Substituted Dihydroisoquinolinones by Iodide-Promoted Cyclocarbonylation of Aromatic α-Amino Acids

Article abstract of DOI:10.1021/acs.orglett.8b03551

Imidazolidinone derivatives of a range of aromatic α-amino acids, on treatment with phosgene and potassium iodide, undergo a mild Bischler-Napieralski-style cyclocarbonylation reaction that generates a tricyclic lactam by insertion of a C=O group between amino acid nitrogen and the ortho position of the aryl substituent. Regio- and diastereoselective functionalization of the lactam generates a library of substituted dihydroisoquinolinones and their congeners in enantioenriched form.

Full text of DOI:10.1021/acs.orglett.8b03551

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Substituted Dihydroisoquinolinones by Iodide-Promoted
Cyclocarbonylation of Aromatic α‑Amino Acids
Mostafa M. Amer,† Ana C. Carrasco,‡ Daniel J. Leonard,† John W. Ward,† and Jonathan Clayden*,†
†School of Chemistry, University of Bristol, Cantock’s Close, Bristol BS8 1TS, U.K.
‡School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, U.K.
S
* Supporting Information
ABSTRACT: Imidazolidinone derivatives of a range of aromatic α-amino
acids, on treatment with phosgene and potassium iodide, undergo a mild
Bischler−Napieralski-style cyclocarbonylation reaction that generates a
tricyclic lactam by insertion of a CO group between amino acid nitrogen
and the ortho position of the aryl substituent. Regio- and diastereoselective
functionalization of the lactam generates a library of substituted
dihydroisoquinolinones and their congeners in enantioenriched form.
Scheme 1. Cyclocarbonylation of Aromatic Amino Acids
he dihydroisoquinoline ring system is found in some key
1
Tbiologically active compounds, not least among them the
Amaryllidaceae alkaloids such as narciclasine and pancratista-
tin.2,3 Dihydroisoquinolines have also been identified as key
scaffolds for fragment-based drug discovery.4 Among synthetic
approaches to this ring system, reactions in which an aromatic
amine precursor is cyclized with addition of one or two carbon
atoms are the most common approaches.5 For example,
aromatic amides or hydroxamic acids give dihydroisoquino-
lones by metal catalyzed C−H activation with alkenes or
alkynes6 or palladium catalyzed cyclocarbonylation of
amines.7,8 Alternatively, Bischler−Napieralski-style cyclization
can give dihydroisoquinolinones by activation of N-carbamoyl
derivatives of secondary homobenzylic amines using highly
electrophilic reagents such as triflic anhydride9,10 or Lewis acid
promoted cyclization of carbamoyl chlorides.11,12
We first noted the Bischler−Napieralski-like cyclization13,14
of B to C as a side reaction that occurs when using the
unusually unreactive carbamoyl chloride B as an electrophile.
Given the limitations of classical Bischler−Napieralski
conditions when applied to amino acids,13,14 this reaction
appeared to offer a very appealing way to make cyclic amino
acid derivatives under mild conditions. Preliminary studies
indicated that a cyclization product was formed only from the
trans diastereoisomer of B, so we first set out to optimize a
practical method for the trans-selective synthesis of N-
chloroformylimidazolidinones B.
N-Chloroformylimidazolinones may be formed non-diaster-
eoselectively by treatment of pivaldimine derivatives of amino
acids with triphosgene in the presence of base.15 In order to
develop a method for the diastereoselective synthesis of trans
imidazolidinones, the cyclization of Phe-derived pivaldimine 1a
was investigated (Scheme 2). Simply stirring the imine 1a with
phosgene at room temperature gave good selectivity for the
trans diastereoisomer, but generally with low yields, probably
as a result of precipitation of an intermediate hydrochloride
salt. Improved yields were obtained in THF, and addition of
pyridine 30 min after the start of the reaction returned the
In this paper we report a practical and operationally simple
carbonylative cyclization that converts aromatic amino acids
into substituted dihydroisoquinolinones and their analogues in
an efficient, versatile, and stereoselective manner, without the
need for powerful activating agents or Lewis acids. The
reaction involves the activation of an easily formed, stable
carbamoyl chloride derivative using iodide, and gives rise to
architecturally varied motifs that can readily be derivatized
stereoselectively to yield families of enantiomerically enriched
cyclic amino acid derivatives.
The cyclofunctionalization at the core of the method is
outlined in Scheme 1. The method entails the formation of the
N-chloroformyl derivative B of a trans imidazolidinone,
followed by its cyclization by intramolecular Friedel−Crafts
acylation to yield the lactam C. This lactam may be readily
elaborated by further alkylation and ring-cleavage reactions to
provide a diverse range of products very efficiently from simple
amino acid precursors A.
Received: November 6, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03551
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Letter
at 170 °C for 2 h provided the cyclized product 3a in 90%
yield (entry 1). The more electron-rich DOPA derivative 2b
gave a yield of 97% of 3b under these conditions (entry 2), but
also turned out to be highly reactive in acetonitrile, cyclizing
quantitatively within 10 s of reaching 150 °C (entry 3). Under
these conditions, a small amount of the 2,3-disubstituted
regioisomer 3b′ was also formed by attack on the ring ortho,
rather than para, to the 3-MeO substituent.
When the 3-fluorophenylalanine derivative 2c was heated
with the same reagents in toluene, the reaction did not go to
completion even after 2 h (entry 4). This reaction produced
34% of the regioisomer 3c formed by cyclization para to the 3-
F substituent, alongside 14% of the ortho regioisomer 3c′ and
49% recovered starting material. Changing the solvent to
acetonitrile accelerated the reaction, but still gave poor
regioselectivity (entry 5). Improved selectivity was ensured
by lowering the temperature: at 120 °C the two regioisomers
were formed in 89% and in 5% yield after 30 min (entry 6).
Shortening the reaction time also appeared to improve
regioselectivity, suggesting equilibration between the re-
gioisomers: at 150 °C, only 2% of the minor regioisomer
was formed, and the major product was isolated in 90% yield
(entry 7).
Cyclization of the 4-nitrophenylalanine derivative 2d was
unsuccessful in toluene (starting material recovered) or
acetonitrile (6% product and many byproducts) even after
prolonged reaction time and elevated temperature (entries 8,
9). Changing the solvent to DMF did however allow a 30%
yield of the product 3i to be isolated from other byproducts
(entry 10). As is usual for Friedel−Crafts substitutions, the
reaction is evidently heavily dependent on the electronic effects
of the substituents on the aryl ring and is accelerated by a polar
solvent. Nonetheless, it is remarkable that the acylation is
successful with a fluoro- or nitro-substituted ring using a
carbamoyl chloride electrophile in the absence of a Lewis acid.
The optimal conditions identified for the cyclization of 2
were applied to a range of aromatic, heteroaromatic, and
unsaturated amino acid derivatives shown in Scheme 3.
Cyclizations up to at least 10 g scale were successful not
only with the phenylalanine derivatives 2a−2d but also with
the tyrosine derivative 2e, and with 1- and 2-naphthylalanine
derivatives 2f and 2g, each of which cyclized in >90% yield.
The retained relative stereochemistry of product 3a (CCDC
1871270), and therefore presumably other products as well,
was confirmed by X-ray crystal structure (Scheme 3b). Other
ring sizes (5-membered in 3h; 7-membered in 3i) formed after
more extended reaction times, albeit in lower yield. An
aliphatic Friedel−Crafts cyclization of the allylglycine deriva-
tive 2j gave dihydropyridone 3j, and the nucleophilic furan and
thiophene heterocycles of 2k−m gave 3k−m by attack at
either the 2- or 3-position. The indole-containing product 3n
was also formed, but without isolation of the N-chloroformyl-
imidazolidinone 2n: the reactivity of the indole precursor 1n is
such that attempted formation of 2n by the method of Scheme
3 led directly to the cyclized product 3n, even without heating
or KI.
Scheme 2. Diastereoselective Formation of trans N-
Chloroformyl Imidazolidinones
a
b
Diastereoisomeric ratio by NMR of crude reaction mixture. Yield of
c
mixture determined by NMR using internal standard. Isolated yield
of major diastereoisomer. Added 30 min after start of reaction.
d
chromatographically stable trans N-chloroformyl-
imidazolidinone 2a in excellent yield (Scheme 2). Triphosgene
also gave good trans diastereoselectivity but lower yields than
phosgene.
Using these optimal reaction conditions, a broad series of N-
chloroformylimidazolidinones 2a−m (see Supporting Informa-
tion) were made from their corresponding amino acid
pivaldimine precursors 1 with excellent trans diastereoselec-
tivity. The trans carbamoyl chlorides were remarkably stable,
and each of 2a−2m could be purified by chromatography on
silica without difficulty. They were also rather unreactive as
electrophiles, and their reaction with neutral nucleophiles
necessitated the use of KI16 to increase their electrophilicity.
During the KI-promoted reaction of 2a with an aniline,15 we
identified a cyclic byproduct, which became the sole product
when 2a was heated with potassium iodide alone. This
product, the benzo-fused lactam 3a (Table 1), is evidently
Table 1. Optimization of the Cyclocarbonylation
entry
SM
time
2 h
2 h
10 s
2 h
solvent
T/°C
product, yield/%
1
2
3
4
5
6
7
8
2a
2b
2b
2c
2c
2c
2c
2d
2d
2d
tol
tol
170
170
150
170
170
120
150
200
170
120
3a, 90
3b, 97
3b, 100 (91:9)
3c, 48 (71:29)
3c, 96 (76:24)
3c, 94 (95:5)
a
CH3CN
tol
CH3CN
CH3CN
CH3CN
tol
bc
,
c
1 h
c
30 min
5 min
4 h
30 min
30 min
c
3c, 92 (98:2)
d
no reaction
d
9
10
CH3CN
DMF
3d, 6
d
3d, 30
a
Isolated with minor 2,3-dimethoxy substituted regioisomer 3b′.
b
c
Ratio determined by 1H NMR. SM recovered in 49% yield. Isolated
with a minor 2-fluoro substituted regioisomer 3c′. Ratio determined
d
1
by H NMR. Using 2.0 equiv of lutidine.
formed by an intramolecular Friedel−Crafts acylation that
amounts to a Bischler−Napieralski cyclization of 2 to 3. The
reaction was optimized with 2a and its electronically varied
derivatives 2b−d, as shown in Table 1.
Treatment of trans phenylalanine-derived carbamoyl chlor-
ide 2a under activating conditions of KI (1.1 equiv) and 2,6-
lutidine (2.0 equiv) in dry toluene under microwave irradiation
We presume that KI promotes formation of a transient
carbamoyl iodide17 and thence maybe a carbamoyl cation,18
with lutidine neutralizing the acid formed during the acylation
(Scheme 3b). The reaction of 2b to give 3b was followed by in
situ infrared spectroscopy (Scheme 3d). Over a period of 4 h
at 70 °C, direct conversion of 2b to 3b was noted, with no
B
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a
Scheme 3. (a) Cyclization of a Range of N-
Scheme 4. Regioselective Alkylations of 3
Chloroformylimidazolidinones; (b) X-ray Crystal Structure
of 3a; (c) Proposed Mechanism for the Cyclization; (d) In
Situ Infrared Trace for the Cyclization of 2b
a
Method A: (1) Degas in THF; (2) E+ (10 equiv) then LDA (2
equiv), −78 °C−rt; Method B: (1) KHMDS (1.5 equiv), THF, 0 °C,
15 min; (2) E+ (5 equiv), 0 °C−rt, 2 h; Method C: (1) LDA (2
equiv), −78 °C, THF; (2) E+ (5 equiv), −78 °C−rt, 2 h; Method D:
(1) KHMDS (1.5 equiv), THF, −78 °C, 15 min; (2) E+ (1 equiv),
−78 °C−rt, 2 h; (3) LDA (3 equiv), −78 °C, THF; (4) E+ (10
a
b
c
d
<1 g scale at 0.15 M 10 g scale at 1 M. For 10 s. 2−5 g scale at
e
f
0.5−1 M. With 2.0 equiv lutidine, for 3 h. H2, Pd/C, EtOH, 18 h.
g
h
On 1 g scale at 0.15 M. Formed directly from 1n.
detectable intermediate. Any carbamoyl iodide intermediate
must react faster than it forms.19
Imidazolidinones are valuable intermediates in the synthesis
of quaternary amino acids by alkylation of their enolate
derivatives.20 The enantiopure products of the cyclization
contain an imidazolidine motif amenable to diastereoselective
alkylation, directed by the tert-butyl substituent. 3a was thus
b
c
equiv), −78 °C−rt, 2 h. Using 4 equiv LDA. Using LiHMDS.
d
e
f
Using method C. Using Method D. Using 2 equiv KHMDS.
