Synthesis of cis -octahydroindoles via intramolecular 1,3-dipolar cycloaddition of 2-acyl-5-aminooxazolium salts

Article abstract of DOI:10.1021/jo301600p

A concise method for the diastereoselective synthesis of octahydroindoles is presented. The products contain 2-amido and 7-hydroxyl substituents. A series of 2-acyl-5-aminooxazoles were prepared in one step. Upon methylation of the oxazole nitrogen atom,

Full text of DOI:10.1021/jo301600p

Note
pubs.acs.org/joc
Synthesis of cis-Octahydroindoles via Intramolecular 1,3-Dipolar
Cycloaddition of 2‑Acyl-5-aminooxazolium Salts
Corey H. Basch,† Jameson A. Brinck,† Joaquin E. Ramos,† Stephen A. Habay,*,† and Glenn P.A. Yap‡
†Department of Chemistry, Henson School of Science and Technology, Salisbury University, 1101 Camden Avenue, Salisbury,
Maryland 21801, United States
‡Department of Chemistry & Biochemistry, University of Delaware, 236 Brown Laboratory, Newark, Delaware 19716, United States
S
* Supporting Information
ABSTRACT: A concise method for the diastereoselective
synthesis of octahydroindoles is presented. The products
contain 2-amido and 7-hydroxyl substituents. A series of 2-
acyl-5-aminooxazoles were prepared in one step. Upon
methylation of the oxazole nitrogen atom, the substrates
underwent rapid intramolecular 1,3-dipolar cycloaddition with a tethered alkene and, after reduction with excess hydride,
produced octahydroindoles with excellent diastereoselectivity. The method allows for the installation of α-quaternary stereogenic
carbon atoms.
he prevalence of cis-octahydroindoles (OHIs) in bio-
differing at the configuration of the 7-hydroxyl group and
Tlogically active natural products and constrained peptides containing a tertiary amide at the 2-position.
We found no examples in the literature of intramolecular 1,3-
has stimulated interest in synthetic methods for their
construction.1−11 The intramolecular 1,3-dipolar cycloaddition
reaction of azomethine ylides with alkenes provides a
dipolar cycloadditions of aminooxazolium salts with alkenes.
The related munchnone imines, a class of mesoionic
compounds derived from Reissert salts, have been well studied
by McEwen.17 Munchnone imines are known to undergo
intramolecular 1,3-dipolar cycloaddition with alkynes to
produce fused-ring pyrroles as well as intermolecular reaction
with alkenes to form pyridones.18 A plausible mechanism for
the cyclization observed in our study, shown in Scheme 2, is
initiated by methylation of the oxazole nitrogen atom of 1a,
followed by resonance of the 5-amino lone pair electrons to
produce a transient 1,3-dipole that is trapped by reaction with
the alkene. Rearrangement of the cycloadduct leads to the
observed iminium salt 2.
straightforward route to this valuable structural motif.12,13
A
variety of precursor compounds have been employed to
generate the reactive azomethine ylide intermediate for
intramolecular reactions.12 Among them, azolium salts are
valuable for their ease of preparation and mild reaction
conditions in generation of the ylide. Nonetheless, methods
introducing novel substitution patterns and functionality such
as amides and quaternary stereogenic carbons remain under-
explored. Efficient access to OHI ring systems would be
advantageous to structure−activity studies of the medicinal
properties of OHI analogues as well as applications to natural
products synthesis. Herein we report a rapid diastereoselective
preparation of cis-octahydroindoles, containing 2-amido and 7-
hydroxyl substituents. 2-Amido-substituted OHIs are a
common structural feature in the aeruginosin family of thrombin
inhibitors,6 whereas 7-hydroxyl substitution is found in such
natural products as gliotoxin and epicoccin G.14 This method
also allows for synthesis of octahydroindoles containing α-
quaternary stereogenic carbon atoms, a desirable aspect of
various peptidomimetic compounds.15
The cycloaddition reaction could be initiated by methylation
of the oxazole nitrogen by addition of 1 equiv of methyl triflate
or trimethyloxonium tetrafluoroborate (Meerwein’s salt). Both
worked equally well, but Meerwein’s salt was preferred for its
longer shelf life and stability to air and moisture. The use of
other activating groups will be investigated further, allowing
flexibility in N-substitution; however, only methylating agents
were tested in this study. Several solvents were screened to find
the optimum conditions for dipolar cycloaddition (CH2Cl2,
DCE, CH3CN, CH3NO2). Reaction in nitromethane gave the
highest and most consistent yields as well as the highest
solubility for Meerwein’s salt (solubility is poor in halogenated
solvents). The maximum concentration of iminium ion 2 was
observed after 2 h at room temperature as determined by
During an investigation into the reactivity of oxazolium salts,
we discovered that 2-acyl-5-aminooxazole 1a underwent facile
intramolecular 1,3-dipolar cycloaddition upon methylation of
the oxazole nitrogen atom with methyl triflate (Scheme 1). The
resultant iminium salt 2 was detected in the 1H NMR spectrum
of the crude reaction mixture as a single diastereomer
1
decrease of alkene resonances in the H NMR of the crude
1
reaction solution.
