NAlkylation of tosylamides using esters as primary and tertiary alkyl sources: Mediated by hydrosilanes activated by a ruthenium catalyst

Article abstract of DOI:10.1002/anie.201201426

Select your group: Either a primary or tertiary alkyl group can be selectively introduced onto the nitrogen atom of tosylamides in a ruthenium-catalyzed reaction employing hydrosilanes through a judicious choice in the esters that serve as the alkyl source (see scheme; Ts= 4-toluenesulfonyl). These N-alkylation reactions are useful for construction of naturally occurring azacyclic skeletons. Copyright

Full text of DOI:10.1002/anie.201201426

Angewandte
Chemie
DOI: 10.1002/anie.201201426
Synthetic Methods
N Alkylation of Tosylamides Using Esters as Primary and Tertiary
Alkyl Sources: Mediated by Hydrosilanes Activated by a Ruthenium
Catalyst**
Takashi Nishikata and Hideo Nagashima*
It is well known that alkyl amines are important functional
groups in organic chemistry, and exploration of their prepa-
rative methods has been a target of current organic syn-
thesis.[1,2] Although nucleophilic substitution reactions of
alkyl halides or sulfonate esters by amines are one of the
most straightforward synthetic routes to alkylamines,[3,4] the
alkyl group is often limited to simple primary alkyl groups,
and the highly polar nature of the amines causes problematic
side reactions, for example, overalkylation and elimination
reactions. Two procedures are often used to solve these
problems: 1) By using a two-step procedure including N al-
kylation of amides with alkyl halides or sulfonate esters, with
subsequent transformation of the amide function,[2,5] and
2) the reductive N alkylation of ammonia or amines using
ketones or aldehydes as an alkyl source.[5,6] However, the
problem still remains unsolved as described in a recent review
by Kan and Fukuyama.[2] Although preparation of primary
and secondary alkyl amines can be achieved by the above
procedures, neither nucleophilic substitution nor reductive
alkylation provides a general method for the preparation of
tertiary alkyl amines.[7] As summarized in a recent review by
Clayden and co-workers,[8] the rearrangements such as the
Curtius rearrangement[9] and sigmatropic rearrangements[10]
of readily available precursors are practical alternatives,
whereas the Ritter reaction,[11] 1,2-addition of an organome-
tallic reagent to an imine,[12] and other metal-catalyzed
amination reactions[13] are used for preparation of limited
number of amines. Herein we report a unique solution of the
problem of N alkylation by using esters as primary and
tertiary alkyl sources under mild reaction conditions.
As shown in Scheme 1, the reaction of primary or
secondary alkyl esters (4; R1CO2R2 where R2 = primary or
secondary alkyl) with the combination of a hydrosilane (2)
and a catalytic amount of the ruthenium complex 1[14] in the
presence of TsNHR3 (3; R3 = H, alkyl) results in the
introduction of the primary alkyl group (R1CH2) to the
nitrogen atom of 3 to give products 5 (“reductive alkylation”).
In contrast, the treatment of tertiary alkyl esters (4; R1CO2R2
where R2 = tertiary-alkyl) with the same catalyst system
Scheme 1. Two types of N-alkylations with an ester. Ts=4-toluene-
sulfonyl.
under similar reaction conditions results in the cleavage of
2
À
the O R bond of 4, thus leading to the introduction of the
tertiary alkyl group to the nitrogen atom of 3 to give products
6 (“tertiary alkylation”). In other words, introductions of both
primary and tertiary alkyl groups to 3 are achieved by simply
changing the hydrosilane 2 and the R2 group of 4.
Typical examples of reductive alkylation and tertiary
alkylation are shown in Table 1 (see details in the Supporting
Information). Treatment of 3a with Ph(CH2)2CO2Me (4a’) in
the presence of 1,1,3,3-tetramethyldisiloxane (TMDS; 2A;
3 equiv) and 1 (1 mol%) at room temperature for 6 hours
gave Ph(CH2)3NHTs (5a) in 96% yield (entry 1). The ethyl
ester 4a also gave 5a in high yield without over alkylation
(entry 2). The isopropyl ester Ph(CH2)2CO2iPr also behaved
as a primary alkyl source, but the yield of 5a was moderate.
