Direct Difluoromethylenation of Carbonyl Compounds by Using TMSCF3: The Right Conditions

Article abstract of DOI:10.1002/ejoc.201601038

A deoxygenative difluoromethylenation of carbonyl compounds has been developed by using readily available, inexpensive trifluoromethyltrimethylsilane, LiI, and PPh₃. The presence of the Li⁺ion prevents the unproductive exhaustion of trifluoromethyltrimethylsilane (TMSCF₃) by keeping the soluble free fluoride concentration in the reaction medium under control. The strategy of combining solvents to increase the reactivity and thereby reduce the reaction temperature and time is disclosed.

Full text of DOI:10.1002/ejoc.201601038

A Journal of
Accepted Article
Title: Direct Difluoromethylenation of Carbonyl Compounds Using TMSCF3: The
Right Conditions
Authors: Surya G. Prakash; Sankarganesh Krishnamoorthy; Jotheeswari Kothan-
daraman; Jacqueline Saldana
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201601038
Link to VoR: http://dx.doi.org/10.1002/ejoc.201601038
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COMMUNICATION
Direct Difluoromethylenation of Carbonyl Compounds Using
TMSCF3: The Right Conditions
Sankarganesh Krishnamoorthy, Jotheeswari Kothandaraman, Jacqueline Saldana and G. K. Surya
Prakash*[a]
Dedicated to Professor George A. Olah on the occasion of his 89th birthday
Abstract:
Using
readily
available,
LiI
inexpensive
and PPh3,
proton (pKa of CF3H = 26)[ 14 ] or react with other electrophiles
(Scheme 2). In addition, for every mole equivalent of
difluoromethylene formed, a mole equivalent of fluoride is produced;
and the presence of the silicophilic fluoride is known to accelerate
the formation of CF3 anion from TMSCF3, which generally result in
autocatalytic[ 15 ] or runaway reactions producing copious amount
CF3H and other undesired singlet difluoromethylene based products.
Such runaway reactions are exacerbated at the elevated
temperatures and therefore limit the higher reaction temperatures
that might be required to achieve some of the desirable chemical
transformations. Therefore, curtailing the amount of nascent fluoride
produced in the process of difluoromethylene formation will allow the
non-fluoride based nucleophiles such as iodide to react with
TMSCF3 at higher temperatures.
trifluoromethyltrimethylsilane
(TMSCF3),
deoxygenative difluoromethylenation of carbonyl compounds is
reported. The Li+ is proposed to prevent the unproductive exhaustion
of TMSCF3 by keeping the soluble free fluoride concentration in the
reaction medium under control. Furthermore, solvent combination
strategy to increase the reactivity and thereby reducing the reaction
temperature and time is disclosed.
The distinct electronic property and reactivity of 1,1-
difluoroalkenes make them invaluable synthetic intermediates
towards fluorinated[ 1 ] as well as non-fluorinated[ 2 ] synthetic
scaffolds. The C=CF2 has been shown to serve as a unique
functionality in rational drug design[3] as a bioisoster of C=O
group,[4] and therefore synthesis of difluoro (C=CF2) analogues
as bioactive C=O containing molecules has garnered significant
attention.[ 5 ] Though there are several approaches that use
various starting materials[6] and reagents[7] to synthesize 1,1-
difluoroalkenes, the direct deoxygenative difluoromethylenation
[8]
of carbonyl compounds via Wittig type processes
has been
deemed efficient as it employs readily available reagents.[9] The
reactive intermediate in these reactions, difluoromethylene
phosphonium ylide, can be generated with phosphine and the
singlet difluoromethylene. Though reagent derived from TMSCF3,
namely, TMSCF2Cl has been reported for such transformation,
the direct use of TMSCF3 has been reported to be unsuccessful
(Scheme 1).[ 10 ] Therefore, direct use of TMSCF3 will prove
superior in terms of safety, synthetic convenience, and cost. [11]
Further, Its preparation has been recently demonstrated from
abundant, non-ozone depleting, TeflonR by-product, CF3H.[12]
Scheme 2. Typical reaction pathways of TMSCF3.
