Highly regioselective synthesis of gem-difluoroallenes through magnesium organocuprate SN2′ substitution

Article abstract of DOI:10.1021/ol052816g

The reaction of gem-difluoropropargyl electrophiles with Grignard reagents is complicated by the inherent difficulty of executing nucleophilic substitutions on a CF₂ group, and the facile formation of carbenoid intermediates arising from α-elimination of fluoride. In the presence of an excess amount of a copper salt, a Grignard reagent reacts with gem-difluoropropargyl bromide via an S_N2′ mechanism to produce gem-difluoroallene in high yield. If desired, the resulting difluoroallene can undergo a second nucleophilic attack on the CF₂ terminus to yield a trisubstituted monofluoroallene through an addition-elimination mechanism.

Full text of DOI:10.1021/ol052816g

ORGANIC
LETTERS
2006
Vol. 8, No. 3
479-482
Highly Regioselective Synthesis of
gem-Difluoroallenes through Magnesium
Organocuprate SN2′ Substitution
Masayuki Mae, Jiyoung A. Hong, Bo Xu, and Gerald B. Hammond*
Department of Chemistry, UniVersity of LouisVille, LouisVille, Kentucky 40292
gb.hammond@louisVille.edu
Received November 21, 2005
ABSTRACT
The reaction of gem-difluoropropargyl electrophiles with Grignard reagents is complicated by the inherent difficulty of executing nucleophilic
substitutions on a CF2 group, and the facile formation of carbenoid intermediates arising from -elimination of fluoride. In the presence of an
excess amount of a copper salt, a Grignard reagent reacts with gem-difluoropropargyl bromide via an SN2 mechanism to produce gem-
difluoroallene in high yield. If desired, the resulting difluoroallene can undergo a second nucleophilic attack on the CF2 terminus to yield a
trisubstituted monofluoroallene through an addition elimination mechanism.
r
′
−
The selective substitution of hydrogen by fluorine is a
valuable strategy that has made available fluoroorganic
compounds with distinctive physicochemical and therapeutic
properties.1 Conceptually, the substitution of one or two
fluorines on the terminal carbon of an allene moiety could
lead to the discovery of novel nucleophilic, electrophilic, or
cyclization reactions, en route to structural diverse targets
with potential biological significance.2 Whereas allenes are
ubiquitous in organic chemistry, both as intermediates and
targets,3 less than a handful of fluorinated allene structures
have been published.4 Our interest in studying the effects of
fluorine on the chemistry of alkynes led us to the discovery
of an indium-mediated SE2′ conversion of gem-difluoropro-
pargyl bromide 1 to allene 3 (Scheme 1).5 If the electrophile
Scheme 1. Nucleophilic and Electrophilic Substitutions of 1
(1) For the most recent compilation of background references see: Kirsch,
P. Modern Fluoroorganic Chemistry; Wiley-VCH Verlag GmbH & Co.
KGaA: Weinheim, Germany, 2004.
(2) Shen, Q.; Hammond, G. B. J. Am. Chem. Soc. 2002, 124, 6534-
6535.
(3) For recent comprehensive coverage see: (a) Ma, S. Chem. ReV. 2005,
105, 2829-2871. (b) Modern Allene Chemistry; Krause, N., Hashmi, S.,
Eds.; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2004;
Vols. 1 and 2. (c) Hashmi, A. S. K. Angew. Chem., Int. Ed. 2000, 39, 3590-
3593.
(4) Hammond, G. B. In Fluorine-Containing Synthons, Soloshonok, V.
A., Ed.; ACS Symp. Ser. No. 911; Oxford University Press/American
Chemical Society: Washington, DC, 2005; Chapter 10, pp 204-217.
was a leaving group (i.e., E ) Br in 3), it reacts with
nucleophiles in an SN2′ fashion to produce 46 thus overcom-
(5) Wang, Z. G.; Hammond, G. B. J. Org. Chem. 2000, 65, 6547-6552.
(6) Xu, B; Hammond, G. B. Angew. Chem., Int. Ed. 2005, 44, 7404-
7407.
10.1021/ol052816g CCC: $33.50
© 2006 American Chemical Society
Published on Web 01/04/2006

