Ortho-Bromo(propa-1,2-dien-1-yl)arenes: Substrates for domino reactions

Article abstract of DOI:10.1021/jo201679s

o-Bromo(propa-1,2-dien-1-yl)arenes exhibit novel and orthogonal reactivity under Pd catalysis in the presence of secondary amines to form enamines (concerted Pd insertion, intramolecular carbopalladation, and terminative Buchwald-Hartwig coupling) and of amides to form indoles (addition, Buchwald-Hartwig cyclization, and loss of the acetyl group). The substrates for these reactions can be accessed in a reliable and highly selective two-step process from 2-bromoaryl bromides.

Full text of DOI:10.1021/jo201679s

Article
pubs.acs.org/joc
ortho-Bromo(propa-1,2-dien-1-yl)arenes: Substrates for Domino
Reactions
Kye-Simeon Masters, Manuela Wallesch, and Stefan Brase*
̈
Institut fur Organische Chemie, Karlsruher Institut fur Technologie (KIT), Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
̈
̈
S
* Supporting Information
ABSTRACT: o-Bromo(propa-1,2-dien-1-yl)arenes exhibit novel and or-
thogonal reactivity under Pd catalysis in the presence of secondary amines
to form enamines (concerted Pd insertion, intramolecular carbopalladation,
and terminative Buchwald−Hartwig coupling) and of amides to form
indoles (addition, Buchwald−Hartwig cyclization, and loss of the acetyl
group). The substrates for these reactions can be accessed in a reliable and
highly selective two-step process from 2-bromoaryl bromides.
in situ presence of nucleophile or equivalent might result in a
INTRODUCTION
■
termination process to return Pd0 catalyst. Specifically, the
application of Pd catalysis with 2-halo-substituted arylallenes is
predicted to give rise to, for example, amines or amides in the
presence of base to effect Buchwald−Hartwig couplings,8
stannanes to give Stille couplings,9 or arylboronic acids to give
Suzuki couplings,10 each of which process would follow an
initial intramolecular insertion of the alkene π-sytem to Ar−
PdII−Br similar to that found in the Heck reaction.11
The synthetic usage of allenes is currently a topic of interest.1
Considerably more reactive than simple alkenes, allenes act as
substrates with transition-metal catalysts in a variety of ways;2
in particular, they are known to undergo facile carbopalladation
processes. As part of our ongoing interest in Pd-catalyzed
domino reactions,3,4 we envisaged that 2-haloarylallenes
(unknown in the literature)5 present themselves as attractive
substrates for transition-metal-catalyzed domino reactions: The
aryl bromide serves as a functionality for Pd0 insertion, while
the allene could be a substrate to PdII-catalyzed carbopallada-
tion. Domino reactions of allenes have hitherto predominantly
involved the use of bifunctional substrates incorporating an
organohalide/nucleophile unit in combination with an allene
partner.6 The alternative strategy, with the allene and
organohalide as a bifunctional substrate, provides relatively
fertile ground for exploration, despite the notable “zipper”-type
reactions from Grigg and co-workers.7
RESULTS AND DISCUSSION
■
The initial coupling of 2-bromobenzyl bromide (1a) with
trimethylsilylacetylene proved to be a surprisingly challenging
reaction (Scheme 2, Table 1). The use of classical Sonogashira
Scheme 2. Conversion of 2-Bromo(bromo)methylbenzene
(1a) to 2-Bromophenylprop-1,2-diene (3a) and 2-Bromo-
phenylprop-2-yne (4a)
We imagined that oxidative insertion of Pd0 would be
followed by a facile insertion of the π-system of the tethered
allene (Scheme 1). The resulting 2-palladium(II) indenyl
Scheme 1. Synthesis of, and Divergent Pd-Catalyzed
Pathways from, o-Bromo(propa-1,2-dien-1-yl)arenes
i) Trimethylsilylacetylene (2.00 equiv), CuI (1.00 equiv), Bu4NI (1.00
equiv), Cs2CO3 (1.05 equiv), MeCN, 65 °C, 65 h, 66% (isolated); ii)
TBAF (1.20 equiv), THF, rt, 0.7 h, 91% (isolated), or K2CO3, MeOH/
THF, rt, 3 h, 80% (isolated); iii) AgNO3 (1.5 equiv) EtOH/H2O,
0.5 h; then KCN (1.00 equiv), 10 min, 87% (isolated).15
intermediates would then be treated with a variety of species for
the achievement of reductive termination pathways: that is, the
Received: September 2, 2011
Published: September 29, 2011
© 2011 American Chemical Society
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a
Table 1. Optimization of Step i: Conditions for the Alkynylation of 2-Bromobenzyl bromide
E
M(L)nXn
solvent
base
NEt3
additive
CuI
T (°C)
time (h)
conv (%)
b
1
2
3
4
5
6
7
8
9
Pd(PPh3)4
Pd(PPh3)4
CuI
THF
rt
48
16
b
THF
NEt3
CuI
45
40
65
65
65
45
65
65
36
dec.
c
MeCN
MeCN
MeCN
MeCN
MeCN
THF
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
Cs2CO3
Bu4NI
Bu4NI
Bu4NI
Bu4NI
CuI, Bu4NI
48
28
CuI
48
69
71
70
CuI
72
CuI
156
108
48
d
Pd(PPh3)2Cl2
100
e
f
Pd(XPhos)
0
g
CuI
MeCN
Bu4NI
65
100
a
Conversion determined by 1H NMR analysis of the crude reaction mixtures. Several alternative methods including alkynyl Grignard and
alkynyllithium·TMEDA complex substitution were attempted without success for this transformation: the use of Grignard methodology giving
debrominated product exclusively and TMEDA−lithium acetylide giving a complex reaction mixture. Pd catalysts Pd(PPh3)4 and Pd(PPh3)2Cl2 were
used in 5 mol % and Pd(OAc)2 in 2 mol % amounts, CuI was used in 1.00 equiv amount, except as an additive, where it was used in 20 mol %
b
amount. Et3N was used in 5.00 equiv, K2CO3 in 2.00 equiv, Cs2CO3 in 1.05 equiv, and Bu4NI in 1.00 equiv amounts. The use of triethylamine as
c
d
base resulted in the generation of considerable amounts of benzyltrimethylammonium halide salts. See ref 13. Complete conversion of substrate,
e
f
however, 70% NMR yield due to formation of a byproduct (30 mol %). Formed in situ from Pd(OAc)2 (2 mol %) and XPhos (6 mol %). See
g
ref 14. These conditions gave only 17% conversion to the aryl bromide coupled species. Isolated yield 66%, scalable to 5 mmol.
