Rapid and efficient access to secondary arylmethylamines

Article abstract of DOI:10.1002/chem.201200831

Ammoniomethyl trifluoroborates are very powerful reagents that can be used to access biologically relevant aryl- and heteroaryl-methylamine motifs via Suzuki-Miyaura cross-couplings. Until now, this method was limited to the production of tertiary and primary amines. The synthesis of a large array of secondary ammoniomethyltrifluoroborates has been achieved through a one step nucleophilic substitution reaction on the potassium bromomethyltrifluoroborate. Smooth cross-coupling conditions have been designed, based on the use of an aminobiphenyl palladium precatalyst, to couple these trifluoroborates efficiently with aryl bromides. This strategy offers a new way to access biologically relevant motifs and allows, with the previously developed methods, access to all three classes of aminomethylarenes. Secondary ammoniomethyltrifluoroborates can be easily synthesized by nucleophilic substitution on potassium bromomethyltrifluoroborate. These reagents have then been used in Suzuki-Miyaura cross-couplings with aryl bromides, offering an effective access to the aminomethylarene structural motif. This new method provides an interesting alternative to the reductive amination procedure (see scheme). Copyright

Full text of DOI:10.1002/chem.201200831

DOI: 10.1002/chem.201200831
Rapid and Efficient Access to Secondary Arylmethylamines
Nicolas Fleury-Brꢀgeot,[a] Jessica Raushel,[a] Deidre L. Sandrock,[a]
Spencer D. Dreher,*[b] and Gary A. Molander*[a]
Abstract: Ammoniomethyl trifluorobo-
ieved through a one step nucleophilic
substitution reaction on the potassium
bromomethyltrifluoroborate. Smooth
cross-coupling conditions have been
designed, based on the use of an ami-
rates are very powerful reagents that
can be used to access biologically rele-
vant aryl- and heteroaryl-methylamine
motifs via Suzuki–Miyaura cross-cou-
plings. Until now, this method was lim-
ited to the production of tertiary and
primary amines. The synthesis of
a large array of secondary ammonio-
methyltrifluoroborates has been ach-
nobiphenyl palladium precatalyst, to
couple these trifluoroborates efficiently
with aryl bromides. This strategy offers
a new way to access biologically rele-
vant motifs and allows, with the previ-
ously developed methods, access to all
three classes of aminomethylarenes.
Keywords:
cross-coupling
·
palladium · secondary aminomethy-
larenes · Suzuki–Miyaura reaction ·
trifluoroborates
Introduction
Nitrogen-containing molecules are among the most impor-
tant classes of organic molecules because of the tremendous
array of applications in which they can be used.[1] Among
them, the aminomethylarene moiety is quite well represent-
ed. A basic search in the literature generates thousands of
hits of bioactive molecules containing this motif. The amino-
methyl-containing molecules displayed below include mole-
cules exhibiting activity against cancer and malaria, in addi-
tion to compounds that are candidates or approved drugs
for the treatment of hypertension and obesity (Figure 1).[2]
Existing methods to introduce such relevant motifs re-
quire, in many cases, the employment of harsh reaction con-
ditions that are not always suitable for use in molecules con-
taining sensitive functional groups. Therefore, access to
those target molecules often involves longer synthetic
routes, including protection/deprotection steps or further
functionalization. The main disconnections that can be envi-
sioned for the construction of this structural motif are sum-
marized in Scheme 1. The most commonly used reaction by
far is the reductive amination, employing reducing agents
such as sodium triacetoxyborohydride or amine-boranes to
Figure 1. Examples of bioactive molecules containing the aminomethyl
moiety.
[a] Dr. N. Fleury-Brꢀgeot, Dr. J. Raushel, Dr. D. L. Sandrock,
Prof. G. A. Molander
Roy and Diana Vagelos Laboratories
Department of Chemistry, University of Pennsylvania
Philadelphia, PA 19104-6323 (USA)
Scheme 1. Possible disconnections to access the aminomethylarene
moiety.
E-mail: gmolandr@sas.upenn.edu
[b] Dr. S. D. Dreher
reduce the in situ generated imine from the reaction be-
Department of Process Chemistry
Merck Research Laboratories
P.O. Box 2000, Rahway, NJ, 07065 (USA)
tween an aldehyde and an amine (routes
a and b,
Scheme 1).[3] Other routes include nucleophilic substitution
on the primary arylmethanamine moiety[4] or longer, similar
sequences starting from the corresponding aryl nitrile or
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201200831.
