Scope and post-transformations for the borane-isocyanide multicomponent reactions: Concise access to structurally diverse heterocyclic compounds

Article abstract of DOI:10.1002/adsc.201300666

A recently described family of multicomponent reactions (MCRs) involving isocyanides, aldehydes, dipolarophiles and alkylboranes that yield highly substituted aziridines, oxazolidines and pyrrolidines has been studied in detail. In this work the scope of these processes is significantly increased by preparing the borane input through hydroboration of alkenes or organometallic processes, in tandem with the MCR. The aldehyde range is also expanded, and indole-3-carbaldehydes yield reactive imines and bis-indolyloxazolidines, depending on the electron density of the heterocycle. Finally, the obtained adducts constitute an ideal platform to generate structurally diverse compounds using simple post-condensation modifications. In this way, indole imines undergo stereoselective hydrocyanation and oxazolidines are reductively opened to give amino alcohols. Additionally, palladium-, ruthenium- and gold-catalyzed processes lead to a variety of complex heterocycles. The methodology is simple, efficient and highly divergent, leading to an array of interesting scaffolds for medicinal chemistry. Copyright

Full text of DOI:10.1002/adsc.201300666

UPDATES
DOI: 10.1002/adsc.201300666
Scope and Post-Transformations for the Borane-Isocyanide
Multicomponent Reactions: Concise Access to Structurally
Diverse Heterocyclic Compounds
Nicola Kielland,a Esther Vicente-Garcꢀa,a Marc Revꢁs,a Nicolas Isambert,a
Marꢀa Josꢁ Arꢁvalo,a and Rodolfo Lavillaa,b,*
a
Barcelona Science Park, Baldiri Reixac 10–12, 08028 Barcelona, Spain
Fax : (+34)-93-402-4539; phone: (+34)-93-403-7106; e-mail: rlavilla@pcb.ub.es
Laboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, Joan XXIII sn, 08028 Barcelona, Spain
b
Received: July 26, 2013; Revised: August 28, 2013; Published online: November 11, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300666.
Abstract: A recently described family of multicom-
ponent reactions (MCRs) involving isocyanides, al-
dehydes, dipolarophiles and alkylboranes that yield
highly substituted aziridines, oxazolidines and pyr-
rolidines has been studied in detail. In this work the
scope of these processes is significantly increased
by preparing the borane input through hydrobora-
tion of alkenes or organometallic processes, in
tandem with the MCR. The aldehyde range is also
expanded, and indole-3-carbaldehydes yield reac-
tive imines and bis-indolyloxazolidines, depending
on the electron density of the heterocycle. Finally,
the obtained adducts constitute an ideal platform to
generate structurally diverse compounds using
simple post-condensation modifications. In this way,
indole imines undergo stereoselective hydrocyana-
tion and oxazolidines are reductively opened to
give amino alcohols. Additionally, palladium-,
ruthenium- and gold-catalyzed processes lead to
a variety of complex heterocycles. The methodology
is simple, efficient and highly divergent, leading to
an array of interesting scaffolds for medicinal
chemistry.
Passerini reactions are ranked among the most pro-
ductive and useful synthetic processes.[2] Furthermore,
MCRs involving heterocyclic compounds constitute
one prolific approach to prepare complex molecules
and generate chemical diversity in a quick manner,
a critical issue in biological and medicinal chemistry
research.[3] In this context, remarkable contributions
by Orru and Martin focus on the design of new
MCRs as flexible strategies towards complexity and
diversity.[4] Whenever a multicomponent process toler-
ates the presence of functional groups not participat-
ing in the reaction mechanism, an easy post-transfor-
mation can be exploited as the first synthetic step to-
wards highly diverse complex structures. Relevant ex-
amples have been described in isocyanide MCRs,
leading to complex heterocycles basically in two-step
sequences.[5]
Following our interest in the development of new
MCRs, we studied the interaction of boranes with iso-
cyanides, as few processes involve boron species in
the MCR field.[6] Remarkably, Hesse described in the
1960s, the reaction of isocyanides, aldehydes and bor-
anes to yield oxazolidines 4 (Scheme 1).[7] Recently,
we redesigned this process into a new family of
MCRs by inclusion of dipolarophiles, allowing in this
way access to aziridines 5 and pyrrolidines 6.[8] The
process proceeds through an azomethine ylide inter-
mediate A, from the interaction of the isocyanide,
borane and aldehyde inputs. The ylide can cyclize to
generate aziridines 5; alternatively it may participate
in formal [3+2]cycloadditions with a second equiva-
lent of aldehyde (leading to oxazolidines 4), or with
Keywords: boranes; heterocycles; isocyanides; mo-
lecular diversity; multicomponent reactions
Introduction
Multicomponent reactions (MCRs) are highly conver- distinct dipolarophiles, yielding the pyrrolidine scaf-
gent processes in which three or more components fold 6 (Scheme 1).
react to give a product containing the essential part of
The scope of all components was explored. The al-
the starting materials, in atom- and step-economical dehyde range included aromatic, heteroaromatic and
protocols.[1] The classic isocyanide-based Ugi and a,b-unsaturated derivatives. Aromatic aldehydes with
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Having in our hands a robust methodology to pre-
pare substituted aziridines, pyrrolidines and oxazoli-
dines, here we report our studies on expanding the
scope of this MCR and on the exploitation of the syn-
thetic potential of the obtained products.
Results and Discussion
In order to overcome the scarcity of trialkylboranes,
we took an alternative approach in which these reac-
tants are prepared by reaction of organometals with
BF3, or by hydroboration of alkenes and used in situ.
First, B(Bu)3 was prepared by reaction of n-BuLi with
BF3,[9] and immediately reacted with isocyanide 1a
and aldehyde 3a to afford oxazolidine 4a (Scheme 2).
In this way, the yield raised to 60% – 20% higher
than with commercially available B(Bu)3.[8]
Scheme 1. Multicomponent reactions of isocyanides, bor-
anes, aldehydes and dipolarophiles.
Similarly, trihomoallylborane 2b was prepared
using a modification of the Lyle procedure[10] and oxa-
electron-donating groups afforded aziridines. Al- zolidine 4b (32%) was thus obtained by addition of p-
though the aliphatic isocyanides were not reactive, methoxyphenyl-(PMP) isocyanide 1b and aldehyde 3a
both electron-rich and electron-poor aromatic isocya- following the general protocol (Scheme 2). Using an
nides yielded the expected products. Several dipolaro- analogous strategy, boranes 2c and 2d were prepared
philes, including N-phenylmaleimide, and activated by hydroboration of the corresponding alkenes with
(electron-deficient) alkenes and alkynes, afforded the borane-dimethyl sulfide complex. On addition of iso-
corresponding pyrrolidines. The borane input resulted cyanide 1b and aldehyde 3a, oxazolidines 4c (46%)
to be the main limitation of the reaction, mainly due and 4d (47%) were generated. With respect to the
to the lack of commercially available trialkylboranes. preparation of oxazolidine 4c, a consideration should
Thus the scope was restricted, in practice, to B(Et)3 be made about the hydroboration: when using
and B(Bu)3.
terminal alkenes, the regioselectivity is usually high
Scheme 2. Borane range (PMP=p-MeO-C6H4).
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Scope and Post-Transformations for the Borane-Isocyanide Multicomponent Reactions
Scheme 3. Cross-over experiment with B(Et)3 and B(Bu)3.