conditions12 did not deliver sufficient conversion (entry 1), and
heating the reaction mixture gave the desired product and
inseparable byproducts (entry 2). Pd-free reaction conditions with
stoichiometric copper iodide, n-tetrabutylammonium iodide, and
potassium carbonate as base in acetontirile, as employed by Wulff
et al.,13 gave cleaner reaction mixtures (entry 3), but complete
conversion could not be achieved. Heating to 65 °C for 48 h
improved the conversion to 69% (entry 4), but the conversion did
not improve with further reaction time (entries 5 and 6). The
addition of Pd catalysts to these latter reaction conditions led to
complete consumption of the starting material, but with the
generation of byproducts (entry 7). The use of conditions
described by Buchwald et al.14 gave aryl coupling (i.e., at the arene
bromide moiety, entry 8). Lastly, the utilization of modified
Wulff conditions (with cesium carbonate as base) gave complete
conversion to the alkyne product (entry 9).
involving electron-deficient arene 1b proved especially high
yielding. In contrast, 1-bromonaphthalenyl substrate 1c readily
converted from trimethylsilylalkyne 2c to alkyne 5c in situ
through a relatively facile desilylation/isomerization process.
The desilylation of 2c with TBAF led to allene 3c alongside the
same alkyne 5c. The 2-bromomethylanisole 1e also underwent
the reaction sequence with high yields to 3e.17 The allenes were
then tested under a variety of Pd-catalyzed reaction conditions.
First, the formal addition of (tethered) Ar and NRR′ across
the allene π-system was accomplished using Buchwald−
Hartwig amination conditions: Pd(OAc)2, rac-BINAP, and an
Table 2. Conversion of o-(Bromo)methylarenes 1 to
a
Trimethylsilylalkynes 2 and then Allenes 3
yield
(%)
yield
(%)
E
conditions
1x
2x
conditions
3x
Application of the optimized conditions to the synthesis of
substituted analogues of 2-bromobenzyl bromide (1a−e,
Scheme 3)16 proved to be generally applicable, giving good
1
2
3
4
5
i
i
i
i
i
1a
1b
1c
1d
1e
2a
2b
2c
2d
2e
66
94
ii
ii
ii
ii
3a
3b
3c
3d
3e
91
87
b
c
46
91
67
87
90
99
Scheme 3. Conversion of o-Bromo(bromo)methylarenes
ii
a
1b−d to o-Bromoarylallenes 3b−d
a
b
c
Isolated yield. Allene 3c as byproduct, 54%. Only 1.0 equiv of
Bu4NF was used; otherwise, 5c was obtained (45%).
excess of Cs2CO3 in toluene gave enamine 7a, almost certainly
by way of carbopalladate intermediate 6a (Scheme 4).
Scheme 4. Buchwald−Hartwig Amination of 2-Bromo-
a
arylallene 3a
a
Key: (i) pyrrolidine (4.0 equiv), Pd(OAc)2 (5 mol %), rac-BINAP
(12 mol %), Cs2CO3 (2.0 equiv), toluene, 100 °C, 14 h, 21−68% yield.
a
For conditions i and ii, see Scheme 2.
Unfortunately, the reaction proved capricious in terms of
reproducibility (21−68% isolated yield); this is largely due to
the nature of enamine 6a as being easily hydrolyzed.
to excellent yields of the allene products in an efficient two-step
process (see Scheme 3 and Table 2). The reaction sequence
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Application of other secondary amines (morpholine, bis-
allylamine, diphenylamine) did not resolve this issue.
ammonia surrogates in Pd-catalyzed reactions appears to not
have been previously reported.21,22
A plausible pathway for the synthetic transformation from
bromides 3a−d and 5c to the indole products 9a−d, and which
accounts for all of the observed byproducts in the various
reactions, is presented below (Scheme 6). The initial
We sought to apply this methodology to the synthesis of
indenylacetamides using the Buchwald−Hartwig amidation
reaction;8 however, under conditions previously reported for
this reaction, an unexpected and selective indole synthesis was
found to occur. Stirring the bromide with palladium acetate,
Xantphos, cesium carbonate, and acetamide in dioxane at
100 °C18 unexpectedly gave 2-methylindole 9a as product in
40% yield, alongside alkyne 10a (R4 = Me, 29%), presumably
an intermediate in the reaction (Scheme 5, Table 3). A marked
Scheme 6. Proposed Pathway of the Domino Addition,
Buchwald−Hartwig Amidation, and Hydrolysis to Indoles 8
and Byproducts
Scheme 5. Indole Formation under Buchwald−Hartwig
a
Amidation Conditions
regioselective addition of amide across the allene gives vinyl
amide 13a−d, which then is hydrolyzed and undergoes intra-
molecular Buchwald−Hartwig coupling (steps a and b may also
occur in the reverse order). Alternative reaction sequences
involving initial Buchwald−Hartwig coupling would result in
product 11b, and a sequence of first π-isomerization23 followed
by Buchwald−Hartwig coupling would result in product 10b.
The cyclization of o-(acyl/benzyl)aminoalkynes of the type
represented by 10a is known.24 The extent to which each
pathway is active under these reaction conditions is highly
substrate-dependent, as demonstrated by the byproduct
generated in each case.
A domino carbopalladation−Suzuki reaction to deliver
derivatives of the type 14a was attempted under modified
Suzuki conditions,25,26 giving always complex product mixtures.
