Isothiourea-Catalyzed Enantioselective Addition of 4-Nitrophenyl Esters to Iminium Ions

Article abstract of DOI:10.1021/acscatal.7b02697

Isothioureas catalyze the enantioselective addition of 4-nitrophenyl esters to tetrahydroisoquinoline-derived iminium ions. 4-Nitrophenoxide, generated in situ from initial N-acylation of the isothiourea by the 4-nitrophenyl ester, is used to facilitate catalyst turnover in this reaction process. Optimization showed that 4-nitrophenyl esters give the best reactivity in this protocol over a range of alternative aryl esters, with the observed enantioselectivity markedly dependent on the nature of the iminium counterion. Highest yields and enantioselectivity were obtained using iminium bromide ions generated in situ via photoredox catalysis using BrCCl₃ and Ru(bpy)₃Cl₂ (0.5 mol %) and commercially available tetramisole (5 mol %) as the Lewis base catalyst. The scope and limitations of this procedure was developed, giving the desired β-amino amide products in up to 96% yield, 79:21 diastereomeric ratio (dr), and er_{major (2R,1′S)} 99.5:0.5.

Full text of DOI:10.1021/acscatal.7b02697

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Article
Isothiourea-Catalyzed Enantioselective Addition
of 4-Nitrophenyl Esters to Iminium Ions
Jude N. Arokianathar, Aileen Frost, Alexandra M. Z. Slawin, Darren Stead, and Andrew D. Smith
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b02697 • Publication Date (Web): 12 Dec 2017
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ACS Catalysis
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Isothiourea-Catalyzed Enantioselective Addition of 4-Nitrophenyl
Esters to Iminium Ions
Jude N. Arokianathar,a Aileen B. Frost,a Alexandra M. Z. Slawin,a Darren Steadb and Andrew D.
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Smith*a
aEaStCHEM, School of Chemistry, University of St Andrews, North Haugh, St Andrews, KY16 9ST.
bAstraZeneca, IMED Oncology, Darwin Building, Unit 310, Cambridge Science Park, Milton Rd, Cambridge, CB4 0WG.
ABSTRACT: Isothioureas catalyze the enantioselective addition of 4ꢀnitrophenyl esters to tetrahydroisoquinolineꢀderived iminium
ions. 4ꢀNitrophenoxide, generated in situ from initial Nꢀacylation of
the isothiourea by the 4ꢀnitrophenyl ester, is used to facilitate catalyst
turnover in this reaction process. Optimization showed that 4ꢀ
nitrophenyl esters give the best reactivity in this protocol over a range
of alternative aryl esters, with the observed enantioselectivity markꢀ
edly dependent upon the nature of the iminium counterion. Highest
yields and enantioselectivity were obtained using iminium bromide
ions generated in situ via photoredox catalysis using BrCCl3 and Ru(bpy)3Cl2 (0.5 mol%) and commercially available tetramisole (5
mol%) as the Lewis base catalyst. The scope and limitations of this procedure was developed, giving the desired βꢀamino amide
products in up to 96% yield, 79:21 dr and ermajor (2R,1′S) 99.5:0.5.
KEYWORDS: isothiourea; iminium ion; counterion dependent enantioselectivity
(1) Traditional strategy for ammonium enolate formal cycloadditions:
INTRODUCTION
R1
O
O
Ammonium enolate intermediates1 generated by the action of
tertiary amines2 in Lewis base catalysis3 have found wideꢀ
spread application in chiral heterocycle synthesis via formal
cycloaddition reactions, with many diverse scaffolds accessiꢀ
ble in high yields and excellent enantiocontrol. While tradiꢀ
tional strategies for ammonium enolate generation utilize the
direct reaction of a Lewis base with ketenes,4 more recently
the use of benchꢀstable carboxylic acids,5 anhydrides6 or acyl
imidazoles7 as ammonium enolate precursors have also been
employed. The nucleophilic ammonium enolate generated in
situ reacts with an electrophilic reagent containing a latent
nucleophile to generate a species capable of catalyst turnover
in an intramolecular fashion (Figure 1, eqn 1). This approach
represents a key limitation in this branch of catalysis, with
ammonium enolate chemistry typically applied in formal
[2+2],8 [3+2]9 or [4+2]10 cycloaddition methodologies. The
established exception to this reactivity issue is the pioneering
work from Lectka and coꢀworkers in the area of enantioselecꢀ
tive halogenations (Figure 1, eqn 2).11 In a series of elegant
manuscripts polyhalogenated quinones were used to affect
enantioselective halogenation of an ammonium enolate.12 Enoꢀ
late addition to an electrophilic polyhalogenated quinone reꢀ
sults in formation of an ammonium aryloxide ion pair, with
the aryloxide generated in situ used for catalyst turnover.13
Further seminal work in exploiting aryloxide “rebound” catalꢀ
ysis was reported by Scheidt,14 who applied this concept to an
NHCꢀcatalyzed formal Mannich process, utilizing αꢀ
aryloxyaldehydes as azolium enolate precursors (Figure 1, eqn
3).
O
formal
[2+2]
R1
N*R3
R3
R1
OR2
N*R3
ammonium enolate
X
X
acid / anhydride
R3
R1
O
O
R1
formal
[3+2]
X
E
X
ketene
Electrophile
N*R3
X
X
E
n
E
O
O
O
R1
R1
R3
R1
R3
formal
[4+2]
N*R3
X
X
n
intramolecular
catalyst
E
X
E
turnover
X = O or N
n
X = O or N
Intramolecular nucleophile required for catalyst turnover
(2) Lectka's aryloxide strategy for ammonium enolate halogenations:
O
Br
Br
O
O
R1
R1
R1
N*R3
Br
O
N*R3
Br Br
Br
Br
Br
ammonium
enolate
Br
6 examples,
up to 76% yield,
up to 99:1 er
Br
Br
O
O
Br
Aryloxide generated in situ used for catalyst turnover
(3) Scheidt's NHC-catalyzed aryloxide "rebound" catalysis:
Ar1
OH
NTs
O
NHTs O
N
NHC
R1
H
N
ArO
H
R1
OAr
aryloxide
"rebound"
N
10 examples,
up to 75% yield,
up to 98:2 er
R
OAr
Ar = 4ꢀNO2C6H4
Figure 1. Strategies for catalyst turnover in ammonium
enolate catalysis
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More recently, activated aryl esters have emerged as alternaꢀ
Page 2 of 8
intramolecular nucleophile as required for a formal cycloaddiꢀ
tion strategy, but instead uses an “external” nucleophile (arꢀ
yloxide) to provide turnover. The origin of enantiocontrol in
isothioureaꢀcatalyzed ammonium enolate transformations is
proposed to rely upon an no to σ*C−S interaction22 between the
enolate oxygen and catalyst sulfur atom. This formally proꢀ
vides a conformational lock, with subsequent addition preferꢀ
entially antiꢀ to the phenyl stereodirecting group promoted by
the 1,5ꢀsynꢀcoplanar S•••O arrangement. Catalyst turnover
would be achieved via nucleophilic attack of the aryloxide
upon acyl ammonium 6, giving the βꢀamino ester product 7.
Notably, in the absence of the aryloxide, catalyst turnover
could not be achieved using ammonium enolates generated
directly at the carboxylic acid oxidation level. This work deꢀ
scribes the successful realization of this goal. Notably, the
enantioselectivity of this process showed a marked dependꢀ
ence on the nature of the iminium counterion, with the optiꢀ
mized protocol using photoredox catalysis to generate the key
reactive iminium bromide salt in situ.
1
2
3
4
5
6
7
8
tive enolate precursors, offering a potentially general solution
to this challenge.15 An attractive feature of aryl ester substrates
is the potential ability of the aryloxide, liberated upon initial
catalyst acylation, to assist catalyst turnover. Expanding on
Chi’s use of aryl esters in NHCꢀcatalyzed formal cycloaddiꢀ
tions (in which the aryloxide generated upon acylation of the
NHC serves solely as a leaving group and is not required to
promote turnover),16 in 2014 we developed an isothioureaꢀ
catalyzed [2,3]ꢀrearrangement of allylic ammonium ylides. In
this process catalyst turnover relied on in situ formed aryloxꢀ
ide,17 with a HOBt coꢀcatalyst necessary for optimum reactiviꢀ
ty (Figure 2, eqn 1).18 Aryloxides have also been utilized stoiꢀ
chiometrically as catalyst turnover agents by Fu and coꢀ
workers in the chiral DMAPꢀcatalyzed αꢀfluorination of keꢀ
tenes.19 Recent reports by first Snaddon (Figure 2, eqn 2)20 and
subsequently Hartwig (Figure 2, eqn 3)21 have elegantly apꢀ
plied this idea in coꢀoperative isothiourea/metalꢀcatalyzed
enolate allylation reactions using pentafluorophenyl ester preꢀ
cursors. In both cases, an isothioureaꢀderived ammonium enoꢀ
late reacts with a metal πꢀallyl complex to affect the allylation
reaction. Snaddon employed palladium catalysis to give a
range of αꢀallyl esters in up to 95% yield and 99:1 er, whereas
Hartwig used a chiral iridium catalyst that preferentially gives
the branched regioisomeric products in up to 99% yield, >20:1
dr and >99:1 er. Through judicious pairing of the enantiomers
of each chiral catalyst all four possible diastereoisomers of the
product were prepared with excellent enantioselectivity.
