Cooperative catalysis approach to intramolecular hydroacylation

Article abstract of DOI:10.1021/jo300779q

Prior examples of hydroacylation to form six- and seven-membered ring ketones require either embedded chelating groups or other substrate design strategies to circumvent competitive aldehyde decarbonylation. A cooperative catalysis strategy enabled intram

Full text of DOI:10.1021/jo300779q

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Cooperative Catalysis Approach to Intramolecular Hydroacylation
Evgeny V. Beletskiy, Ch. Sudheer,† and Christopher J. Douglas*
Department of Chemistry, University of MinnesotaTwin Cities, 207 Pleasant Street SE, Minneapolis, Minnesota 55455, United
States
S
* Supporting Information
ABSTRACT: Prior examples of hydroacylation to form six-
and seven-membered ring ketones require either embedded
chelating groups or other substrate design strategies to
circumvent competitive aldehyde decarbonylation. A cooper-
ative catalysis strategy enabled intramolecular hydroacylation
of disubstituted alkenes to form seven- and six-membered
rings without requiring substrate-embedded chelating groups.
An alternative to substrate-embedded chelating groups is
cooperative catalysis. Over 30 years ago, Suggs suppressed
decarbonylation by forming 3-methyl-2-aminopyridyl aldi-
mines, which functioned as surrogates for aldehydes in
intermolecular hydroacylation.9 Jun expanded upon this work,
describing that 2-aminopicoline-based aldimines can form in
catalytic amounts under intermolecular hydroacylation con-
ditions, again suppressing decarbonylation via transiently
formed chelating groups in a process termed cooperative
catalysis.10,11 Suggs and Jun’s work is largely limited to
monosubstituted alkenes. Recently, Breit and co-workers
described a bifunctional cocatalyst, 6-((diphenylphosphino)-
methyl)-2-aminopicoline, which improved cocatalyst efficiency
relative to 2-aminopicoline in intermolecular hydroacylation
reactions of monosubstituted alkenes.10b Briet also described
increased efficiency in intramolecular hydroacylation reactions
of 2-vinylbenzaldehydes to form the five-membered ring of 1-
indanones. Briet’s cocatalyst is prepared via a five-step sequence
(27% overall yield) from the pivalamide of 6-methyl-2-
aminopyridine. A general metal-catalyzed intramolecular hydro-
acylation approach for the synthesis of six- and larger-
membered rings remains elusive. Moreover, hydroacylation of
1,1-disubstituted alkenes to form ketones bearing stereocenters
has only been reported for the limited substrate classes
discussed above.
INTRODUCTION
■
Medium rings are traditionally challenging to prepare in
synthetic organic chemistry. Although numerous strategies
have been described for their preparation, metal-catalyzed
hydroacylation is a potentially efficient method for the
construction of medium ring ketones from simple alkenes
and aldehydes.1 Existing metal-mediated intramolecular alkene
hydroacylation methods are typically limited to reactions in
which cyclopentanones are generated.2 Larger rings can only be
directly accessed in cases where judiciously placed heter-
oatoms3 are embedded into the starting materials (Scheme
1).4,5 Alternatively, other strategies have employed more
Scheme 1. Medium Rings via Hydroacylation
We were inspired by the above work to develop a general
strategy that would allow traditionally challenging, direct
intramolecular hydroacylation of disubstituted alkenes (Scheme
1). The aminopyridine cocatalyst is a potential platform for
asymmetric catalysis. This work could greatly expand the types
of intramolecular hydroacylation reactions beyond those
currently possible. A potential challenge in this strategy is
that aldimine formation and hydroacylation must be faster than
aldehyde decarbonylation. Therefore, one of our goals was to
enhance aldimine formation. Moreover, we were aware that
competitive isomerization of the alkene to a more substituted
complex substrates that provide a proximal alkene.6 Embedding
a proximal chelating group into the substrate has been
successfully applied in intermolecular hydroacylation, as well.7
The requirement for proximal heteroatoms or alkenes to the
aldehyde is often attributed to competitive aldehyde decarbon-
ylation,8 a process that is slowed by stabilizing the acyl metal
intermediate via chelate formation. These substrate limitations
are severely limiting to the broad applicability of hydro-
acylation.
Received: April 16, 2012
Published: July 10, 2012
© 2012 American Chemical Society
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a
Table 1. Initial Optimization of Hydroacylation
b
entry
Rh(I) cat.
cat. (mol %)
ligand
none
ligand (mol %)
2-aminopyridine (mol %)
yield 2a (%)
1
2
Rh(BF4)(cod)2
Rh(BF4)(cod)2
Rh(BF4)(cod)2
[RhCl(coe)2]2
[RhCl(coe)2]2
RhCl(PPh3)3
5
3 (120)
3 (120)
3 (120)
3 (120)
3 (120)
3 (120)
3 (25)
4 (25)
3 (10)
3 (25)
3 (25)
3 (25)
3 (25)
3 (25)
ND
42
5
PPh3
10
15
c
3
5
PPh3
72
4
5
6
7
8
2.5
2.5
5
none
ND
77
PPh3
5
none
60
[RhCl(coe)2]2
[RhCl(coe)2]2
[RhCl(coe)2]2
[RhCl(coe)2]2
[RhCl(coe)2]2
[RhCl(coe)2]2
[RhCl(coe)2]2
[RhCl(coe)2]2
[RhCl(coe)2]2
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
PPh3
5
5
5
5
5
5
5
5
45
PPh3
76
c
9
PPh3
81
10
11
12
13
14
15
P(o-Tol)3
PPh2Me
PPhMe2
PPhCy2
P(t-Bu)3
P(C6F5)3
ND
68
37
29
ND
ND
5
3 (25)
a
b
1
Conditions: Rh(I) cat, ligand, PhNH2 (1.2 equiv), BzOH (10 mol %), DCE, 100 °C. Yields by H NMR spectroscopy of the crude reaction
c
mixture with 4-methoxyacetophenone as an internal standard; ND = 2a not detected. Entries 3 and 9−15 used PhCF3 as solvent. DCE = 1,2-
dichloroethane, cod = 1,5-cyclooctadiene, coe = cyclooctene.
olefin must be avoided. Our results to these ends are reported
herein.
with 1a or 1a's N-phenyl imine congener was sluggish due to
the poor nucleophilicity of the amino group in 3 due to the
amine’s conjugation with an electron-deficient aromatic system.
To reduce the loading of the 2-aminothiazole derivative to
catalytic levels, we turned to exploring more reactive cocatalysts
in the reaction. Commercially available 2-aminopyridine, 2-
aminothiazole, 1-aminobenzotriazole, and 2-aminobenzimida-
zole gave only traces of product 2a as replacements for 3 in
attempted hydroacylation reactions. However, amine 4 proved
to be significantly more efficient as a cocatalyst (Table 1, entry
8 vs 7). We attribute this observation to the higher
nucleophilicity of the amine in 4 compared to 3 and thus
higher rate of imine equilibration. Cocatalyst 4 can be prepared
from 3 in two steps (46% yield overall) via a straightforward
iodination/amination sequence. See the Experimental Details
for information.
We examined the influence of solvent on reaction by
measuring the yield of 2a at lower temperatures to accentuate
solvent effects in the conversion range of 0−20% (not shown).
We found that reaction rate qualitatively increases in the order
of DCE < THF < PhMe < PhCF3. We could not explain these
observations because they do not track well with trends in
solvent polarity or Lewis basicity. It is well-known, however,
that PhCF3 can be a useful alternative in organic reactions that
are typically conducted in chlorinated solvents.13 In our
hydroacylation reactions, it is superior to DCE as well as
toluene. Changing solvent from DCE to PhCF3 allowed for the
reduction of the cocatalyst loading to 10 mol % while
improving the yield of 2a to 81% (entry 9).
RESULTS AND DISCUSSION
■
We envisioned several strategies to accelerate hydroacylation
and avoid the decomposition pathways outlined above. We
chose to utilize one of Jun’s strategies that was successful in
intermolecular hydroacylation reactions: adding PhNH2 and
BzOH to presumably convert free aldehyde to the aniline-
derived aldimine, providing in situ protection of the aldehyde
from decarbonylation.10d Our initial attempts to convert
aldehyde 1a to cycloheptanone 2a using the temporary
chelating imine strategy with 2-amino-3-picoline 3 (Table 1,
entries 1−7)12 required an excess of 3 (120 mol %) to achieve
acceptable yield of 2a. In attempts with BF4 as the rhodium
counterion, acceptable yields could be obtained once the ratio
of Rh/PPh3 was 1:3 (Table 1, entries 1−3). Without phosphine
in the reaction mixture (Table 1, entry 1), no 2a was detected.
As phosphine was added, the hydroacylation became more
efficient at 1:2 (42%, entry 2) and plateaued at 1:3 (72%, entry
3). The amount of phosphine present also impacted reactions
in which Cl was the rhodium counterion. Without phosphine,
[RhCl(coe)2]2 did not provide a detectable amount of ketone
2a (entry 4). Addition of 5 mol % of PPh3 to give a Rh/PPh3
mole ratio of 1:1 led to an acceptable 77% yield of 2a (entry 5).
Increasing the Rh/PPh3 ratio to 1:3 with Wilkinson’s catalyst
decreased the yield of 2a to 60% (entry 6). The optimal
phosphine to rhodium ratio may have changed with the
counterion due to coordination of Cl, but not BF4, to rhodium
under the reaction conditions.
We examined different phosphine ligands to examine the
impact of phosphine basicity and sterics on the hydroacylation
reaction (Table 1, entries 9−15). Coincidentally, the ligand we
initially chose, triphenylphosphine, appeared to be the best
ligand of those examined (entry 9). Increasing the steric bulk of
the ligand (tri-ortho-tolyl phosphine, Table 1, entry 10)
Taking our best conditions that used a stoichiometric
amount of 3 (entry 5) and attempting to use amine 3 as a
cocatalyst at 25 mol % (entry 7) led to incomplete conversion
and a decrease in the yield of 2a from 77 to 45%. We
hypothesized that aldimine formation of 2-amino-3-picoline 3
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suppressed the formation of 2a to below our detection limit.
Mixed alkyl/aryl phosphine ligands (methyldiphenylphosphine
and dimethylphenylphosphine; entries 11 and 12) decreased
the efficiency of the catalytic system, providing 2a in 68 and
37% yield, respectively when 25 mol % of 3 was employed.
Bulky alkyl phosphine ligands (cyclohexyldiphenyl phosphine
and tri-tert-butylphosphine; entries 13 and 14) proved to be
largely ineffective, providing only a 29% yield of 2a (entry 13).
The steric effect might be attributed to the requirement of an
extra coordination site for the catalytic directing group in these
hydroacylation reactions. This is in contrast to typical
cyclopentanone-forming hydroacylation reactions without 2-
aminopyridine cocatalysts where the alkene serves the dual
purpose of forming a metal chelate to prevent carbon monoxide
loss while still undergoing migratory insertion. Therefore, the
reaction exhibits high sensitivity to the steric bulk of the ligand
compared to the side reactions. A less basic, wide cone angle
phosphine, tris(pentafluorophenyl)phosphine, was also com-
pletely ineffective in hydroacylation (entry 15).
