Copper-catalyzed N- and O-alkylation of amines and phenols using alkylborane reagents

Article abstract of DOI:10.1021/ol400323z

By the reaction of amines with alkylborane reagents in the presence of a catalytic amount of copper(II) acetate Cu(OAc)₂ and di-tert-butyl peroxide, a cross-coupling reaction proceeded and alkylated amines were obtained in good to excellent yields. Phenols are also applicable for this reaction, and the corresponding alkyl aryl ethers were produced.

Full text of DOI:10.1021/ol400323z

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Copper-Catalyzed N- and O‑Alkylation of
Amines and Phenols using Alkylborane
Reagents
Shunsuke Sueki and Yoichiro Kuninobu*
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan, and CREST, Japan Science and Technology
Agency (JST), 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
kuninobu@mol.f.u-tokyo.ac.jp
Received February 4, 2013
ABSTRACT
By the reaction of amines with alkylborane reagents in the presence of a catalytic amount of copper(II) acetate Cu(OAc)2 and di-tert-butyl peroxide,
a cross-coupling reaction proceeded and alkylated amines were obtained in good to excellent yields. Phenols are also applicable for this reaction,
and the corresponding alkyl aryl ethers were produced.
Many bioactive compounds,1 drugs, and organic func-
tional materials2 contain amino and ether functional groups.
Therefore, carbonÀnitrogen (CÀN) and carbonÀoxygen
(CÀO) bond formation reactions play an important role in
the synthesis of such compounds. A large number of CÀN
and CÀO bond formation reactions have been reported.
In the case of CÀN bond formation, however, it is usually
difficult to prevent overalkylation (formation of multialky-
lated amines and ammonium salts).3 Moreover, protectionÀ
deprotection of primary amines is necessary for the synth-
esis of secondary amines.4 To overcome the problem,
a cross-coupling reaction is one of the most useful and
promising synthetic methods (Figure 1). BuchwaldÀ
Hartwig amination5 is a well-known robust and practical
synthetic method of anilines, but this reaction requires
a strong base and β-hydride elimination occurs as a side
reaction in the synthesis of aliphatic amines.6 On the other
hand, a ChanÀLamÀEvans cross-coupling reaction be-
tween organoboronic acids and amines gives both ary-
lated and alkylated amines.7 The yields of the products in
this cross-coupling reaction are high, although this reaction
(7) (a) Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters, M. P.
Tetrahedron Lett. 1998, 39, 2933. (b) Lam, P. Y. S.; Clark, C. G.;
Saubern, S.; Adams, J.; Winters, M. P.; Chan, D. M. T.; Combs, A.
Tetrahedron Lett. 1998, 39, 2941. (c) Collman, J. P.; Zhong, M. Org.
Lett. 2000, 2, 1233. (d) Antilla, J. C.; Buchwald, S. L. Org. Lett. 2001, 3,
2077. (e) Lam, P. Y. S.; Vincent, G.; Clark, C. G.; Deudon, S.; Jadhav,
P. K. Tetrahedron Lett. 2001, 42, 3415. (f) Lam, P. Y. S.; Bonne, D.;
Vincent, G.; Clark, C. G.; Combs, A. P. Tetrahedron Lett. 2003, 44,
1691. (g) Quach, T. D.; Batey, R. A. Org. Lett. 2003, 5, 4397. (h) Lan,
J.-B.; Zhang, G.-L.; You, J.-S.; Chen, L.; Yan, M.; Xie, R.-G. Synlett
€
2004, 1095. (i) Moessner, C.; Bolm, C. Org. Lett. 2005, 7, 2667. (j) Hugel,
H. M.; Rix, C. J.; Fleck, K. Synlett 2006, 2290. (k) Singh, B. K.;
Appukkuttan, P.; Claerhout, S.; Parmar, V. S.; Van der Eycken, E.
Org. Lett. 2006, 8, 1863. (l) Jacobsen, M. F.; Knudsen, M. M.; Gothelf,
K. V. J. Org. Chem. 2006, 71, 9183. (m) Kantam, M. L.; Venkanna,
G. T.; Sridhar, C.; Sreedhar, B.; Choudary, B. M. J. Org. Chem.
2006, 71, 9522. (n) Sreedhar, B.; Venkanna, G. T.; Kumar, K. B. S.;
ꢀ
Balasubrahmanyam, V. Synthesis 2008, 795. (o) Gonzalez, I.; Mosquera,
(1) (a) Arend, M.; Westermann, B.; Risch, N. Angew. Chem., Int. Ed.
