Studies on the Synthesis of the Alkaloid (-)-Gilbertine via Indolidene Chemistry

Article abstract of DOI:10.1021/acs.joc.6b00348

A synthesis route to the pentacyclic alkaloid (-)-gilbertine, which features a cyclization cascade passing through a transient indolidene intermediate, was pursued. A key stereochemical relationship was set via a Nicholas-type enolate alkylation. Ultimately, undesired C-N cyclization thwarted the final projected C-C bond forming ring closure, and gilbertine could not be prepared by this route.

Full text of DOI:10.1021/acs.joc.6b00348

Article
pubs.acs.org/joc
Studies on the Synthesis of the Alkaloid (−)-Gilbertine via Indolidene
Chemistry
Ken S. Feldman* and Tamara S. Folda
Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802, United States
S
* Supporting Information
ABSTRACT: A synthesis route to the pentacyclic alkaloid
(−)-gilbertine, which features a cyclization cascade passing
through a transient indolidene intermediate, was pursued. A
key stereochemical relationship was set via a Nicholas-type
enolate alkylation. Ultimately, undesired C−N cyclization
thwarted the final projected C−C bond forming ring closure,
and gilbertine could not be prepared by this route.
an electrophilic indolidene intermediate 7, which, upon
nucleophilic addition of an alcohol (exemplified by methanol
in Scheme 1), generates the product indole 8.
In the proposed synthesis of gilbertine, an allenyl azide
cyclization of allene 11 should generate indolidene intermediate
10, which could undergo an intramolecular cyclization with the
pendant alcohol to provide the indole ring and set the
stereocenter at C(16) (Scheme 2). The stereochemistry at
C(16) within 9 was anticipated to conform to gilbertine’s
relative stereochemistry based on the expectation that
INTRODUCTION
■
(−)-Gilbertine (1), which was isolated in 1982 from the
Brazilian tree Aspidosperma gilbertii, is a member of the uleine
family of natural products (Figure 1).1 Compared to the rest of
the family, (−)-gilbertine has an extra ring (E) and stereogenic
center at C(16), making it a more complex synthetic target.
Scheme 2. Retrosynthesis of (−)-Gilbertine
Figure 1. Uleine alkaloids.
Blechert completed the only reported synthesis of
(−)-gilbertine in 2004 through a route that utilized a cationic
cyclization to set the C(16) stereocenter.2 Herein, we describe
a different approach toward gilbertine using allenyl azide
cyclization chemistry3 to close the E-ring and set the
stereochemistry at C(16) simultaneously. This allenyl azide-
based cyclization strategy involves a cascade of reactions
initiating with intramolecular [3 + 2] cycloaddition of an allene
and azide, as in 5, which provides triazoline intermediate 6
(Scheme 1).3 Concerted loss of nitrogen gas4 from 6 results in
Scheme 1. Generation of an Indolidene Intermediate from
an Allenyl Azide Precursor; Trapping with Methanol
Received: February 17, 2016
© XXXX American Chemical Society
A
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cyclization will proceed through an energetically favorable chair
transition state with the indolidene unit in a pseudoequatorial
position, as shown in 10. Lactam 9 could then be converted to
gilbertine through a reduction of the amide and subsequent
cationic cyclization of C(3) of the indole nucleus into the
derived iminium ion. Allene 11 could be formed from alkyne
12 through chemistry described earlier.3 Deprotection of the
nitrogen in lactone 13 and subsequent cyclization of the
liberated amine into the proximate lactone carbonyl should
provide lactam 12. Cleavage of the chiral auxiliary in 14 would
generate lactone 13 based on previous work by Jacobi and co-
workers.5 The two stereogenic centers labeled C(15) and
C(20) in gilbertine would be set through a key Nicholas
reaction6 of cobalt complex 16 and oxazolidinone 15.
Scheme 4. Synthesis of a Tosyl- and Nosyl-Protected
Electrophile; Successful Nicholas Reactions
RESULTS
■
Work on this route to gilbertine commenced with the synthesis
of cobalt complex 16 from tert-butyl carbonate (BOC)
protected methylamine 17, as shown in Scheme 3. The
Scheme 3. Synthesis of a BOC-Protected Electrophile;
Failure of the Nicholas Reaction
addition into aldehyde 25a resulted in a 45% yield. Surprisingly,
using either a mixture of CH2Cl2 and toluene or neat CH2Cl2 as
the solvent resulted in a significantly higher yield (72%) of
alcohol 26a. Upon submitting cobalt complex 28a to the
Nicholas reaction, the desired adduct 30a was isolated as
essentially a single diastereomer (1H NMR detection limit <
5%). The relative stereochemistry of this adduct was tentatively
assigned by comparison to the results of a similar Nicholas
reaction reported by Schreiber6 and later confirmed by NOE
measurements on a downstream intermediate (vide infra). The
mechanistic picture proposed by Schreiber6 is encapsulated in
the transition state structure 29. In this depiction, the
stereochemistry in 30a is controlled through the chirality
present in oxazolidinone 15; the methyl and phenyl
substituents of the oxazolidinone block addition of the Nicholas
carbocation to the “top” face of the boron enolate, thereby
setting the C(20) stereocenter. The C(15) stereochemistry is
presumably controlled through reaction via an orientation
featuring an energetically less penalizing steric interaction
between the Lewis acid’s butyl group and the proton on the
carbocation species rather than a more energetically costly
interaction with the methyl group if the carbocation
component’s orientation is flipped by 180°. The Nicholas
adduct 30a was obtained in moderate yield, but if the
temperature of the reaction solution was allowed to warm
above 0 °C, the carbocation was diverted down a different path
Nicholas reaction of cobalt complex 16 with oxazolidinone 15
resulted in the formation of carbamate 22, instead of the
expected Nicholas adduct 14. Carbamate 22 presumably arose
through an intramolecular cyclization of the carbamate’s oxygen
into the transiently formed carbocation derived by Bu2BOTf-
mediated ionization of the methyl ether moiety in 21. To avoid
this undesirable cyclization, a new protecting group for the
nitrogen in 21, p-toluene sulfonyl, was explored.
As shown in Scheme 4, tosyl protected amine 28a was
synthesized using similar chemistry to the BOC protection
series of Scheme 3. One minor point of distinction between the
two routes can be found at the beginning; whereas acrolein was
a suitable partner for BOCNHMe conjugate addition, attempts
to add TsNHMe to acrolein resulted in only trace (∼2%) yields
of the β-tosylamido aldehyde. Fortunately, switching electro-
philes to ethyl acrylate solved the conjugate addition problem,
and β-tosylamido ester 24a could be formed in excellent yield.
Using THF at −78 °C, as in the BOC route, for acetylide
B
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and the major product isolated was alkene 31a (90%). This
species presumably originated through simple deprotonation
from the carbocationic Nicholas intermediate.
32b through cleavage of the chiral auxiliary (Scheme 5).
Initially, the chiral auxiliary was cleaved with lithium hydroxide
monohydrate and hydrogen peroxide, which resulted in a 30−
45% yield of the lactone. Other bases were then explored in an
effort to improve the yield. Sodium hydroxide also generated
inconsistent yields (30−50%), while potassium hydroxide
resulted in a materially lower yield (28%). Cesium hydroxide
was discovered to afford a moderate, but consistent, yield of
lactone 32b. Removal of the nosyl protecting group in 32b was
achieved with sodium thiophenolate, and the nascent amine did
in fact cyclize into the lactone as desired to provide lactam 34
upon TBS protection of the first-formed alcohol. Cleavage of
the alkyne’s TMS group then provided alkyne 12; at this point,
NOESY NMR analysis confirmed the initial mechanism-based
assignment of relative stereochemistry, as illustrated in Scheme
5. Addition of the lithiated alkyne derived from deprotonation
of 12 into azidobenzaldehyde, followed by condensation of the
first-formed alkoxide with ethyl chloroformate, provided
carbonate 35. Methylcuprate addition into the propargyl
carbonate unit of 35 generated allene 36 which, upon removal
of the TBS group with hydrofluoric acid, afforded the key
cyclization cascade precursor, azido allene 11. Allene 11 was
isolated as an inconsequential mixture (∼1:1) of diastereomers.
Attempts at the key allenyl azide cyclization cascade of
alcohol 11 resulted in formation of a single diastereomer 9 in
moderate yield under thermal conditions and in almost
quantitative yield under photochemical conditions (Scheme
6). As discussed earlier, the allenyl azide cyclization of 11
The chiral auxiliary in 30a was cleaved with lithium
hydroperoxide, and the resulting acid cyclized by displacing
the primary bromide to provide lactone 32a in modest yield
(eq 11). Removal of the tosyl protecting group in 32a was
expected to provide lactam 12 through cyclization of the free
amine into the lactone. However, all efforts to cleave the tosyl
protecting group from the nitrogen (Mg/MeOH, Na(Hg), Na/
naphthalene) resulted in either cleavage of the TMS group or
no observed reaction. Thus, it became apparent that, whereas
introduction of the tosyl protecting group solved the Nicholas
reaction problem, it eventually led to a dead end at the
deprotection step. Therefore, a new protecting group was
required, and in this vein, the tosyl group was replaced with the
p-nitrotoluenesulfonyl (nosyl) protecting group.
