Halogen-Bond-Catalyzed Addition of Carbon-Based Nucleophiles to N-Acylimminium Ions

Article abstract of DOI:10.1021/acs.orglett.9b02006

N-acylimminium ions are an important class of synthetic intermediates to produce diverse products upon treatment with different nucleophiles. Most of the reported catalytic protocol involved moisture-sensitive Lewis acids or transition metal. Herein, we reported an organocatalytic version by using halogen-bond catalyst as mild Lewis acid through anion-abstraction strategy. A preliminary result of enantioselective version by employing a chiral BINOL-phosphate anion has also been demonstrated.

Full text of DOI:10.1021/acs.orglett.9b02006

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Halogen-Bond-Catalyzed Addition of Carbon-Based Nucleophiles to
N‑Acylimminium Ions
Yuk-Cheung Chan and Ying-Yeung Yeung*
Department of Chemistry, The Chinese University of Hong Kong, Shatin, NT, Hong Kong, China
S
* Supporting Information
ABSTRACT: N-acylimminium ions are an important class of
synthetic intermediates to produce diverse products upon
treatment with different nucleophiles. Most of the reported
catalytic protocol involved moisture-sensitive Lewis acids or
transition metal. Herein, we reported an organocatalytic version
by using halogen-bond catalyst as mild Lewis acid through anion-
abstraction strategy. A preliminary result of enantioselective
version by employing a chiral BINOL-phosphate anion has also
been demonstrated.
Scheme 1. Halogen-bond (XB)-Catalyzed
Functionalizations of N,O-Aminals
N-acylimminium ions (NAI) are an important class of
synthetic intermediates in organic synthesis.1 This class of
reactive intermediates can be transformed to a wide spectrum
of useful products through reactions with various nucleophiles
such as indoles, malonates, and silyl enol ether.1a For example,
NAI-derived α-oxo-lactams 1 are frequently employed as
intermediates for the synthesis of biologically relevant
molecules. Typically, treatment of commercially available and
inexpensive N,O-aminals 1 with Brønsted or Lewis acids can
generate the highly active NAI in situ, through the elimination
of the OR groups (Scheme 1). Different types of metal
catalysts, including Au/Ag, Pd/Ag, Sn, Sc, and In, have been
proven to be efficient in generating NAI.2 Strongly acidic
promoters, such as BF3, trialkylsilyl triflate, TiCl4 and
trifluoromethanesulfonic acid (TfOH), were also investigated
previously.3 Recently, the use of σ-hole interaction to generate
isoquinoline-derived acylimminium ions has also been
documented.4
The halogen bond (XB) has emerged as a mild Lewis acid
and has received increasing attention in the field of
organocatalysis over the past few years.5 XB has been
successfully applied to CX double bond (X = O, N, S,
etc.) activation6 and anion-binding catalysis.7 For instance,
Huber et al. reported the chloride ion binding of 1-
chloroisochroman, followed by reaction with the ketene silyl
acetal. Takemoto also reported the use of XB to activate silyl
halide for the dehydroxylative coupling of benzyl alcohol
derivatives.8 We hypothesized that XB could serve as a mild
and organocatalytic protocol for the environmentally benign
generation of NAI with high functional group compatibility
and hopefully enantioselective version with diverse class of
nucleophiles. In this context, we disclosed our recent
development of XB-catalyzed C−C bond formation between
carbon-based nucleophiles and in-situ-generated NAI from
N,O-aminals and trimethylsilyl chloride (TMSCl) under
ambient conditions.
At the outset of our investigation, N,O-aminal 1a and
allyltrimethylsilane were employed as the reaction partners.
