Synthesis of cyclopentenimines from N-allyl ynamides via a tandem aza-Claisen rearrangement-carbocyclization sequence

Article abstract of DOI:10.1021/jo400960e

We describe here details of our investigations into Pd-catalyzed and thermal aza-Claisen-carbocyclizations of N-allyl ynamides to prepare a variety of α,β-unsaturated cyclopentenimines. The nature of the ynamide electron-withdrawing group and β-substituent plays critical roles in the success of this tandem cascade. With N-sulfonyl ynamides, the use of palladium catalysis is required, as facile 1,3-sulfonyl shifts dominate under thermal conditions. However, since no analogous 1,3-phosphoryl shift is operational, N-phosphoryl ynamides could be used to prepare similar cyclopentenimines under thermal conditions through zwitter ionic intermediates that undergo N-promoted H-shifts. Alternatively, by employing ynamides bearing tethered carbon nucleophiles, the zwitter ionic intermediates could be intercepted, giving rise rapidly to more complex fused bi- and tricyclic scaffolds.

Full text of DOI:10.1021/jo400960e

Article
pubs.acs.org/joc
Synthesis of Cyclopentenimines from N‑Allyl Ynamides via a Tandem
Aza-Claisen Rearrangement−Carbocyclization Sequence
Xiao-Na Wang,† Gabrielle N. Winston-McPherson,† Mary C. Walton,† Yu Zhang,† Richard P. Hsung,*,†
and Kyle A. DeKorver*,‡
†Division of Pharmaceutical Sciences and Department of Chemistry, 777 Highland Avenue, University of Wisconsin, Madison,
Wisconsin 53705-2222, United States
‡Dow AgroSciences, LLC, 9330 Zionsville Road, Indianapolis, Indiana 46268, United States
S
* Supporting Information
ABSTRACT: We describe here details of our investigations into Pd-
catalyzed and thermal aza-Claisen−carbocyclizations of N-allyl ynamides
to prepare a variety of α,β-unsaturated cyclopentenimines. The nature of
the ynamide electron-withdrawing group and β-substituent plays critical
roles in the success of this tandem cascade. With N-sulfonyl ynamides,
the use of palladium catalysis is required, as facile 1,3-sulfonyl shifts
dominate under thermal conditions. However, since no analogous 1,3-
phosphoryl shift is operational, N-phosphoryl ynamides could be used to
prepare similar cyclopentenimines under thermal conditions through
zwitter ionic intermediates that undergo N-promoted H-shifts.
Alternatively, by employing ynamides bearing tethered carbon
nucleophiles, the zwitter ionic intermediates could be intercepted, giving
rise rapidly to more complex fused bi- and tricyclic scaffolds.
Scheme 1. Initial Discovery of a Pd-Catalyzed
Carbocyclization
INTRODUCTION
■
We have been involved with the chemistry of ynamides for the
last 17 years, and this burgeoning field has attracted an
immense amount of attention from the synthetic community in
recent decade.1−3 In our own effort during the past several
years, we have been heavily interested in using Pd-catalyzed and
thermal aza-Claisen4,5 rearrangements as a means of activating
N-allyl ynamides toward (1) nucleophilic additions of amines6
and alcohols,7 (2) inter-8 and intramolecular9 [2 + 2]
cycloaddition reactions, (3) skeletal rearrangements yielding
nitriles,6c and (4) carbocyclizations10 and cationic polyene
cascades.
We previously reported the initial discovery of a tandem
cascade of Pd-catalyzed aza-Claisen rearrangement and
carbocyclization of TIPS-terminated N-allyl ynamide 1 to
cyclopentenimine6b 3 upon exposure to 5 mol % Pd(PPh3)4
[Scheme 1]. Interestingly, our only success in achieving this
transformation was using TIPS-terminated ynamides; alkyl and
aryl-terminated ynamides underwent facile 1,3-sulfonyl shifts to
generate quaternary nitriles 5.6b,c Furthermore, we demon-
strated that the pathway leading to cyclopenteimine 3 involved
tautomeric Pd-π-allyl ynamide and ketenimine complexes 2a
and 2b, as treatment of the isolable TIPS-ketenimine11 4 to
either Pd(0) or thermal conditions gave no cyclopentenimine
3. We wish to disclose here details of this Pd-catalyzed or
thermal aza-Claisen−carbocyclization sequence using N-allyl
ynamides and the impact of the ynamide electron-withdrawing
group and β-substituents on this tandem cascade.
RESULTS AND DISCUSSION
■
While attempting to render the 1,3-sulfonyl shift leading to
nitrile formation diastereoselective, we uncovered a fascinating
reaction dichotomy with γ-branched ynamides. Upon heating
ynamide 6 in toluene at 110 °C, nitrile 7 was isolated in near
quantitative yield, albeit with modest diastereoselectivity6c
[Scheme 2]. Alternatively, treatment of 6 with 5 mol %
Pd(PPh-3)4 gave cyclopentenimine 8 in 69% yield, and nitrile 7
Received: May 6, 2013
© XXXX American Chemical Society
A
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Scheme 2. 1,3-Sulfonyl Shift versus Carbocyclization
Dichotomy
Table 1. Synthesis of α,β-Unsaturated Cyclopentemines
a
from N-Allyl Ynamides
was not found. This represented the first time we had observed
a carbocyclization of a nonsilyl terminated N-sulfonyl ynamide.
We were intrigued by the possibility of using γ-branched
ynamides as carbocyclization precursors and wanted to further
probe the substrate scope. Unfortunately, the preparation of γ-
branched ynamide 6 was problematic [Scheme 3]. It involved
initial silylation of 3-phenyl-propargyl alcohol 9 followed by
bromination to afford 10. The ensuing standard 15 mol %
CuSO4·5H2O and 30 mol % 1,10-phenanthroline-catalyzed
amidative cross-coupling gave 6 in only 12% yield, likely
because of the steric bulk of the alkynyl bromide. We later
discovered that using 20 mol % CuTC and 40 mol % DMEDA
could improve the yield of the cross coupling to 66%. Still,
assessing the reaction scope using this protocol would have
been a lengthy endeavor.
Alternatively, inspired by a report by Saa,12
we found that
́
ynamide 11, which was readily accessible in gram quantities,
could be lithiated using LHMDS and added to aldehydes such
as pivalaldehyde to directly prepare γ-hydroxy-ynamide 12a in
excellent yield [Scheme 3]. The alcohol could then be
functionalized as desired to afford ynamides such as 13a.
This allowed us to expediently and fully explore the scope of
cyclopentenimine formation.
We soon discovered that the substrate scope for the Pd-
catalyzed carbocyclization was quite broad. As shown in Table
1, a variety of functionalized N-allyl-γ-branched ynamides could
be employed in cyclopentenimine synthesis using 5 mol %
Pd(PPh3)4 in toluene at 70 °C. The reaction nicely tolerated t-
Bu, n-hex, c-hex, and even a spirocyclic cyclohexane at the γ-
position. The tolerance for functionality on the alcohol moiety
was equally general, including methyl, silyl, benzyl, and even
trityl protecting groups. Also, both N-Ts and N-Ns containing
ynamides underwent the desired carbocyclization in compara-
ble yields. Notably, this methodology provided a means of
a
Reaction conditions: 5.0 mol % Pd(PPh3)4, toluene [conc = 0.04 M],
b
70 °C, 1 h. Isolated yields.
preparing α,β-unsaturated cyclopentenimines analogous to the
α,β-unsaturated enones from a Baylis−Hillman13 type reaction.
While exploring a potential Staudinger-type [2 + 2]
cycloaddition of N-phosphoryl N-allyl ynamides to give
azetidinimines 26,14 we discovered another case of cyclo-
pentenimine formation [Scheme 4]. When a mixture of N-
phosphoryl ynamide 25 and N-benzylidineaniline was subjected
to 5 mol % Pd2(dba)3 and 10 mol % xantphos, conditions
which favor reductive elimination of the intermediate Pd-π-allyl
Scheme 3. Preparation of γ-Branched Ynamides
B
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allyl complex was isolated [Scheme 6]. Also, heating of 32 to
185−190 °C for two days did not result in any formation of
31e.
Scheme 4. Unexpected Carbocyclization of an N-Phosphoryl
Ynamide
Scheme 6. Mechanistic Studies Employing an Isolable TIPS-
Ketenimine
ketenimine in our hands, the major product by 1H NMR using
phenanthrene as an internal standard was cyclopentenimine 27.
This was the first time we had observed the carbocyclization of
a phenyl-terminated ynamide. In the analogous phenyl-
terminated N-sulfonyl ynamide, the 1,3-sulfonyl shift leading
to nitriles dominated the carbocyclization pathway. However,
because there was no competing 1,3-phosphoryl shift, heating
of N-phosphoryl ynamide 25 to 125 °C in toluene led to
cyclopentenimine 27 in an isolated 50% yield.
Collectively, the experimental evidence indicated that the
carbocyclization mechanisms for N-sulfonyl and N-phosphoryl
ynamides, even under Pd-catalysis, were unique [Scheme 7].
We soon found that the yield of cyclopentenimine 27 could
be increased to 87% yield using 5 mol % Pd(PPh3)4 in toluene
at 70 °C [Scheme 5]. Ynamides 30b and 30c bearing terminal
Scheme 7. Unique Carbocyclization Pathways for N-Sulfonyl
and N-Phosphoryl Ynamides
Scheme 5. Pd-Catalyzed versus Thermal Carbocyclizations
of N-Phosphoryl Ynamides
We propose that the carbocyclization of N-sulfonyl ynamides
33 occurs through Pd-π-allyl ketenimines 34b via a
Rautenstrauch rearrangement.15,16 In contrast, it seems that
the carbocyclization of N-phosphoryl ynamides 36 occurs
through ketenimine 37 under both palladium-catalyzed and
thermal conditions because of the lack of a competing 1,3-
phosphoryl shift. Following the carbocyclization17,18 that
generates zwitter ionic intermediate 38, a N-promoted 1,2-H
shift gives cyclopentenimine 39.
We were especially excited by the discovery that N-
phosphoryl ynamides participated in the carbocyclization
without the need for palladium catalysis, thereby avoiding any
potential scrambling6b of the allyl moiety through the Pd-π-allyl
intermediates. In suitably substituted N-phosphoryl ynamides,
we demonstrated that N-promoted Meerwein−Wagner alkyl
shifts could compete with the 1,2-H shift leading to fused or
spiro bicyclic products.10 In addition to exploiting the zwitter
ionic intermediates via N-promoted ring expansions and
contractions, we envisioned the possibility of intercepting19
the intermediates with tethered nucleophiles to prepare a
variety of bicyclic scaffolds such as 43a−43c [Scheme 8].
a
b
Isolated yield. 135−140 °C, 14 h.
n-hexyl and TBS-ether moieties were also tolerated using both
thermal and Pd-catalyzed conditions, though the yields were
slightly diminished. Interestingly, the Pd-catalyzed carbocycliza-
tion of γ-branched ynamide 30d was sluggish, giving <10%
yield of the desired cyclopentenimine. The yield could be
improved to 69% by heating to 135 °C in toluene. The
difference in reactivity of γ-branched N-sulfonyl and N-
phosphoryl ynamides under Pd-catalyzed conditions was the
first indication that the carbocyclization pathways may be
different.
Furthermore, treatment of TIPS-terminated N-phosphoryl
ynamide 30e with 5 mol % Pd(PPh3)4 led to no discernible
formation of cyclopentenimine 31e; only ketenimine 32
resulting from reductive elimination of the intermediate Pd-π-
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In addition, we had previously demonstrated that geranyl-
tethered ynamides such as 51 could be used in thermal
carbocyclization cascades to prepare a readily separable mixture
of cis-fused bicycle 52 as a 9:1 mixture of alkene isomers and
tricycle 53 [Scheme 10].10
Scheme 8. Potential Carbocyclization Cascades of N-
Phosphoryl Ynamides
Working from our success thus far in developing
carbocyclization cascades20,21 of geranyl-tethered ynamides,
we wondered if we could extend the cyclization to include
farnesyl-tethered ynamides. The ynamide synthesis is straight-
forward and outlined in Scheme 11. Following a literature
procedure,22 farnesol amine 55 could be prepared from farnesol
54 in 97% over two steps. Then, phosphorylation of farnesol
amine gave 56, which could be subjected to our optimized
amidative cross-coupling conditions to yield TIPS-terminated
ynamide 57 in 65% yield. TBAF-mediated desilylation gave the
terminally unsubstituted ynamide 58, which could then be
lithiated and quenched with MeI to prepare the desired
farnesyl-tethered ynamide 59.