The synthesis of nosyl cobalt complex 28b was achieved by
the same procedure as detailed earlier with the tosyl route, with
one improvement. In this newer route (Scheme 5), aldehyde
25b was converted directly to methyl ether 27b, in 94% yield
without isolation of alcohol intermediate 26b (Scheme 4). The
Nicholas reaction of nosyl cobalt complex 28b and
oxazolidinone 15 resulted in a 7:1 mixture of product
diastereomers, 30b and 30c. The Nicholas adduct 30b, with
the desired syn stereochemistry, was converted to the lactone
Scheme 6. Allenyl Azide−Indolidene Cascade Cyclization
Scheme 5. Use of the Nosyl-Protected Nicholas Product in
Lactam Formation
generates indolidene intermediate 36, which, upon cyclization
of the pendant alcohol, closes the E-ring of the target molecule
and sets the C(16) stereochemistry. NOESY correlations
within 9 (see Scheme 6) suggested that the desired
stereochemical outcome at C(16) necessary for the synthesis
of gilbertine was obtained.
Reduction of the lactam in 9 was expected to form the
iminium ion intermediate 37, which, upon C(3) cyclization of
the indole, would generate gilbertine (1) (Scheme 7).
However, when lactam 9 was reduced with lithium aluminum
hydride, a mixture of over-reduced product 38 and enamine 39
was isolated. These products likely stem from the desired
iminium ion. Apparently, both a second hydride addition to the
putative iminium ion intermediate (→ 38) and deprotonation
of the iminium ion (→ 39) were faster than the desired
cyclization. Other reducing agents were explored in an effort to
avoid the second hydride addition and hopefully generate
gilbertine. Sodium borohydride and Red-Al did not reduce the
C
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Scheme 7. Attempts at Reductive Cyclization of 9
Scheme 9. Synthesis and Reductive Cyclization of the Alkene
Cyclization Precursor
mediated reaction of allenyl azide 43 was explored as well, but
upon irradiation in DMF, 43 led to an inseparable mixture of
the disubstituted alkene 42 and an undesired product with the
alkene between C(15) and C(16) (35−53%). Schwartz
reagent-mediated reduction of indole 42 resulted in a mixture
of C- and N-cyclized products 40 and 44, respectively. This
result is consistent with the notion that accrued ring strain
thwarted C-ring forming cyclization within 37. Whereas both
40 and 44 are isolated as single diastereomers (<5% impurity,
1H NMR detection limit), the relative stereochemistry at C(20)
could not be determined through NOESY NMR. Efforts to
convert the C-cyclized species 40 into gilbertine (1) through a
deprotection and O → C cyclization at C(16) promoted by
trifluoroacetic acid resulted in a mixture of products which
a
Yields determined by integrating key signals in the 1H NMR
spectrum of the mixture
lactam, whereas DIBAL-mediated reduction of 9 resulted in a
mixture of the over-reduced product 38 and enamine 39.
Solely, the enamine product 39 was generated upon reducing
the amide 9 with the Schwartz reagent (Cp2ZrHCl). Attempts
to cyclize enamine 39 (HOAc/H2O) did not lead to gilbertine.
Since closure of the C-ring of the gilbertine structure from
intermediate 9 (or derived iminium ion 37) was problematic,
an alternative end-game strategy was explored. In this
alternative approach, the E-ring of gilbertine would be closed
last (Scheme 8). The hope here was that burgeoning strain
1
could not be separated. The H NMR spectrum of the crude
mixture showed alkene protons, suggesting that no O → C
cyclization had occurred. Treating 40 with acetic acid at room
temperature did not lead to any chemical reaction, whereas
refluxing the reaction mixture indole 40 decomposed the
Scheme 8. An Alternative Approach − C-Ring Closure Prior
to E-Ring Closure
1
indole. According to the H NMR spectrum of the reaction
mixture, the TBS group was cleaved from 40 using hydrofluoric
acid or tetra-butylammonium fluoride. The presumed primary
alcohol resulting from this deprotection could not be purified
through column chromatography, and so, the crude alcohol was
submitted to trifluoroacetic acid in dichloromethane in an
attempt to effect cyclization at C(16). Unfortunately, gilbertine
1
was not identifiable in the crude reaction mixture’s H NMR
spectrum, suggesting that O → C cyclization did not occur.
This result was unexpected since Blechert has shown that
gilbertine can be synthesized in quantitative yield from the
deprotected alcohol of 40 upon treatment with trifluoroacetic
acid.2 It is possible that C(20) epimerization had occurred
during the C-ring closure, and therefore, the E-ring could not
be closed from this incorrect C(20) stereochemistry.
Efforts to convert the N-cyclized product 44 to gilbertine (1)
also were explored. When submitted to acetic acid at reflux for
5 h, N-cyclized species 44 generated a mixture of five products.
upon C-ring closure from 37 was the issue, and therefore, by
attempting C-ring closure from a more “open” and presumably
less constrained substrate 41, this problem with the initial route
can be avoided. In this new approach, gilbertine (1) would be
formed through a deprotection/cycloetherification of 40. A
Schwartz reagent-mediated reduction of the lactam in 42
should provide iminium ion intermediate 41, and the precursor
indole 42 could be generated from an allenyl azide cyclization
of the TBS protected allene 43, which was already in hand.
Indole 42 was formed in good yield from allene 43 upon
simple heating in acetonitrile (Scheme 9). Photochemically
1
On the basis of the H NMR spectrum of the crude reaction
mixture, the five products were all C-cyclized species,
suggesting that acetic acid can successfully convert the N-
cyclized species 44 to C-cyclized products. Once again, no
gilbertine was detected by examination of the 1H NMR
spectrum of this reaction mixture. In an effort to avoid this
mixture of products, intermediate 40 was submitted to
deprotection conditions first. Either hydrofluoric acid or tetra-
butylammonium fluoride successfully cleaved the TBS group
D
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1
based on the H NMR spectrum of the reaction mixture,
Although gilbertine could not be formed through this allenyl
azide approach, the results obtained did provide some insight
into the scope of the allenyl azide cyclization cascade process.
The allenyl azide cyclization cascade of 11 was able to generate
the single product diastereomer 9 in high yield in a reaction
that formed one new C−N bond and one new C−O bond.
Attempts to generate gilbertine (1) through a reduction of the
amide in 9 with traditional hydride sources resulted in a
mixture of over-reduced product 38 and enamine 39,
suggesting that the desired ring closure in this multi-ring
system was too slow to compete. Incipient ring strain may be
the culprit, as a Schwartz reagent-mediated reduction/
cyclization of a presumably less strained system 42 resulted
in a mixture of the C- and N-cyclized products 40 and 44.
These results suggest that the C-ring of gilbertine 1 should be
formed before the E-ring. For reasons that are unclear, efforts
to convert the N- and C-cyclized products 40 and 44 into
gilbertine were unsuccessful.
whereas the use of cesium fluoride resulted in no reaction.
Attempts to convert this N-cyclized alcohol into gilbertine
through treatment with either acetic acid or trifluoroacetic acid
once again failed.
DISCUSSION
■
The issue of cyclization efficiency and cyclization selectivity (N
vs C) for the closure of the C-ring of members of the uleine
family has been an ongoing challenge. Complicating the
cyclization chemistry is the observation that the C(20) position
can epimerize under acidic reaction conditions, Scheme 10. On
Scheme 10. Prior Art for C-Ring Closure of the Uleine
Alkaloids
EXPERIMENTAL SECTION
■
General Procedure 1. Sulfonyl Protection of Methylamine. A
solution of sulfonyl chloride in CH2Cl2 (2 M) was cooled to 0 °C, and
methylamine (40 wt % in water, 2.2 equiv) was added slowly. Upon
consumption of the sulfonyl chloride (determined by TLC), the
mixture was diluted with an equal volume of brine. The layers were
separated, and the organic layer was washed with water and then brine,
dried over Na2SO4, filtered, and concentrated under reduced pressure.
The residue was purified by recrystallization in 95% ethanol to give
pure sulfonamide.
General Procedure 2. Sulfonamide Addition into Ethyl
Acrylate. To the sulfonamide substrate in MeCN (0.35 M) were
added K2CO3 (1.5 equiv) and ethyl acrylate (1.2 equiv). The solution
was brought to 90 °C and held there for the indicated time. At that
time, the solution was cooled to room temperature, diluted with Et2O,
and run through a plug of Celite. The filtrate was concentrated under
reduced pressure, and the residue was purified by flash column
chromatography on SiO2 with the indicated eluent.
General Procedure 3. DIBAH Reduction. The ester in the
indicated solvent (0.3 M) was cooled to −78 °C, and 1.0 M DIBAH in
hexanes (1.1 equiv) was added slowly. After 2 h at −78 °C, EtOH (0.5
equiv) was added, and the solution was warmed to room temperature.
After 30 min, an equal volume of saturated Rochelle’s salt solution was
added, and the mixture was stirred vigorously for 2 h. The layers were
separated, and the aqueous layer was extracted with EtOAc (3×). The
organic layers were combined and washed with brine, dried over
Na2SO4, filtered, and concentrated. The residue was purified by SiO2
flash column chromatography with the indicated eluent.
General Procedure 4. Trimethylsilylacetylene Addition into
an Aldehyde. To a solution of trimethylsilylacetylene in the indicated
solvent (0.3 M) was added 2.5 M n-BuLi in hexanes (1.1 equiv) at −78
°C. After the addition, the solution was warmed to room temperature
and held there for 15 min, and then cooled to −100 °C (Et2O/CO2
bath). The aldehyde in the indicated solvent (0.9 M) was added at
−100 °C. Upon consumption of the aldehyde (determined by TLC),
the solution was diluted with an equal volume of saturated NH4Cl
solution and extracted with CH2Cl2 (3×). The combined organic
layers were dried with Na2SO4, filtered, and concentrated under
reduced pressure. The residue was purified by SiO2 flash column
chromatography with the indicated eluent.
General Procedure 5. Methylation of an Alcohol. The alcohol
substrate in THF (0.2 M) was cooled to −78 °C, and 2.5 M n-BuLi in
hexanes (1 equiv) was added. After 10 min, iodomethane (8 equiv)
was added to the mixture and the solution was warmed to −40 °C
(MeCN/CO2 bath). DMSO (2 equiv) was added at −40 °C, and the
reaction mixture was allowed to warm to room temperature overnight.