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Chem. Eur. J. 2012, 18, 9564 – 9570

FULL PAPER
imine to introduce the desired methylamine group.[5] The re-
duction of carboxamides has also been reported.[6] These
routes may also be limited by the relative lack of available
starting materials (e.g., arylmethanamines or benzylic-type
halides).
using Mattesonꢂs alpha transfer route (e.g., carboxamides,
carbamates, sulfonamides).[9] The different coupling partners
can be used efficiently in cross-coupling reactions with vari-
ous electrophilic partners such as aryl/hetaryl halides and
more recently mesylates.[10]
At the outset of our initial studies, there was no literature
precedent for a disconnection involving the use of aryl hal-
ides and a methylamino carbanion equivalent (Scheme 1,
route c). Our research group has focused on developing
a cross-coupling strategy employing air and moisture stable
ammoniomethyltrifluoroborate salts to create a versatile,
complementary, and convenient method to access the aryl/
heteroarylammoniomethyl moiety (Scheme 2). This new ap-
proach represents the most straightforward route to access
the secondary aminomethylarene moiety starting from an
aryl halide.
Following this strategy, tertiary methylamine groups can
be installed starting from the corresponding ammoniomethyl
trifluoroborate salts. The introduction of primary methyla-
mine groups has been recently achieved through the use of
the Boc-protected aminomethyltrifluoroborate followed by
a deprotection step.[11] Diverse functionalized aminomethyl
groups such as carboxamides, sulfonamides, and very recent-
ly phthalimides can also be prepared and cross-coupled.[12]
Surprisingly, access to secondary alkylaminomethyl groups,
the last structural unit needed to fill a useful gap in our ap-
proach, has been a difficult transformation to achieve.
We report herein the synthe-
sis and cross-coupling of secon-
dary ammoniomethyltrifluoro-
borates with a large array of
aryl bromides as an effective
and straightforward route to
obtain secondary aminomethy-
larenes.
Results and Discussion
After reporting that amino-
methyl based trifluoroborates
exist as the ammoniomethyl in-
ternal salt,[8d] an imperative
need arose for us to design a re-
liable method to access the de-
sired secondary aminomethyl-
containing trifluoroborates. We
based our synthetic route on
the direct nucleophilic substitu-
tion of potassium halogenome-
thyltrifluoroborates, in a mixture
of THF/tBuOH, similar to the
method already used to obtain
Scheme 2. Scope of amino and ammoniomethyltrifluoroborates.
other ammoniomethyl salts.
Unfortunately, the synthesis
The protocol envisioned would also represent the first ex-
ample of direct introduction of the secondary aminomethyl
moiety based on a cross-coupling approach, made feasible
by the unique features offered by organotrifluoroborates.
Organotrifluoroborates are very useful nucleophilic partners
in the Suzuki–Miyaura cross-coupling reaction, overcoming
some drawbacks of other boron-containing reagents, thus
providing unprecedented and suitable synthetic routes to
a variety of interesting substructures.[7] Concerning the am-
moniomethyl moiety, Molander and co-workers have dem-
onstrated that the corresponding trifluoroborates can be ac-
cessed successfully either by direct nucleophilic substitution
on the halogenomethyltrifluoroborate (dialkylamines)[8] or
starting from the chloromethyltrifluoroborate did not work
efficiently even at high temperatures. Better results were ob-
tained using the bromomethyltrifluoroborate and a gradual
increase to the final oil bath temperature. Usually, nucleo-
philic substitutions on the halogenomethyltrifluoroborates
are conducted at high temperatures,[8a] but when using pri-
mary amines, decomposition products of the trifluoroborate
and unidentified polymeric mixtures were often recovered.
Lowering the temperature helped reduce the amount of side
products generated but also hampered the conversion,
making the isolation of the desired secondary ammoniome-
thyltrifluoroborate problematic, owing to large amounts of
unreacted bromomethyltrifluoroborate. The problem was
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G. A. Molander et al.
solved by initiating the reaction in a room temperature oil
bath and heating it gradually to the desired temperature
over 40 min. These conditions allowed access to a large
array of diversely substituted secondary ammoniomethyltri-
fluoroborates. The final temperature as well as the reaction
time varied on a case by case basis, depending on the sub-
strate. The various secondary ammoniomethyltrifluorobo-
rates synthesized (1a–s) are summarized in Table 1.
