Selective Monoacylation of a Diamine Using Intramolecular Delivery by a DMAP Unit.

Article abstract of DOI:10.1021/ol026206h

[reaction: see text] Regioselective monoacylation of a diamine is achieved by including a suitably positioned 4-(dimethylamino)pyridine (DMAP) group within the molecule.

Full text of DOI:10.1021/ol026206h

ORGANIC
LETTERS
2002
Vol. 4, No. 16
2653-2656
Selective Monoacylation of a Diamine
Using Intramolecular Delivery by a
DMAP Unit
T. Ross Kelly* and Marta Cavero
E. F. Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467
ross.kelly@bc.edu.
Received May 17, 2002
ABSTRACT
Regioselective monoacylation of a diamine is achieved by including a suitably positioned 4-(dimethylamino)pyridine (DMAP) group within the
molecule.
We recently reported a prototype of the first rationally
designed, chemically powered molecular motor.1 The opera-
tion of the prototype is summarized in Scheme 1. Addition
of the fuel (phosgene) to 1 initiates a cascade of events
resulting, after cleavage of the urethane (carbamate) in 4, in
the unidirectional 120° rotation of 1 to 5.
With a functioning prototype in hand, the task turned to
extending the original system so that the sequence of events
in Scheme 1 could be achieved repeatedly. A continually
rotating molecular motor would be the result.
the system units that, with the appropriate spatial positioning
and timing, (ii) can capture and deliver Cl2CdO and (iii)
can cleave the urethane. Efforts in all three directions are
underway; we recently described a partial solution to the third
objective: cleavage of the urethane under reaction conditions
compatible with the operation and analysis of the system as
a whole.2 Here we report the results of model studies directed
toward the solution of the second problem: selective delivery
of phosgene to only the amino group in the “firing position”
(Figure 1).
To accomplish that aim, it is necessary to realize three
subgoals (Figure 1): (i) 1 must be modified so that each
blade of the triptycene is ready to be selectively armed at
the appropriate time, and there must also be included within
4-(Dimethylamino)pyridine (DMAP) and other dialkyl
aminopyridines are frequently used as catalysts for the
acylation of sterically hindered alcohols and phenols.3,4 The
process usually takes place via the reaction of DMAP with
Scheme 1. Operation of a Prototype of the First Rationally Designed, Chemically Powered Molecular Motor
10.1021/ol026206h CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/16/2002

