The Reactivity of Difluorocarbene with Hydroxylamines: Synthesis of Carbamoyl Fluorides

Article abstract of DOI:10.1002/adsc.201600308

Carbamoyl fluorides are formed in reactions of hydroxylamines with difluorocarbene generated from sodium bromodifluoroacetate as readily available and non-toxic carbene precursor. The process shows a high functional group tolerance, and the reaction path has been rationalized by computational calculations. (Figure presented.) .

Full text of DOI:10.1002/adsc.201600308

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DOI: 10.1002/adsc.201600308
Very Important Publication
The Reactivity of Difluorocarbene with Hydroxylamines:
Synthesis of Carbamoyl Fluorides
Hannah Baars,a Julien Engel,a Lucas Mertens,a Daniela Meister,a
and Carsten Bolma,*
a
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
Fax : (+49)-241-809-2391; e-mail: Carsten.Bolm@oc.rwth-aachen.de
Received: March 21, 2016; Revised: May 23, 2016; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600308.
Abstract: Carbamoyl fluorides are formed in reac-
tions of hydroxylamines with difluorocarbene gen-
erated from sodium bromodifluoroacetate as readi-
ly available and non-toxic carbene precursor. The
process shows a high functional group tolerance,
and the reaction path has been rationalized by com-
putational calculations.
ic trifluoromethylation of hydroxylamines by Togni
[Scheme 1, b)][10] attracted our attention, and we de-
cided to study the formation of analogous difluorome-
thylated products [Scheme 1, c)].
N,N-Dibenzylhydroxylamine (1a) was chosen as
representative substrate and subjected to typical di-
fluoromethyl etherification procedures (Table 1).
First, the conditions described by Segall[5a] were
tested, using diethyl bromodifluoromethanephospho-
nate (B) as the carbene precursor and potassium hy-
droxide as the base in a mixture of acetonitrile and
water. Indeed, after one hour of reaction time while
warming from ꢀ788C to room temperature the de-
sired product 2a was formed in 26% yield, as deter-
Keywords: carbenes; fluorine; reaction mechanism;
synthetic methods
The unique stability, reactivity and biological proper- mined by 19F NMR (Table 1, entry 1). Unfortunately
ties of organofluorine compounds has led to their however, isolation by column chromatography failed
widespread use in materials, pharmaceuticals and due to formation of a second, unexpected product
agrochemicals.[1] Thus, mild, selective and cost-effec- which could not be separated. This by-product was
tive fluorination strategies are of high interest. Di- identified as carbamic fluoride 3a.
fluorocarbene (CF2, A), as a versatile and reactive in-
Carbamoyl fluorides are interesting compounds in
termediate, offers excellent opportunities for intro- their own right. As such they have been applied as in-
ducing fluorine moieties into organic molecules.[2] Tra- secticides[11] and inhibitors of esterases.[12] Further-
ditionally, difluorocarbene is formed from ozone-de- more, they were used in syntheses of isocyanates[13]
pleting substances such as HCF2Cl and HCF2Br or
from hazardous reagents such as Me3SnCF3 and
CF3HgI.[2] During the last decades, many new and ef-
ficient difluorocarbene sources have been developed.
They were utilized in a variety of transformations in-
cluding trifluoromethylations,[3] difluoromethylations
[5]
of alkynes[4] and X H bonds (X=N, O, S), gem-di-
ꢀ
fluorocyclizations,[5d,f,6] gem-difluoroolefinations,[7] and
transition metal coordinations.[8] With these reactions,
a range of privileged functional motifs could be con-
structed including the difluoromethyl group which
proved to be bioisosteric to amines, hydroxides and
thiols with the ability to form lipophilic hydrogen
bonds.[9]
Intrigued by these reports [Scheme 1, a)] we won-
dered about other substrates to be difluoromethylat-
ed. In this context, the recently published electrophil- Scheme 1. Background and initial aim of this study.
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Table 1. Initial screening of typical difluoromethyl etherification procedures.[a]
Entry
Reagent (equiv.)
t [h]
T [8C]
Solvent
Base (equiv.)
Yield of 2a [%]
Yield of 3a [%]
1
2
3
4
B (2)
C (1)
C (0.33)
D (2)
1
3
1
1.5
ꢀ78 to r.t.
