Rapid microwave-assisted reductive amination of ketones with anilines

Article abstract of DOI:10.1055/s-2006-949639

Using microwave technology, a new protocol has been developed that improves the reaction rate and overall efficiency of the direct reductive amination of ketones with anilines. When using sodium triacetoxyborohydride as the reducing agent, high product yi

Full text of DOI:10.1055/s-2006-949639

2444
LETTER
Rapid Microwave-Assisted Reductive Amination of Ketones with Anilines
R
apid Microwave
-
e
A
ssisted
R
l
e
e
A
minatio
n
nwith
A
nilines V. Bailey, Wesley Heaton, Nigel Vicker, Barry V. L. Potter*
Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, BA2 7AY, UK
Fax +44(0)1225386114; E-mail: B.V.L.Potter@bath.ac.uk
Received 18 May 2006
several different sets of reaction conditions for the direct
Abstract: Using microwave technology, a new protocol has been
developed that improves the reaction rate and overall efficiency of
the direct reductive amination of ketones with anilines. When using
sodium triacetoxyborohydride as the reducing agent, high product
reductive amination of anilines.6a–6c Therefore, we felt
that a more general, user-friendly protocol that would al-
low for the rapid synthesis of aromatic amines would be
yields and increased reaction rates are achieved for a variety of elec- extremely beneficial. Additionally, we were intrigued as
tronically different anilines. Furthermore, we have found that this
protocol can also be applied to aldehydes.
to whether the use of modern microwave technology
could enhance the reaction rate and overall efficiency of
the reductive amination process.11,12 Herein, we present
Key words: reductive amination, anilines, ketones, microwave
synthesis, aldehydes
our initial findings in this area.
At the outset of this study, and in order to optimise a mi-
crowave-assisted direct reductive amination process, the
The synthesis of secondary and tertiary amines by the
general method described by Abdel-Magid and co-work-
reductive amination of carbonyl compounds is a versatile
ers was used as a basis.6a–6c In this regard, a standard reac-
and widely used transformation available to the modern
tion between aniline and cyclohexanone was selected to
synthetic chemist. Additionally as aromatic amines are
carry out an initial time and temperature study. The reac-
present in a large number of marketed pharmaceuticals it
tion was carried out in sealed microwave tubes containing
is not surprising that a variety of protocols have been re-
a solution of aniline, cyclohexanone (2 equiv), sodium tri-
ported in the chemical literature.1,2 These methods can
acetoxyborohydride (2.5 equiv) and acetic acid (3 equiv)
usually be categorised into two distinct areas. The first is
in toluene which was then heated for various times and
an indirect/stepwise method where the intermediate imine
temperatures using
a
CEM Discover® instrument
is pre-formed and then reduced in an independent step.1
The second are direct reductive amination methods that
are much more convenient as prior formation of the imine
is not necessary; the carbonyl compound, the amine and
the reducing agent are all present at the outset of the reac-
tion.3 Traditionally, sodium cyanoborohydride has been
the reducing agent of choice in these direct reactions.4
However, the reagent and its by-products are highly toxic,
which is undesirable. Sodium triacetoxyborohydride has
been identified as a mild and efficient alternative,5 which
exhibits good selectivity and will reduce aldehydes pref-
erentially over ketones. Moreover, imines are much more
basic than their carbonyl counterparts and thus are prefer-
entially reduced by sodium triacetoxyborohydride.
(Table 1).13 It was found that a successful reaction could
be achieved at 100 °C in only ten minutes (entry 1). More-
over, it was discovered that the yields of desired product
could be enhanced to 87% by increasing the temperature
to 140 °C (entry 3). Interestingly, heating beyond this
temperature proved to be detrimental to the product yields
Table 1 The Effects of Time and Temperature on the Reductive
Amination of Cyclohexanone with Anilinea
O
(a)
+
NH2
N
H
Entry
Time (min)
Temp (°C)
100
Yield (%)b
Sodium triacetoxyborohydride has been utilised success-
fully for the reductive amination of a wide variety of
ketones with differing primary and secondary amines.6
However, when anilines are used more extensive reaction
times are necessary.7 Anilines are weakly basic amines
(pKa ~ 4.6,8 compare with 10.7 for cyclohexylamine9) due
mainly to the partial delocalisation of the nitrogen lone
pair into the aromatic benzene ring.10 Anilines are much
less nucleophilic than aliphatic amines and, as a conse-
quence, longer reaction times are needed. Indeed, because
of this Abdel-Magid’s group demonstrated the use of
1
2
3
4
5
6
7
10
10
10
10
10
15
15
70
81
87
81
77
84
86
120
140
160
180
120
140
a Reaction conditions: aniline (1 mmol), cyclohexanone (2 mmol),
NaBH(OAc)3 (2.5 mmol) and AcOH (3 mmol) in toluene (2 mL) were
heated in a CEM Discover® instrument.