1998, 37, 1044. (b) Nicolaou, K. C.; Frederick, M. O.; Aversa, R. J.
Angew. Chem., Int. Ed. 2008, 47, 7182.
J.; Guerrero, C.; Rodrıguez, R.; Cruces, J. Org. Lett. 2009, 11, 1677.
(p) Larrosa, M.; Guerrero, C.; Rodrıguez, R.; Cruces, J. Synlett 2010,
2101. (q) DalZotto, C.; Michaux, J.; Martinand-Lurin, E.; Campagne,
(2) (a) Kulkarni, A. P.; Tonzola, C. J.; Babel, A.; Jenekhe, S. A.
Chem. Mater. 2004, 16, 4556. (b) Tsuji, H. J. Synth. Org. Chem. Jpn.
2010, 68, 1057.
(3) Kan, T.; Fukuyama, T. Chem. Commun. 2004, 353.
(4) Mitsunobu, O. Synthesis 1981, 1.
(5) (a) Paul, F.; Patt, J.; Hartwig, J. F. J. Am. Chem. Soc. 1994, 116,
5969. (b) Guram, A. S.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116,
7901.
(6) (a) Ishiyama, T.; Abe, S.; Miyaura, N.; Suzuki, A. Chem. Lett.
1992, 691. (b) Jana, R.; Pathak, T. P.; Sigman, M. S. Chem. Rev. 2011,
111, 1417.
ꢀ
J.-M. Eur. J. Org. Chem. 2010, 3811. (r) Joubert, N.; Basle, E.; Vaultier,
M.; Pucheault, M. Tetrahedron Lett. 2010, 51, 2994. (s) Reddy, B. V. S.;
Reddy, N. S.; Reddy, Y. J.; Reddy, Y. V. Tetrahedron Lett. 2011, 52,
2547. (t) Raghuvanshi, D. S.; Gupta, A. K.; Singh, K. N. Org. Lett.
2012, 14, 4326. (u) Liu, P.; Li, P.; Wang, L. Synth. Commun. 2012, 42,
2595. (v) Inamoto, K.; Nozawa, K.; Kadokawa, J.; Kondo, Y. Tetra-
hedron 2012, 68, 7794. (w) Naya, L.; Larrosa, M.; Rodrıquez, R.;
Cruces, J. Tetrahedron Lett. 2012, 53, 769. For reviews, see: (x) Ley,
S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400. (y) Qiao,
J. X.; Lam, P. Y. S. Synthesis 2011, 829. (z) Rao, K. S.; Wu, T.-S.
Tetrahedron 2012, 68, 7735.
r
10.1021/ol400323z
XXXX American Chemical Society

usually requires excess amounts of copper salts and sub-
strates, and the stability of some boronic acids is low.
In addition, there have been only a few reports on alkyl-
type cross-coupling reactions.7o,p,w Recently, Yamamoto,
Miyaura, and co-workers reported novel arylation and
alkylation of amines using aryl and alkyl triol borates, which
are prepared in basic conditions.8 This method could be used
in neutral conditions and gives multisubstituted amines in
good to excellent yields. We report herein a copper-catalyzed
cross-coupling reaction between alkylborane reagents and
amines that gave the corresponding alkylated amines in
good to excellent yields. The reaction conditions are applic-
able for alkylation of phenol derivatives. In these reactions,
stable boronates can be used as substrates, and addition of
a strong base is not necessary for a cross-coupling reaction.
Figure 2. Examples ofdrugs that containbenzylic amine moieties.
when the reaction temperature was decreased to 50 °C
(entry 3).11À14 The copper salt Cu(OAc)2 is indispensable
to promote the cross-coupling reaction (entry 4). The
yields of 3a were low when using other copper salts15
or oxidants16 (entries 5À13 and 16). The yield of 3a was
comparable to that in entries 2 and 3 when silver carbonate
Ag2CO3 was used as an oxidant. The following investiga-
tions were carried out using (tBuO)2, however, because
(tBuO)2 is much less expensive than Ag2CO3.
