Synthesis of substituted tetrahydroindoloisoquinoline derivatives via intramolecular Pd-catalyzed alkene carboamination reactions

Article abstract of DOI:10.1021/jo500470m

Intramolecular Pd-catalyzed alkene carboamination reactions of substituted 2-allyl-N-(2-bromobenzyl)anilines are described. The substrates for these reactions are generated in two steps from readily available 2-allylanilines and 2-bromobenzaldehyde derivatives. The transformations afford substituted tetrahydroindoloisoquinolines, an uncommon class of fused bicyclic heterocycles, in good yield. The mechanism of these transformations is described, and a model that accounts for the observed product stereochemistry is proposed.

Full text of DOI:10.1021/jo500470m

Note
pubs.acs.org/joc
Synthesis of Substituted Tetrahydroindoloisoquinoline Derivatives
via Intramolecular Pd-Catalyzed Alkene Carboamination Reactions
Jeremiah Alicea and John P. Wolfe*
Department of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, Michigan 48109-1055, United States
S
* Supporting Information
ABSTRACT: Intramolecular Pd-catalyzed alkene carboamina-
tion reactions of substituted 2-allyl-N-(2-bromobenzyl)anilines
are described. The substrates for these reactions are generated
in two steps from readily available 2-allylanilines and 2-
bromobenzaldehyde derivatives. The transformations afford
substituted tetrahydroindoloisoquinolines, an uncommon class
of fused bicyclic heterocycles, in good yield. The mechanism of these transformations is described, and a model that accounts for
the observed product stereochemistry is proposed.
any interesting biologically active molecules and natural
products contain fused polycyclic heterocycles, and the
access nonoxygenated derivatives such as 4 would require an
additional reduction step.4
M
development of methods for the generation of these
compounds has been of longstanding interest.1 In addition,
new strategies that provide access to scaffolds that are
uncommon or not easily obtained through existing routes
have the potential to lead to interesting classes of compounds
whose biological properties have yet to be explored.2 For
example, tetrahydroindoloisoquinoline derivatives 4 (Scheme
1) resemble scaffolds found in alkaloid natural products, but are
We have previously reported a method for the construction
of benzo-fused tropane derivatives 2 via intramolecular Pd-
catalyzed alkene carboamination reactions of 2-(2-bromo-
phenyl)pent-4-enylamine derivatives 1 (Scheme 1).5,6 These
transformations generate both a C−N bond and a C−C bond
during the ring-forming event and afford the desired products
in good chemical yield with excellent stereocontrol. We
reasoned that analogous transformations of related substrates
in which the 2-bromoaryl unit was tethered to the N atom
rather than attached to the α-carbon could provide access to
fused bicyclic heterocycles. For example intramolecular alkene
carboamination reactions of substrates such as 3 should directly
afford tetrahydroindoloisoquinoline derivatives 4,7,8 and this
route could allow for straightforward installation of substituents
at C6, C11, C11a, or C12 through modification of the
substrate.
Scheme 1. Synthesis of Polycyclic Heterocycles via Pd-
Catalyzed Alkene Carboamination
To explore this hypothesis, the substrates 3 required for
these experiments were prepared via two-step reductive
amination between 2-bromobenzaldehyde derivatives 6 and 2-
allylanilines 5 (Scheme 2). Most of the aldehydes were
obtained from commercial sources, and the 2-allylanilines
were typically generated via aza-Claisen rearrangement of the
corresponding N-allylaniline.9 Condensation of the aniline with
the aldehyde followed by reduction with LiAlH4 provided 3 in
moderate to good yield. This concise and modular approach
allowed for the facile generation of substrates bearing
substituents on either aryl ring, on the alkene, at the benzylic
position, or at the allylic position.
a class of heterocycles that have rarely been prepared. Only one
ring-forming method for the synthesis of tetrahydroindoloiso-
quinolines 4 has been described, which involved treatment of
the HI salt of an N-methyl-3-benzylisoquinoline derivative with
chloranil followed by subsequent N-demethylation.3 A few
transformations have been used to generate related compounds
bearing carbonyl groups at C6, C11, or C12 including
intramolecular aldol condensations, intramolecular Friedel−
Crafts reactions, or Cu-mediated intramolecular C−H
functionalization/alkene carboamination reactions of N-benzo-
yl-2-allylaniline derivatives. However, use of these strategies to
In initial studies we focused on the transformation of 3a to
4a (Table 1, entry 1), and the Pd2(dba)3/PCy3 catalyst system
that provided optimal results in tropane-forming reactions
(Scheme 1) afforded the desired product 4a in 85% yield. A
Received: February 26, 2014
Published: April 11, 2014
© 2014 American Chemical Society
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Note
Scheme 2. Synthesis of Substrates
Table 1. Intramolecular Pd-Catalyzed Alkene
Carboamination Reactions
a
brief examination of other palladium sources and phosphine
ligands did not lead to further improvement in the yield of this
transformation, so we proceeded to explore the scope of these
reactions. As shown in Table 1, the presence of fluorine atoms,
alkoxy groups, or alkyl groups on either aromatic ring was
tolerated. In addition, the sterically hindered 1-bromonaph-
thalene derived substrate 3g was converted to 4g in good yield
(80%, entry 7). The conversion of an alkenyl bromide substrate
(3d) to a polycyclic product (4d) was also successful, although
the yield of this transformation was modest (55%, entry 4).
Substrate 3h, which contains a methyl group on the internal
alkene carbon atom was converted to 4h in good yield (entry
8).10 The reaction of substrate 3i bearing an allylic methyl
group provided 4i in good yield and high diastereoselectivity
(entry 9). In contrast, the transformation of substrate 3j to 4j
provided a 2:1 mixture of diastereomers (entry 10), and
competing intramolecular Heck arylation of this substrate was a
significant problem.11
The mechanism of the tetrahydroindoloisoquinoline forming
reactions is likely similar to that of other Pd-catalyzed alkene
carboamination reactions of aryl halides (Scheme 3).6 Oxidative
addition of the aryl bromide to the Pd(0) complex generated in
situ from Pd2(dba)3 and PCy3 would provide 7, which can react
with NaOtBu to afford palladacyclic amido complex 8. Syn-
migratory insertion of the alkene into the Pd−N bond of 8
would provide 9,12 which upon reductive elimination would
yield the observed product.
The competing Heck arylation13 of substrate 3j, which
affords 12, appears to be due to the presence of the methyl
group at the benzylic position of the substrate. This substituent
may slow the rate of Pd−N bond formation in the conversion
of 7 to 8, or the conversion of 7 to 8 may be reversible and the
rate of alkene carbopalladation from Pd-alkene complex 10
(Scheme 4) could be close to the rate of conversion of 8 to 9
for this substrate.
