One-pot primary aminomethylation of aryl and heteroaryl halides with sodium phthalimidomethyltrifluoroborate

Article abstract of DOI:10.1021/ol301037s

A one-pot primary aminomethylation of aryl halides, triflates, mesylates, and tosylates via Suzuki-Miyaura cross-coupling reactions with sodium phthalimidomethyltrifluoroborate followed by deamidation with ethylenediamine is reported.

Full text of DOI:10.1021/ol301037s

ORGANIC
LETTERS
2012
Vol. 14, No. 11
2818–2821
One-Pot Primary Aminomethylation of
Aryl and Heteroaryl Halides with Sodium
Phthalimidomethyltrifluoroborate
Norio Murai,†,‡ Masayuki Miyano,‡ Masahiro Yonaga,*,†,‡ and Keigo Tanaka*,‡
Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan, and Discovery Research Laboratories, Eisai Co.,
Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan
k6-tanaka@hhc.eisai.co.jp; m-yonaga@hhc.eisai.co.jp
Received April 20, 2012
ABSTRACT
A one-pot primary aminomethylation of aryl halides, triflates, mesylates, and tosylates via SuzukiÀMiyaura cross-coupling reactions with sodium
phthalimidomethyltrifluoroborate followed by deamidation with ethylenediamine is reported.
Aromatic rings bearing a primary aminomethyl group
are widely used in bioactive molecules and their synthetic
precursors (Figure 1).1 Common starting materials for the
synthesis of primary aminomethyl aromatic compounds
include aryl aldehydes,2 cyanides,3 amides,4 oximes,5
methyl halides,6 and methyl azides.5a,7 However, the utility
of these starting materials is limited by the number
of functional groups that are stable under reductive con-
ditions and by the number of commercially available
chemically diverse compounds. There have been several
reports on the use of palladium-catalyzed aminomethyla-
tion reactions of aryl halides with N-protected primary
† University of Tokyo.
‡ Eisai Co., Ltd.
(1) (a) Musher, D. M.; Fainstein, V.; Young, E. J. Antimicrob. Agents
Chemother. 1980, 254. (b) Selness, S. R.; Boehm, T. L.; Walker, J. K.;
Devadas, B.; Durley, R. C.; Kurumbail, R.; Shieh, H.; Xing, L.;
Hepperle, M.; Rucker, P. V.; Jerome, K. D.; Benson, A. G.; Marrufo,
L. D.; Madsen, H. M.; Hitchcock, J.; Owen, T. J.; Christie, L.; Promo,
M. A.; Hickory, B. S.; Alvira, E.; Naing, W.; Blevis-Bal, R.; Devraj,
R. V.; Messing, D.; Schindler, J. F.; Hirsch, J.; Saabye, M.; Bonar, S.;
Webb, E.; Anderson, G.; Monahan, J. B. Bioorg. Med. Chem. Lett. 2011,
21, 4059. (c) Miyamoto, Y.; Banno, Y.; Yamashita, T.; Fujimoto, T.; Oi,
S.; Moritoh, Y.; Asakawa, T.; Kataoka, O.; Yashiro, H.; Takeuchi, K.;
Suzuki, N.; Ikedo, K.; Kosaka, T.; Tsubotani, S.; Tani, A.; Sasaki, M.;
Funami, M.; Amano, M.; Yamamoto, Y.; Aertgeerts, K.; Yano, J.;
Maezaki, H. J. Med. Chem. 2011, 54, 831.
(2) For examples, see: (a) Heinen, A. W.; Peters, J. A.; van Bekkum,
H. Eur. J. Org. Chem. 2000, 2501. (b) Gross, T.; Seayad, A. M.; Ahmad,
M.; Beller, M. Org. Lett. 2002, 4, 2055. (c) Tang, J.; Qian, K.; Zhang,
B.-N.; Chen, Y.; Xia, P.; Yu, D.; Xia, Y.; Yang, Z.-Y.; Chen, C.-H.;
Morris-Natschke, S. L.; Lee, K.-H. Bioorg. Med. Chem. 2010, 18, 4363.
