Cross-coupling of mesylated phenol derivatives with potassium ammonio-and amidomethyltrifluoroborates

Article abstract of DOI:10.1021/ol200128y

A large array of aryl and heteroaryl mesylates have been successfully employed as electrophiles in a Csp²-Csp³ Suzuki-Miyaura cross-coupling with potassium ammonio-and amidomethyltrifluoroborates to afford the corresponding products

Full text of DOI:10.1021/ol200128y

ORGANIC
LETTERS
2011
Vol. 13, No. 5
1242–1245
Cross-Coupling of Mesylated Phenol
Derivatives with Potassium Ammonio-
and Amidomethyltrifluoroborates
Gary A. Molander* and Floriane Beaumard
Roy and Diana A. Vagelos Laboratories, Department of Chemistry, University of
Pennsylvania, Philadelphia, Pennsylvania 19104-6323, United States
gmolandr@sas.upenn.edu
Received January 15, 2011
ABSTRACT
A large array of aryl and heteroaryl mesylates have been successfully employed as electrophiles in a Csp2-Csp3 Suzuki-Miyaura cross-coupling
with potassium ammonio- and amidomethyltrifluoroborates to afford the corresponding products in high yields.
Aliphatic aminesare very importantsynthetic targets for
the scientific community as they exhibit useful properties
for employment in a wide variety of industries.1 More
Scheme 1
specifically, N,N-dialkylaminomethyl- and amidomethyl
compounds are widely encountered in alkaloid natural
products and synthetic therapeutic drugs.2 Reductive ami-
nation of aldehydes3,4 and reduction of nitriles4,5 appear to
be the most common methods utilized to obtain these
compounds. More recently, the development of Csp2-
Previous reports from our laboratory have demon-
Csp3 Suzuki-Miyaura cross-couplings has afforded a
strated the efficiency of the cross-coupling approach to
complementary pathway toward the synthesis of these
aminomethyl-substituted aromatic and heteroaromatic
scaffolds.6 This last method is especially of great interest
compounds. Potassium N,N-dialkylaminomethyl-6i,j and
because of the greater availability of aryl halides in compar-
ison to aryl- or heteroaryl aldehydes or -nitriles (Scheme 1).
(4) Gomez, S.; Peters, J. A.; Maschmeyer, T. Adv. Synth. Catal. 2002,
344, 1037–1057.
(1) Aliphatic Amines. In Ullmann’s Encyclopedia of Industrial Chem-
istry, 7th ed.; Wiley-VCH: Weinheim, 2008; Vol. A2, p 2.
(5) Haddenham, D.; Pasumansky, L.; DeSoto, J.; Eagon, S.; Singaram,
B. J. Org. Chem. 2009, 74, 1964–1970.
(6) For some examples employing alkylboron species in Csp2-Csp3
Suzuki cross-couplings, see: (a) Molander, G. A.; Yun, C.-S. Tetrahe-
dron 2002, 58, 1465–1470. (b) Kondolff, I.; Doucet, H.; Santelli, M.
Tetrahedron 2004, 60, 3813–3818. (c) Ines, B.; Moreno, I.; SanMartin,
R.; Dominguez, E. J. Org. Chem. 2008, 73, 8448–8451. (d) Dreher, S.;
Dormer, P. G.; Sandrock, D. L.; Molander, G. A. J. Am. Chem. Soc.
2008, 130, 9257–9259. (e) Molander, G. A.; Sandrock, D. L. Org. Lett.
2009, 11, 2369–2372. (f) Molander, G. A.; Sandrock, D. L. J. Am. Chem.
Soc. 2008, 130, 15792–15793. (g) Dreher, S.; Lim, S.-E.; Sandrock, D. L.;
Molander, G. A. J. Org. Chem. 2009, 74, 3626–3631. (h) Sandrock,
D. L.; Jean-Gerard, L.; Chen, C.-Y.; Dreher, S.; Molander, G. A. J. Am.
Chem. Soc. 2010, 132, 17108–17110. (i) Molander, G. A.; Sandrock,
D. L. Org. Lett. 2007, 9, 1597–1600. (j) Molander, G. A.; Gormisky,
P. E.; Sandrock, D. L. J. Org. Chem. 2008, 73, 2052–2057. (k) Molander,
G. A.; Hiebel, M.-A. Org. Lett. 2010, 12, 4876–4879.
(2) (a) Roberson, E. D.; Mucke, L. Science 2006, 314, 781–784. (b)
Barbe, G.; Charette, A. B. J. Am. Chem. Soc. 2007, 130, 18–19. (c) Chill,
L.; Aknin, M.; Kashman, Y. Org. Lett. 2003, 5, 2433–2435. (d) Yasuhara,
T.; Nishimura, K.; Yamashita, M.; Fukuyama, N.; Yamada, K.-i.;
Muraoka, O.; Tomioka, K. Org. Lett. 2003, 5, 1123–1126. (e) French,
K. J.; Zhuang, Y.; Maines, L. W.; Gao, P.; Wang, W. X.; Beljanski, V.;
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Ther. 2010, 333, 129–139. (f) Belyk, K. M.; Morrison, H. G.; Jones, P.;
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Drugs Future 2004, 29, 992–997. (h) Ratti, S.; Quarato, P.; Casagrande,
C.; Fumagalli, R.; Corsini, A. Eur. J. Pharmacol. 1998, 355, 77–83.
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2006, 10, 971–1031. (b) Abdel-Magid, A. F.; Carson, K. G.; Harris,
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(c) Baxter, E. W.; Reitz, A. B. Org. React. 2002, 59, 1–714.
r
10.1021/ol200128y
Published on Web 02/04/2011
2011 American Chemical Society

