Synthesis of 2-Substituted Propenes by Bidentate Phosphine-Assisted Methylenation of Acyl Fluorides and Acyl Chlorides with AlMe3

Article abstract of DOI:10.1021/acs.orglett.9b01059

Bidentate phosphine-assisted methylenation of acyl fluorides and acyl chlorides with substituted with aryl, alkenyl, and alkyl groups trimethylaluminum afforded an array of 2-substituted propene derivatives. The addition of a catalytic amount of DPPM increased an efficiency of the reactions. Trimethylaluminum as the methylenation reagent not only eliminates the presynthesis of methylene transfer reagent, but provides an efficient method for the synthesis of a series of 2-substituted propenes.

Full text of DOI:10.1021/acs.orglett.9b01059

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of 2‑Substituted Propenes by Bidentate Phosphine-
Assisted Methylenation of Acyl Fluorides and Acyl Chlorides with
AlMe3
Xiu Wang,† Zhenhua Wang,† Yuya Asanuma,† and Yasushi Nishihara*,‡
†Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushimanaka, Kita-ku, Okayama 700-8530, Japan
‡Research Institute for Interdisciplinary Science, Okayama University, 3-1-1 Tsushimanaka, Kita-ku, Okayama 700-8530, Japan
S
* Supporting Information
ABSTRACT: Bidentate phosphine-assisted methylenation of acyl fluorides and acyl chlorides with substituted with aryl,
alkenyl, and alkyl groups trimethylaluminum afforded an array of 2-substituted propene derivatives. The addition of a catalytic
amount of DPPM increased an efficiency of the reactions. Trimethylaluminum as the methylenation reagent not only eliminates
the presynthesis of methylene transfer reagent, but provides an efficient method for the synthesis of a series of 2-substituted
propenes.
products. In addition, the yields of target compounds were
sometimes unsatisfactory, because of the low reactivity of
phosphonium ylides.6,12,14 Other representative methylenation
reagents such as sulfoximine,5 silylcarbanion,7 sulfone,10 and
titanium−aluminum complex12 have been studied extensively.
On the other hand, late-transition-metal complexes such as
Ni,16 Cu,17 Pd,18 and Rh19 have also been described to catalyze
methylenation of aldehydes and ketones. However, acyl halides
are still rare to be employed toward methylenation reactions,
although they are inexpensive, stable, and widely abundant.20,21
During our continuing studies on the transformation of acyl
halides,22 we discovered a simple and reliable method for the
conversion of acyl halides (X = F and Cl) to 2-substituted
propenes, in which trimethylaluminum acts as the methylena-
tion reagent (Scheme 1b).
2-Substituted propenes including α-methylstyrenes are found
to be prevalent in natural1 and synthetic products,2 as well as
chiral building blocks in catalytic asymmetric processes.3 Thus,
direct and efficient synthesis of such products from the
corresponding carbonyl compounds is an important class of
organic transformations. Pioneering efforts on methylenation
of aldehydes or ketones to the corresponding olefins have been
well-documented by Wittig,4 Johnson,5−7 Peterson,8 Julia,9−11
Tebbe,12−14 and Takai.15 In particular, an appropriate choice
of reagents is a key issue to realize methylenation procedures
(Scheme 1a). Although phosphonium ylides are also well-
known methylene transfer reagents, they suffered from tedious
separation between triphenylphosphine oxide and the target
Scheme 1. Methylenation of Carbonyl Compounds
After a close look at the literature about the transformation
of acyl chlorides to olefins23 via ketones,24 we found that one-
step methylenation generating the corresponding alkenes from
the corresponding carbonyl compounds is in high demand.
