Borrowing hydrogen methodology for the conversion of alcohols into N-protected primary amines and in situ deprotection

Article abstract of DOI:10.1016/j.tetlet.2009.02.129

Alcohols have been converted into a range of protected amines including sulfonamides and N-alkylbenzylamine derivatives. Representative examples of deprotection to afford primary amines are also provided.

Full text of DOI:10.1016/j.tetlet.2009.02.129

Tetrahedron Letters 50 (2009) 3374–3377
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Borrowing hydrogen methodology for the conversion of alcohols into
N-protected primary amines and in situ deprotection
Gareth W. Lamb a, Andrew J. A. Watson a, Katherine E. Jolley a, Aoife C. Maxwell b, Jonathan M. J. Williams a,
*
a Department of Chemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK
b GlaxoSmithKline Research and Development, Gunnels Wood Road, Stevenage SG1 2NY, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Alcohols have been converted into a range of protected amines including sulfonamides and N-alkylben-
Received 15 January 2009
Revised 9 February 2009
Accepted 16 February 2009
Available online 21 February 2009
zylamine derivatives. Representative examples of deprotection to afford primary amines are also
provided.
Ó 2009 Published by Elsevier Ltd.
The alkylation of amines by alcohols using the borrowing
hydrogen strategy provides an alternative approach to the synthe-
sis of amines.1 Water is the only reaction by-product, and tradi-
tional alkylating agents, including potentially mutagenic alkyl
halides, are avoided. The metal-catalysed pathway involves the
temporary removal of hydrogen from an alcohol to form an alde-
hyde, which undergoes imine formation prior to return of the
hydrogen to generate a new C–N bond (Scheme 1).
methoxy-substituted (entries 6 and 7) benzylamines also gave
complete conversion into the alkylated product, as did the use of
the p-methoxyaniline. The isolated yields were more variable,
principally due to the separation of secondary amine from small
amounts of tertiary amine byproduct, formed by over-alkylation.
However, for the alkylation of 1-phenylethylamine, only mono-
alkylation was observed, leading cleanly to the secondary amines.
There have been several iridium2 and ruthenium3 complexes,
which have been shown to be effective for the alkylation of amines
by alcohols, including our own contributions using [Ru(p-cyme-
ne)Cl2]2 in the presence of a diphosphine ligand.4 We were
interested in exploiting this chemistry for the direct formation of
N-protected primary amines, and report our findings in this Letter.
Protected primary amines can either undergo further transforma-
tion elsewhere in the substrate or be deprotected to give primary
amines. The use of ammonia for the direct conversion of alcohols
into primary amines has recently been reported, although imine
formation and other oxidative reactions were observed as byprod-
ucts in some cases.5
Initially, we chose to examine the use of alkylamines such as
benzylamines for the conversion of 3-phenylpropanol 1 into the
corresponding N-protected primary amines 2. The reactions were
performed using the [Ru(p-cymene)Cl2]2/DPEphos combination,
in toluene at reflux for 24 h (Scheme 2).
R'
R
OH
R
N
H
M
MH2
R'
R
R
N
O
H2NR'
Scheme 1. The use of alcohols as alkylating agents by borrowing hydrogen.
The amine alkylation worked well in most cases. Benzylamine
(entry 1) and singly branched analogues (entries 2 and 3) afforded
the alkylated products with complete conversion, although the N-
alkylation of tritylamine gave a lower conversion (entry 4), pre-
sumably for steric reasons. Methoxy-substituted (entry 5) and di-
H2NR
Ph(CH2)3 OH
Ph(CH2)3 NHR
Ru cat.
PhMe, reflux, 24 h
2
1
Ru cat. = 2.5 mol% [Ru(p-cymene)Cl2]2
5 mol% DPEphos
* Corresponding author. Tel.: +44 1225 383 942; fax: +44 1225 386 231.
E-mail address: j.m.j.williams@bath.ac.uk (J.M.J. Williams).
