Borrowing hydrogen methodology for amine synthesis under solvent-free microwave conditions

Article abstract of DOI:10.1021/jo102521a

Application of microwave heating to the Borrowing Hydrogen strategy to form C-N bonds from alcohols and amines is presented, removing the need for solvent and reducing the reaction times while still yielding results comparable with those using thermal heating.

Full text of DOI:10.1021/jo102521a

NOTE
pubs.acs.org/joc
Borrowing Hydrogen Methodology for Amine Synthesis under
Solvent-Free Microwave Conditions
Andrew J. A. Watson,† Aoife C. Maxwell,‡ and Jonathan M. J. Williams*,†
†Department of Chemistry, University of Bath, Claverton Down, Bath BA2 7AY, U.K.
‡GlaxoSmithKline Research and Development, Gunnels Wood Road, Stevenage SG1 2NY, U.K.
S Supporting Information
b
ABSTRACT: Application of microwave heating to the Borrowing Hydrogen
strategy to form C-N bonds from alcohols and amines is presented, removing
the need for solvent and reducing the reaction times while still yielding results
comparable with those using thermal heating.
Scheme 1. Borrowing Hydrogen Strategy for the Alkylation
of Amines with Alcohols
orrowing Hydrogen methodology has been used for a wide
range of coupling reactions using alcohols as nontoxic
B
alkylating agents to form C-C and C-N bonds with a wide
range of nucleophiles1,2 producing water as the only waste
product (Scheme 1). The use of these reactions is increasing
due to the ease in which they can be performed and the wide
range of alcohols which can be used.
Of the Borrowing Hydrogen reactions available in the litera-
ture, the formation of C-N bonds has been applied to the
synthesis of several pharmaceuticals. The ease in which they can
be performed, coupled with the advantages they offer over more
traditional C-N bond-forming reactions (avoiding the use of
toxic reagents, avoiding stoichiometric reducing agents, generat-
ing water as the only byproduct, and the selectivity to form either
secondary or tertiary amines without over alkylation), makes
these reactions synthetically appealing. However, the disadvan-
tage is that typically these reactions are run at high temperatures
for periods of up to 24 h, although temperatures down to 70 °C
have been reported.1n
By screening a range of conditions and applying them to a
model system, a range of catalysts,13 conditions, and solvents
(toluene, dioxane, DME) were tested; however, product was
only observed when no solvent was present. Furthermore, better
results were obtained when an excess of alcohol was used (entry
1, Table 1). Despite screening water and a range of alcohols
(MeOH, IPA, tBuOH) as solvents, the reaction only proceeded
efficiently in an excess of the reagent alcohol. It was then possible
to reduce the excess of alcohol used to 1.6 equiv (entry 3,
Table 1) without affecting the conversion. However, reducing
the amount further led to a reduced conversion (entry 4,
Table 1), and even on prolonged heating, no further gain in
the conversion was obtained (entry 5, Table 1). With the
conditions established, we were pleased to see that increasing
the scale (entry 6, Table 1) in this case had no effect on the
reaction.
After we established suitable reaction conditions, various
secondary amines and alcohols were coupled to evaluate the
reliability of the reaction (Table 2). We were pleased to see that
all of the products could be isolated in high yields, comparable
with thermal heating for longer periods.9c The use of excess
amine instead of alcohol (entry 2, Table 2) was also pleasing as
this meant the least expensive coupling partner, whichever it may
Grigg3 and Watanabe4 independently developed the first exam-
ples of C-N bond formation from alcohols, but more recent
developments have led to more active catalysts and milder condi-
tions. Beller’s group used a ruthenium carbonyl cluster with bulky
phosphine ligands,5 and while Yamaguchi and co-workers have
used [Cp*IrCl2]2,6 Kempe7 and Marr8 have also used iridium-
based catalyst incorporating P-N ligands to achieve good results.
Our own group has also been successful9 in applying the [Ru(p-
cymene)Cl2]2 with diphosphines to couple a wide range of amines,
sulfonamides, alcohols, and diols together.
While the reactions show a wide range of functional group
tolerance,10 the long reaction times are a disadvantage. Grigg and
co-workers have addressed this problem by using solvent-free
microwave heating11 to reduce reaction times significantly, but to
date, this has only been applied to C-C bond formation.12 Using
our simple ruthenium-based catalyst with a diphosphine ligand,9
we have shown that microwave heating can also be applied to C-
N bond-forming reactions of amines, amides, and sulfonamides
with primary alcohols, shortening the reaction times to just a
few hours.
Received: January 5, 2011
Published: February 23, 2011
r
2011 American Chemical Society
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The Journal of Organic Chemistry
NOTE
Table 1. Optimization of Conditionsa
Table 3. Alkylation of 1,2-Diolsa
entry
equiv of alcohol
time (min)
conversionb
1
2
3
4
5
6
3
60
60
>99
>99
>99
94
2
1.6
1.2
1.2
1.6
90
90
120
90
94
>99c
a Reaction conditions: morpholine (1 mmol), benzyl alcohol, [Ru(p-
cymene)Cl2]2 (2.5 mol %), DPEphos (5 mol %), 115 °C. b Determined
by analysis of the 1H NMR spectra. c Reaction scaled by 3 times.
a Reaction conditions: diol (1 mmol), amine (2 mmol), [Ru(p-cymene)
Cl2]2 (2.5 mol %), DPEphos (5 mol %), 115 °C.
Table 2. Alkylation Secondary Aminesa
the catalyst under the concentrated conditions.14 Assuming
this to be the case, we increased the reaction temperature by
10 °C and were pleased to see that the reaction progressed to
full conversion. With the new conditions established, a series of
primary amines were coupled to evaluate the scope of the
reaction (Table 4).
As expected, the results were good, with a range of alcohols
and amines coupling in high yields. Even anilines (entries 1 and 2,
Table 4) gave good results at lower temperatures (115 °C) as the
lone pair on the nitrogen is less nucleophilic, so it will bind less
tightly to the catalyst, reducing deactivation. Bulky amines
(entries 3-5, Table 4) also coupled well and again gave yields
comparable with thermal heating.
Having determined that we could monoalkylate primary
amines, we wanted to see if we could dialkylate using symmetric
diols.4b,6a,9c Again, a slight increase in temperature (135 °C) was
required for the reaction to proceed. With the conditions
established, a range of substrates were screened (Table 5) giving
generally good yields, comparable with our previously reported
results.9c The only exception was furfurylamine (entry 5,
Table 5), which gave a lower yield, consistent with the results
of thermal heating. We were also very pleased to see that, when
an enantiopure amine (entry 4, Table 5) was alkylated, it did not
undergo racemization.
Having screened a series of different amine and alcohol
couplings, we turned our attention toward the alkylation of
sulfonamides.9c,15 To allow the reaction to proceed, an increase
in temperature (165 °C) was required and an increased reaction
time (180 min) to drive the reaction to completion. An increased
amount of alcohol was also necessary; we assume this was
required to dissolve the sulfonamide. However, contrary to
previous reports, the inclusion of an inorganic base to deproto-
nate the sulfonamide was not required. The results of the
sulfonamide couplings (Table 6) were good, with high yields
except for cyclopropylmethanol (entry 3, Table 6). In this case,
the yield was low due to the alcohol undergoing oxidative
dimerization to form the ester.
a Reaction conditions: amine (1 mmol), alcohol (1.6 mmol), [Ru(p-
cymene)Cl2]2 (2.5 mol %), DPEphos (5 mol %), 115 °C. b Equivalent
of amine. c At 125 °C.
be, can be used in excess while still giving good yields. Although
the reactions proceeded well, the increase in temperature
(125 °C) for entry 2, Table 2, was necessary to force the reaction
to completion.
