Regioselective Carbonylative Heteroannulation of o-Iodothiophenols with Allenes and Carbon Monoxide Catalyzed by a Palladium Complex: A Novel and Efficient Access to Thiochroman-4-one Derivatives

Article abstract of DOI:10.1021/jo9913098

The palladium-catalyzed carbonylative ring-forming reactions of 2-iodothiophenol, and the corresponding substituted derivatives, with allenes and carbon monoxide are described. The reactions afford thiochroman-4-ones in good to excellent isolated yields with quite high regioselectivity. The catalytic heteroannulation may involve regioselective addition of the sulfur moiety of the reactants on the more positive end of the allene, arylpalladium formation, CO insertion, subsequent intramolecular cyclization, and then reductive elimination. The regioselectivity is probably governed by electronic effects.

Full text of DOI:10.1021/jo9913098

9646
J . Org. Chem. 1999, 64, 9646-9652
Regioselective Ca r bon yla tive Heter oa n n u la tion of
o-Iod oth iop h en ols w ith Allen es a n d Ca r bon Mon oxid e Ca ta lyzed
by a P a lla d iu m Com p lex: A Novel a n d Efficien t Access to
Th ioch r om a n -4-on e Der iva tives
Wen-J ing Xiao and Howard Alper*
Department of Chemistry, University of Ottawa, 10 Marie Curie, Ottawa, Ontario, Canada K1N 6N5
Received August 17, 1999
The palladium-catalyzed carbonylative ring-forming reactions of 2-iodothiophenol, and the corre-
sponding substituted derivatives, with allenes and carbon monoxide are described. The reactions
afford thiochroman-4-ones in good to excellent isolated yields with quite high regioselectivity. The
catalytic heteroannulation may involve regioselective addition of the sulfur moiety of the reactants
on the more positive end of the allene, arylpalladium formation, CO insertion, subsequent
intramolecular cyclization, and then reductive elimination. The regioselectivity is probably governed
by electronic effects.
In tr od u ction
in principle, acylmetal derivatives can add to π-bonds via
carbometalation.10 As part of our continuing studies on
the scope of palladium-catalyzed carbonylation methodol-
ogy, we would like to explore such synthetic methods
employing carbon monoxide as a direct C-1 resource and
involving insertion of carbon-carbon multiple bonds to
acylpalladation derivatives. Furthermore, in sharp con-
trast with the palladium-catalyzed cyclization of o-iodo-
phenols and anilines with unsaturated substrates, ap-
plication of these methodologies in which o-iodothiophenol
is employed as a reagent instead of its oxo and nitro
analogues seems to be unexplored. A possible reason for
this is the acceptance that sulfur-containing compounds
can act as poisons for noble metals.11 However, we and
others have recently demonstrated that thiols are com-
patible with palladium, in Pd(0)-catalyzed thiolactoniza-
tion12 (eq 1) and thiocarbonylation13(eq 2), as well as with
rhodium, in Rh(I)-catalyzed thioformylation (eq 3).14
Transition metal-catalyzed carbo- and heteroannula-
tions are now emerging as a unique, powerful, and
versatile synthetic approach toward a variety of struc-
tural cores of complex organocarbo- and heterocycles.1
Examples include the palladium-catalyzed intra- and
intermolecular cyclization of unsaturated substrates such
as alkynes,2 1,2-3 and 1,3-dienes,4 vinyl cyclopropanes and
cyclobutanes,5 homoallylic alcohols,6 and imines7 with
functionally substituted aromatic or vinyl3a,8 iodides or
bromides, affording the corresponding benzo[b]furans,
indoles, spiroisoindolinones, and other heterocycles. In
contrast, much less information is available on the
cyclocarbonylation version of such processes,3b,9 although
(1) For reviews, see: (a) Larock, R. C. J . Organomet. Chem. 1999,
576, 111. (b) Ojima, I.; Tzamarioudaki, M.; Li, Z.; Donovan, R. J . Chem.
Rev. 1996, 96, 635. (c) Negishi, E.; Coperet, C.; Ma, S.; Liou, S.-Y.;
Liu, F. Chem. Rev. 1996, 96, 365. (d) Lautens, M.; Klute, W.; Tam, W.
Chem. Rev. 1996, 96, 49. (e) Trost, B. M. Angew. Chem., Int. Ed. Engl.
1995, 34, 259.
(2) For the most recent examples, see: (a) Ma, C.; Liu, X. X.; Yu,
S.; Zhao, S.; Cook, J . M. Tetrahedron Lett. 1999, 40, 657. (b) Larock,
R. C.; Yum, E. K.; Refvik, M. D. J . Org. Chem. 1998, 63, 7652. (c)
Chowdhury, C.; Chaudhui, G.; Guha, S.; Mukherjee, A.; Kundu, N. G.
J . Org. Chem. 1998, 63, 1863. (d) Roesch, K. R.; Larock, R. C. J . Org.
Chem. 1998, 63, 5306. (e) Ujjainwalla, F.; Warner, D. Tetrahedron Lett.
1998, 39, 5355. (f) Kundu, N. G.; Pal, M.; Nandi, B. J . Chem. Soc.,
Perkin Trans. 1, 1998, 561. (g) Xu, L.; Lewis, I. R.; Davidsen, S. K.;
Summers, J . B. Tetrahedron Lett. 1998, 39, 519.
(3) (a) Larock, R. C.; He, Y.; Leong, W. W.; Han, X.; Refvik, M. D.;
Zenner, J . M. J . Org. Chem. 1998, 63, 2154. (b) Okuro, K.; Alper, H.
J . Org. Chem. 1997, 62, 1566. (c) Grigg, R.; Sridharan, V.; Terrier, C.
Tetrahedron Lett. 1996, 37, 4221. (d) Ma, S.; Negishi, E. J . Am. Chem.
Soc. 1995, 117, 6345. (e) Grigg, R.; Sridharan, V.; Xu, L.-H. J . Chem.
Soc., Chem. Commun. 1995, 1903. (f) Larock, R. C.; Zenner, J . M. J .
