Potassium Boc-protected secondary aminomethyltrifluoroborates: Synthesis and Suzuki-Miyaura cross-coupling reactions

Article abstract of DOI:10.1021/ol301955s

Seven potassium Boc-protected secondary aminomethyltrifluoroborates were prepared in a standardized two-step process. The Suzuki-Miyaura cross-coupling reaction was studied with this new class of nucleophiles, and a large variety of aryl and hetaryl chlorides provided the desired products in good to excellent yields, thereby allowing easy access to secondary aminomethyl substructures.

Full text of DOI:10.1021/ol301955s

ORGANIC
LETTERS
2012
Vol. 14, No. 17
4458–4461
Potassium Boc-Protected Secondary
Aminomethyltrifluoroborates: Synthesis
and SuzukiÀMiyaura Cross-Coupling
Reactions
Gary A. Molander* and Inji Shin
Roy and Diana A. Vagelos Laboratories, Department of Chemistry,
University of Pennsylvania, Philadelphia, Pennsylvania 19104-6323, United States
gmolandr@sas.upenn.edu
Received July 14, 2012
ABSTRACT
Seven potassium Boc-protected secondary aminomethyltrifluoroborates were prepared in a standardized two-step process. The SuzukiÀMiyaura
cross-coupling reaction was studied with this new class of nucleophiles, and a large variety of aryl and hetaryl chlorides provided the desired
products in good to excellent yields, thereby allowing easy access to secondary aminomethyl substructures.
Aminomethylated arenes are readily found in many
biologically active compounds and active pharmaceutical
ingredients, with the secondary aminomethyl moiety of
particular interest.
to control. Alkylation methods often give a mixture of
secondary amines, tertiary amines, and even ammonium
salts.2a,b
Secondary aminomethylated arenes can be prepared
by several different synthetic methods. One of the most
popular ways to install this moiety is reductive amination
using the corresponding aldehyde and a primary amine
(Scheme 1, path a).1 However, many functional groups
cannot be embedded in desirable substrates because of the
harsh reduction conditions required for such transforma-
tions. Therefore, this pathway is unsuitable in many cases.
Another conventional approach is the N-alkylation of
primary amines (Scheme 1, path b).2 One of the drawbacks
of this pathway is polyalkylation, which is frequently hard
Scheme 1
A more straightforward route to build secondary ami-
nomethyl substructures would be transition metal cata-
lyzed cross-coupling reactions of aminomethylmetallic
reagents.3 Cross-coupling reactions, especially SuzukiÀ
Miyaura coupling reactions, are normally more functional
group tolerant compared to the reductive amination to
install aminomethyl subunits. Therefore, the reactions are
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H.; Maegawa, T.; Monguchi, Y.; Sajiki, H. Org. Biomol. Chem. 2012, 10,
(3) (a) Molander, G. A.; Fleury-Bregeot, N.; Hiebel, M.-A. Org. Lett.
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r
10.1021/ol301955s
Published on Web 08/29/2012
2012 American Chemical Society