(representative H NMR shifts (CDCl3): δ 5.28 (1H, dd, J =
10, 5.6 Hz, C2−H), 4.10 (1H, m, C3a-H), 3.44 (3H, s,
=NCH3).16 Addition of excess sodium borohydride led to
octahydroindole 3a as a ∼3:1 mixture of diastereomers,
Received: August 1, 2012
Published: October 23, 2012
© 2012 American Chemical Society
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Scheme 1. Observed Cyclization of 2-Acyl-5-aminooxazole To Form an Octahydroindole
Scheme 2. Plausible Reaction Sequence of Cyclization/
Reduction
suggested cis-ring fusion of the octahydroindole (J = 8.4 Hz)
and a cis-orientation between the adjacent C7-H and C7a-H (J
= 4.4 Hz). The X-ray structure of the tetrafluoroborate salt of
octahydroindole 3a confirmed the spectral interpretation and
also revealed the relative configuration of the amido group at
the 2-position of the ring. The cis-relationship between C2-H
and C3a-H suggested that the allylic methylene carbon of the
tether connected to the dipolarophile occupies an orientation
endo to the bridged tricyclic intermediate of Scheme 2. This
result is consistent with the general preference of intra-
molecular 1,3-dipolar cycloadditions with azomethine ylides.12
A trans relationship between C2-H and C3a-H would be
expected from the tether occupying an exo orientation. No
diastereomer resulting from an exo-oriented tether was
observed.
Encouraged by this optimized reaction sequence, several
oxazole substrates (Table 1) were prepared to investigate the
tolerance of the cyclization reaction to oxazole and
dipolarophile substitution with different 5-amino groups and
substituents at the 4-position of the oxazole, generating
quaternary stereogenic carbon atoms at the OHI 2 −position.
Oxazole substrates 1a−j were synthesized in good to excellent
yields (50−90%) using a one-step procedure developed by
Mosetti and co-workers.19 Isonitrile amide reactants (see Table
Subsequent reduction of the iminium ion 2 was accom-
plished initially by addition of excess sodium borohydride. This
led to a ∼3:1 mixture of diastereomeric products that were
difficult to separate by flash column chromatography. After a bit
of experimentation, we found that lowering the temperature to
0 °C followed by addition of sodium triacetoxyborohydride,
NaBH(OAc)3, and slow warming to room temperature yielded
predominantly one major diastereomer product (92:8 dr).
Coupling constant analysis of the C7a-H double doublet of 3a
a
Table 1. Synthesis of 2-Acyl-5-aminooxazoles
a
R1, R2 = 5-amino group of oxazoles. R3 = H, Me, or Bn. R4 = CHCH2, CCH, or C(CH3)CH2.
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Table 2. Synthesis of Octahydroindoles from 2-Acyl-5-aminooxazoles
1) were obtained by reaction of commercially available methyl
isocyanoacetate with primary or secondary amines in the
absence of solvent. Most of the amides precipitated within a
few minutes and were easily isolated by filtration. Those that
did not were isolated in pure form by passing the crude amides
through a pad of silica gel with ethyl acetate. Isocyano amides
underwent cyclization to form oxazoles by treatment with an
appropriate acid chloride in the presence of base. Hex-5-enoyl
chloride20 was used in most cases. Hex-5-ynoyl chloride was
used to prepare oxazole 1h and 5-methylhex-5-enoyl chloride
was used to prepare oxazole 1j.21 Oxazoles 1h and 1i were
synthesized from α-substituted isocyano amides (R3 = Me and
Bn), obtained by alkylation with methyl iodide or benzyl
bromide and using CsOH as the base.22 Oxazole 1f was
synthesized from a Weinreb amide (R1 = Me, R2 = OMe),
prepared by the method of Greger and co-workers.23
The oxazole substrates 1a−e,h−i underwent 1,3-dipolar
cycloaddition with concomitant rearrangement of the cyclo-
adduct to give iminium salts. Reduction of the iminium and
keto groups with excess hydride led to cis-fused octahydroin-
doles 3a−e,g−h with excellent diastereoselectivity in moderate
to good yields (Table 2). In the cases where moderate yields
were obtained, some uncyclized and reduced starting oxazole
was detected in the crude reaction mixture. The minor
diastereomer arises from variability in hydride addition to the
top and bottom faces of the 7-keto group. In two cases (3d and
3g), a trace amount (3% or less) of other minor diastereomers
was detected in the HPLC−MS, presumably arising from some
trans-fused octahydroindole formed during the iminium
reduction step.
In contrast, oxazole 1g, containing a terminal alkyne, produced
only the methylated oxazolium ion, with no cyclization
observed at room temperature or after prolonged heating at
reflux. There have been a few reports of problematic
intramolecular dipolar cycloadditions of munchnones with
terminal alkynes,24 though others report some success.25
Likewise, oxazole 1j did not provide any cyclized product
under similar conditions. Considering that azomethine ylides
are known to be electron-rich species with relatively higher
energy MOs, they may prefer to react with more electron
deficient or unactivated alkenes.26 Alternatively, the reaction
may be hindered by the inability of the alkyne and methyl
alkene to adopt a reactive conformation that allows sufficient
orbital overlap in the transition state.
To better understand the mechanism of 1,3-dipole formation
and subsequent cycloaddition, oxazole 1f was prepared (Table
1, entry 6). For transient formation of the azomethine ylide it is
necessary for the 5-amino lone pair electrons to be in
conjugation with the double bond of the oxazolium ring
(Scheme 2). Conjugation would be inhibited by the methoxy
group in two possible ways. Inductive withdrawal of electron
density from N by the more electronegative O and potential
adoption of a conformation in which electron repulsion
between an O lone pair and the developing p-orbital on N
would both inhibit conjugation, leading to decreased partial
negative charge on the 4-carbon of the oxazolium ring.27 These
1
effects are evident in the H NMR spectra of the oxazole
substrates. The chemical shift of the oxazole ring proton of
compound 1f was noticeably further downfield than all other
oxazole substrates (6.59 ppm for 1f vs ∼6.1 ppm for all others).
This downfield shifting suggests a smaller buildup of partial
negative charge on C-4. As expected, after methylation, oxazole
1f underwent sluggish cyclization and reduction to form
octahydroindole 3f in much lower yield, requiring longer
reaction time at elevated temperature (20 h at 90 °C). This
A variety of cyclic and acyclic tertiary 5-amino groups were
well tolerated on the oxazole ring. Secondary amino groups
were tolerated as well (e.g., 5-aminobenzyloxazole 1d led to
octahydroindole 3d). Substitution at the 4-position of the
oxazole did not seem to hinder cyclization, with no observable
effect on reaction rate or isolated yields of products 3g and 3h.
