Synthesis of 2-iodoynamides and regioselective [2+2] cycloadditions with ketene

Article abstract of DOI:10.1016/j.tetlet.2010.11.002

The first synthesis of 2-iodoynamides is described as well as the first [2+2] cycloadditions of ketene with iodo alkynes.

Full text of DOI:10.1016/j.tetlet.2010.11.002

Tetrahedron Letters 52 (2011) 2111–2114
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of 2-iodoynamides and regioselective [2+2] cycloadditions
with ketene
⇑
Yu-Pu Wang, Rick L. Danheiser
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Available online 12 November 2010
The first synthesis of 2-iodoynamides is described as well as the first [2+2] cycloadditions of ketene with
iodo alkynes.
Ó 2010 Elsevier Ltd. All rights reserved.
Dedicated to Professor Harry Wasserman in
recognition of his contributions to the
science of organic synthesis and his
outstanding record of leadership and service
to the chemistry community
Keywords:
Ynamides
Cyclobutenones
[2+2] cycloadditions
Ketene
1. Introduction
attenuated by the electron-withdrawing substituent on the nitro-
gen atom, do react smoothly with a variety of ketenes to afford
In a now classic 1962 publication in Tetrahedron Letters, Wass-
erman and Dehmlow reported the first systematic investigation
of the reaction of ketenes with alkynyl ethers.1,2 A subsequent full
paper3 expanded on this study, and described a number of interest-
ing transformations of the 3-alkoxycyclobutenone cycloadducts
including reactions with Grignard reagents to afford 3-alkyl and
3-arylcyclobutenones. This latter transformation is of some signif-
icance since it provides access to cyclobutenones that are not
available via direct [2+2] cycloadditions of ketenes with alkyl-
and aryl-substituted acetylenes. Unactivated alkynes only engage
in efficient cycloadditions with highly electrophilic ketenes such
as dichloroketene,4 and simple ketenes require electron-rich,
heterosubstituted alkynes for efficient reaction.5
3-aminocyclobutenone derivatives in good yield.9
Cyclobutenones are valuable synthetic intermediates that par-
ticipate in a variety of novel and useful synthetic transformations.10
In connection with our work on benzannulation strategies based on
the reaction of alkynes with aryl- and vinylketenes,11 we became
interested in the synthesis of 2-iodoynamides and the question of
whether they can function as efficient ketenophiles in [2+2]
cycloadditions. At the outset of this study the feasibility of these
cycloadditions was far from certain. To our knowledge, no success-
ful example of the cycloaddition of a ketene and alkynyl halide had
been reported previously. In fact, in the case of halo-substituted
alkenes, we were aware of only a single example of a ketene
[2+2] cycloaddition, the low-yield reaction of bis(trifluoromethyl)
ketene with methyl trifluorovinyl ether.12,13 Herein we report the
first syntheses of 2-iodoynamides and the finding that these
acetylenes participate in remarkably efficient [2+2] cycloadditions
with ketene.
Ynamines6 comprise another class of heterosubstituted alkynes
that react with ketenes in [2+2] cycloadditions.7 Unfortunately,
these reactions often lead to mixtures of the desired cyclobutenon-
es accompanied by allenyl amides.8 The formation of the allene
byproducts is believed to result from initial addition of the yna-
mine across the ketene carbonyl group via a stepwise pathway to
form an alkylideneoxete. Electrocyclic ring opening then trans-
forms this strained intermediate to the allenyl carboxamide. How-
ever, ynamides, in which the nucleophilicity of the amino alkyne is
2. Preparation of iodo alkynes
For the preparation of the iodo alkynes used in this study we
focused our attention on the iodination of alkynyllithium com-
pounds, an approach that has previously proved efficacious for
the synthesis of simple alkynyl iodides14 and 2-iodo-1-alkoxyacet-
ylenes.15 In this fashion, 1-iodooctyne was prepared in quantitative
⇑
Corresponding author. Tel.: +1 617 253 1842; fax: +1 617 252 1504.