Next, the scope of alkylborane reagents was investi-
gated (Table 2). Benzyl boronic acid pinacol ester (1a)
showed higher reactivity compared with the corresponding
B-benzyl-9-borabicyclo[3.3.1]nonane 1b and borate 1c
(entries 1À3). Therefore, the following investigations were
performed using boronic acid pinacol esters. In a 1.0 mmol
scale reaction, the desired product 3a was obtained in 90%
yield (in the parentheses in entry 1). The cross-coupling
reactions proceeded using benzylic boronic acid pinacol
esters with an electron-donating or -withdrawing group,
1dÀf (entries 4À6). Primary and secondary aliphatic boronic
acid pinacol esters 1gÀj also produced the corresponding
coupling products 3eÀhin 51À82% yields (entries 7À10).17,18
Notably, although the ethoxycarbonyl and cyano groups
are sensitive to bases, the cross-coupling reaction proceeded
by this method without the loss of functional groups.
Reactions of benzyl boronic acid pinacol ester (1a) with
several amines were investigated (Table 3). The corresponding
Figure 1. Several types of cross-coupling reactions for the for-
mation of carbonÀheteroatom bonds.
This reaction is a rare example of catalytic alkylation of
amines and could be applicable to the synthesis of useful
compounds such as lavendustin A9 and methotrexate,10
which behave as tyrosine kinase and folic acid antagonists,
respectively (Figure 2).
At first, we investigated reactions between benzyl boro-
nic acid pinacol ester (1a) and N-methylaniline (2a) with
several copper salts and oxidants (Table 1). A cross-
coupling reaction between 1a and 2a proceeded in the
presence of a catalytic amount of Cu(OAc)2 in toluene at
100 °C for 24 h; however, N-benzyl-N-methylaniline (3a)
was formed in only 4% yield (entry 1). By adding 2 equiv
of (tBuO)2 as an oxidant, the yield of 3a was improved to
47% yield (entry 2), and 3a was obtained quantitatively
(11) The amount of catalyst was reduced to 3 mol % and 1 mol %,
and the yield of 3a was decreased to 70% and 32%, respectively.
(12) The amount of (tBuO)2 was decreased to 1 equiv, and the yield of
3a was 69%.
(13) When the reaction time was shortened to 12 h, the yield of 3a was
decreased to 49%.
(14) Investigation of several solvents, see: hexane, 48%; 1,4-dioxane,
9%; THF, 9%; 1,2-dichloroethane, 50%; N,N-dimethylformamide, 0%;
acetonitrile, 32%; DMSO, 0%.
(15) Several copper (I) salts were less effective than Cu(OAc)2 for the
cross-coupling reaction: CuCl, 9%; CuBr, 9%; CuI, 5%; CuOAc, 19%;
CuOTf 1/2toluene, 19%; MesCu, 5%. Other transition metals were also
3
investigated under the same reaction conditions; however, any satisfac-
tory results were not obtained: Pd(OAc)2, 3%. No reaction: Mn(OAc)2,
Mn(OAc)3, Fe(OAc)2, Co(OAc)2, Ni(OAc)2.
(8) Pd: (a) Yamamoto, Y.; Takizawa, M.; Yu, Z.-Q.; Miyaura, N.
Angew. Chem., Int. Ed. 2008, 47, 928. Cu: (b) Yu, Z.-Q.; Yamamoto, Y.;
Miyaura, N. Chem.;Asian J. 2008, 3, 1517.
(9) Onoda, T.; Iinuma, H.; Sasaki, Y.; Hamada, M.; Isshiki, K.;
Naganawa, H.; Takeuchi, T.; Tatsuta, K.; Umezawa, K. J. Nat. Prod.
1989, 52, 1252.
(16) No reaction: 1,4-benzoquinone, Ce(SO4)2, OXONE, TEMPO,
pyridine N-oxide. UreaÀhydrogen peroxide complex (UHP), 8%.
(17) The reactions did not give the corresponding cross-coupling pro-
duct using phenylboronic acid pinacol ester, N-methyliminodiacetic acid
protected phenyl boronate, and phenylboronic acid neopentylglycol ester.