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O
O
H
R
R
N
OAr
NAr1
OAr
Ph
2
N
S
1
H
7
S
O
H
H
OAr
R
N
O
S
X
N
(1) Smith: [2,3]-rearrangement of allylic ammonium ylides
Isothiourea
catalysis
R
Ar1
Ph
Isothiourea
N
N
N
O
O
O
R1
catalysis
R1
Br
Br
R1
Ph
3
ArO
R3N
6
ArO
N
N
R
R
NR2
R
R
20 examples,
up to 89% yield,
up to >99:1 er,
up to >95:5 dr
S•••O interaction
OAr
base
Ar = 4ꢀNO2C6H4
O
S
X
NAr1
R
N
baseꢀH
N
(2) Snaddon:
Isothiourea/Pd
catalysis
(3) Hartwig:
Isothiourea/Ir
catalysis
O
O
O
4
Ph
Ar1
Ar1
Ar1
5
*
*
ArO
ArO
ArO
Figure 3. This work: isothiourea-catalyzed enantioselective
addition to iminium ions
R
R
X
R
24 examples,
up to >99% yield,
up to >20:1 dr,
up to >99:1 er
RESULTS AND DISCUSSION
19 examples,
up to 95% yield,
up to 99:1 er
Ar = C6F5
X = OCO2t-Bu or OMs
Initial proof of concept studies. Proof of principle investigaꢀ
tions began on a simplified model system to demonstrate the
feasibility of in situ generated aryloxide to provide turnover in
this process. Iminium ion 11 was isolated via stoichiometric
oxidation of Nꢀphenyl tetrahydroisoquinoline with DDQ23 and
used in optimization studies for the isothioureaꢀcatalyzed proꢀ
cess. Iminium 11 and activated 4-nitrophenyl (PNP) ester 8
were treated with benzotetramisole (BTM) 13 (20 mol%) and
iꢀPr2NEt (1.5 equiv) in THF at −10 °C for 24 h. Preliminary
work indicated that lower isolated yields of the corresponding
PNP ester product were obtained than expected by reaction
conversion,24 consistent with this product being unstable to
purification. Consequently, benzylamine (BnNH2) was added
to form a stable isolable amide product 12 in 39% yield and
Figure 2. Recent work exploiting in situ generated arylox-
ide to provide catalyst turnover
Building upon these precedents, it was envisaged that tetrahyꢀ
droisoquinoline derived iminium ions could act as stoichioꢀ
metric reactive electrophiles using ammonium enolates generꢀ
ated from aryl esters. Importantly, catalyst turnover in this
intermolecular process could only be achieved using a exogeꢀ
nous nucleophile to promote catalyst release (in this case an
aryloxide generated in situ from an aryl ester). In this process,
Nꢀacylation of the isothiourea catalyst 1 with an activated aryl
ester 2 would generate the corresponding acyl ammonium
aryloxide ion pair 3, with subsequent deprotonation leading to
ammonium enolate 4 (Figure 3). Reaction of ammonium enoꢀ
late 4 with iminium electrophile 5 would give intermediate 6.
Catalyst release from intermediate 6 cannot be achieved by an
73:27 dr (Table 1, entry 1: ermajor
72:28; erminor
(2R,1′S)
(2R,1′R)
63:37).25 Other isothiourea catalysts were trialed, with Hyperꢀ
BTM 14 giving similar yield and er, but reduced dr (entry 2:
66:34 dr). Tetramisole·HCl 1·HCl gave amide 12 in an imꢀ
proved 64% yield, whilst maintaining the observed levels of
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ACS Catalysis
nation of 16 (1 equiv) and HOBt 17 (1 equiv) was attempted,
diastereoꢀ and enantiocontrol (entry 3: 75:25 dr, ermajor
(2R,1′S)
1
2
3
4
5
6
7
8
72:28; erminor
59:41). Alternative aryl esters were
but led to a decreased yield of 54% without any improvement
in stereoselectivity (entry 3). Performing the reaction with
only 16 as an additive and in the absence of 1·HCl confirmed
that no competitive background reaction was operative under
these conditions (entry 4). Additional controls confirmed that
the observed diastereomeric ratio is consistent throughout the
course of the reaction, and is thus not the result of epimerizaꢀ
tion by BnNH2.27 A solvent screen showed that MeCN (entry
5) and CH2Cl2 (entry 6) were the only other solvents to give
good conversion to product, albeit with reduced enantioselecꢀ
tivity (Table 2).
(2R,1′R)
screened to assess their reactivity and impact on stereoselecꢀ
tivity. The reaction of iminium 11 with 2,4,6ꢀtrichlorophenyl
ester 9 in the presence of 1·HCl produced no observable prodꢀ
uct (entry 4), while 3,5ꢀbis(trifluoromethyl)phenyl ester 10
gave the amide product 12 in 71:29 dr (ermajor (2R,1′S) 94:6; erminor
(2R,1′R) 85:15) but in a poor 22% yield (entry 5). The use of alꢀ
ternative 2,3,5,6ꢀtetrafluoroꢀ and pentafluorophenyl esters
gave poor (<5%) product yields.26 No product was observed in
the absence of 1·HCl when the PNP ester 8 was used, indicatꢀ
ing no competitive baseꢀmediated background reaction being
operative under these conditions (entry 6).
9
10
11
12
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Table 2. Additive and solvent screena
Table 1. Initial proof of concept studiesa
(i) 1—HCl (20 mol%)
additive (1 equiv)
O
O
O
iꢀPr2NEt (1.5 equiv)
H
(i) catalyst (20 mol%)
O
°
solvent, −10 C, 24 h
OPNP
iꢀPr2NEt (1.5 equiv)
H
OAr
NHBn
NPh
8
2
1′
THF, ꢀ 10 °C, 24 h
(ii) BnNH2 (5 equiv)
8, Ar = 4ꢀNO2C6H4
9, Ar = 2,4,6ꢀCl3C6H2
10, Ar = 3,5ꢀ(CF3)2C6H3
PNP = 4ꢀNO2C6H4
NHBn
NPh
°
2
1ʹ
−10 C, 24 h
(ii) BnNH2 (5 equiv)
ꢀ 10 °C, 24 h
+
X =
H
Cl
Cl
X
H
X =
+
NPh
Cl
Cl
12
X
O
OH
NPh
12
O
OH
11
NC
CN
11
NC
CN
N
N
N
iꢀPr
N
O
NO2
NBu4
NBu4 Br
N
N
Ph
Ph
OH
S
N
—HCl
S
N
S
Ph
N
15
16
17
(S)ꢀTetramisole—HCl (S)ꢀBenzotetramisole
(2R,3S)ꢀHyperBTM
Additive
(1 equiv)
15
1—HCl
BTM 13
14
Yield
ermajor
d
erminor
d
Entry
Solvent
drb
(%)c
(2R,1′S)
(2R,1′R)
80:20
73:27
70:30
−
ermajor
d
(2R,1′S)
Yield
(%)c
erminor
d
(2R,1′R)
Entry Ar Catalyst
drb
1
2
3
4
5
6
THF
THF
THF
THF
72:28
73:27
76:24
−
32
63
54
−
89:11
89:11
89:11
−
16
1
2
3
4
5
6
8
8
13
14
73:27
39
40
64
−
72:28 63:37
73:27 52:48
72:28 59:41
16, 17
16
66:34
75:25
−
8
1·HCl
1·HCl
1·HCl
−
16
MeCN 83:17
73
75:25
66:34
66:34
9
−
94:6
−
−
85:15
−
16
CH2Cl2 78:22
59
80:20
10
8
71:29
−
22
−
aReaction conditions: (i) 11 (1 equiv, 0.25 mmol), 8 (1.5 equiv), 1·HCl (20
mol%), additive (1 equiv), iꢀPr2NEt (1.5 equiv), THF (0.18 M), −10 °C, 24
h; (ii) BnNH2 (5 equiv), −10 °C, 24 h. bdr of crude product determined by
1H NMR spectroscopic analysis. cIsolated yields given as a mixture of
aReaction conditions: (i) 11 (1 equiv, 0.25 mmol), 8ꢀ10 (1.5 equiv), cataꢀ
lyst (20 mol%), iꢀPr2NEt (1.5 equiv), THF (0.18 ), −10 °C, 24 h; (ii)
BnNH2 (5 equiv), −10 °C, 24 h. dr of crude product determined by H
NMR spectroscopic analysis. Isolated yields given as a mixture of diaꢀ
stereoisomers. Only the major diastereoisomer is shown. er of major and
d
M
diastereoisomers. Only the major diastereoisomer is shown. er of major
b
1
and minor diastereoisomers determined by chiral HPLC analysis.
c
d
(b) Effect of the iminium counterion. The effect of the iminꢀ
ium counterion upon reactivity and enantioselectivity was
investigated next. A range of iminium ions was prepared by
either oxidation using bromotrichloromethane (BrCCl3) in the
presence of blue light (Table 3, entry 1) or counterion exꢀ
change (entries 2ꢀ5) to examine the effect on the yield and
selectivity. While the diastereoselectivity of the process was
essentially invariant, changing the counterion showed signifiꢀ
cant variation in yield and enantioselectivity. The smaller,
coordinating halide counterions (Br− and Cl−) gave the amide
product 12 in comparable yield to the model system (entries 1
and 2) and with improved enantioselectivity (ermajor (2R,1′S): 97:3
and 96:4 respectively). The larger, nonꢀcoordinating counteriꢀ
minor diastereoisomers determined by chiral HPLC analysis.
Reaction Optimization.
(a) Additive and solvent screen. Previous work in catalytic
enantioselective [2,3]ꢀrearrangements from our laboratory has
identified the role of additives in improving reaction enantiꢀ
oselectivity.17 Addition of tetrabutylammonium bromide 15 (1
equiv) to the 1·HClꢀcatalyzed reaction of iminium 11 and ester
8 resulted in a significant enhancement in enantioselectivity
(Table 2, entry 1: ermajor (2R,1′S) 89:11; erminor (2R,1′R) 80:20), howꢀ
ever the isolated yield dropped to 32%. Addition of tetrabuꢀ
tylammonium 4-nitrophenoxide (TBAPNP) 16 maintained this
improved enantioselectivity and increased the yield to 63%
(entry 2). This increase is likely due to a combination of inꢀ
creased polarity of the reaction mixture and the influence of 4-
nitrophenoxide in facilitating catalyst turnover. A dual combiꢀ
−
ons (BF4−, PF6− and BPh4 ) gave higher yields in comparison
with the model system (entries 3ꢀ5), but with reduced enantiꢀ
oselectivity (ermajor (2R,1′S): 90:10, 87:13 and 82:18). As the synꢀ
thesis of iminium bromide 18 is facile via either oxidation
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using BrCCl3 in the presence of blue light or photoredoxꢀ
catalyzed process, the bromide counterion was chosen for all
further studies (Table 3).
Table 3. Iminium counterion effecta
Page 4 of 8
ganocatalyst 1·HCl loading from 20 mol% to 10 mol% gave
12 in 65% (entry 5) and 5 mol% resulted in 12 in 70% yield
with no loss in selectivity (entry 7). Further reduction of the
loading of 1·HCl gave reduced reactivity, with a severely diꢀ
minished yield observed at 2 mol% (entry 9). Although 0.5
mol% of Ru(bpy)3Cl2 24 showed a marginally better yield and
selectivity than 1 mol% when 10 mol% of 1·HCl was used
(entry 6), the optimal catalyst loading was 5 mol% of 1·HCl
and 0.5 mol% of 24 (entry 8). Attempts to carry out both phoꢀ
toꢀ and organocatalyzed steps simultaneously, rather than seꢀ
quentially, were conducted. Reaction catalyzed by 1 mol% of
Ru(bpy)3Cl2 24 and 20 mol% of 1·HCl in MeCN:THF (2:1)
resulted in formation of amide 12 in 57% yield and 67:33 dr,
but only 56:44 er. Under the developed conditions, attempts to
1
2
3
4
5
6
7
8
O
(i) 1—HCl (20 mol%)
O
TBAPNP 16 (1 equiv)
H
OPNP
iꢀPr2NEt (1.5 equiv)
8
NHBn
NPh
°
THF, −10 C, 24 h
2
1′
PNP = 4ꢀNO2C6H4
(ii) BnNH2 (5 equiv)
+
9
°
−10 C, 24 h
X
NPh
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
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12
18-22
utilize
either
N,Nꢀdimethylaniline
or
NꢀbenzylꢀNꢀ
Yield
ermajor
erminor
d
(2R,1′R)
Entry
X
drb
methylaniline as starting materials rather than 23 did not lead
d
(%)c
to any observable product.26
(2R,1′S)
1
2
3
4
5
Br (18)
Cl (19)
74:26
72:28
80:20
77:23
55
67
87
88
88
97:3
96:4
96:4
95:5
75:25
70:30
67:33
Table 4. Optimizing a sequential photoredox/isothiourea-
catalyzed procedure
BF4 (20)
PF6 (21)
90:10
87:13
82:18
(i) Ru(bpy)3Cl2 24 (mol%)
Br
BPh4 (22) 76:24
aReaction conditions: (i) 18ꢀ22 (1 equiv, 0.25 mmol), 8 (1.5 equiv), 1·HCl
(20 mol%), TBAPNP 16 (1 equiv), iꢀPr2NEt (1.5 equiv), THF (0.18 M),
Blue LEDs
BrCCl3 (1.5 equiv)
solvent 1, rt, 2 h
NPh
NPh
b
−10 °C, 24 h; (ii) BnNH2 (5 equiv), −10 °C, 24 h. dr of crude product
23
determined by 1H NMR spectroscopic analysis. cIsolated yields given as a
mixture of diastereoisomers. Only the major diastereoisomer is shown. der
18
O
of major and minor diastereoisomers determined by chiral HPLC analysis.
(ii)
OPNP
O
8 (1.5 equiv)
1—HCl (mol%)
TBAPNP 16 (1 equiv)
H
(c) Developing
a
sequential photocatalytic oxida-
NHBn
NPh
2
tion/isothiourea-catalyzed procedure. The use of photoredox
catalysis in recent years has emerged as a powerful tool that
has been widely exploited in organic chemistry.28 Applications
in organocatalysis are being realized, with dual catalytic proꢀ
cedures29 involving imidazolidinone,30 NHC,31 prolineꢀ
derived,32 thiourea33 and DABCO34 catalysts already develꢀ
oped. Having shown that highest enantioselectivity was obꢀ
served using the iminium bromide salt, attention turned to
incorporating a photocatalytic oxidation to generate the reꢀ
quired iminium ion. Following Zeitler’s precedent,35 the oxiꢀ
dation of Nꢀphenyl tetrahydroisoquinoline 23 using BrCCl3 in
THF and irradiation with blue LED light at rt for 24 h was
followed. Removal of the light source, followed by the orꢀ
ganocatalytic step gave amide 12 in 59% yield, 75:25 dr and
ermajor (2R,1′S) 95:5 (Table 4, entry 1).36 As an alternative, using
Ru(bpy)3Cl2 24 as a photocatalyst (1 mol%)37 gave complete
oxidation within 2 h, and after organocatalytic functionalizaꢀ
tion gave the desired product 12 in a similar yield with no
change in diastereoꢀ and enantioselectivity (entry 2). When
both photoꢀ and organocatalytic reaction steps were carried out
in MeCN a significant enhancement in yield was observed,
with 12 obtained in 77% yield but with reduced stereoselectivꢀ
ity (entry 3). A screen of THF:MeCN mixtures was carried out
to find a system that delivered high yields without compromizꢀ
ing stereoselectivity. To achieve consistently high yields, it
was necessary to conduct the oxidation step in MeCN. Inꢀ
creased enantioselectivity in the organocatalytic step was
achieved by the addition of THF, with a 3:1 ratio of
THF:MeCN being found to be optimal. Under these condiꢀ
tions, amide 12 was isolated in 78% yield, 77:23 dr and ermajor
(2R,1′S) 95:5 (entry 4). Further studies were undertaken to reduce
the loading of the two catalyst systems. Reduction of the orꢀ
1′
iꢀPr2NEt (1.5 equiv)
°
solvent 2, −10 C, 24 h
H
°
(iii) BnNH2 (5 equiv), −10 C, 24 h
12
Yield ermajor
Entry Solvent 1/2 24a 1·HCla
drb
(%)c
59
56
77
78
65
70
70
78
35
d
(2R,1′S)
1e
2
3
4
5
6
7
8
9
THF/ −
THF/ −
0
1
1
1
1
20
20
20
20
10
10
5
75:25
74:26
64:36
77:23
73:27
70:30
72:28
74:26
70:30
95:5
95:5
92:8
95:5
94:6
95:5
94:6
94:6
93:7
MeCN/ −
MeCN/THFf
MeCN/THFf
MeCN/THFf 0.5
MeCN/THFf
MeCN/THFf 0.5
MeCN/THFf
1
5
1
2
aCatalyst loading in mol%. dr of crude product determined by H NMR
spectroscopic analysis. Isolated yields given as a mixture of diastereoiꢀ
b
1
c
d
somers. Only the major diastereoisomer is shown. er of major diastereoiꢀ
somer determined by chiral HPLC analysis. eOxidation reaction carried
f
out for 24 h. After oxidation was complete the reaction mixture was
cooled to −10 °C and THF was added, such that the second step was carꢀ
ried out in a 3:1 mixture of THF:MeCN.
Reaction scope and generality. With an optimized sequential
photoredox/Lewis baseꢀcatalyzed procedure in hand, the genꢀ
erality of this process was investigated, with the scope of the
ester component examined first (Table 5). For the range of
substituted arylacetic PNP esters studied, both the position and
electronic nature of the substituent markedly influenced their
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reactivity and product enantioselectivity, while the product
76% yield but with reduced er (ermajor (2R,1′S) 76:24). 4-Bromo,
4-phenyl and 2ꢀnaphthyl substitutions were all well tolerated
to give 31, 32 and 33 in approximately 80% yield and ermajor
1
2
3
4
5
6
7
8
diastereoselectivity remained at approximately 75:25 dr. Subꢀ
stitution at the 3ꢀposition of the aromatic ring was successful,
giving 3ꢀmethyl substituted 25 in 85% yield and ermajor (2R,1′S)
90:10. Introduction of a methyl substituent at the 2ꢀposition
however had a deleterious effect on reactivity: 2ꢀmethyl subꢀ
stituted 26 was obtained in a reduced 51% yield and ermajor
90:10, 84:16 and 91:9 respectively. In contrast, 1ꢀ
(2R,1′S)
naphthyl substitution required 10 mol% 1·HCl catalyst loadꢀ
ing, giving 34 in 61% yield and ermajor
82:18. A 3ꢀ
(2R,1′S)
thiophene substituent was tolerated, giving 35 in 85% yield
and ermajor (2R,1′S) 92:8. Although alkyl substituted 4ꢀnitrophenyl
esters did not prove compatible with this methodology,26
alkenylꢀsubstituted 4ꢀnitrophenyl esters were compatible, but
required 10 mol% 1·HCl for optimal product yields, providing
36 and 37 in 64% and 73% yield and good enantioselectivity.
Alternative nucleophilic amines to were also examined to preꢀ
pare a range of isolable amide derivatives. Addition of pyrrolꢀ
idine, NꢀBoc piperazine and morpholine resulted in the correꢀ
sponding amides 38, 39 and 40 in excellent yield (79ꢀ86%),
and comparable stereoselectivity (~75:25 dr, and ermajor (2R,1′S)
95:5).
78:22. Reaction of the phenylacetic acid derivative in
(2R,1′S)
this protocol worked well, giving 27 in 81% yield and ermajor
(2R,1′S) 92:8. Aromatic rings bearing an electronꢀdonating groups
were well tolerated, with 4-methoxy substitution giving 28 in
70% yield and ermajor (2R,1′S) 94:6. A 3ꢀmethoxy substituted aroꢀ
matic ring gave 29 in 56% yield and ermajor (2R,1′S) 91:9, however
attempts to include an 2ꢀmethoxy substituent resulted in a
significant reduction in yield, with the desired product difficult
to isolate.38 Introduction of an electronꢀwithdrawing 4-CF3
substituted aromatic gave reduced reactivity, making it necesꢀ
sary to increase the 1·HCl loading to 20 mol%,39 giving 30 in
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 5. Scope of the sequential photoredox/isothiourea-catalysis: variation of PNP ester and amine nucleophile
a
b
The er of the major diastereoisomer is stated. For the er of the minor diastereoisomer, see SI. 20 mol% 1·HCl catalyst loading. 10mol% 1·HCl catalyst
loading. c10 equiv of amine used for quench.
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Further studies probed the scope of this process with respect to gave 47 in 67% yield and ermajor
Page 6 of 8
94:6. Unfortunately,
(2R,1′S)
1
2
3
4
5
6
7
8
skeletal variation within the tetrahydroisoquinoline (Table 6).
