The dual role of ruthenium and alkali base catalysts in enabling a conceptually new shortcut to N-unsubstituted pyrroles through unmasked α-amino aldehydes

Article abstract of DOI:10.1021/ol4001262

A virtually salt-free and straightforward bimolecular assembly giving N-unsubstituted pyrroles through fully unmasked α-amino aldehydes, which was enabled by the dual effects of a catalytic ruthenium complex and an alkali metal base, is reported. Either solvent-free or acceptorless dehydrogenation facilitates high atom, step, and pot economy, which are otherwise difficult to achieve in multistep operations involving protection/deprotection.

Full text of DOI:10.1021/ol4001262

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
The Dual Role of Ruthenium and Alkali
Base Catalysts in Enabling a Conceptually
New Shortcut to N‑Unsubstituted Pyrroles
through Unmasked R‑Amino Aldehydes
Kazuki Iida,† Takashi Miura,† Junki Ando,† and Susumu Saito*,†,‡
Graduate School of Science, Nagoya University, Chikusa, Nagoya 464-8602, Japan, and
Institute for Advanced Research, Nagoya University, Chikusa, Nagoya 464-8601, Japan
saito.susumu@f.mbox.nagoya-u.ac.jp
Received January 15, 2013
ABSTRACT
A virtually salt-free and straightforward bimolecular assembly giving N-unsubstituted pyrroles through fully unmasked R-amino aldehydes, which was
enabled by the dual effects of a catalytic ruthenium complex and an alkali metal base, is reported. Either solvent-free or acceptorless dehydrogenation
facilitates high atom, step, and pot economy, which are otherwise difficult to achieve in multistep operations involving protection/deprotection.
Fully unmasked R-amino aldehydes (R-AMALs) are
notoriously unstable synthetic intermediates and have rarely
been used in organic synthesis.1 For example, rapid de-
gradation of valinal is accompanied by self-dimerization
giving the symmetric pyrazine.2 To avoid such short-
comings, N-protected3 and C-protected4 R-AMALs have
been isolated and are widely used in natural product
synthesis and asymmetric catalysis. Were it possible to
generate an unmasked R-AMAL in conjunction with
its reaction partner and subsequently incorporate them
into products without isolation of the R-AMALs, the
atom- step-, and pot-economical utility would be increased
significantly. In particular, the transition-metal-catalyzed
“hydrogen autotransfer” strategy5;transfer dehydro-
genation of an unprotected β-amino alcohol, followed
by in situ trapping of the resulting R-AMAL with a carbon
nucleophile;would benefit from the advanced synthetic
utility of R-AMALs. We6 and others7,8 have demonstrated
that, even under basic conditions, aliphatic linear alde-
hydes thus generated in situ undergo negligible aldol self-
condensation. Reported herein is the virtually salt-free and
highly versatile synthesis of N-unsubstituted pyrroles using
a catalytic ruthenium complex 19 (Figure 1) and an alkali
† Graduate School of Science.
‡ Institute for Advanced Research.
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r
10.1021/ol4001262
XXXX American Chemical Society

