N- Allyl- N- sulfonyl ynamides as synthetic precursors to amidines and vinylogous amidines. An unexpected N-to-C 1,3-sulfonyl shift in nitrile synthesis

Article abstract of DOI:10.1021/jo200780x

A detailed study of amidine synthesis from N-allyl-N-sulfonyl ynamides is described here. Mechanistically, this is a fascinating reaction consisting of diverging pathways that could lead to deallylation or allyl transfer depending upon the oxidation state of palladium catalysts, the nucleophilicity of amines, and the nature of the ligands. It essentially constitutes a Pd(0)-catalyzed aza-Claisen rearrangement of N-allyl ynamides, which can also be accomplished thermally. An observation of N-to-C 1,3-sulfonyl shift was made when examining these aza-Claisen rearrangements thermally. This represents a useful approach to nitrile synthesis. While attempts to render this 1,3-sulfonyl shift stereoselective failed, we uncovered another set of tandem sigmatropic rearrangements, leading to vinyl imidate formation. Collectively, this work showcases the rich array of chemistry one can discover using these ynamides.

Full text of DOI:10.1021/jo200780x

ARTICLE
pubs.acs.org/joc
N-Allyl-N-sulfonyl Ynamides as Synthetic Precursors to Amidines
and Vinylogous Amidines. An Unexpected N-to-C 1,3-Sulfonyl Shift
in Nitrile Synthesis
Kyle A. DeKorver, Whitney L. Johnson, Yu Zhang, Richard P. Hsung,* Huifang Dai, Jun Deng,
Andrew G. Lohse, and Yan-Shi Zhang*
Division of Pharmaceutical Sciences and Department of Chemistry, University of Wisconsin, Madison, Wisconsin 53705, United States
S Supporting Information
b
ABSTRACT:
A detailed study of amidine synthesis from N-allyl-N-sulfonyl ynamides is described here. Mechanistically, this is a fascinating
reaction consisting of diverging pathways that could lead to deallylation or allyl transfer depending upon the oxidation state of
palladium catalysts, the nucleophilicity of amines, and the nature of the ligands. It essentially constitutes a Pd(0)-catalyzed aza-
Claisen rearrangement of N-allyl ynamides, which can also be accomplished thermally. An observation of N-to-C 1,3-sulfonyl shift
was made when examining these aza-Claisen rearrangements thermally. This represents a useful approach to nitrile synthesis. While
attempts to render this 1,3-sulfonyl shift stereoselective failed, we uncovered another set of tandem sigmatropic rearrangements,
leading to vinyl imidate formation. Collectively, this work showcases the rich array of chemistry one can discover using these
ynamides.
’ INTRODUCTION
Whitby11 recently reported an interesting usage of isonitrile for
accessing amidines by reacting with aryl or allyl bromides and an
amine using a palladium catalyst. Lastly, there has been extensive
development in constructing amidines through decomposing
N-sulfonyl triazoles [not shown here].12ꢀ15
Amidines1,2 represent a prolific functional group in medicinal
chemistry and an important pharmacophore in drug discovery.3ꢀ6
One notable example is the DNA and RNA binding diamidine
diminazene, which is found in drugs such Azidin, Berenil, or
Pirocide to treat the parasitic protozoan that causes Trypanoso-
niasis of which African sleeping sickness and Chagas disease are a
form.7 There are several different variationsof amidines depending
on the substituents on the nitrogen or the sp2-amidinyl carbon1,2
[Figure 1]. Aliphatic and aromatic amidines are generally prepared
in a very similar manner, frequently from amides, nitriles, and
thioamides with a nitrogen nucleophile.1,2,8 The Pinner reaction
and modified Pinner transformations,9,10 which employ nitriles
and go through an imidate, are the most common protocols for
synthesizing amidines. However, this method is not good for
hindered nitriles and cannot be used for the synthesis of tertiary
amidines. Consequently, amides and thioamides are frequently
used.1,2 Activation of the monosubstituted amide by chlorinating
agents or alkylation of the alkoxy group can yield amidines when
the resulting compound is reacted with an amine. Thioamides can
more directly yield an amidine by simply reacting it with an amine
and a mercury salt to act as a sulfide scavenger [Figure 1].
We recently found that ynamides16ꢀ18 could serve as excellent
precursors for synthesizing amidines via a Pd(0)-catalyzed N-to-
C allyl transfer.19 As shown in Scheme 1, the oxidative addition
[O.A.] of N-allyl-ynamides 1 would lead to novel ynamido-π-
allyl complexes 2a and ketenimino-π-allyl complexes 2b. The
subsequent formation of amidines 4 would occur in the presence
of an amine either through trapping of ketenimines 3, which is
derived from 2b via reductive elimination [R.E.], or through
π-allyl complex 5, which is a result of the amine addition to
complexes 2b prior to R.E. We also found that while amidines 4
represent a successful N-to-C allyl transfer, the reaction did not
always lead to transfer of the allyl group. Instead, a diverging
pathway would lead to amidines 6 that could be prepared with
concomitant deallylation depending upon the amine and the
Received: April 14, 2011
Published: May 12, 2011
r
2011 American Chemical Society
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Scheme 2. Amidine Formation with Pd(II) Catalyst
Table 1. Deallylative Primary Amidine Formation
Figure 1. Amidines and their general preparation.
Scheme 1. Amidine Formation from N-Allyl-ynamides
a All entries utilized ynamide 8a with the exception that in entry 8, Ph-
substituted ynamide 8b was used. All reactions employed 5.0 mol %
PdCl2(PPh3)2, 1.0 equiv K2CO3, THF [concn = 0.05 M], 80 °C, 5ꢀ8 h.
b Isolated yields.
synthesizing amidines, and to avoid complication with the allyl
group issue, we initially focused on deallylation via using 5.0
equiv of the amine. The generality and the effectiveness of this
amidine synthesis could be thoroughly captured in Table 1
through using a wide range of primary amines, as demonstrated
in Table 2 via employing a diverse array of secondary amines as
well as varying the N-allyl-ynamide substitutions. It is noteworthy
that, based on NOE experiments, these amidines adopt an
E-geometry with respect to the CdN bond.19
Deallylation Mechanism and Allyl Transfer. While this is an
interesting amidine synthesis, we were fascinated by its possible
mechanism. Because of their basicity, polarity, and/or volatility,
the respective allyl amine byproducts [R2NꢀCH2CHdCH2]
from deallylation were difficult to isolate. Nevertheless, as shown
in Scheme 3, a mechanistically revealing experiment involved the
use of piperizine, which led to the N-allylated amine 36 in 63%
yield. Consequently, deallylation could be either a Pd(0)- or
Pd(II)-catalyzed process. The former would require oxidative
addition of Pd(0) to N-allyl ynamide 8a, leading to 5 through an
N-to-C allyl transfer from ynamido-palladium πꢀallyl complex
2a, whereas the latter would involve a palladium(II)-substituted
keteniminium ion 7 with Pd(II) serving to activate the alkynyl
motif. Deallylation could take place in either an intramolecular
manner as shown in 5 or an intermolecular manner as shown in 7.
Although attempts were made, these reactions were too fast to
allow NMR studies to be revealing of possible ynamido-π-allyl
nature of the palladium catalyst and ligands. Although it is quite
reasonable to presume that this deallylation could have occurred
through amine attacking the palladium π-allyl complexes 2b, it
could also be envisioned from keteniminium intermediate 7 gener-
ated from 1 with the Pd(II) species serving as a π-Lewis acid. We
recognized that this signifies not only a de novo transformation of
ynamides with an invaluable opportunity to study ynamidoꢀmetal
complexes12ꢀ16,20,21 but also an excellent method for synthesizing
amidines especially given that ynamides are now synthetic readily
available substrates.22ꢀ24 We report here details of our investigation
in developing this amidine synthesis.
’ RESULTS AND DISCUSSION
Deallylative Amidine Formation. We made our initial dis-
covery of the deallylation of ynamides when treating N-allyl-
ynamide 8a with 5 mol % of PdCl2(PPh3)2 with an original intent
to hydroaminate the alkyne [Scheme 2]. Instead, we found that
amidine 9 was formed in high yield when using 10.0 equiv of
H2N-t-Bu and that the allyl group was missing. Intriguingly,
when lowering the amount of the amine to 3.0 equiv, the allyl
resonances visibly reappeared in the proton NMR and no longer
on the nitrogen atom but on the formerly β-carbon of the
ynamide after isolating 10 in 37% yield. We recognized this
unexpected transformation represents an excellent protocol for
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Table 2. Secondary Amidine Formation
Scheme 3. Two Possible Deallylation Pathways
exclusively deallylation.26 The nature of the ligand also mattered.
Those that favored reductive elimination such as xantphos27,28
allowed the isolation of a range of different allyl transferred
amidines such as 39 and 40aꢀe [Scheme 4]. X-phos29 was also
examined and was comparable in terms of yield of allylated
amidines, but xantphos allowed shorter reaction times.19
Furthermore, we found that enamines or vinylogous amides
could also be used as nucleophiles under these conditions for allyl
transfers. As shown in Table 4, vinylogous amidines 45 and 46
[entries 1 and 2] as well as 47 and 51 [entries 3 and 7] could be
accessed utilizing enamine 41 and vinylogous amide 42, respec-
tively. For reasons unknown to us at this moment, the allyl group
did not transfer for vinylogous amidines 48 and 49 [entries 4 and
5], and primary vinylogous amides such as 43 did not work well
[entry 6]. Nevertheless, a general trend for the dichotomy of
deallylation versus N-to-C allyl transfer could be summarized as
shown in Figure 2. Deallylation is favored when using excess of
amine, or Pd(II) sources, and/or more nucleophilic secondary
amines, whereas N-to-C allyl transfer is favored with less
nucleophilic primary amines, Pd(0) sources, and/or R.E. favor-
ing ligands such as xantphos.
Aza-Claisen Rearrangement and 1,3-Sulfonyl Shift. Our
efforts described above allowed us to recognize that these
reactions in essence are aza-Claisen rearrangements30ꢀ32 pro-
moted by palladium catalysts. In fact, aza-Claisen rearrangements
could be carried out thermally without any metal catalysts. As
shown in Scheme 5, a nonpalladium involved pathway would entail
an aza-Claisen transition state [see A], leading to allyl-ketenimine
intermediate B. Trapping of B would then lead to many products,
and in the case of an alcohol, imidates could be accessed.33,34
Trapping of the allyl-ketenimine intermediate such as 55 with
an external amine could also lead to allyl-transferred amidine 39.