With this consideration in mind, we commenced the study by
examining the reaction of acyl chloride 1a and 2 equiv of
trimethylaluminum. Initially, the reaction was conducted in the
presence of the Ni catalyst, but after extensive optimization of
reaction conditions, we finally found that the nickel catalyst is
not necessary (see Tables S1−S4 in the Supporting
Information). Screening several additives revealed the
optimized condition, as shown in Table 1. Monodentate
phosphine PPh3 afforded 59% yield of 2a, along with the
alcohol 3a in 7% yield (Table 1, entry 1). Among bidentate
Received: March 25, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01059
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Letter
a b
,
Table 1. Optimization for Methylenation of 4-Phenybenzoyl
Chloride (1a) with AlMe3
Scheme 2. Scope of Acyl Halides
a
b
Yield (%)
entry
additive
amount (mol %)
2a
3a
1
2
3
4
5
6
7
8
9
PPh3
DPPM
DPPE
24
12
12
12
12
12
24
12
2
59
93 (90)
54
82
3
57
78
70
60
7
0
8
18
3
10
22
3
DPPP
DPPB
Xantphos
Et3N
TMEDA
DPPM
DPPM
DPPM
0
0
0
10
0
12
15
12
c
11
a
Reactions were performed with 1a (0.2 mmol), AlMe3 (2 equiv),
b
toluene (0.5 mL) at 120 °C for 24 h. GC yields. An isolated yield is
given in parentheses. AlMe3 (1 equiv) was used.
c
phosphines investigated (entries 2−6), DPPM showed
superior results; target product 2a was selectively delivered
in 90% isolated yield (Table 1, entry 2). Meanwhile, nitrogen-
containing bases such as triethylamine (Table 1, entry 7) and
tetramethylethylenediamine (TMEDA; see Table 1, entry 8)
also resulted in the conversion of 2a in 78% and 70% yields,
respectively. In a sharp contrast, DPPM-free reaction
conditions gave only 15% yield of 2a (Table 1, entry 10).
The result shown in entry 11 suggested that 2 equiv of AlMe3
are essential for complete transformation into 2a.
a
Reaction conditions: 1 (X = Cl) or 1′ (X = F) (0.2 mmol), AlMe3 (2
b
With the optimized conditions of entry 2 (in Table 1) in
hand, a generality for methylenation of acyl chlorides 1 or
fluorides 1′ with AlMe3 was examined. The results are
summarized in Scheme 2. Both benzoyl chloride (1b) and
benzoyl fluoride (1b′) gave 2b in 83% and 92% yields,
respectively. Acyl halides bearing alkyl and phenyl groups in
various positions afforded 2c−2f in good to high yields. The
substrates bearing oxygen functionalities reacted smoothly to
afford the corresponding products 2g−2k in 65%−72% yields.
Surprisingly, acyl chloride substituted by methoxycarbonyl
group chemoselectively provided the target product 2l in 76%
yield. Functional compatibility of halogen-containing starting
materials in this methylenation was further demonstrated.
Because of the absence of any transition metals, it is
noteworthy that bromide (2o) and iodide (2p) were well-
tolerated. Similarly, naphthoyl chlorides and fluorides readily
yielded 2q and 2r in good yields. Sulfur-containing hetero-
cycles posed no problem in this transformation to give 2s and
2t. Strikingly, this method employing alkenylated acyl chlorides
could be applied for 1,3-dienes synthesis to afford 2u and 2v.
In addition, the reactions of tertiary aliphatic acyl chloride 1w
could readily furnished 2w in 75% yield. In some cases, an
equimolar amount of AlMe3 gave rise to the formation of 2 in
comparable yields obtained with 2 equiv of AlMe3 addition,
indicating that AlMe3 play a role in two methyl-group-donating
reagents.
equiv), DPPM (12 mol %), toluene (0.5 mL), 120 °C, 24 h. Isolated
yields. One mmol.
c
Scheme 3. Scope of Carboxylic Acid Derivatives
methylenation reactions of phenolic ester 5 and thioester 6
could also undergo to give 2a in moderate yields, which is in
sharp contrast to the result for methyl ester (vide supra).
