Halogenated catechols from cycloaddition reactions of η4-(2-ethoxyvinylketene)iron(0) complexes with 1-haloalkynes

Article abstract of DOI:10.1016/j.tetlet.2009.12.029

1-Chloroalkynes and 1-bromohexyne undergo cycloaddition reactions with ethoxyvinylketeneiron(0) complexes to form chloro and bromocatechols. With most substituents, the halogen is incorporated ortho to the phenolic hydroxyl group regioselectively. With ch

Full text of DOI:10.1016/j.tetlet.2009.12.029

Tetrahedron Letters 51 (2010) 921–923
Contents lists available at ScienceDirect
Tetrahedron Letters
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Halogenated catechols from cycloaddition reactions of
g
4-(2-ethoxyvinylketene)iron(0) complexes with 1-haloalkynes
Jimmy Truong a, Vioela Caze a, Ravish K. Akhani a, Gayatribahen K. Joshi a, Lazaros Kakalis b, Nikita
Matsunaga a, Wayne F. K. Schnatter a,
*
a Long Island University, Department of Chemistry and Biochemistry, 1 University Plaza, Brooklyn, NY 11201, USA
b Rutgers, The State University of New Jersey, University Heights, Newark, NJ 07102, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
1-Chloroalkynes and 1-bromohexyne undergo cycloaddition reactions with ethoxyvinylketeneiron(0)
complexes to form chloro and bromocatechols. With most substituents, the halogen is incorporated ortho
to the phenolic hydroxyl group regioselectively. With chloroethyne, chlorohexyne, and methyl chloropro-
piolate, the reverse regioselection is observed. Ab initio calculations reveal that the products are, in most
cases, nearly isoenergetic, which indicates that the intermediate ketene–alkyne adduct geometry must be
important in determining the product distribution.
Received 16 November 2009
Revised 3 December 2009
Accepted 7 December 2009
Available online 11 December 2009
Ó 2009 Elsevier Ltd. All rights reserved.
The efficient, regiospecific synthesis of highly substituted
aromatic rings represents an important challenge in organic
synthesis.1 One convergent approach is the [4+2] cycloaddition of
vinylketenes2 with alkynes, however vinylketenes are usually
unstable and undergo [2+2] cycloaddition upon reaction with al-
kynes as well as themselves. The parent compound, vinylketene
(buta-1,3-dienone) dimerizes in a hetero [4+2] cycloaddition.3
Masked vinylketenes have been used to carry out this transforma-
tion, but often require a deprotection step.4 Danheiser used silicon-
stabilized vinylketenes in Diels–Alder cycloaddition reactions with
alkynes.5 Electrocyclic ring closures of dienyl ketenes, generated
in situ from cyclobutenones, have been developed by Moore,6a
Danheiser,6b and Liebeskind.6c Danheiser also reported a formal
[4+2] reaction of 2-silylvinylketenes with ynolates to form mono-
silylated resorcinol derivatives.7
rhodium-catalyzed reaction.13 These methods use vinylketenes
generated from cyclobutenones, limiting their utility. The avail-
ability of isolable
g
4-vinylketene iron complexes from a variety
of sources14 provides a promising solution to the cycloaddition
problem given the low cost of iron.15 One noteworthy advantage
of iron over chromium in benzannulation reactions is the fact that
the product arenes are not complexed to the metal as they often
are with chromium. Gibson prepared
g
4-complexed vinylketene
iron(0) complexes from
g
4-vinylketone-iron(0) complexes,16 how-
ever the major products of reactions of alkynes with these com-
plexes were alkyne insertion products, which formed
cyclopentenediones, and, rarely, phenols.17 Treatment of the inser-
tion products with FeCl3 resulted in furan-3-(2H)-ones and reac-
tions with CO produced cyclopentenediones and butenolides.18
Our early studies indicated that both electron-poor (i.e., ester,
ketone, and trifluoromethyl substituted) and electron-rich alkynes
(i.e., ynol ethers) readily undergo cycloadditions with vinylketene
iron complexes to form catechol monoethyl ethers upon reaction
with 1a (Table 1, R1 = Ph).19 Tam recently reported ruthenium-cat-
alyzed [2+2] cycloadditions20a of norbornenes with alkynyl halides,
and rhodium-catalyzed intramolecular [4+2] cycloadditions20b of
haloalkyne tethered dienes, which inspired us to examine the reac-
tions of terminal haloalkynes with vinylketene iron(0) complexes.
Our results are summarized in Table 1.
