Breaking the ring through a room temperature catalytic wittig reaction

Article abstract of DOI:10.1002/chem.201300546

One ring no longer rules them all: Employment of 2.5-10 mol % of 4-nitrobenzoic acid with phenylsilane led to the development of a room temperature catalytic Wittig reaction (see scheme). Moreover, these enhanced reduction conditions also facilitated the use of acyclic phosphine oxides as catalysts for the first time. A series of alkenes were produced in moderate to high yield and selectivity. Copyright

Full text of DOI:10.1002/chem.201300546

COMMUNICATION
DOI: 10.1002/chem.201300546
Breaking the Ring through a Room Temperature Catalytic Wittig Reaction
Christopher J. OꢀBrien,* Florie Lavigne, Emma E. Coyle, Andrew J. Holohan, and
Bryan J. Doonan[a]
Discovery of new and refinement of existing synthetic
methodologies are essential if chemistry is to adapt to the
changes and consequent challenges in its application land-
scape.[1] These impediments can be represented in terms of
substrate diversity, energy cost, ease-of-use or deployment.[2]
In regard to organic synthesis this generally relies on the in-
terplay and reactivity of functional groups. Carbon–carbon
double bonds present a multitude of synthetic opportuni-
ties.[2,3] Arguably, the most utilized methodology for the con-
struction of this important functional group is the Wittig re-
action.[4] Consequently, the Wittig reaction has received con-
siderable attention by numerous groups both in applica-
tion[5] and mechanistic understanding.[6] Recently, our labo-
ratory was successful in developing the first catalytic Wittig
reaction (CWR, in phosphine).[7] Though these results were
an advance[7b–c] they represented the start of the process to
develop a robust user-friendly olefination methodology.
Indeed, the reactions were performed at high temperature
(1008C) and were not kinetically highly diastereoselective.
The observed high E selectivity relied on a phosphine-medi-
ated post-olefination isomerization event.[7a] The actual ki-
netic selectivity ranged from E/Z: 2:1 to 3:1. Furthermore,
the protocol was reliant on the use of a cyclic phosphine
oxide. Ideally a catalytic Wittig process performed at room
temperature and/or utilizing readily available acyclic trialkyl
or triaryl phosphine oxides would offer greater synthetic
flexibility and aid wider adoption of the methodology.
the reactivity of either the phosphine oxide (toward reduc-
tion) or silane must be achieved.
To achieve this, two possible strategies can be employed
in isolation or in combination: 1) modify the phosphine
oxide or silane structure or 2) the inclusion of an additive,
for example, a Lewis acid,[10] to increase the rate of reduc-
tion. We were concerned that the use of an organometallic
or boron-based Lewis acid would yield significant chemose-
lectivity issues. The most rudimentary of Lewis acids is a
proton; therefore, could the addition of a protic acid yield
an enhancement in rate of phosphine oxide reduction? This
was postulated based on mechanistic studies of phosphine
oxide reduction by silanes,[11] and supported by re-examina-
tion of results in which aged benzaldehyde was used.[11c]
Consequently we probed the use of aryl carboxylic acids as
reduction aids. To ease integration in the final CWR, reduc-
tions were performed in the presence of base (iPr2NEt) and
mimicked a theoretical 10 mol% catalyst loading based on
the future aldehyde. Employing the same reasoning the
silane would represent 1.4 equivalents. This rationale led to
the final conditions as depicted in Table 1 and the results
were striking. Addition of an equimolar amount of an aryl
carboxylic acid notably enhanced phosphine oxide reduc-
tion.[12] Indeed, the reduction of 1 was almost complete in
just 60 min at room temperature (Table 1, entry 1).
To probe this reduction a series of aryl carboxylic acids
varying in pKa were screened. Diphenylsilane replaced
Yet, both of these enhancements hinge on the key prob-
lem of selective reduction of the phosphine oxide in the
presence of other reactive functionalities. The employment
of silane yielded the answer in our previous work.[7] Subse-
quently others applied this reduction strategy to the Appel
and Staudinger reactions.[8] In regard to the Wittig reaction,
we found that a temperature of 1008C was required to ach-
ieve a viable turnover rate of the phosphine oxide/phos-
phine required for adoption in a catalytic process.[9] Conse-
quently, to decrease the reaction temperature an increase in
phenACTHGNUTERNNUyG lsilane as the lower reactivity of this silane would
offer greater resolution in terms of reactivity differences be-
tween acids. The effect of the pKa of the acid was signifi-
cant, 4-nitrobenzoic acid, which has the lowest pKa (~3.4 in
water, ~9.1 in DMSO), yielded the greatest enhancement in
reduction (Table 1, entries 3–7). A control reaction per-
formed with no carboxylic acid additive yielded just 6%
(entry 2). Moreover, reduction employing phenylsilane and
4-nitrobenzoic acid achieved a high conversion at room tem-
perature in just 2 min (entries 8–10)! Though the rates ob-
served for reduction of cyclic phosphine oxides 1 and 2 were
impressive, a barrier remained, reduction of acyclic phos-
phine oxides. Pleasingly, we observed that 3 and 4 were re-
duced with reasonable yield in just 10 min at 1008C (en-
tries 11 and 12). Further enhancement in reduction of tri-
phenylphosphine oxide was accomplished by substitution of
phenylsilane with 4-(trifluoromethyl)phenylsilane, which
yielded an increase from 50 to 81% yield (footnote [c]).
[a] Dr. C. J. OꢀBrien, Dr. F. Lavigne, Dr. E. E. Coyle, A. J. Holohan,
B. J. Doonan
School of Chemical Sciences, Dublin City University
Glasnevin, Dublin 9 (Ireland)
E-mail: christopher.obrien@dcu.ie
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201300546.
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Table 1. Carboxylic acid enhanced phosphine oxide reduction.[a]
Table 3. Optimization of the CWR with secondary bromides.[a]
Entry 2 [mol%] Acid [mol%] V EtOAc [mL] Yield [%][b] E/Z[c]
1
10
20
20
10
10
5
2.5
2.5
0.33
1.0
2.0
28
75
52
66
87:13
90:10
90:10
90:10
2[d]
3[e]
4[f]
Entry
R3PO
Silane
R1
T [8C]
t [min]
Conv. [%][b]
1
2
3
4
5
6
7
8
1
1
1
1
1
1
1
1
2
2
3
4
PhSiH3
Ph2SiH2
Ph2SiH2
Ph2SiH2
Ph2SiH2
Ph2SiH2
Ph2SiH2
PhSiH3
PhSiH3
PhSiH3
PhSiH3
PhSiH3
H
–
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
100
100
60
60
60
60
60
60
60
2
2
2
10
10
94
6
0.5
[a] For full details of the optimization study see the Supporting Informa-
tion. Benzaldehyde (1.0 mmol), organohalide (1.3 mmol), phosphine
oxide (0.1–0.2 mmol), 4-nitrobenzoic acid (0.025-0.1 mmol), iPr2NEt
(1.4 mmol), phenylsilane (1.2–1.4 mmol), EtOAc (X mL). [b] Isolated
yield. [c] E/Z ratio determined by 1H NMR spectroscopy of the unpuri-
fied reaction mixture. [d] Aldehyde added in four portions every 3 h.
[e] 17.5 mol% tetrabutylammonium tetrafluoroborate was added. [f] Al-
dehyde added in 10 portions every 1.5 h.
OMe
CH3
H
CF3
NO2
NO2
NO2
NO2
NO2
NO2
20
25
34
57
61
74
82
85
73
50[c]
9
10
11
12
was adopted from this point.[6] Following these results, a
brief solvent study was performed that focused on green sol-
vents that would offer the possibility of implementation in
process scale applications.[13] In this regard, cyclopentyl
methyl ether (CPME) and EtOAc were effective solvents
and worked equally well without distillation (entries 3 and
4). Olefinations involving acyclic phosphine oxides also pro-
ceeded smoothly at 1008C and in high conversions and yield
(entries 6 and 7). This is the first time an acyclic phosphine
oxide has been utilized as a catalyst in the CWR and the
use of phosphine oxides 3 and 4 resulted in high kinetic dia-
stereocontrol. Next the RT-CWR was successfully applied to
the production of trisubstituted olefins, as 6 was synthesized
in good yield at room temperature with slow addition of al-
dehyde (Table 3, entry 4).