For example, application of Pd(dppf)Cl2 as catalyst with triethyl-
amine as a base in a mixture of water and tetrahydrofuran,
conditions reported by Banwell and co-workers,26 gave
mixtures too complex to characterize, so lower temperatures
were used in an attempt to increase selectivity (40 °C). The
reactivity of 3 to displayed at this temperature was orthogonal
to that observed for the Buchwald−Hartwig amination and
amidation conditions, in that the aryl bromide functionality
stayed intact under the reaction conditions (i.e., the conversion
from product does not involve oxidative insertion of Pd0 at the
aryl bromide functionality). Instead, the allene π-system was
found to react in arylation processes delivering products with
the net effect of addition across the allene π-system of ArH and
2Ar to give monoarylated and diarylated products (15 and 16,
respectively, Scheme 7). Reaction mixtures were nonetheless
quite complex, and only mixtures of mono- and diarylated
isomers could be separated from one another.
a
Both i and ii utilize Pd(OAc)2 (5 mol %), Xantphos (12 mol %),
Cs2CO3 (2.0 equiv), 1,4-dioxane (0.3 M), 100 °C, 19 h, in combina-
tion with (i) acetamide (1.30 equiv) and (ii) benzamide (1.30 equiv).
a
Table 3. Buchwald−Hartwig Amidation
E
3x
conditions
9x
yield (%)
byproduct
yield (%)
29
1
2
3
4
5
5
3a
3a
3b
3c
3d
5c
i
9a
9a
9b
9c
9d
9c
40
84
49
54
58
43
10a
ii
ii
ii
ii
ii
11b
12c
10
35
12c
50
a
Isolated yields.
increase in yield of 9a (84%) resulted when benzamide was
used as the amide coupling partner (Table 3). Under these
conditions, notably clean reactions resulted in the generation of
indole products 9a−c that were both stable and isolable in fair
to good yields; the major other species isolated from reaction
mixtures were amide 11b from bromide 3b and amide 12c from
either allene 3c or alkyne 5c, which was also tested under the
reaction conditions. While reactions involving the hydro-
amidation of allenes catalyzed by a variety of transition metals
are known,19 the one-pot or domino construction of indoles
from separate aryl halide and amine components under Pd
catalysis has not, to the best of our knowledge, been previously
described.20 Additionally, the use of benzamide or acetamide as
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reaction mixture stirred in an aluminum heating block at 65 °C for
72 h, with daily shaking to loosen up cesium carbonate deposits on the
walls of the reaction vessel. After this time, the magenta suspension
was diluted with diethyl ether (10 mL) and filtered through a Celite
pad. The tetra-n-butylammonium iodide subsequently crystallized, and
a second filtration was made through a cotton wool plug. The crude
was reduced of volatiles on the rotary evaporator (care was taken, as
the products can be volatile at low pressures). The resulting crude was
subjected to column chromatography [silica gel, ethyl acetate/cyclo-
hexane (1:160)] to yield (3-(2-bromophenyl)prop-1-yn-1-yl)trimethyl-
silane (2a) as a colorless oil (353 mg, 1.32 mmol, 66%).
Scheme 7. Addition of Ar-H and 2Ar to Allenes 3a and 3e,
Respectively
a
Example Procedure B: Desilylation/Allene Formation
(3a). (3-(2-Bromophenyl)prop-1-yn-1-yl)trimethylsilane (2a, 335 mg,
1.25 mmol) was dissolved in tetrahydrofuran (5.0 mL) and then
stirred at room temperature. A solution of tetra-n-butylammonium
fluoride in tetrahydrofuran (1.00 M, 1.50 mL, 1.50 mmol) was added
dropwise by syringe at room temperature, and the resulting black
solution was stirred for 0.5 h. After this time, the reaction was
quenched with a saturated solution of ammonium chloride (10 mL)
and extracted with diethyl ether (2 × 15 mL). The organic layers were
combined, washed with saturated sodium hydrogen carbonate solution
(20 mL) and saturated brine (20 mL), dried over sodium sulfate,
filtered, and reduced of volatiles on the rotary evaporator (care was
taken, as the products can be volatile at low pressures). The resulting
crude was subjected to column chromatography (silica gel, pentane)
to give 1-bromo-2-(propa-1,2-dien-1-yl)benzene (3a) as a colorless
volatile oil (221 mg, 1.14 mmol, 91%).
Procedure C: Domino Carbopalladation Buchwald−Hartwig
Amination To Form 1-(1H-Inden-2-yl)pyrrolidine (7a). 1-Bromo-
2-(propa-1,2-dien-1-yl)benzene (3a, 97.6 mg, 0.50 mmol), cesium
carbonate (164 mg, 0.50 mmol), palladium acetate (2.8 mg, 0.013
mmol), rac-BINAP (18.7 mg, 0.03 mmol), and toluene (1.00 mL)
were combined together with a stirring bar in a 20 mL vial, which was
then sealed and degassed (3 × vacuum and backfill with argon while
stirring vigorously) via a needle through the septum. Pyrrolidine
(71.0 mg, 1.00 mmol) was then added, and the reaction mixture
was stirred in an aluminum heating block at 80 °C for 14 h, after
which time it was cooled and diluted with dichloromethane
(5 mL) and the suspension filtered through a small plug of Celite.
The crude was reduced of volatiles on the rotary evaporator (care was
taken, as the products can be volatile at low pressures) and then
crystallized by slow evaporation from the crude in ethyl acetate (7a)
as a pale brown crystalline solid (61.5 mg, 0.34 mmol, 68%). Mp:
117−118 °C.
