One-pot synthesis of N-substituted β-amino alcohols from aldehydes and isocyanides

Article abstract of DOI:10.1002/chem.201500210

A practical two-stage one-pot synthesis of N-substituted β-amino alcohols using aldehydes and isocyanides as starting materials has been developed. This method features mild reaction conditions, broad scope, and general tolerance of functional groups. Based on a less common central carbon-carbon bond disconnection, this protocol complements traditional approaches that involve amines and various carbon electrophiles (epoxides, α-halo ketones, β-halohydrins). Medicinally relevant products can be prepared in a concise and efficient way from simple building blocks, as demonstrated in the synthesis of the antiasthma drug salbutamol. Upgrading the synthesis to an enantioselective variant is also feasible.

Full text of DOI:10.1002/chem.201500210

DOI: 10.1002/chem.201500210
Full Paper
&
Amino Alcohols
One-Pot Synthesis of N-Substituted b-Amino Alcohols from
Aldehydes and Isocyanides
˘
Razvan C. Cioc, Daan J. H. van der Niet, Elwin Janssen, Eelco Ruijter, and
Romano V. A. Orru*[a]
Abstract: A practical two-stage one-pot synthesis of N-sub-
stituted b-amino alcohols using aldehydes and isocyanides
as starting materials has been developed. This method fea-
tures mild reaction conditions, broad scope, and general tol-
erance of functional groups. Based on a less common central
carbon–carbon bond disconnection, this protocol comple-
ments traditional approaches that involve amines and vari-
ous carbon electrophiles (epoxides, a-halo ketones, b-halo-
hydrins). Medicinally relevant products can be prepared in
a concise and efficient way from simple building blocks, as
demonstrated in the synthesis of the antiasthma drug salbu-
tamol. Upgrading the synthesis to an enantioselective var-
iant is also feasible.
preparation of added-value chemicals[3] and ligands for cataly-
sis.[4]
Introduction
The b-amino alcohol moiety is a privileged structural motif in
the pharmaceutical industry. Salbutamol (1) and propranolol
(2) are on the World Health Organization List of Essential Medi-
cines[1] and represent the most important examples of thera-
peutic agents that bear this structural feature. Numerous
others have been released on the market for the treatment of
various circulatory, respiratory, and other diseases (Figure 1). In
addition to their high relevance in drug discovery,[2] N-substi-
tuted b-amino alcohols are important building blocks in the
The construction of the b-amino alcohol fragment is almost
invariably achieved by the nucleophilic attack of an amine on
a suitable electrophilic reaction partner, such as an epoxide, a-
haloketone, or b-halohydrin (Scheme 1). Although robust,
Scheme 1. Synthetic approaches towards N-substituted b-amino alcohols.
there are many drawbacks associated with this synthetic strat-
egy. First, the required starting materials are typically not com-
mercial and their multistep preparation is wasteful and time-
consuming. Second, the substitution approach poses impor-
tant selectivity issues (e.g., regioselectivity in the epoxide
opening), double alkylation of the (unprotected) primary
amine, and low reactivity of poorly nucleophilic and bulky
amines, which thus need to be employed in large excess
amounts.[2c,5] In this respect, the tert-butyl substituent on the
amine has particular importance in drug design as it contrib-
utes both to the drug metabolic stability and selectivity for
a (specific) b-adrenergic receptor.[6] A general alternative strat-
egy to circumvent these problems and employ readily avail-
able building blocks would therefore be a valuable tool for
medicinal as well as process chemistry.
Figure 1. Examples of drugs based on the N-substituted b-amino alcohol
motif.
[a] R. C. Cioc, D. J. H. van der Niet, E. Janssen, Dr. E. Ruijter,
Prof. Dr. R. V. A. Orru
Department of Chemistry & Pharmaceutical Sciences
and Amsterdam Institute for Molecules Medicines
and Systems (AIMMS), VU University Amsterdam
De Boelelaan 1083, 1081 HV Amsterdam (The Netherlands)
E-mail: r.v.a.orru@vu.nl
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201500210.