Previously, we disclosed that the Li+ could be employed in
preventing such runaway reactions by controlling the amount of
soluble free nucleophilic fluoride present in the reaction
solution,[16] which led us to re-examine the conditions reported
by Hu and co-workers (Scheme 1).[10] Contrary to the reported
results, we observed >60% of 2a (Table 1, Entry 1 & 2). Further
optimization of the conditions to improve the yield with NaI
proved challenging. To test the effect of Li+, NaI was replaced
with LiI. As the LiI requires higher temperatures to activate
TMSCF3,
our
previously
developed
conditions,[16a]
LiI/diglyme/170 C, were chosen with PPh3 as an additional
reagent. The very first experiment carried out in the presence of
LiI/PPh3 produced 74% of 2a (Entry 3) and prolonging the
reaction time increased the formation of 2a to 81% (Entry 4).
When the reaction temperature was lowered to 110 C,
decrease in the reaction rate and yield were observed (Entry 5).
To reduce the reaction temperature and increase the reaction
rate, two strategies were considered, 1) employing electron rich
phosphines such as (Me2N)3P to increase the nucleophilicity of
ylide intermediate. However, our investigation at various
temperatures provided less than 15% of 2a (Entry 6-8), which
could be attributed to the competing reaction of the electron-rich
Scheme 1. Previously attempted direct difluoromethylenation with TMSCF3.[10]
In general, employing TMSCF3 poses challenges with
substrates containing fairly acidic protons or reactive electrophilic
functional groups such as carbonyls[13] as the reactive intermediates
(CF3 anion or the pentavalent silicon species) are prone to pick up a
[a]
S. Krishnamoorthy, J. Kothandaraman, J. Saldana and Prof. Dr. G.
K. S. Prakash
17
]
phosphine with the aldehyde.[
Further, use of
Loker Hydrocarbon Research Institute and
Department of Chemistry, University of Southern California,
University Park, Los Angeles, CA 90089-1661 (USA)
E-mail: gprakash@usc.edu
dibenzothiophene (Entry 9) or (PhO)3P (Entry 10) in place of the
PPh3 resulted in less than 8% of 2a. 2) The second strategy was
to study the effect of aprotic polar solvents such as DMF, as
these solvents are commonly used for nucleophilic substitution
reactions involving alkali-metal halides and well known for the
Supporting information for this article is given via a link at the end of
the document.
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European Journal of Organic Chemistry
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COMMUNICATION
activation of silicon centers.[18] Although, TMSCF3 reacted at
room temperature in DMF with LiI, only 10% of the desired
product 2a was obtained (Entry 11) along with 34% of
nucleophilic CF3 addition product. Further reactions were
investigated in solvent systems comprised of DMF and various
less polar solvents (THF, CH3CN, dioxane, diglyme, benzene
and toluene) in different ratios (Entry 12-17). 8% DMF in dioxane
and 16% DMF in toluene were found to be the optimum ratio for
the reactions at 120 C. Further optimization of reagents was
carried out in 8% DMF/dioxane to obtain the conditions
described in Table 2.
heterocyclic aldehydes investigated, 31% of 2p was obtained
with indole-2-carboxaldehyde, whereas only traces of 2q was
detected with indole-3-carboxaldehyde and no product was
observed with pyridine-3-carboxaldehyde. The ,-unsaturated
carbonyls like cinnamaldehyde and 4’-chlorochalcone underwent
reaction to provide the difluoroalkenes 2r (54%) and 2s (24%);
in these cases no CF3 addition to carbonyl groups or
cyclopropanation of double bonds was seen. Under the present
conditions, fluorenone produced traces of 2t, whereas
benzophenone yielded 9% of 2u. When the enolizable 4-
bromoacetophenone was investigated, only 24% of 2v was
observed.