With ynamide 59 in hand, we were able to investigate the
outcome of the intended polyene carbocyclization cascade. As
described in Scheme 12, our hypothesis was that a facile 1,2-H
shift could occur to allow equilibration between carbocationic
intermediates 61a and 61b, which may be followed by a third
cyclization to afford tricycle 64. Unfortunately, when ynamide
59 was heated to 135 °C in toluene, only bicycle 62 resulting
from elimination of 61a and tricycle 63 resulting from a formal
[4 + 2] cycloaddition could be found.
Our initial attempts at trapping the zwitter ionic
intermediates employed tethered carbon nucleophiles, thereby
eliminating any undesired side reactions such as amidine6 or
imidate7 formation. When ynamide 44 featuring a tethered
benzene ring was heated to 135 °C in toluene, only
cyclopentenimine 48 resulting from a 1,2-H shift through 47
was isolated [Scheme 9]. To allow the nucleophilic addition to
Scheme 9. Carbocyclization Cascade vs 1,2-H Shift
CONCLUSIONS
■
We have described here a fascinating study of Pd-catalyzed and
thermal carbocyclizations of N-sulfonyl and N-phosphoryl
ynamides to prepare α,β-unsaturated cyclopentenimines. In
the case of N-sulfonyl ynamides, the use of palladium catalysis
is necessary, as the carbocyclization occurs through Pd-π-allyl
complexes via a Rautenstrach rearrangement; with N-
phosphoryl ynamides, thermal conditions may be employed
to yield cyclopentenimines via N-promoted 1,2-H shifts
through zwitter ionic intermediates. We also demonstrated
the ability to intercept the zwitter ionic intermediates with
tethered alkenyl and aryl nucleophiles to prepare a variety of
fused bicyclic and tricyclic scaffolds.
EXPERIMENTAL SECTION
■
All reactions were performed in flame-dried glassware under a nitrogen
atmosphere. Solvents were distilled prior to use. Chromatographic
separations were performed using 60 Å SiO2. 1H and 13C NMR spectra
were obtained on spectrometers using CDCl3 with TMS or residual
solvent as standard unless otherwise noted. Infrared spectra were
obtained on FTIR, and relative intensities are expressed qualitatively as
s (strong), m (medium), and w (weak). TLC analysis was performed
using 254 nm polyester-backed plates (60 Å, 250 μm) and visualized
using UV and a suitable chemical stain. Low-resolution mass spectra
were obtained using LC/MSD and APCI.
occur, it was clear that we needed to slow the 1,2-H shift. By
introducing a methyl at R1 and tethering a more electron-rich
m-methoxy benzene, ynamide 45 cleanly underwent the desired
thermal aza-Claisen/Friedel−Craft electrophilic aromatic sub-
stitution reaction sequence to give 50 in 85% yield as a mixture
of cis and trans isomers at the ring juncture.10
Scheme 10. Carbocyclization Cascade of Geranyl-Tethered Ynamides
D
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Scheme 11. Synthesis of a Farnesyl Tethered Ynamide
Scheme 12. Attempted Carbocyclization Cascade of Farnesol-Tethered Ynamide 59
General Procedure for the Preparation of γ-Hydroxy-
ynamides. To a flame-dried 50-mL RB-flask was added ynamide 11
(470.0 mg, 2.00 mmol) and THF (20 mL). The solution was cooled to
−78 °C [− 50 °C works equally well], and LHMDS (3.0 mL, 3.0
mmol, 1 M in THF) was added dropwise over ∼1 min. The reaction
mixture was stirred at −78 °C [or −50 °C] for 1 h to ensure complete
lithiation of the ynamide, and then pivalyl aldehyde was added
dropwise over ∼1 min. After 20 min, the cooling bath was removed,
and the reaction was allowed to come to rt. The reaction was
monitered by TLC, and when progress appeared to be complete after
∼2 h, the mixture was diluted with EtOAc (20 mL) and quenched
with water (15 mL). The phases were separated, and the aqueous
phase extracted with EtOAc (20 mL) once. The organic phases were
combined, washed with brine, dried over Na2SO4, and concentrated by
rotary evaporation. The crude residue was purified by flash silica gel
column chromatography (isocratic eluent: 4:1 hexanes/EtOAc + 2%
NEt3 [to buffer the column]) to afford the γ-hydroxy-ynamide 12a
(656.0 mg, 2.00 mmol, ≥95%) as a colorless oil.
(QTOF MS ESI) m/e calcd for C17H23NO3SNa [M + Na]+ 344.1291,
found 344.1307.
12b: (413.2 mg, 79%); (Rf = 0.28 [3:1 hexanes:EtOAc]; pale yellow
oil; 1H NMR (400 MHz, CDCl3) δ 0.90 (t, 3H, J = 6.8 Hz), 1.23−1.42
(m, 8H), 1.59−1.73 (m, 2H), 1.87 (brs, 1H), 2.45 (s, 3H), 3.95 (ddt,
1H, J = 1.2, 6.4, 14.4 Hz), 4.01 (ddt, 1H, J = 1.2, 6.4, 14.4 Hz), 4.48 (t,
1H, J = 6.8 Hz), 5.22 (dq, 1H, J = 1.6, 10.0 Hz), 5.26 (dq, 1H, J = 1.6,
16.4 Hz), 5.77 (ddt, 1H, J = 6.4, 10.0, 16.4 Hz), 7.35 (d, 2H, J = 8.4
Hz), 7.80 (d, 2H, J = 8.4 Hz); 13C NMR (100 MHz, CDCl3) δ 14.2,
21.8, 22.7, 25.3, 29.1, 31.9, 38.0, 54.3, 62.8, 72.4, 78.2, 120.2, 127.9,
129.9, 131.0, 134.8, 144.8; IR (film) cm−1 3376brm, 2925m, 2857m,
2243m, 1597m, 1494w, 1466m, 1419m, 1364s; mass spectrum (ESI)
m/e (% relative intensity) 364 (100) (M − H2O + MeOH + H)+;
HRMS (QTOF MS ESI) m/e calcd for C19H27NO3SNa 372.1604,
found 372.1612.
12c: (211.0 mg, 81%); Rf = 0.21 [3:1 hexanes/EtOAc]; colorless
1
oil; H NMR (400 MHz, CDCl3) δ 0.97−1.33 (m, 6H), 1.64−1.83
(m, 5H), 2.45 (s, 3H), 3.94 (ddt, 1H, J = 1.2, 5.6, 14.0 Hz), 3.99 (ddt,
1H, J = 1.2, 5.6, 14.0 Hz), 4.26 (d, 1H, J = 4.0 Hz), 5.21 (dq, 1H, J =
1.4, 7.2 Hz), 5.25 (dq, 1H, J = 1.4, 14.0 Hz), 5.73 (ddt, 1H, J = 6.4,
10.4, 16.8 Hz), 7.34 (d, 2H, J = 8.4 Hz), 7.79 (d, 2H, J = 8.4 Hz); 13C
NMR (100 MHz, CDCl3) δ 21.8, 26.0, 26.1, 26.5, 28.2, 28.8, 44.5,
54.3, 67.5, 71.4, 78.9, 120.2, 127.9, 129.9, 131.1, 134.8, 144.9; IR (film)
cm−1 2925m, 2853m, 2244m, 1597w, 1364s; mass spectrum (ESI) m/e
(% relative intensity) 362 (100) (M − H2O + MeOH + H)+. HRMS
(TOF MS ESI) m/e calcd for C19H26NO3S [M + H]+ 348.1628, found
348.1639.
12a: (656.0 mg, ≥95%); Rf = 0.27 [3:1 hexanes:EtOAc]; colorless
1
oil; H NMR (500 MHz, CDCl3) δ 0.95 (s, 9H), 2.45 (s, 3H), 3.96
(dq, 2H, J = 1.5, 6.5 Hz), 4.11 (brs, 1H), 5.21 (dq, 1H, J = 1.5, 10.0
Hz), 5.24 (dq, 1H, J = 1.5, 17.0 Hz), 5.72 (ddt, J = 6.5, 10.0, 17.0 Hz),
7.34 (d, 2H, J = 8.0 Hz), 7.79 (d, 2H, J = 8.0 Hz); 13C NMR (100
MHz, CDCl3) δ 21.8, 25.6, 36.4, 54.3, 71.0, 71.7, 78.1, 120.2, 127.9,
129.9, 131.1, 134.9, 144.9; IR (film) cm−1 3519brm, 2956m, 2869w,
2244m, 1597m, 1478m, 1462m, 1362s; mass spectrum (ESI) m/e (%
relative intensity) 336 (100) (M − H2O + MeOH + H)+; HRMS
E
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12d: (184.0 mg, 65%); Rf = 0.30 [3:1 hexanes/EtOAc]; orange oil;
1H NMR (400 MHz, CDCl3) δ 0.97−1.30 (m, 4H), 1.50−1.57 (m,
2H), 1.66−1.84 (m, 5H), 4.02 (ddt, 1H, J = 1.2, 6.4, 14.4 Hz), 4.07
(ddt, 1H, J = 1.2, 6.4, 14.4 Hz), 4.28 (t, 1H, J = 5.6 Hz), 5.25 (dq, 1H,
J = 1.2, 10.4 Hz), 5.28 (dq, 1H, J = 1.2, 16.8 Hz), 5.72 (ddt, 1H, J =
6.4, 10.4, 16.8 Hz), 8.10 (d, 2H, J = 9.2 Hz), 8.40 (d, 2H, J = 9.2 Hz);
13C NMR (100 MHz, CDCl3) δ 25.9, 26.0, 26.5, 28.2, 28.7, 44.4, 54.7,
67.3, 72.1, 77.6, 120.9, 124.5, 129.1, 130.3, 143.2, 150.8; IR (film)
cm−1 3401brm, 2928m, 2854m, 2247m, 1532s, 1372s; mass spectrum
(APCI) m/e (% relative intensity) 393 (100) (M − H2O + MeOH +
H)+.
12e: (55.4 mg, 58%); Rf = 0.25 [3:1 hexanes/EtOAc]; pale yellow
oil; 1H NMR (400 MHz, CDCl3) δ 0.89 (t, 3H, J = 7.2 Hz), 1.22−1.44
(m, 8H), 1.61−1.76 (m, 2H), 1.80 (brs, 1H), 4.01 (ddt, 1H, J = 1.2,
6.4, 14.8 Hz), 4.05 (ddt, 1H, J = 1.2, 6.4, 14.8 Hz), 4.49 (t, 1H, J = 6.4
Hz), 5.24 (dq, 1H, J = 1.2, 10.4 Hz), 5.27 (dq, 1H, J = 1.2, 16.8 Hz),
5.72 (ddt, 1H, J = 6.4, 10.4, 16.8 Hz), 8.10 (d, 2H, J = 9.2 Hz), 8.41 (d,
2H, 9.2 Hz); 13C NMR (100 MHz, CDCl3) δ 14.3, 22.8, 25.4, 29.1,
32.0, 38.1, 54.8, 62.7, 73.3, 77.0, 121.0, 124.6, 129.2, 130.3, 143.2,
150.9; IR (film) cm−1 3379brm, 2928m, 2858m, 2246m, 1607s, 1348s;
mass spectrum (APCI) m/e (% relative intensity) 395 (100) (M −
H2O + MeOH + H)+; HRMS (QTOF MS ESI) m/e calcd for
C18H24N2O5SNa 403.1298, found 403.1292.
residue was purified by flash silica gel column chromatography
(isocratic eluent: 15:1 hexanes/EtOAc + 2% NEt3 [to buffer the
column]) to afford ynamide 13b (86.0 mg, 0.256 mmol, 86%). Note:
For displacement of alkyl bromides, DMF was used as the solvent. During
workup, the organic phase was washed with brine 5 times to remove DMF.
13b: (86.0 mg, 86%); Rf = 0.16 [15:1 hexanes/EtOAc]; colorless
oil; 1H NMR (500 MHz, CDCl3) δ 0.94 (s, 9H), 2.45 (s, 3H), 3.31 (s,
3H), 3.63 (s, 1H), 3.94 (ddt, 1H, J = 1.0, 6.5, 14.5 Hz), 4.01 (ddt, 1H,
J = 1.0, 6.5, 14.5 Hz), 5.21 (dq, 1H, J = 1.0, 10.0 Hz), 5.24 (dq, 1H, J =
1.0, 17.0 Hz), 5.74 (ddt, 1H, J = 6.5, 10.0, 17.0 Hz), 7.33 (d, 2H, J =
8.0 Hz), 7.79 (d, 2H, J = 8.0 Hz); 13C NMR (125 MHz, CDCl3) δ
21.9, 26.1, 36.0, 54.5, 57.3, 68.9, 79.5, 81.1, 120.2, 128.0, 129.9, 131.3,
135.0, 144.9; IR (film) cm−1 2956m, 2926m, 2820w, 2240m, 1597w,
1366s; mass spectrum (APCI) m/e (% relative intensity) 336 (100)
(M + H)+; HRMS (QTOF MS ESI) m/e calcd for C18H25NO3SNa [M
+ Na]+ 358.1447, found 358.1447.