After 14 h, the solution was diluted with an equal volume of saturated
NH4Cl solution and extracted with CH2Cl2 (3×). The layers were
separated, and the combined organic layers were dried over Na2SO4,
the positive side, Ogasawara’s synthesis of uleine proceeded
through iminium ion 45, and the desired C(3) cyclized product
46 was formed with only trace amounts of the C(20) epimer
and no C−N bond formation.7 However, both Bosch8 and
Joule9 observed N-cyclization in their syntheses of dasycarpi-
done. Bosch obtained only trace amounts of the N-cyclized
product 49 from iminium ion 47. In Joule’s synthesis of
dasycarpidone, reaction through an iminium ion derived from
opening the C-ring of 50 resulted in both N-recyclization/
C(20) epimerization (→ 52) and C-cyclization with and
without C(20) epimerization (→ 51, 4) and thus only provided
trace amounts of dasycarpidone (4).
Our initial approach to gilbertine through iminium ion 37
would have skirted the C(20) epimerization problem, since
presumably any C(20) epimer formed could equilibrate with 37
via the iminium ion, and only 37 could cyclize to close the C-
ring. However, since no cyclization of iminium ion 37 was
detected, it is not possible to analyze this premise further. In
the final route toward gilbertine, cyclization of the iminium ion
did occur, but we were unable to ascertain the relative
stereochemistry at C(20) of the two cyclization products 40
and 44. Whereas complete C(20) epimerization within these
species could explain why neither product could be converted
to gilbertine (1), none of the previous approaches toward the
uleine family have reported complete C(20) epimerization
during C-ring closure.
E
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filtered, concentrated under reduced pressure, and purified by SiO2
flash column chromatography with the indicated eluent.
9H), 0.14 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 157.3, 106.6, 88.2,
80.4, 59.1, 44.4, 35.4, 34.4, 28.5, 0.0; LRMS (ESI-TOF) m/z (relative
intensity) 286.2 (16%, M + H+); HRMS (ESI-TOF) m/z: [M + H+];
calcd for C14H28NO3Si 286.1838, found 286.1838.
General Procedure 6. Cobalt Complex Formation. To a
solution of octacarbonyl dicobalt (1 equiv) in Et2O (0.6 M) was added
slowly the alkyne in Et2O (0.6 M). Once no evolution of gas was
visible, the mixture was concentrated under reduced pressure and
purified by the indicated method.
General Procedure 7. Nicholas Reaction. The oxazolidinone
substrate (2 equiv) in the indicated solvent (0.3 M) was cooled to 0
°C. 1.0 M Bu2BOTf in CH2Cl2 (4 equiv) was added, followed by
freshly distilled iPr2NEt (2 equiv). After 15 min at 0 °C, the mixture
was cooled to −78 °C and the cobalt complex in the indicated solvent
(0.5 M) was added slowly. The solution was warmed to the indicated
temperature after the specified time. Upon consumption of the cobalt
complex (determined by TLC), the reaction mixture was diluted with
an equal volume of pH 7 buffer and extracted with CH2Cl2 (3×). The
combined organic layers were dried over Na2SO4, filtered, and
concentrated under reduced pressure.
General Procedure 8. Removal of Co2(CO)6. The Nicholas
adduct was dissolved in acetone (0.05 M), and cerium ammonium
nitrate was added in portions until no bubbles formed. The mixture
was diluted with an equal volume of H2O and extracted with EtOAc
(3×). The organic layers were combined, dried over Na2SO4, filtered,
and concentrated under reduced pressure. The residue was purified by
SiO2 flash column chromatography with the indicated eluent.
General Procedure 9. Cleavage of the Chiral Auxiliary. The
bromide substrate in 3:1 THF:H2O (0.3 M) was cooled to 0 °C. 30%
H2O2 (8 equiv) was added, followed by the indicated base (3.3 equiv)
in H2O (1 M). After the designated time at the specified temperature,
Na2SO3 (8.8 equiv) in H2O (1.2 M) was added. The mixture then was
acidified to pH 1 with the indicated acid and extracted with CH2Cl2
(3×). The organic layers were combined, dried over Na2SO4, filtered,
and concentrated under reduced pressure. The residue was purified by
SiO2 flash column chromatography with the indicated eluent.
General Procedure 10. Thermal Allenyl Azide Cyclization.
The allenyl azide substrate in the indicated solvent (0.005 M) was
heated to the indicated temperature for the specified time. At that
time, the solution was cooled to room temperature and concentrated
under reduced pressure, and the residue was purified by flash column
chromatography with the indicated support and eluent.
tert-Butyl Methylcarbamate (17). Di-tert-butyl dicarbonate (10.91
g, 49.99 mmol) and 2.0 M methylamine in THF (25 mL, 50 mmol)
were added to Amberlyst-15 catalyst (0.23 g, 15% w/w) at room
temperature. More 2.0 M methylamine in THF was added in portions
until all of the di-tert-butyldicarbonate was consumed (determined by
TLC). The mixture was concentrated under reduced pressure and
purified by SiO2 flash column chromatography (10% EtOAc in
hexanes) to give carbamate 17 (6.07 g, 93%) as a clear oil. The derived
spectral data matched those reported by Kumar.10
tert-Butyl (3-Methoxy-5-(trimethylsilyl)pent-4-yn-1-yl)(methyl)-
carbamate (20). Following General Procedure 5, alcohol 19 (0.12
g, 0.40 mmol) was converted to methyl ether 20. The residue was
purified by SiO2 flash column chromatography (10% EtOAc in
hexanes) to give methyl ether 20 (0.11 g, 92%) as a clear oil. IR (thin
film) 2169, 1695 cm−1; 1H NMR (300 MHz, CDCl3) δ 3.94 (t, J = 6.4
Hz, 1H), 3.39−3.32 (m, 5H), 2.85 (s, 3H), 1.91 (q, J = 8.2 Hz, 2H),
1.46 (s, 9H), 0.18 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 155.8,
103.9, 91.1, 79.4, 69.4, 56.4, 45.5, 34.6, 34.1, 28.6, 0.0; LRMS (ESI-
TOF) m/z (relative intensity) 300.2 (100%, M + H+); HRMS (ESI-
TOF) m/z: [M + H+]; calcd for C15H30NO3Si 300.1995, found
300.1980.
tert-Butyl (3-Methoxy-5-(trimethylsilyl)pent-4-yn-1-yl)(methyl)-
carbamate Dicobalt Hexacarbonyl Complex (21). Following
General Procedure 6, alkyne 20 (0.35 g, 1.2 mmol) was converted
to cobalt complex 21. The residue was purified by SiO2 flash column
chromatography (10% Et2O in hexanes) to give cobalt complex 21
1
(0.60 g, 88%) as a red oil. IR (thin film) 2087, 2009, 1696 cm−1; H
NMR (300 MHz, CDCl3) δ 4.29 (s, 1H), 3.54 (s, 3H), 3.50−3.21 (bs,
2H), 2.88 (s, 3H), 2.05−1.78 (m, 2H), 1.46 (s, 9H), 0.32 (s, 9H); 13C
NMR (125 MHz, CDCl3) δ 200.4, 156.0, 80.1, 79.7, 78.9, 58.8, 46.1,
45.9, 37.8, 34.6, 28.6, 1.1; LRMS (ESI-TOF) m/z (relative intensity)
608.0 (26%, M + Na+); HRMS (ESI-TOF) m/z: [M + Na+]; calcd for
C21H29Co2NO9SiNa 608.0173, found 608.0200.
(4R,5S)-3-(4-Bromobutanoyl)-4-methyl-5-phenyloxazolidin-2-
one (15). To a solution of chiral auxiliary (4R,5S)-(+)-4-methyl-5-
phenyl-2-oxazolidinone (0.18 g, 1.0 mmol) in THF (3.16 mL) was
added 2.5 M n-BuLi in hexanes (0.4 mL, 1 mmol) at −78 °C. After 15
min, 4-bromobutyryl chloride (0.14 mL, 1.2 mmol) was added at −78
°C. The mixture was warmed to 0 °C after 15 min. Upon consumption
of the chiral auxiliary (determined by TLC), the solution was diluted
with H2O (10 mL) and extracted with Et2O (3 × 20 mL). The
combined organic layers were dried over Na2SO4, filtered, and
concentrated under reduced pressure. Purification of the residue by
SiO2 flash column chromatography (30% EtOAc in hexanes) gave
oxazolidinone 15 (0.11 g, 92%) as a white solid. [α]2D0 = +29.7 (c =
1
0.14, CHCl3); mp 46−49 °C; IR (thin film) 1777, 1699 cm−1; H
NMR (300 MHz, CDCl3) δ 7.37−7.45 (m, 3H), 7.30 (d, J = 6.3 Hz,
2H), 5.68 (d, J = 7.3 Hz, 1H), 4.76 (apparent pentet, J = 6.7 Hz, 1H),
3.52 (t, J = 6.5 Hz, 2H), 3.13 (q, J = 7.0 Hz, 2H), 2.23 (p, J = 6.7 Hz,
2H), 0.90 (d, J = 6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 171.9,
153.2, 133.3, 129.0, 128.9, 125.8, 79.3, 54.9, 34.2, 32.8, 27.2, 14.7;
LRMS (ESI-TOF) m/z (relative intensity) 326.0 (25%, M + H+);
HRMS (ESI-TOF) m/z: [M + H+]; calcd for C14H17NO3Br 326.0392,
found 326.0382.
tert-Butyl Methyl(2-oxopropyl)carbamate (18). Carbamate 17
(11.00 g, 83.86 mmol) in CH2Cl2 (100 mL) was added to camphor
sulfonic acid (3.90 g, 16.8 mmol). The mixture was cooled to 0 °C,
and acrolein (56 mL, 840 mmol) was added. After 15 min at 0 °C, the
reaction mixture was warmed to room temperature. Upon complete
consumption of 17 (determined by TLC), the solution was diluted
with saturated NaHCO3 (50 mL). The organic layer was dried over
Na2SO4, filtered, and concentrated. The resulting oil was diluted in
Et2O (65 mL) and washed with H2O (25 mL) and then brine (25
mL). The layers were separated, and the organic layer was dried over
Na2SO4, filtered, and concentrated under reduced pressure.