[a] Phosphine oxide (0.1 mmol), 4-substituted benzoic acid (0.1 mmol),
iPr2NEt (1.4 mmol), silane (1.4 mmol), 0.3m in requisite solvent (entries
1–9, THF; entry 10, EtOAc; entries 11 and 12, toluene). For full details
of carboxylic acid enhanced phosphine oxide reduction see the Support-
ing Information. [b] Conversion determined by 31P NMR spectral analy-
sis, triphenylphosphine oxide as a calibrant (not used for entry 12).
[c] Conversion employing 4-(trifluoromethyl)phenylsilane was 81%.
Table 2. Optimization of the CWR with primary bromides.[a]
Entry
R3PO
Solvent
T [8C]
Conv. [%][b,c]
E/Z[d,e]
Following optimization of the cyclic phosphine oxide cata-
lysed room temperature (RT-CWR), and acyclic phosphine
oxide catalysed (AC-CWR) high temperature catalytic
Wittig reactions, substrate studies were performed
(Tables 4–6). Notable results employing the RT-CWR proto-
col (Table 4) were the syntheses of 7–9, 14–16, 19 and 21
that demonstrated the employment of heterocyclic alde-
hydes and/or organobromides. Compound 12 also has struc-
tural similarities to resveratrol and derivatives, which have
anticancer properties, illustrating the medicinal chemistry
applications of this methodology.[14] In all cases, except 14,
good E diastereoselectivity was achieved. The use of a 1,2-
oxazole carboxaldehyde, producing 15 and 16 was notewor-
thy as these heterocycles are often employed in medicinal
chemistry.[15] The mild nature of the protocol was demon-
strated by the toleration of the tert-butoxycarbonyl (BOC)
protecting group yielding compound 14. Erosion of diaster-
eoselectivity in this case most likely results from the BOC
group stabilizing the formation of the cis-oxaphosphetane as
outlined by Byrne and Gilheany.[6a] The reasonable E selec-
tivity in the synthesis of 21 is interesting as the use of bro-
moacetonitrile led to poor selectivity (E/Z: 66:34) in our
previous protocol.[7a]
1
2
3
4
5
6
7
1
2
2
2
3
3
4
THF
THF
RT
RT
RT
RT
100
100
100
100 (91)
100
100
100 (85)
100 (81)
96 (85)
89
75:25
86:14
86:14
86:14
89:11
91:9
CPME
EtOAc
CPME
toluene
toluene
90:10
[a] For full details of the optimization see the Supporting Information.
Benzaldehyde (1.0 mmol), organohalide (1.3 mmol), phosphine oxide
(0.1 mmol), 4-nitrobenzoic acid (0.1 mmol), iPr2NEt (1.4 mmol), silane
(1.4 mmol; entries 1–6, phenylsilane; entry 7, 4-(trifluoromethyl)phenylsi-
lane) 3.0m in requisite solvent. [b] Conversion determined by 1H NMR
spectroscopy. [c] Isolated yields shown in parentheses. [d] E/Z ratio deter-
1
mined by H NMR spectroscopy of the unpurified reaction mixture. [e] A
repeat of entry 4 without acid additive gave a selectivity of E/Z 86:14.
Subsequently, integration into the CWR was undertaken
(Tables 2 and 3). Satisfyingly, the acid-enhanced reduction
strategy was effectively adopted into the CWR resulting in a
room temperature CWR (RT-CWR) with complete conver-
sion of the aldehyde (Table 2, entries 1 and 2). To the best
of our knowledge this is the first time a CWR has been ach-
ieved at room temperature. Alkyl cyclic phosphine oxide 2
as predicted by the literature led to higher E selectivity and
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A Room Temperature Catalytic Wittig Reaction
COMMUNICATION
salt.[17b] 3) In the case of CWRs in which the reduction of
the phosphine oxide was not rate-limiting, the amount of
carboxylic acid additive should be decreased or reduction of
the aldehyde can occur.