Example Procedure D: Domino Buchwald−Hartwig Amida-
tion/Allene Amidation To Form Indoles 9a−c. 1-Bromo-2-
(propa-1,2-dien-1-yl)benzene (3a, 74.0 mg, 0.38 mmol), benzamide
(60.6 mg, 0.50 mmol), cesium carbonate (248 mg, 0.76 mmol),
palladium acetate (2.2 mg, 0.010 mmol), Xantphos (13.9 mg,
0.024 mmol), and dioxane (1.00 mL) were combined together with
a stirring bar in a 20 mL vial, which was then sealed and degassed
(3 × vacuum and backfill with argon while stirring vigorously) via a
needle through the septum. The reaction mixture was stirred in an
aluminum heating block at 100 °C for 19 h, after which time it was
cooled and diluted with dichloromethane (5 mL) and the suspension
filtered through a small plug of Celite. The crude was reduced of
volatiles on the rotary evaporator (care was taken, as the products
can be volatile at low pressures) and then subjected to column
chromatography [silica gel, ethyl acetate/cyclohexane (1:9)] to yield
2-methylindole (9a) as a brown-purple crystalline solid (42.3 mg,
0.32 mmol, 84%). Mp: 51−52 °C.
General Methods. Unless otherwise specified, chemicals were
purchased from commercial suppliers and used without further
purification. All reactions involving moisture-sensitive reactants were
executed under an argon atmosphere using oven-dried glassware. All
solvents were used as commercially available (AR grade), with the
exception of tetrahydrofuran, which was refluxed with sodium/
potassium alloy under argon atmosphere.
a
Conditions i and ii: see Table 4.
The ratio of these products depended on the nature of the
arylboronic acid used (Table 4, entries 1 and 2). It was found
Table 4. Hydroarylation of Allenes
b
compd
yield
(%)
compd
yield
(%)
a
E
3x
Ar-X
conditions
15
16
1
2
3
4
3a
3a
3e
3e
Br
i
o-15a
p-15a
o-15e
p-15e
57
49
51
28
o-16a
p-16a
o-16e
p-16e
30
8
Br
ii
i
OMe
OMe
12
9
ii
a
See Scheme 7. Key: (i) 2-methoxyphenylboronic acid (2.0 equiv),
Pd(dppf)Cl2 (6 mol %), Et3N/H2O/THF (5:2:18), 40 °C, 48 h;
(ii) as with i, but with 4-methoxyphenylboronic acid (2.0 equiv).
b
Yields determined from separation of products into groups of double-
bond isomers and regioisomers.
that the use of 2-methoxyphenylboronic acid gave both a higher
overall reactivity and relative amount of the diaryl-addition
product relative to arylhydride addition in comparison to
4-methoxyphenylboronic acid under identical conditions. The
2-methoxyphenylallene 3e was exposed to the same reaction
conditions, under which it reacted in an analogous manner with
addition of ArH and 2Ar across the allene π-system (entries 3
and 4). In the case of the reaction with 2-methoxyphenylbor-
onic acid, isolation of the trans-stilbene addition product o-15e
was possible in 32% yield (stereochemistry determined by
NOESY). Such a process has been previously reported for the
reaction of allenes and boronic acids in the presence of Pd-
catalyst and acid.27
The further investigation of these multitalented substrates is
currently underway in our laboratories, and we will report
further on their application in other Pd-catalyzed domino reac-
tions in due course.
EXPERIMENTAL SECTION
■
Example Procedure A: Coupling of Trimethylsilylacetylene
with o-Heteroatom-Substituted Aryl Bromides (2a). 2-Bromo-
benzyl bromide (1a, 500 mg, 2.00 mmol), cuprous iodide (381 mg,
2.00 mmol), tetra-n-butylammonium iodide (739 mg, 2.00 mmol),
cesium carbonate (684 mg, 2.10 mmol), and acetonitrile (HPLC
grade, 3.0 mL) were sealed in a 20 mL reaction vial with a stirring bar
and degassed (3 × vacuum and backfill with argon while stirring
vigorously) via a needle through the septum. Trimethylsilylacetylene
(296 mg, 405 μL, 3.00 mmol) was then added by syringe, and the
All reactions were monitored by thin layer chromatography (TLC)
(silica gel 60 on aluminum plate, fluorescence indicator F254, 0.25 mm
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layer thickness). An ultraviolet lamp as well as the Seebach reagent
(phosphomolybdic acid (12 g), cerium(IV) sulfate tetrahydrate (5 g),
concentrated sulfuric acid (30 mL) and ethanol (250 mL)) and
vanillin (vanillin (15 g), concentrated sulfuric acid (2.5 mL) in ethanol
(250 mL)) were used for detection. The separation and the
purification of products from mixtures was performed by means of
column chromatography according to the Stille procedure. Silica gel 60
was used as stationary phase, and eluent system mixtures were
previously distilled.
(CH), 128.2 (CH), 124.4 (C), 104.8 (C), 88.7 (C), 28.5 (CH2), 0.8
(CH3); EI-MS m/z 316.1 (31) [M+], 303 (14) [(C15H14BrSi) +],
+
165.1 (100) [(C13H9) ]; EI-HRMS calcd for C16H17BrSi 316.0283,
found 316.0282.
1H NMR spectra were recorded on either an AC 250 MHz or AM
400 MHz spectrometer. Chemical shifts are reported in parts per
million (δ (ppm)) downfield from tetramethylsilane (TMS), with
CHCl3 or acetone as an internal standard (CHCl3: 7.26 ppm; acetone:
2.05 ppm). Data are reported as follows: chemical shift, multiplicity
(s = singlet, br s = broad singlet, d = doublet, t = triplet, m = multiplet,
dd = doublet of doublets, ddd = doublet of dd, dt = doublet of triplets,
ddt = doublet of dt, mc = centered multiplet), integration, and
coupling constants (Hz). 13C NMR spectra were recorded on either a
63 or 101 MHz NMR spectrometer. Chemical shifts are reported
in ppm with CHCl3 or acetone as an internal standard (CHCl3: 77.2
ppm; acetone: 29.8 ppm). The signal structure was analyzed by DEPT
and is described as follows: C = quaternary C-atom (no DEPT signal),
CH = tertiary C-atom (positive DEPT signal), CH2 = secondary
C-atom (negative DEPT signal) and CH3 = primary C-atom (positive
DEPT signal). MS: The molecular fragments are quoted as the relation
between mass and charge (m/z), the intensities as a percentage value
relative to the intensity of the base signal (100%). The abbreviation
[M]+ refers to the molecular ion.
(3-(2-Methoxyphenyl)prop-1-yn-1-yl)trimethylsilane (2e). After
reaction of benzyl bromide 1e (402 mg, 2.00 mmol) through example
procedure A, silane 2e was isolated as a pale yellow oil (378 mg, 1.74
1
mmol, 87% yield): H NMR (CDCl3, 400 MHz) δ = 7.53 (d, J = 7.4
Hz, 1H), 7.21−7.25 (m, 1H), 6.95−6.99 (m, 1H), 6.83 (d, J = 8,0 Hz,
1H), 3.83 (s, 3H), 3.62 (s, 2H), 0.20 (s, 9H); 13C NMR (CDCl3, 100
MHz) δ = 156.5 (C), 128.6 (CH), 127.6 (CH), 124.6 (C), 120.3
(CH), 109.8 (CH), 104.3 (C), 86.8 (C), 55.2 (CH3), 20.3 (CH2), 0.00
(SiCH3); EI-MS m/z 218.2 (89) [M+], 203.2 (100) [(C12H15OSi)];
EI-HRMS calcd for C13H18OSi 218.1126, found 218.1127.
1-Bromo-2-(propa-1,2-dien-1-yl)benzene (3a). After reaction of
substrate 2a (330 mg, 1.23 mmol) through example procedure B
above, allene 3a was isolated as a pale yellow oil (222 mg, 1.14 mmol,
92% yield): 1H NMR ((CD3)2CO, 400 MHz) δ = 7.60 (d, J = 8.0 Hz,
1H), 7.50 (d, J = 7.7 Hz, 1H), 7.36 (t, J = 7.4 Hz, 1H), 7.16 (t, J = 7.4
Hz, 1H), 6.59 (t, J = 6.9 Hz, 1H), 5.29 (d, J = 6.9 Hz, 2H); 13C NMR
((CD3)2CO, 100 MHz) δ = 212.2 (C), 135.2 (C), 134.8 (CH), 130.5
(CH), 130.2 (CH), 129.7 (CH), 123.6 (C), 94.2 (CH), 80.5 (CH2);
EI-MS m/z 194.0 (23) [M+], 115.0 (100) [(C9H7)+]; EI-HRMS calcd
for C9H7Br 193.97311, found 193.9729.
Compounds and Characterization Data. (3-(2-Bromophenyl)-
prop-1-yn-1-yl)trimethylsilane (2a). After reaction of benzyl bromide
1a (500 mg, 2.00 mmol) through example procedure A, silane 2a was
1
isolated as a colorless oil (353 mg, 1.32 mmol, 66% yield): H NMR
(CDCl3, 400 MHz) δ = 7.64 (ddd, J = 7.8, 0.07, 0.07 Hz, 1H), 7.53
(dd, J = 8.0, 1.2 Hz, 1H), 7.32 (ddd, J = 7.6, 7.6, 1.2, 1H), 7.12 (ddd,
J = 8.0, 7.9, 1.7, 1H), 3.72 (s, 2H), 0.21 (s, 9H); 13C NMR (CDCl3,
100 MHz) δ = 135.7 (C), 132.4 (CH), 129.5 (CH), 128.2 (CH),
127.5 (CH) 123.8 (C), 102.9 (C), 88.3 (C), 21.2 (CH2), 0.4 (CH3);
EI-MS m/z 266.1 (50) [M+], 251.1 (100) [(C11H12SiBr)+]; EI-HRMS
calcd for C12H15SiBr 266.0126, found 266.0128. Data are consistent
with the literature: Kuno, A.; Saino, N.; Kamachi, T.; Okamoto, S.
Tetrahedron Lett. 2006, 47, 2591−2594.
5-Bromo-6-(propa-1,2-dien-1-yl)benzo[d][1,3]dioxole (3b). After
reaction of silane 2b (1.81 g, 5.82 mmol) through example procedure
B above, allene 3b was isolated as a pale yellow solid (1.21 g, 5.04
mmol, 87% yield): mp 42 °C; 1H NMR (CDCl3, 400 MHz) δ = 6.97
(s, 1H), 6.94 (s, 1H), 6.56 (t, J = 6.8 Hz, 1H), 5.98 (s, 2H), 5.17 (d,
J = 6.8 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ = 210.1 (C), 147.6
(C), 147.4 (C), 126.7 (C), 112.9 (C), 112.6 (CH), 107.4 (CH), 101.7
(CH2), 93.2 (CH), 79.3 (CH2); EI-MS m/z 238.0 (100) [M+], 159.1
(40) [(C10H7O2)+]; EI-HRMS calcd for C10H7O2Br 237.9630, found
237.9628.
(3-(6-Bromobenzo[d][1,3]dioxol-5-yl)prop-1-yn-1-yl)-
trimethylsilane (2b). After reaction of benzyl bromide 1b (584 mg,
2.00 mmol) through example procedure A, silane 2b was isolated as a
1
pale orange solid (588 mg, 1.88 mmol, 94% yield): mp 37 °C; H
NMR (CDCl3, 400 MHz) δ = 7.14 (s, 1H), 6.99 (s, 1H), 5.97 (s, 2H),
3.62 (s, 2H), 0.20 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ = 147.4
(C), 147.1 (C), 128.8 (C), 113.8 (C), 112.4 (CH), 109.5 (CH), 103.1
(C), 101.6 (CH2), 88.1 (C), 26.9 (CH2), 0.00 (CH3); EI-MS m/z
310.0 (100) [M+], 295 (38) [(C12H12BrO2Si) +], 173.1 (56)
[(C12H12BrO2Si) +]; EI-HRMS calcd for C13H15BrO2Si 310.0025,
found 310.0027.
1-Bromo-2-(propa-1,2-dien-1-yl)naphthalene (3c). After reaction
of silane 2c (400 mg, 1.26 mmol) through example procedure B above,
using only 1.00 equivalents of Bu4NF, allene 3c was isolated as a pale
yellow solid (281 mg, 1.15 mmol, 91% yield). Also, after reaction of
bromide 1c (600 mg, 2.00 mmol) through standard procedure A
above, allene 3c was isolated as a yellow solid (264 mg, 1.07 mmol,
54% yield). Note: This allene isomerizes to alkyne 5c readily and is
optimally used directly after preparation: mp 41 °C; 1H NMR
((CD3)2CO, 400 MHz) δ = 8.29 (d, J = 8.40 Hz, 1H), 7.93 (d, J = 8.2
Hz, 1H), 7.89 (d, J = 8.6 Hz, 1H) 7.69−7.54 (mc, 3H), 6.95 (t, J = 6.8
Hz, 1H), 5.38 (d, J = 6.8 Hz, 2H); 13C NMR ((CD3)2CO, 100 MHz)
δ = 213.4 (C), 135.8 (C), 134.7 (C), 133.5 (C), 130.4 (CH), 130.1
(CH), 130.0 (CH), 129.2 (CH), 128.7 (CH), 127.2 (CH), 123.0 (C),
95.8 (CH), 81.0 (CH2); EI-MS m/z 244.0 (7) [M+], 234.0 (100)
[(C12H11Br)+]; EI-HRMS calcd for C13H9Br 243.9888, found
243.9890.
(3-(1-Bromonaphthalen-2-yl)prop-1-yn-1-yl)trimethylsilane
(2c). After reaction of benzyl bromide 1c (600 mg, 2.00 mmol)
through example procedure A, silane 2c was isolated as a colorless
crystalline solid (293 mg, 0.92 mmol, 46% yield), alongside allene 3c
(264 mg, 1.07 mmol, 54% yield; see below): mp 51−53 °C; 1H NMR
(CDCl3, 400 MHz) δ = 8.30 (d, J = 8.8 Hz, 1H), 7.99 (d, J = 8.5 Hz,
1H), 7.95 (d, J = 8.1 Hz, 1H), 7.74 (d, J = 8.5 Hz, 1H), 7.69 (ddd, J =
8.5, 6.9, 1.4 Hz, 1H), 7.60 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 4.02 (s, 2H),
0.17 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ = 135.9 (C), 135.4 (C),
133.9 (C), 130.0 (CH), 129.7 (CH), 129.5 (CH), 128.7 (CH), 128.3
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MHz) δ = 133.4 (C), 132.2 (C), 129.4 (CH), 128.2 (CH), 127.8
(CH), 127.7 (CH), 127.4 (CH), 126.8 (CH), 125.9 (C), 124.2 (C),
92.0 (C), 79.9 (C), 4.9 (CH3); EI-MS m/z 244.0 (97) [M+], 165.1
(100) [(C13H9)+]; EI-HRMS calcd for C13H9Br 243.9888, found
243.9890.
Methyl 4-Bromo-3-(propa-1,2-dien-1-yl)benzoate (3d). After re-
action of silane 2d (326 mg, 1.00 mmol) through example procedure
B, allene 3d was isolated as a pale yellow oil (227 mg, 0.90 mmol, 90%
yield): 1H NMR (CDCl3, 400 MHz) δ = 8.15 (d, J = 1.7 Hz, 1H), 7.94
(dd, J = 8.2, 1.7 Hz, 1H), 7.61 (d, J = 8.2 Hz, 1H), 6.64 (t, J = 6.8, 6.8
Hz, 1H), 5.38 (d, J = 6.8 Hz, 1H), 3.89 (s, 3H); 13C NMR (CDCl3,
100 MHz) δ = 213.2 (C), 166.7 (C), 140.2 (C), 135.6 (CH), 132.1
(C), 130.3 (CH), 130.1 (CH), 123.3 (C), 93.9 (CH), 81.8 (CH2),
53.7 (CH3); EI-MS m/z 252.0 (93) [M+], 243.1 (100) [(x)+]; EI-
HRMS calcd for C11H9O2Br: 251.9786, found 251.9789.
1-(1H-Inden-2-yl)pyrrolidine (7a). After reaction of allene 3a
(110 mg, 0.50 mmol) through example procedure C, enamine 7a
was isolated as a pale brown crystalline solid (61.5 mg, 0.34 mmol,
68%): mp 117−118 °C; 1H NMR (CDCl3, 400 MHz) δ = 7.18 (d, J =
7.26 Hz, 1H), 7.09 (t, J = 7.47 Hz, 1H), 6.98 (d, J = 7.45 Hz, 1H), 6.79
(td, J = 7.36, 1.04 Hz, 1H), 5.19 (s, 1H), 3.37 (br s, 2H), 3.24 (mc,
4H), 1.96 (mc, 4H); 13C NMR (CDCl3, 100 MHz) δ = 155.5 (C),
148.6 (C), 136.9 (C), 127.0 (CH), 123.0 (CH), 119.5 (CH), 116.8
(CH), 95.3 (CH), 48.9 (CH2), 38.3 (CH2), 25.8 (CH2); Data are
consistent with the literature: 13C NMR: Edlund, U. Chem. Scripta
1975, V7, 2, 85−89. Preparation (mp 120−121 °C): Blomqvuist, A. T.;
Morricone, E. J. J. Org. Chem. 1961, 26, 3761.
1-Methoxy-2-(propa-1,2-dien-1-yl)benzene (3e). After reaction of
silane 2e (355 mg, 1.63 mmol) through example procedure B above,
allene 3e was isolated as a yellow oil (235 mg, 1.62 mmol, 99% yield):
1H NMR (CDCl3, 400 MHz) δ = 7.40 (dd, J = 7.6, 1.5 Hz, 1H), 7.20
(ddd, J = 8.3, 7.5, 1.5 Hz, 1H), 6.93 (ddd, J = 7.5, 7.6, 0.8 Hz, 1H),
6.86 (d, J = 8.2 Hz, 1H), 6.57 (t, J = 6.9 Hz, 1H), 5.11 (d, J = 6.9 Hz,
2H), 3.84 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ = 210.4 (C), 156.0
(C), 128.2 (CH), 128.0 (CH), 122.6 (C), 121.1 (CH), 111.2 (CH),
88.1 (CH), 78.3 (CH2), 55.9 (CH3); EI-MS m/z 146.1 (11) [M+],
135.1 (100) [(x)+]; EI-HRMS calcd for C10H10O 146.0732, found
146.0734. Data are consistent with the literature: Benoit, B.;
Odabachian, Y.; Gagosz, F. J. Am. Chem. Soc. 2010, 132, 7294−7296.