(3) (a) Nystrom, R. F.; Brown, W. G. J. Am. Chem. Soc. 1948, 70,
3738. For recent examples, see: (b) Saavedra, J. Z.; Resendez, A.;
Rovira, A.; Eagon, S.; Haddenham, D.; Singaram, B. J. Org. Chem.
2012, 77, 221. (c) Cabrita, I.; Fernandes, A. C. Tetrahedron 2011, 67,
8183.
(4) (a) Benington, F.; Morin, R. D.; Clark, L. C., Jr. J. Org. Chem.
€
K.; Junge, K.; Beller, M. Angew. Chem., Int. Ed. 2012, 51, 1662. (c)
1956, 55, 1545. For recent examples, see: (b) Das, S.; Wendt, B.; Moller,
ꢀ
ꢀ
Laval, S.; Dayoub, W.; Pehlivan, L.; Metay, E.; Favre-Reguillon, A.;
Delbrayelle, D.; Mignani, G.; Lemaire, M. Tetrahedron Lett. 2011, 52,
4072.
(5) For recent examples, see: (a) Zishiri, V. K.; Hunter, R.; Smith,
P. J.; Taylor, D.; Summers, R.; Kirk, K.; Martin, R. E.; Egan, T. J. Eur.
J. Med. Chem. 2011, 46, 1729. (b) Yraola, F.; Garcia-Vicente, S.;
ꢀ
Fernandez-Recio, J.; Albericio, F.; Zorzano, A.; Marti, L.; Royo, M.
J. Med. Chem. 2006, 49, 6197.
(6) For recent examples, see: (a) Lehmann, F.; Koolmeister, T.;
Odell, L. R.; Scobie, M. Org. Lett. 2009, 11, 5078. (b) Majumdar,
K. C.; Mondal, S.; De, N. Synthesis 2009, 18, 3127.
(7) For recent examples, see: (a) Norcliffe, J. L.; Conway, L. P.;
Hodgson, D. R. W. Tetrahedron Lett. 2011, 52, 2730. (b) Percec, V.;
Peterca, M.; Tadjiev, T.; Zeng, X.; Ungar, G.; Leowanawat, P.; Aqad,
E.; Imam, M. R.; Rosen, B. M.; Akbey, U.; Graf, R.; Sekharan, S.;
Sebastiani, D.; Spiess, H. W.; Heiney, P. A.; Hudson, S. D. J. Am. Chem.
Soc. 2011, 133, 12197. (c) Chang, M.; Park, S.-R.; Kim, J.; Jang, M.;
Park, J. H.; Park, J. E.; Park, H.-G.; Suh, Y.-G.; Jeong, Y. S.; Park,
Y.-H.; Kim, H.-D. Bioorg. Med. Chem. 2010, 18, 111.
r
10.1021/ol301037s
Published on Web 05/16/2012
2012 American Chemical Society

aminomethyltrifluoroborate derivatives.8 This method is
attractive because the reaction conditions are mild, and
arylhalidesare generallyinexpensiveand are commercially
available with various substitution patterns. However,
several problems with this method remain to be solved:
(i) N-Boc-protected aminomethylation reactions of aryl
mesylates and tosylates do not proceed; (ii) the chemical
yields of aminomethylation reactions of N-phthalimide-
protected compounds are only moderate in many cases;
and (iii) N-deprotection of N-acyl- and N-sulfonyl-pro-
tected aminomethyl compounds commonly requires strongly
basic or acidic conditions.9 Furthermore, although we
previously reported one-pot primary aminomethylation
reactions involving phthalimidomethyltrifluoroborate and
hydrazine, the chemical yields were only low to moderate.8a
viewpoint of cost and commercial availability, as men-
tioned above.
Scheme 1. Preparation of Sodium Phthalimidoylmethyltri-
fluoroborate 1
Table 1. Optimization of the SuzukiÀMiyaura Cross-Coupling
Reaction Conditions
Figure 1. Bioactive compounds containing a primary amino-
methyl-substituted aromatic ring and an N-(arylmethyl)phthalamic
acid.