MeCN:H2O=1:1
MeCN
MeCN
KOH (20)
NaH (7.5)
Na2SO4 (2)
K2CO3 (2)
26[bj
0
0
0
25[b]
21
32
60
45
95
DMF
46
[a]
Performed on a 0.25 mmol scale with respect to N,N-dibenzylhydroxylamine (1a).
[b]
Determined by 19F NMR after column chromatography.
and N,N-dialkylaminosulfenyl carbamate-based insec-
ticides.[14] Usually, carbamoyl fluorides are prepared
from amines with fluorophosgene[11,13,15] or carbonic
fluoride chloride.[15,16] Another possibility is the reac-
tion of a fluoride source with carbamoyl chlorides,[17]
which are accessed from phosgene or triphosgene. All
these transformations involve highly toxic (gaseous)
reagents which makes their handling difficult. Hence,
the synthesis of carbamoyl fluorides via difluorocar-
benes offers an attractive alternative.
To our delight, when applying difluoro(fluorosulfo-
nyl)acetic acid (C) under the conditions reported by
Marcor,[18] carbamic fluoride 3a was selectively
formed, albeit only in 21% yield (Table 1, entry 2).
Applying the same reagent (C) under Wuꢁs condi-
tions,[5b] which involved performing the reaction at
458C instead of 608C and adding sodium sulfate in-
stead of sodium hydride (entry 3), raised the yield of
3a to 32%.[5b] With a combination of sodium bromodi-
fluoroacetate (D) and potassium carbonate in dime-
thylformamide at 958C[5c] 3a was obtained in 46%
yield (entry 4).
Table 2. Reaction optimization.[a]
Entry
VDMF [mL]
T [8C]
t [h]
Yield [%]
1[b]
2[b]
3
4
5
6
7
8
9
2
2
2
1
4
8
8
8
8
95
95
95
95
95
95
150
60
r.t.
1.5
3
46
44
44
34
56
67
51
57
43
1.5
1.5
1.5
1.5
1.5
1.5
1.5
[a]
Reaction conditions: N,N-dibenzylhydroxylamine (1a,
0.25 mmol) and BrCF2CO2Na (D, 0.50 mmol) in DMF.
Addition of K2CO3 (2 equiv.).
[b]
creased to 67% in a more diluted system (entry 6).
Considering the difficulties in the purification of 2a Although no defined side products were identified at
and having achieved an interesting result by obtaining this stage, the observed concentration effects were at-
3a from sodium bromodifluoroacetate (D), we decid- tributed to follow-up reactions between product and
ed to change direction and to focus our attention on starting material, which were less productive in dilute
the synthesis of the latter product type. The respective solution. Also the temperature affected the reaction
experiments are discussed herein. Moreover, compu- outcome (entries 7–9). Both higher and lower temper-
tational studies were performed with the goal to shine atures led to a decrease in yield of 3a. To our surprise,
light on the underlying mechanistic principles of the however, the product could be isolated at room tem-
unprecedented formation of carbamic fluoride 3a via perature, albeit in only moderate yield (43%,
difluorocarbene.
entry 9). Apparently, the decarboxylation of sodium
Initial optimization attempts to increase the yield bromodifluoroacetate to give difluorocarbene oc-
by extending the reaction time (Table 2, entry 2) or curred even at ambient temperature,[5c,19] but then the
by switching to another solvent (see the Supporting subsequent trapping of the carbene with 1a was insuf-
Information, Table S1) remained unsuccessful. Ad- ficient under these conditions.
vantageously, the base was not necessary for the for-
mation of the product (entry 3). Furthermore, the re- strate scope was investigated (Table 3). First, other
agent concentration played a crucial role (entries 4– symmetrical N,N-dibenzylhydroxylamines were
With the optimized conditions in hand, the sub-
6). While the use of less solvent led to a decrease in tested. ortho-Methyl- and meta-methoxy-substituted
the yield of 3a (34%; entry 4), the product amount in- derivatives 1b and 1c provided the corresponding
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Table 3. Synthesis of carbamoyl fluorides 3 from hydroxyl-
ACHTUNGTRENNUNG
amines 1 and sodium bromdifluoroacetate (D).[a]
relevant for the mechanistic interpretation of the data
because they revealed the requirement of a substrate
nitrogen with a good nucleophilicity, which was re-
duced in compounds 1o and 1p by electron lone pair
delocalization. Also methyl ether 1q did not react,
confirming the importance of the free OH group of
the hydroxylamines for the success of the product for-
mation.