This indeed not only is true in the case of 39 but also is highly
effective as shown in Table 5 in giving a wide range of amidines
56ꢀ60 in good yields.35 However, this pathway requires much
higher temperature and longer reaction time. When carried out at
65ꢀ80 °C in THF, the reaction was sluggish and slow,36 thereby
suggesting that the palladium catalyst was indeed promoting
these transformations.
a All reactions utilized 5.0 equiv of the amine, 5.0 mol % PdCl2(PPh3)2,
and 1.0 equiv K2CO3 and were run in THF [concn = 0.05 M] at 80 °C
over 5ꢀ8 h. b Isolated yields.
complexes even at 25 °C. Only the starting ynamide, silyl-keteni-
mine such as 3, and respective amidine product [if the reaction
was run in the presence of an amine] were clearly in display
spectroscopically.
Although both pathways could be operative for the deal-
lylation, we suspected that suppression of the Pd(II)-catalyzed
pathway through directly using a Pd(0) source could lead to
suppression of the deallylation.25 As shown in Table 3, this
predictive assessment turned out to be true. While most Pd(II)
sources led to predominantly the deallylation when using 3.0
equiv of c-hex-NH2, Pd(PPh3)4 gave exclusively the allyl trans-
ferred amidine 37 [entry 6]. This preservation of the allyl group
turned to be general for a number of primary amines, as evident
from amidine products 38aꢀc.
It was during this study that we observed an interesting N-to-C
1,3-sulfonyl shift.37 As shown in Scheme 6, when using ynamides
not substituted with TIPS at the terminal position, we observed
the formation of quaternary nitriles 61 in the absence of an
amine. This observation suggested that allyl ketenimines 3 in
which R ¼ TIPS had undergone a N-to-C 1,3-sulfonyl shift,
However, the use of Pd(PPh3)4 was not sufficient especially in
the case of secondary amines such as pyrrolidine or piperidine,
which are more nucleophilic than primary amines, leading to
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Table 3. Dependence of Deallylation on Palladium Species
Table 4. Vinylogous Amidine Synthesis
a All are isolated yields.
Scheme 4. Use of Xantphos Ligand
a Unless otherwise noted, all reactions utilized 3.0 equiv of the enamine,
5.0 mol % Pd2(dba)3, and 10.0 mol % of xantphos and were run in THF
[concn = 0.05 M]. b Isolated yields. c 2 h at 70 °C. d 2 h at 50 °C with 1.5
equiv of K2CO3. e 12 h at 70 °C with 1.5 equiv of 42, 2.0 mol %
Pd2(dba)3, and 4.0 mol % of xantphos. f 30 min at 50 °C. g 2 h at rt. h 2 h
at 75 °C with 1.5 equiv of K2CO3 and 1.5 equiv of 44.
whereas this was not the case when R = TIPS. Silyl ketenimines
such as 55 were sufficiently stable38,39 and could be trapped
subsequently.
This nitrile formation is very general, including a number of
different sulfonyl groups as demonstrated in Table 6 [see entries
1ꢀ4]. While the 1,3-sulfonyl shift tolerated various substitutions
[entries 5 and 6], again when using 8a containing the TIPS
substitution [entry 7], the 1,3-sulfonyl shift only took place only
when in conjunction with desilylation. It is also noteworthy that
given results in Table 5, the N-to-C 1,3-sulfonyl shift most likely
took place after the aza-Claisen rearrangement. In addition, mon-
itoring the thermal aza-Claisen rearrangement of ynamide 8b using
proton NMR did not reveal any respective ketenimine, thereby
suggesting that the 1,3-sulfonyl shift was very fast at 110 °C.
We then attempted to extend this interesting 1,3-sulfonyl shift
because the formation of tertiary nitriles holds significant merit in
synthesis.40 As shown in Scheme 7, we envisioned that using ynamide
69 containing a propargylic stereocenter could lead to a stereoselec-
tive 1,3-sulfonyl shift to give 70 or 700. The level of selectivity
would depend upon conformational preference of allyl-ketenimine
Figure 2. Dichotomy of deallylation and allyl transfer.
intermediate 72 and 720, and in this case, the conformer 720 could be
more preferred given the A1,2-strain present in 72. This preference
could lead to a facial selective 1,3-sulfonyl shift to give 700. In addition,
we could vary the P group so that it could lead to the conformational
situation shown in 730 in which anchiomeric assistance could take
place, again leading to possible facial selective 1,3-sulfonyl shift.
Unfortunately, after examining a number of such ynamides
[69aꢀd], the best ratio was 2:1 using 69c [entry 3 in Table 7].
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Scheme 5. Thermal Aza-Claisen Rearrangement
Scheme 6. Unexpected N-to-C 1,3-Sulfonyl Shift
Table 5. Amidine Synthesis via Aza-Claisen Rearrangement
Table 6. Tandem Aza-Claisenꢀ1,3-Sulfonyl Shift
a All reactions utilized 3.0 equiv of the amine and were run in toluene
[concn = 0.05 M] at 110 °C over 24 h with the exception that the
reaction time was 48 h for entry 4. b Isolated yields.
a Conditions: toluene, 110 °C, and 14 h. b Isolated yields.
lead to deallylation or allyl transfer depending upon the oxidation
state of palladium catalysts, the nucleophilicity of amines, and the
nature of the ligands. It essentially constitutes a Pd(0)-catalyzed
aza-Claisen rearrangement of N-allyl ynamides, which can also be
accomplished thermally. An observation of N-to-C 1,3-sulfonyl
shift was made when examining these aza-Claisen rearrange-
ments thermally, thereby representing a useful approach to nitrile
synthesis. While attempts to render this 1,3-sulfonyl shift stereo-
selective failed, we uncovered another set of tandem sigmatropic
arrangements, leading to vinyl imidate formation, and thereby
suggesting rich chemistry one can develop using these ynamides.
Most intriguingly, when exploring ynamide 69e [P = N-dimethyl
carbamoyl] and 69d [P = Piv] with hope of the aforementioned
anchiomeric assistance, we obtained R,β-unsaturated imidates 79
and 81, respectively. The double bond geometry was assured using
NOE experiments. In addition, when we went back to crude proton
NMR of the reaction using 69b in which P = Ac, we also saw ∼10%
of the respective imidate. Intriguingly, no nitrile was found in the
case of 69e, due to the increased electron density in the carbamate.
The isolation of these imidates implied a sequence of tandem
sigmatropic rearrangements: an aza-Claisen followed by another
[3,3]-sigmatropic rearrangement through the respective allyl-kete-
nimine intermediates 78 and 80 (Scheme 8).
’ EXPERIMENTAL SECTION
General Procedure for the Preparation of Des-allyl Ami-
dines from N-Allyl Ynamides. To a flame-dried screw-cap vial were
added ynamide 8a (117.0 mg, 0.300 mmol), PdCl2(PPh3)2 (10.5 mg, 0.015
mmol), THF (6 mL), and tert-butyl amine (158.0 μL, 1.50 mmol), and the
vial was then sealed under a dry nitrogen atmosphere and heated to 80 °C
for 2 h. After the reaction was judged to be complete by TLC, the solvent
’ CONCLUSION
We have described here a detailed study of amidine synthesis
from N-allyl-N-sulfonyl ynamides. Mechanistically, this is a
fascinating reaction consisting of diverging pathways that could
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Scheme 7. Diastereoselective N-to-C 1,3-Sulfonyl Shift
Scheme 8. Tandem Sigmatropic Rearrangement
13 (41%): Rf = 0.20 [4:1 hexanes/EtOAc]; white solid; mp =
1
84ꢀ87 °C; H NMR (400 MHz, CDCl3) δ 0.86 (d, 18H, J = 6.4
Hz), 0.90 (sept, 3H, J = 6.4 Hz), 1.88 (s, 2H), 2.42 (s, 3H), 3.82 (s, 3H),
6.90 (d, 2H, J = 8.8 Hz), 7.08 (d, 2H, J = 8.8 Hz), 7.26 (d, 2H, J = 8.0 Hz),
7.83 (d, 2H, J = 8.0 Hz), 9.80 (s, 1H); 13C NMR (100 MHz, CDCl3) δ
11.5, 18.3, 18.6, 21.7, 55.8, 114.8, 126.6, 128.2, 129.2, 130.3, 140.1, 142.7,
159.1, 169.3; IR (film) cmꢀ1 3272 m, 2943 m, 2869 m, 1610 m, 1573s,
1513 m; mass spectrum (ESI) m/e (% relative intensity) 497 (100) (M
þ Na)þ, 475 (40) (M þ H)þ; HRMS (ESI) m/e calcd for
C25H38N2O3SSiNa 497.2265, found 497.2258.
Table 7. Possible Diasteoselective 1,3-Sulfonyl Shift
14 (22%): Rf = 0.31 [4:1 hexanes/EtOAc]; white solid; mp =
1
125ꢀ128 °C; H NMR (500 MHz, CDCl3) δ 0.85 (d, 18H, J = 6.0
Hz), 0.85ꢀ0.95 (m, 3H), 1.94 (s, 2H), 2.42 (s, 3H), 7.17 (d, 2H, J = 7.5
Hz), 7.27 (d, 2H, J = 8.0 Hz), 7.31 (t, 1H, J = 7.5 Hz), 7.40 (t, 2H, J = 7.5
Hz), 7.84 (d, 2H, J = 8.0 Hz), 9.96 (s, 1H); 13C NMR (125 MHz,
CDCl3) δ 11.5, 18.4, 18.6, 21.8, 126.7, 126.8, 127.9, 129.3, 129.7, 137.6,
140.0, 142.8, 168.9; IR (film) cmꢀ1 3338w, 2962 m, 2867 m, 1608 m,
1569 m, 1527s, 1441 m; mass spectrum (ESI) m/e (% relative intensity)
467 (100) (M þ Na)þ, 445 (35) (M þ H)þ; HRMS (ESI) m/e calcd for
C24H36N2O2SSiNa 467.2159, found 467.2173.
15 (22%): Rf = 0.30 [4:1 hexanes/EtOAc]; white solid; mp =
147ꢀ150 °C; 1H NMR (400 MHz, CDCl3) δ 0.87 (s, 18H),
0.90ꢀ1.20 (m, 3H), 1.90 (brs, 2H), 2.42 (s, 3H), 7.05ꢀ7.17 (m, 2H),
7.27 (d, 2H, J = 8.0 Hz), 7.32ꢀ7.42 (m, 2H), 7.81 (d, 2H, J = 8.0 Hz),
9.91 (brs, 1H); 13C NMR (125 MHz, CDCl3) δ 11.6, 18.6, 21.7, 29.9,
126.6, 128.1, 129.3, 129.9, 133.7, 136.2, 139.7, 142.9, 168.7; IR
(film) cmꢀ1 3314 m, 2943 m, 2867 m, 1600 m, 1569s, 1517s, 1493s;
mass spectrum (ESI) m/e (% relative intensity) 501 (100) (M þ Na)þ,
479 (45) (M þ H)þ; HRMS (ESI) m/e calcd for C24H35ClN2O2SSiNa
501.1770, found 501.1766.
a Conditions: Toluene, 110 °C, and 2ꢀ4 h. b Isolated yields. c See
Scheme 8.
was removed in vacuo, and the resulting crude residue was purified via silica
gel flash column chromatography (isocratic eluent, 6:1 hexane/EtOAc) to
afford amidine 9 as a white solid (119.0 mg, 0.282 mmol, 94%).
9: Rf = 0.27 [4:1 hexanes/EtOAc]; white solid; mp = 134ꢀ135 °C; 1H
NMR (400 MHz, CDCl3) δ 1.11 (d, 18H, J = 8.8 Hz), 1.28 (sept, 3H,
J = 8.8 Hz), 1.31 (s, 9H), 2.39 (s, 3H), 2.45 (s, 2H), 4.91 (brs, 1H), 7.25
(d, 2H, J = 10.0 Hz), 7.79 (d, 2H, J = 10.0 Hz); 13C NMR (100 MHz,
CDCl3) δ 11.5, 18.7, 18.8, 21.6, 28.7, 53.4, 126.3, 129.2, 141.7, 141.8,
167.1; IR (film) cmꢀ1 3328 m, 2942 m, 2867 m, 1570 m, 1530s, 1341 m;
mass spectrum (ESI) m/e (% relative intensity) 447 (100) (M þ Na)þ,
425 (40) (M þ H)þ; HRMS (ESI) m/e calcd for C22H40N2O2SSiNa
447.2472, found 447.2476.
16 (30%): Rf = 0.33 [4:1 hexanes/EtOAc]; white solid; mp =
1
74ꢀ76 °C; H NMR (500 MHz, CDCl3) δ 0.87 (d, 18H, J = 7.0
Hz), 0.94ꢀ0.98 (m, 3H), 1.82 (s, 2H), 2.26 (s, 3H), 2.42 (s, 3H),
7.10ꢀ7.17 (m, 1H), 7.20ꢀ7.26 (m, 3H), 7.27 (d, 2H, J = 8.5 Hz), 7.84
(d, 2H, J = 8.5 Hz), 9.79 (brs, 1H); 13C NMR (125 MHz, CDCl3) δ
11.6, 18.2, 18.2, 18.6, 21.8, 126.7, 127.1, 127.5, 128.2, 129.3, 131.5, 134.7,
136.3, 140.0, 142.7, 169.2; IR (film) cmꢀ1 3256 m, 2941 m, 2866 m,
1566s, 1461 m; 1369 m, mass spectrum (ESI) m/e (% relative intensity)
481 (100) (M þ Na)þ, 459 (35) (M þ H)þ; HRMS (ESI) m/e calcd for
C25H38N2O2SSi 481.2316, found 481.2306.
11 (87%):Rf = 0.31 [4:1 hexanes/EtOAc]; white solid; mp = 73ꢀ76 °C;
1H NMR (400 MHz, CDCl3) (showing as two rotamers in 2.3:1 ratio)
major rotamer δ 0.96 (d, 18H, J = 6.0 Hz), 0.96ꢀ1.02 (m, 1H), 1.10 (s,
3H), 1.20ꢀ1.35 (m, 2H), 1.35ꢀ1.50 (m, 2H), 1.60 (pent, 2H, J = 7.2 Hz),
1.85 (s, 2H), 2.39 (s, 3H), 3.27 (t, 2H, J = 7.2 Hz), 7.22 (d, 2H, J = 8.0 Hz),
7.76 (d, 2H, J = 8.0 Hz), 8.28 (brs, 1H); 13C NMR (100 MHz, CDCl3)
major rotamer δ 11.7, 13.9, 18.0, 18.7, 20.1, 21.7, 31.8, 44.6, 126.5, 129.1,
140.4, 142.4, 169.7; IR (film) cmꢀ1 3322 m, 2942 m, 2869 m, 1532s, 1465
m; mass spectrum (APCI) m/e (% relative intensity) 425 (50) (M þ H)þ;
HRMS (ESI) m/e calcd for C22H40N2O2SSiH 425.2653, found 425.2640.
17 (g95%): Rf = 0.19 [4:1 hexanes/EtOAc], colorless oil; 1H NMR
(500 MHz, CDCl3) [showing as two rotamers in a 3:2 ratio] major
rotamer δ 0.97 (d, 18H, J = 6.5 Hz), 1.02 (sept, 3H, J = 6.5 Hz), 2.41
(s, 2H), 2.52 (s, 3H), 4.48 (d, 2H, J = 6.0 Hz), 7.24 (d, 2H, J = 7.0 Hz),
7.39ꢀ7.19 (m, 5H), 7.77 (d, 2H, J = 8.0 Hz), 8.65 (s, 1H); 13C NMR
(125 MHz, CDCl3) major rotamer δ 11.7, 18.3, 18.7, 21.7, 48.5, 126.6,
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127.2, 128.4, 129.2, 129.3, 136.3, 140.2, 142.6, 170.0; IR (film) cmꢀ1
3326brs, 2942 m, 2866 m, 1537s, 1496 m, 1270 m; mass spectrum
(APCI) m/e (% relative intensity) 459 (100) (M þ H)þ; HRMS (ESI)
m/e calcd for C25H38N2O2SSiH 459.2496, found 459.2506.
19 (g95%): Rf = 0.36 [2:1 hexanes/EtOAc]; white solid; mp =
143ꢀ145 °C; 1H NMR (300 MHz, CDCl3) δ 1.15 (d, 18H, J = 7.5 Hz),
1.38 (sept, 3H, J = 7.5 Hz), 2.40 (s, 3H), 2.70 (s, 2 h), 3.57 (brs, 2H),
3.69 (brs, 6H), 7.25 (d, 2H, J = 8.1 Hz), 7.80 (d, 2H, J = 8.1 Hz); 13C
NMR (75 MHz, CDCl3) δ 12.3, 16.3, 18.9, 21.6, 44.1, 47.1, 66.4, 77.6,
126.1, 129.2, 141.7, 142.1, 168.7; IR (film) cmꢀ1 2966 m, 2945 m, 2868
m, 1519s, 1444 m, 1271s, 1089s; mass spectrum (APCI) m/e (% relative
intensity) 439 (100) (M þ H)þ; HRMS (ESI) m/e calcd for
C22H38N2O3SSiNa 461.2265, found 461.2275.
20 (g95%): Rf = 0.28 [1:1 hexanes/EtOAc]; white solid; mp =
125ꢀ132 °C; 1H NMR (400 MHz, CDCl3) δ 1.16 (s, 9H), 2.39 (s, 3H),
3.09 (s, 2H), 3.66 (brs, 8H), 7.23 (d, 2H, J = 8.4 Hz), 7.78 (d, 2H, J = 8.4
Hz); 13C NMR (100 MHz, CDCl3) δ 21.6, 31.0, 31.4, 39.9, 66.8, 126.1,
129.3, 141.9, 142.3, 165.8 [missing one sp3 carbon due to overlap]; IR
(film) cmꢀ1 2960w, 2868w, 1599s, 1459 m, 1398 m, 1293s, 1141 m,
1065s; mass spectrum (APCI) m/e (% relative intensity) 339 (100)
(M þ H)þ; HRMS (ESI) m/e calcd for C17H26N2O3SNa 361.1556,
found 361.1574.
2.36 (s, 3H), 3.20 (q, 2H, J = 7.2 Hz), 3.50 (q, 2H, J = 7.2 Hz), 4.38 (s, 2H),
7.09ꢀ7.27 (m, 7H), 7.76 (d, 2H, J = 8.1 Hz); 13C NMR (75 MHz, CDCl3)
δ 12.0, 13.5, 21.5, 36.6, 43.3, 43.4, 126.2, 126.7, 127.8, 128.8, 129.0, 134.3,
141.4, 141.6, 164.5; IR (film) cmꢀ1 2978w, 2937w, 2359w, 1650w, 1549s,
1475 m, 1274 m, 1143 m; mass spectrum (APCI) m/e (% relative intensity)
345 (100) (M þ H)þ; HRMS (ESI) m/e calcd for C19H24N2O2SNa
367.1451, found 367.1438.
26 (g95%): Rf = 0.09 [4:1 hexanes/EtOAc]; waxy white solid; mp =
30ꢀ31 °C; 1H NMR (500 MHz, CDCl3) δ 0.88 (t, 3H, J = 7.0 Hz), 1.10
(t, 3H, J = 7.0 Hz), 1.22 (t, 3H, J = 7.0 Hz), 1.24ꢀ1.32 (m, 6H),
1.35ꢀ1.40 (m, 2H), 1.58ꢀ1.63 (m, 2H), 2.39 (s, 3H), 2.81ꢀ2.86 (m,
2H), 3.34 (q, 2H, J = 7.0 Hz), 3.44 (q, 2H, J = 7.0 Hz), 7.23 (d, 2H, J = 7.5
Hz), 7.82 (d, 2H, J = 7.5 Hz); 13C NMR (125 MHz, CDCl3) δ 12.3, 14.2,
14.4, 21.6, 22.7, 27.6, 29.0, 30.1, 31.1, 31.8, 43.3, 126.2, 129.1, 141.6,
142.1, 167.8; IR (film) cmꢀ1 2920 m, 2855 m, 1550s, 1474s, 1453s,
1434s; mass spectrum (ESI) m/e (% relative intensity) 375 (100) (M þ
Na)þ, 353 (30) (M þ H)þ; HRMS (ESI) m/e calcd for C19H32N2O2S-
Na 375.2077, found 375.2075.