The stereoselectivity or lack thereof in the reactions of 3i and
3j likely arises during the alkene aminopalladation step of the
catalytic cycle, and in the conversion of 3i to 4i the alkene
insertion step may proceed via transition state 13, in which the
allylic methyl group is in a pseudoequatorial position and A(1,3)
strain between the alkene and the methyl group is minimized
a
Conditions: 1.0 equiv of substrate, 2.0 equiv of NaOtBu, 2 mol %
b
Pd2(dba)3, 8 mol % PCy3·HBF4, toluene (0.1 M), 105 °C. Isolated
yields (average of two or more experiments). This compound
contained ca. 25% of an inseparable impurity tentatively assigned as 6-
methyl-11-methylene-5,6,11,12-tetrahydrodibenzo[b,f ]azocine, which
results from competing intramolecular Heck arylation of the substrate.
c
(Scheme 5). In contrast in the reaction of 3j two possible
transition states for aminopalladation (14 and 15) may be
relatively close in energy, which leads to poor selectivity.
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Note
hyde,15 and 2-(but-3-en-2-yl)aniline5 were prepared according to
published procedures. Toluene and diethyl ether were purified using a
GlassContour solvent system. Structural and stereochemical assign-
ments were made on the basis of 2-D COSY, HSQC, and NOESY
Scheme 3. Catalytic Cycle
1
experiments. Ratios of diastereomers were determined by H NMR
analysis. High resolution ESI mass spectra were acquired using an
instrument equipped with at TOF mass analyzer, and high resolution
EI mass spectra were acquired using an instrument equipped with a
magnetic sector mass analyzer. Yields refer to isolated yields of
1
compounds estimated to be ≥95% pure as determined by H NMR
analysis unless otherwise noted. The yields reported in the Supporting
Information describe the result of a single experiment, whereas the
yields reported in Scheme 2 and Table 1 are average yields of two or
more experiments. Thus, the yields reported in the Supporting
Information may differ from those shown in Scheme 2 and Table 1.
2-Allyl-4-methoxyaniline. A thick-walled glass pressure tube
equipped with a stir bar was sealed with a septum. The pressure tube
was flame-dried and cooled under a vacuum and then purged with
nitrogen. The flask was charged with N-allyl-4-methoxyaniline (2.5 g,
15.2 mmol) and xylenes (30.5 mL). The solution was cooled to 0 °C,
BF3·OEt2 was added dropwise, and the resulting solution was then
allowed to warm to room temperature. The septum was removed, the
pressure tube was replaced with a Teflon screw cap, the tube was
immersed in a 170 °C oil bath, and the reaction mixture was allowed
to stir for 2 h. The mixture was then cooled to room temperature, and
1 M NaOH (15 mL) was added. The resulting mixture was transferred
to a separatory funnel, the layers were separated, and the aqueous layer
was extracted with dichloromethane (3 × 15 mL). The combined
organic layers were dried over anhydrous Na2SO4, filtered, and then
concentrated in vacuo. The crude product was purified via flash
chromatography on silica gel using 5% ethyl acetate:hexanes as the
eluent to afford 870 mg (35%) of the title compound as an orange oil:
1H NMR (700 MHz, CDCl3) 6.66−6.62 (m, 3 H), 5.97−5.91 (m, 1
H), 5.13−5.08 (m, 2 H), 3.74 (s, 3 H), 3.40 (s, br, 2 H), 3.28 (d, J =
5.6 Hz, 2 H); 13C NMR (175 MHz, CDCl3) 152.9, 138.3, 135.7, 125.7,
116.9, 116.2, 116.0, 112.7, 55.7, 36.6; IR (film) 3357, 1500 cm−1; MS
(ESI+) 164.1071 (164.1070 calcd for C10H13NO, M + H+).
Scheme 4. Formation of Heck Arylation Side Product
Scheme 5. Transition States for the Conversion of 3i to 4i
and 3j to 4j
2-(2-Methylallyl)aniline.16 A flame-dried flask equipped a stir bar
was cooled under a vacuum and then purged with nitrogen. This flask
was charged with 2-iodonitrobenzene (3.6 g, 14.5 mmol) and THF
(58 mL). The resulting solution was cooled to −40 °C in a MeCN/
CO2(s) bath, and then a solution of PhMgBr (16 mL, 16.00 mmol, 1 M
in THF) was added dropwise. The resulting mixture was stirred at −40
°C for 5 min, and then a solution of CuCN·2LiCl (29 mL, 29 mmol, 1
M in THF) was added dropwise. The reaction mixture was stirred at
−40 °C for 10 min, and then 2-methylallyl bromide (2.4 g, 17.5
mmol) was added dropwise. The mixture was stirred at −40 °C for 1
h, and then the reaction was quenched with NH4Cl (50 mL) and
transferred to a separatory funnel. Water (50 mL) was added, the
layers were separated, and the aqueous layer was extracted with EtOAc
(2 × 50 mL). The organic layers were then combined, washed with
brine, dried over anhydrous Na2SO4, filtered, and concentrated in
vacuo. The crude product was purified via flash chromatography on
silica gel using 5% ethyl acetate:hexanes as the eluent to yield slightly
impure 2-(2-methylallyl)nitrobenzene (1.8 g, 70% yield), which was
carried on to the next step without further purification.
In conclusion, we have illustrated that the construction of
tetrahydroindoloisoquinoline derivatives can be achieved using
a concise strategy (four steps from commercially available
materials) that employs an intramolecular Pd-catalyzed alkene
carboamination reaction for generation of two rings, a C−C
bond, and a C−N bond. This route allows for the construction
of heterocyclic products bearing substituents on either aromatic
ring, or at the 6, 11a, or 12 positions, and provides
straightforward access to an uncommon class of heterocycles
that have been generated by only a few other methods.
A flame-dried flask equipped with a stir bar was cooled under a
vacuum, purged with nitrogen, and charged with 2-(2-methylallyl)-
nitrobenzene (1.8 g, 10 mmol) and EtOH (67 mL). The resulting
mixture was stirred at rt until the 2-(2-methylallyl)nitrobenzene was
completely dissolved, then powdered zinc (9.9 g, 151 mmol) and
AcOH (8.6 mL, 151 mmol) were added. The resulting mixture
solution was stirred at rt for 1 h and then was filtered through Celite,
and the Celite was washed with Et2O. The organic solutions were
combined and concentrated in vacuo. The crude product was purified
via flash chromatography on silica gel using 2−5% ethyl acetate:hex-
anes as the eluent to afford 1.16 g (54%) of the title compound as a
yellow oil that contained ca. 10% of an unknown aromatic impurity.
EXPERIMENTAL SECTION
■
General Considerations. All reactions were carried out under a
nitrogen atmosphere in oven- or flame-dried glassware. All catalysts
and reagents were obtained from commercial sources and were used
without further purification with the exception of BF3·OEt2, which was
purified by distillation from CaH2. N-Allyl-4-methylaniline,11 2-allyl-4-
methylaniline,14 2-allylaniline,9 2-bromocyclohex-1-ene-1-carbalde-
1
Data are for the major product: H NMR (400 MHz, CDCl3) 7.09−
7.02 (m, 2 H), 6.74 (t, J = 7.6 Hz, 1 H), 6.67 (d, J = 7.6 Hz, 1 H), 4.87
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Note
1
(s, 1 H), 4.74 (s, 1 H), 3.68 (s, br, 2 H), 3.28 (s, 2 H), 1.73 (s, 3 H);
13C NMR (100 MHz, CDCl3) 145.2, 143.6, 131.0, 127.5, 123.9, 118.7,
115.9, 111.6, 41.1, 22.3; IR (film) 3394, 1480 cm−1; MS (ESI+)
148.1125 (148.1121 calcd for C10H13N, M + H+).
10% of an unidentified impurity. Data are for the major product: H
NMR (400 MHz, CDCl3) 7.15 (t, J = 8 Hz, 1 H), 7.04 (d, J = 6.8 Hz,
1 H), 6.70 (t, J = 8 Hz, 1 H), 6.64 (d, J = 8 Hz, 1 H), 6.00−5.90 (m, 1
H), 5.14−5.08 (m, 2 H), 4.12−3.91 (m, 3H), 3.29 (d, J = 6.4 Hz, 2
H), 2.60−2.50 (m, 2 H), 2.18−2.09 (m, 2 H), 1.71−1.60 (m, 4 H);
13C NMR (175 MHz, CDCl3) 146.2, 136.1, 133.9, 129.8, 127.8, 123.6,
121.3, 117.3, 116.3, 110.8, 49.4, 36.8, 36.6, 29.3, 24.7, 22.4; IR (film)
3438, 1508 cm−1; MS (ESI+) 306.0852 (306.0852 calcd for
C16H20BrN, M + H+).
2-Allyl-N-(2-bromo-5-fluorobenzyl)aniline (3e). The coupling
of 2-allylaniline (1.66 g, 12.5 mmol) with 2-bromo-5-fluorobenzalde-
hyde (2.02 g, 10.0 mmol) was conducted according to General
Procedure A. This procedure afforded 2.28 g (72%) of the title
compound as a pale yellow solid: mp 46−47 °C; 1H NMR (700 MHz,
CDCl3) 7.49 (dd, J = 4.9, 8.4 Hz, 1 H), 7.10−7.06 (m, 3 H), 6.83 (t, J
= 7.7 Hz, 1 H), 6.72 (t, J = 7 Hz, 1 H), 6.43 (d, J = 7.7 Hz, 1 H),
6.02−5.96 (m, 1 H), 5.17−5.12 (m, 2 H), 4.38 (s, 2 H), 4.30 (s, br, 1
H), 3.37 (d, J = 4.9, 2 H); 13C NMR (175 MHz, CDCl3) 162.4 (d, J =
245.3 Hz), 145.3, 140.8 (d, J = 6.8 Hz), 136.0, 133.9 (d, J = 7.3 Hz),
130.1, 127.8, 123.7, 117.9, 116.8 (d, J = 2.6 Hz), 116.5, 115.9 (d, J =
23.8 Hz), 115.6 (d, J = 22.9 Hz), 110.8, 48.1, 36.6; IR (film) 3440,
1463 cm−1; MS (ESI+) 320.0450 (320.0445 calcd for C16H15BrFN, M
+ H+).
General Procedure A: Synthesis of Substrates. A flame-dried
flask equipped with a stir bar and a reflux condenser was cooled under
a vacuum and then was purged with nitrogen. The flask was charged
with the appropriate 2-allylaniline derivative (1.25 equiv), the
appropriate 2-bromobenzaldehyde derivative (1.0 equiv), 4 Å
molecular sieves (1 g/mmol), and toluene (0.2 M). The resulting
solution was heated to reflux with stirring overnight. The mixture was
then cooled to rt and filtered, and the solids were washed with EtOAc.
The combined organic solutions were then concentrated in vacuo, and
the resulting crude imine was immediately used without further
purification.
A flame-dried flask with a stir bar was cooled under a vacuum and
then purged with nitrogen. The flask was charged with the crude imine
(1 equiv) and Et2O (0.5 M) and was cooled to 0 °C. A solution of
LiAlH4 (2 equiv, 4 M in Et2O) was added dropwise, and the resulting
solution was allowed to warm to rt and stir overnight. The mixture was
diluted with Et2O, and then water (0.1 mL/mmol of LAH) was
carefully added dropwise to the solution followed by dropwise addition
of 1 M NaOH (0.1 mL/mmol of LAH). Additional water was then
added dropwise until a white solid precipitated and clung to the walls
of the flask. The solution was filtered, the flask was washed with Et2O,
and the resulting solution was also filtered. The combined organic
solutions were then concentrated in vacuo, and the crude product was
then purified via flash chromatography on silica gel using 2−5% ethyl
acetate:hexanes as the eluent.
2-Allyl-N-(2-bromobenzyl)aniline (3a). The coupling of 2-
allylaniline (894 mg, 6.72 mmol) with 2-bromobenzaldehyde (994
mg, 5.37 mmol) was accomplished according to General Procedure A.
This procedure afforded 1.01 g (62%) of the title compound as a white
solid: mp 42−44 °C; 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 8 Hz,
1 H), 7.39 (d, J = 7.6 Hz, 1 H), 7.26−7.22 (m, 1 H), 7.14−7.06 (m, 3
H), 6.71 (t, J = 7.2 Hz, 1 H), 6.53 (d, J = 8 Hz, 1 H), 6.03−5.93 (m, 1
H), 5.16−5.09 (m, 2 H), 4.43 (s, 2 H), 4.27 (s, br, 1 H), 3.35 (d, J = 6
Hz, 2 H); 13C NMR (175 MHz, CDCl3) 145.7, 138.2, 136.0, 132.8,
129.9, 129.0, 128.6, 127.7, 127.5, 123.6, 123.2, 117.6, 116.4, 110.9,
48.2, 36.6; IR (film) 3440, 1512 cm−1; MS (ESI+) 302.0544 (302.0539
calcd for C16H16BrN, M + H+).
2-Allyl-N-[(6-bromobenzo[d][1,3]dioxol-5-yl)methyl]aniline
(3f). The coupling of 2-allylaniline (1.66 g, 12.5 mmol) with 6-bromo-
1,3-benzodioxole-5-carboxaldehyde (2.29 g, 10.0 mmol) was con-
ducted according to General Procedure A. This procedure afforded
2.51 g (73%) of the title compound as a white solid: mp 53−55 °C; 1H
NMR (400 MHz, CDCl3) 7.13−7.06 (m, 2 H), 7.02 (s, 1 H), 6.85 (s,
1 H), 6.71 (t, J = 7.6 Hz, 1 H), 6.51 (d, J = 8.4 Hz, 1 H), 6.03−5.94
(m, 3 H), 5.16−5.09 (m, 2 H), 4.31 (d, J = 5.6 Hz, 2 H), 4.22 (s, br, 1
H), 3.34 (d, J = 6 Hz, 2 H); 13C NMR (175 MHz, CDCl3) 147.6,
147.4, 145.6, 136.0, 131.6, 129.9, 127.7, 123.7, 117.6, 116.4, 113.3,
112.8, 110.9, 109.0, 101.6, 48.1, 36.5; IR (film) 3439, 1478 cm−1; MS
(ESI+) 346.0440 (346.0437 calcd for C17H16BrNO2, M + H+).
2-Allyl-N-[(1-bromonaphthalen-2-yl)methyl]aniline (3g). The
coupling of 2-allylaniline (1.7 g, 12.5 mmol) with 1-bromo-2-
naphthaldehyde (2.35 g, 10.00 mmol) was conducted according to
General Procedure A except after addition of LiAlH4 the reaction
mixture was heated to reflux overnight. This procedure afforded 2.77 g
1
(79%) of the title compound as an orange solid: mp 95−97 °C; H
NMR (400 MHz, CDCl3) 8.34 (d, J = 8.4 Hz, 1 H), 7.80 (d, J = 8 Hz,
1 H), 7.74 (d, J = 8.8 Hz, 1 H), 7.60 (t, J = 7.2 Hz, 1 H), 7.52−7.48
(m, 2 H), 7.10−7.06 (m, 2 H), 6.71 (t, J = 7.2 Hz, 1 H), 6.55 (d, J =
8.8 Hz, 1 H), 6.05−5.95 (m, 1 H), 5.16−5.11 (m, 2 H), 4.66 (s, 2 H),
4.39 (s, br, 1 H), 3.37 (d, J = 6.0 Hz, 2 H); 13C NMR (175 MHz,
CDCl3) 145.8, 136.6, 136.0, 133.9, 132.4, 130.0, 128.1, 127.8, 127.8,
127.4, 126.9, 126.3, 126.1, 123.7, 123.0, 117.6, 116.5, 111.0, 49.2, 36.6;
IR (film) 3442, 1541 cm−1; MS (ESI+) 352.0700 (352.0695 calcd for
C20H18BrN, M + H+).
N-(2-Bromobenzyl)-2-(2-methylallyl)aniline (3h). The cou-
pling of 2-(2-methylallyl)aniline (1.16 g, 7.84 mmol) with 2-
bromobenzaldehyde (1.16 g, 6.28 mmol) was conducted according
to General Procedure A. This procedure afforded 767 mg (39%) of the
title compound as a white solid: mp 43−46 °C; 1H NMR (400 MHz,
CDCl3) 7.56 (d, J = 8 Hz, 1 H), 7.32 (d, J = 6 Hz, 1 H), 7.25−7.21 (m,
1 H), 7.14−7.04 (m, 3 H), 6.70 (t, J = 7.2 Hz, 1 H), 6.51 (d, J = 8 Hz,
1 H), 4.88 (s, 1 H), 4.76 (s, 1 H), 4.42−4.39 (m, 3 H), 3.33 (s, 2 H),
1.73 (s, 3 H); 13C NMR (175 MHz, CDCl3) 146.1, 143.7, 138.3,
132.7, 130.8, 128.8, 128.5, 127.7, 127.5, 123.5, 123.2, 117.4, 112.0,
110.9, 48.1, 41.4, 22.3; IR (film) 3430, 1510 cm−1; MS (ESI+)
316.0692 (316.0695 calcd for C17H18BrN, M + H+).
2-Allyl-N-(2-bromobenzyl)-4-methoxyaniline (3b). The cou-
pling of 2-allyl-4-methoxyaniline (1.22 g, 7.47 mmol) with 2-
bromobenzaldehyde (1.10 g, 5.97 mmol) was conducted according
to General Procedure A. This procedure afforded 1.09 g (55%) of the
title compound as an orange oil: 1H NMR (400 MHz, CDCl3) 7.56 (d,
J = 8 Hz, 1 H), 7.34 (d, J = 7.2 Hz, 1 H), 7.26−7.23 (m, 1 H), 7.12 (t,
J = 8 Hz, 1 H), 6.72−6.63 (m, 2 H), 6.49 (d, J = 8.8 Hz, 1 H), 6.02−
5.92 (m, 1 H), 5.15−5.09 (m, 2 H), 4.38 (s, 2 H), 3.97 (s, br, 1 H),
3.74 (s, 3 H), 3.33 (d, J = 6 Hz, 2 H); 13C NMR (175 MHz, CDCl3)
152.1, 139.8, 138.5, 135.7, 132.7, 129.1, 128.5, 127.5, 125.7, 123.3,
116.6, 116.6, 112.2, 112.1, 55.7, 49.0, 36.5; IR (film) 3428, 1508 cm−1;
MS (ESI+) 332.0645 (332.0645 calcd for C17H18BrNO, M + H+).
2-Allyl-N-(2-bromobenzyl)-4-methylaniline (3c). The coupling
of 2-allyl-4-methylaniline (2.20 g, 15.0 mmol) with 2-bromobenzalde-
hyde (2.21 g, 12.0 mmol) was conducted according to General
Procedure A. This procedure afforded 2.07 g (55%) of the title
compound as an orange oil: 1H NMR (400 MHz, CDCl3) 7.56 (d, J =
8 Hz, 1 H), 7.34 (d, J = 7.6 Hz, 1 H), 7.25−7.21 (m, 1 H), 7.11 (t, J =
7.2 Hz, 1 H), 6.91−6.89 (m, 2 H), 6.44 (d, J = 8.8 Hz, 1 H), 6.03−
5.93 (m, 1 H), 5.14−5.09 (m, 2 H), 4.40 (s, 2 H), 4.14 (s, br, 1 H),
3.32 (d, J = 6.4 Hz, 2 H), 2.23 (s, 3 H); 13C NMR (175 MHz, CDCl3)
143.4, 138.4, 136.1, 132.7, 130.7, 129.0, 128.5, 128.0, 127.5, 126.7,
123.8, 123.3, 116.3, 111.1, 48.5, 36.6, 20.4; IR (film) 3437, 1513 cm−1;
MS (ESI+) 316.0695 (316.0695 calcd for C17H18BrN, M + H+).
2-Allyl-N-[(2-bromocyclohex-1-en-1-yl)methyl]aniline (3d).
The coupling of 2-allylaniline (832 mg, 6.25 mmol) with 2-
bromocyclohex-1-ene-1-carbaldehyde (945 mg, 5.00 mmol) was
conducted according to General Procedure A. This procedure afforded
989 mg (65%) of the title compound as a yellow oil that contained ca.
N-(2-Bromobenzyl)-2-(but-3-en-2-yl)aniline (3i). The coupling
of 2-(but-3-en-2-yl)aniline (298 mg, 2.02 mmol) with 2-bromoben-
zaldehyde (300 mg, 1.62 mmol) was conducted according to General
Procedure A. This reaction afforded 451 mg (88%) of the title
compound as a yellow oil that contained ca. 6% of the analogous crotyl
1
regioisomer. Data are for the major product: H NMR (400 MHz,
CDCl3) 7.57 (d, J = 8 Hz, 1 H), 7.34 (d, J = 7.6 Hz, 1 H), 7.24−7.22
(m, 1 H), 7.15−7.07 (m, 3 H), 6.75 (t, J = 8 Hz, 1 H), 6.54 (d, J = 8
4215
dx.doi.org/10.1021/jo500470m | J. Org. Chem. 2014, 79, 4212−4217

The Journal of Organic Chemistry
Note
Hz, 1 H), 6.03−5.94 (m, 1 H), 5.12−5.07 (m, 2 H), 4.42−4.37 (m, 3
H), 3.52 (quint, J = 6.4 Hz, 1 H), 1.43 (d, J = 7.2 Hz, 3 H); 13C NMR
(175 MHz, CDCl3) 145.2, 142.3, 138.3, 132.8, 129.0, 128.6, 128.5,
127.5, 127.4, 126.9, 123.3, 117.7, 114.2, 111.1, 48.3, 38.1, 18.9; IR
(film) 3434, 1506 cm−1; MS (ESI+) 316.0693 (316.0695 calcd for
C17H18BrN, M + H+).
126.9, 126.3, 126.0, 112.2, 111.6, 107.3, 62.6, 56.0, 49.6, 36.0, 35.4; IR
(film) 2781, 1486 cm−1; MS (EI) 251.1314 (251.1310 calcd for
C17H17NO, M+).
2-Methyl-6,11,11a,12-tetrahydroindolo[1,2-b]isoquinoline
(4c). The cyclization of 3c (162 mg, 0.512 mmol) was conducted
according to General Procedure B to afford 98 mg (81%) of the title
1
compound as a brown solid: mp 68−70 °C; H NMR (400 MHz,
2-Allyl-N-[1-(2-bromophenyl)ethyl]aniline (3j). The coupling
of 2-allylaniline (1.66 g, 12.5 mmol) with 2′-bromoacetophenone
(2.00 g, 10.0 mmol) was conducted according to General Procedure A
except after addition of LiAlH4 the reaction mixture was heated to
reflux overnight. This procedure afforded 1.75 g (55%) of the title
compound as a yellow oil that contained ca. 6% of an unknown
CDCl3) 7.21−7.15 (m, 4 H), 6.97−6.92 (m, 2 H), 6.49 (d, J = 8 Hz, 1
H), 4.58 (d, J = 15.2 Hz, 1 H), 3.98 (d, J = 15.2 Hz, 1 H), 3.52−3.44
(m, 1 H), 3.11 (dd, J = 14.8, 7.6 Hz, 1 H), 3.04−3.02 (d, J = 6.8 Hz, 2
H), 2.74 (dd, J = 14.8, 11.2 Hz, 1 H), 2.27 (s, 3 H); 13C NMR (175
MHz, CDCl3) 149.8, 134.8, 133.7, 129.9, 129.3, 128.0, 127.6, 127.0,
126.4, 126.1, 125.4, 107.0, 62.2, 49.2, 35.7, 35.6, 20.9; IR (film) 2918,
1491 cm−1; MS (EI) 235.1358 (235.1361 calcd for C17H17N, M+).
6,7,8,9,10,11,11a,12-Octahydroindolo[1,2-b]isoquinoline
(4d). The cyclization of 3d (153 mg, 0.500 mmol) was conducted
according to General Procedure B. In order to remove a small amount
of unreacted starting material from the product, the crude product was
dissolved in dichloromethane (2.5 mL), and DMAP (6.1 mg, 0.050
mmol) and Et3N (104 μL, 0.750 mmol) were added to the solution.
Acetic anhydride (61 μL, 0.650 mmol) was added, and the solution
was allowed to stir at rt for 3 h and was then concentrated in vacuo.
The crude product was purified via flash chromatography to afford 62
mg (55%) of the title compound as a brown solid: mp 88−90 °C; 1H
NMR (700 MHz, CDCl3) 7.09−7.06 (m, 2 H), 6.67 (t, J = 7.0 Hz, 1
H), 6.45 (d, J = 7.7 Hz, 1 H), 3.68 (d, J = 15.4 Hz, 1 H), 3.34−3.29
(m, 1 H), 3.18 (d, J = 15.4 Hz, 1 H), 3.03 (dd, J = 7.0, 14.7 Hz, 1 H),
2.61 (t, J = 12.6 Hz, 1 H), 2.21 (t, J = 14.7 Hz, 1 H), 2.12 (d, J = 16.1
Hz, 1 H), 2.02−1.91 (m, 4 H), 1.77−1.71 (m, 2 H), 1.57−1.52 (m, 2
H); 13C NMR (175 MHz, CDCl3) 151.9, 129.6, 127.5, 127.3, 125.7,
124.2, 118.1, 106.8, 61.5, 49.6, 36.5, 35.8, 30.2, 27.7, 22.9, 22.8; IR
(film) 2916, 1607 cm−1; MS (EI) 225.1518 (225.1518 calcd for
C16H19N, M+).
1
impurity: H NMR (400 MHz, CDCl3) 7.54 (d, J = 8 Hz, 1 H), 7.37
(d, J = 7.6 Hz, 1 H), 7.19 (t, J = 7.2 Hz, 1 H), 7.08−7.02 (m, 2 H),
6.97 (t, J = 8 Hz, 1 H), 6.63 (t, J = 7.6 Hz, 1 H), 6.18 (d, J = 8 Hz, 1
H), 6.07−5.97 (m, 1 H), 5.23−5.18 (m, 2 H), 4.84 (quint, J = 6.4 Hz,
1 H), 4.25 (s, br, 1 H), 3.40 (d, J = 6 Hz, 2 H), 1.48 (d, J = 6.4 Hz, 3
H); 13C NMR (175 MHz, CDCl3) 144.7, 143.6, 136.3, 132.9, 129.7,
128.3, 128.0, 127.6, 126.7, 122.9, 122.6, 117.2, 116.3, 111.6, 52.4, 36.9,
23.1; IR (film) 3746, 1506 cm−1; MS (ESI+) 316.0692 (316.0695
calcd for C17H18BrN, M + H+).