metal base, in which readily available and easily varied
ketones (enolates) react with R-AMALs generated in situ
from fully unmasked β-amino alcohols (Scheme 1). Re-
cently, elegant progress has been made based on multi-
component coupling10a,c,11 and preassembled specialty
building blocks for intra-12 and intermolecular13 cycliza-
tion, providing pyrrole structures10,14 not easily generated
via classical routes. The present approach is simpler and
more straightforward than these established methods.15
“Hydrogen autotransfer” starting from transfer dehy-
drogenation of alcohols followed by a cross aldol reaction
is usually carried out using a transition-metal catalyst
based on Ru,7 Ir,7 Ni,8a Pd,6b,8b Ag,8c Cu,6a,8d,8e Fe,8f or
Au8g in the presence of a catalytic or stoichiometric alkali
metal base. Nontransition-metal-based systems, catalytic
NaOH/H2-,6a KOH (or NaOH)/air-16a and stoichiometric
KOBut-promoted versions,16b,c can also be effective. How-
ever, detailed studies are lacking as to which, the transition
metal species or the base, is more responsible for the
catalysis. Thus, this issue was reconsidered using a new
ruthenium complex 1 (Figure 1) we recently introduced9 as
a multifunctional catalyst precursor able to achieve the
reverse processes, namely, the hydrogenation of unacti-
vated amides9 and ketones. Catalyst precursor 1 is readily
available in two steps from commercial resources.17
Figure 1. 1H NMR yield (%) of 4aa and 5a as a function of
[1]0/[KOBut]0 at [KOBut]0 = 74 mM. Data points were obtained
from the reactions as shown above the figure. (b) 5a. ([, red) 4aa.
factors, namely [1]0 (0ꢀ15 mM: 0ꢀ2 mol % relative to 2a),
[KOBut]0 (25, 37, 60, and 74 mM: 10 mol % each), and
[KOBut]0/[1]0 (1/0 to 100/1), on the yields of 4aa were
investigated. A plot of [1]0/[KOBut]0 vs yield % of 4aa at
Scheme 1. Basic Strategy of the Catalytic, Salt-Free, Bimolecular
Reaction, Which Affords an N-Unsubstituted Pyrrole via a Fully
Unmasked R-AMAL
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At the outset, a 1:2 molar ratio of valinol (2a) to prop-
iophenone (3a) was subjected to catalytic 1 and KOBut in
toluene to synthesize pyrrole 4aa. The effects of several
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B
Org. Lett., Vol. XX, No. XX, XXXX

[KOBut]0 = 74 mM results in a bell-shaped curve giving a
maximum yield of 4aa at a specific value of [KOBut]0/[1]0
(Figure 1; for other [KOBut]0, see Figures S3ꢀS6). The
[KOBut]0/[1]0 ratio was more critical than the [2a]0 or [3a]0
to the reaction rate in the dehydrogenation of 2a (which
corresponds to the yield of 5a) and to an increase in the
apparent overall reaction rate leading to 4aa (Figures 1, S3,
and S4). The [KOBut]0/[1]0 ratio which gives the best yield
of 4aa is between 20 and 40 (Figures 1, S3, and S4). To
obtain 4aa in higher yields in the presence of 1 (than in its
absence), [KOBut]0 should be higher than37mM. Without
1, the yield of pyrrole 4aa averaged around 30%. In
contrast, when [KOBut]0 was 25 mM, the best yield of
4aa (∼40%) was obtained without 1 (0.25ꢀ2 mol %). The
addition of 1 was detrimental to the production of 4aa
(Figure S5). In any event, the dual effects of the ruthenium
and alkalimetal base catalysts are obvious within the range
of effective [KOBut]0 for enhancement of product yield.
One of the characteristics of the reaction involving 2a
and 3a is that, at a higher concentration of [KOBut]0 (74mM),
a[KOBut]0/[1]0 of 40 ([1]0 = 1.9 mM) gave the highest yield of
4aa (52%) with 5a/4aa = ∼1.2. The amounts of 4aa and of
H2 trapped by 3a (corresponding to the yield of 5a) were
almost equal, so that, under these conditions, the performance
of the transfer dehydrogenation directly reflects the efficiency
of the conversion of the in situ generated R-AMAL to 4aa.
Therefore, a [KOBut]0 >37mMand[KOBut]0/[1]0 of 40 were
chosen for further screening.
Table 1. Synthesis of 2,3,5-Trisubstituted Pyrroles 4a
a Unless otherwise specified, the solvent-free reaction was carried out
at 165 °C for 24 h under N2 with [KOBut]0 = ca. 260 mM; [KOBut]0/[1]0 =
40; 1/KOBut/2/3 = 1:40:400:800. b Based on 2, determined by 1H NMR
before NaBH4 treatment. The values in parentheses are of isolated, purified
products 4, which were obtained after the final mixture was treated with
NaBH4 for the reduction and facial removal of the remaining 3. c 4 was
isolated without NaBH4 treatment. d Reaction time: 6 h.
Among the higher concentrations of [KOBut]0 tested,
nonsolvent (neat) conditions ([KOBut]0 = ca. 260 mM;
[1]0 = 6ꢀ7 mM) afforded the highest yield of 4aa (77%)
(Table 1). Not more than 1 out of 2 equiv of 3a relative to
2a should be required to work as the H2 acceptor; in fact, a
1:1 mixture of 2a and 3a gave 4aa in lower yield (46%).
Further screening of different amino alcohols 2aꢀd and
simple ketones 3aꢀd shows that the reactions generally
complete within 6ꢀ24 h, demonstrating the structural
diversity of trisubstituted pyrroles. When other ruthenium
complexes, such as CpRuCl(PPh3)2 (0.25 mol %) and
[(p-Cymene)RuCl2]2 (0.125 mol %), were reacted for 6 h
inplace of 1 under the regular conditions, 4aa was obatined
in lower yields (49% and 32%, respectively).
The reaction of 2a with 3e that gives 2,5-disubstituted
pyrrole 4ae was unselective under the solvent-free con-
ditions. Rather, a more dilute toluene solution, with
[KOBut]0 = ca. 90 mM and [1]0 = 2ꢀ3 mM (1 mol %),
was promising for the prevention of the self-dimerization
of 3e (Table 2). The reactions were nearly complete within
3 h. A 1ꢀ1.5:1 ratio of 2aꢀc to 3eꢀg gave more reasonable
yields of the pyrroles, enabling the acceptorless dehydro-
genation18 followed by a bimolecular reaction. Evolution
of H2 was detected in all cases by micro-GC analysis. Even
excess ketone (2a:3e = 1:2; [KOBut]0 = ca. 90 mM) was
unsatisfactory in functioning as an H2 acceptor, and in
fact, only a small amount of the R-phenethyl alcohol (∼5%)
derived from 3e was detected by 1H NMR. Without 3 under
otherwise identical reaction conditions, ca. 20% of 2a was
detected as the dimer of the corresponding R-AMAL,
pyrazine.2a,19 Solvent-free conditions (1: 0.25 mol %; KO-
But: 10 mol %) were employable for a bulky ketone 3h,
since, even with the higher concentration of 3h, its aldol self-
condensation was undetected.
The versatile nature of this approach was further de-
monstrated by the shortest and simplest access to the core
pyrrole (4ai) of Lipitor (Atorvastatin Calcium)14f from
the natural resource and 2,3,4,5-tetraphenyl-1H-pyrrole20
(4ed) (Scheme 2), which was obtained in isolated yields of
33% and 16%, respectively. Inthese cases,4ai and 4edwere
not formed without using 1, as ascertained by 1H NMR. 4ai
was synthesized previously in a more tedious multistep12e
reaction or via three-component coupling11a prior to being
converted to Lipitor through a few synthetic steps.12e
(19) In contrast, transfer dehydrogenation of simple 2° alcohols
using 1 was sluggish or nonselective. A solvent-free reaction of 5a with
1 (0.25 mol %) and KOBut (10 mol %) at 165 °C for 6 h gave 3a in 44%
yield (conversion of 5a: 46%). Conversion of R-phenethyl alcohol (without
using 2) at 3 h under reaction conditions similar to those noted in Table 2
was >95%; however self-aldol condensation of 3e and subsequent transfer
hydrogenation of the R,β-unsaturated bond predominated.
€
(20) (a) Gurdere, M. B.; Budak, Y.; Ceylan, M. Asian J. Chem. 2008,
20, 1425. (b) Kuo, W.-J.; Chen, Y.-H.; Jeng, R.-J.; Chan, L.-H.; Lin,
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Taniguchi, T.; Itami, K. Org. Lett. 2008, 10, 3607. (d) Feng, X.; Tong, B.;
Shen, J.; Shi, J.; Han, T.; Chen, L.; Zhi, J.; Lu, P.; Ma, Y.; Dong, Y.
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S.; Xi, C. Eur. J. Org. Chem. 2010, 5426.
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Yamaguchi, R. Org. Lett. 2011, 13, 2278. (c) Ho, H.-A.; Manna, K.;
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Org. Lett., Vol. XX, No. XX, XXXX
C

Table 2. Synthesis of 2,5-Disubstituted Pyrroles 4a
Figure 2. Possible divergent processes and most likely reaction
pathways a and c. Ru denotes speculative catalytic species such
as (LnRu2þ)•[(ꢀOR)2(KOR)n].
4fa was only slightly detected by FAB-MS analysis. This
nature is different from that reported in other “hydrogen
autotransfer” reactions involving transfer hydrogenation
of R,β-unsaturated bonds (without O2) as a major path-
way.7,8 Although path b could not be fully ruled out,21 path
a, transfer dehydrogenation followed by CꢀC bond for-
mation, would be a more plausible initial step, accordingly.
Since the molar amount of 5 generated (Table 1) and of H2
evolved during the formation of 4af and 4bg (44% and
52% of H2 relative to 3, respectively, Table 2) were
comparable with the amount of 4 produced, the process
in which H2 is removed from 2a and subsequently incor-
poratedintospeculative8 (R4 =H, Scheme3) isnegligible.
The borrowed hydrogen(s) rarely returned to 4fa in the
control experiment. All these results support path c as the
major contribution.
a Unless otherwise specified, the reaction was carried out in toluene
for 3 h under N2 with [KOBut]0 = ca. 90 mM; [KOBut]0/[1]0 = 40;
1/KOBut/2/3 = 1:40:150:100. b Based on 3, determined by 1H NMR.
The values in parentheses are of isolated, purified products 4. c 24 h
instead of 3 h. d 2a:3e = 1:1. e Reaction conditions: those described in
footnote a in Table 1.
Scheme 2. Synthesis of the Core Pyrrole of Lipitor and 2,3,4,5-
Tetraphenyl-1H-pyrrole
Scheme 3. Control Experiment to Elucidate the Reaction
Pathway
The overall process of the pyrrole synthesis may derive
from either one of two alternative steps (Figure 2): one
begins with the dehydrogenation of a β-amino alcohol,
followed by an intermolecular aldol reaction (path a); the
other begins with the dehydrative formation of N,O-acetal
7 (path b).
To verify which pathway would be more likely, control
experiments were carried out by separately preparing N,N-
dibenzylated 2f (R4 = CH2Ph, Scheme 3) and N,O-acetal 7
(R3 = Me). The reaction of 2f or 7 (with or without H2O)
with 3a (165 °C, 24 h) proceeded in a different fashion to
give 4fa and 4aa in ∼40% (Scheme 3) and 0ꢀ10% yields,
respectively. The transfer hydrogenation of the olefin of
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research on Innovative Areas “Mo-
lecular Activation Directed toward Straightforward Syn-
thesis”, MEXT. T.M. acknowledges IGER in chemistry
at NU. The authors wish to thank Dr. K. Oyama and
Y. Maeda (Chemical Instrument Facility of RCMS) for
NMR and MS measurements and Prof. R. Noyori (NU &
RIKEN) for fruitful discussions.
Supporting Information Available. Experimental pro-
cedures, spectroscopic and analytical data of new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(21) When a mixture of 2a and 3a in a 1:2 molar ratio was heated at
165 °C under solvent-free conditions for 1 h in the absence of 1 and
KOBut, conversion of 2a was 70%, giving 7 in 66% yield. In contrast,
conversion of 2a at 1 h was 91%, giving 4aa in 42% yield and 7 in 13%
yield under otherwise identical conditions noted in Table 1.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX