Hexafluoroisopropanol as the Acid Component in the Passerini Reaction: One-Pot Access to β-Amino Alcohols

Article abstract of DOI:10.1021/acs.orglett.8b01561

A new Passerini-type reaction in which hexafluoroisopropanol functions as the acid component is reported. The reaction tolerates a broad range of isocyanides and aldehydes, and the formed imidates can be reduced toward β-amino alcohols under mild and metal-free conditions. In addition, the imidate products were shown to undergo an unprecedented retro-Passerini-type reaction under microwave conditions, providing valuable mechanistic information about the Passerini reaction and its variations.

Full text of DOI:10.1021/acs.orglett.8b01561

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Hexafluoroisopropanol as the Acid Component in the Passerini
Reaction: One-Pot Access to β‑Amino Alcohols
Jordy M. Saya, Rayan Berabez, Pim Broersen, Imme Schuringa, Art Kruithof, Romano V. A. Orru,
and Eelco Ruijter*
Department of Chemistry & Pharmaceutical Sciences and Amsterdam Institute for Molecules, Medicines & Systems (AIMMS),
Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands
S
* Supporting Information
ABSTRACT: A new Passerini-type reaction in which
hexafluoroisopropanol functions as the acid component is
reported. The reaction tolerates a broad range of isocyanides
and aldehydes, and the formed imidates can be reduced
toward β-amino alcohols under mild and metal-free
conditions. In addition, the imidate products were shown to
undergo an unprecedented retro-Passerini-type reaction under microwave conditions, providing valuable mechanistic
information about the Passerini reaction and its variations.
Scheme 1. Novel Passerini-Type Reactions
ulticomponent reactions (MCRs) are widely recognized
Mas important tools to create high molecular diversity
and complexity in an efficient manner.1 MCRs combine three
or more reactants in a single operation to afford products that
contain essentially all of the atoms of the starting materials.
Within this field, isocyanide-based multicomponent reactions
(IMCRs) have claimed a dominant position as a result of the
ambiphilic character of the isocyanide functionality.2 In 1921,
Passerini discovered the first IMCR, i.e., the reaction between
isocyanides, aldehydes, and carboxylic acids to give α-acyloxy
carboxamides.3 Forty years later, Ugi cleverly expanded this
methodology by simply including an amine, thereby creating a
four-component reaction affording peptoid scaffolds.4
Even though the discovery of both the Passerini and Ugi
reaction dates back more than half a century, current research
continues to provide new applications and new variations of
these flexible reactions.5 Next to postcondensation modifica-
tions of traditional Passerini and Ugi products, strategies for
the development of MCR variations can be based on single
reactant replacement (SRR) or diverting or interrupting the
usual reaction pathway.6 For IMCRs, the latter mainly involves
the reactivity of the nitrilium ion intermediate.
We recently showed that in the interrupted Ugi (or
Passerini) reaction of tryptamine-derived isocyanides, the
nitrilium ion could be intercepted by the nucleophilic C3
position of the indole moiety, generating highly congested, sp3-
rich polycylic indolines 4−6 (Scheme 1A).7 An important
feature of this method was the use of the fluorinated protic
solvents 2,2,2-trifluoroethanol (TFE) and 1,1,1,3,3,3-hexa-
fluoroisopropanol (HFIP). The strong hydrogen bond-
donating properties and low nucleophilicity of these solvents
proved ideal for activation of the imine and stabilization of the
nitrilium ion.8 In continuation of our work in this area, we
aimed to expand this concept to other electron-rich arenes in
Passerini- and Ugi-type reactions. When the reaction of 3,4-
dimethoxyphenethyl isocyanide (1b) and pivaldehyde (2a)
was performed in HFIP as the solvent, intermolecular HFIP
addition (to give 8a) surprisingly outcompeted the Bischler−
Napieralski cyclization (leading to 7) despite the nucleophilic
character of the 3,4-dimethoxyphenyl moiety (Scheme 1B).9,10
This serendipitous result prompted us to further investigate
this Passerini-type reaction.
