Stereospecific Electrophilic Fluorination of Alkylcarbastannatrane Reagents

Article abstract of DOI:10.1002/anie.201704672

We report the use of isolable primary and secondary alkylcarbastannatrane nucleophiles in site-specific fluorination reactions. These reactions occur without the need for transition metal catalysis or in situ activation of the nucleophile. In the absence of the carbastannatrane backbone, alkyltin nucleophiles exhibit no activity towards fluorination. When enantioenriched alkylcarbastannatranes are employed, fluorination occurs predominately via a stereoinvertive mechanism to generate highly enantioenriched alkyl fluoride compounds. These conditions can also be extended to stereospecific chlorination, bromination, and iodination reactions.

Full text of DOI:10.1002/anie.201704672

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Stereospecific Electrophilic Fluorination of Alkylcarbastannatrane
Reagents
Authors: Xinghua Ma, Mohamed Diane, Glenn Ralph, Christine Chen,
and Mark R Biscoe
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201704672
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10.1002/anie.201704672
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Stereospecific Electrophilic Fluorination of Alkylcarbastanna-
trane Reagents
Xinghua Ma,[a,b] Mohamed Diane,[a] Glenn Ralph,[a,b] Christine Chen,[a] and Mark R. Biscoe*[a,b]
Abstract: We report the use of isolable primary and secondary
towards the preparation of enantiomerically enriched alkyl
fluoride compounds, which could enable direct, late-stage
access to fluorinated compounds that are inaccessible using
the aforementioned processes. Because chiral secondary
alkylcarbastannatrane nucleophiles in site-specific fluorination
reactions. These reactions occur without the need for transition
metal catalysis or in situ activation of the nucleophile. In the
absence of the carbastannatrane backbone, alkyltin nucleophiles
alkylboron and alkyltin compounds exhibit high
exhibit no activity towards fluorination. When enantioenriched
configurational stability, enantioenriched alkylboron and
alkylcarbastannatranes
are
employed,
fluorination
occurs
alkyltin compounds are ideal candidates for use in
stereospecific fluorination reactions. Aggarwal has nicely
demonstrated the power of this approach using phenyl
predominately via a stereoinvertive mechanism to generate highly
enantioenriched alkyl fluoride compounds. These conditions can
also be extended to stereospecific chlorination, bromination, and
iodination reactions.
lithium-activated,
enantioenriched
alkylboronate
nucleophiles in stereospecific electrophilic substitution
reactions with Selectfluor II (2) (Scheme 1b).9,10 The use of
alkyltin reagents has not been previously reported in this
capacity, yet may offer important synthetic advantages over
other methods.
Incorporation of carbon-fluorine bonds into drug
candidates has been shown to improve pharmacological
properties such as metabolic stability, bioavailability, and
solubility compared to their non-fluorinated analogs.1 Rapid,
late-stage incorporation of 18F into organic molecules also
enables the preparation of new radiochemical probes for
positron emission tomography (PET) imaging.2 Therefore,
efficient methods by which to install C–F bonds rapidly and
reliably are of great synthetic importance.
a) Li (2014)8
R2
R1
R2
AgNO3 (20 mol %)
Selectfluor I (1), TFA
PinB
F
R1
CH2Cl2/H2O, 50 ºC, 8 h
racemic
b) Aggarwal (2015)9
Selectfluor II (2)
Over the past few years, significant advances have been
made in the preparation of aryl fluorides using electrophilic
and nucleophilic fluorine sources.3 However, fewer methods
have been reported that enable the incorporation of fluorine
into aliphatic units with high regiochemical and
stereochemical control. Recently, Ritter4 and Doyle5 have
separately developed powerful methods to effect the
R2
R1
Styrene
O
B O
Ph
R2
PhLi
F
CH3CN
-10 ºC, 2 h
or -30 ºC, 16 h
PinB
THF, 0 ºC
30 min
R1
R1 R2
55–100% es
Scheme 1. Electrophilic fluorination of enantioenriched secondary alkylboron
reagents.
stereoinvertive deoxyfluorination of alcohols.
