Boron trichloride mediated alkyne-aldehyde coupling reactions

Article abstract of DOI:10.3987/COM-09-S(S)80

The boron trichloride mediated reaction of aryl aldehydes and alkynes can be used to selectively generate either (Z,Z)- or (Z,E)-1,5-dichloro-1,4-dienes as major products, depending on the reaction conditions employed. To investigate the mechanism of this

Full text of DOI:10.3987/COM-09-S(S)80

HETEROCYCLES, Vol. 80, No. 2, 2010
779
HETEROCYCLES, Vol. 80, No. 2, 2010, pp. 779 - 785. © The Japan Institute of Heterocyclic Chemistry
Received, 28th July, 2009, Accepted, 4th September, 2009, Published online, 8th September, 2009
DOI: 10.3987/COM-09-S(S)80
BORON
TRICHLORIDE
MEDIATED
ALKYNE-ALDEHYDE
COUPLING REACTIONS
Min-Liang Yao, Michael P. Quinn, and George W. Kabalka*
Departments of Chemistry and Radiology, The University of Tennessee,
Knoxville, Tennessee 37996-1600, USA kabalka@utk.edu
Abstract – The boron trichloride mediated reaction of aryl aldehydes and alkynes
can be used to selectively generate either (Z,Z)- or (Z,E)-1,5-dichloro-1,4-dienes
as major products, depending on the reaction conditions employed. To investigate
the mechanism of this important carbon-carbon bond forming reaction, the boron
trichloride mediated reaction of phenylacetylene with p-bromobenzaldehyde was
chosen as the model system. Interestingly, when the coupling reactions are carried
o
out below –60 C, (E,E)-1,5-dichloro-1,4-dienes are also formed. The ratios of
(Z,Z)-, (Z,E)-, and (E,E)-1,5-dichloro-1,4-dienes were correlated to the reaction
conditions using gas chromatography-mass spectrometry. The results of the
investigation can be used to explain why the ratio of (Z,E)-, (Z,Z)-, and (E,E)-1,5-
dichloro-1,4-pentadiene products change very dramatically when changes are
made in either the sequence of addition of the reagents or the reaction temperature.
INTRODUCTION
Our research group has focused on the chemistry of organoboron halide derivatives for many years and
resulted in the first report of a Grignard-like alkylation of aryl aldehydes using either dialkylboron
chlorides1 or alkylboron dichlorides.2 In a continuation of these studies, we investigated the feasibility of
expanding the reaction to the addition of vinylboron dichloride reagents to aryl aldehydes.3 Surprisingly,
the reaction afforded (Z,Z)-1,5-dichloro-1,4-pentadienes as major products instead of the expected
Grignard-like addition products, if preformed (Z)-vinylphenylboron dichloride reagents3a were used.
Since it has been reported that boron trichloride readily adds to terminal alkynes to generate (Z)-
vinylboron dichlorides,4 we decided to explore a one-pot reaction employing boron trichloride,
o
phenylacetylene and benzaldehyde at 0 C. We found that a diene product formed but, unexpectedly,

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HETEROCYCLES, Vol. 80, No. 2, 2010
(Z,E)-1,5-dichloro-1,4-pentadiene was isolated as the major product instead of the expected (Z,Z)-1,5-
dichloro-1,4-pentadiene. (None of the (E,E)-1,5-dichloro-1,4-pentadiene isomer was detected.)
Several novel reactions were then designed to probe the reaction mechanism.5 During these studies, we
discovered new reactions involving an unprecedented C-O bond cleavage in the R1R2CH-O-BXnR3-n
intermediates; these include a transition-metal-free, formal Suzuki-coupling of alkoxides with vinylboron
dichlorides,5b the boron trichloride mediated coupling of alkoxides with allylsilane,5e and the boron
trihalide mediated haloallylation of aryl aldehydes using allylmetal compounds.5g In addition, we found
that, at low temperature, the reaction of boron trichloride with two equivalents of terminal alkyne yielded
only the vinylboron dichloride product and not the reported divinylboron chloride.3b
Although the methodology required for the stereoselective, boron trihalide mediated alkyne-aldehyde
coupling reactions has been reported,3 the dramatic influence on the stereochemistry of the products due
to the order of reactant addition and reaction temperature had not been investigated in details. To fully
explore these parameters, we chose to study the reaction of phenylacetylene with p-bromobenzaldehyde
as a model system.
RESULTS AND DISCUSSIONS
(Z,Z)-1,5-Dichloro-1,4-pentadiene (1) was synthesized according to reported procedure.3b In the reaction
of (Z,Z)-di(chlorovinyl)boron chloride with p-bromobenzaldehyde (Scheme 1), the halovinyl group
migrates from boron to carbon with retention of stereochemistry.3b,5b,5c Racemization occurred in the
coupling reaction of chiral benzyloxide and vinylboron dihalide suggesting that a cationic mechanism is
involved in this migration.5c
Scheme 1. Reaction of Aldehyde with (Z,Z)-Di(chlorovinyl)boron Chloride
Br
Br
Cl
Cl
B
Cl
Br
DCM
0 oC to rt
Cl
Cl
+
Ph
Ph
Ph
Ph
CHO
1
(Z,Z)-diene
Cl
Cl
B
Cl
Ph
O
Ph