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Note
method) using water/acetonitrile mixtures with 0.1% formic acid.
Mass spectra were acquired using electrospray ionization (ESI) and a
time-of-flight (TOF) mass analyzer. Diastereomer ratios were
estimated from peak integration of the extracted ion mass chromato-
gram (XIC).
behavior establishes clearly the importance of conjugation of
the enamine moiety for efficient reaction.
The hydride reduction reaction also plays a large role in
overall yield of OHI synthesis. We found that the
regioselectivity of the reduction was solvent polarity dependent.
For example, when the cycloaddition/reduction sequence was
performed on oxazole 1d in CH2Cl2, the elimination product 4
was favored (Scheme 3). However, when the hydride reduction
was performed in the more polar CH3NO2, 3d was
predominant.
Representative Procedure for Synthesis of 2-Keto-5-amino-
oxazoles. 2-(Hex-5-enoyl)-5-(piperidin-1-yl)-1,3-oxazole (1a). To a
dried round-bottom flask under N2 atm was added a solution of 2-
isocyano-1-(piperidin-1-yl)acetamide19 (0.694 g, 5.3 mmol) in CH2Cl2
(20 mL). Triethylamine (0.730 mL, 5.3 mmol) was then added. A
solution of hex-5-enoyl chloride20 (0.800 g, 5.3 mmol) in CH2Cl2 (5
mL) was added dropwise. The reaction mixture was monitored by
TLC and was judged complete after 2 h at room temperature. The
reaction was washed with 0.1 M Na2CO3 (aq), dried over MgSO4,
filtered, and concentrated. The crude product was purified by flash
column chromatography on silica gel (10−30% ethyl acetate/hexanes)
to yield oxazole 1 as a yellow oil (1.07g, 82% yield): 1H NMR
(CDCl3) δ 6.16 (s, 1H), 5.80 (dddd, 1H, J = 16.8, 10.0, 6.8, 6.8 Hz),
5.02 (dq, 1H, J = 17.6, 1.6 Hz), 4.97 (dq, 1H, J = 10.4, 1.2 Hz), 3.31
(m, 4H), 2.92 (t, 2H, J = 7.6 Hz), 2.13 (q, 2H, 7.2 Hz), 1.81 (p, 2H, J
= 7.6 Hz), 1.64 (m, 6H); 13C NMR (CDCl3) δ 185.8, 159.4, 150.1,
138.0, 115.2, 103.3, 47.5, 37.0, 33.3, 24.8, 24.0, 23.8; FT-IR (neat)
1674 cm−1; HR-MS (ESI) for C14H20N2O2 (M + H) calcd 249.1598,
found 249.1605.
Scheme 3. Competing Reduction/Elimination Pathways Are
Solvent Dependent
2-(Hex-5-enoyl)-5-morpholino-1,3-oxazole (1b). Following the
representative procedure above, the residue was purified by
recrystallization from EtOAc/hexanes (3 crops) to yield a tan
amorphous solid (0.562 g, 69%): mp (76−77 °C); 1H NMR
(CDCl3) δ 6.19 (s, 1H), 5.80 (dddd, 1H, J = 16.8, 10.0, 6.4, 6.4
Hz), 5.03 (dq, 1H, J = 17.2, 1.6 Hz), 4.97 (dq, 1H, J = 10.4, 1.2 Hz),
3.81 (t, 4H, J = 4.8 Hz), 3.32 (t, 4H, J = 5.2 Hz), 2.94 (t, 2H, 7.2 Hz),
2.13 (q, 2H, J = 7.2 Hz), 1.82 (p, 2H, J = 7.6 Hz); 13C NMR (CDCl3)
δ 186.3, 158.9, 150.7, 137.9, 115.3, 103.8, 65.7, 46.6, 37.1, 33.2, 23.76;
FT-IR (neat) 1685 cm−1; HR-MS (ESI) for C13H18N2O3 (M + H)
calcd 251.1390, found 251.1399.
In summary, we have developed an efficient two-step method
for the production of cis-octahydroindoles containing a 2-amido
and 7-hydroxyl group with excellent diastereoselectivity. We
have presented a 1,3-dipolar cycloaddition reaction and
proposed a plausible mechanism consistent with observed
reactivity and product structural features. We have probed the
generality of the cycloaddtion reaction to combinations of
different oxazole and dipolarophile substitution. Further
examination of the reaction sequence and application to
target-directed synthesis is underway.
2-(Hex-5-enoyl)-5-(pyrrolidin-1-yl)-1,3-oxazole (1c). Following the
representative procedure above, the crude product was purified via
flash column chromatography (10−30% EtOAc/hexanes) to yield an
1
orange oil (1.00 g, 74% yield): H NMR (CDCl3) δ 7.30−7.33 (m,
2H), 7.20−7.24 (m, 3 H), 5.85 (dddd, 1H, J = 16.8, 10.4, 6.8, 6.8 Hz),
5.06 (dq, 1H, J = 17.2, 1.6 Hz), 5.00 (dq, 1H, J = 10.4, 1.2 Hz), 3.54 (t,
4H, J = 4.8 Hz), 2.96 (t, 2H, J = 7.6 Hz), 2.17 (q, 2H, J = 7.2 Hz), 1.95
(t, 4H, J = 6.4 Hz), 1.86 (p, 2H, J = 7.6); 13C NMR (CDCl3) δ 184.9,
154.5, 148.5, 140.7, 138.3, 128.7, 128.1, 126.4, 115.2, 114.2, 48.5, 37.0,
33.4, 32.6, 25.5, 24.3; FT-IR (neat) 1685 cm−1; HR-MS (ESI) for
C13H18N2O3 (M + H) calcd 251.1390, found 251.1399.