(ꢀ95%); on the other hand with phenyl-substituted
alkenes, such as styrene, selectivity is described to
drop to 80%.[11] Therefore a mixture of boranes re-
sults from the hydroboration of styrene, 2c being the
major species. Nevertheless oxazolidine 4c is the only
product detected in the reaction mixture (Scheme 2),
suggesting also clear preferences in the boron to
carbon migration step. This implies that bulky or
branched organoboranes should be less reactive, and
accordingly, benzyl-BBN on interaction with p-chloro-
benzaldehyde 3a and p-methoxyphenyl isocyanide 1b
did not yield any MCR adduct.
With regard to the reaction mechanism, it remained
unclear whether the two alkyl groups transferred to
the isocyanide terminal carbon arise from the same or
different borane molecules. A cross-over experiment
was designed to settle this point, and isocyanide 1b
and aldehyde 3a were reacted with a mixture of
B(Et)3 and B(Bu)3 to afford roughly equimolar
amounts of oxazolidines 4e and 4a having either two
ethyl or two butyl residues, but no mixed products
(Scheme 3). This supports the mechanistic hypothesis
previously described,[8] and demonstrates that the two
alkyl groups of each oxazolidine come from the same
trialkylborane reactant molecule.
Scheme 4. New aldehydes suitable for post-condensation re-
actions.
The aldehyde scope is further explored, with the
objective of adding more functional groups whose re- the same molecular mass as the expected aziridine
activity may enable post-condensation transforma- (D, Scheme 6). Although this compound could not be
tions. For instance, fused pyrrolidine 6a (26%, characterized,[12] treatment of this intermediate with
Scheme 4) was readily prepared from p-iodobenzalde- tetrabutylammonium cyanide yielded the a-amino ni-
hyde, B(Et)3, N-phenylmaleimide and p-methoxy- trile 7b in a stereoselective manner. The structure of
À
phenyl isocyanide 1b, and displays a C I bond, suita- this compound was univocally assigned by X-ray dif-
ble for metal-catalyzed couplings. Furthermore, 2-oct- fraction (Scheme 5).[13] The interpretation of this re-
ACHTUNGTRENNUNGynal is used in a 3-component process to afford the markable result may be related to the formation of
corresponding oxazolidine 4f (70%). This constitutes the expected aziridine, (D, Scheme 6), by ring closure
a quick access to a functionalized dialkynyl moiety, from the azomethine ylide C, since electron-rich alde-
suitable for metal-domino processes or as a building hydes suffer this transformation.[8] In this case, the
block for the preparation of complex structures. This indole-azidirine D is abnormally reactive[14] and suf-
À
compound is present in the reaction crude in high fers a gramine-type C N bond heterolysis to give
amount, but decomposes on chromatographic purifi- zwitterion E which undergoes a [1,3]hydride shift[15]
cation attempts; however it can be used directly in to isomerize to
F which in turn experiences
the next reaction step. With respect to heterocyclic al- a [1,2]alkyl shift[16] to finally yield the putative imine
dehydes, furfural afforded the expected oxazolidine 7a.
4g in 81% yield (Scheme 4).
There is a clear thermodynamic driving force that
On the other hand, the reaction of indole-3-carbal- facilitates this orchestrated rearrangement, as this
dehyde (3b, R=H), p-methoxyphenyl isocyanide 1b imine is considerably more stable than the starting
and B(Et)3 resulted in a novel process leading to the aziridine D.[17] The overall transformation involves the
À
unstable imine 7a (70% conversion, Scheme 5) having formation of three C C bonds, the net insertion of an
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Scheme 5. Oxazolidine and aziridine nucleophilic opening.
Scheme 6. Mechanistic hypothesis for the formation of imine 7a.
indolylmethyl moiety into an alkyl group and the dif- manner.[19] The reaction can be tuned, and when per-
ferentiation of the two ethyl substituents coming from forming the transformation with the N-sulfonylated
the borane component.[18] The whole process takes analogue (3b, R=Ph-SO2-),[20] trans-oxazolidine 4h
place in one operation, just mixing the reactants. Fur- (65%) was satisfactorily obtained (Scheme 5).
thermore, the cyanide addition to the imine leads to
Noticeably, the electronic effect of the N-protecting
the isolated amino nitrile in stereoselective group of the indole is able to modulate the reactivity
a
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Scope and Post-Transformations for the Borane-Isocyanide Multicomponent Reactions
Scheme 7. MCRs of dialdehydes 3c, 3d and isocyanide 1c.
of the aldehyde component, and in this way, the imine plex mixtures of products, in which several oxazoli-
pathway was avoided, as the dipolar cycloaddition to dine adducts can be detected. Interestingly, tere-
another aldehyde unit prevailed. This compound
ACHTUNGTRENpNUNG hthaldehyde (3c) reacted in a clean way to afford
could be deprotected with KOH under phase-transfer the corresponding oxazolidine 4j (21%, Scheme 7)
[21]
À
catalysis to yield the N H derivative 4i (90%), thus bearing two unreacted formyl groups. Additionally,
allowing the preparation of both scaffolds from the alk
A
same indole precursor. The 1,2-(3-indolyl)ethane 1b and B(Et)3. The corresponding cyclooctyne oxazo-
moiety is present in relevant bioactive structures and lidine 4k was detected in trace amounts by HPLC-
natural products.[22] Among them, especially appealing MS, however the dialkynyloxazolidine 4l (15%) was
is Tivantinib (ARQ197, Scheme 5), a new antitumoral the main product and could be properly purified and
in clinical phase III trials, that selectively targets the characterized.
c-Met receptor tyrosine kinase, and is giving promis-
ing results against several cancers.[23] Furthermore, substituted isocyanide 1c properly reacted with cin-
this chemotype is the synthetic precursor of the namaldehyde (3e), N-phenylmaleimide and triethyl-
staurosporine-indolocarbazole class of alkaloids and is borane to afford the fused pyrrolidine 6b (74%,
With regard to new isocyanides, the ortho-bromo
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
readily transformed into these compounds by acid- Scheme 7). On the other hand, de Meijere’s o-isocya-
promoted cyclization.[24] Noteworthy, these ap- nophenylcarbaldehyde[26] led to complex mixtures on
proaches often require long sequences, whereas the attempting MCRs with boranes in the presence or ab-
preparation of derivative 4i takes place with high sence of dipolarophiles. Overall, these results confirm
step-economy.
that the expected reactivity can be observed with sev-
To explore the possibility of promoting intramolec- eral (di)substituted aldehydes and isocyanides, howev-
ular MCRs, the use of dialdehydes is investigated. er the formation of small or medium rings is not fa-
Phthaldialdehyde and isophthalaldehyde gave com-
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Scheme 8. Reductive opening of oxazolidines, Pd- and Ru-catalyzed post-modifications.
vored, and intermolecular pathways are largely fol- (Scheme 8) readily reacted with the corresponding
lowed in these cases. boronic acid in a Suzuki coupling, to afford the thio-
Next we explored the possibility of performing phene derivative 6c in excellent yield. Furthermore,
post-condensation transformations in order to further oxazolidine 4b readily cyclized through ring-closing
increase the complexity of the multicomponent ad- metathesis using the Grubbs catalyst (1st generation)
ducts. First, we considered the reductive opening of to yield the cycloheptene adduct 4m (95%,
oxazolidines to the corresponding amino alcohols. In Scheme 8), overcoming the intrinsic limitation due to
this way, oxazolidine 4e[8] is reacted with DIBAL-H, the lack of reactivity of cyclic boranes.
to selectively yield ethanolamine 8 with conservation
Next, we explored a metal-catalyzed hydroamina-
of the relative stereochemistry (95%, Scheme 8).[27] tion of alkynyloxazolidine 4f. This process was readily
Next, we studied metal-catalyzed transformations. On inducted by catalytic AuCl3, triggering a complex cas-
attempting an intramolecular Heck coupling with pyr- cade reaction and leading to the highly functionalized
rolidine 6b, decomposition of the starting material pyrrole 9a (80%, Scheme 9).
took place. On the other hand, pyrrolidine 6a
Scheme 9. Au-catalyzed hydroamination-hydration of oxazolidine 4f.
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Scope and Post-Transformations for the Borane-Isocyanide Multicomponent Reactions
1
ternal reference. Data for H NMR spectra are reported as
follows: chemical shift (d/ppm), multiplicity, coupling con-
stant (J/Hz) and integration. Data for 13C NMR spectra are
reported in terms of chemical shift relative to the solvent
peak of CDCl3 set at d=77.0 ppm. IR spectra were recorded
with a Thermo Nicolet Nexus spectrometer and are reported
in frequency of absorption (cmÀ1). HPLC analysis were per-
formed on a Waters Alliance 2695 separations module (Em-
power software) connected to a Waters PDA2996 photo-
diode array detection (PDA) system (190–800 nm) and
using a Symmetry column (C18, 5 mm, 4.6ꢃ150 mm). High
resolution mass spectrometry was performed by the Univer-
sity of Barcelona Mass Spectrometry Service.
The reaction is probably initiated by activation of
one triple bond by Au3+, followed by the intramolecu-
lar attack of the nitrogen of the oxazolidine. Subse-
quent rearrangements allow the elimination of penta-
none and, through proton shift and protonolysis of
À
the Au C bond, the generation of pyrrole B. At this
stage the remaining triple bond undergoes a gold-cat-
alyzed hydration, likely taking place during the final
aqueous work-up, to yield the final ketopyrrole 9a.
When the reaction was performed in dry DCM with
a substoichiometric source of chloride anion (from
AuCl3), chlorinated pyrrole 9b was produced in small
amounts. The latter compound, however, is unstable
and tends to convert into oxazolidine 9a during the
work-up. Related transformations leading to pyrroles
have been recently reported.[28]
General Procedure for Oxazolidine Synthesis
A solution of isocyanide (1 mmol, 1 equiv.) and aldehyde
(2 mmol, 1 equiv.) in THF (2 mL) was added slowly into
a
solution of trialkylborane in THF (1M, 1.2 mmol,
1.2 equiv.) at 08C. After 3 min stirring at this temperature,
the ice bath was removed and the reaction mixture was
stirred for 24 h at room temperature. An aqueous saturated
solution of Na2CO3 (10 mL) was added and the mixture was
extracted with dichloromethane (2ꢃ5 mL). The combined
organic extracts were dried (Na2SO4) and filtered. The sol-
vent was removed under reduced pressure and the residue
was purified by column chromatography (SiO2, hexanes/
ethyl acetate) to yield the oxazolidine 4.
Conclusions
In summary, the scope of MCRs involving trialkylbor-
anes, isocyanides, aldehydes and dipolarophiles has
been considerably expanded. The borane input can be
prepared in situ, the aldehyde range includes a,b-un-
saturated and heteroaromatic derivatives (furan,
indole), and the isocyanide scope, although restricted
to the aromatic series,[29] allows an ortho substitution.
Unexpected chemistry has been found for the indole-
3-carbaldehyde MCRs, leading to novel scaffolds and
complex but rational mechanistic pathways. Also, the
generated adducts can be further modified to yield di-
verse structures by simple post-condensation modifi-
cations. Thus, reductive opening leads to amino alco-
hols and metal-catalyzed reactions (Suzuki coupling,
ring-closing metathesis, and gold-promoted hydroami-
nation–hydration sequences) originate a variety of
scaffolds in direct transformations. Although the need
for the specific preparation of some boranes and
scope limitations in some reactants may represent re-
strictions in the practical/industrial applications of this
MCR, the described methodology stands as a very ef-
ficient way to access a wide family of heterocyclic
compounds with relevant presence in biological and
medicinal chemistry.
General Procedure for Pyrrolidine Synthesis
A solution of isocyanide (1 mmol, 1 equiv.) and aldehyde
(1 mmol, 1 equiv.) in THF (2 mL) was added slowly into
a
solution of trialkylborane in THF (1M, 1.2 mmol,
1.2 equiv.) at À108C. Subsequently N-phenylmaleimide was
added to the mixture. After 3 min stirring at this tempera-
ture, the cooling bath was removed and the reaction was
stirred for 24 h at room temperature. An aqueous saturated
solution of Na2CO3 (10 mL) was added and the mixture was
extracted with dichloromethane (2ꢃ5 mL). The combined
organic extracts were dried (Na2SO4) and filtered. The sol-
vent was removed under reduced pressure and the residue
was purified by column chromatography (SiO2, hexanes/
ethyl acetate) to yield the adduct 6.
General Procedure for the Preparation of Trialkyl-
boranes by Hydroboration
The corresponding olefin (4.0 mmol) was slowly added into
a solution of BH3·SMe2 (123 mL, 1.2 mmol) in toluene
(1 mL). The solution was stirred overnight at room tempera-
ture. Afterwards THF (2 mL) was added and the solution
was directly used in the next step.
Experimental Section
Unless stated otherwise, all reactions were carried out under
argon in dried glassware. Commercially available reactants
were used without further purification. Thin-layer chroma-
tography was conducted with Merck silica gel 60 F254
sheets and visualized by UV. Silica gel (particle size 35-
AHCTUNGTREG(NNUN 4RS,5RS)-2,2-Di(but-3-enyl)-4,5-bis(4-chlorophenyl)-
3-(4-methoxyphenyl)oxazolidine (4b)
Prepared as described in the general experimental for oxa-
zolidine synthesis. after preparation the borane solution
BF3·Et2O (185 mL, 1.5 mmol) was added to a suspension of
Mg turnings (138 mg, 5.68 mmol) and a crystal of iodine in
Et2O (4 mL). The reaction was initiated by addition of neat
4-bromobutene followed by a slow addition (1 h) of a solu-
1
70 mm) was used for flash column chromatography. H and
13C NMR spectra were recorded with a Varian Mercury 400
spectrometer (at 400 and 100 MHz, respectively). NMR
spectra were recorded in CDCl3 solution with TMS as an in-
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Nicola Kielland et al.
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tion of 4-bromobutene (523 mL, 5.2 mmol) in Et2O (2 mL).
The mixture was heated to reflux for 2 h, and then cooled to
08C. The solid was left to deposit on the bottom while the
solution was transferred into a round bottom flask using
a cannula and used in the next step (general experimental
procedure for oxazolidine synthesis). Obtained as an amor-
phous solid; isolated yield: 32%). 1H NMR (400 MHz,
CDCl3): d=7.30 (d, J=8.4 Hz, 2H), 7.17 (d, J=8.5 Hz, 2H),
7.09 (d, J=8.4 Hz, 2H), 7.05 (d, J=8.5 Hz, 2H), 6.77 (d, J=
9.1 Hz, 2H), 6.69 (d, J=9.1 Hz, 2H), 6.06–5.94 (m, J=16.8,
10.2, 6.6 Hz, 1H), 5.78–5.66 (m, J=16.9, 10.2, 6.6 Hz, 1H),
5.18 (dd, J=17.1, 1.7 Hz, 1H), 5.05 (dd, J=10.2, 1.6 Hz,
1H), 4.95–4.87 (m, 2H), 4.77 (d, J=8.6 Hz, 1H), 4.46 (d, J=
8.7 Hz, 1H), 3.70 (s, 3H), 2.82–2.71 (m, J=18.3, 8.6, 5.3 Hz,
1H), 2.54–2.42 (m, 1H), 2.30–2.04 (m, 4H), 1.91–1.82 (m,
J=14.1, 11.2, 5.0 Hz, 1H), 1.73–1.64 (m, J=14.0, 11.1,
5.9 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=154.88,
138.70, 138.54, 136.64, 136.49, 135.93, 134.26, 133.55, 129.08,
128.90, 128.71, 128.34, 122.35, 114.86, 114.65, 114.26, 99.18,
85.70, 70.72, 55.45, 39.92, 36.95, 28.69, 28.12; IR (NaCl):
nmax =2936, 2834, 1640, 1597, 1516, 1490, 1441, 1246, 1090,
1013, 912, 828 cmÀ1; MS (EI): m/z (%)=507 (M+, 26), 456
(30), 455 (43), 454 (100), 453 (63), 452 (100), 372 (77), 370
(100), 245 (31) 234 (15), 232 (46), 178 (25), 166 (17), 135
(100), 122 (32), 107 (18), 55 (38); HR-MS: m/z=508.1808,
1H), 6.73 (d, J=9.2 Hz, 2H), 6.68 (d, J=9.2 Hz, 2H), 4.75
(d, J=8.6 Hz, 1H), 4.44 (d, J=8.6 Hz, 1H), 3.70 (s, 2H),
2.20–2.10 (m, 1H), 2.01 (dd, J=15.1, 11.1 Hz, 2H), 1.79
(ddd, J=14.1, 12.0, 4.1 Hz, 1H), 1.69–1.57 (m, 2H), 1.48–
1.35 (m, 7H), 1.28 (d, J=6.8 Hz, 3H), 1.24–1.12 (m, 6H),
0.93 (t, J=7.0 Hz, 3H), 0.84 (t, J=7.0 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=154.38, 137.18, 136.71, 136.39, 134.15,
133.39, 129.03, 128.84, 128.64, 128.41, 121.70, 114.12, 100.04,
85.54, 70.87, 55.47, 41.50, 37.44, 32.20, 31.73, 29.93, 29.70,
24.41, 23.28, 22.94, 22.62, 14.30, 14.19; IR (NaCl): nmax
=
2929, 2858, 1510, 1496, 1441, 1284, 1245, 1189, 1040, 1014,
829 cmÀ1; MS (EI): m/z (%)=567 (M+, 18), 482 (100), 370
(93), 231 (41), 178 (18), 134 (100), 122 (26), 107 (14), 77
+
(13); HR-MS: m/z=568.2732, calcd. for C34H44Cl2NO2 :
568.2744.
(3aRS,6SR,6aSR)-4,4-Diethyl-6-(4-iodophenyl)-5-(4-
methoxyphenyl)-2-phenyltetrahydropyrrolo
role-1,3(2H,3aH)-dione (6a)
ACHTUNGTRENUN[NG 3,4-c]pyr-
AHCTUNGTRENNUNG
Prepared as described in general experimental procedure
for pyrrolidine synthesis. Obtained as an amorphous solid;
1
isolated yield: 26%. H NMR (400 MHz, CDCl3): d=7.51–
7.44 (m, 2H), 7.39 (q, J=7.5 Hz, 2H), 7.34–7.21 (m, 3H),
7.15–7.09 (m, 2H), 6.89–6.83 (m, 2H), 6.64–6.57 (m, 2H),
5.09 (d, J=6.7 Hz, 1H), 3.61 (s, 3H), 3.53 (d, J=10.4 Hz,
1H), 3.23 (dd, J=10.3, 6.6 Hz, 1H), 2.06–1.95 (m, 1H),
1.90–1.78 (m, 2H), 1.70–1.58 (m, 1H), 1.23 (t, J=7.3 Hz,
3H), 0.54 (t, J=7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d=176.7, 175.6, 155.6, 142.3, 137.8, 137.2, 134.3, 129.3, 129.3,
128.8, 126.3, 126.2, 125.4, 113.9, 92.9, 71.7, 65.4, 55.3, 52.2,
33.4, 25.3, 9.5, 8.9; IR (NaCl): nmax =3057, 2969, 2881, 2821,
1777, 1707, 1591, 1507, 1374, 1246, 1169, 1034, 963, 823,
695 cmÀ1; MS (EI): m/z (%)=581 (MH+, 35), 486 (60), 419
(43), 377 (11), 318 (100), 309 (65), 288 (63), 165 (5), 124 (6);
+
calcd. for C30H32Cl2NO2 : 508.1805.
ACHTUNGTRENNUNG(4RS,5RS)-4,5-Bis(4-chlorophenyl)-3-(4-methoxy-
phenyl)-2,2-diphenethyloxazolidine (4c)
Prepared as described in the general experimental proce-
dure for oxazolidine synthesis. The borane component was
prepared from styrene following the general procedure for
the preparation of trialkylboranes by hydroboration. Ob-
1
tained as an amorphous solid; isolated yield: 46%. H NMR
+
HR-MS: m/z=581.1299, calcd. for C29H30IN2O3 : 581.1296.
(400 MHz, CDCl3): d=7.37–7.32 (m, 6H), 7.27–7.21 (m,
4H), 7.21–7.15 (m, J=10.5, 5.4, 3.1 Hz, 4H), 7.10 (d, J=
8.5 Hz, 2H), 6.98 (d, J=7.0 Hz, 2H), 6.87 (d, J=9.0 Hz,
2H), 6.74 (d, J=9.0 Hz, 2H), 4.89 (d, J=8.7 Hz, 1H), 4.57
(d, J=8.7 Hz, 1H), 3.72 (s, 3H), 3.38–3.29 (m, J=12.8,
4.3 Hz, 1H), 3.07–2.97 (m, J=13.0, 4.9 Hz, 1H), 2.80–2.62
(m, 1H), 2.61–2.49 (m, 2H), 2.47–2.36 (m, 1H), 2.21–2.10
(m, 1H), 2.09–1.99 (m, 1H); 13C NMR (100 MHz, CDCl3):
d=154.87, 142.34, 142.20, 136.74, 136.31, 135.89, 134.43,
133.64, 129.04, 128.96, 128.81, 128.76, 128.64, 128.58, 128.45,
128.43, 126.16, 126.01, 122.02, 114.43, 99.19, 85.73, 70.99,
55.55, 43.49, 39.77, 31.00, 30.22; IR (NaCl): nmax =3025,
2933, 1601, 1510, 1491, 1453, 1245, 1080, 1040, 700 cmÀ1; MS
(EI): m/z (%)=607 (M+, 10), 504 (70), 502 (100), 372 (25),
370 (39), 244 (13), 238 (18), 231 (17), 204 (14); HR-MS:
AHCTUNGTREG(NNUN 4RS,5RS)-2,2-Diethyl-4,5-di(hept-1-ynyl)-3-(4-meth-
oxyphenyl)oxazolidine (4f)
Prepared as described in general experimental procedure
for oxazolidine synthesis using 2-octynal as aldehyde compo-
nent. 4f decomposes on silica. Obtained as a dark oil; con-
1
version: 70%. H NMR (400 MHz, CDCl3): d=6.89 (d, J=
9.1 Hz, 2H), 6.81 (d, J=9.2 Hz, 2H), 4.77 (dt, J=8.3,
1.8 Hz, 1H), 4.38 (dt, J=8.3, 1.8 Hz, 1H), 3.77 (s, 3H), 2.26
(td, J=7.1, 1.7 Hz, 2H), 2.11 (td, J=6.9, 1.8 Hz, 2H), 2.00–
1.90 (m, 1H), 1.85 (dt, J=13.1, 6.7 Hz, 1H), 1.75 (dt, J=
14.5, 7.2 Hz, 1H), 1.61–1.51 (m, 3H), 1.46–1.17 (m, 10H),
1.05 (t, J=7.4 Hz, 3H), 0.90 (t, J=7.1 Hz, 3H), 0.84 (t, J=
7.1 Hz, 3H), 0.68 (t, J=7.3 Hz, 3H); MS (EI): m/z (%)=
423 (M+, 2), 395 (5), 394 (18), 338 (9), 337 (21), 282 (6), 281
(12), 280 (55), 231 (18), 134 (6); HR-MS: m/z=423,3130,
+
m/z=608.2115, calcd. for C38H36Cl2NO2 : 608.2118.