HETEROCYCLES, Vol. 80, No. 2, 2010
781
Alternatively, compound 1 can also be prepared by the reaction of p-bromobenzaldehyde with two
equivalents of preformed (Z)-chlorovinylboron dichloride (Scheme 2). The Grignard-like addition of the
(Z)-vinylboron dichloride to the aldehyde followed by a carbon-oxygen bond cleavage affords a
carbocation intermediate. Then the cation adds to a second equivalent of the (Z)-vinylboron dichloride to
generate the observed Z,Z-diene product. It has been demonstrated that electrophiles can add to
vinylboron reagents stereoselectively with retention of configuration of the vinyl group.6
Scheme 2. Reaction of an Aldehyde with Two Equivalents of Z-Chlorovinylboron Dichloride
Br
Br
Cl
Cl
B
DCM
+
0 oC to rt
Cl
Cl
Cl
Ph
Cl
Ph
Ph
CHO
1
(Z,Z)-diene
Br
Br
Cl
Cl
B
Ph
Cl
Cl
Ph
OBCl2
Ph
(Z,E)-1,5-Dichloro-1,4-pentadiene (2) was prepared by adding boron trichloride to a mixture of the p-
o
bromobenzaldehyde and phenylacetylene at 0 C (Scheme 3). Reaction of boron trichloride with the
alkyne first generates the (Z)-chlorovinylboron dichloride. Addition of (Z)-vinylboron dichloride to the
aldehyde, followed by a carbon-oxygen bond cleavage affords a carbocation intermediate which then
adds to the second alkyne to generate the more thermodynamically stable (Z,E)-diene 2 as the major
product. In this case, boron trichloride actually functions as a reactant. The reaction outlined in Scheme 3
presumably competes with one shown in Scheme 2. This assumption is strongly supported by two
observations. The quantity of (Z,Z)-diene 1 increases when the aldehyde is added to a mixture of
phenylacetylene and boron trichloride, a sequence which favors the formation of the vinylboron
dichloride (Scheme 2). However, adding boron trichloride to a mixture of aldehyde and excess
phenylacetylene (3.0 equivalents) at 0 oC increases the chance of quenching carbocation by acetylene and
results in a higher ratio of 2 to 1. Since (Z,Z)-di(chlorovinyl)boron chloride only forms at elevated
temperature (refluxing dichloromethane),3b the reaction pathway shown in Scheme 1 should not be
responsible for the formation of 1 in this investigation.

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HETEROCYCLES, Vol. 80, No. 2, 2010
Scheme 3. BCl3-Mediated Coupling of Aryl Aldehydes and Alkynes.
Br
Br
Br
BCl3, DCM
0 oC to rt
+
Cl
Cl
Cl
Ph
Ph
+
2
Ph
Ph
Ph
Cl
CHO
1
2
(Z,Z)-diene
(Z,E)-diene
Minor
Major
Br
Br
+
Ph
Cl
BCl3
Ph
Br
Cl
Cl
Cl
Cl
- OBCl2
Ph
CHO
1 + 2
B
Ph
OBCl2
Ph
+ Cl
After establishing the analytical GC-MS conditions7 for separating stereoisomers 1 and 2, we examined
the addition of boron trichloride to a mixture of two equivalents of phenylacetylene and one equivalent of
p-bromobenzaldehyde at various temperature (Table 1). The reaction mixtures were subjected to GC-MS
analyses after a simple workup.8 As illustrated in Table 1, (Z,E)-1,5-dichloro-1,4-pentadiene product 2
was always the major product, indicating that the reaction pathway shown in Scheme 3 played a
o
o
predominant role. As the temperature was decreased from 0 C to -42 C, the regioselectivity [(Z,E)-
/(Z,Z)- isomer] increased due to the thermodynamic stability of the (Z,E)-pentadiene, 2. The reaction
pathway outlined in Scheme 2 presumably is also involved but it would be expected to be minimal at
o
temperatures approaching –60 C, because the haloboration reaction generating (Z)-chlorovinylboron
dichloride would be quite slow at such a low temperature; as a consequence, the concentration of (Z)-
chlorovinylboron dichloride should be much lower than that of phenylacetylene. Interestingly, reactions
o
run at temperatures below –60 C also produce (E,E)-1,5-dichloro-1,4-pentadiene, 3. At these low
temperatures, boron trichloride doesn’t participate in haloboration very effectively but still acts as a Lewis
acid to initiate the competing reaction that generates (E,E)-1,5-dichloro-1,4-pentadiene 3 (Scheme 4).
Addition of the alkyne to the boron trichloride activated carbonyl group, followed by C-O bond cleavage,
forms a carbocation bearing a thermodynamically stable (E)-vinyl moiety. Addition of the cation to
another equivalent of phenylacetylene then generates the more thermodynamically stable (E,E)-diene
product 3.
Table 1. The influence of reaction temperature on the ratio of isomers a
Reaction temperature
0 oC
Ratio of (Z,Z)-: (Z,E)-: (E,E)- b
~ 1 : 6 : 0

