after chromatography
(hexanes/EtOAc, 6:4), 23 (769 mg, 2.70 mmol, 66%) as a
56.0 (C); IR (neat) 1533, 1362, 1038, 930, 805, 733 cmK1
;
HRMS (DEI) calcd for C10H10BrNO3S 302.9565, found
302.9557.
2.1.15. 2-Propen-1-yl 2-bromo-3-nitrobenzyl sulfone
(21). To a solution of trifluoroacetic anhydride (0.64 mL,
4.53 mmol) and acetonitrile (10 mL) was added urea/
hydrogen peroxide29 (UHP) crystals (565 mg, 6.00 mmol)
and the mixture was stirred (20 min) at ambient tempera-
ture. To the solution was added 17 (370 mg, 1.62 mmol) and
the resulting solution was stirred at ambient temperature
(21.5 h). The mixture was diluted with water (10 mL) and
extracted with dichloromethane (4!5 mL). The combined
organic phases were dried (MgSO4), filtered, and the
1
faint yellow solid. Mp 120–121 8C; H NMR (270 MHz) d
7.75 (d, JZ7.7 Hz, 1H), 7.62 (d, JZ7.3 Hz, 1H), 7.51 (t,
JZ7.9 Hz, 1H), 6.13 (broad s, 1H), 5.93 (ddt, JZ16.0, 10.9,
5.7 Hz, 1H), 5.31 (d, JZ17.2 Hz, 1H), 5.23 (d, JZ10.1 Hz,
1H), 4.09 (broad s, 2H); 13C NMR (67.5 MHz) d 166.2 (C),
150.6 (C), 141.0 (C), 132.9 (K), 131.2 (K), 128.3 (K),
125.3 (K), 116.8 (C), 111.1 (C), 42.2 (C); IR (neat) 3053,

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3644
2986, 1264, 895, 738 cmK1; HRMS (EI) calcd for
C10H9BrN2O3 283.9797, found 283.9808.
(pentet, JZ6.9 Hz, 1H), 2.41–2.29 (m, 2H); 13C NMR
(150 MHz, APT at 67.5 MHz) d 155.2 (C), 151.8 (C),
143.0 (C), 134.7 (K), 133.9 (K), 128.4 (K), 124.0 (K),
117.3 (C), 116.9 (C), 53.3 (K), 49.3 (C), 32.5 (C); IR
(neat) 1712, 1537, 1383, 908, 650 cmK1; HRMS (EI) calcd
for C12H13BrN2O4 328.0059, found 328.0055.
2.1.18. 2-Bromo-3-nitrophenyl isocyanate (25). To a
solution of diphenylphosporyl azide (2.00 mL,
9.28 mmol), triethylamine (2.4 mL, 17.22 mmol), and
benzene (40 mL) was added 24 (1.99 g, 8.13 mmol). The
resulting solution was stirred at ambient temperature (3 h)
followed by stirring at 100 8C (3 h). The mixture was then
diluted with ammonium chloride (sat. aqueous. 40 mL) and
extracted with dichloromethane (3!30 mL). The combined
organic phases were dried (MgSO4), filtered, and the
solvents were removed under reduced pressure. Purification
by chromatography (in sequence: hexanes/EtOAc, 8:2, 1:1,
and 3:7) gave 25 (558 mg, 2.30 mmol, 28%) as a faint
2.1.21. Dihydro-4-methylene-5-nitro-2H-1-benzopyrane
(3), 4-methyl-5-nitro-2H-1-benzopyrane (4), and
4-methyl-5-nitro-4H-1-benzopyrane (5). A solution of 2
(1.27 g, 4.67 mmol), Pd(OAc)2 (52 mg, 0.23 mmol), and
tri(o-tolyl)phosphine (TTP, 142 mg, 0.47 mmol) in triethyl-
amine (TEA, 23 mL) was heated at 125 8C (1.5 h). The
reaction mixture was filtered (Celite), the filtrate was diluted
with CH2Cl2 (50 mL), and the resulting solution was
washed with HCl (10% aqueous, 3!50 mL). The organic
phase was dried (MgSO4), filtered, and the solvents were
removed by evaporation. Purification of the crude product
by chromatography (hexanes/EtOAc, 19:1) gave, in order of
elution, 5 (30 mg, 0.17 mmol, 3%), a mixture of 4 and 5 (1:1
mixture by 1H NMR, 257 mg, 1.34 mmol, 29%), as yellow
oils and 3 (462 mg, 2.42 mmol, 52%) as pale yellow
1
yellow oil. H NMR (270 MHz) d (CDCl3 and DMSO-d6)
8.12 (d with other fine splitting, JZ8.1 Hz, 1H), 8.02 (dd,
JZ7.9, 1.4 Hz, 0.7H), 7.91 (dd, JZ7.9, 1.3 Hz, 0.3H), 7.81
(d, JZ7.3 Hz, 1H); 13C NMR (67.5 MHz) d (CDCl3 and
DMSO-d6) 149.5 (C), 144.6 (C), 133.03 (K), 132.98 (C),
128.1 (K), 125.1 (K), 114.5 (C); IR (neat) 1717, 1540,
1028, 1008, 952, 644 cmK1; HRMS (EI) calcd for
C7H3BrN2O3 241.9327, found 241.9319.
1
crystals. Data for 3. Mp 30–32 8C; H NMR (270 MHz) d
7.20 (t, JZ8.1 Hz, 1H), 7.00 (dd, JZ7.7, 1.0 Hz, 1H), 6.74
(dd, JZ8.3, 1.2 Hz, 1H), 5.14 (s, 1H), 5.08 (s, 1H), 4.35
(t, JZ5.7 Hz, 2H), 2.69 (t, JZ5.8 Hz, 2H); 13C NMR
(67.5 MHz) d 155.1 (C), 149.1 (C), 132.3 (C), 128.7 (K),
120.1 (K), 115.2 (K), 114.7 (C), 114.1 (C), 68.0 (C),
2.1.19. Methyl N-(2-bromo-3-nitrophenyl) carbamate.
To a solution of 25 (191 mg, 0.78 mmol) in methanol
(5 mL) was added via pipette a solution of sodium
methoxide prepared from sodium (20 mg, 0.86 mmol) and
methanol (5 mL). The resulting mixture was stirred at
ambient temperature (91 h). The mixture was diluted with
HCl (aqueous 5%, 20 mL) and extracted with dichloro-
methane (3!20 mL). The combined organic phases were
dried (MgSO4), filtered, and the solvents were removed
under reduced pressure. Purification by chromatography
(hexanes/EtOAc, 8:2) gave methyl N-(2-bromo-3-nitrophe-
nyl)-carbamate (153 mg, 0.56 mmol, 71%) as a faint yellow
31.7 (C); IR (neat) 1527, 1308, 1248, 1042, 811 cmK1
;
Anal. Calcd for C10H9NO3: C, 62.82; H, 4.74. Found: C,
62.72; H, 4.72.
Data for 4 from a 1:1 mixture of 4 and 5: 1H NMR d 7.26–
7.17 (m, 2H), 7.08 (dd, JZ6.5, 2.8 Hz, 1H), 5.83 (m, 1H),
4.48 (m, 2H), 1.93 (s, 3H); 13C NMR d 128.4 (K), 122.7
(K), 116.7 (K), 64.7 (C), 17.8 (K); 13C NMR d 156.1
(C), 148.3 (C), 128.6 (C), 128.3 (K), 122.6 (K), 119.9
(K), 118.8 (C), 116.7 (K), 64.5 (C), 17.5 (K); IR (neat)
1525, 1468, 1444, 1360, 1301, 1253 cmK1; MRMS (EI) m/z
191.0575 (191.0582 calcd for C10H9NO3).
1
solid. Mp 96–98 8C; H NMR (270 MHz) d (DMSO-d6)
9.43 (bs, 1H), 7.78 (dd, JZ3.6, 1.6 Hz, 1H), 7.75 (dd, JZ
3.8, 1.4 Hz, 1H), 7.58 (t, JZ7.9 Hz, 1H), 3.68 (s, 3H); 13C
NMR (67.5 MHz) d 153.4 (C), 150.7 (C), 137.9 (C),
128.6 (K), 122.8 (K), 119.1 (K), 104.2 (C), 52.9 (K); IR
Data for 5. 1H NMR (270 MHz) d 7.52 (dd, JZ8.1, 1.4 Hz,
1H), 7.19 (t, JZ8.1 Hz, 1H), 7.06 (dd, JZ8.3, 1.4 Hz, 1H),
6.46 (d, JZ6.1 Hz, 1H), 5.00 (t, JZ5.7 Hz, 1H), 4.05 (dq,
JZ6.7, 5.3 Hz, 1H), 1.18 (d, JZ6.7 Hz, 3H); 13C NMR
(67.5 MHz) d 152.3 (C), 149.0 (C), 139.0 (K), 127.2 (K),
121.6 (K), 121.1 (C), 119.8 (K), 107.2 (K), 25.0 (K),
24.8 (K); IR (neat) 1673, 1526, 1352, 1298, 1264, 1191,
1046 cmK1; Anal. Calcd for C10H9NO3: C, 62.82; H, 4.74.
Found: C, 63.07; H, 4.93.
(neat) 3401, 3278, 1746, 1530, 1225, 1077, 957, 796 cmK1
;
GCMS (EI) m/z 275; HRMS (EI) calcd for C8H7BrN2O4
273.9589, found 273.9589.
2.1.20. Methyl N-(2-bromo-3-nitrophenyl)-N-3-buten-1-
yl carbamate (26). To a slurry of hexane washed sodium
hydride (50 mg, 2.06 mmol) in THF (20 mL) was added
methyl N-(2-bromo-3-nitrophenyl) carbamate (299 mg,
1.09 mmol). The reaction mixture was stirred until no
more gas was evolved (1 h). To the resulting solution was
added 4-bromo-1-butene (170 mL, 1.68 mmol) and the
mixture was heated at reflux (80 8C, 138 h). The mixture
was diluted with water (20 mL) and extracted with
dichloromethane (4!15 mL). The combined organic
phases were dried (MgSO4), filtered, and the solvents
were removed on a rotary evaporator at water aspirator
pressure. Purification by chromatography (in sequence:
hexanes/EtOAc, 95:5 then 9:1) gave 26 (93 mg, 0.28 mmol,
2.1.22. 3,4-Dihydro-4-methylene-5-nitro-1H-2-benzo-
pyrane (27), and 4-methyl-5-nitro-1H-2-benzopyrane
(28). Reaction of 8 (630 mg, 2.32 mmol), Pd(OAc)2
(26 mg, 0.12 mmol), and TTP (71 mg, 0.23 mmol) in TEA
(12 mL), as described for 2 (125 8C, 1.5 h), gave after
chromatography (hexanes/EtOAc, 19:1) in order of elution,
28 (90 mg, 0.47 mmol, 20%) and 27 (338 mg, 1.77 mmol,
76%) both as yellow crystals.
1
26%) as a faint yellow oil. H NMR (600 MHz) d 7.71 (d,
JZ7.8 Hz, 1H), 7.48 (t, JZ8.4 Hz, 1H), 7.45 (d, JZ7.2 Hz,
1H), 5.76 (dt, JZ16.2, 6.6 Hz, 1H), 5.12–5.06 (m, 2H), 4.00
(pentet, JZ7.2 Hz, 1H), 3.80 (br s, 1H), 3.65 (s, 3H), 3.40
Analytical data for 27. Mp 67–70 8C; 1H NMR (270 MHz) d
7.44 (d, JZ7.9 Hz, 1H), 7.33 (t, JZ7.7 Hz, 1H), 7.22 (d,
JZ7.7 Hz, 1H), 5.33 (s, 1H), 5.32 (s, 1H), 4.81 (s, 2H), 4.45

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B. C. G. Soderberg et al. / Tetrahedron 61 (2005) 3637–3649
3645
(s, 2H); 13C NMR (67.5 MHz) d 148.6 (C), 138.1 (C),
133.3 (C), 127.8 (K), 127.4 (K), 125.1 (C), 122.1 (K),
115.2 (C), 70.61 (C), 67.8 (C); IR (CCl4) 3084, 2845,
1523, 1361, 1094, 917 cmK1; Anal. Calcd for C10H9NO3:
C, 62.82; H, 4.74. Found: C, 62.69; H, 4.82.
7.38–7.17 (m, 7H), 6.69 (s, 1H), 4.82 (s, 2H), 4.57 (s, 2H);
13C NMR (67.5 MHz) d 148.7 (C), 140.0 (C), 135.3 (C),
131.0 (K), 129.3 (K), 128.4 (C), 128.3 (K), 128.0 (K),
127.7 (C), 127.3 (K), 127.1 (K), 123.1 (K), 67.1 (C),
66.2 (C); IR (neat) 1529, 1359, 908, 732 cmK1; HRMS (EI)
calcd for C16H13NO3 267.0895, found 267.0894.