Next we wanted to determine whether microwave heating had
any affect on the selectivity5d,9c of the reaction for primary/
secondary alcohols. Morpholine was then reacted with a series of
1,2-diols; however, only diols with a benzylic secondary alcohol
were active toward coupling, while the use of alkyl 1,2-diols led to
the oxidation of the secondary alcohol to the ketone. This is in
contrast to previously reported thermal coupling reactions,
suggesting that there may be limitations to the use of microwave
heating in specific cases. With the limitation of the 1,2-diol
substrate evaluated, various secondary amines were screened
against 1-phenyl-1,2-ethanediol5d (Table 3).
Again, the yields gave good results for most substrates (entries
1-3, Table 3); however, the introduction of acyclic amine (entry
4, Table 3) or a larger cyclic amine (entry 5, Table 3) led to a
reduction in yield due to losses in the product isolation.
We then turned our attention to the coupling of primary
amines, which under the previous conditions gave poor con-
version into product. We assume this deactivation of the
catalyst to be the result of the amine binding more tightly to
Satisfied that we could replicate the previous results and
couplings, we decided to see if we could extend our catalyst’s
scope and alkylate primary amides in the same way. Pre-
viously, we have been unsuccessful in this area, although there
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The Journal of Organic Chemistry
NOTE
Table 4. Alkylation of Primary Aminesa
Table 6. Alkylation of Sulfonamidesa
a Reaction conditions: amine (1 mmol), alcohol (1.6 mmol), [Ru(p-
cymene)Cl2]2 (2.5 mol %), DPEphos (5 mol %), 125 °C. b Isolated yield.
c At 115 °C.
a Reaction conditions: amine (1 mmol), alcohol (3 mmol), [Ru(p-
cymene)Cl2]2 (2.5 mol %), DPEphos (5 mol %), 165 °C.
Table 7. Alkylation of Primary Amidesa
Table 5. Reaction of Amines with Diols To Form
N-Heterocyclesa
a Reaction conditions: amide (1 mmol), alcohol (3 mmol), [Ru(p-
cymene)Cl2]2 (2.5 mol %), DPEphos (5 mol %), 175 °C. b At 180 °C.
a Reaction conditions: amine (1 mmol), diol (1.6 mmol), [Ru(p-
cymene)Cl2]2 (2.5 mol %), DPEphos (5 mol %), 135 °C.
are at least three reports in the literature16 of this being
achieved, but with high reaction temperatures. By starting
with the sulfonamide conditions, we quickly determined that
the coupling of primary amides and alcohols was possible,
although to reach full conversion, the reaction temperature
had to be pushed to 175 °C. Despite the high reaction
temperature, the reaction time was shorter than the coupling
of sulfonamides (120 min), and once again, the coupling
proceeded without the need for a base. We were then able
to evaluate the coupling scope in comparison with the system
reported by Yamaguchi et al.16c
Both aromatic (entries 1 and 2, Table 7) and alkyl amides
(entries 4 and 5, Table 7) were coupled with aliphatic and
benzylic alcohols with reasonable yields. The coupling of alkyl
amides was interesting as the yields were better than those
reported by Yamaguchi, even though the reaction temperature
was significantly higher. Finally, we were very pleased to isolate
N-hexylnicotinamide in reasonable yield (entry 3, Table 7),17
thus demonstrating that the reaction was also applicable to
biologically relevant molecules.
With a range of reaction conditions established, we were keen
to apply our chemistry to two pharmaceutical compounds,
piribedil and fentanyl, both of which were isolated in good yield
(Scheme 2).
To conclude, we have shown that the use of microwave
heating can be used to carry out C-N bond formation using
Borrowing Hydrogen methodology. Furthermore, that these
reactions can be conducted more quickly than using thermal
heating methods. Finally, we have expanded the scope of our
catalyst to include the N-alkylation of primary amides as well as
demonstrating that the methodology can be applied to the
synthesis of biologically relevant compounds.
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The Journal of Organic Chemistry
NOTE
Scheme 2. Synthesis of Piribedil and Fentanyla
(i) L€ofberg, C.; Grigg, R.; Keep, A.; Derrick, A.; Sridharan, V.; Kilner, C.
Chem. Commun. 2006, 42, 5000–5002. (j) Pridmore, S. J.; Williams,
J. M. J. Tetrahedron Lett. 2008, 49, 7413–7415. (k) Edwards, M. G.;
Jazzar, R. F. R.; Paine, B. M.; Shermer, D. J.; Whittlesey, M. K.; Williams,
J. M. J.; Edney, J. J. Chem. Commun. 2004, 40, 90–91. (l) Black, P. J.;
Cami-Kobeci, G.; Edwards, M. G.; Slatford, P. A.; Whittlesey, M. K.;
Williams, J. M. J. Org. Biomol. Chem. 2006, 116–125. (m) Black, P. J.;
Edwards, M. G.; Williams, J. M. J. Eur. J. Org. Chem. 2006, 4, 4367–4378.
(n) Blank, B.; Michlik, S.; Kempe, R. Chem.—Eur. J. 2009, 15, 3790–
3799.
(2) For a reviews on Borrowing Hydrogen, see: (a) Hamid, M. H. S.
A.; Slatford, P. A.; Williams, J. M. J. Adv. Synth. Catal. 2007, 349, 1555–
1575. (b) Nixon, T. D.; Whittlesey, M. K.; Williams, J. M. J. Dalton Trans.
2009, 38, 753–762. (c) Dobereiner, G. E.; Crabtree, R. H. Chem. Rev.
2010, 110, 681–703.
(3) Grigg, R.; Mitchell, T. R. B.; Sutthivaiyakit, S.; Tongpenyai, N.
J. Chem. Soc., Chem. Commun. 1981, 12, 611–612.
(4) (a) Watanabe, Y.; Tsuji, Y.; Ohsugi, Y.; Ohta, T. J. Org. Chem.
1984, 49, 3359–3363. (b) Tsuji, Y.; Huh, H.-T.; Ohsugi, Y.; Watanabe.,
Y. J. Org. Chem. 1985, 50, 1365–1370.
a Reaction conditions: diol (1 mmol), amine (2 mmol), [Ru(p-cym-
ene)Cl2]2 (2.5 mol %), DPEphos (5 mol %), 115 °C.
(5) (a) Tillack, A.; Hollmann, D.; Mevius, K.; Michalik, D.; B€ahn, S.;
Beller, M. Eur. J. Org. Chem. 2008, 28, 4745–4750. (b) Hollmann, D.;
Tillack, A.; Michalik, D.; Jackstell, R.; Beller, M. Chem. Asian J. 2007,
2, 403–410. (c) Tillack, A.; Hollmann, D.; Michalik, D.; Beller, M.
Tetrahedron Lett. 2006, 47, 8881–8885. (d) B€ahn, S.; Tillack, A.; Imm,
S.; Mevius, M.; Michalik, M.; Hollmann, D.; Neubert, L.; Beller, M.
ChemSusChem 2009, 2, 551–557.
(6) (a) Fujita, K.; Fujii, T.; Yamaguchi, R. Org. Lett. 2004, 6, 3525–
3538. (b) Yamaguchi, R.; Kawagoe, S.; Asai, C.; Fujita, K. Org. Lett. 2008,
10, 181–184. (c) Fujita, K.; Li, Z.; Ozeki, N.; Yamaguchi, R. Tetrahedron
Lett. 2003, 44, 2687–2690. (d) Fujita, K.; Enoki, Y.; Yamaguchi, R.
Tetrahedron 2008, 64, 1943–1954.
’ EXPERIMENTAL SECTION
General Procedure for the Synthesis of N-Benzylmorpho-
line. DPEphos (26.9 mg, 5 mol %), [Ru(p-cymene)Cl2]2 (15.3 mg,
2.5 mol %), benzyl alcohol (166 μL, 1.6 equiv), and morpholine (87 μL,
1 mmol) were added to a microwave vial containing a stirrer bar. The vial
was then sealed before purging with N2 for 5 min. The reaction was then
heated to 115 °C for 90 min using a microwave. The crude material was
then purified by silica column chromatography (3:1 petroleum ether
(bp 40-60 °C)/EtOAc, Rf = 0.19) to give N-benzylmorpholine (144
1
mg, 81% yield): H NMR δ (CDCl3, 300 MHz, 25 °C) δ 7.20-7.27
(5H, m), 3.66 (4H, t, J = 4.7 Hz), 3.45 (2H, s), 2.39 (4H, t, J = 4.5 Hz);
13C NMR δ (CDCl3, 75.4 MHz, 25 °C) δ 137.7, 129.3, 128.3, 127.2,
67.0, 63.5, 53.6; HRMS(ESI-TOF) calcd for C11H16NOHþ 178.1232,
found 178.1229 (MHþ).