Figure 3. Model compounds studied.
Figure 1. Schematic representation of the concepts underlying the
design of a continually rotating motor (see text).
molecule and (ii) only one of them is situated close enough
to an internal DMAP group for the latter to be involved in
the acylation reaction. To ensure that selective acylation of
6 was due only to the presence of the DMAP moiety and
not to steric or electronic effects, compound 7 was chosen
as a control.
the acylating agent (usually an acid chloride or anhydride),
followed by attack of the nucleophile on the resulting
N-acylpyridinium salt. The acylation of amines with acid
chlorides is usually so fast that it does not require the addition
of any catalyst.3 However, it has been documented that the
DMAP-catalyzed reaction of m-chloroaniline with benzoyl
chloride is about 106 times faster than the noncatalyzed
reaction,5 suggesting a decidedly higher reactivity of acid
chlorides toward DMAP than toward anilines. We thus
envisioned that inclusion of a suitably positioned DMAP
group in our design for the molecular motor would allow
for selective intramolecular delivery of phosgene to only the
amino group situated proximate to the DMAP moiety (Figure
2, curved arrow). To our knowledge, no examples have been
Assuming7 a nucleophilic catalysis mechanism, molecular
modeling (Figure 4, Spartan pBP/DN**//AM1) of compound
Figure 4. Acylpyridinium intermediate in its lowest energy
conformation.
6 shows that once the DMAP unit has reacted with phosgene,
the carbonyl carbon of the resulting acylating species
(acylpyridinium ion) is in very close proximity to the reacting
amine for conformations which are close in energy to the
ground state conformation (by rotation around bond a in
Figure 3). Similar calculations applied to the motor system
in Figure 2 predict that the carbonyl carbon of the acylated
pyridinium moiety is close to only the aniline in the firing
position, by rotation around bond a and/or low energy8
rotation around bond b.
Figure 2. Specific molecular embodiment of the concept for site-
selective delivery of phosgene in a motor molecule (see text).
reported of the use of DMAP as a selective intramolecular
acylation catalyst for amines in a similar setting.6 Therefore,
to ascertain whether the design in Figure 2 had merit, we
set out to test the concept in a simpler system.7
As a model, compound 6 (Figure 3) possesses the desired
characteristics: (i) it contains two aniline groups in the same
(4) For some recent publications involving DMAP derivatives see, inter
alia: (a) Vedejs, E.; Chen, X. J. Am. Chem. Soc. 1996, 118, 1809. (b)
Kawabata, T.; Nagato, M.; Takasu, K.; Fuji, K. J. Am. Chem. Soc. 1997,
119, 3169. (c) Sammakia, T.; Hurley, T. B. J. Org. Chem. 1999, 64, 4652.
(d) Fu, G. C. Acc. Chem. Res. 2000, 33, 412. (e) Spivey, A. C.; Charboneau,
P.; Fekner, T.; Hochmuth, D. H.; Maddaford, A.; Madalier-Jugroot, C.;
Redgrave, A.; Whitehead, M. A. J. Org. Chem. 2001, 66, 7394. (f) Cupperly,
D.; Gros, P.; Fort, Y. J. Org. Chem. 2002, 67, 238.
(1) (a) Kelly, T. R.; de Silva, H.; Silva, R. A. Nature 1999, 400, 150.
(b) Kelly, T. R.; Silva, R. A.; de Silva, H.; Jasmin, S.; Zhao, Y. J. Am.
Chem. Soc. 2000, 122, 6935. (c) Kelly, T. R. Acc. Chem. Res. 2001, 34,
514.
(5) Litvinenko, L. M.; Kirichenko, A. I. Dokl. Akad. Nauk. SSSR 1967,
176, 97 (Dokl. Chem. Engl. Transl. 1967, 763).
(2) Kelly, T. R.; Cavero, M.; Zhao, Y. Org. Lett. 2001, 3, 3895.
(3) For reviews see: (a) Hassner, A.; Krespki, L. R.; Alexanian, V.
Tetrahedron 1978, 34, 2069. (b) Ho¨fle, G.; Steglich, W.; Vorbru¨ggen, H.
Angew. Chem., Int. Ed. Engl. 1978, 17, 569. (c) Ragnarsson, U.; Grehn, L.
Acc. Chem. Res. 1998, 31, 494. (d) Spivey, A.; Maddaford, A.; Redgrave,
A. J. Org. Prep. Proced. Int. 2000, 32, 333. (e) Sheinkman, A. K.; Suminov,
S. I.; Kost, A. N. Russ. Chem. ReV. 1973, 42, 642.
(6) There are a large number of examples in the literature of the use of
DMAP or imidazole units as acylation or phosphorylation catalysts in
enzyme-mimetic (and enzyme) settings which could be considered intramo-
lecular, since the substrate and the catalyst are usually bound during
catalysis. However, most of these examples deal with alcohols (see, for
instance: Sculimbrene, B. R.; Miller, S. J. J. Am. Chem. Soc. 2001, 123,
10125. Faber, K.; Riva, S. Synthesis 1992, 895 and references cited therein);
2654
Org. Lett., Vol. 4, No. 16, 2002

To ensure that 6 was not some kind of electronic special
case, the electrostatic potential of 6 and 7 was mapped onto
their electronic surfaces (Spartan, pBP/DN**//AM1; Figure
5) demonstrating that in each molecule, the two amino groups
Scheme 2. Synthesis of Diamines 6 and 7
Figure 5. Electrostatic potential mapping: red, most electro-
negative; blue, least electronegative.
exhibit virtually identical values for the potential (ca. -45
kcal/mol). This indicates that in the absence of any better
nucleophile7 in the molecule (such as the DMAP in 6) both
anilines should react with an electrophile similarly and no
selectivity should be observed. Therefore, it was expected
that 6 would acylate selectively due to the presence of the
DMAP, whereas 7 would give a mixture of acylated species
under identical conditions.
Drawing from the earlier work of others,9,10 model
compounds 6 and 7 were prepared as described in Scheme
2.
followed by 1 equiv of acetyl chloride, a single product that
contained the two clearly differentiated amide groups was
obtained in >95% yield (14).13
Gratifyingly, all of our predictions were borne out by
experiment. When diamine 6 was treated with 1 equiv of
pivaloyl or acetyl chloride in anhydrous CHCl3 at room
temperature, only the amino group adjacent to the DMAP
unit was acylated (f12/13, Scheme 3).11,12 Similarly, when
6 was treated sequentially with 1 equiv of pivaloyl chloride
Scheme 3. Selective Acylation Experiments
we have found no examples dealing with the selective acylation of anilines.
(7) (a) For the several reasons given in this paragraph, the design of 6
was based on the premise that the acylation would proceed by a nucleophilic
catalysis mechanism. Nonetheless, some referees suggest that in this specific
instance the pyridine nitrogen is operating by intramolecular general base
rather than nucleophilic catalysis, citing refs 4c and 7b. While we still believe
that nucleophilic catalysis is operative here [molecular modeling of low-
energy conformations of 6 (Figure 3) shows no hydrogen bond between
the pyridine nitrogen and the proximate amino hydrogens: such a hydrogen
bond would be necessary, at least in the transition state, if general base
catalysis is operative] we agree with those referees that the verdict is not
yet in. Since the objective of our study was to establish function (selective
acylation), not necessarily prove mechanism, and since we were successful,
more detailed mechanistic studies will be deferred until after the concepts
in Figures 2 and 1 have been reduced to practice. (b) Anderson, H.; Su,
C.-W.; Watson, J. W. J. Am. Chem. Soc. 1969, 91, 482.
Since it was not possible to unequivocally assign the
structure of the formed regioisomer by simple analysis of
1D 1H NMR and 13C NMR spectra,14 we carried out a series
of 2D-COSY and NOESY experiments. Unfortunately, no
NOEs could be observed between the acetyl or pivaloyl
(8) The barrier to full rotation around bond b is 20-25 kcal/mol.
(9) (a) Preparation of 8: see ref 4c. For reactions related to the conversion
of DMAP to 8 see ref 4a and: Kessar, S. V.; Singh, P.; Singh, K. N.; Dutt,
M. J. Chem. Soc., Chem. Commun. 1991, 570. (b) Reduction of 9 to 6:
Perry, P. J.; Reszka, A. P.; Wood, A. A.; Read, M. A.; Gowan, S. M.;
Dosanjh, H. S.; Trent, J. O.; Jenkins, T. C.; Kelland, L. R.; Neidle, S. J.
Med. Chem. 1998, 41, 4873. (c) Reduction of 11 to 7: Krishnamurthy, R.;
Natarajan, S. Synth. Commun. 1992, 22, 3189.
(12) No starting material or bisacylated product peaks could be observed
in the 1H NMR spectra. Bisacylated products (22/23, not shown) were
prepared by treatment of 6 with 2 equiv of pivaloyl or acetyl chloride and
were fully characterized (see Supporting Information) for comparison
purposes.
(13) For additional details on experimental procedures and characteriza-
tion of acylation products see the Supporting Information.
(10) All products were fully characterized by 1H and 13C NMRs and
HRMS. COSY and NOESY 2D spectra are also provided for compounds
6 and 7. See Supporting Information for details.
(11) Reaction was finished after <1 min (TLC). The product was isolated
after a simple workup involving washing with base. The products obtained
by reaction with both pivaloyl and acetyl chloride were >95% pure.
Org. Lett., Vol. 4, No. 16, 2002
2655

hydrogens and any ring hydrogen. This is easily explained
if the amide adopts the more stable and quite rigid trans
conformation in solution.15 Therefore, to render the substit-
uents more freely rotating and to introduce CH2 groups in
closer proximity to the ring hydrogens, the amide groups in
13 and 14 were reduced to the corresponding amines
(Scheme 4).16 Compounds 15 and 16 thus obtained displayed
To provide evidence that the observed regioselectivity was
only due to intramolecular involvement of the DMAP unit
and that no other effects were responsible for the different
reactivity of the two aniline groups, compound 7 was
Scheme 4
Figure 7. Structure of compound 13 as determined by X-ray
diffraction of a single crystal.17
submitted to conditions identical with those used for the
acylation of 6. As anticipated, upon treatment of compound
7 with 1 equiv of either pivaloyl or acetyl chloride, a mixture
of the two possible monoacylated products plus starting
material and doubly acylated product was obtained (ca.
2:1:2:2 in both cases: see Supporting Information).
In conclusion, the results of this study show that it is
possible to achieve regioselective delivery of an acyl group
to one of two amine groups within the same molecule by
introducing a suitably positioned DMAP moiety that acts as
the catalyst in the acylation process. Incorporation of these
concepts into a molecular motor is currently underway.
the NOEs summarized in Figure 6, thereby confirming the
structures of 12/13.
Acknowledgment. We thank NIH (Grant No. GM56262)
for funding. We also wish to thank Ms. Bele´n Mart´ın-Matute
and Drs. Costa Metallinos and Yajun Zhao for useful
suggestions. We are also grateful to Ms. Sumitra Mukho-
padhyay for obtaining X-ray data for compound 13, Dr. John
Boylan for invaluable help with NOESY manipulations, and
Mr. Chris Kowalczyk for expedient delivery of MS data.
Supporting Information Available: Key experimental
procedures and spectral characterization data for new com-
pounds, additional details of experimental procedures used
Figure 6. NOEs observed for compounds 15 and 16.
1
during acylation experiments, H NMR spectra of crude
Subsequently, and to our greater satisfaction, we succeeded
in obtaining crystals of 13 suitable for X-ray diffraction
analysis (Figure 7) and so our assignments were further
verified.
mixtures for each acylation experiment, additional X-ray
diffraction information, and NOESY and COSY spectra of
pertinent compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
(14) Changes in chemical shifts for protons H2′ and H3′ (Figure 3) on
acylation of either of the two amine groups were expected to be quite
different: acylation of the amine closer to the DMAP group would be
expected to have a larger effect on the chemical shift for H3′ but not for
H2′; acylation of the other amine group would result in a large chemical
shift change for both hydrogens. In practice, we observed the first effect,
indicating that the process was working as predicted, but we secured
additional proof.
OL026206H
(17) Crystal data for compound 13: C24H32N5.33O1.33 (unit cell), Mr )
416.55, monoclinic space group C2/c, a ) 32.285(4) Å, b ) 16.713(3) Å,
c ) 20.190(4) Å, U ) 3456.2(8) Å3, Dc ) 1.201 g/cm3, Z ) 6, absorption
coefficient ) 0.077 mm-1, 2250 unique data were produced from 7107
measured reflections (Rint ) 0.0680), R1 ) 0.0814, wR2 ) 0.2219. CCDC-
185843 contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/
retrieving.html (or from the Cambridge Crystallographic Data Center, 12,
Union Road, Cambridge CB2 1EZ, UK; fax (+44)1223-336-033; or
deposit@ccdc.cam.ac.uk).
(15) Robin, M. B.; Bovey, F. A.; Basch, H. In The Chemistry of Amides;
Zabicky, J., Ed.; Wiley-Interscience: New York, 1970; p 1.
1
(16) The H NMR spectra of compounds 12 and 13 are very similar in
the aromatic region and therefore structure-elucidation studies concentrated
on 13 and the structure of 12 was assigned by analogy.
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Org. Lett., Vol. 4, No. 16, 2002