TMSCl was used as an activator that could convert 1a to the
corresponding preactivated N-acylimminium chloride. We
Received: June 11, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02006
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
reasoned that the chloride anion could interact with the XB
catalyst to undergo anion-metathesis and give the highly
reactive N-acylimminium triflate (Scheme 1), which could be
subsequently attacked by nucleophile (Nu−X) to furnish the
allylation product 2a. Only a trace amount of product was
detected in the absence of catalyst (Table 1, entry 1). Reaction
Scheme 2. Substrate Scope
a
Table 1. Conditions Optimization
b
entry
catalyst
yield (%)
1
2
3
4
5
6
7
8
9
none
trace
trace
99
98
98
trace
43
81
3a (R = Mesityl, X = I, A = BF4)
3b (R = Mesityl, X = I, A = OTf)
3c (R = Mesityl, X = I, A = SbF6)
3d (R = Mesityl, X = I, A = NTf2)
3e (R = Mesityl, X = H, A = OTf)
3f (R = 2,6-Dipp, X = I, A = OTf)
3g (R = Me/n-C8H17, X = I, A = OTf)
3h
89
10
3i
79
a
Reactions were performed with 1a (0.05 mmol), catalyst 3 (10 mol
%), TMSCl (0.05 mmol) and allyltrimethylsilane (0.10 mmol) in
b
CDCl3 (0.5 mL) for 12 h at 25 °C. The yield was determined by 1H
NMR analysis, using mesitylene as an internal standard. Mesityl =
1,3,5-trimethylphenyl; 2,6-Dipp = 2,6-diisopropylphenyl.
with 10 mol % of iodine XB[BF4]− catalyst 3a was also found
to be sluggish (Table 1, entry 2). To our delight, the
XB[OTf]− catalyst 3b gave the desired product 2a in 99% yield
(Table 1, entry 3). Similar results were observed when using
XB[SbF6]− 3c and XB[NTf2]− 3d as the catalysts (Table 1,
entries 4 and 5). These results highlighted the intriguing anion
dependence of the catalytic effect in XB catalysis.7a,9 We
speculate that the tetrafluoroborate in 3a might act as a
fluoride source that might poison the XB donor. The catalytic
effect completely diminished when replacing the iodine atom
in catalyst 3b with hydrogen (i.e., 3e), indicating the crucial
role of the XB donor in this catalytic transformation (Table 1,
entry 6). Lower reactivity was observed when replacing the
mesityl (1,3,5-trimethylphenyl) substituents in 3b with n-
octyl/methyl or 2,6-diisopropylphenyl groups (Table 1, entries
7 and 8) or using the bidentate XB donor 3i (Table 1, entry
10), suggesting that steric and/or electronic property of the
substituent might affect the XB strength in the catalysts.10
With the optimized catalyst in hand, various types of silyl
nucleophiles were subjected to the evaluation (Scheme 2).
Generally, the desired products 2a−2f were obtained in good
yield and diastereoselectivity. Other N,O-aminals such as 1b−
1d were also found to be compatible with the catalytic
protocol, giving the corresponding product 2g−2i in good-to-
excellent yields. Other than silyl nucleophiles, different
electron-rich aromatics, including acid sensitive arenes
(thiophene, furan, pyrrole) alkoxybenzenes and indoles were
a
Reactions were performed with substrate 1 (0.1 mmol), catalyst 3b
(10 mol %), TMSCl (0.1 mmol)) and nucleophile (0.2 mmol) in
ethanol-free CHCl3 (1 mL) for 24 h at 25 °C. The yields were
b
1
isolated yields. The diastereomeric ratio (dr) was determined by H
NMR analysis on the crude reaction mixture. cOne h. dNo TMSCl was
added.
also studied. The regioselectivity and chemical yields of 2j−2s
were generally excellent. When phenols were employed as the
nucleophilic partners, the C-attack products 2t−2v were
furnished exclusively.11 1,3-dicarbonyl compound was also
able to deliver the desired C-attack product 2w.
B
DOI: 10.1021/acs.orglett.9b02006
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Letter
The reaction was found to be compatible with substrates 1e
and 1f that are absent of the aryl moiety (Scheme 3). In
that the association between 3b and Cl− was much stronger
than that of 3b and TMSCl, revealing that 3b was likely to be
an anion binder during the catalytic cycle, instead of activating
TMSCl. Indeed, substrate 1a readily reacted with TMSCl in
the absence of catalyst 3b, as evidenced by the NMR study
(see the Supporting Information for details).