Substituent variation of the carbocylic skeleton showed that
incorporation of 6,7ꢀ(MeO)2 substituents gave products 41 and
42 with excellent yields but reduced enantioselectivity with
respect to 12. However, incorporation of either 5ꢀ or 7ꢀCl
substituents proceeded with high enantioselectivity to give 43
and 44.
substrates bearing an electronꢀwithdrawing (4-CF3 phenyl) and
electronꢀdonating (4-methoxyphenyl) aromatic Nꢀsubstitution
were unsuccessful, indicating limited electronic tolerance of
the Nꢀaryl substituent within this protocol.
CONCLUSION
In conclusion, the enantioselective isothioureaꢀcatalyzed addiꢀ
tion of 4ꢀnitrophenyl esters to tetrahydroisoquinolineꢀderived
iminium ions has been demonstrated using ammonium enolate
catalysis. This methodology does not rely on an intramolecular
nucleophile to achieve catalyst turnover, instead the 4ꢀ
nitrophenoxide expelled through Nꢀacylation of the 4ꢀ
nitrophenyl ester is able to reꢀenter the catalytic cycle to faciliꢀ
tate turnover of the catalyst. Control studies showed that reacꢀ
tion enantioselectivity was markedly dependent upon the naꢀ
ture of the iminium counterion. Extensive optimization lead to
a sequential photoredox/isothioureaꢀcatalyzed reaction being
adopted, leading to the synthesis of substituted tetrahydroisoꢀ
quinolines in high yield and excellent er. The substrate scope
with respect to arylacetic and alkenylacetic 4ꢀnitrophenyl esꢀ
ters, variation of the carbocyclic and Nꢀaryl groups within the
tetrahydroisoquinoline skeleton, as well as amine nucleophilic
quench has been examined. Current work in our laboratory is
focused on further applications of using in situ generated arꢀ
yloxides to promote catalyst turnover in Lewis base catalyꢀ
sis.40
Table 6. Scope with variation in N-aryl tetrahydroisoquin-
oline substrate
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
AUTHOR INFORMATION
Corresponding Author
* Eꢀmail: ads10@stꢀandrews.ac.uk
Notes
The authors declare no competing financial interest.
ASSOCIATED CONTENT
Supporting Information (SI). Experimental procedures, characꢀ
terization data, copies of NMR spectra and HPLC chromatoꢀ
grams. This material is available free of charge via the Internet at
http://pubs.acs.org.
ACKNOWLEDGMENT
We thank AstraZeneca and the EPSRC (grant codes
EP/M506631/1; J.N.A. and EP/J018139/1; A.B.F.) for funding.
The European Research Council under the European Union’s
Seventh Framework Programme (FP7/2007ꢀ2013) ERC Grant
Agreement No. 279850 is also acknowledged. A.D.S. thanks the
Royal Society for a Wolfson Research Merit Award. We also
thank the EPSRC UK National Mass Spectrometry Facility at
Swansea University.
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ACS Catalysis
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1
comparable to that analyzed by H NMR spectroscopy of the crude
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BnNH2 quench was monitored by H NMR spectroscopy, and it was
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(34) Feng, Z.ꢀJ.; Xuan, J.; Xia, X.ꢀD.; Ding, W.; Guo, W.; Chen,
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(36) The generality of protocol for the oxidation using BrCCl3 and
blue LEDs in the absence of a photocatalyst was explored with some
substrates, but yields were lower than using the photoredox proceꢀ
dure. See SI for further details.
(37) For an example of nucleophilic trapping of iminium intermeꢀ
diates derived from the oxidation of tetrahydroisoquinolines, see:
Freeman, D. B.; Furst, L.; Condie, A. G.; Stephenson, C. R. J. Org.
Lett. 2012, 14, 94ꢀ97.
(38) The amide product bearing an 2ꢀmethoxy substitution on the
aromatic ring was formed in 58:42 dr and ermajor 65:35 at 10
mol% 1·HCl catalyst loading. Multiple attempts at purification by
column chromatography failed to separate the desired product from
unidentified side products, with an approximate isolated yield of 32%.
See SI for further details.
(39) A reaction involving 4-CF3 PNP ester with iminium bromide
18 in the absence of organocatalyst 1·HCl gave the corresponding
amide product 30 in 68% isolated yield and 58:42 dr. This is conꢀ
sistent with a competitive baseꢀmediated background reaction being
operative under these reaction conditions.
(40) The research data underpinning this publication can be acꢀ
cessed at: http://dx.doi.org/10.17630/12bb1529ꢀ4947ꢀ4d75ꢀb607ꢀ
583606a66652.
(2R,1′S)
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