An efficient synthesis of de novo imidates via aza-Claisen rearrangements of N-allyl ynamides

Article abstract of DOI:10.1055/s-0030-1258544

A novel thermal 3-aza-Claisen rearrangement of N-allyl ynamides for the synthesis of α-allyl imidates is described. Also, a sequential aza-Claisen, palladium-catalyzed Overman rearrangement is described for the synthesis of azapin-2-ones. Georg Thieme Ver

Full text of DOI:10.1055/s-0030-1258544

LETTER
2397
An Efficient Synthesis of de novo Imidates via Aza-Claisen Rearrangements of
N-Allyl Ynamides
S
ynthesis of de no
y
vo
I
midates le A. DeKorver, Troy D. North, Richard P. Hsung*
Division of Pharmaceutical Sciences and Department of Chemistry, Rennebohm Hall, University of Wisconsin,
777 Highland Avenue, Madison, WI 53705, USA
Fax +1(608)2625345; E-mail: rhsung@wisc.edu
Received 22 June 2010
Ts
Ts
N
Abstract: A novel thermal 3-aza-Claisen rearrangement of N-allyl
ynamides for the synthesis of a-allyl imidates is described. Also, a
sequential aza-Claisen, palladium-catalyzed Overman rearrange-
ment is described for the synthesis of azapin-2-ones.
N
R
EtOH (200 equiv)
Ph
OEt
toluene, EtOAc, or hexanes
75 °C
Key words: ynamide, aza-Claisen, imidate, ketenimine, Overman
rearrangement
5a R = TIPS
5b R = Ph
6 (not found)
Ts
N
N
NaOMe, toluene
r.t. → 100 °C
We recently reported the de novo synthesis of pharmaco-
logically useful amidines from N-allyl ynamides1,2 featur-
ing either a Pd-catalyzed3 N-to-C allyl transfer or
unprecedented thermal3,4 3-aza-Claisen5 rearrangement
followed by trapping of the in situ generated ketenimine6
with amine nucleophiles. There has been great interest
within the synthetic community on preparing amidines
and imidates,7 most commonly through interception of the
ketenimine intermediate produced during a Cu-catalyzed
Huisgen [3+2] cycloaddition of azides and alkynes.8–10
Herein, we describe our efforts at the synthesis of imidates
via trapping of ketenimines 3 formed through aza-Claisen
rearrangement of ynamides 1 in the presence of alcoholic
nucleophiles (Scheme 1).
•
– MeOTs
TIPS
8 (>95%)
TIPS
7
Scheme 2 Alkoxide-induced detosylation of the ketenimine
ucts were nitrile 11 formed through a 1,3-sulfonyl4,11
transfer during the ketenimine intermediate and p-toluene-
sulfonamide, which implies that the aza-Claisen did in
fact occur but was not productive towards imidate forma-
tion. Alternatively, when 10 was treated with sodium
hydride to increase the nucleophilicity of the oxygen and
then heated to 80 °C, only enamides 13 and 14 were
formed through 5-exo-dig and 6-endo-dig cyclization
onto the ynamide, respectively (Scheme 3). Since this was
too nucleophilic for the aza-Claisen to occur, we instead
opted to cleave the silyl protecting group of ynamide 9 in
situ to trigger the cyclization, however, again only nitrile
12 was found, demonstrating that the 1,3-sulfonyl shift is
quite facile.
It was quickly discovered that the nucleophilicity of even
simple alcohols such as methanol and ethanol was not suf-
ficient to yield imidates 6 despite the alcohols being used
in 200-fold excess (Scheme 2)! Furthermore, attempts to
trap ketenimine 7 generated from ynamide 5a with more
nucleophilic sodium methoxide led to cleavage of the N-
toluenesulfonamide protecting group furnishing nitrile 8
in quantitative yield.
Finally, we found that heating of ynamides 1 in alcoholic
solvents in the presence of 4 Å molecular sieves led to im-
idates 4 in moderate to excellent yields. The reaction con-
ditions tolerated both silyl and aryl-terminated ynamides
and showed moderate sensitivity to the electron-
withdrawing nature of N-sulfonyl protecting group with
Our subsequent attempts to carry out this transformation
intramolecularly were also met with difficulty. Alcohol 10
could be prepared by simple TBAF-mediated desilylation
of 9. Upon heating of 10 in toluene, the only isolable prod-
EWG
EWG
N
EWG
3
N
EWG
N
•
N
R1
R2OH
thermal
OR2
2
3-aza-
Claisen
1
R1
R1
R1
1
2
3
4
Scheme 1 In situ trapping of a ketenimine intermediate
SYNLETT 2010, No. 16, pp 2397–2402
x
x
.x
x
.2
0
1
0
Advanced online publication: 26.08.2010
DOI: 10.1055/s-0030-1258544; Art ID: S03610ST
© Georg Thieme Verlag Stuttgart · New York

2398
K. A. DeKorver et al.
LETTER
more sterically hindered nucleophiles giving rise to ni-
triles through the competing intramolecular 1,3-sulfonyl
shift in the ketenimine intermediate when R1 = Ph
(Table 1, entries 8 vs. 10). Interestingly, no nitrile forma-
tion was observed in the cases where R1 = TIPS, likely
due to the increased steric bulk preventing the necessary
migration.
Ts
Ts
N
N
N
toluene
110 °C
TBAF, THF
Ts
TBSO
HO
0 °C → r.t.
OH
11 (24%)
+ TsNH2 [36%]
9
10 (85%)
NaH, THF
CsF, toluene
110 °C
0 → 80 °C
Next, we sought to develop a tandem aza-Claisen–
Overman12 rearrangement, which followed by RCM may
be used for the synthesis of useful azapin-2-one scaffolds
17. Ynamide 5a underwent reaction with allyl alcohol to
yield diallyl imidate 15 in moderate yield. Unfortunately,
our attempts at a thermal Overman rearrangement were
unsuccessful, as heating of 15 in n-decane at 140 °C even
for several days resulted in no formation of 16.