HETEROCYCLES, Vol. 80, No. 2, 2010
783
- 20 oC
~ 1 : 24 : 0
~ 1 : 27 : 0
~ 2 : 43 : 1
~ trace : 9 : 1
- 42 oC
- 60 oC
- 78 oC
a. The reaction procedure is outlined in reference 8. The ratios shown in table are the average of
multiple experiments. b. The (Z,Z)-, (Z,E)- and (E,E)-isomers exhibit rather different retention
times upon GC analysis. Their retention times are 42 min, 39 min and 36 min respectively under
optimized GC condition.7
Scheme 4. Lewis Acid Boron Trichloride Initiated Alkyne-Aldehyde Coupling
Br
Br
Cl
BCl3
B
Ph
+
Ph
O
Cl
- OBCl2
- 78 oC
Cl
Ar
Ph
Cl
OBCl2
CHO
* Ar = p-bromobenzyl
Br
Br
Ph
2
+
Ph
Ph
Ph
(Z,E)-diene
Cl
+ Cl
Cl
Cl
3
(E,E)-diene
Compound 3 was isolated by column chromatography. The 1H spectrum of the compound exhibited only
one set of vinyl resonances which supports the formation of the symmetrical (E,E)-1,5-dichloride-1,4-
pentadiene isomer.9 The structure was further confirmed by X-ray crystallography (Figure 1).10
Figure 1. X-Ray crystallography of 3.

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HETEROCYCLES, Vol. 80, No. 2, 2010
The specific proton chemical shifts and coupling constants for vinyl and benzylic protons in the diene
products, as well as the carbon-13 chemical shifts of the benzylic carbons, for the characterization of
(Z,Z)-, (Z,E)-, (E,E)-isomers are tabulated in Table 2.
Table 2. Chemical Shifts and Coupling Constants for Vinyl, Benzylic Proton and Benzylic Carbon
1H NMR
13C NMR
Benzylic carbon
45.3
Isomer
Vinyl proton
Benzylic proton
(Z,Z)-diene
6.30 (d, 2 H, J = 8.97 Hz) 5.39 (t, 1 H, J = 8.97 Hz)
6.21 (d, 1 H, J = 9.1 Hz), 4.81 (dd, 1 H, J = 9.1 and
(Z,E)-diene
(E,E)-diene
45.0
44.8
6.13 (d, 1 H, J = 10.5 Hz)
10.5 Hz)
6.05 (d, 2 H, J = 10.7 Hz) 4.34 (t, 1 H, J = 10.7 Hz)
As summarized in Table 2, both the vinyl and benzylic protons in the (E,E)-diene are upfield when
compared to those in (Z,Z)-diene. Surprisingly, the chemical shift of the benzylic proton in (E,E)-diene
and (Z,Z)-diene approach 1 ppm.
CONCLUSION
The reaction mechanism of phenylacetylene, p-bromobenzaldehyde, and boron trichloride have been
investigated and analyzed. Utilizing GC-MS data, the ratios of (Z,Z)-, (Z,E)-, and (E,E)-1,5-dichloro-1,4-
diene isomers in the crude reaction mixtures obtained under varying reaction conditions were determined.
o
The investigation reveals that, at relatively higher temperature (> - 42 C), the addition of boron
trichloride to phenylacetylene occurs rapidly and boron trichloride functions as a reactant to generate the
key intermediate (Z)-chlorovinylboron dichloride. While, at relative lower temperature, the addition of
boron trichloride to phenylacetylene becomes sluggish and the unreacted boron trichloride acts as a Lewis
acid and leads to formation of the (E,E)-diene.
ACKNOWLEDGMENT
Acknowledgment is made to the Donors of the Petroleum Research Fund for support of this research. We
also wish to thank the U.S. Department of Energy and the Robert H. Cole Foundation for partial support
of this research.
REFERENCES AND NOTES
1. G. W. Kabalka, Z. Wu, S. Trotman, and X. Gao, Org. Lett., 2000, 2, 255.
2. G. W. Kabalka, Z. Wu, and Y. Ju, Tetrahedron, 2001, 57, 1663.