EXPERIMENTAL SECTION
■
General Experimental Methods. All reactions were performed
under N2 atmosphere in flame-dried glassware. Reaction solvents were
dried using an automatic solvent purification system. Nitromethane
was distilled from CaH2. All other chemicals were used as obtained
from the manufacturer. CAUTION: methyl isocyanoacetate has a very
strong odor and should be used only in a fume hood. NMR spectra
5-(Benzylamino)-2-(hex-5-enoyl)-1,3-oxazole (1d). Following the
representative procedure above, the crude product was purified via
flash column chromatography (10−30% EtOAc/hexanes) to yield an
1
1
orange amorphous solid (2.45 g, 65% yield): H NMR (CDCl3) δ
were obtained on a 400 MHz instrument: H NMR (400 MHz) and
13C NMR (100 MHz). Chemical shifts are reported in ppm (δ units)
relative to the solvent residual peak. Data are reported as follows: s =
singlet, d = doublet, t = triplet, q = quartet, p = pentet, dd = doublet of
doublet, dt = doublet of triplets, br = broad. For complex splitting
patterns (i.e., dddd) the multiplicity is reported “as observed”,
recognizing that dddd ≈ p, dq, tt, or ddt where J value degeneracies are
present.28 HR-MS was obtained by ESI (positive ion mode) on TOF
mass analyzer. FT-IR spectra were collected as cast films (from
CH2Cl2 solutions) on NaCl plates. Analytical thin-layer chromatog-
raphy (TLC) was performed on glass-backed silica gel plates coated at
0.25 mm thickness, and visualization was achieved by UV light (254
nm) and phosphomolybdic acid (PMA) staining. Flash column
chromatography was performed on silica gel of 0.06−0.2 mm particle
size. Samples of crude cyclization reaction mixtures were prepared for
HPLC−MS analysis to a concentration of 0.1 mg/mL in a diluent of
15% MeCN/85% H2O, except for sample 3d which was prepared in
100% MeCN. Samples were filtered and injected (2 μL) on an
HPLC−MS instrument and run with a flow rate of 2 mL/min through
a Halo C-18 column (3.0 × 7.5 mm, 2.7 μm) at 40 °C. Gradient
elution was performed (see the Supporting Information for the
7.27−7.39 (m, 5H), 6.12 (s, 1H), 5.79 (dddd, 1H, J = 17.2, 10.4, 6.8,
6.8 Hz), 5.27 (br s, 1H), 5.02 (dq, 1H, J = 17.2, 1.6 Hz), 4.97 (dq, 1H,
J = 11.2, 1.2 Hz), 4.39 (d, 2H, J = 6.0 Hz), 2.91 (t, 2H, 7.6 Hz), 2.12
(q, 2H, J = 7.6 Hz), 1.80 (p, 2H, J = 8.0 Hz); 13C NMR (CDCl3) δ
186.3, 158.0, 149.9, 137.9, 137.0, 128.9, 128.0, 127.3, 115.3, 102.9,
48.0, 37.0, 33.2, 33.8; FT-IR (neat) 3303, 1673 cm−1; HR-MS (ESI)
for C16H18N2O2 (M + H) calcd 271.1441, found 271.1446.
5-(Benzyl(methyl)amino)-2-(hex-5-enoyl)-1,3-oxazole (1e). Fol-
lowing the representative procedure above, the crude product was
purified via flash column chromatography (10−40% EtOAc/hexanes)
1
to yield a yellow oil (1.73 g, 87% yield): H NMR (CDCl3) δ 7.28−
7.38 (m, 3H), 7.22−7.26 (m, 1H), 6.13 (s,1H), 5.81 (dddd, 1H, J =
16.8, 10.0, 6.4, 6.4 Hz), 5.04 (dq, 1H, J = 17.2, 1.6 Hz), 4.98 (dq, 1H, J
= 10.4, 1.2 Hz), 4.50 (s, 2H), 2.95 (s, 3H), 2.94 (t, 2H, 7.6 Hz), 2.14
(q, 2H, J = 7.2 Hz), 1.83 (p, 2H, J = 7.6 Hz); 13C NMR (CDCl3)
δ185.6, 159.3, 150.0, 138.0, 135.7, 128.9, 128.0, 127.7, 115.2, 102.6,
55.0, 37.0, 36.0, 33.3, 24.0; FT-IR (neat) 1674 cm−1; HR-MS (ESI) for
C17H20N2O2 (M + H) calcd 285.1598, found 285.1608.
2-(Hex-5-enoyl)-5-(methoxy(methyl)amino)-1,3-oxazole (1f). Fol-
lowing the representative procedure above, the crude product was
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Note
purified via flash column chromatography (10% EtOAc/hexanes) to
yield a red oil (0.282 g, 50% yield): 1H NMR (CDCl3) δ 6.59 (s, 1H),
5.80 (dddd, 1H, J = 16.8, 10.0, 6.4, 6.4 Hz), 5.04 (dq,1H, J = 17.2, 1.6
Hz), 4.99 (dq, 1H, J = 10.4, 1.2 Hz), 3.77 (s, 1H), 3.12 (s, 1H), 2.99
(t, 2H, J = 7.2 Hz), 2.14 (q, 2H, J = 7.2 Hz), 1.83 (p, 2H, 7.6 Hz); 13C
NMR (CDCl3) δ187.3, 159.4, 153.0, 137.9, 115.4., 109.7, 61.8, 40.9,
37.6, 33.1, 23.3; FT-IR (neat) 1693 cm−1; HR-MS (ESI) for
C11H16N2O3Na (M + Na) calcd 247.1059, found 247.1060.