SYNLETT 2006, No. 15, pp 2444–2448
Advanced online publication: 08.09.2006
DOI: 10.1055/s-2006-949639; Art ID: D14606ST
© Georg Thieme Verlag Stuttgart · New York
1
8
.0
9
.2
0
0
6
b Yield of isolated product.

LETTER
Rapid Microwave-Assisted Reductive Amination with Anilines
2445
(entries 4 and 5). Furthermore, a ten-minute reaction time Table 3 Alternative Reagents for the Reductive Amination of
Cyclohexanone with Anilinea
seemed to be optimal, as heating for a longer time period
showed no significant benefits (entries 6 and 7).
Entry Acid
Reductant
Yield (%)b
In order to further optimise the reductive amination pro-
cess we felt that it was crucial to investigate an array of
solvents that possessed different microwave properties
(Table 2).11,14 Whilst all solvents performed very well, the
yield of 94% that was obtained with 1,2-dichloroethane
(DCE) was particularly impressive (entry 2). Therefore,
all further reactions were carried out using DCE as the sol-
vent. Nevertheless, the result of 91% obtained with aceto-
nitrile (entry 4) is comparable and, if required, this could
be used as an alternative.
1
2
3
4
5
AcOH
NaCNBH4
56
69
45
64
35
c
AcOH
MP-BH(OAc)3
NaBH(OAc)3
NaBH(OAc)3
NaBH(OAc)3
TsOH
Amberlite IRC50-H
MP-TsOHc
a Reaction conditions: aniline (1 mmol), cyclohexanone (2 mmol),
reducing agent (2.5 mmol) and acid (3 mmol) in DCE (2 mL), were
heated in a CEM Discover® instrument at 140 °C for ten minutes.
b Yield of isolated product.
Table 2 The Effects of Solvents Used in Reductive Amination of
Cyclohexanone with Anilinea
c MP = macroporons polystyrene.
Entry
Solvent
Toluene
THF
Yield (%)b
(entry 2). In addition, this reagent does offer the benefit of
a simple filtration rather than an aqueous work-up to ob-
tain the product.
1
2
3
4
5
87
79
81
91
94
Now that optimised microwave conditions had been es-
tablished, reductive aminations were attempted with a
range of electronically different anilines and ketones of
varying reactivity (Table 4).17 Cyclopentanone and hex-
an-2-one reacted extremely readily with aniline to provide
excellent yields of 88% and 92%, respectively (entries 2
and 3). Even the much less reactive cyclooctanone provid-
ed a good yield of 68% in only ten minutes (entry 4). In
almost every instance the use of microwave irradiation to
facilitate the reductive amination of various anilines was
highly successful, with reactions reaching completion in
just ten minutes. Moreover, both p-methoxyaniline and o-
toluidine reacted extremely well with a variety of ketones
(entries 5–11). However, and perhaps not surprisingly,
reactions involving the electron-deficient anilines, o-bro-
moaniline and p-nitroaniline, gave moderate yields (en-
tries 12–15). It should be noted that in these cases it was
still possible to observe some of the starting aniline by
TLC.18 Nevertheless, this protocol still allowed for the
swift formation of synthetically very useful building
blocks.
DCM
Acetonitrile
1,2-DCE
a Reaction conditions: aniline (1 mmol), cyclohexanone (2 mmol),
NaBH(OAc)3 (2.5 mmol) and AcOH (3 mmol) in the stated solvent
(2 mL) were heated in a CEM Discover® instrument at 140 °C for ten
minutes.
b Yield of isolated product.
Next we examined whether the reducing agent and/or the
acid could be substituted for alternative reagents
(Table 3). First, it was found that both sodium cyanoboro-
hydride and resin-bound sodium triacetoxyborohydride15
resulted in inferior yields (entries 1 and 2). Second, the
role of the acetic acid is clearly very important,16 as
attempts to substitute this for other acidic derivatives re-
sulted in lower yields (entries 3–5). However, the yield of
~70% obtained with the use of the reducing agent MP-
sodium triacetoxyborohydride is still synthetically useful
Table 4 Microwave-Assisted Reductive Amination between Anilines and Ketonesa
Entry
Aniline
Ketone
Product
Yield (%)b
9419
O
1
N
H
NH2
O
O
2
3
8819
9219
N
H
N
H
Synlett 2006, No. 15, 2444–2448 © Thieme Stuttgart · New York

2446
H. V. Bailey et al.
LETTER
Table 4 Microwave-Assisted Reductive Amination between Anilines and Ketonesa (continued)
Entry
4
Aniline
Ketone
Product
Yield (%)b
O
6820
N
H
OMe
NH2
O
O
MeO
5
7719
N
H
MeO
MeO
6
7
6419
8720
N
H
O
N
H
O
MeO
8
9
6420
N
H
O
O
Me
Me
9519
N
H
NH2
Me
10
11
8119
9220
N
H
Me
O
O
N
H
Br
Br
12
13
5619
4020
N
H
NH2
Br
O
O
N
H
NO2
NH2
O2N
O2N
14
15
3419
N
H
O
2620
N
H
a Reaction conditions: Aniline (1 mmol), ketone (2 mmol), NaBH(OAc)3 (2.5 mmol) and AcOH (3 mmol) in DCE (2 mL) were
heated in a CEM Discover® instrument at 140 °C for ten minutes.
b Yield of isolated product.
To explore the scope of these newly developed reductive examined (Table 5).21 However, due to the increased reac-
amination conditions, the reaction between various tivity of aldehydes, when using our standard protocol the
anilines and an aldehyde, cyclohexanecarbaldehyde, was di-alkylated compound was found to be the major prod-
Synlett 2006, No. 15, 2444–2448 © Thieme Stuttgart · New York

LETTER
Rapid Microwave-Assisted Reductive Amination with Anilines
2447
Table 5 Microwave-Assisted Reductive Amination between Anilines and Aldehydesa
Entry
1
Aniline
Aldehyde
Product
Yield (%)b
9119
O
H
N
H
NH2
MeO
MeO
2
3
4
5
8319
8819
7519
6119
N
H
NH2
Me
Me
N
H
NH2
Br
Br
N
H
NH2
O2N
O2N
N
H
NH2
a Reaction conditions: Aniline (2 mmol), aldehyde (1 mmol), NaBH(OAc)3 (2.5 mmol) and AcOH (3 mmol) in DCE (2 mL) were heated in a
CEM Discover® instrument at 140 °C for ten minutes.
b Yield of isolated product.
uct. This problem was overcome by utilising the aldehyde
O
O
O
X
as the limiting reagent. Indeed, the desired mono-alkylat-
ed products were then obtained successfully in excellent
yields of up to 91%. Even the very unreactive o-bromoa-
niline and p-nitroaniline provided the desired products in
very good yields of 75% and 61%, respectively (entries 4
and 5).
X
O
+
NH2
N
H
O
when X = H, 82%
when X = Br, 56%
Having established that our newly developed microwave
protocol enhances the direct reductive amination of a
good range of substrates, we were keen to demonstrate the
mildness of this technique. To this end, 1,4-cyclohex-
anedione monoethylene acetal, containing an acid-labile
acetal protecting group, was chosen to undergo reductive
amination with aniline and o-bromoaniline (Scheme 1).
Using our general protocol, the reaction proceeded effi-
ciently to give the desired products in good yields of
~80% and 60%, respectively. Interestingly, Solé et al. re-
quired a reaction time of three days to achieve similar
yields for this transformation with o-bromoaniline.22 Im-
portantly, from this aryl bromide intermediate, Solé et al.
quickly and elegantly access very interesting bridged in-
termediates that have been used in the synthesis of two
members of the Strychnos alkaloid family, the insecticide
Aspernomine23 and the anti-malarial Strycnochromine
(Scheme 1).24 The intermediate has three points where
functionalisation is facile and this allows for rapid diver-
sification of the scaffold. Therefore, we feel that the use
of our protocol allows for an even more efficient approach
to templates of extreme biological interest.
O
H
N
H
H
strycnochromine
Scheme 1 Microwave-assisted reductive amination with an acid-
sensitive substrate. Reagents and conditions: aniline (1 mmol), ketone
(2 mmol), NaBH(OAc)3 (2.5 mmol) and AcOH (3 mmol) in DCE
(2 mL) were heated in a CEM Discover® instrument at 140 °C for ten
minutes.
In summary, the microwave-assisted direct reductive am-
ination procedure reported here offers many advantages
over the more traditional methods. The most beneficial
being the rapid reaction time, with the vast majority of re-
actions producing excellent yields after merely ten min-
utes. Additionally, as demonstrated above, the reaction
conditions are mild and simple; sodium triacetoxyboro-
hydride is much less toxic than the alternative sodium
cyanoborohydride and an acid sensitive functionality is
Synlett 2006, No. 15, 2444–2448 © Thieme Stuttgart · New York

2448
H. V. Bailey et al.
LETTER
(7) Indeed, laboured and inefficient reactions are often
encountered in reductive aminations with anilines, see
reference 3 for examples.
(8) Brown, H. C. In Determination of Organic Structures by
Physical Methods; Braude, E. A.; Nachod, F. C., Eds.;
Academic Press: New York, 1955.
tolerated by our system. A further advantage of this pro-
cedure is that inert atmospheric conditions are not neces-
sary. This, coupled with only minimal work-up and
straightforward flash column chromatography, means that
the reactions are operationally very simple.
(9) Hall, H. K. Jr. J. Am. Chem. Soc. 1957, 79, 5441.
(10) For an overview of pKa data in water, see: CRC Handbook
of Chemistry and Physics, 86th ed.; Lide, D. R., Ed.; CRC
Press: Boca Raton, FL, 2005–2006.
(11) For recent overviews on microwave chemistry, see:
(a) Kappe, C. O. Angew. Chem. Int. Ed. 2004, 43, 6250.
(b) Lidstrom, P.; Tierney, J.; Wathey, B.; Westman, J.
Tetrahedron 2001, 57, 9225. (c) Tierney, J. P.; Lidstrom, P.
Microwave-Assisted Organic Chemistry; Blackwell
Publishing: Oxford, 2005.
(12) (a) For examples using tin Lewis acids and silanes, see:
Kangasmetsa, J. J.; Johnson, T. Org. Lett. 2005, 7, 5653.
(b) For Pt/C examples, see: Miyazawa, A.; Saitou, K.;
Tanaka, K.; Gadda, T. M.; Tashiro, M.; Prakash, G. K. S.;
Olah, G. A. Tetrahedron Lett. 2006, 47, 1437. (c) For
examples on wet clay, see: Varma, R. S.; Dahiya, R.
Tetrahedron 1998, 54, 6293.
(13) CEM Microwave Technology Ltd., 2 Middle Slade,
Buckingham Industrial Park, MK18 1WA, UK; http://
www.cem.com
In conclusion, we have demonstrated that modern focused
microwave reactors are readily utilisable and are reliable
tools for the promotion of the direct reductive amination
of both electron-rich and electron-poor anilines. The use
of this technique results in the formation of functionalised
anilines that are potentially very interesting scaffolds for
the design of drug-like molecules. Indeed, this technique
results in rapid and efficient access to a vast array of very
interesting and versatile aromatic amines.
Acknowledgment
This research was supported by Sterix Ltd., a member of the Ipsen
group. We would also like to thank Ms A. Smith for assistance with
HPLC and LCMS analysis and the ESPRC National Mass Spectro-
metry Service Centre at the University of Wales, Swansea.
References and Notes
(14) Hayes, B. L. Microwave Synthesis: Chemistry at the Speed
of Light; CEM Publishing: Matthews, NC, 2002.
(15) Commercially available from Biotage.
(1) For indirect reductive aminations using a variety of metal
reducing agents, see: (a) Basu, B.; Jha, M. S.; Bhuiyan, M.
H.; Das, P. Synlett 2003, 555. (b) Firouzabadi, H.; Iranpoor,
N.; Alinezhad, H. Bull. Chem. Soc. Jpn. 2003, 76, 143.
(c) Samec, J. S. M.; Bäckvall, J.-E. Chem. Eur. J. 2002, 8,
2955. (d) Ranu, B. C.; Majee, A.; Sarkar, A. J. Org. Chem.
1998, 63, 370. (e) Mattson, R. J.; Pham, K. M.; Leuck, D. J.;
Cowen, K. A. J. Org. Chem. 1990, 55, 2552; and references
cited therein.
(2) For organocatalytic examples, see: (a) Menche, D.;
Hassfield, J.; Li, J.; Menche, G.; Ritter, A.; Rudolph, S. Org.
Lett. 2006, 8, 741. (b) Menche, D.; Arikan, F. Synlett 2006,
841. (c) Storer, R. I.; Carrera, D. E.; Ni, Y.; MacMillan, D.
