Direct: N -alkylation of sulfur-containing amines

Article abstract of DOI:10.1039/d1ob00368b

An efficient ruthenium-catalyzed method has been developed for the direct N-alkylation of sulfur-containing amines with alcohols, for the first time, by a step-economical and environmentally friendly hydrogen borrowing strategy. The present methodology features base-free conditions and broad substrate scope, with water being the only by-product. Moreover, this protocol has been applied to the synthesis of the pharmaceutical drug Quetiapine.

Full text of DOI:10.1039/d1ob00368b

Organic &
Biomolecular Chemistry
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Direct N-alkylation of sulfur-containing amines†
Chen Li, Min-Tong Ge, Liang Bai, Ai-Bao Xia, * Dan-Qian Xu * and
Zhen-Yuan Xu
Cite this: DOI: 10.1039/d1ob00368b
Received 25th February 2021,
Accepted 26th April 2021
DOI: 10.1039/d1ob00368b
rsc.li/obc
An efficient ruthenium-catalyzed method has been developed for pounds in the past few decades. Different primary and second-
the direct N-alkylation of sulfur-containing amines with alcohols, ary amines with various alcohols are commonly used as sub-
for the first time, by a step-economical and environmentally strates in this type of transformation.12 However, sulfur-con-
friendly hydrogen borrowing strategy. The present methodology taining amines, which are widely distributed in pharmaceuti-
features base-free conditions and broad substrate scope, with cals and bioactive natural products (Scheme 1),13 are rarely
water being the only by-product. Moreover, this protocol has been
applied to the synthesis of the pharmaceutical drug Quetiapine.
Amines are widely found in natural products, pharmaceuticals
and fine chemicals, so a study on the chemical modifications
of amines is crucial.1 Among them, N-alkylation is one of the
important synthetic methods for the construction of C–N
bonds.2 In addition to the conventional method of alkylation
via nucleophilic substitution reaction, using alkyl halides,3
which shows poor atom economy and leads to the formation
of stoichiometric amounts of waste, greener processes such as
reductive amination of carbonyl compounds,4 hydroamination
of olefins or alkynes,5 newly developed C–H bond activation/
amination,6 and direct coupling of amines with alcohols7 have
also been developed. However, despite impressive advances in
these catalytic transformations, some issues still need to be
addressed as shown in Fig. 1, and the direct alkylation of
amines with abundant and stable alcohols is a very attractive
Fig. 1 Major strategies for the construction of N-alkylated amines and
the borrowing hydrogen mechanism.
approach owing to its intrinsic step-economical and environ-
mentally benign nature.8 The general mechanism of this kind
of transformation, the hydrogen borrowing strategy,9 follows a
cascade redox type pathway involving in situ alcohol oxidation/
imine formation/imine hydrogenation steps.
Since the applications of the hydrogen borrowing strategy
were reported to realize the amination of alcohols by Grigg10
and Watanabe11 in the early 1980s, considerable progress has
been made in this field to synthesize various valuable com-
Catalytic Hydrogenation Research Center, State Key Laboratory Breeding Base of
Green Chemistry-Synthesis Technology, Zhejiang University of Technology,
Hangzhou 310014, China. E-mail: xiaaibao@zjut.edu.cn, chrc@zjut.edu.cn
†Electronic supplementary information (ESI) available: General procedures and
characterisation data. CCDC 2051969. For ESI and crystallographic data in CIF
or other electronic format see DOI: 10.1039/d1ob00368b
Scheme 1 Sulfur-containing drugs.
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used as reactants in the hydrogen borrowing strategy. The gen- (PPh3)2 (entry 12).19 Based on this promising result, the cata-
erally adopted methods for the N-alkylated modification of lyst RuCl2(H2O)(CO)(PPh3)2 was further synthesized by a new
sulfur-containing amines are still based on the nucleophilic method and the structure of the catalyst RuCl2(H2O)(CO)
substitution principle.14 The absence of direct N alkylation of (PPh3)2 was confirmed by single-crystal X-ray diffraction ana-
sulfur-containing amines with alcohols in the hydrogen bor- lysis (CCDC 2051969†).20 When it was employed, the reaction
rowing strategy may be largely due to sulfur’s strong coordi- yield increased, showing
a
14% increase (entry 13).
nation ability which results in catalytically inactive species.15 Subsequently, the catalyst loading, temperature, solvent and
When Watanabe’s group attempted to synthesize N-substituted molar ratio of 1a to 2a were further optimised (see the ESI,
thiomorpholines from amines and thiodiglycol in 1985, it was Table S1†). Finally, the optimal reaction conditions were deter-
speculated that the sulfide group might inactivate the ruthe- mined. In the case of a 5 : 1 molar ratio of alcohol 1a to thio-
nium catalyst, resulting in synthesis failure.16 To the best of morpholine 2a, with 1.0 mol% catalyst RuCl2(H2O)(CO)(PPh3)2
our knowledge, there are few reports on the use of noble metal loading under a nitrogen atmosphere at 150 °C for 5 h, the
catalysts to further develop the N-alkylation reaction of sulfur- target product 3aa was obtained in 95% isolated yield (Table 1,
containing amines with alcohols via the borrowing hydrogen entry 14).
mechanism. Herein, we document an efficient and practical
method for rapidly assembling sulfur-containing amines and evaluate the scope of the N-alkylation reaction under the opti-
alcohols. mized reaction conditions (Table 2). Remarkably, the reaction
Initially, a broad range of aromatic alcohols were used to
The initial studies towards the development of an efficient was compatible with a variety of aromatic alcohol substrates.
N-alkylation of sulfur-containing amines began with the evalu- As can be seen, regardless of electron donating (Me, MeO,
ation of ruthenium complexes; benzyl alcohol 1a and thiomor- t-Bu, Ph, and PhO) and electron-withdrawing (F, Br, and CF3)
pholine 2a were selected as model substrates. In the absence substituents on the phenyl group, the corresponding
of a catalyst, no product was formed (Table 1, entry 1). Then N-alkylation products 3aa–3ap and 3at–3au were obtained in
some effective literature-known ruthenium and rhodium cata- high to excellent yields (57–98% yields). To our delight, the
lysts for N-alkylation were used in the model reaction (entries iodine group in benzyl alcohol remained intact and the corres-
2–9),11,16,17 and the results showed that only with RuHCl(CO) ponding products 3aq–3as were obtained with extremely high
(PPh3)3 and RuH2(CO)(PPh3)3 as the catalysts at 150 °C, the yields of 92–99%. Furthermore, high yields were observed for
transformation afforded the desired product 3aa in 52% and disubstituted aryl alcohols, such as (3,5-dimethoxyphenyl)
45% isolated yields, respectively (entries 4 and 5). Next [Ru(p- methanol 3av and (3,5-difluorophenyl)-methanol 3aw.
cymene)Cl2]2 and [CpIrCl2]2, which exhibited a good catalytic Pleasingly, when changing to 2-pyridinemethanol and 2-thio-
effect on the N-alkylation of heteroatom-containing cyclic phenemethanol, the desired products 3ax and 3ay were iso-
amines,18 were used to catalyze the model reaction, but no lated in good yields of 80% and 87%, respectively. In addition,
reaction occurred here (entries 10 and 11). Gratifyingly, the the catalytic system was also efficient in the case of 1-naphthyl
yield could be improved to 57% by using RuCl2(CH3CN)(CO) methanol, affording 3az in 64% yield.
Table 1 Optimization of the reaction conditionsa,b
Table 2 Alkylation of thiomorpholine with benzylic alcoholsa,b
Entry
Cat.
Additive
Yield/%
1
2
—
—
—
—
7
RuCl2(PPh3)3
3
4
5
6
7
8
9
RuCl2(PPh3)4
—
—
—
—
—
—
—
dppf
K2CO3
—
—
—
—
52
45
—
—
—
—
—
—
57
71
95
RuHCl(CO)(PPh3)3
RuH2(CO)(PPh3)3
RuCl2(CO)2(PPh3)2
Ru(CO)3(PPh3)2
Ru3(CO)12
RhCl(PPh3)3
[Ru(p-cymene)Cl2]2
[CpIrCl2]2
10c
11d
12
13
14e
RuCl2(CH3CN)(CO)(PPh3)2
RuCl2(H2O)(CO)(PPh3)2
RuCl2(H2O)(CO)(PPh3)2
a Reaction conditions: benzyl alcohol 1a (2.0 mmol), thiomorpholine
2a (1.0 mmol) and catalyst (1.0 mol%) were heated for 5 h under N2. a Reaction conditions: alcohols 1 (5.0 mmol), thiomorpholine 2a
b Isolated yields. c The amount of dppf was 2.0 mol%. d The amount of (1.0 mmol) and RuCl2(H2O)(CO)(PPh3)2 (1.0 mol%), were heated at
K2CO3 was 1.0 mol%. e The ratio of 1a to 2a was 5 : 1.
150 °C for 5 h under N2. b Isolated yields.
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Table 3 Alkylation of thiomorpholine with aliphatic alcoholsa,b
Table 4 Alkylation of amines with alcoholsa,b
a Reaction conditions: alcohols 1 (5.0 mmol), amines 2 (1.0 mmol) and
RuCl2(H2O)(CO)(PPh3)2 (3.0 mol%) were heated at 150 °C for 5 h under
N2. b Isolated yield. c The amount of RuCl2(H2O)(CO)(PPh3)2 was
1.0 mol%. d Yield of 1,4-dibenzylpiperazine.
a Reaction conditions: alcohols 1 (5.0 mmol), thiomorpholine 2a
(1.0 mmol) and RuCl2(H2O)(CO)(PPh3)2 (3.0 mol%), were heated at
150 °C for 5 h under N2. b Isolated yield. c Reaction time: 10 h.
thesis and applications, underwent reactions to give 3ch–3ck
in good yields). Furthermore, sulfur-containing primary
amines also reacted smoothly to deliver bialkylated products
3cl–3cn in 55%–93% yields.
Next, the substrate scope of alkyl alcohols was investigated.
As demonstrated in Table 3, regardless of the pattern of alkyl
alcohols, N-alkylated products were obtained in good to high
yields in all cases. Straight chain (3ba–3bd) and sterically
demanding β-branched (3be and 3bf) primary alcohols were
found to be competent substrates, providing the desired pro-
ducts in 76–89% yields. Notably, cyclic secondary alcohols
were also suitable for the catalytic system to give 3bg and 3bh
in 89% and 81% yields, respectively. As representative
examples, phenyl (3bi and 3bj), alkoxy (3bk and 3bl), trifluoro-
methyl (3bm), carbonyl (3bn), and amide (3bo) groups were
successfully incorporated in this manner, and the desired
adducts 3bi–3bo were obtained with satisfactory yields. As can
be seen, the presence of heteroatom functionalities did not
have an obviously deleterious impact on the reaction perform-
ance. Moreover, 1-adamantane-methanol could react with thio-
morpholine smoothly to deliver 3bp in 52% yield. Butane-1,4-
diol also provided the corresponding 3bq product with a high
chemoselectivity and 71% isolated yield.
The N-alkylation reaction was extended successfully to a
larger preparative scale. As shown in Scheme 2a, on a scale of
10.0 mmol, the reaction proceeded quickly (5 h) using
1.0 mol% catalyst C7 and the desired product 3aa was
obtained in 93% yield. In addition, the sulfur-containing
alcohol, 2-(methylthio)-ethanol, could react well with aniline
(4a, 50% yield). The enantiomerically pure (S)-1-phenylethana-
mine was easily transformed into the corresponding
N-alkylation product (S)-N-(2-(methylthio)ethyl)-1-phenyletha-
namine 4b in 70% yield with chirality retention (Scheme 2b).
Moreover, the developed synthetic methodology is very valu-
able and could be applied for the direct synthesis of the
pharmaceutical drug Quetiapine,13b an effective first-line atypi-
cal antipsychotic agent. In conventional approaches, diethyl-
Finally, encouraged by the above results, the potential of
the N-alkylation reaction with respect to various heteroatom-
containing amines was further evaluated. As shown in Table 4,
a series of heteroatom-containing secondary and primary
amines reacted well to provide the desired products 3ca–3cn in
55%–98% yields. For piperidine, morpholine and piperazine,
the corresponding products 3ca, 3cb and 3cc could be
obtained with yields of 98%, 96% and 64%, respectively. The
reaction of representative thiomorpholine with benzyl alcohol
proceeded well to give the desired products 3cd and 3ce in
62% and 68% yields, respectively. Benzo-fused thiomorpholine
was incorporated with good efficiency (3cf, 58% yield).
Thiomorpholine-1,1-dioxide was a highly effective substrate in
the transformation giving 3cg in an excellent yield of 98%.
Both sulfur-containing secondary amines 4,5,6,7-tetrahy-
drothieno[2,3-c]pyridine and 3-(piperazin-1-yl)benzo[d]isothia-
zole, representative building blocks in medicinal agent syn- Scheme 2 Synthetic applications.
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ene glycol was chlorinated firstly by using a stoichiometric
chlorinating reagent, and then in the presence of a base, the
obtained 2-(2-chloroethoxy)ethanol reacted with 5 to give
Quetiapine. Utilizing the newly developed methodology, the
target 6 could be synthesized directly from sulfur-containing
amine 5 and diethylene glycol in 90% yield, and water was the
only by-product (Scheme 2c).
5142–5148; (c) S. L. Buchwald, C. Mauger, G. Mignani and
U. Scholz, Adv. Synth. Catal., 2006, 348, 23–39.
4 (a) P. N. Kolesnikov, N. Z. Yagafarov, D. L. Usanov,
V. I. Maleev and D. Chusov, Org. Lett., 2015, 17, 173–175;
(b) S. Zhou, S. Fleischer, H. Jiao and M. Beller, Adv. Synth.
Catal., 2014, 356, 3451–3455; (c) A. Pagnoux-Ozherelyeva,
N. Pannetier, M. D. Mbaye, S. Gaillard and J. L. Renaud,
Angew. Chem., Int. Ed., 2012, 51, 4976–4980; (d) C. Wang,
A. Pettman, J. Basca and J. Xiao, Angew. Chem., Int. Ed.,
2010, 49, 7548–7552; (e) S. Gomez, J. A. Peters and
T. Maschmeyer, Adv. Synth. Catal., 2002, 344, 1037–1057.
5 (a) W. Ma, X. Zhang, J. Fan, Y. Liu and W. Tang, J. Am.
Chem. Soc., 2019, 141, 13506–13515; (b) Y. Nakamura,
T. Ohta and Y. Oe, Chem. Commun., 2015, 51, 7459–7462;
(c) T. E. Müller, K. C. Hultzsch, M. Yus, F. Foubelo and
M. Tada, Chem. Rev., 2008, 108, 3795–3892; (d) M. Ahmed,
A. M. Seayad, R. Jackstell and M. Beller, J. Am. Chem. Soc.,
2003, 125, 10311–10318.
6 (a) H. W. Wang, Y. Lu, B. Zhang, J. He and H. J. Xu, Angew.
Chem., Int. Ed., 2017, 56, 7449–7453; (b) K.-H. Ng, Z. Zhou
and W.-Y. Yu, Org. Lett., 2012, 14, 272–275.
7 (a) X. Dai and F. Shi, Org. Biomol. Chem., 2019, 17, 2044–
2054; (b) A. Corma, J. Navas and M. J. Sabater, Chem. Rev.,
2018, 118, 1410–1459; (c) X. Ma, C. Su and Q. Xu, Top. Curr.
Chem., 2016, 374, 27.