2-Methyl-1H-indole (9a). After the reaction of bromide 3a (74 mg,
0.038 mmol) with benzamide according to example procedure D,
indole 9a was isolated as a brown-purple crystalline solid (42.3 mg,
0.322 mmol, 84% yield): mp 52 °C; 1H NMR (CDCl3, 400 MHz) δ =
7.82 (br s, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.29 (d, J = 7.5 Hz, 1H),
7.07−7.15 (m, 2H), 6.23−6.24 (m, 1H), 2,45 (s, 3H); 13C NMR
(CDCl3, 100 MHz) δ = 136.1 (C) 135.1 (C), 129.1 (C), 120.9 (CH),
119,7 (2 × CH), 110.3 (CH), 100.4 (CH), 13.7 (CH3). Data are
consistent with the literature: Kasaya, Y.; Hoshi, K.; Terada, Y.;
Nishida, A.; Shuto, S.; Arisawa, M. Eur. J. Org. Chem., 2009, 27, 4606−
4613.
1-Bromo-2-(prop-2-yn-1-yl)benzene (4a). Following the proce-
dure of Jung and Hagenah,15 silane 2a (202 mg, 0.76 mmol) was
dissolved in 4 mL of ethanol, to which a solution of silver nitrate
(193 mg, 1.13 mmol) dissolved in 0.3 mL of water and 0.7 mL of ethanol
was added dropwise. During the addition, a gumlike oil separated from
the solution. Stirring was continued at room temperature for an addi-
tional 30 min. At this time, a solution of potassium cyanide (523 mg,
7.56 mmol) in 3 mL of water was added. This mixture was stirred until
the oil dissolved, then the solution was diluted with 25 mL of diethyl
ether. The organic layer was washed with water (1 × 10 mL) and
brine (1 × 10 mL), dried over Na2SO4, and concentrated in vacuo to
give a crude gum (152 mg). Column chromatography followed with
pentane and then dichloromethane/pentane delivered the product as a
6-Methyl-5H-[1,3]dioxolo[4,5-f]indole (9b). After the reaction of
bromide 3b (91 mg, 0.038 mmol) with benzamide according to
example procedure D, indole 9b was isolated as a purple crystalline
solid (32.8 mg, 0.187 mmol, 49% yield): mp 118 °C; 1H NMR
(CDCl3, 400 MHz) δ = 7.71 (brs, 1H), 6.91 (s, 1H), 6.76 (s, 1H), 6.09
(s, 1H), 5.91 (s, 2H), 2.38 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ =
143.9 (C), 142.0 (C), 133.6 (C), 130.6 (C), 122.7 (C), 100.6 (CH),
100.4 (CH2), 98.0 (CH), 91.0 (CH), 13.7 (CH3); EI-MS m/z 175.1
(100) [M+], 174.1 (47) [(C10H8NO2)+]; EI-HRMS calcd for
C10H9NO2 175.0633, found 175.0632. Data are consistent with the
literature: Fleming, I.; Woolias, M. J. Chem. Soc., Perkin Trans. 1 1979,
3, 829−837.
1
pale yellow oil (128 mg, 0.66 mmol, 87% yield): H NMR (CDCl3,
400 MHz) δ = 7.61 (d, J = 7.7 Hz, 1H), 7.56 (dd, J = 7.6, 1.2 Hz, 1H),
7.35 (ddd, J = 7.6, 7.6, 1.2 Hz, 1H), 7.18 (ddd, J = 7.7, 7.6, 1.2 Hz,
1H), 3.64 (d, J = 2.8 Hz, 2H), 2.68 (t, J = 2.8 Hz, 1H); 13C NMR
(CDCl3, 100 MHz) δ = 137.9 (C), 134.6 (CH), 131.8 (CH), 130.8
(CH), 130.0 (CH), 125.4 (C), 82.4 (C), 74.2 (CH), 27.3 (CH2); EI-
MS m/z 194.0 (89) [M+], 115.1 (100) [(C9H7)+]. Data are consistent
with the literature: Curran, D. P.; Liu, H.; Josien, H.; Ko, J.-B.
Tetrahedron 1996, 52, 11385−11404.
2-Methyl-1H-benzo[g]indole (9c). After the reaction of bromide
3c (83 mg, 0.38 mmol) with benzamide according to example pro-
cedure D, indole 9c was isolated as a purple crystalline solid (38 mg,
1
1-Bromo-2-(prop-1-yn-1-yl)naphthalene (5c). After reaction of
silane 2c (600 mg, 2.00 mmol) through example procedure B above,
alkyne 5c was isolated as a pale yellow solid (219 mg, 0.90 mmol, 45%
0.20 mmol, 54% yield): mp 131−132 °C; H NMR (CDCl3, 400
MHz) δ = 8.59 (brs, 1H), 7.37−7.95 (m, 6H), 6.38 (s, 1H), 2.55 (s,
3H); 13C NMR (CDCl3, 100 MHz) δ = 133.3 (C), 130.4 (C), 130.2
(C), 128.9 (CH), 125.3 (CH), 125.1 (C), 123.5 (CH), 121.6 (C),
120.7 (CH), 120.5 (CH), 119.3 (CH), 102.5 (CH), 13.8 (CH3);
EI-MS m/z 181.1 (100) [M+], 153.1 (21) [(C10H8NO2)+]; EI-RMS
1
yield): mp 37 °C; H NMR (CDCl3, 400 MHz) δ = 8.05 (d, J = 8.5
Hz, 1H), 7.54 (d, J = 8.1 Hz, 1H), 7.47 (d, J = 8.5 Hz, 1H), 7.33−7.37
(m, 2H), 7.24−7.28 (m, 1H), 1.97 (s, 3H); 13C NMR (CDCl3, 100
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calcd for C13H11N 181.0895, found 181.0891. Data are consistent with
the literature: Gassman, P. G. J. Org. Chem. 1977, 42, 3240−3243.