Interestingly, the reaction of Ph(CH2)2CO2tBu or AcOtBu
under similar reaction conditions gave a mixture of 5a or
EtNHTs (6a’’) and tBuNHTs (6a). Optimization of the
Table 1: Ruthenium-catalyzed N alkylations.
Entry
2
R1
R2
4
Products (yield [%])[c]
1[a]
2[a]
3[b]
4[b]
2A
2A
2B
2B
Ph(CH2)2
Ph(CH2)2
iPr
Me
Et
tBu
tBu
4a’
4a
4b
4b
5a (96)
5a (97)
5a’ (8)
5a’ (1)
6a’ (0)
6a’’ (0)
6a (92)
6a (>99)
[*] Dr. T. Nishikata, Prof. Dr. H. Nagashima
Institute for Materials Chemistry and Engineering
Kyushu University, Kasuga, Fukuoka 816-8580 (Japan)
E-mail: nagashima@cm.kyushu-u.ac.jp
iPr
[a] Conducted at RT for 6 h in the presence of 1 (0.0025 mmol), 2A
(0.75 mmol), 3a (0.25 mmol), and 4a or 4a’ (0.63 mmol) in CH2Cl2.
[b] Conducted at RT for 6 h in the presence of 1 (0.0025 mmol), 2B
(0.75 mmol), 3a (0.25 mmol), and 4b (0.5 mmol) in CH2Cl2. [c] Yield of
isolated product.
[**] This work was supported by the JST, CREST, and the Grant-in-Aid for
Young Scientists (B) (24750043).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201201426.
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!

.
Angewandte
Communications
reaction conditions for tertiary alkylation provided the two
results shown in entries 3 and 4 in Table 1. Use of iPrCO2tBu
(4b) instead of Ph(CH2)2CO2tBu or AcOtBu resulted in the
successful increase of the ratio of 5a’/6a to 8:92 in the reaction
with TMDS (entry 3). Selective preparation of 6a was
achieved by changing the silane from 2A to EtMe2SiH (2B)
as shown in entry 4.[15]
examples, that is, the preparation of 5h and 5i from the bulky
TsNH(nPent) (3c) and TsNH(prenyl) (3d) substrates, respec-
tively.[17]
The reaction of iPrCO2R2 (R2 = tertiary alkyl group) with
EtMe2SiH and 3a resulted in tertiary alkylations at room
temperature as shown in Table 3. The yields of the products
are generally high, but the reaction of 4q gave 6i in low yield
because of the steric bulk, and the E1 reaction of 4q during
the reaction. Steric hindrance of the tertiary alkyl group
contributes to the selective single alkylation of 3a because of
the much slower second alkylation of TsNHR2. The tosyl-
amide 3b having a relatively small Me group, however, can be
alkylated with 4r and 4b under the reaction conditions to give
6k and 6j, respectively, in high yields.
Representative examples for these two reactions under
optimized reaction conditions are summarized in Table 2. For
reductive alkylation,[16] ethyl esters are generally useful as the
primary alkyl source, and the alkylated tosylamides 5b–
e were obtained in good yields from the corresponding ethyl
esters 4c–g and 3a. The reaction is tolerant to halogen groups,
and no racemization was observed in the reaction of (R)-
PhCHMeCO2Et (4h) with 3a. Selective single alkylation of
3a was generally accomplished as a result of the significant
rate difference between the first alkylation of 3a to give
TsNH(CH2R1) and the alkylation of TsNH(CH2R1) (5) to
give TsN(CH2R1)2. The exceptions are MeCO2Et and EtO-
(CH2)2CO2Et (4i), which is accompanied by double alkylation
to give the corresponding TsN(CH2R1)2 as a by-product.
Although the rate difference between the first and second
alkylations is very large, the high reactivity of 4i contributes
to an increase in the alkylation rate of substituted tosylamides
(TsNHR) to the point where the reaction gave two successful
Since azacarbocycles are found in a variety of amino acids,
alkaloids, and other bioactive molecules, efficient construc-
tion of their skeletons is a challenging issue in organic
Table 3: Representative examples for N tertiary alkylation.[a]
3
R3
4
R2
Product
(yield [%])
3a
3a
H
H
4j
p-BrC6H4Me2C
(o-tolyl)Me2C
Table 2: Representative examples for reductive N alkylation.[a]
6b (98)
6c (73)
4k
3a
3a
3a
H
H
H
4l
Ph(Me)EtC
3
R3
4
R1
Product
(yield [%])
6d (80)
3a
3a
3a
3a
3a
H
H
H
H
H
4c
4d
4e
4 f
4g
I(CH2)5
4m
4n
Ph(Me)nPrC
p-BrC6H4(Me)EtC
5b (89)[b]
5c (73)
6e (76)[b]
Cl(CH2)3
6 f (78)[b]
6g (70)[c]
4-BrC6H4CH2
3-MeOC6H4CH2
(nPent)2CHCH2
5d (67)
3a
3a
3a
H
H
H
4o
4p
4q
p-MeOC6H4(CH2)2Me2C
adamantyl
5e (84)[b]
5 f (81)[c,e]
6h (92)
6i (32)[c]
3a
3c
3d
H
4h
(R)-Ph(Me)CH
5g (69) (99% ee)[c,d]
Et2MeC
nPent
prenyl
4i
EtO(CH2)2
3b
3b
Me
Me
4b
4r
tBu
5h (99)[c]
5i (99)[c]
6j (98)[c]
6k (70)[c]
4i
EtO(CH2)2
PhMe2C
[a] Conducted at RT for 6 h in the presence of 1 (0.0025 mmol), 2A
(0.75 mmol), 3 (0.25 mmol) and 4 (0.63 mmol) in CH2Cl2 (0.5 mL).
Reported yields are those for the isolated product. [b] Run for 10 h.
[c] Run for 20 h. [d] 5 equiv of 4 was used. [e] 2 mol% catalyst was used.
See details in the Supporting Information.
[a] Conducted at RT for 6 h in the presence of 1 (0.0025 mmol), 2B
(0.75 mmol), 3 (0.25 mmol) and 4 (0.5 mmol) in CH2Cl2 (0.1 mL). Less
than 5% of the reductive alkylation product 5 was produced. Reported
yields are those for the isolated product. [b] Run for 10 h. [c] Run for 20 h.
See details in the Supporting Information.
2
www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
synthesis. Intramolecular reductive N alkylation of the amide
esters 7 was examined systematically, and five-, six-, and
seven-membered azacycles (8c–e) were synthesized under
the reaction conditions (Scheme 2). Three- and four-mem-
bered rings (8a,b) could not be formed, even at high
temperature.
Scheme 4. Azaspirocycles. Reaction conditions: 1 (0.005 mmol), 2A
(0.75 mmol), 11 (0.25 mmol), CH2Cl2, reflux, 5 h. See details in the
Supporting Information. Reported yields are those for the isolated
product.
Scheme 2. Synthesis of azacycloalkanes. Reaction conditions:
1 (0.0025 mmol), 2A (0.75 mmol), 7 (0.25 mmol), CH2Cl2, RT, 20 h.
See details in the Supporting Information. Reported yields are those
for the isolated product.
azacarbocycles. Additional applications and studies into the
mechanism[22] are currently underway.
Received: February 21, 2012
Published online: && &&, &&&&
Keywords: amination · reduction · ruthenium · silanes ·
synthetic methods
One of the interesting applications of intramolecular
reductive alkylation is the conversion of the glutamic acid
ester 9 into the proline derivative 10 (Scheme 3). To our
astonishment, N-tosylated dimethyl glutamate (9) easily
.
[1] a) S. Patai, The Chemistry Amino, Nitroso and Related Groups,
Wiley, New York, 1996; b) R. N. Salvatore, C. H. Toon, K. W.
Jung, Tetrahedron 2001, 57, 7785.
[2] T. Kan, T. Fukuyama, Chem. Commun. 2004, 353.
[3] O. Mitsunobu, Synthesis 1981, 1.
[4] Classical amination reactions via SN2: a) M. Delꢀpine, Bull. Soc.
Chim. Fr. 1895, 13, S352; b) M. G. Gibson, R. W. Bradshaw,
Angew. Chem. 1968, 80, 986; Angew. Chem. Int. Ed. Engl. 1968,
7, 919.
Scheme 3. Chemoselective cyclization of optically active glutamate.