26.6, 25.8, 25.5, 24.1, 15.1; FT-IR (neat) 3339, 1636 cm−1; HR-MS
(ESI) for C15H26N2O2 (M + H) calcd 267.2072, found 267.2072.
Morpholinyl 7-Hydroxy-1-methyl-cis-octahydroindole-2-carbox-
amide (3b). Following the representative procedure above, the crude
material was purified via flash column chromatography (5−10%
1
MeOH/CH2Cl2) to yield a yellow oil (0.065 g, 61% yield): H NMR
(CD3OD) δ 3.85 (dd, 1H, J = 7.2, 4.4 Hz), 3.69−3.53 (m, 9H), 2.71
(dd, 1H, J = 8.0, 4.4 Hz), 2.43 (s, 3H), 2.64−2.38 (m, 1H), 2.08 (dt,
1H, J = 11.6, 6.8 Hz), 1.97−1.91 (m, 1H), 1.72−1.64 (m, 3H), 1.61−
1.51 (m, 1H), 1.44−1.36 (m, 1H),1.28−1.21 (m, 1H); 13C NMR
(CDCl3) δ 172.7, 67.0, 66.3, 65.5, 65.2,45.5, 42.6, 36.5, 36.4, 29.2,
26.0, 14.1; FT-IR (neat) 3338, 1647 cm−1; HR-MS (ESI) for
C14H24N2O3 (M + H) calcd 269.1860, found 269.1858.
2-(Hex-5-ynoyl)-5-morpholino-1,3-oxazole (1g). Following the
representative procedure above, the crude product was purified
recrystallization from dichloromethane/hexanes to yield white crystals
1
(1.05 g, 73%): mp (89−90 °C); H NMR (CDCl3) δ 6.20 (s, 1H),
3.81 (t, 4H, J = 4.8 Hz), 3.32 (t, 4H, J = 5.2 Hz), 3.07 (t, 2H, J = 7.2
Hz), 2.29 (dt, 2H, J = 7.2, 2.8 Hz), 1.97 (s, 1H), 1.95 (p, 2H, J = 7.2
Hz); 13C NMR (CDCl3) δ 185.8, 159.3, 150.9, 104.3, 83.8, 69.4, 66.1,
47.0, 36.9, 23.4, 18.3; FT-IR (neat) 3300 cm−1, 1685; HR-MS (ESI)
for C13H16N2O3Na (M + Na) calcd 271.1059, found 271.1055.
2-(Hex-5-enoyl)-4-methyl-5-(piperidin-1-yl)-1,3-oxazole (1h). Fol-
lowing the representative procedure above, the crude product was
purified via flash column chromatography (10% EtOAc/hexanes) to
yield a yellow oil (0.918 g, 90%): 1H NMR (CDCl3) δ 5.81 (dddd, 1H,
J = 16.8, 10.0, 6.4, 6.4 Hz), 5.03 (dq, 1H, J = 17.2, 1.6 Hz), 4.97 (dq,
1H, J = 10.4, 1.2 Hz), 3.31 (t, 4H, J = 4.8 Hz), 2.92 (t, 4H, J = 7.6 Hz),
2.23 (s, 3H), 2.13 (q, 2H, J = 6.8 Hz), 1.57−1.70 (m, 6H); 13C NMR
(CDCl3) δ 186.3, 155.5, 149.5, 138.4, 116.5, 115.5, 49.6, 37.4, 33.6,
25.8, 24.2, 24.1, 13.3; FT-IR (neat) 1685 cm−1; HR-MS (ESI) for
C15H23N2O2 (M + H) calcd 263.1754, found 263.1764.
Pyrrolidin-1-yl 7-Hydroxy-1-methyl-cis-octahydroindole-2-car-
boxamide (3c). Following the representative procedure above, the
crude material was purified via flash column chromatography (2.5−
1
10% MeOH/CH2Cl2) to yield a yellow oil (0.618 g, 57% yield): H
NMR (CD3OD) δ 3.85 (ddd, 1H, J = 7.2, 4.4, 3.2 Hz), 3.64 (dt, 1H, J
= 10, 6.8 Hz), 3.57 (dd, 1H, J = 10, 6.4 Hz), 3.51−3.38 (m, 3H), 2.70
(dd, 1H, J = 8.4, 4.4 Hz), 2.45 (s, 3H), 2.38−2.29 (m, 1H), 2.11 (dt,
1H, J = 11.6, 6.8 Hz), 2.03−1.94 (m, 2H), 1.93−1.85 (m, 3H), 1.77−
1.65 (m, 3H), 1.62−1.53 (m, 1H), 1.44−1.36 (m, 1H), 1.30−1.22 (m,
1H); 13C NMR (CDCl3) δ 172.2, 67.1, 66.7, 65.4, 46.3, 46.0, 40.8,
36.5, 35.6, 29.2, 26.2, 26.0, 24.0, 14.5; FT-IR (neat) 3345, 1640 cm−1;
HR-MS (ESI) for C14H24N2O2H (M + H) calcd 253.1916, found
253.1921.
Benzyl 7-Hydroxy-1-methyl-cis-octahydroindole-2-carboxamide
(3d). Following the representative procedure above, the crude material
was purified via flash column chromatography (80−90% EtOAc/
hexanes) to yield a yellow oil (380 mg, 45% yield). 1H NMR δ
(CDCl3) 7.61 (br s, 1 H), 7.29 (m, 5H), 4.49 (dd, 1H, J = 14.8, 6.0
Hz), 4.45 (dd, 1H, J = 14.8, 5.6 Hz), 3.85 (dt, 1H, J = 7.6, 3.6 Hz),
3.13 (dd, 1H, J = 9.2, 5.6 Hz), 2.78 (dd, 1H, J = 6.4, 3.6 Hz), 2.50 (s,
3H), 2.26 (ddd, 1H, J = 16.4, 9.6, 7.2 Hz), 2.10 (m, 1H), 1.74 (dt, 1H,
J = 12.4, 5.2 Hz), 1.58−1.70 (m, 2H), 1.40−1.59 (m, 2H), 1.21−1.31
(m, 2H); 13C NMR (CDCl3) δ 174.3, 138.5, 128.8, 127.7, 127.5, 70.6,
70.3, 68.9, 43.5, 43.1, 38.0, 35.9, 28.8, 27.2, 20.7; FT-IR (neat) 3311,
1652, 1521, 1454, 731, 699 cm−1; HR-MS (ESI) for C17H24N2O2Na
(M + Na) calcd 311.1736, found 311.1738.