can be explained by the volatility of the starting methyla-
mine, the low yield obtained with n-butylamine (Table 1,
entry 3) remains unclear. The reaction conditions are very
specific to each substrate as illustrated by entries 4, 8, and
18, which exhibit no illuminating trend. Secondary alkyla-
mines proved to react very well with the bromomethyltri-
fluoroborate, yielding the desired ammonio salts with good
to excellent yields (Table 1, entries 6–8). Cyclohexylammo-
niomethyltrifluoroborate was obtained in 90% yield on
a 10 mmol scale. More hindered alkylamines, such as tert-bu-
tylamine, tert-octylamine, and even adamantylamine reacted
to afford the desired ammonio salts in very good yields
(Table 1, entries 9–11). Of note, the salt 1k derived from
adamantylamine is so insoluble and hydrophobic that it had
to be purified with water.[14]
Linear alkyl chains of different lengths were tolerated
(Table 1, entries 1–3) in very disparate yields. Although the
29% yield for the methylammoniomethyltrifluoroborate 1a
Table 1. Preparation of secondary ammoniomethyltrifluoroborates.
Amines bearing a second heteroatom were more difficult
to react in good yields and often required the use of method
B to afford the expected trifluoroborate salts (Table 1, en-
tries 12–16 and 19). The presence of tertiary amine moieties,
which could also compete with the desired nucleophilic sub-
stitution, can account for the lower yields observed. The suc-
cess of the reaction might be directly related to the steric
bulk on the ancillary group on the amine. For example, in
entry 12, the 4-amino-N-benzylpiperidine ammonio salt 1l
was obtained in a 67% yield, which increased to 90% when
the piperidine moiety was protected by a bulkier Boc group
(1m; Table 1, entry 13). However, basicity might also play
a role, as the more basic the second nitrogen atom is, the
more likely it will react, leading to undesired side reactions.
Unhindered diamines provided very low yields (Table 1, en-
tries 14, 15). The 35% yield obtained for 1p can be ex-
plained by the low nucleophilicity of the corresponding
para-methoxyaniline compared to alkylamines. On the other
hand, diphenylmethanamine was able to react well, afford-
ing 1q in 85% yield (Table 1, entry 17). Of note, tryptamine,
even with the unprotected indole, led to the formation of
the desired ammonio salt 1s in 44% yield (Table 1,
entry 19). In all cases, the secondary ammoniomethyltri-
fluoroborates were obtained as air and moisture stable
solids that were stored on the bench for weeks without any
observed decomposition.
Entry
1
Product
Method
A
Yield [%][a]
29
1a
1b
1c
1d
1e
2
3
4
5
6
A
B
81
15
A
B
85
58
B
81
92
1 f
1g
A
7
8
A
87
A
B
90[b]
67
1h
9
1i
1j
A
A
74
83
10
11
12
1k
1l
B
B
89
67
13
1m
A
90
As the substitution reactions were performed on bromo-
methyltrifluoroborate, we were concerned by possible con-
tamination of the final internal salts by KBr.[8d] To prevent
this possible issue, work-up conditions were designed using
hot filtration in acetonitrile and/or Soxhlet extraction using
isopropyl acetate, as it was found that KBr has a very low
solubility in those solvents. However, to prevent any prob-
lems, it was decided to use a small excess of the ammonio
salt when performing the cross-coupling reactions to ensure
that enough of the trifluoroborate was still engaged in the
reaction even in the case of trace contamination. We were
also able to grow crystals of two of the secondary ammonio-
methyl trifluoroborates (1h and 1j), and their structures
were elucidated by X-ray crystallography (Figure 2).
14
15
16
1n
1o
1p
B
B
B
9
30
35
17
1q
A
85
A
B
54
69
18
19
1r
1s
A
44
Having synthesized a large array of secondary ammonio-
methyltrifluoroborates through a very direct and effective
Method A: 608C for 4–16 h; Method B: 808C for 2–24 h. [a] Yield of iso-
lated product. [b] Reaction performed on a 10 mmol scale.
