On the regioselectivity of Pd-catalyzed additions of organoboronic acids to unsymmetrical alkynes

Article abstract of DOI:10.1039/b316446b

The Pd-catalyzed reaction of unsymmetrical alkynes 1 with organoboronic acids 2 gave a mixture of products 3 and 4, whose ratios were controlled by the electronic as well as steric effects of the substrates 1.

Full text of DOI:10.1039/b316446b

On the regioselectivity of Pd-catalyzed additions of organoboronic acids
to unsymmetrical alkynes
Nakjoon Kim,a Ki Seong Kim,b Aruna Kumar Guptab and Chang Ho Oh*b
a Center for Organic Photorefractive Materials, Department of Chemistry, Hanyang University,
Sungdong-Gu, Seoul 133-791, Korea
b GOS Lab, Department of Chemistry, Hanyang University, Sungdong-Gu, Seoul 133-791, Korea.
E-mail: changho@hanyang.ac.kr; Fax: +82-2-2299-0762; Tel: +82-2-2290-0932
Received (in Corvallis, OR, USA) 16th December 2003, Accepted 20th January 2004
First published as an Advance Article on the web 9th February 2004
The Pd-catalyzed reaction of unsymmetrical alkynes 1 with
organoboronic acids 2 gave a mixture of products 3 and 4, whose
ratios were controlled by the electronic as well as steric effects of
the substrates 1.
The –OH, –OAc, 2-Py- and 4-Py- moieties were tested as the
directing groups. Methyl-, n-butyl, i-propyl, or t-butyl was attached
to the other site of the alkyne. Our results are summarized in Table
1.
Several features are noteworthy. First, a large directing effect
was observed from a hydroxyl group when it was located in the
propargylic position. Substitution at the 3-position of propargylic
alcohol affected regioselectivities in Pd-catalyzed additions.
2-Butyn-1-ol (1a) reacted with phenyl- and n-hexenylboronic acid
under the Pd-catalysis to give the addition products 3aa and 3ab in
65% and 70% yields, respectively (entry 1).6 As the alkyl
substituent became bulkier from methyl, n-butyl, i-propyl to finally
t-butyl, the formation of regioisomer 4 became predominant. Note
that reaction of 4,4-dimethyl-2-pentyn-1-ol (1e) with both 2a and
2b gave only 4ea and 4eb, respectively. Second, as the distance
between the hydroxyl group and the triple bond increases, the
regioselectivity becomes worse. Substrate 1f, which has two
carbons between the –OH group and the triple bond, showed
reasonably good regioselectivities in these addition reactions (entry
6). Substrate 1g, bearing a t-butyl at the 4-position of 3-butyn-1-ol,
gave exclusive formation of the addition products 4ga and 4gb,
respectively (entry 7). The substrates 1h and 1i, which have three
carbons between the –OH and the triple bond, showed a little
regioselectivity.
Transition-metal catalyzed addition of organometallic compounds
to alkynes has been a subject of intensive work in the area of
organic and organometallic chemistry.1 It has been attained by
copper catalyzed addition of lithium diorganocuprates, nickel-