Table 4. Room temperature substrate study employing 2 as the catalys-
t.[a]
Similarly the utilization of trioctylphosphine oxide 3 and
triphenylphosphine oxide 4 was equally effective (Table 5
and 6). Again heterocyclic aldehydes were well tolerated.
Noteworthy results involving catalysis by 3 include the syn-
theses of 22, 27, 29 and 32. Again the use of bromoacetoni-
trile resulted in good selectivity as 22 and 29 were produced
Table 5. Substrate study employing trioctylphosphine oxide 3 as the cata-
lyst.[a]
[a] For each product the compound number, isolated yield and E/Z ratio,
1
determined by H NMR spectroscopy of the unpurified reaction mixture,
are given. The reactions were performed in duplicate; see the Supporting
[a] For each product the compound number, isolated yield and E/Z ratio,
determined by H NMR spectroscopy of the unpurified reaction mixture,
are given. The reactions were performed in duplicate; see the Supporting
Information for details.
1
Information for details. [b] Only the
E diastereomer was isolated.
[c] When performed on a 19.1 mmol scale, the yield was 72% (4.46 g,
E/Z: 88:12).
During the course of the room temperature substrate
study various factors became apparent that would ensure ac-
ceptable yields. 1) The reduction of the phosphine oxide to
phosphine even at room temperature may not always be
rate-limiting. Indeed, for secondary organohalides the rest-
ing state of the catalyst was often found to be predominant-
ly phosphine and not oxide.[16] This points, in these cases, to
the formation of the phosphonium salt or the actual Wittig
reaction being rate-limiting. 2) At room temperature, the
solubility of the phosphonium salt often became a factor.
For example, in the syntheses of 12 and 18, both a phase-
transfer catalyst (tetrabutylammonium tetrafluoroborate)
and additional solvent were required to achieve optimal
yields.[16] During the standard RT-CWR the generation of
diisopropylethylammonium 4-nitrobenzoate is possible and
may aid in solubilization of the phosphonium salt.[17] Hence,
the addition of 4-nitrobenzoic acid may produce a dual
effect enhancing reduction of the phosphine oxide and
aiding in the solubility of the produced phosphonium
Table 6. Substrate study employing triphenylphosphine oxide 4 as the
catalyst.[a]
[a] For each product the compound number, isolated yield and E/Z ratio,
1
determined by H NMR spectroscopy of the unpurified reaction mixture,
are given. The reactions were performed in duplicate; see the Supporting
Information for details. [b] Only the E diastereomer was isolated.
Chem. Eur. J. 2013, 00, 0 – 0
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C. J. O’Brien et al.
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with a ratio of E/Z: 83:17 (Table 5). Significantly the synthe-
sis of 22 in our previous protocol proceeded with a selectivi-
ty of E/Z: 66:34.[7a] When triphenylphosphine oxide 4 was
employed as a catalyst with 4-(trifluoromethyl)phenylsilane
the same generality was maintained in terms of aldehydes
and organobromides (Table 6). Of note is that compound 27
was produced with total E diastereoselectivity employing 4,
whereas the use of 3 produced small amounts of the Z prod-
uct (compare 27 in Tables 5 and 6). Tables 4–6 taken as a
whole bring a significant degree of synthetic flexibility to
the CWR; reactions can be performed at room temperature
with cyclic phosphine oxides or at higher temperatures with
acyclic phosphine oxides.
In conclusion, the employment of 2.5–10 mol% of 4-nitro-
benzoic acid with phenylsilane led to the development of a
room temperature catalytic Wittig reaction. Furthermore,
these enhanced reduction conditions also facilitated the use
of acyclic phosphine oxides as catalysts. Indeed, triphenyl-
phosphine oxide for the first time is a viable olefination cat-
alyst. A series of di- and trisubstituted alkenes were pro-
duced in moderate to high yield with good to excellent E se-
lectivity, by utilizing heteroaryl, aryl and alkyl aldehydes
and organobromides. The RT-CWR protocol was also dem-
onstrated on scale, 4.46 g of 18 was produced (72% yield)
with 20 mol% loading of 2 (Table 4, footnote [b]). The uti-
lization of process-friendly solvents coupled with both room
temperature and high temperature conditions delivers the
synthetic flexibility that should promote wider adoption of
the methodology.