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Rapid and Efficient Access to Secondary Arylmethylamines
FULL PAPER
Figure 2. X-ray structures of ammoniomethyltrifluoroborates 1h and 1j.
nucleophilic substitution pathway, we then explored their
behavior in the Suzuki–Miyaura cross-coupling reaction to
afford arenemethylamine products. This reaction proved to
be much more difficult than expected and very extensive
screening was required to find suitable and reproducible
conditions. None of the previously reported cross-coupling
conditions with the other ammoniomethyltrifluoroborates
provided a trace of the expected product. Indeed, being able
to perform a cross-coupling on those internal salts bearing
a free amine moiety requires a very effective catalytic
system. Specifically, after the transmetalation step, the
amine moiety could possibly bind intra- or intermolecularly
to the metal, creating aggregates, thus deactivating the cata-
lyst and preventing completion of the catalytic cycle. More-
over, the free amine can also coordinate to the metal as the
reagent or as the product and prevent the reaction. This
transformation is challenging, and those factors could ex-
plain why finding the right catalytic system required such
extensive exploratory investigation. The use of the recently
reported aminobiphenyl precatalysts developed by Buch-
wald et al. proved to be crucial.[15] This precatalyst system
allows rapid formation of the desired active Pd0 species in
the presence of a weak base. After much screening of li-
gands, we determined that the classic Buchwald phosphines
were not suitable for this reaction. The best ligand was
found to be the bulky and electron rich tri-tert-butylphos-
phine.[16] The synthesis of the precatalyst 2 is shown in
Scheme 3.
anisole electrophiles in the presence of catalyst (5 mol%),
and the results are summarized in Table 2.
The best solvent system was found to be a 1:1 mixture of
THF/H2O at a concentration of 0.05m at 608C, yielding 3a
Table 2. Optimization of the reaction conditions.
Entry
X
Solvent[a]
Conc. [m]
Yield [%][b]
1
2
3
4
5
6
Br
Br
Br
Br
Cl
I
CPME
THF
THF
THF
THF
THF
0.05
0.05
0.10
0.50
0.05
0.05
38
83 (66)[c]
42
34
50
30
[a] CPME=cyclopentyl methyl ether. [b] Yields of isolated product.
[c] Reaction performed at 808C.
in 83% isolated yield. When the reaction temperature was
increased to 808C, irreproducible results were obtained with
an average 66% isolated yield (Table 2, entry 2). The very
dilute conditions required can be explained by a possible co-
ordination of the nitrogen of either the boron-containing
amino reagent or the amine product to the palladium that
can lead to its deactivation when the reaction is run at
higher concentration. A solution to overcome this drawback
could be envisioned by using continuous flow technology.[18]
para-Bromoanisole provided the best results, while
chloro- and iodo-derivatives only afforded the desired prod-
uct 3a in 50 and 30% yields, respectively (Table 2 entries 2,
5, 6).
The reaction conditions were optimized using the cyclo-
hexylammoniomethyltrifluoroborate 1h and para-halogeno
Once the conditions were optimized, and to investigate
the method further, various electron rich (Table 3, entries 1–
9) and electron poor (Table 3, entries 10–17) aryl bromides
were examined as electrophiles in the reaction (Table 3).
All the bromides tested afforded the cross-coupled prod-
ucts with yields ranging from 45 to 95%. Interestingly, when
the ortho-bromomethylbenzoate (Table 3 entry 17) was
used, the iso-indolinone 3r was isolated in a 48% yield. This
Scheme 3. Synthesis and X-ray stucture of the palladium biphenyl tri-tert-
butylphosphine precatalyst 2.[17]
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G. A. Molander et al.
Table 3. Scope of the reaction with aryl bromides.
formation of the observed product 3r (Table 3, entry 17). A
very hindered system (Table 3, entry 5) still proceeded to
react, albeit without total conversion, giving a lower yield.
Naphthalene bromides (Table 3, entries 7, 8) cross-coupled
very efficiently, affording 3h and 3i in 95 and 90% yield, re-
spectively. The designed method allows the presence of
functional groups such as ethers, amines, nitriles, esters, and
nitro groups. Fluoro- and trifluoromethyl containing aryl
bromides were also well tolerated (Table 3, entries 12–14).
As a general rule, heteroatom-containing aryl bromides
gave diminished yields, but still reacted efficiently.
Entry
1
Electrophile
Product
Yield [%][a]
53
3b
3c
3d
3e
3 f
3g
3h
2
3
4
5
6
7
77
90
82
42
85
95
To expand the scope of the reaction, the cyclohexylammo-
niomethyl trifluoroborate salt 3h was also reacted with het-
eroaryl bromides under the same conditions with much less
success (Table 4).
Table 4. Scope of the cross-coupling reaction between 1h and various
heteroaryl bromides.
8
9
3i
3j
90
52
Entry
1
Electrophile
Product
Yield [%][a]
36
34[b]
4a
4b
4c
61[b]
10
11
12
3k
3l
81
24
85
57[b,c]
2
3
4
38
3m
4d
31[b]
32[d]
34[d]
13
3n
45
5
6
4e
4 f
14
15
3o
3p
80
86
[a] Yield of isolated products, which might be contaminated with up to
10 mol% of phosphine oxide. [b] 10 mol% of catalyst was used. [c] Reac-
tion time of 48 h. [d] Reaction ran at 758C.
16
17
3q
3r
53
48
When 8-bromo-isoquinoline was employed in the reaction
under the conditions described (Table 4, entry 1), the de-
sired amine 4a was isolated in 36% yield. Increasing the
catalyst loading to 10 mol% did not improve the yield. The
5-bromoquinoline proved to be a better substrate, affording
4b in 61% yield. Extending the reaction time from 24 to
48 h did not impact the yield of the reaction (Table 4,
entry 2). Indole, pyridine, and thiophene derivatives cross-
coupled with yields ranging from 31 to 38% (Table 4, en-
tries 3–6). Harsher reactions conditions (758C) did not im-
prove the outcome of the reaction.
[a] Yield of product isolated after purification, product can contain up to
5% of phosphine oxide.
product corresponds to the intramolecular cyclization of the
amine onto the ester group under basic conditions. Electron
rich bromides provided good to excellent yields. The effect
of steric hindrance was tested with several mono and di
ortho-substituted bromides (Table 3 entries 1, 3, 5, 11, 17).
Depending on the nature of the ortho substituent, the
outcome of the reaction was very different. Although chemi-
cally inert groups (Table 3 entries 1, 3) did not really have
an influence on the yields, other functional groups had a neg-
ative effect (Table 3, entry 11) or even participated in the
The presence of an extra heteroatom that can interact
with the catalyst in a bidentate fashion prevents the reaction
from working well.[19] To avoid this issue, or at least to lower
its impact, we tried performing the cross coupling with the
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Rapid and Efficient Access to Secondary Arylmethylamines
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Table 5. Variation of the trifluoroborate moiety.
sterically hindered ammoniomethyl salt 1k. We were hoping
that the steric bulk of the adamantyl moiety would prevent
the nitrogen of the ammonio salt from interacting with the
palladium, thus avoiding deactivation. Unfortunately, when
using the 5-bromoquinoline, the desired product 5 was only
retrieved in 44% yield (Scheme 4), lower than the one ob-
Entry
1
R
BF3K Product
Yield [%][a]
30[b]
tBu
1i
6a
2
3
iPr
1 f
1e
6b 53[b]
6c 69
6d 72[b]
Scheme 4. Attempts of cross-coupling 1k and 5-bromoquinoline.
4
5
cyclopentyl 1g
tained when using the cyclohexyltrifluoroborate 1h. The 3-
bromopyridine and thiophene did not provide any of the
cross-coupled products. The adamantyl group might be too
bulky, and in addition to surrounding the nitrogen of the
ammoniomethyl, it might also slow down the cross-coupling
reaction. Another hypothesis to explain this lack of reactivi-
ty could also be the very low solubility of this trifluorobo-
rate salt, with subsequent slow conversion into the active
boron species required for the cross-coupling reaction.[20]
To demonstrate the scope of the method on aryl bro-
mides, a variety of ammoniomethyl salts were used in the
cross-coupling reaction using para-bromoanisole under the
previously defined conditions (Table 5). In some cases, for
ease of purification, the products were isolated as their HCl
salt.
The ten different ammoniomethyl salts cross-coupled with
yields ranging from 30 to 83%. Alkylamine-based trifluoro-
borates (Table 5, entries 1–8) proved to be efficient coupling
partners in the reaction. The adamantylammoniomethyltri-
fluoroborate 1k provided the best result with an 83% yield.
The presence of an additional nitrogen (e.g., an NBoc
group) on the nucleophilic partner 1m did not hamper the
outcome of the reaction, as the desired coupled product 6i
bearing two amino groups was obtained in 81% yield. Inter-
estingly, the 2-(2-chlorophenyl)ethylaminomethyltrifluoro-
borate 1r afforded the expected secondary amine 6j in 59%
yield, which could be increased to 64% when using NaOtBu
as the base. Thus, the presence of another halogen did sig-
nificantly inhibit the reaction.
adamantyl
1k
6e
83[b]
6
7
neo-pentyl
tert-octyl
1d
1j
6 f
6g
54[b]
81[b]
8
1q
6h 74[c]
9
1m
1r
6i
6j
81
59
10
64[d]
[a] Yield of isolated products, which might contain up to 5% of phos-
phine oxide. [b] Products isolated as the HCl salt. [c] Contaminated with
5% carbazole. [d] NaOtBu used instead of Cs2CO3.
Scheme 5. Rapid synthesis of indoline derivative 7a from trifluoroborate
1r in two metal-catalyzed reactions.
This product could be used for further functionalization
and even other cross-coupling reactions. For instance, we
were able to use it to perform an intramolecular amination
reaction to yield the corresponding para-methoxybenzylin-
doline 7a in 73% isolated yield, providing an efficient and
short reaction sequence to create this unit (Scheme 5).[21]
Suzuki–Miyaura cross-coupling reaction has been demon-
strated with a wide variety of aryl bromides. This new
method readily allows access to secondary arylmethanamine
moieties via a new disconnection, thus filling a void in the
synthesis of aminomethyl substituted arenes based on the
use of aminomethyltrifluoroborates to access all the differ-
ent classes of arylmethylamines. The cross-coupling with
heteroaryl electrophiles involving unprotected free amines
creates some challenges, but further work is currently under-
way in our laboratory to overcome these issues.
Conclusions
In conclusion, a straightforward and efficient synthesis of
secondary ammoniomethyltrifluoroborate salts has been de-
veloped. Their suitability as coupling partners in the
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G. A. Molander et al.
Cella, S. Adriano, Tetrahedron 2007, 63, 3623–3658; d) S. Darses, J.-
P. GenÞt, Chem. Rev. 2008, 108, 288–325; for mechanistic details on
the advantages of trifluoroborates over other boron reagents in the
Suzuki reaction, see: e) M. Butters, J. N. Harvey, J. Jover, A. J. J.
Lennox, G. C. Lloyd-Jones, P. M. Murray, Angew. Chem. 2010, 122,
5282–5286; Angew. Chem. Int. Ed. 2010, 49, 5156–5160.
[8] For the first examples of ammoniomethyltrifluoroborate syntheses,
see: a) G. A. Molander, J. Ham, Org. Lett. 2006, 8, 2031–2034; for
more examples and their use in Suzuki–Miyaura cross-coupling,
see: b) G. A. Molander, D. L. Sandrock, Org. Lett. 2007, 9, 1597–
1600; c) G. A. Molander, P. E. Gormisky, D. L. Sandrock, J. Org.
Chem. 2008, 73, 2052–2057; for a recent reinvestigation of the am-
moniomethyltrifluoroborates, see: d) J. Raushel, D. L. Sandrock,
K. V. Josyula, D. Pakyz, G. A. Molander, J. Org. Chem. 2011, 76,
2762–2769.
[9] a) G. A. Molander, M.-A. Hiebel, Org. Lett. 2010, 12, 4876–4879;
b) G. A. Molander, N. Fleury-Brꢀgeot, M.-A. Hiebel, Org. Lett.
2011, 13, 1694–1697.
[10] For aryl and heteroaryl halides, see Ref. [8b–d]; for aryl and hetero-
aryl mesylates, see: G. A. Molander, F, Beaumard, Org. Lett. 2011,
13, 1242–1245.
[11] G. A. Molander, I. Shin, Org. Lett. 2011, 13, 3956–3959.
[12] For carboxamides, see ref. [9a]; for sulfonamides, see Ref. [9b] and
for phthalimides, see: R. Devulapally, N. Fleury-Brꢀgeot, G. A. Mo-
lander, D. G. Seapy, Tetrahedron Lett. 2012, 53, 1051–1055.
[13] F. Brotzel, Y. C. Chu, H. Mayr, J. Org. Chem. 2007, 72, 3679–3688.
[14] See the Supporting Information for more details.
Acknowledgements
This research was supported by a National Priorities Research Program
(NRP) grant from the Qatar National Research Fund (Grant No. 08-035-
1-008), the National Science Foundation (GOALI), and the NIH
(R01GM-081376). AllyChem is acknowledged for the generous donation
of bromomethyl potassium trifluoroborate. Dr. Matthew Tudge (Merck
Research Laboratories) is acknowledged for preparing and donating the
aminobiphenyl palladium m-chloro dimer. Dr. Rakesh Kohli (University
of Pennsylvania) is acknowledged for obtaining HRMS data. Dr. Patrick
Caroll (University of Pennsylvania) is acknowledged for performing the
X-ray analysis.
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Received: March 12, 2012
Published online: July 5, 2012
9570
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