Table 1. Reaction conditions screening.[a]
Table 2. Substrate scope of aromatic aldehydes and ketones (Condition A).[a]
CHO
PPh3 (3.0 equiv)
Conditions
CF2
+
TMSCF3
(2.5 equiv)
2a
Entry
[c]1
[c]2
3
Solvent
THF
T C
70
t (h)
10
10
1
MX (equiv)
NaI (0.6)
NaI (6)
Conv (%)[b]
64
69
74
81
47
15
10
15
8
THF
110
170
170
110
70
Diglyme
Diglyme
Diglyme
Diglyme
Diglyme
Diglyme
Diglyme
Diglyme
DMF
LiI (2.0)
LiI (2.0)
LiI (2.0)
LiI (2.0)
LiI (2.0)
LiI (2.0)
LiI (2.0)
LiI (2.0)
LiI (2.0)
LiI (2.0)
LiI (2.0)
LiI (2.0)
LiI (2.0)
LiI (2.0)
LiI (2.0)
4
3
5
37
24
7
[d]6
[d]7
[d]8
[e]9
[f]10
11
12
13
14
15
16
17
110
170
170
170
RT
1
3
3
7
20
24
24
0.5
24
24
15
10
35
77
74
83
78
83
5% DMF/THF
5% DMF/THF
70
110
170
120
120
120
5% DMF/Diglyme
8% DMF/dioxane
8% DMF/CH3CN
16% DMF/Toluene
[a] Reactions were carried out on 0.25 mmol scale with 2.5 mL solvent.
Isolated yield is presented without parenthesis. Conversions in parenthesis
were determined by 19F NMR using C6F6 as an internal standard.
[a] Reactions were carried out on 0.25 mmol scale with 2.5 mL of solvent. [b]
Conversions were determined by 19F NMR using C6F6 as an internal standard.
[c] 3.0 equiv TMSCF3 was used. [d] (Me2N)3P (2.0 equiv) replaced PPh3. [e]
dibenzothiophene (3.0 equiv) replaced PPh3. [f] (PhO)3P (3.0 equiv) replaced
PPh3.
We surmised that the enolization and consequent side
reactions are pronounced at elevated temperatures and
therefore milder conditions might be needed for sensitive
functional groups containing aldehydes and ketones. Thus, the
solvent combination strategy to lower the reaction temperature
was further explored. As we discussed earlier, the singlet
difluoromethylene can be generated with the right combination
of solvent system at various temperatures. Therefore, various
ratios of DMF/THF and DMF/toluene were investigated with 4-
bromoacetophenone as a model substrate to carry out the
reaction around the boiling point of TMSCF3, to avoid TMSCF3
staying in vapour phase in the reaction vessel’s headspace,
30% DMF in toluene or 20% DMF in THF appeared to have
similar reactivity in terms of unreacted TMSCF3. However, 30%
DMF in toluene seemed to produce higher yield of the desired
product. Hence, DMF/toluene combination was chosen for
further optimization. However, the reaction at room temperature
The scope of the optimized conditions on several aromatic
aldehydes was investigated (Table 2). The simple polycyclic
aromatic aldehydes provided greater than 80% yield (2a-2d).
Substrates with electron-donating substituents such as -OMe, -
OCH2Ph and -Ph yielded greater than 60% of the corresponding
1,1-difluoroalkenes (2e-2g). Typically amino groups are
sensitive functional groups for reaction with TMSCF3. However,
under the present conditions, the N,N-dimethylamino
benzaldehyde underwent reaction to give 30% of 2h. Excellent
yields of products, 2i-2l, were obtained with halogen containing
aldehydes. The substrates with electron-withdrawing groups
such as -CN, -NO2 and –CF3 groups also furnished good
product yields (2m-2o). Among the nitrogen containing
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European Journal of Organic Chemistry
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proceeded rather slowly. Therefore, reactions at various
temperatures (45, 55, 65, & 75 C) were investigated, and 45 C
found to be the optimum temperature with 84% conversion to 2v
over 40 hours (Table 3). Further, reducing the amount of PPh3 or
LiI decreased the reaction rate.
phenyl succinimides and the simple aromatic carboxylic ester,
ethyl benzoate. When benzophenone was investigated under
the present milder conditions (B), 21% of 2u was formed. To
avoid steric crowding, which may be an inhibiting factor in the
formation of oxaphosphatane intermediate; the tributylphosphine
(cone angle () = 132) was employed instead of PPh3 (cone
angle () = 145).[19] Consequently, 10% of the expected product
along with the 38% of the TMS protected intermediate 4 was
observed in NMR analyses (Scheme 3; also see SI).20 One can
speculate that the oxaphosphatane formation is hindered and
therefore the betaine picks up a TMS group leading to the
formation of 4. Our attempts to increase the conversion by
increasing the temperature resulted in little improvement in the
yield. For instance, only 17% 2u was obtained at 75 C. No
product was observed when dibenzothiophene, diphenylsulfide
and tetrahydrothiopyran were employed in place of (n-Bu)3P.
Scalability and ease of the experiments were also demonstrated
on the bench top on a gram scale (20 mmol) using 4-
bromoacetophenone to obtain 76% isolated yield (3.46 g) of 2v
(see SI).21
Table 3. Substrate scope of a variety of aldehydes and ketones (Condition
B).[a]
Scheme 3. Difluoromethylenation of benzophenone. Conversions in
parentheses were determined by 19F NMR using C6F6 as an internal standard.
Motivated by the fact that the adamantyl skeleton, referred
in medicinal chemistry as a lipophilic-bullet motif for its compact
nature, found as a key structure in seven approved drugs in the
[a] Reactions were carried out on 0.25 mmol scale with 2.5 mL solvent.
Isolated yield is presented without parenthesis. Conversions in parenthesis
were determined by 19F NMR using C6F6 as an internal standard. [b] Light was
excluded.
22
]
market,[
difluoromethylenation of 2-adamantanone was
investigated. Under the conditions A (Table 2) and B (Table 3),
the 2-admantanone failed to react. Interestingly, when (n-Bu)3P
was employed, 67% 5 was obtained (Scheme 4). However, the
product was volatile, therefore benzene was employed as a co-
solvent for its easy separation.
With milder optimized conditions, several enolizable and
sensitive group containing carbonyl compounds were studied
(Table 3). Propiophenone reacted moderately well to provide 3a
(43%), whereas the cyclic aryl alkyl ketones, indanone and -
tetralone, furnished 3b and 3c, in moderate and poor yields,
respectively.
Cyclic
alkyl
ketones
such
as
4-tert-
butylcyclohexanone and 5α-cholestan-3-one yielded greater
than 50% products (3d & 3e). However, the open chain ketone,
5-nonanone, performed poorly to give 16% of 3f. Aliphatic
enolizable aldehydes such as 2-phenylpropanal and 3-
phenylpropanal also reacted under these conditions, producing
3g (24%) and 3h (54%), respectively. Non-enolizable
cinnamaldehyde yielded 54% of 2r. The difluoromethylene
analogue of polyene containing retinal (3j) was obtained in 56%
isolated yield. The poorly performing aromatic aldehydes (Table
2) at 120 C, namely, 4-(dimethylamino)benzaldehyde, indole-2-
carboxaldehyde and indole-3-carboxaldehyde performed well
under these conditions to provide 2h (60%), 2p (50%) and 2q
(65%) products, accordingly. However, no product was obtained
in the case of pyridine-3-carboxaldehyde. Only, 25% of 2m was
obtained with 4-cyanobenzaldehyde. Furthermore, no desired
product was observed in the reactions with N-methyl and N-
Scheme 4. Difluoromethylenation of 2-adamantanone. Conversions in
parentheses were determined by 19F NMR using C6F6 as an internal standard.
[a] isolated yield.
In the control experiments carried out under the conditions A
and
B
with 2-napthaldehyde and 4-bromoacetophenone,
respectively, in the absence of DMF or LiI or PPh3, no desired
product was observed. Similarly, when the LiI was replaced with
Ph3PO or LiF, the reactions failed to produce product. In all
these cases, majority of the TMSCF3 remained unreacted.
Though the LiF failed to react with TMSCF3 under the reaction
conditions, TMSF was observed in all the reactions, which is
likely formed by the reaction of the in situ formed, more reactive
TMSI or the [Ph3POTMS]+ intermediates. Consequently, the
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European Journal of Organic Chemistry
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COMMUNICATION
Zreika, J. Med. Chem. 1985, 28, 186; c) B. A. Madden, G. D.
Prestwich, Bioorganic Med. Chem. Lett. 1997, 7, 309.
reactions should only require catalytic amount of LiI. When
catalytic amount of LiI (10 mol%) was employed under the
conditions A with 2-napthaldehyde, 68% of the desired alkene
(2c) was obtained. However, prolonging the reaction time did not
improve the product formation. Furthermore, the TMSI produced
in the reaction mixture could be consumed by reacting with the
solvents. 23 Therefore, it is safe to say that the Li+ lowers
reactivity of fluoride such that it only reacts with more Lewis
acidic silicon center before it reacts with TMSCF3. In the
experiments carried out with 2-napthaldehyde in the presence of
1,1-diphenylethylene, the difluoromethylenation of carbonyl
prevailed over the cyclopropanation of the alkene—traces of
gem-difluorocyclopropane. On the other hand, in the absence of
2-napthaldehyde and PPh3, >30% of such product was observed.
Based on the above observations and control experiments, the
following mechanism was proposed (Scheme 5).
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PPh3
CF2
R'
O
CF2
O
LiI
+
Ph3PCF2
+
CF2
+ Ph3PO
Me3SiCF3
PPh3
R
R'
R
R'
R
Scheme 5. Proposed mechanism.
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In conclusion, this work emphasizes the effect of Li+ in the
singlet difluoromethylene generation and prevention of
undesired decomposition of TMSCF3. Furthermore, by finding
the right conditions to activate TMSCF3 in the presence of
phosphines at various temperatures (RT to 170 C), we have
achieved a practical and versatile one-pot procedure for the
synthesis of a series of functionalized gem-difluoroalkenes,
including difluoro analogs of biologically active compounds, from
aldehydes and ketones. The work also demonstrates that the
mixed solvent system can be critical to achieve controlled
depletion of TMSCF3. We believe that the results presented in
this paper will, in addition to providing access to interesting gem-
difluoroalkenes, propel the researchers to discover useful direct
difluoromethylene transfer methods using the readily available
Ruppert-Prakash reagent.
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Acknowledgements
Financial Support from the Loker Hydrocarbon Research
Institute is gratefully acknowledged.
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Keywords: gem-Difluoroolefins • Carbonyls • LiI •
Triphenylphosphine • Ruppert-Prakash reagent
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COMMUNICATION
COMMUNICATION
10.1002/ejoc.201601038
Sankarganesh Krishnamoorthy,
Jotheeswari Kothandaraman, Jacqueline
Saldana and G. K. Surya Prakash*
Page No. – Page No.
Direct Difluoromethylenation of
Carbonyl Compounds Using TMSCF3:
The Right Conditions
What can Li+ do? When Me3SiCF3 is reacted with LiI for the formation of singlet
difluoromethylene, LiF formed is less soluble in the reaction medium allowing
controlled depletion of Me3SiCF3. Such an understanding has offered us the right
conditions for the direct difluoromethylenation of carbonyl compounds using
TMSCF3 with phosphines at various temperatures in a Wittig type reaction.
KEY TOPIC: gem-Difluoroolefin Synthesis
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European Journal of Organic Chemistry
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648; c) J. Zhang, C. Xu, W. Wu, S. Cao, Chem. Eur. J. 2016. DOI: 10.1002/chem.201601483. d) R. T. Thornbury, F. D. Toste, Angew. Chem. Int. Ed. 2016,
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