Additional experiments demonstrated the synthetic
utility of the reaction products. An in situ functionali-
zation occurred in the reaction of ortho-hydroxy-sub-
stituted substrate 1r and dihydro-1,3-benzoxazin-2-
one 4 was obtained in 53% yield [Scheme 2, a)]. Pri-
[a]
[b]
Reaction conditions: hydroxylamine (1, 0.25 mmol),
BrCF2CO2Na (D, 0.50 mmol) in DMF (8 mL).
Determined by 19F NMR using trifluoroethanol as stan-
dard.
products in yields of 31% (for 3b) and 43% (for 3c),
respectively. Substrates 1d and 1e with halo substitu-
ents in para positions reacted better leading to yields
of 55% for 3d and 49% for 3e. Unsymmetrical benzyl-
methylcarbamic fluoride (3f) was isolated in only
Scheme 2. In situ functionalization and product derivatiza-
tion experiments.
14% yield, which we attributed to the high volatility mary hydroxylamine 1s underwent two sequential hy-
of 3f resulting in product loss during work-up. This drogen fluoride eliminations giving in situ isocyanate
hypothesis was confirmed by 19F NMR spectroscopy 5, which could be trapped with diethylamine to give
of the crude reaction mixture, which indicated the for- urea 6 [Scheme 2, b)]. Finally, carbamoyl fluoride 3a
mation of 3f in ca. 63% yield. Increasing the size of reacted with diethylamine and methanol in the pres-
the benzyl substituent of the hydroxylamine affected ence of DBU providing urea 7 and carbamate 8, re-
the reaction efficiency, and benzhydryl-substituted spectively [Scheme 2, c)].
product 3g was obtained in 44% yield. Various func-
To gain a better understanding of the reaction prin-
tional groups were tolerated as reflected by the good ciple, the mechanism was investigated with computa-
results (up to 52% yield) achieved with carbonylic hy- tional methods. N,N-Dibenzylhydroxylamine (1a) was
droxylamine derivatives leading to carbamic fluorides chosen as the model substrate for our study.
3h–k as products. Finally, cyclic N-hydroxytetrahy-
First, the generation of difluorocarbene (A) from
droisoquinolines were applied. These substrates, sodium bromodifluoroacetate (D) under formation of
which are of interest as they resemble natural alkaloid carbon dioxide and sodium bromide was studied.[19]
motifs, provided the corresponding products (3l–n) in Results of Hine suggested that the decomposition of
yields ranging from 46% to 63%.
the related sodium chlorodifluoroacetate occurred in
Attempts to convert hydroxylamines 1o or 1p bear- a single step from the corresponding anion.[20] Our
ing a carbonyl function in the a-position afforded DFT calculations on the decarboxylation process re-
only traces of products. These negative results were vealed a concerted reaction of bromodifluoroacetate
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was found to be disfavored (see the Supporting Infor-
mation for details).
The barrier of 21.0 kcalmolꢀ1 for the decarboxyla-
tion of D was rather high considering the fact that the
reaction also took place at room temperature
(Table 2, entry 9). Xiao and co-workers reported that,
contrary to prior postulations, difluorocarbene was
not the active species in the generation of difluorome-
thylphosphorane Wittig reagents from bromodifluoro-
AHCTUNGTRENNUNG
acetate (D) with phosphines.[7b] Instead, they de-
scribed a substrate-assisted decomposition of the re-
agent which decarboxylated only after addition to the
phosphine. Thus, we also questioned the involvement
of difluorocarbene (CF2, A) in our reaction, and in-
vestigated the nucleophilic attack of the substrate at
the reagent in analogy to the substrate-assisted path-
way of Xiao (Scheme 3, Path 1B). The attack of 1a at
D2 resulted in elimination of bromide and the forma-
tion of 9A (TS1a/9A). As indicated by IRC calculations,
Scheme 3. Formation of 9 from sodium bromodifluoroace-
tate (D) and N,N-dibenzylhydroxylamine (1a) (relative free
energies to D and 1a in kcalmolꢀ1).