27 (70%): Rf = 0.68 [1:1 hexanes/EtOAc]; yellow solid; mp =
1
78ꢀ80 °C; H NMR (400 MHz, CDCl3) δ 0.89 (t, 3H, J = 8.0 Hz),
1.22ꢀ1.49 (m, 20H), 1.56ꢀ1.68 (m, 2H), 2.39 (s, 3H), 2.85ꢀ2.89 (m,
2H), 3.51 (brs, 1H), 4.03 (sept, 1H, J = 6.4 Hz), 7.24 (d, 2H, J = 8.0 Hz),
7.81 (d, 2H, J = 8.0 Hz); 13C NMR (100 MHz, CDCl3) δ 14.3, 20.3,
20.9, 21.6, 22.8, 27.5, 29.1, 30.0, 31.9, 33.0, 48.1, 50.1, 126.3, 129.2,
141.6, 142.2, 166.7; IR (film) cmꢀ1 3479w, 2970w, 2932w, 1539s,
1494 m, 1449 m, 1267 m, 1086s; mass spectrum (APCI) m/e (% relative
intensity) 381(100) (M þ H)þ; HRMS (ESI) m/e calcd for
C21H36N2O2SH 381.2570, found 381.2561.
21 (92%): Rf = 0.36 [1:1 hexanes/EtOAc]; brown oil; 1H NMR (400
MHz, CDCl3) δ 0.04 (s, 6H), 0.88 (s, 9H), 1.57ꢀ1.72 (m, 4H), 2.40 (s,
3H), 2.93ꢀ2.98 (m, 2H), 3.51ꢀ3.53 (m, 2H), 3.62ꢀ3.72 (m, 8H), 7.25
(d, 2H, J = 8.4 Hz), 7.81 (d, 2H, J = 8.4 Hz); 13C NMR (100 MHz,
CDCl3) δ ꢀ5.2, 14.3, 18.4, 21.2, 21.6, 23.5, 26.1, 30.4, 32.3, 60.5, 62.1,
66.5, 126.4, 128.6, 129.3, 132.3, 142.1; IR (film) cmꢀ1 3058 m, 2929 m,
2856 m, 1536s, 1438 m, 1388w, 1359w, 1268s, 1143s, 1117s, 1087s;
mass spectrum (APCI) m/e (% relative intensity) 455 (100) (M þ H)þ;
HRMS (ESI) m/e calcd for C22H38N2O4SSiNa 477.2214, found
477.2222.
28 (g95%): Rf = 0.45 [4:1 hexanes/EtOAc]; brown solid; mp =
182ꢀ184 °C; 1H NMR (400 MHz, CDCl3) δ 1.15 (d, 18H, J = 7.2 Hz),
1.46 (sept, 3H, J = 7.2 Hz), 2.39 (s, 3H), 2.84 (brs, 2H), 3.14 (t, 2H,
J = 8.4 Hz), 4.11 (t, 2H, J = 8.4 Hz), 7.00 (td, 1H, J = 0.8, 7.2 Hz), 7.06 (t,
1H, J = 7.2 Hz), 7.17 (d, 1H, J = 7.2 Hz), 7.25 (dd, 2H, J = 0.4, 8.8 Hz),
7.85 (d, 2H, J = 8.8 Hz), 8.07, (brs, 1H); 13C NMR (100 MHz, CDCl3)
δ 12.8, 19.0, 20.1, 21.7, 27.7, 50.4, 119.8, 124.8, 124.8, 126.5, 127.7,
129.3, 132.9, 141.6, 141.8, 142.6, 166.3; IR (film) cmꢀ1 3055w, 2941w,
2867w, 1541 m, 1481 m, 1265s, 1143 m, 1089 m; mass spectrum (APCI)
m/e (% relative intensity) 471 (100) (M þ H)þ; HRMS (ESI) m/e calcd
for C26H38N2O2SSiNa 493.2316, found 493.2340.
22 (37%): Rf = 0.21 [1:1 hexanes/EtOAc]; yellow foam; mp =
1
54ꢀ60 °C; H NMR (400 MHz, CDCl3) δ 2.37 (s, 3H), 3.24 (t, 2H,
J = 4.8 Hz), 3.33 (t, 2H, J = 4.8 Hz), 3.63 (t, 2H, J = 5.2 Hz), 3.81 (t, 2H,
J= 5.2 Hz), 3.83 (s, 3H), 4.35 (s, 2H), 6.84 (d, 1H, J= 8.0 Hz), 6.85 (td, 1H,
J = 1.2, 7.6 Hz), 7.04 (dd, 1H, J = 1.2, 7.6 Hz), 7.20 (d, 2H, J = 8.0 Hz),
7.21ꢀ7.23 (m, 1H), 7.80 (d, 2H, J = 8.0 Hz); 13C NMR (125 MHz,
CDCl3) δ 21.7, 30.4, 45.2, 46.9, 55.7, 66.5, 66.5, 110.6, 121.2, 122.5, 126.7,
128.5, 128.7, 129.3, 141.1, 142.2, 156.1, 166.4; IR (film) cmꢀ1 2966w,
2858w, 1540s, 1463 m, 1271s, 1069s, 998s; mass spectrum (APCI) m/e (%
relative intensity) 389 (100) (M þ H)þ; HRMS (ESI) m/e calcd for
C20H24N2O4SH 389.1530, found 389.1523.
29 (77%): Rf = 0.67 [1:1 hexanes/EtOAc]; white solid; mp =
1
89ꢀ90 °C; H NMR (400 MHz, CDCl3) [showing as two rotamers
in 1.7:1 ratio] major rotamer δ 1.13 (d, 18H, J = 7.6 Hz), 1.40 (sept, 3H,
J = 7.6 Hz), 2.37 (s, 3H), 2.75 (s, 2H), 3.01 (s, 3H), 4.68 (s, 2H),
7.06ꢀ7.11 (m, 3H), 7.17 (d, 2H, J = 8.4 Hz), 7.22ꢀ7.26 (m, 2H), 7.74
(d, 2H, J = 8.4 Hz); 13C NMR (125 MHz, CDCl3) major rotamer δ 12.6,
17.0, 18.9, 21.6, 36.9, 54.2, 126.2, 127.8, 128.5, 128.7, 129.1, 136.1, 141.4,
142.3, 169.4; IR (film) cmꢀ1 3060w, 2944 m, 2867 m, 2362w, 1530s,
1454 m, 1266s, 1142s, 1088s, 1017 m; mass spectrum (APCI) m/e
(% relative intensity) 473 (100) (M þ H)þ; HRMS (ESI) m/e calcd for
C26H40N2O2SSiH 473.2653, found 473.2676.
23 (39%): Rf = 0.50 [1:1 hexanes/EtOAc]; pale yellow solid; mp =
159ꢀ161 °C; 1H NMR (400 MHz, CDCl3) δ 1.15 (d, 18H, J = 7.2 Hz),
1.37 (sept, 3H, J = 7.2 Hz), 2.71 (s, 2H), 3.53 (brs, 2H), 3.65 (brs, 2H),
3.68 (brs, 2H), 3.73 (brs, 2H), 8.08 (d, 2H, J = 9.2 Hz), 8.29 (d, 2H,
J = 9.2 Hz); 13C NMR (100 MHz, CDCl3) δ 12.3, 17.0, 18.9, 45.5, 47.3,
66.4, 124.1, 127.4, 149.4, 150.4, 169.2; IR (film) cmꢀ1 2983w, 2360w,
1740s, 1526 m, 1444 m, 1374 m, 1242s, 1047s; mass spectrum (APCI)
m/e (% relative intensity) 470 (100) (M þ H)þ; HRMS (ESI) m/e calcd
for C21H35N3O5SSiH 470.2140, found 470.2150.
30a (g95%): Rf = 0.30 [3:1 hexanes/EtOAc]; white solid; mp =
161ꢀ 163 °C; 1H NMR (300 MHz, CDCl3) δ 1.15 (d, 18H, J = 7.2 Hz),
1.41 (sept, 3H, J = 7.2 Hz), 1.87 (quint, 2H, J = 6.6 Hz), 1.98 (quint, 2H,
J = 6.6 Hz), 2.40 (s, 3H), 2.63 (s, 2H), 3.51 (q, 4H, J = 8.7 Hz), 7.23
(d, 2H, J = 8.4 Hz), 7.85 (d, 2H, J = 8.4 Hz); 13C NMR (75 MHz,
CDCl3) δ 12.6 18.3, 18.9, 21.5, 24.4, 26.1, 48.3, 49.0, 126.1, 129.0, 141.3,
142.7, 167.2; IR (film) cmꢀ1 2945w, 2868 m, 1530s, 1463 m, 1421 m,
1337w, 1268 m, 1139 m, 1089s; mass spectrum (APCI) m/e (% relative
intensity) 423 (100) (M þ H)þ; HRMS (ESI) m/e calcd for
C22H38N2O2SSiNa 445.2316, found 445.2329.
24 (g95%): Rf = 0.32 [4:1 hexanes/EtOAc]; white solid; mp =
129ꢀ130 °C; 1H NMR (500 MHz, CDCl3) δ 1.08 (t, 3H, J = 7.5 Hz),
1.18 (d, 18H, J = 7.5 Hz), 1.19 (t, 3H, J = 7.0 Hz), 1.39 (sept, 3H, J = 7.5
Hz), 2.36 (s, 3H), 2.62 (s, 2H), 3.32 (q, 2H, J = 7.0 Hz) 3.42 (q, 2H,
J = 7.0 Hz), 7.20 (d, 2H, J = 8.0 Hz), 7.79 (d, 2H, J = 8.0 Hz); 13C NMR
(125 MHz, CDCl3) δ 12.3, 12.4, 13.6, 16.4, 18.9, 21.5, 43.5, 43.6, 125.9,
129.0, 141.2, 142.7, 167.7; IR (film) cmꢀ1 2941s, 2868 m, 2361w, 1548s,
1469s, 1362 m, 1261 m, 1395s; mass spectrum (APCI) m/e (% relative
intensity) 425 (100) (M þ H)þ; HRMS (ESI) m/e calcd for
C22H40N2O2SSiNa 447.2472, found 447.2479.