not limited by sensitive functional groups and can be much
more general. Additionally, there is a much greater diver-
sity of commercially available aryl and hetaryl halides for
cross-coupling than of corresponding substrate partners
for reductive amination or N-alkylation. To the best of our
knowledge, only one cross-coupling to install secondary
aminomethyl moieties reaction has been reported, and that
approach employed secondary ammoniomethyl trifluoro-
borates as nucleophiles (Scheme 2, path a).4 Even though
this method proved to be a good synthetic pathway to
access the secondary aminomethyl moiety, the scope of the
coupling reactions was limited to bromides as the electro-
phile, which are more expensiveand appear ina less diverse
range of substructures compared to chlorides. Further-
more, this previously developed method proved effective
for only a few select hetaryl bromides.
Table 1. Synthesis of Potassium Boc-Protected Secondary
Aminomethyltrifluoroborates 3aÀg
Scheme 2
a 1 equiv of K2CO3 was added before KHF2 was added. b A mixture
of 3h and Boc-deprotected 3h.
To overcome these limitations and in continuation of
our studies on aminomethylating agents, Boc-protected
secondary aminomethyltrifluoroborates were imagined as
good candidates for the synthesis of the secondary amino-
methyl moieties (Scheme 2, path b).5 Boc-protected pri-
mary aminomethyltrifluoroborate has already proven to
be an excellent nucleophilic coupling partner in SuzukiÀ
Miyaura cross-coupling reactions with a wide variety of
aryl and hetaryl chlorides5a as well as mesylates.5b After
deprotection of the Boc protecting group, the correspond-
ing aminomethylated arenes are readily accessed.6 There-
fore, we expected the development of Boc-protected
secondary aminomethyltrifluoroborates would also be use-
ful to synthesize secondary aminomethylated arenes.
In this contribution, we disclose the synthesis of potas-
sium Boc-protected secondary aminomethyltrifluorobo-
rates and their application as nucleophiles in the SuzukiÀ
Miyaura cross-coupling reaction with a large variety of
aryl and hetaryl chlorides.
the expected secondary aminomethyltrifluoroborates were
synthesized over two steps: N-alkylation of Boc-protected
amines with iodomethylpinacolboronate7 followed by ad-
dition of KHF2 (Table 1). Seven different Boc-protected
secondary aminomethyltrifluoroborates were prepared in
moderate to good yields. The acetal derivative 2g was
successfully synthesized in 75% yield. Initial attempts to
convert the pinacol boronate to the trifluoroborate failed
because of the acidic reaction media. By adding 1 equiv of
K2CO3 before addition of KHF2, the desired acetal 3g was
obtained in 53% isolated yield (Table 1, entry 7). Unfortu-
nately, we were unable to access aniline derivatives under
these conditions (Table, entry 8). Attempts to generate
such substrates provided a mixture of the desired trifluor-
oborate 3h as well as Boc-deprotected material. These two
trifluoroborates were inseparable.
With these aminomethyltrifluoroborates in hand, the
SuzukiÀMiyaura cross-coupling reaction was studied.
n-ButylBoc-protectedaminomethyltrifluoroborate 3aand
4-chloroanisole were chosen as coupling partners to opti-
mize the reaction conditions. Cross-coupling reactions
were screened extensively with many different palladium
catalysts, ligands, bases, solvents, concentrations, tem-
peratures, and times. Buchwald’s second generation pre-
formed catalyst A8 proved to be the most efficient catalyst
(Figure 2), and thus the best conditions found were the
combination of 4 mol % of XPhos-Pd-G2 A and 3 equiv of
Based on the development of Boc-protected primary
aminomethyltrifluoroborate,5 we first tried to synthesize
the secondary version through a ‘one-pot’ process. How-
ever, all methods tried were unsuccessful. As an alternative,
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(4) Fleury-Bregeot, N.; Raushel, J.; Sandrock, D. L.; Dreher, S. D.;
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Molander, G. A.; Shin, I. Org. Lett. 2012, 14, 3138.
(6) (a) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 3rd ed.; John Wiley & Sons: New York, 1999. (b) Kocienski, P. J.
Protecting Groups, 3rd ed.; Georg Thieme: Stuttgart, NY, 2005. (c) du
Vigneaud, V.; Behrens, O. K. J. Biol. Chem. 1937, 117, 27. (d) Kharasch,
M. S.; Priestley, H. M. J. Am. Chem. Soc. 1939, 61, 3425. (e) Snyder,
H. R.; Heckert, R. E. J. Am. Chem. Soc. 1952, 74, 2006. (f) Li, S.; Gortler,
L. B.; Waring, A.; Battisti, A.; Bank, S.; Closson, W. D.; Wriede, P.
J. Am. Chem. Soc. 1967, 89, 5311.
(7) (a) Smoum, R.; Rubinstein, A.; Srebnik, M. Bioorg. Chem. 2003,
31, 464. (b) Matteson, D. S. Chem. Rev. 1989, 89, 1535.
(8) Kinzel, T.; Zhang, Y.; Buchwald, S. L. J. Am. Chem. Soc. 2010,
132, 14073.
Org. Lett., Vol. 14, No. 17, 2012
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Cs2CO3 in toluene/H2O (4:1, 0.5 M) at 85 °C, allowing the
reactions to go to completion in only 3 h.
Table 2. Cross-Coupling of Various Aryl Chlorides with
Secondary Aminomethyltrifluoroborate 3a
Figure 2. Pd preformed catalyst A and XPhos.
We applied these optimized conditions to various sub-
stituted aryl chlorides (Table 2). A large range of aryl
chlorides was successfully cross-coupled to give the corre-
sponding products in good to excellent yields. In general,
arylchloridespossessing electron-neutral(entries1À3)and
electron-donating groups (entries 4À6) on the aromatic
ring were slightly better substrates than those containing
electron-withdrawing groups (entries 7À11). Interestingly,
electrophiles that are sterically hindered at the ortho posi-
tion gave even higher yields than less hindered ones (entries
3 and 5). Several functional groups, such as esters, nitriles,
and nitro groups, were compatible with the reaction con-
ditions, providing the desired products in high yields.
When the reaction was performed on a larger scale
(4 mmol of 4-chloroanisole), the catalyst loading was
lowered to 2 mol %, affording the desired product 4d in
93% isolated yield (entry 4).
Next, the scope of the electrophiles was expanded to
hetaryl chlorides (Table 3). Sulfur, oxygen, and nitrogen
containing hetaryl chlorides proved to be good coupling
partners with secondary aminomethyltrifluoroborates un-
der the same set of reaction conditions. In some cases, a
longer reaction time (18 h instead of 3 h) was required to
complete the reactions (entries 4, 6, 8, 9, and 11). Pyridine
derivatives gave interesting results. The desired product
was obtained in 85% yield with 3-chloropyridine and 92%
yield with 5-chloro-2-methoxypyridine (entries 6 and 7).
However, when 2-chloropyridine was tested, the product
was not formed at all. Interestingly, 2-chloropyridine with
a methoxy substituent on the ring gave the expected prod-
uct in 49% isolated yield (entry 8). In the case of indoles, a
protecting group on the nitrogen was required (entries 12
and 13). The desired products were not detected without
the Boc protecting group. Additionally, in the cross-coupl-
ing of primary aminomethyltrifluoroborate, indole deriva-
tives did not require a protecting group.6a Again, sensitive
functional groups such as esters and aldehydes were toler-
ated throughout the coupling reactions.
a Reaction conditions: 1.0 equiv of aryl chloride, 1.05 equiv of
trifluoroborate, 4 mol % of XPhos-Pd-G2 A, 3 equiv of Cs2CO3,
toluene/H2O = 4:1 (0.5 M), 85 °C, 3 h. b 4 mmol scale of 4-chloroanisole,
2 mol % of XPhos-Pd-G2 A.
1 and 2) and cyclic alkyl groups on the nitrogen (entries 3
and 4) were good coupling partners, yielding the products in
69À97% yield. A benzyl group on the amine nitrogen gave
the product in 90% yield (entry 5). With an electron-donat-
ing group on the benzyl group, however, the yield dropped
significantly to 73% (entry 6). The acetal derivative 3g also
proved to be a good nucleophilic coupling partner, affording
the expected product in 85% isolated yield (entry 7).
To expand the scope of the electrophile, mesylates were
tested as the coupling partners (eq 1). However, these
reactions did not proceed using the same set of reaction
conditionsand onlythe startingmesylates were detected by
1H NMR after 3 and 18 h of stirring at 85 °C. Thus a
We then examined the coupling reactions with seven
different secondary aminomethyltrifluoroborates and
4-chloroanisole using the same set of reaction conditions
developed (Table 4). All of them provided the desired
product in good to excellent yields. Aliphatic alkyl (entries
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Org. Lett., Vol. 14, No. 17, 2012