General Procedure B: Intramolecular Pd-Catalyzed Alkene
Carboamination Reactions. A flame-dried Schlenk tube equipped
with a stir bar was cooled under a vacuum and then purged with
nitrogen. The tube was charged with NaOtBu (96 mg, 1 mmol),
Pd2(dba)3 (9 mg, 0.01 mmol), and PCy3·HBF4 (15 mg, 0.040 mmol).
The substrate (0.5 mmol) was dissolved in toluene (5 mL) and added
to the flask. The resulting solution was heated 105 °C with stirring for
18 h, at which time the substrate was judged to be completely
1
consumed by GC, TLC, or H NMR analysis of an aliquot removed
from the reaction mixture. The mixture was then cooled to rt, and
saturated aqueous NH4Cl (10 mL) was added. The mixture was
transferred to a separatory funnel, the layers were separated, and the
aqueous layer was extracted with EtOAc (3 × 15 mL). The combined
organic layers were then dried over anhydrous Na2SO4, filtered, and
concentrated in vacuo. The crude product was then purified via flash
chromatography on silica gel using 2% ethyl acetate:hexanes as the
eluent to afford a product that still contained small amounts of
impurities. The product was then dissolved in 30% Et2O/hexanes (5
mL, 0.1 M) and 2 M HCl in Et2O (1.5 mL, 3 equiv) was added
dropwise. The resulting solution was stirred at rt for 1 min, and a white
solid (the product HCl salt) precipitated from the solution. The salt
was then filtered and washed with hexanes. The salt was then dissolved
in dicholoromethane (10 mL) and transferred to a separatory funnel.
A solution of 4 M NaOH was added, and the mixture was shaken
vigorously for 1 min. The layers were then separated, and the aqueous
layer was extracted with dichloromethane (3 × 15 mL). The combined
organic layers were dried over anhydrous Na2SO4, filtered, and
concentrated in vacuo to afford the desired product.
8-Fluoro-6,11,11a,12-tetrahydroindolo[1,2-b]isoquinoline
(4e). The cyclization of 3e (161 mg, 0.505 mmol) was conducted
according to General Procedure B to afford 105 mg (87%) of the title
1
compound as a yellow solid: mp 92−93 °C; H NMR (400 MHz,
CDCl3) 7.13−7.07 (m, 3 H), 6.89−6.85 (m, 2 H), 6.73 (t, J = 7.2 Hz,
1 H), 6.54 (d, J = 8 Hz, 1 H), 4.54 (d, J = 15.6 Hz, 1 H), 3.98 (d, J =
15.6 Hz, 1 H), 3.55−3.47 (m, 1 H), 3.15 (dd, J = 4.6, 14.8 Hz, 1 H),
3.02−2.90 (m, 2 H), 2.74 (dd, J = 11.2, 14.8 Hz, 1 H); 13C NMR (175
MHz, CDCl3) 161.3 (d, J = 242.6 Hz), 151.6, 135.4 (d, J = 7 Hz),
130.7 (d, J = 7.5 Hz), 130.3 (d, J = 2.6 Hz), 129.5, 127.6, 124.5, 118.8,
113.6 (d, J = 21 Hz), 113.3 (d, J = 21.7 Hz), 107.1, 61.8, 48.6 (d, J =
1.9 Hz), 35.6, 34.9; IR (film) 2789, 1480 cm−1; MS (EI) 239.1116
(239.1110 calcd for C16H14FN, M+).
5,11,11a,12-Tetrahydro-[1,3]dioxolo[4,5-g]indolo[1,2-b]iso-
quinoline (4f). The cyclization of 3f (173 mg, 0.500 mmol) was
conducted according to General Procedure B to afford 95 mg (72%) of
1
the title compound as a white solid: mp 90−92 °C; H NMR (400
6,11,11a,12-Tetrahydroindolo[1,2-b]isoquinoline (4a). The
cyclization of 3a (151 mg, 0.500 mmol) was conducted according to
General Procedure B to afford 94 mg (85%) of the title compound as a
MHz, CDCl3) 7.12−7.09 (m, 2 H), 6.72 (t, J = 7.2 Hz, 1 H), 6.60 (d, J
= 6.8 Hz, 2 H), 6.53 (d, J = 8 Hz, 1 H), 5.88 (s, 2 H), 4.46 (d, J = 14.8
Hz, 1 H), 3.92 (d, J = 14.8 Hz, 1 H), 3.52−3.43 (m, 1 H), 3.13 (dd, J =
7.6, 15.0 Hz, 1 H), 2.90 (d, J = 7.2 Hz, 2 H), 2.74 (dd, J = 10.8, 15.0
Hz, 1 H); 13C NMR (175 MHz, CDCl3) 151.6, 146.1, 146.1, 129.4,
127.6, 127.4, 126.2, 124.3, 118.5, 108.8, 106.9, 106.5, 100.8, 61.5, 48.5,
35.5, 35.5; IR (film) 2891, 1484 cm−1; MS (EI) 265.1103 (265.1103
calcd for C17H15NO2, M+).
1
yellow solid: mp 125−127 °C; H NMR (400 MHz, CDCl3) 7.20−
7.10 (m, 6 H), 6.72 (t, J = 7.2 Hz, 1 H), 6.55 (d, J = 8 Hz, 1 H), 4.58
(d, J = 15.6 Hz, 1 H), 4.02 (d, J = 15.2 Hz, 1 H), 3.58−3.50 (m, 1 H),
3.15 (dd, J = 7.6, 15.2 Hz, 1 H), 3.05−3.00 (m, 2 H), 2.75 (dd, J =
11.2, 15.0 Hz, 1 H); 13C NMR (175 MHz, CDCl3) 151.8, 134.7, 133.5,
129.5, 129.3, 127.5, 126.9, 126.3, 126.1, 124.4, 118.5, 107.0, 61.6, 48.5,
35.7, 35.6; IR (film) 2778, 1456 cm−1; MS (EI) 221.1201 (221.1204
calcd for C16H15N, M+).
7,13,13a,14-Tetrahydrobenzo[f ]indolo[1,2-b]isoquinoline
(4g). The cyclization of 3g (173 mg, 0.491 mmol) was conducted
according to General Procedure B to afford 106 mg (80%) of the title
compound as a red solid: mp 95−97 °C; 1H NMR (400 MHz, CDCl3)
7.94 (d, J = 8.4 Hz, 1 H), 7.79 (d, J = 8 Hz, 1 H), 7.66 (d, J = 8.4 Hz, 1
H), 7.50 (t, J = 7.2 Hz, 1 H), 7.44 (t, J = 6.8 Hz, 1 H), 7.22 (d, J = 8.4
Hz, 1 H), 7.16−7.12 (m, 2 H), 6.75 (t, J = 7.2 Hz, 1 H), 6.60 (d, J = 8
Hz, 1 H), 4.64 (d, J = 15.6 Hz, 1 H), 4.12 (d, J = 15.6 Hz, 1 H), 3.60−
3.51 (m, 2 H), 3.22 (dd, J = 7.2, 14.8 Hz, 1 H), 3.09 (t, J = 12.8 Hz, 1
H), 2.85 (dd, J = 11.6, 14.2 Hz, 1 H); 13C NMR (175 MHz, CDCl3) δ
151.9, 132.5, 132.4, 130.9, 129.9, 129.8, 128.6, 127.6, 126.6, 126.3,
125.4, 125.4, 124.6, 122.9, 118.8, 107.3, 61.8, 49.3, 36.1, 32.0; IR (film)
2-Methoxy-6,11,11a,12-tetrahydroindolo[1,2-b]isoquinoline
(4b). The cyclization of 3b (166 mg, 0.500 mmol) was conducted
according to General Procedure B except only 1 equiv of 2 M HCl in
Et2O was used. This procedure afforded 86 mg (68%) of the title
1
compound as a yellow solid: mp 134 °C (dec); H NMR (700 MHz,
CDCl3) 7.19−7.14 (m, 4 H), 6.80 (s, 1 H), 6.68 (d, J = 7 Hz, 1 H),
6.50 (d, J = 7 Hz, 1 H), 4.54 (d, J = 14.7 Hz, 1 H), 3.93 (d, J = 14.7
Hz, 1 H), 3.74 (s, 3 H), 3.45−3.40 (m, 1 H), 3.11 (dd, J = 7.7, 14.7
Hz, 1 H), 3.05−3.02 (m, 2 H), 2.73 (dd. J = 11.9, 14.7 Hz, 1 H); 13C
NMR (175 MHz, CDCl3) 153.4, 146.2, 134.6, 133.6, 131.2, 129.3,
4216
dx.doi.org/10.1021/jo500470m | J. Org. Chem. 2014, 79, 4212−4217

The Journal of Organic Chemistry
Note
2924, 1482 cm−1; MS (EI) 271.1351 (271.1361 calcd for C20H17N,
M+).
REFERENCES
■
(1) (a) Liu, D.; Zhao, G.; Xiang, L. Eur. J. Org. Chem. 2010, 3975−
3984. (b) Michael, J. P. Nat. Prod. Rep. 2008, 25, 139−165. (c) Scott,
J. D.; Williams, R. M. Chem. Rev. 2002, 102, 1669−1730.
(2) (a) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003,
103, 893−930. (b) Prakesch, M.; Arya, P.; Naim, M.; Sulea, T.;
Purisima, E.; Denisov, A. Y.; Gehring, K.; Foster, T. L.; Korneluk, R. G.
In Modern Alkaloids: Structure, Isolation, Synthesis, and Biology;
Fattorusso, E., Taglialatela-Scafati, O., Eds.; Wiley-VCH: Weinheim,
2007; pp 521−540.
(3) For prior syntheses of tetrahydroindoloisoquinoline derivatives,
see: (a) Sugasawa, S.; Kodama, K. Chem. Ber. 1941, 74, 1237−1241.
(b) Sugasawa, S.; Kodama, K.; Akatuka, K. Proc. Imp. Acad. (Tokyo)
1941, 17, 102−105.
(4) For prior syntheses of related heterocycles that contain carbonyl
functional groups, see: (a) Fuller, P. H.; Chemler, S. R. Org. Lett. 2007,
9, 5477−5480. (b) Sherman, E. S.; Fuller, P. H.; Kasi, D.; Chemler, S.
R. J. Org. Chem. 2007, 72, 3896−3905. (c) Merour, J.-Y.; Piroelle, S.;
Cossais, F. Heterocycles 1993, 36, 1287−1304. (d) Hooper, M.;
Pitkethly, W. N. J. Chem. Soc., Perkin Trans. 1 1972, 1607−1613.
(e) Fraser, H. L.; Gribble, G. W. Can. J. Chem. 2001, 79, 1515−1521.
(f) de Diesbach, H.; Frossard, M. Helv. Chim. Acta 1954, 37, 701−705.
(5) Schultz, D. M.; Wolfe, J. P. Org. Lett. 2011, 13, 2962−2965.
(6) For recent reviews, see: (a) Wolfe, J. P. Top. Heterocycl. Chem.
2013, 32, 1−38. (b) Schultz, D. M.; Wolfe, J. P. Synthesis 2012, 44,
351−361.
(7) Chemler has previously described a related strategy for the
construction of fused polycyclic nitrogen heterocycles that involves
Cu-mediated intramolecular C−H functionalization/alkene carboami-
nation reactions of 2-allyl aniline derivatives bearing N-benzoyl or N-
arylsulfonyl groups. See: (a) Chemler, S. R. Org. Biomol. Chem. 2009,
7, 3009−3019. (b) Refs 4a and 4b.
11a-Methyl-6,11,11a,12-tetrahydroindolo[1,2-b]iso-
quinoline (4h). The cyclization of 3h (163 mg, 0.517 mmol) was
conducted according to General Procedure B to afford 97 mg (80%) of
1
the title compound as a yellow solid: mp 47−50 °C; H NMR (700
MHz, CDCl3) 7.19−7.14 (m, 3 H), 7.06 (m, 3 H), 6.63 (t, J = 7.0 Hz,
1 H), 6.41 (d, J = 7.7 Hz, 1 H), 4.50 (d, J = 16.1 Hz, 1 H), 4.25 (d, J =
16.1 Hz, 1 H), 3.10 (d, J = 15.4 Hz, 1 H), 2.94 (s, 2 H), 2.70 (d, J =
15.4 Hz, 1 H), 1.15 (s, 3 H); 13C NMR (175 MHz, CDCl3) 150.5,
134.6, 132.9, 129.8, 128.3, 127.6, 126.5, 126.4, 126.0, 124.8, 117.2,
106.2, 62.3, 43.7, 43.7, 40.0, 20.9; IR (film) 2924, 1482 cm−1; MS (EI)
235.1364 (235.1361 calcd for C17H17N, M+).