4-Benzyl-2-(hex-5-enoyl)-5-(pyrrolidin-1-yl)-1,3-oxazole (1i). Fol-
lowing the representative procedure above, the crude product was
purified via flash column chromatography (10−20% EtOAc/hexanes)
to yield a yellow oil (0.683 g, 56% yield): 1H NMR (CDCl3) δ 7.30−
7.33 (m, 2H), 7.20−7.24 (m, 3 H), 5.85 (dddd, 1H, J = 16.8, 10.4, 6.8,
6.8 Hz), 5.06 (dq, 1H, J = 17.2, 1.6 Hz), 5.00 (dq, 1H, J = 10.4, 1.2
Hz), 3.54 (t, 4H, J = 4.8 Hz), 2.96 (t, 2H, J = 7.6 Hz), 2.17 (q, 2H, J =
7.2 Hz), 1.95 (t, 4H, J = 6.4 Hz), 1.86 (p, 2H, J = 7.6 Hz); 13C NMR
(CDCl3) δ 184.9, 154.5, 148.5, 140.7, 138.3, 128.7, 128.1, 126.4, 115.2,
114.2, 48.5, 37.0, 33.4, 32.6, 25.5, 24.3; FT-IR (neat) 1685, 1600, 1500
cm−1; HR-MS (ESI) for C20H25N2O2 (M + H) calcd 325.1911, found
325.1919.
N-Benzyl-N-methyl-7-hydroxy-1-methyl-cis-octahydroindole-2-
carboxamide (3e). Following the representative procedure above, the
crude material was purified via flash column chromatography (2−10%
MeOH/CH2Cl2) to yield a yellow oil (0.161 g, 61%): 1H NMR
(CD3OD) (as a ∼3:2 mixture of amide rotamers at rt) 7.40−7.20 (m,
5H), 4.71 (AB, 0.4H, J = 17.2 Hz), 4.62 (AB, 0.6H, J = 14.8 Hz), 3.87
(dd, 0.6H, J = 7.2, 4.4 Hz), 3.84 (dd, 0.4H, J = 6.8, 4.0 Hz), 3.76 (dd,
0.6H, J = 10, 6.8 Hz), 3.69 (dd, 0.4H, J = 10, 6.4 Hz), 3.02 (s, 1.7H),
2.97 (s, 1.3H), 2.74 (dd, 0.6H, J = 8.0, 4.4 Hz), 2.66 (dd, 0.4H, J = 8.4,
4.4 Hz), 2.48 (s, 1.7H), 2.39 (s, 1.3H), 2.37−2.21 (m, 1H), 2.16 (dt,
0.7H, J = 11.6, 6.8 Hz), 2.02−1.91 (m, 1.4H), 1.81−1.50 (m, 4.3H),
1.46−1.24 (m, 2H); 13C NMR (CDCl3) δ 174.9, 174.2, 137.1, 136.5,
128.9, 128.5, 127.9, 127.6, 127.3, 126.0, 66.3, 66.2, 65.4, 65.2, 52.33,
51.4, 40.63, 40.5, 36.8, 36.4, 36.0, 34.5, 33.9, 33.0, 29.6, 29.1, 25.9,
25.8, 14.1, 14.0; FT-IR (neat) 3350, 1645 cm−1; HR-MS (ESI) for
C18H26N2O2H (M + H) calcd 303.2072, found 303.2066.
N-Methoxy-N-methyl-7-hydroxy-1-methyl-cis-octahydroindole-
2-carboxamide (3f). Following the representative procedure above,
however, the reaction was stirred for 20 h at 90 °C before all starting
material was consumed as monitored by 1H NMR. The crude material
was purified via flash column chromatography (2.5−10% MeOH/
CH2Cl2) to yield a yellow oil (0.015 g, 15% yield): 1H NMR (CD3OD,
50 °C) 3.87 (q, 1H, J = 4.4 Hz), 3.82 (dd, 1H, J = 9.6, 6.8 Hz), 3.74,
(s, 3H) 3.22 (s, 3H), 2.79 (dd, 1H, J = 8.0, 4.4 Hz), 2.50 (s, 3H),
2.41−2.30 (m, 1H), 2.15 (dt, 1H, J = 11.6, 6.8 Hz), 1.97−1.91 (m,
1H), 1.76−1.64 (m, 3H), 1.61−1.52 (m, 1H), 1.44−1.34 (m, 1H),
1.29−1.22 (m, 2H); 13C NMR (CDCl3) 174.8*, 66.5, 65.4, 65.3, 61.6,
40.8, 36.4, 36.2, 32.6, 29.2, 25.9, 14.2 (*from HMBC correlation of
amide CON(Me)(OMe)); FT-IR (neat) 3452, 1652 cm−1; HR-MS
(ESI) for C12H22N2O3Na (M + H) calcd 265.1528, found 265.1528.