(D) to difluorocarbene (A) (Scheme 3, Path 1A). The the reaction proceeded with a concerted proton trans-
barrier for this reaction (TSD2/A) was 21.0 kcalmolꢀ1. fer from the hydroxylamine to the carboxyl group of
The generation of A was slightly endergonic with the reagent. The relative free energy of TS1a/9A of this
a free energy difference of 3.7 kcalmolꢀ1.[21] Other tri- substrate-assisted
decomposition
pathway
was
haloacetates have been reported ꢀto decarboxylate to 22.0 kcalmolꢀ1 relative to D. Although this indicated
give trihalomethyl anions (CX3 ).[22] These anions that the formation of difluorocarbene was favored, it
could then either be protonated to the corresponding has to be noted that the energy difference between
haloform CX3H,[23] or they eliminated halide to form the transition states for both decomposition pathways
the corresponding dihalocarbene. In this respect, our (TSD2/A and TS1a/9A) was rather small (1.0 kcalmolꢀ1).
results remained inconclusive and we could not un- In any case, both pathways gave then rise to the same
equivocally determine whether the process involved zwitterionic structure 9. The transition state for the
difluorocarbene (A) aꢀnd bromide or a bromodifluoro- decarboxylation of 9A to 9 (TS9A/9) had a relative
methyl anion (BrCF2 , A2). We performed an IRC energy of 14.0 kcalmolꢀ1. In this step, the hydroxy
calculation of the corresponding transition state group was regenerated through a proton transfer
TSD2/A. The last calculated point on the reaction coor- from the carboxyl group as shown by IRC calcula-
dinate showed a bromide carbon distance of 2.55 ꢂ. tions. Alternatively, the addition of difluorocarbene
This was shorter than the corresponding distance in (A) to 1a, forming 9, was endergonic with a free
the optimized structure of A2 (2.64 ꢂ). However, the energy difference of 2.5 kcalmolꢀ1 to the separated
dissociation of A2 to A and bromide is driven by en- molecules 1a and A. A transition state for the reac-
tropy. Increasing the distance in A2 monotonically tion of 1a with A could not be obtained since the
raised the electronic energy of the structure until the electronic energy is strictly decreasing from the sepa-
energy of the separated fragments was reached (see rated molecules to 9.
the Supporting Information for details). Nevertheless,
Next, the formation of the carbamoyl fluorides
the Gibbs free energy of the dissociated difluorocar- (Scheme 4, Path 2A) was investigated. Migration of
bene was 7.1 kcalmolꢀ1 lower. Therefore, we conclud- the hydroxy group to the difluoromethylide moiety
ed that the elimination of bromide occurred at a cer- gave alcohol 10 (TS9/10A, Figure 1). This rearrange-
tain bromide–carbon distance. Moreover, A2 could ment step had a barrier of 16.6 kcalmolꢀ1 to 1a and
even be unstable at any bromide–carbon distance. was strongly exergonic with a free energy difference
Within the approximations of the computational of ꢀ84.7 kcalmolꢀ1 for 10 to 1a. After a conformation-
method it was not possible to finally clarify this issue. al rearrangement (TS10A/10B) with a low barrier, the
Regardless of the primary product of the decomposi- elimination of hydrogen fluoride resulted in the ex-
tion of reagent D, our results indicated that difluoro- perimentally observed carbamoyl fluoride 3a. The
carbene (A) could be formed, then becoming an transition state TS10B/3a had a free energy difference of
active species in the reaction with the hydroxyl- ꢀ69.0 kcalmolꢀ1 to 1a and 19.0 kcalmolꢀ1 to the inter-
A
mediate 10.
Experimentally, the formation of the carbamoyl flu-
sodium bromodifluoroacetate (D) with concerted for- orides was found to be favored over the etherification
mation of sodium bromide. However, this pathway when reagents C or D were used. Hence, the calculat-
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Scheme 4. Reaction pathway from N,N-dibenzylhydroxyl-
ACHTUNGTRENNUNGamine (1a) to carbamoyl fluoride 3a (Path 2A) and difluoro-
methyl ether 2a (Path 2B) (free energies to D and 1a in kcal
molꢀ1).
Figure 2. Transition state for the migration of the difluoro-
methyl group (TS11/2a); hydrogen atoms are omitted for
clarity.
Segall and co-workers proposed that the formation
of difluoromethyl ethers with B occurred through ad-
dition of difluorocarbene to the deprotonated hy-
droxy group.[5a] This pathway was not relevant for our
system since no strong base for the deprotonation was
present.
The described pathways rationalized the formation
of the carbamoyl fluorides instead of the expected di-
fluoromethyl ethers from hydroxylamines with
sodium bromodifluoroacetate (D). Nonetheless, they
could not account for the mixture of carbamoyl fluo-
rides and difluoromethyl ethers obtained with diethyl
Figure 1. Transition state for the migration of the hydroxy
group (TS9/10A); hydrogen atoms are omitted for clarity.
ed pathway to give the former products should be bromodifluoromethanephosponate (B). The selectivi-
lower in energy than the one leading to difluorometh- ty of this reaction might have been shifted due to the
yl ether 2a. In the calculated reaction pathway to- strong base or the complex solvent mixture.
wards 2a (Scheme 4, Path 2B) the zwitterionic inter-
In summary, we have investigated and rationalized
mediate 9 could isomerize through a proton transfer an unprecedented reactivity of difluorocarbenes with
step to give 11. In this structure the difluoromethyl hydroxylamines towards carbamoyl fluorides both ex-
group of the product 2a was already shaped. The perimentally and computationally. Preparatively, the
proton transfer step (TS9/11) had a barrier of only new method is interesting because it involves the use
11.8 kcalmolꢀ1 relative to 1a, which was lower than of readily accessible starting materials and the non-
the rearrangement from 9 to 10A. Furthermore, 11 toxic and cheap reagent D, which react rapidly under
was thermodynamically favored over 9, since the neg- experimentally straightforward conditions. Various
ative charge at the oxygen atom was more stable. hydroxylamines were applicable forming the products
Nevertheless, the migration of the difluoromethyl in moderate to good yields. Subsequent (in situ) prod-
group to the oxygen (TS11/2a, Figure 2) had a barrier uct derivatizations provide heterocycles, carbamates,
of 19.2 kcalmolꢀ1 compared to 1a. Hence, this step and ureas.
was disfavored over the rearrangement of 9 to 10A.
Furthermore, the conversion of 9 to 11 should be re-
versible. In contrast, the reaction to 10A was irreversi-
Experimental Section
ble, since the back-reaction from 10A had a barrier of
101.3 kcalmolꢀ1.
Computational Details
The intramolecular attack of the oxygen to the di-
fluoromethyl group in 11 and step-wise elimination of
hydrogen fluoride was found to be non-competitive to
All quantum chemical calculations were performed with the
Gaussian 09 suite[24] at the HPC facilities of the IT Center
Path 2A (see the Supporting Information for details). of RWTH Aachen University. Geometry optimizations were
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performed with the wB97XD long range corrected hybrid
density functional of Head–Gordon.[25] with Dunningꢁs cor-
relation consistent double-z basis set cc-pVDZ.[26] The con-
vergence criteria were increased using the keyword “tight”.
Numerical integrations were performed with the “ultrafine”
grid option of Gaussian 09. Single-point calculations were
done with the correlation consistent cc-pVTZ triple-z basis
set of Dunning and a polarizable continuum solvation
model (PCM) for N,N-dimethylformamide (DMF) as imple-
mented in Gaussian 09. Gibbs free energies were calculated
at a temperature of 298.15 K. A standard state correction
for a 1M ideal solution was added to the energy of each
structure. Minima and transition states were confirmed with
normal mode analysis. The transition states were connected
to the corresponding intermediates with IRC calculations
(see the Supporting Information for details on the IRC cal-
culations).
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General Procedure for the Synthesis of Carbamoyl
fluorides from Hydroxylamines
A solution of hydroxylamine 1 (0.25 mmol) and sodium bro-
modifluoroacetate (D, 98 mg, 0.50 mmol) in DMF (8 mL)
was stirred under argon at 958C for 90 min. Then, water
(10 mL) was added and the reaction mixture was extracted
with EtOAc (3ꢃ25 mL). The combined organic layers were
dried over Na2SO4, and the solvent was evaporated. The
product was purified by column chromatography.
Acknowledgements
[8] a) D. J. Harrison, G. M. Lee, M. C. Leclerc, I. Korob-
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This work was supported by the Deutsche Forschungsgemein-
schaft through the International Research Training Group
Seleca (IGRK 1628). We thank Prof. Dr. P. Kirsch (Merck
KGaA) for encouragement and helpful discussions.
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8 The Reactivity of Difluorocarbene with Hydroxylamines:
Synthesis of Carbamoyl Fluorides
Adv. Synth. Catal. 2016, 358, 1 – 8
Hannah Baars, Julien Engel, Lucas Mertens,
Daniela Meister, Carsten Bolm*
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