E-mail address: danheisr@mit.edu (R.L. Danheiser).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.002

2112
Y.-P. Wang, R. L. Danheiser / Tetrahedron Letters 52 (2011) 2111–2114
yield by reaction of octynyllithium with 1.05 equiv of I2 in THF
(À78 °C to rt, 1.5 h), and iodoethoxyacetylene was generated in
good yield (as previously reported by Vermeer15a) and used with-
out purification due to its instability.
1) 1.1 equiv NBS
5 mol% AgNO3
acetone, rt, 2 h
SiMe3
SiMe3
2) 1.0 equiv BnNHTs
0.1 equiv CuSO4•5H2O
In recent years ynamides have emerged as exceptionally useful
building blocks for organic synthesis.16 Considerably more robust
than simple ynamines, ynamides are more easily stored andhandled,
and more resistant to hydrolysis and polymerization. Ynamides tol-
erate a variety of reaction conditions incompatible with simple
ynamines and have thus proved to be versatile substrates for a vari-
ety of synthetic transformations. To our knowledge, however, no
examples of 2-halo ynamides have been reported previously.
Not surprisingly, initial attempts to prepare 2-iodoynamides via
the reaction of terminal ynamides with NIS in the presence of
catalytic silver nitrate did not appear promising, and so we have
focused most of our attention on reactions of metalated ynamides
with mild iodinating agents such as molecular iodine and
1,2-diiodoethane. The requisite terminal ynamides for metalation
are conveniently prepared via the N-alkynylation of carboxamides
and sulfonamides using (trialkylsilyl)alkynyl halides followed by
protodesilylation.
0.2 equiv 1,10-phenanthroline
H
5
N
Bn
Ts
2.0 equiv K2CO3, toluene
65 °C 21 h
6
40% over two steps
1.5 equiv K2CO3
MeOH, rt, 2 h
36%
1.0 equiv n-BuLi
THF, -15 °C, 3 h; then add
1.05 equiv ICH2CH2I, rt, 48 h
I
H
N
N
60%
Bn
Ts
Bn
Ts
8
7
Scheme 2.
Recent advances in our laboratory17 and that of Hsung18 have
provided the basis for the efficient and convenient synthesis of a
variety of ynamides. We have found these methods to be comple-
mentary, and both procedures were employed in the present study.
Although the protocol developed in our laboratory requires the use
of 1 equiv of CuI, coupling proceeds smoothly at room temperature
and this method thus accommodates the synthesis of a wide range of
alkyne derivatives including thermally unstable systems. Hsung’s
related protocol employs catalytic CuCN or CuSO4 in conjunction
with diamine ligands and requires reaction at elevated tempera-
tures. We have found both methods to be reliable and reproducible
for reactions on both small and large (i.e., multigram) scale.
Scheme 1 outlines the synthesis of the 2-iodoynamide 4. Alky-
nylation of carbamate 119 with iodo(trimethylsilyl)acetylene20
afforded ynamide 2,21 which underwent smooth protodesilylation
on exposure to TBAF at À78 °C.22 Initial attempts to deprotonate 3
with KHMDS led to complex mixtures, possibly triggered by addi-
tion of the acetylide to the carbamate carbonyl group. Improved re-
sults were obtained by slow addition (1.5 h) of the ynamide to a
solution of excess base in THF at À78 °C. Cannulation of the result-
ing solution into a solution of 2.5 equiv of iodine in THF at À78 °C
then led to rapid formation of the desired alkynyl iodide 4 which
was isolated after column chromatography on acetone-deactivated
silica gel as a pale orange solid, mp 56–58 °C. The spectroscopic
data for 4 was fully consistent with the assigned structure, includ-
1.3 equiv MeNHTs
0.1 equiv CuSO4•5H2O
0.2 equiv 1,10-phenanthroline
Si(i-Pr)3
Si(i-Pr)3
2.0 equiv K2CO3, toluene
70 °C 41 h
N
Br
9
Me
Ts
10
91%
1.1 equiv TBAF
THF
-40 °C to rt, 40 min
92%
1.0 equiv n-BuLi
THF, -15 °C, 3 h;
then add 1.0 equiv I2
H
I
°
-78 C to rt, 2 h
N
N
Me
Ts
Me
Ts
47%
12
11
Scheme 3.