Scheme 2. Formation of N-protected primary amines from alcohols.
0040-4039/$ - see front matter Ó 2009 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2009.02.129

G. W. Lamb et al. / Tetrahedron Letters 50 (2009) 3374–3377
3375
Table 1
Table 2
Formation of protected amines 2a
Alkylation of 1-phenylethylamine 4 and hydrogenolysis to give primary amines 6a
Entry
1
Amine product
Conv.b (%)
100 (57)
R
OH
Ph
3
Ph
N
H
Ph
Ru cat
Pd cat
Ph
R
NH2
R
N
H
5
Me
Me
Ph
Ph
H2
EtOH
6
H2N
Me
2
3
4
5
6
7
100 (85)
100 (79)
60 (54)
100 (60)
100 (54)
100 (60)
100
4
Ph
Ph
N
H
Ph
Ph
Entry
Primary amine product
Yieldb (%)
83c
1
2
Ph
NH2
NH2
N
H
68
52
75
54
65
Ph
Ph
Ph
Ph
N
H
Me
Ph
N
H
3
4
5
6
Ph
Ph
NH2
NH2
OMe
OMe
Ph
Ph
N
H
OMe
N
H
p-MeOC6H4
NH2
MeO
OMe
OMe
Ph
NH2
8
a
Reaction conditions; 2.5 mol % [Ru(p-cymene)Cl2]2, 5 mol % DPEphos, alcohol 1
Ph
N
H
(1 mmol), amine (1 mmol), toluene, 110 °C, 24 h, then Pd/C (10 mol %), EtOH, HCl
(6 M), H2 (1 atm), 65 °C, 14 h.8
a
Reaction conditions; 2.5 mol % [Ru(p-cymene)Cl2]2, 5 mol % DPEphos, alcohol 1
amine (1 mmol), toluene, 110 °C, 24 h. DPEphos = bis(2-
diphenylphosphinophenyl)ether.
b
Isolated yield over two steps from the corresponding primary alcohols.
Isolated as the free amine—all others as the HCl salt.
(1 mmol),
c
b
Conversion was determined by analysis of the 1H NMR spectra. Figures in
parentheses are isolated yields.
bamate (entry 6) under these conditions. We have previously re-
ported that sulfonamides can be alkylated by alcohols using
[Ru(p-cymene)Cl2]2 in the presence of DPEphos.4c,10 However, opti-
misation studies showed that the reactions could be performed
successfully using triphenylphosphine in place of DPEphos. These
reactions were performed at 150 °C in xylene, although essentially
complete conversion was also obtained for the alkylation of both p-
toluenesulfonamide and trimethylsilylethanesulfonamide (SES
amide) with benzyl alcohol when the reaction was performed in
toluene at 110 °C. Diphenylphosphinamide was alkylated with
90% conversion under the milder conditions.
The reactions were also repeated with an in situ deprotection of
the sulfonamide or phosphinamide. For entries 1 and 2, this was
achieved using Mg/MeOH,11 where the overall conversion of ben-
zyl alcohol into benzylamine was superior for the p-methyl-substi-
tuted arylsulfonamide (entry 1) compared with the p-methoxy-
substituted variant (entry 2). For the SES amide in entry 3, CsF in
DMF12 was used for the deprotection, and for entry 4, treatment
with acetic acid/formic acid/water (2:2:1) was used.13 All of these
procedures allowed for the conversion of benzyl alcohol into ben-
zylamine without isolation of the protected intermediate.
