In Situ Generation of Formaldehyde and Triphenylphosphine from (Hydroxymethyl)triphenylphosphonium and Its Application in Wittig Olefination

Article abstract of DOI:10.1080/00397911.2015.1043019

The reaction of (hydroxymethyl)triphenylphosphonium with benzylic or allylic halide under basic conditions at room temperature affords terminal alkenes in 61-89% yields. In this reaction, both formaldehyde and triphenylphosphine are in situ generated from (hydroxymethyl)triphenylphosphonium and further undergo Wittig olefination with benzylic or allylic halide.

Full text of DOI:10.1080/00397911.2015.1043019

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In Situ Generation of Formaldehyde
and Triphenylphosphine from
(Hydroxymethyl)triphenylphosphonium and Its
Application in Wittig Olefination
Wenhua Huanga & Jie Xua
a Department of Chemistry, Tianjin University, Tianjin, P. R. China
Accepted author version posted online: 05 May 2015.
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To cite this article: Wenhua Huang & Jie Xu (2015): In Situ Generation of Formaldehyde and Triphenylphosphine from
(Hydroxymethyl)triphenylphosphonium and Its Application in Wittig Olefination, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, DOI: 10.1080/00397911.2015.1043019
To link to this article: http://dx.doi.org/10.1080/00397911.2015.1043019
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In situ generation of formaldehyde and triphenylphosphine from
(hydroxymethyl)triphenylphosphonium and its application in Wittig olefination
Wenhua Huang1, Jie Xu1
1Department of Chemistry, Tianjin University, Tianjin, P. R. China
Corresponding Author: Wenhua Huang, Email: huangwh@tju.edu.cn
Abstract
The reaction of (hydroxymethyl)triphenylphosphonium with benzylic or allylic halide
under basic condition at room temperature affords terminal alkenes in 61-89% yields. In
this reaction, both formaldehyde and triphenylphosphine are in situ generated from
(hydroxymethyl)triphenylphosphonium, and further undergo Wittig olefination with
benzylic or allylic halide.
Graphical Abstract:
1

KEYWORDS: formaldehyde; triphenylphosphine; Wittig olefination;
(hydroxymethyl)triphenylphosphonium; terminal alkene
INTRODUCTION
Formaldehyde is a hazardous, self-reactive chemical and usually in situ generated from
either its oligomer (paraformaldehyde) or aqueous solution (formalin).[1] A large excess
of paraformaldehyde or formalin is often required to complete a reaction, in particular,
under basic condition. For example, in the Wittig olefination of formaldehyde with
semi-stabilized ylides, the molar ratio of formaldehyde to the phosphonium salt is often
5-10,[2–5] and even greater than 50.[6] Therefore, to develop new methods to in situ
generate formaldehyde under basic condition is highly desired. In 2007, Bischoff and
coworkers reported[7] a novel method to in situ generate formaldehyde using
benzotriazolylmethanol or N-hydroxymethyl phtahlimide under basic and anhydrous
conditions, as shown in the upper part of Scheme 1. They have applied this method in the
hydroxymethylation of organolithium reagents and enolates. They have also employed
this method in the Wittig olefination of one semi-stabilized ylide but the corresponding
phosphonium salt needs to be prepared in advance and a strong base (lithium
tetramethylpiperidide) is required. Recently, Suna and coworkers also reported[8] that
methoxymethanol is a source of formaldehyde in the hydroxymethylation of lithium
enamides. Herein, we report an alternative method to in situ generate formaldehyde by
2

treating (hydroxymethyl)phosphonium with K2CO3, as shown in the bottom part of
Scheme 1. Both formaldehyde and the concomitantly released Ph3P are utilized to
participate in Wittig olefination of benzylic or allylic halides to afford terminal alkenes.
RESULTS AND DISCUSSION
Initially we chose (hydroxymethyl)triphenylphosphonium tetrafluorobrate 1a as a model
compound to explore the possibility of the in situ generation of formaldehyde. This salt is
a bench-stable solid and readily prepared from triphenylphosphine and paraformaldehyde
according to the reported method.[9] It is noteworthy that a 1:1 molar ratio of
formaldehyde to triphenylphosphine is used to prepare this salt. In order to utilize the
concomitant release of Ph3P during the in situ generation of formaldehyde, we
hypothesized that a benzylic or allylic halide would trap it to form the corresponding
phosphonium salt which under basic condition would further react with formaldehyde to
form terminal alkene 3, as shown in Scheme 2. Therefore, we chose
2-bromomethylnaphthalene 2a as another model compound to test our hypothesis.
When a mixture of 1a and 2a were treated with K2CO3 in THF, 2-vinylnaphthalene 3a
was obtained in 16% yield (Table 1, entry 1). After screening solvents including CH2Cl2,
DMSO, and CH3CN (entries 2-4), CH3CN was found to be the best solvent to afford 3a
in 87% yield. Replacing 1a with the corresponding iodide 1b and chloride 1c reduced the
3