2-(5-Methylhex-5-enoyl)-5-morpholino-1,3-oxazole (1j). Follow-
ing the representative procedure above, the crude product was purified
via flash column chromatography (10−50% EtOAc/hexanes) to yield
1
an orange oil (1.49 g, 64% yield): H NMR (CDCl3) δ 6.17 (s, 1H),
4.73 (d, 1H, J = 0.9 Hz), 4.69 (d, 1H, J = 0.9 Hz), 3.80 (t, 4H, J = 4.8
Hz), 3.31 (t, 4H, J = 5.2 Hz), 2.89 (t, 2H, J = 7.2 Hz), 2.09 (t, 2H, J =
7.6 Hz), 1.86 (p, 2H, J = 7.6 Hz), 1.72 (s, 3H); 13C NMR (CDCl3) δ
184.9, 159.3, 150.8, 144.6, 110.1, 104.3, 66.0, 46.5, 38.4, 38.3, 22.6,
22.5; FT-IR (neat) 1685 cm−1; HR-MS (ESI) for C14H20N2O3Na (M
+ Na) calcd 287.1372, found 287.1367.
Representative Procedure for Synthesis of Octahydroin-
doles. Piperidin-1-yl 7-Hydroxy-1-methyl-cis-octahydroindole-2-
carboxamide (3a). To a dry flask under N2 atmosphere was added
a solution of trimethyloxonium tetrafluoroborate (0.732 g, 4.70 mmol)
in nitromethane (10 mL). A solution of oxazole 1a (1.00 g, 4.27
mmol) in nitromethane (10 mL) was added dropwise at room
temperature. After 2 h, the reaction was cooled to 0 °C and solid
NaBH(OAc)3 (2.72 g, 12.81 mmol) was added in one portion. The
mixture was slowly warmed to room temperature and stirred for 12 h.
The reaction was quenched with satd NaHCO3 (aq), the layers were
separated, and the aqueous layer was extracted with CH2Cl2 (6 × 15
mL). The combined organic layers were dried (MgSO4) and
concentrated. The crude product was purified via flash column
chromatography (2.5−15% MeOH/CH2Cl2) to yield an orange oil
1
(0.772 g, 72% yield): H NMR (CD3OD) δ 3.84 (ddd, 1H, J = 8.8,
4.4, 2.5 Hz), 3.68 (dd, 1H, J = 10, 6.4 Hz), 3.55 (m, 4H), 2.69 (dd,
1H, J = 8.4, 4.4 Hz), 2.42 (s, 3H), 2.38−2.29 (m, 1H), 2.06 (dt, 1H, J
= 11.6, 6.8 Hz), 1.98−1.92 (m, 1H), 1.72−1.64 (m, 6H), 1.61−1.54
(m, 4H), 1.43−1.35 (m, 1H), 1.29−1.24 (m, 1H); 13C NMR
(CD3OD) δ 173.1, 66.5, 66.3, 65.4, 45.9, 43.3, 39.7, 36.3, 36.1, 28.1,
10420
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The Journal of Organic Chemistry
Note
Piperidin-1-yl 7-Hydroxy-1,2-dimethyl-cis-octahydroindole-2-car-
boxamide (3g). Following the representative procedure above, the
crude material was purified via flash column chromatography (5−10%
(6) Hanessian, S.; Tremblay, M.; Petersen, J. F. W. J. Am. Chem. Soc.
2004, 126 (19), 6064−6071.
(7) Liu, Z.; Rainier, J. D. Org. Lett. 2006, 8 (3), 459−462.
(8) Hoshina, Y.; Doi, T.; Takahashi, T. Tetrahedron 2007, 63 (51),
12740−12746.
1
MeOH/CH2Cl2) to yield a yellow oil (0.161 g, 50% yield): H NMR
(MeOD, 52 °C) δ 3.95 (q, 1H, J = 4.0 Hz), 3.67 (m, 4H), 2.79 (m,
1H), 2.49 (s, 3H), 2.45 (m, 1H), 2.05 (dd, 1H, J = 12.0, 7.6 Hz),
1.88−1.97 (m, 2H), 1.68−1.74 (m, 3H), 1.55−1.64 (m, 6H), 1.42−
1.51 (m, 1H), 1.42 (s, 3H), 1.31−1.41 (m, 1H); 13C NMR (CD3CN)
δ 184.9, 154.5, 148.5, 140.7, 138.3, 128.7, 128.1, 126.4, 115.2, 114.2,
48.5, 37.0, 33.4, 32.6, 25.5, 24.3; FT-IR (neat) 3400, 1625 cm−1; HR-
MS (ESI) for C16H28N2O2H (M + H) calcd 281.2229, found
281.2233.
Pyrrolidin-1-yl 2-Benzyl-7-hydroxy-1-methyl-cis-octahydroin-
dole-2-carboxamide (3h). Following the representative procedure
above, the crude material was purified via flash column chromatog-
raphy (2.5−5% MeOH/CH2Cl2) to yield a yellow oil (0.205 g, 49%
yield): 1H NMR (MeOD) δ 7.20−7.31 (m, 5 H), 3.84 (q, 1H, J = 4.0),
3.40−3.50 (m, 2H), 3.01 (dd, 2H, J = 13.6, 13.6), 2.84 (s, 3H), 2.74
(m, 1H); 13C NMR (CD3CN) δ 177.4, 139.3, 131.4, 128.8, 127.1,
73.2, 66.1, 65.3, 48.6, 39.3, 37.9, 34.1, 33.9, 29.3, 26.6, 14.9; FT-IR
(neat) 3373, 1610 cm−1; HR-MS (ESI) for C21H30N2O2Na (M + Na)
calcd 365.2205, found 365.2210.
(9) Ito, T.; Overman, L. E.; Wang, J. J. Am. Chem. Soc. 2010, 132
(10), 3272−3273.
(10) Sayago, F. J.; Laborda, P.; Calaza, M. I.; Jimenez, A. I.; Cativiela,
C. Eur. J. Org. Chem. 2011, No. 11, 2011−2028.
(11) Faulkner, A.; Bower, J. F. Angew. Chem., Int. Ed. 2012, 51 (7),
1675−1679.