Org. Chem. 1995, 60, 482. (g) Larock, R. C.; Berrios-Pena, N. G.; Fried,
C. A. J . Org. Chem. 1991, 56, 2615.
(4) (a) Back, T. G.; Bethell, R. Tetrahedron Lett. 1998, 39, 5463. (b)
Larock, R. C.; Guo, L. Synlett 1995, 465. (c) O’Connor, J . M.; Stallman,
B. J .; Clark, W. G.; Shu, A. Y. L.; Spada, R. E.; Stevenson, T. M.; Dieck,
H. A. J . Org. Chem. 1983, 48, 807. (d) Larock, R. C.; Berrios-Pena, N.
G.; Narayanan, K. J . Org. Chem. 1990, 55, 3447.
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8, 2307. (b) Negishi, E.; Coperet, C.; Ma, S.; Mita, T.; Sugihara, T.;
Tour, J . M. J . Am. Chem. Soc. 1996, 118, 5904. (c) Negishi, E.; Ma, S.;
Amanfu, J .; Coperet, C.; Miller, J . A.; Tour, J . M. J . Am. Chem. Soc.
1996, 118, 5919.
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Res. 1995, 28, 414. (b) Colquhoun, H. M.; Thompson, D. J .; Twigg, M.
V. Carbonylation: Direct Synthesis of Carbonyl Compounds; Plenum
Press: New York, 1991.
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1991, 56, 2615.
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Heterocycl. Chem. 1999, 36, 297.
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39, 5143.
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Poisoning; Marcel Dekker: New York, 1984. (c) Dubois, M. R. Chem.
Rev. 1989, 89, 1.
10.1021/jo9913098 CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/02/1999

Carbonylative Heteroannulation of o-Iodothiophenols
J . Org. Chem., Vol. 64, No. 26, 1999 9647
Sch em e 1
Accordingly, we envisioned that the carbonylative
heteroannulation of o-iodothiophenols with allenes and
carbon monoxide could be carried out, affording the
corresponding thiochroman-4-one derivatives (eq 4).
Ta ble 1. Op tim iza tion of Ca ta lysts a n d Liga n d sa
Of particular interest is the fact that some 4-thiochro-
manone derivatives are potent antifungal agents15 and
very useful precursors16,17of other heterocyclic com-
pounds. Of the various routes to their preparation,18 the
methodology presented herein is one of the most straight-
forward and efficient ways to afford such compounds.
entry
catalyst
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
ligand
time (h)
yieldb (%)
Resu lts a n d Discu ssion
1
2
3
4
5
6
7
8
9
dppb
dppp
dppe
dppf
PPh3
PCy3
dppf
dppf
dppb
dppf
dppf
24
24
48
24
24
24
48
60
60
60
60
74
58
7c
The starting materials were prepared by standard
methodology.19,20 For example, o-iodothiophenols (1a -c)
were prepared by the reactions shown in Scheme 1.
Initial studies were focused on examining the feasibil-
ity of the carbonylation annulation and optimizing reac-
tion conditions that could be applied to a variety of
allenes and o-iodothiophenol derivatives. The reaction of
2-iodothiophenol (1a ) and 3-methyl-1, 2-butadiene (2a )
with carbon monoxide was chosen as a model reaction.
The optimal reaction conditions used previously for the
palladium-catalyzed carbonylation of o-iodophenols with
allenes3b were initially employed in the present case. This
reaction was run on a 1 mmol scale, using 5 mol % Pd-
(OAc)2 as catalyst, 5 mol % dppb as ligand, 3 equiv of
allene, and 1.5 equiv of N-ethyldiisopropylamine in 5 mL
of benzene, at 100 °C, under a pressure of 400 psi carbon
monoxide for 24 h and gave 3a in 74% isolated yield (eq
5). The effects of varying the catalyst, ligand, solvent,
87
70
45
77
80
64
84
76
Pd2(dba)3
Pd2(dba)3‚CHCl3
Pd2(dba)3‚CHCl3
Pd(PPh3)4
10
11
a
Reaction conditions: 2-iodothiophenol (1 mmol), 3-methyl-1,
2-butadiene (5 mmol), catalyst (0.05 mmol), PPh3 or PCy3 (0.1
mmol, if used), dppb, dppp, dppe, or dppf (0.05 mmol, if used),
b
i-Pr2NEt (1.5 mmol), 400 psi, 100°C, benzene (5 mL). Isolated
yield. c 38% of 1a was recovered.
base, and reaction temperature on the model reaction
were then examined.
(12) Xiao, W.-J .; Alper, H. J . Org. Chem. 1997, 62, 3422.
(13) (a) Xiao, W.-J .; Vasapollo, G.; Alper, H.J . Org. Chem. 1998, 63,
2609. (b) Xiao, W.-J .; Alper, H. J . Org. Chem. 1998, 63, 7939. (c) Xiao,
W.-J .; Vasapollo, G.; Alper, H. J . Org. Chem. 1999, 64, 2080.
(14) Ogawa, A.; Takeba, M.; Kawakami, J .; Ryu, I.; Kambe, N.;
Sonoda, N. J . Am. Chem. Soc. 1995, 117, 7564.
(15) (a) Fang, L.; Guo, C.; Zhang, Q. B. Chin. Chem. Lett. 1997, 8,
939. (b) Fang, L.; Dai, Z.; Zhang, G. Shenyang Yaoke Daxue Xuebao
1998, 15, 116. (c) Kameo, K.; Hatada, Y.; Takahashi, T.; Tomizawa,
K.; Hatayama, K. J P 04059725, 1992; Chem. Abstr. 1992, 117, 97317.
(16) For reviews, see: (a) Lockhart, I. M. In Chromenes, Chro-
manones and Chromones; Ellis, G. P., Ed.; J ohn Wiley and Sons Ltd.:
New York, 1977. (b) Hepworth, J . D. In Comprehensive Heterocyclic
Chemistry; Katritzy, A. R., Rees, C. W., Eds.; Pergamon Press: Oxford,
1984; Vol. 3, p 737.