Ynamide 13c was prepared from 12a following the general
procedure for alkylation.
13c: (98.0 mg, 79%); Rf = 0.17 [15:1 hexanes/EtOAc]; colorless
oil; 1H NMR (500 MHz, CDCl3) δ 0.96 (s, 9H), 2.41 (s, 3H), 3.78 (s,
1H), 3.95 (ddt, 1H, J = 1.0, 6.5, 14.5 Hz), 4.01 (ddt, 1H, J = 1.0, 6.5,
14.5 Hz), 4.38 (d, 1H, J = 12.0 Hz), 4.68 (d, 1H, J = 12.0 Hz), 5.22
(dq, 1H, J = 1.0, 10.0 Hz), 5.25 (dq, 1H, J = 1.0, 17.0 Hz), 5.74 (ddt,
1H, J = 6.5, 10.0, 17.0 Hz), 7.24−7.34 (m, 5H), 7.28 (d, 2H, J = 8.0
Hz), 7.79 (d, 2H, J = 8.0 Hz); 13C NMR (125 MHz, CDCl3) δ 21.8,
26.2, 36.0, 54.5, 69.1, 70.7, 77.9, 79.6, 120.3, 127.6, 127.9, 128.0, 128.4,
129.9, 131.3, 135.0, 138.7, 144.9; IR (film) cm−1 2956m, 2867m,
2241m, 1597w, 1495w, 1365s; mass spectrum (APCI) m/e (% relative
intensity) 336 (100) (M − HOBn + MeOH + H)+, 412 (20) (M +
H)+; HRMS (QTOF MS ESI) m/e calcd for C24H29NO3SNa [M +
Na]+ 434.1760, found 434.1759.
12f: (507.9 mg, ≥95%); Rf = 0.38 [4:1 hexanes/EtOAc]; colorless
1
oil; H NMR (400 MHz, CDCl3) δ 1.06−1.16 (m, 1H), 1.30−1.59
(m, 7H), 1.80 (d, 2H, J = 12.4 Hz), 2.36 (s, 3H), 3.10 (s, 1H), 3.86 (d,
2H, J = 6.4 Hz), 5.09−5.17 (m, 2H), 5.58−5.68 (m, 1H), 7.27 (d, 2H,
J = 8.0 Hz), 7.72 (d, 2H, J = 8.4 Hz); 13C NMR (100 MHz, CDCl3) δ
21.3, 23.0, 24.9, 39.7, 53.8, 68.5, 74.1, 77.2, 119.7, 127.5, 129.5, 130.6,
134.2, 144.5; IR (film) cm−1 3496w, 3399w, 2933s, 2857m, 2242m,
1597w, 1447w, 1362s; mass spectrum (APCI) m/e (% relative
intensity) 334 (24) (M + H)+.
Ynamide 14a was prepared from 12b following the general
General Procedure for the Silylation of γ-Hydroxy-yna-
mides. To a flame-dried screw-cap vial was added ynamide 12a (64.8
mg, 0.20 mmol) and CH2Cl2 (0.57 mL, 0.35 M in ynamide). The
solution was cooled to 0 °C, and then imidazole (34.0 mg, 0.50 mmol)
and TBSCl (37.5 mg, 0.25 mmol) were added. The reaction mixture
was allowed to warm to rt. The reaction was monitered by TLC, and
when the starting material was consumed after ∼45 min, the mixture
was diluted with CH2Cl2 (3 mL) and quenched with water (3 mL).
The phases were separated and the aqueous phase extracted with
CH2Cl2 (3 × 5 mL). The organic phases were combined, washed with
brine, dried over Na2SO4, and concentrated by rotary evaporation. The
crude residue was purified by flash silica gel column chromatography
(isocratic eluent: 15:1 hexanes/EtOAc + 2% NEt3 [to buffer the
column]) to afford ynamide 13a (78.0 mg, 0.18 mmol, 89%).
13a: (78.0 mg, 89%); Rf = 0.48 [8:1 hexanes:EtOAc]; pale yellow
oil; 1H NMR (400 MHz, CDCl3) δ 0.02 (s, 3H), 0.04 (s, 3H), 0.86 (s,
9H), 0.91 (s, 9H), 2.44 (s, 3H), 3.97 (d, 2H, J = 6.4 Hz), 4.03 (s, 1H),
5.21 (dd, 1H, J = 1.2, 10.0 Hz), 5.25 (dd, 1H, J = 1.2, 16.8 Hz), 5.77
(ddt, 1H, J = 6.4, 10.0, 16.8 Hz), 7.33 (d, 2H, J = 8.0 Hz), 7.80 (d, 2H,
J = 8.0 Hz); 13C NMR (100 MHz, CDCl3) δ −5.2, −4.3, 18.3, 21.7,
25.7, 25.9, 37.0, 54.4, 71.5, 71.9, 77.7, 120.0, 127.9, 129.8, 131.3, 135.2,
144.6; IR (film) cm−1 2954m, 2929m, 2856m, 2243w, 1598w, 1462m,
1367s, 1292w, 1250m; mass spectrum (ESI) m/e (% relative intensity)
336 (100) (M − OTBS + MeOH + H)+.
General Procedure for the Alkylation of γ-Hydroxy-
ynamides. To a flame-dried screw-cap vial was added ynamide 12a
(96.0 mg, 0.30 mmol) and THF (1.0 mL, 0.3 M in ynamide). The
solution was cooled to 0 °C, and NaH (16.0 mg, 0.39 mmol, 60%
dispersion in mineral oil) was added carefully. The reaction mixture
was stirred at 0 °C for 30 min to ensure complete deprotonation of the
alcohol, and then MeI (24.0 μL, 0.78 mmol) was added dropwise over
∼1 min. After 30 min, the cooling bath was removed, and the reaction
was allowed to come to rt. The reaction was monitered by TLC, and
when progress appeared to be complete after ∼2 h, the mixture was
diluted with EtOAc (3 mL) and quenched with water (3 mL). The
phases were separated, and the aqueous phase extracted with EtOAc
(10 mL) once. The organic phases were combined, washed with brine,
dried over Na2SO4, and concentrated by rotary evaporation. The crude
procedure for alkylation.
14a: (70.0 mg, 96%); Rf = 0.41 [4:1 hexanes/EtOAc]; colorless oil;
1H NMR (400 MHz, CDCl3) δ 0.88 (t, 3H, J = 6.8 Hz), 1.21−1.34
(m, 6H), 1.34−1.43 (m, 2H), 1.58−1.74 (m, 2H), 2.45 (s, 3H), 3.30
(s, 3H), 3.93 (ddt, 1H, J = 1.2, 6.4, 14.4 Hz), 4.01 (ddt, 1H, J = 1.2,
6.4, 14.4 Hz), 4.04 (t, 1H, J = 6.4 Hz), 5.20 (dq, 1H, J = 1.2, 10.0 Hz),
5.24 (dq, 1H, J = 1.2, 16.4 Hz), 5.73 (ddt, 1H, J = 6.4, 10.0, 16.4 Hz),
7.34 (d, 2H, J = 8.4 Hz), 7.79 (d, 2H, J = 8.4 Hz); 13C NMR (100
MHz, CDCl3) δ 14.3, 21.9, 22.8, 25.5, 29.2, 32.0, 36.0, 54.4, 56.3, 70.1,
71.7, 79.1, 120.2, 128.0, 129.9, 131.1, 134.9, 144.9; IR (film) cm−1
2926m, 2858m, 2240m, 1465w, 1367s; mass spectrum (APCI) m/e (%
relative intensity) 364 (100) (M + H)+.
Ynamide 14b was prepared from 12b following the general
procedure for silylation.
14b: (101.0 mg, ≥95%); Rf = 0.56 [4:1 hexanes/EtOAc]; colorless
1
oil; H NMR (500 MHz, CDCl3) δ 0.89 (t, 3H, J = 7.0 Hz), 1.03 (d,
18H, J = 5.0 Hz), 1.05−1.07 (m, 3H), 1.24−1.34 (m, 7H), 1.34−1.47
(m, 3H), 1.66 (td, 2H, J = 6.0, 8.0 Hz), 2.44 (s, 3H), 3.94 (ddt, 1H, J =
1.5, 5.5, 14.0 Hz), 3.98 (ddt, 1H, J = 1.5, 5.5, 14.0 Hz), 4.56 (t, 1H, J =
6.0 Hz), 5.18 (dq, 1H, J = 1.0, 10.0 Hz), 5.22 (dq, 1H, J = 1.0, 17.0
Hz), 5.73 (ddt, 1H, J = 6.5, 10.0, 17.0 Hz), 7.31 (d, 2H, J = 8.0 Hz),
7.77 (d, 2H, J = 8.0 Hz); 13C NMR (125 MHz, CDCl3) δ 12.5, 14.4,
18.0, 18.3, 18.3, 21.9, 22.9, 25.2, 29.3, 32.1, 39.4, 54.5, 63.5, 73.0,
119.9, 128.0, 129.9, 131.4, 135.2, 144.7; IR (film) cm−1 2941s, 2864s,
2242m, 1597w, 1463m, 1369s; mass spectrum (APCI) m/e (% relative
intensity) 364 (100) (M − HOTIPS + MeOH + H)+.
Ynamide 15a was prepared from 12c following the general
procedure for alkylation.
15a: (60.0 mg, 79%); Rf = 0.11 [15:1 hexanes/EtOAc]; colorless
oil; 1H NMR (500 MHz, CDCl3) δ 1.03−1.26 (m, 5H), 1.58 (tdt, 1H,
J = 3.0, 6.0, 12.0 Hz), 1.65 (d, 1H, J = 12.0 Hz, 1H), 1.74 (t, 4H, J =
14.0 Hz), 2.45 (s, 3H), 3.29 (s, 3H), 3.83 (d, 1H, J = 6.0 Hz), 3.94
(dd, 1H, J = 6.5, 14.5 Hz), 4.02 (dd, J = 6.5, 14.5 Hz), 5.22 (dq, 1H, J
= 1.0, 10.0 Hz), 5.25 (dq, 1H, J = 1.0, 17.0 Hz), 5.74 (ddt, 1H, J = 6.5,
10.0, 17.0 Hz), 7.33 (d, 2H, J = 8.0 Hz), 7.79 (d, 2H, J = 8.0 Hz); 13C
NMR (125 MHz, CDCl3) δ 21.9, 26.2, 26.2, 26.7, 28.6, 29.2, 43.0,
54.5, 56.6, 69.1, 76.7, 79.7, 120.2, 128.0, 129.9, 131.2, 134.9, 144.9; IR
F
dx.doi.org/10.1021/jo400960e | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(film) cm−1 2924m, 2853m, 2239m, 1449m, 1367s; mass spectrum
(APCI) m/e (% relative intensity) 362 (M + H)+.
Ynamide 15b was prepared from 12c following the general
13C NMR (100 MHz, CDCl3) δ 21.6, 22.8, 25.4, 36.8, 50.5, 54.1, 71.4,
74.3, 79.3, 119.9, 127.8, 129.6, 130.9, 134.5, 144.6; IR (film) cm−1
2934s, 2857w, 2360w, 2341w, 2240m, 1447m, 1366s; mass spectrum
(APCI) m/e (% relative intensity) 348 (43) (M + H)+; HRMS
(QTOF MS ESI) calcd for C19H25NO3SNa [M + Na]+ 370.1447,
found 370.1450.
procedure for alkylation.
15b: (72.0 mg, 63%); Rf = 0.49 [3:1 hexanes/EtOAc]; white solid;
mp = 62−64 °C; 1H NMR (400 MHz, CDCl3) δ 0.80−1.28 (m, 5H),
1.56−1.84 (m, 6H), 2.42 (s, 3H), 3.95 (ddt, 1H, J = 1.2, 6.4, 14.4 Hz),
3.96 (d, 1H, J = 6.2 Hz), 4.03 (ddt, 1H, J = 1.2, 6.4, 14.4 Hz), 4.53
(ABq, 2H, ΔvAB = 33.6 Hz, JAB = 11.8 Hz), 5.23 (dq, 1H, J = 1.2, 10.0
Hz), 5.26 (dq, 1H, J = 1.2, 17.2 Hz), 5.76 (ddt, 1H, J = 6.4, 10.0, 17.2
Hz), 7.24−7.35 (m, 7H), 7.80 (d, 2H, J = 8.8 Hz); 13C NMR (100
MHz, CDCl3) δ 21.8, 26.1, 26.1, 26.6, 28.7, 29.2, 43.0, 54.4, 69.3, 70.3,
73.9, 79.7, 120.2, 127.6, 127.9, 128.0, 128.4, 129.8, 131.2, 134.8, 138.4,
144.8; IR (film) cm−1 2925m, 2852m, 2243m, 1597w, 1451m, 1363s;
mass spectrum (APCI) m/e (% relative intensity) 362 (100) (M −
BnOH + MeOH + H)+.
