Effect of fluorine substituents on catalytic functionalizations of alkyl halides with organostannanes

Article abstract of DOI:10.1016/S0040-4039(01)01404-6

Introduction of fluorine atom(s) at the γ- and δ-positions of alkyl iodides increased the selectivities toward palladium-catalyzed cross-coupling reaction with organostannanes. A similar effect of fluorine substituents on the selectivities was also observed in the palladium-catalyzed carbonylative coupling reaction of alkyl iodides with phenyltributyltin under CO pressure.

Full text of DOI:10.1016/S0040-4039(01)01404-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6891–6894
Effect of fluorine substituents on catalytic functionalizations of
alkyl halides with organostannanes
Rie Shimizu and Takamasa Fuchikami*
Sagami Chemical Research Center, 4-4-1 Nishi-Ohnuma, Sagamihara, Kanagawa 229-0012, Japan
Received 12 April 2001; revised 13 July 2001; accepted 27 July 2001
Abstract—Introduction of fluorine atom(s) at the g- and d-positions of alkyl iodides increased the selectivities toward palladium-
catalyzed cross-coupling reaction with organostannanes. A similar effect of fluorine substituents on the selectivities was also
observed in the palladium-catalyzed carbonylative coupling reaction of alkyl iodides with phenyltributyltin under CO pressure.
© 2001 Elsevier Science Ltd. All rights reserved.
First, we examined the palladium-catalyzed cross-cou-
pling reaction of fluorine-substituted alkyl iodides with
organostannanes (Table 1). When 1-iododecane (1a)
was heated with (phenylethynyl)tributyltin (3.0 equiv.)
in benzene at 120°C for 16 h in the presence of
Pd(PPh3)4 (10 mol%), 1-phenyl-1-dodecyne (2a) was
obtained in only 6% yield, along with 1-decene in 47%
yield. Employing 4-fluoro-1-iododecane (1b) and 3-
fluoro-1-iododecane (1d) instead of 1-iododecane (1a)
afforded the corresponding cross-coupling products, 6-
fluoro-1-phenyldodecyne (2b) and 5-fluoro-1-phenyldo-
decyne (2d), in 20 and 18% yields under similar
conditions. The introduction of two fluorine atoms to
the d- and g-positions of the iodide was more effective.
Thus, 4,4-difluoro-1-iododecane (1c) and 3,3-difluoro-1-
iododecane (1e) reacted under the same conditions to
give 6,6-difluoro-1-phenyldodecyne (2c) and 5,5-
difluoro-1-phenyldodecyne (2e) in 33 and 38% yields,
respectively (Eq. (1)).
Organofluorine compounds are well-known for display-
ing unique reactivities and selectivities in the transition-
metal catalyzed functionalization reactions. For
example, we have previously reported that
perfluoroalkyl-substituted alkyl iodides readily undergo
carbonylation and double-carbonylation reactions in
the presence of transition-metal catalysts, where these
halides showed similar reactivities to phenyl or vinyl
halides rather than alkyl halides.1,2 In these reactions,
we have proposed that b-perfluoroalkyl-substituted
alkylmetal species, generated by the oxidative addition
of the halides to low valent transition-metal complexes,
can be stabilized by the internal coordination of
fluorine atom(s) to the metal center so that the insertion
of carbon monoxide takes place more rapidly than the
b-elimination of hydrido-metal species.3 If these
organometallic intermediates are stable enough,4 it may
be possible to develop new carbonꢀcarbon bond form-
ing reactions which have been considered difficult with
non-fluorinated alkyl halides. In the course of these
working hypotheses, we have recently found transition-
metal catalyzed functionalizations of b-perfluoroalkyl-
substituted alkyl halides with Grignard reagents and
organostannanes.5,6 Here, we wish to report that the
introduction of fluorine atom(s) at the g- and d-posi-
tions of alkyl iodides7–9 increased the selectivities
toward palladium-catalyzed cross-coupling and car-
bonylative coupling reactions with organostannanes.
The more distinguished effect of fluorine substituents
on the selectivities was observed in the palladium-cata-
lyzed carbonylative coupling reaction of alkyl iodides
with phenyltributyltin under CO pressure (Table 2).
The treatment of 1-iododecane (1a) with phenyl-
tributyltin (1.1 equiv.) in benzene at 120°C for 16 h in
the presence of Pd(PPh3)4 (10 mol%) under CO pressure
a: R=C10H21
-
(3.0 equiv.)
SnBu3
Ph
b: R=C6H13-CHF-(CH2)3-
c: R=C6H13-CF2-(CH2)3-
d: R=C7H15-CHF-(CH2)2-
e: R=C7H15-CF2-(CH2)2-
R
I
R
Ph
cat. Pd(PPh3)4 (10 mol%)
benzene, 120˚C, 16 h
(1)
1
2
* Corresponding author. Tel.: +81 42 766 7842; fax:+81 42 749 7631; e-mail: scrc1@sagami.or.jp
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01404-6

