Direct reductive aminations with catalytic molybdenum dioxide dichloride and phenylsilane

Article abstract of DOI:10.1016/j.tetlet.2009.06.071

A powerful direct reductive amination (DRA) method is developed, using catalytic MoO₂Cl₂ and phenylsilane (PhSiH₃) as the reducing agent. The alkylation of a range of amines (pK_a 0-7.8) with both an electron-def

Full text of DOI:10.1016/j.tetlet.2009.06.071

Tetrahedron Letters 50 (2009) 4906–4911
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Direct reductive aminations with catalytic molybdenum dioxide dichloride
and phenylsilane
b
c
b
a
Clive A. Smith a, , Laura E. Cross , Kimberley Hughes , Rebecca E. Davis , Duncan B. Judd ,
*
Andrew T. Merritt a
a Discovery Medicinal Chemistry, GlaxoSmithKline Pharmaceuticals, NFSP-North, Harlow, CM19 5AD, UK
b University of Bath, Claverton Down, Bath, BA2 7AY, UK
c University of Strathclyde, Glasgow, G1 1XL, Scotland, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A powerful direct reductive amination (DRA) method is developed, using catalytic MoO2Cl2 and phenyl-
silane (PhSiH3) as the reducing agent. The alkylation of a range of amines (pKa 0–7.8) with both an elec-
tron-deficient and two electron-rich-aldehydes is achieved in good to excellent yields. The novel
employment of this DRA in alcoholic solvents significantly improves the reaction scope and excellent
functional group selectivity is exhibited.
Received 30 March 2009
Revised 26 May 2009
Accepted 12 June 2009
Available online 17 June 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Direct reductive amination (DRA)
Molybdenum dioxide dichloride
Phenylsilane
Sodium triacetoxyborohydride
Aryl PFP-sulfonate esters
Direct reductive amination (DRA) is a powerful method for the
reductive aminoalkylation of aldehydes and ketones with amines
by either hydride-type reducing agents,1 transfer hydrogenation,2
hydrogenation3 or by using a silane-containing reducing agent.4
With the aim of improving the physico-chemical properties of a
chemokine lead series, we wanted to carry out the DRA reaction
on 4-formylphenylsulfonyl chloride (1) prior to any sulfonamide
formation. Simple reaction of 4-formylphenylsulfonyl chloride
with a variety of aryl amines 2 yields sulfonamides 3 as the major
products.5 In order to change the order of reactivity we envisioned
converting 1 into its more stable synthetic equivalent, the penta-
fluorophenyl (PFP) sulfonate ester 4 (Scheme 1). The subsequent
conversion of PFP-sulfonate esters, and more recently 2,4,6-tri-
chlorophenyl (TCP) sulfonate esters,6 into sulfonamides has been
reported by Caddick et al.7 The criteria for success were to find a
reagent and suitable reaction conditions for the desired DRA,
whilst minimizing possible sulfonamide formation or reduction
of the aldehyde or the PFP-sulfonate ester group of 4. Furthermore,
if the product 5 was a 2° amine it has the possibility to react inter-
molecularly with a PFP-sulfonate ester group to form a sulfon-
amide dimer or higher oligomer. Thus, for these DRA reactions,
only the 2° amines 6a–c or the aryl amine 2a were chosen for
use with the PFP-sulfonate ester 4 to yield the higher order amine
5 (65–87%).
Conversion of 4-formylphenylsulfonyl chloride (1) into its PFP-
sulfonate ester 4 was achieved in excellent yield at low tempera-
ture. The gold standard reagent and first choice for DRA reaction
is sodium triacetoxyborohydride1a,b which was successfully em-
ployed for the reactions of this aldehyde 4 with the secondary
amines 6a–c to yield the tertiary benzylamines 5a–c in good yields
(Table 1). These reactions were carried out at room temperature in
a chlorinated solvent mixture, under anhydrous conditions and
with a slight excess of the 2° amine 6a–c over the aldehyde 4. An
excess of acetic acid was also employed in order to both promote
imine formation and to minimize sulfonamide formation. As the
amines 6b and 6c were used as their hydrochloride salts, acetoni-
trile was added to improve their solubility. Carrying out the DRA
reaction at room temperature ensured that the possible competing
sulfonamide formation was relatively insignificant. With the aryl
amine 2a, the procedure gave only a moderate yield of the DRA
product 5d (Table 1).