General Procedure for the Carbocyclization of γ-Branched-
N-Allyl Ynamides. To a flame-dried screw-cap vial containing 4 Å
MS was added ynamide 6 (50.0 mg, 0.100 mmol), Pd(PPh3)4 (5.8 mg,
0.005 mmol), and toluene (2.5 mL, 0.04 M in ynamide). The vial was
sealed under nitrogen and heated to 70 °C for 1 h, at which time TLC
analysis showed consumption of the starting material. The reaction
mixture was cooled to rt, filtered through Celite and purified by flash
silica gel column chromatography (isocratic eluent: 8:1 hexanes/
EtOAc) to afford cyclopentenimine 8 (34.5 mg, 0.069 mmol) in 69%
yield.
Ynamide 16a was prepared from 12d following the general
procedure for silylation.
8: (34.5 mg, 69%); Rf = 0.11 [8:1 hexanes/EtOAc]; colorless oil;
1H NMR (500 MHz, CDCl3) δ 0.91 (d, 9H, J = 7.0 Hz), 0.94 (d, 9H, J
16a: (81.0 mg, 82%); Rf = 0.57 [3:1 hexanes/EtOAc]; white solid;
mp = 61−62 °C; 1H NMR (400 MHz, CDCl3) δ 0.01 (s, 3H), 0.03 (s,
3H), 0.85 (s, 9H), 0.90−1.30 (m, 6H), 1.45 (dtt, 1H, J = 2.8, 6.2, 18.0
Hz), 1.61−1.79 (m, 4H), 4.00 (ddt, 1H, J = 1.2, 6.2, 14.8 Hz), 4.04
(ddt, 1H, J = 1.2, 6.2, 14.8 Hz), 4.18 (d, 1H, J = 6.0 Hz), 5.22 (dq, 1H,
J = 1.2, 10.4 Hz), 5.25 (dq, 1H, J = 1.2, 16.8 Hz), 5.70 (ddt, 1H, J =
6.4, 10.0, 16.8 Hz), 8.08 (d, 2H, J = 9.2 Hz), 8.37 (d, 2H, J = 9.2 Hz);
13C NMR (100 MHz, CDCl3) δ −5.0, −4.4, 18.3, 25.8, 26.1, 26.1,
26.6, 28.7, 28.7, 45.3, 54.8, 67.8, 72.8, 76.5, 120.8, 124.4, 129.2, 130.5,
143.5, 150.7; IR (film) cm−1 2929m, 2855m, 2248m, 1535s, 1376m,
1349m; mass spectrum (APCI) m/e (% relative intensity) 393 (100)
(M − HOTBS + MeOH + H)+; HRMS (QTOF MS ESI) m/e calcd
for C24H36N2O5SSiNa [M + Na]+ 515.2006, found 515.1992.
Ynamide 16b was prepared from 12d following the general
procedure for silylation, but with Ph3C−Cl (1.3 equiv), NEt3 (2
equiv), and DMAP (0.1 equiv) in CH2Cl2.
= 7.0 Hz), 1.01 (sept, 3H, J = 7.0 Hz), 2.44 (s, 3H), 2.63 (ddt, 1H, J =
2.5, 6.0, 20.5 Hz), 2.73 (ddt, 1H, J = 2.5, 6.0, 20.5 Hz), 3.06 (ddd, 1H,
J = 1.5, 6.0, 20.5 Hz), 3.20 (ddd, 1H, J = 1.5, 6.0, 20.5 Hz), 5.57 (s,
1H), 7.15 (dd, 2H, J = 2.0, 5.0 Hz), 7.29 (d, 2H, J = 8.0 Hz), 7.30−
7.32 (m, 3H), 7.57 (td, 1H, J = 1.5, 2.5 Hz), 7.75 (d, 2H, J = 8.0 Hz);
13C NMR (125 MHz, CDCl3) δ 12.3, 18.1, 18.2, 21.8, 30.9, 33.2, 70.0,
126.7, 127.2, 127.4, 128.0, 129.5, 138.5, 143.1, 143.5, 151.4, 157.2,
189.4; IR (film) cm−1 2942m, 2865m, 1591s, 1461m, 1317s; mass
spectrum (APCI) m/e (% relative intensity) 498 (100) (M + H)+.
19a: (54.1 mg, 71%); Rf = 0.26 [8:1 hexanes:EtOAc]; yellow oil; 1H
NMR (400 MHz, CDCl3) δ −0.24 (s, 3H), −0.04 (s, 3H), 0.78 (s,
9H), 0.84 (s, 9H), 2.43 (s, 3H), 2.70−2.73 (m, 2H), 3.11 (ddd, 1H, J
= 2.4, 5.6, 20.4 Hz), 3.29 (ddd, 1H, J = 2.4, 5.6, 20.4 Hz), 4.27 (s, 1H),
7.31 (d, 2H, J = 8.0 Hz), 7.38 (t, 1H, J = 2.4 Hz), 7.84 (d, 2H, J = 8.0
Hz); 13C NMR (100 MHz, CDCl3) δ −5.2, −4.5, 18.1, 21.7, 25.7,
25.9, 30.9, 32.4, 36.3, 72.9, 127.1, 129.4, 138.4, 143.4, 149.5, 160.4,
190.9; IR (film) cm−1 2954m, 2928m, 2857w, 1587s, 1471m, 1438m,
1389m, 1304m; mass spectrum (ESI) m/e (% relative intensity) 436
(100) (M + H)+; HRMS (QTOF MS ESI) calcd for C23H37NO3SSiNa
[M + Na]+ 458.2156, found 458.2165.
19b: (49.4 mg, 77%); Rf = 0.25 [4:1 hexanes/EtOAc]; white solid,
mp = 113−114 °C; 1H NMR (500 MHz, CDCl3) δ 0.79 (s, 9H), 2.43
(s, 3H), 2.78 (dq, 2H, J = 3.0, 5.0 Hz), 3.12 (dddd, 1H, J = 1.0, 3.0,
5.0, 21.0 Hz), 3.14 (s, 3H), 3.35 (dddd, 1H, J = 1.0, 3.0, 5.0, 21.0 Hz),
3.82 (s, 1H), 7.31 (d, 2H, J = 8.5 Hz), 7.35 (t, 1H, J = 3.0 Hz, 1H),
7.84 (d, 2H, J = 8.5 Hz); 13C NMR (125 MHz, CDCl3) δ 21.8, 25.9,
31.1, 32.7, 35.8, 57.8, 82.6, 127.2, 129.6, 138.5, 143.6, 146.3, 160.1,
192.2; IR (film) cm−1 2955m, 2870m, 1586s, 1315s; mass spectrum
(APCI) m/e (% relative intensity) 336 (100) (M + H)+; HRMS
(QTOF MS ESI) calcd for C18H26NO3S [M + H]+ 336.1628, found
336.1637.
16b: (89.0 mg, 55%); Rf = 0.51 [3:1 hexanes/EtOAc]; yellow foam;
1H NMR (500 MHz, CDCl3) δ 1.09−1.19 (m, 6H), 1.43 (d, 1H, J =
10.0 Hz), 1.63 (t, 2H, J = 8.0 Hz), 1.72 (d, 1H, J = 6.5 Hz), 1.86 (d,
1H, J = 10.0 Hz), 3.70 (dd, 1H, J = 6.5, 15.0 Hz), 3.79 (d, 1H, J = 3.5
Hz), 3.88 (dd, 1H, J = 6.5, 15.0 Hz), 5.16 (d, 1H, J = 16.5 Hz), 5.18
(d, 1H, J = 10.0 Hz), 5.53 (ddt, 1H, J = 6.5, 10.0, 16.5 Hz), 7.11−7.31
(m, 9H), 7.47 (d, 6H, J = 8.0 Hz), 8.00 (d, 2H, J = 9.0 Hz), 8.34 (d,
2H, J = 9.0 Hz); 13C NMR (125 MHz, CDCl3) δ 26.3, 26.3, 26.8, 28.0,
29.3, 43.6, 54.6, 69.3, 71.5, 78.3, 87.5, 120.3, 124.5, 126.9, 127.2, 127.5,
127.8, 128.2, 128.2, 128.5, 128.6, 129.2, 129.2, 129.7, 130.8, 143.7,
144.9, 147.1, 150.7; IR (film) cm−1 3059w, 3031w, 2930m, 2853m,
2246m, 1717m, 1605m, 1531s, 1491m, 1447m, 1348s; mass spectrum
(APCI) m/e (% relative intensity) 293 (100) (p-Ns-allylamine+H)+,
393 (10) (M − HOCPh3 + MeOH + H)+.
Ynamide 17 was prepared from 12e following the general procedure
for silylation.
19c: (65.9 mg, 84%); Rf = 0.31 [4:1 hexanes/EtOAc]; pale yellow
oil; 1H NMR (400 MHz, CDCl3) δ 0.83 (s, 9H), 2.44 (s, 3H), 2.67−
2.78 (m, 2H), 3.11 (ddd, 1H, J = 2.8, 5.6, 20.4 Hz), 3.31 (ddd, 1H, J =
2.8, 5.6, 20.4 Hz), 4.05 (s, 1H), 7.22−7.29 (m, 5H), 4.29 (ABq, 2H,
ΔvAB = 18.5 Hz, JAB = 11.8 Hz), 7.31 (d, 2H, J = 8.0 Hz), 7.38 (td, 1H,
J = 0.8, 2.8 Hz), 7.84 (d, 2H, J = 8.0 Hz); 13C NMR (125 MHz,
CDCl3) δ 21.8, 26.0, 31.1, 32.6, 35.9, 71.8, 80.2, 127.2, 127.6, 127.8,
128.4, 129.6, 138.5, 138.9, 143.6, 146.5, 160.5, 191.8; IR (film) cm−1
2955m, 2867m, 1584s, 1364m, 1314s; mass spectrum (APCI) m/e (%
relative intensity) 412 (100) (M + H)+; HRMS (QTOF MS ESI)
calcd for C24H29NO3SNa [M + Na]+ 434.1760, found 434.1779.
20a: (48.3 mg, 70%); Rf = 0.17 [4:1 hexanes/EtOAc]; pale yellow
oil; 1H NMR (400 MHz, CDCl3) δ 0.85 (t, 3H, J = 7.2 Hz), 1.18−1.26
(m, 8H), 1.43−1.63 (m, 2H), 2.43 (s, 3H), 2.72−2.76 (m, 2H), 3.20
(ddd, 1H, J = 2.8, 5.2, 20.4 Hz), 3.25 (s, 3H), 3.27 (ddd, 1H, J = 2.8,
5.2, 20.4 Hz), 4.03 (dddt, 1H, J = 1.8, 2.8, 4.4, 5.8 Hz), 7.31 (d, 2H, J =
8.0 Hz), 7.33 (td, 1H, J = 1.2, 2.8 Hz), 7.86 (d, 2H, J = 8.0 Hz); 13C
NMR (100 MHz, CDCl3) δ 14.3, 21.8, 22.8, 25.2, 29.3, 31.0, 31.9,
33.1, 34.8, 57.6, 76.2, 127.2, 129.6, 138.5, 143.6, 148.1, 157.6, 191.0; IR
(film) cm−1 2924m, 2864m, 1587s, 1464m, 1381m, 1316s; mass
spectrum (APCI) m/e (% relative intensity) 364 (100) (M + H)+;
17: (88.4 mg, 90%); Rf = 0.36 [8:1 hexanes/EtOAc]; colorless oil;
1H NMR (500 MHz, CDCl3) δ 0.04 (s, 3H), 0.05 (s, 3H), 0.87 (s,
9H), 1.22−1.41 (m, 10H), 1.57−1.69 (m, 3H), 4.01 (ddt, 1H, J = 1.0,
6.5, 14.5 Hz), 4.05 (ddt, 1H, J = 1.0, 6.5, 14.5 Hz), 4.44 (t, 1H, J = 6.5
Hz), 5.23 (dq, 1H, 1.0, 10.0 Hz), 5.26 (dq, 1H, J = 1.0, 17.0 Hz), 5.71
(ddt, 1H, J = 6.5, 10.0, 17.0 Hz), 8.09 (d, 2H, J = 9.0 Hz), 8.38 (d, 1H,
J = 9.0 Hz); 13C NMR (125 MHz, CDCl3) δ −4.8, −4.3, 14.3, 18.4,
22.8, 25.5, 26.0, 29.2, 32.1, 39.0, 54.9, 63.3, 73.8, 76.1, 120.9, 124.5,
129.2, 130.5, 143.5, 150.8; IR (film) cm−1 2954m, 2928m, 2857m,
2245m, 1606w, 1534s, 1377m, 1348s; mass spectrum (APCI) m/e (%
relative intensity) 395 (100) (M − HOTBS + MeOH + H)+; HRMS
(QTOF MS ESI) m/e calcd for C24H38N2O5SSiNa [M + Na]+
517.2163, found 517.2158.
Ynamide 18 was prepared from 12f following the general procedure
for alkylation.
18: (596.6 mg, ≥95%); Rf = 0.38 [6:1 hexanes/EtOAc]; white solid;
mp = 50−51 °C; 1H NMR (400 MHz, CDCl3) δ 1.23−1.28 (m, 1H),
1.39−1.54 (m, 5H), 1.59−1.63 (m, 2H), 1.84−1.88 (m, 2H), 2.45 (s,
3H), 3.26 (s, 3H), 3.97 (dt, 2H, J = 6.4, 1.2 Hz), 5.19−5.26 (m, 2H),
5.68−5.77 (m, 1H), 7.34 (d, 2H, J = 8.0 Hz), 7.79 (d, 2H, J = 8.4 Hz);
G
dx.doi.org/10.1021/jo400960e | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
HRMS (QTOF MS ESI) calcd for C20H29NO3SNa [M + Na]+
386.1760, found 386.1758.
(t, 3H, J = 7.2 Hz), 0.87 (s, 9H), 1.12−1.29 (m, 8H), 1.41−1.61 (m,
2H), 2.55−2.92 (m, 3H), 3.21−3.35 (m, 2H), 4.44 (tdt, 1H, J = 1.6,
3.2, 5.2 Hz), 7.48 (td, 1H, J = 1.2, 3.2 Hz), 8.16 (d, 2H, J = 8.8 Hz),
8.37 (d, 2H, J = 8.8 Hz); 13C NMR (100 MHz, CDCl3) δ −4.7, −4.5,
14.2, 18.3, 22.8, 24.8, 26.0, 29.3, 31.0, 31.9, 33.9, 36.9, 67.7, 124.3,
128.5, 147.1, 150.3, 151.0, 160.2, 191.8; IR (film) cm−1 2954m,
2928m, 2857m, 1580s, 1531s, 1348s; mass spectrum (APCI) m/e (%
relative intensity) 495 (100) (M + H)+; HRMS (QTOF MS ESI)
calcd for C24H38N2O5SSiNa [M + Na]+ 517.2173, found 517.2190.
24: (23.8 mg, 34%); Rf = 0.17 [6:1 hexane/EtOAc]; pale yellow oil;
1H NMR (400 MHz, CDCl3) δ 1.42−1.73 (m, 10H), 1.96 (td, 2H, J =
13.6, 4.8 Hz), 2.44 (s, 3H), 2.67−2.70 (m, 2H), 3.14 (s, 3H), 3.25−
3.27 (m, 2H), 7.27−7.33 (m, 3H), 7.88 (d, 2H, J = 8.4 Hz); 13C NMR
(100 MHz, CDCl3) δ 21.3, 21.5, 25.3, 29.9, 32.1, 33.5, 49.9, 76.5,
126.8, 129.4, 138.7, 143.2, 149.3, 159.2, 190.2; IR (film) cm−1 2931s,
2856m, 1585s, 1448m, 1302s, 1153s; mass spectrum (APCI) m/e (%
relative intensity) 348 (64) (M + H)+; HRMS (QTOF MS ESI) calcd
for C19H25NO3SNa [M + Na]+ 370.1447, found 370.1452.
Preparations of Ynamides 30b, 30c, and 44. Method A. To a
flame-dried screw-cap vial was added (in the following order) the
appropriate phosphoramidate (309.0 mg, 1.50 mmol), CuTC (58.0
mg, 0.30 mmol), Cs2CO3 (976.0 mg, 3.00 mmol), dioxane (3.9 mL,
0.4 M in amide), ( )-N,N′-dimethyl-1,2-cyclohexanediamine (94.0
μL, 0.60 mmol), and the alkynyl bromide (369.0 mg, 1.95 mmol)
under a nitrogen atmosphere. The vial was evacuated under a vacuum
and flushed with nitrogen three times, and then sealed under nitrogen
and heated to 60 °C. When the reaction was judged to be complete by
TLC after 48 h, the mixture was cooled to rt, filtered through Celite,
and purified by flash silica gel column chromatrography (isocratic
eluent: 2:1 hexanes/EtOAc + 2% NEt3) to afford ynamide 30b (373.0
mg, 1.19 mmol, 79%).
20b: (92.0 mg, 92%); Rf = 0.43 [4:1 hexanes/EtOAc]; colorless oil;
1H NMR (500 MHz, CDCl3) δ 0.97 (d, 9H, J = 5.5 Hz), 0.99 (d, 9H, J
= 4.5 Hz), 1.05 (s, 3H), 1.53−1.67 (m, 2H), 2.43 (s, 3H), 2.66−2.74
(m, 2H), 3.17 (dt, 1H, J = 4.0, 20.5 Hz), 3.23 (dt, 1H, J = 4.0, 20.5
Hz), 4.70 (td, 1H, J = 1.0, 5.0 Hz), 7.30 (d, 2H, J = 8.5 Hz), 7.42 (td,
1H, J = 1.0, 2.5 Hz), 7.83 (d, 2H, J = 8.5 Hz); 13C NMR (125 MHz,
CDCl3) δ 12.5, 14.3, 17.9, 18.3, 18.3, 21.8, 22.9, 23.8, 29.6, 30.8, 32.0,
33.2, 36.9, 67.5, 127.2, 129.6, 138.6, 143.5, 151.0, 158.6, 190.2; IR
(film) cm−1 2925m, 2865m, 1587s, 1463m, 1382m, 1317m; mass
spectrum (APCI) m/e (% relative intensity) 506 (100) (M + H)+;
HRMS (QTOF MS ESI) calcd for C28H47NO3SSiNa [M + Na]+
528.2938, found 528.2949.
21a: (52.1 mg, 88%); Rf = 0.24 [3:1 hexanes/EtOAc]; pale yellow
1
oil; H NMR (400 MHz, CDCl3) δ 0.87−0.97 (m, 1H), 1.00−1.18
(m, 4H), 1.43 (d, 1H, J = 12.0 Hz), 1.50 (tdt, J = 3.2, 5.6, 11.2 Hz),
1.55−1.73 (m, 4H), 2.44 (s, 3H), 2.75−2.78 (m, 2H), 3.17 (ddd, 1H, J
= 3.2, 4.8, 20.4 Hz), 3.19 (s, 3H), 3.29 (ddd, 1H, J = 3.2, 4.8, 20.4 Hz),
3.88 (dd, 1H, J = 0.8, 5.6 Hz), 7.32 (d, 2H, J = 8.0 Hz), 7.85 (d, 2H, J
= 8.0 Hz); 13C NMR (100 MHz, CDCl3) δ 21.8, 26.3, 26.4, 26.6, 28.1,
29.2, 31.1, 33.0, 42.6, 57.9, 80.2, 127.2, 129.6, 138.5, 143.6, 146.8,
158.7, 191.5; IR (film) cm−1 2925m, 2851m, 1586s, 1449m, 1314s;
mass spectrum (APCI) m/e (% relative intensity) 362 (100) (M +
H)+; HRMS (QTOF MS ESI) calcd for C20H27NO3SNa [M + Na]+
384.1604, found 384.1615.
21b: (88.5 mg, ≥95%); Rf = 0.31 [3:1 hexanes/EtOAc]; pale yellow
oil; 1H NMR (400 MHz, CDCl3) δ 0.80−1.18 (m, 5H), 1.41 (d, 1H, J
= 10.0 Hz), 1.49−1.72 (m, 4H), 1.74 (d, 1H, J = 12.8 Hz), 2.44 (s,
3H), 2.70−2.76 (m, 2H), 3.17 (ddd, 1H, J = 3.6, 4.4, 20.4 Hz), 3.27
(ddd, 1H, J = 3.6, 4.4, 20.4 Hz), 4.09 (d, 1H, J = 5.2 Hz), 4.32 (ABq,
2H, ΔvAB = 20.2 Hz, JAB = 11.7 Hz), 7.22−7.29 (m, 5H), 7.31 (d, 2H, J
= 8.4 Hz), 7.36 (t, 1H, J = 2.7 Hz), 7.85 (d, 2H, J = 8.4 Hz);13C NMR
(100 MHz, CDCl3) δ 21.8, 26.2, 26.4, 26.6, 28.3, 29.4, 31.1, 32.9, 42.8,
71.9, 77.9, 127.2, 127.7, 127.9, 128.5, 129.6, 138.5, 138.7, 143.6, 147.3,
159.2, 191.3; IR (film) cm−1 2925m, 2852m, 1585s, 1451m, 1314s,
1302s; mass spectrum (APCI) m/e (% relative intensity) 438 (100)
(M + H)+; HRMS (QTOF MS ESI) calcd for C26H31NO3SNa [M +
Na]+ 460.1917, found 460.1919.
30b: (373.0 mg, 79%); Rf = 0.36 [1:1 hexanes/EtOAc]; pale yellow
solid; mp = 47−49 °C; 1H NMR (400 MHz, CDCl3) δ 0.89 (t, 3H, J =
6.8 Hz), 1.05 (s, 3H), 1.16 (s, 3H), 1.24−1.31 (m, 5H), 1.37 (pent,
2H, J = 7.2 Hz), 1.47 (pent, 2H, J = 7.2 Hz), 2.22 (td, 2H, J = 3.2, 7.2
Hz), 3.87 (ddt, 2H, J = 1.6, 6.2, 9.2 Hz), 4.08 (dd, 2H, J = 11.2, 14.4
Hz), 4.21 (dd, 2H, J = 9.6, 11.2 Hz), 5.24 (dd, 1H, J = 1.6, 10.4 Hz),
5.31 (dq, 1H, J = 1.6, 17.2 Hz), 5.90 (ddt, 1H, J = 6.2, 10.4, 17.2 Hz);
13C NMR (100 MHz, CDCl3) δ 14.2, 18.5, 21.4 (d, J = 11.3 Hz), 22.7,
28.6, 29.3, 31.5, 32.3 (d, J = 6.4 Hz), 53.4 (d, J = 6.3 Hz), 60.5, 65.2,
75.3, 77.9 (d, J = 6.4 Hz), 118.6, 133.0 (d, J = 1.5 Hz); 31P NMR (162
MHz, CDCl3) δ 0.63; IR (film) cm−1 2929m, 2895m, 2855m, 2256m,
1469m, 1367m, 1255s; mass spectrum (APCI) m/e (% relative
intensity) 314 (20) (M + H)+, 346 (100) (M + MeOH + H)+.
30a: (231.7 mg, 71%); Rf = 0.23 [1:1 hexanes:EtOAc]; pale yellow
22a: (39.6 mg, 80%); Rf = 0.21 [8:1 hexanes/EtOAc]; white solid;
1
mp = 137−140 °C [decomp]; H NMR (400 MHz, CDCl3) δ −0.15
(s, 3H), −0.02 (s, 3H), 0.86 (s, 9H), 0.98−1.15 (m, 5H), 1.35−1.45
(m, 2H), 1.48 (d, 1H, J = 13.2 Hz), 1.54−1.73 (m, 3H), 2.72−2.82
(m, 2H), 3.23 (ddd, 1H, J = 3.2, 4.4, 20.4 Hz), 3.30 (ddd, 1H, J = 3.2,
4.4, 20.4 Hz), 4.27 (d, 1H, J = 2.9 Hz), 7.44 (td, 1H, J = 1.2, 2.8 Hz),
8.16 (d, 2H, J = 8.8 Hz), 8.38 (d, 2H, J = 8.8 Hz); 13C NMR (100
MHz, CDCl3) δ −4.9, −4.4, 18.3, 25.9, 26.3, 26.5, 26.6, 26.9, 29.9,
31.0, 33.7, 43.4, 71.2, 124.2, 126.5, 128.3, 133.6, 150.0, 161.1, 192.0; IR
(film) cm−1 2931m, 2855m, 1557s, 1384s, 1348s; mass spectrum
(APCI) m/e (% relative intensity) 493 (100) (M + H)+; HRMS
(QTOF MS ESI) calcd for C24H36N2O5SSiNa [M + Na]+ 515.2006,
found 515.2013.
1
solid; mp = 108−109 °C; H NMR (400 MHz, CDCl3) δ 1.09 (s,
3H), 1.19 (s, 3H), 4.02 (ddt, 2H, J = 1.6, 6.2, 9.2 Hz), 4.14−4.22 (m,
4H), 5.30 (d, 1H, J = 10.4 Hz), 5.39 (dd, 1H, J = 1.6, 17.2 Hz), 5.97
(ddt, 1H, J = 6.2, 10.4, 17.2 Hz), 7.23−7.30 (m, 3H), 7.31−7.34 (m,
2H); 13C NMR (100 MHz, CDCl3) δ 21.5, 21.5, 32.5, 53.9 (d, J = 6.1
Hz), 66.3 (d, J = 5.7 Hz), 78.3 (d, J = 6.3 Hz), 85.3 (d, J = 4.1 Hz),
119.2, 123.7 (d, J = 2.1 Hz), 127.5, 128.5, 131.2 (d, J = 1.5 Hz), 132.8
(d, J = 1.4 Hz); 31P NMR (162 MHz, CDCl3) δ 1.01; IR (film) cm−1
3081w, 2970w, 2896w, 2244s, 1370m, 1326m, 1254s; mass spectrum
(ESI) m/e (% relative intensity) 306 (100) (M + H)+;
22b: (73.4 mg, 83%); Rf = 0.26 [5:1 hexanes/EtOAc]; white solid;
mp = 93−95 °C; 1H NMR (400 MHz, CDCl3) δ 0.43 (qd, 1H, J = 3.6,
12.4 Hz), 0.97 (qt, 1H, J = 3.2, 12.8 Hz), 1.12 (qt, 1H, J = 3.2, 12.8
Hz), 1.20−1.34 (m, 2H), 1.37 (d, 1H, J = 12.4 Hz), 1.54 (d, 1H, J =
12.4 Hz), 1.62 (d, 1H, J = 12.4 Hz) 1.78 (d, 1H, J = 12.8 Hz), 1.84
(ddt, 1H, J = 3.6, 12.0, 19.6 Hz), 2.01−2.13 (m, 2H), 2.43 (dd, 1H, J =
6.0, 19.6 Hz), 2.69 (dd, 1H, J = 6.0, 20.4 Hz), 2.87 (dd, 1H, J = 6.0,
20.4 Hz), 4.38 (d, 1H, J = 4.0 Hz), 7.03 (t, 1H, J = 3.6 Hz), 7.17−7.27
(m, 11H), 7.35−7.40 (m, 4H), 8.02 (d, 2H, J = 8.8 Hz), 8.30 (d, 2H, J
= 8.8 Hz); 13C NMR (100 MHz, CDCl3) δ 26.3, 26.6, 26.7, 26.8, 29.6,
31.1, 32.9, 44.3, 71.1, 87.3, 124.2, 127.3, 128.1, 128.3, 129.1, 144.6,
146.4, 147.3, 150.1, 162.9, 192.22; IR (film) cm−1 3058w, 3032w,
2929m, 2853m, 1736m, 1576s, 1530s, 1448m, 1349s; mass spectrum
(APCI) m/e (% relative intensity) 605 (100) (M + H)+; HRMS
(QTOF MS ESI) calcd for C37H36N2O5SNa [M + Na]+ 643.2237,
found 643.2262.
30e: (86.3 mg, 57%); Rf = 0.17 [2:1 hexanes:EtOAc]; colorless oil;
1H NMR (400 MHz, CDCl3) δ 1.05 (s, 18H), 1.06 (s, 3H), 1.08 (s,
3H), 1.14 (s, 3H), 3.93 (dd, 2H, J = 6.8, 8.8 Hz), 4.11−4.25 (m, 4H),
5.27 (d, 1H, J = 10.0 Hz), 5.35 (d, 1H, J = 16.8 Hz), 5.96 (ddt, 1H, J =
6.8, 10.0, 16.8 Hz); 13C NMR (100 MHz, CDCl3) δ 11.5, 18.7, 21.2,
21.4, 32.3 (d, J = 6.8 Hz), 53.8 (d, J = 6.1 Hz), 60.4, 63.4 (d, J = 4.6
Hz), 78.3 (d, J = 6.9 Hz), 99.5 (d, J = 3.8 Hz), 119.1, 132.3 (d, J = 1.6
Hz); 31P NMR (162 MHz, CDCl3) δ −2.20; IR (film) cm−1 2942m,
2865m, 2163m, 1740w, 1464m, 1373w, 1313m, 1277s; mass spectrum
(APCI) m/e (% relative intensity) 386 (100) (M + H)+.
Method B. To a flame-dried screw-cap vial was added (in the
following order) the appropriate phosphoramidate (554.0 mg, 2.70
mmol), CuSO4·5H2O (103.0 mg, 0.41 mmol), 1,10-phenanthroline
(145.8 mg, 0.81 mmol), K3PO4 (1.14 g, 5.40 mmol), toluene (6.8 mL,
0.4 M in amide), and the alkynyl bromide (1.02 g, 3.51 mmol) under a
23: (27.8 mg, 56%); Rf = 0.23 [6:1 hexanes/EtOAc]; pale yellow
oil; 1H NMR (400 MHz, CDCl3) δ −0.08 (s, 3H), 0.00, (s, 3H), 0.83
H
dx.doi.org/10.1021/jo400960e | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
nitrogen atmosphere. The vial was evacuated under a vacuum and
flushed with nitrogen three times, and then sealed under nitrogen and
heated to 60 °C. When the reaction was judged to be complete by
TLC after 48 h, the mixture was cooled to rt, filtered through Celite,
and purified by flash silica gel column chromatrography (isocratic
eluent: 2:1 hexanes/EtOAc + 2% NEt3) to afford ynamide 30c (253.1
mg, 0.61 mmol, 23%).
30d: (218.8 mg, 72%); Rf = 0.25 [3:1 hexanes/EtOAc]; white solid;
mp = 45−46 °C; 1H NMR (400 MHz, CDCl3) δ 0.03 (s, 3H), 0.08 (s,
3H), 0.85 (s, 9H), 0.89 (s, 9H), 1.06 (s, 6H), 3.81−3.88 (m, 2H), 3.98
(d, 1H, J = 3.6 Hz), 4.01−4.15 (m, 4H), 5.20 (dq, 1H, J = 1.1, 10.4
Hz), 5.28 (dq, 1H, J = 1.6, 17.2 Hz), 5.85 (ddt, 1H, J = 6.0, 10.4, 17.2
Hz); 13C NMR (100 MHz, CDCl3) δ −5.4, −4.4, 18.1, 21.2, 25.5,
25.7, 32.1 (d, J = 6.1 Hz), 36.6, 53.3 (d, J = 6.1 Hz), 65.6 (d, J = 6.1
Hz), 71.8, 77.7 (dd, J = 6.9, 14.6 Hz), 80.0 (d, J = 5.3 Hz), 118.6, 132.6
(d, J = 1.5 Hz); 31P NMR (162 MHz, CDCl3) δ −0.45; IR (film) cm−1
1255s, 1275s, 2247m, 2858m, 2892m, 2931m, 2957m; mass spectrum
(APCI) m/e (% relative intensity) 330 (100) (M − TBS + MeOH +
H)+. HRMS (TOF MS ESI) m/e calcd for C21H44N2O4PSi [M +
NH4]+ 447.2803, found 447.2820.
General Procedure for the Carbocyclization of N-Phosphor-
yl Ynamides. Method A. To a flame-dried screw-cap vial containing
∼60 mg 4 Å MS was added ynamide 30a (61.2 mg, 0.20 mmol),
Pd(PPh3)4 (11.6 mg, 0.01 mmol), and toluene (5.0 mL, 0.04 M in
ynamide). The vial was sealed under nitrogen and heated to 70 °C for
90 min, at which time TLC analysis showed consumption of the
starting material. The reaction mixture was cooled to rt, filtered
through Celite, and purified by flash silica gel column chromatography
(isocratic eluent: 1:3 hexanes/EtOAc) to afford cyclopentenimine 31a
(53.0 mg, 0.17 mmol) in 87% yield.
30c: (253.1 mg, 23%); Rf = 0.51 [3:1 hexanes/EtOAc]; brown
1
solid; mp = 42−43 °C; H NMR (400 MHz, CDCl3) δ 0.08 (s, 6H),
0.77 (s, 9H), 0.94 (s, 3H), 1.04 (s, 3H), 1.40−1.50 (m, 4H), 2.12−
2.15 (m, 2H), 3.49 (t, 2H, J = 6.0 Hz), 3.74 (t, 2H, J = 7.6 Hz), 3.97
(dd, 2H, J = 12.4, 14.0 Hz), 4.07 (dd, 2H, J = 10.4 Hz), 5.11 (d, 1H, J
= 10.4 Hz), 5.19 (dd, 1H, J = 1.6, 17.2 Hz), 5.72−5.82 (m, 1H); 13C
NMR (100 MHz, CDCl3) δ −5.6, 17.9, 18.0, 20.9, 21.0, 25.4, 25.7,
31.7, 31.8 (d, J = 6.1 Hz), 53.0 (d, J = 6.9 Hz), 62.3, 64.5 (d, J = 5.4
Hz), 75.1 (d, J = 4.5 Hz), 77,5 (d, J = 6.9 Hz), 118.1, 132.5 (d, J = 1.5
Hz); 31P NMR (162 MHz, CDCl3) δ 0.24; IR (film) cm−1 2929m,
2858m, 2256w, 1472m, 1309w, 1255s; mass spectrum (APCI) m/e (%
relative intensity) 416.3 (43) (M + H)+; HRMS (QTOF MS ESI)
calcd for C20H38NO4PSiNa [M + Na]+ 438.2200, found 438.2182.
Ynamide 44 was prepared via following Method B.
44: (1.20 g, 28%); Rf = 0.51 [1:1 hexanes/EtOAc]; pale yellow oil;
1H NMR (400 MHz, CDCl3) δ 1.08 (s, 3H), 1.16 (s, 3H), 2.40 (q,
2H, J = 7.2 Hz), 2.70 (dt, 2H, J = 8.4, 7.2 Hz), 3.93−3.97 (m, 2H),
Method B. To a flame-dried screw-cap vial containing ∼60 mg 4 Å
MS was added ynamide 30a (61.2 mg, 0.20 mmol) and toluene (5.0
mL, 0.04 M in ynamide). The vial was sealed under nitrogen and
heated to 125 °C for 2 h, at which time TLC analysis showed
consumption of the starting material. The reaction mixture was cooled
to rt, filtered through Celite, and purified by flash silica gel column
chromatography (isocratic eluent: 1:3 hexanes/EtOAc) to afford
cyclopentenimine 31a (30.8 mg, 0.10 mmol) in 50% yield.
4.18 (ABX, 4H, ΔvAB = 25.8 Hz, JAB = 10.8 Hz, JAX = 10.8 Hz, JBX
=
13.2 Hz), 5.61−5.69 (m, 1H), 5.84 (dt, 2H, J = 15.2, 6.8 Hz), 7.14−
7.18 (m, 4H), 7.23−7.34 (m, 6H); 13C NMR (100 MHz, CDCl3) δ
20.77, 20.80, 31.7 (d, J = 6.1 Hz), 33.7, 35.1, 52.6 (d, J = 6.1 Hz), 65.8
(d, J = 6.1 Hz), 77.7 (d, J = 6.1 Hz), 85.0 (d, J = 4.6 Hz), 124.4 (d, J =
1.6 Hz), 125.5, 126.9, 127.9, 128.0, 128.06, 128.10, 130.5 (d, J = 1.5
Hz), 134.9, 141.2; 31P NMR (162 MHz, CDCl3) δ −1.02; IR (film)
cm−1 2966w, 2933m, 2239s, 1371m, 1274s; mass spectrum (APCI) m/
e (% relative intensity) 410 (21) (M + H)+. HRMS (QTOF MS ESI)
calcd for C24H28NO3PNa [M + Na]+ 432.1699, found 432.1705.
Preparation of Ynamide 30d. To a flame-dried 25-mL RB-flask
was added ynamide 30e (493.0 mg, 1.30 mmol) and THF (8.5 mL,
0.15 M in ynamide). The flask was cooled to 0 °C, and TBAF (1.65
mL, 1.65 mmol, 1.0 M in THF) was added dropwise. After the
addition was complete, the reaction was allowed to warm to rt. The
reaction was judged to be complete by TLC analysis after 2 h, and the
solvent was removed by rotary evaporation. The crude residue was
purified by flash silica gel column chromatography (isocratic eluent:
1:1 hexanes/EtOAc + 2% NEt3) to afford ynamide 30f (290.0 mg, 1.27
mmol, 97%) as a white solid.
31a: (Method A: 53.0 mg, 87%); Rf = 0.17 [1:2 hexanes/EtOAc];
1
pale yellow oil; H NMR (500 MHz, CDCl3) δ 0.83 (s, 3H), 1.32 (s,
3H), 2.77 (dd, 2H, J = 3.5, 7.5 Hz), 3.15 (dd, 2H, J = 3.5, 7.5 Hz), 3.89
(dd, 2H, J = 10.5, 19.5 Hz), 4.17 (d, 2H, J = 10.5 Hz), 7.34−7.40 (m,
2H), 7.47 (t, 1H, J = 7.5 Hz), 7.62−7.70 (m, 3H); 13C NMR (125
MHz, CDCl3) δ 21.0, 22.5, 29.8, 32.7 (d, J = 5.8 Hz), 35.6 (d, J = 10.0
Hz), 77.9 (d, J = 7.3 Hz), 128.3 (d, J = 11.1 Hz), 128.5, 128.8 (d, J =
12.3 Hz), 132.4 (d, J = 9.8 Hz), 145.9 (d, J = 28.3 Hz), 159.0, 194.6 (d,
J = 2.9 Hz); 31P NMR (162 MHz, CDCl3) δ 0.64; IR (film) cm−1
2962m, 2884m, 1638s, 1593m, 1276s; mass spectrum (APCI) m/e (%
relative intensity) 306 (100) (M + H)+; HRMS (QTOF MS ESI)
calcd for C16H20NO3PNa [M + Na]+ 328.1073, found 328.1079.