Ts
N
Ts
O
N
N
Ts
O
+
OTBS
14 (5%)
12 (43%)
13 (65%)
Scheme 3 Attempts at intramolecular imidate formation
However, to our delight, exposure of 15 to a catalytic
amount of PdCl2(PhCN)2 at room temperature led to [3,3]
rearrangement product 16 in >95% yield.9b With 16 in
hand, efficient ring-closing metathesis13 was achieved us-
ing Grubbs first-generation catalyst to provide azapin-2-
one 1714 in 90% yield (Scheme 4).
p-Ns providing the corresponding imidates in the highest
yields due to increased electrophilicity of the ketenimine
(Table 1, entries 3 vs. 6 and 4 vs. 7). Notably, there was
no reaction observed with N-Boc or N-Ac ynamides even
at temperatures of >140 °C, indicating the strong electron-
ic effect on the initial aza-Claisen rearrangement. There
was also a clear sensitivity to steric effects with the use of
Herein, we have disclosed a novel synthesis of a-allyl
imidates via a thermal 3-aza-Claisen rearrangement of
Table 1 Synthesis of a-Allyl Imidates
EWG
OR2
EWG
N
N
R1
R2OH [solvent, 0.04 M]
4 Å MS, 2–5 d
R1
1
4
Entry
Alcohol
Temp (°C)
Time (d)
Imidatea
Yield (%)b
Ts
4a R2 = Me, 81%
4b R2 = Et, 43%
4c R2 = i-Pr, 39%
4d R2 = c-Pent, 45%
N
1
2
3
4
MeOH
EtOH
i-PrOH
c-Pentanol
75
75
90
2
2
5
5
TIPS
OR2
110
p-Ns
OR2
N
5
6
7
EtOH
i-PrOH
c-Pentanol
85
90
115
3
4
4
4e R2 = Et, 76%
TIPS
4f R2 = i-Pr, 76%
4g R2 = c-Pent, 71%
Ts
N
8
9
10
MeOH
EtOH
i-PrOH
75
75
75
2
2
5
4h R2 = Me, 95%c
4i R2 = Et, 75%
Ph
Ph
OR2
4j R2 = i-Pr, 47%d
MBS
OR2
N
11
12
EtOH
c-Pentanol
75
75
2
2
4k R2 = Et, 82%
4l R2 = c-Pent, 38%
a MBS = p-methoxybenzenesulfonyl.
b Isolated yields.
c No nitrile observed in crude 1H NMR.
d Estimated nitrile yield by crude 1H NMR = 20%.
Synlett 2010, No. 16, 2397–2402 © Thieme Stuttgart · New York

LETTER
Synthesis of de novo Imidates
2399
(6) For reviews on the chemistry of ketenimines, see: (a)Krow,
G. R. Angew. Chem., Int. Ed. Engl. 1971, 10, 435.
(b) Gambaryan, N. P. Usp. Khim. 1976, 45, 1251.
(c) Dondoni, A. Heterocycles 1980, 14, 1547. (d) Barker,
M. W.; McHenry, W. E. In The Chemistry of Ketenes,
Allenes and Related Compounds, Part 2; Patai, S., Ed.;
Wiley-Interscience: Chichester, 1980, 701–720.
(e) Alajarin, M.; Vidal, A.; Tovar, F. Targets Heterocycl.
Syst. 2000, 4, 293.
Ts
N
Ts
Ts
N
N
n-dXecane
TIPS
HO
TIPS
O
O
4 Å MS, 95 °C
2 d
140 °C
TIPS
5a
15 (51%)
16
PdCl2(PhCN)2
DCE, r.t., 3 h, >95%
(7) For examples of imidates serving as prodrugs, see:
(a) Maryanoff, B. E.; McComsey, D. F.; Costanzo, M. J.;
Yabut, S. C.; Lu, T.; Player, M. R.; Giardino, E. C.;
Damiano, B. P. Chem. Biol. Drug. Des. 2006, 68, 29.
(b) Poon, S. F.; Stock, N.; Payne, J. E.; McGuire, A. R.;
Stearns, B.; Yang, X.; Chen, W.; Munoz, B.; Smith, N. D.
Bioorg. Med. Chem. Lett. 2005, 15, 2259. (c) Bundgaard,
H.; Drustrup Larsen, J. J. Med. Chem. 1988, 31, 2066.
(8) For recent examples of amidine formation, see: (a) Shang,
Y.; He, X.; Hu, J.; Wu, J.; Zhang, M.; Yu, S.; Zhang, Q. Adv.
Synth. Catal. 2009, 351, 2709. (b) She, J.; Jiang, Z.; Wang,
Y. Synlett 2009, 2023. (c) Yu, R. T.; Rovis, T. J. Am. Chem.
Soc. 2008, 130, 3262. (d) Yoo, E. J.; Ahlquist, M.; Bae, I.;
Sharpless, B.; Fokin, V.; Chang, S. J. Org. Chem. 2008, 73,
5520.
Ts
O
N
TIPS
Ts
Grubbs I
TIPS
N
O
DCE, 70 °C
16 h, 90%
16
azapine-2-one 17
Scheme 4 Construction of an azapin-2-one scaffold
N-allyl ynamides. We found that it is necessary to use the
alcohol as solvent to avoid a competing 1,3-sulfonyl
transfer forming nitriles. Also, the use of alkoxides inter-
molecularly led to efficient desulfonylation, while in-
tramolecularly gave 5-exo-dig cyclization of the alkoxide
onto the ynamide. In addition, we have demonstrated the
use of a sequential 3-aza-Claisen–Overman rearrange-
ment, which followed by ring-closing metathesis may be
used to provide access to azapin-2-one scaffolds.
(9) For recent examples of imidate formation, see: (a) Song,
W.; Lu, W.; Wang, J.; Lu, P.; Wang, Y. J. Org. Chem. 2010,
75, 3481. (b) Yoo, E. J.; Park, S. H.; Lee, S. H.; Chang, S.
Org. Lett. 2009, 11, 1155. (c) Yoo, E. J.; Bae, I.; Cho, S. H.;
Han, H.; Chang, S. Org. Lett. 2006, 8, 1347.
(10) For a recent example of a-functionalization of imidates, see:
Matsubara, R.; Berthiol, F.; Kobayashi, S. J. Am. Chem. Soc.
2008, 130, 1804.
Acknowledgment
(11) For a related 1,3-shift, see: Bendikov, M.; Duong, H. M.;
Bolanos, E.; Wudl, F. Org. Lett. 2005, 7, 783.
Authors thank NIH [GM066055] for financial support.
(12) (a) For leading references, see: Anderson, C. E.; Overman,
L. E. J. Am. Chem. Soc. 2003, 125, 12412. (b) For a review,
see: Overman, L. E. Acc. Chem. Res. 1980, 13, 218. Also
see: (c) Overman, L. E. J. Am. Chem. Soc. 1974, 96, 597.
(d) Overman, L. E. J. Am. Chem. Soc. 1976, 98, 2901.
(13) Tomooka, K.; Suzuki, M.; Uehara, K.; Shimada, M.;
Akiyama, T. Synlett 2008, 2518.
References and Notes
(1) For reviews, see: (a) DeKorver, K. A.; Li, H.; Lohse, A. G.;
Hayashi, R.; Lu, Z.; Zhang, Y.; Hsung, R. P. Chem. Rev.
2010, 110, in press. (b) Evano, G.; Coste, A.; Jouvin, K.
Angew. Chem. Int. Ed. 2010, 49, 2840.
(2) For examples in 2010, see: (a) Li, H.; Antoline, J. E.; Yang,
J.-H.; Al-Rashid, Z. F.; Hsung, R. P. New J. Chem. 2010, 34,
in press. (b) Kramer, S.; Madsen, J. L. H.; Rottländer, M.;
Skrydstrup, T. Org. Lett. 2010, 12, 2758. (c) Banerjee, B.;
Litvinov, D. N.; Kang, J.; Bettale, J. D.; Castle, S. L. Org.
Lett. 2010, 12, 2650. (d) Gourdet, B.; Rudkin, M. E.; Lam,
H. W. Org. Lett. 2010, 12, 2554. (e) Jia, W.; Jiao, N. Org.
Lett. 2010, 12, 2000. (f) Burley, G. A.; Davies, D. L.;
Griffith, G. A.; Lee, M.; Singh, K. J. Org. Chem. 2010, 75,
980. (g) Yamasaki, R.; Terashima, N.; Sotome, I.;
Komagawa, S.; Saito, S. J. Org. Chem. 2010, 75, 480.
(3) Zhang, Y.; DeKorver, K. A.; Lohse, A. G.; Zhang, Y.-S.;
Huang, J.; Hsung, R. P. Org. Lett. 2009, 11, 899.
(14) Selected Experimental Procedures and
Characterizations
Synthesis of Nitrile 8
To a stirring solution of ynamide 5a (75.0 mg, 0.19 mmol)
in toluene (2 mL) at r.t. was slowly added freshly prepared
NaOMe (31.0 mg, 0.58 mmol). After addition, the reaction
mixture was sealed under dry nitrogen and heated to 100 °C
for 1 h. Over the course of the reaction, TsOMe was
observed to precipitate out of solution and was subsequently
removed by filtration of the crude reaction mixture through
a plug of CeliteTM to afford the pure nitrile 8 (45.6 mg, 0.19
mmol, >95% yield) as a colorless oil.
Rf = 0.45 (hexanes–EtOAc, 4:1). 1H NMR (500 MHz,
CDCl3): d = 1.00–1.41 (m, 21 H), 2.05 (dd, 1 H, J = 7.5, 4.0
Hz), 2.28–2.34 (m, 1 H), 2.35–2.44 (m, 1 H), 5.14 (d, 1 H,
J = 10.5 Hz), 5.17 (d, 1 H, J = 18.0 Hz), 5.88–5.98 (m, 1 H).
13C NMR (125 MHz, CDCl3): d = 11.3, 14.4, 18.9, 31.8,
117.2, 122.7, 136.2. IR (film): 2946 (m), 2869 (m), 2222
(w), 1595 (m), 1377 (m) cm–1. MS (APCI): m/e (%) = 238
(100) [M + H]+.
(4) DeKorver, K. A.; Hsung, R. P.; Lohse, A. G.; Zhang, Y. Org.
Lett. 2010, 12, 1840.
(5) For leading reviews on aza-Claisen rearrangements, see:
(a) Majumdar, K. C.; Bhayyacharyya, T.; Chattopadhyay,
B.; Nandi, R. K. Synthesis 2009, 2117. (b) Nubbemeyer, U.
Top Curr. Chem. 2005, 244, 149. For some examples of
aza-Claisen rearrangements, see: (c) Majumdar, K. C.;
Samanta, S.; Chattopadhyay, B.; Nandi, R. K. Synthesis
2010, 863. (d) Cheung, L. L. W.; Yudin, A. K. Org. Lett.
2009, 11, 1281. (e) Cant, A. A.; Bertrand, G. H. V.;
Henderson, J. L.; Roberts, L.; Greaney, M. F. Angew. Chem.
Int. Ed. 2009, 48, 5199.
Synthesis of Alcohol 10
To a stirring solution of ynamide 9 (315.0 mg, 0.77 mmol)
in THF (2 mL) at r.t. was slowly added TBAF (0.85 mL, 1.0
M in THF). After 2 h, the solvent was removed via rotary
evaporation, and the crude oil was purified by flash silica gel
column chromatography [isocratic eluent: hexanes–EtOAc,
Synlett 2010, No. 16, 2397–2402 © Thieme Stuttgart · New York

2400
K. A. DeKorver et al.
LETTER
1:1] to afford the alcohol 10 (191.0 mg, 0.65 mmol, 85%
yield) as a pale yellow oil.
silica gel column chromatography afforded the respective
imidate.
Rf = 0.09 (hexanes–EtOAc = 2:1). 1H NMR (500 MHz,
CDCl3): d = 1.52 (br s, 1 H), 1.73 (pent, 2 H, J = 6.5 Hz),
2.38 (t, 2 H, J = 7.0 Hz), 3.71 (d, 2 H, J = 7.0 Hz), 3.91 (d, 2
H, J = 7.0 Hz), 5.19 (d, 1 H, J = 10.5 Hz), 5.24 (d, 1 H,
J = 17.5 Hz), 5.72 (ddt, 1 H, J = 17.5, 10.5, 7.0 Hz), 7.34 (d,
2 H, J = 8.0 Hz), 7.78 (d, 2 H, J = 8.0 Hz). 13C NMR (125
MHz, CDCl3): d = 15.4, 21.9, 31.8, 54.4, 61.9, 69.9, 73.8,
120.0, 128.0, 130.0, 131.4, 135.0, 144.8. IR (film): 3200 (br
s), 2981 (m), 2878 (m), 1644 (m) cm–1. MS (APCI):
m/e (%) = 294 (100) [M + H]+.
Imidate 4a
Rf = 0.45 (hexanes–EtOAc, 4:1). 1H NMR (500 MHz,
CDCl3): d = 1.15 (d, 9 H, J = 7.5 Hz), 1.20 (d, 9 H, J = 7.5
Hz), 1.35 (sept, 3 H, J = 7.5 Hz), 2.46 (s, 3 H), 2.50 (m, 1 H),
2.62 (ddd, 1 H, J = 20.5, 12.5, 8.5 Hz), 3.71 (dd, 1 H, J = 3.0,
12.0 Hz), 3.73 (s, 3 H), 4.92 (dd, 1 H, J = 10.0, 1.0 Hz), 5.00
(ddt, 1 H, J = 17.0, 3.0, 1.5 Hz), 5.73 (dddd, 1 H, J = 22.5,
14.0, 8.5, 5.5 Hz), 7.31 (d, 2 H, J = 8.0 Hz), 7.86 (d, 2 H,
J = 8.0 Hz). 13C NMR (125 MHz, CDCl3): d = 11.8, 19.1,
19.1, 21.8, 32.6, 34.2, 54.0, 115.8, 126.9, 129.4, 137.5,
140.2, 143.0, 178.4. IR (film): 2948 (m), 2868 (m), 1582 (s),
1288 (s) cm–1. MS (APCI): m/e (%) = 424 (100) [M + H]+.
ESI-HRMS: m/e calcd for C22H37NO3SSiNa: 446.2156;
found: 446.2161.
Nitrile 12
Rf = 0.41 (hexanes–EtOAc, 8:1). 1H NMR (400 MHz,
CDCl3): d = 0.02 (s, 6 H), 0.86 (s, 9 H), 1.66–1.85 (m, 2 H),
2.05 (dd, 2 H, J = 8.4, 6.8 Hz), 2.48 (s, 3 H), 2.67–2.79 (m,
2 H), 3.59 (t, 2 H, J = 6.0 Hz), 5.24 (d, 1 H, J = 16.8 Hz),
5.26 (d, 1 H, J = 10.0 Hz), 5.82 (ddt, 1 H, J = 17.6, 10.0, 7.2
Hz), 7.40 (d, 2 H, J = 8.0 Hz), 7.88 (d, 2 H, J = 8.4 Hz).
13C NMR (100 MHz, CDCl3): d = 5.2, 18.4, 22.0, 26.1, 28.3,
28.7, 36.8, 62.1, 65.8, 116.9, 121.9, 129.8, 130.2, 131.0,
131.7. IR (film): 2929 (m), 2857 (m), 2238 (w), 1596 (m),
1331 (s), 1150 (s) cm–1. MS (APCI): m/e (%) = 408 (100)
[M + H]+, ESI-HRMS: m/e calcd for C21H33NO3SSiNa:
430.1843; found: 430.1860.
Imidate 4b
Rf = 0.38 (hexanes–EtOAc, 4:1). 1H NMR (500 MHz,
CDCl3): d = 1.11 (d, 9 H, J = 7.5 Hz), 1.16 (d, 9 H, J = 7.5
Hz), 1.24 (t, 3 H, J = 7.0 Hz), 1.31 (sept, 3 H, J = 7.5 Hz),
2.41 (s, 3 H), 2.59 (dt, 1 H, J = 13.5, 9.0 Hz), 3.64 (dd, 1 H,
J = 12.5, 3.0 Hz), 4.04–4.17 (m, 2 H), 4.87 (d, 1 H, J = 10.0
Hz), 4.95 (d, 1 H, J = 16.5 Hz), 5.63–5.73 (m, 1 H), 7.26 (d,
2 H, J = 7.5 Hz), 7.80 (d, 2 H, J = 8.5 Hz). 13C NMR (125
MHz, CDCl3): d = 11.7, 13.9, 19.1, 19.1, 21.7, 32.4, 34.2,
64.2, 115.7, 126.8, 129.3, 137.5, 140.2, 142.8, 177.8. IR
(film): 2948 (m), 2871 (m), 1965 (w), 1575 (s), 1289 (s),
1155 (s) cm–1. MS (APCI): m/e (%) = 438 (100) [M + H]+.
ESI-HRMS: m/e calcd for C23H39NO3SSiNa: 460.2313;
found: 460.2295.
Synthesis of Compound 13
To a solution of ynamide 10 (75.0 mg, 0.26 mmol) in THF
(5 mL) at 0 °C was added NaH (19.0 mg, 0.46 mmol, 60%
wt/wt in mineral oil). The reaction mixture was warmed to
r.t. and stirred for 20 min to allow for complete deproto-
nation and then sealed under dry nitrogen and heated to
85 °C for 3 h. The reaction mixture was quenched with H2O,
and the organic phase was extracted with EtOAc and then
dried over Na2SO4. Removal of the solvent by rotary
evaporation and purification by flash silica gel column
chromatography (hexanes–EtOAc, 4:1) afforded 13 (50.0
mg, 0.17 mmol, 65% yield) as a colorless oil.
Imidate 4c
Rf = 0.19 (hexanes–EtOAc, 15:1). 1H NMR (500 MHz,
CDCl3): d = 1.13 (d, 9 H, J = 7.5 Hz), 1.14 (d, 3 H, J = 6.0
Hz), 1.15 (d, 9 H, J = 7.5 Hz), 1.25 (d, 3 H, J = 6.0 Hz), 1.31
(sept, 3 H, J = 7.5 Hz), 2.41 (s, 3 H), 2.40–2.48 (m, 1 H),
2.57 (dt, 1 H, J = 14.0, 8.5 Hz), 2.84 (dd, 1 H, J = 12.0, 3.0
Hz), 4.86 (d, 1 H, J = 10.0 Hz), 4.96 (dd, 1 H, J = 17.0, 1.0
Hz), 5.03 (sept, 1 H, J = 6.0 Hz), 5.68 (dddd, 1 H, J = 17.0,
10.0, 8.5, 5.5 Hz), 7.26 (d, 2 H, J = 8.0 Hz), 7.80 (d, 2 H,
J = 8.0 Hz). 13C NMR (125 MHz, CDCl3): d = 11.8, 19.2,
21.6, 21.7, 21.8, 32.4, 34.4, 71.9, 115.8, 126.8, 129.3, 137.4,
140.4, 142.7, 177.2. IR (film): 2946 (m), 2868 (m), 1570 (s),
1464 (m), 1287 (m), 1153 (s) cm–1. MS (APCI): m/e (%) =
410 (100) [M – propene + H]+. ESI-HRMS: m/e calcd for
C24H41NO3SSiNa: 474.2469; found: 474.2446.
Compound 13
Rf = 0.35 (hexanes–EtOAc, 4:1). 1H NMR (500 MHz,
CDCl3): d = 1.90 (pent, 2 H, J = 9.5 Hz), 2.40 (s, 3 H), 2.49
(td, 2 H, J = 9.5, 2.0 Hz), 3.96 (t, 2 H, J = 8.0 Hz), 3.97 (d, 2
H, J = 8.5 Hz), 4.86 (s, 1 H), 5.06 (dd, 1 H, J = 13.0, 2.0 Hz),
5.14 (dd, 1 H, J = 20.0, 2.0 Hz), 5.76 (ddt, 1 H, J = 20.0,
13.0, 8.5 Hz), 7.26 (d, 2 H, J = 9.5 Hz), 7.70 (d, 2 H, J = 9.5
Hz). 13C NMR (125 MHz, CDCl3): d = 21.8, 24.6, 28.4, 52.3,
72.0, 94.9, 117.6, 127.7, 129.4, 134.1, 136.9, 143.1, 157.4.
IR (film): 3055 (m), 2980 (m), 1597 (s), 1337 (s) cm–1.
MS (APCI): m/e (%) = 294 (100) [M + H]+. ESI-HRMS:
m/e calcd for C15H19NO3SNa: 316.0978; found: 316.0986.
Compound 14
Imidate 4d
Rf = 0.41 (hexanes–EtOAc, 4:1). 1H NMR (500 MHz,
CDCl3): d = 1.12 (d, 9 H, J = 9.5 Hz), 1.15 (d, 9 H, J = 9.5
Hz), 1.31 (sept, 3 H, J = 9.5 Hz), 1.50–1.82 (m, 8 H), 2.41 (s,
3 H), 2.40–2.47 (m, 1 H), 2.55 (dt, 1 H, J = 18.0, 10.5 Hz),
3.64 (dd, 1 H, J = 15.5, 4.0 Hz), 4.86 (d, 1 H, J = 12.5 Hz),
4.94 (d, 1 H, J = 21.0 Hz), 5.12–5.16 (m, 1 H), 5.62–5.74 (m,
1 H), 7.25 (d, 2 H, J = 10.0 Hz), 7.80 (d, 2 H, J = 10.0 Hz).
13C NMR (125 MHz, CDCl3): d = 11.8, 19.2, 21.7, 23.8,
24.2, 32.2, 32.9, 34.4, 81.4, 115.6, 126.8, 129.3, 137.6,
140.5, 142.7, 117.5. IR (film): 2946 (m), 2869 (m), 1571 (s),
1463 (w), 1287 (m), 1153 (s) cm–1. MS (APCI): m/e (%) =
410 (100) [M – cyclopentene + H]+. ESI-HRMS: m/e calcd
for C26H43NO3SSiNa: 500.2626; found: 500.2618.
Imidate 4e
Rf = 0.38 (hexanes–EtOAc, 4:1). 1H NMR (500 MHz,
CDCl3): d = 1.99 (pent, 2 H, J = 7.0 Hz), 2.43 (s, 3 H), 2.80
(td, 2 H, J = 8.0, 2.0 Hz), 3.66 (d, 2 H, J = 6.5 Hz), 4.16 (t, 2
H, J = 6.5 Hz), 4.76 (t, 1 H, J = 2.0 Hz), 5.08–5.13 (m, 2 H),
5.70 (ddt, 1 H, J = 17.0, 10.0, 6.5 Hz), 7.30 (d, 2 H, J = 8.0
Hz), 7.67 (d, 2 H, J = 8.5 Hz). 13C NMR (125 MHz, CDCl3):
d = 21.8, 24.4, 28.1, 54.8, 72.1, 97.8, 119.1, 127.9, 129.8,
133.1, 135.0, 143.5, 166.8. MS (APCI): m/e (%) = 294 (20)
[M + H]+.