(17) (a) Fisera, L.; J aroskova, L.; Levai, A.; J edlovska, E.; Toth, G.;
Polakova, M. Heterocycles 1997, 45, 1651. (b) Gabbutt, C. D.; Hepworth,
J . D.; Heron, B. M. J . Chem. Soc., Perkin Trans. 1 1992, 3015. (c) Adam,
W.; Golsch, D.; Hadjiarapoglou, L.; Levai, A.; Nemes, C.; Patonay, T.
Tetrahedron 1994, 50, 13113. (d) Gabbutt, C. D.; Hepworth, J . D.;
Heron, B. M.; Kanjia, M. Tetrahedron 1994, 50, 827.
(18) (a) Clayton, S. E.; Gabbutt, C. D.; Hepworth, J . D.; Heron, B.
M. Tetrahedron 1993, 49, 939. (b) Gabbutt, C. D.; Hepworth, J . D.;
Heron, B. M. Tetrahedron 1994, 50, 5245. (c) Sowmithran, D.; Prasad,
R. Synthesis 1985, 545. (d) Arnoldi, A. Synthesis 1984, 856. (e) Yu, X.;
Liu, J .; Li, X.; Zhang, G.; Fang, L. Huaxi Yaoxue Zazhi 1997, 12, 230.
(f) Truce, W. E.; Milionis, J . P. J . Am. Chem. Soc. 1952, 74, 974.
(19) Furniss, B. S.; Hannaford, A. T.; Rogers, V.; Smith, P. W. G.;
Tatchell, A. R. Vogel’s Textbook of Practical Organic Chemistry, 4th
ed.; Longman: England, 1978; p 676.
Table 1 shows the results of the reaction using several
palladium catalysts and mono- and bis-phosphine ligands.
These results show that both palladium(0) and palla-
dium(II) complexes were excellent catalysts for the
carbonylative heteroannulation, although palladium(0)
complexes catalyzed this reaction at a slower rate. The
ligands employed played an important role in this
transformation, with 1,1′-bis(diphenylphosphino)fer-
rocene (dppf) being an excellent ligand for both pal-
ladium(0) and palladium(II) catalysts (Table 1, entries 4
and 7-11). In particular, the use of Pd(OAc)2 with 1 equiv
of dppf was the most effective catalyst system for the
formation of 3a in 87% yield (Table 1, entry 4). Although
1,3-bis(diphenylphosphino)propane (dppp) and 1, 4-bis-
(diphenylphosphino)butane (dppb) were also effective as
added ligands for this palladium-catalyzed reaction, the
results were generally inferior to those of dppf (Table 1,
entries 1, 2, and 9). Compared to other bidentate phos-
phines, 1,2-bis(diphenylphosphino)ethane (dppe) is al-
most ineffective (Table 1, entry 3). This may be due to
(20) Arnau, N.; Morenv-Manas, M.; Pleixats, R. Tetrahedron 1993,
49, 11019.

9648 J . Org. Chem., Vol. 64, No. 26, 1999
Xiao and Alper
Ta ble 2. Op tim iza tion of Solven ts, Ba ses, a n d Rea ction
Tem p er a tu r ea
These results show that solvents and bases are interde-
pendent. For example, when benzene was employed as
the solvent, N-ethyldiisopropylamine and triethylamine
were observed to be very effective for the reaction.
However, the use of K2CO3, KOAc, DBU, and DABCO
resulted in decreased yields (Table 2, entries 7-11). It
is worth noting that in DMF, K2CO3 is a better base for
the model reaction than i-Pr2NEt (Table 2, entries 2 and
12), while both benzene/Et3N and DMF/KOAc systems
are similarly effective for this carbonylative heteroan-
nulation (Table 2, entries 9 and 13). DBU and DABCO,
which were used in the palladium-catalyzed carbonyla-
tive coupling of 2-hydroxylaryl iodides with ethynyl-
arenes22b and annulation of iodoanilines and ketones,23
respectively, did not work well in the present reaction
(Table 2, entries 10 and 11).
The reaction temperature is another critical factor for
the successful carbonylative heteroannulation, with the
best result being attained at 100 °C. Variations of the
temperature from this value have been shown to be
detrimental to the reaction. For instance, increasing the
temperature to 150 °C gave only 44% yield (Table 2, entry
16), while decreasing the temperature to 70 °C gave
exclusively the decarbonylation product in 74% yield
(Table 2, entry 14).
We did not rigorously examine the effect of CO pres-
sure on the reaction; however, we found that no carbo-
nylation product was formed when the pressure of CO
was lower than 100 psi, and when the pressure was
raised beyond 1000 psi, a complicated mixture was
obtained. In subsequent studies, 400 psi of carbon
monoxide was usually used, consistent with our previous
experience with other carbonylation reactions.3b,13
The heteroannulation of allenes is also sensitive to the
concentration of the allene. The reaction gave poor yields
when only 1 equiv of the allene (relative to 2-iodothiophe-
nol) was used, while 87% yield was attained when 3-5
equiv of allene was employed.
There has been much interest recently in intramolecu-
lar Heck-type coupling reactions24 that employ aromatic
chlorides25 or bromides26 as substrates. However, the
carbonylative reaction of 2a with commercially available
2-bromothiophenol (7) afforded the bromothioether (8)
rather than thiochroman-4-one (3a ) (eq 6). The difference
in behavior may be a result of the lower rate of oxidative
addition to an Ar-Br moiety, compared with Ar-I. Note
that the iodo analogue of 8 was formed in 72% yield when
1a was treated with 2a and CO using 10% Pd/C as the
catalyst.