Conclusions
In summary, a catalytic direct N-alkylation of sulfur-containing
compounds with alcohols using RuCl2(H2O)(CO)(PPh3)2 as a
catalyst has been developed for the first time by a hydrogen
borrowing strategy. The efficiency and practicality of this new
and green methodology were demonstrated with (1) alcohol to
amine molar ratio 5 : 1 and base-free conditions, (2) broad sub-
strate scope with wide functional group tolerance and chirality
retention, (3) good chemoselectivity and generally good yields,
and (4) water as the only generated by-product. In addition,
this protocol provided a step economical route to prepare the
pharmaceutical drug Quetiapine, which could avoid the use of
a stoichiometric toxic chlorinating reagent and base. Further
application of this methodology for the synthesis of other
drugs with sulfur-containing amine frameworks is now being
investigated.
8 (a) C. Risi, M. Calamante, E. Cini, V. Faltoni and
E. Petricci, Green Chem., 2020, 22, 327–331;
(b) A. Charvieux, J. B. Giorgi, N. Duguet and E. Métay,
Green Chem., 2018, 20, 4210–4216.
9 (a) C. Gunanathan and D. Milstein, Science, 2013, 341,
1229712; (b) A. J. Watson and J. M. J. Williams, Science,
2010, 329, 635–636; (c) G. Guillena, D. J. Ramón and
Conflicts of interest
There are no conflicts to declare.
M.
Yus,
Chem.
Rev.,
2010,
110,
1611–1641;
(d) M. H. S. A. Hamid, P. A. Slatford and J. M. J. Williams,
Adv. Synth. Catal., 2007, 349, 1555–1575; (e) M. G. Edwards,
R. F. Jazzar, B. M. Paine, D. J. Shermer and
M. K. Whittlesey, Chem. Commun., 2004, 90–91.
Acknowledgements
This work was financially supported by the Zhejiang Natural
Science Foundation (LY18B020017), Zhejiang Key Course of
Chemical Engineering and Technology, and Zhejiang Key 10 R. Grigg, T. R. B. Mitchell, S. Sutthivaiyakit and
Laboratory of Green Pesticides and Cleaner Production
Technology.
N. Tongpenyai, J. Chem. Soc., Chem. Commun., 1981, 611–
612.
11 Y. Watanabe, Y. Tsuji, H. Ige, Y. Ohsugi and T. Ohta, J. Org.
Chem., 1984, 49, 3359–3363.
12 (a) G. Balamurugan, R. Ramesh and J. G. Malecki, J. Org.
Chem., 2020, 85, 7125–7135; (b) D. Ye, R. Huang, H. Zhu,
L.-H. Zou and D. Wang, Org. Chem. Front., 2019, 6, 62–69;
(c) Y. Wu, Y. Huang, X. Dai and F. Shi, ChemSusChem, 2019,
12, 3185–3191; (d) M. Subaramanian, S. P. Midya,
P. M. Ramar and E. Balaraman, Org. Lett., 2019, 21, 8899–
8903; (e) J. Gour, S. Gatadi, S. Malasala, M. V. Yaddanpudi
and S. Nanduri, J. Org. Chem., 2019, 84, 7488–7494;
(f) S. Genc, B. Arslan, S. Gulcemal, S. Gunnaz and
B. Cetinkaya, J. Org. Chem., 2019, 84, 6286–6297;
(g) R. Fertig, T. Irrgang and F. Freitag, ACS Catal., 2018, 8,
8525–8530; (h) J. J. A. Celaje, X. Zhang, F. Zhang, J. Zander
and R. Kempe, ACS Catal., 2017, 7, 1136–1142; (i) Z. Yin,
H. Zeng, J. Wu and G. Zhang, ACS Catal., 2016, 6, 6546–
Notes and references
1 (a) M. Andrs, J. Korabecny, D. Jun, Z. Hodny and J. Bartek,
J. Med. Chem., 2015, 58, 41–71; (b) J. Chatterjee,
F. Rechenmacher and H. Kessler, Angew. Chem., Int. Ed.,
2013, 52, 254–269.
2 (a) A. Trowbridge, S. M. Walton and M. J. Gaunt, Chem.
