Preparation of Bicyclo[1.1.1]pentyl Stannanes and Their Applications in
Palladium-Catalyzed Cross Coupling Reactions
Niecia Flikweert, John Elenbaas and Dr. Michael Barbachyn
Calvin College, Department of Chemistry and Biochemistry, 1726 Knollcrest Circle SE, Grand Rapids, MI 49546
v
Introduction
Despite the fact that it was first prepared by Wiberg
and co-workers approximately 45 years ago,1 the
How much text should
in thecontinues
poster? to
bicyclo[1.1.1]pentane
(BCP) be
moiety
receive
considerable
research
attention
from
the
If there’s
too much
text
the
readers
will
chemistry community.2 For example, the BCP moiety
lose
interest
and
move
on.
Limit
your
has been described as a useful surrogate for aryl rings
3,4 Improved
to the baredrug
minimum
and give
more
intext
therapeutic
candidates.
permeability,
oral bioavailability,
and to
metabolic
detailed information
in a handout
3,4 We
stability
are
often
observed
for
BCP
derivatives.
interested viewers. If possible use bullet
decided to target the known1-(tri-npoints and phrases over whole
butylstannyl)bicyclo[1.1.1]pentane
in the hope that it
paragraphs.
a BCP
would
provide One
facilesource
entry suggested
into elaborated
5
derivatives
of
some
utility
in
the
drug
discovery
area.
maximum of 800 words.
Br
Br
PhLi
R3SnH
H
SnR
Some
conferences
require
the
(n-Bu) O, Et O
Cl
-60 to 0 °C
R =be
Me, n-Bu,
-78 °C to rt, hν to
Introduction and conclusion
in c-C
a H , Ph
larger
font
sizewas
than
rest ofcatalyzed
the crossOur
initial
focus
on the
palladium
coupling
poster. reactions of this BCP stannane with aryl
Cl
3
2
2
O O
Palladium-Mediated Cross Couplings: Preliminary Results
Aryl halides with electron-donating groups:
Aryl halides with electron-withdrawing groups:
Inserting photos:5-10 mol% (Ph P) PdCl
Columns can be altered.
3
O2N
5-10 mol% (Ph 3P) 2PdCl 2
The columns are part of the
background. To edit
1,4-dioxane,
go to
~50% conversion
HO
I
+
SnBu 3
48 point text. The body text of a poster
should beBCP
aboutIdentification
24-36 point. 18 point for
captions and labels.
To choose a background other than this
“parchment paper” look: choose design menu/
background styles/format background/fill then
click on desired options and apply.
H
H
Characteristic BCP 1H NMR “Fingerprint”
1H
The
NMR spectrum for 1-(tri-nbutylstannyl)bicyclo[1.1.1]pentane exhibits two
easily-identifiable singlet signals at δ 1.97 for the six
About
backgrounds…
bridge protons
and at δ 2.88 ppm for the lone bridgehead proton (see Figure 1).5
•  In the ink jet process, dark backgrounds takes much
After the cross-coupling
more ink (therefore lighter backgrounds are
Hb
reactions were run, a careful
encouraged).
examination of the crude
1His NMR
• product
Contrast
important.
If your background is dark use
spectrum,
white text
everything bolder. Thin lines will
focusing
on and
the make
“fingerprint”
have signals,
to be thicker.
region
was Fonts
foundthat
to have thin letters might
bold or
in a sans-serif
be beabetter
useful
vehicle
for font.
extent
of cross- It’ll make the text harder
• assessing
Avoid a the
“busy”
background.
coupling
in the
targeted with a photo is cool but
to read. Filling
a background
reactions.
it can easily compete with your information.
•  If the text doesn’t stand out from the background edit
the text Hblock to have a background color. Select the
b
Hb
textbox
then
choose
Format Menu / shape/fill:
Bu3Sn
Ha
color.H Or just put aHbcolor box behind the text.
b
Hb
•  To rearrange
the
white
boxes in the background
H
aH
b
choose view menu/masters/slide master
•  Figure
To add
an additional
heading just copy and paste an
1. Proton
data for 1-(tri-nbutylstannyl)bicyclo[1.1.1]pentane
existing heading and edit its text.
2
2
O
O
Inserting Excel charts:
5-10 mol% (Ph P) PdCl
3C
HH3C
+
OO
++
5-10
mol%
(Ph
3P)2PdCl2
5-10
mol%
(Ph
3P)2PdCl2
SnBu3
SnBu
3
O
O
1,4-dioxane or chloroform, Δ
1.  Pd(PPh3)4, 1,4-dioxane: partial (~30%) conversion by 1H NMR
description of this figure
2
SM
•  Only
use internet
photos withPreparation
copyright
Future
Directions:
of BCP Silanes and Trifluoroborates
permission. I recommend a stock
photography sight such as istockphoto.com
Depression
An awareness of the safety liabilities that often accompany the use of tin reagents Anxiety
has led us to target,
in the future,
or clipart.com. You will pay a small fee but
Physiological
the corresponding BCP silanes and trifluoroborates via the approaches outlined in Figure 2. The BCP silanes, once
have
much
higher
quality
images.
converted into the corresponding hypervalent silicon species in situ, should be useful in these cross-coupling
-“Anxiety is so physical”
-“Thought I was having a heart
attack”
-Rapid breathing
-Sweating palms
-Can’t sleep
-Nausea
-Tired
-Exhaustion
-Loss of appetite
-Racing thoughts
-Downward spiral
-Lack of motivation
-Pessimism
-Worthlessness
-Suicidal thoughts
reactions.6 The BCP trifluoroborates are even more compelling, due to their crystallinity, ease of purification,
Background photos
stability, and overall safety profile.7 Our initial BCP trifluoroborate target
Cognitiveis shown in Figure 3.
•  If you use PhSH
a photo for the poster background
SPh
don’t
use a busy, detailed image. It could
R MgBr
distract from the text of the poster. The image
must be high resolution.RASiHtextured
reductive lithiation
background or gradient fill may be a better
background
option.
R SiX
R SiX
Br
3
R1
Calvin Logo
Li
SiR3
3
R1
The Calvin Logo is in the top right. If you need
a logo in Calvin maroon or black, contact
1. B(OR)
1. B(OR)
Instructional
GraphicsR at 526-8614.
BF K
3
2. KHF2
1
3
3
2. KHF2
Figure 2. Preparation of BCP silanes and trifluoroborates
-Restlessness
- Can’t sit still
-Nail biting
-Hair pulling
-“You do anything to get rid of it”
Behavioral
1
3
N
H
Br
Cl
Affective
MgBr
Cl
MeLi•LiBr
-Tearfulness
-Isolation
-Poor personal hygiene
PhMgBr
-Desperation
Et2O
-Fear
-No peace
-Urgency
H
NHOH
N
H
O
NHOH
O
O
N
R
Conclusions
Printing
2.  (Ph3P)2PdCl2, CHCl3: complete conversion by 1H NMR; isolated yield >90%
+
H
O O
SnBu3
Cl
complete and clean
conversion by 1H
NMR
3
O
1,4-dioxane,
1,4-dioxane,
ΔΔ
5-10 mol% Pd(PPh3)4 or (Ph3P)2PdCl2
+
1,4-dioxane, Δ
•  Unless you find photos made for
downloading and printing, the resolution is
likely to be too low.
The
photos
will print
5-10 mol%
(Ph P)
PdCl
+
SnBu
I
HO
HO
1,4-dioxane, Δ
real grainy.
Once the coupling methodology is further refined, additional
work will be done to identify the best method for BCP
incorporation into more complex molecules, such as the
indicated LpxC inhibitor, modeled on CHIR-090.8 LpxC is an
essential amidase that catalyzes the 1st committed and ratelimiting step in the biosynthesis of lipid A. Lipid A is the
anchor for lipopolysaccharide (LPS) residues found on the
surface of Gram-negative bacteria. We are envisioning BCP
synthons as useful surrogates for the usual alkynyl and aryl
subunits in the hydrophobic chain of existing LpxC inhibitors.
These novel compounds would then be assessed for their
antibacterial activity potential via a standard minimum
inhibitory concentration (MIC) determinations against a panel
OH
ofCaption
bacteria.for your photoOH
O
CHIR-090
Acid chlorides:
H3CO
Pictures from the Internet:
SnBu
SnBu3 3
2
H
O
Ultimate Goal: Incorporation of
BCP into Antibacterial Agents
inmixture?
a mixture?
in a
2
SnBu3
+
2
5-10 mol% (Ph3P)3 2PdCl
2
H
O
H3H
C3C
BrBr
•  View your poster at 100% to see if your
photos are high enough
5-10 mol%resolution.
(Ph P) PdCl
2
2
1,4-dioxane,
Δ
Select the chart in Excel.
Copy
1,4-dioxane,
Δ it (edit menu/
in a mixture?
in a mixture?
copy). Return to PowerPoint. Paste it. (edit
menu/paste).
•  Scans images the size you want them in the
poster at 180 dpi. For pictures from your own
digital camera, uses the largest file setting.
3
• If you insert graphics from a Microsoft Office
product please include a copy when sending
ON
5-10 mol%
(Ph P) PdCl
theBrposter.
Occasionally
I
have
trouble with the
+
SnBu
1,4-dioxane,
graphics
and
it
helps
to
have the original F
F
documents
~55% conversion
Br
Br
Scans and digital photos
+
O2N
3
Background Color
Br
SnBu 3
3
Mac: View/masters/slide master.
H3CO
2
1,4-dioxane,
• To insert a photo choose
insert menu/picture
complete and clean
O2N
2
2
conversion by 1H
NMR
PC: View/Slide master
3
+
Br
HO
6 11
halides bearing both electron-donating and
Font sizes:
Make
titles
about
withdrawing
groups,
as the
well section
as with acid
chlorides.
0
-Sadness
-Darkness
-Hopelessness
2. KHF2
Figure 3. Preparation of phenyl BCP trifluoroborate
saving it as an Acrobat file (.pdf). We can
print .pdf . It willReferences
make printing easier for us,
missing fonts are not as much of a problem.
1.  Wiberg, K. B.; Connor, D. S.; Lampman, G. Tetrahedron Lett. 1964, 5, 531.
2.  Levin, M. D.; Kaszynski,
P.; Michl, J. Chem.alter
Rev. 2000,anything
100, 169-234.
However
we
cannot
once it is in
3.  Stepan, A. F.; et al. J. Med. Chem. 2012, 155, 3414-3424.
4.  Barbachyn, M. R.; et al. Bioorg. Med. Chem. Lett. 1993, 3, 671-676.
that
format.
5.  Toops,
D. S.; Barbachyn, M. R. J. Org. Chem. 1993, 58, 6505-6508.
6.
7.
8.
description of this figure
1. B(OMe)3
MgBr
We have been able to successfully react 1-(tri-nYou can email your poster to:
butylstannyl)bicyclo[1.1.1]pentane with aryl bromides
graphics@calvin.edu or deliver the file on
and iodides bearing both electron-donating and
flashdrive orgroups.
CD/DVD.
Please the
allow
one week
withdrawing
In general,
reactions
proceed
foraprinting.
any graphics,
photos or
fonts
to
greater Include
extent with
electron-deficient
aromatic
in a folder
aschallenge
well in case
need
re-insertis the
partners.
One
yet we
to be
fullytoresolved
anything.ofCall
us at 526-8614.
removal
organotin
by-products from the coupled
products, especially tributyltin halides. Fluoride
treatment to convert the tributyltin bromide/iodide byPlease indicate
you worked
on tin
a Mac
or
products
to the whether
corresponding
insoluble
fluoride
PC to design
yourbeen
poster.
species
has not
successful to date. Further
optimization work is needed. Nevertheless, we have
been able to demonstrate the successful transfer of the
Printing
as ato.pdf
BCP
moiety
aryl file
and benzoyl halides. It is our hope
that
these
results with
will carry
into
thecan
next
When
finished
your over
poster
you
getphase
a of
work
silanes
and,poster
especially,
trifluoroborates.
goodwith
ideaBCP
of what
your
will look
like by
BF3K
Denmark, S. E. and Ober, M. H. Aldrichimica Acta 2003, 36, 75-85.
Molander, G. A. Curr. Opin. Drug Discov. Devel.. 2009, 12, 811-823.
Barb, A. W.; Jiang, L.; Raetz, C. R. H.; Zhou, P. Proc. Natl. Acad. Sci. 2007, 104, 18433.
Acknowledgments
•  Rich Huisman
Lastname, James M., & Witte, Kenneth L. (1988).
•  Scott Prentice
Lasdkjf ;klj sdfkl jlk;jsdf lk;sjdf klj. Bulletin of the
•  Society
ISRI-HHMI
funding
12 (4), 325-328.
•  Brummel Chair funding