entry
solvent
base
T (°C)
time (h)
yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12e
13
14
15
16
benzene
DMF
THF
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
KOAc
100
100
100
100
100
100
100
100
100
100
100
100
100
70
24
24
24
24
24
24
60
60
24
24
24
48
48
36
24
24
87
58
52
33
66
78
24
29
64
34
37
69
63
0f
DMSO
CH3CN
toluene
benzene
benzene
benzene
benzene
benzene
DMF
K2CO3
Et3N
DBUc
DABCOd
K2CO3
DMF
KOAc
benzene
benzene
benzene
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
130
150
70
44
a
Reaction conditions: 2-iodothiophenol (1 mmol), 3-methyl-1,
2-butadiene (5 mmol), Pd(OAc)2 (0.05 mmol), dppf (0.05 mmol),
i-Pr2Et, Et3N, DBU, or DABCO (1.5 mmol, if used), K2CO3 or KOAc
b
(3 mmol, if used), solvent (5 mL), 400 psi. Isolated yield. c 1,8-
d
Diazabicyclo[5.4.0]under-7-ene. 1,4-Diazabicyclo[2.2.2]octane.e Us-
ing a 9:1 DMF/water mixture afforded 3a in 18% yield, plus many
other products. An inseparable mixture of numerous products
resulted using water as the solvent. f The decarbonylation product,
o-iodophenyl 3-methyl-2-butenyl sulfide, was obtained in 74%
yield.
the fact that the rate of carbon monoxide insertion into
a Pd-C bond is faster for those alkylpalladium bisphos-
phine complexes that contain a more flexible metal ligand
chelate ring.21 The monodentate ligands, like PPh3 and
PCy3, can be used for this reaction, but they are not as
effective as dppf (Table 1, entries 5 and 6). Therefore, it
was decided to use Pd(OAc)2 with dppf as the catalyst
system and examine the effect of different solvents, bases,
and reaction temperature on the carbonylative heteroan-
nulation.
It can be concluded from the results summarized in
Table 2 that the reaction is significantly influenced by
the solvent and base employed. For example, when
N-ethyldiisopropylamine is used as a base, the reaction
works very well in benzene and gives the product 3a in
87% isolated yield (Table 2, entry 1); however, under the
same conditions, using DMF as a solvent, the yield of 3a
decreased to 58% (Table 2, entry 2). This was of interest,
as previous studies noted that DMF was the solvent of
choice.22 Other solvents, such as THF, DMSO, CH3CN,
and toluene, can be employed as the solvent for the
reaction, but none appears to be as effective as benzene
(compare entries 1-6 in Table 2).
In addition to N-ethyldiisopropylamine, we have ex-
amined a variety of other bases, including inorganic and
organic ones, for the reaction (Table 2, entries 7-13).
(23) Chen, C.; Lieberman, D. R.; Larsen, R. D.; Verhoeven, T. R.;
Reider, P. J . J . Org. Chem. 1997, 62, 2676.
(24) For examples, see: (a) Brown, A.; Grigg, R. Ravishankar, T.;
Thornton-Pett, M. Tetrahedron Lett. 1994, 35, 2753. (b) Okita, T.; Isobe,
M. Tetrahedron 1994, 50, 11143.
(25) For examples, see: (a) Wu, G.-Z.; Lamaty, F.; Negishi, E. I.J .
Org. Chem. 1989, 54, 2507. (b) Reetz, M. T.; Lohmer, G.; Schwickardi,
R. Angew. Chem., Int. Ed. 1998, 37, 481.
(21) (a) Dekker: G. P. C. M.; Elsevier: C. J .; Vrieze, K.; van
Leeuwen, P. W. N. M. Organometallics 1992, 11, 1598. (b) Dekker, G.
P. C. M.; Elsevier: C. J .; Vrieze, K.; van Leeuwen, P. W. N. M. J .
Organomet. Chem. 1992, 430, 357. (c) Yu, W.-Y.; Alper, H. J . Org.
Chem. 1997, 62, 5684.
(22) (a) Kalinin, V. N.; Shostakovsky, M. V.; Ponomaryov, A. B.
Tetrahedron Lett. 1990, 31, 4073. (b) Ciattini, P. G.; Morera, E.; Ortar,
G.; Rossi, S. S. Tetrahedron 1991, 47, 6449.
(26) For examples, see: (a) Dankwardt, J . W. Flippin, L. A. J . Org.
Chem. 1995, 60, 2312. (b) Hong, F.; Xia, J .; Xu, Y. J . Chem. Soc., Perkin
Trans. 1 1994, 1665.

Carbonylative Heteroannulation of o-Iodothiophenols
J . Org. Chem., Vol. 64, No. 26, 1999 9649
Ta ble 3. P a lla d iu m -Ca ta lyzed Ca r bon yla tive Heter oa n n u la tion of Allen es w ith o-Iod oth iop h en ols a n d Ca r bon
Mon oxid e (Eq 4)a
b
b
a
Reaction conditions: o-iodothiophenol (1 mmol), allene (2-5 mmol), CO (400 psi), i-Pr2NEt (1.5 mmol), Pd(OAc)2 (0.05 mmol), dppf
(0.05 mmol), benzene (5 mL), 100 °C. Isolated yield. c Reaction time: 36 h. Reaction time: 60 h. e The ratio of E to Z (E/Z ) 1.5:1) was
b
d
determined by 1HNMR.
The above experiments indicated that the standard
reaction conditions, with substitution of dppf for dppb,
gave the best overall yield. Using these reaction condi-
tions, the reactions of a variety of o-iodothiophenols and
allenes were studied and the results are summarized in
Table 3.
tion by prolonging the reaction time to 60 h, affording
the corresponding product 2f in 72% yield (Table 3, entry
6). The more bulky allene, tetramethylallene (2b), has
been successfully employed in this reaction without any
problem, and to our knowledge, this is the first time that
it has been used in this type of annulation process (Table
3, entry 2). Unlike palladium-catalyzed annulation of
allene with functionalized vinylic halides,3a attempts to
carry out the reaction of methoxyallene (9) with o-
iodothiophenol and CO were unsuccessful (eq 7).