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With this goal in mind, we envisioned the construction of
the N-substituted b-amino alcohol motif by means of a less
straightforward central CÀC bond retrosynthetic disconnection
through addition rather than substitution by using aldehydes
and isocyanides[7] as building blocks. Aldehydes are good start-
ing points for (combinatorial) synthesis since a remarkable vari-
ety of derivatives is available from numerous suppliers, where-
as isocyanides are readily accessible from the corresponding
amines.[8] Combining these two inputs with carboxylic acids
leads to a-acyloxy amides by means of the well-known Passeri-
ni three-component reaction, which upon ester hydrolysis and
amide reduction would afford the targeted b-amino alcohols.
This approach was demonstrated in the 1970s but has severe
limitations in scope and productivity owing to the need for
three distinct operations, intermediary purifications, and harsh
reaction conditions.[9] Alternatively, SiCl4 can be used as an acid
component in a Passerini-type addition that leads to a-trichlor-
osilyloxy imidoyl chlorides as shown by Denmark and Fan.[10]
We envisioned that the reduction of the imidoyl chloride func-
tionality can be achieved in the same pot with a mild reducing
agent to deliver the desired b-amino alcohol in a faster and
potentially more general way than the existing methods.
Table 1. Aldehyde scope for one-pot N-tert-butyl b-amino alcohol synthe-
sis.[a]
Entry
Aldehyde
1a
R
Product
4a
Yield[b] [%]
1
2
4-MeC6H4À
74
83
93[c,d]
78
70
80
78
90
80
82
71
68[d]
1b
Ph
4b
3
4
5
6
7
8
9
10
11
1c
1d
1e
1 f
1g
1h
1i
2-naphthyl
mesityl
4c
4d
4e
4 f
4g
4h
4i
4-ClC6H4À
2-BrC6H4À
4-NCC6H4À
4-MeOCOC6H4À
4-CF3C6H4À
2-F3CC6H4À
4-O2NC6H4À
1j
1k
4j
4k
12
1l
4l
88[d]
13
14
15
16
1m
1n
1o
1p
4-MeSC6H4À
3-HCꢀCHCH2OC6H4À
3,5-(MeO)2C6H3À
4-AcNHC6H4À
4m
4n
4o
4p
77
89
76
73[d]
Results and Discussion
17
1q
4q
67
We started our optimization efforts with 4-methylbenzalde-
hyde and tert-butyl isocyanide as convenient benchmark
inputs considering the relevance of tert-butyl substitution in
the pharmacology of b-amino alcohols. Initial experiments
showed that the SiCl4-mediated isocyanide addition step can
be performed at 0–58C in a variety of solvents (dichlorome-
thane, toluene, THF, MeTHF, ethyl acetate, dimethyl carbonate).
Ethyl acetate was chosen for further optimization in view of its
green credentials.[11] Lewis bases catalyze the isocyanide addi-
tion[10] by complexation to SiCl4, which favors the expulsion of
a chloride ion to generate a strongly activating silyl cation.[12]
Under our preset conditions, hexamethylphosphoramide
(HMPA) gave the best results[13] with complete conversion of
the aldehyde within one hour at 08C at a level of 10 mol%.
We next investigated several boron hydrides for the selective
double reduction of the imidoyl chloride functionality.[14] The
best performance was obtained with ammonia borane com-
plex, which is an air-stable solid with good compatibility with
organic solvents.[15] The use of 1.5 equiv[16] of technical-grade
18
19
20
1r
1s
1t
PhCH2CH2À
Cy
Cl3CÀ
4r
4s
4t
83
78
44
21
1u
4u
58
22
1v
4v
55
23
1w
4w
66
24
25
1x
1y
3-pyridyl
4x
4y
<20[e]
<20[e]
[a] Standard conditions: Aldehyde (1 mmol), HMPA (10 mol%), SiCl4
(1.1 equiv), and tert-butyl isocyanide (1.2 equiv) in AcOEt (2 mL) for 1 h at
0–58C, then BH3NH3 (technical grade, 1.5 equiv) for 3 h at room tempera-
ture. [b] Isolated yield after chromatography. [c] 5 mmol scale. [d] Isolated
by precipitation as HCl salt. [e] Crude yield on the basis of NMR spectros-
copy with external standard.
[17]
BH3NH3 gave nearly quantitative yield for the desired amino
alcohol product in a relatively short reaction time according to
NMR spectroscopic analysis of the crude product.