[5] Modern Reduction Methods (Eds.: P. G. Andersson, I. J. Mun-
slow), Wiley-VCH, Weinheim, 2008.
reacts with TMDS in the presence of 1 to give the methyl
ester of N-tosylated proline in good yields. No racemization
took place during the cyclization. Successful synthesis of the
proline derivative is ascribed to the selective reaction of only
one of the ester groups with the other remaining intact. It is
likely that the ester function very close to N-tosyl group is
somehow protected from the reaction towards the ruthenium-
catalyzed hydrosilane reduction.
Another challenge for the synthesis of azacarbocycles is
the construction of the azaspirocycles 12, which are skeletons
often seen in alkaloids.[18] The compounds 12a–d, which
comprise azaspirocycle structures, were synthesized in mod-
erate to high yields using 2A (Scheme 4). These are important
skeletons of bioactive compounds.[19] For example, 12b is
included as a partial structure of a synthetic intermediate for
androgen receptor antagonists[20] and alkaloids such as
lilolidine and julolidine derivatives.[21] Although a number
of approaches have been reported for the synthesis of those
molecules, the construction of spirocyclic structures from an
N-tertiary alkylation reaction with an ester is rare.
[6] a) R. F. Borch, A. I. Hassid, J. Org. Chem. 1972, 37, 1673;
b) W. S. Emerson, Org. React. 1990, 14, 174; c) P. Veeraragha-
van Ramachandran, P. D. Gagare, K. Sakavuyi, P. Clark, Tetra-
hedron Lett. 2010, 51, 3167; d) T. Gross, A. M. Seayad, M.
Ahmad, M. Beller, Org. Lett. 2002, 4, 2055; e) S. Fleischer, S.
Zhou, K. Junge, M. Beller, Chem. Asian J. 2011, 6, 2240, and
references therein.
[7] A Lewis acid promoted SN1 reaction was reported for the
preparation of adamantyl amines: T. Sasaki, A. Nakanishi, M.
Ohno, Chem. Pharm. Bull. 1982, 30, 2051.
[8] J. Clayden, M. Donnard, J. Lefranc, D. J. Tetlow, Chem.
Commun. 2011, 47, 4624.
[9] a) T. Curtius, Ber. Dtsch. Chem. Ges. 1890, 23, 3023; b) T.
Curtius, J. Prakt. Chem. 1894, 50, 275; c) P. A. S. Smith, Organic
Reactions, Vol. III, Wiley, New York, 1946, p. 337.
[10] Sigmatropic rearrangement leading to tertiary alkylamines:
K. C. Majumdar, T. Bhattacharyya, B. Chattopadhyay, B.
Sinha, Synthesis 2009, 2117. Also see Ref. [8].
[11] a) J. J. Ritter, P. P. Minieri, J. Am. Chem. Soc. 1948, 70, 4045;
b) L. I. Krimen, D. J. Cota, Org. React. 1969, 17, 213.
[12] For reviews, see: a) M. Shibasaki, M. Kanai, Chem. Rev. 2008,
108, 2853; b) S. Kobayashi, H. Ishitani, Chem. Rev. 1999, 99,
1069.
À
In summary, we have developed unique C N bond-
3
À
[13] Csp N bond formation with allylic alcohols as an alkyl source:
forming reactions by using esters as an alkyl source in the
presence of hydrosilanes and a ruthenium catalyst. This
reaction is applicable to cyclization reactions producing
a) J. Muzart, Eur. J. Org. Chem. 2007, 3077; b) J. He, J. W. Kim,
K. Yamaguchi, N. Mizuno, Angew. Chem. 2009, 121, 10072;
Angew. Chem. Int. Ed. 2009, 48, 9888; c) T. Nishikata, B. H.
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
These are not the final page numbers!

.
Angewandte
Communications
Lipshutz, Org. Lett. 2009, 11, 2377; d) B. Das, P. R. Reddy, C.
We confirmed that the Ts groups 5a is easily removed by HBr
and AcOH.
[18] For a review, see: J. Dake, Tetrahedron 2006, 62, 3467.
[19] H.-Y. He, D. J. Faulkner, J. Org. Chem. 1991, 56, 5369.
[20]
3
À
N
Sudhakar, M. Lingaiah, Tetrahedron Lett. 2011, 52, 3521; Csp
bond formation with allylic esters, ethers, carbonates, and nitriles
as an alkyl source: e) “Transition Metal Reagents and Catalysts,
Innovation”: J. Tsuji in Organic Synthesis, Wiley, Chichester,
2000; f) T. Nishikata, B. H. Lipshutz, Chem. Commun. 2009,
6472; g) M. Johannsen, K. A. Jørgensen, Chem. Rev. 1998, 98,
1689; h) H. Sajiki, T. Ikawa, K. Hirota, Org. Lett. 2004, 6, 4977;
Hydroaminations of olefins: i) M. Utsunomiya, R. Kuwano, M.
Kawatsura, J. F. Hartwig, J. Am. Chem. Soc. 2003, 125, 5608;
Csp3-H amination: j) S. A. Reed, M. C. White, J. Am. Chem. Soc.
2008, 130, 3316; k) S. Ueno, R. Shimizu, R. Kuwano, Angew.
Chem. 2009, 121, 4613; Angew. Chem. Int. Ed. 2009, 48, 4543.
[14] a) K. Matsubara, T. Iura, T. Maki, H. Nagashima, J. Org. Chem.
2002, 67, 4985; b) S. Hanada, T. Ishida, Y. Motoyama, H.
Nagashima, J. Org. Chem. 2007, 72, 7551; c) H. Nagashima, Y.
Kubo, M. Kawamura, T. Nishikata, Y. Motoyama, Tetrahedron
2011, 67, 7667, and references therein.
L. G. Hamann, R. I. Higuchi, L. Zhi, J. P. Edwards, X.-N. Wang,
K. B. Marschke, J. W. Kong, L. J. Farmer, T. K. Jones, J. Med.
Chem. 1998, 41, 623.
[21] A. Palma, J. S. Agredo, C. Carrillo, V. Kouznetsov, E. Stashenko,
A. Bashsas, J. Amaro-Luis, Tetrahedron 2002, 58, 8719.
[22] We currently hypothesize that the reaction mechanism is as
follows: We reported earlier the ruthenium-catalyzed hydro-
silane reduction of carboxylic acid derivatives in which TMDS is
an efficient reducing reagent.[14] The reduction of esters in the
presence of 1,3,5-trimethoxybenzene leads to aromatic primary
alkylation,[14c] which is explained by electrophilic substitution of
intermediary species with the aromatic ring. A similar reaction
of electrophilic intermediates with tosyl amides leads to N-
primary alkylation. We also reported removal of the tBu esters
under reaction conditions similar to those for tertiary alkylation
[15] O-tertiary butylation: a) H. Liang, S. Ito, M. Yoshifuji, Org. Lett.
2005, 7, 427; b) A. Procopio, P. Costanzo, M. Curini, M. Nardi,
M. Oliverio, R. Paonessa, Synthesis 2011, 73.
[16] For reductive Friedel–Crafts alkylation or acylation with esters,
see: a) Y. Nishimoto, S. A. Babu, M. Yasuda, A. Baba, J. Org.
Chem. 2008, 73, 9465; b) N. Sakai, K. Kawana, R. Ikeda, Y.
Nakaike, T. Konakahara, Eur. J. Org. Chem. 2011, 3178.
À
presented in this paper; the heterolytic cleavage of O tBu is
induced by the hydrosilanes activated by 1. The resulting
cationic tBu species is replaced by tosylamide to accomplish
tertiary alkylation.[23]
[23] S. Hanada, A. Yuasa, H. Kuroiwa, Y. Motoyama, H. Nagashima,
Eur. J. Org. Chem. 2010, 1021.
[17] We checked other protecting groups, such as Ns, Ms, Bn,
(PhO)2P, and Ph2P(O), and found that they did not work well.
4
www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Communications
Synthetic Methods
T. Nishikata,
H. Nagashima*
&&&& — &&&&
N Alkylation of Tosylamides Using Esters
as Primary and Tertiary Alkyl Sources:
Mediated by Hydrosilanes Activated by
a Ruthenium Catalyst
Select your group: Either a primary or
tertiary alkyl group can be selectively
introduced onto the nitrogen atom of
tosylamides in a ruthenium-catalyzed
reaction employing hydrosilanes through
a judicious choice in the esters that serve
as the alkyl source (see scheme; Ts=4-
toluenesulfonyl). These N-alkylation
reactions are useful for construction of
naturally occurring azacyclic skeletons.
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!