ing in particular the dramatic upshield shift of the C-2 carbon to
À13.3 ppm in the 13C NMR spectrum due to the large diamagnetic
shielding by the iodine atom (‘heavy atom effect’).23
1 equiv KHMDS, 1 equiv CuI
pyr-THF; then add
Schemes 2 and 3 describe syntheses of the related N-sulfonyl
iodoynamides 8 and 12. Witulski and Stengel have previously
reported the synthesis of ynamide 7 via an N-alkynylation protocol
based on phenyl(trimethylsilylethynyl)iodonium triflate;24 we
found it more convenient to access this ynamide via the copper-
catalyzed N-alkynylation of readily available bromo(trimethyl-
silyl)acetylene.25 Surprisingly, reaction of 7 with either KHMDS
or n-butyllithium followed by addition of iodine failed to afford
any of the desired iodoynamide. However, in this case formation
of 8 in good yield could be achieved by employing 1,2-diiodoeth-
ane as the iodinating agent. The desired ynamide 8, mp 89–93 °C,
was obtained in 60% yield after low-temperature recrystallization
from ether/pentane.23
The preparation of iodoynamide 12 proceeded in a similar fash-
ion beginning with the known bromo alkyne 9.26 In this case,
iodination with molecular iodine was successful and afforded
iodoynamide 12 as colorless crystals, mp 95–98 °C, after recrystal-
lization at À20 °C from ether/pentane.23
SiMe3
I
SiMe3
0.94 equiv
BnNHCO2Me
1
rt 16 h
58%
N
Bn
CO2Me
2
1.1 equiv TBAF
THF
-78 °C, 10 min
81%
add to 2.5 equiv KHMDS
THF, -78 °C, 1.5 h;
then add to 2.5 equiv I2
THF, -78 °C, 5 min
I
H
N
N
3
Bn
CO2Me
Bn
CO2Me
40-41%
4
Scheme 1.

Y.-P. Wang, R. L. Danheiser / Tetrahedron Letters 52 (2011) 2111–2114
2113
Iodoynamides 4, 8, and 12 proved to be relatively stable
Methyl ynamide 20
Iodo ynamide 8
Methyl cyclobutenone 21
Iodo cyclobutenone 16
compounds, and can be stored for weeks as solutions in dichloro-
methane below 0 °C without noticeable decomposition. Though
somewhat sensitive to silica gel, column chromatography can be
carried out without significant losses by employing triethyl-
amine-deactivated silica gel.
100
80
60
40
20
0
3. [2+2] cycloadditions
With efficient routes to the requisite iodo alkynes in hand, we
turned our attention to examining the feasibility of their [2+2] cyc-
loadditions with ketene. For these reactions, ketene was generated
by pyrolysis of acetone in a Hurd ‘ketene lamp’ as described previ-
ously27 and bubbled into a 0.05–0.1 M solution of the ynamide in
THF.28 Table 1 summarizes our results. The reaction of iodo yna-
mide 12 with ketene was examined first. Complete consumption
of alkyne was observed after 4 h and a single crystalline cyclobute-
none was formed which was isolated in 86% yield after purification
by silica gel chromatography followed by recrystallization from
acetonitrile at À20 °C.29 A heteronuclear multiple bond correlation
(HMBC) experiment permitted assignment of the regiochemistry of
the cycloadduct to be that of cyclobutenone 15 in which the nitro-
gen substituent is attached at the C-3 carbon and the iodine at
0
1
2
3
4
Time (h)
Figure 1. Comparison of rate of [2+2] cycloaddition of ketene with iodoynamide 8
and propynylynamide 20.