amidomethyltrifluoroborates6k have been successfully
cross-coupled with high yields using aryl halide electro-
philes.
Less toxic and easier to handle sulfonate groups have
recently expanded the scope of nucleofuges in cross-cou-
pling protocols.7,8 Among these, mesylates appear to be
themostattractive substratesinterms of stabilityand atom
economy even though they are known to be the least
reactive species.8 In the past few years, significant progress
on Csp2-Csp2 Suzuki-Miyaura cross-coupling has been
achieved with these electrophiles, but much work still
remains on the more challenging Csp2-Csp3 cross-cou-
plings. Alkylboron species are known to undergo the
requisite transmetalation step with the intermediate orga-
nometallic species with more difficulty than with sp2-
hybridized organoborons.6,8h Actually, to our knowledge,
only two cross-coupling examples have been reported with
an alkylboron species and a mesylated aryl counterpart.
Buchwald disclosed a palladium-catalyzed cross-coupling
of a mesylated quinoline in the presence of a single
alkylboron species, methylboronic acid, with a yield of
84%.8b In 2010, Kwong employed his indoyl phosphine
ligand to cross-couple the 4-tert-butylphenyl mesylate with
n-butylboronic acid and its potassium trifluoroborate
counterpart with moderate yields of 48% and 62%,
respectively.8c Both methods used a large excess of boron
reagent (2 equiv) in the presence of 2 mol % of Pd(OAc)2.
Moreover, all the attempts up to now to provide the
cross-coupled compound from a more reactive tosylate
starting material with both potassium N,N-dialkylam-
monio- and amidomethyltrifluoroborates have been un-
successful.6i-k
Figure 1. Structure of ligands.
As a starting point, a small survey of Pd(OAc)2/ligand
systems was carried out with the mesylated naphthol 1a
and the N-(trifluoroboratomethyl)piperidine internal salt9
as model substrates. Either SPhos, RuPhos, or XPhos
(Figure 1) appeared to be suitable, affording the desired
compound 2a with complete conversion.10 Moreover, the
catalyst loading could be reduced to 1 mol %, and only 1.3
equiv of potassium trifluoroborate was necessary to obtain
2a with 84% yield after 1 h. Tosylates could also be
employed in the reaction as the electrophile, providing an
81% yield of 2a under the same reaction conditions (Table 1,
entry 1).
After optimizing the conditions for the cross-coupling, we
next studied the reaction of mesylated naphthol 1a with an
Table 1. Scope of Ammoniomethyltrifluoroborate Internal
Salts
Herein, the first general protocol for the Csp2-Csp3
Suzuki-Miyaura cross-coupling of aryl- and heteroaryl
mesylates with potassium aminomethyltrifluoroborates is
reported. Additionally, this system has also proven to be
very efficient with potassium amidomethyltrifluorobo-
rates.
(7) For recent examples of Suzuki cross-coupling of aryl tosylates,
see: (a) Nguyen, H. N.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc.
2003, 125, 11818–11819. (b) Roy, A. H.; Hartwig, J. F. Organometallics
2004, 23, 194–202. (c) Petersen, M. D.; Boye, S. V.; Nielsen, E. H.;
Willumsen, J.; Sinning, S.; Wiborg, O.; Bols, M. Bioorg. Med. Chem.
2007, 15, 4159–4174. (d) Zhang, L. A.; Meng, T. H.; Wu, J. J. Org. Chem.
2007, 72, 9346–9349. (e) So, C. M.; Lau, C. P.; Chan, A. S. C.; Kwong,
F. Y. J. Org. Chem. 2008, 73, 7731–7734. (f) Percec, V.; Golding, G. M.;
Smidrkal, J.; Weichold, O. J. Org. Chem. 2004, 69, 3447–3452. (g) Tang,
Z. Y.; Hu, Q. S. J. Am. Chem. Soc. 2004, 126, 3058–3059. (h) Tang,
Z.-Y.; Spinella, S.; Hu, Q.-S. Tetrahedron Lett. 2006, 47, 2427–2430. (i)
Lipshutz, B. H.; Butler, T.; Swift, E. Org. Lett. 2008, 10, 697–700. (j)
Zim, D.; Lando, V. R.; Dupont, J.; Monteiro, A. L. Org. Lett. 2001, 3,
3049–3051.
(8) For recent examples of Suzuki cross-coupling of aryl mesylates,
see: (a) So, C. M.; Lau, C. P.; Kwong, F. Y. Angew. Chem., Int. Ed. 2008,
47, 8059–8063. (b) Bhayana, B.; Fors, B. P.; Buchwald, S. L. Org. Lett.
2009, 11, 3954–3957. (c) Chow, W. K.; So, C. M.; Lau, C. P.; Kwong,
F. Y. J. Org. Chem. 2010, 75, 5109–5112. (d) Percec, V.; Bae, J. Y.; Hill,
D. H. J. Org. Chem. 1995, 60, 1060–1065. (e) Ueda, M.; Saitoh, A.;
Oh-tani, S.; Miyaura, N. Tetrahedron 1998, 54, 13079–13086. (f)
Kobayashi, Y.; William, A. D.; Mizojiri, R. J. Organomet. Chem.
2002, 653, 91–97. (g) Kuroda, J. I.; Inamoto, K.; Hiroya, K.; Doi, T.
Eur. J. Org. Chem. 2009, 2251–2261. (h) Molander, G. A.; Beaumard, F.
Org. Lett. 2010, 12, 4022–4025. (i) Rosen, B. M.; Quasdorf, K. W.;
Wilson, D. A.; Zhang, N.; Resmerita, A.-M.; Garg, N. K.; Percec, V.
Chem. Rev. 201010.1021/cr100259t.
a Time = 1 h.
Org. Lett., Vol. 13, No. 5, 2011
1243