1
Analytical data for 28. Mp 58–61 8C; H NMR d 7.39 (dd,
JZ7.5, 2.0 Hz, 1H), 7.26–7.17 (m, 2H), 6.63 (q, JZ1.4 Hz,
1H), 4.96 (s, 2H), 1.81 (d, JZ1.4 Hz, 3H); 13C NMR d
147.3 (K), 145.7 (C), 132.7 (C), 126.7 (K), 126.6 (K),
123.1 (K), 124.8 (C), 109.4 (C), 68.1 (C), 12.8 (K); IR
(neat) 1518 cmK1; Anal. Calcd for C10H9NO3: C, 62.82; H,
4.74. Found: C, 62.53; H, 4.84.
2.1.26. 5-Methylene-6-nitro-1,3,4,5-tetrahydrobenzo-
[cd]oxepine (33). Reaction of 12 (870 mg, 3.04 mmol),
Pd(OAc)2 (48 mg, 0.22 mmol), and TTP (260 mg,
0.85 mmol) in TEA (13 mL), as described for 2 (120 8C,
22.5 h), gave after chromatography (hexanes/EtOAc, 9:1)
33 (506 mg, 2.47 mmol, 81%) as a faint yellow oil. 1H NMR
(270 MHz) d 7.60 (dd, JZ7.9, 1.4 Hz, 1H), 7.38 (dd, JZ
7.3, 1.4 Hz, 1H), 7.31 (t, JZ7.7 Hz, 1H), 5.26 (s, 1H), 4.99
(s, 1H), 4.65 (s, 2H), 4.07 (t, JZ5.2 Hz, 2H), 2.66 (t, JZ
5.4 Hz, 2H); 13C NMR (67.5 MHz) d 149.9 (C), 143.9 (C),
139.8 (C), 137.4 (C), 131.1 (K), 127.5 (K), 122.6 (K),
116.3 (C), 75.4 (C), 74.3 (C), 38.3 (C); IR (neat) 1530,
1362, 908, 733 cm K1; GCMS (EI) m/z 159 (MC); HRMS
(EI) calcd for C11H11NO3 205.0739, found 205.0740.
2.1.23. 3-Methyl-4-methylene-5-nitro-isochroman (29)
and 3,4-dimethyl-5-nitro-1H-isochromene (30). Reaction
of 9 (108 mg, 0.38 mmol), Pd(OAc)2 (6 mg, 0.03 mmol),
and TTP (34 mg, 0.11 mmol) in TEA (13 mL), as described
above for 2 (120 8C, 24 h), gave after chromatography
(hexanes/EtOAc, 9:1) in order of elution 30 (19 mg,
0.09 mmol, 25%) and 29 (56 mg, 0.27 mmol, 73%) as
faint yellow oils.
2.1.27. 11-Methylene-10-nitro-6,11-dihydro-dibenzo-
[b,e]oxepine (34) and 10-nitro-6H-5-oxa-dibenzo[a,e]-
cyclooctene (35). Reaction of 14 (202 mg, 0.61 mmol),
Pd(OAc)2 (10 mg, 0.04 mmol), and TTP (53 mg,
0.18 mmol) in TEA (13 mL), as described for 2 (120 8C,
18.5 h), gave after chromatography (hexanes/EtOAc, 9:1) a
1.7:1 ratio (1H NMR) of an inseparable mixture of 35 and 34
(149 mg, 0.59 mmol, 97%) as a faint yellow solid.
Analytical data for the inseparable mixture of 34 and 35.
Mp 142–153 8C; 1H NMR (270 MHz) d 8.01 (d, JZ8.3 Hz),
7.74 (d, JZ7.9 Hz), 7.55 (d, JZ7.5 Hz), 7.45–7.38 (m),
7.21 (d, JZ7.3 Hz), 7.08–6.97 (m), 6.88–6.74 (m), 5.63 (s),
5.46 (s), 5.15 (s); 13C NMR (67.5 MHz) d 155.1 (C), 154.5
(C), 142.3 (C), 137.4 (C), 136.9 (C), 136.0 (K), 134.3
(C), 133.7 (K), 133.0 (K), 131.4 (K), 130.6 (K), 130.3
(K), 129.0 (K), 128.3 (K), 128.1 (K), 125.1 (K), 124.3
(C), 124.0 (K), 123.7 (K), 122.3 (C), 121.8 (K), 121.0
(K), 120.1 (K), 119.0 (K), 118.4 (C), 70.1 (C), 69.6 (C);
IR (neat) 1524, 1481, 1345, 758.
1
Analytical data for 29: H NMR (270 MHz) d 7.50 (d, JZ
7.9 Hz, 1H), 7.33 (t, JZ7.7 Hz, 1H), 7.25 (d, JZ10.7 Hz,
1H), 5.30 (s, 1H), 5.26 (s, 1H), 4.77 (d, JZ14.6 Hz, 1H),
4.66 (d, JZ14.6 Hz, 1H), 4.57 (pent, JZ6.3 Hz, 1H), 1.46
(d, JZ6.5 Hz, 3H); 13C NMR (67.5 MHz) d 148.9 (C),
139.1 (C), 138.6 (C), 127.5 (K), 127.3 (K), 126.7 (C),
122.4 (K), 113.9 (C), 73.9 (K), 66.2 (C), 20.2 (K); IR
(neat) 1529, 1369, 1090, 909, 732 cmK1
.
1
Spectral data for 30: H NMR (270 MHz) d 7.48 (dd, JZ
7.1, 2.6 Hz, 1H), 7.23–7.15 (m, 2H), 4.87 (s, 2H), 2.01 (d,
JZ0.8 Hz, 3H), 1.81 (d, JZ0.8 Hz, 3H); 13C NMR
(67.5 MHz) d 156.3 (C), 145.3 (C), 133.6 (C), 127.4
(C), 126.7 (K), 125.4 (K), 123.7 (K), 104.7 (C), 68.0 (C),
17.0 (K), 13.0 (K); IR (neat) 1625, 1525, 1361, 1183,
1056; GCMS (EI) m/z 159 (MC).
2.1.24. 4-Ethenyl-5-nitroisochroman (31). Reaction of 10
(436 mg, 1.53 mmol), Pd(OAc)2(26 mg, 0.12 mmol), and
TTP (135 mg, 0.44 mmol) in TEA (13 mL), as described for
2 (120 8C, 23 h), gave after chromatography (hexanes/
EtOAc, 8:2) 31 (242 mg, 1.19 mmol, 78%) as a faint yellow
2.1.28. 11-Methylene-10-nitro-11,12-dihydro-6H-5-oxa-
dibenzo[a,e]cyclooctene (36) and 6,13-dihydro-10-nitro-
5-oxa-dibenzo[a,e]cyclononene (37) and 3-[2-(2-propen-
1-yl)phenoxymethyl]-1-nitrobenzene. Reaction of 15
(454 mg, 1.30 mmol), Pd(OAc)2 (21 mg, 0.09 mmol), and
TPP (114 mg, 0.37 mmol) in TEA (13 mL), as described for
2 (120 8C, 20.5 h), gave after chromatography (hexanes/
1
oil. H NMR (270 MHz, CDCl3 and DMSO-d6) d 7.73 (d,
JZ7.7 Hz, 1H), 7.35 (t, JZ7.7 Hz, 1H), 7.26 (d, JZ7.5 Hz,
1H), 5.94 (ddd, JZ17.4, 10.3, 7.5 Hz, 1H), 5.10 (d, JZ
10.3 Hz, 1H), 4.95–4.78 (m, 3H), 4.24–4.21 (m, 1H), 3.96
(d, JZ11.5 Hz, 2H); 13C NMR (67.5 MHz) d (CDCl3 and
DMSO-d6) 148.0 (C), 135.9 (K), 135.6 (C), 127.9 (K),
127.1 (C), 125.6 (K), 121.3 (K), 114.9 (C), 67.2 (C),
1
EtOAc, 9:1) a 1.37:1 ratio (by H NMR) of an inseparable
mixture of 36 and 37 (106 mg, 0.40 mmol, 31%)
and 3-[2-(2-propen-1-yl)phenoxymethyl]-1-nitrobenzene
(30 mg, 0.11 mmol, 8%) as faint yellow solids. Analytical
data for the inseparable mixture of 36 and 37. Mp 116–
65.8 (C), 35.8 (K); IR (neat) 1526, 1352, 1113, 924 cmK1
;
HRMS (EI) calcd for C11H11NO3 205.0739, found
205.0739.
1
119 8C; H NMR (270 MHz) d 7.89–6.95 (m, 14H, major
and minor), 6.41 (d, JZ11.1 Hz, 1H, minor), 6.26 (dt, JZ
10.9, 7.7 Hz, 1H, minor), 5.31–4.91 (m, 6H, major and
minor), 4.01 (s, 2H, major), 3.43 (d, JZ7.3 Hz, 2H, minor);
13C NMR (67.5 MHz) d 156.8 (C), 156.6 (C), 151.1 (C),
149.9 (C), 144.9 (C), 140.1 (C), 138.5 (C), 136.5 (C),
134.1 (C), 133.3 (C), 133.1 (K), 131.4 (K), 130.3 (K),
130.2 (K), 129.2 (K), 128.9 (K), 128.6 (C), 128.2 (K),
127.8 (K), 127.0 (K), 125.7 (K), 124.9 (K), 124.7 (K),
2.1.25. 3,4-Dihydro-4-phenylmethylene-5-nitro-1H-2-
benzopyrane (32). Reaction of 11 (244 mg, 0.70 mmol),
Pd(OAc)2(11 mg, 0.05 mmol), and TTP (60 mg,
0.20 mmol) in TEA (13 mL), as described for 2 (120 8C,
43 h), gave after chromatography (hexanes/EtOAc 9:1)
32 (153 mg, 0.57 mmol, 82%) as a faint yellow solid. Mp
1
79–81 8C; H NMR (270 MHz) d 7.56 (d, JZ7.7 Hz, 1H),

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3646
123.6 (K), 123.3 (K), 121.5 (K), 119.9 (K), 114.1 (C),
75.8 (C, major), 74.8 (C, minor), 41.0 (C, major), 31.1
(C, minor); IR (neat) 1530, 1489, 1359, 1104, 1013.
crystals. The mixture was repurified by chromatography
(hexanes/EtOAc, 9:1) affording 41 (94 mg, 0.31 mmol,
10%), a mixture of 41:40 (71 mg, 23 mmol, 8%, endo–exo,
1:1) and 40 (261 mg, 0.85 mmol, 28%).
Spectral data for 3-[2-(2-propen-1-yl)phenoxymethyl]-1-
nitrobenzene. Mp 43–46 8C; 1H NMR (270 MHz) d 8.33 (s,
1H), 8.19 (d, JZ8.3 Hz, 1H), 7.78 (dd, JZ7.5, 0.6 Hz, 1H),
7.57 (t, JZ7.9 Hz, 1H), 7.23–7.16 (m, 2H), 6.96 (dt, JZ7.3,
1.0 Hz, 1H), 6.88 (d, JZ8.3 Hz, 1H), 6.02 (ddt, JZ17.6,
9.5, 6.5 Hz, 1H), 5.17 (s, 2H), 5.10–5.09 (m, 1H), 5.06–5.03
(m, 1H), 3.47 (d, JZ6.5 Hz, 2H); 13C NMR (67.5 MHz) d
155.8 (C), 148.4 (C), 139.5 (C), 136.7 (K), 132.8 (K),
130.2 (K), 129.5 (K), 128.9 (C), 127.4 (K), 122.7 (K),
121.9 (K), 121.4 (K), 115.6 (C), 111.5 (K), 68.6 (C),
34.4 (C); IR (neat) 3055, 1733, 1532, 1493, 1049; HRMS
(EI) calcd for C16H15NO3 269.1052, found 269.1044.
Analytical data for 40. Mp 97–100 8C; 1H NMR d 7.38 (dd,
JZ7.3, 1.6 Hz, 1H), 7.34 (d with further fine splitting, JZ
5.9 Hz, 1H), 7.28 (t, JZ7.7 Hz, 1H), 5.25 (s, 1H), 5.17 (s,
1H), 3.72 (s, 6H, 3.35 (s, 2H), 3.11 (s, 2H); 13C NMR d
170.5 (C), 148.8 (C), 136.8 (C), 134.7 (C), 131.4 (K),
128.0 (C), 127.8 (K), 121.7 (K), 117.4 (C), 54.8 (C),
52.9 (K, 2C), 37.8 (C), 34.9 (C); IR (neat) 1735, 1528,
1259 cmK1; Anal. Calcd for C15H15NO6: C, 59.02; H, 4.95.
Found: C, 59.08; H, 5.01.
Analytical data for 41. Mp 104–106 8C; 1H NMR d 7.5–7.2
(m, 3H), 6.25 (s, 1H), 3.73 (s, 6H), 3.36 (s, 2H), 2.00 (s, 3H);
13C NMR d 169.7 (C), 148.5 (C), 136.5 (C), 131.8 (C),
130.9 (K), 127.9 (K), 127.3 (C), 127.1 (K), 122.6 (K),
53.9 (C), 53.1 (K, 2C), 34.9 (C), 18.8 (K); IR (neat) 1736,
1528, 1274, 1235 cmK1; HRMS (EI) calcd for C15H15NO6
305.0899, found 305.0887.
2.1.29.
2-Acetyl-4-methylene-5-nitro-1,2,3,4-tetra-
hydroisoquinoline (38), and 2-acetyl-4-methyl-5-nitro-
1,2-dihydroisoquinoline (39). A solution of 19 (2.13 g,
6.80 mmol), Pd(OAc)2 (76 mg, 0.34 mmol), and TTP
(207 mg, 0.68 mmol) in TEA (25 mL) was heated at
100 8C (1.5 h). The reaction mixture was filtered (Celite)
and the solvent was removed. The residue was dissolved in
CH2Cl2 (30 mL), and the resulting solution was washed
with HCl (10% aqueous, 4!25 mL). The organic phase was
dried (MgSO4), filtered, followed by removal of solvent.
