A Mitsunobu reaction to functionalized cyclic and bicyclic N-arylamines

Article abstract of DOI:10.1016/j.tetlet.2017.12.017

The scope of an unexpected Mitsunobu cyclisation to prepare N-arylated Fsp³-enriched azacycles was investigated. In the current study, we have identified whether a pKa-dependent Mitsunobu cyclodehydration or a pKa-independent Mitsunobu intramolecular reaction was in operation. A Mitsunobu reaction, creating a leaving group, followed by intramolecular nucleophilic displacement was determined to be the dominant pathway.

Full text of DOI:10.1016/j.tetlet.2017.12.017

Accepted Manuscript
A Mitsunobu reaction to functionalized cyclic and bicyclic N-arylamines
Daniel M. Gill, Matthew Iveson, Ian Collins, Alan M. Jones
PII:
S0040-4039(17)31509-5
https://doi.org/10.1016/j.tetlet.2017.12.017
TETL 49518
DOI:
Reference:
Tetrahedron Letters
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21 November 2017
4 December 2017
Please cite this article as: Gill, D.M., Iveson, M., Collins, I., Jones, A.M., A Mitsunobu reaction to functionalized
cyclic and bicyclic N-arylamines, Tetrahedron Letters (2017), doi: https://doi.org/10.1016/j.tetlet.2017.12.017
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A Mitsunobu reaction to functionalized cyclic
and bicyclic N-arylamines
Daniel M. Gill,ab Matthew Ivesonc, Ian Collinsd, Alan M. Jonesa*

1
Tetrahedron Letters
A Mitsunobu reaction to functionalized cyclic and bicyclic N-arylamines
Daniel M. Gill,a,b Matthew Ivesonc, Ian Collinsd, Alan M. Jonesa
a School of Pharmacy, University of Birmingham, Edgbaston, B15 2TT, UK
b School of Chemistry, University of Birmingham, Edgbaston, B15 2TT, UK
c Division of Chemistry and Environmental Science, Manchester Metropolitan University, M1 5GD, UK
d Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, UK
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The scope of an unexpected Mitsunobu cyclisation to prepare N-arylated Fsp3-enriched
azacycles was investigated. In the current study, we have identified whether a pKa-dependent
Mitsunobu cyclodehydration or a pKa-independent Mitsunobu intramolecular reaction was in
operation. A Mitsunobu reaction, creating a leaving group, followed by intramolecular
nucleophilic displacement was determined to be the dominant pathway.
Available online
Keywords:
Mitsunobu
2009 Elsevier Ltd. All rights reserved.
Cyclodehydration
Nucleophilic Aromatic Substitution
Intramolecular
Cyclisation
The Mitsunobu cyclodehydration reaction1 is defined as the
formation of azacycles from α,ω-aminoalcohols via a
During the course of our research programme, we encountered
Mitsunobu cyclisation reactions occurring in examples where the
calculated pKa of the NH group was significantly greater than 15;
e.g. for 1 (calculated pKa 18.8) (Scheme 1).8
phosphonium intermediate. Due to the mild reaction conditions
and stereoinversion at the reacting centre, the Mitsunobu reaction
has found widespread use.2 The Mitsunobu cyclodehydration
approach has found specialist uses, although less widespread
application,3 due to a variety of alternative methods to access
azacycles,4 including acid catalysed dehydration,
functionalisation of the alcohol to an appropriate leaving group,
and the Appel reaction amongst others. An elegant application of
the Mitsunobu cyclodehydration reaction has been reported by
Park and co-workers5 to access trans-2,3-disubstituted indolines
from N-pivaloyl-2-aminophenethyl alcohols (Fig. 1). The
reported mechanism abides by the pKa rule for the Mitsunobu
reaction (pKa < 15 for the nucleophilic component)6 with the
pKa of the anilide NH calculated7 as ca. 14, and whereby the
bulky electron withdrawing pivaloyl group is a pre-requisite for
the reaction to occur.
Scheme 1. Previous work8 involving structural reassignment of the
Mitsunobu products resulting from macroetherification.
As shown in Scheme 1, we recently reassigned8 the structure
of a cyclin-dependent kinase (CDK) inhibitor as an alternative
Mitsunobu product to the proposed macrocyclic ether, that
occurred via a Mitsunobu cyclodehydration. Most likely, the
phenolic hydroxyl group in 1 acted as an initiating group for the
Mitsunobu reaction to deliver 3 over the expected 2.
In an unrelated medicinal chemistry program and the focus of
this paper, we again unexpectedly observed the occurrence of a
Mitsunobu cyclisation reaction affording the novel structure 8
(Scheme 2).9
Figure 1. The Mitsunobu cyclodehydration reaction reported by Park and co-
workers.5
———
 Corresponding author. (A.M.J.) Tel.: +44-(0)121-414-7288; e-mail: A.M.Jones.2@bham.ac.uk; web:
www.jonesgroupresearch.wordpress.com