(12) Coldham, I.; Hufton, R. Chem. Rev. 2005, 105 (7), 2765−2810.
(13) Burrell, A. J. M.; Coldham, I. Curr. Org. Synth. 2010, 7 (4), 312−
331.
(14) (a) Fukuyama, T; Kishi, Y. J. Am. Chem. Soc. 1976, 98 (21),
6723−6724. (b) Nicolaou, K. C.; Totokotsopoulos, S.; Giguere, D.;
̀
Sun, Y-.P.; Sarlah, D. J. Am. Chem. Soc. 2011, 133 (21), 8150−8153.
(15) Sayago, F. J.; Calaza, M. I.; Jimenez, A. I.; Cativiela, C.
Tetrahedron 2009, 65 (27), 5174−5180 and references cited therein.
(16) Chemical shifts were comparable to literature values for similar
iminium ion salts. For example: Wenkert, D.; Chen, T-.F.;
Ramachandran, K.; Valasinas, L.; Weng, L-.L; McPhail, A. T. Org.
Lett. 2001, 3 (15), 2301−2303.
N-Benzyl-1-methyl-7-oxo-2,3,4,5,6,7-hexahydroindole-2-carbox-
amide (4). Following the representative procedure above, except that
the reaction was performed in CH2Cl2. The crude material was
purified via flash column chromatography (50−90% EtOAc/hexanes)
(17) McEwen, W. E.; Grossi, A. V.; MacDonald, R. J.; Stamegna, A.
P. J. Org. Chem. 1980, 45 (7), 1301−1308.
(18) (a) Perrin, S.; Monnier, K.; Laude, B.; Kubicki, M. M.; Blacque,
O. Tetrahedron Lett. 1998, 39 (13), 1753−1754. (b) Gribble, G. W. In
The Chemistry of Heterocyclic Compounds; Palmer, D. C., Ed.; Oxazoles:
Synthesis, Reactions, and Spectroscopy, Vol. 60, Part A; John Wiley &
Sons, Inc: Hoboken, 2003; pp 473−576 and references cited therein.
(19) Mossetti, R.; Pirali, T.; Tron, G. C.; Zhu, J. Org. Lett. 2010, 12
(4), 820−823.
1
to yield a yellow oil (0.326 g, 54% yield): H NMR (CDCl3) δ 7.65
(br s, 1H), 7.22−7.38 (m, 5H), 4.50 (dd, 1H, J = 14.8, 6.4 Hz), 4.41
(dd, 1H, J = 14.8, 6.0 Hz), 3.59 (dd, 1H, J = 11.2, 9.2 Hz), 3.20 (ddt,
1H, J = 19.2, 11.5, 2.0, 2.0 Hz), 2.78 (s, 3H), 2.59 (ddt, 1H, J = 19.2,
9.6, 2.0, 2.0 Hz), 2.22−2.50 (m, 4H), 2.01 (p, 2H, J = 7.6 Hz); 13C
NMR (CDCl3) δ 193.0, 172.8, 143.3, 141.8, 138.2, 128.7, 127.7, 127.5,
69.3, 42.9, 40.7, 38.7, 38.6, 25.4, 23.3; FT-IR (neat) 3322, 1665, 1522
cm−1; HR-MS (ESI) for C17H20N2O2Na (M + Na) calcd 307.1422,
found 307.1417.
(20) Prepared according to: Ahrendt, K. A.; Williams, R. M. Org. Lett.
2004, 6 (24), 4539−4541.
(21) 5-Methylhex-5-enoic acid prepared according to: Lee, E. E.;
Rovis, T. Org. Lett. 2008, 10 (6), 1231−1234.
ASSOCIATED CONTENT
■
(22) Domling, A.; Beck, B.; Fuchs, T.; Yazbak, A. J. Comb. Chem.
̈
S
2006, 8 (6), 872−880.
* Supporting Information
(23) Greger, J. G.; Yoon-Miller, S. J. P.; Bechtold, N. R.; Flewelling,
S. A.; MacDonald, J. P.; Downey, C. R.; Cohen, E. A.; Pelkey, E. T. J.
Org. Chem. 2011, 76 (20), 8203−8214.
NMR spectra for all new compounds, HPLC−MS data, and X-
ray crystallographic data for the BF4 salt of compound 3. This
material is available free of charge via the Internet at http://
pubs.acs.org
(24) Nayyar, N. K.; Hutchison, D. R.; Martinelli, M. J. J. Org. Chem.
1997, 62 (4), 982−991.
(25) Pinho e Melo, T. M. V. D.; Barbosa, D. M.; Ramos, P. J. R. S.;
Rocha Gonsalves, A. M. d’A.; Gilchrist, T. L.; Beja, A. M.; Paixao, J. A.;
Silva, M. R.; da Veiga, L. A. J. Chem. Soc., Perkin Trans. 1 1999, No. 9,
1219−1223.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: sahabay@salisbury.edu.
Notes
(26) Pandey, G.; Banerjee, P.; Gadre, S. R. Chem. Rev. 2006, 106
(11), 4484−4517.
The authors declare no competing financial interest.
(27) These effects are observed in N-methoxyenamines. See: Ahmed,
M. G.; Ahmed, S. A.; Hickmott, P. W. J. Chem. Soc, Perkin Trans. 1
1980, 2383−2386.
ACKNOWLEDGMENTS
■
(28) Hoye, T. R.; Zhao, H. J. Org. Chem. 2002, 67 (12), 4014−4016.
High-resolution mass spectrometry analysis support from Jay
Khalin and Dr. John Greaves and HPLC−MS assistance from
Dr. Stephen Chan is gratefully acknowledged. This research
was supported by awards from Research Corporation for
Science Advancement and Salisbury University.
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