Purification of the crude product by chromatography
(hexanes/EtOAc, 3:7) gave, in order of elution, 39
(410 mg, 1.77 mmol, 26%) and 38 (1.093 g, 4.71 mmol,
69%) both as yellow crystals.
2.1.31. 4-Methylene-5-nitro-3,4-dihydro-2H-isoquinolin-
1-one (42). Reaction of 23 (287 mg, 1.01 mmol), Pd(OAc)2
(17 mg, 0.07 mmol), and TTP (87 mg, 0.29 mmol) in TEA
(13 mL), as described for 2 (ambient temp. 5.5 h then
120 8C, 74 h), gave after chromatography (in sequence
hexanes/EtOAc, 6:4, 1:1, and 3:7) 42 (105 mg, 0.52 mmol,
1
51%) as a faint yellow solid. Mp 185–187 8C; H NMR
(270 MHz) d 8.25 (d, JZ7.5 Hz, 1H), 7.70 (d, JZ7.7 Hz,
1H), 7.48 (t, JZ7.3 Hz, 1H), 7.20 (s, 1H), 5.44 (s, 1H), 5.28
(s, 1H), 4.16 (s, 2H); 13C NMR (67.5 MHz) d 163.2 (C),
148.0 (C), 131.6 (C), 131.4 (K), 130.3 (C), 129.8 (C),
128.8 (K), 127.1 (K), 119.5 (C), 47.5 (C); IR (neat) 2962,
1678, 1534, 1261, 907, 650.
Analytical data for 38. Mp 89–92 8C; 1H NMR d 7.6–7.3 (m,
3H), 5.47 (s, minor), 5.45 (major), 5.29 (s, 1H), 4.72 (s,
major), 4.57 (s, minor), 4.40 (s, minor), 4.33 (s, major), 2.20
(s, minor), 2.17 (major); 13C NMR d 169.5, 137.6 (C),
133.6 (C), 133.5, 129.6 (K), 128.7 (K), 128.4 (K), 128.2
(K), 128.1, 122.8 (K), 122.5 (K), 117.6 (C), 117.2 (C),
51.2 (C), 48.0 (C), 47.7 (C), 43.5 (C), 21.8 (K), 21.7
(K); IR (neat) 1647, 1528, 1420 cmK1; Anal. Calcd for
C12H12N2O3: C, 62.06; H, 52.06. Found: C, 61.93; H, 5.21.
2.1.32. 4-Methylene-5-nitro-3,4-dihydro-2H-quinoline-
1-carboxylic acid methyl ester (43) and 4-methyl-5-
nitro-4H-quinoline-1-carboxylic acid methyl ester and
4-methyl-5-nitro-2H-quinoline-1-carboxylic acid methyl
ester. Reaction of 26 (93 mg, 0.28 mmol), Pd(OAc)2 (5 mg,
0.02 mmol), and TTP (26 mg, 0.09 mmol) in TEA (13 mL),
as described for 2 (120 8C, 39.75 h), gave after chroma-
tography (hexanes/EtOAc, 95:5) 4-methyl-5-nitro-4H-
quinoline-1-carboxylic acid methyl ester (4 mg,
0.02 mmol, 6%), 4-methyl-5-nitro-2H-quinoline-1-carb-
oxylic acid methyl ester (4 mg, 0.02 mmol, 6%), and 43
(33 mg, 0.13 mmol, 47%) as a faint yellow oil.
1
Analytical data for 39. Mp 103–105 8C; H NMR d 7.45–
7.24 (m, 3H), 6.69 (s, 1H), 4.86 (s, 2H), 2.21 (s, 3H), 1.96 (s,
3H); 13C NMR d 168.1 (C), 147.1 (C), 135.1 (C), 128.6
(K). 128.5 (K), 127.3 (K), 125.5 (C), 122.9 (K), 114.8
(C), 44.0 (C0, 21.1 (K), 15.6 (K); IR (neat) 1672, 1624,
1524, 1397, 1347 cmK1; HRMS (EI) calcd for C12H12N2O3
232.0848, found 232.0843.
1
2.1.30. Dimethyl 3,4-dihydro-4-methylene-5-nitro-
2,2,(1H)-naphthalenedicarboxylate (40), and dimethyl
4-methyl-5-nitro-2,2,(1H)-naphthalenedicarboxylate
(41). A solution of 22 (1.16 g, 3.00 mmol), Pd(OAc)2
(34 mg, 0.15 mmol), and TTP (91 mg, 0.30 mmol) in TEA
(10 mL) was heated at 100 8C (2 h). The reaction mixture
was filtered (Celite), the filtrate was diluted with CH2Cl2
(50 mL), and the resulting solution was washed with HCl
(10% aqueous, 3!50 mL). The organic phase was dried
(MgSO4), and filtered, followed by solvent evaporation.
Purification of the crude product by chromatography
(hexanes/EtOAc, 9:1) gave, in order of elution, a mixture
of 41:40 and 40 (367 mg, 1.20 mmol, 40%) both as yellow
Spectral data for 43: H NMR (270 MHz) d 7.83 (dd, JZ
6.2, 3.6 Hz, 1H), 7.33–7.31 (m, 2H), 5.23 (t, JZ1.4 Hz,
1H), 5.19 (s, 1H), 3.85 (t, JZ6.9 Hz, 2H), 3.81 (s, 3H), 2.85
(t, JZ7.1 Hz, 2H); 13C NMR (150 MHz, APT at 67.5 MHz)
d 154.8 (C), 148.7(C), 140.1 (C), 134.3 (C), 127.5 (K),
127.0 (K), 124.5 (C), 119.1 (K), 115.6 (C), 53.3 (K),
44.8 (C), 32.9 (C); IR (neat) 1708, 1528, 1439, 1376,
1218, 909; GCMS (EI) m/z 248 (MC).
Analytical data for 4-methyl-5-nitro-4H-quinoline-1-carb-
oxylic acid methyl ester. 1H NMR (270 MHz) d 8.21 (d, JZ
8.5 Hz, 1H), 7.66 (dd, JZ8.1, 1.2 Hz, 1H), 7.35 (t, JZ
8.3 Hz, 1H), 6.96 (d, JZ7.3 Hz, 1H), 5.48 (t, JZ6.9 Hz,

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3647
1H), 3.92 (pent, JZ6.9 Hz, 1H), 3.91 (s, 3H), 1.30
(d, JZ6.9 Hz, 3H); 13C NMR (150 MHz) d 152.9, 148.6,
138.2, 128.6, 126.4, 126.4, 125.8, 120.8, 116.0, 53.7,
28.6, 22.0.
0.55 mmol, 80%) as a faint yellow solid. Mp 127–130 8C;
1H NMR (270 MHz) d 8.08 (broad s, 1H), 7.16–7.09 (m,
2H), 6.81–6.70 (m, 1H), 6.76 (t, JZ1.8 Hz, 1H), 5.07 (dq,
JZ6.4, 1.2 Hz, 1H) overlapping peak centered at 5.01 (m,
2H), 1.63 (d, JZ6.5 Hz, 3H); 13C NMR (67.5 MHz) d 133.6
(C), 129.6 (C), 124.2 (C), 123.0 (K), 117.0 (C), 115.4
(K), 112.6 (K), 109.0 (K), 70.5 (K), 66.6 (C), 20.5 (K);
IR (neat) 3293, 1448, 1340, 1016, 908, 731; GCMS (EI) m/z
173; HRMS (EI) calcd for C11H11NO 173.0842, found
173.0842.
Analytical data for 4-methyl-5-nitro-2H-quinoline-1-carb-
oxylic acid methyl ester. 1H NMR (270 MHz) d 7.83 (d, JZ
7.7 Hz, 1H), 7.42 (dd, JZ7.9, 1.2 Hz, 1H), 7.32 (t, JZ
8.1 Hz, 1H), 6.04 (dt, JZ5.3, 1.6 Hz, 1H), 4.25 (dd, JZ5.2,
1.4 Hz, 2H), 3.82 (s, 3H), 1.94 (d, JZ1.4 Hz, 3H); 13C NMR
(150 MHz) d 154.2, 148.4, 139.4, 130.1, 127.7, 127.1,
126.8, 124.6, 120.1, 53.7, 42.6, 18.0.
2.1.36. 1,5-Dihydro-2-phenyl-3H-pyrano[3,4,5-cd]indole
(48). Reaction of 32 (105 mg, 0.39 mmol), Pd(dba)2 (14 mg,
0.03 mmol), dppp (12 mg, 0.03 mmol), and 1,10-phenan-
throline monohydrate (10 mg, 0.05 mmol) in DMF (5 mL),
as described for 6 (6 atm CO, 120 8C, 22 h), gave after
purification by chromatography (hexanes/EtOAc, 8:2) 48
(63 mg, 0.27 mmol, 68%) as a faint yellow solid. Mp 189–
192 8C; 1H NMR (600 MHz) d 8.13 (broad s, 1H), 7.47–7.41
(m, 4H), 7.32 (dt, JZ6.6, 2.4 Hz, 1H), 7.22 (d, JZ7.8 Hz,
1H), 7.16 (dt, JZ7.8, 1.2 Hz, 1H), 6.83 (d, JZ6.6 Hz, 1H),
5.21 (s, 2H), 4.98 (s, 2H); 13C NMR (150 MHz) d 134.0,
132.5, 129.7, 129.6, 129.2, 127.3, 125.8, 125.6, 123.3,
113.0, 109.1, 109.0, 66.6, 65.0; IR (neat) 1601, 1448, 864,
737, 692 cmK1; HRMS (EI) calcd for C16H13NO 235.0997,
found 235.0998.
2.1.33. 3,5-Dihydro-2H-pyrano[4,3,2-cd]indole (6). To an
oven-dried threaded ACE glass pressure tube was added 3
(81 mg, 0.42 mmol), Pd(OAc)2 (10 mg, 0.042 mmol), dppp
(42 mg, 0.10 mmol), and DMF (3 mL). The tube was fitted
with a pressure head where after the solution was saturated
with CO (four cycles to 4 atm of CO), and the reaction
mixture was heated to 120 8C (oil bath temperature) under
CO (4 atm, 70 h). The black reaction mixture was diluted
with HCl (10% aqueous, 10 mL), and extracted with Et2O
(3!10 mL). The combined organic phases were washed
with HCl (10% aqueous, 10 mL), and dried (MgSO4), and
the solvents were removed. The crude product was purified
by chromatography using hexanes/EtOAc (19:1) as eluent to
give 6 (42 mg, 0.265 mmol, 63%) as faint yellow crystals.
2.1.37. 2,6,8,9-Tetrahydro-7-oxa-2-aza-benzo[cd]azulene
(49). Reaction of 33 (412 mg, 2.01 mmol), Pd(dba)2 (74 mg,
0.13 mmol), dppp (52 mg, 0.13 mmol), 1,10-phenanthroline
monohydrate (45 mg, 0.25 mmol) in DMF (5 mL), as
described for 6 (6 atm CO, 120 8C, 24 h), gave after
chromatography (hexanes/EtOAc, 9:1) 49 (287 mg,
1.66 mmol, 83%) as a faint yellow solid. Mp 115–116 8C;
1H NMR (270 MHz) d 8.35 (broad s, 1H), 7.09–6.98 (m,
2H), 6.79–6.67 (m, 2H), 5.07 (s, 2H), 4.02 (t, JZ4.9 Hz,
2H), 3.03 (t, JZ5.5 Hz, 2H); 13C NMR (67.5 MHz) d 136.5
(C), 134.0 (C), 124.8 (C), 121.3 (K), 121.2 (K), 114.3
(K), 113.7 (C), 109.3 (K), 76.4 (C), 73.3 (C), 29.7 (C);
IR (neat) 3413, 2934, 1432, 908, 731 cmK1; HRMS (EI)
calcd for C11H11NO 173.0841, found 173.0836.
A similar reaction of 3 (345 mg, 1.80 mmol), Pd(OAc)2
(24 mg, 0.11 mmol), and triphenylphosphine (112 mg,
0.43 mmol) in MeCN (4 mL) under CO (4 atm, 100 8C,
70 h) gave after work up and chromatography, in order of
elution, 3 (110 mg, 0.57 mmol, 32%), and 6 (107 mg,
0.67 mmol, 37%) as faint yellow crystals. Mp 54–57 8C; 1H
NMR (270 MHz) d 8.04 (br s, 1H), 7.19 (t, JZ7.9 Hz, 1H),
6.96 (d, JZ8.1 Hz, 1H), 6.78 (br s, 1H), 6.64 (d, JZ7.5 Hz,
1H), 4.48 (t, JZ5.5 Hz, 2H), 3.13 (t, JZ4.9 Hz, 2H); 13C
NMR d 150.9 (C), 135.1 (C), 123.6 (K), 117.9 (C), 116.0
(K), 107.6 (C), 103.7 (K), 101.9 (K), 68.2 (C), 23.2 (C);
IR (neat) 3406, 1631, 1610, 1504, 1341, 1267, 1234 cmK1
;
Anal. Calcd for C10H9NO: C, 75.45; H, 5.70. Found: C,
75.24; H, 5.78.
