Grignard-mediated rearrangement of trifluoroacetyl from dihydroisoquinoline enamides to afford tertiary trifluoromethylcarbinols

Article abstract of DOI:10.1039/c7ob03079g

Treatment of the trifluoroacetyl enamides of dihydroisoquinolines 2 with diverse Grignard reagents afforded tertiary trifluoromethyl-carbinols 4 by facilitating the addition of tertiary carbinols to the β-carbon of enamides 2. Based on the confirmed formation of vinylogous amides 3, the transformation likely proceeds via unique acyl group rearrangement to the β-carbon of the enamide and subsequent nucleophilic addition of the Grignard reagent. Given the synthetic utility and novelty of this reaction, this work may open new avenues for the synthesis of pharmaceutically important tertiary trifluoromethylcarbinols on cyclic enamide systems.

Full text of DOI:10.1039/c7ob03079g

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Takeharu Haino et al.
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DOI: 10.1039/C7OB03079G
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Grignard-Mediated Rearrangement of Trifluoroacetyl from
Dihydroisoquinoline Enamides to Afford Tertiary
Trifluoromethylcarbinols
Raghavendra Achary,a,b Gangadhar Rao Mathi,a,b Seulgi Kim,a,c Jong Yeon Hwang,a,b Pilho Kim,*,a,b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Treatment of trifluoroacetyl enamides of dihydroisoquinolines 2
with diverse Grignard reagents afforded tertiary trifluoromethyl-
carbinols 4 by facilitating the addition of tertiary carbinols to the β-
carbon of enamides 2. Based on the confirmed formation of
vinylogous amides 3, the transformation likely proceeds via unique
acyl group rearrangement to the β-carbon of the enamide and
subsequent nucleophilic addition of the Grignard reagent. Given
the synthetic utility and novelty of this reaction, this work may
open new avenues for the synthesis of pharmaceutically important
tertiary trifluoromethylcarbinols on cyclic enamide systems.
While tetrahydroisoquinoline (THIQ) fragments are prevalent in
natural and pharmaceutical products,1 the enamides of
dihydroisoquinolines (DHIQs) are important structural motifs
useful in the synthesis of various building blocks through diverse
transformations, such as asymmetric hydrogenation,2 metal-
catalyzed α- or β-functionalization,3 and cycloaddition.4 In
general, the α-position of enamides is electrophilic, while the β-
position is nucleophilic.3,5 Several examples of nucleophilic
addition at the α-carbon of enamides have been reported. For
instance, various indoles were stereoselectively introduced at
the α-carbon of enamides via Friedel–Crafts reactions using
chiral Brønsted catalysts (Scheme 1).6 An alkoxide was also
regioselectively and asymmetrically introduced at the α-carbon
of acyclic enamides using copper(I) catalysts and iminoiodane.7
As for additions at the β-carbon of DHIQ enamides, abundant
reports have also been published,8-11 such as palladium-
catalyzed direct β-arylation,12 oxidative rearrangement of the
trifluoroacetyl group to the β-carbon of the exocyclic double
bond,13 Cu(I)-mediated radical cycloaddition using n-
Bu3SnH/AIBN,14 and Heck reactions providing polyannular
Scheme 1 (a) Previous examples of enamide reactions, (b) unique
generation of tertiary trifluoromethylcarbinol 4a in this study.
heterocyclic compounds.15
During the course of developing novel methods to prepare
C1-substituted THIQs, we opted to utilize the enamide of DHIQ
as a key precursor. When trifluoroacetyl enamide 2a was
treated with methylmagnesium bromide, trifluoromethyl-
carbinol 4a was unexpectedly obtained in excellent yield
(Scheme 1). To our knowledge, chemistry enabling the addition
of tertiary trifluoromethylcarbinols to the β-carbon of DHIQ
enamides has not been previously reported.
Moreover, pharmaceutically important trifluoromethyl-
carbinols could be straightforwardly prepared by this synthetic
methodology.16 Trifluoromethylation has been quite
instrumental in the field of pharmaceutics, agrochemicals, and
a.Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology,
Daejeon 34114, Korea. E-mail: pkim@krict.re.kr
b.Department of Medicinal Chemistry and Pharmacology, University of Science &
Technology, Daejeon 34113, Korea.
c. Department of Chemistry, Chungnam National University, Daejeon 34134, Korea
Electronic Supplementary Information (ESI) available: [Experimental and spectral
data; NMR spectra of all products; crystallographic data of the products 4g and 3d.
CCDC 1532366 and 1532365]. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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material sciences. While numerous methods for trifluoro-
methylation are known,17,18 such as those employing Umemoto
reagents,19 Togni reagents,20 and trifluoromethyltrimethyl-
silane,21 this kind of unique reaction for the construction of
multi-substituted trifluoropropyl alcohols at the C1 position of
THIQ is unprecedented. Considering the novelty and application
potential of this reaction, the scope and limitations of this
chemistry were extensively explored with the aim of preparing
tertiary trifluromethylcarbinol analogs of DHIQs and cyclic imine
systems in a convenient way.
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DOI: 10.1039/C7OB03079G
At first, trifluoroacetyl enamides 2a–f were prepared from
DHIQs 1a-f (see Supplementary Information) under modified
enamide generation conditions.22 With enamides 2a–f in hand,
the scope of the reaction was evaluated. It turned out that DHIQ
enamides 2a–f are applicable for this reaction regardless of the
substituents, affording the corresponding trifluoromethyl-
Figure 1 X-ray crystal structure of trifluoromethylcarbinol 4g
.
The structure of 4g was unequivocally confirmed by X-ray
crystallography (Figure 1; CCDC-1532366). However, acyclic
enamide 2h afforded 4-methoxy-acetophenone instead of the
trifluoromethylcarbinol (entry 8), suggesting that this chemistry
is only compatible with cyclic enamides. We also demonstrated
that the reaction could be performed in a one-pot manner to
afford trifluoromethylcarbinol 4a directly from DHIQ 1a in 64%
yield, while the two-step processes gave 81% overall yield.
Likewise, the scope of the reaction was explored using
various Grignard reagents with DHIQ enamide 2a (Table 2).
Methyl- and ethylmagnesium bromides gave instantaneously
trifluoromethylcarbinols 4a and 4h, respectively, in high yields
(entries 1 and 2). In the case of phenyl-, 4-chlorophenyl, and 4-
methoxyphenyl magnesium bromides, the reactions took
longer (2 h) and the yields were in the range of 61–66% (entries
3-5) without any side-products. Benzylmagnesium chloride
carbinols 4a–f in good yields (entries 1–6 in Table 1). In the case
of pyrido[3,4-b]indole enamide 2g, a non-DHIQ enamide,
trifluoromethylcarbinol 4g was obtained in 80% yield using
three equivalents of methylmagnesium bromide (entry 7).
Table 1 Scope of the reaction with various enamidesa
afforded
a slightly better yield than phenylmagnesium
bromides (entry 6). When isopropyl, cyclopentyl, and
cyclohexylmagnesium bromides were reacted with 2a, only
vinylogous amide 3a was obtained without generation of
corresponding trifluoromethylcarbinols (entries 7-9). The
structure of 3a was elucidated by X-ray crystallography
(Supporting Information; CCDC-1819355). These data suggest
Table 2 Compatibility of Grignard reagentsa
a Reaction conditions: 2a
-h (0.18 mmol, 1.0 eq), MeMgBr (0.27-
0.54 mmol, 1.5-3.0 eq), THF (0.5 mL), rt. bisolated yield.
a Reaction conditions: 2a (0.18 mmol), RMgX (0.27-0.54 mmol), THF
(0.5 mL), rt, 10 min to 2 h. bisolated yield.
2 | J. Name., 2012, 00, 1-3
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Scheme 2 Formation of vinylogous amide 3d during enamide
Table 3 The scope of acyl groups
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synthesis.
DOI: 10.1039/C7OB03079G
Scheme 3 Crossover experiment.
vinylogous amide 3c was finally obtained as the sole product
without the generation of 4n (entry 7). However, neither 3b nor
3c was reactive with Grignard reagents to afford the
corresponding tertiary carbinols. In addition to the above acyl
groups, when monochloro-, dichloro-, trichloroacetyls, and
trifluoromethylsulfonyl enamides were applied in this reaction,
neither
4 nor 3 was observed, suggesting that the
rearrangement is heavily dependent on the acyl groups.
a isolated yield. bMeMgBr (3 eq).
Another crucial observation for the elucidation of the
underlying mechanism was that treatment of 6-methoxy-DHIQ
1d with trifluoroacetic anhydride (TFAA) and triethylamine gave
rise to vinylogous amide 3d in 90% yield as a sole product (entry
1 in Scheme 2). The structure of 3d was unambiguously
confirmed by X-ray crystallography (Supporting Information;
CCDC-1532365). With TFAA and no triethylamine, enamide 2d
was initially observed as a major product, which was gradually
converted to 3d in 20 min (entry 2). In the presence of 1.0 equiv.
of TFAA, the reaction underwent smoothly to afford only 2d in
78% yield (entry 3). These results clearly suggest that vinylogous
that, although the reaction appears to be compatible with alkyl
and aryl Grignard reagents to afford trifluoromethylcarbinols,
bulky Grignard reagents give rise to vinylogous amide 3a
,
implying a hint of the reaction mechanism.
In order to understand the mechanism of this
transformation, the typical reaction conditions (entry 1 in Table
3) were modified and the reactions were performed at lower
temperatures. When 2a was treated with methylmagnesium
bromide at -78 °C, no product was generated and the starting
material was recovered intact (entry 2). In a reaction left to
warm up from -5 °C to rt, 4a was generated in low yield (entry
3) without observing any other compounds as plausible reaction
intermediates.
amide 3d is generated from enamide 2d through
a
rearrangement of the acyl group, presumably due to resonance
effects of the 6-methoxy group in the enamide. Indeed, when a
solution of 2d in THF was treated with triethylamine at room
temperature, the enamide was completely converted into 3d
within 30 min.22
On the other hand, 7-methoxy enamide 2a was intact under
basic conditions, such as triethylamine and potassium
carbonate. Moreover, treatment of 2a with Lewis acids, such as
MgBr2, AlCl3, LiCl, did not give rise to 3a, implying that metal
chelation itself was not enough for the acyl group
rearrangement. It is also worth mentioning that enamide 2a
was converted to 4a in 57% yield by treatment of methyllithium,
indicating that this chemistry might be applicable to other
nucleophiles in addition to Grignard reagents.
Additionally, acetyl enamide 2i and benzoyl enamide 2j
were prepared to investigate the electronic effect of acyl groups
in this reaction. When 2i was treated with methylmagnesium
bromide at 0 °C to rt, vinylogous amide 3b was obtained as well
as methylcarbinol 4m (entry 4). These results imply that 3b
might be structurally related to an intermediate that also
affords 4m 23-25
At room temperature, the yield of 4m was
.
slightly higher than that of 3b (entry 5).26 It is worth mentioning
that the reaction of 2i is much slower than that of 2a. In the case
of 2j, 1.5 equivalents of methylmagnesium bromide were not
effective for the transformation of the starting material 2j
(entry 6). When three equivalents of the Grignard reagent were
used,
To perform a crossover experiment, equimolar amounts of
2b and 2i were treated with methylmagnesium bromide, and
the reaction was monitored by LC/MS (Scheme 3). While none
of crossover products, 3e, 4a, and 4o, were detected in LC/MS,
4b (72%), 4m (10%), 3d (3%), and 2i (62%) were isolated,
complying with the reaction trends of 2b and 2i, respectively.
This results support that the acyl group migration of enamide
would go through an intramolecular fashion.
In the case of acetyl enamide 2i, the undisputable detection
of both 3b and 4m suggests a mechanism with a common
intermediate for both products. Thus, we propose the following
reaction mechanism (Scheme 4): i) facilitated by chelation of
methylmagnesium bromide on the enamide,27 rearrangement
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Notes and references
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DOI: 10.1039/C7OB03079G
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Scheme 4 Proposed mechanism.
of the acyl group to the β-carbon of the enamide to deliver β-
iminoketone
four-membered ring transition state;24,28,29 ii) migration of the
imine double bond in intermediate to afford vinylogous amide
3b 23,25,30
and/or iii) nucleophilic addition of the Grignard
reagent to the carbonyl carbon of intermediate to afford 4m
Since the intermediate from trifluoroacetyl enamide 2a
would be more favorable for nucleophilic addition by the
Grignard reagent due to the relatively high electrophilicity of
i, an intermediate for both 3b and 4m, through a
7
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the trifluoroacetyl group, i affords only trifluoromethylcarbinol
4a with no vinylogous amide 3a. However, bulky Grignard
reagents would prefer to be utilized as a base to deliver 3a
(entries 7-9 in Talbe 2).31 In the case of the intermediate
i
from
both decreased electrophilicity and cross-
conjugation may be driving forces to deliver only vinylogous
amide 3c (Table 3). It appears that intermediate goes through
either nucleophilic addition of the Grignard reagent to give
tertiary carbinols or tautomerization to furnish vinylogous
amides depending on the acyl group of the enamide and
14 C.-S. Lee, T.-C. Yu, J.-W. Luo, Y.-Y. Cheng, C.-P. Chuang,
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In conclusion, we have shown that treatment of Grignard
reagents on trifluoroacetyl enamides of 1-methyldihydro-
isoquinolines 2 affords tertiary trifluoromethylcarbinols 4, resulting
in the extraordinary addition of tertiary trifluoromethylcarbinols at
the β-carbon of the enamides. The scope of this reaction was
confirmed for a variety of Grignard reagents as well as trifluoroacetyl
enamides of DHIQs and pyrido[3,4-b]indole. Given the irrefutable
identification of β-amino vinylogous amides 3 and tertiary carbinols
4
, we have proposed a reaction mechanism featuring an
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unusual acyl group rearrangement to the β-carbon of the
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reagent. This unique reaction has great potential for the
preparation of pharmaceutically important tertiary trifluoro-
methylcarbinols on cyclic enamide systems.
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Conflicts of interest
There are no conflicts to declare.
Acknowledgements
This work was supported by Korea Research Institute of
Chemical Technology (SI1607-01 and KK1703-B00) and by the
National
Research
Foundation
of
Korea
(NRF-
2012M3A9A9054902).
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DOI: 10.1039/C7OB03079G
Table of Contents
Grignard-Mediated Rearrangement of Trifluoroacetyl from
Dihydroisoquinoline Enamides to Afford Tertiary
Trifluoromethylcarbinols
Raghavendra Achary,a,b Gangadhar Rao Mathi,a,b Seulgi Kim,a,c Jong Yeon Hwang, a,b Pilho
Kim,*,a,b
aBio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Korea
bDepartment of Medicinal Chemistry and Pharmacology, University of Science & Technology, Daejeon 34113,
Korea
cDepartment of Chemistry, Chungnam National University, Daejeon 34134, Korea
A novel approach for the addition of tertiary trifluoromethylcarbinols at the β-position of cyclic enamide
has been developed.
S1