Acyclic, cyclic, terminal, and internal 1,2-dienes can
be successfully employed in the reaction together with
o-iodothiophenols containing electron-withdrawing or
-donating groups (Table 3), to give the corresponding
thiochromanone derivatives in good to excellent isolated
yields. The regioselectivity of this carbonylative hetero-
annulation methodology is generally quite high. The
terminal disubstituted allene, 3-methyl-1, 2-butadiene
(2a ), reacted with 1a , 1b, and 1c to give only the exo-
methylene products 3a , 3h , and 3k with little variation
in yields (Table 3, entries 1, 8, and 11). The reactions of
monosubstituted allenes, like that of 2a , are regioselec-
tive with nucleophilic attack of the -SH group occurring
exclusively at the more substituted carbon of the allene
unit (Table 3, entries 3 and 4). When the cyclic internal
allene 2e was employed, the expected product 3e was
obtained in 72% yield (Table 3, entry 5). When the
unsymmetrical acyclic internal allene 2g was employed
as the substrate, thiochromanone 3g was isolated in 90%
yield as the sole product (Table 3, entry 7). The reaction
is slower when the allene (2f) contains an electron-with-
drawing group, but the reaction can proceed to comple-
Such behavior was also observed for the palladium-
catalyzed carbonylation3b of o-iodophenols with allenes.
When the reaction was carried out with 2 equiv of dppf
(relative to Pd catalyst) at 110 °C, the thiocarbonylation
product 11 was isolated in 57% yield and no carbonylative
heteroannulation product was obtained.

9650 J . Org. Chem., Vol. 64, No. 26, 1999
Xiao and Alper
Sch em e 2
one derivatives in good to excellent yields. To our
knowledge, this is the first example of this type of
annulation employing thiophenols as direct reactants.
This one-pot procedure, the mild reaction conditions, and
the easy access to the starting materials make this
methodology of value to the area of thiochromanone
chemistry.
Exp er im en ta l Section
Allen es. 3-Methyl-1,2-butadiene (2a ), tetramethylallene
(2b), and cyclohexylallene (2c) are commercially available.
Methoxyallene (9),29 1-phenyl-2,3-pentadiene (2g),30 1,2-cy-
clononadiene (2e),31 1,2-nonadiene (2d ),32 and ethyl 2,3-pen-
tadienoate (2f)33 were prepared according to the previously
reported methods.
Gen er a l P r oced u r e for th e P r ep a r a tion of o-Iod o-
a n ilin e 4b a n d 4c. Into a 100 mL beaker were placed
4-methylaniline (2.14 g, 0.02 mol) (for 4b) or 4-chloroaniline
(2.55 g, 0.02 mol) (for 4c), NaHCO3 (2.50 g, 0.03 mol), and
water (20 mL). The mixture was cooled to 10-15 °C by the
addition of a small amount of crushed ice. With stirring,
powdered and resublimed iodine (5.08 g, 0.02 mol) was
introduced in portions of 1 g at intervals of 3-5 min, after
which time the color of the free iodine in the solution had
practically disappeared and the reaction was complete. The
organic phase was extracted from the reaction mixture with
diethyl ether. The extracts were combined and dried with
MgSO4. Removal of the solvent and recrystallization of the
crude product from n-hexane afforded 4b and 4c in 73 and
68% yields, respectively.
4-Meth yl-2-iod oa n ilin e (4b): needles; mp39-40 °C; IR
1
(KBr) 3358, 3447 cm-1; H NMR (200 MHz, CDCl3) δ 2.20 (s,
3H), 3.85 (br, s, 2H), 6.66 (d, 1H, J ) 8.0 Hz), 6.95 (m, 1H),
7.45 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 19.80, 84.28, 114.63,
129.49, 130.00, 138.98, 114.25; MS (EI) m/z 233 (M+); HRMS
calcd for C7H8IN 232.9701, found 232.9686. Anal. Calcd for
C7H8IN: C, 36.08; H, 3.46. Found: C, 36.16; H, 3.55.
Gen er a l P r oced u r e for th e P r ep a r a tion of o-Iod o-
th iop h en ols 1a , 1b, a n d 1c. A solution of sodium nitrite
(0.704 g, 0.01 mol) in water (2 mL) was added during 30 min
to an ice -cooled solution of o-iodoaniline (0.01 mol) in 35%
aqueous HCl (1.67 mL, 0.02 mol) containing ice (2.0 g), while
potassium ethylxanthate was prepared by rapid stirring of a
mixture of potassium hydroxide (0.796 g, 0.012 mol), ethanol
(1.34 mL), water (2.5 mL), and carbon disulfide (1.332 g, 0.018
mol) for 2.5 h. The first solution of o-iodobenzenediazonium
salt was added slowly to the prepared potassium ethylxanthate
at 0-5 °C. After the addition, the mixture was heated at 50-
55 °C for 0.5 h, cooled, and then extracted with ether. The
organic phase was dried (MgSO4) and evaporated to dryness
in vacuo. The residue was refluxed with KOH (3.0 g, 0.046
mol) in absolute ethanol for 10 h, neutralized with 10% HCl,
and extracted with ether. The combined organic phase was
dried (MgSO4) and evaporated to afford crude o-iodothiophenol,
which was purified by chromatography using silica gel (eluant,
hexane/ethyl acetate ) 5:1). The isolated yields of 1a , 1b, and
1c are 63, 54, and 66%, respectively.
Note that the regioselectivity of this reaction is con-
sistent with palladium-catalyzed carboannulation of
functionally substituted aryl halides with 1,2-dienes and
its asymmetric as well as carbonylative versions3b,f,g and
can be explained on the basis of electronic factors.3b,f
A probable mechanism for the carbonylative heteroan-
nulation of 1,2-dienes with o-iodothiophenols is outlined
in Scheme 2 (illustrated for 1a and 2a ). It is conceivable
that this reaction may proceed through initial palladium
acetate reduction to palladium(0) in situ,27 followed by
oxidative addition of the o-iodothiophenol to palladium-
(0)28 to form 12 and insertion of allene to 12 to produce
a σ-allylpalladium intermediate 14 (via 13). Reductive
elimination of 14 would give the iodothioether (15).