ing the intrinsic barrier of RCF2Br toward SN2 substitutions.7
In principle, a synthetically attractive approach to the
nucleophilically substituted difluoroallene 2 is the copper-
mediated SN2′displacement of bromide from 1sthe only
readily available difluoropropargyl electrophile.8 Although
this type of reaction has been utilized in the synthesis of
allenes,3b its application to gem-difluoro systems is severely
impaired because of the facile loss of fluorine through
R-elimination, which may lead to carbenoid intermediates
and complex mixtures.9 We are now pleased to report a
highly regioselective synthesis of difluoroallene 2 from
difluoropropargyl 1, employing an excess amount of a
Grignard reagent and Cu(I) salt.
This difference in charge density is caused by the strong
electron withdrawing effect of two fluorine atoms on the C1-
carbon. If 2b was synthesized from 1b by using an SN2′
displacement, its CF2 terminus would undergo a competitive
nucleophilic attacksdriven by an energetically favorable
addition-elimination process (â-elimination of fluoride
ion)11syielding complicated mixtures of products (see also
Scheme 2).
Table 1 summarizes the results of our SN2′ optimization
study in the reaction between a Grignard nucleophile
(EtMgBr) and difluoropropargyl bromides 1c or 1d. Loss
of fluorine was observed in the absence of a copper source,
most likely via a bromine-magnesium exchange, leading
to a carbenoid intermediate that undergoes two succesive
R-eliminations of F- (Table 1, entry 1). The combination of
Ab initio calculations of NBO (natural bond order)10
charge densities in propargyl bromide 5 vis-a`-vis its fluori-
nated analogue 1 (Figure 1) demonstrate why SN2′ substitu-
Table 1. Optimization of the Synthesis of Difluoroallene 2
temp,
equiv of
EtMgBr CuX (equiv) (°C, min) (°C, h)
incubationa time
2
(%)b
entry
1
1
2
3
4
5
6
7
8
9
1c
1c
1c
1c
1c
1c
1c
1d
1d
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
1.0
none
-40, 1
-40, 1
-78, 1
-15, 5
+20, 5
-15, 5
-15, 5
-15, 5
-60, 30
-40, 3
-40, 3
-78, 1 NR
-78, 1 81 (70)c
-78, 1 14
CuCl (1.1)
CuCl (4.0)
CuCl (4.0)
CuCl (4.0)
CuBr (4.0)
CuCN (4.0)
CuCl (4.0)
CuBr (2.0)
LiBr (2.0)
CuBr (2.0)
LiBr (2.0)
CuBr (2.0)
LiBr (2.0)
CuBr (2.0)
S(Me)2 (2.0)
CuBr (2.0)
S(Me)2 (2.0)
8
-78, 1 38
-78, 1 NR
-78, 1 51d
-60, 2 52
10
11
12
13
1d
1d
1d
1c
1.5
1.7
1.7
1.7
-60, 30
-60, 30
-60, 30
-60, 30
-60, 2 82
Figure 1. Ab initio calculation of gem-difluoropropargyl bromides
and their nonfluorinated counterparts. Numbers refer to NBO
(natural bond order) charge densities.
-60, 1 89
-60, 1 94 (91)c
-60, 1 80
tion is problematic in the fluorinated model. Electron
densities on the C1- and C3-carbons of 5a and 5b indicate
that the C3-carbon in both species is significantly more
electrophilic than the C1-carbon and therefore prone to
undergo an SN2′ attack. Conversely, the charge densities on
the C1- and C3-carbons in gem-difluopropargyl bromides
1a or 1b reveal that both C1- and C3-carbons are electro-
philic. To complicate matters further, the C1-carbon of
difluoroallene 2b has a positive charge density, whereas its
nonfluorinated counterpart 6 does not (+0.337 vs -0.875).
a Reactions were conducted in 1 mmol scale. A rbf was charged with
the copper salt and THF and cooled to the temperature indicated, after which
the Grignard reagent was introduced and the solution was stirred for an
indicated period of time. Substrate was introduced at the end of the
incubation time. b Yield was determined by 19F NMR, using R,R,R-
trifluorotoluene as an internal standard. c Isolated yield. d Major byproduct
was monofluoro allene 7a:
(7) Chambers, R. D. Fluorine in Organic Chemistry; Blackwell Publish-
ing Ltd./CRC Press: Boca Raton, FL, 2004; p 123.
(8) Xu, B.; Mae, M.; Hong, J. A.; Li, Y.; Hammond, G. B. Synthesis. In
press.
(9) Pohmakotr, M.; Ieawsuwan, W.; Tuchinda, P.; Kongsaeree, P.;
Prabpai, S.; Reutrakul, V. Org. Lett. 2004, 6, 4547-4550.
(10) Computational analysis was carried out with Gaussian 03, Revision
C.02 at the B3LYP/6-311+g(3d) level of theory. Frisch, M. J., et al., see
Supporting Information.
CuCl and EtMgBr yields the desired product 2c in low yield
(8%, Table 1, entry 2). A purple color in the solution of the
Grignard reagent and the copper salt signaled the formation
(11) For synthetic applications that take advantage of fluoride elimination
see: Ichikawa, J.; Wada, Y.; Fujiwara, M.; Sakoda, K. Synthesis 2002,
1917-1936.
480
Org. Lett., Vol. 8, No. 3, 2006

of the magnesium organocuprate complex (incubation).
Increasing the temperature during the incubation, and the
amount of copper(I), improved the yield of 2c notably (Table
1, entry 4). Incubation at -78 °C or room temperature has
a deleterious effect (Table 1, entries 3 and 5). Among the
different copper salts screened (Table 1, entries 4, 6, and 7),
the best yield of 2c (R ) phenyl) was recorded with CuCl;
but when R ) n-hexyl, the yield of 2d was only 51% (Table
1, entry 8). Copper salts soluble in THF, such as CuBr‚LiBr
and CuBr‚S(Me)2, yielded better results (Table 1, entries
9-13). The best results were obtained with 2 equiv of CuBr‚
S(Me)2 and 1.7 equiv of the Grignard reagent (method A)
(Table 1, entries 12 and 13).
Table 2. Synthesis of Substituted gem-difluoroallenes
With optimized reaction conditions in hand, we investi-
gated the scope of the reaction (Table 2). Method A or B
(CuCl, 4.0 equiv; R′MgBr, 2.2 equiv) gave very good to
excellent yields of 2a-f (Table 2, entries 1-7). Method A
failed with 1,3-dioxolan-2-ylmethylmagnesium bromide (Table
2, entry 8). This was attributed to a stabilizing complexation
of the copper intermediate with the oxygen atoms of the
dioxolane moiety. To our satisfaction, Method B overcame
this problem, producing 2g and 2h (Table 2, entries 9 and
10) in good yields. With benzyloxypropylmagnesium bro-
mide, the major product obtained was monofluoroallene 7b
(62% yield) (Table 2, entry 11). A bulkier substitutent on
the C3-carbon reduced the efficiency of the SN2′ attack
(Table 2, entry 12).
Difluoroarylallenes are highly unstable. Of all the aryl-
containing substrates screened, only phenyl difluoroallene
2c could be isolated by using a refrigerated column. Its
homologue 2i decomposed during purification (Table 2, entry
13). On the other hand, alkyl- and silyl-substituted difluo-
roallenes can be chromatographed at room temperature.
Decomposition with loss of fluorine was observed if the
product was stored at ambient temperatures for 24 h. At 0
°C, these difluoroallenes could be stored neat for a month
without noticeable decomposition. Electron-donating (p-
OMe, o-Me) or -withdrawing (p-CF3) aryl substitutents led
to highly unstable arylallenes.12
Scheme 2 illustrates a plausible mechanism for the copper-
mediated SN2′ substitution reaction. The initially formed
Scheme 2. Proposed Mechanism for the Formation of
Difluoroallene 2 and Monofluoroallene 7
a Method A: CuBr‚S(Me)2 (2.0 equiv) and Grignard reagent (1.7
equiv) were used. After the incubation time (30 min, -60 °C), the substrate
was syringed in. b Method B: CuCl (4.0 equiv) and Grignard reagent (2.2
equiv) were used. After the incubation (10 min, ca. -20 °C), the mixture
was cooled to -78 °C and the substrate was syringed in. c Isolated yield.
d Yield in parentheses was determined by 19F NMR, using R,R,R-
trifluorotoluene as the internal standard. e Cold (-15 °C) jacketed column
chromatography was used in the isolation. f Using CuCN (2.2 equiv)/
HexMgBr (2.2 equiv), the 19F NMR yield was only 58%. g Difluoroallene
was obtained as the minor product (33%). h Product decomposed upon
purification.
Org. Lett., Vol. 8, No. 3, 2006
481

copper intermediate reacted at the C3-carbon of difluoro-
propargyl bromide 1 in an SN2′ fashion, with elimination of
bromide. The interaction of a copper-centered d-orbital with
σ and π* orbitals of the substrate led to the formation of a
σ-copper(III) species,3b which undergoes a reductive elimina-
tion to furnish the nucleophilically substituted difluoroallene
2. If the reaction conditions are not properly controlled, a
second nucleophilic attack by the cuprate complex produces
monofluoroallene 7.
7b, and 7c were significantly more stable than their diflu-
orinated counterparts.
In summary, disubstituted gem-difluoroallenes have been
synthesized from their difluoropropargyl bromide precursors
in good to excellent yields, using a magnesium organocuprate
intermediate. Aryl substitution destabilizes difluoroallenes.
Difluoroallenes can react again with a magnesium organo-
cuprate to give trisubstituted monofluoroallenes. Synthetic
applications from these reactions are ongoing in our labora-
tory.
Experimental evidence that supports the formation of 7
from 2 is shown in eq 1; the trisubstituted monofluoroallene
Acknowledgment. The authors are grateful to the Na-
tional Science Foundation (CHE-0513483) for its financial
support and to the University of Kentucky for use of its
supercomputing facility.
Supporting Information Available: Experimental pro-
cedures and analytical or spectroscopic data for compounds
1a-d, 2a-h, 7b,c. This material is available free of charge
via the Internet at http://pubs.acs.org.
7c was obtained in 63% (unoptimized yield), using similar
reaction conditions to those employed for the synthesis of
the parent material 2h. The ease of formation of monoflu-
oroallene 7 could prove advantageous if one seeks to prepare
a trisubstituted fluoroallene. Trisubstituted monofluoroallenes
OL052816G
(12) Using method A and HexMgBr the 19F NMR yields were as
follows: 38% (R ) p-MeC6H4); 34% (R ) p-MeOC6H4); 37% (R )
p-CF3C6H4).
482
Org. Lett., Vol. 8, No. 3, 2006