(10) Kremer, J. M.; Lee, J. K. Arthritis Rheum. 1986, 29, 822.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Investigation of Several Transition-Metal Salts and
Oxidantsa
Table 2. Copper-Catalyzed Cross-Coupling Reactions between
Several Organoboron Reagents 1 and N-Methylaniline (2a)a
entry
catalyst
oxidant
none
yieldb (%)
1
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
none
4
47
99
1
2
(tBuO)2
(tBuO)2
(tBuO)2
(tBuO)2
(tBuO)2
(tBuO)2
(tBuO)2
tBuOOBz
PhI(OAc)2
K2S2O8
Me3NO
AgOAc
3c
4
5
CuCl2
17
4
6
CuBr2
7
Cu(OTf)2
Cu(OMe)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
6
8
4
9
12
<1
5
10
11
12
13
14
15c
16
33
31
55
96
13
Ag2CO3
Ag2CO3
O2 (1.0 atm)
a 1a (0.125 mmol), 2a (0.138 mmol, 1.1 equiv). b 1a (1.0 mmol), 70 °C.
c 2a (1.5 equiv), 0.50 M. d Hexane was used as a solvent. e 1i (2.0 equiv).
Bpin = pinacol borate.
a 2a (1.1 equiv). b Yield was determined by 1H NMR. c 50 °C. Bpin:
pinacol borate.
cross-coupling products 3iÀl were obtained in excellent
yields without the loss of the functional groups using
aniline derivatives with an electron-donating or
-withdrawing group 2bÀe (entries 1À4). The cross-
coupling reaction also proceeded in the presence of a
steric hindrance (entry 5). The desired product was also
produced when tosylamide 2g was used as a substrate
(entry 6). Functional group selectivity is important for the
synthesis of highly functionalized complex molecules. The
cross-coupling reaction proceeded only at the amino group,
even in the presence of a hydroxy group (entry 7). When
using primary anilines 2i and 2j, both mono- and dialky-
lated products can be formed. Interestingly, only mono-
alkylated products 3p and 3q were provided in 78% and
97% yields, respectively (entries 8 and 10). In entry 8, the
reaction was carried out using 2 equiv of 1a. As a result,
monobenzylated product 3p and dibenzylated product (N,
N-dibenzyl-4-methoxyaniline) 3q were obtained in 20%
and 60% yields, respectively (entry 9). In this reaction
system, a nitrogen-containing heteroaromatic compound
could also be applicable, and the desired benzylated pro-
duct 3s was afforded using carbazole (2k) (entry 11). The
corresponding product 3t was obtained in 65% yield using
phthalimide (2l) as a substrate (entry 12). The desired cross-
coupling reaction did not proceed using aliphatic amines,
such as butylamine and morpholine.
1.5 equiv of 1d gave 3p and the desired product 3u in 25%
and 70% yields, respectively (eq 1).
Phenols could be used instead of amines (Table 4).19 The
reaction of benzyl boronic acid pinacol ester (1a) with
phenol derivatives bearing an electron-donating or -with-
drawing group gave the corresponding benzyl aryl ethers
5aÀd in 42À70% yields (entries 1À4). In entry 3, the
yield of 5a was 62% (1.0 mmol scale). The reaction with
p-cyanophenol (4e) gave the product 5e in 44% yield with
functional group tolerance (entry 5). It is noteworthy that the
reactions using tyrosine derivative 4f and 17β-estradiol (4g)
provided the O-benzylated products 5f20 and 5g in 91% and
44% yields, respectively (entries 6 and 7). In entry 6, racemiza-
tion of the stereocenter of the tyrosine derivative occurred
in ca. 5%. The reaction did not proceed with thiophenol.
The proposed mechanism for the cross-coupling reaction is
shown in Scheme 1: (1) formation of copper(II) amide (or
aryloxycopper(II)) intermediate A from Cu(OAc)2 and an
(19) (a) Evans, D. A.; Katz, J. F.; West, T. R. Tetrahedron Lett. 1998,
39, 2937. (b) Quach, T. D.; Batey, R. A. Org. Lett. 2003, 5, 1381. (c)
Shade, R. E.; Hyde, A. M.; Olsen, J.-C.; Merlic, C. A. J. Am. Chem. Soc.