NMR yield (%)a
entry
X
Cs2CO3 (equiv)
3
2
4
5
Therefore, we have been working on developing a more
general, higher yielding method for the introduction of a
primary aminomethyl group into aromatic rings.
1
Br
Br
Br
Br
Br
Br
Br
Cl
Cl
Br
Cl
Br
0.6
1.2
1.8
2.4
3.0
4.0
3.0
3.0
3.0
3.0
3.0
3.0
16
58
57
29
2
61
<1
<1
<1
<1
<1
<1
42
<1
<1
<1
<1
12
15
9
2
6
3
16
60
72
73
95
18
86
92
82
95
In addition, we hoped to use the developed method
for the synthesis of compounds with an N-(arylmethyl)-
phthalamic acid moiety, which is also found in various bio-
active compounds (Figure 1).10 N-(Arylmethyl)phthalamic
acids are commonly synthesized by reactions of arylmethyl
amines with either phthalic anhydride11 or phthalic acid.12
Tothe bestof our knowledge, there havebeen noreports of
the synthesis of N-(arylmethyl)phthalamic acids directly
from aryl halides, which are ideal substrates from the
4
6
5
5
6
2
5
7b
8b
9
1
3
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
10b,c
11d
12b,e
a Determined by 1HNMR. b Pd(dba)2 was used instead of Pd(OAc)2.
c 5.0 mol % of Pd(dba)2 and 12 mol % of S-phos. d 5.0 mol % of
Pd(OAc)2 and 12 mol % of S-phos. e 3.0 equiv of Na2CO3 was used
instead of Cs2CO3.
(8) (a) Tanaka, K. WO2008007670, priority application July 2006.
(b) Molander, G. A.; Hiebel, M.-A. Org. Lett. 2010, 12, 4876. (c) Molander,
G. A.; Fleury-Bregeot, N.; Hiebel, M.-A. Org. Lett. 2011, 13, 1694. (d)
ꢀ
Molander, G. A.; Shin, I. Org. Lett. 2011, 13, 3956. (e) Devulapally, R.;
ꢀ
Fleury-Bregeot, N.; Molander, G. A.; Seapy, D. G. Tetrahedron Lett.
2012, 53, 1051.
(9) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 4th ed.; John Wiley & Sons: New York, 2007.
Herein, we report a versatile method for one-pot pri-
mary aminomethylation of aryl and heteroaryl halides,
triflates, mesylates, and tosylates using sodium phthalimi-
domethyltrifluoroborate (1). Furthermore, we report
the first example of direct synthesis of N-(arylmethyl)-
phthalamic acid derivatives from aryl and heteroaryl
halides with 1.
Borate 1 was prepared by reaction of 2-(bromomethyl)-
4,4,5,5-tetramethyl-1,3,2-dioxaborolane with phthalimide,
NaH, and NaHF2 in 49% yield (Scheme 1).
(10) (a) Hodgson, S. T.; Lacroix, Y. M.; Procopiou, P. A. U.S. Pat.
Appl. Publ. 20100216860 A1, 2010. (b) Proschak, E.; Zettl, H.; Tanrikulu,
Y.; Weisel, M.; Kriegl, J. M.; Rau, O.; Schubert-Zsilavecz, M.; Schneider, G.
ChemMedChem 2009, 4, 41. (c) Shao, P. P.; Ok, D.; Fisher, M. H.;
Garcia, M. L.; Kaczorowski, G. J.; Li, C.; Lyons, K. A.; Martin, W. J.;
Meinke, P. T.; Priest, B. T.; Smith, M. M.; Wyvratt, M. J.; Ye, F.;
Parsons, W. H. Bioorg. Med. Chem. Lett. 2005, 15, 1901.
(11) (a) Temperini, A.; Terlizzi, R.; Testaferri, L.; Tiecco, M. Synth.
Commun. 2010, 40, 295. (b) Naik, S.; Bhattacharjya, G.; Talukdar, B.;
Patel, B. K. Eur. J. Org. Chem. 2004, 1254. (c) Sun, W. S.; Park, Y. S.;
Yoo, J.; Park, K. D.; Kim, S. H.; Kim, J.-H.; Park, H.-J. J. Med. Chem.