CH3
ketene
THF (0.05 M)
rt
H3C
O
PhCH2
N
21
N
C-2.30,31 Ynamides
4 and 8 react with ketene with similar
Bn
SO2Ar
SO2Ar
20
efficiency, but cycloadditions with the alkynyl ether 13 and iodooc-
tyne were not successful. In the case of 13, complete consumption
Scheme 4.
Table 1
of the alkynyl ether occurred within 3 h, but no cyclobutenone
cycloadduct could be detected in the resulting complex mixture.
Bubbling ketene into a solution of iodooctyne for 39 h failed to pro-
duce any cycloadduct, and unreacted alkynyl iodide was recovered
in 78% yield after chromatography.
[2+2] cycloadditions of iodo alkynes with ketene
THF
rt 3-5 h
I
O
I
O
Z
H
H
Z
The enhanced reactivity of the iodo ynamides 4, 8, and 12 rela-
tive to iodooctyne is expected due to the activating effect of the
electron-donating nitrogen substituent in ketene cycloadditions.
The failure of the iodo alkynyl ether 13 to afford cyclobutenone
is attributed to the relative instability of this sensitive alkyne. With
regard to the effect of the iodine substituent on the reactivity of the
acetylenes, a comparison of the rate of the reactions of iodoyna-
mide 8 and terminal ynamide 7 indicated that the iodine substitu-
ent is somewhat deactivating relative to hydrogen. Interestingly,
however, iodoynamide 8 reacts more rapidly as compared to the
propynyl ynamide 20 which bears a methyl group at C-2 in place
of iodine. Figure 1 compares the rates of the reaction of 8 with ke-
tene with the cycloaddition of 20 (Scheme 4) run as a separate par-
allel reaction.32 Reaction of the iodoynamide is complete in ca. 2 h,
while at 3 h only ca. 50% of the propyne derivative was found to
have reacted.
Entry
1
Alkyne
Cycloadduct
Yielda (%)
86
I
O
SO2Ar
CH3
I
I
N
H3C
15
N
12
8
SO2Ar
Ar = p-CH3C6H4
I
O
SO2Ar
2
3
N
81
99
PhCH2
Bn
16
N
SO2Ar
I
O
CO2Me
Bn
4. Synthetic utility of the cycloadducts
I
N
PhCH2
17
N
4
Cross-coupling of the 2-iodocyclobutenones produced in these
reactions should provide the basis for their elaboration to cyclob-
utenones bearing a variety of other substituents. For example,
Sonogashira coupling of 15 with (trimethylsilyl)acetylene affords
the expected 2-alkynylcyclobutenone in 92% yield (Scheme 5).
CO2Me
I
O
O
I
I
OEt
Hex
4
5
0
EtO
13
18
19
H
3.0 equiv Me3Si
Me3Si
I
0.13 equiv PdCl2(PPh3)2
0.18 equiv CuI, 10 equiv Et3N
THF, rt 24 h
I
O
O
0b
Hex
14
H3C
H3C
N
N
92%
aIsolated yields of products purified by column chromatography.
22
Ts 15
Ts
bReaction was run for 39 h. Unreacted iodooctyne was isolated in 78% yield after
column chromatography.
Scheme 5.

2114
Y.-P. Wang, R. L. Danheiser / Tetrahedron Letters 52 (2011) 2111–2114
17. (a) Dunetz, J. R.; Danheiser, R. L. Org. Lett. 2003, 5, 4011; (b) Kohnen, A. L.;
Further studies are underway in our laboratory to investigate
Dunetz, J. R.; Danheiser, R. L. Org. Synth. 2007, 84, 88.
the synthetic utility of 2-iodoynamides including, in particular,
their participation as novel ketenophile components in benzannu-
lation reactions with vinyl- and arylketenes.