With the optimized reaction conditions in hand, we next ex-
plored the synthetic potential of this novel method. To our de-
light, diverse aldehydes 1 (aromatic, heteroaromatic, and ali-
phatic) reacted with tert-butyl isocyanide to afford the corre-
sponding b-amino alcohols 4 in high yields without additional
optimization.[18] The results are summarized in Table 1. With
the exception of aliphatic aldehydes and electron-rich aromatic
aldehydes,[19] the isocyanide addition step proceeds to near
completion for all substrates within one hour. A lower rate in
the reduction of the imidoyl chloride functionality was ob-
served for sterically hindered and electron-deficient substrates
(1d, 1 f, 1j, 1k, 1t), but even in these cases the desired prod-
ucts were obtained in satisfactory yield. Notably, the reaction
tolerates a variety of functional groups, including halogens,
nitro groups, (thio)ethers, nitriles, esters, amides, alkenes, al-
kynes, and so forth. Interestingly, N-tert-butyl 1-arylaziridine
formation was observed as a minor side-reaction pathway (up
to 20%) for electron-rich substrates, which accounted for the
slightly lower yields of products 4p, 4q, and 4v (Table 1, en-
tries 16, 17, and 22). In this case, the CÀOSiCl3 bond is most
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10 min of reaction time for each of the two stages. Next, chro-
matographic purification can be successfully replaced with pre-
cipitation of the products 4 as the corresponding hydrochlo-
ride salts from ethereal solvents, as demonstrated by the more
polar products (4k, 4l, 4p)[22] and the 5 mmol-scale synthesis
of 4b. Combined with the broad substrate scope, this makes
our method ideal for the rapid generation of large libraries of
compounds required for bioactivity screening in a lead optimi-
zation project, especially in cases in which extensive variation
in the aldehyde moiety is required.
Scheme 2. Formation of aziridine from 1q.
likely elongated and the resulting partial positive charge at the
benzylic position favors aziridine formation (Scheme 2).[20] This
undesired reaction pathway can be minimized by increasing
the borane concentration and shortening the reaction time in
the imidoyl chloride reduction stage.
Importantly, this new approach efficiently converts commer-
cial starting materials to products that are challenging targets
for methods based on the conventional CÀN disconnection.
Bulky aldehydes such as 2,4,6-trimethylbenzaldehyde 1d and
chloral 1t work satisfactorily; thioethers and alkenes (inputs
1m and 1u), which are incompatible with epoxide formation
through oxidation (required for the traditional approach) as
well as nucleophile-sensitive inputs (aldehyde 1l with a reactive
CarÀF bond), are well tolerated in our reaction, whereas regio-
selectivity issues of epoxide opening with styrene derivatives
are avoided. However, nicotinic aldehyde was found to be in-
compatible with this methodology (Table 1, entry 24), possibly
owing to the competing nucleophilicity of the pyridine nitro-
gen atom, whereas the 3-amino-1-alkoxypropan-2-ol motif rep-
resents another synthetic challenge (Table 1, entry 25).
A typical distribution of products is shown for substrate 1q
in Table 2. A simple adjustment of the time parameter leads to
a significant improvement in the conversion of 1q to 4q from
Table 2. Reaction optimization for substrate 1q.
Regarding the N-substitution, bulky substituents that typical-
ly reduce the amine propensity for nucleophilic attack in the
classical approach are not problematic in our reaction, as the
bulk is further away from the reacting center in isocyanides
(the ‘divalent’ carbon atom). Bearing this in mind, we investi-
gated other bulky tertiary isocyanides to generalize this feature
of our approach (Table 3). Thus, tert-octyl isocyanide displayed
similar reactivity to its lower-molecular-weight homologue;
cumyl isocyanide[23] also afforded the expected products in
good yields, both for aliphatic and aromatic aldehydes (prod-
ucts 9a, 9b). These results have significance in a medicinal
chemistry context, since, in recent years, it has been demon-
strated that a,a-dimethylbenzyl substitution (and variations)
on the nitrogen atom of b-amino alcohols represents an attrac-
tive handle to optimize bioactivity and pharmacological prop-
erties.[2b,24]
Entry
Stage 1
BH3NH3 [equiv]
Stage 2
Yield[a] [%]
4q
77
5q
6q
7q
1
2
1 h
2 h
1.5
2.0
3 h
20 min
7
3
1
1
15
1
95
[a] Crude yield on the basis of NMR spectroscopy with external standard.