These
Our research group has recently begun to investigate the
use of alkylcarbastannatranes in organic synthesis. We have
demonstrated that secondary alkylcarbastannatrane reagents
(3) can be employed in stereospecific Pd-catalyzed cross-
coupling reactions with aryl (Scheme 2a) and acyl (Scheme
2b) electrophiles.11,12 The transannular N–Sn interaction in
the carbastannatrane backbone selectively activates its apical
substituent, which facilitates the transfer of alkyl groups that
Pd(dba)2 (5 mol %)
deoxyfluorination reactions, as well as earlier processes using
DAST and Deoxofluor,6 directly employ enantioenriched
alcohols as the source of stereochemistry. Gandelman7 and
Li8 (Scheme 1a) have reported transition-metal-catalyzed
approaches towards the preparation of alkylfluorides. These
processes proceed through radical intermediates, and
therefore the stereochemistry of the resulting alkyl fluoride is
difficult to control in a general manner. Stereospecific
electrophilic fluorination of configurationally stable
organometallic nucleophiles constitutes an alternative route
R2
JackiePhos (6-10 mol %)
R2
Ar
a)
CuCl, KF
Ar–Br
N
Sn
R1
R1
CH3CN, 60 ºC
3
97%–99% es
[a]
X. Ma, M. Diane, G. Ralph, C. Chen, Prof. Dr. M. Biscoe
Department of Chemistry
The City College of New York (CCNY)
160 Convent Avenue, New York, NY 10031
E-mail: mbiscoe@ccny.cuny.edu
O
Pd(PPh3)4 (2 mol %)
CuCl (2 equiv)
O
R2
b)
3
+
Ar
Ar
X
CH3CN, 60 ºC
R1
X = Cl, SPh
93%–100% es
[b]
X. Ma, G. Ralph, Prof. Dr. M. Biscoe
Scheme 2. Use of enantioenriched alkylcarbastannatranes in stereospecific
Pd-catalyzed cross-coupling reactions.
The Graduate Center of the City University of New York (CUNY)
365 Fifth Avenue, New York, NY 10016
Supporting information for this article is given via a link at the end of
the document
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10.1002/anie.201704672
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are otherwise unactivated towards transmetallation.13,14 identical conditions, no formation of the corresponding
Enantioenriched alkylcarbastannatranes can also be stored alkylfluoride resulted (Scheme 3c). Thus, the
indefinitely under ambient conditions without erosion of carbastannatrane backbone facilitates direct alkyl fluorination
enantiopurity. During product isolation, tin byproducts from via reaction with 1 in the absence of transition metal catalysis
carbastannatranes are easily removed by standard column or exogenous activation. This again demonstrates the unique
chromatography. Thus, alkylcarbastannatrane reagents have ability of the carbastannatrane backbone to facilitate the
tremendous potential for broad application as isolable sources selective transfer of alkyl groups that are otherwise
of stereodefined alkyl nucleophiles in organic synthesis. unactivated towards transfer. In this case, however, alkyl
Herein, we report the use of isolable primary and secondary transfer does not occur via a transmetallation reaction, but by
alkylcarbastannatrane
nucleophiles
in
site-specific direct reaction with a non-metal electrophile.
fluorination reactions. These reactions occur without the
need for transition metal catalysis or in situ activation. When
enantioenriched alkylcarbastannatranes are employed,
fluorination occurs predominately via a stereoinvertive
mechanism to generate highly enantioenriched alkyl fluoride
compounds. These conditions can also be extended to
stereospecific chlorination, bromination, and iodination
Table 1. Optimization of the catalyst-free electrophilic fluorination of 5.
N
Sn
F
1 (1.5 equiv)
CH3
CH3
CH3CN, rt, 5 min
5
6
reactions.
Thus,
isolable,
enantioenriched
alkylcarbastannatranes can serve as general building blocks
for broad use in the preparation of enantiomerically enriched
alkyl halides.
Entry
Variations from above
Yield (%)[a]
1
2
3
4
5
6
7
none
62
50
50
31
0
Electrophilic fluorination reactions constitute
a
0 ºC instead of rt; 2 h instead of 5 min
Selectfluor II (2) instead of 1
NSFI (7) instead of 1
standard strategy through which organofluorine compounds
are prepared.3 Using Selectfluor I (1) as the electrophilic
source of fluorine, Ritter has developed methods for the
silver-mediated and silver-catalyzed fluorination of
aryltributylstannanes.15 However, this method has not been
applied to the fluorination of alkylstannanes. Because the
carbastannatrane backbone selectively labilizes its apical
substituent, we felt that alkylcarbastannatranes might
undergo selective alkyl fluorination using the fluorination
8 instead of 1
DMSO instead of CH3CN; 2 h instead of 5 min
DMF instead of CH3CN; 2 h instead of 5 min
0
45
8
9
methanol instead of CH3CN; 2 h instead of 5 min
39
0b
method developed by Ritter.
When primary
Cy4Sn instead of 5; 2 h instead of 5 min
alkylcarbastannatrane 4 was subjected to silver-mediated
fluorination conditions, n-decyl fluoride was generated at
room temperature, though only in 28% yield (Scheme 3a). In
control reactions where the silver additive was omitted, we
were surprised to observe that 4 underwent electrophilic
fluorination much more efficiently, with an improved yield of
64% (Scheme 3b). When tetraoctylstannane was subjected to
R
O F O
N
Ph S N S Ph
N
N
2BF4
OTf
O
O
F
F
R = CH2Cl: Selectfluor I (1)
R = CH3: Selectfluor II (2)
NFSI (7)
8
[a] Yields determined by GC analysis. [b] Yield of fluorocyclohexane.
Having established the ability of alkylcarbastannatranes
to undergo direct fluorination reactions with 1, we
investigated the effect of variations in the reaction conditions.
Because the transfer of secondary alkyl groups from tin is
more challenging than the transfer of primary alkyl groups, we
chose to employ secondary alkylcarbastannatrane 5 to
optimize the reaction conditions (Table 1). Using 1 in
acetonitrile, we found that the fluorination of 5 was complete
in five minutes at room temperature. Use of other
electrophilic fluorinating reagents and solvents resulted in
lower yields. The fluorinated product (6) formed exclusively,
without evidence of protodestannylation (See Supporting
Information for gas chromatograph data). As was observed
AgOTf (2 equiv)
Selectfluor I (1) (1.5 equiv)
n-C10H21
28% yield
F
a)
b)
c)
n-C10H21
Sn
N
CH3CN, rt
4
1 (1.5 equiv)
n-C10H21
F
4
CH3CN, rt
64% yield
1 (1.5 equiv)
Sn(n-C8H17 4
)
No reaction
CH3CN, rt
Scheme 3. Electrophilic fluorination of primary alkylstannanes with and
without silver.
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10.1002/anie.201704672
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using tetraoctylstannane (primary alkyl groups) in place of 4 suggests that this work could be extended to the use of
(Scheme 3), Cy4Sn (secondary alkyl groups) was inert electrophilic 18F sources for the preparation of radiolabeled
towards the fluorination conditions used for carbastannatrane compounds for applications in PET imaging.2,17
5.