Table 2. Scope of Intramolecular Hydroacylation
With the identification of several acceptable conditions
(Table 1, entries 8 and 9), we turned to examine the substrate
scope (Table 2). Variation of the substituent on the aryl ring
(entries 1−4) did not require changes in reaction conditions
from those used to obtain acceptable yields of 2a (Table 1,
entry 9). Substrates containing both electron-donating (R1 =
CH3 or OCH3, entries 1 and 3) and electron-withdrawing
groups (R1 = CF3 or F, entries 2 and 4) para to the aldehyde
underwent hydroacylation in acceptable yields (76−85%) using
10 mol % of cocatalyst 3. We examined substitution of the
alkene portion of the substrate. Replacing the alkene methyl
group with an ethyl substituent (1f, R2 = Et, entry 5), the
corresponding hydroacylation product 2f was obtained in 86%
yield using 10 mol % of cocatalyst 3. Changing R2 from an alkyl
to an aryl group, however, made the hydroacylation more
challenging. Phenyl-substituted alkene 1g required a higher
loading (25 mol %) of the more nucleophilic cocatalyst 4 to
provide an acceptable 77% yield of cycloheptanone 2g.14−16
Allylic oxygenation on the alkene also rendered the alkene
less reactive (1h, entry 7), requiring cocatalyst 4 (10 mol %) to
provide 2h in 78% yield (entry 6). Since 1h was not completely
consumed when 3 was the cocatalyst, the more reactive
cocatalyst 4 was used. These results show the impact of alkene
substitution beyond simple alkyl groups. A more reactive
catalyst system is required when additional functional groups
are proximal to the alkene.
We also examined substrates in which the alkene and
aldehyde are linked via heterocycles rather than a benzene ring.
Note that in pyrrole 1i and indole 1j (entries 8 and 9), the
nitrogen is not a suitable donor for chelation stabilization of the
rhodium hydride intermediate. These substrates reacted
sluggishly under hydroacylation conditions and required 25
mol % of cocatalyst 4, 5 mol % of [RhCl(coe)2]2, and 10 mol %
PPh3 to provide 63 and 66% yield of dihydropyrroloazepineone
2i and dihydroazepinoindolone 2j, respectively. We attribute
the lower reactivity of these substrates to increased conjugation
to the carbonyl, which may lower its electrophilicity and slow
imine formation and/or subsequent hydroacylation steps.
We note that the high preference for 7-endo cyclization is
completely reversed from the 6-exo selectivity recently reported
for N-heterocyclic carbene (NHC)-catalyzed intramolecular
hydroacylation with 1g reported by Grimme, Glorius, and co-
workers, which proceeds by a completely different mecha-
nism.17 The regioselectivity in NHC- compared to Rh-catalyzed
a
Conditions: [RhCl(coe)2]2 (2.5 mol %), PPh3 (5 mol %), PhNH2
b
(1.2 equiv), BzOH (10 mol %), PhCF3, 100 °C. Isolated yield after
silica gel chromatography. Except where noted, regioisomeric
hydroacylation products were not observed, indicating regioselectivity
c
was >10:1. Contaminated with a minor <5% of the corresponding
indanone; pure sample could be obtained by preparative TLC.
d
Conditions: [RhCl(coe)2]2 (5 mol %), PPh3 (10 mol %), PhNH2
e
1
(1.2 equiv), BzOH (10 mol %). Yield by H NMR spectroscopy of
the crude reaction mixture with 4-methoxyacetophenone as an internal
standard. An attempt with 25% 4 gave 30% yield of 2k after a
challenging purification by chromatography.
reactions provides chemists with a powerful means of
complementary regiochemical control in hydroacylation
reactions.
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a
Six-membered rings are also traditionally challenging to form
via metal-catalyzed intramolecular hydroacylation. As we
expanded our study to target six-membered ring products, we
were somewhat surprised that these substrates (1k−1n, Table
2, entries 10−13) reacted much more slowly than their longer-
tether counterparts. Typically, six-membered ring formation is
more facile than seven-membered ring construction.18 In our
case, however, higher loadings of aminopyridine 4 were
required to achieve yields ranging from 48 to 69%, and in
some cases, a full equivalent of 4 was required (entries 11 and
13). The poorer behavior of 1k−1n compared to congeners
targeting seven-membered rings might be explained by slower
migratory insertion in these substrates compared their higher
homologues. We speculate that the more proximal alkene might
lead to a stable alkene complex after C−H activation, perhaps
raising the barrier to migratory insertion. Alternatively,
reductive elimination may be slower from the presumptive
seven-membered metallacycle in the formation of 2k−2n
compared to their congeners that should proceed via an eight-
membered metallacycle. Typically, reductive elimination is rate-
limiting in intramolecular hydroacylation reactions.19
Table 3. Effects of Chiral Ligands
Interestingly, substrate 1o, containing a monosubstituted
alkene, also required higher loadings of cocatalyst for successful
hydroacylation to form 1-benzosuberone (2o, Scheme 2). We
a
Conditions: [RhCl(coe)2]2 (2.5 mol %), ligand (5 mol %), PhNH2
b
(1.2 equiv), BzOH (10 mol %), PhCF3, 100 °C. Yield after silica gel
chromatography; ND = 2a not detected. Determined by HPLC
(Chiralcel OD-H, n-hexane/IPA (9:1), λ = 220 nm). 1a, PhNH2, and
BzOH in PhCF3 were premixed before adding [RhCl(coe)2]2, ligand,
c
d
a
Scheme 2. Monosubstituted Alkene Hydroacylation
and 3.
used as additives, although yields were low in all cases
examined. Given the high sensitivity of the efficiency of
hydroacylation to the structure of the phosphorus-containing
ligand (Table 3 and Table 2, entries 9−15), we curtailed our
investigation of these types of ligands and sought new ways to
induce asymmetry in the reaction.
Since our optimization studies had conclusively shown that
cocatalysts 3 and 4 were also necessary for hydroacylation, we
hypothesized that incorporating chirality into the 2-amino-3-
picoline structure would provide an entry to asymmetric
hydroacylation. We decided to use analogues of 4 with a chiral
5-amino group, due to ease of preparation of these compounds
and expected high reactivity from the electron-donating
group.20
a
Conditions: [RhCl(coe)2]2 (2.5 mol %), PPh3 (5 mol %), BzOH (10
mol %), PhNH2 (1.2 equiv), PhCF3, 100 °C.
Our initial studies with 5 (Scheme 3), which was derived
from a chiral oxazolidinone, showed that it is less reactive than
found that, without cocatalyst 3, isomerization from the
terminal to the internal alkene (1o → 1p) occurred to form
a mixture of trans/cis-1p. Thus higher loadings of cocatalyst are
required to suppress this side reaction. With low loadings of
cocatalyst 3, the isomerization is prevailing and no 2o is
observed. Instead, indanone 2p is formed as the major product
under these reaction conditions, presumably by cyclization of
1p. A small amount of 2-methyl dihydronaphthalenone was
also observed in this attempt. We also note that, under many of
our optimization reactions in Table 1, a minor amount of 2-
isopropyl-2,3-dihydroindenone (tentatively assigned) was
observed in the crude product mixtures.
Given recent advances in asymmetric hydroacylation, we
performed a preliminary investigation on asymmetric hydro-
acylation, using the conversion 1a to 2a as our test reaction. No
reaction was observed when bidentate ligands (BINAP,
DUPHOS, dppe, or dppp) were used as additives to various
rhodium species (results not shown). Product 2a was observed
when chiral monodentate ligands (entries 2−4, Table 3) were
a
Scheme 3. Enantioselective Hydroacylation
a
Conditions: [RhCl(coe)2]2 (2.5 mol %), PPh3 (5 mol %), PhNH2
(1.2 equiv), BzOH (10 mol %), 5 (25 mol %), PhCF3, 80 °C
4 and even 3. However, the reaction could still be successfully
accomplished with 25 mol % loading of cocatalyst 5. Promising
enantioselectivity was observed in this case (2a, 82% yield, 31%
ee). Although not yet synthetically useful, this showcases a new
strategy for inducing asymmetry in hydroacylation reactions.
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191.9, 144.96, 144.92, 144.7, 132.3, 131.6, 131.3, 127.3, 110.5, 40.1,
31.1, 22.5, 21.7; IR (film) 3047, 2973, 2919, 1691, 1607, 1451, 1300
cm−1; HRMS (CI) calcd for [C13H16O + NH4]+ m/z 206.1539, found
206.1544.
Our approach is a significant departure from prior work based
on chiral phosphorus-containing ligands in hydroacylation
chemistry. Given the high degree of recent interest in
asymmetric hydroacylation, these results should inspire addi-
tional work, which we envision will achieve high levels of
enantioinduction in the fullness of time.
2-(3-Methylbut-3-en-1-yl)-4-(trifluoromethyl)benzaldehyde (1c).
See general procedure for the synthesis of aldehydes 1b−1e. Reaction
was carried out with 2-methyl-4-trifluoromethylbenzaldehyde (188
mg, 1.0 mmol). The crude mixture was purified by silica gel column
chromatography (1:6 EtOAc/Hex) to afford 203 mg (84% yield) of 1c
CONCLUSION
■
1
as a colorless oil: Rf 0.50 (1:4 EtOAc/Hex); H NMR (300 MHz,
In conclusion, we have reported the first effective method for
metal-catalyzed synthesis of six- and seven-membered ring
ketones via hydroacylation that is free of the requirement of
chelating groups embedded into the substrate. The develop-
ment of electron-rich 2-amino-3-picolines 4 and 5 enables the
incorporation of a temporary chelate scaffold on the aldehyde
that avoids decomposition via aldehyde decarbonylation and
alkene isomerization pathways. For challenging substrates, 4
may also be used in stoichiometric amounts. The regiochem-
istry of the hydroacylation is complementary to NHC-catalyzed
hydroacylation reactions,17 which should prove useful in
synthesis planning. Chiral 2-aminopyridines such as 5 represent
a new strategy for asymmetric catalysis in hydroacylation.
Future work will be directed at improvement of the asymmetric
induction in hydroacylation and applications in target-directed
synthesis.
CDCl3) δ 10.34 (s, 1H), 7.96 (d, J = 8.1 Hz, 1H), 7.63 (d, J = 8.1 Hz,
1H), 7.55 (s, 1H), 4.79−4.71 (m, 2H), 3.26−3.20 (m, 2H), 2.33 (t, J =
8.1 Hz, 2H), 1.81 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 191.1,
145.6, 144.1, 136.0, 134.8 (q, J = 32.3 Hz), 131.9, 127.8 (q, J = 3.2
Hz), 123.5 (q, J = 272.9 Hz), 123.4 (q, J = 3.7 Hz), 111.2, 39.9, 30.9,
22.4; IR (film) 3056, 2983, 2939, 1706, 1498, 1422, 1330, 1266,
1173,1132 cm−1; HRMS (CI) calcd for [C13H13F3O + H]+ m/z
243.0991, found 243.1015.
4-Methoxy-2-(3-methylbut-3-en-1-yl)benzaldehyde (1d). See gen-
eral procedure for the synthesis of aldehydes 1b−1e. Reaction was
carried out with 4-methoxy-2-methylbenzaldehyde (345 mg, 2.3
mmol). The crude mixture was purified by silica gel column
chromatography (1:4 EtOAc/Hex) to afford 388 mg (83% yield) of
1
1d as a colorless oil: Rf 0.40 (1:4 EtOAc/Hex); H NMR (300 MHz,
CDCl3) δ 10.10 (s, 1H), 7.78 (d, J = 8.7 Hz, 1H), 6.85 (dd, J = 2.7, 8.7
Hz, 1H), 6.76 (d, J = 2.4 Hz, 1H), 4.74 (d, J = 11.4 Hz, 2H), 3.87 (s,
3H), 3.17−3.11 (m, 2H), 2.32−2.27 (m, 2H), 1.79 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 190.7, 163.7, 147.6, 144.9, 134.8, 127.3, 116.1,
111.6, 110.6, 55.4, 39.8, 31.3, 22.5; IR (film) 3056, 2934, 2841, 1687,
1601, 1567, 1496, 1461 cm−1; HRMS (CI) calcd for [C13H16O2 + H]+
m/z 205.1223, found 205.1235.