2
Tetrahedron
chloroquinazoline and 12 to microwave assisted SNAr conditions
afforded 13 in modest yield. It was found that subjection of 13 to
the standard Mitsunobu cyclodehydration reaction conditions of
triphenylphosphine and di-tert-butylazodicarboxylate (DTBAD)
did not afford 14 either with or without acetic acid. Instead,
recovered starting material and decomposition products resulted.
This outcome suggested that steric compression from the 2’,3’
protected alcohols played a significant factor in the high yielding
formation of 8 (Scheme 2) possibly due to a pseudo-Thorpe
Ingold rate acceleration.17 To further probe the difference
between 6 containing an sp3-sp3 bridge and 13 containing an sp2-
sp2 bridge, compound 13 was reduced to afford 15. When
subjected to standard Mitsunobu conditions, 15 did not afford a
cyclised product, supporting the assertion that the original
architecture of 6 enhanced the formation of Mitsunobu
Scheme 2. An unexpected Mitsunobu cyclodehydration reaction afforded 8
over the expected 7.
The routine conversion of the 5’-alcohol of a carbosugar 6,
prepared via microwave assisted SNAr of 4 and 5, to a thioacetate
group using thioacetic acid (measured pKa 3.3)10 under standard
Mitsunobu conditions did not afford the expected product 7.
Instead a novel product resulting from the NH group (calculated
pKa 17.6)7 cyclising onto, the presumably, activated 5’-alcohol
was isolated in quantitative yield (99%). Representative nOe
correlations that demonstrate the 3D structure and connectivity of
8 are shown in Figure 2.11
cyclisation product 8 over Mitsunobu substitution product 7.
Figure 2. Selected nuclear Overhauser exchange (nOe) correlations detected
in the NMR spectrum of 8 that demonstrate the new C-N connectivity
resulting from Mitsunobu cyclodehydration.11
Prompted by these results and other examples of both
Mitsunobu cyclisation and cyclodehydration reactions,12 as well
as the Mitsunobu pKa rule13 we considered several factors as to
why 8 was formed in preference to 7:
Scheme 3. Preparation of model compounds 13 and 15 for attempted
Mitsunobu cyclisations.
pKa and ring size effects in model systems
It became apparent that steric compression played a factor in
the formation of 8, enabling the amino and 5’-hydroxyl groups to
be in close proximity. However, the question of whether this
Mitsunobu cyclodehydration reaction would be possible in
simpler and potentially more often encountered systems
remained to be studied. Therefore, a simplified system probing
the pKa of the secondary amine NH of the aryl amino group and
its effect on Mitsunobu cyclisation was investigated. Examples of
the reaction precursors prepared are shown in Table 1.
 Is a thio-Mitsunobu reagent formed?
 Is there a steric requirement to cyclisation?
 Can the pKa rule be extended?
These observations are addressed in the following sections.
The presence of both triphenylphosphine oxide and
triphenylphosphine thioxide were detected by mass spectrometry
of the crude reaction mixture from the conversion of 6 to 8
(Scheme 2A). The reaction was repeated under identical
conditions with the replacement of thioacetic acid by acetic acid
to probe if a thio-Mitsunobu mechanism was operating. Under
analogous conditions with acetic acid, 8 was again isolated
exclusively, thus ruling out this pathway. The observation of
PPh3=S presumably from the reaction of triphenylphosphine with
thioacetic acid14 was therefore shown to be not involved in the
reaction pathway of 6 to 8 (Scheme 2A).
To probe whether steric compression in 6 caused by the acetal
protected diol (between the N-orbital of the quinazoline and the
hydroxyl leaving group) was the cause or enhanced the rate of
cyclisation of 6 to 8, two control compounds 13 and 15 were
synthesised without the dihydroxy sugar motif (Scheme 3).
Molecular modelling using MM2 calculations showed 13 and 15
to have comparable distances between the reacting NH and OH
centres as in 6 (3.7 Å (15) -4.8 Å (13) vs. 5.0 Å (6),
Table 1. Preparation of model SNAr products. Isolated yield from
microwave irradiation reported in brackets. aComparative yield for thermal
SNAr conditions; n.d. not determined. Reagents and conditions: heteroaryl
chloride (1.0 eq.), aminoalcohol (1.1 eq.), NEt3 (1.5 eq.) and n-BuOH (1 mL)
were either irradiated at 125 oC (30 W) in a microwave reactor for 1 h or
heated at reflux for 16 h.
respectively).15 The preparation of 13 began with di-tert-
butyldicarbonate protection of vince lactam 9 to afford 10 in
excellent yield. Sodium borohydride mediated reductive ring
cleavage of 10 afforded the ring-opened product, 11.16,17 Acid
mediated deprotection of 11 proved facile yielding 12 as the
hydrochloride salt. Subjection of a mixture of 4-