31b: (Method A: 35.2 mg, 56%); Rf = 0.19 [1:1 hexane/EtOAc];
1
pale yellow oil; H NMR (400 MHz, CDCl3) δ 0.87−0.91 (m, 3H),
30f: (290.0 mg, 97%); Rf = 0.26 [1:1 hexanes/EtOAc]; white solid;
mp = 55−57 °C; 1H NMR (400 MHz, CDCl3) δ 1.02 (s, 3H), 1.07 (s,
3H), 2.39 (d, 2H, J = 4.0 Hz), 3.82−3.86 (m, 2H), 4.10 (ABX, 4H,
ΔvAB = 25.8 Hz, JAB = 10.8 Hz, JAX = 11.2 Hz, JBX = 10.4 Hz), 5.21 (d,
1H, J = 10.4 Hz), 5.28 (d, 1H, J = 17.2 Hz), 5.84 (ddt, 1H, J = 6.2,
10.4, 17.2 Hz); 13C NMR (100 MHz, CDCl3) δ 21.3, 21.3, 32.3 (d, J =
6.3 Hz), 53.2 (d, J = 5.3 Hz), 54.0 (d, J = 5.6 Hz), 78.2 (d, J = 6.3 Hz),
78.7 (d, J = 4.8 Hz), 119.0, 132.2 (d, J = 1.6 Hz); 31P NMR (162 MHz,
CDCl3) δ 0.64; IR (film) cm−1 2972m, 2923m, 2134m, 1473m,
1373m, 1308s, 1276s; mass spectrum (APCI) m/e (% relative
intensity) 230 (10) (M + H)+, 261 (100) (M + MeOH + H)+.
Ynamide 30g was prepared from 30f following the general
procedure for preparation of γ-hydroxy-ynamides.
30g: (206.3 mg, 51%); Rf = 0.25 [3:1 hexanes/EtOAc]; white solid;
mp = 45−46 °C; 1H NMR (400 MHz, CDCl3) δ 0.97 (s, 3H), 1.09 (s,
3H), 1.13 (s, 3H), 2.16 (br, 1H), 3.87−3.92 (m, 2H), 4.09−4.21 (m,
5H), 5.26 (dd, 1H, J = 1.2, 10.4 Hz), 5.33 (dd, 1H, J = 1.2, 16.8 Hz),
5.90 (ddt, 1H, J = 6, 10.4, 16.4 Hz); 13C NMR (100 MHz, CDCl3) δ
21.1, 21.2, 25.4, 32.1 (d, J = 6.9 Hz), 36.0, 53.3 (d, J = 5.3 Hz), 65.4 (d,
J = 6.1 Hz), 71.5, 77.9 (dd, J = 3.0, 6.1 Hz), 80.9 (d, J = 4.6 Hz), 118.9,
132.4 (d, J = 2.3 Hz); 31P NMR (162 MHz, CDCl3) δ −0.62; IR
(film) cm−1 3402brm, 2966s, 2870m, 2246s, 1474m, 1363w, 1273s;
mass spectrum (APCI) m/e (% relative intensity) 316.2 (39) (M +
H)+.
0.90 (s, 3H), 1.29−1.32 (m, 6H), 1.31 (s, 3H), 1.48−1.54 (m, 2H),
2.22−2.26 (m, 2H), 2.60−2.62 (m, 2H), 2.91−2.94 (m, 2H), 3.92
(ddt, 2H, J = 1.2, 10.8, 18.8 Hz), 4.18 (dd, 2H, J = 4.0, 10.4 Hz),
7.15−7.17 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 14.0, 20.7, 22.0,
22.5, 25.5, 27.7, 29.1, 29.5, 31.6, 32.4 (d, J = 5.3 Hz), 34.2 (d, J = 10.0
Hz), 77.5 (d, J = 6.9 Hz), 148.0 (d, J = 28.4 Hz), 156.3, 197.1 (d, J =
3.1 Hz); 31P NMR (162 MHz, CDCl3) δ 1.44; IR (film) cm−1 2959m,
2928s, 2857m, 1638s, 1615s, 1470w, 1275s; mass spectrum (APCI)
m/e (% relative intensity) 314 (100) (M + H)+.
31c: (Method A: 21.1 mg, 34%); Rf = 0.18 [1:1 hexane/EtOAc];
1
pale yellow oil; H NMR (400 MHz, CDCl3) δ 0.04 (s, 6H), 0.89 (s,
12H), 1.30 (s, 3H), 1.54−1.57 (m, 4H), 2.25 (t, 2H, J = 6.4 Hz),
2.59−2.60 (m, 2H), 2.91−2.94 (m, 2H), 3.62 (t, 2H, J = 6.2 Hz), 3.92
(ddd, 2H, J = 1.2, 9.6, 18.8 Hz), 4.16 (dd, 2H, J = 3.6, 10.4 Hz), 7.15−
7.17 (m, 1H); 13C NMR (100 MHz, CDCl3) δ −5.3, 18.3, 20.8, 22.0,
24.0, 25.2, 25.9, 29.5, 32.4 (d, J = 6.1 Hz), 32.6, 34.3 (d, J = 10.0 Hz),
62.9, 77.5 (d, J = 6.8 Hz), 147.8 (d, J = 28.5 Hz), 156.3, 197.0; 31P
NMR (162 MHz, CDCl3) δ 1.39; IR (film) cm−1 2954m, 2928m,
2858m, 1615m, 1471w, 1257s; mass spectrum (APCI) m/e (% relative
intensity) 416 (100) (M + H)+; HRMS (QTOF MS ESI) calcd for
C20H38NO4PSiNa [M + Na]+ 438.2200, found 438.2197.
31d: (41.4 mg, 69%); Rf = 0.14 [1:1 hexanes/EtOAc]; pale yellow
oil; 1H NMR (400 MHz, CDCl3) δ −0.18 (s, 3H), 0.84 (s, 3H), 0.85
(s, 9H), 0.86 (s, 9H), 1.32 (s, 3H), 2.57−2.71 (m, 2H), 2.84 (ddt, 1H,
J = 2.8, 6.0, 20.0 Hz), 3.04 (ddt, 1H, J = 2.8, 6.0, 20.0 Hz), 3.82−3.93
Ynamide 30d was prepared from 30g following the general
procedure for silylation
I
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(m, 2H), 4.14 (ddd, 2H, J = 2.4, 10.8, 21.2 Hz), 4.36 (s, 1H), 7.40 (dd,
1H, J = 2.8, 6.0 Hz); 13C NMR (100 MHz, CDCl3) −5.1, −4.4, 18.2,
20.8, 22.3, 25.9 (d, J = 3.9 Hz), 29.8, 32.5 (d, J = 6.0 Hz), 34.5 (d, J =
10.0 Hz), 36.3, 73.1, 77.5 (d, J = 7.9 Hz), 150.0 (d, J = 27.1 Hz), 160.2,
196.0 (d, J = 2.9 Hz); 31P NMR (162 MHz, CDCl3) δ 0.84; IR (film)
cm−1 2957m, 2930m, 2885m, 2857m, 1632m, 1613m, 1472m, 1281m,
1257m; mass spectrum (APCI) m/e (% relative intensity) 430 (100)
(M + H)+; HRMS (QTOF MS ESI) calcd for C21H40NO4PSiNa [M +
Na]+ 452.2356, found 452.2359.
48: (71.2 mg, 87%); Rf = 0.41 [1:1 DCM/EtOAc]; pale yellow oil;
1H NMR (400 MHz, CDCl3) δ 0.73 (s, 3H), 1.26 (s, 3H), 2.75 (t, 2H,
J = 4.0 Hz), 2.82−2.85 (m, 4H), 3.04−3.07 (m, 2H), 3.77 (ddd, 2H, J
= 1.2, 9.6, 19.6 Hz), 4.01 (dd, 2H, J = 1.6, 10.4 Hz), 7.08−7.12 (m,
4H), 7.19−7.35 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 20.5, 22.1,
32.2 (d, J = 6.1 Hz), 32.5, 33.2 (d, J = 1.6 Hz), 33.7, 33.8 (d, J = 10.8
Hz), 77.5 (d, J = 7.7 Hz), 126.3, 127.5, 127.7, 128.1, 128.5, 129.5,
132.4, 140.4, 142.7 (d, J = 29.2 Hz), 173.5, 195.1 (d, J = 1.5 Hz); 31P
NMR (162 MHz, CDCl3) δ 0.79; IR (film) cm−1 2963w, 2929w,
1617s, 1592s, 1268s; mass spectrum (APCI) m/e (% relative intensity)
410 (100) (M + H)+; HRMS (QTOF MS ESI) calcd for
C24H28NO3PNa [M + Na]+ 432.1699, found 432.1699.
Characterization of N-Phosphoryl-TIPS-Ketenimine 32. 32:
(41.1 mg, 53%); Rf = 0.17 [4:1 hexanes:EtOAc]; yellow wax; mp =
47−50 °C; 1H NMR (400 MHz, CDCl3) δ 0.86 (s, 3H), 1.13 (d, 18H,
J = 6.0 Hz), 1.18 (sept, 3H, J = 6.0 Hz), 1.29 (s, 3H), 2.77 (ddt, 2H, J
= 1.2, 6.8, 8.0 Hz), 3.95 (dd, 2H, J = 11.2, 22.0 Hz), 4.18 (d, 2H, J =
10.4 Hz), 5.10 (dd, 1H, J = 1.2, 10.0 Hz), 5.21 (dq, 1H, J = 1.6, 3.2,
17.2 Hz), 5.98 (ddt, 1H, J = 6.4, 10.0, 16.4 Hz); 13C NMR (100 MHz,
CDCl3) δ 11.9, 17.9, 18.7, 20.5, 22.2, 29.0 (d, J = 5.4 Hz), 32.4 (d, J =
6.1 Hz), 40.0 (d, J = 15.3); 76.9 (d, J = 31.3 Hz), 116.3 (d, J = 3.8 Hz),
136.1 (d, J = 3.1 Hz), 187.9; 31P NMR (162 MHz, CDCl3) δ −9.05;
IR (film) cm−1 2943m, 2890w, 2866m, 1993s, 1464m, 1372w, 1341w,
1301s; mass spectrum (ESI) m/e (% relative intensity) 387 (100) (M
+ H)+; HRMS (QTOF MS ESI) calcd for C19H36NO3PSiNa [M +
Na]+ 408.2094, found 408.2091.
Preparation of Farnesyl-Tethered Ynamide 59. To a flame-
dried 25-mL RB-flask was added CH2Cl2 (7.0 mL, 0.5 M in allyl
amine), farnesyl amine (752.0 mg, 3.39 mmol), and NEt3 (0.70 mL,
5.09 mmol) under a nitrogen atmosphere. The reaction flask was
cooled to 0 °C, and 2-chloro-5,5-dimethyl-1,3,2-dioxaphosphorinane
2-oxide (753.0 mg, 4.07 mmol) was added slowly dropwise. Once the
addition was complete, the reaction was allowed to warm to rt and stir
overnight. After the reaction was judged to be complete by TLC, water
(10 mL) was added, the organic layer was separated, and the aqueous
phase was extracted with CH2Cl2 (3 × 25 mL). The combined organic
phase was washed with sat. NaCl and dried over Na2SO4. The crude
material was purified by flash silica gel column chromatrography (1:1
EtOAc:CH2Cl2) to afford phosphoramidate 56 (943.0 mg, 2.56 mmol,
75%).