EXPERIMENTAL DETAILS
■
Trifluorotoluene (PhCF3) was distilled over phosphorus pentoxide,
degassed by four freeze−pump−thaw cycles in a Straus flask and then
stored in a nitrogen-filled glovebox. All rhodium complexes were
purchased and used as received, except [RhCl(coe)2]2 which was
prepared by a known procedure.21 The preparations of aldehydes 1a,22
1k,23 1g,21 and 1o21 have been previously reported, and new
procedures for the preparations of 1k and 1g are reported below.
Aldehyde 1o was prepared in analogy to 1b. All rhodium-catalyzed
processes were carried out in a N2-filled glovebox in 1 dram vials with
polytetrafluoroethylene-lined caps, and heating was applied by
aluminum block heaters. HRMS measurements using electrospray
ionization (ESI) were performed with a time-of-flight (TOF) mass
analyzer, and HRMS measurements using chemical ionization (CI)
were performed with a magnetic sector mass analyzer.
4-Fluoro-2-(3-methylbut-3-en-1-yl)benzaldehyde (1e). See gen-
eral procedure for the synthesis of aldehydes 1b−1e. Reaction was
carried out with 2-methoxy-4-methylbenzaldehyde (303 mg, 2.2
mmol). The crude mixture was purified by silica gel column
chromatography (1:6 EtOAc/Hex) to afford 340 mg (80% yield) of
1
1e as a colorless oil: Rf 0.60 (1:4 EtOAc/Hex); H NMR (300 MHz,
CDCl3) δ 10.18 (s, 1H), 7.87−7.81 (m, 1H), 7.07−6.94 (m, 2H),
4.77−4.69 (m, 2H), 3.19−3.14 (m, 2H), 2.32−2.27 (m, 2H), 1.80 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 190.5, 165.7 (d, J = 256.6 Hz),
148.4 (d, J = 9.1 Hz), 144.3, 134.7 (d, J = 10.0 Hz), 130.3 (d, J = 2.6
Hz), 117.6 (d, J = 21.7 Hz), 113.8 (d, J = 21.7 Hz), 111.0, 39.5, 30.8,
22.4; IR (film) 3054, 2984, 2937, 1695, 1606, 1583, 1491, 1266 cm−1;
HRMS (CI) calcd for [C12H13FO + NH4]+ m/z 210.1289, found
210.1292.
General Procedure for the Synthesis of Aldehydes 1b−1e.24
N,N,N-Trimethylethyldiamine (0.41 mL, 3.2 mmol) in THF (8 mL)
was added to a flame-dried flask under nitrogen, the solution was
cooled to −78 °C, and n-BuLi (2.5 M in hexanes, 1.35 mL, 3.10
mmol) was added dropwise. The reaction was allowed to stir for 30
min at −78 °C, followed by slow addition of 2-methylbenzaldehyde
derivative (3.0 mmol). The solution was warmed to −15 °C for 20
min and recooled to −55 °C for the dropwise addition of t-BuLi (1.7
M in pentane, 5.3 mL, 9.0 mmol). The resulting deep red solution was
stirred at −55 °C for 2.5 h and recooled to −78 °C. Isobutenyl
chloride (1.75 mL, 18 mmol) was added rapidly, and the pale yellow
solution was allowed to warm to room temperature and stirred for 30
min. The solution was poured onto cold 1.0 M HCl (15 mL), stirred
for 10 min, and the layers were separated. The aqueous layer was
extracted with Et2O (3 × 15 mL), and the combined organics were
washed with brine, dried over Na2SO4, and concentrated in vacuo.
Silica gel chromatography (EtOAc/Hex) afforded compounds 1b−1e
in reported yields.
2-(3-Methylenepentyl)benzaldehyde (1f). N,N,N-Trimethylethyl-
diamine (0.40 mL, 3.15 mmol) in THF (8 mL) was added to a flame-
dried flask under nitrogen, the solution was cooled to −78 °C, and n-
BuLi (2.5 M in hexanes, 1.24 mL, 3.10 mmol) was added dropwise.
The reaction was allowed to stir for 30 min at −78 °C, followed by
slow addition of 2-methylbenzaldehyde (0.35 mL, 3.0 mmol). The
solution was warmed to −15 °C for 20 min and recooled to −55 °C
for the dropwise addition of t-BuLi (1.7 M in pentane, 3.5 mL, 6.0
mmol). The resulting deep red solution was stirred at −55 °C for 4 h.
2-Methylenebutyl-4-methylbenzenesulfonate20 (2.16 g, 9 mmol) in
THF (2 mL) was added rapidly, and the pale yellow solution was
allowed to warm to room temperature and stirred for 30 min. The
solution was poured onto cold 1.0 M HCl (15 mL) and stirred for 10
min. PhMe (50 mL) was added, the layers were separated, and the
organic extracts were concentrated in vacuo. Silica gel chromatography
(1:30 EtOAc/Hex) afforded compound 1f (322 mg, 1.71 mmol, 57%)
1
as a colorless oil: Rf 0.60 (1:4 EtOAc/Hex); H NMR (300 MHz,
4-Methyl-2-(3-methylbut-3-en-1-yl)benzaldehyde (1b). See gen-
eral procedure for the synthesis of aldehydes 1b−1e. Reaction was
carried out with 308 mg (2.3 mmol) of 2,4-dimethylbenzaldehyde.
The crude product mixture was purified by silica gel column
chromatography (1:6 EtOAc/Hex) to afford 360 mg (83% yield) of
CDCl3) δ 10.27 (s, 1H), 7.83 (dd, J = 1.5, 8.9 Hz, 1H), 7.53 (dt, J =
1.5, 7.5 Hz, 1H), 7.37 (dt, J = 0.9, 7.5 Hz, 1H), 7.28 (dd, J = 0.6, 7.5
Hz, 1H), 4.78−4.76 (m, 2H), 3.20−3.14 (m, 2H), 2.32−2.29 (m, 2H),
2.10 (dq, J = 0.3, 7.2 Hz, 2H), 1.05 (t, J = 7.2 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 192.3, 150.5, 145.1, 133.8, 131.8, 131.0, 126.5, 110.1,
108.5, 38.7, 31.3, 28.8, 12.3; IR (film) 2964, 2728, 1693, 1599 cm−1;
HRMS (ESI) calcd for [C13H16O + Na]+ m/z 211.1093, found
211.1098.
1
1b as a colorless oil: Rf 0.60 (1:4 EtOAc/Hex); H NMR (300 MHz,
CDCl3) δ 10.20 (s, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.17 (d, J = 7.8 Hz,
1H), 7.09 (s, 1H), 4.77−4.72 (m, 2H), 3.15−3.10 (m, 2H), 2.39 (s,
3H), 2.31−2.26 (m, 2H), 1.81 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
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2-(3-Phenylbut-3-en-1-yl)benzaldehyde (1g). N,N,N-Trimethyle-
thyldiamine (0.40 mL, 3.15 mmol) in THF (8 mL) was added to a
flame-dried flask under nitrogen, the solution was cooled to −78 °C,
and n-BuLi (2.5 M in hexanes, 1.24 mL, 3.10 mmol) was added
dropwise. The reaction was allowed to stir for 30 min at −78 °C,
followed by slow addition of 2-methylbenzaldehyde (0.35 mL, 3.0
mmol). The solution was warmed to −15 °C for 20 min and recooled
to −55 °C for the dropwise addition of t-BuLi (1.7 M in pentane, 3.5
mL, 6.0 mmol). The resulting deep red solution was stirred at −55 °C
for 3 h and cooled to −78 °C. 3-Bromo-2-phenylpropene25 (1.76 g, 9
mmol) in THF (2 mL) was added rapidly, and the pale yellow solution
was allowed to warm to room temperature and stirred for 30 min. The
solution was poured onto cold 1.0 M HCl (15 mL) and stirred for 10
min. PhMe (50 mL) was added, the layers were separated, and the
organic layer was concentrated in vacuo. Silica gel chromatography
(1:30 EtOAc/Hex) afforded compound 1g (306 mg, 1.30 mmol, 43%)
as a colorless oil: Rf 0.55 (1:4 EtOAc/Hex). The characterization data
are consistent with those previously reported.21
and the mixture was maintained at reflux for 2 h. The resulting
solution was added dropwise to a stirred solution of 3-bromo-2-
phenylpropene (1.48 g, 7.5 mmol) and suspension of CuI (95 mg, 0.5
mmol) in THF (5 mL) at 0 °C. The reaction mixture was stirred for 2
h at 0 °C and then allowed to warm to room temperature overnight.
CH2Cl2 (10 mL) was added, and the mixture was washed with a
saturated aqueous NH4Cl solution. The organic phase was separated
and concentrated in vacuo. TsOH (20 mg, 0.1 mmol), water (10 mL),
and acetone (10 mL) were added, and the resulting solution was
heated at reflux for 2 h. The reaction mixture was extracted with
CH2Cl2 (40 mL). The organic phase was separated, dried over
Na2SO4, and concentrated in vacuo. Silica gel chromatography (1:20
EtOAc/Hex) afforded compound 1l (445 mg, 2.00 mmol, 40%) as a
colorless oil: Rf 0.60 (1:4 EtOAc/Hex); 1H NMR (300 MHz, CDCl3)
δ 10.22 (s, 1H), 7.86 (dd, J = 1.5, 7.5 Hz, 1H), 7.51−7.22 (m, 8H),
5.45 (t, J = 0.9 Hz, 1H), 4.71 (dd, J = 1.5, 2.4 Hz, 1H), 4.23 (s, 1H);
13C NMR (75 MHz, CDCl3) δ 192.2, 147.4, 141.7, 140.8, 134.1, 133.8,
131.5, 131.4, 128.3, 127.7, 127.0, 125.9, 114.8, 37.6; IR (film) 3055,
3029, 2855, 2753, 1696, 1599, 1210 cm−1; HRMS (ESI) calcd for
[C16H14O + Na]+ 245.0942, found 245.0951.