Replacing the carboxylic acid in the Passerini reaction by
other acid components has been previously demonstrated by
several groups.11 However, these reactions typically involve an
irreversible Mumm- or Smiles-type rearrangement after the
imidate formation, generating a thermodynamically favored
amide product. Alternative acid components include electron-
deficient (hetero)aromatic alcohols.5b Given its comparable
pKA, (9.3 vs ∼7−9 for phenol derivatives), HFIP plausibly
Received: May 17, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01561
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Organic Letters
Letter
a,b
undergoes a similar addition to the nitrilium ion, which
produces a stable imidate 8 that cannot undergo a Mumm-type
rearrangement.12 As these imidates could be considered
chemical equivalents of the nitrilium ion synthon, we decided
to further investigate this reaction.
Scheme 2. Scope of the Passerini-Type Reaction
We began our optimization with n-pentyl isocyanide (1c)
and propionaldehyde (2b) as the benchmark substrates (Table
1). To our surprise, no product formation could be observed
a
Table 1. Optimization of Passerini-Type Reaction
b
temp
entry (°C)
[1c]
(M)
time
(h)
HFIP
(equiv)
yield
(%)
solvent
8b/9
1
2
3
4
5
6
7
8
rt
rt
rt
rt
rt
rt
0.1
1
1
1
1
1
1
1
HFIP
HFIP
20
20
20
20
1
1
1
1
0
0
0
58
82
82
62
>99
CHCl3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
3
3
3
10
3
3
a
Standard conditions: isocyanide (1 mmol), aldehyde (1.3 mmol),
100:0
100:0
100:0
100:0
b
c
HFIP (3 mmol) in CH2Cl2 (1 M), rt. Isolated yields. HFIP (0.1 M)
was used as the solvent.
40
rt
c
0:100
by their lower basicity, making degradation pathways less
favorable. As for the aldehyde scope, aliphatic aldehydes
underwent isocyanide addition effectively, though less reactive
aromatic aldehydes and ketones proved to be beyond the
scope of this method. Only the relatively reactive p-
(trifluoromethyl)benzaldehyde reacted to give the product
(8h), albeit in HFIP as the solvent with 144 h of reaction time.
Having established the limitations of this novel Passerini-
type reaction, we investigated the possibility to further diversify
these products. Given our earlier experience in Passerini/
reduction sequences to valuable β-amino alcohols, we aimed to
achieve a similar procedure.14 We started this endeavor with
aromatic imidate 8i, given its comparably low electrophilicity.
After some optimization of the reaction conditions, we found
that treatment with BH3·NH3 (3 equiv) and TFA (5 equiv) in
HFIP gave the highest yield (for details, see the Supporting
Information). Due to the higher basicity of imidates derived
from aliphatic isocyanides, addition of TFA was not necessary
to activate the imidate in these cases.15 Pleasingly, the two
steps could be combined in a one-pot sequence given the
compatible conditions.
A broad range of isocyanides and aliphatic aldehydes were
screened in this Passerini/reduction method (Scheme 3).
Moderate to excellent yields of amino alcohols 10a−k could be
obtained using aromatic isocyanides. Even α-heterosubstituted
and highly electrophilic aldehydes smoothly reacted to give the
desired product. Surprisingly, even chloroacetaldehyde, a
usually problematic reactant in Passerini-type reactions, was
converted to the corresponding amino alcohol 10j, albeit in
only 17% yield. Aliphatic isocyanides also exhibited clean
conversion, however, the resulting products 10l−o were
generally obtained in slightly lower yields. This can be
attributed to the lower stability of these imidates in HFIP,
leading to competition between β-amino alcohol formation
and imidate decomposition. Nevertheless, it is noteworthy that
these reactions generally gave higher isolated yields in this one-
pot, two-stage sequence compared to the corresponding
imidate synthesis alone (cf. imidate 8b and β-amino alcohol
a
Standard conditions: propionaldehyde (0.65 mmol), n-pentyl
isocyanide (0.5 mmol), and HFIP in solvent, stirred at the indicated
temperature and time. Based on NMR analysis with 2,5-
dimethylfuran as internal standard. With 1.2 equiv of AcOH.
b
c
by 1H NMR after subjecting the reactants to the initial
conditions (entries 1 and 2). We reasoned that HFIP might be
too acidic as a solvent, leading to decomposition of the
isocyanide and/or the imidate product rather than activation of
the aldehyde. When we switched to CH2Cl2 as the solvent with
a moderate excess of HFIP (3 equiv), the desired product 8b
was obtained in 58% yield after 20 h and only 37% after 66 h
(entry 4), supporting our hypothesis. We then started
1
monitoring conversion over time by H NMR analysis. This
experiment revealed that our reaction reached its optimal yield
after only 1 h. Although the isocyanide was not completely
consumed after 1 h (entry 5), longer reaction times led to
lower yields (based on internal standard), most likely as a
result of product decomposition. Increasing the stoichiometry
of HFIP (entry 6) or the temperature (entry 7) did not lead to
improved yields. To evaluate the chemoselectivity of the
reaction, we conducted a competition experiment between
HFIP and acetic acid, which led to quantitative conversion to
the classical Passerini product 9 within 1 h (entry 8).
Having optimized the conditions, we moved our focus
toward the scope of this reaction. We were pleased to see that
all isocyanides were efficiently converted to the Passerini-type
product (Scheme 2), with the exception of tert-butyl
isocyanide. When the reaction was performed in CD2Cl2 and
monitored by 1H NMR analysis, competition between product
formation and decomposition was observed. Imidates derived
from tBuNC are relatively basic, leading to increased
decomposition via the protonated imidate.13 Another interest-
ing observation is the relation between isocyanide nucleophil-
icity and product stability. Less nucleophilic isocyanides
needed 6 h to reach maximal yields; however, these products
showed less decomposition over time. This can be explained
B
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naphthyloxy)acetaldehyde (2c) and isopropyl isocyanide
(74% yield). The reductive Passerini-type reaction of 1e
(readily accessible from commercial 11) and (Cbz-amino)-
acetaldehyde smoothly afforded 10q, which was further
converted to ( )-rivaroxaban (12) in three straightforward
steps. These applications highlight the robustness of this
Passerini/reduction method, which is a mild extension of our
earlier work.14
Scheme 3. Scope of the One-Pot β-Amino Alcohol
Synthesis
a,b
We then shifted our attention back to our initial attempt to
synthesize 3,4-dihydroisoquinoline 7. Given the potential
electrophilicity of imidates, and with the Bischler−Napieralski
reaction in mind, we considered the possibility of converting
imidate 8a to dihydroisoquinoline 7. Unfortunately, treatment
with Brønsted or Lewis acids only led to decomposition or
imidate hydrolysis. However, when we subjected 8a to
microwave irradiation (200 °C, 10 min) under neutral
conditions, we surprisingly observed full conversion back to
isocyanide 1b. In toluene-d8 under the same conditions, using
2,6-dimethylfuran as an internal standard, we could clearly
observe reformation of all the reactants of the initial Passerini-
1
type reaction (1b, 2a, and HFIP) by H NMR analysis. We
were intrigued by the unprecedented reversibility of this
Passerini-type reaction, not in the least because computational
studies have shown that imidate formation is highly exothermic
in both Passerini and Ugi reactions.17 To evaluate the
generality of this retro-Passerini reaction, we selected a small
set of imidates (8c,d,f−h) and subjected them to microwave
irradiation (200 °C) in 10 min cycles to determine the
conversion over time (Table 2).18 As anticipated, imidate 8c
a
Standard conditions: isocyanide (1 mmol), aldehyde (1.3 mmol),
HFIP (3 mmol) in CH2Cl2 (1 M), rt, next diluted with HFIP (0.1
b
M), then BH3·NH3 (3 mmol) and TFA (5 mmol). Isolated yields.
c
No TFA.
a
Table 2. Reversible Passerini-Type Reaction
10l). This can again be rationalized by the stability issues of
these imidates.
As the β-amino alcohol moiety is a structural motif
frequently appearing in APIs, we sought to apply the developed
methodology in the synthesis of representative pharmaceut-
icals. This was successfully achieved with the synthesis of
propranolol (10p) and ( )-rivaroxaban (12, Scheme 4).
Propranolol, a β blocker used in the treatment of heart
disease,16 was readily accessible by reaction of (1-
b
b
compd time (min) conv (%) compd time (min) conv (%)
8c
8d
8f
10
90
60
83
67
65
8g
8h
240
270
84
77
a
Standard conditions: 8 (0.1 mmol) in toluene-d8 (0.1 M) under
Scheme 4. Synthesis of Propranolol and ( )-Rivaroxaban
b
microwave irradiation in 10 min cycles at 200 °C. Monitored by 1H
NMR analysis with 2,5-dimethylfuran as internal standard.
also showed near complete conversion (83%). Interestingly,
aromatic R1 as well as R2 substituents led to considerably
slower retro-Passerini reaction. Although full conversion was
not reached, a clear trend in reaction rate could be observed
between these imidates. Retro-Passerini reaction of imidates 8g
and 8h showed clear first order kinetics, as expected for a
unimolecular process. The retro-reaction of imidate 8d reached
a steady state after 40 min, possibly reflecting a thermody-
namic equilibrium under these conditions. After the samples
were allowed to sit for 2 weeks at room temperature, all of the
crude mixtures were reconverted to the corresponding imidates
8, with the exception of 8d and 8h.
Theoretical studies have already provided some insight in
the conventional Passerini reaction, mainly focusing on the
involvement of a nitrilium ion intermediate. Morokuma et al.
proposed a mechanism including this nitrilium intermediate.17c
Our results on this retro-Passerini-type reaction, however,
rather suggest a more concerted mechanism, considering the
electrophilicity of the nitrilium ion and its resulting propensity
C
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to undergo Bischler−Napieralski-type cyclizations.9,19 The
formation of a nitrilium ion suggests that fragmentation of
the C−CN+R bond would outcompete nucleophilic addition
of electron-rich arenes (as in imidates 8f and 8a). Since the
resulting Bischler−Napieralski product is not detected (not
even in trace amounts) we believe that a concerted mechanism
is more likely in both the forward Passerini-type reaction and
the reverse reaction (Scheme 5). The effect of the conditions
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hydroxy imidates with HFIP as a novel acid component. By
combining this procedure in one pot with a subsequent
reduction step, we efficiently synthesized a series of β-amino
alcohols. The scope of this procedure proved to be
complementary to our previous Passerini/reduction strategy.14
In addition, the utility of this mild transformation was
demonstrated by the synthesis of the two APIs, propranolol
and ( )-rivaroxaban. Finally, we showed these α-hydroxy
imidates undergo an unprecedented retro-Passerini-type
reaction under microwave irradiation. This observation
provides new insight into the Passerini reaction and
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01561.
Experimental details, characterization data, and copies of
1H and 13C NMR spectra (PDF)
̈
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(13) In general, combinations with aliphatic isocyanides were less
stable, making isolated yields drastically lower than the crude yields.
(14) Cioc, R. C.; van der Niet, D. J. H.; Janssen, E.; Ruijter, E.; Orru,
R. V. A. Chem. - Eur. J. 2015, 21, 7808.
(15) The use of TFA with imidates derived from aliphatic
isocyanides led to complete decomposition, likely due to its high
acidity.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: e.ruijter@vu.nl.
ORCID
Eelco Ruijter: 0000-0002-1105-3947
Notes
(16) WHO. Essential Medicines List, 20th ed.; WHO, 2017.
(17) (a) Maeda, S.; Komagawa, S.; Uchiyama, M.; Morokuma, K.
The authors declare no competing financial interest.
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(18) Reactions were stopped before reaching full conversion due to
the observation of competing decomposition.
(19) Bischler, A.; Napieralski, B. Ber. Dtsch. Chem. Ges. 1893, 26,
1903.
ACKNOWLEDGMENTS
The Netherlands Organization of Scientific Research (NWO)
is acknowledged for financial support. We thank Elwin Janssen
for technical assistance and NMR maintenance and Jurrien
Collet for HRMS measurements (both Vrije Universiteit
Amsterdam).
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DOI: 10.1021/acs.orglett.8b01561
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