18. (a) Zhang, Y.; Hsung, R. P.; Tracey, M. R.; Kurtz, K. C. M.; Vera, E. L. Org. Lett.
2004, 6, 1151; (b) Zhang, X.; Zhang, Y.; Huang, J.; Hsung, R. P.; Kurtz, K. C. M.;
Oppenheimer, J.; Petersen, M. E.; Sagamanova, I. K.; Shen, L.; Tracey, M. R. J. Org.
Chem. 2006, 71, 4170; (c) Sagamanova, I. K.; Kurtz, K. C. M.; Hsung, R. P. Org.
Synth. 2007, 84, 359.
19. Kost, D.; Zeichner, A.; Sprecher, M. S. J. Chem. Soc., Perkin Trans. 2 1980, 317.
20. Amatore, C.; Blart, E.; Genêt, J. P.; Jutand, A.; Lemaire-Audoire, S.; Savignac, M. J.
Org. Chem. 1995, 60, 6829.
Acknowledgments
We thank the National Institutes of Health (GM 28273), Boeh-
ringer Ingelheim Pharmaceuticals, and Merck Research Laborato-
ries for generous financial support.
21. For an alternative route to 2 beginning with phenyl(trimethylsilylethynyl)
iodonium triflate, see Tanaka, K.; Takeishi, K.; Noguchi, K. J. Am. Chem. Soc.
2006, 128, 4586.
22. For an alternative preparation of ynamide 3, see Yamasaki, R.; Terashima, N.;
Sotome, I.; Komagawa, S.; Saito, S. J. Org. Chem. 2010, 75, 480.
23. Characterization data for iodoynamides: For 4: mp 56–58 °C; IR (neat) 2955,
Supplementary data
2200, 1712, 1446, 1367, 1261, 1116, 942, 759, and 698 cmÀ1 1H NMR
;
(300 MHz, CDCl3) d 7.30-7.41 (m, 5H), 4.63 (s, 2H), and 3.83 (s, 3H); 13C NMR
(125 MHz, CDCl3) d 155.8, 135.9, 128.8, 128.5, 128.4, 83.7, 54.5, 53.7, and
À13.3; HRMS-DART m/z [M+H]+ calcd for C11H10INO2, 315.9829; found
315.9835. For 8: mp 89–93 °C; IR (neat) 3032, 2188, 1597, 1496, 1455, 1363,
Supplementary data (proton and carbon NMR spectra for
iodoynamides and cyclobutenones) associated with this article
can be found, in the online version, at doi:10.1016/
j.tetlet.2010.11.002.
1169, 1088, and 601 cmÀ1 1H NMR (300 MHz, CDCl3) d 7.72 (d, J = 8.5 Hz, 2H),
;
7.24–7.35 (m, 7H), 4.50 (s, 2H), and 2.45 (s, 3H); 13C NMR (125 MHz, CDCl3) d
145.0, 134.8, 134.4, 130.0, 128.9, 128.7, 128.6, 127.9, 83.5, 55.4, 21.9, and
À12.5; HRMS-ESI [M+Na]+ calcd for C16H14INO2S, 433.9682; found 433.9672.
For 12: mp 95–98 °C; IR (neat) 2936, 2186, 1363, 1170, 1088, 978, and
References and notes
715 cmÀ1 1H NMR (300 MHz, CDCl3)
; d 7.77 (d, J = 8.4 Hz, 2H), 7.38 (d,
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28. Reaction at higher concentration led to precipitation of the cyclobutenone
product and clogging at the outlet of the needle in the reaction mixture.
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electrically heated metal filament using the apparatus described by Williams
and Hurd. A 20-mL test tube equipped with a stir bar, rubber septum, and
argon inlet needle was charged with iodo ynamide 12 (0.188 g, 0.560 mmol)
and 11.2 mL of THF. The argon inlet needle was replaced with a 15-gauge
needle connected via Tygon tubing to the ketene generator. The septum was
fitted with an outlet needle connected via tubing to a column of CaSO4 leading
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was then concentrated to afford 0.308 g of
a brown solid. Column
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chromatography on 20 g of silica gel (gradient elution with 15–55% EtOAc–
hexanes) afforded 0.200 g of an off-white solid. Recrystallization from 3 mL of
CH3CN at À20 °C furnished 0.181 g (86%) of cyclobutenone 15 as colorless
needles.