2-(3-(((tert-Butyldimethylsilyl)oxy)methyl)but-3-en-1-yl)-
benzaldehyde (1h). N,N,N-Trimethylethyldiamine (0.14 mL, 1.1
mmol) in THF (5 mL) was added to a flame-dried flask under
nitrogen, the solution was cooled to −78 °C, and n-BuLi (2.5 M in
hexanes, 0.44 mL, 1.10 mmol) was added dropwise. The reaction was
allowed to stir for 30 min at −78 °C, followed by slow addition of 2-
methylbenzaldehyde (0.12 mL, 1.0 mmol). The solution was warmed
to −15 °C for 20 min and recooled to −55 °C for the dropwise
addition of t-BuLi (1.7 M in pentane, 0.88 mL, 1.5 mmol). The
resulting deep red solution was stirred at −55 °C for 3 h and cooled to
−78 °C. ((2-(Bromomethyl)allyl)oxy)(tert-butyl)dimethylsilane26
(619 mg, 2.34 mmol) in THF (1 mL) was added rapidly, and the
pale yellow solution was stirred for 5 min and quenched with 1.0 M
HCl (3 mL). The reaction mixture was allowed to warm to room
temperature, PhMe (10 mL) was added, the layers were separated, and
the organic extracts were concentrated in vacuo. Silica gel
chromatography (1:50 EtOAc/Hex) afforded compound 1h (74 mg,
General Procedure for the Synthesis of Pyrrole- and Indole-
Containing Aldehydes (1i, 1j, 1m, 1n). Aldehyde (5 mmol), 18-
crown-6 (5 mmol), and powdered KOH (10 mmol) were refluxed in
benzene (5 mL) for 2 h. 4-Iodo-2-methyl-1-butene or isobutenyl
chloride (15.0 mmol) was added as a solution in benzene (2.5 mL),
and reflux was maintained for an additional 6 h. The solution was
washed with water, and the layers were separated. The aqueous layer
was extracted with Et2O (3 × 15 mL), and the combined organic
phases were washed with brine, dried over Na2SO4, and concentrated
in vacuo. Silica gel chromatography (EtOAc/Hex) afforded 1i, 1j, 1m,
or 1n as yellow oils in the reported yields.
1-(3-Methylbut-3-en-1-yl)-1H-pyrrole-2-carbaldehyde (1i). See
general procedure for the synthesis of pyrroles and indoles 1i, 1j,
1m, and 1n. Reaction was carried out with 1H-pyrrole-2-carbaldehyde
(475 mg, 5.0 mmol). The crude product mixture was purified by silica
gel column chromatography (1:3 EtOAc/Hex) to afford 407 mg (50%
1
0.24 mmol, 24%) as a colorless oil: Rf 0.50 (1:4 EtOAc/Hex); H
1
NMR (300 MHz, CDCl3) δ 10.20 (s, 1H), 7.76 (dd, J = 1.3, 7.5 Hz,
1H), 7.43 (dt, J = 1.5, 7.5 Hz, 1H), 7.32 (dt, J = 1.5, 7.5 Hz, 1H), 7.21
(dd, J = 1.5, 7.5 Hz, 1H), 5.01 (d, J = 1.8 Hz, 1H), 4.80 (dd, J = 1.2,
2.7 Hz, 1H), 4.04 (s, 2H), 3.11 (m, 2H), 2.24 (t, J = 8.1 Hz, 2H), 0.83
(s, 9H), 0.01 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 192.3, 147.6,
144.8, 133.8, 133.7, 131.9, 131.0, 126.6, 109.5, 65.9, 35.0, 31.3, 25.9,
18.4, −5.4; IR (film) 2953, 2928, 2855, 2730, 1697, 1600, 1249, 1114,
1086 cm−1; HRMS (ESI) calcd for [C18H28O2Si + Na]+ m/z 327.1756,
found 327.1754.
yield) of 1i as a yellow oil: Rf 0.35 (1:3 EtOAc/Hex); H NMR (300
MHz, CDCl3) δ 9.53 (s, 1H), 6.92 (d, J = 3.6 Hz, 2H), 6.19 (t, J = 3.6
Hz, 1H), 4.77−4.76 (m, 1H), 4.64−4.63 (m, 1H), 4.41 (t, J = 7.2 Hz,
1H), 2.44 (t, J = 7.3 Hz, 1H), 1.74 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 179.0, 141.7, 131.2, 131.0, 124.7, 112.4, 109.3, 47.5, 39.2,
22.2; IR (film) 3052, 2983, 2810, 1671, 1613, 1466, 1264 cm−1;
HRMS (CI) calcd for [C10H13NO + H]+ m/z 164.1070, found
164.1086.
1-(3-Methylbut-3-en-1-yl)-1H-indole-2-carbaldehyde (1j). See the
general procedure for the synthesis of pyrroles and indoles 1i, 1j, 1m,
and 1n. Reaction was carried out with 1H-indole-2-carbaldehyde (290
mg, 2.0 mmol). The crude product mixture was purified by silica gel
column chromatography (1:3 EtOAc/Hex) to afford 225 mg (53%
2-(2-Methyallyl)benzaldehyde (1k). In a round-bottom flask
equipped with a reflux condenser and magnetic stir bar under
nitrogen, Mg (150 mg, 6.25 mmol) and a small crystal of I2 were
placed. The flask was flame-dried under high vacuum. THF (3 mL)
and 2-(2-bromophenyl)-1,3-dioxolane27 (1.15 g, 5 mmol) were added,
and the mixture was maintained at reflux for 2 h. The resulting
solution was allowed to cool to room temperature then added
dropwise to a stirred solution of isobutenyl chloride (0.74 mL, 7.5
mmol) and suspension of CuI (95 mg, 0.5 mmol) in THF (5 mL) at 0
°C. The reaction mixture was stirred for 2 h at 0 °C and then allowed
to warm to room temperature overnight. CH2Cl2 (10 mL) was added,
and the mixture was washed with a saturated aqueous NH4Cl solution.
The organic phase was separated and concentrated in vacuo. TsOH
(20 mg, 0.1 mmol), water (10 mL), and acetone (10 mL) were added,
and the resulting solution was heated at reflux for 2 h. The reaction
mixture was extracted with CH2Cl2 (40 mL). The organic phase was
separated, dried over Na2SO4, and concentrated in vacuo. Silica gel
chromatography (1:20 EtOAc/Hex) afforded compound 1k (345 mg,
2.16 mmol, 43%) as a colorless oil: Rf 0.65 (1:4 EtOAc/Hex). The
characterization data are consistent with those previously reported.21
2-(2-Phenylallyl)benzaldehyde (1l). In a round-bottom flask
equipped with a reflux condenser and magnetic stir bar under
nitrogen, Mg (150 mg, 6.25 mmol) and a small crystal of I2 were
placed. The flask was flame-dried under high vacuum. THF (3 mL)
and 2-(2-bromophenyl)-1,3-dioxolane25 (1.15 g, 5 mmol) were added,
1
yield) of 1j as a yellow oil: Rf 0.50 (1:3 EtOAc/Hex); H NMR (300
MHz, CDCl3) δ 9.89 (s, 1H), 7.74 (dt, J = 8.1, 0.9 Hz, 1H), 7.44−7.42
(m, 3H), 7.23−7.16 (m, 1H), 4.79 (q, J = 1.5 Hz, 1H), 4.71−4.70 (m,
1H), 4.67 (t, J = 2.1 Hz, 1H), 4.64 (s, 1H), 2.46 (t, J = 7.8 Hz), 1.84
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 182.5, 142.4, 140.1, 135.2,
126.8, 126.4, 123.4, 120.9, 117.9, 112.3, 110.5, 43.6, 38.3, 22.6; IR
(film) 3075, 2968, 2806, 1664, 1526, 1322, 1266, 1216 cm−1; HRMS
(CI) calcd for [C14H15NO + H]+ m/z 214.1226, found 214.1236.
1-(2-Methylallyl)-1H-pyrrole-2-carbaldehyde (1m). See general
procedure for the synthesis of pyrroles and indoles 1i, 1j, 1m, and
1n. This was started with 380 mg (4.0 mmol) of 1H-pyrrole-2-
carboxaldehyde. The crude mixture was purified by silica gel column
chromatography (1:3 EtOAc/Hex) to afford 423 mg (71% yield) of
1
1m as yellow oil: Rf 0.35 (1:3 EtOAc/Hex); H NMR (300 MHz,
CDCl3) δ 9.54 (s, 1H), 6.95−6.93 (m, 2H), 6.26 (t, J = 3.2 Hz, 1H),
4.90 (s, 2H), 4.84 (s, 1H), 4.48 (s, 1H), 1.71 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 179.4, 142.0, 131.5, 124.4, 111.6, 109.8, 53.8, 19.9; IR
(film) 3056, 2983, 2924, 1665, 1529, 1479, 1371, 1267 cm−1; HRMS
(CI) calcd for [C9H11NO + H]+ m/z 150.0913, found 150.0926.
1-(2-Methylallyl)-1H-indole-2-carbaldehyde (1n). See general
procedure for the synthesis of pyrroles and indoles 1i, 1j, 1m, and
5889
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Featured Article
1n. This was started with 290 mg (2.0 mmol) of 1H-indole-2-
carbaldehyde. The crude mixture was purified by silica gel column
chromatography (1:3 EtOAc/Hex) to afford 258 mg (65% yield) of 1n
as yellow oil: Rf 0.50 (1:3 EtOAc/Hex); 1H NMR (300 MHz, CDCl3)
δ 9.89 (s, 1H), 7.76 (d, J = 8.1 Hz, 1H), 7.44−7.41 (m, 1H), 7.39 (s,
1H), 7.29 (s, 1H), 7.22−7.17 (m, 1H), 5.17 (s, 2H), 4.82 (s, 1H), 4.41
(s, 1H), 1.73 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 182.5, 141.2,
140.6, 135.3, 126.9, 126.3, 123.3, 121.0, 117.9, 111.0, 110.8, 49.9, 19.9;
IR (film) 3054, 2984, 2818, 1671, 1614, 1464, 1266 cm−1; HRMS (CI)
calcd for [C13H13NO + H]+ m/z 200.1070, found 200.1089.
glovebox. PhCF3 (0.30 mL) and chlorobis(cyclooctene)rhodium(I)
dimer (5.4 mg, 0.0075 mmol) were added. The resulting solution was
stirred for 15 h at 100 °C, and the reaction vial was removed from the
glovebox. Et2O (1 mL) and 1 M aqueous HCl (0.5 mL) were added,
and the mixture was vigorously stirred for 10 min. To the mixture was
added H2O (5 mL). The aqueous layer was extracted with Et2O (3 ×
10 mL). Combined organic layers were washed with brine (10 mL),
dried over anhydrous Na2SO4, and concentrated in vacuo. Silica gel
chromatography (EtOAc/Hex) gave the ketones 2 in the reported
yields.
2-(But-2-en-1-yl)benzaldehyde (mixture of E and Z) (1p). 2-(But-
3-en-1-yl)benzaldehyde 1o (38.6 mg, 0.24 mmol), aniline (32 mg, 0.34
mmol), benzoic acid (2.9 mg, 0.024 mmol), and triphenylphosphine
(3.1 mg, 0.012 mmol) were added to a 1 dram vial with a magnetic stir
bar in the nitrogen atmosphere of the glovebox. PhCF3 (0.50 mL) and
chlorobis(cyclooctene)rhodium(I) dimer (4.3 mg, 0.006 mmol) were
added. The resulting solution was stirred for 16 h at 100 °C, and the
reaction vial was removed from the glovebox. Aqueous HCl (1.0 mL,
1M) was added, and the mixture was vigorously stirred for 10 min.
The organic phase was separated and concentrated in vacuo. Column
chromatography on silica gel (30:1 Hex/EtOAc) afforded 1p as a
colorless oil, which could not be separated from minor impurities (15
mg, 0.09 mmol, 39%): Rf 0.58 (4:1 Hex/EtOAc). Peaks corresponding
2,7-Dimethyl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one
(2b). See general procedure for the hydroacylation of aldehydes 1b−
1e. Reaction was carried out with 56 mg (0.3 mmol) of aldehyde 1b.