3
The SNAr reaction (Table 1) proved robust with 10 high
yielding reaction products from 12 reactions, with no discernible
difference in yield based on the carbon chain length of the
aminoalcohol. In two cases, 23c and 24c, the aminopentanol
reaction gave a complex mixture which prevented isolation
(compared with 21c and 22c, respectively). This may be due to
competitive N- and O- nucleophilic substitution when a less
reactive electrophile is employed.
group) was attempted. Syringe-pump addition of 4.0 M HCl in
dioxane to reaction mixtures without a competent acid group
(based on calculated pKa) failed to deliver the cyclised products
26, 27 and 30. This information, combined with the previous
experiments suggests in the original example (6  8)19 the pKa
effect of the NH group is not as important as the formation of a
leaving group on the hydroxyl group and therefore 8 was most
likely formed via a Mitsunobu cyclisation instead of a
cyclodehydration reaction. Our results suggest the Mitsunobu
pKa argument holds.
Four direct comparisons of microwave irradiation and
traditional thermal heating were examined, 21a-b and 23a-b. In
all cases microwave irradiation proved superior, delivering
higher conversions and subsequently, isolated yields of the SNAr
products. All successful SNAr products were subjected to the
standard Mitsunobu conditions (Table 2).
Herein, we report a complex example of an unexpected
Mitsunobu cyclisation reaction. The mode of reaction, steric
parameters and pKa effects that induced this reaction were
investigated, revealing the steric compression required for 5’-
activation in the carbosugar. Furthermore, we investigated a
range of potential ring sizes that could be accessed via Mitsunobu
cyclisation in a series of 10 aryl aminoalcohols prepared via SNAr
chemistry. It is of importance to note that when the NH group is
insufficiently acidic to initiate a cyclodehydration reaction, an
additional Mitsunobu-competent acid can rescue the reaction. In
this case a traditional Mitsunobu intramolecular reaction creating
a leaving group, followed by an intramolecular displacement that
no longer involves the Mitsunobu reagents occurs, but remains
dependent on the nucleophilicity of the NH group.
Acknowledgments
Table 2. Transformation of selected examples of 21-24 to azacycles 25-
30. awithout AcOH; baddition of AcOH (1.0 equiv.); c addition of AcSH (1.0
equiv.). Reagents and conditions: aminoalcohol (1.0 eq.), (thio)acetic acid
(1.0 eq.), PPh3 (1.5 eq.), DTBAD (1.5 eq.) and THF (5 mL) was stirred at 0
oC to 25 oC for 24-48 h.
The authors thank the Institute of Cancer Research (London),
Manchester Metropolitan University, and the Centre for
Chemical and Materials Analysis in the School of Chemistry at
the University of Birmingham for analytical support. D.M.G.
thanks the Institute of Clinical Sciences and the College of
Medical and Dental Sciences (University of Birmingham) for
PhD funding.
Table 2 demonstrates that in examples where the pKa of the
NH group is greater than 15 (calculated pKa range 16-22), only
trace yields of the cyclised product formed when a more acidic
proton donor (AcOH) was not present. In selected examples
where an additional proton donor is present (1.0 equiv. of acetic
acid), reactions that previously did not deliver the azacycle
proceeded in modest yield. Most likely, in these examples an
acetate leaving group was installed via a classic Mitsunobu
reaction followed by cyclisation.18 Evidence for the acetate
leaving group formation was identified in the crude 1H NMR
spectra. This is also a plausible mechanism by which 8 formed
from 6 in Scheme 2A, via a (thio)acetate leaving group.
However, the use of a stronger acid source, thioacetic acid,
proved counterproductive in examples 26-28 and 30. All
examples of the aminopropanol containing compounds failed to
deliver the corresponding 4-membered azacycles (not shown),
which could be attributed to the ring strain that would result. The
fact that a trace reaction occurred in selected reactions (without
an additional proton donor), suggests it may be a possible for the
competing Mitsunobu cyclodehydration to operate but may also
be due to adventitious water initiating the reaction giving rise to
the capricious nature of these reactions when the pKa of the NH
group is greater than 15. In all the successful examples of the
cyclisation, it was found that heating the reaction, to try to force
the reaction to completion, reduced the yield of the product.
Importantly, the successful reactions in Table 2 demonstrate that
an intramolecular hydrogen bond between the 5’-OH group and
one of the oxygens of the acetal in 6 that could possibly activate
the alcohol in the Mitsunobu reaction to 8 was not essential for
reactivity.
References and notes
1.
For recent reviews of the Mitsunobu and cyclodehydration
reactions see: (a) Fletcher, S. Org. Chem. Front. 2015, 2, 739-752;
(b) But, T. Y. S.; Toy, P. H. Chem. Asian J. 2007, 2, 1340-1355.
Swamy, K. C. K.; Kumar, N. N. B.; Balaraman, E.; Kumar, K. V.
P. P. Chem. Rev. 2009, 109, 2551-2651.
(a) Wang, F.; Hauske, J. R. Tetrahedron Lett. 1997, 38, 6529-
6532; (b) Whiting, E.; Lanning, M. E.; Scheenstra, J. A.; Fletcher,
S. J. Org. Chem. 2015, 80, 1229-1234; (c) Garcia-Delgado, N.;
Riera, A.; Verdaguer, X. Org. Lett. 2007, 9, 635-638.
(a) Wang, Y.; Oriez, R.; Kuwano, S.; Yamaoka, Y.; Takasu, K.;
Yamada, K.-I. J. Org. Chem. 2016, 81, 2652-2664; (b) Davies, S.
G.; Fletcher, A. M.; Foster, E. M.; Houlsby, I. T. T.; Roberts, P.;
Schofield, T. M.; Thomson, J. E. Org. Biomol. Chem. 2014, 12,
9223-9235
2.
3.
4.
5.
6.
Kang, K. H.; Kim, Y.; Im, C.; Park, Y. S. Tetrahedron 2013, 69,
2542-2549.
For pKa effects in the Mitsunobu reaction see: (a) Mitsunobu, O.
Synthesis, 1981, 1, 2; (b) Huges, D. L. Organic Reactions, 1992,
42, 335 (John Wiley & Sons, Inc., New York); (c) Wada, M.;
Mitsunobu, O. Tetrahedron Lett. 1972, 13, 1279.
7.
ACE & JChem® pKa calculator, available at:
https://epoch.uky.edu/ace/public/pKa.jsp
8.
9.
Jones, A. M. Molbank 2015, M859.
(a) Cheeseman, M. D.; Westwood, I. M.; Barbeau, O.; Rowlands,
M.; Dobson, S.; Jones, A. M.; Jeganathan, F.; Burke, R.; Kadi, N.;
Workman, P.; Collins, I.; van Montfort, R. L. M.; Jones, K. J.
Med. Chem. 2016, 59, 4625−4636; (b) Jones, A. M., Westwood, I.
M., Osborne, J. D., Matthews, T. P., Cheeseman, M. D.,
Rowlands, M. G., Jeganathan, F., Burke, R., Lee, D., Kadi, N.,
Liu, M., Richards, M.; McAndrew, C., Yahya, N., Dobson, S. E.,
Jones, K., Workman, P., Collins, I., van Montfort, R. L. M. Sci.
Rep. 2016, 6, 34701.
Finally, to probe whether a non-competent mineral acid (eg.
HCl) could be used to activate the azodicarboxylate compound to
form the betaine Mitsunobu intermediate (but not form a leaving
10. Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456-463.
11. See ESI.