catalyzed additions of arylmagnesium or arylzinc reagents into the
alkynes or by titanium-catalyzed hydrozincations of alkynes.2 The
rhodium-catalyzed hydroarylation was independently accom-
plished by Miura, Hyashi, and Lautens.3 Although the Rh-catalyzed
hydroarylation of alkynes has advantages over other methods due to
high syn-selectivity and high efficiency, this reaction is only
applicable to internal alkynes and arylboronic acids.
Recently, we reported Pd-catalyzed hydroarylation and hydro-
alkenylation which are widely applicable to terminal as well as
internal alkynes.4 The hydroarylation of internal alkynes with
organoboronic acids, however, gave a mixture of regioisomeric
products. In further studies even with a terminal alkyne bearing a
remote keto-group, we isolated the unexpected regioisomer as a
minor product (eqn. (1)).
Third, we tested acetylated substrates of 1a and 1e in order to
confirm the –OH effect. The absence of the –OH group decreased
the regioselectivity dramatically for the present additions (eqn. (3)).
The substrate 5a with phenylboronic acid (2a) under the present
conditions gave a 5 : 1 mixture of the products 6aa and 7aa in 60%
yield. Even tert-butyl-substituted alkyne 5e gave a 5 : 1 mixture of
the products 6ea and 7ea in 75% yield.
(1)
We postulated that incorporation of a specific functional group or
a sterically bulky group into the alkynes could play a role in
controlling regioselectivity. Mechanistically, we anticipated that
oxygen or nitrogen atoms present in the alkyne substrate would
bind the Lewis acidic RB(OH)2 group and thereby direct the
addition site. On the other hand, bulky substituents might block
addition to one end of the alkyne. A similar directing effect has
been used in developing molecular color sensors for mono-
saccharides.5 Here we wish to report the palladium catalyzed
hydroarylation (and hydroalkenylation) of unsymmetrical alkynes,
where high regioselectivity and syn-stereoselectivity can be
attained by properly incorporating a directing group or a bulky
group (eqn. (2)).
Table 1 Reactions of organoboronic acids 2 with alkynes 1
Temp. (°C)/
Entry Alkyne R1B(OH)2 time (h)
Yield Ratio
Products
(%)a
(3 : 4)b
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
2a
2b
2a
2b
2a
2b
2a
2b
2a
2b
2a
2b
2a
2b
2a
2b
2a
2b
60/5
60/5
60/5
60/5
3aa
3ab
65
70
50
71
80
60
75
78
75
82
75
73
95
80
81
84
87
91
Only 3
Only 3
3 : 1
2 : 1
3 : 1
2 : 1
2 : 3
1 : 2
Only 4
Only 4
10 : 1
5 : 1
Only 4
Only 4
2 : 1
2 : 1
1 : 3
1 : 2
3ba, 4ba
3bb, 4bb
3ca, 4ca
3cb, 4cb
3da, 4da
3db, 4db
4ea
80/12
60/30
80/12
80/15
80/12
80/15
80/12
80/12
80/12
80/12
80/12
80/15
80/20
80/20
(2)
4eb
3fa, 4fa
3fb, 4fb
4ga
1g
1h
1i
4gb
3ha, 4ha
3hb, 4hb
3ia, 4ia
3ib, 4ib
a Isolated yields. b Ratios were determined by 1H NMR analysis of the crude
products.
618
C h e m . C o m m u n . , 2 0 0 4 , 6 1 8 – 6 1 9
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

(3)
In order to maximize the site selectivity, we postulated that a
certain type of nitrogen might be a better directing group than
oxygen. Among the many possible nitrogen-containing directing
groups, we have chosen the nitrogen of pyridine. Thus, 1-(2-pyr-
idyl)propyne 8a under these conditions gave 9ab exclusively in
87% yield, whereas 1-(4-pyridyl)propyne 8c gave a 1 : 1 mixture of
products 9cb and 10cb in 75% yield. Substitution with the 2- and
4-pyridyl group at the 3-position of propargyl alcohol showed a
dramatic effect on regioselectivity. Notably, an interesting direct-
ing group effect was observed in 2-pyridyl-substituted propargyl
alcohol. While the 4-pyridyl-substituted propargyl alcohol 8d with
2b gave an almost 1 : 1 mixture of the corresponding products in
84% yield, 2-pyridyl-substituted propargyl alcohol 8b with 2a
under these conditions gave the product 9bb exclusively in 70%
yield.
Scheme 1
mechanistic studies are needed to figure out the origin of the
regioselectivities shown here, the present work could have a good
synthetic applicability in preparing stereo- and regiodefined
trisubstituted olefins from readily available alkynes.
We thank the Center of Molecular Design and Synthesis
(CMDS) and Creative Research Initiatives for support of this
research. K. S. Kim is grateful for a graduate fellowship supported
by the BK21 project.
Notes and references
1 (a) N. Miyaura and A. Suzuki, Chem. Rev., 1995, 95, 2457; (b) A. Suzuki,
J. Organomet. Chem., 1999, 576, 147.
2 (a) A. Alexakis, A. Commercon, C. Coulentianos and J. F. Normant,
Tetrahedron Lett., 1984, 40, 715; (b) For a review on the Ni-catalyzed
addition: I. N. Houpis and J. Lee, Tetrahedron, 2000, 56, 817; (c) For a
review on the organozinc reagents: P. Knochel, J. J. Almena Perea and P.
Jones, Tetrahedron, 1998, 54, 8275; (d) For a review on organotitanium
reagents: F. Sato, H. Urabe and S. Okamoto, Chem. Rev., 2000, 100,
2835.
3 (a) K. Oguma, M. Miura, T. Satoh and M. Nomura, J. Am. Chem. Soc.,
2000, 122, 10464; (b) M. Lautens, A. Roy, K. Fukuoka, K. Fagnou and
B. Martin-Matute, J. Am. Chem. Soc., 2001, 123, 5358; (c) M. Lautens
and M. Yoshida, Org. Lett., 2002, 4, 123; (d) T. Hayashi, K. Inoue, N.
Taniguchi and M. Ogasawara, J. Am. Chem. Soc., 2001, 123, 9918.
4 C. H. Oh, H. H. Jung and K. S. Kim, Angew. Chem., Int. Ed., 2003, 42,
805.
Here the catalytic reaction was highly stereoselective with the
organic group on boronic acid adding to the triple bond in syn
fashion. The stereochemistry of the products was confirmed by a
NOESY study. We observed the formation of E-isomer solely for
all cases. A plausible explanation for the formation of the
compound 3 is shown in Scheme 1.
5 J. W. Christopher, P. Prakash and D. J. Tony, Org. Lett., 2002, 4, 477.
6 General procedure: A 10 mL round-bottomed flask was charged with
2-butynol (1a, 45.0 mg, 0.64 mmol), phenylboronic acid (2a, 93.6 mg,
0.77 mmol), and Pd(PPh3)4 (22.1 mg, 0.019 mmol) and then 1,4-dioxane
(1.0 mL) was added at 0 °C. The mixture was purged with a dry argon gas
and was treated with acetic acid (3.7 mL, 0.064 mmol) via a 10 mL
gastight syringe at 0 °C. Then the mixture was stirred at 60 °C for 5 h. On
completion of the reaction, the mixture was allowed to cool to 0 °C,
quenched with water, and then extracted with ether. The organic portion
was washed with saturated sodium chloride solution, dried over
anhydrous magnesium sulfate, and concentrated in vacuo. The residue
was purified by flash chromatography (ethyl acetate–hexane = 1 : 4) to
give 3aa (61.7 mg, 65%) as a colorless oil. The structures of the products
Organoboronic acids (2) can interact with the hydroxyl group of
the substrate 1 attractively to form intermediate A. Oxidative
addition of the intermediate A into PdL2 forms the intermediate B.
The intermediate B can undergo carbopalladation regioselectively
to form C. Cleavage of the C–Pd bond by a proton from either
acetic acid or boronic acid gives the product 3. As the size of the R-
group in the substrate 1 increases, carbopalladation of B might be
retarded to eventually form the product 4.
In conclusion, we have shown an electronic factor and steric
factors that control the regioselectivity in Pd-catalyzed additions of
organoboronic acids to unsymmetrical alkynes. Strong directing
groups such as –OH and 2-pyridyl groups might control the site of
addition by chelation as shown in Scheme 1 and bulky groups such
as tert-butyl give the regioisomer 4 by blocking one site. Although
have been satisfactorily characterised by means of FT-IR, 1H NMR, 13
C
NMR, HRMS and stereochemistry was assigned by NOESY experi-
mentation.
C h e m . C o m m u n . , 2 0 0 4 , 6 1 8 – 6 1 9
619