Scheme 3. Other Substrates and Scale-Up Reaction
We also studied the effect of additive on the reaction. It was
found that the addition of TBACl (10 mol %, equimolar to 3b)
completely shut down the reaction; this was attributed to the
interaction of chloride with XB, which would poison the
catalyst (Figure 1). On the other hand, the same additive has
no negative impact on the reaction catalyzed by TfOH.14 This
study further highlighted the role of catalyst as an anion binder
during the catalysis.
A plausible catalytic cycle is depicted in Scheme 4. Substrate
1 first reacted with TMSCl to generate N-acylimminium
Scheme 4. A Plausible Reaction Mechanism
addition, the reaction was readily scalable in which 2a was still
obtained in quantitative yield when the reaction was conducted
at 1 mmol scale. In addition, the XB catalyst could be recycled
quantitatively and reused in the new rounds of reactions
without diminishment of catalytic performance, which was not
readily achievable using moisture-sensitive Lewis acids (see the
Supporting Information for details).12
Several experiments were performed to gain insight into the
mechanism. First, 13C NMR experiment on the XB catalyst was
conducted (Figure 1). Upon mixing equimolar of 3b and tetra-
chloride, which might then undergo anion binding (meta-
thesis) with the XB catalyst 3b through halogen-bond
interaction to give N-acylimminium triflate as the active
intermediate. After nucleophilic attack of the N-acylimminium
triflate by Nu−X (X = H or TMS) to give the desired product
2, the chloride anion of the halogen-bond complex was then
captured by the X+ to regenerate the catalyst 3b (see the
Supporting Information for details).
Further experimentations indicated that achieving the
reaction with both high yield and diastereomeric ratio (dr) is
not a trivial task. For instance, Lewis acids [Ti(OiPr)4,
Cu(CH3CN)4BF4, AuOTf, Zn(OTf)2], Brønsted acid
(TfOH), and dihydrogen bond catalyst (Schreiner’s thiourea)
gave either low efficiency or low dr (Table 2, entries 1−6). In
sharp contrast, XB catalysts 3b−3d with various counter-
anions furnished 2c in good yield and dr (Table 2, entries 7−
9). These results highlighted the unique and tunable
performance of XB in the reaction.
Motivated by the diastereoselectivity offered by counter-
anion depicted in Table 2, we briefly explored the asymmetric
variant of the reaction. Preliminarily, when catalyst 3j with (S)-
BINOL derived phosphate anion was employed, 35% yield and
44% enantiomeric excess (ee) of 2o was obtained. In contrast,
31% ee of 2o was observed in the case of corresponding
phosphoric acid catalysis. (See Scheme 5.) These results
Figure 1. Control experiments.
n-butylammonium chloride (TBACl), the ipso carbon signal of
C−I was found to exhibit an ∼11 ppm downfield shift.13
However, a negligible chemical shift was observed for the
mixture of 3b and TMSCl. Thus, unlike Takemoto’s case,
whereas the XB might interact with TMSI to generate a better
Lewis acidic silicon center for the activation of the benzylic
hydroxyl substrates,8 the above-mentioned results suggested
C
DOI: 10.1021/acs.orglett.9b02006
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 2. Catalyst Comparison
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: yyyeung@cuhk.edu.hk.
ORCID
Ying-Yeung Yeung: 0000-0001-9881-5758
Notes
b
b
The authors declare no competing financial interest.
entry
catalyst
Ti(OiPr)4
Cu(CH3CN)4BF4
AuOTf
Zn(OTf)2
TfOH
Schreiner’s thiourea
3b
3c
3d
yield (%)
diastereomeric ratio, dr
1
2
3
4
5
6
7
8
9
0
99
99
70
99
0
80
85
88
ND
1:1.6
1:1.5
1.4:1
1:1.2
ND
10:1
4:1
6:1
ACKNOWLEDGMENTS
■
We thank the financial support from Research Grant Council
of the Hong Kong Special Administration Region (Project No.
CUHK14305317) and The Chinese University of Hong Kong
Direct Grant (Project No. 4053279).
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02006.
Experimental procedures and characterization data for
all new compounds (PDF)
D
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