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3. (a) G. W. Kabalka, Z. Wu, and Y. Ju, Org. Lett., 2002, 4, 1491; (b) G. W. Kabalka, M.-L. Yao, S.
Borella, Z.-Z. Wu, Y.-H. Ju, and T. Quick, J. Org. Chem., 2008, 73, 2668.
4. M. F. Lappert and B. Prokai, J. Organometal. Chem., 1964, 1, 384.
5. (a) G. W. Kabalka, Z. Wu, and Y. Ju, Org. Lett., 2004, 6, 3929; (b) G. W. Kabalka, M.-L. Yao, S.
Borella, and Z.-Z. Wu, Chem. Commun., 2005, 2492; (c) G. W. Kabalka, M.-L. Yao, S. Borella, and Z.-
Z. Wu, Org. Lett., 2005, 7, 2865; (d) G. W. Kabalka, M.-L. Yao, and S. Borella, Org. Lett., 2006, 8,
879; (e) G. W. Kabalka, M.-L. Yao, and S. Borella, J. Am. Chem. Soc., 2006, 128, 11320; (f) G. W.
Kabalka, M.-L. Yao, S. Borella, and L. K. Goins, Organometallics, 2007, 26, 4112; (g) M.-L. Yao, S.
Borella, T. Quick, and G. W. Kabalka, J. Chem. Soc. Dalton, 2008, 776; (h) M.-L. Yao, M. S. Reddy,
W.-B. Zeng, K. Hall, I. Walfish, and G. W. Kabalka, J. Org. Chem., 2009, 74, 1385; (i) M.-L. Yao, T.
Quick, Z.-Z. Wu, M. P. Quinn, and G. W. Kabalka, Org. Lett., 2009, 11, 2647.
6. (a) S. Hara, H. Dojo, S. Takinami, and A. Suzuki, Tetrahedron Lett., 1983, 24, 731; (b) S. K. Stewart
and A. Whiting, Tetrahedron Lett., 1995, 36, 3925; (c) A. P. Lightfoot, G. Maw, C. Thirsk, S. J. R.
Twiddle, and A. Whiting, Tetrahedron Lett., 2003, 44, 7645; (d) G. W. Kabalka and A. R. Mereddy,
Organometallics, 2004, 23, 4519; (e) A. S. Batsanov, J. P. Knowles, and A. Whiting, J. Org. Chem.,
2007, 72, 2525.
7. GC-MS studies were run on Hewlett packard: HP 6890 series GC System with 5973 Mass Selective
Detector; Column: Agilent 19091S-433E, 30.0mm x 0.25mm x 0.25m; Gas (He) flow rate: 0.8
mL/min; Initial temperature; 50 oC (hold 1 min); Ramp temperature rate: 7 oC/min to maximum 280 oC.
8. Phenylacetylene (204 mg, 2.0 mmol) and p-bromobenzaldehyde (185 mg, 1.0 mmol) and were placed
in a dry argon-flushed, 50 mL round-bottomed flask equipped with a stirring bar and dissolved in 15
mL dry CH2Cl2. The solution was cooled to desired temperature, and boron trichloride (1.1 mmol, 1.1
mL of a 1.0 M CH2Cl2 solution) was added via a syringe. The solution was allowed to stir for 1 h at that
temperature. The resulting mixture was hydrolyzed with water (20 mL) and extracted with hexanes (2 x
30 mL). The organic layer was separated and passed through a short silicon gel column to remove the
trace of water and acidic by-product.
9. Spectral data for (E,E)-1,5-dichloro-1,4-diene (3): 1H NMR (250 MHz, CDCl3): σ 7.47-7.01 (m, 14 H),
13
6.05 (d, 2 H, J = 10.7 Hz), 4.34 (t, 1 H, J = 10.7 Hz). C NMR: σ 140.60, 136.19, 132.89, 131.98,
128.84, 128.64, 128.22, 128.16, 121.01, 44.78.
10. Crystal structure analysis for (E,E)-diene 3: (C23H17BrCl2, Mr=444.18), monoclinic, space group
P2(1)/n, a=8.730(2) Å, b= 13.248(3) Å, c=16.912(4) Å, α=90.00, β=95.957(4), γ=90.00, V=1945.4(8)
Å3, Z=4, T=173(2), 17368 collected, 3899 crystallographic independent and 3442 reflexes mit I>2s(I),
MoKa radiation, λ=0.71073 Å, θmax=26.20, R[I>2s(I)]: R1=0.0375, wR2= 0.0963, wR2=0.1008 (all data).