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R. Shimizu, T. Fuchikami / Tetrahedron Letters 42 (2001) 6891–6894
Table 1. Catalytic coupling reaction with alkyl iodides with (phenylethynyl)tributyltina,b
Entry
1
Iodoalkane
Yield of product (%)
6
Yield of alkene (%)
47
(1a)
(1b)
I
I
2
20
32
F
3
4
(1c)
(1d)
33
18
30
12
I
F
F
F
I
5
(1e)
36
8
F
F
I
a Yields were determined by GLC. Iodides were completely consumed under the reaction conditions, respectively.
b Typical procedure: see Ref. 10.
(50 atm) afforded undecanophenone (3a) in 39% yield.
The yield was not improved at all by using excess (1.7
equiv.) of the tin reagent in the case of the nonfluori-
nated halide (run 2). The selectivity toward the cou-
pling reaction increased by the introduction of fluorine
atom(s) to the d-position of the iodide. Thus, 4-fluoro-
1-iododecane (1b) and 4,4-difluoro-1-iododecane (1c)
afforded the desired fluorinated ketones, 5-fluorounde-
canophenone (3b) and 5,5-difluoroundecanophenone
(3c), in 53 and 62% yields on using 1.7 equiv. of the tin
reagent (runs 3 and 4). In the present carbonylative
coupling reaction, the introduction of fluorine atom(s)
to the g-position of the iodide was found to be very
effective. The treatment of 3-fluoro-1-iododecane (1d)
and 3,3-difluoro-1-iododecane (1e) instead of 1a with
1.1 equiv. of the tin reagent under similar conditions
gave the corresponding carbonylative products, 4-
fluoroundecanophenone (3d) and 4,4-difluorounde-
canophenone (3e), in 52 and 65% yields, respectively
(runs 5 and 7). In the reaction of 1d, the yield of the
desired ketone (3d) reached 81% by using 1.7 equiv. of
phenyltributyltin (run 6) (Eq. (2)).
urated 3-fluoropropyl palladium complexes, cis-
FCH2CH2CH2-PdI(CO), using LANL2DZ as a basis
set gave two stable conformers 4A and 4B (Fig. 1). In
the conformer 4A, the g-fluorine atom of the 3-fluoro-
propyl group is located at the trans position to the
iodide atom, in which the bond length between Pd and
F is calculated to be 2.22 A.13 On the other hand, in the
,
conformer 4B, b-hydrogen atom of 3-fluoropropyl
group is situated at the trans position to the iodide,
,
where the bond length between Pd and H is 2.66 A.
This conformer 4B may be thought to be the intermedi-
ate to b-elimination of palladium hydride, which is
calculated to be less stable than the conformer 4A by
8.60 millihartrees (5.40 kcal/mol). The transition struc-
ture calculation from these two comformers 4A and 4B
using Opt=QST2 as a keyword easily met the station-
ary point. In the predicted transition structure 4TS, the
palladium atom is weakly linked to both hydrogen and
,
,
fluorine atoms (PdꢀH=2.78 A, PdꢀF=3.66 A), and the
energy difference between the transition structure 4TS
and the stable conformer 4A is calculated to be 12.5
millihartrees (7.87 kcal/mol). Similar calculations for
cis-4-fluorobutyl-PdI(CO) derivatives also gave the two
stable isomers 5A and 5B, and the transition structure
5TS. In this case, the energy difference (5.15 milli-
hartrees, 3.23 kcal/mol) between the transition structure
We have examined the theoretical considerations using
Gaussian 98 program.12 The B3LYP DFT (Density
Functional Theory) optimization of coordinately unsat-
PhSnBu3 (1.1-1.7 equiv.)
CO (50 atm)
a: R=C10H21
-
O
b: R=C6H13-CHF-(CH2)3-
c: R=C6H13-CF2-(CH2)3-
d: R=C7H15-CHF-(CH2)2-
e: R=C7H15-CF2-(CH2)2-
(2)
R
I
cat. Pd(PPh3)4 (10 mol%)
benzene, 120˚C, 16 h
R
Ph
1
3