Transition metals, through their ability to stabilize reactive
intermediates, offer powerful alternatives for the synthesis of
highly substituted aromatic systems. The reaction of Fischer car-
bene complexes with alkynes to form hydroquinones has been
extensively studied and modified.8 A wealth of evidence indicates
that this important transformation proceeds through the interme-
diacy of vinylketene complexes. Chromium-promoted variants of
the electrocyclization of dienylketenes have also been exploited
by Merlic9a,b and Wulff,9c who first isolated an
g
4-vinylketene
chromium complex from the reaction of a Fischer carbene complex
with an alkyne.10 Liebeskind reported the synthesis of phenols
from alkynes and cobalt-complexed vinylketenes, which were pre-
pared from cyclobutenones,11 and subsequently discovered a nick-
el-catalyzed variation.12 Recently, Kondo and Mitsudo reported a
Initially, we compared the reactions of 1-iodohexyne, 1-bro-
mohexyne, and 1-chlorohexyne with 1a. Heating 1a with iodohex-
yne for 96 h in DMF at 120 °C provided mostly unreacted
iodohexyne with two putative cycloadducts (m/z = 396), which
were detected by GC–MS. Bromohexyne was more promising, giv-
ing 3a in 5% yield after refluxing in THF for 24 h. Heating 1a with
bromohexyne in DMF at reflux for 48 h produced the bromocate-
chol 3a in 28% yield. A NOESY experiment was used to verify the
* Corresponding author. Tel.: +1 718 488 1453; fax: +1 718 488 1465.
E-mail address: Wayne.Schnatter@liu.edu (W.F.K. Schnatter).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.029

922
J. Truong et al. / Tetrahedron Letters 51 (2010) 921–923
Table 1
with 1a, which exhibited proton and carbon NMR spectra consis-
tent with the alkyne insertion product, (Scheme 1, compound 6,
R1 = Ph, R2 = Et, R3 = H). Injection (300 °C) into the GC–MS provided
a peak with retention time and mass coincident with 4b. Thermol-
ysis of a sample at 110 °C for 24 h in THF resulted in complete con-
version to 4b. In the other compounds studied to date the chlorine
was found ortho to the phenolic hydroxyl. Reaction with chloroe-
thynyl cyclopropane (entry 4) did not produce any ring opening
product, suggesting that a slow radical reaction is unlikely.
Although most reactions were carried out in refluxing THF, reac-
tion with tert-butylethynyl chloride at 90 °C (entry 6) produced
both isomers of the cycloadduct in a 1:4 ratio, indicating that reg-
ioselection is temperature dependent. GC–MS analysis of aliquots
taken from a reaction of 1a with chlorohexyne (entry 7) revealed
that formation of the product 4f was detectable after a few minutes
at room temperature.
The reaction with methyl chloropropiolate (entry 10) was com-
plicated by dechlorination resulting in a lower yield of halocate-
chol. GC-MS studies are consistent with the observation that the
dechlorination occurs after incorporation of the chloroalkyne.
Reaction of 1a with methyl propiolate provided large amounts of
the two cyclotrimers, neither of which was observed in this reac-
tion, suggesting that dechlorination may not be occurring prior
to reaction with the vinylketene complex. GC–MS analysis of ali-
quots taken from this reaction showed initial formation of the de-
sired product soon after the reaction was started. The
dechlorinated catechol was not detected until after 24 h and then
increased at the expense of the desired product. Trace amounts
of dechlorination product were detected (GC–MS) with chloroethy-
nyltrimethylsilane, chlorohexyne, and chloroethyne.
Cyclization of vinylketeneiron(0) complexes with 1-haloalkynesa
OH
EtO
R1
X
R2
X
O
EtO
R1
3
+
Fe(CO)3
R2
2
OH
EtO
R1
R2
X
1a R1 = Ph
1b R1 = Me
4
Entry
Complex
R2
X
Product (%)
D
Eb (kcal/mol)
1
2
3
4
5
6
1a
1a
1a
1a
1a
1a
Bu
H
Cl
cyc-Pr
t-Bu
t-Bu
Br
3a (28)c
4b (33)d
3c (45)d
3d (62)
3e (55)
3e (44)
4e (11)e
4f (72)
3g (62)
3h (42)
3i (14)
4i (23)f
3j (49)
3k (43)
Cl
Cl
Cl
Cl
Cl
3b 1.1
4d 0.2
7
8
9
1a
1a
1a
1a
Bu
Ph
SiMe3
COOMe
Cl
Cl
Cl
Cl
4g À0.8
4h À3.5
3i 5.6
10
11
12
1b
1b
Bu
Ph
Cl
Cl
a
Unless otherwise stated all reactions were carried out with 0.3–1.5 mmol of
vinylketene complex with 1.0 equiv of haloalkyne in 3–15 mL THF heated at reflux
for 24–48 h.
b
Positive (negative) value indicates 3 (4) is more stable.
DMF, reflux 48 h.