yield of 3a to 38% and 59%, respectively, indicating that the anion might play a key role
in the reaction. We have also prepared tricyclohexyl(hydroxymethyl)phosphonium
tetrafluoroborate 1d according to the similar method for the preparation of 1a. This salt
could also lead to the formation of 3a albeit in a lower yield (53%).
We next examined a variety of benzylic and allylic halides, and the results were
summarized in Table 2. For benzylic bromides 2b-d with an electron-donating group at
the para-position of aromatic ring, 3b-d were obtained in 73-79% yields (entries 2-4).
1,4-Bis(bromomethyl)benzene 2e underwent diolefination smoothly to give 3e in 69%
yield when 2 equiv of 1a was used (entry 5). Allylic halides such as cinnamyl bromide 2f
and -bromomethylstyrene 2h afforded the corresponding 1,4-dienes in 82% and 61%
yields (entries 6 and 8), respectively. Benzylic bromides with an electron-withdrawing
group at either ortho- or para- or meta-position of aromatic ring furnished olefination in
good yields (81-89%) (entries 9, 10, and 12-18). For cinnamyl chloride 2g and
4-chlorobenzyl chloride 2k, however, 3f and 3i was obtained in very low yields (entries 7
and 11), probably because the reaction of Ph3P is slower with benzylic or allylic chloride
than with the corresponding bromide. By replacing 1a with 1b, the yields of 3f and 3i
dramatically increased to 61% and 69%, respectively, possibly due to the chloride-iodide
exchange to form benzylic or allylic iodide which is much more reactive toward Ph3P
4

than the corresponding chloride. Attempts to expend this reaction to alkyl halides other
than benzylic or allylic halides were unsuccessful.
CONCLUSIONS
In conclusion, we have demonstrated that (hydroxymethyl)triphenylphosphonium salts
can be used as a source of both formaldehyde and tiphenylphophine, which can be
applied in Wittig olefination of benzylic and allylic halides. This olefination can be
carried out under mild conditions, and avoid using a large excess of formaldehyde and
preparing benzylic or allylic triphenylphosphonium salts.
EXPERIMENTAL
Triphenylphosphine and benzylic and allylic halides were purchased from a local
company and used as received. All melting points were measured on a melting point
apparatus with a microscope and a hot stage and were uncorrected. 1H and 13C NMR
spectra were recorded on a Bruker Avance 400 or 600 NMR spectrometer. IR spectra
were recorded on a Thermo Nicolet Avatar 360 IR spectrometer. HRMS spectra were
recorded on a Varian 7.0 T FTMS. PE = Petroleum ether, bp 60-90 C. Phosphonium salts
1a,[9] 1b,[10] and 1c[10] were prepared according to the literature procedure.
5

General Procedure For Wittig Olefination Using
(Hydroxymethyl)Triphenylphosphonium Salts
To a round-bottom flask (25 mL), 1 (0.5 mmol), 2 (0.5 mmol), K2CO3 (1.0 mmol) and
solvent (5 mL) were added. After stirring at room temperature overnight, the reaction
mixture was evaporated under reduced pressure, and the residue was separated by
preparative TLC (silica gel, eluted with PE or PE:EtOAc 50:1) to afford the alkene 3.
ACKNOWLEDGEMENT
We thank the National Natural Science Foundation of China for their financial support of
our program (Grant No. 21272170)
SUPPORTING INFORMATION
Full experimental detail, 1H and 13C NMR spectra for this article can be accessed on the
publisher’s website.
REFERENCES
1. Shreiber, E. H.; Roberts, G. W. Chem. Ind. (Dekker) 2001, 82, 391.
2. Medard, G. Tetrahedron 2014, 70, 186.
3. Markovac, A.; LaMontagne, M. P. J. Med. Chem. 1980, 23, 1198.
4. Jacober, S. P.; Hanzlik, R. P. J. Am. Chem. Soc. 1986, 108, 1594.
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5. Garcia-Rubin, S.; Gonzalez-Rodriguez, C.; Garcia-Yebra, C.; Varela, J. A.;
Esteruelas, M. A.; Saa, C. Angew. Chem., Int. Ed. 2014, 53, 1841.
6. Jiang, X.-K.; Ji, G.-Z.; Wang, D. Z.-R. J. Fluorine Chem. 1996, 79, 173.
7. Deguest, G.; Bischoff, L.; Fruit, C.; Marsais, F. Org Lett 2007, 9, 1165.
8. Priede, M.; Kazak, M.; Kalnins, T.; Shubin, K.; Suna, E. J. Org. Chem. 2014, 79,
3715.
9. Burton, D. J.; Wiemers, D. M. J Fluorine Chem 1985, 27, 85.
10. Davis, M. C.; Parrish, D. A. Synthetic Commun 2008, 38, 3909.
7

Table 1. Exploration of reaction conditions for Wittig olefination using
(hydroxymethyl)phosphoniuma
Entry
R
X
Solvent
Yieldb
(%)
16
1
1
2
3
4
5
6
7
Ph
BF4
BF4
BF4
BF4
I
THF
1a
1a
1a
1a
1b
1c
1d
Ph
CH2Cl2
DMSO
CH3CN
CH3CN
CH3CN
CH3CN
40
Ph
61
Ph
87
Ph
38
Ph
Cl
59
Cyclohexyl
BF4
53
a Reaction conditions: 1 (0.5 mmol), 2a (0.5 mmol), K2CO3 (1.0 mmol), solvent (5 mL),
rt, overnight. b Isolated yield by preparative TLC.
8

Table 2. Synthesis of terminal alkenes using (hydroxymethyl)phosphonium saltsa
Entry
3, yieldb
Entry
3, yieldb
2
2
a Reaction conditions: 1a (0.5 mmol), 2 (0.5 mmol), K2CO3 (1.0 mmol), CH3CN (5 mL),
rt, overnight (15-20 h, monitored by TLC). b Isolated yield by preparative TLC. c Using
1a (1.0 mmol) and K2CO3 (2.0 mmol). d Using 1b instead of 1a which gave 3f in only
17% yield. e Using 1b instead of 1a which gave 3i in only 19% yield.
9

Scheme 1. In situ generation of formaldehyde under basic condition
10

Scheme 2. Wittig olefination using (hydroxymethyl)phosphonium salt
11