Chelation controlled reductive amination of cyclic ketones to trans-4-methoxycyclohexylamines: 9-BBN reduction mediated with FeCl3

Article abstract of DOI:10.1016/j.tetlet.2012.02.023

A novel trans-diastereoselective reductive amination of 4-substituted cyclohexanones is described using 9-BBN as reducing agent in the presence of FeCl₃. The method permits efficient synthesis of structurally diverse 4-trans-alkoxycyclohexylami

Full text of DOI:10.1016/j.tetlet.2012.02.023

Tetrahedron Letters 53 (2012) 1982–1986
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Chelation controlled reductive amination of cyclic ketones to
trans-4-methoxycyclohexylamines: 9-BBN reduction mediated with FeCl3
⇑
Bo Qu , Nizar Haddad, Sonia Rodriguez, Heewon Lee, Shengli Ma, Xingzhong Zeng, Diana C. Reeves,
Kanwar P.S. Sidhu, Jon C. Lorenz, Nelu Grinberg, Carl A. Busacca, Dhileepkumar Krishnamurthy,
Chris H. Senanayake
Chemical Development US, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT 06877, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel trans-diastereoselective reductive amination of 4-substituted cyclohexanones is described using
9-BBN as reducing agent in the presence of FeCl3. The method permits efficient synthesis of structurally
diverse 4-trans-alkoxycyclohexylamines.
Received 21 November 2011
Revised 5 February 2012
Accepted 6 February 2012
Available online 13 February 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Reductive amination
Diastereoselective
9-BBN
FeCl3
Chelation
Introduction
hindrance induced by substitution on the nitrogen atom, therefore
leading to the formation of cis-selective cyclohexylamines (Fig. 1b).
Reductive amination is an important synthetic tool in organic
synthesis. Various reducing agents have been utilized to carry
out this direct process,1 for example, catalytic hydrogenation,2
reduction using boranes or amine boranes,3 sodium- or zinc
borohydride in the presence of BrØnsted or Lewis acids,4 sodium
cyanoborohydride,5 sodium triacetoxyborohydride,6 silanes in the
presence of Lewis acids7 and organocatalytic reductive amina-
tions.8 However, few of these procedures targeted stereoselective
reduction of in situ generated cyclohexylimines. Reductive amina-
tion of 4-substituted cyclohexanones usually affords a mixture of
1,4-cis- and 1,4-trans diastereomers without significant selectivity,
which was attributed to the steric interaction of substituents on
the nitrogen atom of the imine functionality.9 Reductions of cyclo-
hexanones are more amenable to generating alcohols with high
trans-selectivity by varying the steric hindrance of the incoming
hydrides (Fig. 1a). Relatively unhindered LiAlH4, for example, will
approach the ketone from the axial position to produce exclusively
the trans-4-tert-butylcyclohexanol. Bulky hydrides such as LiBH
(sec-Bu)3 will attack from the less hindered equatorial side, leading
to diastereoselective production of cis-4-tert-butylcyclohexanol.
For cyclohexylimines, the least congested direction of hydride at-
tack appears to be from the equatorial position due to steric
In contrast to the well precedented diastereoselective reduction of
substituted cyclohexanones, few cis-diastereoselective syntheses
of 4-axial cyclohexylphenyl amines have recently been reported,10
and one trans-selective reductive amination of 4-substituted cyclo-
hexanones applying Zn(BH4)2 reduction supported on silica gel has
been described.4c
Herein, we report highly trans-selective reductive amination of
4-alkoxycyclohexylamines using 9-borabicyclo(3,3,1)nonane (9-
BBN) as reducing agent in the presence of FeCl3. To our knowledge,
9-BBN has not been reported as the reducing agent in reductive
amination reactions, even though it has been widely applied for
the reduction of aldehydes and ketones.11
Reductive amination of the electron-deficient aniline methyl 2-
aminobenzoate (1a) containing a labile ortho ester group was
examined with 4-methoxycyclohexanone (2a). Ph3SiH reduction
7d
catalyzed by SnBu2Cl2 yielded 4-methoxycyclohexylamines in a
trans/cis isomeric ratio of 35:65 (Table 1, entry 1) with cis-amine
as the major product. However, trans-4-methoxycyclohexylamine
was required for our current project. Different reducing agents
were tested in an effort to increase the selectivity toward the
trans-amine. No product formation was detected with metal bori-
dohydrides in the absence of Lewis acids even when dehydrating
reagents such as activated molecular sieves or orthoformate was
added to the reaction mixture (entry 2). Lewis acids are known to
facilitate imine formation, therefore BF3ÁEt2O was examined.
⇑
Corresponding author.
E-mail address: bo.qu@boerhinger-ingelheim.com (B. Qu).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.02.023

B. Qu et al. / Tetrahedron Letters 53 (2012) 1982–1986
1983
a
axial attack
trans : cis
H
H
O
t-Bu
92 : 8
LiAlH4
t-Bu
OH
LiBH(sec-Bu)3
1 : >99
H equatorial
H
attack
b
trans : cis
H
NaBH4
54 : 46
H
N
NHPh
t-Bu
H
t-Bu
equatorial
attack
LiBH(sec-Bu)3
1 : 99
H
H
less
hindered
side
Figure 1. Reductions of ketone (a) and imine (b) with hydride reagents.9
Table 1
Screening of the reductive amination reactions
O
COOCH3
COOCH3
COOCH3
+
+
N
H
3a-cis
N
H
NH2
OCH3
OCH3
1a
3a-trans
OCH3
2a
Entry
Reducing agent
Lewis acide (or catalyst)
Additive
3a trans/cisa,12
Conv.b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
PhSiH3
SnBu2Cl2
—
BF3Et2O
FeCl3
FeCl3
—
—
4 Å
HOAc
HOAc
35:65
—
35:65
49:51
65:35
—
82:18
76:24
72:28
74:26
52:48
55:45f
71:29
65:34
52:48
100%c
0d
NaBH(OAc)3
NaBH(OAc)3
NaBH(OAc)3
tBuNH2BH3
9-BBN
9-BBN
9-BBN
9-BBN
9-BBN
9-BBN
9-BBN
9-BBN
9-BBN
7%d
30%d
45%d
Trace
100%
100%
88%
100%
100%
100%
94%
FeCl3
Fe(OTf)3
In(OTf)3
BF3Et2O
BH3THF
TiCl4
Ga(OTf)3
AlCl3
FeCl3
100%
100%
BH3THF
a
b
c
d
e
f
Ratio and conv refer to HPLC analysis.
1.0 mmol aniline, 1.1 mmol ketone, 3.0 mmol reducing agent in THF at 0 °C for 3–6 h. 9-BBN was added as 0.5 M solution in THF.
1.2 mmol silane and 0.1 mmol SnBu2Cl2 in THF at 40 °C for 12 h.
Room temperature for 12 h.
1.2 mmol Lewis acid was added unless specified otherwise.
Same ratio was obtained with 1.0 mmol and 2.0 mmol of TiCl4, respectively.
O
COOCH3
COOCH3
9-BBN
+
B
R
LA
N
H
NH2
OR
H
O
1a
OR
trans : cis
N
2a
: OR = OCH3
2b: OR = OH
2c: OR = CH3
3a
3b
3c
82 : 18
78 : 12
9 : 91
H3COOC
Figure 2. Proposed structure of the reaction intermediate.
Improved conversion was observed, however favoring the unde-
sired cis-isomer (entry 3). Several Lewis acids were evaluated,
among them FeCl3 and GaCl3 with NaBH(OAc)3 produced a 1:1 mix-
ture of trans/cis-amines (entry 4). Due to the hygroscopic nature of
GaCl3, FeCl3 was selected for further optimization. Increased
trans-selectivity was obtained when the reducing agent tBu2NHÁBH3
was used. Trans-4-methoxycyclohexylamine was obtained for the first
time as the major product in a trans/cis ratio of 65:35 (entry 5). Incom-
plete reaction, however, was observed even after the addition of ex-
cess tBu2NHÁBH3. Other amine boranes such as NH3ÁBH3,

1984
B. Qu et al. / Tetrahedron Letters 53 (2012) 1982–1986
Table 2
Reductive amination of aryl and heteroaryl amines with 4-methoxycyclohexylketone
R
R
R
O
OCH3
N
H
N
H
OCH3
NH2
1
2a
3-trans
3-
c is
OCH3
Entry
1
Amine (1)
COOCH3
Ratio of trans/cis (3)
Yielda,17 (%)
82:18
94
a
NH2
NH2
2
3
72:28
75
96
d
Br
86:14b
Br
NH2
e
H3COOC
4
5
6
82:18b
82:18
81:19
85
86
92
f
NH2
EtOOC
NH2
g
i
COO Pr
h
NH2
O
O
7
83:17
93
NH2
i
COOCH3
8
9
89:11b
84:16b
90
95
Cl
NH2
j
O2N
Cl
NH2
k
H2N
10
11
61/39
79:21
75:25
85
67
89
l
N
H
S
H2N
m
N
NH2
Br
12c
N
N
n
o
13
34:66
72
NH2
a
b
c
Isolated overall yield.
In MeTHF at 10 °C.
Trans/cis ratio of 84:16 in MeTHF at 10 °C.
morpholine borane or picoline borane resulted in low selectivity of
the trans-amine with low conversion. To our delight, 9-BBN was
found to be the most selective reducing agent and an 82:18 trans/
cis isomeric ratio was obtained in combination with FeCl3 (entry
7). Various Lewis acids were then evaluated with 9-BBN. FeCl3 pro-
duced the highest selectivity for trans-4-methoxycyclohexylamine.
Recently FeCl3 has been reported as catalyst for reductive
amination of aldehydes using poly(methylhydrosiloxane) as a hy-
dride source.13 9-BBN itself without additional Lewis acid was not
effective enough to activate the ketone for imine formation (entry
6). Even though 9-BBN has been reported to reduce ketones11d,e
;
4-methoxycyclohexanol was only observed in trace amounts if
reactions were run at ambient temperature. Stronger Lewis acids
TiCl4 (entry 12) and AlCl3 (entry 14) furnished complete conversion,

B. Qu et al. / Tetrahedron Letters 53 (2012) 1982–1986
1985
but low selectivity of trans-4-methoxycyclohexylamine was ob-
served. Brown et al. have shown that 9-BBN has the ability to re-
duce FeCl3 to a lower valence state,14 however a test of FeCl2 as
Lewis acid resulted in no product formation, suggesting this is not
the underlying mechanism.
Highly trans-selective reductive amination of anilines with 4-
methoxycyclohexanone was demonstrated on a series of aryl
amines (Table 2). In all cases, good to high yields were achieved
with the trans-amine as the major product. Reaction of 1a with ke-
tone 2a produced a 94% overall yield of trans- and cis-amine in a
ratio of 82:18 (Table 2, entry 1). 2-Propylaniline (1d) with an ortho
alkyl group furnished a trans- to cis-amine ratio of 72:28 in a 75%
overall yield, indicating no effect of the ester functionality (entry
2). Ester groups either para or meta to amine on the aminobenzo-
ates are well tolerated, and the same ratio of trans/cis diastereo-
mers 82:18 and overall yields of 85% were obtained (entries 4
and 5). Increasing the steric hindrance of the ortho-ester group
did not affect the selectivity or reactivity when compared to the
methyl ester (entries 6 and 7). Electron-poor anilines (1j and 1k)
produced high percentage of trans-amines; trans/cis isomeric ratios
of 89:11 with a 90% yield and 84:16 with a 95% yield were ob-
tained, respectively (entries 8 and 9). Less basic anilines with
strong electron-withdrawing groups on the phenyl ring are usually
unreactive for reductive amination with NaBH(OAc)3.6b Unlike
nucleophilic metal hydride reducing agents, 9-BBN is an electro-
philic reducing reagent, therefore the conditions are tolerant of
many different functional groups, such as halides and nitro groups
(entries 3, 8 and 9), which are incompatible with other reducing
methods. It has been reported that successful 9-BBN reductions
were achieved in the presence of nitro and halogen functional
groups.6 One drawback of this methodology, however, is that the
conditions are not tolerant of alkoxy groups on the aniline, proba-
bly due to the coordinating effect of alkoxy group with the boron
atom of 9-BBN.
To expand the generality of this process, we examined the
reductive amination conditions of heteroaryl amines with 4-meth-
oxycyclohexanone. Similarly, moderate to good yields were ob-
tained with the trans-amines as the major products. Reaction of
1H-indol-5-amine (1i) with 4-methoxycyclohexanone generates
amines in a trans/cis diastereomeric ratio of 61:39 with a total yield
of 85% in THF (Table 2, entry 10). Benzo[d]thiazol-6-amine pro-
duced trans/cis 4-methoxycyclohexylamines in a ratio of 79:21
with an overall yield of 67% (entry 11). 2-Bromopyridin-3-amine
generated 75:25 of trans/cis-amines in an 89% yield. A higher
trans/cis-amine ratio of 84:16 was generated in MeTHF at 10 °C,
but with a compromised yield (entry 12). Most interestingly, con-
trary to trans-preferred reductive amination, 8-aminoquinoline
produced the cis-amine as a major isomer in a trans/cis ratio of
34:66 (entry 13). We suspect this may be due to the chelating ef-
fect of the boron atom to the neighboring nitrogen atom, which
limits its coordination with OMe group on the 4-substituted imine
to result cis favored product.
The high percentage of trans-amine formation may be due to
the coordination of the boron atom with the oxygen atom of 4-
methoxy in cyclohexanone, so that the hydride has to approach
the C@N bond from the same side of the OMe group, leading to
trans-4-methoxycyclohexylamine as the preferred product. This
hypothesis was supported by evaluating the reductive amination
conditions on two additional ketones in the presence or absence
of coordinating groups at the 4-position of the cyclohexanone
(Fig. 2). Interestingly, –OMe or –OH substitution resulted in the
trans-isomer as the major product, an 82:18 and 78:22 of trans/
cis isomeric amines were obtained, respectively. When the coordi-
nating atom was absent as in 4-methylcyclohexanone, the lack of
chelation led to a preference for the hydride to approach from
the least congested equatorial side, leading predominantly to the
cis-4-methylcyclohexylamine in a trans/cis ratio of 9:91. The coor-
dinating effect may explain the low trans-selectivity in the pres-
ence of strong Lewis acid such as TiCl4 due to its stronger
coordination to the 4-methoxy group, yielding equal amounts of
trans- and cis-amines (Table 1, entry 12). Various boranes were
evaluated for the reaction of aniline 1a with ketone 2a; inferior
trans-selectivity compared to 9-BBN was found in all cases. Bor-
anes that have low affinity to complex with the oxygen atom of
the methoxy group in ketone 2a resulted in low trans-selectivity.
Pinacolborane generated a trans/cis ratio of 50:50, while N,N-dieth-
ylanilineborane and BH3ÁNH3 gave isomeric ratios of 60:40 and
50:50, respectively. Boranes that are more prone to complex with
the –OMe of ketone 2a produced higher trans-amine formation,
however steric hindrance of the borane reagent then interferes
with the chelating effect and leads to lower selectivity when com-
pared to 9-BBN: (Ipc)2BH gave a trans/cis ratio 70:30 and disi-
amylborane produced a similar ratio of 62:38. Interestingly,
reductive amination with BH3ÁTHF resulted in low trans/cis-selec-
tivity (Table 1, entry 15).15
The reductive amination occurred significantly faster in THF
than in other solvents, which is attributed to the formation of
the more reactive 9-BBN-THF complex.6 Both commercially avail-
able solid (9-BBN)2 and 0.5 M 9-BBN in THF are effective. (9-
BBN)2 has poor solubility in other solvents at 0 °C such as in
CH2Cl2, toluene, and tert-butylmethyl ether, which leads to slower
reaction rates. However, in MeTHF, higher trans-isomer ratios were
observed for some amines, but a longer reaction time was required.
(9-BBN)2 has low solubility in MeTHF, reactions need to be per-
formed at a slightly higher temperature of 10 °C for completion
after 12 h. Selectivity was marginally affected by the reaction tem-
perature, and even when the reaction temperature was reduced to
–78 °C in THF, an 85:15 trans/cis ratio was observed for the reac-
tion of aniline 1a and ketone 2a. Zn(BH4)2 supported on silica gel
has been reported to reduce N-phenyl-4-methylcyclohexylimine
with high diastereoselectivity for the trans amine product.4c
Reductive amination of 1a and 2a with silica-supported Zn(BH4)2
resulted in low trans-selectivity and poor conversion. At least three
molar equivalents of 9-BBN were required for complete conver-
sion,11c,16 while theoretically only one molar equivalent was neces-
sary for the reduction. We suspected that one equivalent of 9-BBN
was decomposed by water generated from the imine formation,
and a second equivalent of 9-BBN was required for complexation
with Lewis bases in the reaction mixture. This was confirmed by
the addition of two molar equivalents of ketone instead of one.
In this case, four molar equivalents of 9-BBN instead of three were
then required to achieve full conversion.
In summary, we have developed a trans-selective reductive ami-
nation protocol to prepare 4-trans-methoxycyclohexylamines uti-
lizing 9-BBN as the reducing agent in the presence of FeCl3. This
methodology is tolerant of many functional groups which otherwise
are not stable under typical metal hydride reduction conditions. The
initially observed preferential cis-selectivity using tin-catalyzed si-
lane reduction was reversed to instead favor the trans-isomer
through careful optimization. Taking advantage of the coordination
of the 4-methoxy group with the boron atom of 9-BBN allowed for
the preferred approach of the hydride from the same face of the
methoxy group, furnishing the trans-amines as major products.
Supplementary data
Supplementary data (1H and 13C NMR spectra of compounds
3a–3o including both cis- and trans-amines) associated with this
article can be found, in the online version, at doi:10.1016/
j.tetlet.2012.02.023.

1986
B. Qu et al. / Tetrahedron Letters 53 (2012) 1982–1986
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12. Ratio of two diastereomers was determined by HPLC analysis, Agilent Zorbax
XDB-C8, 3.5
lM, 4.6 Â 50 mm; A, H2O with 0.5% formic acid; B, acetonitrile
with 0.5% formic acid, 2 mL/min, 5% B–95% B in 3.5 min and hold at 95% B for
1 min. Trans-amines elute faster than cis-amines.
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were carried out under nitrogen atmosphere and monitored by HPLC.
Representative
procedure
for
the
synthesis
of
methyl
2-(4-
methoxycyclohexylamino) benzoate (3a): To a stirred solution of 194.6 mg
(1.2 mmol) of FeCl3 and 2 mL of anhydrous THF at 0 °C under nitrogen
atmosphere were added 151.2 mg (1.0 mmol) of methyl 2-aminobenzoate (1)
and 141.0 mg (1.1 mmol) of 4-methoxycyclohexanone (2a). 6.0 mL of 0.5 M 9-
BBN in THF (3.0 mmol) was then added slowly to maintain internal
temperature below 5 °C. The reaction mixture was further stirred at 0 °C for
2 h. After completion of the reaction (monitored by HPLC), 290 lL (3.0 mmol)
of diethanolamine was added to the reaction mixture at 0 °C and stirred for
30 min to remove 9-BBN by forming an insoluble solid. After filtering out the
precipitate, the crude mixture of 3a was purified by column chromatography
over silica gel using pure hexanes to 10% ethyl acetate in hexanes as eluent to
give 247 mg of 3a (0.94 mmol) as light yellow oil after drying. The
corresponding trans-3a and cis-3a were further purified on silica gel.
8. (a) Menche, D.; Hassfeld, J.; Li, J.; Menche, G.; Ritter, A.; Rudolph, S. Org. Lett.
2006, 8, 741; (b) Tuttle, J. B.; Ouellet, S. G.; MacMillan, D. W. C. J. Am. Chem. Soc.
2006, 128, 12662.