56: (943.0 mg, 75%); Rf = 0.20 [1:1 EtOAc/CH2Cl2]; colorless oil;
1H NMR (400 MHz, CDCl3) δ 0.90 (s, 3H), 1.21 (s, 3H), 1.60 (s,
6H), 1.65 (s, 3H), 1.68 (s, 3H), 2.12−1.94 (m, 8H), 2.65 (brs, 1H),
3.59 (dt, 2H, J = 6.8, 9.2 Hz), 3.81 (ddt, 2H, J = 1.2, 11.2, 19.6 Hz),
4.29 (dd, 2H, J = 4.4, 11.2 Hz), 5.09 (t, 2H, J = 6.8 Hz), 5.25 (tq, 1H, J
= 1.6, 6.8 Hz); 13C NMR (100 MHz, CDCl3) δ 16.1, 16.3, 17.8, 20.9,
22.1, 25.8, 26.4, 26.8, 32.0 (d, J = 5.2 Hz), 39.2, 39.6, 39.8, 76.2 (d, J =
5.5 Hz), 122.0 (d, J = 7.3 Hz), 123.8, 124.4, 131.4, 135.5, 139.1; 31P
NMR (162 MHz, CDCl3) δ 6.37; IR (film) cm−1 3210brm, 2965m,
2917m, 1447m, 1374m, 1231m; mass spectrum (APCI) m/e (%
relative intensity) 370 (100) (M + H)+. HRMS (TOF MS ESI) m/e
calcd for C20H37NO3P [M + H]+ 370.2506, found 370.2523.
57: (298.0 mg, 65%); Rf = 0.16 [3:1 hexanes/EtOAc]; colorless oil;
1H NMR (400 MHz, CDCl3) δ 1.04 (s, 18H), 1.03−1.06 (m, 3H),
1.06 (s, 3H), 1.14 (s, 3H), 1.59 (d, 3H, J = 1.2 Hz), 1.60 (d, 3H, J =
0.8 Hz), 1.68 (d, 3H, J = 1.2 Hz), 1.69 (d, 3H, J = 1.2 Hz), 1.94−2.17
(m, 8H), 3.94 (t, 2H, J = 7.6 Hz), 4.15 (ABX, 4H, ΔvAB = 32.8 Hz, JAB
= 11.2 Hz, JAX = 10.7 Hz, JBX = 10.9 Hz), 5.06−5.14 (m, 2H), 5.38 (tq,
1H, J = 1.2, 6.8 Hz); 13C NMR (100 MHz, CDCl3) δ 11.6, 16.1, 16.7,
17.8, 18.8, 18.8, 21.3, 21.6, 25.8, 26.5, 26.9, 32.4 (d, J = 6.9 Hz), 39.8,
48.7 (d, J = 5.4 Hz), 63.0 (d, J = 4.5 Hz), 77.4, 78.3 (d, J = 6.8 Hz),
118.8 (d, J = 2.3 Hz), 124.0, 124.5, 131.4, 135.4, 141.4; 31P NMR (162
MHz, CDCl3) δ 1.65; IR (film) cm−1 2923m, 2864m, 2161m, 1463m,
1380m, 1235m; mass spectrum (APCI) m/e (% relative intensity) 370
(70) (M − CCTIPS + H)+, 571 (10) (M + H)+.
To a flame-dried 10-mL RB-flask was added ynamide 57 (298.0 mg,
0.54 mmol) and THF (2.2 mL, 0.25 M in ynamide). The flask was
cooled to 0 °C, and TBAF (0.65 mL, 0.65 mmol, 1.0 M in THF) was
added dropwise. After the addition was complete, the reaction was
allowed to warm to rt. The reaction was judged to be complete by
TLC analysis after 2 h, and the solvent was removed by rotary
evaporation. The crude residue was purified by flash silica gel column
chromatography (isocratic eluent: 2:1 hexanes/EtOAc + 2% NEt3) to
afford ynamide 58 (174.0 mg, 0.44 mmol, 82%) as a colorless oil.
58: (174.0 mg, 82%); Rf = 0.29 [2:1 hexanes/EtOAc]; colorless oil;
1H NMR (400 MHz, CDCl3) δ 1.09 (s, 3H), 1.12 (s, 3H), 1.60 (s,
3H), 1.60 (s, 3H), 1.68 (d, 3H, J = 0.8 Hz), 1.71 (d, 3H, J = 0.8 Hz),
1.97 (t, 2H, J = 7.6 Hz), 2.01−2.14 (m, 6H), 2.40 (d, 1H, J = 3.6 Hz),
3.94 (t, 2H, J = 7.6 Hz), 4.15 (ABX, 4H, ΔvAB = 23.5 Hz, JAB = 10.9
Hz, JAX = 11.0 Hz, JBX = 8.8 Hz), 5.07−5.13 (m, 2H), 5.37 (tq, 1H, J =
1.2, 6.8 Hz); 13C NMR (100 MHz, CDCl3) δ 16.2, 16.6, 17.8, 21.3,
21.4, 25.8, 26.5, 26.9, 32.4 (d, J = 6.3 Hz), 39.8, 39.8, 48.2 (d, J = 5.0
Hz), 53.8 (d, J = 5.8 Hz), 77.4, 78.1 (d, J = 6.3 Hz), 118.6 (d, J = 2.3
Hz), 123.9, 124.5, 131.4, 135.4, 141.9; 31P NMR (162 MHz, CDCl3) δ
0.22; IR (film) cm−1 2965m, 2920m, 2133m, 1769w, 1666w, 1448m,
1305s, 1275s; mass spectrum (APCI) m/e (% relative intensity) 394
(100) (M + H)+.
To a flame-dried 25-mL RB-flask was added ynamide 58 (174.0 mg,
0.44 mmol) and THF (4.4 mL, 0.1 M in ynamide) under a nitrogen
atmosphere. The flask was cooled to −78 °C, and LHMDS (0.89 mL,
0.88 mmol, 1 M in THF) was added dropwise. The reaction was kept
at −78 °C for 1 h to ensure complete deprotonation, and then MeI
(83.0 μL, 1.32 mmol) was added dropwise. The reaction was allowed
to warm to rt overnight, at which time TLC analysis showed
consumption of the starting material. The reaction was diluted with
EtOAc (5 mL) and quenched with water (5 mL). The layers were
separated, the aqueous layer was extracted with EtOAc (3 × 10 mL),
and then the combined organic layers were washed with brine and
dried over Na2SO4. Purification of the crude residue by flash silica gel
column chromatography (isocratic eluent: 1:1 hexanes/EtOAc + 2%
NEt3) afforded ynamide 59 (147.2 mg, 0.36 mmol, 82%).
59: (147.2 mg, 82%); Rf = 0.16 [2:1 hexanes/EtOAc]; colorless oil;
1H NMR (400 MHz, CDCl3) δ 1.03 (s, 3H), 1.17 (s, 3H), 1.60 (s,
6H), 1.68 (s, 3H), 1.70 (d, 3H, J = 0.8 Hz), 1.85 (d, 1H, J = 3.2 Hz),
1.97 (t, 2H, J = 7.6 Hz), 2.04−2.14 (m, 6H), 3.89 (t, 2H, J = 8.0 Hz),
4.03 (dd, 2H, J = 11.2, 14.8 Hz), 4.20 (dd, 2H, J = 9.2, 10.8 Hz), 5.07−
5.14 (m, 2H), 5.36 (tq, 1H, J = 1.2, 6.8 Hz); 13C NMR (100 MHz,
CDCl3) δ 3.2 (d, J = 1.9 Hz), 16.1, 16.5, 17.8, 21.3, 21.4, 25.8, 26.5,
26.9, 32.3 (d, J = 6.1 Hz), 39.8 (d, J = 4.4 Hz), 48.2 (d, J = 3.7 Hz),
60.2 (d, J = 5.8 Hz), 74.6 (d, J = 4.6 Hz), 77.6 (d, J = 6.2 Hz), 78.0 (d,
J = 3.7 Hz), 119.3 (d, J = 2.2 Hz), 123.9, 124.5, 131.4, 135.3, 141.2;
31P NMR (162 MHz, CDCl3) δ 1.41; IR (film) cm−1 2968m, 2919m,
2262w, 1737m, 1447m, 1373m, 1271m; mass spectrum (APCI) m/e
(% relative intensity) 408 (100) (M + H)+; HRMS (QTOF MS ESI)
calcd for C23H38NO3PNa [M + Na]+ 430.2482, found 430.2489.
Carbocyclization of Farnesyl-Tethered Ynamide 59. 62: (41.7
1
mg, 43%); Rf = 0.18 [1:2 hexanes/EtOAc]; colorless oil; H NMR
(400 MHz, CDCl3) all isomers δ 0.98 (s, 9H), 1.08 (s, 3H), 1.09 (s,
3H), 1.11 (s, 3H), 1.13 (s, 3H), 1.14 (s, 3H), 1.19−1.37 (m, 6H), 1.47
(s, 3H), 1.48 (s, 3H), 1.48 (s, 3H), 1.60 (s, 12H), 1.67 (s, 6H), 1.69 (s,
6H), 1.70−1.75 (m, 2H), 1.91−2.11 (m, 16H), 2.17−2.38 (m, 6H),
2.40−2.49 (m, 1H), 2.53−2.60 (m, 1H), 2.62−2.72 (m, 2H), 2.91−
3.00 (m, 2H), 3.87 (ddd, 6H, J = 1.5, 11.5, 16.5 Hz), 4.18−4.30 (m,
8H), 4.33 (d, 2H, J = 8.0 Hz), 4.68 (s, 1H), 4.83 (s, 1H), 5.94−5.19
(m, 3H); 31P NMR (162 MHz, CDCl3) all isomers δ 1.56, 1.57, 1.63;
IR (film) cm−1 2962m, 2930m, 1737s, 1670m, 1456m, 1373m; mass
spectrum (APCI) m/e (% relative intensity) 408 (100) (M + H)+.
HRMS (TOF MS ESI) m/e calcd for C23H39NO3P [M + H]+
408.2663, found 408.2675.
63: (36.8 mg, 38%); Rf = 0.47 [1:2 hexanes/EtOAc]; colorless oil;
1H NMR (500 MHz, CDCl3) 0.76 (s, 3H), 0.80 (s, 3H), 0.86 (s, 3H),
J
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0.93 (s, 3H), 0.93 (ddd, 1H, J = 6.0, 11.0, 13.5 Hz), 1.13 (ddd, 1H, J =
6.0, 11.0, 13.5 Hz), 1.30 (s, 3H), 1.43 (t, 2H, J = 11.0 Hz), 1.52 (ddt,
1H, J = 3.0, 5.5, 11.5 Hz), 1.56 (s, 3H), 1.63 (s, 3H), 1.65−1.76 (m,
1H), 1.88 (ddd, 2H, J = 6.5, 13.5, 19.0 Hz), 1.92 (s, 1H), 2.00 (s, 1H),
2.69 (t, 2H, J = 3.0 Hz), 3.87 (dddd, 2H, J = 3.0, 11.0, 19.0, 41.0 Hz),
4.16 (ddd, 2H, J = 3.5, 11.0, 43.0 Hz), 4.97−5.00 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ 7.3, 16.6, 17.8, 20.2, 20.9, 22.3, 23.7, 25.9, 27.3,
30.0, 32.6 (d, J = 5.7 Hz), 36.1 (d, J = 11.3 Hz), 40.3 (d, J = 6.6 Hz),
47.1, 49.9, 56.9, 64.3 (d, J = 23.1 Hz), 77.8 (d, J = 7.5 Hz), 124.8,
131.4, 206.0 (d, J = 7.4 Hz); 31P NMR (162 MHz, CDCl3) δ 1.71; IR
(film) cm−1 2959m, 2931m, 2877m, 1738m, 1689m, 1460m, 1374m;
mass spectrum (APCI) m/e (% relative intensity) 408 (100) (M +
H)+; HRMS (QTOF MS ESI) calcd for C23H38NO3PNa [M + Na]+
430.2482, found 430.2486.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, characterization data for all new
compounds, and 1H/13C NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: rhsung@wisc.edu, kadekorver@dow.com.
■
Notes
The authors declare no competing financial interest.
(4) For reviews on Claisen rearrangements, see: (a) Castro, A. M. M.
Chem. Rev. 2004, 104, 2939. (b) Ito, H.; Taguchi, T. Chem. Soc. Rev.
1999, 28, 43. (c) Enders, D.; Knopp, M.; Schiffers, R. Tetrahedron:
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Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford,
1991; Vol. 5, p 827. (e) Hill, R. K. In Asymmetric Synthesis; Morrison, J.
D., Ed.; Academic Press: New York, 1984.
(5) For leading reviews on aza-Claisen rearrangments, see:
(a) Majumdar, K. C.; Bhayyacharyya, T.; Chattopadhyay, B.; Nandi,
R. K. Synthesis 2009, 2117. (b) Nubbemeyer, U. Top. Curr. Chem.
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(c) DeKorver, K. A.; Johnson, W. L.; Zhang, Y.; Hsung, R. P.; Dai, H.;
Deng, J.; Lohse, A. G.; Zhang, Y.-S. J. Org. Chem. 2011, 76, 5092.
(7) DeKorver, K. A.; North, T. D.; Hsung, R. P. Synlett 2010, 2397.
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ACKNOWLEDGMENTS
■
Authors thank the NIH [GM066055] for financial support.
K.A.D. thanks the American Chemical Society for a Division of
Medical Chemistry Predoctoral Fellowship.
REFERENCES
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