77% under the standard conditions to 95%. In this way we
were able to prepare the antiasthmatic drug salbutamol ace-
tate 4z from the protected aldehyde 1z in a 75% yield upon
acetal cleavage under acidic conditions (Scheme 3).[21]
Reactions that employ cyclohexyl isocyanide, another fre-
quently used benchmark isocyanide, gave only slightly lower
yields than tertiary isocyanides (compounds 10a and 10b,
Table 3). In contrast, we were surprised to note a significant
difference in the reaction outcome when isopropyl isocyanide
was employed. Owing to side reactions, a modest yield (35%)
was obtained under the standard conditions for dichloroiso-
prenaline (DCI; 11 a), the first clinically used beta-blocking
agent.[25] We identified double isocyanide addition as the
major undesired pathway. Most likely, unproductive consump-
tion of the isocyanide upon activation by SiCl4 also accounts
for the lower yield. A noteworthy improvement in the reaction
selectivity was achieved by resorting to a less polar solvent, di-
chloromethane, and lowering the temperature for the isocya-
nide addition to À208C: DCI could be isolated in a pleasing
78% yield by using this modified procedure. This protocol al-
A noteworthy benefit of our method is the reduced reaction
time, which is on the order of a few hours, compared to con-
ventional options that need at least two separate operations
and an intermediate purification. Moreover, the productivity
can be improved at the expense of a slight loss in yield: for ex-
ample, product 4b was synthesized in a 71% yield in only
Scheme 3. Synthesis of salbutamol acetate.
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side-product formation even under the modified conditions.
Presumably, multiple coordination of sterically unencum-
bered isocyanides to SiCl4 initiates unproductive events.[27]
To counteract this problem, we resorted to a stronger Lewis
base to minimize competition of the isocyanide for the sili-
con center. Accordingly, the use of catalytic pyridine oxide
instead of HMPA in the n-pentyl isocyanide addition gave
the desired 2-(n-pentylamino)-1-phenylethanol in a syntheti-
cally useful yield (compound 15; Table 3). However, sterical-
ly similar but a-acidic methylisocyanoacetate presented
complications in the imidoyl chloride reduction, and the de-
sired product could not be isolated.
Table 3. Isocyanide scope for one-pot N-substituted b-amino alcohol synthe-
sis.[a,b]
The substrate scope evaluation demonstrates the gener-
ality of our method, which ideally complements the chemi-
cal space of readily available N-substituted b-amino alcohols
with bulky derivatives both at the carbinol side as well as
the amine position.
For adrenergic agents, the (R) enantiomer is typically re-
sponsible for the biological effect,[6] but most often the
drug is marketed as the racemate.[28] Nevertheless, rapid
access to both enantiomers in good optical purity is of
utmost importance for the complete biological profiling of
drug candidates and therefore intensive research has been
conducted towards enantioselective arylethanolamine prep-
aration.[28] Our protocol can be conveniently upgraded to
an asymmetric synthesis by resorting to commercially avail-
able bisphosphoramide catalyst 17 as chiral HMPA analogue
in the isocyanide addition (Scheme 4).[10] This simple modifi-
cation applied to benzaldehyde as benchmark aldehyde
input allowed the isolation of (R)-2-(tert-butylamino)-1-phe-
nylethanol in 79% yield with 99% ee.
[a] Standard conditions: Aldehyde (1 mmol), HMPA (10 mol%), SiCl4
(1.1 equiv), and isocyanide (1.2 equiv) in AcOEt (2 mL) for 1 h at 0–58C, then
BH3NH3 (technical grade, 1.5 equiv) for 3 h at room temperature. [b] Isolated
yield after chromatography. [c] Isolated by precipitation as HCl salt. [d] Isocy-
anide addition performed in CH2Cl2 at À208C for 4 h. [e] 1:1 mixture of dia-
stereoisomers. [f] Pyridine oxide instead of HMPA under conditions as in [d].
[g] Crude yield on the basis of NMR spectroscopy with external standard.
Conclusion
In conclusion, we have developed an efficient two-stage
one-pot synthesis of pharmaceutically important N-substi-
tuted b-amino alcohols from aldehydes and isocyanides
lowed the general application of secondary isocyanides with
both aromatic and aliphatic aldehyde inputs. Chiral isocyanides
such as (S)-a-methylbenzyl isocyanide also reacted satisfactori-
ly (however with no asymmetry induction).[7e,10a] Naphthyl iso-
cyanide gave a complex reaction mixture, most likely owing to
oligomerization processes, which are facile for unhindered aro-
matic isocyanides. A notable exception is the 2,6-dimethyl-
phenyl derivative, which reacted cleanly, albeit with lower rate
in the imidoyl chloride reduction stage (compounds 14a and
14b; Table 3). This extension represents an important synthetic
advantage, since bulky aromatic substituents are generally in-
compatible with conventional approaches towards b-amino al-
cohols owing to the poor reactivity of the corresponding
amines.[26]
Scheme 4. Asymmetric variant using chiral bisphosphoramide 17.
based on a SiCl4-mediated Passerini-type addition and subse-
quent ammonia borane reduction. This method has high func-
tional-group tolerance and broad aldehyde and isocyanide
scope. Furthermore, the best performance is achieved in chal-
lenging circumstances for conventional approaches: oxidation-
sensitive functional groups, nucleophilic substitution-sensitive
substrates, and non-nucleophilic amines. The good availability
At this stage it became evident that the steric properties of
the isocyanide markedly influence the outcome of the reaction.
Consistent with our previous observations, less bulky primary
isocyanides proved more problematic and led to extensive
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of the required building blocks, the reduced reaction time, and
the easy extension to a catalytic asymmetric version recom-
mend this method for both combinatorial and medicinal
chemistry applications.
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Experimental Section
An isocyanide (1.2 equiv, 1 mmol) was added to a solution (2 mL
AcOEt, normal grade) of an aldehyde (1 mmol), hexamethylphos-
phoramide (0.1 equiv, 0.1 mmol), and SiCl4 (1.1 equiv, 1.1 mmol) at
0–58C. After stirring for one hour at 0–58C, technical-grade BH3NH3
(1.5 equiv, 1.5 mmol) was added. The ice bath was removed and
the reaction mixture was stirred for another 3 h. Next, the mixture
was diluted (in three portions) with CH2Cl2 (10 mL) and transferred
(cautiously on account of gas evolution) to an aqueous solution of
Na2CO3 (10 wt%, 20 mL). The mixture was stirred for 30 min at
room temperature. The solution was filtered, and the filter was
washed with more CH2Cl2 (10 mL). The layers were separated, and
the aqueous layer was extracted with CH2Cl2 (20 mL) in two por-
tions. The combined organic layers were dried over Na2SO4 and
concentrated under reduced pressure. The product was isolated
after column chromatography on silica gel or by precipitation as
the hydrochloride salt from tert-butyl methyl ether.
Acknowledgements
The research for this work received funding from the Innova-
tive Medicines Initiative joint undertaking project CHEM21
(https://www.chem21.eu/; grant no. 115360), resources of
which are composed of financial contributions from the Euro-
pean Union’s Seventh Framework Programme (FP7/2007–2013)
and EFPIA companies in-kind contribution. We thank Florentine
Veenstra for her contribution to the experimental part.
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option.
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addition yielded 57% of the N-(tert-butyl)-2-hydroxy-2-(p-tolyl)aceta-
mide after aqueous workup. Lewis bases screened for the isocyanide
addition: triphenylphosphine oxide (71%), N,N’-dimethylpropyleneurea
(70%), pyridine oxide (76%).
Keywords: aldehydes · amino alcohols · isocyanide · Lewis
bases · salbutamol
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Received: January 17, 2015
Published online on && &&, 0000
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FULL PAPER
&
Amino Alcohols
R. C. Cioc, D. J. H. van der Niet, E. Janssen,
E. Ruijter, R. V. A. Orru*
&& – &&
Retrosynthesis revisited: A practical
and general two-stage one-pot synthe-
sis of N-substituted b-amino alcohols
using aldehydes and isocyanides as
starting inputs is described (see
and efficient way from simple building
blocks, as demonstrated by the synthe-
sis of the antiasthmatic drug salbuta-
mol. The reaction can readily be made
asymmetric by using a chiral Lewis base
catalyst.
One-Pot Synthesis of N-Substituted b-
Amino Alcohols from Aldehydes and
Isocyanides
scheme). Medicinally relevant com-
pounds can be prepared in a concise
Chem. Eur. J. 2015, 21, 1 – 7
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ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers! ÞÞ