The crude mixture was purified by silica gel flash column
chromatography (1:9 EtOAc/Hex) to afford 47 mg (84% yield) of
inseparable mixture of ketone 2b and a very minor amount of the
corresponding indanone derivative as colorless oil. Pure compound for
NMR was obtained by preparative thin layer chromatography (Hex/
C6H6/CHCl3 11:2:2, 6 elutions): Rf 0.50 (1:4 EtOAc/Hex); 1H NMR
(300 MHz, CDCl3) δ 7.66 (d, J = 8.1 Hz, 1H), 7.09 (d, J = 7.8 Hz,
1H), 7.01 (s, 1H), 2.98−2.93 (m, 1H), 2.85 (dd, J = 6.1, 3.5 Hz, 1H),
2.78 (d, J = 3.9 Hz), 2.73 (d, J = 3.9 Hz, 1H), 2.58 (dd, J = 14.5, 9.2
Hz, 1H), 2.35 (s, 3H), 2.14−1.94 (m, 1H), 1.57−1.45 (m, 1H), 1.05
(d, J = 6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 204.1, 142.7,
142.5, 136.1, 130.5, 128.7, 127.2, 49.0, 34.4, 32.1, 28.4, 21.8, 21.4; IR
(neat film NaCl) 2956, 2927, 1702, 1671, 1608, 1459, 1234 cm−1;
HRMS (CI) calcd for [C13H16O + NH4]+ m/z 206.1539, found
206.1538.
1
to (E)-1p: H NMR (300 MHz, CDCl3) δ 10.28 (s, 1H), 7.86−7.82
(m, 1H), 7.55−7.49 (m, 1H), 7.40−7.34 (m, 1H), 7.30−7.28 (m, 1H),
5.67−5.59, 5.49−5.39, 3.74 (d, J = 6.3 Hz, 2H), 1.74−1.65 (m, 3H).28
7-Methyl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (2a). Al-
dehyde 1a (51.3 mg, 0.29 mmol), amine 3 (3.5 mg, 0.030 mmol, 10
mol %), aniline (33 mg, 0.36 mmol), benzoic acid (4.4 mg, 0.036
mmol), and triphenylphosphine (3.9 mg, 0.015 mmol) were added to
a 1 dram vial with a magnetic stir bar and brought into a nitrogen
atmosphere glovebox. PhCF3 (0.60 mL) and chlorobis(cyclooctene)-
rhodium(I) dimer (5.4 mg, 0.0075 mmol) were added. The resulting
solution was stirred for 15 h at 100 °C, and the reaction vial was
removed from the glovebox. CH2Cl2 (1 mL) and 1 M aqueous HCl
(0.6 mL) were added, and the mixture was vigorously stirred for 10
min. The organic layer was concentrated with silica gel in vacuo. Silica
gel chromatography with CH2Cl2/Hex (2:1) provided 2a as a colorless
7-Methyl-2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-benzo[7]-
annulen-5-one (2c). See general procedure for the hydroacylation of
aldehydes 1b−1e. Reaction was carried out with 63 mg (0.26 mmol)
of aldehyde 1c. The crude mixture was purified by silica gel flash
column chromatography (1:9 EtOAc/Hex) to afford 48 mg (76%
1
yield) of ketone 2c as a colorless oil: Rf 0.40 (1:4 EtOAc/Hex); H
NMR (300 MHz, CDCl3) δ 7.78 (d, J = 7.8 Hz, 1H), 7.53 (d, J = 8.1
Hz, 1H), 7.47 (s, 1H), 3.11−2.90 (m, 2H), 2.80 (dd, J = 14.8, 4.5 Hz,
1H), 2.60 (dd, J = 14.7, 9.3 Hz, 1H), 2.16−1.99 (m, 2H), 1.64−1.50
(m, 1H), 1.08 (d, J = 6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
203.6, 142.7, 141.7, 133.1 (q, J = 32.2 Hz), 128.9, 126.6 (q, J = 3.4
Hz), 123.7 (q, J = 272.6 Hz), 123.3 (q, J = 3.4 Hz), 48.8, 34.1, 32.1,
28.7, 21.6; IR (neat film NaCl) 3032, 2957, 2929, 2872, 1686, 1577,
1330, 1168 cm−1; HRMS (CI) calcd for [C13H13F3O + H]+ m/z
243.0991, found 243.1008.
1
oil (41.7 mg, 0.24 mmol, 81%): Rf 0.43 (2:1 CH2Cl2/Hex); H NMR
(500 MHz, CDCl3) δ 7.72 (dd, J = 7.5 Hz, 1.5 Hz, 1H), 7.41−7.38 (m,
1H), 7.30−7.26 (m, 1H), 7.20 (d, J = 7.5 Hz, 1H), 3.04−2.99 (m,
1H), 2.90−2.75 (m, 1H), 2.77 (dd, J = 15 Hz, 4.5 Hz, 1H), 2.60 (dd, J
= 15 Hz, 9.0 Hz, 1H), 2.10−2.00 (m, 2H), 1.55−1.51 (m, 1H), 1.06
(d, J = 6.6 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 204.5, 142.4,
138.8, 131.9, 129.7, 128.4, 126.5, 49.0, 34.3, 32.1, 28.6, 21.7; IR (neat
film NaCl) 2954, 2926, 2870, 1679, 1599, 1299, 1292, 1279 cm−1;
HRMS (ESI) calcd for [C12H14O + Na]+ m/z 197.0942, found
197.0934. The structure was also confirmed by COSY, HMQC, and
HMBC.
2-Methoxy-7-methyl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-
one (2d). See general procedure for the hydroacylation of aldehydes
1b−1e. Reaction was carried out with 67 mg (0.33 mmol) of aldehyde
1d. The crude mixture was purified by silica gel flash column
chromatography (1:5 EtOAc/Hex) to afford 57 mg (85% yield) of
1
ketone 2d as colorless oil: Rf 0.30 (1:4 EtOAc/Hex); H NMR (300
MHz, CDCl3) δ 7.77 (d, J = 8.7 Hz, 1H), 6.79 (dd, J = 8.7, 2.4 Hz,
1H), 6.69 (d, J = 2.4 Hz, 1H), 3.83 (s, 3H), 3.05−2.95 (m, 1H), 2.88−
2.81 (m, 1H), 2.71 (d, J = 3.9 Hz, 1H), 2.58 (dd, J = 14.7, 8.9 Hz, 1H),
2.13−1.95 (m, 2H), 1.56−1.44 (m, 1H), 1.04 (d, J = 6.6 Hz, 3H); 13C
NMR (75 MHz, CDCl3) δ 202.6, 162.4, 145.3, 131.5, 131.1, 114.9,
111.6, 55.3, 48.9, 34.2, 32.5, 28.2, 21.8; IR (neat film NaCl) 3055,
2961, 1712, 1600, 1362, 1266, 1221 cm−1; HRMS (CI) calcd for
[C13H16O2 + H]+ m/z 205.1223, found 205.1219.
2-Fluoro-7-methyl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-
one (2e). See general procedure for the hydroacylation of aldehydes
1b−1e. Reaction was carried out with 67 mg (0.35 mmol) of aldehyde
1e. The crude mixture was purified by silica gel flash column
chromatography (1:9 EtOAc/Hex) to afford 54 mg (80% yield) of
inseparable mixture of ketone 2e and a minor amount of the
corresponding indanone derivative as colorless oil. Pure compound for
NMR was obtained by preparative thin layer chromatography (Hex/
C6H6/CHCl3 11:2:2, 6 elutions): Rf 0.50 (1:4 EtOAc/Hex); 1H NMR
(300 MHz, CDCl3) δ 7.77 (dd, J = 8.7, 6.0 Hz, 1H), 7.0−6.88 (m,
2H), 3.06−3.0 (m, 1H), 2.90−2.79 (m, 2H), 2.75 (d, J = 4.2 Hz, 1H),
2.58 (dd, J = 14.7, 9.0 Hz, 1H), 2.13−1.97 (m, 1H), 1.58−1.47 (m,
1H), 1.06 (d, J = 6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 202.7,
(−)-7-Methyl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one,
(−)-2a. Aldehyde (34.0 mg, 0.20 mmol), amine 5 (22 mg, 0.05 mmol,
25 mol %), aniline (22 mg, 0.24 mmol), benzoic acid (2.4 mg, 0.02
mmol), and triphenylphosphine (5.2 mg, 0.02 mmol) were added to a
1 dram vial with a magnetic stir bar in the nitrogen atmosphere of the
glovebox. PhCF3 (0.2 mL) and chlorobis(cyclooctene)rhodium(I)
dimer (7.2 mg, 0.01 mmol) were added. The resulting solution was
stirred for 15 h at 80 °C, and reaction vial was removed from the
glovebox. Aqueous HCl (1.0 mL, 1M) and CH2Cl2 (1 mL) were
added, and the mixture was vigorously stirred for 10 min. The organic
phase was separated and concentrated in vacuo. Column chromatog-
raphy on silica gel (1:2 Hex/CH21Cl2) afforded (−)-2a as a colorless oil
(27.9 mg, 0.16 mmol, 82%): Rf, H NMR, 13C NMR, IR, and HRMS
data as reported above for ( )-2a. HPLC analysis: ee 31% (Chiracel
OD, 1:19 isopropyl alcohol/hexanes, 1.0 mL/min, 254 nm, tR1 = 5.5
min, tR2 = 5.9 min); [α]25 = −15 (c = 0.80, CHCl3).
D
General Procedure for Preparation of Ketones 2b−2e.
Aldehyde (0.30 mmol), amine 3 (3.5 mg, 0.030 mmol, 10 mol %),
aniline (33 mg, 0.36 mmol), benzoic acid (4.4 mg, 0.036 mmol), and
triphenylphosphine (3.9 mg, 0.015 mmol) were added to a 1 dram vial
with a magnetic stir bar and brought into a nitrogen atmosphere
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164.6 (d, J = 252.8 Hz), 145.7 (d, J = 8.1 Hz), 135.0, 131.3 (d, J = 9.7
Hz), 116.4 (d, J = 21.3 Hz), 113.5 (d, J = 21.3 Hz), 48.8, 34.1, 32.1,
28.3, 21.7; IR (neat film NaCl) 3061, 2957, 2928, 2870, 1708, 1677,
1606, 1582, 1459, 1247 cm−1; HRMS (CI) calcd for [C12H13FO +
NH4]+ m/z 210.1289, found 210.1280.
2855, 1679, 1253, 1111 cm−1; HRMS (ESI) calcd for [C18H28O2Si +
Na]+ m/z 327.1756, found 327.1755.
General Procedure for the Hydroacylation of Aldehydes 1i,
1j, 1m, and 1n. Aldehyde (0.30 mmol), amine 4 (13 mg, 0.075
mmol, 25 mol %), aniline (33 mg, 0.36 mmol), benzoic acid (4.4 mg,
0.036 mmol), triphenylphosphine (8.0 mg, 0.03 mmol) and PhCF3
(0.30 mL) were added to a 1 dram vial with a magnetic stir bar and
brought into a nitrogen atmosphere glovebox. Chlorobis-
(cyclooctene)rhodium(I) dimer (11.0 mg, 0.015 mmol) was added.
The resulting solution was stirred for 36 h at 100 °C, and the reaction
vial was removed from the glovebox. Et2O (1 mL) and 1 M aqueous
HCl (0.5 mL) were added, and the mixture was vigorously stirred for
10 min. To the mixture was added H2O (5 mL). The aqueous layer
was thoroughly extracted with Et2O (4 × 15 mL). Combined organic
layers were washed with brine (10 mL), dried over anhydrous Na2SO4,
and concentrated in vacuo. Silica gel chromatography (EtOAc/Hex)
gave the ketones 2 in the reported yields.