Relative configurations of 5a and 6a were assigned by NOE.
alkylated by treatment with base followed by an electrophile
(Scheme 4).
C
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Alkylation of the indigo-violet solution generated by
deprotonation with LDA occurred at the benzylic position β
to the imidazolidinone carbonyl group, to give 4a (from MeI)
and 4b (from EtI) with full diastereoselectivity.21 X-ray
crystallography (Scheme 4) and NOE experiments confirmed
the relative stereochemistry of the products 4a and 4b (CCDC
1871271 and 1871272), which are consistent with both
retentive quench of the coordinated anion 3-Li and with
alkylation anti to the tert-butyl group. Quenching with benzyl
bromide similarly gave the β-alkylated product 4c, but as a
70:30 mixture of diastereoisomers.22 Formation of an extended
‘arylogous’ enolate 3-Li at the β position is possible, but it
seems unlikely that the β proton is thermodynamically more
acidic than the α; plausibly, benzylic β-lithiation is directed by
coordination to the amide carbonyl group23 and is favored over
removal of the encumbered proton at the ring junction cis to
the tert-butyl group.24
yields of 6a−c were higher than the stepwise alkylation
procedure.
The products 4−6 contain an imidazolidinone motif which
is prone to acid-catalyzed hydrolysis. As shown in Scheme 5
valuable carboxyisoquinolone products 7 and 8 are formed by
microwave irradiation in a mixture of hydrochloric and
trifluoroacetic acid.25
In summary, mild carbonylative cyclization of aromatic
amino acids may be achieved by intramolecular Friedel−Crafts
acylation of trans N-chloroformylimidazolidinones, promoted
simply by potassium iodide. The product lactams may be
further functionalized by regio- and diastereoselective
alkylation, and the imidazolidinones may be hydrolyzed to
reveal enantiopure heterocyclic carboxylic acids of potential
value in drug discovery programmes.4
ASSOCIATED CONTENT
* Supporting Information
■
S
Enolate formation was evident in the synthesis of the
valuable spirocycle 4d (CCDC 1871273), which was formed in
86% yield by treating 3a first with 1,3-dibromopropane and
then with two portions each of 2 equiv of LDA at −78 °C
(Scheme 4). We expected a weaker base, or one with a less
coordinating counterion, to be more selective for enolization of
the amide. 3a was therefore treated instead with KHMDS at 0
°C for 30 min, and the anion, this time red, was quenched with
D2O (Scheme 4). 3a-D was returned with 67% incorporation
of D at the α-position (by NMR analysis of the crude mixture).
By treating the substrate with KHMDS (1.5 equiv) at 0 °C for
3 h in THF (0.1 M) followed by methyl iodide (5 equiv), the
α-methylated product 5a was formed as a single diaster-
eoisomer in 96% yield (Scheme 4). A similar result (91%) was
obtained with LiHMDS. Excellent yields of single diaster-
eoisomers of 5b and 5c were likewise obtained with allyl
bromide and benzyl bromide. Alkylation of 3e, b, l, n likewise
gave excellent yields of diastereoisomerically pure products
5d−5j. The stereochemistry of 5e was confirmed by X-ray
crystallography (CCDC 1871269; Scheme 4).
A second alkylation of the products 5 was possible by
treatment with LDA at −78 °C for 30 min, followed by a
second electrophile. The products 6a−c were formed as single
diastereoisomers for which NOE studies (of 6a) and X-ray
crystallography (of 6c; CCDC 1872068) confirmed that the
new alkyl group lies anti to both the first-introduced alkyl
group and the tert-butyl group. Double alkylation can be
achieved in a one-pot reaction by first forming an enolate with
KHMDS and second with LDA. By this method (method D)
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03551.
Full experimental details and NMR spectra of all new
compounds (PDF)
Accession Codes
CCDC 1871269−1871273 and 1872068 contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/
cif, or by emailing data_request@ccdc.cam.ac.uk, or by
contacting The Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: j.clayden@bristol.ac.uk.
ORCID
John W. Ward: 0000-0001-7186-6416
Jonathan Clayden: 0000-0001-5080-9535
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Presidential Leadership
Programme of Egypt, the European Research Council (AdG
ROCOCO), the EPSRC, and the EU Erasmus Programme.
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