Although the sodium triacetoxyborohydride method (Method
A) showed reasonable selectivity with the 2° alkylamines, the reac-
tion scope was relatively poor, especially for aromatic amines. As
the nucleophilicity of the amine decreases, so does the rate of
imine formation and hence the relative rate of aldehyde reduction
increases. This suggested the need to find a reducing system, which
favoured reduction of an imine over the aldehyde 4. Recently,
* Corresponding author. Tel.: +44 01992 586639.
E-mail addresses: cliveadriansmith@googlemail.com (C.A. Smith), duncan.b.
judd@gsk.com (D.B. Judd).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.071

C. A. Smith et al. / Tetrahedron Letters 50 (2009) 4906–4911
4907
F
O
O
C6F5O- +HNEt3
F
F
Cl
O
F
S
S
O
O
O
O
4
1
99%
F
R1
NH2
HNR3R4
NaHB(OAc)3
R2
2a: R1,R2 = H,
2b: R1 = H, R2 = Cl
2c: R1, R2 = Cl
O
H
R1
R3
N
F
F
N
S
O
F
F
O
F
O
R4
R2
S
O
R3 = R4 = alkyl
O
R3 = H, R4 = aryl
3a: R1,R2 = H, 98%
3b: R1 = H, R2 = Cl, 65%
3c: R1, R2 = Cl, 75%
5
Scheme 1.
Table 1
catalytic MoO2Cl2/PhSiH3 system, in CH2Cl2–THF–MeCN (1:1:1)
at 50 °C, in the presence of a slight excess of acetic acid, although
the yield of 5b was only moderate (41%). Changing the reaction sol-
vent to 1,4-dioxane (Method B, Table 2) and carrying out the reac-
tion at reflux improved both the isolated yield and the reaction
scope of the benzylamine product 5. Methanol has been reported
to be superior to both THF and 1,2-dichloroethane (DCE) in
increasing both the rate and extent of imine formation in solution
as judged by 1H NMR and GC.1b As the MoO2Cl2/PhSiH3 reduction
system behaved well in the presence of acetic acid, it was reasoned
that it should also tolerate an alcoholic reaction solvent. We found
this was the case and using MoO2Cl2/PhSiH3 in refluxing ethanol
(Method C, Table 2) not only gave improved yields, but also further
increased the reaction scope. Finally, two examples using metha-
nol as the reaction solvent (Method D, Table 2) have been included
for comparison.
The use of catalytic MoO2Cl2 and PhSiH3 in refluxing 1,4-diox-
ane (Method B, Table 2) gave essentially identical results to those
obtained when using sodium triacetoxyborohydride (Method A,
Table 1) at room temperature with aldehyde 4. Changing the reac-
tion solvent to refluxing ethanol (Method C, Table 2) showed an
improvement in yield and also increased the scope of the reaction,
allowing the use of the less nucleophilic amines 2b (pKa 4.0) and 2c
(pKa 2.9). In the reaction of aniline 2a with aldehyde 4, replace-
ment of acetic acid with hydrogen chloride showed essentially
no difference. However, omission of the acetic acid from this reac-
tion appeared to show a slight improvement in yield. The two
examples using methanol as the reaction solvent at room temper-
ature (Method D, Table 2) suggest that this is an even more selec-
tive DRA procedure. The first example shows an improvement in
yield of product 5e (84%) and the reaction scope is further im-
proved with amine 2e (pKa 1.7) giving 5h (81%) in good yield. Prob-
ably even more notable is that no anhydrous precautions were
taken with Method D and that HPLC grade methanol was used as
the reaction solvent, again with the relatively electron-deficient
aldehyde 4.
Direct reductive amination of aldehyde 4 with the 2° amines 6a–c and aryl amine 2a
using sodium triacetoxyborohydride
Amine
Structure
Product
Yield (%)
N
N
PFPO
O
6a
O
69
HN
O
S
S
5a
5b
O
O
F
F
F
6b
6c
2a
75a
87b
65
PFPO
O
HN
HN
F
N
F
F
PFPO
O
F
S
S
F
O
O
5c
N
H
PFPO
O
H2N
5d
Method A: NaHB(OAc)3 (1.0 mol equiv), CH2Cl2–THF (1:1), AcOH (1.1 mol equiv),
amine (1.1 mol equiv), 4 Å molecular sieves, room temperature, 16–20 h.
a
Reaction solvent: CH2Cl2–THF–MeCN (1:1:1), NaHB(OAc)3 (1.5 mol equiv).
Reaction solvent: DCE–THF–MeCN (60:8:4), NaHB(OAc)3 (1.5 mol equiv).
b
the use of catalytic MoO2Cl2 and phenylsilane (PhSiH3), in THF at
reflux, has been reported for reduction of imines derived from a
variety of benzaldehydes with either aniline or 2-chloroaniline.8
The reported yields are generally excellent for the more electron-
deficient benzaldehydes (4-NO2, 4-F, 4-CF3, 4-CO2Me), but only
moderate with more electron-rich benzaldehydes (4-H, 4-OMe).
It was encouraging to observe that the DRA was possible using a
The reported use of catalytic MoO2Cl2 and PhSiH3, in anhydrous
THF, for the indirect reductive amination (IRA) of the imines
formed between aniline 2a and a series of aryl aldehydes showed

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C. A. Smith et al. / Tetrahedron Letters 50 (2009) 4906–4911
Table 2
Comparison of the direct reductive amination of aldehyde 4 with MoO2Cl2/PhSiH3, in either 1,4-dioxane (Method B), ethanol (Method C) or methanol (Method D), with 2° amines
6b, c and the aryl amines 2a–e
Amine
pKa
Product structure
Method B yield (%)
Method C yield (%)
Method D yield (%)
N
N
F
PFPO
S
6b
7.8
77
78
—
F
F
O
O
5b
5c
O
PFPO
6c
2a
6.6
4.6
81
61
81
—
—
S
S
F
O
N
H
PFPO
93
98a
91b
O
5d
O
N
H
Cl
Cl
PFPO
2b
2c
4.0
2.9
36
51
84
S
S
5e
5f
O
O
O
N
H
PFPO
—
60
—
51c
Cl
O
N
H
O
PFPO
2d
2e
5.2
1.7
—
—
82
—
S
S
O
O
5g
5h
O
N
H
N
PFPO
—
81
O
Method B: MoO2Cl2 (10 mol %), PhSiH3 (3.0 mol equiv), AcOH (1.1 mol equiv), amine (1.1 mol equiv), 4 Å molecular sieves, 1,4-dioxane, reflux, 16–20 h.
Method C: MoO2Cl2 (10 mol %), PhSiH3 (3.0 mol equiv), AcOH (1.1 mol equiv), amine (1.1 mol equiv), 4 Å molecular sieves, ethanol, reflux, 16–20 h.
Method D: MoO2Cl2 (5 mol %), PhSiH3 (1.5 mol equiv), AcOH (1.1 mol equiv), amine (1.1 mol equiv), methanol, rt, 3–4 h.
a
No AcOH added.
HCl (4.0 M in 1,4-dioxane, 1.1 mol equiv) used in place of AcOH.
Reaction in a microwave reactor for 2 h at 80 °C.
b
c
that the most electron-rich example, 4-methoxybenzaldehyde 7a,
gave the lowest reported yield of 2° benzylamine 8a (50%)8 (Table
3). In order to compare this IRA reaction with the DRA reaction
methods C (ethanol) and D (methanol) four reactions were carried
out between aniline 2a and the aldehydes 4-methoxybenzalde-
hyde 7a and 2,4-dimethoxybenzaldehyde 7b to give the 2° benzyl-
amines 8a and 8b, respectively (Table 3). Both DRA methods C and
D gave excellent results for the preparation of 8a, but only method
D gave a good yield of 8b (77%). Therefore, we sought to optimize
the DRA methods C and D with the more problematical and elec-
tron-rich aldehyde, 2,4-dimethoxybenzaldehyde 7b, and in the
process of doing so, further improve the reaction scope. During
optimization, we investigated the effects of the stoichiometry of
the catalyst and PhSiH3, the reaction temperature, the nature of
the alcoholic solvent and the presence of additives, especially
water (Table 3).
Whilst processing the MoO2Cl2 for these reactions, it was noted
that the catalyst was slightly hygroscopic. As such, we could not be
sure how much water we were adding to our reactions. In order to
minimize any unintentional addition of water for methods A and B,
the addition of both molecular sieves and anhydrous solvents was
used. However, to be more confident of the possible effects of the
presence of water in our reactions we decided to use it as an addi-
tive during imine formation (5–30 min) and preceding the addition

C. A. Smith et al. / Tetrahedron Letters 50 (2009) 4906–4911
4909
Table 3
Comparison of the direct reductive amination using MoO2Cl2/PhSiH3, with Method C (ethanol) or Method D (methanol), with aldehydes 7a, b and aryl amines 2a, e-n
R1
R1
Method C: cat. MoO2Cl2,PhSiH3,
AcOH (1.1 mol equiv), EtOH, 80 oC
H
N
R
O
O
O
7a, R1 = H
Method D: cat. MoO2Cl2, PhSiH3,
AcOH (1.1 mol equiv), MeOH, RT
7b, R1 = OMe
8
Aryl amine (R)
pKa
Aldehyde
MoO2Cl2 (mol %)
PhSiH3 (mol equiv)
Method
H2O (mol equiv)
Product yield
C6H5 2a
C6H5 2a
C6H5 2a
C6H5 2a
4.6
4.6
4.6
4.6
7a
7a
7b
7b
10
5
10
5
3.0
1.5
3.0
1.5
C
D
C
D
1.0
0
1.0
0
8a,11 96%
8a,11 89%
8b, 38%
8b, 77%
N
4.0
7b
5
5
1.5
D
1.0
1.0
8f, 71%
N
N
2f
N
2g
3.6
7b
1.5
D
8g, 68%
Br
4-MeO2CC6H4 2h
4-MeO2CC6H4 2h
4-MeO2CC6H4 2h
2.5
2.5
2.5
7b
7b
7b
10
10
10
1.5
1.2
2.0
Ca
Da
Da
1.0
1.0
1.0
8h, 51%
8h, 69%
8h, 78%
O
N
N
2i
2i
2.4
2.4
7b
7b
10
10
3.0
1.5
C
1.0
1.0
8i, 9%
O
D
8i, 82%
2-Cl-4-IC6H3 2j
4-NCC6H4 2e
4-NCC6H4 2e
4-NCC6H4 2e
4-O2NC6H4 2k
4-O2NC6H4 2k
4-O2NC6H4 2k
4-O2NC6H4 2k
1.9
1.7
1.7
1.7
1.0
1.0
1.0
1.0
7b
7b
7b
7b
7b
7b
7b
7b
5
10
10
5
10
10
5
1.5
1.5
1.5
1.5
2.0
1.2
1.5
1.5
D
D
D
D
C
1.0
1.0
10.5
1.0
1.0
1.0
8j, 83%
8e, 49%
8e, 63%
8e, 82%
8k, 31%
8k, 70%
8k, 90%
8k, 93%
Da
D
D
1.0
10.5
5
O
N
2l
0.3
0.3
7b
7b
5
5
1.5
1.5
D
D
1.0
8l, 68%
8l, 52%
Br
O
N
2l
10.5
Br
2-F-5-O2NC6H3 2m
3-F-2-O2NC6H3 2n
0.0
0.0
7b
7b
5
5
1.5
1.5
D
D
10.5
10.5
8m, 88%
8n, 74%
Method C: MoO2Cl2 (10 mol %), PhSiH3 (1.2–3.0 mol equiv), AcOH (1.1 mol equiv), amine (1.1 mol equiv), ethanol, reflux, 16–20 h.
Method D: MoO2Cl2 (5–10 mol %), PhSiH3 (1.2–2.0 mol equiv), AcOH (1.1 mol equiv), amine (1.1 mol equiv), methanol, rt, 3–4 h.
HPLC grade solvents were used in all experiments.
Adamantis Pro (GSK’s proprietary physico-chemical and ADMET comparison software) was used to calculate the pKa of the amines, with values between 0 and 14.
a
Reaction carried out at 50 °C.

4910
C. A. Smith et al. / Tetrahedron Letters 50 (2009) 4906–4911
O
O
SiH2Ph
Ar1
X
X
ArN=CHAr1
Mo
H
N
Ar
ROH
O
O
X
X
O
H
SiH2Ph
O
O
O
SiH2Ph
X
X
X
X
Mo
Mo
Mo
SiH2Ph
Ar1
H
N
N
OR
Ar1
Ar
Ar
Ar(Ar1CH2)NH +
ROSiH2Ph
Ar(Ar1CH2)NSiH2Ph
O
O
X
X
X
X
Mo
O
Mo O
PhSiH3
H
SiH2Ph
ROH
O
R = H, Me or Ac
X = Cl, OR
Cl
Cl
Mo O
Scheme 2. Proposed reaction mechanism for the direct reductive amination of an imine with MoO2Cl2/PhSiH3 in methanol with acetic acid and water additives.
of the MoO2Cl2 catalyst and PhSiH3 in ethanol (Method C) and
methanol (Method D). The interpretation of the results shown in
Table 3 is that addition of at least one equivalent of water gave
good yields, and generally the addition of 10.5 equiv of water
was, in most cases, beneficial. The reactions performed in metha-
nol at room temperature were better in all cases than those carried
out in ethanol at reflux, except for one example when water was
not added. All the reactions carried out in methanol were more
efficient at room temperature than when carried out at 50 °C and
also when less catalyst (5 mol %) was employed. The reactions car-
ried out in methanol gave the desired reductive amination product
more quickly at ambient temperature than those performed in eth-
anol at reflux. The reaction conditions do not appear to be sensitive
to oxygen as none of the reaction solvents were degassed, but all
the reactions were carried out under an inert gas atmosphere in or-
der to control the amount of water available to the reaction sys-
tem. As the preferred DRA protocol uses a number of potential
oxygen nucleophiles (ROH, where R = Ac, Me or H) we cannot be
sure whether the active catalyst is MoO2Cl2, MoO2Cl(OR),
MoO2(OR)2 or even some other Mo(VI) species. The mechanism
of the imine reduction is possibly similar to that proposed for the
hydrosilation of aldehydes and ketones with MoO2Cl2/PhSiH3,9a,b
with an initial [2+2]-addition of the Si–H bond to the metal oxide
(Mo@O), resulting in the formation of the active reducing agent,
Si–O–Mo–H being most likely.9b Following hydride transfer to
the iminium carbon, either the iminium nitrogen could pick up
the silane or the catalyst could be regenerated by direct attack of
an oxygen nucleophile (ROH, where R = Ac, Me or H) on the silane
itself. Although we cannot rule out the possibility of a radical
mechanism, the rate enhancement observed on moving to more
polar solvents suggests the presence of polar or charged transition
state complexes. For simplicity, the proposed mechanism in
Scheme 2 depicts a fully concerted process taking place; however,
a stepwise process could be equally likely. The replacement of
MoO2Cl2 with MoO3 failed to reproduce the DRA reaction to any
appreciable level. Interestingly, the reactions were chemoselective;
notably we failed to observe any appreciable nitro or ester reduc-
tion, as has been reported with MoO2Cl2/PhSiH3 in refluxing
toluene.10
In summary we have developed a novel and powerful method
of carrying out DRA on both electron-deficient aldehyde 4 and
the electron-rich aldehyde 7b with amines possessing a wide pKa
range. The protocol is tolerant of a number of reducible functional
groups (F, Cl, I, OMe, NO2, CO2Me, SO3PFP and CN) and heterocyclic
ring systems 2f, g, i, l. The reactions are environmentally friendly,
in that methanol is used in place of the standard chlorinated sol-
vents (CH2Cl2 and DCE), and are carried out at ambient tempera-
ture. Method D requires only the use of commercial HPLC grade
methanol and the addition of water (1.0 mol equiv) is recom-
mended, as is a slight excess of acetic acid (1.1 mol equiv) to in-
crease the rate of imine formation. The MoO2Cl2 catalyst
(5 mol %), PhSiH3 (1.5 mol equiv), with respect to the aldehyde,
water, acetic acid and amine stoichiometry have not been opti-
mized by a design of experiments procedure, as all reaction param-
eters are best examined for a particular reaction of interest. The
addition of a large excess of water (10.5 mol equiv) is not only tol-
erated, but generally has a small positive effect on the yield. The
tolerance of this protocol to relatively high water concentrations
may be beneficial both to dissolve more polar or charged sub-
strates, or with substrates with variable water content. Finally,
the reactions are not sensitive to oxygen and are highly amenable
to scale-up.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.06.071.
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7. (a) Caddick, S.; Wilden, J. D.; Judd, D. B. J. Am. Chem. Soc. 2004, 126, 1024; (b)
Caddick, S.; Wilden, J. D.; Bush, H. D.; Judd, D. B. QSAR Comb. Sci. 2004, 23, 902;
(c) Wilden, J. D.; Judd, D. B.; Caddick, S. Tetrahedron Lett. 2005, 46, 7637; (d)
Caddick, S.; Wilden, J. D.; Judd, D. B. Chem. Commun. 2005, 2727.
8. Fernandes, A. C.; Romão, C. C. Tetrahedron Lett. 2005, 46, 8881.
9. (a) Fernandes, A. C.; Fernandes, R.; Romão, C. C.; Royo, B. Chem. Commun. 2005,
213; (b) Costa, P. J.; Romão, C. C.; Fernandes, A. C.; Royo, B.; Reis, P. M.;
Calhorda, M. J. Chem. Eur. J. 2007, 13, 3934.
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