Table 3. Cross-Coupling of Various Hetaryl Chlorides with
Secondary Aminomethyltrifluoroborate 3a
Table 4. Cross-Coupling of 4-Chloroanisole with Various Sec-
ondary Aminomethyltrifluoroborates 3aÀg
a Reaction conditions: 1.0 equiv of 4-chloroanisole, 1.05 equiv
of trifluoroborate, 4 mol % of XPhos-Pd-G2 A, 3 equiv of Cs2CO3,
toluene/H2O = 4:1 (0.5 M), 85 °C, 3 h.
In conclusion, a method has been developed to synthe-
size potassium Boc-protected secondary aminomethyltri-
fluoroborates, and seven such derivatives have been
prepared. The SuzukiÀMiyaura cross-coupling reaction
of these aminomethyltrifluoroborates with various aryl
and hetaryl chlorides was investigated. Employing this
method, secondary aminomethylated arenes could be
readily prepared after Boc deprotection.
Acknowledgment. We thank NIGMS (1 R01 GM081376)
for their support of this research. We are grateful to
Johnson Matthey for providing the catalysts for this study.
We also acknowledge Dr. Rakesh Kohli (University of
Pennsylvania) for obtaining HRMS data.
a Reaction conditions: 1.0 equiv of hetaryl chloride 1.05 equiv of
trifluoroborate, 4 mol % of XPhos-Pd-G2 A, 3 equiv of Cs2CO3,
toluene/H2O = 4:1 (0.5 M), 85 °C, 3 h. b 18 h.
different set of conditions will have to be developed for
successful coupling of these electrophiles.
Supporting Information Available. Experimental pro-
cedures and spectral data of all compounds synthesized.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 17, 2012
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