( )-(11aS,12R)-12-Methyl-6,11,11a,12-tetrahydroindolo[1,2-
b]isoquinoline (4i). The cyclization of 3i (64 mg, 0.202 mmol) was
conducted according to General Procedure B to afford 36 mg (75%) of
the title compound as a yellow oil. This product was judged to have
been formed with 18:1 dr by 1H NMR analysis. Data are for the major
1
isomer: H NMR (700 MHz, CD3OD) 7.19−7.15 (m, 4 H), 7.09−
7.06 (m, 2 H), 6.76 (t, J = 7.7 Hz, 1 H), 6.62 (d, J = 7.7 Hz, 1 H), 4.58
(d, J = 15.4 Hz, 1 H), 3.83 (d, J = 14.7 Hz, 1 H), 3.06 (d, J = 14.7 Hz,
1 H), 2.92−2.84 (m, 3 H), 1.37 (d, J = 6.3 Hz, 3 H); 13C NMR (175
MHz, CD3OD) 152.7, 136.1, 135.6, 134.6, 130.3, 128.4, 127.9, 127.4,
127.1, 123.5, 120.3, 108.7, 71.5, 50.3, 43.3, 35.0, 16.1; IR (film) 3676,
1506 cm−1; MS (EI) 235.1363 (235.1361 calcd for C17H17N, M+).
6-Methyl-6,11,11a,12-tetrahydroindolo[1,2-b]isoquinoline
(4j). The cyclization of 3j (165 mg, 0.500 mmol) was conducted
according to the General Procedure B to afford 64 mg (52%) of the
title compound as a yellow oil. This material was judged to be an
inseparable ca. 2:1:1 mixture of the two possible diastereomers and a
side product tentatively assigned as 6-methyl-11-methylene-5,6,11,12-
tetrahydrodibenzo[b,f ]azocine, which results from competing intra-
molecular Heck reaction.11 Data are for the mixture: H NMR (700
1
MHz, CDCl3) 7.26−7.24 (m, 1 H), 7.22−7.20 (m, 1.5 H), 7.19−7.16
(m, 2.5 H), 7.16−7.14 (m, 2.5 H), 7.12−7.07 (m, 4.5 H), 7.02 (d, J =
7.7 Hz, 1 H), 6.97 (t, J = 10.5 Hz, 1 H), 6.68−6.63 (m, 2 H), 6.60 (d, J
= 7.7 Hz, 0.5 H), 6.48 (d, J = 8.4 Hz, 1 H), 6.45 (d, J = 7.7 Hz, 0.5
Hz), 6.29 (ddd, J = 3.5, 10.5, 17.3 Hz, 0.5 H), 5.23−5.13 (m, 1 H),
4.84−4.78 (m, 1.5 H), 4.53−4.50 (m, 1 H), 3.97−3.92 (m, 1 H),
3.76−3.60 (m, 1 H), 3.23 (dd, J = 8.4, 14.7 Hz, 1 H), 3.06−2.92 (m, 4
H), 2.77−2.72 (m, 1.5 H), 1.55 (d, J = 6.3 Hz, 1.5 H), 1.53 (d, J = 7.0
Hz, 1.5 H), 1.36 (d, J = 7.0 Hz, 3 H); 13C NMR (175 MHz, CDCl3)
151.3, 149.8, 146.0, 143.5, 140.9, 140.4, 139.8, 139.2, 134.5, 134.0,
132.6, 130.2, 129.6, 129.3, 129.0, 128.8, 127.7, 127.7, 127.5, 127.4,
127.4, 127.2, 127.1, 127.0, 126.5, 126.3, 126.0, 124.5, 124.2, 123.5,
122.3, 117.9, 117.8, 117.5, 117.3, 115.3, 106.9, 106.3, 62.7, 56.4, 54.6,
53.9, 50.6, 48.0, 36.3, 36.1, 35.8, 35.3, 24.9, 19.2, 17.2; IR (film) 3362,
1617 cm−1; MS (ESI+) 236.1442 (236.1434 calcd for C17H17N, M +
H+).
(8) For examples of intramolecular Pd-catalyzed alkene carboamina-
tion reactions that afford attached-ring heterocycles, see: Nakhla, J. S.;
Kampf, J. W.; Wolfe, J. P. J. Am. Chem. Soc. 2006, 128, 2893−2901.
(9) Anderson, W. K.; Lai, G. Synthesis 1995, 1287−1290.
(10) Efforts to prepare a substrate bearing an internal alkene were
not successful. As such, reactions of substrates that contain internal
alkenes were not examined.
(11) Intramolecular Heck arylation of closely related substrates
bearing N-tosyl protecting groups have been previously described. See:
Majumdar, K. C.; Chattopadhyay, B.; Samanta, S. Tetrahedron Lett.
2009, 50, 3178−3181.
(12) For studies on the mechanism of syn-migratory insertion of
alkenes into Pd−N bonds, see: (a) Neukom, J. D.; Perch, N. S.; Wolfe,
J. P. J. Am. Chem. Soc. 2010, 132, 6276−6277. (b) Hanley, P. S.;
́
Markovic, D.; Hartwig, J. F. J. Am. Chem. Soc. 2010, 132, 6302−6303.
(c) Neukom, J. D.; Perch, N. S.; Wolfe, J. P. Organometallics 2011, 30,
1269−1277. (d) Hanley, P. S.; Hartwig, J. F. J. Am. Chem. Soc. 2011,
133, 15661−15673. (e) White, P. B.; Stahl, S. S. J. Am. Chem. Soc.
2011, 133, 18594−18597.
ASSOCIATED CONTENT
■
S
* Supporting Information
(13) For a review on intramolecular Heck reactions, see: Link, J. T.
Org. React. 2002, 60, 160−534.
(14) Bovino, M. T.; Chemler, S. R. Angew. Chem., Int. Ed. 2012, 51,
3923−3927.
1
Assignment of relative stereochemistry of 4i and copies of H
and 13C NMR spectra for all substrates and products. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(15) Park, C.-M.; Bruncko, M.; Adickes, J.; Bauch, J.; Ding, H.;
Kunzer, A.; Marsh, K. C.; Nimmer, P.; Shoemaker, A. R.; Song, X.;
Tahir, S. K.; Tse, C.; Wang, X.; Wendt, M. D.; Yang, X.; Zhang, H.;
Fesik, S. W.; Rosenberg, S. H.; Elmore, S. W. J. Med. Chem. 2008, 51,
6902−6915.
AUTHOR INFORMATION
■
Corresponding Author
(16) Li, C.; Li, X.; Hong, R. Org. Lett. 2009, 11, 4036−4039.
*E-mail: jpwolfe@umich.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the NIH-NIGMS (GM098314 for financial
support of this work.
4217
dx.doi.org/10.1021/jo500470m | J. Org. Chem. 2014, 79, 4212−4217