2003, 46, 5619.
(12) (a) Martin, B.; Sekljic, H.; Chassaing, C. Org. Lett. 2003, 5, 1851.
(b) Francis, C. J.; Guoliang, L.; Zehong, W.; Hongxing Y. U.S. Pat. Appl.
Publ. 20090197871, 2009. (c) Petersson, M. J.; Marchal, C.; Loughlin, W. A.;
Jenkins, I. D.; Healy, P. C.; Almesaker, A. Tetrahedron. 2007, 63, 1395.
(13) For review, see: (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95,
2457. (b) Kotha, S.; Lahiri, K.; Kashinath, D. Tetrahedron 2002, 58,
9633.
Org. Lett., Vol. 14, No. 11, 2012
2819

Table 2. Synthesis of N-(Arylmethyl)phthalamic Acid Using
SuzukiÀMiyaura Cross-Coupling Reactiona
Table 3. One-Pot Primary Aminomethylation of Aryl and Het-
eroaryl Halides and Triflatesa
a Reaction conditions: 1.0 equiv of substrate, 5 mol % of [Pd], 12 mol %
of S-phos, 1.5 equiv of borate 1, 4.5 equiv of Na2CO3, 1,4-dioxane/
H2O (2/1), reflux. b Method A: [Pd] = Pd(OAc)2. Method B: [Pd] =
Pd(dba)2.
With 1 in hand, we optimized the conditions for the
SuzukiÀMiyaura cross-coupling reaction.13 We initially
selected S-phos/Pd(OAc)214 as the catalyst, Cs2CO3 as the
base, and dioxane/H2O as the solvent. Preliminary results
indicated that the optimal dioxane/H2O ratio was 2/1; at
this ratio, all the reaction materials, including the reaction
intermediates, were dissolved; and the chemical yields and
reproducibility were the highest. In addition, a higher than
usual S-phos/Pd(OAc)2 ratio (2.4À3.0/1.0 compared to
2.0/1.0) gave high reproducibility with commercially avail-
able solvents that had not been distilled prior to use, as is
the case for palladium-catalyzed hydroxymethylation re-
actions of aryl halides and triflates.15 We then used these
initial reaction conditions to optimize the base and the
palladium source (Table 1). When the Cs2CO3/borate 1
ratio was 1.2À1.8/1.2, the major product was phthalimide
3, accompanied by phthalamic acid 5 (Table 1, entries 2
and 3). In contrast, 5 was efficiently obtained when the
Cs2CO3/borate 1 ratio was 3.0À4.0/1.2 (Table 1, entries 5
and 6).
a Reaction conditions: 1.0 equiv of substrate, 5 mol % of [Pd], 12 mol %
of S-phos, 1.5 equiv of borate 1, 4.5 equiv of Na2CO3, dioxane/H2O
(2/1), reflux; then 7.0 equiv of ethylenediamine and 1-propanol were
added, and the mixture was stirred at reflux for 24 h. b Method A: [Pd] =
Pd(OAc)2. Method B: [Pd] = Pd(dba)2. c 7.0 equiv of ethylenediamine
and t-BuOH was added after isolation of phthalamic acid 6d; then the
reaction mixture was stirred at reflux for 24 h. d 10 mol % of Pd(OAc)2
and 24 mol % of S-phos.
palladium sources were Pd(dba)2 for the aryl triflate, and
Pd(OAc)2 for the tosylate and the mesylate. The catalyst
loading could be reduced to 5 mol % (Table 1, entries 10
and 11). As the base, Cs2CO3 and Na2CO3 gave similar
yields of 5 (Table 1, entry 12). Forsubsequent reactions, we
selected Na2CO3 because it gave a better yield in the one-
pot deamidation reaction.