General Procedure for the Synthesis of Imidates 4a–l
To a flame-dried vial containing 4 Å MS was added the
appropriate ynamide and anhydrous alcohol solvent (0.04 M
in ynamide). The reaction mixture was sealed under dry
nitrogen and heated to 75–95 °C for 2–5 d. Upon cooling to
Rf = 0.42 (hexanes–EtOAc, 4:1). 1H NMR (500 MHz,
CDCl3): d = 1.12 (d, 9 H, J = 9.0 Hz), 1.16 (d, 9 H, J = 9.5
Hz), 1.26 (t, 3 H, J = 9.0 Hz), 1.32 (sept, 3 H, J = 9.5 Hz),
2.44–2.52 (m, 1 H), 2.61 (dt, 1 H, J = 17.5, 11.0 Hz), 3.59
(dd, 1 H, J = 15.5, 4.0 Hz), 4.05–4.15 (m, 2 H), 4.93 (d, 1 H,
J = 12.5 Hz), 4.99 (d, 1 H, J = 21.0 Hz), 5.71–5.82 (m, 1 H),
r.t., the mixture was filtered through a plug of CeliteTM
.
Removal of the alcohol solvent in vacuo followed by flash
8.09 (d, 2 H, J = 11.5 Hz), 8.32 (d, 2 H, J = 11.5 Hz). 13
C
Synlett 2010, No. 16, 2397–2402 © Thieme Stuttgart · New York

LETTER
NMR (125 MHz, CDCl3): d = 11.8, 13.9, 19.0, 19.1, 33.5,
Synthesis of de novo Imidates
2401
J = 7.5 Hz), 7.44 (d, 2 H, J = 8.0 Hz), 7.75 (d, 2 H, J = 8.5
Hz). 13C NMR (125 MHz, CDCl3): d = 21.3, 21.4, 21.7, 38.1,
48.9, 72.5, 117.7, 126.8, 127.7, 128.7, 128.8, 129.5, 134.8,
137.9, 139.7, 143.1, 174.0. IR (film): 2984 (w), 1592 (s),
1302 (s), 1156 (s) cm–1. MS (APCI): m/e (%) = 330 (100)
[M – propene + H]+. ESI-HRMS: m/e calcd for
34.3, 64.8, 116.1, 124.2, 128.0, 137.3, 148.6, 179.5. IR
(film): 2943 (w), 2868 (w), 1566 (s), 1531 (s), 1295 (s), 1159
(s) cm–1. MS (APCI): m/e (%) = 469 (100) [M + H]+. ESI-
HRMS: m/e calcd for C22H36N2O5SSiNa: 491.2007; found:
491.2007.
Imidate 4f
C21H25NO3SNa: 394.1448; found: 394.1440.
Imidate 4k
Rf = 0.27 (hexanes–EtOAc, 15:1). 1H NMR (400 MHz,
CDCl3): d = 1.14 (d, 9 H, J = 7.2 Hz), 1.15 (d, 3 H, J = 6.4
Hz), 1.17 (d, 9 H, J = 7.6 Hz), 1.28 (d, 3 H, J = 6.4 Hz), 1.32
(sept, 3 H, J = 7.6 Hz), 2.46–2.52 (m, 1 H), 2.60 (dt, 1 H,
J = 14.4, 8.8 Hz), 3.61 (dd, 1 H, J = 12.0, 3.6 Hz), 4.93 (d, 1
H, J = 10.0 Hz), 4.96–5.04 (m, 2 H), 5.76 (dddd, 1 H,
J = 17.0, 10.0, 8.8, 5.2 Hz), 8.10 (d, 2 H, J = 9.2 Hz), 8.33
(d, 2 H, J = 8.8 Hz). 13C NMR (125 MHz, CDCl3): d = 11.8,
19.1, 19.1, 21.5, 21.8, 33.4, 34.4, 72.9, 116.1, 124.2, 128.0,
137.3, 148.7, 149.9, 178.9. IR (film): 2946 (m), 2869 (m),
1562 (s), 1531 (s), 1349 (s), 1296 (s), 1156 (s) cm–1. MS
(APCI): m/e (%) = 441 (30) [M – propene + H]+. ESI-
HRMS: m/e calcd for C23H38N2O5SSiNa: 505.2163; found:
505.2164.
Rf = 0.33 (hexanes–EtOAc, 4:1). 1H NMR (500 MHz,
CDCl3): d = 1.25 (t, 3 H, J = 7.0 Hz), 2.62 (dt, 1 H, J = 13.5,
7.0 Hz), 2.83 (dt, 1 H, J = 15.5, 8.5 Hz), 3.84 (s, 3 H), 4.09
(dq, 1 H, J = 11.0, 7.0 Hz), 4.18 (dq, 1 H, J = 11.0, 7.0 Hz),
4.99–5.04 (m, 2 H), 5.09 (d, 1 H, J = 17.0 Hz), 5.70–5.59 (m,
1 H), 6.91 (d, 2 H, J = 9.0 Hz), 7.26 (t, 1 H, J = 7.5 Hz), 7.32
(d, 2 H, J = 7.5 Hz), 7.45 (d, 2 H, J = 7.5 Hz), 7.81 (d, 2 H,
J = 9.0 Hz). 13C NMR (100 MHz, CDCl3): d = 13.7, 37.9,
48.8, 55.7, 64.8, 114.0, 117.7, 127.7, 128.8, 128.9, 128.9,
133.1, 134.9, 137.8, 162.9, 174.4. IR (film): 2986 (w), 1593
(s), 1499 (m), 1298 (s), 1150 (s) cm–1. MS (APCI):
m/e (%) = 374 (100) [M + H]+. ESI-HRMS: m/e calcd for
C20H23NO4SNa: 396.1231; found: 396.1240.
Imidate 4g
Imidate 4l
Rf = 0.36 (hexanes–EtOAc, 10:1). 1H NMR (400 MHz,
CDCl3): d = 1.13 (d, 9 H, J = 7.2 Hz), 1.16 (d, 9 H, J = 7.6
Hz), 1.33 (sept, 3 H, J = 7.6 Hz), 1.50–1.88 (m, 8 H), 2.46–
2.51 (m, 1 H), 2.58 (dt, 1 H, J = 14.0, 8.4 Hz), 3.60 (dd, 1 H,
J = 12.0, 3.2 Hz), 4.92 (d, 1 H, J = 10.0 Hz), 5.00 (d, 1 H,
J = 16.8 Hz), 5.09–5.14 (m, 1 H), 5.70–5.82 (m, 1 H), 8.11
(d, 2 H, J = 8.4 Hz), 8.33 (d, 2 H, J = 8.8 Hz). 13C NMR (125
MHz, CDCl3): d = 11.8, 19.1, 23.8, 24.1, 32.2, 32.9, 33.2,
34.4, 82.2, 116.0, 124.1, 128.0, 137.4, 148.7, 149.9, 179.1.
IR (film): 2947 (m), 2871 (m), 1565 (s), 1531 (s), 1349 (s),
1303 (m), 1157 (s) cm–1. MS (APCI): m/e (%) = 441 (30)
[M – cyclopentene + H]+. ESI-HRMS: m/e calcd for
C25H40N2O5SSiNa: 531.2320; found: 530.2333.
Imidate 4h
Rf = 0.20 (hexanes–EtOAc, 4:1). 1H NMR (500 MHz,
CDCl3): d = 1.55–1.83 (m, 8 H), 2.59 (dt, 1 H, J = 12.5, 6.5
Hz), 2.79 (dt, 1 H, J = 17.0, 8.0 Hz), 3.85 (s, 3 H), 4.99 (dd,
1 H, J = 9.0, 7.0 Hz), 5.02 (d, 1 H, J = 11.0 Hz), 5.09 (dd, 1
H, J = 17.0, 1.5 Hz), 5.12–5.17 (m, 1 H), 5.74 (dddd, 1 H,
J = 17.0, 10.0, 7.5, 5.5 Hz), 6.92 (d, 2 H, J = 9.0 Hz), 7.24–
7.28 (m, 1 H), 7.31 (t, 2 H, J = 7.0 Hz), 7.43 (d, 2 H, J = 7.5
Hz), 7.81 (d, 2 H, J = 9.0 Hz). 13C NMR (125 MHz, CDCl3):
d = 24.0, 32.4, 32.6, 38.0, 48.8, 55.8, 81.8, 114.0, 117.6,
127.7, 128.7, 128.8 128.8, 134.6, 134.9, 137.9, 162.7, 173.9.
IR (film): 2968 (w), 2850 (w), 1579 (s), 1294 (s), 1257 (s),
1150 (s) cm–1. MS (APCI): m/e (%) = 346 (100) [M –
cyclopentene + H]+. ESI-HRMS: m/e calcd for
C23H27NO4SNa: 436.1553; found: 436.1552.
Rf = 0.30 (hexanes–EtOAc, 4:1). 1H NMR (400 MHz,
CDCl3): d = 2.43 (s, 3 H), 3.59 (tt, 2 H, J = 6.0, 1.2 Hz), 3.69
(s, 3 H), 4.49 (t, 1 H, 6.0 Hz), 5.10 (ddt, 1 H, J = 10.4, 2.8,
1.6 Hz), 5.16 (ddt, 1 H, J = 17.2, 2.8, 1.6 Hz), 5.72 (ddt, 1 H,
J = 17.2, 10.4, 6.0), 7.24–7.34 (m, 7 H), 7.76 (d, 2 H, J = 8.4
Hz). 13C NMR (100 MHz, CDCl3): d = 21.6, 41.3, 45.8, 52.2,
117.7, 127.2, 127.3, 128.7, 129.4, 129.8, 133.2, 134.1,
137.1, 143.6, 172.2. IR (film): 3034 (m), 2951 (m), 1735 (s),
1597 (m), 1325 (s) cm–1. MS (APCI): m/e (%) = 344 (100)
[M + H]+. ESI-HRMS: m/e calcd for C19H21NO3SNa:
366.1135; found: 366.1150.
Imidate 15
Rf = 0.50 (hexanes–EtOAc, 4:1). 1H NMR (400 MHz,
CDCl3): d = 1.11 (d, 9 H, J = 7.6 Hz), 1.17 (d, 9 H, J = 7.6
Hz), 1.31 (sept, 3 H, J = 7.6 Hz), 2.41 (s, 3 H), 2.43–2.48 (m,
1 H), 2.61 (td, 1 H, J = 13.6, 8.8 Hz), 3.67 (dd, 1 H, J = 12.0,
3.2 Hz), 4.47 (dd, 1 H, J = 12.8, 6.0 Hz), 4.59 (dd, J = 12.8,
6.0 Hz), 4.87 (d, 1 H, J = 10.0 Hz), 4.95 (d, 1 H, J = 17.2
Hz), 5.22 (d, 1 H, J = 10.4 Hz), 5.28 (dd, 1 H, J = 16.0, 1.2
Hz), 5.63–5.74 (m, 1 H), 5.87 (ddt, 1 H, J = 16.8, 10.0, 6.0
Hz), 7.26 (d, 2 H, J = 8.0 Hz), 7.80 (d, 2 H, J = 8.4 Hz).
13C NMR (100 MHz, CDCl3): d = 11.8, 19.1, 21.7, 32.5,
34.2, 69.1, 115.9, 119.8, 126.8, 126.9, 129.4, 131.6, 137.4,
140.1, 142.9, 177.4 cm–1. IR (film): 2943 (m), 2869 (m),
1584 (s), 1302 (m), 1155 (s) cm–1. MS (APCI): m/e (%) =
450 (100) [M + H]+. ESI-HRMS: m/e calcd for
Imidate 4i
Rf = 0.48 (hexanes–EtOAc, 4:1). 1H NMR (500 MHz,
CDCl3): d = 1.26 (t, 3 H, J = 7.0 Hz), 2.41 (s, 3 H), 2.63 (dt,
1 H, J = 13.5, 6.5 Hz) 2.83 (dt, 1 H, J = 16.5, 8.0 Hz), 4.09
(dq, 1 H, J = 11.0, 7.0 Hz), 4.19 (dq, 1 H, J = 11.0, 7.0 Hz),
4.98–5.04 (m, 2 H), 5.10 (dd, 1 H, J = 17.0, 1.5 Hz), 5.70–
5.80 (m, 1 H), 7.23–7.28 (m, 3 H), 7.32 (t, 2 H, J = 8.0 Hz),
7.46 (d, 2 H, J = 7.5 Hz), 7.77 (d, 2 H, J = 8.0 Hz). 13C NMR
(125 MHz, CDCl3): d = 13.7, 21.7, 36.0, 37.9, 48.9, 64.6,
117.7, 126.9, 127.8, 128.8, 129.0, 129.5, 134.9, 137.8,
143.3, 174.6. IR (film): 2985 (w), 1592 (s), 1301 (s), 1152
(s) cm–1. MS (APCI): m/e (%) = 358 (100) [M + H]+. ESI-
HRMS: m/e calcd for C20H23NO3SNa: 380.1291; found:
380.1287.
C24H39NO3SSiNa: 472.2313; found: 472.2305.
Synthesis of Amide 16
To a stirring solution of imidate 15 (35.0 mg, 0.078 mmol)
in DCE (0.4 mL) was added PdCl2(PhCN)2 (1.5 mg, 0.004
mol). The reaction was stirred under a nitrogen atmosphere
for 3 h at r.t., and then the solvent was removed by rotary
evaporation. The crude residue was purified by flash silica
gel column chromatography [isocratic eluent: hexanes–
EtOAc, 20:1] to afford the amide 16 (35.0 mg, 0.078 mmol,
>95% yield) as a colorless oil.
Imidate 4j
Rf = 0.50 (hexanes–EtOAc, 4:1). 1H NMR (400 MHz,
CDCl3): d = 1.05 (d, 9 H, J = 6.8 Hz), 1.11 (d, 9 H, J = 6.8
Hz), 1.13–1.25 (m, 3 H), 2.26 (dd, 1 H, J = 11.6, 6.4 Hz),
2.43 (s, 3 H), 2.66 (td, 1 H, J = 13.2, 7.2 Hz), 3.00 (br s, 1 H),
4.34 (dd, 1 H, J = 16.4, 6.8 Hz), 4.47–4.54 (m, 1 H), 4.69 (d,
1 H, J = 10.0 Hz), 4.82 (d, 1 H, J = 16.8 Hz), 5.21 (d, 1 H,
Rf = 0.32 (hexanes–EtOAc, 6:1). 1H NMR (500 MHz,
CDCl3): d = 1.14 (d, 3 H, J = 6.0 Hz), 1.25 (d, 3 H, J = 6.5
Hz), 2.40 (s, 3 H), 2.59 (dt, 1 H, J = 12.5, 5.5 Hz), 2.80 (dt,
1 H, J = 14.5, 8.5 Hz), 4.97 (m, 3 H), 5.10 (d, 1 H, J = 17.5
Hz), 5.70–5.79 (m, 1 H), 7.22–7.27 (m, 3 H), 7.31 (t, 2 H,
Synlett 2010, No. 16, 2397–2402 © Thieme Stuttgart · New York

2402
K. A. DeKorver et al.
LETTER
J = 10.0 Hz), 5.27 (d, 1 H, J = 17.2 Hz), 5.21–5.37 (m, 1 H),
7.29 (d, 2 H, J = 8.8 Hz), 7.83 (d, 2 H, J = 8.4 Hz). 13C NMR
(100 MHz, CDCl3): d = 11.8, 18.8, 19.2, 21.8, 34.8, 49.5,
116.0, 119.0, 128.0, 128.8, 129.5, 133.6, 137.4, 144.6,
176.0. IR (film): 2950 (m), 2870 (m), 1678 (s), 1352 (s)
cm–1. MS (APCI): m/e (%) = 450 (100) [M + H]+. ESI-
HRMS: m/e calcd for C24H39NO3SSiNa: 472.2313; found:
472.2317.
hexanes–EtOAc, 10:1] to afford azapin-2-one 17 (29.5 mg,
0.070 mmol, 90% yield) as a white solid.
Rf = 0.30 (hexanes–EtOAc, 8:1). Mp 129–130 °C.
1H NMR (500 MHz, CDCl3): d = 0.95 (d, 9 H, J = 7.5 Hz),
0.99 (d, 9 H, J = 7.5 Hz), 1.18 (sept, 3 H, J = 7.5 Hz), 2.28–
2.40 (m, 1 H), 2.41 (s, 3 H), 2.41–2.48 (m, 1 H), 2.90 (dd, 1
H, J = 13.0, 2.5 Hz), 4.49 (dt, 1 H, J = 18.0, 3.0 Hz), 4.81
(dd, 1 H, J = 18.0, 8.0 Hz), 5.75–5.79 (m, 1 H), 5.83–5.88
(m, 1 H), 7.26 (d, 2 H, J = 8.0 Hz), 7.83 (d, 2 H, J = 8.0 Hz).
13C NMR (120 MHz, CDCl3): d = 11.2, 19.3, 21.8, 28.1,
31.0, 43.1, 123.9, 128.5, 129.3, 133.6, 136.8, 144.3, 175.4.
IR (film): 2943 (m), 2866 (m), 1963 (s), 1597 (w), 1350 (s)
cm–1. MS (APCI): m/e (%) = 422 (100) [M + H]+. ESI-
HRMS: m/e calcd for C22H35NO3SSiNa: 444.2000; found:
444.2000.
Synthesis of Azapin-2-one 17
To a solution of amide 16 (35.0 mg, 0.078 mmol) in DCE
was added Grubbs I catalyst (3.2 mg, 0.004 mmol). The
reaction vial was flushed with dry nitrogen, sealed, and
heated to 70 °C for 16 h. The solvent was removed by rotary
evaporation, and the crude residue was purified by flash
silica gel column chromatography [isocratic eluent:
Synlett 2010, No. 16, 2397–2402 © Thieme Stuttgart · New York