R. Shimizu, T. Fuchikami / Tetrahedron Letters 42 (2001) 6891–6894
6893
Table 2. Carbonylative coupling reaction with alkyl iodides with phenyltributyltina,b
Entry
1
Iodoalkane
PhSnBu3 (equiv.)
1.1
Conversion of 1 (%)
Yield of 3 (%)
(1a)
74
39
I
I
I
2
3
(1a)
(1b)
1.7
1.7
96
100
38
53
F
4
5
(1c)
(1d)
1.7
1.1
100
88
62
52
F
F
F
I
6
7
(1d)
(1e)
1.7
1.1
91
89
81
65
F
F
I
a Yields were determined by GLC.
b Typical procedure: see Ref. 11.
Figure 1.
5TS and the stable conformer 5A is calculated to be
much less than that between 4TS and 4A in 3-fluoro-
propyl derivatives.
selectivities toward palladium-catalyzed functionaliza-
tions with organostannanes. It seems that these
results support our working hypotheses that the oxida-
tive addition of these fluorinated alkyl halides
generates alkylmetal species, which can be stabilized
by the internal coordination of fluorine atom(s) into
In conclusion, the introduction of fluorine atom(s) at
the g- and d-positions of alkyl iodides increased the

6894
R. Shimizu, T. Fuchikami / Tetrahedron Letters 42 (2001) 6891–6894
metal center to prevent from b-elimination of metal-
Pd(PPh3)4 (0.025 mmol; 10 mol%), and dry benzene (0.75
ml) in a Pyrex tube. The reaction mixture was stirred at
120°C for 16 h under Ar. The GLC analysis revealed that
5,5-difluoro-1-dodecyne (2e) was obtained in 38% yield.
11. General procedure for carbonylative coupling reaction
(Table 2). Tributylphenyltin (0.43 mmol) was added to a
mixture of 3-fluoro-1-iododecane (1d, 0.25 mmol),
Pd(PPh3)4 (0.025 mmol; 10 mol%), and dry benzene (0.75
ml) in an autoclave (10 ml). The reaction mixture was
stirred under CO pressure (50 atm) at 120°C for 16 h.
The GLC analysis revealed that 4-fluoroundecanophe-
none (3d) was obtained in 81% yield in addition to 9% of
unchanged 1d.
12. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria,
G. E.; Robb, M. A.; Cheeseman, J. R.; Zakrzewski, V.
G.; Montgomery, Jr., J. A.; Stratmann, R. E.; Burant, J.
C.; Dapprich, S.; Millam, J. M.; Daniels, A. D.; Kudin,
K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.;
Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.;
Adamo, C.; Clifford, S.; Ochterski, J.; Petersson, G. A.;
Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick, D. K.;
Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.;
Cioslowski, J.; Ortiz, J. V.; Baboul, A. G.; Stefanov, B.
B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.;
Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T.;
Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challa-
combe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.;
Wong, M. W.; Andres, J. L.; Gonzalez, C.; Head-Gor-
don, M.; Replogle, E. S.; Pople J. A. Gaussian 98,
Revision A.9, Gaussian, Inc., Pittsburgh PA, 1998.
13. The trans isomer, trans-FCH2CH2CH2-PdI(CO), having
a similar structure is calculated to be less stable than the
cis isomer by 0.53 millihartrees.
hydride.
References
1. Urata, H.; Kosukegawa, O.; Ishii, Y.; Yugari, H.;
Fuchikami, T. Tetrahedron Lett. 1989, 30, 4403–4406.
2. Urata, H.; Ishii, Y.; Fuchikami, T. Tetrahedron Lett.
1989, 30, 4407–4410.
3. Urata, H.; Maekawa, H; Takahashi, S.; Fuchikami, T. J.
Org. Chem. 1991, 56, 4320–4322.
4. The increases of reactivities by intramolecular metal–
fluorine interaction were reported. For example: (a) Karl,
J.; Erker, G. Chem. Ber. 1997, 130, 1261–1267; (b)
Yamazaki, T.; Ando, M.; Kitazume, T.; Kubota, T.;
Omura, M. Org. Lett. 1999, 1, 905–908.
5. Shimizu, R.; Yoneda, E.; Fuchikami, T. Tetrahedron
Lett. 1996, 37, 5557–5560.
6. Shimizu, R.; Fuchikami, T. Tetrahedron Lett. 1996, 37,
8405–8408.
7. Monofluoro iodides 1b and 1d were prepared by DAST-
fluorination of the corresponding iodoalcohols, 1-iodo-4-
decanol and 1-iodo-3-decanol, respectively.8 Difluoro-
iododecanes 1c and 1e were similarly synthesized by
treatment of DAST with the corresponding iodoketones
in the presence of a catalytic amount of water in CH2Cl2
at rt for several days, respectively.9
8. Middleton, W. J. J. Org. Chem. 1975, 40, 574–578.
9. Middleton, W. J. US Patent 3,914,265.
10. General procedure for coupling reaction (Table 1).
(Phenylethynyl)tributyltin (0.75 mmol) was added to a
mixture of 3,3-difluoro-1-iododecane (1e, 0.25 mmol),