2.1.38. 2,6-Dihydro-7-oxa-2-aza-dibenzo[cd,h]azulene
(50) and 6H-5-oxa-dibenzo[a,e]cyclooctene-10-ylamine
(51). Reaction of a 1.7:1 mixture (estimated by 1H NMR) of
34 and 35 (266 mg, 1.05 mmol), Pd(dba)-2 (37 mg,
0.06 mmol), dppp (27 mg, 0.07 mmol), and 1,10-phenan-
throline monohydrate (24 mg, 0.13 mmol) in DMF (5 mL),
as described for 6 (6 atm CO, 120 8C, 20.5 h), gave after
chromatography (hexanes/EtOAc acetate, 9:1 then hexanes/
EtOAc, 1:1) two fractions containing 50 and 51, respect-
ively. However, both fractions contained residual DMF. The
fraction containing 51 was each dissolved in diethyl ether
(10 mL) and washed with water (4!10 mL). The organic
phase was dried (MgSO4), filtered, and the solvent was
removed under reduced pressure to give 51 (98 mg,
0.42 mmol, 64%) as a faint yellow solid. The fraction
containing 50 was dissolved in diethyl ether (10 mL) and
washed with water (4!10 mL). The organic phase was
dried (MgSO4), filtered, and the solvent was removed
under reduced pressure. The residue was purified by
chromatography (hexanes/EtOAc, 7:3) affording 50
(38 mg, 0.17 mmol, 44%) as a faint yellow solid.
2.1.34. 1,5-Dihydro-3H-pyrano[3,4,5-cd]indole (46).
Reaction of 27 (109 mg, 0.57 mmol), Pd(OAc)2 (13 mg,
0.058 mmol), dppp (136 mg, 0.14 mmol) in DMF (5 mL), as
described for 6 (4 atm CO, 120 8C, 120 h), gave after
chromatography (hexanes/EtOAc, 19:1 followed by 9:1) 46
(71 mg, 0.45 mmol, 78%) as faint pink crystals. Mp 168–
170 8C; 1H NMR (270 MHz) d 7.96 (br s, 1H), 7.19 (d, JZ
8.1 Hz, 1H), 7.15 (t, JZ6.5 Hz, 1H), 6.87 (s, 1H), 6.82 (d,
JZ6.7 Hz, 1H), 5.04 (s, 2H), 4.95 (s, 2H); 13C NMR
(67.5 MHz) d 133.5 (C), 129.4 (C), 124.1 (K), 115.6 (K),
112.6 (K), 111.3 (C), 109.1 (K), 66.7 (C), 64.5 (C); IR
(neat) 3308, 1445, 1086 cmK1; HRMS (EI) calcd for
C10H9NO 159.0684, found 159.0678.
2.1.35. 1,5-Dihydro-2-methyl-3H-pyrano[3,4,5-cd]indole
(47). Reaction of 29 (141 mg, 0.69 mmol), Pd(dba)2 (25 mg,
0.04 mmol), dppp (18 mg, 0.04 mmol), and 1,10-phenan-
throline monohydrate (16 mg, 0.09 mmol) in DMF (5 mL),
as described for 6 (6 atm CO, 120 8C, 29 h), gave after
chromatography (hexanes/EtOAc, 9:1) 47 (95 mg,

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B. C. G. Soderberg et al. / Tetrahedron 61 (2005) 3637–3649
3648
Analytical data for 50. Mp 197–198 8C; 1H NMR
(600 MHz) d 8.35 (broad s, 1H), 7.70 (dd, JZ6.6, 1.8 Hz,
1H), 7.54 (d, JZ2.4 Hz, 1H), 7.34 (d, JZ7.8 Hz, 1H), 7.21–
7.12 (m, 4H), 6.95 (d, JZ6.6 Hz, 1H), 5.28 (s, 2H); 13C
NMR (150 MHz, APT at 67.5 MHz) d 158.3 (C), 136.0
(C), 133.5 (C), 128.0 (C), 126.5 (K), 126.1 (K), 124.6
(K), 124.2 (K), 122.8 (K), 122.3 (K), 120.2 (K), 116.6
(K), 115.3 (C), 110.7 (C), 75.2 (C); IR (neat) 908, 732,
650; HRMS (EI) calcd for C15H11NO 221.0841, found
221.0837.
112.9 (K), 112.2 (K), 109.1 (K), 108.6 (K), 108.1 (C),
107.7 (C), 46.8 (C), 43.6 (C), 41.9 (C), 38.8 (C), 21.6
(K), 21.5 (K); IR (neat) 3294, 1626, 1606, 1444, 1441,
1248, 767 cmK1. The compound decompose relatively fast
at ambient temperature forming highly colored products.
2.1.41. Dimethyl 1,3-dihydro-4,4(5H)-benz[cd]indole-
5,5-dicarboxylate (55). Reaction of 40 (225 mg,
0.74 mmol), Pd(OAc)2 (17 mg, 0.074 mmol), and dppp
(75 mg, 0.18 mmol) in MeCN (5 mL), as described for 6
(4 atm CO, 120 8C, 48 h), gave after chromatography
(hexanes/EtOAc, 9:1) gave 55 (131 mg, 0.48 mmol, 65%)
Analytical data for 51. Mp 99–102 8C; 1H NMR (270 MHz)
d 7.12–6.98 (m, 4H), 6.90–6.79 (m, 3H), 6.64–6.49 (m, 1H),
6.27 (d, JZ12.7 Hz, 1H), 5.25 (s, 2H), 3.68 (broad s, 2H);
13C NMR (67.5 MHz) d 156.1 (C), 144.6 (C), 135.2 (C),
134.2 (K), 131.3 (K) 128.5 (K), 128.4 (K), 124.3 (C),
123.1 (C), 122.9 (K), 120.60 (K), 120.58 (K), 120.3 (K),
115.6 (K), 71.4 (C); IR (neat) 3373, 2955, 1618, 1486,
1437, 1255, 1114, 909; GCMS (EI) m/z 223; HRMS (EI)
calcd for C15H13NO 223.0997, found 223.1001.
1
as a white solid. Mp 154–155 8C; H NMR (270 MHz) d
7.94 (br s, 1H), 7.08–6.92 (m, 2H), 6.78 (d, JZ6.4 Hz, 1H),
6.68 (s, 1H), 3.53 (s, 6H), 3.45 (s, 2H), 3.38; 13C NMR
(67.5 MHz) d 171.6 (C), 133.4 (C), 127.5 (C), 125.4 (C),
122.8 (K), 118.3 (K), 115.9 (K), 109.4 (C), 108.7 (K),
56.2 (C), 52.7 (K), 33.8 (C), 28.7 (C); IR (neat) 3391,
1721 cmK1; Anal. Calcd for C15H15O4: C, 65.92; H, 5.53.
Found: C, 65.81; H, 5.59.