Volatile alkynes were used in excess as solutions that were heated at 70 °C in
c
Complex 1b behaved similarly, but it was noted that under the
reaction conditions similar to those used with the phenyl complex,
unreacted 1b was isolated along with pyrocatechols even after ex-
tended reaction times. Again, the regioselectivity appears to be
controlled primarily by steric effects. The regioselectivity exhibited
in this study is most often precisely the opposite exhibited by the
Dötz benzannulation8 of chromium carbene complexes: the more
sterically demanding substituent is incorporated meta rather than
ortho to the inserted carbonyl group which forms the phenol.
A mechanism is suggested in Scheme 1. Formation of a coordin-
atively unsaturated iron complex through decomplexation of one
d
pressure vessels equipped with Young valves.
e
Reaction was carried out at 90 °C.
Dechlorinated product, 4i with X = H, was also obtained in 39% yield.
f
structure. Reaction of one equivalent of chlorohexyne with 1a in
THF produced 4f in 72% yield. Cyclotrimers were not a significant
contributor to the mass balance of the reactions, although detect-
able quantities of cyclotrimerization products were found with
GC–MS in the Single Ion Monitoring (SIM) mode.
We focused our subsequent efforts in this preliminary study on
1-chloroalkynes. For chloroethyne (entry 2), chlorohexyne (entry
7), and methyl chloropropiolate (entry 10), the chlorine of the ma-
jor product was incorporated meta to the phenolic hydroxyl group.
An intermediate was isolated from the reaction of chloroethyne
of the
p
bonds of the diene leads to formation of the g2 alkyne
complex.21 It seems most likely that the regioselectivity is estab-
lished when the
g
2-complex forms the insertion product. Analogy
with the work of Gibson17,18,22 suggests that insertion occurs first
Cl
R2
R2
Cl
O
O
O
Cl
EtO
R1
EtO
R1
EtO
R1
FeLn
+
or
FeLn
FeLn
R2
2
1
FeLn
R2
FeLn
Cl
R2
O
O
O
R2
Cl
O
EtO
R1
EtO
R1
Cl
R2
EtO
R1
EtO
R1
Cl
FeLn
FeLn
5
6
OH
OH
EtO
R1
R2
Cl
EtO
R1
Cl
R2
4
3
Scheme 1. Proposed mechanism of the formation of chlorocatechols.

J. Truong et al. / Tetrahedron Letters 51 (2010) 921–923
923
at the ketene carbonyl rather than at the terminal allylic carbon of
the vinylketene. Reductive elimination to form a cyclohexadie-
none, followed by tautomerization provides the catechol.
associated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2009.12.029.
In an attempt to understand the regioselectivity of the products,
ab initio calculations are performed for various alkynes and some
of the products. The Löwdin population analysis on the chloro-
alkyne at the various levels of the theory shows the general trend
for the alkyne carbon connected to R2 is electron-rich or electron-
deficient in accordance with the electronegativity difference be-
tween chlorine and the R2 group. Therefore, the product distribu-
tion in Table 1 cannot be understood by the alkyne electronic
structure. The thermodynamic stability of the products alone does
not explain the product distribution, either. As shown in Table 1,
using the MP2/6-31G(d,p) level of theory including the zero-point
energy from the RHF/6-31G(d,p) level, R2 = H, cyclo-Pr, and Ph
substituted model products are nearly isoenergetic. In the case of
R2 = SiMe3, 4h is more stable than 3h by 3.5 kcal/mol. The largest
difference among the calculated products is R2 = COOH, and 3i is
6 kcal/mol more stable than 4i. The major products of the latter
two substitutions are in fact opposite of what thermodynamic sta-
bility of the products should be. From these considerations, it is
likely that steric factors in the formation of reactive intermediates
play a more important role in the formation of the observed prod-
ucts. Hence the ketene-alkyne adduct geometry must be important
in determining the product distribution, and we are currently
investigating this aspect computationally. We are actively probing
the electronic and steric parameters that influence the
regioselectivity.
References and notes
1. An entire issue of Tetrahedron 2008, 64, 757–968 focuses on the use of
benzannulation and cycloaddition reactions to form aromatic rings.
2. For a comprehensive review of ketene chemistry see: Tidwell, T. T. Ketenes;
Wiley: New York, 1995.
3. Trahanovsky, W. S.; Surber, B. W.; Wilkes, M. C.; Preckel, M. M. J. Am. Chem. Soc.
1982, 104, 6779–6781. and references cited therein.
4. Corey, E. J.; Kozikowski, A. P. Tetrahedron Lett. 1975, 16, 2389–2392.
5. (a) Loebach, J. L.; Bennett, D. M.; Danheiser, R. L. J. Org. Chem. 1998, 63, 8380–
8389; (b) Danheiser, R. L.; Sard, H. J. Org. Chem. 1980, 45, 4810–4812.