4
Tetrahedron
12. Selected examples of Mitsunobu macrocyclisation: (a) Lucking,
U.; Siemeister, G.; Schafer, M.; Briem, H.; Kruger, M.; Lienau,
P.; Jautelat, R. ChemMedChem 2007, 2, 63-77; (b) Arasappan, A.;
Chen, K. X.; Njoroge, C. F. G.; Parekh, T. N.; Girijavallabhan, V.
J. Org. Chem. 2002, 67, 3923-3926; (c) Chen, K. X.; Njoroge, F.
G.; Pichardo, J.; Prongay, A.; Butkiewicz, N.; Yao, N.; Madison,
V.; Girijavallabhan, V. J. Med. Chem. 2006, 49, 567-574.
13. For references to the pKa rule see: (a) Mitsunobu, O. Synthesis
1981, 1-28; (b) Huges, D. L. The Mitsunobu Reaction “Organic
Reactions” Vol. 42, eds, by P. Beak, et al., John Wiley & Sons,
Inc., New York, 1992, 335; (c) Wada, M.; Mitsunobu, O.
Tetrahedron Lett. 1972, 13, 1279-1282.
14. (a) Guzaev, A. P. Tetrahedron Lett. 2011, 52, 434-437; (b)
Sugimoto, H.; Tatemoto, S.; Toyota, K.; Ashikari, K.; Kubo, M.;
Ogura, T.; Itoh, S. Chem. Commun. 2013, 49, 4358-4360; (c)
Tran, C. T.; Williard, P. G.; Kim, E. J. Am. Chem. Soc. 2014, 236,
11874-11877; (d) Attanasi, O. A.; Bartoccini, S.; Favi, G.;
Filippone, P.; Perrulli, F. R.; Santeusanio, S. J. Org. Chem. 2012,
77, 9338-9343.
15. See ESI for molecular modelling comparisons.
16. Kudoh, T.; Fukuoka, M.; Ichikawa, S.; Murayama, T.; Ogawa, Y.;
Hashii, M.; Higashida, H.; Kunerth, S.; Weber, K.; Guse, A. H.;
Potter, B. V. L.; Matsuda, A.; Shuto, S. J. Am. Chem. Soc. 2005,
127, 8846.
17. Hensbergen, A. W., Mills, V. R., Collins, I., Jones, A. M.
Tetrahedron Lett. 2015, 56, 6478-6483.
18. Chuchani, G.; Al-Awadi, N.; Dominguez, R. M.; Kaul, K. J. Phys.
Org. Chem. 2001, 14, 180-186.
19. Typical procedure: (3aR,4S,7S,7aS)-2,2-Dimethyl-5-(quinazolin-
4-yl)hexahydro-4,7-methano[1,3]dioxolo[4,5-c]pyridine (8). The
heterocycle-substituted amino alcohol (1.0 eq.), thioacetic acid
(1.0 eq.), triphenylphosphine (1.5 eq.) and di-tert-butyl
azodicarboxylate (DTBAD) (1.5 eq.) were dissolved in anhydrous
THF (5 mL) at 0 oC and allowed to gradually warm to 25 oC with
stirring over 24 h. The reaction mixture was purified by gradient
elution flash column chromatography (Ethyl acetate : petroleum
ether; 25:75) to afford 8 as a clear oil (45 mg, 99%). 1H NMR
(500 MHz, CDCl3) δ = 8.57 (s, 1H), 8.02 (dd, J = 8.5, 1.5 Hz, 1H),
7.80 (dd, J = 8.5 Hz, 1.5 Hz, 1H), 7.69 (dd, J = 7.0 Hz, 1.5 Hz,
1H), 7.38 (ddd, J = 8.5, 7.0, 1.5 Hz, 1H), 4.94 (dd, J = 2.0, 1.0 Hz,
1H), 4.46 (dt, J =5.5, 1.5 Hz, 1H), 4.27 (dd, J = 5.5, 1.5 Hz, 1H),
3.98 (dd, J = 10.0, 4.0 Hz, 1H), 3.24 (dd, J = 10.0, 1.5 Hz, 1H),
3.11 (s, 1H), 2.74 (dd, J = 4.0, 2.0 Hz, 1H), 1.65 (dt, J = 10.5, 1.5
Hz, 1H), 1.49 (s, 3H), 1.32 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
= 158.8, 154.5, 151.6, 133.1, 132.1, 128.7, 124.9, 116.0, 110.5,
80.2, 79.1, 60.9, 51.4, 40.6, 30.5, 25.6, 24.3; LCMS (100% AUC)
ESI: m/z 298 [M+H]+; HRMS calcd. 298.1556 (C17H20N3O2,
[M+H]+); found 298.1533.
Supplementary Material
Characterisation and experimental details of novel and known
compounds and 1H, 13C NMR spectra associated with this article
can be found in the online version, at XXX
Highlights



An unexpected Mitsunobu route to N-arylated
azacycles
Mitsunobu Cyclodehydration versus
Intramolecular cyclisation investigated
Reaction scope, ring size, steric and pKa effects
studied in model systems