Purification of the residue by SiO2 flash column chromatography
(10% EtOAc in hexanes) gave aldehyde 18 (11.10 g, 71%) as a yellow
oil. The spectral data matched those reported by Xiao.11
tert-Butyl (3-Hydroxy-5-(trimethylsilyl)pent-4-yn-1-yl)(methyl)-
carbamate (19). Following General Procedure 4, aldehyde 18 (0.37
g, 2.0 mmol) in THF was converted to alcohol 19. The residue was
purified by SiO2 flash column chromatography (10% EtOAc in
hexanes) to give alcohol 19 (0.54 g, 95%) as a clear oil. IR (thin film)
3400, 2171, 1670 cm−1; 1H NMR (300 MHz, CDCl3) δ 4.42−4.35 (m,
2H), 3.60−3.17 (m, 2H), 2.82 (s, 3H), 1.89−1.86 (m, 2H), 1.44 (s,
3-Methyl-6-((trimethylsilyl)ethynyl)-1,3-oxazinan-2-one Dicobalt
Hexacarbonyl Complex (22). Following General Procedure 7,
oxazolidinone 15 (0.03 g, 0.1 mmol) in CH2Cl2 and cobalt complex
21 (0.03 g, 0.05 mmol) in CH2Cl2 were stirred at −78 °C for 10 min
before warming to 0 °C. The residue was purified by SiO2 flash
column chromatography (20% Et2O in hexanes) to give carbamate 22
1
(11 mg, 43%) as a red oil. IR (thin film) 2090, 2002, 1690 cm−1; H
NMR (360 MHz, CDCl3) δ 5.38 (dd, J = 10.8, 2.5 Hz, 1H), 3.55 (td, J
= 11.7, 5.2 Hz, 1H), 3.31 (ddd, J = 11.7, 6.1, 2.1 Hz, 1H), 3.03 (s, 3H).
2.35−2.25 (m, 1H), 2.12−2.20 (m, 1H), 0.28 (s, 9H); 13C NMR (125
MHz, C6D6) δ 200.3, 152.1, 108.5, 80.2, 76.9, 46.1, 36.5, 31.1, 0.9;
LRMS (ESI-TOF) m/z (relative intensity) 497.9 (100%, M + H+);
HRMS (ESI-TOF) m/z: [M + H+]; calcd for C16H18Co2NO8Si
497.9466, found 497.9445.
N-4-Dimethyl-benzenesulfonamide (23a). Following General
Procedure 1, tosyl chloride (15.3 g, 80.0 mmol) was converted to
sulfonamide 23a, recovered as white crystals (13.8 g, 93%). The
spectral data matched those reported by Xu.12
N-Methyl-4-nitrobenzenesulfonamide (23b). Following General
Procedure 1, 4-nitrobenzenesulfonyl chloride (11 g, 50 mmol) was
F
DOI: 10.1021/acs.joc.6b00348
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The Journal of Organic Chemistry
Article
converted to sulfonamide 23b, recovered as white crystals (9.77 g,
90%). The spectral data matched those reported by Maclean.13
Ethyl 3-((N,4-Dimethylphenyl)sulfonamide)propanoate (24a).
Following General Procedure 2, tosylamide 23a (5.22 g, 28.2 mmol)
was converted to ester 24a after stirring at 90 °C for 16 h. The residue
was purified by column chromatography on SiO2 (30% ethyl acetate in
hexanes) to give ester 24a as a colorless oil (7.67 g, 96%). IR (thin
film) 1730 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.67 (d, J = 8.2 Hz,
2H), 7.32 (d, J = 8.1 Hz, 2H), 4.13 (q, J = 7.1 Hz, 2H), 3.31 (t, J = 7.2
Hz, 2H), 3.76 (s, 3H). 2.61 (t, J = 7.2 Hz, 2H). 2.43 (s, 3H), 1.26 (t, J
= 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 171.3, 143.3, 130.0,
129.8, 127.4, 60.8, 46.0, 35.7, 34.1, 21.6, 14.3; LRMS (ESI-TOF) m/z
(relative intensity) 286.1 (100%, M + H+); HRMS (ESI-TOF) m/z:
[M + H+]; calcd for C13H20NO4S 286.1113, found 286.1109.
Ethyl 3-(N-Methyl-4-nitrophenyl)sulfonamide)propanoate (24b).
Following General Procedure 2, nosylamide 23b (1.85 g, 8.56 mmol)
and ethyl acrylate were heated to 90 °C and held there for 3 h. The
residue was purified by flash column chromatography on SiO2 (30%
EtOAc in hexanes) to give 24b as a light yellow solid (2.52 g, 93%).
mp 95−97 °C; IR (thin film) 1734, 1527 cm−1; 1H NMR (300 MHz,
CDCl3) δ 8.37 (d, J = 8.8 Hz, 2H), 7.97 (d, J = 8.8 Hz, 2H), 4.13 (q, J
= 7.1 Hz, 2H), 3.37 (t, J = 7.1 Hz, 2H), 2.84 (s, 3H), 2.63 (t, J = 7.1
Hz, 2H), 1.25 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
171.1, 150.2, 143.7, 128.6, 124.6, 61.1, 46.3, 35.7, 33.9, 14.3; LRMS
(ESI-TOF) m/z (relative intensity) 317.1 (50%, M + H+); HRMS
(ESI-TOF) m/z: [M + H+]; calcd for C12H17N2O6S 317.0807, found
317.0820.
2H), 4.73−4.69 (m, 1H), 3.42−3.33 (m, 1H), 3.14−3.06 (m, 1H),
2.83 (s, 3H), 2.38 (d, J = 5.0 Hz, 1H), 1.97 (p, J = 6.7 Hz, 2H), 0.17
(s, 9H); 13C NMR (75 MHz, CDCl3) δ 150.2, 143.6, 128.6, 124.6,
150.4, 90.4, 59.7, 46.6, 35.6, 35.3, −0.1 ; LRMS (ESI-TOF) m/z
(relative intensity) 371.1 (100%, M + H+); HRMS (ESI-TOF) m/z:
[M + H+]; calcd for C15H23N2O5SSi 371.1079, found 371.1097.
N-(3-Methoxy-5-(trimethylsilyl)pent-4-yn-1-yl)-N,4-dimethyl-
benzenesulfonamide (27a). Following General Procedure 5, alcohol
26a (0.41 g, 1.2 mmol) was converted to ether 27a. The residue was
purified by SiO2 flash column chromatography (10% EtOAc in
hexanes) to give methyl ether 27a (0.35 g, 89%) as a colorless oil. IR
(thin film) 2169, 1740 cm−1; 1H NMR (360 MHz, CDCl3) δ 7.67 (d, J
= 8.2 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 4.04 (t, J = 6.3 Hz, 1H), 3.39
(s, 3H), 3.38−3.17 (m, 1H), 3.05−3.00 (m, 1H), 2.73 (s, 3H), 2.43 (s,
3H), 1.93 (q, J = 6.6 Hz, 2H) 0.18 (s, 9H); 13C NMR (75 MHz,
CDCl3) δ 143.4, 134.5, 129.8, 127.6, 103.7, 91.3, 68.8, 56.7, 46.8, 35.5,
34.2, 21.6, 0.0; LRMS (ESI-TOF) m/z (relative intensity) 354.2
(100%, M + H+); HRMS (ESI-TOF) m/z: [M + H+]; calcd for
C17H28NO3SSi 354.1559, found 354.1561.
N-(3-Methoxy-5-(trimethylsilyl)pent-4-yn-1-yl)-N-methyl-4-nitro-
benzenesulfonamide (27b). Method A. Trimethylsilyl acetylene (6.4
mL, 46 mmol) in THF (23 mL) was cooled to −78 °C. 2.5 M n-BuLi
in hexanes (19.9 mL, 49.7 mmol) was added, and the reaction mixture
was warmed to room temperature for 15 min. The solution was cooled
to −100 °C (Et2O/CO2 bath), and aldehyde 25b (12.30 g, 45.19
mmol) in THF (226 mL) was added. Iodomethane (22.5 mL, 362
mmol) was added after 45 min, and the reaction solution was warmed
to −40 °C (MeCN/CO2 bath). DMSO (6.4 mL, 90. mmol) was
added, and the reaction mixture was allowed to warm to room
temperature overnight. A 150 mL portion of saturated NH4Cl solution
was added, the layers were separated, and the aqueous phase was
extracted with CH2Cl2 (3 × 100 mL). The organic layers were
combined, dried over Na2SO4, filtered, and concentrated under
reduced pressure to give an oily red residue. The residue was purified
by SiO2 flash column chromatography (10% EtOAc in hexanes) to
give alkyne 27b (12.60 g, 73%) as a light yellow solid. Method B.
Following General Procedure 5, alcohol 26b (2.50 g, 7.45 mmol) was
converted to ether 27b. The residue was purified by SiO2 flash column
chromatography (20% EtOAc in hexanes) to give ether 27b (1.50 g,
58%) as a light yellow solid. mp 103−104 °C; IR (thin film) 2170,
N-4-Dimethyl-N-(3-oxopropyl)benzenesulfonamide (25a). Fol-
lowing General Procedure 3, ester 24a (0.97 g, 3.4 mmol) in toluene
was converted to aldehyde 25a. The residue was purified by SiO2 flash
column chromatography (20% EtOAc in hexanes) to give aldehyde
1
25a (0.79 g, 96%) as a colorless oil. IR (thin film) 1721 cm−1; H
NMR (360 MHz, CDCl3) δ 9.80 (t, J = 1.1 Hz 1H), 7.67 (d, J = 8.3
Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 3.30 (t, J = 6.8 Hz, 2H), 2.78 (td, J
= 6.8, 1.1 Hz, 2H), 2.75 (s, 3H), 2.44 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 143.8, 134.3, 129.9 (2), 127.6, 46.2, 35.9, 21.7; LRMS (ESI-
TOF) m/z (relative intensity) 242.1 (100%, M + H+); HRMS (ESI-
TOF) m/z: [M + H+]; calcd for C11H16NO3S 242.0851, found
242.0843.
N-Methyl-4-nitro-N-(3-oxopropyl)benzenesulfonamide (25b).
Following General Procedure 3, ester 24b (3.68 g, 11.6 mmol) in
CH2Cl2 was converted to aldehyde 25b. Purification of the residue by
SiO2 flash column chromatography (20% EtOAc in hexanes) gave
aldehyde 25b (2.72 g, 86%) as an orange solid. mp 72−74 °C; IR (thin
1
1527 cm−1; H NMR (300 MHz, CDCl3) δ 8.35 (d, J = 8.7 Hz, 2H),
7.96 (d, J = 8.7 Hz, 2H), 4.01 (t, J = 6.0 Hz, 1H), 3.36 (s, 3H), 3.29−
3.24 (m, 1H), 3.17−3.03 (m, 1H), 2.79 (s, 3H), 1.94 (q, J = 6.4 Hz,
2H), 0.16 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 150.1, 143.7, 128.6,
124.5, 103.2, 91.6, 68.6, 56.7, 46.8, 35.3, 34.0, −0.1; LRMS (ESI-TOF)
1
film) 1718, 1523 cm−1; H NMR (300 MHz, CDCl3) δ 9.98 (s, 1H),
+
m/z (relative intensity) 402.1 (100%, M + NH4 ); HRMS (ESI-TOF)
8.37 (d, J = 8.7 Hz, 2H), 7.97 (d, J = 8.7 Hz, 2H), 3.38 (t, J = 6.7 Hz,
2H), 2.85−2.82 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 199.6, 150.2,
143.2, 128.6, 124.6, 43.9, 42.9, 35.8; LRMS (ESI-TOF) m/z (relative
+
m/z: [M + NH4 ]; calcd for C16H28N3O5SSi 402.1519, found
402.1504.
+
N-(3-Methoxy-5-(trimethylsilyl)pent-4-yn-1-yl)-N-4-dimethyl-
benzenesulfonamide Dicobalt Hexacarbonyl Complex (28a).
Following General Procedure 6, alkyne 27a (0.18 g, 0.51 mmol)
was converted to cobalt complex 28a. The residue was purified by
SiO2 flash column chromatography (10% Et2O in hexanes) to give
cobalt complex 28a (0.31 g, 96%) as a red solid. mp 38−40 °C; IR
(thin film) 2959, 2087, 2008, 1738 cm−1; 1H NMR (300 MHz,
CDCl3) δ 7.69 (d, J = 8.1 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 4.48 (dd,
J = 10.0, 2.2 Hz, 1H), 3.68−3.48 (m, 4H), 2.83−2.81−2.67 (m, 4H),
2.44 (s, 3H), 1.98−1.95 (m, 1H), 1.86−1.81 (m, 1H), 0.32 (s, 9H);
13C NMR (125 MHz, CDCl3) δ 200.4, 143.6, 134.1, 129.9, 127.7,
intensity) 290.1 (19%, M + NH4 ); HRMS (ESI-TOF) m/z: [M +
+
NH4 ]; calcd for C10H16N3O5S 290.0811, found 290.0829.
N-(3-Hydroxy-5-(trimethylsilyl)pent-4-yn-1-yl)-N,4-dimethyl-
benzenesulfonamide (26a). Following General Procedure 4, aldehyde
25a (0.20 g, 0.85 mmol) in CH2Cl2 was converted to alcohol 26a.
Purification of the residue by SiO2 flash column chromatography (30%
EtOAc in hexanes) gave alcohol 26a (0.21 g, 72%) as a colorless oil. IR
1
(thin film) 3497, 2171, 1737 cm−1; H NMR (360 MHz, CDCl3) δ
7.67 (d, J = 8.2 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 4.61−4.56 (m, 1H),
3.36−3.32 (m, 1H), 2.96−2.89 (m, 1H), 2.76 (s, 3H), 2.50 (d, J = 5.4
Hz, 1H), 2.43 (s, 3H), 1.97−1.88 (m, 2H), 0.18 (s, 9H); 13C NMR
(75 MHz, CDCl3) δ 143.6, 134.2, 129.8, 127.4, 105.9, 89.7, 59.7, 46.5,
35.7, 35.4, 21.6, −0.1; LRMS (ESI-TOF) m/z (relative intensity)
340.1 (100%, M + H+); HRMS (ESI-TOF) m/z: [M + H+]; calcd for
C16H26NO3SSi 340.1403, found 340.1402.
111.2, 79.1(2), 59.1, 47.3, 37.3, 35.1, 21.6, 1.1; LRMS (ESI-TOF) m/z
(relative intensity) 608.0 (100%, M − OMe−); HRMS (ESI-TOF) m/
z: [M − OMe−]; calcd for C22H24Co2NO8SSi 607.9656, found
607.9659.
N-(3-Hydroxy-5-(trimethylsilyl)pent-4-yn-1-yl)-N-methyl-4-nitro-
benzenesulfonamide (26b). Following General Procedure 4, aldehyde
25b (15.7 g, 57.9 mmol) in CH2Cl2 was converted to alcohol 26b.
Purification of the residue by SiO2 flash column chromatography (30%
EtOAc in hexanes) gave alcohol 26b (17.5 g, 82%) as an orange solid.
mp 98−100 °C; IR (thin film) 3514, 3112, 2171, 1528 cm−1; 1H NMR
(300 MHz, CDCl3) δ 8.38 (d, J = 8.7 Hz, 2H), 7.98 (d, J = 8.7 Hz,
N-(3-Methoxy-5-(trimethylsilyl)pent-4-yn-1-yl)-N-methyl-4-nitro-
benzenesulfonamide Dicobalt Hexacarbonyl Complex (28b).
Following General Procedure 6, alkyne 27b (7.44 g, 19.4 mmol)
was converted to cobalt complex 28b. The residue was purified
through trituration with hexanes to give cobalt complex 28b (12.01 g,
93%) as a red solid. mp 95−97 °C; IR (thin film) 2086, 1990, 1524
1
cm−1; H NMR (300 MHz, CDCl3) δ 8.38 (d, J = 8.6 Hz, 2H), 7.99
G
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(d, J = 8.6 Hz, 2H), 4.45 (ad, J = 10.0 Hz, 1H), 3.83−3.64 (m, 1H),
3.53 (s, 3H), 2.99−2.88 (m, 1H), 2.82 (s, 3H), 2.04−1.97 (m, 1H),
1.87−1.82 (m, 1H), 0.32 (s, 9H); 13C NMR (75 MHz, CDCl3) δ
200.3, 150.2, 143.3, 128.7, 124.6, 110.5, 79.1, 78.9, 59.0, 47.3, 37.1,
35.0, 1.1; LRMS (ESI-TOF) m/z (relative intensity) 692.9 (38%, M +
Na+); HRMS (ESI-TOF) m/z: [M + Na+]; calcd for C22H24-
Co2N2O11SSiNa 692.9432, found 692.9409.
N-((3S,4S)-6-Bromo-4-(4R,5S)-4-methyl-2-oxo-5-phenyloxazoli-
dine-3-carbonyl)-3-((trimethylsilyl)ethynyl)hexyl)-N,4-dimethyl-
benzenesulfonamide (30a). Following General Procedure 7,
oxazolidinone 15 (1.54 g, 4.73 mmol) in toluene and cobalt complex
28a (1.51 g, 2.37 mmol) in toluene were stirred at −78 °C for 10 min
before warming the solution to 0 °C. The resulting crude oil was
converted to Nicholas product 30a following General Procedure 8.
Purification of the resulting yellow residue by SiO2 flash column
chromatography (100% hexanes to 10% Et2O in hexanes) gave
Nicholas adduct 30a (0.91 g, 60%) as a white solid. [α]2D0 = −2.8 (c =
0.05, CHCl3); mp 65−69 °C; IR (thin film) 2168, 1778, 1694 cm−1;
1H NMR (500 MHz, CDCl3) δ 7.67 (d, J = 8.2 Hz, 2H), 7.44−7.35
30c following General Procedure 8. Purification of the residue by SiO2
flash column chromatography (10% Et2O in hexanes) gave Nicholas
adduct 30b (3.94 g, 64%) as a yellow foam and Nicholas adduct 30c
(0.56 g, 9%) as a yellow foam.
30b: [α]2D0 = +5.9 (c = 0.01, CH3Cl); mp 59−60 °C; IR (thin film)
2168, 1778, 1693, 1530 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.38 (d,
J = 8.8 Hz, 2H), 7.98 (d, J = 8.7 Hz, 2H), 7.45−7.36 (m, 3H), 7.30 (d,
J = 7.0 Hz, 2H), 5.69 (d, J = 7.2 Hz, 1H), 4.82 (p, J = 6.8 Hz, 1H),
4.28−4.23 (m, 1H), 3.47−3.43 (m, 1H), 3.38−3.33 (m, 1H), 3.24 (t, J
= 7.2 Hz, 2H), 2.89−2.82 (m, 4H), 2.40−2.35 (m, 1H), 2.22−2.17 (m,
1H), 1.92−1.87 (m, 1H), 1.68−1.59 (m, 1H), 0.88 (d, J = 6.5 Hz,
3H), 0.12 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 172.6, 152.5,
150.0, 143.4, 133.1, 128.8, 128.7, 128.5, 125.6, 124.4, 104.8, 89.1, 78.8,
55.0, 48.5, 44.6, 35.7, 32.4, 32.1, 30.7, 29.9, 14.6, 13.9, −0.05; LRMS
+
(ESI-TOF) m/z (relative intensity) 695.2 (95%, M + NH4 ); HRMS
+
(ESI-TOF) m/z: [M + NH4 ] calcd for C29H40N4O7BrSSi 695.1570,
found 695.1572.
30c: [α]2D0 = +34.2 (c = 0.02, CH3Cl); mp 50−52 °C; IR (thin film)
1
1777, 1699, 1530 cm−1; H NMR (360 MHz, CDCl3) δ 8.38 (d, J =
(m, 3H), 7.33−7.30 (m, 4H), 5.68 (d, J = 7.3 Hz, 1H), 4.81 (p, J = 6.8
Hz, 1H), 4.23 (d, J = 7.2 Hz, 2H), 3.45−3.42 (m, 1H), 3.38−3.34 (m,
1H), 3.15 (t, J = 7.2 Hz, 2H), 2.74 (s, 3H), 2.42−2.34 (m, 4H), 2.28−
2.21 (m, 1H), 1.85−1.81 (m, 1H), 1.65−1.60 (m, 1H), 0.93 (d, J = 5.4
Hz, 3H), 0.11 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 172.8, 152.8,
143.3, 134.5, 133.2, 129.7, 128.9, 128.8, 127.6, 125.8, 104.5, 89.9, 79.1,
55.1, 48.3, 45.1, 35.4, 32.9, 32.5, 31.2, 31.1, 21.6, 14.7, 0.1; LRMS
(ESI-TOF) m/z (relative intensity) 647.1 (38%, M + H+); HRMS
(ESI-TOF) m/z: [M + H+]; calcd for C30H40N2O5SSiBr 647.1611,
found 647.1639.
8.6 Hz, 2H), 8.00 (d, J = 8.6 Hz, 2H), 7.37−7.44 (m, 3H), 7.31 (d, J =
6.8 Hz, 2H), 5.71 (d, J = 7.3 Hz, 1H), 4.82 (p, J = 6.8 Hz, 1H), 4.09−
4.03 (m, 1H), 3.54−3.51 (m, 1H), 3.41 (q, J = 6.8 Hz, 1H), 3.36−3.18
(m, 2H), 2.98 (q, J = 6.7 Hz, 1H), 2.81 (s, 3H), 2.52−2.47 (m, 1H).
2.28−2.22 (m, 1H), 1.93−1.73 (m, 2H), 0.91 (d, J = 6.5 Hz, 3H), 0.13
(s, 9H); 13C NMR (75 MHz, CDCl3) 172.8, 153.0, 150.1, 143.8,
133.1, 129.0, 128.9, 128.7, 125.8, 124.5, 104.1, 90.2, 79.2, 55.3, 48.3,
45.0, 35.3, 32.8, 32.6, 31.2, 31.1,14.6, 0.1; LRMS (ESI-TOF) m/z
+
(relative intensity) 695.1 (95%, M + NH4 ); HRMS (ESI-TOF) m/z:
+
[M + NH4 ] calcd for C29H40N4O7BrSSi 695.1570, found 695.1572.
N,4-Dimethyl-N-(5-(trimethylsilyl)pent-2-en-4-yn-1-yl)benzene-
sulfonamide (31a). Following General Procedure 7, oxazolidinone 15
(0.05 g, 0.2 mmol) in toluene and cobalt complex 28a (0.05 g, 0.08
mmol) in toluene were stirred at −78 °C for 10 min before warming
to room temperature. The resulting crude oil was converted to the
enyne 31a following General Procedure 8. Purification of the resulting
residue by SiO2 flash column chromatography (100% hexanes to 10%
Et2O in hexanes) gave enyne 31a (0.04 g, 90%) as a yellow oil. IR
(thin film) cm−1 2135, 1597; 1H NMR (300 MHz, CDCl3) δ 7.64 (d, J
= 8.2 Hz, 2H), 7.31 (d, J = 8.2 Hz, 2H), 6.02 (dt, J = 15.9, 6.3 Hz,
1H), 5.63 (d, J = 15.9 Hz, 1H), 3.63 (d, J = 6.3 Hz, 2H), 2.64 (s, 3H),
2.41 (s, 3H), 0.28 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 143.7,
138.3, 134.2, 129.8, 127.5, 113.8, 102.3, 95.9, 52.0, 34.6, 21.6, −0.1;
LRMS (ESI-TOF) m/z (relative intensity) 322.0 (59%, M + H+);
HRMS (ESI-TOF) m/z: [M + H+]; calcd for C16H24NO2SSi
322.1297, found 322.1308.
N-Methyl-4-nitro-N-((S)-3-((S)-2-oxotetrahydrofuran-3-yl)-5-
(trimethylsilyl)pent-4-yn-1-yl)benzenesulfonamide (32b). Following
General Procedure 9, CsOH and H2O2 were added to alkyne 30b
(0.16 g, 0.24 mmol) at −5 °C. After 30 min at −5 °C, the solution was
warmed to room temperature. After 30 min at room temperature,
Na2SO3 was added. The mixture was acidified to pH 1 with 1 N
phosphoric acid and extracted with EtOAc. Purification of the residue
by SiO2 flash column chromatography (20% EtOAc in hexanes) gave
lactone 32b (52 mg, 50%) as a light yellow solid. [α]2D0 = −35.9 (c =
0.04, CH3Cl); mp 105−107 °C; IR (thin film) 2170, 1748, 1530 cm−1;
1H NMR (300 MHz, CDCl3) δ 8.37 (d, J = 8.6 Hz, 2H), 7.97 (d, J =
8.6 Hz, 2H), 4.39 (td, J = 8.8, 4.0 Hz, 1H), 4.23 (q, J = 8.2 Hz, 1H),
3.29−3.26 (m, 1H), 3.17−3.13 (m, 1H), 2.93−2.78 (m, 5H), 2.47−
2.43 (m, 1H), 2.29−2.25 (m, 1H), 1.99−1.88 (m, 2H), 0.14 (s, 9H);
13C NMR (75 MHz, CDCl3) δ 176.7, 150.1, 143.4, 128.6, 124.5, 104.8,
88.6, 66.8, 48.4, 42.2, 35.1, 30.7, 29.4, 26.3, 0.0; LRMS (ESI-TOF) m/
z (relative intensity) 439.2 (10%, M + H+); HRMS (ESI-TOF) m/z:
[M + H+]; calcd for C19H27N2O6SSi 439.1359, found 439.1351.
(3S,4S)-3-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-1-methyl-4-
((trimethylsilyl)ethynyl)piperidin-2-one (34). A solution of lactone
32b (0.15 g, 0.34 mmol) and NaSPh (0.09 g, 0.7 mmol) in 3.4 mL of
DMF was heated to 90 °C. After 1 h at 90 °C, the solution was cooled
to room temperature, diluted with H2O (10 mL), and extracted with
EtOAc (3 × 5 mL). The organic layers were combined and washed
with H2O (2 × 5 mL). The organic layer was dried over Na2SO4,
filtered, and concentrated under reduced pressure to give the crude
alcohol product (labeled S3 in the Supporting Information). Imidazole
(0.05 g, 0.7 mmol) was added to this crude alcohol in DMF (3.4 mL)
at 0 °C. After 10 min, TBSCl (0.06 g, 0.4 mmol) was added at 0 °C.
After 5 min, the reaction mixture was warmed to room temperature
and stirred for 1 h. The solution was diluted with H2O (10 mL) and
extracted with EtOAc (3 × 5 mL). The organic layers were combined
and washed with H2O (2 × 5 mL). The organic layer was dried over
Na2SO4, filtered, and concentrated under reduced pressure.
Purification of the residue by SiO2 flash column chromatography
(10−20% EtOAc in hexanes) gave lactam 34 (0.08 g, 65%) as a yellow
oil. [α]2D0 = +57.8 (c = 0.05, MeOH); IR (thin film) 2167, 1646 cm−1;
1H NMR (300 MHz, CDCl3) δ 3.76−3.70 (m, 2H), 3.59 (td, J = 11.4,
N-4-Dimethyl-N-((S)-3-((S)-2-oxotetrahydrofuran-3-yl)-5-
(trimethylsilyl)pent-4-yn-1-yl)benzenesulfonamide (32a). Following
General Procedure 9, alkyne 30a (0.05 g, 0.08 mmol), LiOH·H2O, and
30% H2O2 were kept at 0 °C for 2 h before the addition of Na2SO3.
Purification of the residue by SiO2 flash column chromatography (20%
EtOAc in hexanes) gave lactone 32a (12 mg, 40%) as a white solid,
and some starting material 30a was recovered (6.8 mg, 6%). [α]D20
=
−35.4 (c = 0.05, CHCl3); mp 61−63 °C; IR (thin film) 2166, 1761
1
cm−1; H NMR (300 MHz, CDCl3) δ 7.65 (d, J = 8.2 Hz, 2H), 7.31
(d, J = 8.0 Hz, 2H), 4.40 (td, J = 8.7, 4.3 Hz, 1H), 4.23 (q, J = 8.0 Hz,
1H), 3.28−3.23 (m, 1H), 3.02−2.84 (m, 3H), 2.71 (s, 3H), 2.46−2.42
(m, 1H), 2.43 (s, 3H), 2.31−2.25 (m, 1H), 2.95 (q, J = 6.8 Hz, 2H),
0.14 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 177.0, 143.6, 134.1,
129.8, 127.6, 105.3, 88.2, 66.9, 48.3, 41.8, 35.3, 30.9, 29.5, 26.6, 21.6,
0.1; LRMS (ESI-TOF) m/z (relative intensity) 408.1 (88%, M + H+);
HRMS (ESI-TOF) m/z: [M + H+]; calcd for C20H30NO4SSi
408.1665, found 408.1668.
N-((3S,4S)-6-Bromo-4-((4R,5S)-4-methyl-2-oxo-5-phenyloxazoli-
dinine-3-carbonyl)-3-((trimethylsilyl)ethynyl)hexyl)-N-methyl-4-
nitrobenzenesulfonamide (30b) and N-((3R,4S)-6-Bromo-4-
((4R,5S)-4-methyl-2-oxo-5-phenyloxazolidinine-3-carbonyl)-3-
((trimethylsilyl)ethynyl)hexyl)-N-methyl-4-nitrobenzenesulfonamide
(30c). Following General Procedure 7, oxazolidinone 15 (5.85 g, 17.9
mmol) in toluene and cobalt complex 28b (6.00 g, 8.96 mmol) in
toluene were stirred at −78 °C for 10 min before warming to 0 °C.
The resulting crude oil was converted to Nicholas adducts 30b and
5.5 Hz, 1H), 3.25−3.15 (m, 1H), 3.03 (q, J = 5.1 Hz, 1H), 2.88 (s,
3H), 2.51−2.44 (m, 1H), 2.35−2.25 (m, 1H), 1.98−1.90 (m, 2H),
1.75−1.67 (m, 1H), 0.85 (s, 9H), 0.09 (s, 9H), 0.01 (s, 6H); 13C NMR
H
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The Journal of Organic Chemistry
Article
(75 MHz, CDCl3) δ 171.1, 104.8, 88.5, 61.0, 46.8, 41.5, 34.8, 31.7,
29.6, 27.4, 26.0, 18.3, 0.1, −5.2, −5.3; LRMS (ESI-OF) m/z (relative
intensity) 368.2 (100%, M + H+); HRMS (ESI-TOF) m/z: [M + H+];
calcd for C19H38NO2Si2 368.2441, found 368.2464.
intensity) 441.2 (100%, M + H+); HRMS (ESI-TOF) m/z: [M + H+];
calcd for C24H37N4O2Si 441.2686, found 441.2684.
(3S,4S)-4-(4-(2-Azidophenyl)-3λ5-buta-2,3-dien-2-yl)-3-(2-
hydroxylethyl)-1-methylpiperidin-2-one (11). In a plastic vial, azide
43 (0.03 g, 0.08 mmol) was dissolved in MeCN (1 mL). HF (8 μL, 0.4
mmol) was added, and the mixture was stirred for 1 h at room
temperature. The reaction mixture was diluted with H2O (5 mL) and
extracted with EtOAc (3 × 5 mL). The combined organic layers were
dried over Na2SO4, filtered, and concentrated under reduced pressure.
Purification of the residue by SiO2 flash column chromatography (20−
80% EtOAc in hexanes) gave alcohol 11 (0.02 g, 79%) as a yellow oil
(1:1 mixture of diastereomers). [α]2D01 = +29.7 (c = 0.04, CH3Cl); IR
(thin film) 3398, 2121, 1620 cm−1; H NMR (300 MHz, CDCl3) δ
7.40−7.20 (m, 1H), 7.19−7.00 (m, 1H), 7.14−7.04 (m, 2H), 6.42 (q, J
= 3.2 Hz, 1H), 4.55 (dd, J = 6.9, 4.8 Hz, 1H), 4.43 (t, J = 6.0 Hz, 1H),
3.79−3.69 (m, 2H), 3.35−3.25 (m, 2H), 2.96−2.93 (m, 2H), 2.85−
2.70 (m, 2H), 2.62−2.54 (m, 1H), 2.01−1.62 (m, 7H); 13C NMR (75
MHz, CDCl3) δ 204.1, 204.0, 173.6, 136.5, 136.4, 128.3, 128.2, 128.1,
128.0, 126.5, 126.4, 125.0, 124.8, 118.7, 103.1, 103.0, 90.7, 90.4, 62.6,
62.4, 49.0, 48.7, 43.2, 42.3, 41.7, 41.3, 34.9, 34.8, 31.1, 30.9, 24.0, 23.7,
17.8, 17.6; LRMS (ESI-TOF) m/z (relative intensity) 327.1 (100%, M
+ H+); HRMS (ESI-TOF) m/z: [M + H+]; calcd for C18H23N4O2
327.1821, found 327.1796.
(3S,4S)-3-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-4-ethynyl-1-
methylpiperidin-2-one (12). To lactam 34 (0.14 g, 0.38 mmol) in
MeOH (4 mL) was added K2CO3 (0.16 g, 1.1 mmol). After stirring for
1 h, the mixture was diluted with H2O (5 mL) and extracted with
EtOAc (3 × 5 mL). The organic layers were combined, dried with
Na2SO4, filtered, and concentrated under reduced pressure. The
residue was purified by SiO2 flash column chromatography with the
indicated eluent. Purification of the residue by SiO2 flash column
chromatography (30% EtOAc in hexanes) gave 12 (0.11 g, 95%) as a
yellow oil. [α]2D0 = +45.8 (c = 0.08, MeOH); IR (thin film) 3230, 1716,
1643; cm−1; 1H NMR (300 MHz, CDCl3) δ 3.74−3.63 (m, 2H), 3.60
(td, J = 11.6, 5.5 Hz, 1H), 3.22−3.10 (m, 1H), 3.09−2.98 (m, 1H),
2.86 (s, 3H), 2.60−2.49 (m, 1H), 2.44−2.34 (m, 1H), 2.05 (d, J = 2.4
Hz, 1H), 1.98−1.90 (m, 2H), 1.66 (m, 1H), 0.81 (s, 9H), 0.01 (s,
6H); 13C NMR (75 MHz, CDCl3) δ 170.8, 82.2, 72.0, 60.8, 46.6, 41.1,
34.8, 31.5, 28.4, 27.2, 25.9, 18.2, −5.3, −5.4; LRMS (ESI-TOF) m/z
(relative intensity) 296.2 (100%, M + H+); HRMS (ESI-TOF) m/z:
[M + H+]; calcd for C16H30NO2Si 296.2046, found 296.2062.
1-(2-Azidophenyl)-3-((3S,4S)-3-((tert-butyldimethylsilyl)oxy)-
ethyl)-1-methyl-2-oxopiperidin-4-yl)prop-2-yn-1-yl Ethyl Carbonate
(35). 2.5 M n-BuLi in hexanes (0.13 mL, 0.32 mmol) was added to
alkyne 12 (0.10 g, 0.32 mmol) in THF (4.6 mL) at −78 °C. After 1 h,
2-azidobenzaldehyde (52 mg, 0.35 mmol) in THF (1.2 mL) was added
dropwise, and the solution was warmed to 0 °C. Ethyl chloroformate
(33 μL, 0.35 mmol) was added 2.5 h later, and the reaction mixture
was allowed to warm to room temperature. Upon consumption of the
intermediate alcohol (determined by TLC), the reaction was diluted
with saturated NH4Cl solution (15 mL) and extracted with Et2O (3 ×
10 mL). The organic layers were combined, dried over Na2SO4,
filtered, and concentrated under reduced pressure. Purification of the
residue by SiO2 flash column chromatography (20% EtOAc in
hexanes) gave azide 35 (0.14 g, 86%) as a yellow oil. [α]2D0 = +34.0 (c
= 0.13, CHCl3); IR (thin film) 2126, 1749, 1644 cm−1; 1H NMR (300
MHz, CDCl3) δ 7.57 (d, J = 7.9 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H),
7.15−7.11 (m, 2H), 6.45 (s, 1H), 4.19 (q, J = 7.0 Hz, 2H) 3.76−3.68
(m, 2H), 3.65−3.53 (m, 1H), 3.21−3.13 (m, 2H), 2.88−2.86 (m, 3H),
2.68−2.50 (m, 1H), 2.42−2.31 (m, 1H), 2.04−1.93 (m, 2H), 1.78−
1.62 (m, 1H), 1.28 (t, J = 7.1 Hz, 3H), 0,84 (s, 9H), 0.01 (s, 6H); 13C
NMR (75 MHz, CDCl3) δ 170.8, 154.0, 137.9, 130.6, 129.4, 129.2,
127.5, 125.0, 118.3, 87.0, 79.5, 64.5, 60.9, 46.7, 41.4, 34.8, 31.7, 28.9,
27.2, 25.9, 18.2, 14.3, −5.2, −5.3; LRMS (ESI-TOF) m/z (relative
intensity) 515.2 (100%, M + H+); HRMS (ESI-TOF) m/z: [M + H+];
calcd for C26H39N4O5Si 515.2690, found 515.2667.
(1R,4aS,8aS)-1-(1H-Indol-2-yl)-1,6-dimethylhexahydro-1H-
pyrano[4,3-c]pyridine-5(3H)-one (9). Method A: Following General
Procedure 10, azide 11 (10 mg, 0.031 mmol) in MeCN was brought to
90 °C and held there for 24 h. The residue was purified by SiO2 flash
column chromatography (50−80% EtOAc in hexanes) to give indole 9
(5.7 mg, 63%) as a yellow oil. Method B: The allenyl azide 11 (0.10 g,
0.31 mmol) in MeCN (62 mL) was irradiated at 254 nm for 2 h. The
residue was concentrated under reduced pressure and purified by SiO2
flash column chromatography (50−80% EtOAc in hexanes) to give
indole 9 (0.09 g, 99%) as a yellow oil. [α]2D0 = +22.8 (c = 0.04,
CH3Cl); IR (thin film) 3275, 1626 cm−1; 1H NMR (400 MHz,
CDCl3) δ 8.72 (s, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.35 (d, J = 7.6 Hz,
1H), 7.17 (t, J = 7.1 Hz, 1H), 7.08 (t, J = 6.9 Hz, 1H), 6.37 (s, 1H),
3.85−3.70 (m, 1H), 3.46−3.40 (m, 3H), 3.12−3.00 (m, 1H), 2.97 (s,
3H), 2.57 (d, J = 12.5 Hz, 1H), 2.31−2.10 (m, 1H), 2.09−1.95 (m,
1H), 1.85−1.71 (m, 3H), 1.48 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 172.1, 141.0, 136.1, 128.3, 122.1, 120.5, 119.8, 110.8, 100.5, 74.5,
63.2, 49.2, 38.7, 37.1, 34.6, 29.0, 25.2, 18.8; LRMS (ESI-TOF) m/z
(relative intensity) 299.2 (100%, M + H+); HRMS (ESI-TOF) m/z:
[M + H+]; calcd for C18H23N2O2 299.1760, found 299.1747.
(3S,4S)-4-(1H-Indol-2-yl)vinyl)3-(2-((tert-butyldimethylsilyl)oxy)-
ethyl)-1-methylpiperidin-2-one (42). Following General Procedure
10, azide 43 (0.21 g, 0.46 mmol) in MeCN was heated to 90 °C and
held there for 30 h. The residue was purified by alumina flash column
chromatography (100% hexanes to 30% EtOAc in hexanes) to give
indole 42 (0.15 mg, 77%) as a light yellow foam. [α]2D0 = −21.6 (c =
(3S,4S)-4-(4-(2-Azidophenyl)-3λ5-buta-2,3-dien-2-yl)-3-(2-((tert-
butyldimethylsilyl)oxy)ethyl)-1-1-methylpiperidin-2-one (43). 3 M
methylmagnesium bromide in Et2O (0.20 mL, 0.60 mmol) was added
to copper iodide (0.12 g, 0.60 mmol) and lithium bromide (52 mg,
0.60 mmol) in THF (7 mL) at 0 °C. After stirring for 30 min at room
temperature, alkyne 35 (0.03 g, 0.06 mmol) in THF (0.6 mL) was
added to the mixture. After 30 min at room temperature, the solution
was washed with saturated NH4Cl solution (3 × 10 mL) and H2O (3
× 10 mL). The organic layer was dried over Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified by
SiO2 flash column chromatography (20−30% EtOAc in hexanes) to
give azide 43 (23 mg, 87%) as a yellow oil (2:1 mixture of
diastereomers). [α]2D0 = +39.8 (c = 0.09, CH3Cl); IR (thin film) 2123,
1716, 1643 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.32−7.26 (m, 1H),
7.24−7.19 (m, 1H), 7.12−7.03 (m, 2H), 6.42−6.40 (m, 1H), 3.83−
3.76 (m, 2H), 3.29−3.21 (m, 2H), 2.87 (s, 3H, minor isomer), 2.72 (s,
3H, major isomer), 2.98−2.59 (m, 2H), 1.93−1.70 (m, 7H), 0.90−
0.79 (m, 9H), 0.08−0.04 (m, 6H); 13C NMR (75 MHz, CDCl3) δ
204.1, 203.9, 172.4, 172.3, 136.3, 136.2, 128.2, 128.0, 127.9, 126.7,
126.6, 124.9, 124.7, 118.6, 118.5, 103.5, 103.2, 90.3, 89.9, 61.8, 61.7,
48.5, 48.3, 40.7, 40.6, 39.9, 39.4, 34.5, 34.4, 31.7, 31.2, 26.1, 26.0, 24.1,
23.9, 18.4, 18.3, 17.7, 17.5, −5.2(3); LRMS (ESI-TOF) m/z (relative
1
0.05, CH3Cl); mp 46−50 °C; IR (thin film) 3280, 1622 cm−1; H
NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 7.55 (d, J = 7.8 Hz, 1H),
7.32 (d, J = 8.1 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 7.08 (t, J = 7.4 Hz,
1H), 6.55 (s, 1H), 5.53 (s, 1H), 4.97 (s, 1H), 3.69−3.56 (m, 2H),
3.39−3.33 (m, 3H), 2.94 (s, 3H), 2.90−2.80 (m, 1H), 2.07−2.04 (m,
2H), 2.03−1.90 (m, 1H), 1.80−1.62 (m, 1H), 0.79 (s, 9H), 0.09 (s,
6H); 13C NMR (75 MHz, CDCl3) δ 172.9, 138.7, 137.3, 136.6, 128.7,
122.8, 120.8, 120.0, 110.8, 110.4, 101.0, 61.9, 48.1, 40.8, 39.1, 34.8,
31.1, 26.0, 25.0, 18.3, −5.3; LRMS (ESI-TOF) m/z (relative intensity)
413.1 (100%, M + H+); HRMS (ESI-TOF) m/z: [M + H+]; calcd for
C24H37N2O2Si 413.2624, found 413.2641.
(1S,5S,13S)-13-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-2-methyl-6-
methylene-1,2,3,4,5,6-hexahydro-1,5-methano[1,3]diazocino[1,8-
a]indole (40) and (1S,5S,12S)-12-(2-((tert-Butyldimethylsilyl)oxy)-
ethyl)-2-methyl-6-methylene-2,3,4,5,6,7-hexahydro-1H-1,5-
methanodiazocino[4,3-b]indole (44). Lactam 42 (0.09 g, 0.2 mmol)
in THF (2 mL) was added to the Schwartz reagent (0.11 g, 0.44
mmol). Once the mixture became clear, it was heated to 70 °C for 14
h. Purification of the residue by alumina flash chromatography (10%
EtOAc in hexanes to 100% EtOAc) of the residue gave N-cyclized
I
DOI: 10.1021/acs.joc.6b00348
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The Journal of Organic Chemistry
Article
product 44 (34 mg, 39%) and C-cyclized produce 40 (33 mg, 38%) as
yellow oils.
(12) Xu, C.; Xu, M.; Jia, Y.; Li, C. Org. Lett. 2011, 13, 1556−1559.
(13) Maclean, D.; Hale, R.; Chen, M. Org. Lett. 2001, 3, 2977−2980.
44: [α]2D0 = −53.6 (c = 0.01, CHCl3); IR (thin film) cm−1 3274,
1
1768; H NMR (300 MHz, CDCl3) δ 7.57 (d, J = 7.8 Hz, 1H), 7.39
(d, J = 8.1 Hz, 1H), 7.19−7.00 (m, 2H), 6.72 (s, 1H), 5.85 (s, 1H),
5.18 (s, 1H), 5.05 (s, 1H), 3.56 (t, J = 6.1 Hz, 1H), 2.77 (m, 1H),
2.54−2.47 (m, 2H), 2.34 (s, 3H), 2.22−2.12 (m, 3H), 1.85−1.75 (m,
1H), 1.25−1.17 (m, 2H), 0.87 (s, 9H), 0.0 (s, 6H); 13C NMR (125
MHz, CDCl3) δ 138.5, 128.1, 121.6, 120.4, 199.9, 111.3, 110.1, 95.7,
70.9, 61.7, 46.0, 44.3, 39.2, 38.6, 34.9, 33.6, 26.1, 18.4, 1.13, −5.3;
LRMS (ESI-TOF) m/z (relative intensity) 397.1 (100%, M + H+);
HRMS (ESI-TOF) m/z: [M + H+]; calcd for C24H37N2OSi 397.2675,
found 397.2667.
40: [α]2D0 = +45.5 (c = 0.01, CHCl3); IR (thin film) cm−1 3227,
1611; 1H NMR (300 MHz, CDCl3) δ 8.17 (s, 1H), 7.54 (d, J = 7.8 Hz,
1H), 7.34 (d, J = 8.0 Hz, 1H), 7.15 (td, J = 7.5, 1.1 Hz, 1H), 7.10 (td, J
= 6.9, 1.0 Hz, 1H), 5.17 (s, 1H), 4.93 (s, 1H), 3.97 (s, 1H), 3.77 (t, J =
6.2 Hz, 1H), 2.69−2.59 (m, 1H), 2.50−2.45 (m, 1H), 2.29−2.16 (m,
7H), 2.11−1.88 (m, 2H), 1.40 (d, J = 13.0 Hz, 1H), 0.87 (s, 9H), 0.04
(s, 6H); 13C NMR (125 MHz, CDCl3) δ 142.2, 136.6, 135.9, 128.7,
122.8, 120.0, 119.8, 110.9, 104.6, 62.0, 55.8, 46.5, 45.0, 39.7, 38.9, 34.0,
28.9, 26.1, 25.9, 18.5, −5.2; LRMS (ESI-TOF) m/z (relative intensity)
397.2 (100%, M + H+); HRMS (ESI-TOF) m/z: [M + H+]; calcd for
C24H37N2OSi 397.2675, found 397.2656.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.6b00348.
■
S
General methods; copies of 1H spectra for 17 and 18; 1H
NMR and 13C NMR spectra for 9, 11, 12, 15, 19−22,
23a/b−28a/b, 30a/b−32a/b, 30c, 34, 35, 40, 42−44;
and HMBC, HSQC, COSY, NOESY of 9 and 12 (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: ksf@chem.psu.edu.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the Chemical Synthesis Division of the National
Science Foundation for funding (CHE1361260).
■
REFERENCES
■
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