Double methylenation with 4 equiv of AlMe3 was tested for
the bifunctional acyl chloride 1x. As a result, 1,4-
diisopropenylbenzene (2x) was formed in 82% yield. In
addition, with the use of phenolic ester 1y, 2x was delivered in
90% yield (Scheme 4a). As shown in Scheme 4b, acyl chloride
1z with a keto group provided the unsymmetrical 1,4-
methylenation product 2z, which has been frequently used in
the polymerization.25 Otherwise, 2z is not readily synthesized
by other synthetic methods. Large-scale synthesis of 4-bromo-
Next, a series of ester derivatives was also evaluated (Scheme
3). Perfluoro-phenolic ester 4 showed good reactivity with the
aid of DPPM and afforded 2a in 97% yield. In addition, the
B
DOI: 10.1021/acs.orglett.9b01059
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Letter
was formed in 74% yield with the aid of 12 mol % of DPPM,
whereas, without DPPM, byproduct 7 was obtained in 96%
yield. These results are also supported with the time course of
the reactions of benzoyl chloride (1b) or benzoyl fluoride
(1b′) with 2 equiv of AlMe3 with or without DPPM (see
Figures S1 and S2 in the Supporting Information). Therefore,
we concluded that the present methylenation is promoted by
the in-situ-formed AlMe2X (X = F or Cl).
Scheme 4. Application
With the results obtained shown in Scheme 5 in hand, we
propose the reaction mechanism, as shown in Scheme 6. Acyl
Scheme 6. Reaction Mechanism
halides 1 or 1′ react with the first equivalent of AlMe3 to afford
ketone 8, along with the formation of AlMe2X. Successively,
the formed ketone 8 reacts with the second equivalent of
AlMe3 to form intermediate 3.24c Finally, the AlMe2X27 formed
in situ acts as a Lewis acid to promote the elimination of
Me2AlOAlMe2, giving rise to the products 2. Although a role of
DPPM has not been clarified, the bidentate nature of DPPM
might support a nucleophilic attach of AlMe3 to acyl halides
and tune the acidity in the catalytic system, which retards the
Brønsted or Lewis acid-triggered dimerization of 2.
2-propenylbenzene (2o) was successful without a loss in yield
(89%, 1.05 g) (Scheme 4c).
To shed light on the reaction mechanism, additional
experiments were performed to prove the existence of
intermediates and a role of DPPM. The reaction of 1b with
2 equiv of AlMe3 was conducted (Scheme 5a). In the reaction
Scheme 5. Mechanistic Studies
In summary, we have developed a practicable, scalable, and
one-step method to form 2-substituted propenes from various
aryl, alkenyl, and alkyl acyl halides, as well as other esters. This
protocol features good functional tolerance of halogens and
chemoselectivity for esters, which would be a useful comple-
ment to other methylenation processes.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01059.
1
More-detailed results of methylenation and H NMR
spectra of the products (PDF)
AUTHOR INFORMATION
■
at room temperature for 24 h, the starting material 1b was
completely consumed, along with the formation of alcohol 3b
quantitatively, but neither 2b, nor 2,3-dihydro-1H-indene
derivative 7,26 the dimerized product of 2b, was observed.
On the other hand, when the same reaction was performed at
120 °C, 83% yield of 2b was obtained, which indicates that the
high reaction temperature is important for transformation from
3b to 2b. The plausible intermediate acetophenone (8b) was
subjected to the reaction with or without DPPM or AlMe2Cl
(Scheme 5b). As a result, the reactions of 8b with 1 equiv of
AlMe3 in the presence of 12 mol % DPPM afforded 2b in 92%
NMR yield, whereas the yield of 2b decreased to 57% without
DPPM, along with 34% of 7. Without AlMe2Cl, only alcohol
3b was obtained with or without DPPM. This result suggests
that the in-situ-formed AlMe2Cl plays an important role for
transformation of 3b to 2b. Subsequently, the reactions of the
intermediate alcohol 3b with an equimolar amount of AlMe2Cl
were elucidated (Scheme 5c). As expected, a single product 2b
Corresponding Author
*E-mail: ynishiha@okayama-u.ac.jp.
ORCID
Yasushi Nishihara: 0000-0001-5409-4207
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This study was partly supported by Marubun Research
Promotion Foundation. We gratefully thank the SC-NMR
Laboratory (Okayama University) for the NMR spectral
measurements.
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