array of various N,N-dialkylammoniomethyltrifluorobo-
rates. It is important to note that all these N,N-dialkylam-
moniomethyltrifluoroborates are prepared as the internal
salts following a new procedure, which avoids the KBr
salt contamination of previous processes.9 Both cyclic
(piperidine, morpholine, N-protected piperazine) and acyclic
tertiary ammoniomethyl salts are very well tolerated by the
reaction conditions. The corresponding desired compounds
2a,b,d-h were all obtained with yields ranging from 72% to
97% (Table 1, entries 1, 2, and 4-8). Even a thiomorpholine
derivative, known to be a more difficult substrate because
sulfides often poison the catalyst,11 worked well with a
modest yield of 53% (Table 1, entry 3). Access to bifunctio-
nalized compounds such as 2e are of particular interest
because N-Boc deprotection and substitution of the resulting
free amine compound can be envisioned, leading to more
highly elaborated molecular platforms.
Table 3. Scope of Heteroaryl Mesylates
Table 2. Scope of Functionalized Mesylated Phenols
a Isolated as the HCl salt. b [Pd] (5 mol %) and L (10 mol %). The HCl
salt was hydrolyzed with 1 M KOH to obtain the amine. c Isolated
directly as the free amine.
We further examined the reactivity of a range of
functionalized aryl mesylates in the presence of the
N-(trifluoroboratomethyl)piperidine internal salt. The re-
action exhibits high functional group compatibility by
proceeding well with ketone, ester, ether, nitrile and alde-
hyde functional groups. The desired compounds were
obtained with yields ranging from 44% to 91%. Even
hindered substrates afford the cross-coupled products
3g-i with yields up to 83% (Table 2, entries 7-9). The
loading of Pd(OAc)2 was adjustedto 5 mol % inthese cases
to enable the reaction to proceed to completion. Surpris-
ingly, aryl mesylates bearing electron-donating groups are
more efficient than mesylates bearing electron-withdraw-
ing groups. By increasing the scale of the reaction to 5
mmol, we were able to decrease the loading of palladium to
0.5 mol % to obtain 3a with a yield of 75% (compared to
85% on a 0.25 mmol scale with 2 mol % catalyst loading).
It is important to note that almost all these desired
compounds were isolated without purification by column
chromatography. Instead, they were converted directly
into their corresponding hydrochloride salt.
We next investigated the reactivity of heteroaryl mesylates
as electrophilic partners in the Csp2-Csp3 cross-coupling.
a Isolated as the HCl salt. b Ph-OMs (1 equiv), N-(trifluorobora-
tomethyl)piperidine internal salt (1.3 equiv), Pd(OAc)2 (0.5 mol %),
XPhos (1 mol %), and K3PO4 (7.2 equiv), 110 °C, 24 h. c The HCl salt
was hydrolyzed with 1 M KOH to obtain the amine. d [Pd] (5 mol %) and
L (10 mol %).
(9) Raushel, J.; Sandrock D. L.; Josyula, K. V.; Pakyz, D.; Molander,
G. A. Manuscript in preparation.
(10) Relative GC yield = 100% for all using dodecane as the internal
standard.
(11) Wise, H. Stud. Surf. Sci. Catal. 1991, 68, 497–504.
1244
Org. Lett., Vol. 13, No. 5, 2011