(7) (a) Blank, B.; Madalska, M.; Kempe, R. Adv. Synth. Catal. 2008,
350, 749–758. (b) Blank, B.; Michlik, S.; Kempe, R. Adv. Synth. Catal.
2009, 351, 2903–2911.
(8) Liu, S.; Rebros, M.; Stephens, G.; Marr, A. C. Chem. Commun.
2009, 45, 2308–2310.
(9) (a) Hamid, M. H. S. A.; Williams, J. M. J. Tetrahedron Lett. 2007,
48, 8263–8265. (b) Hamid, M. H. S. A.; Williams, J. M. J. Chem.
Commun. 2007, 43, 725–727. (c) Hamid, M. H. S. A.; Allen, C. L.; Lamb,
G. W.; Maxwell, A. C.; Maytum, H. C.; Watson, A. J. A.; Williams, J. M. J.
J. Am. Chem. Soc. 2009, 131, 1766–1774.
’ ASSOCIATED CONTENT
S
SupportingInformation. General experimental conditions,
b
analytical data, and 1H and 13C NMR data of products. This material
is available free of charge via the Internet at http://pubs.acs.org.
(10) For a review on C-N Borrowing Hydrogen reactions, see:
Guillena, G.; Ramꢀon, D. J.; Yus, M. Chem. Rev. 2010, 110, 1611–1641.
(11) Microwave papers: (a) Grigg, R.; Whitney, S.; Sridharan, V.;
Keep, A.; Derrick, A. Tetrahedron 2009, 65, 4375–4383. (b) L€ofberg, C.;
Grigg, R.; Whittaker, M. A.; Keep, A.; Derrick, A. J. Org. Chem. 2006,
71, 8023–8027.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: j.m.j.williams@bath.ac.uk.
(12) Palladium-catalayzed amine-amine coupling using Borrowing
Hydrogen methodology in a microwave was reported during the
preparation of this paper: Lubinu, M. C.; De Luca, L.; Giacomelli, G.;
Porcheddu, A. Chem.—Eur. J. 2010, 17, 82–85.
’ ACKNOWLEDGMENT
We thank GlaxoSmithKline, Pfizer, AstraZeneca, Novartis, and
the EPSRC for providing a studentship (to A.J.A.W.) through the
collaborative EPSRC-Pharma-Synthesis Programme. We also
thank Christopher Tame for his support and enthusiasm.
(13) [IrCp*Cl2]2 was active under the conditions, although in our
hands the combination of Ru3(CO)12 and tri(o-tolyl)phospine was not.
ꢀ
(14) Samec, J. S. M.; Ell, A. H.; Åberg, J. B.; Privalov, T.; Eriksson, L.;
B€ackvall, J.-E. J. Am. Chem. Soc. 2006, 128, 14293–14305.
(15) Zhu, M.; Fujita, K.; Yamaguchi, R. Org. Lett. 2010, 12, 1336–
1339.
(16) (a) Watanabe, Y.; Ohta, T. Y. Bull. Chem. Soc. Jpn. 1983,
56, 2647–2651. (b) Jenner, G. J. Mol. Catal. 1989, 55, 241–246. (c)
Fujita, K.; Komatsubara, A.; Yamaguchi, R. Tetrahedron 2009, 65, 3624–
3628.
’ REFERENCES
(1) (a) Grigg, R.; Lofberg, C.; Whitney, S.; Sridharan, V.; Keep, A.;
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(17) The reaction went to 84% conversion, and the low yield is
attributed to difficulties in purification by silica column chromatography.
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