7-Methyl-7,8-dihydro-5H-pyrrolo[1,2-a]azepin-9(6H)-one (2i).
See general procedure for the hydroacylation of aldehydes 1i, 1j,
1m, and 1n. Reaction was carried out with 48 mg (0.29 mmol) of
aldehyde 1i. The crude mixture was purified by silica gel flash column
chromatography (1:1 EtOAc/Hex) to afford 30 mg (63% yield) of
ketone 2i as light yellow oil: Rf 0.25 (1:3 EtOAc/Hex); 1H NMR (300
MHz, CDCl3) δ 6.99 (dd, J = 3.9, 1.8 Hz, 1H), 6.78 (t, J = 2.1 1H),
6.13 (dd, J = 4.1, 2.4 Hz, 1H), 4.28−4.09 (m, 2H), 2.78−2.61 (m,
2H), 2.31−2.12 (m, 2H), 1.68−1.58 (m, 1H), 1.07 (d, J = 6.6 Hz);
13C NMR (75 MHz, CDCl3) δ 190.5, 134.2, 128.1, 117.0, 108.7, 47.9,
7-Ethyl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (2f). Alde-
hyde 1f (39.4 mg, 0.21 mmol), amine 3 (0.021 mmol, 10 mol %),
aniline (0.45 mmol), benzoic acid (2.4 mg, 0.02 mmol), and
triphenylphosphine (2.6 mg, 0.01 mmol) were added to a 1 dram
vial with a magnetic stir bar and brought into a nitrogen atmosphere
glovebox. PhCF3 (0.18 mL) and chlorobis(cyclooctene)rhodium(I)
dimer (3.6 mg, 0.005 mmol) were added. The resulting solution was
stirred for 15 h at 100 °C, and the reaction vial was removed from the
glovebox. CH2Cl2 (1 mL) and 1 M aqueous HCl (0.6 mL) were
added, and the mixture was vigorously stirred for 10 min. The organic
layer was concentrated with silica gel in vacuo. Silica gel
chromatography with CH2Cl2/Hex (2:1) provided 2f as a colorless
1
oil (33.7 mg, 0.18 mmol, 86%): Rf 0.39 (2:1 CH2Cl2/Hex); H NMR
(300 MHz, CDCl3) δ 7.73 (d, J = 7.8 Hz, 1H), 7.42−7.25 (m, 2H),
7.20 (d, J = 7.5 Hz, 1H), 3.06−2.76 (m, 3H), 2.63−2.55 (m, 1H),
2.07−1.97 (m, 1H), 1.85−1.76 (m, 1H), 1.60−1.49 (m, 1H), 1.45−
1.35 (m, 2H), 0.92 (t, J = 7.5 Hz); 13C NMR (75 MHz, CDCl3) δ
204.5, 142.4, 138.6, 131.9, 129.7, 128.4, 126.4, 46.8, 34.9, 32.0, 31.9,
28.7, 11.6; IR (neat film NaCl) 2960, 2929, 1677, 1599, 1460, 1449,
1290, 1254, 1245 cm−1; HRMS (ESI) calcd for [C13H16O + Na]+ m/z
211.1093, found 211.1100.
7-Phenyl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (2g). Al-
dehyde 1g (31.9 mg, 0.135 mmol), amine 4 (6 mg, 0.015 mmol, 25
mol %), aniline (0.15 mmol), benzoic acid (1.7 mg, 0.014 mmol), and
triphenylphosphine (1.8 mg, 0.0068 mmol) were added to a 1 dram
vial with a magnetic stir bar and brought into a nitrogen atmosphere
glovebox. PhCF3 (0.15 mL) and chlorobis(cyclooctene)rhodium(I)
dimer (2.4 mg, 0.0034 mmol) were added. The resulting solution was
stirred for 15 h at 100 °C, and the reaction vial was removed from the
glovebox. CH2Cl2 (1 mL) and 1 M aqueous HCl (0.6 mL) were
added, and the mixture was vigorously stirred for 10 min. The organic
layer was concentrated with silica gel in vacuo. Silica gel
chromatography with CH2Cl2/Hex (2:1) provided 2g as a colorless
oil (24.7 mg, 0.10 mmol, 77%): Rf 0.29 (2:1 CH2Cl2/Hex). The
characterization data are not consistent with those previously
reported:14 1H NMR (500 MHz, acetone-d6) δ 7.68 (d, J = 7.0 Hz,
1H), 7.51 (t, J = 7.5 Hz, 1H), 7.39−7.29 (m, 6H), 7.23−7.19 (m, 1H),
3.29−3.22 (m, 2H), 3.15−3.08 (m, 1H), 3.00 (dt, J = 15 Hz, 4.5 Hz,
1H), 2.85 (dd, J = 16 Hz, 2.5 Hz, 1H), 2.23−2.16 (m, 1H), 2.06−1.99
(m, 1H); 13C NMR (75 MHz, acetone-d6) δ 203.7, 147.0, 142.2,
139.6, 133.2, 130.8, 129.5, 129.3, 128.0, 127.6, 127.3, 48.6, 40.3, 35.8,
32.8; IR (neat film, NaCl) 2935, 1667, 1599, 1449, 1289. HRMS (ESI)
calcd for [C17H16O + Na]+ m/z 259.1099, found 259.1101. The
structure was also confirmed by COSY, 1H NMR decoupling
experiments, HMQC, and HMBC.29
7-(((tert-Butyldimethylsilyl)oxy)methyl)-6,7,8,9-tetrahydro-5H-
benzo[7]annulen-5-one (2h). Aldehyde (25.9 mg, 0.085 mmol),
amine 4 (1.5 mg, 0.0085 mmol, 10 mol %), aniline (0.11 mmol),
benzoic acid (1.0 mg, 0.009 mmol), and triphenylphosphine (1.1 mg,
0.0043 mmol) were added to a 1 dram vial with a magnetic stir bar and
brought into a nitrogen atmosphere glovebox. PhCF3 (0.17 mL) and
chlorobis(cyclooctene)rhodium(I) dimer (1.5 mg, 0.0021 mmol) were
added. The resulting solution was stirred for 15 h at 100 °C, and the
reaction vial was removed from the glovebox. CH2Cl2 (1 mL) and 1 M
aqueous HCl (0.4 mL) were added, and the mixture was vigorously
stirred for 10 min. The organic layer concentrated with silica gel in
vacuo. Silica gel chromatography with CH2Cl2/Hex (2:1) provided 2h
as a colorless oil (16.7 mg, 0.055 mmol, 78%): Rf 0.24 (2:1 CH2Cl2/
Hex); 1H NMR (300 MHz, CDCl3) δ 7.70 (d, J = 7.8 Hz, 1H), 7.37−
7.34 (m, 1H), 7.25 (t, J = 7.5 Hz, 1H), 7.16 (d, J = 7.5 Hz, 1H), 3.52−
3.44 (m, 2H), 3.05−2.95 (m, 1H), 2.89−2.75 (m, 2H), 2.66−2.58 (m,
1H), 2.06−1.86 (m, 2H), 0.84 (s, 9H), 0.01 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 204.5, 142.1, 138.6, 132.1, 129.7, 128.5, 126.6, 66.6,
44.0, 35.9, 31.8, 28.7, 25.9, 18.3, −5.4; IR (neat film NaCl) 2952, 2927,
47.4, 35.2, 27.6, 22.2; IR (neat film NaCl) 3053, 2985, 1646, 1526,
1421, 1265 cm−1; HRMS (ESI) calcd for [C10H13NO + Na]+ m/z
186.0895, found 186.0898.
8-Methyl-8,9-dihydro-6H-azepino[1,2-a]indol-10(7H)-one (2j).
See general procedure for the hydroacylation of aldehydes 1i, 1j,
1m, and 1n. Reaction was carried out with 42 mg (0.20 mmol) of
aldehyde 1j. The crude mixture was purified by silica gel flash column
chromatography (1:3 EtOAc/Hex) to afford 28 mg (66% yield) of
1
ketone 2j as colorless oil: Rf 0.35 (1:3 EtOAc/Hex); H NMR (300
MHz, CDCl3) δ 7.70 (d, J = 7.8 Hz, 1H), 7.37 (d, J = 3.9 Hz, 2H),
7.25 (s, 1H), 7.19−7.10 (m, 1H), 4.40−4.35 (m, 2H), 2.91 (dd, J =
14.5, 4.1 Hz, 1H), 2.76 (dd, J = 14.2, 8.9 Hz, 1H), 2.39−2.21 (m, 2H),
1.82−1.72 (m, 1H), 1.14 (d, J = 6.6 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 193.7, 139.0, 126.2, 125.3, 123.2, 120.6, 110.2, 108.5, 48.6,
42.6, 35.5, 28.1, 22.1; peak at 139.0 ppm corresponds to two carbons;
this was confirmed by recording 13C NMR in CD3OD, see spectra; 13
C
NMR (75 MHz, CD3OD) δ 196.4, 140.8, 140.0, 127.6, 126.8, 124.1,
121.9, 111.8, 109.4, 43.7, 36.7, 29.6, 22.5; one of the NMR signals for
aliphatic carbons is obscured by solvent peaks; IR (neat film NaCl)
3053, 2986, 1663, 1518, 1421, 1266 cm−1; HRMS (ESI) calcd for
[C14H15NO + Na]+ m/z 236.1046, found 236.1051.
3-Methyl-3,4-dihydronaphthalen-1(2H)-one (2k). Aldehyde 1k
(49.5 mg, 0.30 mmol), amine 4 (13.2 mg, 0.075 mmol, 25 mol %),
aniline (0.36 mmol), benzoic acid (3.6 mg, 0.03 mmol), and
triphenylphosphine (3.9 mg, 0.015 mmol) were added to a 1 dram
vial with a magnetic stir bar and brought into a nitrogen atmosphere
glovebox. PhCF3 (0.60 mL) and chlorobis(cyclooctene)rhodium(I)
dimer (5.4 mg, 0.0075 mmol) were added. The resulting solution was
stirred for 15 h at 100 °C, and the reaction vial was removed from the
glovebox. CH2Cl2 (2 mL) and 1 M aqueous HCl (1.0 mL) were
added, and the mixture was vigorously stirred for 10 min. The organic
layer was concentrated with silica gel in vacuo. Silica gel
chromatography with Hex/MeOH (98:2) provided 2k as a colorless
oil (15.0 mg, 0.094 mmol, 30%). This separation of 2k from side
products in the crude reaction mixture was challenging, and we
attribute the low yield to this factor: Rf 0.39 (2:1 CH2Cl2/Hex). The
characterization data are consistent with those previously reported.30
The reaction was repeated with aldehyde (34.8 mg, 0.22 mmol),
amine 4 (35.4 mg, 0.20 mmol, 0.9 equiv), and accordingly scaled
amounts of other reagents. 1H NMR analysis of reaction mixture after
HCl workup with 4′-methoxyacetophenone as an internal standard
showed 65% yield of 2k.