2010, 132, 1202. (d) Medda, A.; Pal, G.; Singha, R.; Hossain, T.; Saha,
A.; Das, A. R. Synth. Commun. 2013, 43, 169. See also ref 7a,7xÀ7z.
(20) Compound 5f is a intermediate for synthesis of some biologically
active compounds; see: (a) Yuan, W.; Munoz, B.; Wong, C.-H. J. Med.
Chem. 1993, 36, 211. (b) Cheng, X.-C.; Wang, R.-C.; Dong, Z.-K.; Li, J.;
Li, Y.-Y.; Li, R.-R. Bioorg. Med. Chem. 2012, 20, 5738.
Based on the result in Table 3, entry 9, introduction of
two different benzylic groups was investigated. The reac-
tion of 2i with 1.0 equiv of 1a and successive treatment with
(18) The cross-coupling reaction did not proceed using butylboronic
acid instead of butylboronic acid pinacol ester.
Org. Lett., Vol. XX, No. XX, XXXX
C

Table 3. Copper-Catalyzed Cross-Coupling Reactions between
Benzylpinacolborane (1a) and Several Amines 2a
Table 4. Copper-Catalyzed Cross-Coupling Reactions between
Benzylpinacolborane (1a) and Several Phenols 4a
a 1a (0.125 mmol), 4 (0.138 mmol, 1.1 equiv). b 1a (1.0 mmol).
Scheme 1. Proposed Mechanism of Copper-Catalyzed Cross-
Coupling Reactions between Alkylborane Reagents 1 and
Amines 2 (or Phenols 4)
a 2 (1.1 equiv). b 0.5 M. c 100 °C. d O-Benzylated product was not
formed. e 1a (2.0 equiv).
amine (or phenol);7s (2) generation of alkylcopper(II) species B
by transmetalation between Aand an alkylboronic acid pinacol
ester;19a and (3) oxidativeÀreductive elimination21 of the cop-
per catalyst with (tBuO)2 to give the cross-coupling product.
In the above estimated catalytic cycle, Cu(OtBu)2 is a
possible catalytic species. To examine this further, a reaction
of benzyl boronic acid pinacol ester (1a) with N-methylaniline
(2a) was performed in the presence of a catalytic amount of
Cu(OtBu)2 and (tBuO)2 (eq 2). N-Benzyl-N-methylaniline
(3a) was obtained in 62% yield. This result suggests that
Cu(OtBu)2 is a catalytic species after the first cycle.
In summary, we achieved a copper-catalyzed cross-
coupling reaction between aliphatic pinacol boronic acid
esters and amines. Corresponding secondary and tertiary
amines were obtained in good to excellent yields. Although
the generated Cu(OtBu)2 may work as a base, this reaction
does not require strong basic conditions, which is obtained
by using an oxidant, therefore, it can be applicable for use with
substrates having base-sensitive functional groups. In addi-
tion, this reaction system could also be applicable for alkyla-
tion of aza-heteroaromatic compounds and phenols. We
think that this reaction will become a useful synthetic
method for multisubstituted amines and aryl ethers.
In the 11B NMR spectrum in benzene-d6, the signal of
1a (32.5 ppm) disappeared completely following treatment
of 1a with 2a (1.1 equiv) in the presence of Cu(OAc)2
(5.0 mol %, 50 °C, 24 h) and new signals (1.01 ppm in 1H
NMR and 22.2 ppm in 11B NMR) appeared. The chemical
Acknowledgment. This work was supported in part by
CREST-JST. We thank Prof. M. Kanai at the University
of Tokyo for his generous support, fruitful discussions,
and unrestricted access to analytical facilities.
1
shifts are consistent with the reported H and 11B NMR
spectra of HO-Bpin,22 which must be generated from
tBuO-Bpin by hydrolysis in the workup operation. This
result shows that boronate C should be formed in situ.
Supporting Information Available. General experimen-
tal procedure and characterization data for cross-coupling
products 3aÀu and 5aÀg. This material is available free of
charge via the Internet at http://pubs.acs.org.
(21) Grimes, K. D.; Gupte, A.; Aldrich, C. C. Synthesis 2010, 1441.
(22) Bettinger, H. F.; Filthaus, M.; Bornemann, H.; Oppel, I. M.
Angew. Chem., Int. Ed. 2008, 47, 4744.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX