Iridium-catalyzed 1,5-(aryl)aminomethylation of 1,3-enynes by alkenyl-to-allyl 1,4-iridium(i) migration

Article abstract of DOI:10.1039/C8CC09238A

A novel multicomponent coupling reaction involving the iridium-catalyzed 1,5-difunctionalization of 1,3-enynes with arylboronic acids and triazinanes is described. A key step in this 1,5-(aryl)aminomethylation reaction is the alkenyl-to-allyl 1,4-iridium(i) migration.

Full text of DOI:10.1039/C8CC09238A

ChemComm
View Article Online
View Journal | View Issue
COMMUNICATION
Iridium-catalyzed 1,5-(aryl)aminomethylation
of 1,3-enynes by alkenyl-to-allyl 1,4-iridium(I)
migration†
Cite this: Chem. Commun., 2019,
55, 838
Received 20th November 2018,
Accepted 14th December 2018
ab
Rebecca E. Ruscoe,
Stamatis E. Korkis
Michael Callingham,ab Joshua A. Baker,ab
ab
ab
and Hon Wai Lam
*
DOI: 10.1039/c8cc09238a
rsc.li/chemcomm
A novel multicomponent coupling reaction involving the iridium- the utility of this chemistry in new areas, we questioned
catalyzed 1,5-difunctionalization of 1,3-enynes with arylboronic whether cyclic imines could be replaced with triazinanes, which
acids and triazinanes is described. A key step in this 1,5-(aryl)amino- are known to produce formaldimines upon heating.8 Our initial
methylation reaction is the alkenyl-to-allyl 1,4-iridium(I) migration. experiments (Table 1) focused on the reaction of 1,3-enyne 2a,
triazinane 1a (0.5 equiv.), and PhB(OH)2 (1.5 equiv.). Although
Difunctionalization reactions, not including (formal) cycloaddi- the use of rhodium(I) catalysis under various conditions led
tions that result in overall annulation, are a diverse family only to complex mixtures, we were pleased to observe that
of useful transformations. Although 1,2-difunctionalizations of heating the three reactants in dioxane at 80 1C for 24 h in the
alkenes are the most common,1 other reaction types such as presence of [Ir(cod)Cl]2 (2.5 mol%) and K2CO3 (1.5 equiv.)
1,1-difunctionalization,2 1,3-difunctionalization,3 and 1,4-difunc- successfully gave a three-component coupling product in 14%
tionalizations4 of p-unsaturated systems or cyclopropanes are yield as determined by 1H NMR analysis (entry 1).12 Unexpectedly
also known. However, to the best of our knowledge, 1,5- however, the product was 1,3-diene 3a, in which the 1,3-enyne
difunctionalizations are rare, and are restricted to reactions of underwent 1,5-(aryl)aminomethylation, in contrast to our pre-
vinylcyclopropanes.5 Addressing this methodological gap could vious 1,3-difunctionalization using cyclic imines.9 Variation of
provide new opportunities in synthesis and enable the rapid the base led to increased yields of 3a (entries 2–4), which was
generation of molecular complexity.
Herein, we report the first example of an iridium-catalyzed
multicomponent coupling between 1,3-enynes, arylboronic acids,
and triazinanes that results in a novel 1,5-functionalization to
give 1,3-dienes. The key step in this reaction involves an alkenyl-
to-allyl 1,4-iridium(I) migration that enables the functionalization
of an otherwise unreactive C-H bond. This overall 1,5-(aryl)-
aminomethylation6 reaction introduces nitrogen functionality
with the concomitant formation of two new carbon–carbon bonds,
thus complementing more well-known hydroaminomethylation
and hydroamidomethylation reactions that result in only one
new carbon–carbon bond.7,8
Recently, we reported the enantioselective rhodium-catalyzed
three-component coupling of arylboronic acids, 1,3-enynes, and
cyclic imines,9 in which an alkenyl-to-allyl 1,4-rhodium(I)
migration10,11 is a key step (Scheme 1A). In seeking to increase
a The GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry,
University of Nottingham, Jubilee Campus, Triumph Road, Nottingham, NG7 2TU,
UK. E-mail: hon.lam@nottingham.ac.uk
b School of Chemistry, University of Nottingham, University Park, Nottingham,
NG7 2RD, UK
† Electronic supplementary information (ESI) available: Experimental procedures,
Scheme 1 Three-component couplings of 1,3-enynes, arylboronic acids,
full spectroscopic data for new compounds. See DOI: 10.1039/c8cc09238a
and imines by alkenyl-to-allyl 1,4-metal migration.
838 | Chem. Commun., 2019, 55, 838--841
This journal is ©The Royal Society of Chemistry 2019

View Article Online
Communication
ChemComm
Table 1 Evaluation of reaction conditionsa
4.3 : 1 (entry 4). Although changing the solvent to MeCN or
THF gave inferior results (entries 5 and 6), the addition of 3 Å
molecular sieves was beneficial and gave 3a in 53% NMR yield
as a 5.0 : 1 E/Z mixture (entry 7).14
With effective conditions in hand, the scope of the reaction
with respect to the triazinane was examined in reactions with
1,3-enyne 2a and PhB(OH)2, which gave products 3a–3e and 3g
in 52–74% isolated yield (Table 2). Column chromatography
partially removed the minor Z-isomer along with unreacted 2a. As
well as triazinane 1a, triazinanes containing para-methoxyphenyl
or para-fluorophenyl groups reacted successfully to give 1,3-dienes
3b and 3c, respectively. A disubstituted aryl group on the tri-
azinane was tolerated (3d), as was a methoxypyridyl group (3e).
Finally, N-alkyltriazinanes were examined. Although 1,3,5-
trimethyl-1,3,5-triazinane was ineffective (none of 3f was obtained
and unreacted 2a was returned), the corresponding N-isopropyl
analogue performed well to give 1,3-diene 3g in 58% yield as a
6.8:1 mixture of E/Z isomers.
Entry
Base
Solvent
Yieldb (%)
E : Z ratioc
1
2
3
4
5
6
7e
K2CO3
Et3N
KF
K3PO4
K3PO4
K3PO4
K3PO4
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
MeCN
THF
1,4-Dioxane
14
26
50
50
15
43
53
n.d.d
3.3 : 1
4.0 : 1
4.3 : 1
3.5 : 1
2.7 : 1
5.0 : 1
a
b
Reactions were conducted with 0.05 mmol of 2a. Determined by
1H NMR analysis of the crude reaction mixtures using 1,3,5-trimethoxy-
benzene as an internal standard. Determined by 1H NMR analysis
c
d
e
A range of different arylboronic acids with varying steric and
electronic properties are tolerated in this process, as shown by
of the crude reaction mixtures. Not determined. Using 30 mg of 3 Å
molecular sieves.
Table 3 Scope of the boronic acida
obtained as a mixture of E- and Z-isomers at the methyl-
substituted alkene.13 K3PO4 gave the highest E : Z ratio of
Table 2 Scope of the triazinanea
a
a
Reactions were conducted with 0.30 mmol of 2a and 100 mg of 3 Å
Reactions were conducted with 0.30 mmol of 2a and 100 mg of 3 Å
molecular sieves. The E : Z ratios quoted after the yields are of a mixture molecular sieves. The E : Z ratios quoted after the yields are of a mixture
b
of inseparable isomers obtained after purification. Range of E : Z ratios of inseparable isomers obtained after purification. PMP = para-methoxy-
c
b
of the crude mixtures as determined by 1H NMR analysis. The reaction phenyl. Range of E: Z ratios of the crude mixtures as determined by
was conducted with 0.26 mmol of 2a.
1H NMR analysis.
This journal is ©The Royal Society of Chemistry 2019
Chem. Commun., 2019, 55, 838--841 | 839

View Article Online
ChemComm
Communication
their reactions with 1,3-enyne 2a and either triazinane 1a or 1b
(Table 3). For example, 1,5-(aryl)aminomethylation products
were successfully obtained from reactions of arylboronic acids
containing para- (3h, 3k, and 3l), meta- (3j, 3m, and 3n), or
ortho-substituents (3i and 3o). However, the yield of 3o was only
16%, presumably because of steric hindrance. Attempted reac-
tions using 1-phenylvinylboronic acid in place of arylboronic
acids were unsuccessful, and only starting 1,3-enyne 2a was
recovered.
Finally, we investigated a range of 1,3-enynes in reactions
with PhB(OH)2 and either triazinane 1a or 1b (Table 4). As well
as a phenethyl group (3q and 3r; see also Tables 2 and 3),
various other aliphatic substitutents at the alkynyl position R3
are tolerated, including primary (3p, 3s, 3u, and 3v) and
secondary (3t) alkyl groups with functional groups such as a
silyl ether (3p) or a ketone (3u and 3v). When the substituent
R2 (trans- to the alkyne) was modified from a methyl group to a
hydrogen atom (3q), the yield decreased but the stereoisomeric
ratio increased. However, replacing this group with a phenyl
group resulted in a higher yield at the expense of a lower stereo-
isomeric ratio (3r and 3s). The presence of a methyl group cis- to
the alkyne in the 1,3-enyne is essential for the reaction to proceed,
as shown by the failure to provide any three-component coupling
product from a 1,3-enyne without this structural feature.15
Scheme 2 Possible catalytic cycle.
Table 4 Scope of the 1,3-enynea
A possible catalytic cycle for these reactions is shown in
Scheme 2. After the formation of iridium complex 4, which
could have chloride, hydroxide, or phosphate counterions from
the species present in the reaction,16 transmetalation of 4 with
the arylboronic acid gives aryliridium species 5. Coordination
of 5 with the 1,3-enyne 2, followed by migratory insertion with
the alkyne leads to alkenyliridium species 6, which can undergo
an alkenyl-to-allyl 1,4-iridium(I) migration9 to give allyliridium
species 7. Although allylation of formaldimine 8 (derived from
cracking of triazinane 1) could occur with 7 through a chairlike
conformation 9 to give 1,3-difunctionalized product 10,9 this
mode of addition was not observed. Instead, 7 can undergo
interconversion with allyliridium species 11 through a s–p–s
isomerization. Now, allylation of 8 with 11 through a chairlike
conformation 12, in which the trisubstituted alkene occupies a
pseudoequatorial position, gives the iridium amide 13. Proto-
nolysis of 13 releases the product 3 (major stereoisomer) and
regenerates the active iridium complex 4. The formation of the
minor stereoisomer of 3 can be explained by allylation through
an alternative conformation 14, in which the trisubstituted
alkene occupies a pseudoaxial position. This stereochemical
model is consistent with the decreasing ratios of geometric
isomers observed when R2 changes from hydrogen to methyl to
phenyl (see Table 4), as increasing the steric effect of this sub-
a
Reactions were conducted with 0.30 mmol of 2 and 100 mg of 3 Å stituent will disfavor allylation through 12 because of increasing
unfavorable non-bonding interactions of R2 with the pseudo-
molecular sieves. The E : Z ratios quoted after the yields are of a mixture
of inseparable isomers obtained after purification. PMP = para-methoxy-
b
equatorial trisubstituted alkene. The formation of 1,5-difunc-
tionalized products 3 rather than 1,3-difunctionalized products
phenyl. Range of ratios of geometric isomers of the crude mixtures as
determined by 1H NMR analysis.
840 | Chem. Commun., 2019, 55, 838--841
This journal is ©The Royal Society of Chemistry 2019

View Article Online
Communication
ChemComm
and J. P. Morken, J. Am. Chem. Soc., 2009, 131, 9134–9135;
(d) R. J. Ely and J. P. Morken, Org. Lett., 2010, 12, 4348–4351;
(e) M. S. McCammant and M. S. Sigman, Chem. Sci., 2015, 6,
1355–1361; ( f ) Z. Wu, J. Zhang, Y. Li and W. Zhang, Tetrahedron
Lett., 2017, 58, 2640–2643; (g) M. Okumura, S. M. N. Huynh,
J. Pospech and D. Sarlah, Angew. Chem., Int. Ed., 2016, 55,
15910–15914; (h) M. Okumura, A. S. Shved and D. Sarlah, J. Am.
Chem. Soc., 2017, 139, 17787–17790; (i) Q. Sun, Y.-Y. Zhang, J. Sun,
Y. Han, X. Jia and C.-G. Yan, Org. Lett., 2018, 20, 987–990.
5 (a) Z.-R. Li, X.-X. Bao, J. Sun, J. Shen, D.-Q. Wu, Y.-K. Liu, Q.-H. Deng
and F. Liu, Org. Chem. Front., 2016, 3, 934–938; (b) Z. Liu and Z.-Q.
Liu, Org. Lett., 2017, 19, 5649–5652; (c) N. Fu, G. S. Sauer and
S. Lin, J. Am. Chem. Soc., 2017, 139, 15548–15553; (d) Z.-R. Li,
D.-Q. Wu, J. Sun, J. Shen and Q.-H. Deng, Asian J. Org. Chem.,
2018, 7, 432–438.
6 For 1,2-(aryl)aminomethylation of alkenes, see: F. Lebreux, B. Quiclet-
Sire and S. Z. Zard, Org. Lett., 2009, 11, 2844–2847.
7 For reviews, see: (a) P. Kalck and M. Urrutigoity, Chem. Rev., 2018,
118, 3833–3861; (b) C. Y. Chen, X. Q. Dong and X. M. Zhang, Org.
Chem. Front., 2016, 3, 1359–1370; (c) S. Raoufmoghaddam, Org.
Biomol. Chem., 2014, 12, 7179–7193; (d) D. Crozet, M. Urrutigoity
and P. Kalck, ChemCatChem, 2011, 3, 1102–1118.
10 results from the imine employed, as cyclic imines give
1,3-difunctionalized products under similar conditions.9 How-
ever, the reasons for this selectivity, which likely arises from
energy differences between 9 and 12/14, are currently not clear.
In conclusion, we have developed a novel iridium-catalyzed
three-component coupling reaction of 1,3-enynes with arylboronic
acids and formaldimines derived from triazinanes, to give multi-
substituted 1,3-dienes. Key to the success of this reaction is an
alkenyl-to-allyl 1,4-iridium(I) migration. This 1,5-(aryl)amino-
methylation reaction complements more well-known hydro-
aminomethylation and hydroamidomethylation reactions7,8 by
forming two, rather than one new carbon–carbon bond. Further
work is ongoing in our laboratory to increase the scope of
catalytic 1,4-metal migrations.17
This work was supported by the Leverhulme Trust [grant
number RPG-2016-341]; the University of Nottingham; and
GlaxoSmithKline.
8 For hydroaminomethylation of allenes or 1,3-dienes, see: (a) S. Oda,
B. Sam and M. J. Krische, Angew. Chem., Int. Ed., 2015, 54,
8525–8528; (b) S. Oda, J. Franke and M. J. Krische, Chem. Sci.,
2016, 7, 136–141.
9 M. Callingham, B. M. Partridge, W. Lewis and H. W. Lam, Angew.
Chem., Int. Ed., 2017, 56, 16352–16356.
Conflicts of interest
There are no conflicts to declare.
10 For other examples of alkenyl-to-allyl 1,4-rhodium migration, see:
(a) D. J. Burns and H. W. Lam, Angew. Chem., Int. Ed., 2014, 53,
9931–9935; (b) D. J. Burns, D. Best, M. D. Wieczysty and H. W. Lam,
Angew. Chem., Int. Ed., 2015, 54, 9958–9962; (c) B. M. Partridge,
M. Callingham, W. Lewis and H. W. Lam, Angew. Chem., Int. Ed.,
2017, 56, 7227–7232; (d) J. D. Dooley and H. W. Lam, Chem. – Eur. J.,
2018, 24, 4050–4054.
11 For reviews of 1,4-metal migrations, see: (a) S. Ma and Z. Gu, Angew.
Chem., Int. Ed., 2005, 44, 7512–7517; (b) F. Shi and R. C. Larock, Top.
Curr. Chem., 2009, 292, 123–164; (c) M. F. Croisant, R. Van Hoveln
and J. M. Schomaker, Eur. J. Org. Chem., 2015, 5897–5907.
12 During our study of enantioselective rhodium-catalyzed three-
component coupling of arylboronic acids, 1,3-enynes, and cyclic
imines, [Ir(cod)Cl]2 was found to be effective in providing racemic
products. See ref. 9.
References
1 For selected reviews, see: (a) X. Wu, S. Wu and C. Zhu, Tetrahedron
Lett., 2018, 59, 1328–1336; (b) R. K. Dhungana, S. KC, P. Basnet and
R. Giri, Chem. Rec., 2018, 18, 1314–1340; (c) G. Y. Yin, X. Mu and
G. S. Liu, Acc. Chem. Res., 2016, 49, 2413–2423; (d) R. M. Romero,
T. H. Woste and K. Muniz, Chem. – Asian J., 2014, 9, 972–983;
(e) D. M. Schultz and J. P. Wolfe, Synthesis, 2012, 351–361;
( f ) C. J. R. Bataille and T. J. Donohoe, Chem. Soc. Rev., 2011, 40,
114–128; (g) K. H. Jensen and M. S. Sigman, Org. Biomol. Chem.,
2008, 6, 4083–4088; (h) H. C. Kolb, M. S. VanNieuwenhze and
K. B. Sharpless, Chem. Rev., 1994, 94, 2483–2547.
2 (a) A. Rodriguez and W. J. Moran, Eur. J. Org. Chem., 2009,
1313–1316; (b) L. Liao, R. Jana, K. B. Urkalan and M. S. Sigman,
J. Am. Chem. Soc., 2011, 133, 5784–5787; (c) V. Saini and M. S.
Sigman, J. Am. Chem. Soc., 2012, 134, 11372–11375; (d) V. Saini,
L. Y. Liao, Q. F. Wang, R. Jana and M. S. Sigman, Org. Lett., 2013, 15,
13 Assignment of the stereochemistry of the E/Z isomers was made on
the basis of NOESY spectra. See the ESI† for details.
14 The reason for the beneficial effect of 3 Å molecular sieves is not
currently known.
´
5008–5011; (e) H. M. Nelson, B. D. Williams, J. Miro and F. D. Toste,
15 The following 1,3-enyne did not provide any three-component
coupling products under these conditions. For similar observations
in Rh(III)-catalyzed oxidative annulations of 1,3-enynes, see ref. 10a
and b
J. Am. Chem. Soc., 2015, 137, 3213–3216; ( f ) E. Yamamoto, M. J. Hilton,
M. Orlandi, V. Saini, F. D. Toste and M. S. Sigman, J. Am. Chem. Soc.,
2016, 138, 15877–15880; (g) M. Orlandi, M. J. Hilton, E. Yamamoto,
F. D. Toste and M. S. Sigman, J. Am. Chem. Soc., 2017, 139, 12688–12695.
3 (a) M. S. McCammant, T. Shigeta and M. S. Sigman, Org. Lett., 2016,
18, 1792–1795; (b) R. T. Thornbury, V. Saini, T. d. A. Fernandes,
C. B. Santiago, E. P. A. Talbot, M. S. Sigman, J. M. McKenna and
F. D. Toste, Chem. Sci., 2017, 8, 2890–2897; (c) S. M. Banik, K. M.
Mennie and E. N. Jacobsen, J. Am. Chem. Soc., 2017, 139, 9152–9155. 16 The hydroxide counterions could arise from H2O produced in the
4 (a) S. T. Staben, X. Linghu and F. D. Toste, J. Am. Chem. Soc., trimerization of the arylboronic acid to the boroxine.
2006, 128, 12658–12659; (b) F. Louerat, Y. Fort and V. Mamane, 17 The research data associated with this publication can be found at
¨
Tetrahedron Lett., 2009, 50, 5716–5718; (c) H. E. Burks, L. T. Kliman
DOI: 10.17639/nott.6172.
This journal is ©The Royal Society of Chemistry 2019
Chem. Commun., 2019, 55, 838--841 | 841