30b (g95%): Rf = 0.28 [4:1 hexanes/EtOAc]; white solid; mp =
121ꢀ122 °C; 1H NMR (300 MHz, CDCl3) δ 1.15 (d, 18H, J = 7.5 Hz),
1.39 (sept, 3H, J = 7.5 Hz), 1.54 (brs, 2H), 1.64 (brs, 4H), 2.39 (s, 3H),
2.69 (s, 2H), 3.45 (brs, 2H), 3.70 (brs, 2H), 7.28 (d, 2H, J = 8.4 Hz), 7.80
25 (g95%): Rf = 0.29 [2:1 hexanes/EtOAc]; pale yellow oil; 1H NMR
(300 MHz, CDCl3) δ 0.94 (t, 3H, J = 7.2 Hz), 1.16 (t, 3H, J = 7.2 Hz),
5098
dx.doi.org/10.1021/jo200780x |J. Org. Chem. 2011, 76, 5092–5103

The Journal of Organic Chemistry
ARTICLE
(d, 2H, J = 8.4 Hz); 13C NMR (75 MHz, CDCl3) δ 12.3, 16.5, 18.9, 21.5,
24.3, 25.5, 26.4, 46.3, 48.1, 126.0, 129.0, 141.3, 142.7, 167.9; IR
(film) cmꢀ1 2943 m, 2867 m, 1526s, 1468 m, 1445 m, 1271 m, 1144s,
1089s; mass spectrum (APCI) m/e (% relative intensity) 437 (100)
(M þ H)þ; HRMS (ESI) m/e calcd for C23H40N2O2SSiNa 459.2472,
found 459.2461.
30c (g95%): Rf = 0.34 [4:1 hexanes/EtOAc]; white solid; mp =
150ꢀ152 °C; 1H NMR (300 MHz, CDCl3) δ 1.15 (d, 18H, J = 7.2 Hz),
1.39ꢀ1.73 (m, 11H), 2.40 (s, 3H), 2.68 (s, 2H), 3.49 (t, 2H, J = 6.0 Hz),
3.61 (t, 2H, J = 6.0 Hz), 7.23 (d, 2H, J = 7.8 Hz), 7.81 (d, 2H, J = 8.1 Hz);
13C NMR (75 MHz, CDCl3) δ 12.4, 16.4, 18.9, 21.5, 26.3, 26.4, 26.7,
29.0, 50.0, 50.1, 125.9, 129.0, 141.2, 142.6, 168.4; IR (film) cmꢀ1 2939 m,
2866 m, 1533s, 1473 m, 1370w, 1271 m, 1143 m, 1089 m; mass
spectrum (APCI) m/e (% relative intensity) 451 (100) (M þ H)þ;
HRMS (ESI) m/e calcd for C24H42N2O2SSiNa 473.2629, found
473.2643.
13C NMR (75 MHz, CDCl3) δ 12.3, 12.4, 16.5, 18.9, 19.0, 21.6, 71.6, 126.1,
129.2, 141.7, 142.2, 168.4; IR (film) cmꢀ1 2973 m, 2870 m, 1523s, 1463 m,
1271 m, 1148s, 1093s; mass spectrum (APCI) m/e (% relative intensity) 467
(100) (M þ H)þ; HRMS (ESI) m/e calcd for C24H42N2O3SSiH 467.2758,
found 467.2747.
35 (82%): Rf = 0.64 [1:1 hexanes/EtOAc]; brown oil; 1H NMR (400
MHz, CDCl3) δ 0.91 (d, 18H, J = 7.6 Hz), 1.18 (sept, 3H, J = 7.6 Hz), 2.42
(s, 3H), 2.73 (s, 2H), 3.27 (s, 3H), 3.82 (s, 3H), 6.92 (d, 2H, J = 8.4 Hz),
7.12 (d, 2H, J = 8.4 Hz), 7.25 (d, 2H, J = 7.6 Hz), 7.88 (d, 2H, J = 7.6 Hz);
13C NMR (100 MHz, CDCl3) δ 12.2, 17.3, 18.6, 18.8, 21.6, 55.9, 113.8,
115.1, 115.2, 126.2, 128.9, 129.2, 141.6, 159.3, 169.9; IR (film) cmꢀ1 2945
m, 2868 m, 2252w, 1608 m, 1509s, 1463 m, 1406 m; mass spectrum (APCI)
m/e (% relative intensity) 498 (100) (M þ H)þ; HRMS (ESI) m/e calcd
for C26H40N2O3SSiNa 511.2421, found 511.2411.
General Procedure for the Preparation of r-Allyl Ami-
dines from Secondary Amines using Pd2(dba)3 and
Xantphos3. To a flame-dried vial filled with nitrogen were added
Pd2(dba)3 (8.90 mg, 0.010 mmol), xantphos (11.2 mg, 0.020 mmol),
and anhyd THF (4 mL). The resulting solution was stirred at rt for 10 min.
Subsequently, a respective ynamide (79.0 mg, 0.20 mmol), K2CO3
(27.8 mg, 0.20 mmol), and pyrollidine (49.0 μL, 0.60 mmol) were
added. The reaction mixture was stirred under nitrogen at 65 °C for 6 h.
The progress of the reaction was monitored by TLC. After complete
consumption of the starting ynamide, the crude reaction mixture was
filtered through Celite and concentrated in vacuo. Purification of the crude
residue via silica gel flash column chromatography [isocratic eluent, 5:1
hexanes/EtOAc] afforded amidine 39 (95.0 mg, 0.20 mmol, g95%).
39: Rf = 0.22 [5:1 hexanes/EtOAc]; white solid; mp 75ꢀ76 °C; 1H
NMR (400 MHz, CDCl3) δ 0.98 (d, 18H, J = 6.0 Hz), 1.16 (m, 3H),
1.76ꢀ1.82 (m, 1H), 1.92ꢀ2.08 (m, 3H), 2.17ꢀ2.22 (m, 1H),
2.26ꢀ2.29 (m, 1H), 2.38 (s, 3H), 2.44ꢀ2.52 (m, 1H), 3.56 (q, 1H,
J = 8.0 Hz), 3.68 (td, 1H, J = 2.4, 8.0 Hz), 4.22 (brs, 2H), 4.97 (d, 1H, J =
10.8 Hz), 5.02 (d, 1H, J = 17.6 Hz), 5.81 (m, 1H), 7.20 (d, 2H, J = 8.4
Hz), 7.78 (d, 2H, J = 8.4 Hz); 13C NMR (125 MHz, CDCl3) δ 11.5,
19.1, 21.5, 25.4, 25.8, 35.8, 35.9, 51.8, 53.2, 116.0, 126.1, 128.8, 137.8,
140.9, 143.2, 167.1; IR (neat) cmꢀ1 2924 ms, 2863 m, 1547s, 1414s,
1274s, 1139s; mass spectrum (APCI) m/e (% relative intensity) 463
(100) (M þ H)þ; HRMS (ESI) m/e calcd for C25H42N2O2SSiNa
485.2628, found 486.2630.
31 (91%): Rf = 0.64 [1:1 hexanes/EtOAc]; pale solid; mp =
1
92ꢀ96 °C; H NMR (400 MHz, CDCl3) [showing as two rotamers
in a 2.0:1 ratio] major rotamer δ 1.10ꢀ1.24 (m, 21H), 1.33ꢀ1.40
(m, 3H), 1.86ꢀ2.04 (m, 4H), 2.36 (s, 3H), 2.43 (d, 1H, J = 12.4 Hz),
2.73 (d, 1H, J = 12.4 Hz), 3.41ꢀ3.53 (m, 2H), 4.27ꢀ4.30 (m, 1H), 7.20
(d, 2H, J = 8.4 Hz), 7.79 (d, 2H, J = 8.4 Hz); 13C NMR (100 MHz,
CDCl3) major rotamer δ 12.7, 18.4, 19.0, 19.0, 21.6, 23.8, 31.8, 48.6, 55.8,
126.1, 129.1, 141.3, 142.7, 166.9; IR (film) cmꢀ1 2972 m, 2868 m, 2839
m, 2361 m, 1781w, 1738s, 1517s, 1461 m, 1240s; mass spectrum (APCI)
m/e (% relative intensity) 437 (100) (M þ H)þ; HRMS (ESI) m/e calcd
for C23H40N2O2SSiNa 459.2472, found 459.2471.
32 (g95%): Rf = 0.80 [1:1 hexanes/EtOAc]; [R] 23 = ꢀ63.5 (c 0.43,
D
1
dichloromethane); pale yellow oil; H NMR (400 MHz, CDCl3) δ
1.13ꢀ1.16 (m, 18H), 1.40 (sept, 3H, J = 6.8 Hz), 1.92ꢀ1.99 (m, 2H),
2.09ꢀ2.16 (m, 2H), 2.39 (s, 3H), 2.43 (d, 1H, J = 12.4 Hz), 2.95 (d, 1H,
J = 12.4 Hz), 3.34 (s, 3H), 3.59ꢀ3.60 (m, 1H), 3.66ꢀ3.72 (m, 1H), 4.45
(dd, 1H, J = 4.0, 8.4 Hz), 7.21 (d, 2H, J = 8.4 Hz), 7.74 (d, 2H, J = 8.4
Hz); 13C NMR (100 MHz, CDCl3) δ 12.6, 18.0, 19.0, 21.6, 24.8, 29.5,
48.7, 52.0, 61.5, 126.4, 129.0, 141.6, 142.0, 167.6, 172.3; IR (film) cmꢀ1
3058w, 2949 m, 2871 m, 2364w, 1747s, 1519s, 1459 m, 1367w, 1267s,
1142 m; mass spectrum (APCI) m/e (% relative intensity) 481 (100)
(M þ H)þ; HRMS (ESI) m/e calcd for C29H40N2O4SSiNa 503.2370,
found 503.2348.
1
2
General Procedure for the Preparation of Vinylogous
Amidines. To a flame-dried screw-cap vial were added ynamide 8a
(75.0 mg, 0.192 mmol), Pd2(dba)3 (8.8 mg, 0.0096 mmol), xantphos
(11.1 mg, 0.019 mmol), THF (2.0 mL), and enamine 41 (77.0 μL, 0.576
mmol), and the vial was then sealed under a dry nitrogen atmosphere
and heated to 70 °C for 2 h. After the reaction was judged to be complete
by TLC, the solvent was removed in vacuo, and the resulting crude
residue was purified via silica gel flash column chromatography (isocratic
eluent, 1:1 hexane/EtOAc þ 5% NEt3 buffer) to afford the vinylogous
amidine 45 as an orange solid (52.4 mg, 0.099 mmol, 52%).
33a (g95%): Rf = 0.46 [95:5 CH Cl2:MeOH]; pale yellow oil; H
NMR (300 MHz, CDCl3) δ 1.15 (d, 18H, J = 7.5 Hz), 1.38 (sept, 3H,
J = 7.5 Hz), 2.30 (s, 3H), 2.39 (brs, 4H), 2.40 (s, 3H), 2.70 (s, 2H), 3.51
(brs, 2H), 3.74 (brs, 2H), 7.24 (d, 2H, J = 8.4 Hz), 7.81 (d, 2H, J = 8.4
Hz); 13C NMR (75 MHz, CDCl3) δ 12.2, 16.5, 18.9, 21.6, 44.8, 45.9,
46.6, 54.4, 54.9, 77.2, 128.6, 133.2, 141.5, 142.3, 168.4; IR (film) cmꢀ1
2943 m, 2868 m, 2796 m, 1525s, 1452 m, 1363w, 1271 m, 1143 m, 1092 m;
mass spectrum (APCI) m/e (% relative intensity) 452 (100) (M þ H)þ;
HRMS (ESI) m/e calcd for C23H41N3O2SSiH 452.2672, found 452.2668.
33b (g95%): Rf = 0.50 [2:1 hexanes/EtOAc]; white solid; mp =
126ꢀ127 °C; 1H NMR (300 MHz, CDCl3) δ 1.19 (d, 18H, J = 7.2 Hz),
1.43 (sept, 3H, J = 7.2 Hz), 2.42 (s, 3H), 2.77 (s, 2H), 3.17 (brs, 2H),
3.24 (brs, 2H), 3.71 (brs, 2H), 3.92 (brs, 2H), 6.92ꢀ6.98 (m, 3H),
7.26ꢀ7.35 (m, 4H), 7.85 (d, 2H, J = 8.1 Hz); 13C NMR (75 MHz,
CDCl3) δ 12.0, 16.2, 18.6, 21.3, 44.4, 46.3, 48.5, 49.2, 116.3, 120.6,
125.9, 128.9, 129.2, 141.4, 141.9, 150.3, 168.3; IR (film) cmꢀ1 3029w,
2945 m, 2868 m, 1600 m, 1525s, 1453 m, 1277 m, 1143 m, 1091 m; mass
spectrum (APCI) m/e (% relative intensity) 514 (100) (M þ H)þ;
HRMS (ESI) m/e calcd for C28H43N3O2SSiNa 536.2738, found
536.2737.
45: Rf = 0.23 [1:1 hexanes/EtOAc]; orange solid, mp = 95ꢀ97 °C; 1H
NMR (400 MHz, CDCl3) [spectrum complicated by rotamers] δ 1.07 (d,
9H, J = 6.4 Hz), 1.11 (d, 9H, J = 5.2 Hz), 1.10ꢀ1.20 (m, 3H), 1.83ꢀ1.90
(m, 2H), 1.90ꢀ2.01 (m, 3H), 2.01ꢀ2.15 (m, 2H), 2.25ꢀ2.35 (m, 1H),
2.34 (s, 3H), 2.50 (d, 1H, J = 11.2 Hz), 2.57ꢀ2.72 (m, 2H), 2.80 (t, 1H, J =
4.8 Hz), 2.85ꢀ2.92 (m, 1H), 3.18 (brs, 2H), 3.89 (brs, 2H), 4.66 (d, 1H, J=
18.8 Hz), 4.67 (d, 1H, J = 9.2 Hz), 5.51ꢀ5.62 (m, 1H), 7.14 (d, 2H, J = 8.4
Hz), 7.76 (d, 2H, J = 8.4 Hz); 13C NMR (125 MHz, CDCl3) δ 12.3, 19.3,
19.4, 21.6, 21.7, 25.4, 29.9, 35.2, 36.2, 40.4, 53.0, 111.4, 113.6, 126.0, 128.7,
131.1, 140.0, 140.2, 143.7, 148.1; IR (film) cmꢀ1 2944 m, 2865 m, 1736 m,
1579 m, 1469s, 1445s, 1342 m; mass spectrum (ESI) m/e (% relative
intensity) 529 (100) (M þ H)þ; HRMS (ESI) m/e calcd for C30H48N2
34 (g95%): Rf = 0.59 [1:1 hexanes/EtOAc]; yellow solid; mp =
125ꢀ126 °C; 1H NMR (400 MHz, CDCl3) δ 1.12 (d, 18H, J = 7.2 Hz),
1.10ꢀ1.20 (m, 6H), 1.34 (sept, 3H, J = 7.2 Hz), 2.28ꢀ2.31 (m, 1H), 2.37 (s,
3H), 2.62ꢀ2.74 (m, 2H), 3.47ꢀ3.68 (m, 3H), 3.37 (sext, 1H, J = 4.8 Hz),
4.62 (d, 1H, J = 13.2 Hz), 7.20 (d, 2H, J = 7.6 Hz), 7.75 (d, 2H, J = 7.6 Hz);
O2SSiH 529.3279, found 529.3269.
1
46 (71%): Rf = 0.18 [1:1 hexanes/EtOAc], orange oil; H NMR
(400 MHz, CDCl3) [spectrum complicated by rotamers] δ 1.05 (d, 9H,
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ARTICLE
J = 6.4 Hz), 1.09 (d, 9H, J = 5.2 Hz), 1.09ꢀ1.15 (m, 3H), 1.70ꢀ2.10
(m, 9H), 2.32 (brs, 1H), 2.48 (d, 1H, J = 11.2 Hz), 2.57ꢀ2.70 (m, 2H),
2.76 (brs, 1H), 2.80ꢀ2.90 (m, 1H), 3.13 (brs, 2H), 3.80 (s, 3H), 3.83
(brs, 2H), 4.63 (d, 1H, J = 5.6 Hz), 4.65 (d, 1H, J = 10.8 Hz), 5.48ꢀ5.60
(m, 1H), 6.81 (d, 2H, J = 8.8 Hz), 7.79 (d, 2H, J = 8.8 Hz); 13C NMR
(100 MHz, CDCl3) δ 12.3, 19.3, 19.4, 21.7, 25.4, 35.1, 36.2, 40.3, 52.9,
55.5, 113.2, 113.6, 127.9, 139.0, 139.8, 139.9, 160.9 [missing two sp2
signals due to rotamers]; IR (film) cmꢀ1 2943 m, 2866 m, 1596 m, 1590
m, 1468s, 1249s; mass spectrum (APCI) m/e (% relative intensity) 545
(100) (M þ H)þ; HRMS (ESI) m/e calcd for C30H48N2O3SSiH
545.3228, found 545.3240.
47 (58%): Rf = 0.12 [1:2 hexanes/EtOAc]; orange solid, mp =
69ꢀ72 °C; 1H NMR (500 MHz, CDCl3) δ 1.98 (pent, 2H, J = 6.5 Hz),
2.02 (brs, 4H), 2.32 (t, 2H, J = 8.5 Hz), 2.34 (t, 2H, J = 8.5 Hz), 2.71 (t,
2H, J = 6.5 Hz), 3.07 (t, 2H, J = 6.5 Hz), 3.30ꢀ3.55 (m, 4H), 4.92 (dq,
1H, J = 1.5, 10.0 Hz), 5.00 (dq, 1H, J = 1.5, 17.0 Hz), 5.81 (ddt, 1H, J =
6.5, 10.5, 17.0 Hz), 8.30 (d, 2H, J = 9.0 Hz), 8.05 (d, 2H, J = 9.0 Hz); 13C
NMR (125 MHz, CDCl3) δ 19.3, 25.3, 31.2, 32.1, 38.1, 41.8, 52.5, 109.7,
115.2, 124.1, 128.0, 137.7, 148.6, 149.7, 169.5, 186.5, 193.0; IR
(film) cmꢀ1 3062 m, 2954 m, 2877 m, 1634 m, 1608 m, 1527s, 1436s,
1349s; mass spectrum (ESI) m/e (% relative intensity) 454 (100) (M þ
Na)þ, 432 (15) (M þ H)þ; HRMS (ESI) m/e calcd for C21H25N3O5S
Na 454.1408, found 454.1402.
48 (54%): Rf = 0.14 [1:1 hexanes/EtOAc]; orange solid; mp =
104ꢀ107 °C; 1H NMR (500 MHz, CDCl3) δ 0.00 (s, 6H), 0.84 (s, 9H),
1.22 (s, 2H), 1.51ꢀ1.56 (m, 4H), 1.71ꢀ1.79 (m, 6H), 2.35 (s, 3H), 2.57
(t, 2H, J = 7.5 Hz), 2.61 (t, 2H, J = 7.5 Hz), 2.75ꢀ2.78 (m, 2H), 3.32 (t,
4H, J = 6.5 Hz), 3.55 (t, 2H, J = 6.5 Hz), 7.19 (d, 2H, J = 8.0 Hz), 7.78 (d,
2H, J = 8.0 Hz); 13C NMR (125 MHz, CDCl3) δ ꢀ5.1, 18.5, 21.3, 21.6,
25.0, 25.6, 26.2, 32.8, 33.3, 36.6, 37.1, 53.8, 62.9, 107.0, 126.8, 129.2,
141.6, 142.4, 165.8, 176.9; IR (film) cmꢀ1 2928 m, 2855 m, 1569s,
1470s, 1416s; mass spectrum (ESI) m/e (% relative intensity) 505 (100)
(M þ H)þ; HRMS (ESI) m/e calcd for C27H44N2O3SSiH 505.2915,
found 505.2894.
(isocratic eluent, 5:1 hexanes/EtOAc) afforded the amidine 56 (77.4
mg, 0.19 mmol, 94% yield).
56: Rf = 0.33 [5:1 hexanes/EtOAc]; white solid; mp = 106ꢀ108 °C;
1H NMR (400 MHz, CDCl3) [showing as two rotamers in 2.5:1 ratio]
major rotamer δ 0.80ꢀ1.40 (m, 6H), 1.40ꢀ1.70 (m, 3H), 1.70ꢀ1.95
(m, 2H), 2.41 (s, 3H), 2.82 (pent, 1H, J = 7.2 Hz), 3.47 (brs, 1H), 3.64
(t, 1H, J = 7.2 Hz), 4.89 (d, 1H, J = 11.2 Hz), 4.93 (d, 1H, J = 19.2 Hz),
5.55ꢀ5.68 (m, 1H), 7.21 (brs, 5H), 7.25 (d, 2H, J = 7.6 Hz), 7.78 (d, 2H,
J = 8.4 Hz), 8.34 (d, 1H, J = 8.4 Hz); 13C NMR (125 MHz, CDCl3)
major rotamer δ 21.7, 24.6, 24.7, 25.1, 33.3, 34.3, 39.3, 48.7, 52.6, 117.3,
126.5, 127.7, 128.0, 129.0, 129.3, 135.7, 139.5, 140.0, 142.7, 166.9; IR
(film) cmꢀ1 3320brs, 2933 m, 2856 m, 1532s, 1451 m; mass spectrum
(ESI) m/e (% relative intensity) 844 (30) (2M þ Na þ H), 433 (100)
(M þ Na)þ; HRMS (ESI) m/e calcd for C48H60N4O4S2Na (2M þ Na)
843.3949, found 843.3962.
1
60 (93%): Rf = 0.12 [4:1 hexanes/EtOAc]; colorless oil; H NMR
(400 MHz, CDCl3) δ 1.03 (s, 18H), 1.15ꢀ1.30 (m, 3H), 2.18ꢀ2.32 (m,
2H), 2.32ꢀ2.61 (m, 1H), 3.45ꢀ4.20 (m, 8H), 4.99 (d, 1H, J = 16.8 Hz),
5.00 (d, 1H, J = 10.0 Hz), 5.65ꢀ5.85 (m, 1H), 8.06 (d, 2H, J = 9.2 Hz),
8.30 (d, 2H, J = 9.2 Hz); 13C NMR (125 MHz, CDCl3) δ 11.6, 19.1,
34.0, 35.0, 51.6, 66.7, 116.7, 123.9, 127.3, 137.2, 149.2, 150.6 170.7; IR
(film) cmꢀ12947 m, 2869 m, 1640w, 1529s, 1425 m, 1350 m; mass
spectrum (ESI) m/e (% relative intensity) 532 (100) (M þ Na)þ;
HRMS (ESI) m/e calcd for C24H39N3O5SSiNa 532.2272, found
532.2264.
General Procedure for the Preparation of Nitriles and
Unsaturated Imidates via Tandem Thermal Rearrange-
ments. To a flame-dried screw-cap vial were added ynamide 8i
(100.0 mg, 0.306 mmol) and anhyd toluene (2.5 mL). The vial was
flushed with nitrogen and heated to 110 °C overnight. When the
reaction was judged to be complete by TLC, removal of the solvent in
vacuo followed by purification via silica gel flash column chromatography
(isocratic eluent, 10:1 hexanes/EtOAc) afforded the nitrile 63 (52.7 mg,
0.161 mmol, 53% yield).
49 (57%): Rf = 0.17 [1:2 hexanes/EtOAc]; orange solid; mp =
79ꢀ83 °C; 1H NMR (500 MHz, CDCl3) δ 1.69 (pent, 2H, J = 7.5 Hz),
1.82ꢀ1.85 (m, 4H), 2.40 (t, 2H, J = 7.5 Hz), 2.53 (t, 2H, J = 7.5 Hz), 3.43
(t, 4H, J = 7.5 Hz), 3.81 (s, 3H), 4.24 (s, 2H), 6.85 (d, 2H, J = 9.0 Hz),
7.13ꢀ7.22 (m, 5H), 7.84 (d, 2H, J = 9.0 Hz); 13C NMR (125 MHz,
CDCl3) δ 21.2, 25.6, 32.8, 36.4, 42.6, 53.8, 55.7, 108.2, 113.7, 126.1,
128.4, 128.7, 129.2, 137.0, 137.6, 161.9, 166.9, 172.6; IR (film) cmꢀ1
2953 m, 2870 m, 1665 m, 1594 m, 1494 m, 1412s; mass spectrum (ESI)
m/e (% relative intensity) 425 (100) (M þ H)þ; HRMS (ESI) m/e calcd
for C24H28N2O3SH 425.1894, found 425.1897.
51 (62%): Rf = 0.15 [1:1 hexanes/EtOAc]; yellow solid; mp =
177ꢀ179 °C; 1H NMR (500 MHz, d8-toluene, 90 °C) spectrum not
resolved due to rotamers δ 1.00ꢀ1.30 (m, 8H), 1.30ꢀ1.60 (m, 6H),
1.75ꢀ1.85 (m, 2H), 1.95ꢀ2.10 (m, 2H), 2.32 (brs, 4H), 2.55ꢀ2.62
(m, 3H), 2.83 (brs, 6H), 3.05ꢀ3.13 (m, 1H), 3.31 (brs, 1H), 3.79 (dd,
1H, J = 6.5, 15.0 Hz), 4.65ꢀ4.75 (m, 2H), 4.76ꢀ4.85 (m, 2H), 5.52
(brs, 1H), 5.60ꢀ5.65 (m, 1H), 6.80ꢀ7.20 (m, 10H), 7.40 (brs, 2H),
7.52 (d, 2H, J = 7.5 Hz), 7.65 (d, 2H, J = 6.5 Hz), 7.65ꢀ7.80 (m, 2H).
13C NMR (125 MHz, CDCl3) could not obtain spectrum due to
rotamers; IR (film) cmꢀ1 2970 m, 2924w, 1738s, 1621 m, 1527s,
1432s, 1350s; mass spectrum (APCI) m/e (% relative intensity) 508
(100) (M þ H)þ; HRMS (ESI) m/e calcd for C27H29N3O5SH
508.1901, found 508.1900.
63: Rf = 0.32 [4:1 hexanes/EtOAc]; waxy white solid; mp =
1
50ꢀ53 °C; H NMR (400 MHz, CDCl3) δ 3.32 (dd, 1H, J = 7.2,
14.0 Hz), 3.45 (dd, 1H, J = 6.8, 14.0 Hz), 3.85 (s, 3H), 5.18 (dd, 1H, J =
1.2, 10.0 Hz), 5.30 (dd, 1H, J = 1.2, 16.8 Hz), 5.55 (dddd, 1H, J = 6.8, 7.2,
10.0, 16.8 Hz), 6.84 (d, 2H, J = 9.2 Hz), 7.33ꢀ7.35 (m, 2H), 7.38ꢀ7.41
(m, 3H), 7.44 (d, 2H, J = 9.2 Hz); 13C NMR (100 MHz, CDCl3) δ 36.1,
56.0, 72.2, 114.2, 116.6, 122.2, 125.1, 128.8, 128.9, 129.0, 129.3, 130.2,
133.2, 164.9; IR (film) cmꢀ1 2946 m, 2843 m, 2238w, 1641s, 1592s,
1495s, 1365s; mass spectrum (ESI) m/e (% relative intensity 350 (100)
(M þ Na)þ; HRMS (ESI) m/e calcd for C18H17NO3SNa 350.0822,
found 350.0818.
64 (53%): Rf = 0.21 [4:1 hexanes/EtOAc]; yellow solid; mp =
125ꢀ128 °C; 1H NMR (400 MHz, CDCl3) δ 3.39 (dd, 1H, J = 7.2, 14.0
Hz,), 3.49 (dd, 1H, J = 6.4, 14.0 Hz), 5.24 (d, 1H, J = 10.0 Hz), 5.35 (d,
1H, J = 16.8 Hz), 5.60ꢀ5.50 (m, 1H), 7.44ꢀ7.34 (m, 5H), 7.71 (d, 2H,
J = 8.4 Hz), 8.22 (d, 2H, J = 8.4 Hz); 13C NMR (100 MHz, CDCl3) δ
35.7, 72.6, 115.8, 123.1, 123.9, 127.8, 128.4, 128.9, 129.4, 130.9, 132.3,
139.5, 151.6; IR (film) cmꢀ1 3104 m, 2932 m, 2850 m, 2240w, 1606 m,
1530s, 1450 m; mass spectrum (ESI) m/e (% relative intensity) 365
(100) (M þ Na)þ; HRMS (ESI) m/e calcd for C17H14N2O4SNa
365.0566, found 365.0559.
65 (64%): Rf = 0.22 [4:1 hexanes/EtOAc]; white solid; mp =
1
48ꢀ50 °C; H NMR (400 MHz, CDCl3) δ 2.83 (s, 3H), 3.28ꢀ3.30
General Procedure for the Preparation of r-Allyl Ami-
dines via Thermal Aza-Claisen Rearrangement. To a flame-
dried screw-cap vial were added ynamide 8b (62.0 mg, 0.20 mmol),
cyclohexylamine (69 μL, 0.60 mmol) and anhyd toluene (2.0 mL). The
vial was flushed with nitrogen and heated to 110 °C overnight. When the
reaction was judged to be complete by TLC, removal of the solvent in
vacuo followed by purification via silica gel flash column chromatography
(m, 3H), 5.22 (dd, 1H, J = 1.2, 10.0 Hz), 5.31 (dd, 1H, J = 1.2, 16.8 Hz),
5.55 (ddt, 1H, J = 7.2, 10.0, 16.8 Hz), 7.48ꢀ7.53 (m, 3H), 7.69ꢀ7.73
(m, 2H); 13C NMR (100 MHz, CDCl3) δ 35.9, 37.1, 70.8, 116.1, 122.8,
128.4, 128.7, 128.7, 129.7, 130.8; IR (film) cmꢀ1 3008 m, 2930 m,
2241w, 1642 m, 1599 m, 1450s; mass spectrum (ESI) m/e (% relative
intensity) 258 (100) (M þ Na)þ; HRMS (ESI) m/e calcd for
C12H13NO2SNa 258.0559, found 258.0552.
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74 (91%, 1.5:1 dr): Rf = 0.41 [6:1 hexanes/EtOAc], colorless oil; 1H
NMR (400 MHz, CDCl3) major isomer δ 1.06 (s, 18H), 1.05ꢀ1.08
(m, 3H), 1.50 (d, 3H, J = 6.0 Hz), 2.48 (s, 3H), 2.82ꢀ3.00 (m, 2H), 4.50
(q, 1H, J = 6.0 Hz), 5.12ꢀ5.22 (m, 1H), 5.28 (dd, 1H, J = 1.2, 17.6 Hz),
5.90 (ddtd, 1H, J = 1.2, 7.2, 10.0, 17.2 Hz), 7.41 (d, 2H, J = 8.4 Hz), 7.90
(d, 2H, J = 8.4 Hz); minor isomer δ 0.98ꢀ1.02 (m, 21H), 1.60 (d, 3H, J =
6.4 Hz), 2.48 (s, 3H), 2.82ꢀ3.00 (m, 2H), 4.73 (q, 1H, J = 6.4 Hz),
5.12ꢀ5.22 (m, 2H), 5.68ꢀ5.78 (m, 1H), 7.38 (d, 2H, J = 8.4 Hz), 7.90
(d, 2H, J = 8.4 Hz); 13C NMR (125 MHz, CDCl3) both isomers δ 12.9,
13.1, 18.2, 18.3, 18.3, 18.4, 19.2, 21.6, 22.0, 22.0, 32.1, 34.8, 69.5, 71.9,
116.4, 116.7, 120.3, 121.0, 130.0, 130.1, 130.6, 131.0, 131.1, 131.3, 132.5,
133.7, 146.4, 146.8; IR (film) cmꢀ1 2945 m, 2868 m, 2256w, 1596 m,
1493 m, 1330 m; mass spectrum (ESI) m/e (% relative intensity) 458
(100) (M þ Na)þ; HRMS (ESI) m/e calcd for C23H37NO3SSiNa
458.2156, found 458.2171.
(m, 7H), 7.75 (d, 2H, J = 8.5 Hz); 13C NMR (125 MHz, CDCl3) δ 22.1,
27.2, 34.7, 39.2, 70.0, 73.0, 115.4, 121.5, 128.5, 128.7, 129.8, 130.0, 130.4,
131.2, 132.2, 134.4, 146.7, 175.8; IR (film) cmꢀ1 3069w, 2978 m, 2937
m, 2874w, 2244w, 1746s, 1597 m, 1495 m, 1338s; mass spectrum (ESI)
m/e (% relative intensity) 448 (100) (M þ Na)þ; HRMS (ESI) m/e
calcd for C24H27NO4SNa 448.1553, found 448.1566.
79 (74%): Rf = 0.28 [2:1 hexanes/EtOAc]; white solid; mp =
80ꢀ84 °C; 1H NMR (400 MHz, CDCl3) δ 1.70 (d, 3H, J = 7.2 Hz),
2.43 (s, 3H), 2.93 (d, 2H, J = 6.4 Hz), 3.18 (s, 6H), 4.92 (dq, 1H, J = 2.0,
10.2 Hz), 4.95 (dq, 1H, J = 2.0, 16.8 Hz), 5.64 (ddt, 1H, J = 6.4, 10.2, 16.8
Hz), 6.06 (q, 1H, J = 7.2 Hz), 7.31 (d, 2H, J = 8.4 Hz), 7.98 (d, 2H, J = 8.4
Hz); 13C NMR (100 MHz, CDCl3) δ 14.2, 22.0, 32.3, 116.4, 129.4,
129.6, 133.4, 134.1, 134.3, 136.3, 145.3, 152.1, 169.0 [missing NMe2
carbon signal]; IR (film) cmꢀ1 2927 m, 2251w, 1703s, 1641 m, 1598 m,
1495 m, 1448 m, 1359s; mass spectrum (ESI) m/e (% relative intensity)
373 (100) (M þ Na)þ; HRMS (ESI) m/e calcd for C17H22N2O4SNa
373.1193, found 373.1188.
75 (50%, 1.3:1 dr): Rf = 0.18 [4:1 hexanes/EtOAc]; colorless oil; 1H
NMR (400 MHz, CDCl3) major diastereomer δ 1.47 (d, 3H, J = 6.4 Hz),
1.90 (s, 3H), 2.49 (s, 3H), 2.81ꢀ3.04 (m, 2H), 5.25ꢀ5.30 (m, 2H), 5.46
(q, 1H, J = 6.4 Hz), 5.85ꢀ5.98 (m, 1H), 7.42 (d, 2H, J = 8.4 Hz), 7.89 (d,
2H, J = 8.4 Hz); minor diastereomer δ 1.50 (d, 3H, J = 6.4 Hz), 1.97 (s,
3H), 2.49 (s, 3H), 2.81ꢀ3.04 (m, 2H), 5.25ꢀ5.30 (m, 2H), 5.46 (q, 1H,
J = 6.4 Hz), 5.85ꢀ5.98 (m, 1H), 7.43 (d, 2H, J = 8.4 Hz), 7.91 (d, 2H, J =
8.4 Hz); 13C NMR (125 MHz, CDCl3) both diastereomers δ 16.6, 17.8,
21.0, 21.1, 22.1, 31.8, 34.3, 34.7, 68.6, 69.2, 69.3, 71.6, 115.4, 121.7,
121.7, 129.8, 130.0, 130.2, 130.3, 130.8, 131.2, 132.4, 133.2, 147.0, 147.1,
169.1, 169.2 [missing one sp2 carbon from minor]; IR (film) cmꢀ1 2923
m, 2243w, 1752s, 1642 m, 1597 m, 1374, 1335s; mass spectrum (ESI)
m/e (% relative intensity) 344 (100) (M þ Na)þ; HRMS (ESI) m/e
calcd for C16H19NO4SNa 344.0927, found 344.0914.
81 (30%): Rf = 0.41 [6:1 hexanes/EtOAc]; white solid; mp =
1
65ꢀ67 °C; H NMR (400 MHz, CDCl3) δ 1.46 (s, 9H), 2.43 (s,
3H), 3.28 (d, 2H, J = 5.6 Hz), 5.08 (d, 1H, J = 10.4 Hz), 5.11 (d, 1H, J =
17.2 Hz), 5.89 (ddt, 1H, J = 5.6, 10.4, 17.2 Hz), 7.31 (d, 2H, J = 8.4 Hz),
7.40 (s, 6H), 7.54 (s, 1H), 7.85 (d, 2H, J = 8.4 Hz); 13C NMR (125 MHz,
CDCl3) δ 21.9, 27.4, 32.2, 39.9, 116.9, 127.4, 128.9, 129.6, 130.0, 130.0,
132.2, 134.4, 134.9, 138.3, 143.7, 144.0, 162.1, 174.4; IR (film) cmꢀ1
2966 m, 1765s, 1740s, 1601s, 1481 m, 1326s; mass spectrum (ESI) m/e
(% relative intensity) 448 (100) (M þ Na)þ; HRMS (ESI) m/e calcd for
C24H27NO4SNa 448.1553, found 448.1543.
’ ASSOCIATED CONTENT
76 (g95%, 2.0:1 dr): Rf = 0.23 [8:1 hexanes/EtOAc]; colorless oil;
1H NMR (500 MHz, CDCl3) major diastereomer δ 0.99 (s, 18H), 1.02
(s, 3H), 2.40 (s, 3H), 3.08 (ddd, 1H, J = 1.0, 7.0, 15.0 Hz), 3.18 (ddd, 1H,
J = 1.0, 7.0, 15.0 Hz), 5.13 (d, 1H, J = 9.0 Hz), 5.16 (d, 1H, J = 16.0 Hz),
5.54 (s, 1H), 5.74 (ddt, 1H, J = 7.0, 9.0, 16.0 Hz), 7.21 (d, 2H, J = 8.0
Hz), 7.25ꢀ7.30 (m, 2H), 7.34ꢀ7.37 (m, 1H), 7.50 (d, 2H, J = 7.0 Hz),
7.63 (d, 2H, J = 8.0 Hz); minor diastereomer δ 0.99 (s, 18H), 1.02 (s, 3H),
2.44 (ddd, 1H, J =1.0, 6.5, 15.5 Hz), 2.45 (s, 3H), 2.64 (ddd, 1H, J = 1.0,
6.5, 15.5 Hz), 4.81 (d, 1H, J = 17.0 Hz), 4.93 (d, 1H, J = 10.0 Hz); 5.45
(ddt, 1H, J = 6.5, 10.0, 17.0 Hz), 5.81 (s, 1H), 7.25ꢀ7.30 (m, 2H), 7.31
(d, 2H, J = 8.0 Hz), 7.34ꢀ7.37 (m, 1H), 7.54ꢀ7.59 (m, 2H), 7.89 (d,
2H, J = 8.0 Hz); 13C NMR (125 MHz, CDCl3) both diastereomers δ
13.02, 13.12, 18.19, 18.23, 21.95, 22.02, 34.99, 35.38, 72.86, 72.87, 75.50,
75.66, 116.02, 120.06, 120.84, 128.29, 129.14, 129.24, 129.26, 129.43,
129.56, 129.62, 129.65, 129.89, 130.52, 130.89, 130.93, 131.25, 131.31,
133.47, 138.58, 145.94 [missing two sp2 signals from minor]; IR
(film) cmꢀ1 2945 m, 2893 m, 2867 m, 2240w, 1639w, 1596 m, 1494 m,
1365 m; mass spectrum (ESI) m/e (% relative intensity) 520 (100)
(M þ Na)þ; HRMS (ESI) m/e calcd for C28H39NO3SSiNa 520.2313,
found 520.2322.
S
Supporting Information. Experimental procedures,
b
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; yanshi.zhang@lubrizol.com.
’ ACKNOWLEDGMENT
The authors thank the NIH [GM066055] for financial sup-
port. K.A.D. thanks the American Chemical Society for a Divi-
sion of Medical Chemistry Predoctoral Fellowship. H.D. thanks
China Scholarship Council for a Visiting Scholar Fellowship.
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1
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5101
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