2.1.39. Compound 52 and 10-amino-6H-dibenz[b,f]-
oxocine (53). Reaction of a 1.37:1 mixture (estimated by
1H NMR) of 36 and 37 (106 mg, 0.40 mmol), Pd(dba)2
(13 mg, 0.02 mmol), dppp (10 mg, 0.02 mmol), and 1,10-
phenanthroline monohydrate (10 mg, 0.05 mmol) in DMF
(5 mL), as described for 6 (6 atm CO, 120 8C, 98 h), gave
after chromatography (in sequence: hexanes/EtOAc, 9:1,
1:1, 0:1) a mixture of 52 and 53. The mixture was purified
by chromatography (hexanes/EtOAc, 98:2 followed by
hexanes/EtOAc, 95:5) to give 52 (20 mg, 0.09 mmol,
37%) as a faint yellow solid followed by a 1:1.7 mixture
of 52 to 53 (10 mg, ca. 0.02 mmol 52, 0.03 mmol 53, 7% 52,
15% 53) as a faint yellow solid.
2.1.42. 3,4-Dihydro-1H-pyrrolo[4,3,2-de]isoquinoline-5-
one (56). Reaction of 42 (145 mg, 0.71 mmol), Pd(dba)2
(26 mg, 0.05 mmol), dppp (20 mg, 0.05 mmol), and 1,10-
phenanthroline monohydrate (16 mg, 0.09 mmol) in DMF
(5 mL), as described for 6 (6 atm, 120 8C, 26.5 h), gave
after purification by chromatography (hexanes/EtOAc, 2:8
followed by EtOAc) 56 (74 mg, 0.43 mmol, 61%) as a faint
1
yellow solid. Mp 207–210 8C; H NMR (270 MHz, CDCl3
and DMSO-d6) d 10.81 (broad s, 1H), 7.47 (d, JZ2.8 Hz,
1H), 7.44 (d, JZ4.0 Hz, 1H), 7.33 (s, 1H), 7.17 (t, JZ
7.3 Hz, 1H), 7.05 (s, 1H), 4.90 (s, 2H); 13C NMR d (CDCl3
and DMSO-d6) 163.9 (C), 132.1 (C), 127.5 (C), 120.9
(K), 119.2 (C), 117.6 (K), 114.2 (K), 113.4 (K), 103.9
(C), 41.0 (C); IR (neat) 1657, 1054, 911, 644; HRMS (EI)
calcd for C10H7N2O 171.0558, found 171.0555.
Analytical data for 52. Mp 173–175 8C; 1H NMR
(270 MHz) d 7.88 (broad s, 1H), 7.20–6.94 (m, 7H), 6.80
(dd, JZ7.3, 1.2 Hz, 1H), 5.71 (s, 2H), 4.11 (s, 2H); 13C
NMR (67.5 MHz) d 158.3 (C), 138.4 (C), 135.0 (C),
132.7 (C), 129.2 (K), 127.8 (K), 123.8 (K), 123.5 (C),
122.0 (K), 121.6 (K), 120.6 (K), 117.2 (C), 116.1 (K),
109.9 (K), 76.7 (C), 31.0 (C); IR (neat) 911, 728,
650 cmK1; HRMS (EI) calcd for C16H12NO 234.0919,
found 234.0914.
2.1.43. 3,4-Dihydro-1H-pyrrolo[4,3,2-de]quinoline-5-
carboxylic acid methyl ester (57). Reaction of 43
(36 mg, 0.15 mmol), Pd(dba)2 (5 mg, 0.01 mmol), dppp
(4 mg, 0.01 mmol), and 1,10-phenanthroline monohydrate
(3 mg, 0.02 mmol) in DMF (5 mL), as described for 6
(6 atm CO,120 8C, 43.5 h), gave after chromatography
(hexanes/EtOAc, 9:1) 57 (10 mg, 0.05 mmol, 33%) as a
faint yellow oil. 1H NMR (270 MHz) d 7.98 (broad s, 1H),
7.36 (broad s, 1H), 7.15 (t, JZ7.9 Hz, 1H), 7.5 (d, JZ
8.1 Hz, 1H), 6.84 (s, 1H), 4.11 (t, JZ5.5 Hz, 2H), 3.86 (s,
3H), 3.01 (dt, JZ6.3, 1.0 Hz, 2H); 13C NMR (67.5 MHz) d
155.4 (C), 134.5 (C), 132.7 (C), 123.1 (K), 120.6 (C),
116.9 (K), 110.3 (C), 109.9 (K), 106.0 (K), 52.9 (K),
45.6 (C), 22.9 (C); IR (neat) 1696, 1439, 1385, 1215, 907,
732, 650; GCMS (EI) m/z 216; HRMS (EI) calcd for
C12H12N2O2 216.0899, found 216.0896.
1
Analytical data for 53 from the mixture of 52 and 53: H
NMR (270 MHz) d 6.37 (d, JZ11.3 Hz, 1H), 6.07 (dt, JZ
11.1, 8.1 Hz, 1H), 5.21 (broad s, 2 Hz, 1H), 3.76 (broad s,
2H), 3.21 (d, JZ7.7 Hz, 2H).
2.1.40. 4-Acetyl-1,3,4,5,-tetrahydropyrrolo[4,3,2-de]iso-
quinoline (54).30 Reaction of 38 (350 mg, 1.51 mmol),
Pd(OAc)2 (34 mg, 0.151 mmol), dppp (124 mg,
0.302 mmol) in MeCN (5 mL), as described for 6 (4 atm
CO, 120 8C, 2 h), gave after chromatography (EtOAc) 54
(124 mg, 0.62 mmol, 41%) as a light yellow crystals
followed by 38 (21 mg, 0.092 mmol, 9%) Analytical data
Acknowledgements
1
for 54. Mp 207–209 8C, H NMR (270 MHz) d 8.02 (br s,
1H), 7.22–7.13 (overlapping m, 2H), 6.94 (s, 1H), 6.88 (d,
JZ6.9 Hz, 1H), 5.02 (d, JZ1.8 Hz, 2H), 4.83 (s, 1H), 4.82
(s, 1H), 2.20 (s, 3H); 13C NMR (67.5 MHz) d 169.2 (C),
133.0 (C), 132.9 (C), 126.6 (C), 125.8 (C), 124.7 (C),
124.6 (C), 121.9 (K), 121.6 (K), 116.8 (K), 116.3 (K),
This work was supported by a research grant from the
National Institute of General Medical Sciences, National
Institutes of Health (R01 GM57416). NSF-EPSCoR (Grant
#1002165R) is gratefully acknowledged for the funding of
a 600 MHz Varian Inova NMR and the NMR facility in

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B. C. G. Soderberg et al. / Tetrahedron 61 (2005) 3637–3649
3649
¨
12. Scott, T. L.; Soderberg, B. C. G. Tetrahedron 2003, 59,
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the C. Eugene Bennett Department of Chemistry at West
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