Oxidative addition of the latter to Pd(0) would generate
complex 16, which on subsequent CO insertion and
intramolecular cyclization9b,c would afford 3a and regen-
erate the catalyst.
1
2-Iod oth iop h en ol (1a ): oil; H NMR (200 MHz, CDCl3) δ
3.98 (s, 1H), 6.94-6.98 (m, 1H), 7.10-7.16 (m, 1H), 7.32 (d,
1H, J ) 8.6 Hz), 7.50 (d, 1H, J ) 8.6 Hz); 13C NMR (75 MHz,
CDCl3) δ 121.98, 126.02, 127.84, 129.44, 133.07, 134.12; MS
Con clu sion
In summary, this research has resulted in the regio-
selective carbonylative heteroannulation of 1,2-dienes
with o-iodothiophenols and carbon monoxide catalyzed
by palladium acetate and dppf to form thiochroman-4-
(29) (a) Merz, A. Angew. Chem., Int. Ed. Engl. 1973, 12, 846. (b)
Meyer, A.; McCabe, D. J .; Curtis, M. D. Organometallics 1987, 6, 1491.
(30) Skattebol, L.; Solomon, S. Organic Syntheses; Wiley: New York,
1973; Collect. Vol. V, p 306.
(31) (a) Bach, R. D.; Mazur, U.; Brummel, R. N.; Lin, L.-H. J . Am.
Chem. Soc. 1971, 93, 7120. (b) Okude, Y.; Hiyama, T.; Nozaki, L.
Tetrahedron Lett. 1977, 43, 3829.
(27) (a) Amatore, C.; J utand, A.; M’Barki, M. Organometallics 1992,
11, 3009. (b) Amatore, C.; Carre, E.; J utand, A.; M’Barki, M. Organo-
metallics 1995, 14, 1818.
(32) Crabbe, P.; Nassim, B.; Robert-Lopes, M.-T. Organic Syntheses;
Wiley: New York, 1990; Collect. Vol. VII, p 276.
(28) Ogawa, A.; Ikeda, T.; Kimura, K.; Hirao, T. J . Am. Chem. Soc.
1999, 121, 5108.
(33) Lang, R. W.; Hansen, H.-J . Organic Syntheses; Wiley: New
York, 1990; Collect. Vol. VII, p 232.

Carbonylative Heteroannulation of o-Iodothiophenols
J . Org. Chem., Vol. 64, No. 26, 1999 9651
(EI) m/z 236.0 (M+); HRMS calcd for C5H5IS 235.9157, found
235.9194.
118.22, 123.30, 125.14, 135.06, 136.12, 153.64, 155.06, 170.78,
186.75; MS (EI) m/z 262 (M+); HRMS Calcd for C14H14O3S
262.0664, found 262.0670. Anal. Calcd for C14H14O3S: C, 64.11;
H, 5.38. Found: C, 64.18, H, 5.44.
Typ ica l P r oced u r e for th e P a lla d iu m -Ca ta lyzed Ca r -
bon yla tive Heter oa n n u la tion of Allen es w ith o-Iod o-
th iop h en ols a n d Ca r bon Mon oxid e. A mixture of the allene
(2-5 mmol), o-iodothiophenol (1 mmol), Pd(OAc)2 (0.05 mmol),
dppf (0.05 mmol), i-Pr2NEt (1.5 mmol), and anhydrous benzene
(5.0 mL) was heated to 100 °C with stirring, under an
atmosphere of carbon monoxide (400 psi), in a stainless steel
autoclave for 24-60 h. After the reaction, the autoclave was
cooled to room temperature, excess carbon monoxide was
released, and the crude reaction mixture was passed through
a plug of Florisil, using hexane/ethyl acetate (1:1) as the
eluant. The light yellow solution was evaporated to dryness
and purified by column chromatography on silica gel using
n-hexanes-ethyl acetate (95:5) as an eluant.
2-Met h yl-3-(2-p h en ylvin yl)-2,3-d ih yd r o-4H -1-b en zo-
th iop yr a n -4-on e (3g) (a mixture of stereoisomers): oil; IR
1
(neat) 1668 cm-1 (CdO); H NMR (200 MHz, CDCl3) δ 1.46-
1.53 (m, 3H), 3.24-3.36 (m, 1H), 3.74-3.78 (m, 1H), 6.05-
6.22 (m, 1H), 6.52-6.70 (m, 1H), 6.95-7.08 (m, 2H), 7.20-
7.52 (m, 6H), 7.85-7.92 (m, 1H); 13C NMR (75 MHz, CDCl3) δ
17.72, 18.01, 47.36, 48.04, 56.38, 56.76, 116.88, 118.47, 119.50,
119.78, 121.04, 121.49, 126.73, 127.37, 127.62, 127.93, 128.50,
128.59, 128.74, 129.84, 135.90, 135.97, 135.63, 136.26, 136.37,
138.50, 147.62, 148.13, 189.72, 189.85; MS (EI) m/z 280.1 (M+);
HRMS calcd for C18H16OS 280.0922, found 280.0926. Anal.
Calcd for C18H16OS: C, 77.12; H, 5.76. Found: C, 77.16; H,
5.71.
3-Meth ylen e-2, 2-d im eth yl-2, 3-d ih yd r o-4H-1-ben zoth i-
op yr a n -4-on e (3a ): oil; IR (neat) 1670 cm-1 1H NMR (200
;
3-Meth yl-2,2,6-tr im eth yl-2, 3-d ih yd r o-4H-1-ben zoth io-
1
p yr a n -4-on e (3h ): oil; IR (neat) 1666 cm-1 (CdO); H NMR
MHz, CDCl3) δ 1.60 (s, 6H), 5.46 (d, 1H, J ) 0.69 Hz), 6.06 (d,
1H, J ) 0.69 Hz), 7.18-7.19 (m, 2H), 7.22-7.39 (m, 1H), 8.15
(dd, 1H, J ) 8 and 1.6 Hz); 13C NMR (75 MHz, CDCl3) δ 27.44,
46.73, 118.78, 125.37, 127.83, 129.69, 130.62, 133.52, 140.41,
(200 MHz, CDCl3) δ 1.60 (s, 6H), 2.34 (s, 3H), 5.45 (d, 1H, J )
0.8 Hz), 6.06 (d, 1H, J ) 0.8 Hz), 7.13 (d, 1H, J ) 8.0 Hz),
7.25 (d, 1H, J ) 8.0 Hz), 7.97 (s, 1H); 13C NMR (50 MHz,
CDCl3) δ 20.84, 27.43, 46.61, 118.64, 127.78, 129.86, 130.41,
134.67, 135.25, 136.99, 150.80, 187.03; MS (EI) m/z 218.1 (M+);
HRMS calcd for C13H14OS 218.0765, found 218.0751. Anal.
Calcd for C13H14OS: C, 71.53; H, 6.47. Found: C, 71.62; H,
6.45.
2-Cycloh exyl-6-m eth yl-3-m eth ylen e-2,3-d ih yd r o-4H-1-
ben zoth iop yr a n -4-on e (3i): oil; IR (neat) 1670 cm-1 (CdO);
1H NMR (200 MHz, CDCl3) δ 0.95-1.24 (m, 4H), 1.64-1.78
(m, 6H), 2.12-2.20 (m, 1H), 2.34 (s, 3H), 3.45 (d, 1H, J ) 7.4
Hz), 5.42 (s, 1H), 6.10 (s, 1H), 7.18-7.25 (m, 2H), 7.95 (s, 1H);
13C NMR (75 MHz, CDCl3) δ 20.84, 25.50, 25.85, 28.03, 31.22,
32.60, 39.39, 53.78, 123.11, 127.71, 128.07, 129.82, 130.47,
131.35, 134.70, 144.18, 186.12; MS (EI) m/z 272.1 (M+); HRMS
Calcd for C17H20OS 272.1235, found 272.1229. Anal. Calcd for
150.56, 186.84; MS (EI) m/z 204.1 (M+); HRMS calcd for C12H12
-
OS 204.0609, found 204.0598. Anal. Calcd for C12H12OS: C,
70.57; H, 5.93. Found: C, 70.62; H, 5.88.
3-(Dim et h ylm et h ylen e)-2,2-d im et h yl-2,3-d ih yd r o-4H-
1-ben zoth iop yr a n -4-on e (3b): oil; IR (neat) 1671 cm-1 (Cd
O); 1H NMR (200 MHz, CDCl3) δ 1.43 (s, 3H), 1.52 (s, 3H),
1.85 (s, 3H), 1.88 (s, 3H), 7.15-7.19 (m, 2H), 7.34-7.38 (m,
1H), 8.09-8.13 (m, 1H); 13C NMR (50 MHz, CDCl3) δ 23.10,
26.03, 29.82, 29.96, 48.84, 117.47, 124.68, 127.31, 127.43,
128.71, 135.05, 139.70, 141.02, 195.15; MS (EI) m/z 232.1 (M+);
HRMS calcd for C14H16OS 232.0922, found 232.0916. Anal.
Calcd for C14H16OS: C, 72.39; H, 6.95. Found: C, 72.44; H,
6.88.
2-Cycloh exyl-3-m eth ylen e-2,3-d ih yd r o-4H-1-ben zoth i-
op yr a n -4-on e (3c): oil; IR (neat) 1670 cm-1 (CdO); 1H NMR
(200 MHz, CDCl3) δ 0.88-1.16 (m, 4H), 1.54-1.74 (m, 6H),
2.16-2.24 (m, 1H), 3.46 (d, 1H, J ) 7.4 Hz), 5.43 (s, 1H), 6.11
(s, 1H), 7.15-7.24 (m, 2H), 7.36-7.42 (m, 1H), 8.14 (d, 1H, J
) 8.0 Hz); 13C NMR (125 MHz, CDCl3) δ 25.82, 26.60, 27.72,
28.40, 29.72, 32.31, 53.75, 115.55, 123.24, 125.24, 127.44,
128.02, 129.21, 132.96, 143.88, 185.88; MS (EI) m/z 258.1 (M+);
HRMS Calcd for C16H18OS 258.1078, found 258.1075. Anal.
Calcd for C16H18OS: C, 74.39; H, 7.03. Found: C, 74.46; H,
7.10.
C
17H20OS: C, 74.97; H, 7.41. Found: C, 74.88; H, 7.45.
2-n -Hexyl-6-m eth yl-3-m eth ylen e-2,3-d ih yd r o-4H-1-ben -
zoth iop yr a n -4-on e (3j): oil; IR (neat) 1669 cm-1 (CdO); H
NMR (200 MHz, CDCl3) δ 0.88 (t, 3H, J ) 7.0 Hz), 1.20-1.88
(m, 10H), 2.36 (s, 3H), 3.88-3.92 (m, 1H), 5.52 (d, 1H, J ) 1.0
Hz), 6.32 (d, 1H, J ) 1.0 Hz), 7.33-7.40 (m, 2H), 7.77 (d, 1H,
J ) 0.6 Hz); 13C NMR (50 MHz, CDCl3) δ 14.07, 20.38, 23.52,
27.83, 28.90, 31.78, 33.40, 56.68, 119.04, 120.46, 122.05,
127.50, 128.33, 136.37, 139.63, 142.54, 187.60; MS (EI) m/z
274.1 (M+); HRMS Calcd for C17H22OS 274.1391, found
1
274.1393. Anal. Calcd for
Found: C, 74.43; H, 8.04.
C17H22OS: C, 74.41; H, 8.09.
2-n -Hexyl-3-m eth ylen e-2,3-d ih yd r o-4H-1-ben zoth iop y-
r a n -4-on e (3d ): oil; IR (neat) 1672 cm-1 (CdO); 1H NMR (200
MHz, CDCl3) δ 0.87 (t, 3H, J ) 7.0 Hz), 1.13-1.70 (m, 10H),
3.50-3.54 (m, 1H), 5.49 (d, 1H, J ) 0.8 Hz), 6.23 (d, 1H, J )
0.8 Hz), 6.92-7.04 (m, 2H), 7.33-7.50 (m, 1H), 7.86 (dd, 1H,
J ) 8.0, 1.8 Hz); 13C NMR (50 MHz, CDCl3) δ 14.07, 22.70,
24.50, 29.47, 31.70, 33.24, 47.76, 118.42, 120.53, 125.78,
127.66, 130.85, 135.40, 139.76, 141.92, 188.51; MS (EI) m/z
260 (M+); HRMS calcd for C16H20OS 260.1235, found 260.1241.
Anal. Calcd for C16H20OS: C, 73.81; H, 7.75. Found: C, 73.88;
H, 7.75.
6-Ch lor o-2,2-d im eth yl-3-m eth ylen e-2,3-d ih yd r o-4H-1-
b en zot h iop yr a n -4-on e (3k ): oil; IR (neat) 1674 cm-1 (Cd
O); 1H NMR (200 MHz, CDCl3) δ 1.59 (s, 6H), 5.49 (s, 1H),
6.09 (s, 1H), 7.14 (d, 1H, J ) 8.4 Hz), 7.33 (dd, 1H, J ) 8.4,
2.0 Hz), 8.10 (d, 1H, J ) 2.0 Hz); 13C NMR (50 MHz, CDCl3)
δ 27.33, 46.80, 119.64, 129.25, 131.51, 131.62, 133.41, 138.74,
149.73, 185.66; MS (EI) m/z 238.0 (M+); HRMS calcd for C12H11
-
ClOS 238.0219, found 238.0200. Anal. Calcd for C12H11ClOS:
C, 60.50; H, 4.66. Found: C, 60.58; H, 4.72.
6-Ch lor o-2-cycloh exyl-3-m eth ylen e-2,3-d ih yd r o-4H-1-
ben zoth iop yr a n -4-on e (3l): mp 76.5-77 °C; IR (KBr) 1674
cm-1 (CdO); 1H NMR (200 MHZ, CDCl3) δ 0.87-1.26 (m, 4H),
1.54-1.78 (m, 6H), 2.14-2.23 (m, 1H), 3.50 (d, 1H, J ) 7.5
Hz), 5.43 (d, 1H, J ) 0.8 Hz), 6.11 (d, 1H, J ) 0.8 Hz), 7.20-
7.27 (m, 1H), 7.80-7.84 (m, 2H); 13C NMR (50 MHz, CDCl3) δ
25.15, 25.23, 27.00, 31.88, 34.02, 39.64, 54.64, 119.84, 122.36,
129.68, 130.60, 133.13, 135.47, 138.37, 139.45, 190.02; MS (EI)
m/z 292.1 (M+); HRMS Calcd for C16H17ClOS 292.0689, found
292.0688. Anal. Calcd for C16H17ClOS: C, 65.74; H, 5.87.
Found: C, 65.78; H, 5.84.
2, 3-Dih yd r o-3′-cyclon on en a [2,3-b]-4H-1-ben zoth iop y-
r a n -4-on e (3e): mp 57-58 °C; IR (KBr) 1672 cm-1 (CdO); 1H
NMR (200 MHz, CDCl3) δ 1.31-1.60 (m, 4H), 2.05-2.42 (m,
8H), 3.95 (t, 1H, J ) 7.4 Hz), 6.24 (t, 1H, J ) 7.0 Hz), 7.14-
7.36 (m, 4H); 13C NMR (50 MHz, CDCl3) δ 24.04, 25.78, 26.93,
27.14, 30.88, 33.04, 58.04, 116.35, 126.34, 126.55, 130.08,
132.33, 135.76, 137.70, 142.36, 184.96; MS (EI) m/z 258.1 (M+);
HRMS calcd for C16H18OS 258.1078, found 258.1080. Anal.
Calcd for C16H18OS: C, 74.39; H, 7.03. Found: C, 74.46; H,
7.06.
2-Meth yl-3-eth oxyca r bon ylm eth yl-4H-1-ben zoth iop y-
r an -4-on e (3f): mp 71.5-72.0 °C; IR (KBr) 1673 cm-1 (PhCO-),
6-Ch lor o-2-(n -h exyl)-3-m eth ylen e-2,3-dih ydr o-4H-1-ben -
zoth iop yr a n -4-on e (3m ): mp 61-62 °C; IR (KBr) 1673 cm-1
(CdO); 1H NMR (200 MHz, CDCl3) δ 0.86 (t, 3H, J ) 7.0 Hz),
1.19-1.46 (m, 10H), 3.63-3.70 (m, 1H), 5.53 (d, 1H, J ) 0.8
Hz), 6.32 (d, 1H, J ) 0.8 Hz), 6.90 (d, 1H, J ) 8.5 Hz), 7.24-
7.36 (m, 1H), 7.64-7.83 (m, 1H); 13C NMR (50 MHz, CDCl3) δ
1
1738 cm-1 (-CO2C2H5); H NMR (200 MHz, CDCl3) δ 1.24 (t,
3H, J ) 7.4 Hz), 2.38 (s, 3H), 3.41 (s, 2H), 4.10 (q, 2H, J ) 7.4
Hz), 7.18-7.20 (m, 2H), 7.22-7.40 (m, 1H), 8.09-8.15 (m, 1H);
13C NMR (75 MHz, CDCl3) δ 14.12, 20.86, 31.02, 60.89, 114.76,

9652 J . Org. Chem., Vol. 64, No. 26, 1999
Xiao and Alper
14.07, 22.35, 27.59, 30.42, 31.63, 33.47, 57.35, 119.80, 123.63,
126.88, 133.13, 133.97, 138.42, 139.63, 142.07, 185.04; MS (EI)
m/z 294.1 (M+); HRMS calcd for C16H19ClOS 294.0845, found
294.0851. Anal. Calcd for C16H19ClOS: C, 65.29; H, 6.51.
Found: C, 65.24; H, 6.56.
Ack n ow led gm en t. We are grateful to the Natural
Sciences and Engineering Council of Canada for support
of this research.
J O9913098