Applications of the palladium-catalyzed carbonylative annulation of internal alkynes to the synthesis of medium-sized rings

Full text of DOI:10.1016/j.mencom.2007.03.006

Mendeleev
Communications
Mendeleev Commun., 2007, 17, 74–76
Applications of the palladium-catalyzed carbonylative annulation
of internal alkynes to the synthesis of medium-sized rings
†
Dmitry V. Kadnikov and Richard C. Larock*
Department of Chemistry, Iowa State University, Ames, IA 50011-3111, USA. Fax: +1 515 294 0105;
e-mail: larock@iastate.edu
DOI: 10.1016/j.mencom.2007.03.006
Seven- and eight-membered ring lactones were synthesized by the palladium-catalyzed carbonylative annulation of internal
alkynes, and scope and limitations of the process were examined.
Unsaturated molecules, such as alkenes, alkynes, or carbon
monoxide, undergo facile insertion into the carbon–palladium
bond, and these insertions have given rise to a wide variety
O
R
PdI
R
PdI CO
R
R
of synthetic transformations now widely used in organic syn-
thesis.1
–3
PdI
Our laboratories have been actively involved in
Nu
Nu
O
Nu
exploring the utility of these insertion processes for the syn-
thesis of carbo- and heterocycles.4,5 We have developed a
widely applicable methodology for the synthesis of such rings
based on the reactions of aryl and vinylic halides bearing
neighbouring nucleophilic substituents with alkenes, dienes and
internal or terminal alkynes. Indoles, isoquinolines, benzofurans,
benzopyrans, isocoumarins, α-pyrones, indenones, naphthalenes
and phenanthrenes can all be efficiently prepared using this
methodology. We have also developed processes in which two
unsaturated molecules undergo sequential insertion into the
carbon–palladium bond. Thus, 2-iodophenols and N-substituted
R
?
CO
fast
Nu
R
very slow
Scheme 2
insertion of an internal alkyne is irreversible. We have suggested
that the insertion of an internal alkyne into an acylpalladium
bond is quite slow, and in the absence of nucleophiles an acyl-
palladium complex can react only by undergoing decarbonyla-
tion back to the arylpalladium complex. Since alkyne insertion
is irreversible, eventually all starting material is going to be
channeled into the annulation product.
2
-iodoanilines react with an internal alkyne and carbon monoxide
6,7
in the presence of a palladium catalyst to afford coumarins
and 2-quinolones in good yields (Scheme 1).
8
Since six-membered rings are formed very efficiently utilizing
our carbonylative annulation methodology, we were interested
in investigating whether larger rings can also be synthesized
employing the same strategy. The results are presented in this
communication.
R
R
I
R
O
5
% Pd(OAc)2
+
+ CO
2
1
pyridine
OH
O
R
Bu NCl
4
R
DMF
20 °C, 24 h
1
I
5 mol% Pd(OAc)2
R
+ 5 Pr
Pr
Pr + CO
I
R
O
2 pyridine
OH
5
% Pd(OAc)2
pyridine
1
Bu NCl
+
+
CO
4
2
DMF
NHCO Et
N
H
2
1 Bu NCl
4
R
DMF
Pr
O
100 °C, 12 h
O
+
O
Scheme 1
O
The remarkable feature of these two reactions is the selec-
tivity of the insertion into the carbon–palladium bond. We have
not observed any products arising from initial insertion of carbon
monoxide, followed by insertion of an alkyne, which would
lead to chromones and 4-quinolones. This fact is noteworthy
since it is well-established that the insertion of carbon monoxide
1
2
Scheme 3
We began our studies with the reaction of 2-iodobenzyl
alcohol and 4-octyne under one atmosphere of carbon monoxide
Scheme 3). If the reaction proceeds in the same way as the
reaction with 2-iodophenol, the formation of seven-membered
ring lactone 1 is anticipated. However, in the case of 2-iodo-
benzyl alcohol, an internal nucleophile capable of capturing an
acylpalladium intermediate is now available. Thus, the forma-
tion of five-membered ring lactone 2 is expected to compete
with the formation of the desired product. Indeed, under our
standard reaction conditions developed for the synthesis of
(
into a carbon–palladium bond is faster than the insertion of an
internal alkyne.9
–12
To account for these inconsistencies, we
have previously proposed the mechanism shown in Scheme 2.
Insertion of carbon monoxide is fast but reversible, while
†
A former student of the Higher Chemical College of the RAS (1991–
1
997). Current address: Department of Chemistry and Biochemistry,
Northern Illinois University, DeKalb, IL, USA.
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Mendeleev Commun., 2007, 17, 74–76
Table 1 Optimization of chemoselectivity (Scheme 3).‡
Isolated yield (%)
coumarins, both of these products were obtained in 43 and
4% isolated yields, respectively (Table 1, entry 1). We were
gratified to see that even in the presence of an internal
nucleophile capable of trapping an acylpalladium complex,
carbonylative annulation remains competitive.
We then explored the effect of several reaction parameters on
the yield and ratio of the products. The results are summarized
in Table 1. It can be seen that the temperature of the reaction
has a dramatic effect on the reaction outcome (entries 1–3). The
rate of CO insertion into the arylpalladium bond apparently does
not significantly depend on the reaction temperature, while the
2
Entry
Catalyst (mol%)
T/°C
t/h
1
2
1
2
3
4
5
Pd(OAc) (5)
120
100
80
4
8
24
4
43
28
<5
42
37
40
24
45
67
24
19
19
2
Pd(dba) (5)
120
2
Pd(OAc) (10)
2
a
6
Pd(OAc) (5)
2
aThe reaction was run in 1 ml of DMF.
Table 2 Synthesis of seven- and eight-membered ring heterocycles by the palladium-catalysed carbonylative annulation of internal alkynes.§
Entry
1
Alcohol
Alkyne
Products
Ph
Isolated yield (%)
16 + 46
Ph
Pr
O
I
I
Ph
Ph
Pr
Pr
Pr
O
O
+
+
O
OH
OH
O
O
3
2
6
Pr
O
O
2
3
Pr
Pr
Pr
0 + 78
42 + 16
0 + 58
4
5
Pr
Pr
O
I
O
O
+
+
OH
O
7
8
9
Pr
Pr
O
I
4
O
NTs
NHTs
NTs
1
0
1
1
12
rate of alkyne insertion drops substantially when the reaction
temperature is lowered to 80 °C. The use of a different palladium
‡
Typical reaction procedure: 2-iodobenzyl alcohol (0.5 mmol), an alkyne
2.5 mmol), pyridine (1.0 mmol), n-Bu NCl (0.5 mmol), Pd(OAc) (5 mol%,
.025 mmol) and DMF (5 ml) were placed in a 4 dram vial. The vial was
(
0
4
2
catalyst, Pd(dba) (entry 4), or the use of higher amounts of
2
the palladium catalyst (entry 5) do not significantly alter the
outcome of the reaction. A five-fold reduction of the reaction
volume (to 1 ml, entry 6) should lead to a five-fold increase in
the alkyne/carbon monoxide ratio. This change, however, did
not have a favorable effect on the reaction progress. While, the
ratio of seven-membered ring lactone 1 to five-membered ring
lactone 2 improved slightly (2.1:1 vs. 1.8:1, entries 6 and 1,
respectively), the overall yield of lactone 1 decreased (40 vs.
purged with CO for 2 min, then connected to a balloon of CO, and the
reaction mixture was heated. For the reaction temperatures and times,
see Table 1.
1
4,5-Dipropyl-1,3-dihydrobenzo[c]oxepin-3-one 1: colourless oil. H NMR
(
CDCl ) d: 7.37–7.48 (m, 3H), 7.31 (ddd, 1H, J 1.2, 7.2 and 7.6 Hz),
3
5
2
.04 (d, 1H, J 7.6 Hz), 4.81 (d, 1H, J 7.6 Hz), 2.66–2.75 (m, 3H),
.51–2.58 (m, 1H), 1.59–1.68 (m, 2H), 1.34–1.46 (m, 2H), 1.03 (t, 3H,
1
3
J 7.2 Hz), 0.90 (t, 1H, J 7.2 Hz). C NMR (CDCl ) d: 171.0, 143.5,
3
1
2
2
39.5, 135.7, 133.2, 129.5, 128.5, 128.3, 127.3, 68.3, 35.1, 34.2, 23.3,
4
3%). Thus, the standard coumarin reaction conditions appear
–
1
2.5, 14.5, 14.4. IR (CHCl , n/cm ): 2959, 2872, 1707. MS, m/z (%):
3
+
at present to be the best to obtain the highest yields of seven-
membered ring lactones.
We then examined several other internal alkynes and alcohols
in this reaction. The results are shown in Table 2. The reaction
of diphenylacetylene with 2-iodobenzyl alcohol afforded only
a 16% yield of seven-membered ring lactone 3, along with a
44 (45, M ), 216 (28), 201 (71), 173 (100). HRMS, found: 244.1468;
calc. for C H O : 244.1463.
1
6
20
2
§
Typical reaction procedure: the alcohol or tosylamide (0.5 mmol), an
alkyne (2.5 mmol), pyridine (1.0 mmol), n-Bu NCl (0.5 mmol), Pd(OAc)2
4
(5 mol%, 0.025 mmol) and DMF (5 ml) were placed in a 4 dram vial.
The vial was purged with CO for 2 min, then connected to a balloon of
CO, and the reaction mixture was heated at 120 °C for 4 h.
4
6% yield of five-membered ring lactone 2 (entry 1). Only five-
4
,5-Diphenyl-1,3-dihydrobenzo[c]oxepin-3-one 3: white crystals,
membered ring lactone 6 was observed when tertiary iodo-
benzylic alcohol 4 was substituted for 2-iodobenzyl alcohol
1
mp 200–203 °C. H NMR (CDCl ) d: 7.44–7.50 (m, 3H), 7.39 (ddd, 1H,
3
J 1.2, 7.2 and 8.0 Hz), 7.31 (ddd, 1H, J 1.2, 7.6 and 8.4 Hz), 7.12–7.19
(
entry 2). However, to our delight, the reaction of 2-iodo-
1
3
(
m, 6H), 6.96–6.98 (m, 3H), 5.51 (br. s, 1H), 5.05 (br. s, 1H). C NMR
phenethyl alcohol 7 afforded, as the major product, the product
of the initial alkyne insertion, eight-membered ring lactone 8,
in 42% yield. Six-membered ring lactone 9 was also obtained in
16% yield. We have also attempted to synthesize a seven-mem-
(
CDCl ) d: 169.3, 145.3, 140.4, 140.2, 136.7, 136.1, 133.0, 131.3, 131.2,
3
1
30.7, 129.5, 129.4, 128.4, 128.1, 128.0, 127.9, 127.7, 68.6. IR (CHCl ,
3
–1
+
n/cm ): 3057, 1718. MS, m/z (%): 312 (29, M ), 235 (42), 233 (100),
60 (51). HRMS, found: 312.1155; calc. for C H O : 312.1150.
2
2
2
16
2
–
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Mendeleev Commun., 2007, 17, 74–76
bered ring lactam. Unfortunately, the reaction of 4-octyne and
carbon monoxide with N-(2-iodobenzyl)-p-toluenesulfonamide
0 resulted in formation of only five-membered ring lactam 12
References
1
2
N. E. Schore, Chem. Rev., 1988, 88, 1081.
1
J. Tsuji, Palladium Reagents and Catalysts: Innovations in Organic
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R. C. Larock, J. Organomet. Chem., 1999, 576, 111.
in 58% yield.
3
4
5
6
7
8
9
These results illustrate the delicate balance between the
formation of products from initial insertion of an alkyne or
initial insertion of carbon monoxide. Factors affecting the
rates of alkyne insertion and of trapping of the acylpalladium
intermediate can significantly shift this equilibrium. Diphenyl-
acetylene is less reactive toward insertion than 4-octyne. Thus,
the yield of the seven-membered ring lactone decreases and the
yield of the five-membered ring lactone increases, when diphenyl-
acetylene is substituted for 4-octyne. To favour the direct CO
insertion product, the nucleophile must either possess sufficient
strength, as with the tosylamide, or adopt a proper conforma-
tion, as with the tertiary benzylic alcohol, to rapidly trap the
acylpalladium intermediate.
R. C. Larock, Pure Appl. Chem., 1999, 71, 1435.
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1
1
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In conclusion, we have demonstrated that the palladium-
catalyzed carbonylative annulation of internal alkynes can be
used to synthesize medium-sized rings, provided that an alkyne
and the nucleophile are appropriately selected to maximize
the rate of the desired reaction and minimize the rate of the
undesired process. The exploration of various strategies to fine
tune these rates, for example, the use of labile protecting groups,
might further expand the scope of this process.
Received: 20th November 2006; Com. 06/2824
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