6. (a) Moore, H. W.; Decker, O. H. W. Chem. Rev. 1986, 86, 821–830; (b) Sun, L.;
Danheiser, R. L.; Brisbois, R. G.; Kowalczyk, J. J.; Miller, R. F. J. Am. Chem. Soc.
1990, 112, 3093–3100; (c) Liebeskind, L. S. J. Org. Chem. 1995, 60, 8194–
8203.
7. Austin, W. F.; Zhang, Y.; Danheiser, R. L. Org. Lett. 2005, 7, 3905–3908.
8. For a comprehensive review of the Dötz benzannulation see: Waters, M. L.;
Wulff, W. D. Org. React. 2008, 70, 121–623; And for a general updated review
see: Dötz, K. H.; Stendal, J., Jr. Chem. Rev. 2009, 109, 3227–3274.
9. (a) Merlic, C. A.; Aldrich, C. C.; Albaneze-Walker, J.; Saghatelian, A.; Mammen, J.
J. Org. Chem. 2001, 66, 1297–1309; (b) Merlic, C.; Xu, D.; Gladstone, B. G. J. Org.
Chem. 1993, 58, 538–545; (c) Rawat, M.; Wulff, W. D. Org. Lett. 2004, 6, 329–
332.
10. Anderson, B. A.; Wulff, W. D.; Rheingold, A. L. J. Am. Chem. Soc. 1990, 112, 8615–
8617.
11. (a) Huffman, M. A.; Liebeskind, L. S.; Pennington, W. T. Organometallics 1992,
11, 255–266; (b) Huffman, M. A.; Liebeskind, L. S. J. Am. Chem. Soc. 1990, 112,
8617–8618.
12. Huffman, M. A.; Liebeskind, L. S. J. Am. Chem. Soc. 1991, 113, 2771–2772.
13. Kondo, T.; Niimi, M.; Nomura, M.; Wada, K.; Mitsudo, T. Tetrahedron Lett. 2007,
48, 2837–2839.
14. For a comprehensive review of vinylketene complexes see: Gibson, S. E.;
Peplow, M. A. Adv. Organomet. Chem. 1999, 44, 275–353.
15. For recent reviews of iron chemistry in organic synthesis see: Sherry, B. D.;
Fürstner, A. Acc. Chem. Res. 2008, 41, 1500–1511; Bolm, C.; Legros, J.; Le Paih, J.;
Zani, L. Chem. Rev. 2004, 104, 6217–6254.
Acknowledgments
16. Alcock, N. W.; Richards, C. J.; Thomas, S. E. Organometallics 1991, 10, 231–238.
17. Morris, K. G.; Saberi, S. P.; Thomas, S. E. J. Chem. Soc., Chem. Commun. 1993,
209–211.
18. Saberi, S. P.; Salter, M. M.; Slawin, A. M. Z.; Thomas, S. E.; Williams, D. J. J. Chem.
Soc., Perkin Trans. 1 1994, 167–171.
19. Akhani, R. K.; Rehman, A.; Schnatter, W. F. K. Tetrahedron Lett. 2009, 50, 930–
932; Darbasie, N. D.; Schnatter, W. F. K.; Warner, K. F.; Manolache, N.
Tetrahedron Lett. 2006, 47, 963–966.
20. (a) Villeneuve, K.; Ridell, N.; Jordan, R. W.; Tsui, G. C.; Tam, W. Org. Lett. 2004, 6,
4543–4546; Allan, A.; Villenueve, K.; Cockburn, N.; Fatila, E.; Riddell, N.; Tam,
W. Eur. J. Org. Chem. 2008, 4178–4192; (b) Yoo, W.-J.; Allen, A.; Villeneuve, K.;
Tam, W. Org. Lett. 2005, 7, 5853–5856.
We acknowledge financial support through an Intramural Re-
search grant to N.M. and W.F.K.S., and a grant to W.F.K.S. from
the NIH (SC2GM082276). The NSF provided funds for the purchase
of a GC–MS (CHE-0840432). We also thank the Department of
Chemistry and Biochemistry of Rutgers University, Newark for ac-
cess to instrumentation. We thank Mr. William. A. Helwig, Mr. Ru-
hul Q. Chowdhury, Ms. Kerry McKenzie, Mr. Dean Aquino, and Ms.
Jeunesse Lewis (Harlem Childrens Society intern) for assistance.
21. Diphenylketene–alkyne Ir(I) complexes have been shown to undergo
cyclization to form iridabenzopyrans: Lo, H. C.; Grotjahn, D. B. J. Am. Chem.
Soc. 1997, 119, 2958–2959.
Supplementary data
22. Benyunes, S. A.; Gibson (née Thomas), S. E.; Peplow, M. A. Tetrahedron:
Asymmetry 1997, 8, 1535–1538. and references cited therein.
Supplementary data (detailed experimental procedures, spec-
troscopic data, NMR spectra, and details of ab initio calculations)