+
calcd. for C28H41NO2 : 423,3137.
ACHTUNGTRENNUNG(4RS,5RS)-4,5-Bis(4-chlorophenyl)-2,2-dihexyl-3-(4-
methoxyphenyl)oxazolidine (4d)
AHCTUNGTREG(NNNU 4RS,5RS)-2,2-Diethyl-4,5-di(furan-2-yl)-3-(4-meth-
oxyphenyl)oxazolidine (4g)
Prepared as described in the general experimental proce-
dure for oxazolidine synthesis. The borane component was
prepared from hexene following the general procedure for
the preparation of trialkylboranes by hydroboration. Ob-
tained as an amorphous solid; isolated yield: 46%. H NMR
(400 MHz, CDCl3): d=7.29 (d, J=8.4 Hz, 2H), 7.17 (d, J=
8.5 Hz, 2H), 7.10 (d, J=8.4 Hz, 2H), 7.05 (d, J=8.4 Hz,
Prepared as described in the general experimental proce-
dure for oxazolidine synthesis using furfural as aldehyde
component. Obtained as an amorphous solid; isolated yield:
1
1
81%. H NMR (400 MHz, CDCl3): d=7.48–7.46 (m, J=1.8,
0.8 Hz, 1H), 7.26–7.25 (m, J=1.8, 0.8 Hz, 1H), 6.87 (d, J=
3280
asc.wiley-vch.de
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 3273 – 3284

Scope and Post-Transformations for the Borane-Isocyanide Multicomponent Reactions
9.1 Hz, 2H), 6.74 (d, J=9.1 Hz, 2H), 6.42–6.40 (m, J=3.3,
0.7 Hz, 1H), 6.38–6.35 (m, J=3.3, 1.8 Hz, 1H), 6.22–6.19
(m, J=3.2, 1.8 Hz, 1H), 6.18–6.16 (m, J=3.3, 0.7 Hz, 1H),
5.18 (s, 2H), 3.73 (s, 3H), 2.14–1.96 (m, 2H), 1.91–1.80 (m,
1H), 1.65–1.56 (m, 1H), 1.25 (t, J=7.4 Hz, 3H), 0.80 (t, J=
7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=154.17,
152.11, 151.06, 143.34, 142.15, 137.58, 120.79, 114.07, 110.43,
110.38, 109.57, 108.00, 100.66, 77.03, 61.51, 55.49, 34.31,
29.96, 8.62, 7.60; IR (NaCl): nmax =2950, 2875, 1593, 1490,
1472, 1329, 1254, 1122, 1087, 995, 841, 811 cmÀ1; MS (EI):
m/z (%)=368 (MH+, 90), 310 (5), 282 (100), 272 (27), 269
(5), 142 (10), 104 (5), 102 (9); HR-MS: m/z=368.1861,
8.2; IR (NaCl): nmax =2920, 2734, 1772, 1550, 1595, 1421,
1374, 934, 647 cmÀ1; HR-MS: m/z=466.2491, calcd for
C30H32N3O2 (M+H+): 466.2489.
AHCTUNGTREG(NNNU 2RS,3RS)-2-Ethyl-4-(1H-indol-3-yl)-2-(4-methoxy-
phenylamino)-3-methylbutanenitrile (7b)
A cold solution of triethylborane in THF (1M, 1.2 mL,
1.2 mmol) was added dropwise onto a mixture of 4-methox-
yphenyl isocyanide (133 mg, 1 mmol) and indole-3-carbalde-
hyde (145 mg, 1 mmol) in THF (2 mL) at 08C. After 10 min
the ice bath was removed and the mixture was stirred under
nitrogen overnight. A solution of tetrabutylammonium cya-
nide (403 mg, 1.5 mmol) in MeOH (5 mL) was added and
the mixture was stirred for 16 h at room temperature. Water
(10 mL) was added and the mixture was extracted with
Et2O (3ꢃ10 mL). The combined organic extracts were dried
(Na2SO4) and filtered. The solvent was removed under re-
duced pressure and the residue was purified by column
chromatography (SiO2, hexanes/ethyl acetate) to afford
amino nitrile 7b as a white solid; isolated yield: 142 mg
+
calcd. for C22H26NO4 : 368.1856.
ACHTUNGTRENNUNG(4RS,5RS)-2,2-Diethyl-3-(4-methoxyphenyl)-4,5-bis[1-
(phenylsulfonyl)-1H-indol-3-yl]oxazolidine (4h)
Prepared as described in the general experimental proce-
dure for oxazolidine synthesis, using 1-(phenylsulfonyl)-1H-
indole-3-carbaldehyde as aldehyde component. Obtained as
an amorphous solid; isolated yield: 65%. 1H NMR
(400 MHz, CDCl3): d=7.86 (d, J=8.4 Hz, 1H), 7.76–7.70
(m, 3H), 7.49–7.42 (m, 2H), 7.40–7.30 (m, 6H), 7.20–7.11
(m, 3H), 7.05–6.96 (m, 2H), 6.85–6.79 (m, 1H), 6.76–6.70
(m, 2H), 6.71–6.60 (m, 2H), 6.60–6.54 (m, 2H), 5.19 (d, J=
8.7 Hz, 1H), 5.01 (d, J=8.8 Hz, 1H), 3.66 (s, 3H), 2.22–2.10
(m, 1H), 2.06–1.94 (m, 1H), 1.88–1.77 (m, 1H), 1.64–1.53
(m, 1H), 1.28 (t, J=7.3 Hz, 3H), 0.87 (t, J=7.4 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=154.8, 138.2, 137.6, 137.1,
135.4, 135.3, 134.0, 133.6, 129.8, 129.5, 129.2, 128.9, 126.9,
126.5, 125.6, 125.0, 124.8, 124.7, 123.3, 123.2, 122.7, 120.3,
120.23, 120.20, 119.7, 114.1, 113.8, 113.7, 99.9, 79.1, 62.0,
55.4, 32.9, 30.1, 8.9, 8.3; IR (NaCl): nmax =3058, 2975, 2937,
2879, 3058, 1444, 1367, 1175 cmÀ1; MS (EI): m/z (%)=745
(M+, 100), 410 (68), 300 (22), 142 (46), 101 (66); HR-MS:
m/z=746.2353, calcd. for C42H40N3O6S2 (M+H+): 746.2346.
1
(31%). H NMR (400 MHz, CDCl3): d=7.97 (s, 1H), 7.34
(d, J=8.2 Hz, 1H), 7.24–7.13 (m, 2H), 7.07–6.97 (m, 3H),
6.94 (s, 1H), 6.87 (d, J=8.9 Hz, 2H), 3.81 (s, 3H), 3.49 (s,
1H), 3.22 (d, J=12.7 Hz, 1H), 2.53 (s, 2H), 2.01 (s, 1H),
1.92 (s, 1H), 1.19 (t, J=7.4 Hz, 3H), 1.08 (d, J=6.4 Hz,
3H); 13C NMR (100 MHz, CDCl3): d=157.65, 139.57,
137.53, 135.71, 133.44, 133.08, 131.46, 130.85, 128.85, 128.23,
127.86, 113.88, 73.55, 72.79, 67.37, 55.52, 25.98, 25.21, 11.49,
11.35 ppm. IR (NaCl) nmax =2911, 2743, 1764, 1563, 1515,
1462, 1344, 661 cmÀ1; MS (EI): m/z (%)=458 (M+, 100), 310
(8), 424 (5), 318 (14), 316 (23), 282 (7), 208 (13), 194 (8), 102
+
(10); HR-MS: m/z=458.1650, calcd. for C26H30Cl2NO2 :
458.1648.
4,4’-[(4RS,5RS)-2,2-Diethyl-3-(4-methoxyphenyl)-
oxazolidine-4,5-diyl]dibenzaldehyde (4j)
Prepared as described in the general experimental proce-
dure for oxazolidine synthesis using terephthaldehyde as al-
dehyde component. Obtained as an amorphous solid; isolat-
ed yield: 21%. 1H NMR (400 MHz, CDCl3): d=10.02 (s,
1H), 9.93 (s, 1H), 7.84 (d, J=8.1 Hz, 2H), 7.73 (d, J=
8.1 Hz, 2H), 7.33 (t, J=7.4 Hz, 4H), 6.78 (d, J=9.0 Hz,
2H), 6.68 (d, J=9.0 Hz, 2H), 4.95 (d, J=8.7 Hz, 1H), 4.63
(d, J=8.7 Hz, 1H), 3.68 (s, 3H), 2.31–2.20 (m, 1H), 2.14–
2.03 (m, 1H), 1.95–1.84 (m, 1H), 1.75–1.64 (m, 1H), 1.33 (t,
J=7.3 Hz, 3H), 0.95 (t, J=7.4 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=191.81, 191.68, 154.57, 144.74, 144.69,
136.62, 136.45, 136.15, 129.98, 129.76, 128.29, 127.37, 121.80,
114.06, 100.68, 85.54, 71.20, 55.26, 33.02, 29.88, 8.64, 7.99; IR
(NaCl): nmax =2934, 2834, 2735, 1701, 1608, 1578, 1463, 1246,
1206, 1037, 947, 815 cmÀ1; MS (EI): m/z (%)=444 (MH+,
52), 414 (45), 358 (91), 269 (10), 239 (15), 191 (58), 129 (24),
ACHTUNGTRENNUNG(4RS,5RS)-2,2-Diethyl-4,5-di(1H-indol-3-yl)-3-(4-
methoxyphenyl)oxazolidine (4i)
This deprotection step was accomplished through a modified
version of Liuꢄs procedure.[21] Tetrabutylammonium bromide
(86 mg, 268 mmol) and KOH (15 mg, 286 mmol) were added
to a solution of oxazolidine 4h (20 mg, 27 mmol) in THF
(0.5 mL) and H2O (0.2 mL). The mixture was refluxed at
658C until completion of the reaction (3 h). Water (5 mL)
was added and the mixture was extracted with ethyl acetate
(2ꢃ5 mL). The combined organic extracts were dried
(Na2SO4) and filtered. The solvent was removed under re-
duced pressure and the residue was purified by column
chromatography (SiO2, hexanes/ethyl acetate) to yield the
oxazolidine 4i as an amorphous solid; isolated yield: 12 mg
1
(90%). H NMR (400 MHz, CDCl3): d=7.86 (br. 1H), 7.78
+
(br, 1H), 7.53 (d, J=7.9 Hz, 1H), 7.28–7.21 (m, 2H), 7.18–
7.10 (m, 2H), 7.05–6.99 (m, 2H), 6.94–6.87 (m, 2H), 6.87–
6.77 (m, 3H), 6.69–6.61 (m, 2H), 5.39 (d, J=9 Hz, 1H), 5.33
(d, J=9 Hz, 1H), 3.64 (s, 3H), 2.34–2.23 (m, 1H), 2.22–2.10
(m, 1H), 2.05–1.94 (m, 1H), 1.76–1.64 (m, 1H), 1.38 (t, J=
7.3 Hz, 3H), 0.96 (t, J=7.4 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=153.9, 138.5, 136.8, 136.4, 126.6, 126.2, 124.1,
123.5, 122.1, 121.69, 121.66, 120.10, 119.9, 119.7, 119.2, 113.9,
113.6, 113.4, 111.3, 111.1, 99.4, 80.2, 62.1, 55.4, 33.3, 29.9, 9.1,
121 (100); HR-MS: m/z=444.2172, calcd. for C28H30NO4 :
444.2169.
2,2’-{2,2’-[(4RS,5RS)-2,2-Diethyl-3-(4-methoxy-
phenyl)oxazolidine-4,5-diyl]bis(2,1-phenylene)}bis-
(ethyne-2,1-diyl)dibenzaldehyde (4l)
Prepared as described in the general experimental proce-
dure for oxazolidine synthesis using 2,2’-(ethyne-1,2-diyl)di-
Adv. Synth. Catal. 2013, 355, 3273 – 3284
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3281

Nicola Kielland et al.
UPDATES
benzaldehyde as aldehyde component. Obtained as an
amorphous solid; isolated yield: 15%. H NMR (400 MHz,
1H NMR (400 MHz, CDCl3): d=7.08 (d, J=8.5 Hz, 2H),
7.01 (t, J=8.8 Hz, 4H), 6.89 (d, J=9.0 Hz, 2H), 6.79 (d, J=
9.0 Hz, 2H), 6.53 (d, J=8.5 Hz, 2H), 5.13 (s, 1H), 4.65 (d,
J=9.8 Hz, 1H), 4.05 (d, J=9.8 Hz, 1H), 3.82 (s, 3H), 3.01–
2.93 (m, 1H), 1.62–1.48 (m, 3H), 1.43–1.31 (m, J=14.2,
7.3 Hz, 1H), 0.99 (t, J=7.3 Hz, 3H), 0.92 (t, J=7.4 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=157.65, 139.57, 137.53,
135.71, 133.44, 133.08, 131.46, 130.85, 128.85, 128.23, 127.86,
113.88, 73.55, 72.79, 67.37, 55.52, 25.98, 25.21, 11.49, 11.35;
IR (NaCl): nmax =2931, 2874, 1703, 1595, 1569, 1463, 1383,
1246, 1091, 1013, 830, 746 cmÀ1; MS (EI): m/z (%)=458
(M+, 100), 310 (8), 424 (5), 318 (14), 316 (23), 282 (7), 208
(13), 194 (8), 102 (10); HR-MS: m/z=458.1650, calcd. for
1
CDCl3): d=10.27 (d, J=0.6 Hz, 1H), 10.21 (d, J=0.7 Hz,
1H), 7.83 (m, J=14.0, 7.8, 1.4 Hz, 2H), 7.78–7.74 (m, 1H),
7.65–7.60 (m, 1H), 7.47 (m, J=17.6, 7.5, 1.4 Hz, 2H), 7.41–
7.33 (m, 2H), 7.33–7.27 (m, 2H), 7.24 (dd, J=7.7, 1.2 Hz,
2H), 6.98–6.93 (m, 2H), 6.77–6.71 (m, 3H), 6.71–6.66 (m,
1H), 6.65–6.59 (m, 2H), 5.53 (d, J=8.7 Hz, 1H), 5.24 (d, J=
8.7 Hz, 1H), 3.60 (s, 3H), 2.28–2.16 (m, 1H), 2.14–2.02 (m,
1H), 1.95–1.83 (m, 1H), 1.74–1.62 (m, 1H), 1.34 (t, J=
7.3 Hz, 3H), 0.94 (t, J=7.4 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=191.64, 191.51, 154.31, 140.47, 140.00, 137.42,
135.59, 135.50, 133.63, 133.54, 133.36, 133.25, 132.46, 132.34,
130.00, 129.65, 128.62, 128.51, 128.11, 127.56, 127.36, 126.95,
126.71, 122.35, 121.63, 121.46, 114.24, 100.30, 93.94, 93.82,
89.28, 88.45, 83.45, 68.62, 55.42, 33.54, 31.74, 30.21, 22.80,
14.27, 8.90, 8.20; IR: (NaCl): nmax =3065, 2975, 2924, 2824,
2834, 2738, 1700, 1597, 1508, 1245 cmÀ1; HR-MS: m/z=
644.2791, calcd, for C44H38NO4 (M+H+): 644.2795.
+
C26H30Cl2NO2 : 458.1648.
(3aRS,6SR,6aSR)-4,4-Diethyl-5-(4-methoxyphenyl)-2-
phenyl-6-[4-(thiophen-2-yl)phenyl]tetrahydro-
pyrroloACHTUNTRGENN[GU 3,4-c]pyrrole-1,3ACHTUGNTREN(NNGU 2H,3aH)-dione (6c)
A Schlenk vessel was charged with pyrrolidine 6a (150 mg,
258 mmol), 2-thienylboronic acid (43 mg, 336 mmol), and KCl
(58 mg, 775 mmol). After three argon/vacuum cycles, toluene
(3 mL) and ethanol (0.8 mL) were added followed by a 2M
water solution of Na2CO3 (1.29 mL, 2.58 mmol). After three
argon/vacuum cycles, the mixture was stirred for 10 min,
(3aRS,6SR,6aSR)-5-(2-Bromo-4-methoxyphenyl)-4,4-
diethyl-2-phenyl-6-styryltetrahydropyrrolo
role-1,3(2H,3aH)-dione (6b)
ACHTUNGTRENUN[NG 3,4-c]pyr-
ACHTUNGTRENNUNG
Prepared as described in the general experimental proce-
dure for pyrrolidine synthesis. Obtained as an amorphous
solid; overall yield: 74% (minor diastereomer of a 6:4 mix-
ture described). 1H NMR (400 MHz, CDCl3): d=7.54–7.48
(m, J=7.6 Hz, 2H), 7.44–7.40 (m, J=7.5 Hz, 1H), 7.40–7.35
(m, J=7.2 Hz, 2H), 7.26 (s, 1H), 7.21–7.18 (m, J=4.3 Hz,
3H), 7.18–7.14 (m, 2H), 7.07 (d, J=2.9 Hz, 1H), 6.76 (dd,
J=8.8, 2.9 Hz, 1H), 6.39 (d, J=15.7 Hz, 1H), 6.04 (dd, J=
15.7, 9.2 Hz, 1H), 4.50 (dd, J=9.0, 7.7 Hz, 1H), 3.72 (s, 3H),
3.49 (t, J=7.7 Hz, 1H), 3.34 (d, J=7.8 Hz, 1H), 2.30–2.18
(m, 1H), 1.99–1.89 (m, 2H), 1.88–1.78 (m, J=14.4, 7.3 Hz,
1H), 1.04 (t, J=7.3 Hz, 3H), 0.46 (t, J=7.5 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=)176.13, 175.27, 158.23,
136.83, 135.70, 134.20, 132.48, 130.57, 129.78, 129.36, 128.68,
128.43, 127.60, 127.24, 126.92, 126.86, 117.89, 113.86, 71.06,
66.58, 55.58, 51.01, 48.83, 26.97, 22.71, 9.57, 8.09; IR (NaCl):
nmax =2881, 1774, 1710, 1597, 1493, 1384, 1285, 1220, 1916,
966, 736, 639 cmÀ1; MS (EI): m/z (%)=559 (MH+, 43), 513
(20), 502 (9), 483 (10), 473 (7), 201 (15), 141 (43), 137 (45),
then PdACHTNUGTRNEUNG(PPh3)4 (10%, 30 mg, 26 mmol) was added quickly
under a flow of argon. Three more argon/vacuum cycles
were made, and the mixture was stirred at 1008C overnight.
The mixture was cooled to room temperature and filtered
through a celite pad, washing with ethyl acetate. The result-
ing solution was extracted with ethyl acetate (3ꢃ10 mL).
The combined organic extracts were dried (Na2SO4) and fil-
tered. The solvent was removed under reduced pressure and
the residue was purified by column chromatography (SiO2,
hexanes/ethyl acetate) to yield the thiophene derivative 6c
as an amorphous solid; isolated yield; 129 mg (93%).
1H NMR (400 MHz, CDCl3): d=7.40 (d, J=6.9 Hz, 5H),
7.39–7.29 (m, 2H), 7.29–7.22 (m, 2H), 7.18–7.11 (m, 2H),
6.95 (dd, J=5.1, 3.6 Hz, 1H), 6.90 (d, J=9.0 Hz, 2H), 6.61
(d, J=9.0 Hz, 2H), 5.16 (d, J=6.6 Hz, 1H), 3.61 (s, 3H),
3.56 (d, J=10.4 Hz, 1H), 3.31 (dd, J=10.3, 6.6 Hz, 1H),
2.07–1.98 (m, 1H), 1.87 (s, 2H), 1.73–1.62 (m, 1H), 1.27 (t,
J=7.2 Hz, 3H), 0.57 (t, J=7.5 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=176.87, 175.80, 155.47, 144.26, 141.86,
137.51, 133.56, 131.96, 129.33, 128.77, 128.05, 127.73, 126.40,
126.30, 125.27, 124.72, 123.03, 113.89, 71.70, 65.62, 55.33,
52.33, 52.14, 33.56, 25.39, 9.51, 8.99; IR: (NaCl): nmax =3064,
2962, 2930, 2879, 2251, 1777, 1706, 1591, 1501 cmÀ1, HR-MS:
m/z=537.2210, calcd. for C33H33N2O3S (M+H+): 537.2206.
122
(100);
HR-MS:
m/z=559.1581,
calcd.
for
+
C31H32BrN2O3 : 559.1591.
ACHTUNGTRENNUNG
A
solution of DIBAL-H in heptanes (1M, 383 mL,
383 mmol) was added dropwise in 10 min into a solution of
oxazolidine 4e (45 mg, 110 mmol) in dry toluene (0.7 mL) at
À788C under nitrogen. The solution was allowed to slowly
reach room temperature and stirred overnight. Ethyl acetate
(10 mL) and a saturated water solution of sodium potassium
tartrate (10 mL) were added and the mixture stirred for
a further 30 min. The mixture was extracted with ethyl ace-
tate (3ꢃ10 mL). The combined organic extracts were dried
(Na2SO4) and filtered. The solvent was removed under re-
duced pressure and the residue was purified by column
chromatography (SiO2, hexanes/ethyl acetate) to yield
amino alcohol 8 as an oil; isolated yield: 48 mg (95%).
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
A solution of oxazolidine 4b (40 mg, 79 mmol) in dichloro-
methane (15 mL) was treated with Cl2A(PCy3)2Ru=CHPh
CTHUNGTRENNUNG
(5%, 3 mg, 4 mmol) and stirred overnight at room tempera-
ture. The mixture was filtered through a celite pad washing
with dichloromethane. The solvent was evaporated in
vacuum and the resulting residue was purified by column
chromatography (SiO2, hexanes/ethyl acetate). Obtained as
1
an amorphous solid; isolated yield: 36 mg (95%). H NMR
(400 MHz, CDCl3): d=7.29 (d, J=8.4 Hz, 2H), 7.15 (d, J=
3282
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ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 3273 – 3284

Scope and Post-Transformations for the Borane-Isocyanide Multicomponent Reactions
8.4 Hz, 2H), 7.11 (d, J=8.3 Hz, 2H), 7.06 (d, J=8.5 Hz,
2H), 6.89 (d, J=9.0 Hz, 2H), 6.68 (d, J=9.0 Hz, 2H), 5.88–
5.74 (m, 2H), 4.78 (d, J=8.5 Hz, 1H), 4.41 (d, J=8.5 Hz,
1H), 3.69 (s, 3H), 2.54–2.44 (m, 1H), 2.43–2.31 (m, 2H),
2.22–2.04 (m, 2H), 1.99–1.86 (m, 1H), 1.86–1.78 (m, J=11.8,
7.0, 1.3 Hz, 1H), 1.63–1.55 (m, J=13.6, 9.1, 1.8 Hz, 1H);
13C NMR (100 MHz, CDCl3): d=155.65, 136.73, 136.68,
135.84, 134.05, 133.41, 132.27, 132.24, 129.29, 128.72, 128.60,
128.35, 124.62, 114.04, 99.34, 84.42, 71.12, 55.41, 41.03, 37.21,
23.32, 22.27; IR (NaCl): nmax =2933, 2834, 1598, 1510, 1490,
1284, 1244, 1180, 1132, 1076, 1039, 1013, 828 cmÀ1; MS (EI):
m/z (%)=480 (M+, 100), 454 (25), 447 (28), 410 (68), 370
(35), 320 (35), 300 (22), 142 (46), 101 (66); HR-MS: m/z=
1499; f) D. J. Ramꢅn, M. Yus, Angew. Chem. 2005, 117,
1628–1661; Angew. Chem. Int. Ed. 2005, 44, 1602–1634;
g) B. B. Tourꢁ, D. G. Hall, Chem. Rev. 2009, 109, 4439–
4486.
[2] For an overview, see: Isocyanide Chemistry, (Ed. V. Ne-
najdenko), Wiley-VCH, Weinheim, 2012; for represen-
tative reviews, see: a) A. Dçmling, I. Ugi, Angew.
Chem. 2000, 112, 3300–3344; Angew. Chem. Int. Ed.
2000, 39, 3168–3210; b) A. Dçmling, Chem. Rev. 2006,
106, 17–89; c) A. Dçmling, Chem. Rev. 2012, 112, 3083–
3135.
[3] a) For an overview, see: Synthesis of Heterocycles via
Multicomponent Reactions, (Vols. I and II), in: Topics
in Heterocyclic Chemistry, (Eds.: R. V. A. Orru, E.
Ruijter), Springer, Berlin, Heidelberg, 2010; b) or
a review, see: N. Isambert, R. Lavilla, Chem. Eur. J.
2008, 14, 8444–8454.
+
480.1476, calcd. for C28H28Cl2NO2 : 480.1492.
1-[1-(4-Methoxyphenyl)-5-pentyl-1H-pyrrol-2-yl]-
heptan-1-one (9a)
[4] a) E. Ruijter, R. Scheffelaar, R. V. A. Orru, Angew.
Chem. 2011, 123, 6358–6371; Angew. Chem. Int. Ed.
2011, 50, 6234–6246; b) J. D. Sunderhaus, S. F. Martin,
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A solution of oxazolidine 4f (50 mg, 118 mmol) in MeOH
(1 mL) was treated with AuCl3 (5%, 1.8 mg, 6 mmol). After
5 h stirring at room temperature ethyl acetate (5 mL) and
a saturated solution of Na2CO3 (5 mL) were added. The
layers were separated and the aqueous phase was extracted
with ethyl acetate (2ꢃ5 mL). The combined organic extracts
were dried over Na2SO4, the solvent was evaporated under
vacuum and the residue was purified by column chromatog-
raphy (SiO2, Hexanes/Ethyl acetate). Obtained as an amor-
phous solid; isolated yield: 34 mg (80%). 1H NMR
(400 MHz, CDCl3): d=7.10–7.04 (m, J=8.0, 4.0 Hz, 2H),
7.02 (d, J=4.0 Hz, 1H), 6.97–6.91 (m, J=8.0, 4.0 Hz, 2H),
6.06 (d, J=3.9 Hz, 1H), 3.85 (s, 3H), 2.68 (t, J=8.0 Hz,
2H), 2.29 (t, J=8.0 Hz, 2H), 1.64–1.54 (m, 2H), 1.48 (m, J=
14.9, 7.4 Hz, 2H), 1.34–1.19 (m, 10H), 0.88–0.80 (m, 6H);
13C NMR (100 MHz, CDCl3): d=189.75, 159.15, 144.28,
132.67, 132.07, 128.74, 119.01, 114.18, 107.17, 55.59, 39.15,
31.91, 31.63, 29.33, 28.50, 26.70, 25.22, 22.74, 22.53, 14.27,
14.11; IR (NaCl): nmax =2955, 2858, 1652, 1609, 1600, 1465,
1377, 1249, 1170, 1107, 1032, 833 cmÀ1; MS (EI): m/z (%)=
355 (M+, 32), 298 (22), 286 (21), 285 (100), 270 (49), 228
(18), 186 (17), 164 (31); HR-MS: m/z=356.2579, calcd. for
[5] For representative examples, see: a) L. Banfi, A. Basso,
R. Riva, Synthesis of Heterocycles via Multicomponent
Reactions, (Vol. I), in: Topics in Heterocyclic Chemistry,
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delberg, 2010, Vol. 23, pp 1–39; b) I. Akritopoulou-
Zanze, S. W. Djuric, Heterocycles 2007, 73, 125–147;
c) J. Oble, L. El Kaꢆm, M. Gizzi, L. Grimaud, Heterocy-
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Herdtweck, A. Dçmling, Chem. Eur. J. 2013, 19, 8048–
8052; e) P. Janvier, H. Bienaymꢁ, J. Zhu, Angew. Chem.
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[6] For representative examples, see: a) N. A. Petasis, in:
Multicomponent Reactions, (Eds.: J. Zhu, H. Bien-
yamꢁ), Wiley-VCH, Weinheim, 2005, Chapter 7,
pp 199–222; b) S. J. Patel, J. F. Jamison, Angew. Chem.
2003, 115, 1402–1405; Angew. Chem. Int. Ed. 2003, 42,
1364–1367; c) N. Christinat, R. Scopelliti, K. Severin,
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Morin, Y. Lu, D. A. Black, B. A. Arndtsen, J. Org.
Chem. 2012, 77, 2013–2017; f) Y. Luan, S. E. Schaus,
Org. Lett. 2011, 13, 2510–2513.
+
C23H33NO2 : 356.2584.
Acknowledgements
This work was supported by DGICYT, Spain (project BQU-
CTQ2012-30930), and Generalitat de Catalunya (project
2009 SGR 1024). Dr. Albert Palomer (Grupo Ferrer, Barcelo-
na) is thanked for generous support.
[7] a) H. Witte, W. Gulden, G. Hesse, Justus Liebigs Ann.
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asc.wiley-vch.de
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 3273 – 3284