Since the trimethylsilylethanesulfonamide group is one of the
most readily removed sulfonamides,14 we investigated further
reactions with sulfonamide 11. Various alcohols were converted
into the corresponding SES-protected amines in good yields, and
in the alkylation/deprotection sequence, the primary amine could
be obtained in good yield without isolation of the intermediate sul-
fonamide (Table 4). Typical procedures for deprotections are
provided.8,15
All of the amine-protecting groups shown in Table 1 have been
reported to be removed relatively easily.6 We chose to investigate
the use of the 1-phenethyl protection (entry 2) for a range of other
substrates, and to couple this with in situ deprotection. Therefore,
alcohols 3 were coupled with 1-phenethylamine 4 to give the pro-
tected primary amines 5, which were then hydrogenolysed by
addition of Pd/C (10 wt %) and ethanol to the reaction mixture, fol-
lowed by heating under 1 atm of hydrogen.7 The so-formed pri-
mary amines 6 were obtained in good yields (Table 2). We were
unable to identify conditions where the ruthenium catalyst used
for the N-alkylation was able to effect hydrogenolysis.
The overall transformation of alcohol was observed by NMR to
lead to the primary amine very selectively, although the isolated
yields were somewhat variable. For entry 1, the amine was isolated
by acid/base extraction, and was obtained in good yield. For the
other examples, the product was isolated by crystallisation of the
hydrochloride salt (the HCl salts were insufficiently soluble in
the aqueous layer).
The use of benzyl-protecting groups was anticipated to lead to
problems for the conversion of benzyl alcohols into benzylamines,
due to the difficulty of selectively removing the correct benzyl
group from intermediates of the type ArCH2NHCH2Ar0.9 We there-
fore considered the use of alternative amine protecting groups
involving amides and related groups. The coupling of benzyl alco-
hols 7 with a range of sulfonamides was successful (Table 3, entries
1–3) as well as with diphenylphosphinamide (entry 4), although
we were unable to achieve coupling of an amide (entry 5) or a car-

3376
G. W. Lamb et al. / Tetrahedron Letters 50 (2009) 3374–3377
Table 3
Table 4
Conversion of benzyl alcohol into benzylamine via amination and deprotection
Conversion of alcohols into primary amines via intermediate SES-protected amines
R
OH
Ph
OH
7
3
Ru cat
Ru cat
SES
deprotect
CsF
Ph
NH2
R
N
R
NH2
Ph
NHR
H2NR
H2NSES
10
13
H
12
9
11
8
Yield 9a (%)
Product 13
Yield 12a (%)
Yield 13b (%)
Entry
1
Intermediate 9
Yield 10b (%)
Entry
1
O2
S
86
74
Ph
NH2
Ph
Ph
N
H
84
92
87
71
0
86
Me
O2
S
2
3
4
5
89
71
81
95
81
72
75
72
78
67
p-MeOC6H4
p-ClC6H4
p-F3CC6H4
2-Naphth
NH2
N
H
2
3
4
5
45
74
90
—
OMe
NH2
O2
S
Ph
N
H
SiMe3
NH2
O
P
Ph
Ph
Ph
Ph
Ph
N
H
NH2
O
O
N
H
Ph
O
O
NH2
6
t-Bu
6
0
—
a
N
H
O
Isolated yield of the protected amine 12 (as the HCl salt). 2.5 mol % [Ru(p-
cymene)Cl2]2, 10 mol % PPh3, 10 mol % K2CO3, alcohol 3 (1 mmol), sulfonamide 11
(1 mmol), xylene, 150 °C, 24 h.
Isolated yield of primary amine 13 over the two-step, one-pot amination/
deprotection sequence. Crude alkylated sulfonamides reacted with CsF (10 mmol),
a
Isolated yield of the protected amine 9. 2.5 mol % [Ru(p-cymene)Cl2]2, 10 mol %
PPh3, 10 mol % K2CO3, alcohol 7 (1 mmol), sulfonamide or phosphinamide (1 mmol),
xylene, 150 °C, 24 h.
b
b
DMF, 110 °C, 48 h.
Isolated yield of benzylamine 10 (as its HCl salt) over the two-step, one-pot
amination/deprotection sequence. Crude protected amine reacted with; Mg
(20 mmol), MeOH, 80 °C, 24 h (entries 1 and 2). CsF (10 mmol), DMF, 110 °C, 48 h
(entry 3). MeCO2H/HCO2H/H2O (2:2:1), 80 °C, 24 h (entry 4).
Michalik, D.; Jackstell, R.; Beller, M. Chem. Asian J. 2007, 2, 403; (e) Naskar, S.;
Bhattacharjee, M. Tetrahedron Lett. 2007, 48, 3367; (f) da Costa, A. P.; Viciano,
M.; Sanau, M.; Merino, S.; Tejeda, J.; Peris, E.; Royo, B. Organometallics 2008, 27,
1305.
In summary, alcohols have been successfully converted into pri-
mary amines using ruthenium-catalysed borrowing hydrogen
methodology coupled with deprotection of a range of N-protected
intermediates.
4. (a) Hamid, M. H. S. A.; Williams, J. M. J. Chem. Commun. 2007, 725; (b) Hamid,
M. H. S. A.; Williams, J. M. J. Tetrahedron Lett. 2007, 48, 8263; (c) Hamid, M. H. S.
A.; Williams, J. M. J. J. Am. Chem. Soc. 2009, 131, 1766.
5. Gunanathan, C.; Milstein, D. Angew. Chem., Int. Ed. 2008, 47, 8661.
6. (a) Kocienski, P. J. Protecting Groups, 3rd ed.; Georg Thieme: Stuttgart, 2005; (b)
Wuts, P. G. M.; Greene, T. W. Greene’s Protective Groups in Organic Synthesis, 4th
ed.; John Wiley and Sons: New York, 2006.
Acknowledgements
7. (a) Davies, S. G.; Ichihara, O. Tetrahedron: Asymmetry 1991, 2, 183; (b) Fujita, K.;
Fujii, T.; Yamaguchi, R. Org. Lett. 2004, 6, 3525.
We thank the EPSRC and GlaxoSmithKline for funding.
References and notes
8. Typical procedure for the alkylation of 1-phenylethylamine 4 with alcohols and
subsequent deprotection. To an oven-dried, nitrogen-purged carousel tube
containing [Ru(p-cymene)Cl2]2 (45.9 mg, 0.075 mmol) and DPEphos (80.8 mg,
0.150 mmol) were added primary alcohol (3 mmol), 1-phenylethylamine
(3 mmol) and anhydrous toluene (3 mL). The reaction mixture was then
heated to 110 °C for 24 h. The solvent was removed under vacuum, and the
alkylated amine was isolated by column chromatography (SiO2, EtOAc) or the
crude material was cleaved in situ. After cooling to room temperature, Pd/C
(10 wt %, 10% in Pd), EtOH (11 mL) and HCl (6 M, 1.1 mL) were added to the
solution. The carousel tube was then purged with H2 before heating to 65 °C for
14 h. The reaction mixture was cooled to room temperature, filtered to remove
Pd/C, and concentrated under vacuum to a solid, which was recrystallised from
by dissolving in minimal EtOH (approx. 2 mL) and addition of EtOAc (approx
20 mL).
1. For reviews on borrowing hydrogen methodology, see: (a) Hamid, M. H. S. A.;
Slatford, P. A.; Williams, J. M. J. Adv. Synth. Catal. 2007, 349, 1555; (b) Guillena,
G.; Ramón, D. J.; Yus, M. Angew. Chem., Int. Ed. 2007, 46, 2358; (c) Lamb, G. W.;
Williams, J. M. J. Chim. Oggi 2008, 26, 17; (d) Nixon, T. D.; Whittlesey, M. K.;
Williams, J. M. J. Dalton Trans. 2009, 753.
2. (a) Fujita, K.; Li, Z.; Yamaguchi, R. Tetrahedron Lett. 2003, 44, 2687; (b) Fujita, K.;
Yamaguchi, R. Synlett 2005, 560; (c) Cami-Kobeci, G.; Williams, J. M. J. Chem.
Commun. 2004, 1072; (d) Cami-Kobeci, G.; Slatford, P. A.; Whittlesey, M. K.;
Williams, J. M. J. Bioorg. Med. Chem. Lett. 2005, 15, 535; (e) Gnanamgari, D.;
Sauer, E. L. O.; Schley, N. D.; Butler, C.; Incarvito, C. D.; Crabtree, R. H.
Organometallics 2009, 28, 321.
9. Bull, S. D.; Davies, S. G.; Fenton, G.; Mulvaney, A. W.; Prasad, R. S.; Smith, A. D. J.
Chem. Soc., Perkin Trans. 1 2000, 3765.
10. Very recently, Beller and co-workers have also reported a ruthenium-catalysed
N-alkylation of sulfonamides by alcohols: Shi, F.; Tse, M. K.; Zhou, S.; Pohl, M.-
3. (a) Grigg, R.; Mitchell, T. R. B.; Sutthivaiyakit, S.; Tongpenyai, N. J. Chem. Soc.,
Chem. Commun. 1981, 611; (b) Watanabe, Y.; Tsuji, Y.; Ige, H.; Ohsugi, Y.; Ohta,
T. J. Org. Chem. 1984, 49, 3359; (c) Del Zotto, A.; Baratta, W.; Sandri, M.;
Verardo, G.; Rigo, P. Eur. J. Inorg. Chem. 2004, 524; (d) Hollmann, D.; Tillack, A.;

G. W. Lamb et al. / Tetrahedron Letters 50 (2009) 3374–3377
3377
M.; Radnik, J.; Hübner, S.; Jähnisch, K.; Brückner, A.; Beller, M. J. Am. Chem. Soc.
2009, 131, 1779.
11. (a) Brown, A. C.; Carpino, L. A. J. Org. Chem. 1985, 50, 1749; (b) Burtoloso, A. C.
B.; Correia, C. R. D. Tetrahedron 2008, 64, 9928.
12. Weinreb, S. M.; Demko, D. M.; Lessen, T. A.; Demers, J. P. Tetrahedron Lett. 1986,
27, 2099.
13. Slusarska, E.; Zwierzak, A. Synthesis 1981, 155.
14. Ribière, P.; Declerck, V.; Martinez, J.; Lamaty, F. Chem. Rev. 2006, 106, 2249.
15. Typical procedure for the formation of sulfonamides and their deprotection.To an
oven-dried, nitrogen-purged carousel tube containing [Ru(p-cymene)Cl2]2
(15.3 mg, 0.025 mmol), PPh3 (26.2 mg, 0.1 mmol), and K2CO3 (14 mg,
0.1 mmol) were added primary sulfonamide (1 mmol), alcohol (1 mmol) and
anhydrous xylene (1 mL). The reaction mixture was stirred under a nitrogen
atmosphere at room temperature for 10 min and then heated to 150 °C for
24 h. The solvent was removed under vacuum, and the alkylated sulfonamide
was either isolated by column chromatography (SiO2, CH2Cl2/MeOH 98:2) or
the crude material was cleaved in situ. Arylsulfonamides were cleaved by the
addition of fresh Mg turnings (0.486 g, 20 mmol) and MeOH (5 mL) to the
crude residue. This mixture was then heated at 80 °C for 24 h, and cooled to
room temperature. After filtration, the clear solution was acidified using 1 M
HCl in diethyl ether before reducing to dryness in vacuo. The resulting yellow
solid was washed with CH2Cl2 to give the amine hydrochloride salt as a
colourless solid. Trimethylsilylethanesulfonamides (SES) were cleaved by
addition of CsF (0.152 g, 10 mmol) and DMF (2 mL) to the crude residue. This
mixture was then heated at 110 °C for 48 h, cooled to room temperature,
filtered and isolated as above. The phosphinamide (Table 3, entry 4) was
cleaved by removal of the solvent in vacuo from the crude reaction mixture,
addition of acetic acid (1 mL), formic acid (1 mL) and water (0.5 mL) and
heating at 80 °C for 24 h. After removal of the solvent under vacuum, the
resulting solid was washed with CH2Cl2 to give the amine hydrochloride salt as
a colourless solid.