Iridium-Catalyzed Reductive Alkylations of Secondary Amides

Article abstract of DOI:10.1002/anie.201806747

Reported herein is the first direct, metal-catalyzed reductive functionalization of secondary amides to give functionalized amines and heterocycles. The method is shown to have exceptionally broad scope with respect to suitable nucleophiles, which cover both hard and soft C nucleophiles as well as a P nucleophile. The reaction exhibits good chemoselectivity and tolerates several sensitive functional groups.

Full text of DOI:10.1002/anie.201806747

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Iridium-Catalyzed Reductive Alkylations of Secondary Amides
Authors: Wei Ou, Feng Han, Xiu-Ning Hu, Hang Chen, and Pei-Qiang
Huang
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201806747
Angew. Chem. 10.1002/ange.201806747
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http://dx.doi.org/10.1002/ange.201806747

10.1002/anie.201806747
Angewandte Chemie International Edition
COMMUNICATION
Iridium-Catalyzed Reductive Alkylations of Secondary Amides
†
†
Wei Ou,[a] Feng Han,[a] Xiu-Ning Hu,[a] Hang Chen,[a] and Pei-Qiang Huang*[a,b]
Dedicated to Professor Guo-Qiang Lin on occasion of his 75th
birthday
reductive functionalization of secondary amides leading to -
substituted amines remains unknown. Nevertheless, such
transformations with broad nucleophile diversity are in high
demand given the easy availability[7] and widespread use of
secondary amides in organic synthesis,[1,2,8] and the presence of
-substituted secondary amine motifs in many medicinal
agents[9a] and bioactive alkaloids.[9b] In this regard, medicinal
agents such as fendiline (an anti-anginal agent in clinical use for
the treatment of coronary heart disease) and tamsulosin (a
selective 1-adrenergic antagonist), and alkaloid histrionicotoxin
(Figure 1, A) are just some representatives among many others.
Among them, four entered the list of top 200 brand-name drugs
by total US prescriptions in 2012.[9a] More importantly, known
methods for the reductive functionalization of amides are
generally restricted to some special classes of nucleophiles such
as allyltrimethylsilane or allyltributyltin. Very often, several steps
are required for the elaboration of the introduced allyl groups
into the desired functionalized alkyl groups.
Abstract: We report the first direct, iridium-catalyzed reductive
functionalization of secondary amides to give functionalized amines
and heterocycles. The method is shown to have exceptionally broad
scope with respect to suitable nucleophiles, which cover both hard
and soft C-nucleophiles as well as a P-nucleophile. The reaction
exhibits good chemoselectivity and tolerates several sensitive
functional groups.
Carbon–carbon bond formation reactions constitute a core class
of transformations in organic synthesis. In the field of total
synthesis of alkaloids and N-containing medicinal agents,
reductive alkylation of amides and lactams, namely, the
transformations of amides into amines with C–C bond formation,
has become one of the most important and fundamental
transformations.[1,2] Indeed, from the selected classical synthesis
of (perhydro)histrionicotoxin by Corey,[2a] Kishi,[2b] and Evans,[2c]
respectively, (+)-pumiliotoxin C by Oppolzer,[2d] peduncularine by
Speckamp,[2e] indolizomycin by Danishefsky,[2g] to the recent
total synthesis of seven-membered-ring-containing lycopodium
alkaloids by Shair (Figure 1, A),[2k] the reductive alkylation of
amides has served as an indispensable transformation.[2]
However, the high stability of amides means that it is necessary
to pre-transform an amide into a more reactive intermediate
before addition of a nucleophile and acid-mediated reduction. All
these methods involve multiple-step transformations.
In recent years, the direct reductive alkylation of amides has
attracted considerable attention, leading to the development of
several synthetically useful methods[3,4] (Figure 1, B1). In these
reactions, a stoichiometric amount of an activating agent/base
combination [triflic anhydride (Tf2O)/ 2-fluoropyridine (2-F-Pyr.)]
or the Schwartz reagent [Cp2ZrHCl] is required. In view of the
increasing importance of catalysis as a green technology in both
academic research and in the pharmaceutical industry,[5] the
development of catalytic reductive functionalization of amides is
highly desirable. In this context, breakthroughs in the catalytic
reductive functionalization of tertiary amides have recently been
achieved by the groups of Dixon, Chida/ Sato, Huang, and
Adolfsson, respectively (Figure 1, B2).[6] However, the catalytic
As part of our efforts to develop efficient C–C bond-forming
reactions based on nucleophilic addition to amides,[4a,h-l,6a,h]
herein, we report the [IrCl(COE)2]2-catalyzed reductive
functionalization of secondary amides.
O
OH
N
Me
A
Me
H
H
N
N
H
N
Me
O
OH
N
Indolizomycin
(Danishefsky)
(1993)
HTX 283A
(perhydro)histrionicotoxin
(Corey; Kishi;Evans)
(1975; 1975; 1982)

( )-himeradine
(Shair, 2014)
Me
Me
Reductive functionalization of amides using stoichiometric activating reagents
B1
Huang
one-pot
1) Tf2O/ 2-F-Pyr.
Chida/ Sato
one-pot
Nu
Nu
O
1) Cp2ZrHCl
R2
R2
R2
R1
N
R3(H)
R1
N
R3(H)
R1
N
2) Nu
3) [H]
2) Nu
Lewis acid (cat.)
R3(H)
B2 Catalytic reductive functionalization of
-amides employing Vaska's Ir
tert
complex or Mo-catalyst : Dixon, Chida/ Sato, Huang, Adolfsson
by
IrCl(CO)(PPh 3)2 (cat.)
(Vaska's complex)
or Mo(CO)6
O
Nu
R2
R2
R1
N
R1
N
R3
R3
:Nu
tert-amides
This work
C
First catalytic reductive functionalization of sec-amides
one-pot
O
[a]
Dr. W. Ou, F. Han, X.-N. Hu, H. Chen, and Prof. Dr. P.-Q. Huang
Department of Chemistry, Fujian Provincial Key Laboratory of
Chemical Biology, and iChEM (Collaborative Innovation Center of
Chemistry for Energy Materials), College of Chemistry and Chemical
Engineering, Xiamen University, Xiamen, Fujian 361005, P. R.
China
FG
[IrCl(COE) 2]2 (cat.)/ Silane;
R2
Nu
R1
N
H
FG
R2
R1
N
Lewis acid, Nu
FG
FG
H
sec-amides
Good chemoselectivity
Nucleophile diversity
Catalytic
Broad substrate scope
Mild conditions
E-mail: pqhuang@xmu.edu.cn
[b]
Prof. Dr. P.-Q. Huang
State Key Laboratory of Applied Organic Chemistry, Lanzhou
University, Lanzhou 730000, P. R. China
† These authors contributed equally to this work.
Figure 1. A) Representative alkaloids synthesized by employing multistep
protocols for the reductive alkylation of amides. B) Recent methods for the
direct reductive alkylation of amides. C) Our plan for the direct, Ir-catalyzed
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
reductive alkylation of secondary amides. Nu
cyclopentadienyl, FG = functional group.
= nucleophile, Cp =
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10.1002/anie.201806747
Angewandte Chemie International Edition
COMMUNICATION
To develop an efficient method for the one-pot catalytic
reductive functionalization of secondary amides, we needed a
catalytic method for partial reduction of secondary amides. In
2012, Brookhart reported a catalytic reduction of secondary
amides to either secondary amines or imines using catalytic
[IrCl(COE)2]2, which is a commercially available complex.[10]
Inspired by this work and by our own work,[6a,h] we devised a
catalytic reductive functionalization of secondary amides that
proceeds through sequential Ir-catalyzed reduction and Lewis
acid-promoted nucleophilic trapping of imines generated in situ.
The reductive allylation of 1a using allyl magnesium bromide
was chosen as a model reaction to identify optimal reaction
conditions (Tables SI-1 and 2 in SI). The optimized conditions
were found to involve treating amide 1a (1.0 equiv) with 0.1 mol%
of [IrCl(COE)2]2, 2.0 equiv of Et2SiH2, 1.5 equiv of BF3·OEt2, and
2.5 equiv of allyl magnesium bromide at room temperature for 3
h. Under these conditions, the desired amine 2a was isolated in
85% yield (Table 1, entry 1).
With the optimized reaction conditions in hand, the scope of
the reaction was investigated by varying the nucleophilic
trapping reagent and the amide. Using N-benzylbenzamide (1a)
as a prototype amide substrate, we examined the scope of the
nucleophile (Table 1). Simple and functionalized Grignard
reagents including primary (entry 2), secondary (entry 3), and
alkene- (entry 4) or siloxy-containing substrates (entry 5),
proceeded efficiently to produce the corresponding amines (2b–
e) in high yields (85–86%). Alkyl, heteroaryl, and alkynyl lithium
reagents were also viable nucleophiles for the reductive
functionalization reaction (2f–i, 66–85% yields; entries 6–9).
Stabilized carbanions such as the lithium enolate of t-butyl
acetate or the hindered lithium enolate derived from ethyl
isobutyrate reacted to afford -amino esters 2j and 2k in 76%
and 80% yield, respectively (entries 10 and 11).
(Dimethoxyphosphoryl)methyl]lithium reacted similarly, to
provide -amino phosphonate 2l in 79% yield (entry 12).
other hand, attempted reductive allylation of 1f using
stoichiometric Tf2O proved unsuccessful.[4h]
Table 1. Scope of the reaction with respect to the nucleophile used
[IrCl(COE) ] (0.1 mol%)
2 2
O
H
Nu
Et SiH (2.0 equiv), CH Cl , RT;
2
2
2
2
Bn
Bn
Ph
N
H
Ph
N
BF •Et O (1.5 equiv)
H
3
2
2
1a
Nu (2.5 equiv), RT, 3 h
Nucleophile Product (%Yield)a
Nucleophile Product (%Yield)a
TMS
Entry
Entry
2a
85
MgBr
MgBr
1
2
3
9
TMS
Li
Bn
2i
76
Ph
N
H
Bn
Ph
Ph
N
H
Me
2b
86
t
Me
CO2 Bu
Bn
OLi
OtBu
Ph
N
H
10
11
2j
76
Bn
N
H
Me
Ph
Me
Me
MgBr
Me
2c
86
Me
OLi
Bn
CO2Et
N
H
2k
80
Me
Ph
Me
OEt
Bn
N
Me
H
4
2d
85
MgBr
4
Bn
4
OMe
Ph
N
O
P
MeO
H
P
Li
OMe
O
2l
79
OTBS
OMe
12
13
14
Bn
N
Ph
4
TBSO
Me
MgBr
5
6
2e
85
H
Bn
4
Ph
N
H
Me
Bn
SnBu3
Li
2f
85
2a
78
Bn
N
Ph
N
H
Ph
H
S
CN
2g
66
7
8
2m
76
Bn
Li
TMSCN
O
S
N
H
Ph
Bn
Ph
Ph
N
H
Ph
OMe
2n
82
MeO
Ph
P
O
MeO
P
H
Ph
Li
15
2h
73
Bn
OMe
N
H
Bn
N
H
aIsolated yield. TMS = trimethylsilyl, TBS = tert-butyldimethylsilyl.
Soft nucleophiles allyl tributyltin and TMSCN (TMS =
trimethyl) participated in the reaction to give homoallylamine 2a
and -aminonitrile 2m in 78% and 76% yield, respectively (Table
1, entries 13 and 14). Moreover, dimethyl phosphonate reacted
smoothly to yield -amino phosphonate 2n in 82% yield (entry
15).
The chiral induction deserves comments. Whereas the
reductive allylation and alkynylation of chiral amide 1i (racemic
substrate used), and the reductive cyanation of amide ()-1l
yielded the corresponding products 2v, 2w, and 2ab in poor
diastereoselectivities (dr = 1.1–1.2:1), the reductive allylation of
chiral amide ()-1l produced the corresponding homoallylic
amine 2ac in excellent diastereoselectivities with dr = 24:1
(determined by HPLC, cf. SI; the relative stereochemistry
undetermined).
Finally, the chemoselectivity and functional group tolerance
of the method were examined. To our delight, besides electron-
rich aroyl amides such as 1h, the reaction also tolerated
benzamide derivatives bearing an electron-withdrawing group
such as CF3 (1m) and ester (1n) groups, to give the desired
products 2ae and 2af in 78% and 80% yield, respectively. In
addition, amides bearing an OTBS group (1o) could survive the
reaction using Grignard reagents as a nucleophile (2ag: 81%).
Moreover, with the use of soft nucleophiles such as dimethyl
phosphonate, the reaction took place chemoselectively at the
amide group of 1n and 1p to give the corresponding -amino
phosphonates 2af and 2ah, respectively, in high yields, leaving
the more reactive acetate and ester groups intact.
We then investigated the scope of the reaction with respect
to the amide. Benzamides bearing primary (1b–d, Table 2, A)
and secondary (1e) alkyl N-substituents, as well as an N-phenyl
group (1f) reacted smoothly with allyl magnesium bromide to
yield the corresponding homoallylamines 2o–s in high yields
(80–85%, Table 2, B). The R1 group of the amide could be more-
hindered o-tolyl (1g), heteroaryl groups such as 2-furanyl (1h),
or primary (1i), secondary (1j and 1l), and tertiary (1k) alkyl
groups. The reductive functionalization of 1g–l afforded the
corresponding functionalized amines 2t–ad in 72–85% yields. In
this manner, the anti-anginal agent fendiline (2q)[9a] was
prepared in 82% yield. Notably, amide 1i is a product of C–H
functionalization,[11] and amide 1l is a product of Fu’s method.[7b]
Moreover, the smooth reductive allylation of N-phenylbenzamide
(1f) to give amine 2s in high yield (80%) is significant in two
respects: on the one hand, N-arylamides such as 1f are
common substrates for C–H functionalization,[12] and, on the
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10.1002/anie.201806747
Angewandte Chemie International Edition
COMMUNICATION
Table 2. Scope of the reaction with respect to the amide used
trifluoromethylation
of
N-phenyl-p-fluorobenzamide
(1q)
produced tetrafluoroamine 3b[4k] in 70% yield (Scheme 1, b).
Ugi multicomponent reactions[15] offer a powerful approach to
the preparation of functionalized compounds. We were
interested in exploring the possibility of merging the Ir-catalytic
reductive transformation of amides with the Ugi reaction.
Pleasingly, subjecting the imine, generated in situ by Ir-catalytic
reduction of N-isopropylbenzamide 1r, to the modified Ugi
reaction conditions (in the absence of BF3·OEt2, for optimization
of reaction conditions, see Table SI-4 in SI) afforded the
expected product 4a[4j] in 64% yield (Scheme 1, c). Similarly, the
Ir-catalytic reductive transformation of aliphatic amide 1s
provided 4b in 71% yield (Scheme 1, d).
[IrCl(COE) 2]2 (0.1 mol%)
O
Nu
Et2SiH2 (2.0 equiv), CH2Cl2, RT;
R2
R2
R1
N
R1
N
H
BF3•Et2O (1.5 equiv)
H
1
a
Nu (2.5 equiv), RT, 3 h
2
: %yield
A
O
O
OMe
CHPh2
c-Hex
1e
Ph
R2
=
R2
H2C
Ph
N
H
S
CH2
CH2
1d
1f
1b
1c
O
O
O
Me
Bn
Pr-i
Bn
R1
N
N
H
N
H
Me
N
H
H
O
S
1
1j
i
. R = -Pr
Ph
1g
1k. R1 = t-Bu
1h
1i
O
Me
O
1m. X = CF3, R2 = Bn
R2 1n. X = CO2Me, R2 = Bn
N
H
N
. X = CH2OTBS, R2 = Bn
. X = OAc, R2 = c-Hex
CF3
O
1o
1p
[IrCl(COE) 2]2 (0.1 mol%)
H
Ph
1l
Ph
Et2SiH2 (2.0 equiv), CH Cl , RT;
Ph
X
2
2
N
N
H
H
TBAT (0.15 equiv)
TMSCF3 (3.0 equiv)
THF, RT, 1 h
X
X
B
OMe
CH2
CHPh2
1f. X = H
. X = F
3a
3b
. X = H, 72%
. X = F, 70%
c-Hex
Ph
2s
(a)
(b)
R2
=
H2C
R2
1q
S
CH2
2q
Ph
N
2r
: 80
: 83
H
2o: 85 2p
: 85
: 82
Fendiline
O
Me
Me
[IrCl(COE) 2 2
Et2SiH2 (2.0 equiv)
]
(0.1 mol%)
, CH Cl , RT;
Me
O
Me
Me
N
Me
*
Me
2
2
4
O
R1
N
Me
*
iPr
R1
Bn
S
Ph
N
H
N
N
H
H
CF3CH2OH, AcOH, Et3N
H
HN
O
1r. R1 = Ph
1s. R1 = c-hex
2v: 80 (dr = 1.2: 1)b
c-hex
CN c-hex
2u
: 84
4a. R1 = Ph, 64%
4b. R1 = c-hex, 71%
2t: 82
(c)
(d)
R
4
Me
Ph
CO2Et
Me
Bn
Me
Me
Bn
Me
N
Bn
Me
*
Me
Scheme 1. Catalytic reductive trifluoromethylation combined with the Ugi
reaction. TBAT = tetrabutylammonium triphenyl-difluorosilicate.
H
N
N
Me
*
iPr
H
H
Me
2aa: 83
Ph
2w
N
H
Me
Ph
2y (R = CH=CH2): 81
2z (R = OTBS): 85
c
2x
: 83
: 78 (dr = 1.1: 1)
R
Me
*
*
We then investigated the catalytic reductive annulation and
reductive cycloaddition of amides. Organozinc reagents are a
class of versatile and chemoselective organometallic reagents
for C–C bond formation.[16] Villiéras and co-workers have
reported the annulation of imines with functionalized allylic zinc
N
Bn
H
Me
Me
Bn
N
N
H
H
2ab (R = CN): 72 (dr = 1.2: 1)b
2ac (R = allyl): 75 (dr = 24: 1)d
Me
F3C
2ae
: 78
2ad
: 79
OMe
O
MeO
Me
OMe
P
OMe
Bn
O
P
reagent
generated
in
situ
from
methyl
2-
Bn
(bromomethyl)acrylate.[17] Considering the important bioactivity
and multiple functionality possessed by -methylene -
lactams,[18a] which are attractive for the total synthesis of
structurally complex alkaloids,[18b] the direct transformation of
amides into -methylene -lactams was investigated. By
subjecting N-methylbenzamide 1t to the catalytic partial
N
N
H
N
H
H
TBSO
MeO2C
AcO
2af: 80
2ag: 81
2ah
: 81
a Isolated yield; b Diastereoisomeric ratio (dr) determined by 1H NMR; c dr determined
d dr
.
determined by HPLC analysis (cf SI).
via separation of diastereomers;
Attempts to further expand the reaction scope to catalytic
reductive trifluoromethylation, reductive Ugi reaction, reductive
lactamization, and reductive imino-Diels–Alder reaction were
unsuccessful. Thus, we focused our attention on defining
specific reaction conditions for each of these reactions. In view
of the importance of trifluoromethylated amines in biological and
medicinal chemistry as well as in the agrochemical field,[13]
catalytic reductive trifluoromethylation of amides was first
examined. It was found that, after the Ir-catalyzed partial
reduction of amide 1f in CH2Cl2, by switching the solvent to THF
(form screening of solvent, see Table SI-3 in SI), and treating
the imine intermediate with (trifluoromethyl)trimethylsilane
(TMSCF3) and with a catalytic amount of tetrabutylammonium
reduction
followed
by
reaction
with
(methoxycarbonyl)allyl)zinc(II) bromide (1.1 equiv) at room
temperature for 3 h, the expected -exo-methylene--lactam 5a
was produced in 71% yield (Scheme 2, a). Remarkably, when
ester-group-bearing benzamide derivative 1n was employed as
a substrate, the tandem reaction proceeded chemoselectively at
the amide group to yield ester-lactam 5b in 72% yield (Scheme
2, b).
Finally, the direct catalytic reductive cycloaddition of amides with
Danishefsky’s diene (6)[19] was investigated. The established
conditions consist of the Ir-catalyzed partial reduction of amide
1t in CH2Cl2, switching the solvent to MeOH,[20] and treating the
presumed imine intermediate with anhydrous ZnCl2 and
Danishefsky’s diene (6). In this manner, the cycloadduct 7a[4l]
was isolated in 70% yield (Scheme 2, c). Similarly, the reductive
triphenyl-difluorosilicate
(TBAT),[14]
the
desired
trifluoromethylated amine 3a[4k] could be isolated in 72% yield
(Scheme 1, a). Similarly, the Ir-catalyzed reductive
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10.1002/anie.201806747
Angewandte Chemie International Edition
COMMUNICATION
cycloaddition of amide 1u produced 7b[4l] in 74% yield (Scheme
2, d).
Evans, E. W. Thomas, R. E. Cherpeck, J. Am. Chem. Soc. 1982, 104,
3695-3700; d) W. Oppolzer, C. Fehr, J. Wameke, Helv. Chim. Acta
1977, 60, 48-58; e) W. J. Klaver, H. Hiemstra, W. N. Speckamp, J. Am.
Chem. Soc. 1989, 111, 2588-2595; f) M. P. Heitz, L. E. Overman, J.
Org. Chem. 1989, 54, 2591-2596; g) G. Kim, M. Y. Chu-Moyer, S. J.
Danishefsky, G. K. Schulte, J. Am. Chem. Soc. 1993, 115, 30-39; h) P.
Schär, P. Renaud, Org. Lett. 2006, 8, 1569–1571; i) B. Dhudshia, B. F.
T. Cooper, C. L. B. Macdonaldzand, A. N. Thadani, Chem. Commun.
2009, 463–465; j) K. Shirokane, T. Wada, M. Yoritate, R. Minamikawa,
N. Takayama, T. Sato, N. Chida, Angew. Chem. 2014, 126, 522-526;
Angew. Chem. Int. Ed. 2014, 53, 512−516; k) A. S. Lee, B. B. Liau, M.
D. Shair, J. Am. Chem. Soc. 2014, 136, 13442–13452; l) K. Annadi, A.
G. H. Wee, J. Org. Chem. 2015, 80, 5236–5251; m) P. W. Tan, J.
Seayad, D. J. Dixon, Angew. Chem. 2016, 128, 13634 –13638; Angew.
Chem. Int. Ed. 2016, 55, 13436–13440.
O
[IrCl(COE)2]2 (0.1 mol%)
R2
Et2SiH2 (2.0 equiv), CH Cl , RT;
2
2
N
O
H
N
X
R2
X
BrZn
CO2Me
. X = H, R2 = Me, 71%
5b. X = CO2Me, R2 = Bn, 72%
1t. X = H, R2 = Me
1n. X = CO2Me, R2 = Bn
5a
(a)
(b)
1.1 equiv in THF
O
OTMS
O
[IrCl(COE) 2 2
]
(0.1 mol%)
R2
+
N
Et2SiH2 (2.0 equiv), CH Cl , RT;
2
2
Ph
H
Ph
N
ZnCl2 (2.0 equiv)
(2.0 equiv), MeOH
OMe
Danishefsky's
R2
6
7a. R2 = Me, 70% (c)
7b. R2 = n-Bu, 74%
1t. R2 = Me
1u. R2 = n-Bu
(d)
6
diene ( )
[3] For reviews, see: a) T. Sato, Y. Makoto, H. Tajima, N. Chida, Org. Biomol.
Chem. 2018, 16, 3864-3875; b) D. Kaiser, N. Maulide, J. Org. Chem.
2016, 81, 4421−4428; c) T. Sato, N. Chida, J. Syn. Org. Chem. Jpn.
2016, 74, 599−610; d) V. Pace, W. Holzer, B. Olofsson, Adv. Synth.
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Acknowledgements
The authors are grateful for financial support from the National
Key R&D Program of China (grant No. 2017YFA0207302), the
National Natural Science Foundation of China (21332007 and
21672176), and the Program for Changjiang Scholars and
Innovative Research Team in University (PCSIRT) of Ministry of
Education.
Conflict of interest
The authors declare no conflict of interest.
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Entry for the Table of Contents
COMMUNICATION
A
versatile, direct,
Ir-catalyzed
Wei Ou, Feng Han, Xiu-Ning Hu, Hang
Chen, and Pei-Qiang Huang
reductive functionalization reactions of
secondary
functionalized
amides
to
give
and
Page No. – Page No.
amines
Iridium-Catalyzed Reductive
Alkylations of Secondary Amides
heterocycles is developed. A broad
substrate scope for both the amide
and nucleophile was observed. Viable
nucleophiles include reactive and soft
C-nucleophiles as well as
a
P-
nucleophile. The reaction exhibited
good chemoselectivity and tolerated
several sensitive functional groups.
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