Rev., 2020, 120, 2613–2692; (b) T. Irrgang and R. Kempe,
Chem. Rev., 2019, 119, 2524–2549; (c) S. Bähn, S. Imm,
L. Neubert, M. Zhang and H. Neumann, ChemCatChem,
2011, 3, 1853–1864.
3 (a) J. M. Dennis, N. A. White, R. Y. Liu and S. L. Buchwald,
J. Am. Chem. Soc., 2018, 140, 4721–4725; (b) O. Navarro,
N. Marion, J. Mei and S. P. Nolan, Chem. – Eur. J., 2006, 12,
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2021

View Article Online
Organic & Biomolecular Chemistry
Communication
6550; ( j) P. Satyanarayana, G. M. Reddy, H. Maheswaran
and M. L. Kantam, Adv. Synth. Catal., 2013, 355, 1859–
1867; (k) M. Bala, P. K. Verma, U. Sharma, N. Kumar and
Y. Unoh, R. A. Bohmann, T. Satoh and K. Hirano, Chem.
Lett., 2015, 44, 1104–1106; (d) J. Louie and J. F. Hartwig,
J. Am. Chem. Soc., 1995, 117, 11598–11599.
B. Singh, Green Chem., 2013, 15, 1687–1693; (l) A. Zhu, 16 Y. Tsuji, K. T. Huh, Y. Ohsugi and Y. Watanabe, J. Org.
L. Li, J. Wang and K. Zhuo, Green Chem., 2011, 13, 1244– Chem., 1985, 50, 1365–1370.
1250; (m) Z. Sahli, B. Sundararaju, M. Achard and 17 (a) D. Hollmann, A. Tillack, D. Michalik, R. Jackstell and
C. Bruneau, Org. Lett., 2011, 13, 3964–3967;
(n) B. Sundararaju, Z. Tang, M. Achard, G. V. M. Sharma,
L. Toupet and C. Bruneau, Adv. Synth. Catal., 2010, 352,
M. Beller, Chem.
(b) Y. Watanabe, Y. Morisaki, T. Kondo and T. Mitsudo,
J. Org. Chem., 1996, 61, 4214–4218.
–
Asian J., 2007, 2, 403–410;
3141–3146; (o) C. Gonzalez-Arellano, K. Yoshida, R. Luque 18 (a) A. J. Watson, A. Maxwell and J. M. J. Williams, J. Org.
and P. L. Gai, Green Chem., 2010, 12, 1281–1287.
13 (a) M. D. Ganesh, K. Ashok, S. Dharmendra,
A. V. Ramaswamy and W. B. Suresh, J. Serb. Chem. Soc.,
2008, 73, 385–391; (b) L. Daniel, The Organic Chemistry of
Drug Synthesis, Wiley Online Books, 2007.
Chem., 2011, 76, 2328–2331; (b) O. Saidi, A. J. Blacker,
G. W. Lamb, S. P. Marsden and J. M. J. Williams, Org.
Process Res. Dev., 2010, 14, 1046–1049; (c) M. Hamid,
C. L. Allen, G. W. Lamb, A. C. Maxwell and
J. M. J. Williams, J. Am. Chem. Soc., 2009, 131, 1766–1774.
14 (a) Z. Xie, R. Chen, M. Ma, L. Kong and J. Liu, Appl. 19 W. R. Roper and A. H. Wright, J. Organomet. Chem., 1982,
Organomet. Chem., 2019, 33, e5124; (b) H. Huang and
J. Y. Kang, J. Org. Chem., 2017, 82, 6604–6614.
15 (a) W. Malone, J. Matos and A. Kara, Surf. Sci., 2018, 669,
121–129; (b) Z. J. Cai, C. X. Liu, Q. Gu and S. L. You, Angew.
Chem., Int. Ed., 2018, 57, 1296–1299; (c) Y. Yokoyama,
233, C59–C63.
20 (a) R. Colton and R. H. Farthing, Aust. J. Chem., 1971, 24,
903–909; (b) R. Colton and R. H. Farthing, Aust. J. Chem.,
1969, 22, 2011–2012; (c) R. Colton and R. H. Farthing,
Aust. J. Chem., 1967, 20, 1283–1286.
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