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3-Phenyl-3,4-dihydronaphthalen-1(2H)-one (2l). Aldehyde 1l
(66.8 mg, 0.30 mmol), amine 4 (53.1 mg, 0.30 mmol, 100 mol %),
aniline (0.36 mmol), benzoic acid (3.6 mg, 0.03 mmol), and
triphenylphosphine (3.9 mg, 0.015 mmol) were added to a 1 dram
vial with a magnetic stir bar and brought into a nitrogen atmosphere
glovebox. PhCF3 (0.60 mL) and chlorobis(cyclooctene)rhodium(I)
dimer (5.4 mg, 0.0075 mmol) were added. The resulting solution was
stirred for 15 h at 100 °C, and the reaction vial was removed from the
glovebox. CH2Cl2 (1 mL) and 1 M aqueous HCl (0.6 mL) were
added, and the mixture was vigorously stirred for 10 min. The organic
layer was concentrated with silica gel in vacuo. Silica gel
chromatography with CH2Cl2/Hex (2:1) provided 2l as a colorless
oil (38.9 mg, 0.18 mmol, 58%): Rf 0.33 (2:1 CH2Cl2/Hex). The
characterization data are consistent with those previously reported.14
6-Methyl-6,7-dihydroindolizin-8(5H)-one (2m). See general pro-
cedure for the hydroacylation of aldehydes 1i, 1j, 1m, and 1n. Reaction
was carried out with 60 mg (0.4 mmol) of aldehyde 1m. The crude
mixture was purified by silica gel flash column chromatography (1:1
EtOAc/Hex) to afford 40 mg (67% yield) of ketone 2m as light yellow
3-Methyl-5-(pyrrolidin-1-yl)pyridin-2-amine (4). A mixture of 2-
amino-5-iodopicoline33 (1.17 g, 5 mmol), pyrrolidine (1.07 g, 15
mmol), K2CO3 (1. 38 g, 10 mmol), CuI (95 mg, 0.5 mmol), and L-
proline (115 mg, 1 mmol) in 5 mL of DMSO was heated in a vial at 75
°C.34 The reaction was monitored by TLC. Upon completion, the
cooled mixture was diluted with 30 mL of ethyl acetate and was
filtered through a pad of Celite. The Celite pad was washed with ethyl
acetate (50 mL). The filtrates were combined and washed with water
(3 × 20 mL), brine (15 mL), dried over Na2SO4, and concentrated in
vacuo. The residual paste was purified by silica gel flash
chromatography (97.8:2:0.2 EtOAc/MeOH/Et3N) to afford 580 mg
(65%) of picoline 4: Rf 0.10 (20:1 EtOAc/MeOH), pale yellow solid;
mp 129−130 °C; 1H NMR (300 MHz, CDCl3) δ 7.37 (d, J = 2.7 Hz,
1H), 6.7 (d, J = 2.7 Hz, 1H), 3.88 (s, 2H), 3.17 (t, J = 6.6 Hz, 4H),
2.12 (s, 3H), 1.98−1.94 (m, 4H); 13C NMR (75 MHz, CDCl3) δ
148.2, 139.2, 128.7, 123.4, 117.6, 48.1, 25.1, 17.5; IR (neat film NaCl)
3377, 3175, 2906, 2829, 1646, 1476, 1437, 1335, 1255, 1172,1140
cm−1; HRMS (ESI) calcd for [C10H15N3 + Na]+ m/z 200.1158, found
200.1155.
(S)-3-(6-Amino-5-methylpyridin-3-yl)-4-benzyl-5,5-diphenyloxa-
zolidin-2-one (5). 2-Amino-5-iodo-3-picoline31 (234 mg, 1 mmol),
(S)-(−)-5-benzyl-4,4-diphenyl-1,3-oxazolidinone (329 mg, 1 mmol),
copper(I) iodide (19 mg, 0.1 mmol), potassium phosphate (636 mg, 3
mmol), N,N′-dimethylethylenediamine (22 μL, 0.2 mmol), toluene (2
mL), and a magnetic stir bar were placed in 1 dram vial. The vial was
flushed with nitrogen and capped. The reaction mixture was stirred at
100 °C for 24 h, diluted with CH2Cl2 (10 mL), and washed with
saturated aqueous NH4Cl (10 mL). The organic phase was separated,
dried over Na2SO4, and concentrated in vacuo. Purification by column
chromatography on silica gel (EtOAc) followed by recrystallization
from PhCF3 afforded 5 as light yellow crystals (154 mg, 0.35 mmol,
35%): Rf 0.25 (EtOAc); mp 239−240 °C; 1H NMR (300 MHz,
CDCl3) δ 7.80 (d, J = 2.4 Hz, 1H), 7.58−7.55 (m, 2H), 7.43−7.18 (m,
9H), 7.04−7.02 (m, 2H), 6.64 (dd, J = 1.8 Hz, 5.4 Hz, 2H), 5.21 (t, J =
6.6 Hz, 1H), 4.39 (br s, 2H), 2.74 (d, J = 6.6 Hz, 2H), 1.99 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 156.0, 155.6, 143.2, 142.0, 139.2, 137.1,
1
oil: Rf 0.25 (1:3 EtOAc/Hex); H NMR (300 MHz, CDCl3) δ 7.01
(dd, J = 4.2, 1.5 Hz, 1H), 6.84 (t, J = 2.1 Hz, 1H), 6.25 (dd, J = 4.2, 2.4
Hz, 1H), 4.15 (ddd, J = 12.3, 4.2, 1.2 Hz, 1H), 3.72 (dd, J = 12.3, 9.9
Hz, 1H), 2.65 (ddd, J = 16.7, 4.0, 1.5 Hz, 1H), 2.59−2.46 (m, 1H),
2.29 (dd, J = 16.6, 10.8 Hz, 1H), 1.14 (d, J = 6.6 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ 187.1, 130.1, 125.8, 113.8, 110.4, 51.6, 44.4, 30.4,
18.3; IR (neat film NaCl) 3053, 2985, 1662, 1558, 1420, 1265 cm−1;
HRMS (CI) calcd for [C9H11NO + H]+ m/z 150.0913, found
150.0926.
7-Methyl-7,8-dihydropyrido[1,2-a]indol-9(6H)-one (2n). See gen-
eral procedure for the hydroacylation of aldehydes 1i, 1j, 1m, and 1n.
Reaction was carried out with 60 mg (0.30 mmol) of aldehyde 1n. The
crude mixture was purified by silica gel flash column chromatography
(1:3 EtOAc/Hex) to afford 41 mg (69% yield) of ketone 2n as a
colorless solid: mp 116 °C; Rf 0.35 (1:3 EtOAc/Hex); 1H NMR (300
MHz, CDCl3) δ 7.75−7.72 (m, 1H), 7.39−7.37 (m, 2H), 7.27 (s, 1H),
7.20−7.14 (m, 1H), 4.41−4.36 (m, 1H), 3.81−3.73 (m, 1H), 2.84−
2.77 (m, 1H), 2.70−2.59 (m, 1H), 2.46 (ddd, J = 16.5, 11.1, 0.9 Hz,
1H), 1.25 (dd, J = 6.6, 0.9 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ
190.2, 137.2, 133.2, 126.8, 125.6, 123.4, 121.1, 110.3, 105.5, 48.0, 45.2,
30.1, 18.6; IR (neat film NaCl) 3053, 2986, 1675, 1527, 1421, 1265
cm−1; HRMS (ESI) calcd for [C13H13NO + Na]+ m/z 222.0889,
found 222.0887.
1-Benzosuberone (2o). Aldehyde 1o (81.7 mg, 0.51 mmol), amine
3 (58.6 mg, 0.54 mmol, 100 mol %), aniline (56 mg, 0.60 mmol),
benzoic acid (6.1 mg, 0.05 mmol), and triphenylphosphine (6.6 mg,
0.025 mmol) were added to a 1 dram vial with a magnetic stir bar and
brought into a nitrogen atmosphere glovebox. PhCF3 (2.50 mL) and
chlorobis(cyclooctene)rhodium(I) dimer (9.0 mg, 0.0125 mmol) were
added. The resulting solution was stirred for 20 h at 100 °C, and the
reaction vial was removed from the glovebox. Aqueous HCl (3.0 mL,
1M) was added, and the mixture was vigorously stirred for 10 min.
The organic layer was separated and concentrated in vacuo. Silica gel
chromatography on silica gel (20:1 Hex/EtOAc) afforded 2o as a
colorless oil (41.5 mg, 0.26 mmol, 51%): Rf 0.22 (30:1 Hex/EtOAc).
The characterization data are consistent with those previously
reported.31
2-Ethyl-2,3-dihydro-1H-inden-1-one (2p). Aldehyde (161.1 mg,
1.00 mmol), amine 3 (15.9 mg, 0.13 mmol, 13 mol %), aniline (112
mg, 1.2 mmol), benzoic acid (12 mg, 0.1 mmol), and triphenylphos-
phine (13.1 mg, 0.05 mmol) were added to a 1 dram vial with a
magnetic stir bar in the nitrogen atmosphere of the glovebox. PhCF3
(3.0 mL) and chlorobis(cyclooctene)rhodium(I) dimer (18.0 mg,
0.025 mmol) were added. The resulting solution was stirred for 16 h at
100 °C, and the reaction vial was removed from the glovebox.
Aqueous HCl (3.0 mL, 1M) was added, and the mixture was
vigorously stirred for 10 min. The organic phase was separated and
concentrated in vacuo. Column chromatography on silica gel (30:1
Hex/EtOAc) afforded 2p as a colorless oil (39.9 mg, 0.25 mmol,
25%): Rf 0.22 (30:1 Hex/EtOAc). The characterization data are
consistent with those previously reported.32
135.0, 129.5, 129.3, 128.9, 128.8, 127.5, 126.9, 126.6, 125.8, 117.4,
88.0, 68.2, 37.8, 17.8 (two signals in the aromatic region are not
resolved); HRMS (ESI) calcd for [C28H25N3O2 + H]+ m/z 436.2020,
found 436.2015; [α]25 −234 (c = 0.68, CHCl3).
D
ASSOCIATED CONTENT
* Supporting Information
■
S
NMR spectra for new compounds and new preparations of
known compounds, assignment diagram for 2g, and HPLC
chromatograms for ( )-2a and (−)-2a are provided. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: cdouglas@umn.edu.
■
Present Address
†Department of Chemistry, University of WisconsinEau
Claire, 105 Garfield Ave., Eau Claire, WI 54702.
ACKNOWLEDGMENTS
■
The donors of the ACS Petroleum Research Fund (47565-G1),
Research Corporation for Science Advancement (Cottrell
Scholar Award to C.J.D.), and the University of Minnesota
funded this work. The authors thank Dr. Letitia Yao and Giang
T. Hoang (UMN) for assistance with NMR spectroscopy, Dr.
Joe Dalluge and Sean Murray (UMN) for assistance with mass
spectrometry, Rosalind Douglas (UMN) for constructive
comments during the preparation of this manuscript, and
Prof. Andrew Harned (UMN) for use of a shared HPLC.
5892
dx.doi.org/10.1021/jo300779q | J. Org. Chem. 2012, 77, 5884−5893

The Journal of Organic Chemistry
Featured Article
Sapmaz, S. Chem. Commun. 2001, 2558. (d) Jun, C.-H.; Lee, D.-Y.;
Lee, H.; Hong, J.-B. Angew. Chem., Int. Ed. 2000, 39, 3070. (e) Jun, C.-
H.; Hong, J.-B. Org. Lett. 1999, 1, 887. (f) Jun, C.-H.; Lee, H.; Hong,
J.-B. J. Org. Chem. 1997, 62, 1200.
REFERENCES
■
(1) For reviews on hydroacylation, see: (a) Gonzal
́
ez-Rodríguez, C.;
Willis, M. C. Pure Appl. Chem. 2011, 83, 577. (b) Willis, M. C. Chem.
Rev. 2010, 110, 725. (c) Fu, G. C. In Modern Rhodium-Catalyzed
Organic Reactions; Evans, P. A., Ed.; Wiley-VCH: New York, 2005; pp
79−91. (d) Tanaka, M.; Sakai, K.; Suemune, H. Curr. Org. Chem.
2003, 7, 353. (e) Bosnich, B. Acc. Chem. Res. 1998, 31, 667.
(11) An alternative approaches for suppression of undesired
pathways in hydroacylation: (a) Roy, A. H.; Lenges, C. P.;
Brookhart, M. J. Am. Chem. Soc. 2007, 129, 2082. (b) Lenges, C. P.;
White, P. S.; Brookhart, M. J. Am. Chem. Soc. 1998, 120, 6965.
́ ́
(2) (a) Marce, P.; Díaz, Y.; Matheu, M. I.; Castillon, S. Org. Lett.
1
(12) Compound 2a was characterized by H, 13C, COSY, HMQC,
2008, 10, 4735. (b) Kundu, K.; McCullagh, J. V.; Morehead, A. T. J.
Am. Chem. Soc. 2005, 127, 16042. (c) Cyclobutanones also formed:
Tanaka, K.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 8078. (d) Tanaka,
M.; Imai, M.; Fujio, M.; Sakamoto, E.; Takahashi, M.; Eto-Kato, Y.;
Wu, X.-M.; Funakoshi, K.; Sakai, K.; Suemune, H. J. Org. Chem. 2000,
65, 5806. (e) Barnhart, R. W.; McMorran, D. A.; Bosnich, B. Chem.
Commun. 1997, 589. (f) Barnhart, R. W.; Wang, X.; Noheda, P.;
Bergens, S. H.; Whelan, J.; Bosnich, B. J. Am. Chem. Soc. 1994, 116,
1821. (g) Taura, Y.; Tanaka, M.; Wu, X.-M.; Funakoshi, K.; Sakai, K.
Tetrahedron 1991, 47, 4879. (h) Larock, R. C.; Oertle, K.; Potter, G. F.
J. Am. Chem. Soc. 1980, 102, 190. (i) Lochnow, C. F.; Miller, R. G. J.
Am. Chem. Soc. 1976, 98, 1281. (j) Sakai, K.; Ide, J.; Oda, O.;
Nakamura, N. Tetrahedron Lett. 1972, 1287.
and HMBC NMR spectroscopy experiments, IR spectroscopy, and
mass spectrometry. See Supporting Information for details.
(13) Ogawa, A.; Curran, D. P. J. Org. Chem. 1997, 62, 450.
(14) Compound 2g was reportedly prepared by an alternative
synthesis, but our spectroscopic data did not match those provided in
this preparation: Fillion, E.; Fishlock, D.; Wilsily, A.; Goll, J. M. J. Org.
Chem. 2005, 70, 1316. We hypothesize that the compound prepared
in this report was 3-phenethyl-2,3-dihydroinden-1-one.
1
(15) We assigned 2g as the benzosuberone system using H, 13C,
COSY, HMQC, HMBC NMR spectroscopy experiments, selected
frequency-decoupled 1H NMR, IR spectroscopy (carbonyl at 1667
cm−1), and mass spectrometry. Prof. Fillion concurs with our
assignment of 2g.16
(3) (a) Coulter, M. M.; Dornan, P. K.; Dong, V. M. J. Am. Chem. Soc.
2009, 131, 6932. (b) Shen, Z.; Dornan, P. K.; Khan, H. A.; Woo, T. K.;
Dong, V. M. J. Am. Chem. Soc. 2009, 131, 1077. (c) Bendorf, H. D.;
Colella, C. M.; Dixon, E. C.; Marchetti, M.; Matukonis, A. N.;
Musselman, J. D.; Tily, T. A. Tetrahedron Lett. 2002, 43, 7031.
(4) The use of acrylamides as the alkene in intermolecular
hydroacylation avoids this limitation: (a) Shibata, Y.; Tanaka, K. J.
Am. Chem. Soc. 2009, 131, 12552. (b) Tanaka, K.; Shibata, Y.; Suda,
T.; Hagiwara, Y.; Hirano, M. Org. Lett. 2007, 9, 1215.
(5) For alternative hydrogenation or transfer hydrogenation
approaches, see: (a) Shibahara, F.; Bower, J. F.; Krische, M. J. J. Am.
Chem. Soc. 2008, 130, 14120. (b) Hong, Y.-T.; Barchuk, A.; Krische,
M. J. Angew. Chem., Int. Ed. 2006, 45, 6885.
(6) Medium rings can be formed by hydroacylation of more elaborate
substrates, wherein a proximal alkene can stabilize metal acyl
intermediates. For an intramolecular hydroacylation with 1,3-dienes
to form cycloheptenones, see: (a) Oonishi, Y.; Mori, M.; Sato, Y.
Synthesis 2007, 2323. (b) Sato, Y.; Oonishi, Y.; Mori, M. Angew. Chem.,
Int. Ed. 2002, 41, 1218. For ring-expanding intramolecular
hydroacylation of vinyl cyclopropanes, see: (c) Aloise, A. D.; Layton,
M. E.; Shair, M. D. J. Am. Chem. Soc. 2000, 122, 12610. For cascade-
type cyclization reactions involving hydroacylation and multicompo-
nent insertions to form six-membered and larger rings, see:
(d) Oonishi, Y.; Hosotani, A.; Sato, Y. J. Am. Chem. Soc. 2011, 133,
10386. (e) Tanaka, K.; Hojo, D.; Shoji, T.; Hagiwara, Y.; Hirano, M.
Org. Lett. 2007, 9, 2059. (f) Tanaka, K.; Hagiwara, Y.; Hirano, M.
Angew. Chem., Int. Ed. 2006, 45, 2734. (g) Tanaka, K.; Hagiwara, Y.;
Noguchi, K. Angew. Chem., Int. Ed. 2005, 44, 7260. (h) Tanaka, K.; Fu,
G. C. Org. Lett. 2002, 4, 933.
(16) Personal communication with Prof. Fillion, April 11th, 2011 and
May 26th, 2011.
(17) Piel, I.; Steinmetz, M.; Hirano, K.; Frolich, R.; Grimme, S.;
̈
Glorius, F. Angew. Chem., Int. Ed. 2011, 50, 4983.
(18) Kinetics of six- versus seven-membered ring forming reactions:
(a) Norman, R. O. C.; Coxon, J. M. Principles of Organic Synthesis, 3rd
ed.; CRC Press: Boca Raton, FL, 1993, p 67. From a synthesis
standpoint, seven-membered rings are often prepared by ring
expansion of six-membered rings. For a review, see: (b) Kantorowski,
E. J.; Kurth, M. J. Tetrahedron 2000, 56, 4317.
(19) Hyatt, I. F. D.; Anderson, H. K.; Morehead, A. T.; Sargent, A. L.
Organometallics 2008, 27, 135 and references therein.
(20) For related approaches to asymmetric catalysis using
cooperative catalysis, i.e., chiral scaffolding ligands, see: (a) Joe, C.
L.; Tan, K. L. J. Org. Chem. 2011, 76, 7590. (b) Worthy, A. D.; Joe, C.
L.; Lightburn, T. E.; Tan, K. L. J. Am. Chem. Soc. 2010, 132, 14757.
(21) Van der Ent, A.; Onderdelinden, A. L. Inorg. Synth. 1990, 90.
(22) Dreis, A. M.; Douglas, C. J. J. Am. Chem. Soc. 2009, 131, 412.
(23) Watson, I. D. G.; Ritter, S.; Toste, F. D. J. Am. Chem. Soc. 2009,
131, 2056.
(24) Conditions for these alkylations were adapted from the
following: Bailey, W. F.; Wachter-Jurcsak, N. M.; Pineau, M. R.;
Ovaska, T. V.; Warren, R. R.; Lewis, C. E. J. Org. Chem. 1996, 61,
8216.
(25) Prepared by allylic bromination of 2-phenylpropene according
to Miyamura, H.; Akiyama, R.; Ishida, T.; Matsubara, R.; Takeuchi, M.;
Kobayashi, S. Tetrahedron 2005, 61, 12177. Residual 2-phenylpropene
was removed by column chromatography on silica (hexanes as eluent)
prior to use.
(7) Salicylaldehyde derivatives: (a) Murphy, S. K.; Coulter, M. M.;
Dong, V. M. Chem. Sci. 2012, 3, 355. (b) Murphy, S. K.; Petrone, D.
A.; Coulter, M. M.; Dong, V. M. Org. Lett. 2011, 13, 6216. (c) Zhang,
H.-J.; Bolm, C. Org. Lett. 2011, 13, 2900. (d) Coulter, M. M.; Kou, K.
G. M.; Galligan, B.; Dong, V. M. J. Am. Chem. Soc. 2010, 132, 16330.
(e) Phan, D. H. T.; Kou, K. G. M.; Dong, V. M. J. Am. Chem. Soc.
2010, 132, 16354. (f) Stemmler, R. T.; Bolm, C. Adv. Synth. Catal.
2007, 349, 1185. (g) Imai, M.; Tanaka, M.; Nagumo, S.; Kawa-rara,
N.; Suemune, H. J. Org. Chem. 2007, 72, 2543. (h) Imai, M.; Tanaka,
M.; Tanaka, K.; Yamamoto, Y.; Imai-Ogata, N.; Shimowatari, M.;
Najumo, S.; Kawahara, N.; Suemune, H. J. Org. Chem. 2004, 69, 1144.
(i) Aldehydes containing a chelating sulfide: Osborne, J. D.; Randell-
Sly, H. E.; Currie, G. S.; Cowley, A. R.; Willis, M. C. J. Am. Chem. Soc.
2008, 130, 17232.
(26) Levine, S. R.; Krout, M. R.; Stolz, B. M. Org. Lett. 2009, 11, 289.
(27) Bonnaventure, I.; Charette, A. B. J. Org. Chem. 2008, 73, 6330.
(28) Previous preparation: Kirmse, W.; Hoberger, G. J. Am. Chem.
̈
Soc. 1991, 113, 3925.
(29) See Supporting Information for an assignment diagram
summarizing key data.
(30) Roy, H. N.; Rahman, A. F. M. M.; Islam, M. A. J. Chem. Res.
2003, 594.
(31) Zhang, T.; Huang, X.; Xue, J.; Sun, S. Tetrahedron Lett. 2009, 50,
1290.
(32) Adamczyk, M.; Watt, D.; Netzel, D. J. Org. Chem. 1984, 49,
4226.
(33) Gram-scale iodination of 2-aminopicoline (3) was previously
described: Tao, L.; McLaughlin, L. W. J. Am. Chem. Soc. 2000, 122,
6512.
(34) Procedure adapted from Zhang, H.; Cai, Q; Ma, D. J. Org. Chem.
2005, 70, 5164.
(8) Tsuji, J.; Ohno, K. Tetrahedron Lett. 1965, 6, 3969.
(9) Suggs, J. W. J. Am. Chem. Soc. 1979, 101, 489.
(10) Review: (a) Park, Y. J.; Par, J.-W.; Jun, C.-H. Acc. Chem. Res.
2008, 41, 222. Leading references: (b) Vautravers, N. R.; Regent, D.
D.; Breit, B. Chem. Commun. 2011, 47, 6635. (c) Willis, M. C.;
5893
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