To explore the scope of this transformation with respect
Using the optimized conditions, we explored the to electrophilic halogenation reactions, we employed the
substrate scope of this fluorination reaction. We found that standard fluorination conditions in chlorination, bromination,
primary alkyl, secondary alkyl, and benzylic carbastannatrane and iodination reactions. Using primary and secondary
derivatives could be successfully fluorinated (Scheme 4) alkylcarbastannatrane nucleophiles, the corresponding
under these conditions. Yields generally fall within the range chlorinated, brominated, and iodinated products were cleanly
of 50-70% with no concurrent formation of produced in good yield (Scheme 5) through reactions with
protodestannylated byproducts in any reaction. Due to the trichloroisocyanuric acid (TCCA), N-bromosuccinimide
mild conditions of this reaction, sensitive functional groups (NBS),
and
iodine,
respectively.
Thus,
such as alcohols (14), esters (13 and 20), boronate esters alkylcarbastannatranes can be broadly utilized in electrophilic
(15), and silyl ethers (21) are well tolerated. Fluorination of halogenation reactions with one set of reaction conditions.
an oxygen-containing heterocycle (19) also proceeded
smoothly. Secondary alkylcarbastannatrane derivatives
R1
R2
R1
R2
consistently undergo fluorination reactions within minutes at
rt, while primary derivatives tend to require slightly longer
reaction times (ca. 1 h) in the absence of heating. Because the
C–Sn bond of 9 tolerates even the harshest reduction
conditions, remote functional groups can be readily modified
without disturbing the carbastannatrane fragment.16 Thus,
our fluorination process should enable late-stage access to
potentially important fluorinated molecules that would be
particularly difficult, if not impossible, to prepare using
existing methods of direct fluorine incorporation. The speed
and simplicity of these reactions, combined with the unique
stability/reactivity properties of alkylcarbastannatranes,
CH3CN
rt, 1 h
N
Sn
X
X
9
Cl
Br
I
22, 65% (with TCCA) 23, 82% (with NBS)
Cl Br
24, 68% (with I2)
I
CH3
CH3
CH3
27, 63% (with I2)
25, 62% (with TCCA) 26, 60% (with NBS)
Scheme 5. Electrophilic halogenation of alkylcarbastannatranes using TCCA,
Cl
R1
R2
R1
R2
NBS, and iodine.
CH3CN
N
N
N
Sn
F
rt
2BF4
F
5 min–1 h
F
9
1
To probe the stereochemical course of this process, we
subjected enantioenriched secondary alkylcarbastannatranes
(28) to the fluorination conditions of Scheme 4. These
reactions generated optically active alkyl fluorides with net
inversion of absolute configuration. Aggarwal has previously
demonstrated that styrene is effective as a radical inhibitor in
electrophilic fluorination reactions of alkylboronates.9
Consistent with these results, we observed enhanced
stereospecificity when styrene was included in fluorination
reactions using enantioenriched 28. When the fluorination
reactions are conducted at -5 ºC in the presence of styrene,
enantioenriched alkyl fluoride products form with % es
values18 ranging from 83-90%. In the absence of styrene,
fluorinated products are obtained with depressed
enantiospecificities (% es values approximately 15-20%
lower). This is the first example of an enantiospecific
fluorination reaction involving an enantioenriched
alkylstannane, and also the first system that enables
stereospecific electrophilic fluorination without the
requirement for exogenous activation of the organometallic
nucleophile.9 The juxtaposition of ambient stability and high
F
F
CH3
CH3
H3C
CH3
8
10, 65%
11, 55%
12, 60%
O
F
F
F
BPin
BPin
EtO
CH3
H3C
OH H3C
14, 50%
15, 58%
13, 64%
t-Bu
H3C
F
F
7
F
16, 52%
17, 66%
18, 56%
F
O
F
O
F
H3C
O
H3C
OTBS
21, 62%
19, 53%
20, 70%
Scheme 4. Electrophilic fluorination of alkylcarbastannatranes.
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reactivity through a stereospecific pathway is a particularly configuration. Thus, stereospecific fluorination, chlorination,
special feature of this system. In contrast, enantioenriched bromination, and iodination of enantioenriched
alkylboron nucleophiles require in situ activation with phenyl alkylcarbastannatranes can be achieved using the reaction
lithium to generate highly nucleophilic alkylboronate conditions of Scheme 6.
intermediates, which potentially limits the intrinsic functional
group compatibility of the system. When an enantioenriched
benzylcarbastannatrane was employed in this fluorination
reaction, low stereospecificity was observed.19 This is
consistent with the increased propensity of benzylic
nucleophiles to react via radical pathways when in the
presence of strongly oxidizing reagents such as Selectfluor I
(1).
The mechanism of these reactions is consistent with a
stereoinvertive SE2 polar mechanism (Scheme 7).10 Aggarwal9
and Jensen10g have previously demonstrated that the use of
polar solvents such as acetonitrile and methanol support a
stereoinvertive SE2 mechanism in which charge separation is
expected to occur in the transition state. Consistent with
Aggarwal’s observation that electrophilic reactions of
secondary alkylboronates result in net stereoinversion, we
have previously observed that transmetallation of unactivated
R1
R1
secondary
alkylboron
nucleophiles
to
palladium
CH3CN
predominately occurs through a stereoinvertive pathway.20
However, our observation that alkylcarbastannatranes
undergo predominately stereoinvertive transfer in reactions
with electrophilic halogenating reagents contrasts with the
preferred stereoretentive transmetallation pathway observed
when enantioenriched alkylcarbastannatranes are employed
in Pd-catalyzed cross-coupling reactions (see Scheme 2).11,21
This cautions against inferring the stereochemical pathway of
alkyl transfer from related, but non-identical systems, and
underscores the potential sensitivity of the stereochemical
X
N
Sn
28
X
-5 ºC, 2 h
R2
R2
net inversion of
configuration
97%–99% ee
F
F
CH3
HO
CH3
29, 56%[a] (86% es)
30, 59%[a] (90% es)
O
F
O
F
O
CH3
EtO
CH3
32, 65%[a] (89% es)
R2
H
31, 49%[a] (88% es)
H
H
E+
R2
R1
R2
R1
N
Sn
E
E
N
Sn
Cl
R1
SE2 invertive
F
CH3
t-BuMe2SiO
CH3
outcome to changes in reaction conditions.
34, 81%[b] (96% es)
33, 43%[a] (83% es)
Scheme 7. Proposed mechanism of electrophilic substitution.
Br
I
CH3
CH3
In summary, we have demonstrated that the
carbastannatrane backbone activates primary and secondary
alkyl groups towards electrophilic fluorination reactions.
These reactions occur without the need for transition metal
catalysis or in situ activation of the nucleophile. Using one set
of reaction conditions, we have successfully fluorinated
primary alkyl, secondary alkyl, and benzylic carbastannatrane
derivatives. When an enantioenriched alkylcarbastannatrane
reagent is employed, the reactions proceed primarily through
35, 71%[c] (98% es)
36, 52%[d] (94% es)
Scheme 6. Stereosepecific electrophilic halogenations of enantioenriched
alkylcarbastannatranes. [a] 1 (1.5 equiv), styrene (1 equiv), pyridine (0.5
equiv); [b] TCCA (1.5 equiv); [c] NBS (1.5 equiv); [d] NIS (1.5 equiv).
Previous use of enantioenriched tetraalkylstannanes in
electrophilic chlorination, bromination, and iodination
reactions resulted in highly variable enantiospecificities for
halogen transfer, which depended intimately upon the steric
properties of the spectator alkyl groups.10e-10i Using our
standard conditions with TCCA, NBS, and NIS,
a stereoinvertive mechanism.
This enables the direct
preparation of optically active alkyl fluorides from
enantioenriched alkylcarbastannatranes. These reaction
conditions can also be extended to stereospecific chlorination,
bromination, and iodination reactions. This reaction
constitutes an exceedingly rare example of the direct,
stereospecific functionalization of configurationally stable,
isolable, main group organometallic nucleophiles. Because
secondary alkyl transfer from tetraalkyltin compounds was
stereospecific
halogenation
of
enantioenriched
alkylcarbastannatranes can be achieved with only nominal
loss of enantiopurity. Like the analogous fluorination process,
these halogenation reactions occur with net inversion of
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few methods are available through which to prepare
enantioenriched alkylstannanes.16 This constitutes the current
bottleneck to wider adoption of stereospecific
alkylcarbastannatrane chemistry, which we are actively
addressing. We are also currently investigating extensions of
this chemistry to stereospecific carbon-carbon bond-forming
reactions, as well the use of other isolable metallatrane-based
nucleophiles to improve the yields and enantiospecificity of
halogenation reactions. Details of this work will be reported
in due course.
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Acknowledgements
We thank the National Institutes of Health (1SC1GM110010),
the Alfred P. Sloan Foundation, and PSC-CUNY for financial
support. We thank Prof. Donald Watson (Univ. of Delaware) for
performing chiral HPLC analysis during initial investigations. We
gratefully acknowledge the National Science Foundation for an
instrumentation grant (CHE-0840498).
Keywords: fluorination • stereospecific • carbastannatrane •
halogenation • Selectfluor
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17, 544-547.
[16] Alkylcarbastannatranes can be prepared using an alkylmetal
nucleophile with carbastannatrane chloride, or via the umpolung
process using an alkyl mesylate with lithium carbastannatrane. If
sensitive functional groups are present, alkylzinc nucleophiles or
zincated carbastannatrane can be employed (See Supporting
Information).
[17] 18F conditions are typically very different than standard batch scale
conditions. To better mimic 18F conditions, we employed 50-fold and
100-fold excesses of 9 under dilute conditions (0.02 M Selectfluor I).
After only 10 min and without further reaction optimization, GC yields
(product 10) of 30% and 25% were cleanly obtained, respectively.
[18] Enantiospecificity (es) = (eeproduct/eestarting material) x 100%.
[5]
[6]
[7]
M. K. Nielson, C. R. Ugaz, W. Li, A. G. Doyle, J. Am. Chem. Soc. 2015,
137, 9571-9574.
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M. Shreeve, Synthesis 2002, 2561-2578.
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Am. Chem. Soc. 2014, 136, 9548-9551.
[19] Fluorination of
a representative benzylcarbastannatrane (99% ee)
generated the corresponding benzyl fluoride in 50% yield and 53% ee.
See Supporting Information for more details.
[8]
[9]
Z. Li, Z. Wang, L. Zhu, X. Tan, C. Li, J. Am. Chem. Soc. 2014, 136,
16439-16443.
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[21] Stille showed a preference for stereoinvertive transmetallation for a
primary benzylic tin nucleophile in a Pd-catalyzed acylation reaction.
See: J. W. Labadie, J. K. Stille, J. Am. Chem. Soc. 1983, 105, 6129-
6137.
[10] Additional reports of stereospecific electrophilic substitution reactions of
configurationally stable alkylboron and alkyltin reagents: for alkylboron,
see: (a) K. Feeney, G. Berionni, H. Mayr, V. K. Aggarwal, Org. Lett.
2015, 17, 2614-2617; (b) M. Mohiti, C. Rampalakos, K. Feeney, D.
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10.1002/anie.201704672
Angewandte Chemie International Edition
COMMUNICATION
Layout 2:
COMMUNICATION
Author(s), Corresponding Author(s)*
Cl
R1
R2
R1
R2
CH3CN
N
N
Page No. – Page No.
N
Sn
F
X
rt
2BF4
5 min–1 h
Title
F
R1
R2
R1
R2
CH3CN
N
Sn
X
source
-5 ºC, 2 h
X = F, Cl, Br, I
97–99% ee
83–98% es
This article is protected by copyright. All rights reserved.