Pyridine, quinoline, and isoquinoline substrates all pro-
vided the aminomethyl compounds 4a,c,d with very high
yields ranging from 89% to 98%. The 2-methylpyridin-3-
yl mesylate appears to be much less reactive, even if the
loading of catalyst was increased to 5 mol %, affording 4b
with a modest 41% yield (Table 3, entry 2). A 60% yield
was obtained when the N-unprotected indole is used in the
reaction (Table 3, entry 5).
Extension of this reaction to potassium amidomethyltri-
fluoroborates turned out to be successful under the stan-
dard conditions with the naphthol mesylate 1a. Aryl,
cyclic, and acyclic alkyl carboxamides can be used as
nucleophilic partners with great efficiency. The desired
compounds 5a-e are obtained with yields up to 88%. To
favor the completion of the reaction with the cyclopropyl-
carboxamide substrate, 5 mol % of Pd(OAc)2 was used to
afford 5c with a 70% yield (Table 4, entry 3). Moreover,
this protocol is also compatible with aryl- and heteroaryl
mesylates to afford pivalamides 5e-h with yields up to
94% (Table 4, entries 5-8).
Table 4. Scope of Potassium Amidomethyltrifluoroborates
In summary, we have developed a general method for
Csp2-Csp3 Suzuki-Miyauracross-couplings ofmesylates
with N,N-dialkylammoniomethyltrifluoroborates. Both
cyclic and acyclic ammoniomethyl salts were successfully
cross-coupled withhigh yields. This system hasalsoproven
to be well-tolerant of a large variety of functionalized aryl-
and heteroaryl mesylates. Moreover, the scope of the
reaction was extended to the carboxamidomethyltrifluoro-
borates with success. The versatility and the wide scope of
this reaction should facilitate the introduction of the
aminomethyl moiety into complex organic molecules.
Acknowledgment. This research was supported by a
National Priorities Research Program (NPRP) grant from
the Qatar National Research Fund (Grant No. 08-035-1-
008) and the NIH (R01 GM-081376). We acknowl-
edge Frontier Scientific for its donation of Pd(OAc)2.
Dr. Rakesh Kohli (University of Pennsylvania) is acknowl-
edged for obtaining HRMS data.
Supporting Information Available. Experimental pro-
cedures and spectral data. This material is available free
of charge via the Internet at http://pubs.acs.org.
a [Pd] (5 mol %) and L (10 mol %), 110 °C, 18 h. b [Pd] (2 mol %) and
L (4 mol %), 110 °C, 18 h.
Org. Lett., Vol. 13, No. 5, 2011
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