W. C. J. Am. Chem. Soc. 2006, 128, 84.
(3) For direct reductive aminations using a variety of metal
reducing agents, see: (a) Alinezhad, H.; Tajbakhsh, M.;
Zamani, R. Synlett 2006, 431. (b) Sato, S.; Sakamoto, T.;
Miyazawa, E.; Kikugawa, Y. Tetrahedron 2004, 60, 7899.
(c) Berdini, V.; Cesta, M. C.; Curti, R.; D' Anniballe, G.; Di
Bello, N.; Nano, G.; Nicolini, L.; Topai, A.; Allegretti, M.
Tetrahedron 2002, 58, 5669. (d) Apodaca, R.; Xiao, W.
Org. Lett. 2001, 3, 1745. (e) Saxena, I.; Borah, R.; Sarma, J.
C. J. Chem. Soc., Perkin Trans. 1 2000, 503. (f) Micovic, I.
V.; Ivanovic, M. D.; Piatak, D. M.; Bojic, V. D. Synthesis
1991, 1043; and references cited therein.
(4) (a) Borch, R. F.; Bernstein, M. D.; Dupont Durst, H. J. Am.
Chem. Soc. 1971, 93, 2897. For a review on sodium
cyanoborohydride, see: (b) Lane, C. F. Synthesis 1975, 135.
(5) Gribble, G. W.; Ferguson, D. C. Chem. Commun. 1975, 535.
(6) (a) Abdel-Magid, A.; Maryanoff, C. A. Synlett 1990, 537.
(b) Abdel-Magid, A.; Maryanoff, C. F.; Carson, K. G.
Tetrahedron Lett. 1990, 31, 5595. (c) Abdel-Magid, A.;
Carson, K. G.; Harris, B. D.; Maryanoff, C. A.; Shah, R. D.
J. Org. Chem. 1996, 61, 3849. (d) Zhao, M.; Yin, J.;
Huffman, M. A.; McNamara, J. M. Tetrahedron 2006, 62,
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Lett. 2003, 5, 553.
(16) The acetic acid is believed to protonate the intermediate
imine which assists in its reduction, see reference 6.
(17) Representative experimental procedure for the reductive
amination of ketones: To a solution of aniline (100 mg, 1.07
mmol) and cyclohexanone (210 mg, 2.14 mmol) in DCE (2.1
mL) in a microwave vial, was added NaBH(OAc)3 (567 mg,
2.68 mmol) and AcOH (193 mg, 3.21 mmol). The vial was
capped and the resulting solution was heated in a CEM
Discover® microwave for ten minutes (fixed hold time) at
140 °C. The reaction was quenched with NaHCO3 (10 mL,
sat. aq) and then extracted with CH2Cl2 (3 × 20 mL). The
combined organic phases were dried (MgSO4), filtered and
concentrated in vacuo. Purification by flash column
chromatography (eluting with CH2Cl2) gave
cyclohexylphenylamine as a viscous oil (177 mg, 94%).19
(18) It should be noted that in these cases the starting aniline was
not isolated.
(19) All known compounds exhibited spectroscopic data
consistent with that reported in the chemical literature.
(20) All new compounds exhibited the expected NMR, HPLC,
LCMS and IR data which will be reported in a full
publication in due course.
(21) Representative experimental procedure for the reductive
amination of aldehydes: To a solution of aniline (200 mg, 2.2
mmol) and cyclohexanecarbaldehyde (123 mg, 1.1 mmol) in
DCE (2.1 mL) in a microwave vial, was added NaBH(OAc)3
(567 mg, 2.68 mmol) and AcOH (193 mg, 3.21 mmol). The
reaction was then subjected to the same procedure described
in reference 17. Purification gave cyclohexylmethylphenyl-
amine as a viscous oil (185 mg, 91%).19
(22) Solé, D.; Vallverdú, L.; Solans, X.; Font-Bardia, M.;
Bonjoch, J. J. Am. Chem. Soc. 2003, 125, 1587.
(23) Staub, G. M.; Gloer, J. B.; Dowd, P. F.; Wicklow, D. T. J.
Am. Chem. Soc. 1992, 114, 1015.
(24) Quetin-Leclercq, J.; Angenot, L.; Dupont, L.; Dideberg, O.;
Warin, R.; Delaude, C.; Coune, C. Tetrahedron Lett. 1991,
32, 4295.
Synlett 2006, No. 15, 2444–2448 © Thieme Stuttgart · New York