Interestingly, we found that the optimal palladium
sources differed for the aryl bromide and the aryl chloride
(Table 1, entries 7À9): Pd(OAc)2 was optimal for the
aryl chloride, whereas Pd(dba)2 was optimal for the aryl
bromide. Further investigation revealed that the optimal
Next, we used the optimized reaction conditions for the
direct synthesis of phthalamic acid derivatives from aryl
and heteroaryl halides using an amount (1.5 equiv) of
(14) Barder, T. E.; Buchwald, S. L. Org. Lett. 2004, 6, 2649.
(15) Murai, N.; Yonaga, M.; Tanaka, K. Org. Lett. 2012, 14, 1278.
2820
Org. Lett., Vol. 14, No. 11, 2012

borate 1 that was sufficient to give high reproducibility
(Table 2). Aldehyde, ester, and cyano groups were compa-
tible with the reaction conditions (Table 2, entries 2 and 3).
Moreover, heteroaryl halides containing thiophene and
pyridine rings were converted to the corresponding phtha-
lamic acids in 62% and 42% yields, respectively (Table 2,
entries 4 and 5).
85%, whereas the yield from the iodide was slightly lower
(53%;Table2, entry1). Theelectron densityofthe benzene
ring had little effect on the yield (Table 3, entries 2À6). The
reactionconditionswere compatible withcyano, nitro, and
ketone functional groups. To our surprise, an ester group
remained intact as long as the reaction was conducted
by a stepwise process involving the isolation of phthalamic
acid 6d followed by deamidation with ethylenediamine
in 2-methyl-2-propanol (Table 3, entry 6). The primary
aminomethylation of heteroaryl halides and triflates pro-
ceeded smoothly to afford the desired primary amino-
methyl compounds in moderate to good yields (Table 3,
entries 7À10).
Table 4. One-Pot Primary Aminomethylation of Aryl and Het-
eroaryl Mesylates and Tosylatesa
Scheme 2. Concise Synthesis of Sodium Channel Blocker 11
To explore the scope of the reaction, we examined the
primary aminomethylation of aryl and heteroaryl mesy-
lates and tosylates (Table 4). As we expected, we obtained
primary aminomethyl compounds in yields ranging from
35% to 85% (Table 4, entries 1À5).
To demonstrate the utility of these methods for medic-
inal chemistry, we used them to synthesize sodium channel
blocker 1110c (Scheme 2). We synthesized 11 in fewer than
the eight or nine reaction steps required for the previously
reported synthesis.
a Reaction conditions: 1.0 equiv of substrate, 7.5 mol % of Pd(OAc)2,
18 mol % of S-phos, 1.5 equiv of borate 1, 4.5 equiv of Na2CO3, dioxane/
H2O (2/1), reflux, 48 h; then 7.0 equiv of ethylenediamine and 1-propanol
were added, and the mixture was stirred at reflux for 24 h.
In summary, we developed two versatile synthetic meth-
ods involving sodium phthalimidomethyltrifluoroborate
(1): (i) a one-pot primary aminomethylation of aryl and
heteroaryl halides, triflates, mesylates, and tosylates and
(ii) a direct synthesis of N-(arylmethyl)phthalamic acids from
aryl and heteroaryl halides. Moreover, we used the methods
for a concise synthesis of a bioactive compound 11.
Next, we optimized the conditions for the primary
aminomethylation of aryl halides via the one-pot deami-
dation of N-(arylmethyl)phthalamic acid. We found that
the addition of an alcohol as a cosolvent was necessary for
the one-pot deamidation reaction. 1-Propanol was optimal
because the reflux temperature of the reaction mixture was
higher than that with methanol or 2-methyl-2-propanol,
and the higher temperature promoted the deamidation
reaction. Ethylenediamine was selected as the amine be-
causeitismorereactiveand safer thanhydrazine, which we
used previously.8a
Acknowledgment. We acknowledge Ms. Yumi Asai
and Ms. Mami Gomibuchi of Eisai Co., Ltd. for IR and
HRMS data.
Supporting Information Available. Experimental pro-
cedures and spectral data for relevant compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
We used the optimized primary aminomethylation con-
ditions for reactions of various aryl and heteroaryl halides
and triflates (Table 3). 2-Naphthyl chloride, bromide, and
triflate were converted to 7a in yields ranging from 71% to
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 11, 2012
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