[9] If a catalyst loading of 10 mol% is employed with a maximum reac-
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ieve 100% yield. Therefore, a synthetically viable catalytic system
requires each cycle to be complete within 2.4 h.
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Acknowledgements
We thank Peakdale Molecular Ltd for the gift of heterocyclic aldehydes
and Dr. M. Feeney, Trinity College Dublin, for HRMS. Financial support
for this work was received from Dublin City University (DCU, Career
Start) and Enterprise Ireland (EI, grant no. CF/2011/1029).
[12] Whilst this manuscript was in preparation a similar enhancement in
silane reduction of acyclic phosphine oxides was reported by Y. Li,
L.-Q. Lu, S. Das, S. Pisiewicz, K. Junge, M. Beller, J. Am. Chem.
Soc. 2012, 134, 18325–18329. The results in this work were first pre-
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the 23rd August 2012. Details can be found at http://investigator.ias.-
tuwien.ac.at/index.shtml. Furthermore, in the synthesis of 11
(Table 4), 4-nitrobenzoic acid was found to be more effective than
bis(4-nitrophenyl)phosphonate and isolated yields of 11 with each
additive were 76 and 34%, respectively, after 12 h. This demon-
strates the difficulty in adopting an acid-catalyzed reduction strategy
into the CWR, thus achieving a high yield of alkene.
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Knight, M. A. Nagy, D. A. Perry, M. Stefaniak, Green Chem. 2008,
10, 31–36.
Keywords: alkenes · homogeneous catalysis · olefination ·
room temperature · Wittig reaction
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mary halides that the main 31P species were the phosphine oxide
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A Room Temperature Catalytic Wittig Reaction
COMMUNICATION
and phosphonium salt, which indicates a rapid reaction between the
phosphine and halide. For secondary halides, phosphine predominat-
ed, which indicates that formation of the phosphonium salt proceeds
slowly. See the Supporting Information for details. b) Phosphonium
bromides were poorly soluble in the reaction solvents. 31P NMR
spectroscopic experiments demonstrated that the utilization of a
phase-transfer catalyst improved solubility significantly.
and in acetone it is ~16. See: J. Jover, R. Bosque, J. Sales, QSAR
Comb. Sci. 2008, 27, 563–581 and S. D. Lepore, A. Khoram, D. C.
Bromfield, P. Cohn, V. Jairaj, M. A. Silvestri, J. Org. Chem. 2005, 70,
7443–7446; b) diisopropylethylammonium 4-nitrobenzoate was as
efficient as 4-nitrobenzoic acid, yet tetrabutylammonium benzoate
was ineffective. This indicates that the presence of an acidic proton
on iPr2NEt may be essential; studies are ongoing.
[17] a) The position of this equilibrium is unclear, the pKa of iPr2NEt
and 4-nitrobenzoic acid may be similar in EtOAc. The pKa of
iPr2NEt in DMSO is 8.5, for 4-nitrobenzoic acid in DMSO it is ~9,
Received: February 11, 2013
Published online: && &&, 0000
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C. J. O’Brien et al.
One ring no longer rules them all:
Homogeneous Catalysis
Employment of 2.5–10 mol% of 4-
nitrobenzoic acid with phenylsilane led
to the development of a room temper-
ature catalytic Wittig reaction (see
scheme). Moreover, these enhanced
reduction conditions also facilitated
the use of acyclic phosphine oxides as
catalysts for the first time. A series of
alkenes were produced in moderate to
high yield and selectivity.
C. J. OꢀBrien,* F. Lavigne, E. E. Coyle,
A. J. Holohan, B. J. Doonan &&&& — &&&&
Breaking the Ring through a Room
Temperature Catalytic Wittig Reaction
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