30. Strong J-coupling was observed between the alkene carbon bearing the nitrogen
substituent and the C-4 methylene protons. Strong coupling was also observed
between the C-1 carbonyl carbon and these protons. Only weak coupling of the
alkene carbon bearing iodine to the methylene protons was noted.
31. Characterization data for cyclobutenones: For 15: mp 160 °C (dec); IR (neat)
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5.
14. For reviews discussing the synthesis of simple halo acetylenes, see (a) Hopf, H.;
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202.
2924, 1781, 1757, 1563, 1405, 1371, 1162, 1003, and 668 cmÀ1 1H NMR
;
(500 MHz, CDCl3) d 7.74 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 3.80 (s, 2H),
3.64 (s, 3H), and 2.49 (s, 3H); 13C NMR (125 MHz, CDCl3) d 182.6, 166.7, 146.3,
134.4, 130.8, 127.7, 57.1, 51.5, 35.8, and 21.9; HRMS-DART m/z [M+H]+ calcd
for C12H12INO3S, 377.9655; found 377.9639. For 16: IR (neat) 3064, 3033, 2928,
1763, 1557, 1373, 1319, 1172, and 1048 cmÀ1 1H NMR (500 MHz, CDCl3) d
;
7.45 (d, J = 8.5 Hz, 2H), 7.29–7.36 (m, 3H), 7.20–7.28 (m, 4H), 5.36 (s, 2H), 3.82
(s, 2H), and 2.42 (s, 3H); 13C NMR (125 MHz, CDCl3) d 182.2, 166.6, 146.0,
135.4, 135.0, 130.3, 129.0, 128.3, 127.9, 127.6, 57.9, 51.5, 51.4, and 21.8;
HRMS-DART m/z [M+H]+ calcd for C18H16INO3S, 453.9968; found 453.9959. For
17: IR (neat) 3032, 2956, 1767, 1746, 1573, 1449, 1353, 1223, 1113, and
1040 cmÀ1 1H NMR (500 MHz, CDCl3) d 7.27–7.40 (m, 5H), 5.27 (s, 2H), 3.89 (s,
;
2H), and 3.85 (s, 3H); 13C NMR (125 MHz, CDCl3) d 183.5, 168.3, 153.2, 136.0,
129.0, 128.2, 127.0, 59.2, 54.9, 52.1, and 50.0; HRMS-DART m/z [M+H]+ calcd
for C13H12INO3, 357.9935; found 357.9922.
32. Solutions of each ynamide (0.20 mmol) in THF (4 mL) containing 1,4-
dimethoxybenzene (0.20 mmol) as internal standard were simultaneously
treated with ketene which was generated as described above29 and then split
into two streams prior to introduction into the reaction mixtures. Aliquots
were analyzed by 1H NMR spectroscopy (500 MHz, CDCl3) at 1-h intervals to
determine the concentration of ynamide and cyclobutenone versus the
internal standard.
15. (a) Verboom, W.; Westmijze, H.; Bos, H. J. T.; Vermeer, P. Tetrahedron Lett. 1978,
16, 1441; (b) Sörensen, H.; Greene, A. E. Tetrahedron Lett. 1990, 31, 7597.
16. For recent reviews, see (a) DeKorver, K. A.; Li, H.; Lohse, A. G.; Hayashi, R.; Lu,
Z.; Zhang, Y.; Hsung, R. P. Chem. Rev. 2010, 110, 5064; (b) Evano, G.; Coste, A.;
Jouvin, K. Angew. Chem., Int. Ed. 2010, 49, 2840–2859.