(CO), 136.0 (C), 134.3 (C), 134.0 (CH), 131.2 (C), 131.0 (C),
130.5 (CH), 128.8 (CH), 128.8 (CH), 126.0 (C), 125.2 (CH), 123.4
(CH), 123.2 (CH), 121.8 (C), 121.5 (CH), 119.5 (CH), 105.9 (CH),
14.2 (CH3); EI-MS m/z 285.1 (55) [M+], 166.1 (100) [C13H10+•]; EI-
HRMS calcd for C20H15NO 285.1154, found 285.1152.
Methyl 2-methyl-1H-indole-5-carboxylate (9d). After the reaction
of bromide 3d (126 mg, 0.50 mmol) with benzamide according to
example procedure D, indole 9d was isolated as a pale beige solid
1
(55 mg, 0.20 mmol, 58% yield): H NMR (CDCl3, 400 MHz) δ =
8.38 (br s, 1H), 8.07 (s, 1H), 7.77 (dd, J = 8.3, 1.4 Hz), 7.51 (d, J = 8.3
Hz, 1H), 6.86 (br s, 1H), 3.93 (s, 3H), 2.46 (s, 3H); 13C NMR
(CDCl3, 100 MHz) δ = 168.5 (C), 138.8 (C), 136.7 (C), 135.3 (CH),
133.0 (C), 122.3 (CH), 120.8 (CH), 119.0 (CH), 112.5 (C), 100.9
(C), 51.8 (CH3), 13.8 (CH3); EI-MS m/z 189.1 (100) [M+], 158.1
(98) [(C10H8NO)+]; EI-RMS calcd for C11H11NO2 189.0790, found
189.0788. Data are consistent with the literature: Ambrogio, I.; Cacchi,
S.; Fabrizi, G.; Prastaro, A. Tetrahedron 2009 65, 8916−8929.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR data for compounds. This material is
available free of charge via the Internet at http://pubs.acs.org/.
AUTHOR INFORMATION
Corresponding Author
*E-mail: braese@kit.edu.
■
ACKNOWLEDGMENTS
K.-S.M. acknowledges the generous funding and support
provided by the Alexander von Humboldt Foundation.
N-(2-(Prop-1-yn-1-yl)phenyl)acetamide (10a). After reaction of
bromide 3a (74 mg, 0.38 mmol scale) with acetamide through example
procedure D above, amide 9e was isolated (alongside 8a, see above) as
a pale brown crystalline solid (19.5 mg, 0.11 mmol, 29% yield): mp
75 °C; 1H NMR (CDCl3, 400 MHz) δ = 8.37 (d, J = 8.3 Hz, 1H), 7.91
(brs, 1H), 7.35 (dd, J = 7.7, 1.1 Hz, 1H), 7.28 (m, 1H), 7.00 (dd, J =
7.5, 7.5 Hz, 1H), 2.22 (s, 3H), 2.15 (s, 3H); 13C NMR (CDCl3, 100
MHz) δ = 168.2 (C), 138.9 (C), 131.7 (CH), 128.9 (CH), 123.2
(CH), 119.1 (CH), 112.5 (C), 93.2 (C) 75.1 (C), 25.0 (CH3), 4.6
(CH3); EI-MS m/z 173.1 (95) [M+], 131.1 (100) [(C9H9N)+], 130.0
(98)) [(C9H8N)+]; EI-HRMS calcd for C11H11NO 173.0841, found
173.0838. Data are consistent with the literature: Miyagi, T.
Tetrahedron Lett. 2004, 45, 6303−6305.
■
REFERENCES
■
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(11b). After reaction of bromide 3b (91 mg, 0.038 mmol) through
example procedure D above, amide 10b was isolated as a beige solid
(11.0 mg, 0.039 mmol, 10% yield): mp 129−135 °C; 1H NMR
(CDCl3, 400 MHz) δ = 7.79 (d, J = 7.6 Hz, 2H), 7.51−7.42 (m, 3H),
6.86 (s, 1H), 6.74 (s, 1H), 6.60 (brs, 1H), 5.96 (s, 2H), 5.92 (s, 1H),
5.11 (s, 1H), 4.19 (s, 1H) 13C NMR (CDCl3, 100 MHz) δ = 200.4
(C), 167.5 (CO), 147.1 (C), 141.5 (C), 137.9 (C), 134.1 (C),
131.7 (CH), 128.6 (CH), 128.6 (C), 127.0 (CH), 104.7 (CH), 100.9
(CH), 100.8 (CH), 100.0 (CH2), 77.2 (CH2); EI-MS m/z 279.1 (70)
[M+], 174.1 (75) [(C10H8NO2)+], 105.0 (100) [(C7H5O)+]; EI-
HRMS calcd for C17H13NO3 279.0895, found 279.0893.
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(2-Methyl-1H-benzo[g]indol-1-yl)(phenyl)methanone (12c). After
reaction of bromide 5c (83 mg, 0.38 mmol) through example pro-
cedure D above, amide 12c was isolated as a pale brown gum (55 mg,
0.19 mmol, 50% yield): 1H NMR (CDCl3, 400 MHz) δ = 7.87 (d, J =
8.3 Hz, 1H), 7.74 (J = dd, 8.3, 1.2 Hz, 2H), 7.68−7.59 (m, 3H), 7.57
(mc, 1H), 7.39 (dd, J = 7.8, 7.8 Hz, 2H), 7.29 (ddd, J = 8.01, 8.0, 1.1
Hz, 1H), 7.21 (ddd, J = 8.3, 6.9, 1.3 Hz, 1H), 6.54 (d, J = 0.9 Hz, 1H),
2.38 (d, J = 0.8 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ = 172.5
(4) Tietze, L. F.; Brasche, G.; Gericke, K. M. Domino Reactions in
Organic Synthesis, 1st ed.; Wiley-VCH: Weinheim, 2006.
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